Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C(N(CC)CC)C.[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([CH2:32][C:33](=O)[CH3:34])[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=O)=[CH:19][CH:18]=1>C(O)C.C(Cl)Cl>[F:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:32]=[C:33]([CH3:34])[N:2]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:24]=2[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:21][CH:22]=1
Reactant: CC(=O)CC(C(=O)c1ccccc1)c1ccc(F)cc1
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)Cn1c(C)cc(-c2ccc(F)cc2)c1-c1ccccc1
Temperature: 100 °C
Yield: 42.9 %

Procedure:
Ethyl 2-aminoacetate hydrochloride (0.775 g, 5.55 mmol) was diluted with ethanol (5 ml) then triethylamine was added (1.160 ml, 8.32 mmol), followed by 2-(4-fluorophenyl)-1-phenylpentane-1,4-dione (1.5 g, 5.55 mmol), added as a solution in DCM. The reaction was heated at 100° C. overnight, after which TLC showed a new spot (less polar, Rf˜0.9 in 20% EtOAc/hexanes). The reaction was diluted with 10 mL DCM and washed with water (10 mL) and the aqueous layer was back-extracted with DCM (10 mL×2). The organics were combined, dried, filtered, and concentrated under vacuum to yield a crude orange oil. This oil was loaded onto a SiO2 column and purified using a 0-20% gradient of EtOAc in hexanes, affording the desired product ethyl 2-(3-(4-fluorophenyl)-5-methyl-2-phenyl-1H-pyrrol-1-yl)acetate (0.804 g, 2.383 mmol, 42.9% yield). 1H NMR (400 MHz, CDCl3) δ (ppm) 7.36-7.34 (m, 3H), 7.26-7.22 (m, 2H), 7.11-7.07 (m, 2H), 6.85-6.81 (m, 2H), 6.20 (b, 1H), 4.42 (s, 2H), 4.21 (q, 2H), 2.26 (s, 3H), 1.25 (t, 3H).
Reaction SMILES: [CH3:1][C@:2]1([CH2:9][S:10]([N:13]2[CH2:18][CH:17]=[C:16]([C:19]#[C:20][Si](C)(C)C)[CH2:15][CH2:14]2)(=[O:12])=[O:11])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[F-].[K+]>CO>[C:19]([C:16]1[CH2:17][CH2:18][N:13]([S:10]([CH2:9][C@@:2]2([CH3:1])[NH:6][C:5](=[O:7])[NH:4][C:3]2=[O:8])(=[O:12])=[O:11])[CH2:14][CH:15]=1)#[CH:20]
Reactant: C[C@]1(CS(=O)(=O)N2CC=C(C#C[Si](C)(C)C)CC2)NC(=O)NC1=O
Agent: [F-]
Agent: [K+]
Solvent: CO
Product: C#CC1=CCN(S(=O)(=O)C[C@@]2(C)NC(=O)NC2=O)CC1
Yield: 101.5 %

Procedure:
(5S)-5-Methyl-5-({[4-[(trimethylsilyl)ethynyl]-3,6-dihydropyridin-1(2H) -yl]sulfonyl}methyl)imidazolidine-2,4-dione (2.27 g, 6.0 mmol) and potassium fluoride (1.07 g, 18.4 mmol) were stirred overnight at room temperature in methanol (50 mL). The solvent was evaporated off, the residue dissolved in EtOAc, washed with water followed by brine, dried (sodium sulphate) and evaporated. The residue was purified by column chromatography eluting with iso-hexane/EtOAc 1:1 to give a solid product (1.81 g).
Reaction SMILES: [CH2:1]([P:3]([OH:5])[OH:4])[CH3:2].[C:6](#[N:10])[C:7]([CH3:9])=[CH2:8].CC(N=NC(C#N)(C)C)(C#N)C>C(O)(=O)C>[CH2:1]([P:3]([CH2:8][CH:7]([C:6]#[N:10])[CH3:9])(=[O:5])[OH:4])[CH3:2]
Reactant: CCP(O)O
Reactant: C=C(C)C#N
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CC(=O)O
Product: CCP(=O)(O)CC(C)C#N
Yield: 72.6 %

