Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10](=[O:25])[CH:11]=[C:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)[CH3:8].[CH3:26][N+:27]([O-:29])=[O:28].Cl>O.CS(C)=O>[CH2:7]([O:9][C:10](=[O:25])[CH2:11][C:12]1([CH2:26][N+:27]([O-:29])=[O:28])[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)[CH3:8]
Reactant: CCOC(=O)C=C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: C[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)CC1(C[N+](=O)[O-])CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Into a 3000-mL 4-necked round-bottom flask was placed potassium carbonate (93.2 g, 662 mmol, 0.50 equiv) and DMSO (2000 mL). The resulting solution was heated to 80° C. This was followed by the addition of tert-butyl 4-(2-ethoxy-2-oxoethylidene)piperidine-1-carboxylate (368 g, 1.30 mol, 1.00 equiv, 95%) and CH3NO2 (417 g, 6.70 mol, 5.00 equiv, 98%) slowly. The resulting solution was stirred for 120 min at 90° C. After being cooled to room temperature, the reaction mixture was adjusted to ph 5 with HCl (0.5 mol/L) and diluted with 2000 mL of water. The resulting solution was extracted with 3×1500 mL of ether. The organic layers were combined, washed with 1×2000 mL of water and 1×2000 mL of saturated brine, dried and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:20-1:15-1:10) to afford the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:23])[N:9]3[C:16]4[CH:17]=[C:18]([CH3:22])[C:19]([CH3:21])=[CH:20][C:15]=4[NH:14][C:10]3=[N:11]2)=[CH:6][CH:5]=1)[CH3:2].[CH2:24](Br)[CH:25]([CH3:27])[CH3:26]>>[CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:23])[N:9]3[C:16]4[CH:17]=[C:18]([CH3:22])[C:19]([CH3:21])=[CH:20][C:15]=4[N:14]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:10]3=[N:11]2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc2c(=O)n3c(nc2c1)[nH]c1cc(C)c(C)cc13
Reactant: CC(C)CBr
Product: CCOc1ccc2c(=O)n3c4cc(C)c(C)cc4n(CC(C)C)c3nc2c1

Procedure:
3-Ethoxy-6-isobutyl-8,9-dimethylbenzimidazo[2,1-b]-quinazolin-12(6H)one is prepared with 3-ethoxy-8,9-dimethylbenzimidazo[2,1-b]quinazolin-12(6H)one and isobutyl bromide.
Reaction SMILES: [CH3:1][S:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[Br:12]Br>C(Cl)(Cl)Cl>[Br:12][C:10]1[CH:9]=[CH:8][C:6]2[N:7]=[C:3]([S:2][CH3:1])[O:4][C:5]=2[CH:11]=1
Reactant: BrBr
Reactant: CSc1nc2ccccc2o1
Solvent: ClC(Cl)Cl
Product: CSc1nc2ccc(Br)cc2o1
Reaction time: 0.75 h

Procedure:
2-(Methylthio)benzoxazole (5.8 g, see (a) above) was dissolved in chloroform (75 ml) and a solution of bromine (6.0 g) in chloroform (30 ml) was added dropwise, with stirring, over a period of 45 minutes. The mixture was allowed to stand overnight at room temperature and the solvent removed by distillation under reduced pressure to give a brown oil. The oil was washed with aqueous sodium metabisulfite and crystallised from ethanol/water to give the title compound as pink platelets (2.0 g), mp 95°-96° C.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH:5]([NH:16][C:17](=[O:20])[CH2:18][Cl:19])[N:6]([C:11]1[N:12]=[CH:13][S:14][CH:15]=1)[C:7](=[O:10])[CH2:8][Cl:9])C.[OH-].[K+]>C(O)C.O>[Cl:19][CH2:18][C:17]([NH:16][CH:5]([C:4]([OH:21])=[O:3])[N:6]([C:11]1[N:12]=[CH:13][S:14][CH:15]=1)[C:7](=[O:10])[CH2:8][Cl:9])=[O:20]
Reactant: CCOC(=O)C(NC(=O)CCl)N(C(=O)CCl)c1cscn1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(CCl)NC(C(=O)O)N(C(=O)CCl)c1cscn1
Yield: 73 %

