Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10](=[S:18])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:20][C:21]#[N:22].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[C:1]1([C:7]2[C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[C:10]([S:18][CH2:20][C:21]#[N:22])[NH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: S=C1NN=C(c2ccccc2)C1c1ccccc1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCSc1[nH]nc(-c2ccccc2)c1-c1ccccc1
Reaction time: 2 h
Yield: 90.1 %

Procedure:
To a solution of 3,4-diphenyl-1H-pyrazole-5(4H)-thione (0.49 g, 1.981 mmol) in DMF (5 mL), were added 2-bromoacetonitrile (0.253 g, 1.981 mmol) and K2CO3 (0.274 g, 1.981 mmol) at room temperature. After stirring for 2 h, the reaction was poured into water and extracted with ethyl acetate. The organic extract was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (0.52 g). LCMS m/z=292.1
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([CH3:17])[CH:11]=1)[CH2:4][CH:5]([CH3:7])[CH3:6].[OH-].[Na+].Cl[CH2:22][O:23][CH3:24]>CN(C=O)C>[CH3:22][O:23][CH2:24][O:1][CH2:2][C@H:3]([NH:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([CH3:17])[CH:11]=1)[CH2:4][CH:5]([CH3:7])[CH3:6]
Reactant: COCCl
Reactant: Cc1ccc(C(=O)N[C@@H](CO)CC(C)C)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COCOC[C@@H](CC(C)C)NC(=O)c1ccc(C)c(C)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a solution of (R)—N-(1-hydroxy-4-methylpentan-2-yl)-3,4-dimethylbenzamide (Example 71a) (0.24 mmol) dissolved in dry DMF (2 mL) was added at 0° C. powdered NaOH (0.36 mmol, 14.5 mg, 1.5 eq) and the mixture was stirred for 1 hr at 0° C. Then chloro-methoxy-methane (19.3 μl, 1 eq) was added and the reaction stirred at 0° C. for 1 hour. The reaction was quenched with water (30 mL) and the mixture was extracted with dichloromethane. The organic phase was dried over MgSO4 and evaporated. The crude product was purified by preparative TLC (20% ethyl acetate/hexanes) to give 37.7 mg of (R)—N-(1-(methoxymethoxy)-4-methylpentan-2-yl)-3,4-dimethylbenzamide (53%). 1H NMR (500 MHz, CDCl3): δ 0.98-1.00 (t, 6H), 1.49-1.53 (m, 1H), 1.58-1.64 (m, 1H), 1.69-1.73 (m, 2H), 2.32-2.33 (d, 6H), 3.38-3.39 (t, 3H), 3.64-3.72 (ddd, 2H), 4.41-4.44 (m, 1H), 4.65-4.69 (dd, 2H), 6.37-6.39 (d, 1H), 7.19-7.21 (d, 1H), 7.50-7.52 (dd, 1H), 7.60 (sb, 1H).
Reaction SMILES: [NH2:1][CH:2]([C:4]1[CH:31]=[CH:30][C:7]([C:8]([NH:10][C:11]2[C:16]([CH3:17])=[CH:15][C:14]([C:18]([F:27])([C:23]([F:26])([F:25])[F:24])[C:19]([F:22])([F:21])[F:20])=[CH:13][C:12]=2[CH2:28][CH3:29])=[O:9])=[CH:6][CH:5]=1)[CH3:3].[C:32](O)(=[O:34])[CH3:33].Cl.C(N=C=NCCCN(C)C)C.CN(C1C=CC=CN=1)C>C(Cl)Cl>[C:32]([NH:1][CH:2]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][C:11]2[C:16]([CH3:17])=[CH:15][C:14]([C:18]([F:27])([C:19]([F:20])([F:21])[F:22])[C:23]([F:24])([F:25])[F:26])=[CH:13][C:12]=2[CH2:28][CH3:29])=[O:9])=[CH:30][CH:31]=1)[CH3:3])(=[O:34])[CH3:33]
Reactant: CC(=O)O
Reactant: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(C(C)N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Product: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(C(C)NC(C)=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
4-(1-Aminoethyl)-N-[2-ethyl-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-methylphenyl]benz amide (0.4 g) was dissolved in methylene chloride (15 ml). To the solution, acetic acid (0.06 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.26 g) and an catalytic amount of dimethylaminopyridine were added and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure and the residue was added with water followed by extraction twice with ethyl acetate. The organic phases were combined, washed with water and dried over anhydrous magnesium sulfate. After filtering off the drying agent, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography to obtain 4-(1-acetamidoethyl)-N-[2-ethyl-4-(1,1,1,2,3,3,3-heptafluoro propan-2-yl)-6-methylphenyl]benzamide (0.35 g, yield 95%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:21])[C:10]=2[C:9]([Cl:22])=[CH:8][CH:7]=1.OS(O)(=O)=O>>[Cl:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][C:14]([N+:1]([O-:4])=[O:2])=[CH:15][CH:16]=3)[C:11](=[O:21])[C:10]=2[C:9]([Cl:22])=[CH:8][CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: O=C1c2ccccc2C(=O)c2c(Cl)ccc(Cl)c21
Agent: O=S(=O)(O)O
Product: O=C1c2ccc([N+](=O)[O-])cc2C(=O)c2c(Cl)ccc(Cl)c21
Temperature: 25 °C

