Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C@@H:11]([OH:13])[CH3:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N:14]([C:17]1[CH:22]=[CH:21][C:20]([B:23]2[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]2)=[CH:19][C:18]=1[O:32][CH3:33])=[C:15]=[O:16]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:33][O:32][C:18]1[CH:19]=[C:20]([B:23]2[O:27][C:26]([CH3:28])([CH3:29])[C:25]([CH3:30])([CH3:31])[O:24]2)[CH:21]=[CH:22][C:17]=1[NH:14][C:15](=[O:16])[O:13][C@H:11]([CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH3:12]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1N=C=O
Reactant: C[C@H](O)CCO[Si](C)(C)C(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)O[C@@H](C)CCO[Si](C)(C)C(C)(C)C
Temperature: 40 °C
Reaction time: 18 h
Yield: 67.2 %

Procedure:
To (S)-4-(tert-butyldimethylsilyloxy)butan-2-ol (1.649 mmol, 337 mg) in dichloromethane (4 ml) were added mol sieves (4A), 2-(4-isocyanato-3-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.374 mmol, 378 mg) and 4-dimethylaminopyridine (0.275 mmol, 33.6 mg) were added and the mixture was stirred at 40° C. (oil bath temperature) for 18 hours. The mol sieves were removed by filtration and the filtrate washed with water, dried (sodium sulfate) and concentrated in vacuo to give a crude product which was purified by column chromatography (silica gel, heptanes with gradient 10% to 50% of ethyl acetate) to afford (S)-4-(tert-butyldimethylsilyloxy)butan-2-yl 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (443 mg). Tetrabutylammonium fluoride (1M in tetrahydrofuran, 1.22 mmol, 1.22 ml) was added to (S)-4-(tert-butyldimethylsilyloxy)butan-2-yl 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (240 mg) in tetrahydrofuran (1 ml) at room temperature. After 20 hours water was added to the reaction mixture, extracted with dichloromethane, the organic extract dried (sodium sulfate) and concentration in vacuo to yield (S)-4-hydroxybutan-2-yl 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (268 mg) which was used in the next step without further purification.
Reaction SMILES: [CH3:1]O.S(Cl)(Cl)=O.[CH3:7][C:8]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]>CN(C=O)C>[CH3:7][C:8]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([O:12][CH3:1])=[O:11]
Reactant: CO
Reactant: Cc1cccc(C(=O)O)c1C
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(C)c1C

Procedure:
To 160 ml of methanol cooled to -10° C. was dropwise added 46.4 ml of thionyl chloride while stirring. To the solution was added a mixture of 24 g of 2,3-dimethyl benzoic acid and 1 ml of DMF, and the mixture was stirred at room temperature for 4 days. After concentration, the residue was dissolved in ether. The solution was washed with water, 5% sodium carbonate, and water in this order. The solvent was evaporated and the residue was purified by vacuum distillation to obtain 25.1 g of methyl 2,3-dimethylbenzoate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[O:5][C@H:6]1[CH2:10][C@@H:9]([N:11]2[CH:19]=[N:18][C:17]3[C:12]2=[N:13][C:14](Cl)=[N:15][C:16]=3[NH:20][CH2:21][CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:8]=[CH:7]1)[CH3:2].[CH3:37][O:38][C:39](C1N=C2C(N=CN2[C@@H]2C[C@H](O)C=C2)=C(NCC(C2C=CC=CC=2)C2C=CC=CC=2)N=1)=[O:40]>>[CH3:37][O:38][C:39]([C:14]1[N:13]=[C:12]2[C:17]([N:18]=[CH:19][N:11]2[C@@H:9]2[CH2:10][C@H:6]([O:5][C:4]([O:3][CH2:1][CH3:2])=[O:36])[CH:7]=[CH:8]2)=[C:16]([NH:20][CH2:21][CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:15]=1)=[O:40]
Reactant: COC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@H]3C=C[C@@H](O)C3)c2n1
Reactant: CCOC(=O)O[C@@H]1C=C[C@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)C1
Product: CCOC(=O)O[C@@H]1C=C[C@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)OC)nc32)C1

