Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[O:2]=[C:3]1[C:11]2([CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:20]C(=O)OC(C)(C)C)[CH:17]=3)[CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4]1>CCOC(C)=O>[NH2:20][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[CH2:12][C:11]1([C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[NH:4][C:3]1=[O:2])[CH2:19]2
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)CC1(C2)C(=O)Nc2ccccc21
Agent: Cl
Solvent: CCOC(C)=O
Product: Nc1ccc2c(c1)CC1(C2)C(=O)Nc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
HCl (g) was bubbled through a solution of (±)-tert-butyl (2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-indol]-5-yl)carbamate from Step C (19.0 mg, 0.054 mmol) in EtOAc (5 mL) for 15 min. The reaction mixture was stirred at ambient temperature for 1 h and then concentrated in vacuo to give the title compound as the hydrochloride salt. MS: m/z=251 (M+1).
Reaction SMILES: [C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:28])[C:11]2[CH:17]=[C:16]([C:18]#[C:19][CH2:20][O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[CH:15]=[N:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].CO.N1C2C(=CC=CC=2)C=CC=1.[H][H]>[Pd].CCOCC.C(Cl)(Cl)Cl>[C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:28])[C:11]2[CH:17]=[C:16]([CH:18]=[CH:19][CH2:20][O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[CH:15]=[N:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:4])([CH3:5])[CH3:3]
Reactant: CC(C)(C)C(=O)Nc1nc(O)c2cc(C#CCOC3CCCCO3)cnc2n1
Reactant: [H][H]
Agent: [Pd]
Solvent: c1ccc2ncccc2c1
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CC(C)(C)C(=O)Nc1nc(O)c2cc(C=CCOC3CCCCO3)cnc2n1
Yield: 86.5 %

Procedure:
A mixture of 2 g (5.2 mm) of 2-pivaloylamino-4-hydroxy-6-(3-tetrahydropyr-2-yloxyprop-1-yn-1-yl)-pyrido[2,3-d]pyrimidine, 40 ml of methanol, 20 ml of chloroform, 40 mg of 5% palladium on barium sulfate, and 40 mg of synthetic quinoline was stirred under 1 atm hydrogen pressure for 40 min. The solvent then was removed by evaporation and the residue diluted with methylene chloride. The methylene chloride solution was filtered through silica gel with 2% methanol in methylene chloride to remove catalyst and the filtrate then concentrated to give an oil which upon adding ether yielded 1.74 g (86.6%) of 2-pivaloylamino-4-hydroxy-6-(3-tetrahydropyr-2-yloxyprop-1-en-1-yl)-pyrido[2,3-d]pyrimidine as yellow crystals which was further purified through column chromatography eluting with ethyl acetate and recrystallization using ethyl acetate. mp 166°-167° C. Analysis: Calculated for C20H26O4N4 : C, 62.16; H, 6.78; N, 14.50. Found: C, 62.30; H, 6.88; N, 14.74. NMR (CDCl3), delta, 1.35 (s, 9H), 1.54-1.88 (m, 6H), 3.51-3.58 (m, 1H), 3.85-3.93 (m, 1H), 4.26-4.33 (m, 1H), 4.51-4.57 (m, 1H), 4.70 (t, 1H, J=3.4 Hz), 6.07-6.15 (m, 1H), 6.62 (d, 1H, J=12.1 Hz), 8.35 (brs, NH), 8.37 (d, 1H, J=2.5 Hz), 8.79 (d, 1H, J=2.5 Hz), 12.7 (brs, NH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]([OH:18])=O)[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.[NH2:21][CH2:22][C:23]1[NH:24][C:25](=[O:34])[C:26]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][C:27]=2[N:28]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][C:16]([NH:21][CH2:22][C:23]3[NH:24][C:25](=[O:34])[C:26]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][C:27]=4[N:28]=3)=[O:18])[CH2:13][CH2:14]2)=[O:8])=[CH:19][CH:20]=1
Reactant: NCc1nc2c(c(=O)[nH]1)CCCCC2
Reactant: COc1ccc(C(=O)C2CCN(CC(=O)O)CC2)cc1
Product: COc1ccc(C(=O)C2CCN(CC(=O)NCc3nc4c(c(=O)[nH]3)CCCCC4)CC2)cc1
Yield: 43.7 %

