Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[C:9]([CH2:11]Cl)[N:10]=[C:4]2[CH:3]=1.[CH3:13][O-:14].[Na+]>CO>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[C:9]([CH2:11][O:14][CH3:13])[N:10]=[C:4]2[CH:3]=1
Reactant: ClCc1cn2ccc(Br)cc2n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCc1cn2ccc(Br)cc2n1
Temperature: 25 °C
Yield: 33.9 %

Procedure:
To a solution of 81 mg (0.33 mmol) of 7-bromo-2-chloromethylimidazo[1,2-a]pyridine, prepared according to the protocol described in step 8.3, in 3 mL of anhydrous methanol, stirred at room temperature under an inert atmosphere, are added 35 mg (0.99 mmol) of sodium methoxide. The reaction mixture is stirred at 100° C. for 4 hours. After this time, the reaction medium, cooled to room temperature, is concentrated under reduced pressure, diluted with 10 mL of chloroform and then washed with 10 mL of saturated aqueous NaCl solution. The crude reaction product obtained after evaporating off the solvent under reduced pressure is purified by chromatography on a column of silica gel, eluting with a mixture of dichloromethane and methanol. 27 mg of the expected product are thus obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[C:9]([C:17](=[O:19])[CH3:18])[C:10]([OH:16])=[CH:11][CH:12]=2)[CH:7]=1.[Br:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:20])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[C:9]([C:17](=[O:19])[CH3:18])[C:10]([O:16][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][Br:21])=[CH:11][CH:12]=2)[CH:7]=1
Reactant: BrCCCCCBr
Reactant: COC(=O)COc1ccc2ccc(O)c(C(C)=O)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc2ccc(OCCCCCBr)c(C(C)=O)c2c1
Yield: 100.1 %

Procedure:
A mixture of 1.1 g of [[8-acetyl-7-hydroxy-2-naphthalenyl]oxy]acetic acid methyl ester, 9.2 g of 1,5-dibromopentane and 0.83 g of anhydrous potassium carbonate in 30 ml of anhydrous acetone was stirred at reflux for 17 hours. The reaction mixture was filtered and filtrate was concentrated at 60° C./0.15 mm to an oil which was purified by flash column chromatography to yield 1.7 g of [[8-Acetyl-7-(5-bromopentyloxy)-2-naphthalenyl]oxy]acetic acid methyl ester as an oil.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Br)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][CH3:20])=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[Cu][C:23]#[N:24]>CN(C)C=O>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([C:23]#[N:24])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][CH3:20])=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Br)c2ccc(OC)cc2c1O
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: CCCCOC(=O)c1nc(C#N)c2ccc(OC)cc2c1O
Temperature: 25 °C
Yield: 48.7 %

Procedure:
A mixture of 1-bromo-4-hydroxy-6-methoxy-isoquinoline-3-carboxylic acid butyl ester (290 mg, 0.82 mmol) and copper(I) cyanide (147 mg, 1.64 mmol) in anhydrous dimethylformamide (4 mL) was refluxed for ten minutes before it was cooled to room temperature and quenched with water. The resulting slurry was stirred with chloroform/isopropanol (3:1, 40 mL) and water for ten minutes and was then filtered. The organic layer of the filtrate was separated, washed with water, and brine, before it was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of methanol and dichloromethane to give the title compound as a white solid (120 mg): MS: (+) m/z 301.01 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([CH3:23])[CH:13]([OH:14])[CH:12]([N:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]2=[O:21])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH2:22])[CH:10]=2)[O:5]1.[CH:24](O)=[O:25]>N1C=CC=CC=1>[CH3:1][O:2][CH2:3][C:4]1([CH3:23])[CH:13]([OH:14])[CH:12]([N:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]2=[O:21])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:22][CH:24]=[O:25])[CH:10]=2)[O:5]1
Reactant: O=CO
Reactant: COCC1(C)Oc2ccc(N)cc2C(n2ccccc2=O)C1O
Solvent: c1ccncc1
Product: COCC1(C)Oc2ccc(NC=O)cc2C(n2ccccc2=O)C1O

