Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([OH:16])=[C:8]2[CH:14]=[C:13]([CH3:15])[S:12][C:9]2=[N:10][CH:11]=1)=[O:5])C.[OH-].[K+].[CH2:19](I)[CH3:20].Cl>O.C(O)C>[CH2:19]([N:10]1[CH:11]=[C:6]([C:4]([OH:3])=[O:5])[C:7](=[O:16])[C:8]2[CH:14]=[C:13]([CH3:15])[S:12][C:9]1=2)[CH3:20]
Reactant: CCI
Reactant: CCOC(=O)c1cnc2sc(C)cc2c1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCn1cc(C(=O)O)c(=O)c2cc(C)sc21

Procedure:
A mixture of 1.4 parts of ethyl-4-hydroxy-2-methylthieno-[2,3-b]pyridine-5-carboxylate, 12 parts by volume of 10 percent aqueous potassium hydroxide, 48 parts by volume of ethanol, 60 parts by volume of water and 1.8 parts by volume of ethyl iodide is refluxed for about 3 hours. After cooling, the reaction mixture is added to 60 parts by volume of water containing 3 parts by volume of concentrated hydrochloric acid and the resulting crystals are collected by filtration to give 7-ethyl-4,7-dihydro-2-methyl-4-oxothieno[2,3-b]pyridine-5-carboxylic acid as colorless crystals. Recrystallization from chloroform-ethanol yields colorless prisms melting at 229°-230° C.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH2:10]([N:14]1[CH2:31][CH:30]([CH2:32]O)[O:29][C:16]2([CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH2:15]1)[C:11]#[C:12][CH3:13].CO.ClCCl>ClCCl>[CH2:10]([N:14]1[CH2:31][CH:30]([CH2:32][F:7])[O:29][C:16]2([CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH2:15]1)[C:11]#[C:12][CH3:13]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC#CCN1CC(CO)OC2(CCN(C(=O)OC(C)(C)C)CC2)C1
Solvent: ClCCl
Solvent: CO
Product: CC#CCN1CC(CF)OC2(CCN(C(=O)OC(C)(C)C)CC2)C1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 45.6 %

Procedure:
To a solution of diethylaminosulfur trifluoride (19.5 μL, 0.148 mmol) in dichloromethane (1.0 mL) at −78° C. was added dropwise a solution of tert-butyl 8-but-2-ynyl-10-(hydroxymethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (50.0 mg, 0.148 mmol) in dichloromethane (1 mL). The reaction was stirred for 10 min at −78° C. then allowed to warm to room temperature and stirred for 16 h. Silica gel chromatography (4 g silica, 0-15% methanol/dichloromethane) provided tert-butyl 8-but-2-ynyl-10-(fluoromethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (23.0 mg, 46%). ESI-MS m/z calc. 340.2. found 341.3 (M+1)+; Retention time: 1.16 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 4.52-4.40 (m, 1H), 4.39-4.28 (m, 1H), 4.06-3.91 (m, 1H), 3.71 (br s, 2H), 3.35-3.14 (m, 3H), 3.08 (t, J=11.4 Hz, 1H), 2.78 (d, J=10.3 Hz, 1H), 2.58 (d, J=11.1 Hz, 1H), 2.31 (d, J=13.5 Hz, 1H), 2.06 (t, J=12.5 Hz, 2H), 1.84 (t, J=2.3 Hz, 3H), 1.57-1.44 (m, 12H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18]([O:20]C)=[O:19])=[CH:15][CH:16]=2)[N:11]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[N:10]=1.[OH-].[Na+]>CO.O1CCCC1>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18]([OH:20])=[O:19])=[CH:15][CH:16]=2)[N:11]([C:22]2[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=2)[N:10]=1
Reactant: COC(=O)c1ccc2c(-c3c(F)cccc3F)nn(-c3ccc(C)cc3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(-n2nc(-c3c(F)cccc3F)c3ccc(C(=O)O)cc32)cc1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 99.3 %