Procedure:
94 g (1 mol) of ethylphosphonous acid (produced as in Example 1) and 67 g (1 mol) of methacrylonitrile are initially charged in 200 ml of glacial acetic acid in a four-neck round-bottom flask equipped with stirrer, reflux condenser, thermometer and nitrogen inlet and heated. At about 100° C., 98.4 g of a 5% solution of AIBN in glacial acetic acid are added dropwise over 1 h. Thereafter, the solvent was distilled off in vacuo to leave 117 g (80% of theory) of ethyl(2-cyano-2-methylethyl)phosphinic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:19]Br)[CH:17]=2)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:28]=[N+:29]=[N-:30].[Na+]>CS(C)=O.O>[C:1]([O:5][C:6]([N:8]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:19][N:28]=[N+:29]=[N-:30])[CH:17]=2)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2ccc(CBr)cc12
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2ccc(CN=[N+]=[N-])cc12
Temperature: 85 °C
Yield: 78.2 %

Procedure:
A mixture of bis-tert-butoxycarbonyl-(7-bromomethyl-isoquinolin-1-yl)amine (280 mg, 0.64 mmol) and NaN3 (300 mg, 4.6 mmol) in 3 mL of DMSO was heated at 85° C. for 1 h. Then the solution was cooled down to rt, diluted with water and extracted with 50% EtOAc in hexane. The combined organic layers were washed with water. Removal of solvents furnished the crude product as a yellow oil (200 mg).
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]2[CH2:13][C@@H:12]([C:14](=[O:21])[CH2:15][C:16](OCC)=[O:17])[CH2:11][CH2:10][N:9]2[C:22]([O:24][CH3:25])=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl.[NH2:29]O.Cl>CO.CO.O>[CH:1]1([CH2:7][C@H:8]2[CH2:13][C@@H:12]([C:14]3[O:21][NH:29][C:16](=[O:17])[CH:15]=3)[CH2:11][CH2:10][N:9]2[C:22]([O:24][CH3:25])=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](CC2CCCCC2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1CC1CCCCC1
Reaction time: 0.5 h
Yield: 53.1 %

Procedure:
A solution of cis-methyl 2-(cyclohexylmethyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate, from a preparation of Example 20, Step 1 (1.28 g, 3.62 mmol) in MeOH (3 mL) was added dropwise to a solution of NaOH (0.159 g) in MeOH/H2O (3 mL/0.2 mL) at −30° C. After stirring for 10 minutes a solution of hydroxylamine hydrochloride (0.50 g, 7.24 mmol) and NaOH (0.29 g, 7.24 mmol) in methanol/water (5 mL/5 mL) was added at −30° C. Stirring was continued for 30 minutes at −30° C. The solution was added dropwise to HCl (6M) at 80° C. Stirred 30 minutes at 80° C. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was isolated, dried with Na2SO4, filtered through Celite® and the solvent was evaporated. Acidic reversed phase chromatography, gradient 35% to 75% acetonitrile gave cis-methyl 2-(cyclohexylmethyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.62 g, 53.1%). Chiral separation using Chiralpac IC, mobile phase heptane/isopropyl alcohol 80/20 at the temperature 40° C. gave (2R,4R)-methyl 2-(cyclohexylmethyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.28 g), e.e. 98.5% and (2S,4S)-methyl 2-(cyclohexylmethyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.27 g), e.e 98.5%. 1H NMR (600 MHz, cdcl3, RR) δ 0.67-0.88 (m, 2H), 0.98-1.20 (m, 5H), 1.28 (dd, 1H), 1.56 (dd, 5H), 1.75-1.86 (m, 2H), 1.92-2.06 (m, 2H), 2.87-2.99 (m, 1H), 3.02-3.15 (m, 1H), 3.65 (s, 3H), 3.88 (dd, 1H), 4.15 (p, 1H), 5.65 (d, 1H). [α]20D −30.7 (MeCN, c=1); 1H NMR (600 MHz, cdcl3, SS) δ 0.70-0.87 (m, 2H), 0.97-1.20 (m, 5H), 1.28 (dd, 1H), 1.51-1.65 (m, 5H), 1.77-1.85 (m, 2H), 1.96-2.05 (m, 2H), 2.87-2.96 (m, 1H), 3.03-3.14 (m, 1H), 3.65 (s, 3H), 3.88 (dd, 1H), 4.15 (p, 1H), 5.65 (d, 1H) [α]20D +29.9 (MeCN, c=1).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][CH2:20][N:21](C)[C:22](=O)OC(C)(C)C)[CH:18]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:30][C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)[CH2:6][C@@H:5]1[CH3:37])(=[O:3])[CH3:2]>ClCCl>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][CH2:20][NH:21][CH3:22])[CH:18]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:30][C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)[CH2:6][C@@H:5]1[CH3:37])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3cnn(CCN(C)C(=O)OC(C)(C)C)c3)cc2[C@H](Nc2cccnc2)C[C@@H]1C
Solvent: ClCCl
Product: CNCCn1cc(-c2ccc3c(c2)[C@H](Nc2cccnc2)C[C@H](C)N3C(C)=O)cn1
Reaction time: 1 h
Yield: 91 %