Procedure:
80 g of a mixed acid containing 33% of HNO3 are added dropwise at 5° to 10° C. in the course of 2 to 4 hours to a solution of 110.0 g of 1,4-dichloroanthraquinone in 600 ml of 96% strength H2SO4. The mixture is allowed slowly to warm to room temperature, and is then stirred for a further few hours, and the precipitated 1,4-dichloro-5-nitroanthraquinone (112.6 g) is filtered off with suction. The mother liquor is stirred into 2 liters of water. The solids are then filtered off with suction, and the press cake is washed with water until neutral and dried at 100° C. 12.7 g of 1,4-dichloro-6-nitroanthraquinone are isolated.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13](=[O:25])[NH:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]O)=[CH:17][C:16]=1[O:23][CH3:24].CCCCCCC>ClCCl>[CH3:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13](=[O:25])[NH:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][Cl:3])=[CH:17][C:16]=1[O:23][CH3:24]
Reactant: COc1cc(CO)ccc1NC(=O)Nc1ccccc1C
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCCCCCC
Product: COc1cc(CCl)ccc1NC(=O)Nc1ccccc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.1 %

Procedure:
7.65 ml (104.8 mmol) of thionyl chloride were added dropwise with ice cooling to a suspension of 15 g (52.4 mmol) of 4-(3-(2-methylphenyl)ureido)-3-methoxybenzyl alcohol in 300 ml of dichloromethane. The reaction mixture was subsequently stirred at room temperature for 3 hours, allowed to stand overnight and then poured onto 1000 ml of n-heptane. The heptane was decanted off from the deposited oil, the residue was again suspended with n-heptane and the heptane was decanted off. This process was repeated a further two times. The residue was then dissolved in dichloromethane and poured into 800 ml of ice-cold diisopropyl ether. It was subsequently stirred with ice cooling for 2 hours, and the product was filtered off with suction and washed with diisopropyl ether. After drying over phosphorus pentoxide, 12 g (75%) of the title compound were obtained.
Reaction SMILES: C([N:9]=[C:10]=[S:11])(=O)C1C=CC=CC=1.[CH:12]1[C:13]2[C:28](=[O:29])[C:27]([C:30]([OH:32])=[O:31])=[CH:26][N:25]([CH:33]3[CH2:35][CH2:34]3)[C:14]=2[CH:15]=[C:16]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:17]=1[F:18].[Na]>C1COCC1>[NH2:9][C:10](=[S:11])[N:22]1[CH2:21][CH2:20][N:19]([C:16]2[CH:15]=[C:14]3[C:13]([C:28](=[O:29])[C:27]([C:30]([OH:32])=[O:31])=[CH:26][N:25]3[CH:33]3[CH2:34][CH2:35]3)=[CH:12][C:17]=2[F:18])[CH2:24][CH2:23]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Reactant: O=C(N=C=S)c1ccccc1
Agent: [Na]
Solvent: C1CCOC1
Product: NC(=S)N1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1
Temperature: 5 °C
Reaction time: 20 h

