Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][C:7](OC)=[O:8].CO.[OH-].[Li+]>O1CCCC1>[O:8]=[C:7]1[NH:1][CH2:2][CH2:3][CH2:4][N:5]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1
Reactant: COC(=O)CN(CCCN)C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCNC(=O)C1
Reaction time: 6 h

Procedure:
To a solution of methyl N-(3-aminopropyl)-N-(tert-butoxycarbonyl)glycinate (10.2 g) in tetrahydrofuran (THP)/methanol (2/1, 300 mL) was added 1M aqueous lithium hydroxide solution (60 mL). The resultant mixture was stirred at room temperature overnight. An additional 20 ML of 1M aqueous lithium hydroxide solution was added and the mixture was stirred for 6 h. Solvent was removed under reduced pressure, and the residue was dissolved in 50 mL of methanol and 200 mL of toluene and concentrated in vacuo. To the residue in dichloromethane (300 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC, 9.6 g) and 1-hydroxybenzotriazole (HOBT, 6.8 g). The mixture was stirred at room temperature for three days, then treated with saturated aqueous ammonium chloride solution and extracted with three portions of ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography (silica gel, eluting with 4 to 5% [10:1 methanol/aqueous ammonium hydroxide] in dichloromethane) to yield the title compound. MS 215.0 (M+1).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:14])[CH2:12][C:11](=[O:13])[NH:10][NH:9]2)=[CH:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([O-])=[CH:18][CH:17]=1.[Na+]>CN(C=O)C>[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3([CH3:14])[CH2:12][C:11](=[O:13])[NH:10][NH:9]3)=[CH:4][CH:3]=2)=[CH:18][CH:17]=1
Reactant: CC1(c2ccc(I)cc2)CC(=O)NN1
Reactant: [O-]c1ccc(F)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(c2ccc(-c3ccc(F)cc3)cc2)CC(=O)NN1

Procedure:
A solution of 30.2 g of 3-p-iodophenyl-3-methyl-pyrazolidin-5-one (obtainable from p-iodoacetophenone via 3-hydroxy-3-p-iodophenyl-butyric acid ethyl ester and 3-p-iodophenyl-2-butenoic acid ethyl ester) and 13.4 g of sodium p-fluorophenolate in 200 ml of DMF is warmed for 8 hours at 130°. Working up in the usual manner gives 3-(4'-fluoro-4-biphenylyl)-3-methyl-pyrazolidin-5-one, m.p. 194°-196°.
Reaction SMILES: Br[C:2]1[C:17]([O:18][CH2:19][C@@H:20]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:16][C:5]2[N:6]([CH3:15])[C:7](=[O:14])[C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[N:10][CH:9]=3.[CH:33]1(B(O)O)[CH2:35][CH2:34]1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.O.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>[CH:33]1([C:2]2[C:17]([O:18][CH2:19][C@@H:20]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:29])[CH3:30])[CH2:21][CH:22]([CH3:23])[CH3:24])=[CH:16][C:5]3[N:6]([CH3:15])[C:7](=[O:14])[C:8]4[C:13]([C:4]=3[CH:3]=2)=[CH:12][CH:11]=[N:10][CH:9]=4)[CH2:35][CH2:34]1
Reactant: CC(C)C[C@@H](COc1cc2c(cc1Br)c1ccncc1c(=O)n2C)NC(=O)OC(C)(C)C
Reactant: OB(O)C1CC1
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: [Cs+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)C[C@@H](COc1cc2c(cc1C1CC1)c1ccncc1c(=O)n2C)NC(=O)OC(C)(C)C
Temperature: 90 °C
Yield: 50.5 %