Procedure:
The title compound (89 mg, 44% yield) was prepared following the general procedure of Example 1 from 2-(4-(4-methoxybenzoyl)piperidin-1-yl)acetic acid (124 mg, 0.45 mmol) and 2-(aminomethyl)-6,7,8,9-tetrahydro-3H-cyclohepta[d]pyrimidin-4(5H)-one (87 mg, 0.45 mmol). 1H NMR (400 MHz, CDC3) δ 11.36 (br. s., 1H), 8.01 (br. s., 1H), 7.83-7.89 (m, J=9.1 Hz, 2H), 6.85-6.91 (m, 2H), 4.30 (d, J=5.6 Hz, 2H), 3.81 (s, 3H), 3.12-3.29 (m, 1H), 2.97-3.12 (m, 2H), 2.92 (br. s., 2H), 2.55-2.83 (m, 4H), 2.30 (br. s., 2H), 1.67-1.94 (m, 6H), 1.40-1.67 (m, 4H). HRMS calculated for C23H32N4O4 453.2502. found (ESI, [M+H]+), 453.2509. Retention time=3.09.
Reaction SMILES: C[Si]([C:5]#[CH:6])(C)C.C([Li])CCC.[CH2:12]([CH:16]1[C:25](=[O:26])[CH2:24][CH:23]2[N:18]([CH2:19][CH2:20][C:21]3[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[CH:27][C:22]=32)[CH2:17]1)[CH:13]([CH3:15])[CH3:14]>C1COCC1>[OH:26][C:25]1([C:5]#[CH:6])[CH2:24][CH:23]2[N:18]([CH2:19][CH2:20][C:21]3[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[CH:27][C:22]=32)[CH2:17][CH:16]1[CH2:12][CH:13]([CH3:15])[CH3:14]
Reactant: C#C[Si](C)(C)C
Reactant: COc1cc2c(cc1OC)C1CC(=O)C(CC(C)C)CN1CC2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C#CC1(O)CC2c3cc(OC)c(OC)cc3CCN2CC1CC(C)C
Temperature: 20 °C
Yield: 53.7 %

Procedure:
Trimethylsilylacetylene (2 eqs.; 20.4 mmol; 2.88 mL) was dissolved in 80 mL of dry THF and stirred under a nitrogen atmosphere at -5° to 0° C. n-Butyl lithium (20.4 mmol, 12.72 mL) was added dropwise with stirring followed by dropwise addition of a solution of 3-isobutyl-9-,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-benzo[a]quinolizin-2-one (TBZ) in 30 mL dry THF. The reaction mixture was stirred at -5° to 0° C. for 1 h, allowed to warm slowly to 20° C., and stirred for 2 h at 20° C. The reaction was quenched while cold with saturated NH4Cl. The solvent was evaporated under reduced pressure and the resulting aqueous solution was extracted with ethyl acetate (3×100 mL). The organic phase was washed with water (2×50 mL) and brine (50 mL) and concentrated. The residue was dissolved in 30 mL MeOH and 5 mL 5N KOH, and heated to 65° C. with stirring for 30 min. The reaction was cooled and quenched with NH4Cl. The methanol was evaporated and the aqueous phase extracted with ethyl acetate (3×75 mL). The organic phase was washed with water (50 mL) and brine (50 mL), dried over Na2SO4, and concentrated to yield the product (53.7%) as slightly brown solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25]CC3C=CC=CC=3)[CH:20]=2)([C:9]2[CH:10]=[N:11][N:12]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH:13]=2)[N:3]=1>C(O)C.[Pd]>[NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=2)([C:9]2[CH:10]=[N:11][N:12]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH:13]=2)[N:3]=1
Reactant: CN1C(=O)C(c2cccc(OCc3ccccc3)c2)(c2cnn(CC(F)(F)F)c2)N=C1N
Agent: [Pd]
Solvent: CCO
Product: CN1C(=O)C(c2cccc(O)c2)(c2cnn(CC(F)(F)F)c2)N=C1N
Yield: 95.6 %