Procedure:
[6R-[6a,7b]]-3-[[[(3-Carboxy-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1-quinolinyl)-4-piperazinyl]iminomethyl]thio methyl]-8-oxo-7-[(2-thienylacetyl)amino]-5-thia-1-azabicyclo [4.2.0]oct-2-ene-2-carboxylic acid sodium salt, of the following formula ##STR330## according to this invention, is made as follows. A solution of benzoyl isothiocyanate 10.92 g) in THF (20 ml) is added to a mixture of ciprofloxacin sodium salt (2.0 g) in THF (300 ml), and the reaction is stirred for 20 hours. The reaction is concentrated to dryness and the residue is triturated with acetone. The resultant benzoylurea is added to a preheated at approximately 80° C. (176° F.) solution of 5% aqueous NaOH and the reaction is stirred for 30 minutes. The mixture is cooled to approximately 5° C. (41° F.) and acidified with 1N HCl. The solid is collected by filtration and recrystallized from DMF to yield 7-[4-(aminothioxomethyl)-1-piperazinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](O)[CH:8]=[C:7]2[NH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1.O=P(Cl)(Cl)[Cl:24]>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([Cl:24])[CH:8]=[C:7]2[NH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1cc(Nc2ccc(Cl)c(Cl)c2)c2cccc(F)c2n1
Product: Fc1cccc2c(Nc3ccc(Cl)c(Cl)c3)cc(Cl)nc12
Yield: 20 %

Procedure:
Prepared using general procedure 3; 8-Fluoro-2-hydroxy-4-(3,4-dichlorophenyl)aminoquinoline (3.2 g, 9.90 mmol) and 23 mL of POCl3 were heated to 120° C. for 4 h. Isolation afforded 0.69 g of material (1.98 mmol, 20%). 1H NMR (300 MHz, DMSO): 9.50(s, 1H), 8.17(d, ?H, J=7.67 Hz), 8.04(d, 1H, J=5.25 Hz), 7.79(d, 1H, J=5.65 Hz), 7.71(d, 1H, J=8.88 Hz), 7.61(m, 1H), 7.45(dd, 1H, J=8.88, 2.42 Hz), 6.88(s, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][CH:10]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:9]1.[CH2:23]([O:30][CH2:31][CH:32]=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([O:30][CH2:31][CH2:32][N:8]1[CH2:12][CH2:11][CH:10]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:9]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=S(=O)(c1ccc(O)cc1)C1CCNC1
Reactant: O=CCOCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccc(O)cc1)C1CCN(CCOCc2ccccc2)C1

Procedure:
The title compound, MS: m/e=362.2 (M+H+) was prepared from (RS)-4-(pyrrolidine-3-sulfonyl)-phenol trifluoroacetic acid salt and benzyloxyacetaldehyde.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C:11](=[CH:12][C:13](=[O:22])[CH2:14][C@@H:15]1[CH3:21])[CH2:10][CH2:9]3.[CH2:23](O)[CH2:24][OH:25].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:23]1[CH2:24][O:25][C:13]2([CH2:14][C@H:15]([CH3:21])[C@@:16]3([CH3:17])[C:11](=[CH:10][CH2:9][C@@H:8]4[C@@H:18]3[CH2:19][CH2:20][C@@:3]3([CH3:4])[C@H:5]4[CH2:6][CH2:7][C@@H:2]3[OH:1])[CH2:12]2)[O:22]1
Reactant: C[C@H]1CC(=O)C=C2CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@]21C
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: C[C@H]1CC2(CC3=CC[C@H]4[C@@H]5CC[C@H](O)[C@@]5(C)CC[C@@H]4[C@]31C)OCCO2
Yield: 25 %

Procedure:
A solution of 7.0 g of 17β-hydroxy-1α-methyl-4-androsten-3-one in 500 ml of benzene is combined with 80 ml of 1,2-ethanediol and 400 mg of p-toluenesulfonic acid and the evolving water is distilled off azeotropically within 20 hours. After cooling of the reaction mixture, the latter is combined with 5 ml of pyridine, washed with water, dried over sodium sulfate, and concentrated under vacuum. The residue is chromatographed on silica gel, thus obtaining with hexane-ethyl acetate gradients (25-30% ethyl acetate) 6.3 g of 3,3-ethylenedioxy-1α-methyl-5-androsten-17β-ol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[CH:46][C:6]([CH2:7][N:8]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([CH:31](O)[C:32]([F:35])([F:34])[F:33])[CH:19]=[N:20][C:21]=3[NH:22][C:23]3[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)[N:10]=2)=[CH:5][CH:4]=1.[Cl:48]CCl.C(N(CC)CC)C.CS(Cl)(=O)=O>>[Cl:48][CH:31]([C:18]1[CH:17]=[C:16]([C:11]2[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([N:8]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=3)[CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:47][CH:46]=3)[N:10]=2)[C:21]([NH:22][C:23]2[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)=[N:20][CH:19]=1)[C:32]([F:35])([F:34])[F:33]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(O)C(F)(F)F)cnc3Nc3ccc(OC)nc3)n2)cc1
Reactant: ClCCl
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(Cl)C(F)(F)F)cnc3Nc3ccc(OC)nc3)n2)cc1
Reaction time: 1.5 h
Yield: 10 %