Procedure:
To a solution of 3.54 g of 2-chloroacetamidothiazol-4-yl N-chloroacetylglycine ethyl ester in 30 ml of ethanol is added dropwise a solution of 1.68 g of potassium hydroxide in 15 ml of water under ice-cooling, followed by the stirring for 15 minutes. Ethanol is distilled under reduced pressure and the residue is made acidic with 10% hydrochloric acid, followed by the extraction with ethyl acetate. The ethyl acetate layer is washed with water and dried. The distillation of ethyl acetate gives 2.38 g of 2-chloroacetamidothiazol-4-yl N-chloroacetylglycine as colorless crystals. Melting point: 184°-186° C.
Reaction SMILES: [F:1][C:2]1([C:10]2[N:14]([CH3:15])[N:13]=[CH:12][C:11]=2[N+:16]([O-:18])=[O:17])[CH2:9][CH2:8][CH:7]2[CH:5]([O:6]2)[CH2:4][CH2:3]1.[Cl-].[NH4+].[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C=O)C.O>[N:21]([CH:7]1[CH2:8][CH2:9][C:2]([F:1])([C:10]2[N:14]([CH3:15])[N:13]=[CH:12][C:11]=2[N+:16]([O-:18])=[O:17])[CH2:3][CH2:4][CH:5]1[OH:6])=[N+:22]=[N-:23]
Reactant: Cn1ncc([N+](=O)[O-])c1C1(F)CCC2OC2CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ncc([N+](=O)[O-])c1C1(F)CCC(O)C(N=[N+]=[N-])CC1
Temperature: 100 °C
Yield: 47.7 %

Procedure:
A solution of 5-(4-fluoro-8-oxabicyclo[5.1.0]octan-4-yl)-1-methyl-4-nitro-1H-pyrazole (260 mg, 1.02 mmol) in DMF/water (10 mL/1 mL) was treated with ammonium chloride (135 mg, 2.55 mmol) and sodium azide (332 mg, 5.1 mmol) and the mixture was heated at 100° C. for 48 hrs. The reaction mixture was extracted with EtOAc (100 mL) and the organic layer was washed with water (7×20 mL), washed with brine (20 mL), separated, dried over MgSO4, and concentrated under reduced pressure. Purification via silica gel column chromatography (40% EtOAc/isohexane) gave 2-azido-5-fluoro-5-(1-methyl-4-nitro-1H-pyrazol-5-yl)cycloheptanol as a white solid (145 mg, 48%). 1H NMR (400 MHz, CDCl3) δ 8.06 and 8.05 (2s, 1H), 4.08 and 4.06 (2s, 3H), 3.83 (dd, J=10.7, 8.2 Hz, 1H), 3.65-3.58 (m, 1H), 2.87-2.55 (m, 2H), 2.33-2.21 (m, 2H), 2.17-1.98 (m, 3H), 1.98-1.84 (m, 2H).
Reaction SMILES: [C@@H:1]12[CH2:8][C:7](=[O:9])[CH2:6][C@@H:5]1[CH2:4][C:3](=[O:10])[CH2:2]2.[N-:11]=[N+]=[N-].[Na+].[OH-].[Na+]>Cl>[CH2:4]1[C@H:5]2[CH2:6][C:7](=[O:9])[CH2:8][C@H:1]2[CH2:2][C:3](=[O:10])[NH:11]1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1C[C@H]2CC(=O)C[C@H]2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C1C[C@@H]2CNC(=O)C[C@@H]2C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 150.7 %

