Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:3]=1.[NH3:17]>C(O)CO>[NH2:17][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:3]=1
Reactant: N
Reactant: Fc1ccc2nc(C(F)(F)F)cc(Cl)c2c1
Solvent: OCCO
Product: Nc1cc(C(F)(F)F)nc2ccc(F)cc12
Temperature: 25 °C

Procedure:
A mixture of 4-chloro-6-fluoro-2-(trifluoromethyl)quinoline (1 g, 4.01 mmol) and NH3 (3 mL) in ethylene glycol (20 mL) is prepared at −78° C. in a sealed tube. After warming up to room temperature, the sealed tube is gradually heated to 100° C. overnight. After cooling to −78° C., the sealed tube is opened and the contents are concentrated by rotary evaporator. The residue is purified by flash chromatography on silica gel (1:3 EtOAc/hexanes) to give 4-amino-6-fluoro-2-(trifluoromethyl)quinoline as a light yellow solid.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:14][O:15][C:16]=2[C:17]([F:20])([F:19])[F:18])=[N:6][CH:5]=1.COC(=O)[C:31]1C=CC(OCC2C(C3C=CC(Cl)=CC=3)=NOC=2C)=[N:33][CH:32]=1.C(N)C>>[CH2:32]([NH:33][C:3](=[O:2])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:14][O:15][C:16]=2[C:17]([F:18])([F:19])[F:20])=[N:6][CH:5]=1)[CH3:31]
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C(F)(F)F)nc1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(Cl)cc3)noc2C)nc1
Agent: CCN
Product: CCNC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C(F)(F)F)nc1

Procedure:
As described for example 117, 6-(3-phenyl-5-trifluoromethyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (100 mg, 0.26 mmol), 6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (144 mg, 0.4 mmol) was converted, using ethylamine (2 M in THF) instead of 2,2,2-trifluoroethylamine, to the title compound (80 mg, 77 which was obtained as a white solid. MS: m/e=392.3 [M+H]+.
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH:13]=[CH:14][C:15]([O:20]C)=[CH:16][C:17]=4[CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@:4]2([C:26](=[O:28])[CH3:27])OC(=O)C)[CH3:2].[Li].N.CO>O1CCOCC1>[CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17]([CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[C:26](=[O:28])[CH3:27])=[CH:16][C:15](=[O:20])[CH2:14][CH2:13]4)[CH3:2]
Reactant: CC[C@]12CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@@H]1CC[C@@]2(OC(C)=O)C(C)=O
Agent: N
Agent: [Li]
Solvent: CO
Solvent: C1COCCO1
Product: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2C(C)=O
Yield: 36.7 %

Procedure:
Add 13β-ethyl-3-methoxy-17α-acetyl-17β-acetoxy-gona-1,3,5(10)triene (0.24 g.) in dioxan (5 cc.) to a stirred solution of lithium (0.15 g.) in liquid ammonia (100 cc.). After 30 minutes add methanol (8 cc.) followed by lithium (0.5 g.) in small pieces. Add water, extract with ether and work up to a gum (0.218 g.). Reflux this product with 4N hydrochloric acid (5 cc.) and methanol (8 cc.) for 15 minutes. Add water, extract with ether, work up and dissolve the resulting gum in acetone (30 cc.) containing anhydrous magnesium sulphate (0.5 g.) and add 8N-chromic acid dropwise with swirling until the solution assumes a permanent yellowish-orange color. Add excess isopropanol and evaporate the solution almost to dryness. Add water, extract with ether, wash, dry and evaporate the organic solution, filter the product through alumina with benzene-ether and recrystallize the product from ethyl acetate to obtain the title product (0.072 g.), m.p. 138°-142°; infrared absorption peaks at 5.9, 6 μ.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[OH:14][C:15]1[CH:16]=[C:17]([CH:24]=[CH:25][CH:26]=1)[O:18][CH2:19][CH2:20][CH2:21][C:22]#[N:23].[OH-].[Na+]>CS(C)=O>[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][C:4]=1[CH2:3][O:14][C:15]1[CH:16]=[C:17]([CH:24]=[CH:25][CH:26]=1)[O:18][CH2:19][CH2:20][CH2:21][C:22]#[N:23]
Reactant: N#CCCCOc1cccc(O)c1
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: N#CCCCOc1cccc(OCc2ccc3ccccc3n2)c1
Yield: 66.3 %