Procedure:
Methyl 3-(2,6-difluorophenyl)-1-(4-methylphenyl)-1H-indazole-6-carboxylate (101.2 mg, 0.267 mmol) was dissolved in methanol (1.30 mL) and tetrahydrofuran (1.90 mL). 1M sodium hydroxide (1.60 mL, 0.267 mmol) was added. The reaction mixture was heated to 50° C. and allowed to stir for 1.5 h. Reaction stopped, cooled to room temperature, quenched by addition of 1M hydrochloric acid (ca 1.60 mL) till pH<3, and the solvent evaporated under reduced pressure. The title compound (199.5 mg, 0.265 mmol, 99% yield, with 6 equivalents of sodium chloride) was recovered as a white solid. LC-MS: [M+1]=365.2.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH2:12].Cl[C:14]1[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][N:17]=[C:16]([Cl:25])[CH:15]=1.Cl>CCO>[Cl:25][C:16]1[CH:15]=[C:14]([NH:12][C:3]2[CH:4]=[CH:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]=2[Cl:1])[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][N:17]=1
Reactant: Nc1ccc2ccccc2c1Cl
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cnc(Cl)cc1Nc1ccc2ccccc2c1Cl
Yield: 22 %

Procedure:
1-Chloro-2-naphthalenamine and ethyl 4,6-dichloronicotinate were reacted in a mixture of EtOH and conc. HCl as described for example 33, step A. The resultant solid was isolated by filtration and washed with 10% Et2O/Hexane, giving ethyl 6-chloro-4-[(1-chloro-2-naphthyl)amino]nicotinate (22%). 1H NMR [400 MHz, (CD3)2SO] δ 10.07 (br s, 1H), 8.75 (s, 1H), 8.23 (d, J=8.7 Hz, 1H), 8.09-8.05 (m, 2H), 7.77-7.71 (m, 2H), 7.66 (ddd, J=8.0, 6.9, 1.1 Hz, 1H), 6.75 (s, 1H), 4.41 (q, J=7.1 Hz, 2H), 1.38 (t, J=7.1 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.F[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[CH3:20][C:16]1[N:15]=[C:14]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]3)[CH:19]=[CH:18][CH:17]=1
Reactant: Cc1cccc(F)n1
Reactant: O=C1CCCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(Oc2ccc3c(c2)CCCC3=O)n1
Temperature: 150 °C
Reaction time: 8 h
Yield: 26.3 %

Procedure:
A suspension of 6-hydroxy-1-tetralone (3.0 g, 18 mmol), 2-fluoro-6-methylpyridine (2.06 g, 18.5 mmol) and Cs2CO3 (12.1 g, 37.0 mmol) in DMF (150 mL) was stirred at 150° C. in a sealed vessel overnight under N2. The reaction was poured into water (300 mL) and extracted with EtOAc (3×50 mL). Organics were dried (Na2SO4) and concentrated. Purification by silica gel chromatography (PE:EA=5:1) gave 1.2 g (26%) of the title compound as a red oil. [M+H] calc'd for C16H15NO2, 254. found 254.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C@@H:4]([NH:13][C:14]([C:16]1[CH:17]=[C:18]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[CH:19]=[CH:20][C:21]=1[OH:22])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1.[F:34][C:35]([F:46])([F:45])[C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1>>[CH3:1][O:2][C:3](=[O:33])[C@@H:4]([NH:13][C:14]([C:16]1[CH:17]=[C:18]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[CH:19]=[CH:20][C:21]=1[OH:22])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:39]2[CH:40]=[CH:41][C:36]([C:35]([F:46])([F:45])[F:34])=[CH:37][CH:38]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)ccc1O
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)NC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)ccc1O
Yield: 45.4 %

Procedure:
The resin-bound 3-(4-bromo-phenyl)-(2S)-[(4′-trifluoromethyl-4-hydroxy-biphenyl-3-carbonyl)-amino]-propionic acid methyl ester (30 mg, 0.09 mmol) prepared as described in Example 1 was reacted with 4-trifluoromethyl-phenyl boronic acid (86 mg, 0.45 mmol) by following procedure D to give the title compound (24 mg).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]1([C:17](Cl)=[O:18])[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH:8]=[CH:7][CH2:6]1.[NH3:20]>C(Cl)Cl>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]1([C:17]([NH2:20])=[O:18])[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH:8]=[CH:7][CH2:6]1
Reactant: O=C(Cl)C1(CCCCl)CC=CCC1c1ccccc1
Reactant: N
Solvent: ClCCl
Product: NC(=O)C1(CCCCl)CC=CCC1c1ccccc1
Reaction time: 16 h
Yield: 85 %

