Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C@@:12]3([C@H:18]([C:19]4[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=4)[CH2:17][NH:16][CH2:15]3)[N:11]([CH3:27])[C:10]2=[O:28])[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl[CH2:30][C:31](Cl)=[O:32].CCN(C(C)C)C(C)C.[CH2:43]([NH2:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C1COCC1.CN(C1C=CN=CC=1)C>[CH2:43]([NH:50][CH2:30][C:31]([N:16]1[CH2:17][C@@H:18]([C:19]2[CH:20]=[CH:21][C:22]([C:23]#[N:24])=[CH:25][CH:26]=2)[C@:12]2([N:11]([CH3:27])[C:10](=[O:28])[N:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:13]2=[O:14])[CH2:15]1)=[O:32])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: O=C(Cl)CCl
Reactant: NCc1ccccc1
Reactant: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CNC[C@H]2c1ccc(C#N)cc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CN(C(=O)CNCc1ccccc1)C[C@H]2c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 16.6 %

Procedure:
To a solution of Example 15 (41.5 mg, 0.1 mmol) in 1 ml THF, were added TEA (0.0194 ml, 0.14 mmol) and chloroacetyl chloride (0.0095 ml, 0.12 mmol). After 15 min. at RT, the reaction mixture was evaporated to dryness to yield 47.8 mg of crude intermediate. To this intermediate (37.7 mg, 0.077 mmol) in 1 ml THF, were added PS-DIEA (Argonaut, 21 mg, 0.06 mmol), benzylamine (4.9 μl, 0.045 mmol) and PS-DMAP (Argonaut, 20 mg, 0.06 mmol). The reaction mixture was stirred for 24 h at RT before evaporation to dryness. The residue was purified by reverse phase HPLC (gradient from CH3CN/H2O/TFA: 5/95/0.05 to CH3CN/H2O/TFA: 80/20/0.05) to yield the titled compound (4.2 mg). Retention time: 10.65 min., 563 (M+1); (LCMS conditions: HP 1100 MSD platform (APCI−, DAD (210-400 nm)), Column: TSK gel Super ODS 4.6 mm ID×10 cm, Flow rate: 1 mL/min, Gradient: from 5% to 95% eluent B in 15 min., with a plateau with 95% eluent B during 5 min. Eluent A: H2O (0.1% ammonium formate), Eluent B: CH3CN). 1H NMR (CDCl3): 7.75-7.6 (2H, d), 7.6-7.15 (8H, m), 7.75 (2H, d), 4.25 (2H, s), 4.2-3.6 (7H,m), 3.3-3.05 (3H, m).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.[Br:12]Br.O>C(Cl)(Cl)Cl>[Br:12][C:4]1[C:5]([OH:6])=[C:7]([O:8][CH3:9])[CH:10]=[CH:11][C:3]=1[CH:2]=[O:1]
Reactant: COc1ccc(C=O)cc1O
Reactant: BrBr
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1ccc(C=O)c(Br)c1O

Procedure:
Isovanillin (76.1 g, 0.5 m) was suspended in 750 ml of chloroform. Bromine (27.3 ml, 0.5 m) in 200 ml of chloroform was added at 0° slowly. Water was added to give the desired 2-bromo-3-hydroxy-4-methoxy-benzaldehyde, m.p. 197°-203°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10]>C1COCC1.CCOC(C)=O>[C:12]1([O:11][C:9](=[O:10])[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccccn1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Nc1ccccn1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 124.2 %

Procedure:
To a solution of 2-aminopyridine (3.0 g) in dry THF (30 mL) was added phenyl chloroformate (1.0 g, 0.8 mL) dropwise at 0° C., followed by another batch of phenyl chloroformate (1.0 g, 0.8 mL). The reaction mixture was allowed to warm to rt. After 18 h, the mixture was diluted with EtOAc (100 mL) and washed with satd. aq. NaHCO3 (20 mL). The organic layer was dried (MgSO4) and concentrated. The residue was chromatographed to give a white solid (1.7 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][C@H:10]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:27][CH:26]([C:28]([OH:30])=[O:29])[CH2:25]3)=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.[ClH:32].[NH2:33][OH:34].C(=O)([O-])O.[Na+]>>[Cl:32][CH2:27][CH:26]([CH2:25][NH:24][C:21]1[CH:22]=[CH:23][C:18]([C@H:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH2:9]/[C:8](=[N:33]\[OH:34])/[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)=[CH:19][CH:20]=1)[C:28]([OH:30])=[O:29]
Reactant: NO
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(N3CC(C(=O)O)C3)cc2)c2ccccc2C)ccn1
Reactant: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(C[C@H](c2ccc(NCC(CCl)C(=O)O)cc2)c2ccccc2C)=N/O)ccn1