Procedure:
This compound is prepared by an analogous procedure to carbonic acid (1S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-cyclopent-2-enyl ester ethyl ester (Intermediate AA3) by replacing (1S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-cyclopent-2-enol with 6-(2,2-diphenyl-ethylamino)-9-((1R,4S)-4-hydroxy-cyclopent-2-enyl)-9H-purine-2-carboxylic acid methyl ester (step 2) MS (ES+) m/e 528.3 (MH+).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:11]([O:13][C:14](=[O:32])[CH:15]([O:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[CH:27]1[O:31][CH2:30][CH2:29][O:28]1)[CH2:16][CH2:17][CH3:18])[CH3:12].I[CH2:34][CH2:35][CH3:36]>C1COCC1.C(OCC)(=O)C>[CH2:11]([O:13][C:14](=[O:32])[C:15]([O:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[CH:27]1[O:31][CH2:30][CH2:29][O:28]1)([CH2:34][CH2:35][CH3:36])[CH2:16][CH2:17][CH3:18])[CH3:12]
Reactant: CCCI
Reactant: CCCC(Oc1ccc(Cl)cc1C1OCCO1)C(=O)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC(CCC)(Oc1ccc(Cl)cc1C1OCCO1)C(=O)OCC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 67.4 %

Procedure:
Lithium bis(trimethylsilyl)amide (26 mL, 26 mmol, 1 M in THF) was slowly added to a solution of 2-(4-Chloro-2-[1,3]dioxolan-2-yl-phenoxy)-pentanoic acid ethyl ester (6.6 g, 20 mmol) in 60 mL of anhydrous THF at −78° C. After the mixture was stirred for 30 min at −78° C., 1-Iodopropane (4 mL, 40 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 2 h. Then the mixture was diluted with ethyl acetate, washed with a saturated aqueous solution of NH4Cl, dried over anhydrous Na2SO4 and concentrated to give the title compound as a yellow oil (5 g).
Reaction SMILES: Br[CH:2]([CH2:6][CH2:7][CH3:8])[C:3]([OH:5])=[O:4].C(=O)(O)[O-].[Na+].[CH3:14][NH:15][CH3:16]>>[CH3:14][N:15]([CH3:16])[CH2:8][CH2:7][CH2:6][CH2:2][C:3]([OH:5])=[O:4]
Reactant: CCCC(Br)C(=O)O
Reactant: CNC
Agent: O=C([O-])O
Agent: [Na+]
Product: CN(C)CCCCC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Bromovaleric acid (2 g) was dissolved in aqueous solution of dimethylamine and stirred at room temperature overnight. The solvent was removed on a rotovap and the residue treated with an aqueous solution containing one equivalent of sodium bicarbonate. The solvent was removed, the residue suspended in ethanol and filtered. The solvent was removed from the filtrate and the residue suspended in methylene chloride and suspended again. After filtration, removal of the solvent from the filtrate yielded an oil (1.3 g) that slowly crystallized on storage.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+].[CH:22]([NH2:24])=[O:23]>O>[CH:22]([NH:24][CH2:8][C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:12]([OH:13])=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:10]=1)=[O:23]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: NC=O
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Product: CC(C)(C)c1cc(CNC=O)cc(C(C)(C)C)c1O
Temperature: 170 °C
Yield: 76 %

Procedure:
A mixture of 11.09 g (47 mmol) 3,5-di-tert.butyl-4-hydroxybenzaldehyde, 40 g ammonium formate and 40 mL formamide were stirred and heated to 170° C. for 30 minutes. The mixture was allowed to cool down to room temperature and treated with 100 mL water. The crude N-formyl-3,5-di-tert.butyl-4-hydroxybenzyl-amine precipitated from the mixture, was isolated by filtration, washed with water and dried. The crude N-formyl-3,5-di-tert.butyl-4-hydroxybenzyl-amine was recrystallized from toluene/heptane 1/1. 9.36 g (76%) of N-formyl-3,5-di-tert.butyl-4-hydroxybenzyl-amine was isolated (130-1° C.)
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:23]=[N:24][CH:25]=[C:26]([O:28][CH3:29])[CH:27]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].[OH-].[Na+]>C(#N)C>[C:9]([O:13][C:14]([N:16]1[CH2:17][CH2:18][N:19]([C:22]2[CH:23]=[N:24][C:25]([Br:1])=[C:26]([O:28][CH3:29])[CH:27]=2)[CH2:20][CH2:21]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cncc(N2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)cnc1Br
Reaction time: 2 h