Procedure:
1-(3-chloropropyl)-6-phenyl-3-cyclohexane-1-carboxylic acid (4.95 g, 17.6 mmol) was dissolved in methylene chloride and stirred under N2 at ambient temperature. Oxalyl chloride (2 equiv., 4.47 g) was added and the solution was allowed to stir for 16 hrs. The solution was concentrated to vacuo to afford the corresponding acid chloride (5.18 g, 100% yield) as a light yellow mobile oil. The infrared spectrum indicated the disappearance of the carboxyl carbonyl stretch of the starting material at 1700 cm-1 and the appearance of the acid chloride carbonyl stretch at 1790 cm-1. 1-(3-Chloropropyl)-6-phenyl-3-cyclohexene-1-carbonyl chloride (11.40 g, 38.6 mmol) was dissolved in methylene chloride (100 ml) into which ammonia is bubbled into the solution for 15 mins. via a gas dispersion tube. After stirring for 16 hrs. water was added to the solution and the organic fraction was dried over MgSO4, filtered and concentrated in vacuo to afford 9.05 g (85% yield) of 1-(3-chloro-propyl)-6-phenyl-3-cyclohexene-1-carboxamide as a viscous oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[C:9]([C:13]1[O:17][N:16]=[C:15]([NH:18][C:19]([C@@H:21]2[CH2:25][C@@H:24]([OH:26])[CH2:23][NH:22]2)=[O:20])[CH:14]=1)([CH3:12])([CH3:11])[CH3:10].Cl.C(N(C(C)C)CC)(C)C>C(O)C>[C:9]([C:13]1[O:17][N:16]=[C:15]([NH:18][C:19]([C@@H:21]2[CH2:25][C@@H:24]([OH:26])[CH2:23][N:22]2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)=[O:20])[CH:14]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: Clc1ccnc(Cl)n1
Reactant: CC(C)(C)c1cc(NC(=O)[C@@H]2C[C@@H](O)CN2)no1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2C[C@@H](O)CN2c2ccnc(Cl)n2)no1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,4-Dichloropyrimidine (33.2 mg, 0.223 mmol) is added to the solution of (2S,4R)-4-Hydroxy-pyrrolidine-2-carboxylic acid (5-tert-butyl-isoxazol-3-yl)-amide; hydrochloride (66 mg, 0.223 mmol) and diisopropylethylamine (0.078 mL, 0.446 mmol) in ethanol (2 mL). The reaction is stirred at room temperature overnight. The reaction is quenched with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate twice. The organics are combined and washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by chromatography on silica eluting with methanol/dichloromethane provides the title compound. ESI m/z 366 [M+H+].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=1.[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.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:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=2)=[CH:16][CH:15]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCC(=O)c1ccc(Br)cc1
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: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Yield: 88.3 %

Procedure:
To a solution of 1-(4-bromophenyl)propan-1-one (10 g, 46.9 mmol) in toluene/ethanol (47/47 ml) is added 4-trifluoromethylphenylboronic acid (10.63 g, 51.6 mmol), tetrakis(triphenylphosphine)palladium (2.7 g, 2.3 mmol), and 2 N potassium carbonate (47 mL). The reaction mixture is heated at reflux overnight, cooled to rt, and partitioned between ethyl acetate and water. The organic layer is dried and concentrated, then loaded onto silica gel and eluted using hexanes with an ethyl acetate gradient from 0% to 60% giving 1-(4′-trifluoromethylbiphenyl-4-yl)propan-1-one (11.52 g).
Reaction SMILES: [Br:1][C:2]1[CH:20]=[C:19]2[C:5]([C:6](=[O:22])[C:7](=[O:21])[C:8]3[S:18][CH2:17][C:11]4([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]4)[O:10][C:9]=32)=[CH:4][CH:3]=1.[CH2:23]([C@H:30]1[CH2:32][O:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[Br:1][C:2]1[CH:20]=[C:19]2[C:5]([C:6](=[O:22])[C:7](=[O:21])[C:8]3[S:18][CH2:17][C:11]4([CH2:16][CH2:15][N:14]([CH2:32][C@@H:30]([OH:31])[CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH2:13][CH2:12]4)[O:10][C:9]=32)=[CH:4][CH:3]=1
Reactant: c1ccc(C[C@H]2CO2)cc1
Reactant: O=C1C(=O)c2ccc(Br)cc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccc(Br)cc2C2=C1SCC1(CCN(C[C@@H](O)Cc3ccccc3)CC1)O2

