Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1.S(Cl)(Cl)=O.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[S:29][C:30]3[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:31]=3[N:32]=2)=[CH:24][CH:23]=1>C(Cl)(Cl)Cl.N1C=CC=CC=1>[F:15][C:2]([F:1])([F:16])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]3[S:29][C:30]4[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:31]=4[N:32]=3)=[CH:26][CH:27]=2)=[O:12])=[CH:13][CH:14]=1
Reactant: O=C(O)c1ccc(OCCC(F)(F)F)cc1
Reactant: COc1ccc2nc(-c3ccc(N)cc3)sc2c1
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc2nc(-c3ccc(NC(=O)c4ccc(OCCC(F)(F)F)cc4)cc3)sc2c1
Temperature: 25 °C
Yield: 89.8 %

Procedure:
A mixture of 4-(3,3,3-trifluoropropoxy)benzoic acid (0.32 g, 1.39 mmol) and thionyl chloride (0.33 g, 2.78 mmol) in chloroform (5 ml) was heated under reflux for 5 h. The reaction mixture was cooled to room temperature and the excess reagent and solvent was removed under reduced pressure to give the crude acid chloride. The amide was prepared as described in the Amide Coupling section using the crude acid chloride and 2-(4-aminophenyl)-6-methoxybenzothiazole (0.36 g, 1.39 mmol) in dry pyridine (10 ml) to give the title compound (0.59 g, 90%) as a pale yellow solid after work-up.
Reaction SMILES: [CH3:1][N:2]1S[C:6]2[CH2:8][CH2:9][CH2:10][C:5]=2[C:3]1=[O:4].[S:11]([S:14]([O-])=O)([O-])=O.[Na+].[Na+]>O>[CH3:1][NH:2][C:3]([C:5]1[CH2:10][CH2:9][CH2:8][C:6]=1[S:11][S:14][C:6]1[CH2:8][CH2:9][CH2:10][C:5]=1[C:3]([NH:2][CH3:1])=[O:4])=[O:4]
Reactant: Cn1sc2c(c1=O)CCC2
Reactant: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CNC(=O)C1=C(SSC2=C(C(=O)NC)CCC2)CCC1

Procedure:
2-methyl-4,5-trimethylene-4-isothiazolin-3-one (1 part) was stirred in distilled water (25 parts) at 20°-25° C. Sodium hydrosulphite (2×0.2 parts) was added in two portions over 30 minutes. Analysis by HPLC indicated the formation of two products.
Reaction SMILES: F[CH:2]1[CH:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=O)[CH:6]=[CH:5][CH:4]=[C:3]1[C:16]([F:19])([F:18])[F:17].O.[NH2:21][NH2:22]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1.[Cl-].[Na+].O.CCOC(C)=O>[N:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:8]1[NH:21][N:22]=[C:2]2[C:7]=1[CH:6]=[CH:5][CH:4]=[C:3]2[C:16]([F:19])([F:18])[F:17]
Reactant: O=C(c1ccccn1)C1C=CC=C(C(F)(F)F)C1F
Reactant: NN
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: FC(F)(F)c1cccc2c(-c3ccccn3)[nH]nc12
Yield: 76 %

Procedure:
Next, a solution of (6-fluoro-5-trifluoromethyl-cyclohexa-2,4-dienyl)-pyridin-2-yl-methanone (1.5 g, 5.6 mmol), 4-dimethylaminopyridine (0.5 g) and hydrazine hydrate (5 mL) in pyridine (20 mL) was heated at 100° C. overnight. The reaction mixture was cooled and diluted with brine and EtOAc. The organics were washed with water (3×25 mL), then brine (25 mL) and dried over MgSO4. The reaction mixture was concentrated in vacuo and purified by flash chromatography (silica gel 60, EtOAc/CH2Cl2, 19:1) to afford 3-pyridin-2-yl-7-(trifluoromethyl)-2H-indazole as a pale yellow solid (1.1 g, 76%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.COC1C=C(O)C=CC=1C.[Cl:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[C:24](=[O:45])[C:25](=[O:44])[N:26]2[CH:31]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(N1C2C(=CC=CC=2)C(=O)C1=O)(C1C=CC=CC=1)C1C=CC=CC=1>>[Cl:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[C:24]([OH:45])([C:8]1[C:7]([OH:10])=[CH:6][C:5]3[O:1][CH2:2][CH2:3][C:4]=3[CH:9]=1)[C:25](=[O:44])[N:26]2[CH:31]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: Oc1ccc2c(c1)OCC2
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2cccc(Cl)c21
Agent: COc1cc(O)ccc1C
Agent: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2cccc(Cl)c2C1(O)c1cc2c(cc1O)OCC2