Procedure:
A mixture of 2-amino-5-[3-(benzyloxy)phenyl]-3-methyl-5-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl]-3,5-dihydro-4H-imidazol-4-one (330 mg, 0.74 mmol) and Pd/C (33 mg) in ethanol (10 ml) is hydrogenated at 45 psi overnight. After removal of the catalyst by filtration, the filtrate is concentrated. The crude material is purified by flash chromatography (silica gel, EtOAc/2.0M ethanolic NH3: 90/10 to 80/20) to afford the title compound as a solid 250 mg (95%). mp: 118-120° C. MS (+) ES: 354 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[CH:6]=[C:5]([OH:17])[N:4]=1)[CH3:2].Cl.Cl[CH2:20][C:21]1[C:22]([NH:33][CH2:34][CH3:35])=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][C:27]([O:31][CH3:32])=[CH:26][CH:25]=2.ClCC1C(NCC)=NC2C(C=1)=CC(OC)=CC=2.[Li+].[OH-]>C1(C)C=CC=CC=1.C(Cl)Cl>[CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6]([CH2:20][C:21]2[C:22]([NH:33][CH2:34][CH3:35])=[N:23][C:24]3[C:29]([CH:30]=2)=[CH:28][C:27]([O:31][CH3:32])=[CH:26][CH:25]=3)=[C:5]([OH:17])[N:4]=1)[CH3:2]
Reactant: CCNc1nc2ccc(OC)cc2cc1CCl
Reactant: CCc1nc(O)cc2cc(OC)c(OC)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCNc1nc2ccc(OC)cc2cc1Cc1c(O)nc(CC)c2cc(OC)c(OC)cc12
Temperature: 150 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 1-ethyl-6,7-dimethoxyisoquinolin-3-ol SLA 28136 (250 mg, 1.07 mmol) in toluene (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 3-(chloromethyl)-N-ethyl-6-methoxyquinolin-2-amine hydrochloride SLA 28166 (308 mg, 1.07 mmol) followed by 2N aq. LiOH solution (1.07 ml, 2.14 mmol) and the mixture was stirred for 1.5 h at 150° C. under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (150 mL) and washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent EtOAc:MeOH=100:0 to 95:5) followed by a new purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 92:8) provided 29 mg of 1-ethyl-4-((2-(ethylamino)-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxyisoquinolin-3-ol as a brown solid. This product was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (0.55 mL). The reaction mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum to afford 1-ethyl-4-((2-(ethylamino)-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxyisoquinolin-3-ol dihydrochloride 40 as a yellow solid (20 mg, 4% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([CH2:31][O:32][C:4]=2[CH:3]=1)[C:16]1[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[N:10]([CH:17]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:9]3=[O:30].[C-]#N.[Na+].[CH3:36][N:37]1CCCC1=O>C(OCC)(=O)C.O.O.O.O.O.O.[Ni](Cl)Cl>[C:18]1([CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]3([C:5]4[CH:6]=[CH:7][C:2]([C:36]#[N:37])=[CH:3][C:4]=4[O:32][CH2:31]3)[C:9]2=[O:30])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1cc(Br)ccc12
Reactant: CN1CCCC1=O
Agent: Cl[Ni]Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1ccc2c(c1)OCC21C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Temperature: 25 °C
Yield: 100 %