Procedure:
In analogy to example 132, step 6, from 1-{4-[(R)-3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-phenyl}-azetidine-3-carboxylic acid (example 279, step 1) and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a yellow foam, MS (ESI+): m/z=466.2 ([M+H]+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C@H:5]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:6][C@@H:7]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[NH:8][C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.[N:49]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][C:57]=2[S:59](Cl)(=[O:61])=[O:60])[CH:52]=[CH:51][CH:50]=1.O>ClCCl>[N:49]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][C:57]=2[S:59]([O:1][CH2:2][CH2:3][CH2:4][C@H:5]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:6][C@@H:7]([C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])[NH:8][C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)(=[O:61])=[O:60])[CH:52]=[CH:51][CH:50]=1
Reactant: CC(C)(C)OC(=O)[C@@H](CCCO)C[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)[C@@H](CCCOS(=O)(=O)c1cccc2cccnc12)C[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 51.8 %

Procedure:
To a solution of di-tert-butyl (4S)-4-(3-hydroxypropyl)-N-trityl-L-glutamate (203.4 mg, 0.36 mmol) and triethylamine (150 μL, 1.09 mmol) in dichloromethane (5.0 mL) was added quinoline-8-sulfonyl chloride (124.1 mg, 0.55 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 3 h and at room temperature for overnight and then water was added. The organic layer was separated, and aqueous layer was extracted with dichloromethane. Combined organic solution was dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography (MeOH/CH2Cl2=1/99) to give the desired product (140 mg, 51%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][CH:7]2[S:11][C:10](=[O:12])[NH:9][C:8]2=[O:13])=[CH:4][CH:3]=1.F[C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1.C([O-])([O-])=O.[Cs+].[Cs+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.C(OCC)(=O)C>[O:12]=[C:10]1[NH:9][C:8](=[O:13])[CH:7]([CH2:6][C:5]2[CH:14]=[CH:15][C:2]([O:1][C:17]3[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=3)=[CH:3][CH:4]=2)[S:11]1
Reactant: O=C1NC(=O)C(Cc2ccc(O)cc2)S1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(Oc2ccc(CC3SC(=O)NC3=O)cc2)cc1
Temperature: 100 °C
Yield: 65.6 %

Procedure:
To a solution of 52 (5.35 g, 24 mmol) in DMF (150 mL) was added 4-fluorobenzaldehyde (3.00 g, 24 mmol) and Cs2CO3 (20 g, 62 mmol) and the mixture was heated to 100° C. for 2 h. The mixture was poured over vigorously stirring 10% citric acid (200 mL) and ethyl acetate (200 mL). The organic layer was washed with water (300 mL), brine (300 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude product was triturated in hexanes-ethyl acetate (2:1) to yield a white solid (5.15 g, 65%). 1H NMR: (400 MHz, DMSO-d6): δ 12.07 (bs, 1H), 9.92 (s, 1H), 7.92 (d, J=8.8 Hz, 2H), 7.35 (d, J=8.4 Hz, 2H), 7.12 (d, J=8.4 Hz, 2H), 7.09 (d, J=8.4 Hz, 2H) 4.94 (dd, J=8.4 and 4.4 Hz, 1H), 3.41 (dd, J=14.4 and 4.4 Hz, 1H), 3.17 (dd, J=14.4 and 9.2 Hz, 1H).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.O[NH:38][C:39](=[NH:48])[C:40]1[CH:45]=[CH:44][C:43]([CH2:46][OH:47])=[CH:42][CH:41]=1>CN(C=O)C>[CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]2[O:11][N:48]=[C:39]([C:40]3[CH:45]=[CH:44][C:43]([CH2:46][OH:47])=[CH:42][CH:41]=3)[N:38]=2)=[CH:12][CH:13]=1)([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1
Reactant: N=C(NO)c1ccc(CO)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2nc(-c3ccc(CO)cc3)no2)cc1
Temperature: 140 °C
Reaction time: 2 h
Yield: 58.1 %