Procedure:
A mixture of 15.3 g of 2-chloromethylquinoline hydrochloride, 12.6 g of 4-(3-hydroxyphenoxy)butyronitrile and 5.7 g of sodium hydroxide was stirred with 80 ml of dimethylsulfoxide at room temperature for 4 hours. The reaction mixture was partitioned between water and ether. The ether extract was evaporated to yield 23.9 g, of crude product. Crystallization from ethyl acetate:hexane and then from ethanol:hexane gave 15 g of grey needles, m.p. 84°-85° C.
Reaction SMILES: C[O:2][C:3]1[C:8]2[CH:9]=[N:10][S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.Br>C(O)(=O)C.[Ta]>[OH:2][C:3]1[C:8]2[CH:9]=[N:10][S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2sncc12
Agent: [Ta]
Agent: Br
Solvent: CC(=O)O
Product: Oc1cccc2sncc12
Yield: 69.9 %

Procedure:
50 g of 4-methoxy-1,2-benzisothiazole are suspended in 700 ml of acetic acid containing 10% by weight of hydrogen bromide and 5 g of red phosphorus, and the suspension is heated in a tantalum autoclave at 100° C. for 30 hours. When it has cooled, the product is concentrated under reduced pressure and the residue is partitioned between methylene chloride and 2 N sodium hydroxide solution. The aqueous phase is freed from insoluble matter by filtration, and is washed with methylene chloride, acidified with hydrochloric acid and finally extracted repeatedly with methylene chloride. The combined extracts are dried over magnesium sulfate and concentrated under reduced pressure. 32 g (65% of theory) of 4-hydroxy-1,2-benzisothiazole of melting point 133°-134° C. are obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[N:18]([S:22]([C:25]1[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=1)(=[O:24])=[O:23])[C:17]1[CH:16]=[N:15][C:14]([C:32](=[O:34])[CH3:33])=[C:13]([CH2:35][O:36][CH3:37])[C:12]2=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-:38].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[N:18]([S:22]([C:25]1[CH:26]=[CH:27][C:28]([CH3:29])=[CH:30][CH:31]=1)(=[O:24])=[O:23])[C:17]1[CH:16]=[N:15][C:14]([C:32](=[O:34])[CH2:33][Br:38])=[C:13]([CH2:35][O:36][CH3:37])[C:12]2=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [Br-]
Reactant: COCc1c(C(C)=O)ncc2c1c1cc(OCc3ccccc3)ccc1n2S(=O)(=O)c1ccc(C)cc1
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: COCc1c(C(=O)CBr)ncc2c1c1cc(OCc3ccccc3)ccc1n2S(=O)(=O)c1ccc(C)cc1

Procedure:
2.29 g of 6-benzyloxy-4-methoxymethyl-3-acetyl-9-tosyl-β-carboline is stirred with the double molar amount of phenyltrimethylammonium tribromide in 100 ml of absolute tetrahydrofuran for 4 days at room temperature. The reaction mixture is evaporated to dryness, taken up in methylene chloride, washed with saturated NaCl solution, dried on Sikkon and concentrated by evaporation. The crude product is chromatographed on silica gel (cyclohexane/ethyl acetate=8+2). 1.9 g of 6-benzyloxy-3-bromoacetyl-4-methoxymethyl-9-tosyl-β-carboline is obtained. Melting point 165° C. (decomposition).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[O:10][CH3:11].[Li]CCCC.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C1COCC1>[F:1][C:2]1[C:3]([O:10][CH3:11])=[CH:4][CH:5]=[C:6]([O:8][CH3:9])[C:7]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)Cl
Reactant: COc1ccc(OC)c(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1c(OC)ccc(OC)c1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 68.3 %