Procedure:
(cis)-Bicyclo[3.3.0]octane-3,7-dione 14c (1.80 g, 13 mmol) was dissolved in 25 mL of concentrated hydrochloric acid in an ice-water bath, added with sodium azide (1.10 g, 16.90 mmol) in batches, then heated to room temperature and stirred for 12 hours. The reaction solution was added dropwise with 20% sodium hydroxide solution to adjust pH to 10 to 11, extracted with dichloromethane (50 mL×3). The combined organic phase was washed with saturated sodium chloride solution (50 mL×3), then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to obtain the title compound (cis)-2,4,4a,5,7,7a-hexahydro-1H-cyclopenta[c]pyridine-3,6-dione 14d (3 g, yield: 100.0%) as a white solid.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[C:27]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:32]=[CH:31][C:30]([C:33](O)=[O:34])=[CH:29][CH:28]=1>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:33]([C:30]3[CH:31]=[CH:32][C:27]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)=[CH:28][CH:29]=3)=[O:34])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1)c1ccc(-c2ccccc2)cc1

Procedure:
The title compound, yellow solid (119 mg, 94%), MS (ISP) m/z=507.3 [(M+H)+], mp 235° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and biphenyl-4-carboxylic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[C:5]2[CH2:13][N:14]1[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[C@@H:16]([CH3:27])[CH2:15]1.CS(O[CH2:33][C:34]1([CH2:37][O:38][Si](C(C)(C)C)(C)C)[CH2:36][CH2:35]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].[CH:52]1([NH:55][C:56](=[O:74])[C:57]2[CH:62]=[C:61](B3OC(C)(C)C(C)(C)O3)[C:60]([CH3:72])=[C:59]([F:73])[CH:58]=2)[CH2:54][CH2:53]1>CN(C=O)C.O>[CH:52]1([NH:55][C:56](=[O:74])[C:57]2[CH:62]=[C:61]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[C:8](=[O:12])[N:7]([CH2:33][C:34]3([CH2:37][OH:38])[CH2:35][CH2:36]3)[CH:6]=[C:5]4[CH2:13][N:14]3[CH2:19][CH2:18][NH:17][C@@H:16]([CH3:27])[CH2:15]3)[C:60]([CH3:72])=[C:59]([F:73])[CH:58]=2)[CH2:53][CH2:54]1
Reactant: CC(C)(C)[Si](C)(C)OCC1(COS(C)(=O)=O)CC1
Reactant: C[C@H]1CN(Cc2c[nH]c(=O)c3ccc(Br)cc23)CCN1C(=O)OC(C)(C)C
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3(CO)CC3)cc(CN3CCN[C@@H](C)C3)c2c1
Temperature: 75 °C
Reaction time: 3 h
Yield: 15.8 %

Procedure:
A solution of tert-butyl (2S)-4-[(6-bromo-1-oxo-1,2-dihydroisoquinolin-4-yl)methyl]-2-methylpiperazine-1-carboxylate (Example 34b, 0.26 g) dissolved in DMF (5 mL) was treated with [1-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopropyl]methyl methanesulfonate (example 34d, 0.351 g) and cesium carbonate (0.582 g) under nitrogen. The resulting mixture was stirred at 75° C. for 3 h. The mixture was treated with N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.266 g) and Pd-118 (0.019 g) before heating at 80° C. for 1 h. The reaction mixture was diluted with water (250 mL), and extracted with ethyl acetate (250 mL). The organic was dried (MgSO4), filtered and evaporated. The crude product was purified (SiO2 chromatography, elution 100% ethyl acetate). Pure fractions of [tert-butyl (2S)-4-[(6-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-2-{[1-(hydroxymethyl)cyclopropyl]methyl}-1-oxo-1,2-dihydroisoquinolin-4-yl)methyl]-2-methylpiperazine-1-carboxylate] were evaporated to dryness. The mixture was treated with trifluoroacetic acid/DCM (1:1, 10 mL) and stirred for 1 h at room temperature. The mixture was evaporated to dryness and the crude material was dissolved in acetonitrile (25 mL) and loaded on to a 10 g SCX cartridge. The impurities were washed through with acetonitrile (50 mL) and discarded. The product was eluted with 1 N methanolic ammonia (100 mL) and evaporated in vacuo. The product was purified by preparative HPLC (XBridge column using a 95-40% gradient of aqueous 0.1% ammonia in acetonitrile as eluent). The fractions were evaporated to afford the title compound (0.050 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([Cl:9])[C:7]=1F.[NH2:14][C:15]1[N:19]=[CH:18][NH:17][N:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[NH2:14][C:15]1[N:16]([C:7]2[C:2]([Cl:1])=[CH:3][C:4]([C:10]([F:13])([F:12])[F:11])=[CH:5][C:6]=2[Cl:9])[N:17]=[CH:18][N:19]=1
Reactant: Nc1nc[nH]n1
Reactant: Fc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 100 °C