Procedure:
A solution of 4-iso-propoxybenzoic acid (2.0 g, 11.1 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.13 g, 11 mmol), 1-hydroxybenzotriazole hydrate (1.50 g, 11.1 mmol) and DMF (14 mL) was stirred at room temperature for 30 minutes. N-hydroxyl-4-(hydroxylmethyl)benzamidine (1.84 g, 11.1 mmol) was added to the reaction mixture and stirred at 140° C. for 2 hours. The reaction mixture was cooled to room temperature, quenched with water (20 mL) and the aqueous layer was extracted with EtOAc (100 mL). The combined organic layers were washed with 1N HCl and sat. NaHCO3, dried (Na2SO4), filtered and concentrated in vacuo to provide the title compound (2.0 g, 58% yield) as a pale yellow solid.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[F:14])=[O:5])#[N:2].CO/[CH:17]=[CH:18]/[C:19](=O)[CH3:20].N12CCN(CC1)CC2>COCCO.Cl.O1CCCC1.C(OCC)(=O)C>[F:14][C:8]1[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=1[N:6]1[C:19]([CH3:20])=[CH:18][CH:17]=[C:3]([C:1]#[N:2])[C:4]1=[O:5]
Reactant: CO/C=C/C(C)=O
Reactant: N#CCC(=O)Nc1ccc(F)cc1F
Agent: C1CN2CCN1CC2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: COCCO
Solvent: C1CCOC1
Product: Cc1ccc(C#N)c(=O)n1-c1ccc(F)cc1F
Temperature: 120 °C
Reaction time: 12 h
Yield: 9.4 %

Procedure:
To a solution of 2-cyano-N-(2,4-difluorophenyl)acetamide (5.5 g, 28 mmol) and (3E)-4-methoxybut-3-en-2-one (3.65 g, 36.5 mmol) in dimethyleneglycol monomethylether (50 mL) was added 1,4-diazabicyclo[2.2.2]octane (3.14 g, 28 mmol), and the mixture was stirred at 120° C. for 12 hr. The reaction mixture was diluted with 2N hydrochloric acid, tetrahydrofuran and ethyl acetate, and extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure. The obtained residue was washed with ethyl acetate to give a slightly yellow solid. The slightly yellow solid was suspended in tetrahydrofuran at 80° C., and the suspension was stirred for 30 min. The suspension was filtrated, and the obtained solid was washed with tetrahydrofuran to give the title compound (650 mg, 9.4%) as a white solid.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4](C2CCCCO2)[N:5]=[CH:6][C:7]=1Cl.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=1[OH:24].C[O:26][C:27](=[O:36])[CH:28](Br)[CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH:30]1([CH2:29][CH:28]([N:4]2[C:3](=[O:15])[CH:2]=[C:7]([O:24][C:18]3[C:17]([F:16])=[CH:22][CH:21]=[CH:20][C:19]=3[F:23])[CH:6]=[N:5]2)[C:27]([OH:26])=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: COC(=O)C(Br)CC1CCCC1
Reactant: Oc1c(F)cccc1F
Reactant: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Product: O=C(O)C(CC1CCCC1)n1ncc(Oc2c(F)cccc2F)cc1=O
Yield: 58 %

Procedure:
In an analogous manner to the stepwise sequence outlined in intermediate 19, starting from 4,5-dichloro-2-(tetrahydropyran-2-yl)-2H-pyridazin-3-one (Intermediate 20) and 2,6-difluoro-phenol and alkylating with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10) afforded 3-cyclopentyl-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (13.2 g, 58%) as a white solid; ESI-MS 364 [M+H+]; HPLC: >98% (purity). 1H-NMR (300 MHz, CDCl3) δ 7.93-7.94 (d, 1H), 7.22-7.39 (m, 1H), 7.03-7.09 (m, 2H), 6.00 (s, 1H), 5.51-5.56 (m, 1H), 2.29-2.39 (m, 1H), 2.08-2.16 (m, 1H), 1.44-1.81 (m, 7H), 1.10-1.25 (m, 2H).
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[NH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][C:14]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][CH2:12]1>C1(C)C=CC=CC=1>[C:17]1([C:14]2([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:13][CH2:12][N:11]([CH2:10][CH2:9][CH2:8][NH:7][C:4](=[O:5])[CH2:3][C:2]([CH3:1])=[O:6])[CH2:16][CH2:15]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C=C1CC(=O)O1
Reactant: NCCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)NCCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Reaction time: 48 h
Yield: 78.2 %

