Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(C)C)(=O)C.[Si:8]([O:15][C:16]1[C:17]([CH3:26])=[C:18]([CH:23]=[CH:24][CH:25]=1)[C:19]([O:21][CH3:22])=[O:20])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].C1(O)C=CC=CC=1.[Br:34]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>>[Br:34][CH2:26][C:17]1[C:16]([O:15][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:9])[CH3:10])=[CH:25][CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)c1cccc(O[Si](C)(C)C(C)(C)C)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Oc1ccccc1
Solvent: CC(=O)OC(C)C
Product: COC(=O)c1cccc(O[Si](C)(C)C(C)(C)C)c1CBr
Temperature: 70 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
The isopropyl acetate solution of methyl 3-((tert-butyldimethylsilyl)oxy)-2-methylbenzoate (157 g, 560 mmol, from step 2, with an amount of residue free phenol≦0.2%) was added to a 3 liter jacketed bottom drop reactor. Additional isopropyl acetate was added and the mixture was distilled under vacuum at 40 to 55° C., if necessary, to bring total volume to about 9× (1410 mL, KF≦0.05%). 1-Bromopyrrolidine-2,5-dione (NBS, 103.6 g, 580 mmol, 0.66×) and 2,2′-(diazene-1,2-diyl)bis(2-methylpropanenitrile) (AIBN, 1.9 g, 11 mmol, 0.012×) were added to the solution. The reaction mixture was heated to 70° C. over at least 2 hours and stirred at 70° C. for 2 hours. The color changed from orange to yellow. If conversion was less than 95%, additional 0.05 molar equiv. of NBS was added and the mixture was stirred at 70° C. for 1 hour. The process was repeated, in necessary, until conversion reached 95%. The mixture was cooled to 20° C. and held at 20° C. for at least 1 hour. The solid (succinimide) was filtered and washed with isopropyl acetate (75 mL, 0.5×). The filtrate was washed with solution of sodium sulfite (157 g, 1×) in water (1413 mL, 9×), followed by water (315 mL, 2×). The organic layer was distilled under vacuum at 30 to 40° C. to ˜2× volume. Additional isopropyl acetate (315 mL, 2×) was added and distilled back to 2× volume, if necessary, until KF was no more than 0.1%. Then the organic layer was distilled at 30 to 40° C. to give methyl 2-(bromomethyl)-3-((tert-butyldimethylsilyl)oxy)benzoate as an oil (expected 180 g, 90% yield); 1H NMR (DMSO-d6, 300 MHz) δ 7.47 (dd, J=7.8, 1.2 Hz, 1H), 7.37 (t, J=8.1 Hz, 1H), 7.15 (dd, J=8.1, 1.2 Hz, 1H), 4.96 (s, 2H), 3.86 (s, 3H), 1.03 (s, 9H), 0.30 (s, 6H) ppm.
Reaction SMILES: O[CH2:2][C@H:3]1[O:5][C@H:4]1[C@H:6]([O:15][CH2:16][O:17][CH3:18])[CH2:7][C:8](=[CH2:14])[C:9]([O:11][CH2:12]C)=[O:10].[C:19]([O-])([O-])=O.[K+].[K+].C(C(CC)C(=O)C(P(=O)([O-])[O-])=[N+]=[N-])C>CS(C)=O.CO.C(OCC)C>[C:2]([C@H:3]1[O:5][C@H:4]1[C@H:6]([O:15][CH2:16][O:17][CH3:18])[CH2:7][C:8](=[CH2:14])[C:9]([O:11][CH3:12])=[O:10])#[CH:19]
Reactant: C=C(C[C@@H](OCOC)[C@@H]1O[C@@H]1CO)C(=O)OCC
Reactant: O=C([O-])[O-]
Agent: CCC(CC)C(=O)C(=[N+]=[N-])P(=O)([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CO
Solvent: CCOCC
Product: C#C[C@H]1O[C@H]1[C@@H](CC(=C)C(=O)OC)OCOC
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