Procedure:
A solution of 1,1-dimethylethyl (2-{4-[(2S,4R)-1-acetyl-2-methyl-4-(3-pyridinylamino)-1,2,3,4-tetrahydro-6-quinolinyl]-1H-pyrazol-1-yl}ethyl)methylcarbamate (for a preparation see intermediate 58) (84 mg, 0.166 mmol) in dichloromethane (DCM) (3 mL) at room temperature under nitrogen was treated with trifluoroacteic acid TFA (0.5 mL, 6.49 mmol) and the resulting mixture was stirred at this temperature for 1 h then concentrated in vacuo. The residue was loaded onto a 10 G SCX cartridge and eluted with MeOH (2×20 mL) then with a 2N NH3 in MeOH (20 mL). The ammonia fractions were collected and concentrated in vacuo to give (2S,4R)-1-acetyl-2-methyl-6-{1-[2-(methylamino)ethyl]-1H-pyrazol-4-yl}-N-3-pyridinyl-1,2,3,4-tetrahydro-4-quinolinamine (61 mg, 0.151 mmol, 91%) as a brown oil.
Reaction SMILES: [C:1]1([CH2:13][C:14]2[C:15](=[O:29])[NH:16][C:17](=[O:28])[C:18]=2[C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.[Mg]>CO>[C:1]1([CH2:13][C@H:14]2[C@H:18]([C:19]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[NH:21][CH:20]=3)[C:17](=[O:28])[NH:16][C:15]2=[O:29])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1
Reactant: O=C1NC(=O)C(c2c[nH]c3ccccc23)=C1Cc1cn2c3c(cccc13)CCC2
Agent: [Mg]
Solvent: CO
Product: O=C1NC(=O)[C@@H](c2c[nH]c3ccccc23)[C@@H]1Cc1cn2c3c(cccc13)CCC2

Procedure:
To a solution of 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-ylmethyl)-4-(1H-indol-3-yl)-pyrrole-2,5-dione (207 mg, 0.54 mmol) in anhydrous methanol (12 ml) was added magnesium turnings (264 mg, 10.7 mmol). The mixture was heated to reflux for 1.5 hours. The mixture was separated between ethyl acetate (200 ml) and water (600 ml), the organic layer dried over anhydrous magnesium sulfate and evaporated to dryness to give a pale yellow brown solid. The solid was triturated with methanol and the solids filtered off and washed with ice cold methanol to yield (±)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-ylmethyl)-4-(1H-indol-3-yl)-pyrrolidine-2,5-dione as an off white powder (83 mg). M.p.=215-218° C.; 400 MHz 1H NMR (DMSO-d6) δ: 11.28 (s, 1H), 11.00 (s, 1H), 7.35-6.75 (m, 9H), 4.07 (m, 2H), 3.98 (d, J=5.2 Hz, 1H), 3.26-3.16 (m, 3H), 2.89 (m, 2H), 2.09 (m, 2H); LCMS: 384 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1/[CH:9]=[CH:10]/[CH:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1>C(O)C.Cl.C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1/[CH:9]=[CH:10]/[CH:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]1
Reactant: Cc1cccc(Cl)c1/C=C/C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCO
Product: Cc1cccc(Cl)c1/C=C/C1CCNCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 144.2 %