Procedure:
A mixture of (S)-tert-butyl (1-((9-bromo-6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (150 mg, 0.297 mmol) (as prepared in Ex. 3, Part A), cyclopropylboronic acid (28.1 mg, 0.327 mmol), tetrakis(triphenylphosphine)palladium (17.2 mg, 0.015 mmol) and Cs2CO3 (291 mg, 0.892 mmol) in toluene (5 mL) and water (0.43 mL) mixture was purged with nitrogen for 5 min then heated at 90° C. overnight (16 h). After cooling, toluene was removed under reduced pressure and the product was extracted with ethyl acetate (20 mL). The organic phase was washed with brine (2×20 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (EtOAc-hexane) to afford (S)-tert-butyl (1-((9-cyclopropyl-6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (70 mg, 0.150 mmol, 51% yield) as an off-white gummy solid. LC/MS (ESI) m/z 466.4 [(M+H)+, calcd for C27H36N3O4 466.3]; LC/MS retention time (method E): tR=1.19 min.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[C:5]([Cl:17])=[CH:4][N:3]=1.[Cl:18][C:19]1[C:20]([N:28]2[CH2:33][CH2:32][CH:31]([N:34]3[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]3)[CH2:30][CH2:29]2)=[CH:21][C:22]([O:26][CH3:27])=[C:23]([CH:25]=1)[NH2:24]>>[Cl:17][C:5]1[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)=[N:7][C:2]([NH:24][C:23]2[CH:25]=[C:19]([Cl:18])[C:20]([N:28]3[CH2:29][CH2:30][CH:31]([N:34]4[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]4)[CH2:32][CH2:33]3)=[CH:21][C:22]=2[O:26][CH3:27])=[N:3][CH:4]=1
Reactant: Clc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Reactant: COc1cc(N2CCC(N3CCN(C)CC3)CC2)c(Cl)cc1N
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)c(Cl)cc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1

Procedure:
Starting materials: 3-(2,5-dichloropyrimidin-4-yl)-1H-indole (INTERMEDIATE 2) and 5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (INTERMEDIATE 55).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:32])[CH2:4][NH:5][C:6](=[O:31])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:17][C:16]([C:22]3[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=3)([C:18]([F:21])([F:20])[F:19])[O:15][N:14]=2)=[CH:9][C:8]=1[CH3:30].N1C=CC=CC=1.[S:39](Cl)(Cl)=[O:40].Cl>ClCCl>[Cl:28][C:26]1[CH:27]=[C:22]([C:16]2([C:18]([F:20])([F:21])[F:19])[O:15][N:14]=[C:13]([C:10]3[CH:11]=[CH:12][C:7]([C:6]([NH:5][CH2:4][CH:3]4[O:32][S:39](=[O:40])[NH:1][CH2:2]4)=[O:31])=[C:8]([CH3:30])[CH:9]=3)[CH2:17]2)[CH:23]=[C:24]([Cl:29])[CH:25]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCC(O)CN
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCC1CNS(=O)O1
Reaction time: 4 h

Procedure:
A solution of N-(3-amino-2-hydroxy-propyl)-4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzamide (0.2 g) in dichloromethane (10 ml) was cooled to 0° C., treated with pyridine (0.32 ml) and thionyl chloride (0.06 ml), and stirred for 4 hours. The mixture was diluted with dichloromethane (50 ml), neutralized with 2N hydrochloric acid, and washed with water (50 ml). The organic layer was separated, dried over sodium sulfate and concentrated. Purification by chromatography on silica gel (eluent hexane/ethyl acetate 40:60) gave the title compound (20 mg). LCMS (Method G) 3.88 min, (M−H)− 534. 1HNMR (CDCl3, 400 MHz): 7.45-7.52 (m, 6H), 6.50 (m, 1H), 4.05 (d, 1H), 3.98 (m, 1H), 3.72 (d, 1H), 3.62 (m, 1H), 3.51 (m, 3H), 2.46 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:32])[C:9]2[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:11][C:10]=2[O:24]CC2C=CC=CC=2)=[CH:3][CH:2]=1.CN1CCN(C)C1=O.[H][H]>[C+4].[OH-].[Pd+2].[OH-].[OH-].[OH-].[OH-].[OH-].C(O)C>[N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:32])[C:9]2[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])=[CH:11][C:10]=2[OH:24])=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)Nc2ccncc2)c(OCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [C+4]
Agent: [OH-]
Solvent: CN1CCN(C)C1=O
Solvent: CCO
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)Nc2ccncc2)c(O)c1
Yield: 69.1 %