Procedure:
Following the procedure as described in PREPARATION 3A, and making non-critical variations using 2,3-dihydrobenzofuran-6-ol to replace 3-methoxy-4-methylphenol, and 4-chloro-1-(diphenylmethyl)-1H-indole-2,3-dione to replace 1-benzhydrylindoline-2,3-dione, 4-chloro-1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one was obtained (87%) as a beige solid: 1H NMR (300 MHz, CDCl3) δ 8.66 (br s, 1H), 7.36-7.16 (m, 10H), 7.05-7.01 (m, 2H), 6.89 (s, 1H), 6.58 (s, 1H), 6.45-6.38 (m, 2H), 4.57-4.49 (m, 2H), 4.03 (br s, 1H), 3.13-2.91 (m, 2H); MS (ES+) m/z 505.9 (M+1), 507.9 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH:5]([CH3:12])[CH:6]([NH:8][CH:9]1[CH2:11][CH2:10]1)[CH3:7])[CH3:2].[Cl:14][C:15]1[N:20]=[C:19](Cl)[C:18]([N+:22]([O-:24])=[O:23])=[CH:17][N:16]=1.C(=O)(O)[O-].[K+]>O.C(OCC)C>[CH2:1]([O:3][C:4](=[O:13])[CH:5]([CH3:12])[CH:6]([N:8]([C:17]1[C:18]([N+:22]([O-:24])=[O:23])=[CH:19][N:20]=[C:15]([Cl:14])[N:16]=1)[CH:9]1[CH2:11][CH2:10]1)[CH3:7])[CH3:2]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CCOC(=O)C(C)C(C)NC1CC1
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)C(C)C(C)N(c1nc(Cl)ncc1[N+](=O)[O-])C1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.7 %

Procedure:
A solution of 0.93 g (0.005 mole) of (rac)-3-cyclopropylamino-2-methyl-butanoic acid ethyl ester in 20 mL of water was added dropwise to a solution of 0.97 g (0.005 mole) of 2,4-dichloro-5-nitro-pyrimidine in 20 mL of ethyl ether. At 0 degrees, 1.0 g (0.010 mole) of potassium bicarbonate was added. The mixture was stirred at ambient temperature for 3 hours. The layers were then separated, and the aqueous layer extracted twice with 30 mL of ether. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with hexanes-ethyl acetate (100:0-80:20) gave 1.4 g of (rac)-3-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopropyl-amino]-2-methyl-butanoic acid ethyl ester (IV-46).
Reaction SMILES: [OH:1][CH2:2][C:3](=[O:25])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C:18](=[CH:19][CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH:14]=[CH:15]2)[CH2:10][CH2:9]3)[CH2:6][C@H:5]1[CH3:24].C(N(CC)CC)C.[N+:33]([C:36]1[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=1)([O-:35])=[O:34].O>O1CCCC1>[CH3:24][C@@H:5]1[CH2:6][C@@H:7]2[C@:21]([CH3:22])([CH2:20][CH:19]=[C:18]3[C@H:8]2[CH2:9][CH2:10][C:11]2[C@:16]3([CH3:17])[CH:15]=[CH:14][C:13](=[O:23])[CH:12]=2)[C@H:4]1[C:3](=[O:25])[CH2:2][O:1][S:42]([C:39]1[CH:38]=[CH:37][C:36]([N+:33]([O-:35])=[O:34])=[CH:41][CH:40]=1)(=[O:43])=[O:44]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@H]1C(=O)CO
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@H]1C(=O)COS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
After dissolving 10.0 g (29.4 mmoles) of 21-hydroxy-16α-methylpregna-1,4,9(11)-triene-3,20-dione in 100 ml of tetrahydrofuran, 7.14 ml (51.4 mmoles) of triethylamine, then at 0° C. 11.4 g (51.4 mmoles) of 4-nitrobenzenesulfonyl chloride are added to the above solution. Subsequently, the reaction mixture is stirred at room temperature for 2 hours, then dropwise added to 450 ml of water while stirring. The precipitate is filtered off, dried and recrystallized from ether to obtain the title compound in a yield of 13.5 g (87.66%), m.p.:151°-160° C.
Reaction SMILES: [CH3:1][C:2](Cl)([CH3:7])[CH2:3][CH2:4][CH2:5][CH3:6].[C:9]1([CH2:15][CH:16]([CH3:19])[CH2:17][Cl:18])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)(Cl)Cl>[CH3:1][C:2]([C:12]1[CH:13]=[CH:14][C:9]([CH2:15][CH:16]([CH3:19])[CH2:17][Cl:18])=[CH:10][CH:11]=1)([CH3:7])[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCC(C)(C)Cl
Reactant: CC(CCl)Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCCCC(C)(C)c1ccc(CC(C)CCl)cc1
Temperature: 50 °C
Reaction time: 14 h
Yield: 73.8 %