To a solution of epoxy alcohol 12 (1.4 g, 4 mmol) in DMSO (5 mL) in a round-bottomed flask was added IBX (1.68 g, 6 mmol) in one portion and the reaction mixture was stirred for 1 h at ambient temperature (25° C.). The reaction mixture was quenched with diethylether (5 mL), H2O (0.5 mL) and filtered through a pad of celite. The residue was repeatedly washed with diethyl ether (50 mL). The filtrate was washed with H2O, brine, dried (Na2SO4) and concentrated to give the crude aldehyde, which was pure enough and used in the next step without further purification. To a solution of crude aldehyde and K2CO3 (900 mg, 8 mmol) in 20 mL dry MeOH and diethyl-1-diazo-2-oxopropylphosphonate (1.26 g, 6 mmol) were added under continuous stirring till completion of the reaction was indicated by TLC (2 h) (25° C.). The reaction mixture was diluted with diethylether (100 mL), washed with aq. solution of NaHCO3 and dried over Na2SO4. Evaporation of solvent yielded analytically pure terminal alkyne 13
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:17]([F:25])[CH:16]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[CH:6][N:7]=1.CO.[C:28]1([CH2:34][NH2:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[BH4-].[Na+]>C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:17]([F:25])[CH:16]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([NH:35][CH2:34][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:10][CH2:9]2)=[CH:6][N:7]=1
Reactant: NCc1ccccc1
Reactant: COC(=O)c1ccc(-c2nc(C3CCC(=O)CC3)cnc2N)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(-c2nc(C3CCC(NCc4ccccc4)CC3)cnc2N)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.7 %

Procedure:
To methyl 4-(3-amino-6-(4-oxocyclohexyl)pyrazin-2-yl)-2-fluorobenzoate (300 mg, 0.874 mmol) was added MeOH (4 mL), phenylmethanamine (112 mg, 1.048 mmol) and last dry 4 Å molecular sieves. The reaction was stirred at room temperature for 16 h. Then NaBH4 (165 mg, 4.37 mmol) was added and stirred at room temperature for 2 h followed by LCMS. To the reaction was added 150 mL of ethyl acetate, washed with saturated sodium bicarbonate, water (2×), saturated salt solution, dried over sodium sulfate, filtered and concentrated to residue to give 352 mg of the desired product in 2:1 trans to cis ratio, used as is (93%). LCMS (m/z): 435.3 (MH+), 0.68 min and 0.72 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[F:17][C:18]1[CH:25]=[C:24]([OH:26])[CH:23]=[CH:22][C:19]=1[C:20]#[N:21]>CC(C)=O>[F:17][C:18]1[CH:25]=[C:24]([O:26][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:23]=[CH:22][C:19]=1[C:20]#[N:21]
Reactant: N#Cc1ccc(O)cc1F
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(COc2ccc(C#N)c(F)c2)cc1
Temperature: 25 °C
Yield: 93.6 %

Procedure:
4-Methoxybenzyl chloride (5.0 g) and potassium carbonate (8.3 g) were added to an acetone (0.5 L) solution of 2-fluoro-4-hydroxybenzonitrile (4.1 g), and stirred with heating under reflux for 15 hours. After cooled to room temperature, the reaction solution was evaporated under reduced pressure, water (50 mL) was added to the residue, extracted with ethyl acetate, dried with sodium sulfate and concentrated under reduced pressure. The crude product was purified through silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a white solid (7.2 g).