Procedure:
To a solution of 3,5-dichloro-4-fluorobenzotrifluoride (1.0 g) in dimethylformamide (5 ml) was added 3-amino-1,2,4-triazole (360 mg) and potassium carbonate (296 mg), the mixture was heated at 100° C. for 2hrs. The reaction was cooled to room temperature, diluted with water (100 mL) and extracted with ether (100 ml). The organic extracts were evaporated to dryness to give the title compounds as pale yellow crystals.
Reaction SMILES: O[CH2:2]/[CH:3]=[CH:4]/[C@:5]1([CH3:29])[S:11][C@H:10]2[N:7]([C:8](=[O:12])[CH2:9]2)[C@H:6]1[C:13]([O:15][CH:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].[F:30][C:31]([F:44])([F:43])[S:32]([O:35]S(C(F)(F)F)(=O)=O)(=[O:34])=[O:33].[N:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>C(Cl)Cl>[F:30][C:31]([F:44])([F:43])[S:32]([O-:35])(=[O:34])=[O:33].[CH:16]([O:15][C:13]([C@H:6]1[C@@:5]([CH:4]=[CH:3][CH2:2][N+:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)([CH3:29])[S:11][C@H:10]2[N:7]1[C:8](=[O:12])[CH2:9]2)=[O:14])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: c1ccncc1
Reactant: C[C@@]1(/C=C/CO)S[C@@H]2CC(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: C[C@@]1(C=CC[n+]2ccccc2)S[C@@H]2CC(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Product: O=S(=O)([O-])C(F)(F)F
Temperature: -40 °C

Procedure:
410 mg (1.0 mmol) of benzhydryl (E)-(2S,3S,5R)-3-(3-hydroxy- propenyl)-3-methyl-7-oxo-4-thia-1-aza-bicyclo[3.2.0]heptane-2-carboxylate were dissolved in 6 ml of methylene chloride, cooled to -40° C. and treated with 250 μl (1.5 mmol) of trifluoromethanesulfonic anhydride. After 5 minutes 200 μl (2.50 mmol) of pyridine were added, the mixture was stirred at the same temperature for a further hour and subsequently the cooling bath was removed. The solvent was removed on a rotary evaporator at room temperature, the reaction mixture was taken up in 20 ml of methylene chloride and washed twice with 10 ml of saturated sodium chloride solution each time. Drying over magnesium sulfate, filtration and concentration on a rotary evaporator were carried out. The residual red resin was oxidized without further purification. Yield: 600 mg (97%) of red resin MS: (M+) 471.6 IR (KBr): 1777, 1743, 1630, 1160, 987 cm-1
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:3]=1[NH:4][C:5]1[S:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[C:6]=1[C:14](OCC)=O.[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C1(OC)C=CC=CC=1>[Ti](Cl)(Cl)(Cl)Cl>[F:24][C:20]1[C:21]([F:23])=[CH:22][C:2]2[N:1]=[C:14]([N:29]3[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]3)[C:6]3[C:7]4[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=4[S:9][C:5]=3[NH:4][C:3]=2[CH:19]=1
Reactant: CCOC(=O)c1c(Nc2cc(F)c(F)cc2N)sc2ccccc12
Reactant: CN1CCNCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: COc1ccccc1
Product: CN1CCN(C2=Nc3cc(F)c(F)cc3Nc3sc4ccccc4c32)CC1