Procedure:
342 g of 1,1-dimethylpentyl chloride were added dropwise to a mixture of 428 g of 3-phenyl-2-methylpropyl chloride and 40.6 g of FeCl3 at 35° C., and the mixture was stirred for 7 hours at 50° C. and for 14 hours at room temperature. The crude product was dissolved in 2 l of CHCl3, and the solution was washed with dilute HCl and water, dried over Na2CO3 and concentrated. Distillation of the residue gave 500 g of (XII) of boiling point 126°-132° C./0.2 mbar.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([O:11][C:12]2[CH:13]=[C:14]([NH2:19])[C:15]([NH2:18])=[CH:16][CH:17]=2)=[CH:3][CH:2]=1.[N:20]([C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)=[C:21]=S.C(Cl)CCl>CC#N>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([O:11][C:12]2[CH:17]=[CH:16][C:15]3[NH:18][C:21]([NH:20][C:23]4[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:27][CH:28]=4)=[N:19][C:14]=3[CH:13]=2)=[CH:3][CH:2]=1
Reactant: Nc1ccc(Oc2ccnc3ccccc23)cc1N
Reactant: FC(F)(F)c1ccc(N=C=S)cc1
Solvent: CC#N
Solvent: ClCCCl
Product: FC(F)(F)c1ccc(Nc2nc3cc(Oc4ccnc5ccccc45)ccc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4-(quinolin-4-yloxy)-benzene-1,2-diamine (Step B, 227 mg) in CH3CN (60 mL) was added over 5 min, a solution of 1-isothiocyanato-4-trifluoromethyl-benzene (183 mg) in CH3CN 10 mL). The mixture was stirred for 12 h at RT and EDC (260 mg) was added, followed by CH3CN (30 mL). The resulting mixture was heated at 80° C. for 2 h, then cooled to RT. The solvent was evaporated and the residue was dissolved in EtOAc and washed with water. The organic phase was dried, filtered and evaporated. The residue was purified by flash chromatography in EtOAc to give an orange-brown solid. MS (MH+)=420.9, MW: 420.18 Calc'd for: C23H15F3N4O.
Reaction SMILES: CC1C=CC(S(O[CH:12]2[CH2:16][C:15]3[CH:17]=[CH:18][CH:19]=[C:20]([C:21]4[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:28])[C:14]=3[O:13]2)(=O)=O)=CC=1.[CH2:29]([NH2:31])[CH3:30].Cl.[CH3:33]S(C)=O>O.C(OCC)(=O)C.C(O)(C)C>[Cl:27][C:26]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:28])[C:21]=1[C:20]1[C:14]2[O:13][CH:12]([CH2:33][NH:31][CH2:29][CH3:30])[CH2:16][C:15]=2[CH:17]=[CH:18][CH:19]=1
Reactant: CS(C)=O
Reactant: CCN
Reactant: Cc1ccc(S(=O)(=O)OC2Cc3cccc(-c4c(Cl)cccc4Cl)c3O2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)O
Product: CCNCC1Cc2cccc(-c3c(Cl)cccc3Cl)c2O1
Temperature: 60 °C
Reaction time: 12 h
Yield: 57 %