Procedure:
A solution of 1 g of 2-methoxymethyl-2-methyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-6-amino-3-chromanol in 15 ml of formic acid and 1 ml of pyridine is boiled for 24 hours and evaporated. Customary working up gives 2-methoxymethyl-2-methyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-6-formamido-3-chromanol.
Reaction SMILES: [NH:1]1[CH2:5][CH:4]=[CH:3][CH2:2]1.Cl[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]>C(Cl)Cl>[N:1]1([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C1=CCNC1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CC=CC1
Reaction time: 1 h
Yield: 68 %

Procedure:
To a solution of 2,5-dihydro-1H-pyrrole (3.3 mL, 43.4 mmol) and Et N (9 mL, 65.1 mmol) in DCM (200 mL) at 0° C. was added dropwise benzyl chloroformate (7.3 mL, 52 mmol). After 1 h, the solution was partitioned between H O-DCM. The organic phase was back extracted several times with DCM and the combined organic fractions were dried (Na SO), concentrated and purified via column chromatography (silica, DCM) yielding the title compound (6 g, 68%) as a yellow oil: LCMS ES (m/e) 204 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]([N:9]([CH3:21])[CH2:10][CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]([OH:20])=O)[CH2:14][CH2:13]2)=[O:8])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH2:30]([O:32][C:33](=[O:38])[CH2:34][CH2:35][NH:36][CH3:37])[CH3:31].CCN(CC)CC>C(Cl)Cl.CN(C=O)C>[CH2:30]([O:32][C:33](=[O:38])[CH2:34][CH2:35][N:36]([C:18]([C@H:15]1[CH2:14][CH2:13][C@H:12]([CH2:11][CH2:10][N:9]([C:7]([O:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:23][CH:22]=2)=[O:8])[CH3:21])[CH2:17][CH2:16]1)=[O:20])[CH3:37])[CH3:31]
Reactant: CN(CC[C@H]1CC[C@H](C(=O)O)CC1)C(=O)Oc1ccc(Cl)cc1
Reactant: CCOC(=O)CCNC
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CCN(C)C(=O)[C@H]1CC[C@H](CCN(C)C(=O)Oc2ccc(Cl)cc2)CC1
Reaction time: 1.5 h