Procedure:
A mixture of 3-chloro-5-methoxypyridine (40.0 g, 0.279 mol), piperazine (48.0 g, 0.557 mol), potassium-tert-butoxide (62.5 g, 0.557 mol) and tetrakis-(triphenylphosphine)palladium(0) (1.6 g, 1.39 mmol) was refluxed for 2 hours. The workup procedure was performed according to method A. 1-(5-Methoxy-3-pyridyl)piperazine fumaric acid salt was isolated as intermediate product. Yield 22.6 g (26%). A mixture of 1-(5-methoxy-3-pyridyl)-piperazine fumaric acid salt (23.1 g, 74.7 mmol), aqueous sodium hydrogen carbonate (224 ml, 1 M), di-tert-butyldicarbonate (16.3 g, 74.7 mmol) and dichloromethane (200 ml) was stirred at room temperature for 1 hour. The phases were separated. The organic phase gave 4-tert-butoxycarbonyl-1-(5-methoxy-3-pyridyl)-piperazine in quantitative yield. N-Bromosuccinimide (1.82 g, 10.2 mmol) was added to a mixture of 4-tert-butoxycarbonyl-1-(5-methoxy-3-pyridyl)-piperazine (3.0 g, 10.2 mmol) and acetonitrile (50 ml) at 0° C. The reaction was allowed to reach room temperature and was stirred for 2 hours. Aqueous sodium hydroxide (100 ml, 4 M) was added followed by extraction twice with ethyl acetate (2×100 ml). Chromatography on silica gel with ethyl acetate:petroleum (1:3) gave 4-tert-butoxycarbonyl-1-(6-bromo-5-methoxy-3-pyridyl)-piperazine as free base. Yield 2.6 g, 68%. This compound (2.32 g, 6.23 mmol) was deprotected by stirring with a mixture of trifluoroacetic acid (4.8 ml) and dichloromethane (30 ml) for 6 hours. The mixture was evaporated, and aqueous sodium hydroxide (100 ml, 1 M) was added. The mixture was extracted three times with ethyl acetate (3×100) and gave the title compound as the free base. The corresponding salt was obtained by addition of a diethyl ether and methanol mixture (9:1) saturated with fumaric acid in quantitative yield. Mp 202-218° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH3:8])=[CH:5][CH:4]=[C:3]1[C:9]([C:11]1[N:15]2[CH2:16][CH2:17][CH:18]([C:19]([O:21]CC)=[O:20])[C:14]2=[CH:13][C:12]=1[CH3:24])=[O:10].[OH-].[Na+].[Cl-].[Na+]>CO>[CH3:1][N:2]1[C:6]([S:7][CH3:8])=[CH:5][CH:4]=[C:3]1[C:9]([C:11]1[N:15]2[CH2:16][CH2:17][CH:18]([C:19]([OH:21])=[O:20])[C:14]2=[CH:13][C:12]=1[CH3:24])=[O:10]
Reactant: CCOC(=O)C1CCn2c1cc(C)c2C(=O)c1ccc(SC)n1C
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CSc1ccc(C(=O)c2c(C)cc3n2CCC3C(=O)O)n1C
Yield: 97.9 %