Procedure:
Compound 188 was synthesized using 9-bromospiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2S)-2-benzyloxirane and conditions outlined in procedure Y. M.p.=82-83° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.82-7.76 (m, 3H), 7.29-7.21 (m, 4H), 7.19-7.14 (m, 1H), 4.47-4.44 (m, 1H), 3.89-3.82 (m, 1H), 3.08 (s, 2H), 2.82-2.69 (m, 3H), 2.63-2.54 (m, 1H), 2.42-2.27 (m, 4H), 2.20-1.94 (m, 2H), 1.86-1.77 (m, 2H); LCMS: 514 [M+H].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=O)[CH2:10][CH2:11][C:12]1[C:13]([O:30][CH3:31])=[C:14]2[C:18](=[C:19]([F:21])[CH:20]=1)[N:17]([CH2:22][CH3:23])[CH:16]=[C:15]2[CH2:24][C:25]([N:27]([CH3:29])[CH3:28])=[O:26].O.C([O-])(O)=O.[Na+]>C(O)(=O)C>[NH:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:9]1[CH2:10][CH2:11][C:12]1[C:13]([O:30][CH3:31])=[C:14]2[C:18](=[C:19]([F:21])[CH:20]=1)[N:17]([CH2:22][CH3:23])[CH:16]=[C:15]2[CH2:24][C:25]([N:27]([CH3:29])[CH3:28])=[O:26]
Reactant: CCn1cc(CC(=O)N(C)C)c2c(OC)c(CCC(=O)Nc3ccccc3N)cc(F)c21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCn1cc(CC(=O)N(C)C)c2c(OC)c(CCc3nc4ccccc4[nH]3)cc(F)c21
Temperature: 25 °C
Yield: 68.3 %

Procedure:
A solution of 29-2 (230 mg, 0.52 mmol) in acetic acid (10 mL) was heated to 80° C. for 3 h. After cooled to room temperature, water (10 mL) and sat. aqueous NaHCO3 (30 mL) were added. The mixture was extracted with ethyl acetate (3×20 mL). The combined organic layer was dried with MgSO4, filtered and evaporated to afford 29-3 (150 mg, 68%) as yellow oil. LRMS: calc 422.5 and found: 423.2 [M+1].
Reaction SMILES: CC(C)(C)C[O:4][C:5](=[O:34])[C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]=1[C:16]1[CH:25]=[C:24]2[C:19]([C@H:20]([OH:33])[C@@H:21]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:22][O:23]2)=[CH:18][CH:17]=1.[OH-].[Na+].O>C(O)(C)C>[CH2:26]([C@@H:21]1[C@@H:20]([OH:33])[C:19]2[C:24](=[CH:25][C:16]([C:7]3[CH:8]=[C:9]([C:12]([F:15])([F:13])[F:14])[CH:10]=[CH:11][C:6]=3[C:5]([OH:34])=[O:4])=[CH:17][CH:18]=2)[O:23][CH2:22]1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)COC(=O)c1ccc(C(F)(F)F)cc1-c1ccc2c(c1)OC[C@H](Cc1ccccc1)[C@H]2O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: O=C(O)c1ccc(C(F)(F)F)cc1-c1ccc2c(c1)OC[C@H](Cc1ccccc1)[C@H]2O
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.3 %