Procedure:
To a solution of (±)-7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl 4-methylbenzenesulfonate (0.2 g, 0.46 mmol) in dimethylsulfoxide (5 mL) was added ethylamine (0.20 g, 4.4 mmol) and the reaction mixture was allowed to stir at 60° C. for 12 h. The reaction was diluted with water (10 mL) and ethyl acetate (2×10 mL). The combined organic layers were washed with water (3×20 mL) and saturated aqueous sodium chloride (20 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give an oil. The oil was re-dissolved in isopropanol (0.5 mL) and hydrogen chloride (0.5 mL, 1.0 M in diethyl ether) was added. The resulting precipitate was filtered, washed (diethyl ether), to give 0.084 g (57%) of (±)-N-{[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}ethanamine as a white solid, hydrochloride salt. mp 195-197° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=4)[CH:15]=3)[CH:10]=[CH:9]2)[CH:3]=1.[NH3:26].C(O)(C)C.O>CS(C)=O>[N+:23]([C:19]1[CH:18]=[C:17]([C:14]2[CH:15]=[C:16]3[C:11]([CH:10]=[CH:9][N:8]3[C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH2:26])[CH:3]=3)=[CH:12][CH:13]=2)[CH:22]=[CH:21][CH:20]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1cccc(-c2ccc3ccn(-c4cc(Cl)ncn4)c3c2)c1
Reactant: N
Solvent: CC(C)O
Solvent: CS(C)=O
Solvent: O
Product: Nc1cc(-n2ccc3ccc(-c4cccc([N+](=O)[O-])c4)cc32)ncn1
Temperature: 100 °C
Reaction time: 15 h

Procedure:
1-(6-Chloropyrimidin-4-yl)-6-(3-nitrophenyl)-1H-indole (1 g, 2.86 mmol) was dissolved in DMSO (15 mL) in a sealed reactor. After adding 2.0 M ammonia solution in isopropanol (15 mL, 30 mmol), the reaction mixture was stirred at 100° C. for 15 hours. After cooling to room temperature and adding water (70 mL), the reaction mixture was stirred at room temperature for 1 hour. Thus prepared solid was filtered, washed with water, and dried in the air. 6-(6-(3-Nitrophenyl)-1H-indol-1-yl)pyrimidin-4-amine (850 mg) was yielded as white solid.
Reaction SMILES: [CH2:1]([C:18]([OH:56])([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]/[CH:46]=[CH:47]\[CH2:48]/[CH:49]=[CH:50]\[CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[CH:19]([OH:37])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].N1C=CC=CC=1.[O:63]=[C:64](Cl)OC(Cl)(Cl)Cl>CCOCC>[CH2:1]([C:18]1([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]/[CH:46]=[CH:47]\[CH2:48]/[CH:49]=[CH:50]\[CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[CH:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[O:37][C:64](=[O:63])[O:56]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCC(O)(CCCCCCC/C=C\C/C=C\CCCCC)C(O)CCCCCCC/C=C\C/C=C\CCCCC
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCCCC/C=C\C/C=C\CCCCCCCCC1(CCCCCCC/C=C\C/C=C\CCCCC)OC(=O)OC1CCCCCCC/C=C\C/C=C\CCCCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.5 %

Procedure:
To a solution of (6Z,9Z,28Z,31Z)-19-((8Z,11Z)-heptadeca-8,11-dienyl)heptatriaconta-6,9,28,31-tetraene-18,19-diol (540 mg, 0.67 mmol) in anhydrous ether (5 mL) was added pyridine (81 μL, 1.0 mmol). To this solution was added diphosgene (132 μL, 1.1 mmol) slowly over 5 minutes. The solution was stirred for 2 hours at room temperature then concentrated in vacuo to dryness and purified by column chromatography on silica gel 60 (eluted with 5% ether in hexanes) to afford 4,5-di((8Z,11Z)-heptadeca-8,11-dienyl)-4-((9Z,12Z)-octadeca-9,12-dienyl)-1,3-dioxolan-2-one as a colorless oil (310 mg, 57%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:21]=[CH:20][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])=O)=[CH:7][CH:6]=1)=[O:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:21]=[CH:20][C:8]([C:9](=[S:31])[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])=[CH:7][CH:6]=1)=[O:4]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COC(=O)c1ccc(C(=O)Nc2ccccc2OC)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C(=S)Nc2ccccc2OC)cc1
Temperature: 25 °C
Yield: 96.6 %

