Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([O:32][CH3:33])[CH:26]=2)[CH:6]=[CH:5][C:4]=1[OH:34].C(OC([N:42]1[CH2:47][CH2:46][C:45]2[N:48]([C:57](C)(C)[O:58][SiH2]C(C)(C)C)[C:49]([C:51]3[CH:56]=[CH:55][N:54]=[CH:53][CH:52]=3)=[CH:50][C:44]=2[C:43]1=[O:66])=O)(C)(C)C.[ClH:67]>O1CCOCC1>[CH3:33][O:32][C:27]1[CH:26]=[C:25]([CH2:24][NH:23][CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12][CH2:11][NH:10][CH2:9][C:7]2[CH:6]=[CH:5][C:4]([OH:34])=[C:3]([O:2][CH3:1])[CH:8]=2)[CH:30]=[CH:29][C:28]=1[OH:31].[ClH:67].[OH:58][CH2:57][N:48]1[C:45]2[CH2:46][CH2:47][NH:42][C:43](=[O:66])[C:44]=2[CH:50]=[C:49]1[C:51]1[CH:52]=[CH:53][N:54]=[CH:55][CH:56]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(cc(-c3ccncc3)n2C(C)(C)O[SiH2]C(C)(C)C)C1=O
Agent: COc1cc(CNCCCNCCCCNCCCNCc2ccc(O)c(OC)c2)ccc1O
Agent: Cl
Solvent: C1COCCO1
Product: O=C1NCCc2c1cc(-c1ccncc1)n2CO

Procedure:
A solution of 50 mg of DL-6-(tert-butyl-dimethyl-silanyloxymethyl)-4-oxo-2-pyridin-4-yl 1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester in 5 mL of 4M HCl in dioxane was stirred for 4 hours at room temperature. The solution was concentrated and the title compound recovered.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH2:10].[OH-].[Na+].CN([CH:16]=[N:17][C:18](=O)[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)C>O.O1CCOCC1.C(O)(=O)C>[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:18]([C:19]2[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=2)=[N:17][CH:16]=[N:10]1
Reactant: CN(C)C=NC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: NNc1ccccc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1ccc(-c2ncnn2-c2ccccc2F)cc1

Procedure:
A 25.0 g. portion of o-fluorophenylhydrazine hydrochloride is dissolved in 150 ml. of p-dioxane with warming and 31.0 ml. of 5 N sodium hydroxide is added. After solution is complete, 80 ml. of glacial acetic acid and 210 ml. of water are added followed by 28.1 g. of N-(dimethylaminomethylene)-p-nitrobenzamide in 100 ml. of warm p-dioxane. This reaction mixture is heated at 90°-95° C. for 1.5 hours, then cooled and poured into 1500 ml. of water. The solid is collected by filtration, washed with water, dried and crystallized from 200 ml. of ethanol, giving 13.9 g. of the desired product as a tan solid, mp. 143°-145° C.
Reaction SMILES: COC(=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)=[O:6].CN(C)C(=O)C.Cl.C(N(CC)CC)C.O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5](=[O:6])[CH3:4])=[CH:8][CH:9]=1
Reactant: COC(=O)CC(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(=O)c1ccc(Cl)cc1
Temperature: 140 °C
Reaction time: 3 h