Procedure:
Diketene (0.44 mL, 5.68 mmol, 1.3 equiv, Aldrich) was added at room temperature to a stirred solution of 1-(3-aminopropyl)-4-,4-diphenylpiperidine (1.288 g, 4.37 mmol, 1.0 equiv) in anhydrous toluene (15 mL) under argon, and stirring was continued for 48 hours. The mixture was concentrated to give 1.294 g (78%) of white solid, which was used for the next reaction without purification: 1H NMR (300 MHz, CDCl3) δ 1.70 (tt, J=6.4, 6.4 Hz, 2H), 2.23 (s, 3H), 2.44 (br t, J=6.5 Hz), 2.49-2.67 (m, 8H), 3.32 (br t, J=5.8 Hz), 3.36 (s, 2H), 7.16 (m, 2H), 7.27 (m, 8H).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:29](/[CH:30]=[CH:31]/[CH:32]=[O:33])=[C:28]([CH3:34])[N:27]=[C:26]([CH3:35])[N:25]=2)=[CH:20][CH:19]=1>O1CCCC1>[F:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[C:29]([CH:30]=[CH:31][CH:32]([OH:33])[CH2:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])=[C:28]([CH3:34])[N:27]=[C:26]([CH3:35])[N:25]=2)=[CH:22][CH:23]=1
Reactant: Cc1nc(C)c(/C=C/C=O)c(-c2ccc(F)cc2)n1
Reactant: CCOC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CC(O)C=Cc1c(C)nc(C)nc1-c1ccc(F)cc1
Temperature: 0 °C

Procedure:
A solution of ethyl acetoacetate (11.65 mL, 0.0914 mol) in 50 mL of anhydrous tetrahydrofuran was added dropwise with stirring to a suspensionof sodium hydride (2.39 g, 0.0992 mol) in anhydrous tetrahydrofuran at 0° C. under nitrogen. The resulting mixture was stirred at 0° C. for ten minutes, after which n-butyl lithium (38.1 mL, 2.4M solution in tetrahydrofuran, 0.0914 mol) was added dropwise. The resultingorange solution was stirred for an additional ten minutes and then cooled to -78° C. A solution of (E)-3-[4-(4-fluorophenyl)-2,6-dimethyl-5-pyrimidinyl]-2-propenal (21.27 g,0.083 mol) in 100 mL of anhydrous tetrahydrofuran was added dropwise. The resulting solution was stirred for thirty minutes, and the cooling bath was removed, after which the reaction was quenched by the addition of 12 mL of glacial acetic acid.
Reaction SMILES: [C:1]([CH2:3][C:4](O)=O)#[N:2].[OH:7][C:8]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C=O.[C:22](=O)=O>O1CCOCC1>[OH:7][C:8]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:13][CH2:12][N:11]([CH2:22][C:3](=[CH2:4])[C:1]#[N:2])[CH2:10][CH2:9]1
Reactant: N#CCC(=O)O
Reactant: O=C=O
Reactant: OC1(c2ccccc2)CCNCC1
Agent: C=O
Solvent: C1COCCO1
Product: C=C(C#N)CN1CCC(O)(c2ccccc2)CC1
Reaction time: 8 h

Procedure:
A solution of cyanoacetic acid (4.3 g., 0.05 mole) in 15 ml. of dioxane was cooled with an ice bath, and 4-hydroxy-4-phenylpiperidine (8.8 g., 0.05 mole) added while maintaining an internal temperature of 20°-25° C. Upon complete addition and a further fifteen minutes of stirring 37% aqueous formaldehyde (9 gm., 0.10 mole) was added dropwise in approximately five minutes. When approximately half was added carbon dioxide evolution was observed, the maximum internal temperature was 28° C. The reaction mixture was stirred overnight, mixed with 100 ml. of methylene chloride, the organic phase separated, washed with water and salt solution. Upon removal of solvent the product was obtained as an oil, 10.5 g., in practically analytical purity.
Reaction SMILES: CSC.B.[CH3:5][Si:6]([CH3:14])([CH3:13])[CH2:7][CH2:8][CH2:9][C:10](O)=[O:11]>O1CCCC1>[CH3:5][Si:6]([CH3:14])([CH3:13])[CH2:7][CH2:8][CH2:9][CH2:10][OH:11]
Reactant: C[Si](C)(C)CCCC(=O)O
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: C[Si](C)(C)CCCCO
Yield: 71.9 %