Reaction SMILES: C1(CC(Cl)=O)C=CC=CC=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[O:19][C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][CH:21]=1)[NH2:15].[C:34]1([CH2:40][C:41]([N:43]=[C:44]=[S:45])=[O:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1(C)C=CC=CC=1.C(O)C>[C:34]1([CH2:40][C:41]([N:43]=[C:44]=[S:45])=[O:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[Cl:11][C:12]1[CH:13]=[C:14]([NH:15][C:44]([NH:43][C:41](=[O:42])[CH2:40][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[S:45])[CH:16]=[CH:17][C:18]=1[O:19][C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: O=C(Cc1ccccc1)N=C=S
Agent: O=C(Cl)Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
2-Phenylethanoyl isothiocyanate was prepared using commercially available 2-phenylethanoyl chloride (80 mg) as a starting compound according to the description of the literature. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2-phenylethanoyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (41 mg, yield 53%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]([NH:26][C@H:27]([C:34]([NH:36]N)=[O:35])[CH2:28][C:29]1[N:33]=[CH:32][NH:31][CH:30]=1)=[O:25])[CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(N[C@@H:46]([CH2:60][CH:61]([CH3:63])[CH3:62])[C@@H:47]([OH:59])[CH2:48][C:49]([O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:50])=O)(C)(C)C>>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]([NH:26][C@H:27]([C:34]([NH:36][C@@H:46]([CH2:60][CH:61]([CH3:63])[CH3:62])[C@@H:47]([OH:59])[CH2:48][C:49]([O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:50])=[O:35])[CH2:28][C:29]1[N:33]=[CH:32][NH:31][CH:30]=1)=[O:25])[CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CC(=O)OCc1ccccc1
Reactant: NNC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)OCc1ccccc1
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)OCc1ccccc1)[C@@H](O)CC(=O)OCc1ccccc1
Yield: 26.8 %

Procedure:
The procedure described in Example 1(c) was repeated, but using 300 mg (0.6 mmole) of N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanyl-L-histidine hydrazide and 180 mg of benzyl 4(S)-t-butoxycarbonylamino-3(S)-hydroxy-6-methylheptanoate. The resulting syrup was purified by silica gel column chromatography eluted with mixtures of chloroform and methanol ranging from 20:1 to 5:1. The solvent was removed by distillation under reduced pressure from the active fractions, and diethyl ether was added to the residue, to solidify it. This solid was finely pulverized and separated by filtration, giving 97 mg of the title compound as a white powdery solid, melting at 102°-109° C., [α]24 -31.0° (C=0.5 methanol).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][OH:14])[C:3]=1[C:4]#[N:5].[S:15](Cl)(=[O:18])(=[O:17])[NH2:16]>>[S:15](=[O:18])(=[O:17])([O:14][CH2:13][CH2:12][CH2:11][O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([NH:1][S:15](=[O:18])(=[O:17])[NH2:16])[C:3]=1[C:4]#[N:5])[NH2:16]
Reactant: NS(=O)(=O)Cl
Reactant: N#Cc1c(N)cccc1OCCCO
Product: N#Cc1c(NS(N)(=O)=O)cccc1OCCCOS(N)(=O)=O
Yield: 30 %

Procedure:
Prepared as in Example 215a from 2-amino-6-(3-hydroxypropoxy)benzonitrile (Example 238b) and sulfamoyl chloride in 30% yield. 1H NMR (400 MHz, DMSO-d6) δ 2.11-2.14 (m, 2H), 4.16-4.21 (m, 4H), 6.96 (d, J=8.0 Hz, 1H), 7.15 (d, J=7.6 Hz, 1H), 7.26 (s, 2H), 7.49 (s, 2H), 7.56 (t, J=8.4 Hz, 1H), 9.46 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17][CH2:16][CH2:15][C@H:14]4[CH3:18])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:21][C:22]1[CH:23]=[CH:24][C:25](=[O:28])[NH:26][N:27]=1.N1NC(=O)C=CC=1>>[CH3:21][C:22]1[CH:23]=[CH:24][C:25](=[O:28])[N:26]([C:2]2[CH:20]=[CH:19][C:5]3[N:6]=[C:7]([C@H:9]4[CH2:12][C@H:11]([N:13]5[CH2:17][CH2:16][CH2:15][C@@H:14]5[CH3:18])[CH2:10]4)[S:8][C:4]=3[CH:3]=2)[N:27]=1