Procedure:
The 4-methoxycarbonyl-2'-methoxybenzanilide (123.2 g) obtained in (1) was dissolved in 400 ml of toluene, and 96.1 g of Lawesson's reagent was added. The mixture was refluxed for 2 hours. After the reaction, the reaction mixture was hot-filtered. The filtrate was left to stand until it cooled to room temperature. The precipitated crystals were collected by filtration and washed with a small amount of benzene to give 69.2 g of 4-methoxycarbonyl-2'-methoxybenzothioanilide.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]C(Cl)(Cl)Cl)=[CH:4][N:3]=1>C(N)=O.O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[S:15][C:4]=2[N:3]=1
Reactant: Clc1ncc(-c2ccccc2SC(Cl)(Cl)Cl)c(Cl)n1
Solvent: O
Solvent: NC=O
Product: Clc1ncc2c(n1)sc1ccccc12
Temperature: 60 °C
Yield: 67.8 %

Procedure:
A solution of 2,4-dichloro-5-(2-((trichloromethyl)thio)phenyl)pyrimidine (12.5 g, 33.4 mmol) in formamide (498 ml) was degassed with nitrogen and heated at 60° C. overnight. The reaction solution was cooled to room temperature, diluted with water, filtered and washed with water and a small amount of cold ethanol. White precipitate was recrystallized from EtOH to afford 5.0 g (68% yield) of 2-chlorobenzo[4,5]thieno[2,3-d]pyrimidine as white needles.
Reaction SMILES: [F:1][C:2]1([F:11])[CH2:7][CH2:6][CH:5]([C:8](=O)[CH3:9])[CH2:4][CH2:3]1.C([O-])(=O)C.[NH4+].[BH3-]C#[N:19].[Na+]>C1COCC1.CO>[F:1][C:2]1([F:11])[CH2:7][CH2:6][CH:5]([CH:8]([NH2:19])[CH3:9])[CH2:4][CH2:3]1
Reactant: [BH3-]C#N
Reactant: CC(=O)C1CCC(F)(F)CC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(N)C1CCC(F)(F)CC1
Reaction time: 48 h
Yield: 54.1 %

Procedure:
To a solution of 1-(4,4-difluorocyclohexyl)ethanone (1 g, 6.17 mmol) in THF (5 mL) was added a solution of ammonium acetate (9.51 g, 123.4 mmol) and NaBH3CN (3.82 g, 61.7 mmol) in MeOH. The mixture was stirred for 48 hr. The reaction mixture was quenched with aqueous NaHCO3 and extracted with tert-Butyl-methyl ether (20 mL*3). The combined organic layers were washed with 1N HCl, and the organic and aqueous layer were separated. The aqueous layer was brought to above pH 8 with 2N NaOH and extracted with ethyl acetate (20 mL*3). The organic layer was washed with brine, dried over sodium sulfate. The organic layer was concentrated to give 1-(4,4-difluorocyclohexyl)ethanamine (545 mg, crude) for next step.
Reaction SMILES: C(N(CC)[C@H]1C2C(=CC=CC=2)C[C@H]1O[C:14]([C@H:16]1[C@H:18]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[O:17]1)=[O:15])C.C(OC([C@H]1[C@H](C2C=CC(OC)=CC=2)O1)=O)(C)(C)C.[NH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[SH:54].CC1C=CC=CC=1>C1(C)C(C)=CC=CC=1.CO>[OH:17][C@H:16]1[C:14](=[O:15])[NH:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=2[S:54][C@H:18]1[C:19]1[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=1
Reactant: Nc1ccccc1S
Reactant: CCN(CC)[C@H]1c2ccccc2C[C@H]1OC(=O)[C@@H]1O[C@H]1c1ccc(OC)cc1
Agent: COc1ccc([C@@H]2O[C@H]2C(=O)OC(C)(C)C)cc1
Solvent: Cc1ccccc1C
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1ccc([C@@H]2Sc3ccccc3NC(=O)[C@@H]2O)cc1
Temperature: 120 °C
Reaction time: 6 h