Procedure:
A solution of 0.41 g (1.20 mmol) of trans-4-{2-[(4-chloro-phenoxycarbonyl)-methyl-amino]-ethyl}-cyclohexanecarboxylic acid in 12 mL of CH2Cl2 was treated at RT with 1 drop of DMF, followed by 0.11 mL (1.32 mmol, 1.1 eq) of oxalyl chloride within 5 min and stirring was continued for 90 min. The solution was evaporated and the residue was redissolved in 12 mL of CH2Cl2. At 0° C. this solution was added to a solution of 0.20 g (1.56 mmol, 1.3 eq) of 3-methylamino-propionic acid ethyl ester and 0.84 mL (6.00 mmol, 5 eq) of Et3N in 4 mL of CH2Cl2. The reaction mixture was kept at RT for 1.5 h, then the substance was partitioned between Et2O (×3)/aqueous 10% KHSO4. The organic phases were washed once with aqueous 10% NaCl, dried over Na2SO4 and evaporated to give 0.51 g (94%) of trans-3-[(4-{2-[(4-chloro-phenoxycarbonyl)-methyl-amino]-ethyl}-cyclohexanecarbonyl)-methyl-amino]-propionic acid ethyl ester, MS: 453 (MH+, 1Cl).
Reaction SMILES: Cl.[F:2][C:3]1[C:4]([CH2:9][O:10][C:11]2[C:12]3[N:13]([C:18]([C:22](O)=[O:23])=[C:19]([CH3:21])[N:20]=3)[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[N:5][CH:6]=[CH:7][CH:8]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.Cl.[NH2:55][CH:56]([CH2:61][C:62]([F:65])([F:64])[F:63])[C:57]([O:59][CH3:60])=[O:58]>CN(C=O)C.O>[F:63][C:62]([F:64])([F:65])[CH2:61][CH:56]([NH:55][C:22]([C:18]1[N:13]2[CH:14]=[C:15]([CH3:17])[CH:16]=[C:11]([O:10][CH2:9][C:4]3[C:3]([F:2])=[CH:8][CH:7]=[CH:6][N:5]=3)[C:12]2=[N:20][C:19]=1[CH3:21])=[O:23])[C:57]([O:59][CH3:60])=[O:58]
Reactant: COC(=O)C(N)CC(F)(F)F
Reactant: Cc1cc(OCc2ncccc2F)c2nc(C)c(C(=O)O)n2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(CC(F)(F)F)NC(=O)c1c(C)nc2c(OCc3ncccc3F)cc(C)cn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
250 mg (0.71 mmol) of 8-[(3-fluoropyridin-2-yl)methoxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylic acid hydrochloride from Example 121A were initially charged in 4.1 ml of DMF, and 274 mg (0.85 mmol) of TBTU and 0.47 ml (4.26 mmol) of 4-methylmorpholine were added. 221 mg (1.07 mmol) of methyl 2-amino-4,4,4-trifluorobutanoate hydrochloride from Example 75A were then added, and the reaction mixture was stirred at RT overnight. About 32 ml of water were added to the mixture. The precipitated solid was filtered off, washed with water and dried under high vacuum. This gave 298 mg (68% of theory, purity 76%) of the target compound.
Reaction SMILES: CC1SC(C([O-])=S)=CC=1.[NH2:10][C:11](=[S:22])[C:12]1[CH:13]=[C:14]([C:18]([O:20][CH3:21])=[S:19])[S:15][C:16]=1[CH3:17].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([C:33](=O)[CH2:34]Br)[CH:28]=[CH:29][C:30]=1[O:31][CH3:32]>>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([C:33]2[N:10]=[C:11]([C:12]3[CH:13]=[C:14]([C:18]([O:20][CH3:21])=[S:19])[S:15][C:16]=3[CH3:17])[S:22][CH:34]=2)[CH:28]=[CH:29][C:30]=1[O:31][CH3:32]
Reactant: COC(=S)c1cc(C(N)=S)c(C)s1
Reactant: COc1ccc(C(=O)CBr)cc1OC
Agent: Cc1ccc(C([O-])=S)s1
Product: COC(=S)c1cc(-c2nc(-c3ccc(OC)c(OC)c3)cs2)c(C)s1
Yield: 89.2 %

Procedure:
Methyl 4-4-(3,4-dimetioxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate: 105 mg (0.424 mmol) of methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (Maybridge Chemical Co. LTD., Cornwall, U.K.) was reacted with 1-(3,4-dimethoxyphenyl)-2-bromoethan-1-one (0.467 mmol; 120 mg) in a manner similar to Example 22, step (a) to afford 148 mg (85% yield) of methyl 4-[4-(3,4-dimethoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[S:14]([C@H:17]1[CH2:21][N:20]([C:22]([C:24]2([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[CH2:26][CH2:25]2)=[O:23])[C@H:19]([C:34](O)=[O:35])[CH2:18]1)(=[O:16])=[O:15].[CH:37]1([NH:40][C:41](=[O:49])[C:42](=[O:48])[C@@H:43]([NH2:47])[CH2:44][CH2:45][CH3:46])[CH2:39][CH2:38]1>>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[S:14]([C@H:17]1[CH2:21][N:20]([C:22]([C:24]2([C:27]3[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=3)[CH2:25][CH2:26]2)=[O:23])[C@H:19]([C:34]([NH:47][C@@H:43]([CH2:44][CH2:45][CH3:46])[C:42](=[O:48])[C:41]([NH:40][CH:37]2[CH2:39][CH2:38]2)=[O:49])=[O:35])[CH2:18]1)(=[O:15])=[O:16]
Reactant: O=C(O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(N3CCOCC3)cc2Cl)CN1C(=O)C1(c2ccc(Cl)cc2)CC1
Reactant: CCC[C@H](N)C(=O)C(=O)NC1CC1
Product: CCC[C@H](NC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(N3CCOCC3)cc2Cl)CN1C(=O)C1(c2ccc(Cl)cc2)CC1)C(=O)C(=O)NC1CC1