Procedure:
In the same manner as in Example 1 and using ethyl 2-(2-amino-4,5-difluoroanilino)benzo[b]thiophene-3-carboxylate, 1-methylpiperazine, anisole and titanium tetrachloride, 8,9-difluoro-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH2:13])[S:11][CH:12]=2)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:23]([O:26][CH2:27][C:28](Cl)=[O:29])(=[O:25])[CH3:24]>C(Cl)Cl.C(OCC)(=O)C>[C:23]([O:26][CH2:27][C:28]([NH:13][C:10]1[S:11][CH:12]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[N:9]=1)=[O:29])(=[O:25])[CH3:24]
Reactant: Nc1nc(-c2ccc(Br)cc2)cs1
Reactant: CC(=O)OCC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)OCC(=O)Nc1nc(-c2ccc(Br)cc2)cs1
Temperature: 0 °C
Reaction time: 2 h
Yield: 41.7 %

Procedure:
4-(4-Bromophenyl)-1,3-thiazol-2-ylamine (2.00 g, 7.84 mmol) was dissolved in methylene chloride, diisopropylethylamine (1.50 mL, 8.62 mmol) was added and the mixture was cooled to 0° C. Acetoxy acetyl chloride (0.920 mL, 8.62 mmol) was added dropwise, the mixture was stirred for 2 h and then diluted with ethyl acetate. The mixture was washed with NaHCO3, water, brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. Flash chromatography (20% acetone/hexane) followed by recrystallization from acetone/hexane afforded 1.16 g of 2-{[4-(4-bromophenyl)-1,3-thiazol-2-yl]amino}-2-oxoethyl acetate (1.16 g, 42%) as a white solid. HRMS: calcd for C13H, BrN2O3S+H+, 354.97465; found (ESI, [M+H]+), 354.9738. Analytical HPLC: retention time 9.8 min, 210-370 nm the Xterra® RP18 column, 3.5%, 150×4.6 mm 40° C. 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min, 1.2 mL/min 5 μL injection.
Reaction SMILES: O.CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:23]C)C=C4)N(CC2)C1.[CH2:60]([O:62][C:63](=[O:77])[C:64]1[CH:69]=[CH:68][C:67]([NH:70][C:71](=[O:73])[CH3:72])=[C:66](CC=C)[CH:65]=1)[CH3:61].S([O-])([O-])=O.[Na+].[Na+].[C:84]([OH:88])(C)([CH3:86])[CH3:85]>>[CH2:60]([O:62][C:63](=[O:77])[C:64]1[CH:69]=[CH:68][C:67]([NH:70][C:71](=[O:73])[CH3:72])=[C:66]([CH2:85][CH:84]([OH:88])[CH2:86][OH:23])[CH:65]=1)[CH3:61]
Reactant: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Reactant: C=CCc1cc(C(=O)OCC)ccc1NC(C)=O
Reactant: CC(C)(C)O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1ccc(NC(C)=O)c(CC(O)CO)c1
Temperature: 0 °C
Reaction time: 0.1 h
Yield: 65 %

Procedure:
To a solution of 1:1 water and tert-butanol (10 mL), AD-mix-β (Aldrich, 1.4 g) was added and the mixture stirred for 0.1 h. The mixture had two layers; the lower layer was yellow in color. To this mixture, ethyl-4-acetylamino-3-allylbenzoate (9.092 g, 0.00037 mol) was added in one portion and stirred at room temperature for 48 h. The reaction mixture was cooled to 0° C. and sodium sulphite (1.5 g, 0.0119 mol) was added. The reaction was stirred at 0° C. for 0.3 h and then at room temperature for 0.5 h. It was extracted with ethyl acetate (3×15 mL), the combined organic layers were dried over sodium sulphate, filtered, and concentrated. The residue was passed through a column of silica gel eluting first with 1:1 ethyl acetate:hexane to recover the starting material, and then with pure ethyl acetate to give 0.068 g (65%) of ethyl-4-acetylamino-3-(2',3'-dihydroxypropyl)benzoate (isomer B) as a white powder, mp 116°-117° C. The optical rotation of this solid was 0° C. at 589 nm.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][C:16]=1[F:17])[NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[O:5].CNC(N1C[C@H](P(C2CCCCC2)C2CCCCC2)C[C@@H]1CP(C1C=CC=CC=1)C1C=CC=CC=1)=O.C(N(CC)CC)C.[H][H]>CO>[NH2:2][CH2:3][C@@H:4]([C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][C:16]=1[F:17])[NH:9][S:10]([CH3:13])(=[O:11])=[O:12])[OH:5]
Reactant: CS(=O)(=O)Nc1ccc(F)c(C(=O)CN)c1
Reactant: [H][H]
Agent: CNC(=O)N1C[C@H](P(C2CCCCC2)C2CCCCC2)C[C@@H]1CP(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1ccc(F)c([C@@H](O)CN)c1
Yield: 85.7 %