Procedure:
To a solution of 645 mg of tert-butyl 4-[(E)-2-(2-chloro-6-methylphenyl)vinyl]piperidine-1-carboxylate in 4 ml of ethanol, 3 ml of 35% hydrogen chloride-ethanol was added, followed by stirring at ambient temperature for 5 hours. The reaction mixture was evaporated under reduced pressure and the residue was azeotropically distilled with 5 ml of toluene 3 times to give crystals. The collected crystals were recrystallized from ethanol-ethyl acetate to give 377 mg of 4-[(E)-2-(2-chloro-6-methylphenyl)vinyl]piperidine hydrochloride.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:8][C:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([NH:20][C:21](=[O:37])[C:22]3[C:27]([F:28])=[CH:26][CH:25]=[C:24]([NH:29][S:30]([CH2:33][CH2:34][CH3:35])(=[O:32])=[O:31])[C:23]=3[F:36])[CH:18]=2)[NH:13][CH:12]=1)=[O:10]>CCO>[F:36][C:23]1[C:24]([NH:29][S:30]([CH2:33][CH2:34][CH3:35])(=[O:32])=[O:31])=[CH:25][CH:26]=[C:27]([F:28])[C:22]=1[C:21]([NH:20][C:17]1[CH:18]=[C:19]2[C:11]([C:9](=[O:10])[CH2:8][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:12][NH:13][C:14]2=[N:15][CH:16]=1)=[O:37]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(C(=O)CCl)c3c2)c1F
Reactant: C1CCNCC1
Solvent: CCO
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(C(=O)CN4CCCCC4)c3c2)c1F
Temperature: 60 °C
Reaction time: 1 h
Yield: 54.5 %

Procedure:
Piperidine (0.0105 mL, 0.106 mmol) was added to N-(3-(2-chloroacetyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (0.005 g, 0.0106 mmol) in EtOH (0.2 mL), which was stirred at 60° C. for 1 hour. The reaction mixture was cooled and concentrated under reduced pressure. The residue was purified via column chromatography (10% MeOH/EtOAc, to 30% MeOH (7N NH3/EtOAc). The pooled fractions were taken up in 10% MeOH/DCM and filtered to provide 2,6-difluoro-N-(3-(2-(piperidin-1-yl)acetyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (3 mg, 54.4%). 1H NMR (400 MHz, CD3OD) δ 9.05-9.07 (m, 1H), 8.54-8.57 (m, 1H), 8.44 (s, 1H), 7.63-7.69 (m, 1H), 7.12-7.17 (m, 1H), 4.71 (s, 2H), 3.59 (s, 2H), 3.10-3.14 (m, 2H), 1.92-1.99 (m, 6H), 1.84-1.90 (m, 2H), 1.04-1.08 (m, 3H); m/z (APCI-pos) M+1=520.2.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20]N1C(=O)CCC1=O.O[CH2:29][C:30]1[O:35][CH2:34][N:33]([C:36]([CH3:45])([CH3:44])[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:32](=[O:46])[C:31]=1[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>O1CCCC1>[Cl:20][CH2:29][C:30]1[O:35][CH2:34][N:33]([C:36]([CH3:45])([CH3:44])[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:32](=[O:46])[C:31]=1[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)C(C)(C)N1COC(CO)=C(c2ccccc2)C1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C)(C)N1COC(CCl)=C(c2ccccc2)C1=O
Reaction time: 8 h
Yield: 70.7 %