Procedure:
The title compound was prepared in analogy to Example 1, using (2S,4R)-4-(2-Chloro-4-morpholin-4-yl-benzenesulfonyl)-1-[1-(4-chloro-phenyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid and (S)-3-Amino-2-oxo-hexanoic acid cyclopropylamide in step 1. MS (m/e)=719.20 [M+H+].
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[Br:13][CH2:14][CH2:15]O>CO.ClCCl>[Br:13][CH2:14][CH2:15][C:2]([C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4])=[O:1]
Reactant: OCCBr
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: ClCCl
Solvent: CO
Product: O=C(CCBr)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 25 °C
Reaction time: 4 h

Procedure:
DOWEX 50Wx4 resin (Alfa Aesar, Ward Hill, Mass.) was washed with deionized water to remove color. A mixture of 225 gm D-glucose (1.25 mol; 1 equiv., Alfa Aesar) and 140 gm DOWEX 50Wx4 was treated with 2.2 L 2-bromoethanol (30.5 mol, 25 equiv.; 124.97 gm/mol; 1.762 gm/mL; BP=150 C; Alfa Aesar) and the stirred mixture heated to 80 C for 4 hours. The reaction was monitored by TLC (20% methanol/dichloromethane (DCM)). Reaction was complete after about four hours, and it was allowed to cool to room temperature. The solution was filtered to remove the resin, and the resin washed with ethyl acetate and DCM. The resulting filtrate was stripped to an amber oil in a rotory evaporator to give a total of 400 g after stripping.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH:3]([OH:8])[CH2:4][CH2:5][CH2:6][CH3:7].[C:11](=O)(OCC)[O:12][CH2:13]C.[OH-].[K+]>C(O)C>[OH:8][CH:3]([C:4]1([CH2:5][CH2:6][CH3:7])[CH2:13][O:12][CH2:11]1)[C:2]([F:10])([F:9])[F:1]
Reactant: CCOC(=O)OCC
Reactant: CCCCC(O)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCC1(C(O)C(F)(F)F)COC1
Reaction time: 0.5 h

Procedure:
A mixture of 3,3-di-hydroxymethyl)-1,1,1-trifluorohexan-2-ol (2.8 g.), diethyl carbonate (1.6 ml.), potassium hydroxide (0.1 g) and dry ethanol (4.0 mls) was refluxed gently (oil bath 110°), under a current of nitrogen, for 30 minutes. The ethanol was then removed by distillation. Distillation gave (3-(1-hydroxy-2,2,2-trifluoroethyl)-3-n-propyloxetane (1.7 g.), a colourless oil (b.p. 112°, 20-25 m.m.).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][N:4]([CH3:7])[N:3]=1.C[O:9][C:10]([C:12]1[CH:22]=[C:21]([O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26]([F:32])[CH:25]=2)[C:15]2[CH2:16][C:17]([CH3:20])([CH3:19])[O:18][C:14]=2[CH:13]=1)=O>>[CH3:7][N:4]1[CH:5]=[CH:6][C:2]([NH:1][C:10]([C:12]2[CH:22]=[C:21]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26]([F:32])[CH:25]=3)[C:15]3[CH2:16][C:17]([CH3:20])([CH3:19])[O:18][C:14]=3[CH:13]=2)=[O:9])=[N:3]1
Reactant: Cn1ccc(N)n1
Reactant: COC(=O)c1cc(Oc2ccc(C#N)c(F)c2)c2c(c1)OC(C)(C)C2
Product: Cn1ccc(NC(=O)c2cc(Oc3ccc(C#N)c(F)c3)c3c(c2)OC(C)(C)C3)n1