Procedure:
3'-(2-Aminoacetyl)-4'-fluoromethanesulfonanilide hydrochloride (21 g) was suspended in 210 ml of methanol, then a catalyst prepared from 50 mg of (2R,4R)-N-methylcarbamoyl-4-dicyclohexylphosphino-2-diphenylphosphinomethylpyrrolidine and 18 mg of di-μ-chlorobis(cyclooctadiene)dirhodium (I) was added thereto together with 19 mg of triethylamine and the mixture was reduced at 50° C. in an atmosphere of hydrogen of 20 atm. The reaction mixture was concentrated and made into a free base using ion exchange resin (Dowex 50W X2) to give 15.8 g of crude (R)-(-)-3'-(2-amino-1-hydroxyethyl)-4'-fluoromethanesulfonanilide.
Reaction SMILES: [OH:1][C@H:2]([CH2:13][NH:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][C:22]2=[O:27])=[CH:17][CH:16]=1)[CH2:3][NH:4][C:5]([C:7]1[S:8][C:9]([Cl:12])=[CH:10][CH:11]=1)=[O:6].[C:28](N1C=CN=C1)(N1C=CN=C1)=[O:29]>C1(C)C=CC=CC=1.CN1CCCC1=O>[Cl:12][C:9]1[S:8][C:7]([C:5]([NH:4][CH2:3][C@@H:2]2[O:1][C:28](=[O:29])[N:14]([C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][C:22]4=[O:27])=[CH:19][CH:20]=3)[CH2:13]2)=[O:6])=[CH:11][CH:10]=1
Reactant: O=C(NC[C@H](O)CNc1ccc(N2CCOCC2=O)cc1)c1ccc(Cl)s1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN1CCCC1=O
Solvent: Cc1ccccc1
Product: O=C(NC[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1)c1ccc(Cl)s1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
Under an atmosphere of nitrogen to a suspension of 14.85 g of 5-chlorothiophen-2-carboxylic acid-{(R)-2-hydroxy-3-[4-(3-oxomorpholin-4-yl)phenylamino]propyl}amide (MW=409.89; 1 eq.) in 145 mL toluene and 22 mL N-methylpyrrolidone were added 7.13 g (MW=162.15; 1.2 eq.) of 1,1′-carbonyldiimidazol. The reaction mixture was heated to 80° C. After stirring for 30 minutes the mixture was heated to 110° C. and stirred at this temperature for 2 hours. Then the mixture was cooled to 22° C. After stirring for 1 hour at ambient temperature the product was isolated by filtration and washed with 60 mL of toluene and 60 mL of water. The wet product was dried at 30° C. in vacuo to yield 15.99 g (MW=435.89; 1.013 eq.) of the title compound (90% of theory).
Reaction SMILES: Br[CH:2]1[CH2:17][CH2:16][C:5]2=[C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:7][C:8]([S:9][CH3:10])=[C:4]2[C:3]1=O.[C:19]([NH2:22])(=[S:21])[CH3:20]>C(O)C>[CH3:20][C:19]1[S:21][C:2]2[CH2:17][CH2:16][C:5]3=[C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:7][C:8]([S:9][CH3:10])=[C:4]3[C:3]=2[N:22]=1
Reactant: CCOC(=O)c1sc(SC)c2c1CCC(Br)C2=O
Reactant: CC(N)=S
Solvent: CCO
Product: CCOC(=O)c1sc(SC)c2c1CCc1sc(C)nc1-2
Yield: 44.2 %