Procedure:
1.5 ml (11.4 mmol) of a 1 molar solution of borane dimethylsulfide was added to a cooled (0° C.) solution of 0.61 g (3.8 mmol) of 4-(trimethylsilyl)-butanoic acid in 20 ml of dry tetrahydrofuran. After work-up using the standard procedure (methanol, tetramethylethylene diamine) and flash chromatography purification on silica gel eluted with a 9:1 mixture of hexane and ethyl acetate, 0.4 g of 4-(trimethylsilyl)-1-butanol was obtained as a colorless liquid.
Reaction SMILES: [C:1]([O:5]C(OC(OC(C)(C)C)=O)=O)(C)(C)C.[CH2:16]([NH:19][C:20]1[N:21]=[C:22]([NH2:30])[C:23]2[S:28][CH:27]=[C:26]([CH3:29])[C:24]=2[N:25]=1)[CH:17]=[CH2:18].[CH:31]1([NH2:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>C(#N)C>[CH2:16]([NH:19][C:20]1[N:21]=[C:22]([NH:30][C:1](=[O:5])[NH:37][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[C:23]2[S:28][CH:27]=[C:26]([CH3:29])[C:24]=2[N:25]=1)[CH:17]=[CH2:18]
Reactant: C=CCNc1nc(N)c2scc(C)c2n1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: NC1CCCCC1
Solvent: CC#N
Product: C=CCNc1nc(NC(=O)NC2CCCCC2)c2scc(C)c2n1
Reaction time: 0.33 h
Yield: 49.8 %

Procedure:
122 mg (1.0 mmol) of N,N-dimethylaminopyridine was added to a solution of 306 mg (1.4 mmol) of di-t-butyldicarbonate in acetonitrile at room temperature, followed by stirring 20 minutes. After 220 mg (1.0 mmol) of 2-allylamino-4-amino-7-methylthieno[3,2-d]pyrimidine was added to the reaction solution, the mixture was stirred at room temperature for 2 hours. Further, 139 mg (1.4 mmol) of cyclohexylamine was added thereto, followed by heating under reflux for 16 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was purified by a silica gel chromatography (eluent: ethyl acetate-hexane=1/4) to give 172 mg (yield: 49.9%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]([NH2:21])[CH:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[O:17][CH:18]([CH3:20])[CH3:19])[NH:10][CH:9]=1)[CH3:7])[CH3:2].O.[C:24]([OH:28])(=[O:27])[CH:25]=O.C([O-])([O-])=O.[K+].[K+]>C(OC(=O)C)C.O>[CH:18]([O:17][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:16]=1[C:8]1[CH:6]([CH3:7])[CH:5]([C:4]([O:3][CH2:1][CH3:2])=[O:22])[NH:21][CH:25]([C:24]([OH:28])=[O:27])[C:9]=1[NH:10]2)([CH3:20])[CH3:19]
Reactant: CCOC(=O)C(N)C(C)c1c[nH]c2cccc(OC(C)C)c12
Reactant: O=CC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C1NC(C(=O)O)c2[nH]c3cccc(OC(C)C)c3c2C1C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of 27.25 g 2-amino-3(4-isopropoxyindole-3-yl)butanoic acid ethylester in 70 ml ethylacetate was added 9.99 g glyoxylic acid hydrate dissolved in 70 ml water. The mixture was adjusted to pH 4 (10% K2CO3 -solution) and further stirred at room temperature for 6 hours. The yellow precipitate was collected by filtration, washed with ethylacetate and dried.
Reaction SMILES: Cl[C:2]1[C:10]2[C:5](=[N:6][C:7]([NH:11][CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[N:8][CH:9]=2)[N:4]([CH3:19])[N:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=2)O1>>[NH2:32][C:31]1[CH:33]=[CH:34][C:28]([C:2]2[C:10]3[C:5](=[N:6][C:7]([NH:11][CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[N:8][CH:9]=3)[N:4]([CH3:19])[N:3]=2)=[CH:29][CH:30]=1
Reactant: CCN(CC)CCNc1ncc2c(Cl)nn(C)c2n1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Product: CCN(CC)CCNc1ncc2c(-c3ccc(N)cc3)nn(C)c2n1