Procedure:
To a solution of 1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-2,2,2-trifluoroethanol (0.172 g, 0.266 mmol) in dichloromethane (3.00 mL, 0.266 mmol) was added triethylamine (0.093 mL, 0.664 mmol) and methanesulfonyl chloride (0.042 mL, 0.531 mmol) at 0° C. and the mixture was stirred at the same temperature for 1.5 h. The reaction was quenched with saturated NH4Cl and water at 0° C., and the separated aqueous layer was extracted with DCM (2×10 mL) and the combined organic layers were dried over Na2SO4, and concentrated and dried under vacuum to give the crude 4-(5-(1-chloro-2,2,2-trifluoroethyl)-2-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.177 g, 0.0266 mmol), which was used directly in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9](Cl)[C:3]=1[CH2:4][S:5]([NH2:8])(=[O:7])=[O:6].C(=O)([O-])[O-].[K+].[K+]>[Cu].CN(C)C1C=CC=CC=1>[O:6]=[S:5]1(=[O:7])[CH2:4][C:3]2[C:2]([Cl:1])=[CH:12][CH:11]=[CH:10][C:9]=2[NH:8]1
Reactant: NS(=O)(=O)Cc1c(Cl)cccc1Cl
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)c1ccccc1
Product: O=S1(=O)Cc2c(Cl)cccc2N1
Temperature: 170 °C
Reaction time: 4 h
Yield: 58.7 %

Procedure:
The 2,6-dichlorobenzylsulfonamide (8 g, 33.47 mmol) was added to potassium carbonate (4.62 g, 33.47 mmol), copper powder (560 milligrams (hereinafter“mg”)) and N,N-dimethylaniline (10 ml) in flask. The reaction mixture was stirred at 170° C. for 4 hours, then it was cooled to room temperature and partitioned between ethyl acetate and 10% aqueous HCl. The combined organic phase was dried and concentrated. Chromatography of the residue on silica gel (30% Ethyl acetate/Hexane) gave desired product (4 g, 59%). MS(EI) m/e 204.5 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[N:9]=[CH:8][NH:7][C:6]2=O.CN(C=O)C.S(Cl)([Cl:31])=O>>[Cl:31][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCCN1CCCCC1
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCCC1
Yield: 76 %

Procedure:
A solution of 6-methoxy-7-(3-piperidinopropoxy)-3,4-dihydroquinazolin-4-one (1.5 g, 4.7 mmol) in thionyl chloride (15 ml) containing DMF (1.5 ml) was heated at reflux for 3 hours. After cooling, the volatiles were removed under vacuum. The residue was azeotroped with toluene. The solid was partitioned between methylene chloride and sodium hydrogen carbonate. The aqueous layer was adjusted to pH10 with 6M aqueous sodium hydroxide. The organic layer was separated, washed with brine, dried (MgSO4) and the volatiles were removed by evaporation. The residue was purified by column chromatography to give 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (1.21 g, 76%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:10]([C:19](N2[C@@H](CC3C=CC=CC=3)COC2=O)=[O:20])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:10]([CH2:19][OH:20])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1OC[C@H](Cc2ccccc2)N1C(=O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 3-(1-benzyl-4-(S)-phenylpyrrolidine-3-(R)-carbonyl)-4-(S)-benzyl oxazolidin-2-one (from Step B) in 2.5 L of THF at 10° C. was treated with 1.18 L of 1.0 M lithium aluminum hydride solution in THF over a period of 2 h. The resulting mixture was warmed to rt and stirred for 20 h. The reaction was quenched by adding 40 mmL of H2O, then 40 mL of 2.0 N NaOH, then 115 mL of H2O and then was stirred at rt for 1.5 h. The mixture was filtered and the filtrate was concentrated. Chromatography on 4 kg of silica using 4:1 hexanes/acetone (14 L), then 7:3 hexanes/acetone as the eluant afforded the title compound: 1H NMR (400 MHz, CDCl3) δ2.38-2.46 (m, 2H), 2.78-2.88 (3H), 3.20-3.26 (2H), 3.65 (dd, J=12.0, 4.0 1H), 3.66 (app s, 2H), 3.74 (dd, J=12.0, 4.0, 1H), 7.18-7.34 (10H); ESI-MS 268 (M+H); HPLC A: 2.35 min.
Reaction SMILES: C([O:5][C:6]([C@:8]1([CH3:13])[CH2:12][CH2:11][CH2:10][NH:9]1)=O)CCC.[NH3:14]>CO>[CH3:13][C@@:8]1([C:6]([NH2:14])=[O:5])[CH2:12][CH2:11][CH2:10][NH:9]1
Reactant: N
Reactant: CCCCOC(=O)[C@]1(C)CCCN1
Solvent: CO
Product: C[C@@]1(C(N)=O)CCCN1