Procedure:
N-(4-Pyridyl)-2benzyloxy-4-tert-butoxycarbonylaminomethylbenzamide (3.38 g) was subjected to catalytic reduction using 10% palladium hydroxide carbon (1 g) in a solution of ethanol (10 ml) and dimethylimidazolidinone (70 ml) in a stream of hydrogen. After the reaction, the catalyst was removed by filtration, and the mixture was concentrated under reduced pressure to give 1.85 g of N-(4-pyridyl)-4-tert-butoxycarbonylaminomethyl-2-hydroxybenzamide.
Reaction SMILES: [NH2:1][CH:2]1[CH:6]([O:7][CH2:8][C:9]([F:12])([F:11])[F:10])[CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.C(O)C.[ClH:23]>O>[ClH:23].[ClH:23].[NH2:1][CH:2]1[CH:6]([O:7][CH2:8][C:9]([F:12])([F:10])[F:11])[CH2:5][NH:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC(N)C(OCC(F)(F)F)C1
Agent: Cl
Solvent: CCO
Solvent: O
Product: NC1CNCC1OCC(F)(F)F
Reaction time: 8 h

Procedure:
A mixture of 1.61 g (0.006 mole) of 3-amino-1-t-butoxycarbonyl-4-(2,2,2-trifluoroethoxy)pyrrolidine [prepared as described in step (b) above], 30 ml of ethanol, 2 ml of concentrated aqueous hydrochloric acid and 4 ml of water was allowed to stand overnight at room temperature after which it was evaporated to dryness under reduced pressure, to afford 1.60 g of 3-amino-4-(2,2,2-trifluoroethoxy)pyrrolidine dihydrochloride as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C@@H:17]([CH3:22])[C:18]([CH3:21])([OH:20])[CH3:19])[N:11]=2)=[CH:5][CH:4]=1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]=[C:31]=[O:32]>ClC(Cl)C.C(Cl)Cl>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][C:31](=[O:32])[N:9]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C@@H:17]([CH3:22])[C:18]([OH:20])([CH3:21])[CH3:19])[N:11]=1)[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1
Reactant: COc1ccc(Nc2ccnc(N[C@@H](C)C(C)(C)O)n2)cc1
Reactant: O=C=Nc1ccccc1Cl
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: COc1ccc(N(C(=O)Nc2ccccc2Cl)c2ccnc(N[C@@H](C)C(C)(C)O)n2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (3S)-3-[4-(4-methoxy-phenylamino)pyrimidin-2-ylamino]-2-methyl-butan-2-ol, 2, (129 mg, 0.427 mmol) in dichloroethane (3 mL) is added 2-chlorophenyl isocyanate (57 μL, 0.469 mmol) dropwise via syringe. The reaction is stirred at room temperature for 2 hours. Additional 2-chloroisocyanate (57 μL, 0.469 mmol) is added and the reaction mixture stirred at room temperature for 16 hours after which the reaction mixture is diluted with CH2Cl2 (30 mL), and washed with saturated aqueous sodium bicarbonate solution (20 mL). The aqueous layer is extracted with CH2Cl2 (20 mL) and the combined organic layers washed with water and brine and dried over sodium sulfate, filtered and concentrated in vacuo to afford a crude residue which is purified over silica (5% to 20% Et2O/CH2Cl2 to 10% MeOH/CH2Cl2) to afford the desired product as a white solid. 1H NMR (300 MHz, CDCl3) δ 13.04 (br s, 1H), 8.41 (d, J=8.0 Hz, 1H), 7.92 (d, J=6.0 Hz, 1H), 7.37-7.16 (m, 4H), 7.17 (d, J=8.9 Hz, 2H), 7.02 (d, J=8.9 Hz, 2H), 5.56 (m, 2H), 4.05 (m, 1H), 3.85 (s, 3H), 1.30 (s, 3H), 1.25 (d, J=6.9 Hz, 3H), 1.23 (s, 3H); MS (ESI) m/z 456 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2/[C:10](=[CH:18]/[C:19]2[NH:20][C:21]([CH3:27])=[CH:22][C:23]=2[C:24](O)=[O:25])/[C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH:28]1([NH:31][C:32]([C@@H:34]2[CH2:39][CH2:38][CH2:37][NH:36][CH2:35]2)=[O:33])[CH2:30][CH2:29]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[CH:28]1([NH:31][C:32]([C@@H:34]2[CH2:39][CH2:38][CH2:37][N:36]([C:24]([C:23]3[CH:22]=[C:21]([CH3:27])[NH:20][C:19]=3/[CH:18]=[C:10]3\[C:11](=[O:17])[NH:12][C:13]4[C:9]\3=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[CH:16]=[CH:15][CH:14]=4)=[O:25])[CH2:35]2)=[O:33])[CH2:30][CH2:29]1
Reactant: O=C(NC1CC1)[C@@H]1CCCNC1
Reactant: Cc1cc(C(=O)O)c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4)c32)[nH]1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1cc(C(=O)N2CCC[C@@H](C(=O)NC3CC3)C2)c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4)c32)[nH]1
Yield: 37.1 %