Procedure:
Ethyl 5-(1-methyl-5-methylthio-2-pyrroyl)-1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate (500 mg) was stirred with 10 ml of methanol and 10 ml of 10% NaOH for two hours. 200 ml of saturated sodium chloride solution was added to the resulting mixture and the methanol distilled off under reduced pressure. The aqueous solution was acidified with 3N HCl while stirring, cooled and the resulting precipitate collected by filtration. The residue was washed with water, air dried and recrystallized from ethylacetate-hexane to yield 450 mg of 5-(1-methyl-5-methylthio-2-pyrroyl)-1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid, m.p. 182°-184° C.
Reaction SMILES: CO[C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH3:20])=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH2:22][CH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[CH3:17][C:16]1[O:15][N:14]=[C:13]([CH2:18][CH2:19][CH3:20])[C:12]=1[CH2:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([NH:22][CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:21])=[CH:5][N:6]=1
Reactant: NC1CCOCC1
Reactant: CCCc1noc(C)c1COc1ccc(C(=O)OC)cn1
Product: CCCc1noc(C)c1COc1ccc(C(=O)NC2CCOCC2)cn1
Yield: 19 %

Procedure:
As described for example 1e, 6-(5-methyl-3-propyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (145 mg, 0.50 mmol) was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (35 mg, 19%) which was obtained as a white solid after purification by chromatography (silica, 0-6% methanol in dichloromethane) and after trituration with diisopropyl ether. MS: m/e=360.3 [M+H]+.
Reaction SMILES: [Na].[O-]CC.[Na+].[NH2:6][C:7]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][NH:9][N:8]=1.[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[NH2:6][C:7]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][N:9]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:8]=1
Reactant: ClCc1ccccc1
Reactant: CCOC(=O)c1c[nH]nc1N
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)c1cn(Cc2ccccc2)nc1N
Yield: 55.2 %

Procedure:
Sodium (1.9 g) was dissolved in anhydrous ethanol (100 ml) to prepare a solution of sodium ethoxide. To this, were added 3-amino-4-ethoxycarbonylpyrazole (12.4 g) and benzyl chloride (10 g), and the resulted mixture was refluxed for 1 h. After filtration of the hot mixture, the filtrate was concentrated to quarter volume, and cooled to crystallize. The crude product was recrystallized from an ether-water mixture to give 3-amino-1-benzyl-4-ethoxycarbonylpyrazole (10.7 g, yield 44%). To a solution of 3-amino-1-benzyl-4-ethoxycarbonylpyrazole (0.2 g) in dried toluene (30 ml), were added propyl isocyanate (0.307 ml) and triethylamine (0.11 ml), and the mixture was refluxed in a sealed tube for 8 h. The reaction mixture was evaporated under reduced pressure followed by silica-gel column chromatography (toluene : ethyl acetate=20:1) to give the title compound (0.129 g, yield 48%). 1H-NMR (CDCl3) δ ppm: 0.92 (3H, t, J=7Hz, CH2CH2CH3 ), 1.32 (3H, t, J=7Hz, COOCH2CH3 ), 1.57 (2H, 6th, CH2CH2CH3), 4.28 (2H, q, J=7Hz, COOCH2CH3), 5.14 (2H, s, CH2 --Ph), 7.25 (5H, m, CH2 --Ph), 7.91 (2H, brs, NH), 8.00 (1H, s, C5-H)
Reaction SMILES: C(OC([N:8]1[CH2:26][CH2:25][C:11]2([C:15](=[O:16])[N:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=3)[CH2:13][CH2:12]2)[CH2:10][CH2:9]1)=O)(C)(C)C.O1CCOCC1.[ClH:33]>>[ClH:33].[Br:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][N:14]2[CH2:13][CH2:12][C:11]3([CH2:10][CH2:9][NH:8][CH2:26][CH2:25]3)[C:15]2=[O:16])=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(Cc1ccc(Br)cc1)C2=O
Agent: Cl
Solvent: C1COCCO1
Product: O=C1N(Cc2ccc(Br)cc2)CCC12CCNCC2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 4.62 g of crude 2-(4-bromobenzyl)-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester from preparation 1 were added 50 mL of 4N solution of dioxane/HCl. The reaction mixture was agitated 15 minutes at room temperature and 3.05 g (77.8%) of 2-(4-bromobenzyl)-2,8-diaza-spiro[4.5]decan-1-one hydrochloride was collected, as a colorless solid, after filtration and subsequent wash steps with diethyl ether.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[C:39]([CH2:40][N:41]([CH3:43])[CH3:42])=[CH:38][N:37]=[N:36]2)[CH:30]=1)=[O:28])(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[C:39]([CH2:40][N:41]([CH3:43])[CH3:42])=[CH:38][N:37]=[N:36]2)[CH:30]=1)=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)Cc1cnnn1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Product: CN(C)Cc1cnnn1-c1cccc(C(=O)CC(=O)Nc2cc(Cl)c(N(C)C)cc2NC(=O)OC(C)(C)C)c1