Procedure:
A solution of (S)-2-methyl-pyrrolidine-2-carboxylic acid butyl ester (2.3 g) in a 7 M solution of ammonia in methanol (22.2 ml) is heated in a bomb at 70° C. for 10 days. Evaporation of the reaction mixture and trituration with hexanes (20 ml) gives the title compound as an off-white solid. 1H nmr (d6-DMSO, 400 MHz) 7.40 (s, 1H), 6.89 (s, 1H), 2.95-2.84 (m, 1H), 2.72-2.60 (m, 1H), 2.06-1.95 (m, 1H), 1.66-1.44 (m, 2H), 1.42-1.30 (m, 1H), 1.22 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16](Cl)[N:15]=[C:14]([NH:19][CH3:20])[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:21][NH:22][CH3:23]>C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([N:22]([CH3:23])[CH3:21])[N:15]=[C:14]([NH:19][CH3:20])[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CNc1nc(Cl)cc(NS(=O)(=O)c2ccc(N)cc2)n1
Reactant: CNC
Solvent: CCO
Product: CNc1nc(NS(=O)(=O)c2ccc(N)cc2)cc(N(C)C)n1
Yield: 93.1 %

Procedure:
0.314 g (0.001 mol) of 4-amino-N-(6-chloro-2-methylamino-pyrimidin-4-yl)-benzenesulfonamide and 18 ml (0.1 mol) of dimethylamine in ethanol (5.6M) were stirred in an autoclave at 130° C. for 4 hours. The reaction mixture was freed from solvent, the residue was suspended in 5 ml of ethanol and treated in an ultrasound bath for 15 min. The precipitate was filtered off, dissolved in 10 ml of 0.1N NaOH and filtered. The filtrate was adjusted to pH 6 with 0.1N HCl. The precipitate was filtered off under suction, washed with water and dried. There was obtained 0.30 g (78%) of 4-amino-N-(6-dimethylamino-2-methylamino-pyrimidin-4-yl)-benzenesulfonamide as beige crystals; m.p.: >300° C.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=CC1C=C[C:16](O)=[C:13]([O:14]C)[CH:12]=1>CCCCCC.C(OCC)C>[OH:8][CH2:1][C:2]1[CH:7]=[CH:6][C:5]2[O:14][CH:13]([CH3:16])[CH2:12][C:4]=2[CH:3]=1
Reactant: COc1cc(C=O)ccc1O
Reactant: OCc1ccccc1
Solvent: CCCCCC
Solvent: CCOCC
Product: CC1Cc2cc(CO)ccc2O1