Procedure:
A 10 mL microwave reaction vessel was charged with 6-bromo-1′-(diphenylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (0.51 g, 1.1 mmol), nickel chloride hexahydrate (0.25 g, 1.1 mmol), sodium cyanide (0.10 g, 2.1 mmol) and 1-methyl-2-pyrrolidinone (1 mL). The solution was irradiated at 200° C. for 20 min in a microwave reactor. The solution was allowed to cool to ambient temperature, diluted with ethyl acetate (25 mL) and filtered. The filtrate was washed with brine (3×15 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography and eluted with a 15% to 50% gradient of ethyl acetate in hexanes to afford 1′-(diphenylmethyl)-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-6-carbonitrile (0.50 g, 100%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.44-7.22 (m, 10H), 7.21-7.18 (m, 1H), 7.14-6.93 (m, 5H), 6.72 (d, J=7.8 Hz, 1H), 6.55 (d, J=7.5 Hz, 1H), 5.07 (d, J=9.2 Hz, 1H), 4.80 (d, J=9.2 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:21][C@H:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)[CH3:23]>>[Cl:1][C:2]1[CH:10]=[C:6]([C:7]([NH:21][C@H:22]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=2)[CH3:23])=[O:9])[C:5]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[N:4][CH:3]=1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: O=C(O)c1cc(Cl)cnc1COc1cccc(Cl)c1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2COc2cccc(Cl)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-chloro-2-[(3-chlorophenoxy)methyl]nicotinic acid (step 1) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 5 of Example 1):
Reaction SMILES: [CH3:1][C:2]1([C:12]#[N:13])[CH2:11][CH2:10][C:5]2(OCC[O:6]2)[CH2:4][CH2:3]1.[OH-].[Na+]>C1COCC1.Cl>[CH3:1][C:2]1([C:12]#[N:13])[CH2:11][CH2:10][C:5](=[O:6])[CH2:4][CH2:3]1
Reactant: CC1(C#N)CCC2(CC1)OCCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1(C#N)CCC(=O)CC1
Temperature: 40 °C
Reaction time: 5 h
Yield: 73.3 %

Procedure:
8-methyl-1,4-dioxa-spiro[4.5]decane-8-carbonitrile (3.29 g, 18.1 mmol) was dissolved in a 1:1 mixture of THF and 3N HCl aqueous solution (60 mL). The resulting mixture was stirred at 40° C. for 5 h, cooled to 0° C. and neutralized using about 30 mL of a 3N NaOH aqueous solution until a basic pH was reached. It was extracted with ether (4×75 mL). The organic portions were combined, dried over anhydrous Na2SO4 and concentrated. The crude was purified by silica gel column chromatography using a gradient from 15% EtOAc:hexanes to 20% EtOAc:hexanes as eluent to afford 1-Methyl-4-oxo-cyclohexanecarbonitrile as a white solid (1.82 g, 73%).
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]([CH3:25])[C:6]1[S:7][C:8]2[CH:14]=[C:13]([NH:15][C:16](=[O:24])[C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=3)[CH:12]=[CH:11][C:9]=2[N:10]=1.[Cl:27][C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:29]=1B(O)O>>[CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]([CH3:25])[C:6]1[S:7][C:8]2[CH:14]=[C:13]([NH:15][C:16]([C:17]3[CH:22]=[CH:21][C:20]([C:29]4[CH:30]=[CH:31][C:32]([C:34]([F:37])([F:36])[F:35])=[CH:33][C:28]=4[Cl:27])=[CH:19][CH:18]=3)=[O:24])[CH:12]=[CH:11][C:9]=2[N:10]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1Cl
Reactant: CN(C)CCN(C)c1nc2ccc(NC(=O)c3ccc(I)cc3)cc2s1
Product: CN(C)CCN(C)c1nc2ccc(NC(=O)c3ccc(-c4ccc(C(F)(F)F)cc4Cl)cc3)cc2s1

Procedure:
The title compound is prepared by following a procedure analogous to Example 113, Step 1, using N-{2-[(2-dimethylamino-ethyl)-methyl-amino]-benzothiazol-6-yl}-4-iodo-benzamide (0.10 g, 0.21 mmol) and 2-chloro-4-trifluoromethyl-phenyl boronic acid (0.056 g, 0.25 mmol) to afford 0.045 g (40%). LC/MS, Retention time=5.34 min; (m/z): calcd for C26H24ClF3N4OS: 533.0; found: 533.0.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)[CH3:16])=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30](=[O:50])[CH2:31][C:32]1([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)[CH3:28]>>[CH2:27]([O:29][C:30](=[O:50])[CH2:31][C:32]1([C:35]2[CH:36]=[CH:37][C:38]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([C:17]4[CH:26]=[CH:25][C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[CH:18]=4)[CH3:16])=[CH:6][CH:7]=3)=[CH:39][CH:40]=2)[CH2:33][CH2:34]1)[CH3:28]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)c1ccc2ccccc2c1
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)c4ccc5ccccc5c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-(1-naphthalen-2-yl-ethyl)-amine and {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: C[O:2][C:3]([C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[N:8]=1)(OC)[CH3:4].Cl>O1CCCC1>[NH2:13][C:9]1[N:8]=[C:7]([C:3](=[O:2])[CH3:4])[CH:12]=[CH:11][N:10]=1
Reactant: COC(C)(OC)c1ccnc(N)n1
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)c1ccnc(N)n1
Reaction time: 8 h
Yield: 83.1 %