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-dimethylamino-phenyl)-carbamic acid tert.-butyl ester (Example J1) (143 mg, 0.5 mmol) and 3-[3-(5-dimethylaminomethyl-[1,2,3]triazol-1-yl)-phenyl]-3-oxo-propionic acid tert.-butyl ester (Example K8) (172 mg, 0.5 mmol) according to the general procedure M. Obtained as an amorphous yellow substance (176 mg).
Reaction SMILES: [CH2:1]([N:3]1[C:8]2[N:9]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=3)[N:11]=[CH:12][C:7]=2[C:6](=[O:21])[CH:5]=[CH:4]1)[CH3:2].[I-].[Li+].N1C(C)=CC(C)=CC=1C>CCCCCC>[CH2:1]([N:3]1[C:8]2[N:9]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[N:11]=[CH:12][C:7]=2[C:6](=[O:21])[CH:5]=[CH:4]1)[CH3:2]
Reactant: CCn1ccc(=O)c2cnc(-c3ccc(OC)cc3)nc21
Agent: [I-]
Agent: [Li+]
Solvent: CCCCCC
Solvent: Cc1cc(C)nc(C)c1
Product: CCn1ccc(=O)c2cnc(-c3ccc(O)cc3)nc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 81.1 %

Procedure:
C-4. 8-Ethyl-2-(4-hydroxyphenyl)pyrido[2,3-d]pyrimidin-5(8H)-one--A mixture containing 2.4 g of 8-ethyl-2-(4-methoxyphenyl)pyrido[2,3-d]pyrimidin-5(8H)-one, 8.1 g of anhydrous lithium iodide, 125 ml of collidine and one drop of dicyclohexyl-12-crown-4 was refluxed with stirring for 24 hours and then allowed to cool to room temperature. The reaction mixture was diluted with n-hexane (900 ml) to complete the precipitation of the product. The oily material that separated solidified on standing at room temperature. The solid was collected, washed with n-hexane and then dissolved in water. The water solution and washed with ether, acidified with hydrochloric acid and the resulting mixture was slurried, treated with an excess of sodium bicarbonate and again slurried. The solid was collected, washed with water and dried at 65° C. in vacuo to yield 1.85 g of 8-ethyl-2-(4-hydroxyphenyl)pyrido[2,3-d]pyrimidin-5(8H)-one, m.p. 320°-324° C. This product was combined with 12 g of product obtained in five other runs and the combined material was suspended in about 350 ml of boiling ethanol after which dimethylformamide was added portionwise until dissolution was complete. The hot solution was treated with decolorizing charcoal, filtered, and the filtrate cooled. The separated product was collected, washed with cold ethanol and dried in vacuo at 60° C. to produce 2.6 g of 8-ethyl-2-(4-hydroxyphenyl)pyrido[2,3-d]pyrimidin-5(8H)-one, m.p. 323°-325° C. The filtrate was stripped in vacuo, the solid residue was recrystallized from ethanoldimethylformamide to yield another 0.8 g of product, 8-ethyl-2-(4-hydroxyphenyl)pyrido[2,3-d]pyrimidin-5(8H)-one, m.p. 321°-322° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:11][O:10][C:9]1([CH3:22])[CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([C:30]1[CH:35]=[CH:34][C:33](I)=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CN(C)CC(O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.ClCCl>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][C:33]3[CH:34]=[CH:35][C:30]([CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:31][CH:32]=3)=[CH:18][CH:19]=2)[CH2:11][O:10][C:9]1([CH3:22])[CH3:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Ic1ccc(Cc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2ccc(O)cc2)COC1(C)C
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@@H](Cc2ccc(Oc3ccc(Cc4ccccc4)cc3)cc2)COC1(C)C
Temperature: 25 °C
Yield: 98.5 %