Procedure:
The title compound was prepared in a similar manner as described for Example 1, from 3-amino-1-methyl-pyrazole (478 mg, 4.92 mmol) and 4-(4-cyano-3-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (183a) (168 mg, 0.49 mmol) to give a white solid (176 mg, 88% yield). 1H NMR (400 MHz, CDCl3) δ 9.19 (s, 1 H) 7.56 (dd, J=8.59, 7.33 Hz, 1 H) 7.16-7.32 (m, 1 H) 7.07 (d, J=3.03 Hz, 2 H) 6.68-6.83 (m, 3 H) 3.71 (s, 3 H) 2.87 (s, 2 H) 1.48 (s, 6 H); LCMS for C22H19FN4O3 m/z 407.00 (M+H+).
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=2)[C:10](=[O:11])[NH:9][C:8](=[O:12])[NH:7]1)[CH:2]=[CH2:3].Br[C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([C:29]([F:32])([F:31])[F:30])[CH:22]=1>CC(N(C)C)=O.[Cu-]=O>[O:12]=[C:8]1[NH:7][C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=2)([CH2:5][O:4][CH2:1][CH:2]=[CH2:3])[C:10](=[O:11])[N:9]1[C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([C:29]([F:30])([F:32])[F:31])[CH:22]=1
Reactant: C=CCOCC1(c2cccc(C)c2)NC(=O)NC1=O
Reactant: N#Cc1ccc(Br)cc1C(F)(F)F
Agent: O=[Cu-]
Solvent: CC(=O)N(C)C
Product: C=CCOCC1(c2cccc(C)c2)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Temperature: 130 °C

Procedure:
To a solution of 4-[(2-propenyloxy)methyl]-4-(3-methylphenyl)imidazolidine-2,5-dione (899 mg) and 4-bromo-2-(trifluoromethyl)benzonitrile (863 mg) in DMAC (5 mL) is added copper (I) oxide (395 mg). The mixture is refluxed overnight at 130° C. The mixture is concentrated, taken in ethyl acetate, washed with a 10% aqueous ammonia solution and brine. The organic phase is dried over magnesium sulfate, concentrated under vacuum and purified on silica gel (ethyl acetate/cyclohexane 0/100 to 50/50) to give the desired compound.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:22][CH3:23])[CH2:4][NH:5][C:6](=[O:21])[C@H:7]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH2:8][C:9]#[CH:10].[F:24][C:25]([F:44])([F:43])C1C=C(S(N[C@H](CC#C)C(O)=O)(=O)=O)C=CC=1>>[CH3:23][O:22][CH:3]([O:2][CH3:1])[CH2:4][NH:5][C:6](=[O:21])[C@H:7]([NH:11][S:12]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([C:25]([F:44])([F:43])[F:24])[CH:20]=1)(=[O:14])=[O:13])[CH2:8][C:9]#[CH:10]
Reactant: C#CC[C@@H](NS(=O)(=O)c1cccc(C(F)(F)F)c1)C(=O)O
Reactant: C#CC[C@@H](NS(=O)(=O)c1ccccc1)C(=O)NCC(OC)OC
Product: C#CC[C@@H](NS(=O)(=O)c1cccc(C(F)(F)F)c1)C(=O)NCC(OC)OC

Procedure:
Using the same procedure describe for the synthesis of 39, (R)-2-(3-trifluoromethylbenzenesulfonamido)pent-4-ynoic acid afforded the title compound. 1H NMR (300 MHz, CDCl3): δ 2.05 (s, 1H), 2.65 (m, 2H), 2.85 (s, 3H), 2.96 (s, 3H), 3.35 (m, 2H), 3.96 (t, 6.3 Hz, 1H), 4.32 (t, 5.4 Hz, 1H), 6.86 (t, 5.4 Hz, 1H), 7.68 (t, 7.8 Hz, 1H), 7.82 (d, 7.8 Hz, 1H), 7.97 (s5; 1H), 8.03 (d, 7.8 Hz, 1H), 8.11 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8](F)[CH:9]=1)[C:5]#[N:6].Br[C:12]1C=CC=C(Br)C=1C.CN(C=O)C.[Cu]C#N>N1C=CC=CC=1>[Br:1][C:2]1[C:3]([CH3:12])=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6]
Reactant: N#Cc1cc(F)cc(Br)c1
Reactant: Cc1c(Br)cccc1Br
Agent: N#C[Cu]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cc1c(Br)cccc1C#N
Yield: 35 %