Procedure:
To a stirred solution of 4-(1,1-dimethoxyethyl)pyrimidin-2-amine (2a) (180 g) in tetrahydrofuran (2 L) was added 2M hydrochloric acid solution (980 mL) and stirring continued at room temperature overnight. Most of the solvent was removed in vacuo and remaining aqueous solution was poured into an aqueous saturated sodium hydrogen carbonate solution. The sandy coloured precipitate was filtered off and dried in vacuo at 40° C. to give the title compound (112 g).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:18])[CH:8]=2)[N:3]=1.[CH2:19]([NH2:25])[C:20]1[O:24][CH:23]=[CH:22][CH:21]=1>O>[Cl:18][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:25][CH2:19][C:20]1[O:24][CH:23]=[CH:22][CH:21]=1)[N:11]=[C:10]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Clc1ccc2nc(Cl)nc(-c3ccccc3)c2c1
Reactant: NCc1ccco1
Solvent: O
Product: Clc1ccc2nc(NCc3ccco3)nc(-c3ccccc3)c2c1
Yield: 83.4 %

Procedure:
A mixture of 275 mg of 2,6-dichloro-4-phenylquinazoline (compound No. Ia1-3) and 486 mg of furfurylamine was stirred at 85° C. for 40 minutes and then poured into 50 ml of water. The mixture was extracted with ethyl acetate and the resultant extract was washed with water and then concentrated. The resulting residue was recrystallized from ethanol to obtain 280 mg of the titled compound. Mp.142.0° C. 1H NMR (CDCl3): 4.77 (2H, d, J=5.6 Hz), 5.70 (1H, br. t, J=5.6 Hz), 6.29-6.32 (2H, m), 7.36 (1H, dd, J=1.8, 0.9 Hz), 7.53-7.70 (7H, m), 7.78 (1H, d, J=2.2 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([CH:8]([C:18]#[N:19])[NH:9][C:10]([CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[O:11])[CH:7]=1.NC(=O)C(NC(=O)CC(O[Si](C(C)(C)C)(C)C)(C)C)C1C=C(Cl)C=CC=1[O:32]C>>[NH2:19][C:18](=[O:32])[CH:8]([NH:9][C:10]([CH:12]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1)=[O:11])[C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[O:20][CH3:21]
Reactant: COc1ccc(Cl)cc1C(NC(=O)CC(C)(C)O[Si](C)(C)C(C)(C)C)C(N)=O
Reactant: COc1ccc(Cl)cc1C(C#N)NC(=O)C1CCOCC1
Product: COc1ccc(Cl)cc1C(NC(=O)C1CCOCC1)C(N)=O