Procedure:
In 3-(4-chlorophenyl)-3-oxopropionic acid methyl ester (1.0 g, 0.0047 mol), N,N-dimethylacetamide (1 mL) and triethylamine hydrochloride (0.97 g, 0.0047×1.5 mol) were added and stirred at 140° C. for 3 hours under an argon atmosphere. In the reaction liquid, ethyl acetate and saturated sodium bicarbonate water were added, and the mixture was partitioned. After extracting the aqueous layer using ethyl acetate, the organic layer was dried using anhydrous sodium sulfate and concentrated. Thereafter, the dried and concentrated product was purified using a silica gel column, and a target product was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH2:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])=[O:9])[CH:6]=1.[CH2:19]([O:26][C:27]1[CH:36]=[C:35]2[C:30]([C:31](Cl)=[N:32][CH:33]=[N:34]2)=[CH:29][CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl.O1CCOCC1>CC(N(C)C)=O.ClCCl>[CH2:19]([O:26][C:27]1[CH:36]=[C:35]2[C:30]([C:31]([NH:1][C:2]3[CH:3]=[N:4][N:5]([CH2:7][C:8]([NH:10][C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=4[F:18])=[O:9])[CH:6]=3)=[N:32][CH:33]=[N:34]2)=[CH:29][CH:28]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Clc1ncnc2cc(OCc3ccccc3)ccc12
Reactant: Nc1cnn(CC(=O)Nc2cccc(F)c2F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: O=C(Cn1cc(Nc2ncnc3cc(OCc4ccccc4)ccc23)cn1)Nc1cccc(F)c1F
Temperature: 90 °C
Yield: 87.4 %

Procedure:
2-(4-amino-1H-pyrazol-1-yl)-N-(2,3-difluorophenyl)acetamide (504 mg, 2 mmol) was added to a solution of 7-(benzyloxy)-4-chloroquinazoline (541 mg, 2 mmol) in dimethylacetamide (10 ml) under argon. A solution of 4.0 N hydrochloric acid in dioxane (500 μl, 2 mmol) was added and the mixture was heated at 90° C. for 1.5 hours. The mixture was cooled, diluted with dichloromethane and the resultant precipitate recovered by filtration. The solid was washed with dichloromethane and diethyl ether and dried in vacuo to yield 2-(4-{[7-(benzyloxy)quinazolin-4-yl]amino}-1H-pyrazol-1-yl)-N-(2,3-difluorophenyl)acetamide (850 mg, 81% yield):
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6](C(C)C)[C:5]=1[O:13][CH2:14][C:15]1C=CC=[CH:17][CH:16]=1)([CH3:3])[CH3:2]>C(O)C.C(O)(=O)C.[Pd]>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:13][CH2:14][CH:15]=[CH:16][CH3:17])([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc(C(C)C)c1OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CC=CCOc1ccccc1C(C)C

Procedure:
Benzyl (2,6-diisopropylphenyl) ether 60 mg was dissolved in 20 ml of anhydrous ethanol solution of 5% acetic acid. After adding 30 mg of active carbon in 10% palladium thereinto, it was dissolved under hydrogen gas for 15 hours. Thus-obtained mixture Was washed with water and saturated sodium chloride aqueous solution. The resultant was dried with anhydrous magnesium sulfate and then concentrated.
Reaction SMILES: C[O-].[Na+].[C:4]([CH2:6][C:7]([O:9][CH3:10])=[O:8])#[N:5].[F:11][C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:13]=1[CH:20]=[CH:21][C:22]([O:24][CH2:25]C)=[O:23]>CO>[C:4]([CH:6]([CH:20]([C:13]1[CH:14]=[C:15]([F:19])[C:16]([F:18])=[CH:17][C:12]=1[F:11])[CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:7]([O:9][CH3:10])=[O:8])#[N:5]
Reactant: CCOC(=O)C=Cc1cc(F)c(F)cc1F
Reactant: COC(=O)CC#N
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CC(c1cc(F)c(F)cc1F)C(C#N)C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 15 mL (64 mmol, 25% in methanol) of sodium methoxide in 200 mL of methanol was added 5.5 mL (62 mmol) of methyl cyanoacetate and the mixture was stirred at ambient temperature for 30 min. To this solution was added 14 g (62 mmol) of the product of step A in 50 mL of methanol and the resulting yellow mixture was heated to reflux for 6 h. The mixture was then quenched carefully at ambient temperature with 1N aqueous hydrochloric acid (100 mL) and concentrated to remove methanol. The resulting mixture was extracted with three 300-mL portions of ethyl acetate, and the organic phases combined and washed sequentially with 1N hydrochloric acid, saturated aqueous sodium bicarbonate solution, and saturated aqueous brine (100 mL each). The organic phase was then dried over magnesium sulfate, filtered, and evaporated in vacuo to yield a viscous oil. The crude material was purified by flash chromatography on a Biotage Horizon® system (silica gel, 0 to 25% ethyl acetate/hexanes gradient) to give the title compound as a mixture of stereoisomers.
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]([NH:7][C:8]2[C:9]([C:15]([NH:17][CH2:18][CH2:19][OH:20])=[O:16])=[CH:10][NH:11][C:12](=[O:14])[CH:13]=2)=[C:5]([F:23])[CH:4]=1)#[CH:2]>CO.C1COCC1.[Pd]>[CH2:1]([C:3]1[CH:22]=[CH:21][C:6]([NH:7][C:8]2[C:9]([C:15]([NH:17][CH2:18][CH2:19][OH:20])=[O:16])=[CH:10][NH:11][C:12](=[O:14])[CH:13]=2)=[C:5]([F:23])[CH:4]=1)[CH3:2]
Reactant: C#Cc1ccc(Nc2cc(=O)[nH]cc2C(=O)NCCO)c(F)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1ccc(Nc2cc(=O)[nH]cc2C(=O)NCCO)c(F)c1
Yield: 100 %