Procedure:
This compound was prepared in a manner similar to that described for 3-bromo-5-fluorobenzonitrile from commercially available 2,6-dibromotoluene (1.80 g, 7.20 mmol), DMF (11 mL), pyridine (1.1 mL), and copper (I) cyanide (0.52 g, 5.76 mmol). The crude product was purified by flash column chromatography (100 mL silica, hexane) to afford 50 mg (35%) of 3-bromo-2-methylbenzonitrile. Data for 3-bromo-2-methylbenzonitrile: 1H NMR (400 MHz, acetone-d6) 7.88 (d, J=8.0, 1H), 7.73 (d, J=8.0, 1H), 7.32 (t, J=15.8, 7.9, 1H), 2.58 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][C:24](=[O:27])[CH2:25]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][C:24](=[O:27])[CH2:25][N:14]1[CH2:13][CH:12]=[C:11]([C:6]2[C:5]3[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=3)[NH:8][CH:7]=2)[CH2:16][CH2:15]1
Reactant: Clc1ccc2c(C3=CCNCC3)c[nH]c2c1
Reactant: O=C(CCl)Nc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CN1CC=C(c2c[nH]c3cc(Cl)ccc23)CC1)Nc1ccccn1
Temperature: 90 °C
Yield: 30.4 %

Procedure:
A mixture of 5.0 gm (21.5 mMol) 6-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole, 4.0 gm (23.6 mMol) N-(2-pyridinyl)-2-chloroacetamide and 4.45 gm (32 mMol) potassium carbonate in 25 mL dimethylformamide were heated to about 90° C. for 2 hours under nitrogen. The reaction mixture was concentrated under reduced pressure and was then partitioned between chloroform and water. The organic phase was separated, washed sequentially with water and saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue was crystallized from ethanol to give 2.4 gm (30.4%) of the title compound as a yellow solid.
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[CH3:17][O:18][C:19](=[O:31])[CH2:20][C@H:21]1[C:25]2[CH:26]=[CH:27][C:28]([OH:30])=[CH:29][C:24]=2[O:23][CH2:22]1.[Br:32][C:33]1[CH:41]=[CH:40][C:39]([F:42])=[C:38]2[C:34]=1[CH2:35][CH2:36][C@@H:37]2O.C(P(CCCC)CCCC)CCC.C([O-])(O)=O.[Na+]>O1CCCC1>[CH3:17][O:18][C:19](=[O:31])[CH2:20][C@H:21]1[C:25]2[CH:26]=[CH:27][C:28]([O:30][C@H:37]3[C:38]4[C:34](=[C:33]([Br:32])[CH:41]=[CH:40][C:39]=4[F:42])[CH2:35][CH2:36]3)=[CH:29][C:24]=2[O:23][CH2:22]1
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Reactant: O[C@H]1CCc2c(Br)ccc(F)c21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: CCCCP(CCCC)CCCC
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Reaction time: 0.5 h

Procedure:
A solution of di-tert-butyl azodicarboxylate (18.0 g) in tetrahydrofuran (80 mL) is added dropwise over 45 min to a solution of [(S)-6-hydroxy-2,3-dihydro-benzofuran-3-yl]-acetic acid methyl ester (11.0 g), (S)-4-bromo-7-fluoro-2,3-dihydro-1H-inden-1-ol (12.0 g) and tributylphosphine (19.3 mL) in tetrahydrofuran (320 mL) at −10° C. The resulting solution is stirred for 30 min and then poured into saturated aqueous NaHCO3 solution. The mixture is extracted with dichloromethane, and the combined organic phases are dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 90:10→70:30) to give the title compound. LC (method 1): tR=1.41 min; Mass spectrum (ESI+): m/z=421 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:16][CH3:17])=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[F:18][C:19]1[CH:25]=[C:24]([CH3:26])[C:23]([OH:27])=[CH:22][C:20]=1[NH2:21].Cl>C1(O)CCCCC1.CCOCC>[F:18][C:19]1[CH:25]=[C:24]([CH3:26])[C:23]([OH:27])=[CH:22][C:20]=1[NH:21][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:16][CH3:17])=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(F)c(N)cc1O
Reactant: COC(=O)c1cc2c(Cl)ccnc2cc1OC
Agent: Cl
Solvent: OC1CCCCC1
Solvent: CCOCC
Product: COC(=O)c1cc2c(Nc3cc(O)c(C)cc3F)ccnc2cc1OC
Temperature: 100 °C