Procedure:
Prepared as described above in Example 15 starting from N′-(3-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-N,N-diethyl-ethane-1,2-diamine and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline to give the title compound N-[3-(4-amino-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-N′,N′-diethyl-ethane-1,2-diamine; 1H-NMR (MeOH): δ 1.38 (m, 6H), 3.36 (m, 4H), 3.82 (m, 2H), 3.92 (m, 2H), 3.98 (s, 3H), 7.46 (d, 2H, J=8.4 Hz), 8.09 (d, 2H, J=8.4 Hz), 9.18 (s, 1H), LC/MS (m/e)=340.2 (MH+), Rt=0.98 min.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:10]3[CH2:12][CH:13]([CH3:16])[CH2:14][CH2:15][C:9]=3[C:8]([CH3:18])([CH3:17])[O:7][C:6]=2[CH:5]=[C:4]([CH:19]([CH3:29])[CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:3]=1.[ClH:30].[O:31]1[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][CH2:39][C:40](O)=[O:41])[CH2:33][CH2:32]1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[ClH:30].[O:31]1[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][CH2:39][C:40]([O:1][C:2]2[C:11]3[C:10]4[CH2:12][CH:13]([CH3:16])[CH2:14][CH2:15][C:9]=4[C:8]([CH3:17])([CH3:18])[O:7][C:6]=3[CH:5]=[C:4]([CH:19]([CH3:29])[CH2:20][CH2:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:3]=2)=[O:41])[CH2:33][CH2:32]1
Reactant: CC1CCC2=C(C1)c1c(O)cc(C(C)CCCc3ccccc3)cc1OC2(C)C
Reactant: O=C(O)CCCN1CCOCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: CC1CCC2=C(C1)c1c(OC(=O)CCCN3CCOCC3)cc(C(C)CCCc3ccccc3)cc1OC2(C)C

Procedure:
0.91 g. (2.33 mmoles) of 1-hydroxy-3-(4-phenyl-1-methylbutyl)-6,6,9-trimethyl-7,8,9,10-tetrahydro-5H-dibenzo [b,d]pyran, prepared according to the method of Example 4, 0.48 g. (2.28 mmoles) of γ-morpholinobutyric acid hydrochloride (Cruickshank and Sheehan, J. Am. Chem. Soc. 83, 2891 (1961), m.p. 180° - 182° ) and 0.48 g. (2.35 mmoles) of dicyclohexylcarbodiimide (Aldrich) are combined with 35 ml. of methylene chloride and stirred at room temperature for a total of 40 hours. The insoluble by-product of dicyclohexylurea is removed using a rotary evaporator. The resulting residue is dissolved in about 20 ml. of benzene and a small amount of insoluble material is removed by filtration. The benzene is evaporated and the residue dried in vacuo to give 0.7 g. of material. Crystallization from benzene/pet ether yields the crystalline product.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[F:15][C:16]([F:25])([F:24])[C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.O>[N+:12]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[CH:5]=[CH:4][N:3]=[C:2]2[O:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:16]([F:15])([F:24])[F:25])[CH:18]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cccc2c(Cl)nccc12
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=[N+]([O-])c1cccc2c(Oc3cccc(C(F)(F)F)c3)nccc12
Yield: 374 %

Procedure:
To a solution of 1-chloro-5-nitroisoquinoline (Step-1, Intermediate-1, 200 mg, 0.96 mmol) in CH3CN (2 mL) were added 3-(trifluoromethyl)phenol (233 mg, 1.4 mmol) and K2CO3 (265 mg, 1.92 mmol). The reaction mass was heated at reflux for 5 h and it was diluted with water and extracted with chloroform. The organic layer was separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 1.2 g of the title product. 1H NMR (300 MHz, DMSO d6): δ 8.82 (d, J=8.4 Hz, 1H), 8.58 (d, J=7.8 Hz, 1H), 8.17 (s, 2H), 7.76 (t, J=8.4 Hz, 1H), 7.61-7.47 (m, 4H); MS (m/z): 335.12 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([CH2:16][CH2:17][CH2:18][O:19][CH3:20])[CH:15]=1)[C:9]([O:11]C)=[O:10].[OH-].[Na+]>C1COCC1.CO.CCOC(C)=O>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([CH2:16][CH2:17][CH2:18][O:19][CH3:20])[CH:15]=1)[C:9]([OH:11])=[O:10]
Reactant: COCCCc1cc(CCCOC)cc(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: COCCCc1cc(CCCOC)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of methyl 3,5-bis(3-methoxypropyl)benzoate (1 eq.) from the previous step in THF/MeOH (2:1 v/v, 0.1 M) was added 2 M aqueous NaOH (2 eq.). After stirring at rt for 72 h, the reaction was diluted with EtOAc. The organic extract was washed with 10% aqueous HCl solution, brine, dried over MgSO4, and concentrated in vacuo to afford the title compound as an oil.