Procedure:
4-(4-Ethynyl-2-fluoroanilino)-N-(2-hydroxyethyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide was hydrogenated in MeOH/THF in the presence of 5% Pd/C as for example 3. Purification of the crude oil was carried out by column chromatography on silica gel (10% MeOH/CH2Cl2 as eluant) to give 4-(4-ethyl-2-fluoroanilino)-N-(2-hydroxyethyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide as a white solid (100%), m.p. (EtOAc/MeOH) 256-258° C. 1H NMR [(CD3)2SO, 400 MHz] δ 11.29 (br s, 1H), 10.00 (s, 1H), 8.43 (t, J=5.2 Hz, 1H), 7.93 (s, 1H), 7.33 (t, J=8.4 Hz, 1H), 7.19 (dd, J=11.9, 1.5 Hz, 1H), 7.08 (dd, J=8.2, 1.5 Hz, 1H), 5.32 (s, 1H), 4.71 (t, J=5.7 Hz, 1H), 3.49 (q, J=5.9 Hz, 2H), 3.29-3.24 (m, 2H), 2.62 (q, J=7.6 Hz, 2H), 1.21 (t, J=7.6 Hz, 3H). Anal. Calcd for C16H18FN3O3: C, 60.2; H, 5.7; N, 13.2. Found: C, 60.2; H, 5.7; N, 13.4.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:29]([CH3:30])=[CH:28][C:8]([O:9][C:10]2[CH:11]=[CH:12][C:13]([N+:25]([O-])=O)=[C:14]([N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:15]=2)=[C:7]([CH3:31])[C:6]=1[CH3:32]>[Pd].CO>[NH2:25][C:13]1[CH:12]=[CH:11][C:10]([O:9][C:8]2[CH:28]=[C:29]([CH3:30])[C:5]([O:4][CH2:3][O:2][CH3:1])=[C:6]([CH3:32])[C:7]=2[CH3:31])=[CH:15][C:14]=1[N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22]
Reactant: COCOc1c(C)cc(Oc2ccc([N+](=O)[O-])c(N(C)C(=O)OC(C)(C)C)c2)c(C)c1C
Agent: [Pd]
Solvent: CO
Product: COCOc1c(C)cc(Oc2ccc(N)c(N(C)C(=O)OC(C)(C)C)c2)c(C)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
A mixture of 57.0 g of t-butyl N-[5-(4-methoxymethoxy-2,3,5-trimethylphenoxy)-2-nitrophenyl]-N-methylcarbamate, 3 g of 10% palladium on carbon and 500 ml of methanol was vigorously stirred at room temperature for 8 hours under a hydrogen atmosphere. The palladium on carbon in the reaction mixture was filtered off and the filtrate was concentrated by evaporation. The residue was purified by chromatography through a silica gel column (eluting solvent: n-hexane/ethyl acetate=3/1), whereby 52.5 g of the title compound were obtained.
Reaction SMILES: Br[C:2]1[O:3][C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>FC(F)(F)C1C=CC=CC=1.CCOC(C)=O>[N:16]1([C:2]2[O:3][C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: C1CCNCC1
Reactant: CCOC(=O)c1oc(Br)nc1C(F)(F)F
Solvent: FC(F)(F)c1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1oc(N2CCCCC2)nc1C(F)(F)F
Temperature: 120 °C
Yield: 88 %