Procedure:
A suspension of 4-chloro-7-methoxy-6-methoxycarbonylquinoline (0.252 g, 1 mmol), (prepared as described for the starting material in Example 55), and 2-fluoro-5-hydroxy-4-methylaniline (0.15 g, 1.2 mmol), (prepared as described for the starting material in Example 1), in cyclohexanol (5 ml) containing 1M ethereal hydrogen chloride (1.2 ml) was heated at 100° C. for 2 hours. The mixture was cooled to ambient temperature and diluted with ether. The solid was collected by filtration then absorbed onto silica using methylene chloride/methanol (1/1) containing ammonium hydroxide (1 ml). The product was eluted with methylene chloride/methanol (100/0 increasing to 94:6). Removal of the solvent by evaporation and trituration of the solid with ether followed by collection of the solid by filtration gave 4-(2-fluoro-5-hydroxy-4-methylanilino)-7-methoxy-6-methoxycarbonylquinoline as a cream solid. (195 mg, 54%).
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([NH2:13])=[N:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>>[CH2:1]([C:8]1[S:12][C:11]([NH:13][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=2[O:23][CH3:22])=[N:10][C:9]=1[C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(-c2nc(N)sc2Cc2ccccc2)cc1
Reactant: COc1ccccc1C(=O)Cl
Product: COc1ccc(-c2nc(NC(=O)c3ccccc3OC)sc2Cc2ccccc2)cc1
Yield: 65.6 %

Procedure:
A procedure similar to that in Example 4 was used. 5-benzyl-4-(4-methoxy-phenyl)-thiazol-2-ylamine prepared in Example 1 and o-methoxybenzoyl chloride prepared in the step 1 were used as starting materials, allowed to react at room temperature overnight, followed by post-treatment to obtain a crude product, which was purified by a silica gel column chromatography eluted with a gradient of dichloromethane and ethyl acetate (100:0-10:1) to obtain a product as a white solid in a yield of 65.6%, mp: 147-148└. 1H-NMR (CDCl3, 400 MHz) δ: 3.84 (3H, s, OCH3), 4.09 (3H, s, OCH3), 4.21 (2H, s, CH2), 6.97 (2H, d, J=8.68 Hz, ArH), 7.05 (1H, d, J=8.12 Hz, ArH), 7.14 (1H, t, J=8.12 Hz, ArH), 7.22˜7.32 (5H, m, ArH), 7.53˜7.56 (3H, m, ArH), 8.28 (1H, dd, J=7.84 Hz, 1.68 Hz, ArH), 11.05 (1H, br, CONH); EI-MS m/e (%): 430.2 (M+, 89), 135.1 (100); HREI-MS Calcd. for C25H22N2O3S: 430.1351. found: 430.1357.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:8]=[C:7]([O:9][CH:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)[CH:6]=[N:5][CH:4]=1>CO>[Cl:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([O:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[N:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cncc(Cl)n2)CC1
Agent: Cl
Solvent: CO
Product: Clc1cncc(OC2CCNCC2)n1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
Aqueous 3.0 M HCl (12 mL) was added to a solution of the product obtained in Step 1 above (5.00 g, 15.9 mmol) in methanol (200 mL). The reaction mixture was stirred at 50° C. for 5 h and concentrated in vacuo. The residue was dissolved in water (50 mL) and basified with K3PO4. The aqueous phase was extracted with ethyl acetate (5×40 mL), dried (MgSO4), and concentrated in vacuo. This gave 3.08 g (91%) of the title compound as a colorless oil which slowly decomposed upon standing. HRMS m/z calcd for C9H12ClN3O (M)+ 213.0669, found 213.0663.