Procedure:
A solution of (3S, 4R)-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoic acid 2,2-dimethyl-propyl ester (2.34 g, 4.69 mmol) in isopropyl alcohol (23 mL) was treated with 10% aqueous sodium hydroxide (2.3 mL, 6.4 mmol) and heated at reflux for 3 hours. The reaction mixture was cooled to ambient temperature, poured into water (34 mL), and extracted with hexanes (23 mL) and isopropyl ether (13 mL). The aqueous layer was separated and extracted with hexanes (23 mL) and isopropyl ether (13 mL), adjusted to pH 2 with 6N aqueous hydrochloric acid, and extracted with ethyl acetate (two times 40 mL). The combined ethyl acetate extracts were washed with brine (40 mL), dried over magnesium sulfate, filtered and concentrated to a white foam which was recrystallized from toluene/hexanes. The resulting solids were filtered and washed with hexanes, and the wet cake was stirred with hexanes (20 mL) for 1 hour. The mixture was filtered, and the resulting solids were dried under vacuum to provide 1.01 g (50% yield) of (3S, 4R)-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoic acid as a white solid: 1H NMR (400 MHz, CDCl3) δ 8.00 (d, J=8.1 Hz, 1H), 7.67 (d, J=8.1 Hz, 1H), 7.64 (s, 1H), 7.18-7.36(m, 6H), 6.91 (dd, J=7.9, 1.7 Hz, 1H), 6.86 (d, J=1.7 Hz, 1H), 4.53 (d, J=4.2 Hz, 1H), 4.24 (dd, J=11.2, 2.7 Hz, 1H, 3.97 (dd, J=11.0, 4.0 HZ, 1H), 2.76 (dd, J=13.9, 6.4 Hz, 1H), 2.53 (dd, J=13.7, 9.3 Hz, 1H), 2.24-2.26 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH2:14]([Sn](CCCC)(CCCC)C=C)[CH2:15]CC.CCOC(C)=O>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:14]([C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1)=[CH2:15]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CCOC(=O)Cc1cccc(Br)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=Cc1cccc(CC(=O)OCC)c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
To a mixture of ethyl 2-(3-bromophenyl)acetate (1.5 g, 6.1 mmol) in anhydrous DMF (15 mL) was added tributyl(vinyl)stannane (2.1 mL, 7.4 mmol) and tetrakis(triphenylphosphine) palladium (400 mg, 0.5 mmol) under nitrogen atmosphere. The resulting mixture was stirred at 110° C. for 8 hours. Followed a standard aqueous/EtOAc workup. Purified by silica gel column chromatography (petroleum:ether/ethyl acetate=15:1) (640 mg, yield 54%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2Cl.[O-:13][CH2:14][CH3:15].[Na+]>C(O)C.C(=O)(O)[O-].[Na+]>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[O:13][CH2:14][CH3:15]
Reactant: CC[O-]
Reactant: Clc1ccnc2ccc(Br)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOc1ccnc2ccc(Br)cc12
Temperature: 120 °C
Yield: 90.2 %

Procedure:
To a solution of 6-bromo-4-chloroquinoline (17 g, 70.10 mmol) in ethanol (400 mL) was added sodium ethoxide (23.85 g, 350.5 mmol) at room temperature. Then, the reaction mixture was heated to 120° C. for 15 h in a sealed reaction flask. After cooling to room temperature, the ethanol was removed under the vacuum and the residue was diluted with water. The aqueous suspension was neutralized with 3.0N hydrochloric acid until the precipitate formed and later it was diluted with saturated sodium bicarbonate solution. Then, the solids were collected by filtration and washed with water. After drying in air, 15.94 g (90.2% yield) of 6-bromo-4-ethoxy-quinoline was isolated as a white solid which can be crystallized from acetonitrile: EI-HRMS m/e calcd for C11H10BrNO (M+) 250.9946, found 250.9946.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:17])[CH2:10][CH2:11][S:12][CH2:13][C:14]([OH:16])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:51]1[CH2:56][CH2:55][S:54][CH2:53][CH2:52]1>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:17])[CH2:10][CH2:11][S:12][CH2:13][C:14](=[O:16])[N:51]1[CH2:56][CH2:55][S:54][CH2:53][CH2:52]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CSCCN1
Reactant: O=C(O)CSCCC(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCSCC(=O)N1CCSCC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 3-Carboxymethylsulfanyl-propionic acid benzyl ester (763 mg, 3 mmol), HBTU (1.71 g, 4.5 mmol) and DIPEA (2.05 mL, 12 mmol) in DCM (10 mL) is added thiomorpholine (283 uL, 3 mmol). After stirring at rt during 2 h and evaporation of the solvent, the residue is dissolved with ethylacetate and washed with an aqueous 1N HCl solution and an aqueous saturated NaHCO3 solution. The organic phase is dried and evaporated to afford the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[CH2:12]([O:14][C:15](=[O:31])[CH2:16][C@H:17]1[C:25]2[C:20](=[CH:21][C:22]([O:26][CH2:27][CH2:28][CH2:29]Br)=[CH:23][CH:24]=2)[CH2:19][CH2:18]1)[CH3:13].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH2:12]([O:14][C:15](=[O:31])[CH2:16][C@H:17]1[C:25]2[C:20](=[CH:21][C:22]([O:26][CH2:27][CH2:28][CH2:29][O:11][C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:2]([CH3:1])[CH:3]=[CH:4]4)=[CH:23][CH:24]=2)[CH2:19][CH2:18]1)[CH3:13]
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCBr)ccc21
Reactant: Cn1ccc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc4c(ccn4C)c3)ccc21
Temperature: 40 °C
Reaction time: 16 h
Yield: 46.5 %