Procedure:
2-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (108 mg, 0.3 mmol) was coupled with (R)-piperidine-3-carboxylic acid cyclopropylamide (69.3 mg, 1.5 eq.), HOBt (40.5 mg, 1 eq.), EDC (86 mg, 1.5 eq.) and TEA (0.06 mL) in DMF (1 mL) to give 57 mg (37%) of the titled compound.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[CH3:8][O:9][C:10](=[O:19])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([NH2:18])[CH:12]=1.CCN(CC)CC>C(Cl)Cl>[CH3:8][O:9][C:10](=[O:19])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([NH:18][C:5](=[O:6])[CH2:4][CH2:3][CH2:2][Cl:1])[CH:12]=1
Reactant: COC(=O)c1ccc(Cl)c(N)c1
Reactant: O=C(Cl)CCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(Cl)c(NC(=O)CCCCl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.4 %

Procedure:
4-Chlorobutyryl chloride (2.82 g, 20 mmol, 2.0 equiv) in CH2Cl2 (5 ml) was added over 2 min to a stirred solution of 3-amino-4-chloro-benzoic acid methyl ester (D27c) (1.66 g, 10 mmol, 1 equiv) and NEt3 (2.22 g, 22 mmol, 2.2 equiv) in CH2Cl2 (40 ml). The resulting mixture was stirred for 1 h at room temperature then washed with 2N aqueous HCl solution, dried over MgSO4 and concentrated in vacuo. The residue was triturated with CH2Cl2 to give 4-chloro-3-(4-chloro-butanoylamino)-benzoic acid methyl ester (D28c) (1.81 g, 48%) as a pale pink solid.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1>ClCCl>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([S:19]([C:20]([F:23])([F:21])[F:22])=[O:9])=[CH:17][CH:18]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: FC(F)(F)Sc1ccc(Br)cc1
Solvent: ClCCl
Product: O=S(c1ccc(Br)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 47.6 %