Procedure:
A mixture of ethyl 5-bromo-4,5,6,7-tetrahydro-3-methylthio-4-oxobenzo[c]thiophene-1-carboxylate (2.09 g), thioacetamide (0.90 g) and ethanol (100 ml) was refluxed under heating for 7 hours, after which it was concentrated under reduced pressure, diluted with water (50 ml) and extracted with ethyl acetate. The organic layer was washed with water and dried (MgSO4), after which the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:19 to 1:9, v/v) to yield ethyl 4,5-dihydro-2-methyl-8-methylthiothieno[3,4-e]benzothiazole-6-carboxylate (0.86 g, 44%), which was then recrystallized from ethyl acetate-hexane. Yellow prisms. Melting point 143-144° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([N+]([O-])=O)[CH:5]=[CH:4][N+:3]=1[O-:12].C([Br:16])(=O)C.C(=O)([O-])[O-].[NH4+].[NH4+]>>[Br:16][C:6]1[CH:5]=[CH:4][N+:3]([O-:12])=[C:2]([CH3:1])[C:7]=1[CH3:8]
Reactant: CC(=O)Br
Reactant: Cc1c([N+](=O)[O-])cc[n+]([O-])c1C
Agent: O=C([O-])[O-]
Agent: [NH4+]
Product: Cc1c(Br)cc[n+]([O-])c1C
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
To 2,3-Dimethyl-4-nitropyridine N-oxide (3.00 g) which had been cooled to 0° C., added was acetyl bromide (18.0 ml), followed by stirring at 50° C. for 20 minutes and then at 75° C. for 15 minutes. The reaction mixture was charged in ice water and neutralized with an aqueous solution of ammonium carbonate. The neutralized solution was separated using methylene chloride. The organic layer was dried over anhydrous sodium sulfate and the filtrate was concentrated, whereby a crudely purified product of 4-bromo-2,3-dimethylpyridine N-oxide was obtained.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[C:5]([Cl:11])=[C:4]([Cl:12])[C:3]=1[Cl:13].S(=O)(=O)(O)[OH:15]>>[OH:1][C:2]1[C:7]([C:8]([NH2:9])=[O:15])=[C:6]([Cl:10])[C:5]([Cl:11])=[C:4]([Cl:12])[C:3]=1[Cl:13]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1c(O)c(Cl)c(Cl)c(Cl)c1Cl
Product: NC(=O)c1c(O)c(Cl)c(Cl)c(Cl)c1Cl
Yield: 97 %

Procedure:
a 10.0 g portion of this hydroxy-tetrachlorobenzonitrile was heated under an inert atmosphere at 130° C. for 15 minutes with 150 ml concentrated sulfuric acid. The product, hydroxytetrachlorobenzamide was readily isolated by filtering the H2O-diluted reaction mixture; yield 97.0%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(N(CC)CC)C.Cl.[Cl:28][C:29]1[C:34]([C:35](Cl)=[O:36])=[CH:33][N:32]=[CH:31][CH:30]=1.O>O1CCCC1>[Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:19]=[CH:18][C:16]([NH:17][C:35](=[O:36])[C:34]3[C:29]([Cl:28])=[CH:30][CH:31]=[N:32][CH:33]=3)=[CH:15][CH:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: O=C(Cl)c1cnccc1Cl
Reactant: Nc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1)c1cnccc1Cl

Procedure:
A solution of 150 mg of 4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)aniline and 116 mg of triethylamine in 5 mL of tetrahydrofuran was stirred with 100 mg of 4-chloronicotinoyl chloride hydrochloride for about 50 minutes, and after addition of water, the precipitated crystals were recovered by filtration. The recovered crystals were washed with ether and dried to 106 mg of N-(4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenyl)-4-chloronicotinamide having a melting point of 178-180° C. (decomposition).