Procedure:
A solution of triphenylphosphine (1.82 g) in tetrahydrofuran was added dropwise to a stirred solution of N-chlorosuccinimide (1.08 g) in tetrahydrofuran. After 10 minutes a solution of tert butyl 2-(2,3-dihydro-6-hydroxymethyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanoate (2.0 g) in tetrahydrofuran was added. The mixture was stirred overnight and partitioned between ether and water, and the organic phase washed (brine), dried (magnesium sulphate) and evaporated. The residue was purified by dry column chromatography on silica gel, eluting with dichloromethanelhexane (2:1) to give tert butyl 2-(6-chloromethyl-2,3-dihydro-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanoate (1.49 g) as a white solid, m.p. 128-129° C.
Reaction SMILES: [OH:1][CH:2]1[C:11]2[C:6](=[C:7]([CH3:16])[C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[S:5][CH2:4][CH2:3]1.S(=O)(=O)(O)O.[CH2:22](O)[CH3:23]>>[CH2:22]([O:1][CH:2]1[C:11]2[C:6](=[C:7]([CH3:16])[C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[S:5][CH2:4][CH2:3]1)[CH3:23]
Reactant: COC(=O)c1ccc2c(c1C)SCCC2O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC1CCSc2c1ccc(C(=O)OC)c2C

Procedure:
13.8 g (0.058 mol) of methyl 4-hydroxy-8-methylthiochroman-7-carboxylate are heated at boiling point for 4 hours in 60 ml of ethanol with addition of 1 g of sulfuric acid. The solvent is then distilled off and the residue is taken up with water. The aqueous phase is extracted with ethyl acetate. The organic phase is washed with sodium hydrogen carbonate solution, dried and concentrated. The product is purified by chromatography.
Reaction SMILES: [C:1](=[N:9][OH:10])([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:2].O.Cl.Cl[CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.[OH-].[Na+]>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[N:16]1([CH2:15][CH2:14][O:10][N:9]=[C:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH3:2])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: ClCCN1CCOCC1
Reactant: CC(=NO)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=NOCCN1CCOCC1)c1ccccc1
Temperature: 75 °C

Procedure:
To a solution of acetophenone oxime (20 g) in toluene (700 mL) was added subsequently tetrabutylammonium bromide (4.77 g), water (8 mL), 4-(2-chloroethyl)morpholine hydrochloride (30.31 g) and finally 50% sodium hydroxide (aq, 52 mL). The resulting mixture was heated at 75° C. overnight. After cooling to room temperature water was added, to dissolve all the salts, the layers were separated, and the aqueous layer was extracted with toluene. The organic layers were dried (MgSO4), and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, CH2Cl2/MeOH 95/5) to afford acetophenone O-[2-((morpholin-4-yl))ethyl]oxime as an oil. The obtained oil was dissolved in 6M HCl (aq, 500 mL) and heated under reflux for 5 hours and subsequently stirred overnight at room temperature. The mixture was extracted with ether and concentrated in vacuo. The residue was crystallized from ethanol, to afford O-[2-((morpholin-4-yl))ethyl]hydroxylamine dihydrochloride. 24.8 g (77%)
Reaction SMILES: Cl.[CH:2]1([NH:5][C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]=[C:17]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]4[CH3:30])[C:18]4[CH2:23][NH:22][CH2:21][C:19]=4[N:20]=3)=[C:11]([F:31])[CH:10]=2)=[O:7])[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:39](Cl)(=[O:43])[CH:40]([CH3:42])[CH3:41]>CN(C=O)C>[CH:2]1([NH:5][C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]=[C:17]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]4[CH3:30])[C:18]4[CH2:23][N:22]([C:39](=[O:43])[CH:40]([CH3:42])[CH3:41])[CH2:21][C:19]=4[N:20]=3)=[C:11]([F:31])[CH:10]=2)=[O:7])[CH2:3][CH2:4]1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2F)nc2c1CNC2
Reactant: CC(C)C(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)C(=O)N1Cc2nc(-c3ccc(NC(=O)NC4CC4)cc3F)nc(N3CCOC[C@@H]3C)c2C1
Reaction time: 8 h
Yield: 44.6 %