Procedure:
To a solution of 853 mg (4.14 mmole) ethyl 2-methyl-2,3-dihydrobenzofuran-5-carboxylate in 9 ml dry tetrahydrafuran under nitrogen was added 157 mg (4.14 mmole) lithium aluminum hydride in portions and the resulting mixture was stirred at room temperature overnight. The mixture was worked up as described in Preparation A, Part (v), to afford 752 mg of product. The NMR spectrum showed the presence of a band at 4.5 ppm, characteristic of a benzyl alcohol CH2 group. TLC with 1:1 hexane/ethyl ether showed one spot at Rf 0.2 (vanillin spray).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[CH3:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:9]=1[NH:15][C:16]([NH:18][CH3:19])=[S:17]>C(Cl)Cl>[CH3:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:9]=1[N:15]1[C:2](=[O:3])[C:1](=[O:5])[N:18]([CH3:19])[C:16]1=[S:17]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CNC(=S)Nc1c(C)cccc1C
Solvent: ClCCl
Product: Cc1cccc(C)c1N1C(=O)C(=O)N(C)C1=S
Yield: 65.9 %

Procedure:
Oxalyl chloride (8.4 g; 0.066 mol) was added dropwise to the stirring solution of N-(2,6-dimethyl phenyl)-N′-methylthiourea (6.4 g; 0.033 mol) in methylene chloride (100 mL). The mixture was heated at reflux for 2 hours then evaporated to dryness. Ethanol (100 mL) was added and the mixture was heated at reflux for 1 hour. The solvent was concentrated. The precipitated solid was collected by filtration and dried to give 5.4 g of 1-(2,6-Dimethylphenyl)-3-methyl-2-thioxo-4,5-imidazolidinedione, m.p. 144–146° C. Mass spectrum; (El, M.+) m/z248. 1H-NMR (DMSO-d6; 300 MHz): δ 7.30 (t, 1H), 7.18 (d, 2H), 3.33 (s, 3H), and 2.08 ppm (s, 6H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1[C:10](=[O:15])[CH2:11][S:12]([CH3:14])=[O:13].[N:16]([O-])=O.[Na+]>O>[Cl:9][C:6]1[CH:5]=[C:4]2[C:3](=[CH:8][CH:7]=1)[NH:2][N:16]=[C:11]([S:12]([CH3:14])=[O:13])[C:10]2=[O:15]
Reactant: CS(=O)CC(=O)c1cc(Cl)ccc1N
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CS(=O)c1n[nH]c2ccc(Cl)cc2c1=O

Procedure:
500 ml of 3N HCl was chilled to 0° in an ice-salt bath, and 10 g of 2'-amino-5'-chloro-2-(methylsulfinyl)acetophenone was added. The mixture was stirred until a clear solution was obtained, and a solution of 3.45 g of NaNO2 in 20 ml of H2O was added with stirring at ca. 0°-3°. The solution became first orange colored, and then a yellow precipitate formed. The ice bath was removed, and the mixture was stirred until room temperature was attained. The precipitate was filtered off, washed with H2O, and recrystallized from dimethylformamide, mp. 267°-72°; yield 5 g (44%).
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:8]12[CH:23]([O:24][CH2:25][C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)[CH:12]([CH:13]([N:15]3[CH:20]=[CH:19][C:18](=[O:21])[NH:17][C:16]3=[O:22])[O:14]1)[O:11][NH:10][CH2:9]2)([CH3:4])([CH3:3])[CH3:2].C=O.[BH3-][C:51]#N.[Na+].CCOC(C)=O>CC(O)=O>[C:1]([SiH2:5][O:6][C:7]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:8]12[CH:23]([O:24][CH2:25][C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)[CH:12]([CH:13]([N:15]3[CH:20]=[CH:19][C:18](=[O:21])[NH:17][C:16]3=[O:22])[O:14]1)[O:11][N:10]([CH3:51])[CH2:9]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[SiH2]OC(c1ccccc1)(c1ccccc1)C12CNOC(C(n3ccc(=O)[nH]c3=O)O1)C2OCc1ccc2ccccc2c1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CN1CC2(C(O[SiH2]C(C)(C)C)(c3ccccc3)c3ccccc3)OC(n3ccc(=O)[nH]c3=O)C(O1)C2OCc1ccc2ccccc2c1

Procedure:
To a solution of compound 52 (1 mmol) in CH3COOH (5 mL) and trithylortoformate (1 mL), 20% aq. HCHO (0.16 mL, 1.1 mmol) was added at 0° C. After 15 minutes NaBH3CN (2 mmol) is added. After an additional 1 hour the mixture is poured into EtOAc (250 mL), washed with saturated aqueous NaHCO3 (2×250 mL), dried over anhydrous Na2SO4, filtered and evaporated. Purification by silica gel chromatography gave compound 53 in 90% isolated yield.