Procedure:
To a solution of ethyl 2-bromo-4-trifluoromethyloxazole-5-carboxylate (A-2) (0.85 mL) in α,α,α-trifluorotoluene (10 mL) at RT was added piperidine (1.1 mL). The reaction mixture was heated at 120° C. for 20 min by microwave then cooled to RT and diluted with EtOAc (100 mL). The organic solution was washed with H2O (2×100 mL), saturated NH4Cl (1×100 mL), brine (1×100 mL), dried over Na2SO4, filtered, and concentrated to give ethyl 2-(1-piperidinyl)-4-trifluoromethyloxazole-5-carboxylate (A-3) as a yellow solid (1.28 g, 88% yield). LCMS (ESI) calcd for [M+1]+ 293.1. found 293.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.O.[N:15]1[CH:20]=[C:19](B(O)O)[CH:18]=[N:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.[OH-].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][C:8]([C:5]1[CH:6]=[CH:7][C:2]([C:19]2[CH:20]=[N:15][CH:16]=[N:17][CH:18]=2)=[CH:3][CH:4]=1)([CH3:13])[C:9]([OH:11])=[O:10]
Reactant: CC(C)(C(=O)O)c1ccc(Br)cc1
Reactant: OB(O)c1cncnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C(=O)O)c1ccc(-c2cncnc2)cc1
Temperature: 80 °C
Yield: 73.8 %