Procedure:
Using N-((5-chloro-2-methoxyphenyl)(cyano)methyl)tetrahydro-2H-pyran-4-carboxamide, the title compound was prepared following the synthetic procedures described for N-(2-amino-1-(5-chloro-2-methoxyphenyl)-2-oxoethyl)-3-(tert-butyldimethylsilyloxy)-3-methylbutanamide to give N-(2-amino-1-(5-chloro-2-methoxyphenyl)-2-oxoethyl)tetrahydro-2H-pyran-4-carboxamide as a white solid. LCMS (ESI) m+H=327.3; 1H NMR (400 MHz, DMSO-d6): δ 8.30 (d, br, 1H); 7.31-7.31 (m, 2H); 7.24 (s, br, 1H); 7.13 (s, br, 1H); 7.05-7.01 (d, 1H); 5.62 (d, 1H); 3.91-3.81 (m, 2H); 3.79 (s, 3H); 3.30-3.24 (m, 2H); 2.55-2.54 (m, 1H); 1.56-1.55 (m, 4H).
Reaction SMILES: [Cl:1][CH:2]([CH2:6][OH:7])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:35])([C:13]([F:34])([F:33])[C:14]([F:32])([F:31])[C:15]([F:30])([F:29])[C:16]([F:28])([F:27])[C:17]([F:26])([F:25])[C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])[CH2:10][CH2:11]O.Cl>C(OCC)C>[F:8][C:9]([F:35])([C:13]([F:33])([F:34])[C:14]([F:31])([F:32])[C:15]([F:29])([F:30])[C:16]([F:27])([F:28])[C:17]([F:25])([F:26])[C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])[CH2:10][CH2:11][O:4][C:3](=[O:5])[CH:2]([Cl:1])[CH2:6][OH:7]
Reactant: O=C(O)C(Cl)CO
Reactant: OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: Cl
Solvent: CCOCC
Product: O=C(OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(Cl)CO
Temperature: 65 °C

Procedure:
In a 50 mL RB with a condenser, 2-chloro-3-hydroxypropionic acid (6.0 g, 0.05 mol) and 3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluoro-1-decanol (18.0 g, 0.04 mol) and a catalytic amount of hydrochloric acid were taken together and heated up to 65° C. for 36 h. Product was dissolved in 300 mL of ethyl ether and washed twice with 100 mL of dil. NaHCO3 aq. sol. and once with 100 mL of sat. aq. NaCl sol. and then dried over anhy. Na2SO4. Solution was filtered, solvent was removed by rotary evaporation and unreacted alcohol was sublimed off at 70° C. under vacuum. Yield=15.0 g (67%). 1H-NMR (CDCl3, 7.27 ppm): 2.54 (m, —CH2CF2). 3.05-3.35 (broad, —OH), 4.01 (m, —CH2OH), 4.42 (m, —CHCl), 4.52 (m, —CO2CH2CH2).
Reaction SMILES: [CH3:1][N:2]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[NH:3][C:4]([C:6]1[S:36][C:9]2[N:10](C(OC(C)(C)C)=O)[N:11]=[C:12]([NH:13][C:14](=[O:28])[C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:16]=3)[C:8]=2[CH:7]=1)=[O:5].ClC1C=CC(N(C)NC(C2SC3N(C(OC(C)(C)C)=O)N=C(NC(=O)C4C=CC=C(CN5CCOCC5)C=4)C=3C=2)=O)=CC=1>CO>[CH3:1][N:2]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[NH:3][C:4]([C:6]1[S:36][C:9]2[NH:10][N:11]=[C:12]([NH:13][C:14](=[O:28])[C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:16]=3)[C:8]=2[CH:7]=1)=[O:5]
Reactant: CN(NC(=O)c1cc2c(NC(=O)c3cccc(CN4CCOCC4)c3)nn(C(=O)OC(C)(C)C)c2s1)c1ccccc1
Agent: CN(NC(=O)c1cc2c(NC(=O)c3cccc(CN4CCOCC4)c3)nn(C(=O)OC(C)(C)C)c2s1)c1ccc(Cl)cc1
Solvent: CO
Product: CN(NC(=O)c1cc2c(NC(=O)c3cccc(CN4CCOCC4)c3)n[nH]c2s1)c1ccccc1