Procedure:
A solution of (S)-1-cyclopropyl-3-(3-fluoro-4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea hydrochloride (example 149) (115 mg, 0.279 mmol) and triethylamine 0.558 mmol) in anhydrous DMF (2 ml) was stirred at RT for 1 hour. After this time, isobutyryl chloride (35 μl, 0.335 mmol) was added and stirring was continued at RT overnight. The reaction was partitioned between water and EtOAc and the aqueous phase was extracted into EtOAc. The organic extracts were combined, dried over magnesium sulphate and concentrated in vacuo. The sample was then purified via preparative HPLC at low pH to yield the title compound (60 mg, 45%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:3]=1[C:4]#[N:5].O=[C:22]([CH3:29])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[CH2:27]([O:26][C:24]([C:23]1[C:22]([CH3:29])=[N:1][C:2]2[C:3]([C:4]=1[NH2:5])=[C:6]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:7]=[CH:8][CH:9]=2)=[O:25])[CH3:28]
Reactant: N#Cc1c(N)cccc1OCCCOc1ccccc1
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)c1c(C)nc2cccc(OCCCOc3ccccc3)c2c1N

Procedure:
Prepared as in Example 2a from 2-amino-6-(3-phenoxypropoxy)benzonitrile (Example 33b) and ethyl 3-oxobutanoate as a yellow solid (47%). 1H NMR (400 MHz, DMSO-d6) δ 1.33 (t, J=8.0 Hz, 3H), 2.34 (m, 2H), 2.57 (s, 3H), 4.19 (t, J=4.0 Hz, 2H), 4.33 (q, J=8.0 Hz, 2H), 4.37 (t, J=4.0 Hz, 2H), 6.91-6.97 (m, 4H), 7.24-7.29 (m, 3H), 7.53 (t, J=8.0 Hz, 1H), 8.17 (s, 2H). MS 381 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].C(NCCNC(C)C)(C)C.[Cl:20][CH2:21][C:22](Cl)=[O:23].CCOC(C)=O>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[O:9][C:22](=[O:23])[CH2:21][Cl:20]
Reactant: Cc1cccc(C)c1O
Reactant: O=C(Cl)CCl
Agent: CC(C)NCCNC(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cccc(C)c1OC(=O)CCl
Temperature: -78 °C
Yield: 94.6 %

Procedure:
Under a nitrogen atmosphere: 2,6-dimethylphenol (1.0 equivalent, 40 mmoles) was dissolved in dichloromethane (40 mL) and diisopropyl ethylene diamine (1.3 equivalents, 53.2 mmoles). This solution was cooled to −78° C. Chloroacetylchloride was added all at once. The reaction was followed by 1TLC (25 EtOAc:75 Hexanes) until reaction was complete (˜10 minutes). The reaction was extracted using water and ether. The ether layer was washed with water and then brine, dried (MgSO4), filtered, rinsed with ether, and concentrated under vacuum. The concentrate was purified by silica gel column chromatography using hexanes as eluant, to afford 10.5 grams (94.6% yield) of chloro-acetic acid 2,6-dimethyl-phenyl ester product as a tan oil.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=[O:14])=[CH:8][CH:7]=2)=[O:5])[CH2:3][CH2:2]1.[CH2:16](O)[CH3:17]>S(=O)(=O)(O)O>[CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:8][CH:7]=2)=[O:5])[CH2:2][CH2:3]1
Reactant: O=C(O)Cc1ccc(C(=O)C2CC2)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1ccc(C(=O)C2CC2)cc1
Reaction time: 24 h
Yield: 88 %

Procedure:
Dissolve 4-(cyclopropylcarbonyl)benzeneacetic acid in ethanol (150 mL) containing concentrated sulfuric acid (10 drops). Stir 24 hours. Add triethylamine (2 mL) and concentrate the solution. Dissolve the residue in water/ethyl acetate. Wash the organic phase with saturated sodium hydrogen carbonate solution, dry over anhydrous magnesium sulfate and concentrate. Purify by silica gel chromatography (400 mL silica gel, 20% ethyl acetate/heptane as eluent) to give the title compound (7.0 g, 88%).
Reaction SMILES: [OH-].[NH4+:2].C[O:4][C:5]([C:7]1[C:11]2[N:12]=[CH:13][N:14]=[CH:15][C:10]=2[S:9][CH:8]=1)=O>O1CCOCC1>[N:12]1[C:11]2[C:7]([C:5]([NH2:2])=[O:4])=[CH:8][S:9][C:10]=2[CH:15]=[N:14][CH:13]=1
Reactant: COC(=O)c1csc2cncnc12
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: NC(=O)c1csc2cncnc12
Temperature: 100 °C