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Reactant: Cc1ccc(=O)[nH]n1
Agent: O=c1cccn[nH]1
Product: Cc1ccc(=O)n(-c2ccc3nc([C@H]4C[C@H](N5CCC[C@@H]5C)C4)sc3c2)n1

Procedure:
The title compound was prepared according to the procedure described in Example 22, substituting the product of Example 11A for the product of Example 1E, and substituting 6-methyl-3(2H)-pyridazinone for 3(2H)-pyridazinone. 1H NMR (500 MHz, CDCl3) δ ppm 8.12 (m, 1H) 8.00 (m, 1H) 7.67 (dd, J=8.73, 1.87 Hz, 1H) 7.16 (m, 1H) 7.01 (m, 1H) 3.57-3.67 (m, 1H) 3.15-3.24 (m, 1H) 3.02-3.11 (m, 1H) 2.73-2.86 (m, 1H) 2.56-2.68 (m, 1H) 2.45-2.55 (m, 2H) 2.41 (s, 3H) 2.30-2.37 (m, 1H) 1.92-2.04 (m, 1H) 1.77-1.87 (m, 1H) 1.67-1.74 (m, 1H) 1.44-1.61 (m, 2H) 1.15 (s, 3H). MS: (M+H)+=381.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:25][CH2:24][CH:23]([N:26]([CH3:28])[CH3:27])[CH2:22]2)=[CH:17][CH:16]=1>>[C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:9](=[O:11])[NH:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][CH2:24][CH:23]([N:26]([CH3:28])[CH3:27])[CH2:22]3)=[CH:17][CH:16]=2)=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1
Reactant: CN(C)C1CCN(c2ccc(N)cc2)C1
Product: CC(=O)Oc1ccc(C(=O)Nc2ccc(N3CCC(N(C)C)C3)cc2)cc1

Procedure:
4-Acetoxybenzoic acid was reacted with [1-(4-aminophenyl)pyrrolidin-3-yl]dimethylamine by method E-b. This resulted in the product with the molecular weight of 367.19 (C21H25N3O3); MS (ESI): 368 (M+H+) as hydrotrifluoroacetate.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[F:15][C:16]([F:30])([F:29])[C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33].CO>C(OCC)(=O)C>[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:26]3[CH2:25][CH2:24][N:23]([C:20]4[CH:19]=[CH:18][C:17]([C:16]([F:29])([F:30])[F:15])=[CH:22][CH:21]=4)[CH2:28][CH2:27]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: FC(F)(F)c1ccc(N2CCNCC2)cc1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCN(c2ccc(C(F)(F)F)cc2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 1-(4-trifluoromethylphenyl)piperazine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 89% overall yield. FDMS m/e=419 (M+ of free base). α[D]589 =-7.78 (c=0.72, methanol).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][C@H:13]([NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH2:12]3)O1.Br[C:27]1[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:35])[F:34])=[N:31][CH:32]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[F:34][C:33]([F:36])([F:35])[C:30]1[N:31]=[CH:32][C:27]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][C@H:13]([NH:18][S:19]([CH:22]([CH3:23])[CH3:24])(=[O:20])=[O:21])[CH2:12]3)=[CH:28][CH:29]=1
Reactant: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C1
Reactant: FC(F)(F)c1ccc(Br)cn1
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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(-c3ccc(C(F)(F)F)nc3)cc2C1

Procedure:
To a solution of N-[(2S)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide (190 mg, 0.52 mmol) in dry 1,4 dioxane (5 ml), polymer supported Pd(PPh3)4 (10 mg, 0.5 mmol/g, 0.005 mmol) was added along with 5-bromo-2-(trifluoromethyl)pyridine (176 mg, 0.78 mmol) and 500 μl of a 2M Na2CO3 solution in water. The resulting mixture was heated at 90° degrees for 3 hours. Then after cooling the resin was removed by filtration and then the solvent was removed under reduced pressure. The residue was taken up with DCM, washed with water and loaded on a 25M+ silica cartridge eluating with a cyclohexane/AcOEt 75/25 mixture. 150 mg of title compound were recovered as whitish solid (75%). Due to the use of chiral Intermediate 7, the final compound is believed to be N-{(2S)-5-[6-(trifluoromethyl)-3-pyridinyl]-2,3-dihydro-1H-inden-2-yl}-2-propanesulfonamide.