Procedure:
A solution of 257 mg (0.44 mmol) of an approximately 70:30 mixture of tert-butyl 5-(N′-methyl-N′-phenylhydrazinocarbonyl)-3-(3-morpholin-4-ylmethylbenzoylamino)thieno[2,3-c]pyrazole-1-carboxylate and tert-butyl 5-(N′-(4-chlorophenyl)-N′-methylhydrazinocarbonyl)-3-(3-morpholin-4-ylmethylbenzoylamino)thieno[2,3-c]pyrazole-1-carboxylate in 4 mL of methanol is introduced into a microwave oven tube. The tube is stoppered and the reaction mixture is irradiated at a temperature in the region of 100° C. for 30 minutes. The reaction mixture is then concentrated to dryness under vacuum (2 kPa) at a temperature in the region of 40° C. The residue is purified by preparative LC/MS (conditions B). 105 mg of N-[5-(N′-methyl-N′-phenylhydrazinocarbonyl)-1H-thieno[2,3-c]pyrazol-3-yl]-3-morpholin-4-ylmethylbenzamide are thus obtained in the form of a yellow powder melting from 168 to 178° C. 1H NMR (400 MHz, (CD3)2SO-d6, δ in ppm): observation of the salt of the expected structure, with an 80%-20% mixture of conformers, such that: 3.16 (partially masked broad m, 2H); 3.18 (s, 3H); 3.32 (broad m, 2H); 3.63 (broad m, 2H); 3.98 (m, 2H); 4.44 (broad s, 2H); 6.77 (t, J=7.5 Hz, 0.8H); 6.82 (d, J=8.0 Hz, 1.6H); 6.94 (t, J=8.0 Hz, 0.2H); 7.02 (d, J=8.0 Hz, 0.4H); 7.22 (t, J=8.0 Hz, 1.6H); 7.31 (d, J=8.0 Hz, 0.4H); 7.66 (t, J=8.0 Hz, 1H); 7.74 (d, J=8.5 Hz, 1H); 8.15 (m, 3H); 9.70 (s, 0.2H); 10.0 (broad multiplet, 1H); 10.75 (s, 0.8H); 11.25 (s, 0.2H); 11.35 (s, 0.8H); 12.95 (very broad m, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([CH:13]=[O:14])[C:3]1=[O:15].C([O:20][C:21](=[O:24])[CH2:22][CH3:23])(=O)CC>>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:5](=[O:12])[CH2:6][CH3:7])=[C:4]([CH:13]([O:20][C:21](=[O:24])[CH2:22][CH3:23])[O:14][C:13](=[O:14])[CH2:4][CH3:3])[C:3]1=[O:15]
Reactant: CCC(=O)OC(=O)CC
Reactant: Cn1c(=O)c(C=O)c(O)c2ccccc21
Product: CCC(=O)Oc1c(C(OC(=O)CC)OC(=O)CC)c(=O)n(C)c2ccccc12

Procedure:
Following the procedure of Example 5, 1-methyl-3-formyl-4-hydroxy-2(1H)-quinolinone (from Preparation B) was acylated with propanoic anhydride to give 1-methyl-3-[di-(1-oxopropoxy)]methyl-4-(1-oxopropoxy)-2(1H)-quinolinone. That the expected product was obtained was confirmed by the spectral data: MS (CI): m/e 390 (M.+ +1); NMR (CDCl3): δ1.14 (t, 6H, 2 x CH3CH2), 1.38 (t, 3H, CH3CH2), 2.39 (m, 4H, 2 x CH2CO), 2.83 (q, 2H, CH3CH2CO), 3.74 (s, 3H, NCH3), 8.10 (s, 1 H, (CH3CH2COO)2CH) ppm.
Reaction SMILES: [CH:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(CC)[CH3:2].C(#N)C.[OH:14]N1C(=O)C2=CC=CC=C2C1=O.O=O>C(OO)(CC)C>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:14])[CH3:2]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CCC(C)c1ccccc1
Agent: CCC(C)OO
Agent: O=O
Solvent: CC#N
Product: CC(=O)c1ccccc1
Yield: 11 %

Procedure:
A solution of 10 mL of sec-butylbenzene (64.3 mmoles), 3.75 mL of acetonitrile and 0.64 mmoles of N-hydroxyphthalimide is stirred at 70° C. for 24 hours in an atmosphere of oxygen at a pressure of 1 bar. 1H-NMR analysis of the reaction mixture showed a secbutylbenzene conversion of 20% with a selectivity in sec-butyl hydroperoxide of 89% (result confirmed by iodometric titration) and 11% of acetophenone. The acetonitrile is removed by distillation and 0.57 mmoles of N-hydroxyphthalimide are recovered.