Procedure:
Ammonium hydroxide (concentrated, 2 mL) was added to a solution of thieno[3,2-d]pyrimidine-7-carboxylic acid methyl ester (40 mg) in 1,4-dioxane (2 mL) and the resulting mixture was heated in a sealed tube at 100° C. overnight. The reaction mixture was then cooled and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (DCM/MeOH, 95/5) to give 12 mg of thieno[3,2-d]pyrimidine-7-carboxylic acid amide as a light brown solid. MS=180 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]3[C:23]4[C:18](=[C:19]([O:24]C)[N:20]=[CH:21][CH:22]=4)[N:17]([CH3:26])[CH:16]=3)=[CH:13][C:12]([N+:27]([O-:29])=[O:28])=[CH:11][N:10]=2)=[CH:4][CH:3]=1.Cl>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]3[C:23]4[CH:22]=[CH:21][NH:20][C:19](=[O:24])[C:18]=4[N:17]([CH3:26])[CH:16]=3)=[CH:13][C:12]([N+:27]([O-:29])=[O:28])=[CH:11][N:10]=2)=[CH:4][CH:3]=1
Reactant: COc1nccc2c(-c3cc([N+](=O)[O-])cnc3Nc3ccc(Cl)cc3)cn(C)c12
Agent: Cl
Product: Cn1cc(-c2cc([N+](=O)[O-])cnc2Nc2ccc(Cl)cc2)c2cc[nH]c(=O)c21
Temperature: 25 °C

Procedure:
A mixture of Example 69b (0.25 g, 0.610 mmol) and hydrogen chloride (12.20 mL, 48.8 mmol, 4 M in dioxane) was heated at 90° C. overnight. The reaction mixture was cooled to ambient temperature, and the solvent was removed under reduced pressure to give the crude product, which was used directly for the next reaction.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]([O:19]CC2C=CC=CC=2)[CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][N:13]=[C:14]2[CH2:27][C:28]1[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[C:30]([O:38][CH3:39])[CH:29]=1)C1C=CC=CC=1.[ClH:40].C(O)C.Cl.C(O)C>[H][H].[Pt](=O)=O>[ClH:40].[OH:8][C:9]1[CH:18]=[C:17]([OH:19])[CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][NH:13][CH:14]2[CH2:27][C:28]1[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[C:30]([O:38][CH3:39])[CH:29]=1
Reactant: COc1cc(Cc2nccc3c(OCc4ccccc4)cc(OCc4ccccc4)cc23)cc(OC)c1OC
Reactant: [H][H]
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCO
Product: COc1cc(CC2NCCc3c(O)cc(O)cc32)cc(OC)c1OC

Procedure:
A mixture of 1.4 g of 5,7-dibenzyloxy-1-(3,4,5-trimethoxybenzyl)-isoquinoline, 0.7 g of platinum dioxide, 100 ml of a hydrochloric acid-ethanol solution (the content of hydrochloric acid: 9%) and 50 ml of ethanol is shaken at 25° C in hydrogen atmosphere. After 150 ml of hydrogen are absorbed, the catalyst is removed by filtration. The filtrate is evaporated to remove solvent, whereby a mixture of 5,7-dihydroxy-1-(3,4,5-trimethoxybenzyl)-isoquinoline hydrochloride and 5,7-dihydroxy-1-(3,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride is obtained. This mixture is recrystallized 33 times from ethanol, whereby 0.3 g of 5,7-dihydroxy-1-(3,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydrolsoquinoline hydrochloride is obtained. Yield: 40% The physiocochemical properties of this product are identical with those of the compound obtained in Example 1.