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH2-:21][C:22]([CH3:24])=[O:23].S(O[CH2:36][C@H:37]([OH:40])[CH2:38]O)(C1C=CC(C)=CC=1)(=O)=O.[Na+].[I-]>CN(C=O)C>[CH3:21][C:22]1([CH3:24])[O:40][C@@H:37]([CH2:38][O:1][C:2]2[CH:18]=[CH:17][C:5]([C:6]([C:8]3[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=3)=[O:7])=[CH:4][CH:3]=2)[CH2:36][O:23]1
Reactant: O=C(c1ccc(O)cc1)c1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](O)CO)cc1
Reactant: [CH2-]C(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OC[C@H](COc2ccc(C(=O)c3ccc([N+](=O)[O-])cc3)cc2)O1
Yield: 63.3 %

Procedure:
1 g of 4-hydroxy-4'-nitrobenzophenone was added to 8 ml of DMF containing 110 mg of NaH. The mixture was heated at 40°-50° C. for 30 minutes, then treated with 1.29 g of (R)-3-tosyloxy-1,2-propanediol acetonide and a trace of NaI and heated at 150° C. (oil-bath) under argon for 4 hours. After working-up and purification there were obtained 930 mg (64%) of 4-[[(S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy]-4'-nitrobenzophenone, m.p. 92°-93° C., [α]D20 +5.3° (c 1%, MeOH).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9](O)([CH3:12])([CH3:11])[CH3:10].S(=O)(=O)(O)O.C([O-])(O)=O.[Na+]>C(Cl)(Cl)(Cl)Cl.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])=[C:4]([OH:8])[CH:3]=1
Reactant: CC(C)(C)O
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CC(C)(C)c1ccc(Br)cc1O
Temperature: 25 °C
Reaction time: 84 h

Procedure:
To a solution of 29.46 g (170.3 mmol) of 3-bromophenol (distilled) and 16.41 g (20.9 ml, 221.3 mmol) of t-butanol in 100 ml of carbon tetrachloride was added 20.0 ml of conc. sulfuric acid. The clear, colorless solution turned a dark magenta color and became hot. The solution was cooled in water (ambient temperature) and allowed to stir at room temperature for 84 hours. The reaction mixture was neutralized with sat. aqueous NaHCO3 solution (pH~7.0), partitioned between 300 ml of water and 500 ml of dichloromethane, and the organic and aqueous layers were separated. The aqueous phase was washed with 2×500 ml-portions of dichloromethane. All organic phases were combined, washed with 400 ml of brine solution, dried over MgSO4, filtered and concentrated in vacuo to a purple oil. Purification by flash chromatography (silica, 5% ethyl acetate in hexane) followed by kugelrohr distillation yielded the title compound as a clear, slightly yellow oil.
Reaction SMILES: C(C1C=CC(C(C)(CCCCC(=O)CCCCC(C2C=CC(CC(C)C)=CC=2)(C)C(O)=O)C(O)=O)=CC=1)C(C)C.C([O:43][C:44](=[O:68])[C:45]([CH3:67])([CH3:66])[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][C:51](=[O:65])[CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][C:57]([CH3:64])([CH3:63])[C:58]([O:60]CC)=[O:59])C.[OH-].[K+]>C(O)C.O>[CH3:63][C:57]([CH3:64])([CH2:56][CH2:55][CH2:54][CH2:53][CH2:52][C:51](=[O:65])[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][C:45]([CH3:67])([CH3:66])[C:44]([OH:68])=[O:43])[C:58]([OH:60])=[O:59]
Reactant: CCOC(=O)C(C)(C)CCCCCC(=O)CCCCCC(C)(C)C(=O)OCC
Agent: CC(C)Cc1ccc(C(C)(CCCCC(=O)CCCCC(C)(C(=O)O)c2ccc(CC(C)C)cc2)C(=O)O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(CCCCCC(=O)CCCCCC(C)(C)C(=O)O)C(=O)O
Yield: 56.8 %

Procedure:
According to the procedure given for 210f, 209g (8.54 g, 21.4 mmol) was saponified with KOH (85%, 4.53 g, 68.6 mmol) in ethanol (13 mL) and water (5 mL) at reflux for 4 h. The solid product obtained after usual workup was recrystallized from Et2O/hexanes (50 mL/50 mL), affording 210g (4.16 g, 57%) as colorless needles. Mp 82-83° C. 1H NMR (CDCl3): δ 11.53 (br., 2H), 2.39 (t, 4H, J=7.3), 1.60-1.50 (m, 8H), 1.30-1.20 (m, 8H), 1.18 (s, 12H). 13C NMR (CDCl3): δ 211.7, 185.0, 42.8, 42.3, 40.4, 29.7, 25.1, 24.8, 23.8. HRMS (LSIMS, gly): Calcd for C19H35O5 (MH+): 343.2484. found: 343.2444. HPLC: 92.6% pure. Anal. (C19H34O5) C, H.