Procedure:
2-(4-Bromophenyl)-2-methylpropanoic acid (5.71 g, 23.5 mmol) was dissolved in DME (140 mL) and water (35 mL) and pyrimidin-5-ylboronic acid (2.92 g, 23.5 mmol) and potassium carbonate (11.4 g, 82.2 mmol) were added to the solution. The mixture was degassed using an argon stream, and Pd(PPh3)4 (1.35 g, 1.17 mmol) was added. The mixture was heated (80° C.) under argon overnight then cooled to room temperature. The solution was diluted with 1M NaOH (20 mL) and washed with EtOAc. The aqueous phase was acidified with 6N aq. HCl to pH 4-5 and extracted with EtOAc (3×). The combined extract was successively washed with water and brine, dried over MgSO4, filtered and evaporated to yield 4.2 g (74%) of the crude 2-Methyl-2-(4-(pyrimidin-5-yl)phenyl)propanoic acid (MS+H, 243) that was used in the next step without further purification.
Reaction SMILES: [CH3:1][C@@H:2]([OH:6])[C@H:3]([OH:5])[CH3:4].O.[H-].[Na+].[Br:10][C:11]1[C:12](Cl)=[N:13][C:14]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[NH:26])=[O:25])=[CH:20][CH:19]=2)=[N:15][CH:16]=1>CS(C)=O>[Br:10][C:11]1[C:12]([O:5][C@H:3]([CH3:4])[C@H:2]([OH:6])[CH3:1])=[N:13][C:14]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([S:24]([CH3:27])(=[NH:26])=[O:25])=[CH:22][CH:23]=2)=[N:15][CH:16]=1
Reactant: C[C@@H](O)[C@@H](C)O
Reactant: CS(=N)(=O)c1ccc(Nc2ncc(Br)c(Cl)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C[C@@H](O)[C@@H](C)Oc1nc(Nc2ccc(S(C)(=N)=O)cc2)ncc1Br
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 674 mg (7.5 mmol) of (R,R)-(−)-2,3-butanediol in 6 ml of DMSO is mixed while being cooled with water in portions with 330 mg of sodium hydride (55-60%), and then stirred for 45 minutes at room temperature. The batch is mixed with 196 mg (0.54 mmol) of (RS)—S-{4-[(5-bromo-4-chloropyrimidin-2-yl)amino]phenyl}-S-methyl sulfoximide in 0.5 ml of DMSO and stirred overnight. It is mixed again with 191 mg (0.53 mmol) of (RS)—S-{4-[(5-bromo-4-chloropyrimidin-2-yl)amino]phenyl}-S-methyl sulfoximide in 0.5 ml of DMSO and stirred for another two hours. Finally, it is mixed with 190 mg of (RS)—S-{4-[(5-bromo-4-chloropyrimidin-2-yl)amino]phenyl}-S-methyl sulfoximide (0.53 mmol) in 0.5 ml of DMSO and stirred for one hour. The batch is added to ice water and extracted from ethyl acetate (4×). The combined organic phases are washed with NaCl solution, filtered through a Whatman filter and concentrated by evaporation. The remaining residue is purified by chromatography (DCM/EtOH 9:1). 166 mg (0.41 mmol, corresponding to 25% of theory) of the product is obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:15][C:16](=[O:36])[N:17]2[CH2:21][CH2:20][CH2:19][C@H:18]2[C:22](=[O:35])[NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:34])([F:33])[F:32])[CH:25]=2)[CH:7]=1)=[O:5])C.[OH-].[Na+]>CO.O>[O:36]=[C:16]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22](=[O:35])[NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:34])([F:33])[F:32])[CH:25]=1)[CH2:15][N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([C:4]([OH:5])=[O:3])=[CH:7]1
Reactant: CCOC(=O)c1cn(CC(=O)N2CCC[C@H]2C(=O)Nc2cccc(OC(F)(F)F)c2)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cn(CC(=O)N2CCC[C@H]2C(=O)Nc2cccc(OC(F)(F)F)c2)c2ccccc12
Temperature: 80 °C
Reaction time: 0.54 h

Procedure:
To a solution of 1-{2-oxo-2-[(S)-2-(3-trifluoromethoxy-phenylcarbamoyl)-pyrrolidin-1-yl]ethyl}-1H-indole-3-carboxylic acid ethyl ester (314 mg, 0.62 mmol) in MeOH (12 mL) and water (1.2 mL) was added NaOH 1N (1.87 mL, 1.87 mmol) and the mixture was heated at 80° C. for 6 h. MeOH was concentrated, HCl 1N was added and the residue was extracted with EtOAc. The organic extracts were dried with Na2SO4, filtered and concentrated. The crude residue was purified by preparative HPLC (Interchrom C18-ODB, 10 μm, 28×250 mm, 20% CH3CN in H2O 2.5 min, then 20% to 100% CH3CN in H2O in 32.5 min, CH3CN and H2O containing 0.1% HCOOH; flow: 40 mL/min) to give after lyophilization of the purified fractions the desired compound. TLC, Rf (EtOAc)=0.05; MS (LC/MS): 498.1 [M+Na]+, 474.1 [M−H]−; tR (HPLC conditions a): 3.48 min.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([Cl:7])=[C:4]([C:8](O)=O)[CH:3]=1.[C:11]1([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[Br:1][C:2]1[S:6][C:5]([Cl:7])=[C:4]([CH2:8][C:19]2[S:18][C:17]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[CH:21][CH:20]=2)[CH:3]=1
Reactant: c1ccc(-c2cccs2)cc1
Reactant: O=C(O)c1cc(Br)sc1Cl
Product: Clc1sc(Br)cc1Cc1ccc(-c2ccccc2)s1