Procedure:
Meta-Chloroperbenzoic acid (1.2 g, 11.7 mmol) was added to a solution of (4-bromophenyl)(trifluoromethyl)sulfane (1.7 g, 6.61 mmol) in dichloromethane (30 mL). After stirring at rt for 12 h, the reaction mixture was poured into ice-water and extracted with EtOAc (3×60 mL). The combined organic layers were dried (MgSO4), concentrated, and purified by column chromatography on silica gel (EtOAc/petroleum ether=0:100 to 1:50) to give 859 mg of 1-bromo-4-((trifluoromethyl)sulfinyl)benzene as a white solid. 1H NMR (CDCl3, 400 MHz): δ 7.79-7.75 (m, 2H), 7.66 (d, 2H). 13C NMR (CDCl3, 100 MHz): δ 134.8, 133.0, 128.7, 127.4, 124.4 (q, J=330 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH3:29])[C:10]([C:12]1[S:21][C:20]2[C:19]3[CH:22]=[C:23]([C:26](O)=[O:27])[CH:24]=[CH:25][C:18]=3[O:17][CH2:16][CH2:15][C:14]=2[CH:13]=1)=[O:11].Cl.[CH3:31][NH:32][CH3:33]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH3:29])[C:10]([C:12]1[S:21][C:20]2[C:19]3[CH:22]=[C:23]([C:26]([N:32]([CH3:33])[CH3:31])=[O:27])[CH:24]=[CH:25][C:18]=3[O:17][CH2:16][CH2:15][C:14]=2[CH:13]=1)=[O:11]
Reactant: CNC
Reactant: CN(C(=O)c1cc2c(s1)-c1cc(C(=O)O)ccc1OCC2)c1ccc(Cl)cc1Cl
Agent: Cl
Product: CN(C)C(=O)c1ccc2c(c1)-c1sc(C(=O)N(C)c3ccc(Cl)cc3Cl)cc1CCO2

Procedure:
2-[(2,4-Dichloro-phenyl)-methyl-carbamoyl]-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-9-carboxylic acid and dimethylamine hydrochloride salt were reacted in the general amide coupling procedure to give 288. NMR: (CDCl3): 2.73-3.04 (6 H, br m), 2.95-3.00 (2 H, m), 3.29 (3 H, s, Me), 4.17-4.20 (2 H, m), 6.79 (1 H, s, Ar), 6.93 (1 H, d, J 8.3, Ar), 7.19-7.29 (3 H, m, Ar) and 7.47-7.48 (2 H, m, Ar). MS: (ESI+) MH+=475.04
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:11][N:10]([CH:12]2[CH2:17][CH2:16][CH:15]([C:18]3[N:22]=[C:21]([C:23]([Cl:26])([Cl:25])[Cl:24])[O:20][N:19]=3)[CH2:14][CH2:13]2)[CH2:9]1)(C)(C)C.[C:28]([OH:34])([C:30]([F:33])([F:32])[F:31])=[O:29]>C(Cl)Cl>[Cl:25][C:23]([Cl:24])([Cl:26])[C:21]1[O:20][N:19]=[C:18]([CH:15]2[CH2:16][CH2:17][CH:12]([N:10]3[CH2:11][CH:8]([NH2:7])[CH2:9]3)[CH2:13][CH2:14]2)[N:22]=1.[C:28]([OH:34])([C:30]([F:33])([F:32])[F:31])=[O:29]
Reactant: CC(C)(C)OC(=O)NC1CN(C2CCC(c3noc(C(Cl)(Cl)Cl)n3)CC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CN(C2CCC(c3noc(C(Cl)(Cl)Cl)n3)CC2)C1
Reaction time: 2 h