Procedure:
To a solution of 1-methyl-1H-indol-5-ol (44.0 mg, 0.30 mmol) (Example 47) and ethyl[(1S)-5-(3-bromopropoxy)-2,3-dihydro-1H-inden-1-yl]acetate (Example 45, 100 mg, 0.29 mmol) in DMF (4.0 mL) were added Cs2CO3 (114.6 mg, 0.35 mmol) and water (3 drops). The reaction mixture was stirred at 40° C. for 16 h, then cooled to rt, and concentrated under reduced pressure. Water was added and the aqueous layer was extracted with EtOAc (2×). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by silica gel flash chromatography (EtOAc/Hexane (v/v)=1:13) yielded 55 mg (46%) of the title compound as a clear oil. 1H NMR (400 MHz, CDCl3): δ 1.28 (t, 3H), 1.76 (m, 1H), 2.26 (m, 2H), 2.39 (m, 2H), 2.71 (dd, 1H), 2.88 (m, 2H), 3.50 (m, 1H), 3.78 (s, 3H), 4.18 (m, 6H), 6.38 (d, 1H), 6.72 (dd, 1H), 6.80 (s, 1H), 6.89 (d, 1H), 7.02 (s, 1H), 7.06 (d, 1H), 7.10 (s, 1H), 7.20 (d, 1H).
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:9](Cl)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH-].[K+]>O.C(O)C>[CH2:9]([O:7][C:6]1[C:1]([CH3:8])=[CH:2][CH:3]=[CH:4][CH:5]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: ClCc1ccccc1
Reactant: Cc1ccccc1O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccccc1OCc1ccccc1
Yield: 76.4 %

Procedure:
o-Cresol (50 g), 70 g of benzyl chloride and 38.5 g of potassium hydroxide were boiled in a mixture of 100 ml of water and 500 ml of ethanol for 4 hours. The solvent was then distilled off and the residue was shaken with 500 ml each of water and diethyl ether. The diethyl ether layer was washed with 10% sodium hydroxide and water in that order, and distilled under reduced pressure to give 70 g of an O-benzylcresol fraction boiling at 130°-133° C./5 mmHg.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(N(CC)CC)C.Cl[CH2:28][CH2:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:30]([CH:29]=[CH2:28])(=[O:32])=[O:31])[CH2:16][CH2:15]1
Reactant: O=S(=O)(Cl)CCCl
Reactant: NC(=O)c1cc(Br)cc2c(C3CCNCC3)c[nH]c12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reaction time: 0.5 h
Yield: 28 %

Procedure:
To a solution of 5-bromo-3-(4-piperidinyl)-1H-indole-7-carboxamide (500 mg, 1.3 mmol) in methylene chloride at room temperature, triethylamine (0.44 mL, 3.2 mmol) and 2-chloroethylsulfonyl chloride (0.168 mL, 1.6 mmol) were added. The reaction mixture was stirred for 30 min. Removed the solvent, the residue was purified by combiflash to give the title compound (150 mg, 75%).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:7](=[N:15][NH2:16])[NH:8][C@@H:9]([CH3:14])[C:10]([F:13])([F:12])[F:11])[S:5][CH:6]=1.[CH2:17](OC(OCC)OCC)C>>[Br:1][C:2]1[N:3]=[C:4]([C:7]2[N:8]([C@@H:9]([CH3:14])[C:10]([F:13])([F:11])[F:12])[CH:17]=[N:16][N:15]=2)[S:5][CH:6]=1
Reactant: CCOC(OCC)OCC
Reactant: C[C@H](NC(=NN)c1nc(Br)cs1)C(F)(F)F
Product: C[C@H](n1cnnc1-c1nc(Br)cs1)C(F)(F)F
Yield: 77 %

Procedure:
(S)-4-bromo-N-(1,1,1-trifluoropropan-2-yl)thiazole-2-carbohydrazonamide (55 g,) in triethoxymethane (500 ml) was stirred at 90° C. for 3 hours and then at 130° C. overnight and the reaction was concentrated. The residue was purified by column to obtain 44 g (77% y) of (S)-4-bromo-2-(4-(1,1,1-trifluoropropan-2-yl)-4H-1,2,4-triazol-3-yl)thiazole.