Procedure:
5-Bromo-2-chloro-3-thiophenecarboxylic acid (see Japanese Unexamined Patent Publication No. 10-324632) and 2-phenylthiophene were treated in a manner similar to Reference Example 5 to give the target compound as a colorless solid. APCI-Mass m/Z 367/369 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[CH2:22]([O:28][C:29](Cl)=[O:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C1C=CC=CC=1>[C:29](=[O:30])([O:28][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1
Reactant: CCCCCCOC(=O)Cl
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCCCCCOC(=O)Oc1ccc(-c2ccc(C#N)cc2)cc1

Procedure:
0.976 G. of 4'-cyano-4-hydroxy-biphenyl are dissolved in 10 ml. of absolute pyridine and reacted with 0.988 g. of chloroformic acid n-hexyl ester as in Example 1. The 1.675 g. of yellowish, turbid, partially crystallized oil obtained according to the procedure described in Example 1 is dissolved in benzene and chromatographed on 80 g. of silica gel. Benzene elutes 1.530 g. of colorless crystals which are recrystallized from ether-hexane up to constant melting point and clearing point. The pure 4'-cyano-4-biphenylyl n-hexyl carbonate obtained melts at 87.1°-87.5° and is liquid crystalline (monotrope) upon cooling to 62.7°. UV (EtOH): ε270 = 26,300.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][C@@H:5]([CH:7]2[CH2:9][N@@:8]2[S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])[O:4][C:3]1=[O:22].[CH3:23][C:24]1([CH3:39])[CH2:29][N:28]([C:30]2[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=2[CH3:37])[C:27](=[O:38])[CH2:26][NH:25]1>C1(C)C=CC=CC=1>[CH3:23][C:24]1([CH3:39])[CH2:29][N:28]([C:30]2[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=2[CH3:37])[C:27](=[O:38])[CH2:26][N:25]1[CH2:9][C@H:7]([NH:8][S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])[C@@H:5]1[CH2:6][C@@H:2]([CH3:1])[C:3](=[O:22])[O:4]1
Reactant: Cc1ccc(F)cc1N1CC(C)(C)NCC1=O
Reactant: C[C@@H]1C[C@@H](C2C[N@@]2S(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Agent: C[C@@H]1C[C@@H](C2C[N@]2S(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Solvent: Cc1ccccc1
Product: Cc1ccc(F)cc1N1CC(C)(C)N(C[C@H](NS(=O)(=O)c2ccccc2[N+](=O)[O-])[C@@H]2C[C@@H](C)C(=O)O2)CC1=O
Yield: 95.4 %