Procedure:
{1-[4-(5-Trichloromethyl-[1,2,4]oxadiazol-3-yl)-cyclohexyl]-azetidin-3-yl}-carbamic acid tert-butyl ester (as prepared in the previous step) was treated with 1:1 ratio of DCM and TFA at room temperature. After 2 hours, the solvent was removed in vacuo and the residue was dried overnight to give the title compound as TFA salt (colorless oil).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](C[C@H]4C[O:21]C(=O)N4)[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.Cl.N(C1C=CC(C[C@@H:32]2[CH2:36][O:35][C:34](=[O:37])[NH:33]2)=CC=1)N.O.CN1CC=C(C2C3C(=CC=C(C[C@@H]4COC(=O)N4)C=3)NC=2)CC1.Cl>>[OH2:21].[CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C@@H:32]4[CH2:36][O:35][C:34](=[O:37])[NH:33]4)[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CN1CC=C(c2c[nH]c3ccc(C[C@H]4COC(=O)N4)cc23)CC1
Reactant: NNc1ccc(C[C@@H]2COC(=O)N2)cc1
Agent: CN1CC=C(c2c[nH]c3ccc(C[C@@H]4COC(=O)N4)cc23)CC1
Agent: Cl
Solvent: O
Product: CN1CC=C(c2c[nH]c3ccc([C@@H]4COC(=O)N4)cc23)CC1

Procedure:
By steps analogous to steps (a) to (c) of Synthetic Example 14, the product from step (a) was converted to (R)-3-(1-methyl -1,2,3,6-tetrahydro-4-pyridyl)-5-(2-oxo-1,3-oxazolidin-4-ylmethyl) -1H-indole hydrate, mp 229°-231° C., [α]D18 +24.9° (c=0.5, IN aqu. HCl). Elemental analysis and 1H NMR were consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([SH:31])([C:27]([F:30])([F:29])[F:28])[CH2:10][C:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([NH:19][CH:20]3[CH2:23][S:22][CH2:21]3)=[O:18])=[C:15]([CH3:26])[CH:14]=2)=O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH2:32]OS(O)(=O)=O.[OH-].[K+]>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:27]([F:30])([F:29])[F:28])[S:31][N:32]=[C:11]([C:13]3[CH:25]=[CH:24][C:16]([C:17]([NH:19][CH:20]4[CH2:23][S:22][CH2:21]4)=[O:18])=[C:15]([CH3:26])[CH:14]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1cc(C(=O)CC(S)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)NC1CSC1
Reactant: NOS(=O)(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C2=NSC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NC1CSC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-[3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-3-mercapto-butyryl]-2-methyl-N-thietan-3-yl-benzamide (493 mg) dissolved in a minimum amount of tetrahydrofuran then was added Hydroxylamine-O-sulfonic acid (2 equiv.). Then a solution of potassium hydroxide (5.6 equiv.) in water (19 mL) was added dropwise. After stirring at room temperature for 30 minutes, the mixture was quenched with a solution of hydrochloric acid (1N), extracted with ethyl acetate and washed with brine. The collected organic phases were dried over magnesium sulfate, filtered and the filtrate was evaporated under vacuo. The crude mixture was then redissolved in a minimum amount of tetrahydrofuran then was added Hydroxylamine-O-sulfonic acid (2 equiv.) Then a solution of potassium hydroxide (5.6 equiv.) in water (19 mL) was added dropwise. After stirring at room temperature for 30 minutes, the mixture was quenched with a solution of hydrochloric acid (1N), extracted with ethyl acetate and washed with brine. The collected organic phases were dried over magnesium sulfate, filtered and the filtrate was evaporated under vacuo. The residue was purified by chromatography on silica gel (eluent: cyclohexane/dichloromethane) to give 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isothiazol-3-yl]-2-methyl-N-thietan-3-yl-benzamide (128 mg)
Reaction SMILES: [Cl:1][C:2]1[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[SH:15].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>O.[OH-].[Na+]>[CH2:16]([S:15][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])[C:2]=1[Cl:1])[C:6]([OH:8])=[O:7])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc(S)c1Cl
Reactant: BrCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NS(=O)(=O)c1cc(C(=O)O)cc(SCc2ccccc2)c1Cl
Reaction time: 18 h