Procedure:
To a solution of (S)-4-(4-Hydroxy-benzyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (240 mg, 0.75 mmol, 1 eq. obtained from Brian Bock, Lot No: MCLS1172-077-1), 4-benzyliodobenzene (294 mg, 1 mmol, 1.3 eq.) in dioxane (4 ml) was added CuI(I) (30 mg, 0.75 mmol, 0.1 eq.), N,N-dimethylglycine (45 mg, 0.23 mmol, 0.3 eq.) and cesium carbonate (500 mg, 1.5 mmol, 3 eq.). The resulting mixture was stirred under Ar at reflux overnight. After cooling to room temperature, the volatile material was removed under reduced pressure to give a residue, which was partitioned between water (10 ml) and ethyl acetate (10 ml). The ethyl acetate layer was separated and dried over anhydrous MgSO4. Evaporation of solvent under reduced pressure gave a residue, which was passed through a plug of silica gel using dichloromethane (50 ml) as eluent to give 350 mg of desired product containing the starting iodide, which was forwarded to the next step without further purification.
Reaction SMILES: [CH2:1]([N:8]([CH2:29][CH:30]1[CH2:32][CH:31]1[CH3:33])[C:9]1[CH:10]=[C:11]([CH:18]=[C:19]([N:21]([S:23]([CH:26]([CH3:28])[CH3:27])(=[O:25])=[O:24])[CH3:22])[N:20]=1)[C:12](N(OC)C)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][Mg]Br.[Cl-].[NH4+]>C1COCC1>[C:12]([C:11]1[CH:10]=[C:9]([N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:29][CH:30]2[CH2:32][CH:31]2[CH3:33])[N:20]=[C:19]([N:21]([CH3:22])[S:23]([CH:26]([CH3:28])[CH3:27])(=[O:24])=[O:25])[CH:18]=1)(=[O:13])[CH3:34]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1cc(N(Cc2ccccc2)CC2CC2C)nc(N(C)S(=O)(=O)C(C)C)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)c1cc(N(Cc2ccccc2)CC2CC2C)nc(N(C)S(=O)(=O)C(C)C)c1
Temperature: 0 °C

Procedure:
To a −78° C. solution of 2-{benzyl[(2-methylcyclopropyl)methyl]amino}-6-[(isopropylsulfonyl)(methyl)amino]-N-methoxy-N-methylisonicotinamide (860 mg, 1.81 mmol) from Step A in 6 mL dry THF was added methylmagnesium bromide (3.62 mL, 10.8 mmol, 3M solution in diethyl ether). The reaction mixture was allowed to slowly warm to 0° C. over 1 h, at which time it was poured onto 20 mL of sat. ammonium chloride and extracted with ethyl acetate (3×30 mL). The combined organics were washed with brine (30 mL), dried over sodium sulfate, and concentrated. Purification by automated flash chromatography (silica gel cartridge, 0-100% ethyl acetate/hexanes over 35 minutes) afforded N-(4-acetyl-6-{benzyl[(2-methylcyclopropyl)methyl]amino}pyridin-2-yl)-N-methylpropane-2-sulfonamide as a bright yellow solid. LCMS [M+H]=430.1.
Reaction SMILES: [CH2:1]([C:3]1[S:29][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[C:16]([F:28])[CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)=[O:33].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH2:1]([C:3]1[S:29][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[C:16]([F:28])[CH:15]=3)[C:8](=[O:12])[N:9]([CH2:31][C:32]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)=[O:33])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)c(F)c3)c2s1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)cc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)c(F)c3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
To a mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]-2′-fluorobiphenyl-2-carbonitrile (1.6 g), 2-bromo-1-(4-methoxyphenyl)ethanone (1.1 g) and N,N-dimethylformamide (19 mL) was added 60% sodium hydride (0.23 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (1.8 g, 86%).