Reaction SMILES: FC(F)(F)C1C=C(S(O[CH2:13][C@@H:14]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)(=[O:19])=[O:18])[CH3:15])(=O)=O)C=CC=1.CC([O-])(C)C.[K+]>C1COCC1>[CH3:13][CH:14]1[CH2:15][N@@:16]1[S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)(=[O:19])=[O:18]
Reactant: C[C@@H](COS(=O)(=O)c1cccc(C(F)(F)F)c1)NS(=O)(=O)c1cccc(C(F)(F)F)c1
Agent: CC(C)(C)[O-]
Agent: CC1C[N@]1S(=O)(=O)c1cccc(C(F)(F)F)c1
Agent: [K+]
Solvent: C1CCOC1
Product: CC1C[N@@]1S(=O)(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
(S)-2-(3-(Trifluoromethyl)benzenesulfonamido)propyl 3-(trifluoromethyl)benzene-sulfonate (1.60 g, 3.26 mmol) was dissolved in 25 mL dry THF and treated with KOtBu (5.0 g, 4.9 mmol). The resulting mixture was stirred for 20 h at RT. Thee reaction mixture was quenched with sat. NH4Cl and the solvent was removed. The residue was partitioned between EtOAc/H2O. The organic layer was washed with sat. NH4Cl, H2O, brine, dried over MgSO4 and concentrated. The residue was purified by SiO2 (90% hexanes: 10% Acetone) to afford the final compound. MS (m/z): 266.1 (M+H) (Calc'd for C10H10F3NO2S: 265.25).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[F:7][C:8]([F:24])([F:23])[C:9]1[C:18]([C:19](Cl)=[O:20])=[C:17]([OH:22])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1>N1C=CC=CC=1>[F:24][C:8]([F:7])([F:23])[C:9]1[C:18]([C:19]([NH:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)=[O:20])=[C:17]([OH:22])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: Nc1nccs1
Reactant: O=C(Cl)c1c(C(F)(F)F)nc2ccccc2c1O
Solvent: c1ccncc1
Product: O=C(Nc1nccs1)c1c(C(F)(F)F)nc2ccccc2c1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
7.5 g of 2-amino-thiazole and 20 ml of pyridine were added to a solution of the product of Step F in 120 ml of anhydrous pyridine and the mixture was heated at 80°-85° C. for one hour. The mixture was stirred at room temperature for 16 hours and was then evaporated to dryness. The residue was triturated with 200 ml of water and was then vacuum filtered. The filter was washed and the combined wash water and filtrate were cooled in ice and acidified with concentrated hydrochloric acid. The mixture was vacuum filtered and the recovered product was washed with water and dried to obtain 13.7 g of 2-trifluoromethyl-4-hydroxy-N-(2-thiazolyl)-3-quinoline-carboxamide melting at >280° C.
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][O:9][CH2:10][CH:3]1[CH2:4][N:5]([C:11]1[CH:12]=[N:13][C:14]([N+:17]([O-])=O)=[CH:15][CH:16]=1)[CH2:6]2.[H][H]>C1COCC1.CO.[Pd]>[CH3:1][N:2]1[CH:7]2[CH2:8][O:9][CH2:10][CH:3]1[CH2:4][N:5]([C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[N:13][CH:12]=1)[CH2:6]2
Reactant: [H][H]
Reactant: CN1C2COCC1CN(c1ccc([N+](=O)[O-])nc1)C2
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CN1C2COCC1CN(c1ccc(N)nc1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
To a solution of 112i (800 mg, 3.0 mmol) in THF (80 ml) was added Pd/C (50 mg) in MeOH (20 ml) at room temperature. The reaction mixture was hydrogenated at atmospheric hydrogen pressure and stirred at room temperature overnight. The mixture was filtered and the filtrate was evaporated to give 112j as a colorless oil (680 mg, 90%).MS: [M+H]+: 235