Procedure:
2.0 grams (4.8 mmol) of the mixture of (2R,3S)-3-(4-methoxyphenyl)oxirane-2-carboxylic (1S,2R)-1-(diethylamino)-2-indanyl ester (diastereomeric ratio 89:11) and (2R,3S)-3-(4-methoxyphenyl)oxirane-2-carboxylic tert-butyl ester (enantiomeric excess 80%) of Example V was dissolved in 20 ml of xylene+1 ml of methanol. This solution was heated to 120° C. and 600 mg (5.0 mmol) of 2-aminothiophenol was added drop by drop in 5 min. After 6 hours' heating at 120° C. the solution was cooled to 20° C. and 1.1 grams (6,0 mmol) of p-toluene sulphonic monohydrate was added. This was followed by 6 hours' heating at reflux temperature, during which 1-2 ml of a xylene/methanol mixture was removed through distillation. After cooling, the brown solution was dissolved in dichloromethane and washed with a 5% Na2CO3 solution in water and a 0.5M KH2PO4 solution in water. After drying with the aid of Na2SO4 and evaporation, the chemically pure product was obtained after chromatography using silica gel (eluant:toluene/ethyl acetate 2:1). 85% enantiomeric excess (determined with the aid of anisochrony in 1H NMR, see C. Giordano et al.; J. Org. Chem. 1991, (59), 2270). The enantiomeric excess was increased to >95% through one recrystallisation from toluene. White needles. Melting point: 200-202° C. [α]20D +109 (c=0.4, methanol). 1H NMR (200 MHz, CDCl3): 2.93 (d, 1H), 3.71 (s, 3H), 4.41 (dd, 1H), 5.02 (d, 1H), 6.74 (d, 2H), 7.03-7.21 (m, 2H), 7.29-7.44 (d+m, 3H), 7.61 (d, 1H) and 8.47 (br s, 1H). The (1S,2R)-1-(diethylamino)-2-indanol was recovered from the 0.5M KH2PO4 extraction solution.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.[S:16](Cl)([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl.O>[S:16]([O:1][CH2:2][C@H:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CO)C1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CN(C(=O)OC(C)(C)C)CCO2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
A solution of (S)-tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (1.0 equiv.), tosyl chloride (1.10 equiv.), triethylamine (1.40 equiv.) and N,N-dimethylpyridin-4-amine (0.1 equiv.) in dichloromethane (0.1 M) at RT. The resulting mixture was stirred at RT for 2 hours. The reaction mixture was then diluted with water and the aqueous layer was separated and washed sequentially with NaOH (1 M), water, brine dried over sodium sulfate then concentrated in vaccuo to yield (S)-tert-butyl 2-((tosyloxy)methyl)morpholine-4-carboxylate as a pale yellow oil in 99% yield. LCMS (m/z) (M+H)=390.2, Rt=0.84 min.
Reaction SMILES: C(OC(=O)C)(=O)C.[Cl:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=2)[C:19]([OH:21])=[O:20])[CH:12]=[CH:11][C:10]=1[C:25]([F:28])([F:27])[F:26].S(=O)(=O)(O)O.[N+:34]([O-])([OH:36])=[O:35]>C(OCCCC)(=O)C>[N+:34]([C:22]1[CH:23]=[CH:24][C:16]([O:15][C:13]2[CH:12]=[CH:11][C:10]([C:25]([F:26])([F:27])[F:28])=[C:9]([Cl:8])[CH:14]=2)=[CH:17][C:18]=1[C:19]([OH:21])=[O:20])([O-:36])=[O:35]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1cccc(Oc2ccc(C(F)(F)F)c(Cl)c2)c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Solvent: CCCCOC(C)=O
Product: O=C(O)c1cc(Oc2ccc(C(F)(F)F)c(Cl)c2)ccc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 85 %

Procedure:
Acetic anhydride (37.7 g) was added to 3-(2-chloro-α,α,α-trifluoro-4-tolyloxy)-benzoic acid (86% strength, 45 g) in n-butyl acetate (85.8 g) at 35° C. Sulphuric acid (98%, 12.2 g) was added slowly and the mixture cooled to 0° C. Nitric acid (90%, 10.4 g) was then added slowly over about 3 hours such that the temperature was maintained at -5 to 0° C. On completion of the nitric acid addition the reaction was quenched with water (60 g) at 0° C. The mixture was warmed to 50-60° C. and the aqueous layer removed. The solvent layer was washed with water (2×100 g) at 60° C. and the aqueous layer removed. The solvent and acetic acid were removed by distillation to give 2-nitro-5-(2-chloro-α,α,α-trifluoro-4-tolyloxy) benzoic acid (85%), 2'-nitro isomer (7.5 to 8.5 pph), total dinitro's (~0.5 pph).