Procedure:
A solution of 844 mg of (3R,5S)-3-methyl-5-[(S)-1-(2-nitrobenzenesulfonyl)aziridin-2-yl]dihydrofuran-2-one obtained in Example (76g) (2.59 mmol) and 733 mg of 5,5-dimethyl-1-(5-fluoro-2-methylphenyl)piperazin-2-one obtained in Example (70d) (3.10 mmol) in toluene (26 ml) was stirred at 110° C. for two hours. After cooling, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/ethyl acetate=3/1-1/1) to obtain 1.39 g of the title compound (yield: 95%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@H:17]3[N:8]([C:9](=O)[C@@H:10]4[C@H:15]([CH2:16]3)[N:14]([S:21]([CH3:24])(=[O:23])=[O:22])[CH2:13][CH2:12][CH2:11]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1.[BH4-].[Na+].B(F)(F)F.CCOCC.[ClH:37]>O1CCCC1>[ClH:37].[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@H:17]3[N:8]([CH2:9][C@@H:10]4[C@H:15]([CH2:16]3)[N:14]([S:21]([CH3:24])(=[O:23])=[O:22])[CH2:13][CH2:12][CH2:11]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)CCN1C(=O)[C@H]3CCCN(S(C)(=O)=O)[C@H]3C[C@@H]21
Agent: Cl
Agent: FB(F)F
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc2c(c1)CCN1C[C@H]3CCCN(S(C)(=O)=O)[C@H]3C[C@@H]21
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
A slurry of 4.894 Kg of (8aS,12aS,13aS)-3-methoxy-12-methanesulfonyl-5,6,8a,9,10,11,12,12a, 13,13a-decahydroisoquino[2,1-g][1,6]naphthyridin-8-one (7) in 60 Kg of tetrahydrofuran was stirred with 1.103 Kg of sodium borohydride at about 10° C. This mixture was maintained at 10° C. while 5.836 Kg of boron trifluoride etherate was added. Upon completion of the addition the reaction mixture was refluxed for 30 minutes, cooled to 20° C., and 67 litres of 1N hydrochloric acid added cautiously. The majority of the solvent was then removed by distillation at atmospheric pressure, the residue cooled to below 30° C. and aqueous 6N sodium hydroxide solution added until the pH reached 12.2 (about 35 litres). The reaction mixture was then extracted with methylene chloride, and the combined extracts washed with water. The solvent was removed by distillation at atmospheric pressure, replacing the methylene chloride with ethanol until the pot temperature reached 78° C. The solution was then cooled to about 70° C. and concentrated aqueous hydrochloric acid (1.3 litres) was added. The slurry was stirred at about 70° C. for 10 minutes, cooled to 20° C. and then stood for 12 hours The product was filtered, washed with 33 Kg of cold ethanol and dried under vacuum at 40°-45° C., giving (8aR,12aS,13aS)-3-methoxy-12-methanesulfonyl-5,6,8a,9,10,11,12,12a,13,13a-decahydro-8H-isoquino[2,1-g][1,6]naphthyridine hydrochloride, m.p. 257°-258° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:11]3[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>CO.C(Cl)Cl.[Pt]>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[C:11]3[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1c[nH]c2ncnc(-c3cccc([N+](=O)[O-])c3)c12
Agent: [Pt]
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)c1c[nH]c2ncnc(-c3cccc(N)c3)c12
Reaction time: 8 h

Procedure:
To ethyl 4-(3-nitrophenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (7.60 g, 24.3 mmol) in methanol (40.6 mL) and CH2Cl2 (40.6 mL) was added 3% Pt on carbon doped with 0.6% V (4.75 g, 0.730 mmol) and the mixture was stirred under a H2 balloon overnight. The mixture was filtered with celite and washed with DCM and MeOH solution to give ethyl 4-(3-aminophenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate after removal of solvent. LRMS (ESI) calc'd for C15H15N4O2 [M+H]+: 283, found 283. 1H NMR (600 MHz, DMSO-D6) δ 12.85 (s, 1H), 8.85 (s, 1H), 8.22 (s, 1H), 7.09 (t, J=7.8 Hz, 1H), 6.90 (s, 1H), 6.71 (d, J=7.2 Hz, 1H), 6.67 (d, J 6.0 Hz, 1H), 5.17 (s, 2H, NH2), 3.86 (q, J=7.2 Hz, 2H), 0.84 (t, J=7.2 Hz, 3H).
Reaction SMILES: [C:1](Cl)(=O)C(Cl)=O.[N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]([O-:19])=[O:18])=[CH:9][N:8]=1.[K+].N1C=CC=CC=1.CO>C1(C)C=CC=CC=1>[N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]([O:19][CH3:1])=[O:18])=[CH:9][N:8]=1
Reactant: O=C([O-])c1cnnc2ccccc12
Reactant: O=C(Cl)C(=O)Cl
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: c1ccncc1
Product: COC(=O)c1cnnc2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 0.64 g of oxalyl chloride in 5 ml of dry toluene was added over 5 minutes to a stirred suspension of 0.98 g of 2 in 10 ml of dry toluene, at 0° C. The resulting mixture was stirred for 20 minutes at 0° C., for 30 minutes at room temperature, and for one hour at 80° C. The mixture was cooled and added in portions over 5 minutes to a stirred ice cold mixture of 0.4 g of pyridine, 0.32 g of methanol and 10 ml of dry toluene. The resulting mixture was held overnight at room temperature, then stripped in a rotary evaporator, and the residue was chromatographed over silica gel, using 5% ethyl acetate/methylene chloride mixture as eluent, to give 4, as yellow crystals, m.p.: 57°-58° C.