Procedure:
4-Chloro-3-mercapto-5-sulfamylbenzoic acid (0.27 g) is dissolved in water (25 ml) by addition of 1 N sodium hydroxide until pH 8. Benzyl bromide (0.15) is added and the reaction mixture stirred for 18 hours. Addition of 4 N hydrochloric acid until pH 1.5 precipitates a crude material which is collected by filtration, washed with water, and recrystallized from aqueous ethanol to yield 3-benzylthio-4-chloro-5-sulfamylbenzoic acid with a melting point of 241° - 242.5°C.
Reaction SMILES: [S:1]1(=[O:9])(=[O:8])[CH2:6][CH2:5][CH2:4][CH:3]([OH:7])[CH2:2]1.CC(C)=O.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>C(O)(C)C>[S:1]1(=[O:9])(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1
Reactant: O=S1(=O)CCCC(O)C1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: CC(C)=O
Product: O=C1CCCS(=O)(=O)C1
Yield: 67.5 %

Procedure:
To a solution of tetrahydrothiopyran-3-ol-1,1-dioxide (7.5 g, 0.05 moles) and acetone (150 mL) was slowly added enough Jones reagent to maintain a brown color for at least 10 minutes without need for additional reagent. The excess reagent was reduced by addition of isopropanol (5 mL). The mixture was filtered through anhydrous magnesium sulfate and the chromium salts were washed 3× with acetone. The solvent was removed in vacuo to give a solid which was triturated with ethanol. The resulting crystals were isolated by filtration and rinsed 3× with diethyl ether. After drying, 5.0 g of product was obtained. H' NMR CDCl3 4.0 (singlet, 2H) 3.3 (triplet, 2H) 2.6 (triplet, 2H) 2.3 (multiplet, 2H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17].[CH2:20]([C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH:34]=[O:35])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>O1CCCC1>[CH3:13][O:14][CH:15]([CH:34]([OH:35])[C:33]1[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:16]([O:18][CH3:19])=[O:17]
Reactant: CCCCCCCCCCCCc1ccccc1C=O
Reactant: COCC(=O)OC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCCCCCCCCCCc1ccccc1C(O)C(OC)C(=O)OC
Reaction time: 0.25 h

Procedure:
To a solution of di-i-propylamine (0.77 ml, 5 mmoles) in tetrahydrofuran (10 ml) at -78° C. was added n-butyl lithium (2.1 ml, 5.5 mmoles) under argon atmosphere. After 15 minutes, methyl methoxyacetate (0.52 g, 5 mmoles) in tetrahydrofuran (2 ml) was added dropwise, with stirring. The resulting enolate solution was stirred at -78° C. for 45 minutes. A solution of 2-dodecylbenzaldehyde (1.65 g, 6 mmoles) in tetrahydrofuran (2 ml) was added. The resulting light-blue mixture became a suspension after 1.5 hours. The reaction mixture was quenched with saturated ammonium chloride solution, diluted with ether and ice-water. The aqueous phase was extracted with ether. The combined organic extract was washed with saturated sodium chloride solution, dried over magnesium sulfate, and evaporated to give the product, which was purified by flash column chromatography (silica, 15% ethyl acetate/hexane). The fractions were pooled to give 620 mg (33%).
Reaction SMILES: [CH:1]1([CH2:6][C:7](Cl)=[O:8])[CH2:5]CC[CH2:2]1.[NH2:10][C:11]1[S:12][C:13]([C:16]([O:18]C)=[O:17])=[CH:14][N:15]=1.NC1C=CC(C(OC)=O)=CC=1>>[CH3:5][CH:1]([CH3:2])[CH2:6][C:7]([NH:10][C:11]1[S:12][C:13]([C:16]([OH:18])=[O:17])=[CH:14][N:15]=1)=[O:8]
Reactant: COC(=O)c1cnc(N)s1
Reactant: O=C(Cl)CC1CCCC1
Agent: COC(=O)c1ccc(N)cc1
Product: CC(C)CC(=O)Nc1ncc(C(=O)O)s1

Procedure:
The title compound was prepared as described in Example 52A, substituting 3-methylbutanoyl chloride for 2-cyclopentylacetyl chloride and methyl 2-aminothiazole-5-carboxylate for methyl 4-aminobenzoate.