Procedure:
To a solution of 2-fluoro-1,4-dimethoxybenzene (8.1 g, 52.0 mmol) in anhydrous THF at −78° C., n-BuLi (2.5 M in hexane, 22 mL, 55 mmol) was added dropwise. The resulting mixture was stirred at −78° C. for 1 h, and then ethyl chloroformate (5 mL, 52.1 mmol) was added dropwise. The reaction mixture was stirred at −78° C. for additional 2 h and quenched with water (200 mL). The mixture was extracted with ethyl acetate (2×180 mL). The combined organic layers were washed with brine (200 mL), dried (Na2SO4), and concentrated in vacuo. The residue was purified by silica gel column chromatography (1:5 EtOAc/petroleum ether) to give ethyl 2-fluoro-3,6-dimethoxybenzoate (8.1 g).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:32]=[CH:33][C:34]=1[N+:35]([O-:37])=[O:36])[C:8]([C:10]1[N:18]2[C:13]([CH:14]=[C:15]([NH:19][CH3:20])[CH:16]=[CH:17]2)=[C:12]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[C:11]=1[CH3:31])=[O:9].[CH3:38]I.Cl>CN(C)C=O.ClCCl>[CH3:20][N:19]([CH3:38])[C:15]1[CH:16]=[CH:17][N:18]2[C:13]([CH:14]=1)=[C:12]([C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[C:11]([CH3:31])=[C:10]2[C:8](=[O:9])[C:7]1[CH:32]=[CH:33][C:34]([N+:35]([O-:37])=[O:36])=[C:5]([O:4][CH3:3])[CH:6]=1
Reactant: CI
Reactant: CNc1ccn2c(C(=O)c3ccc([N+](=O)[O-])c(OC)c3)c(C)c(C(=O)OCc3ccccc3)c2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(C(=O)c2c(C)c(C(=O)OCc3ccccc3)c3cc(N(C)C)ccn23)ccc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 0.17 h
Yield: 81.1 %

Procedure:
80 mg (1.67 mmol) of sodium hydride (60% as a dispersion in oil) at room temperature are added in portions to 525 mg (1.11 mmol) of benzyl [3-(3-methoxy-4-nitrobenzoyl)-2-methyl-7-methylaminoindolizin-1-yl]carboxylate in solution in 10 mL of dimethylformamide. After 10 minutes, 138 μL (2.22 mmol) of methyl iodide are added to the reaction mixture. The medium is stirred at 40° C. for 2 hours, poured into a molar solution of hydrochloric acid and then extracted with ethyl acetate. The organic phase is washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The solid obtained is taken up in dichloromethane and filtered. 439 mg of a light orange-coloured solid are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([C:11]3[N:12]=[C:13]([CH:16]4[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]4)[S:14][CH:15]=3)[N:6]2[N:5]=[CH:4][N:3]=1.[Br:29]N1C(C)(C)C(=O)N(Br)C1=O>CN(C=O)C.CC(O)=O>[NH2:1][C:2]1[C:7]2=[C:8]([Br:29])[CH:9]=[C:10]([C:11]3[N:12]=[C:13]([CH:16]4[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]4)[S:14][CH:15]=3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc4c(N)ncnn34)cs2)CC1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3cc(Br)c4c(N)ncnn34)cs2)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 109.1 %

Procedure:
To a cooled (−20° C.) solution of tert-butyl 4-[4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-1,3-thiazol-2-yl]piperidine-1-carboxylate (914 mg. 2.28 mmol) in DMF (12.6 mL) and AcOH (5 mL) was added 1,3-dibromo-5,5-dimethylhydantoin (326 mg, 1.14 mmol) in 3 portions over 10 minutes. The mixture was stirred at 0° C. for 3 h. The reaction was quenched with the addition 5% aqueous K2CO3 (50 mL) and was allowed to warm to rt. The mixture was extracted with ethyl acetate (3×50 mL). The combined organics were washed with brine, dried (Na2SO4) and evaporated. The crude material was purified by ISCO® chromatography using a gradient of 50% to 75% ethyl acetate in hexanes to afford 596 mg (54%) of the desired product. ES-MS m/z 480.85 [M+H]+, HPLC RT (min) 3.45.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([C:13]#[N:14])[CH:11]=2)[N:6]=[CH:5][CH:4]=1.CO.[F:19][C:20]1[CH:26]=[C:25]([CH3:27])[C:24]([OH:28])=[CH:23][C:21]=1[NH2:22]>C(O)(C)C>[ClH:2].[C:13]([C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][C:9]=1[O:15][CH3:16])[N:6]=[CH:5][CH:4]=[C:3]2[NH:22][C:21]1[CH:23]=[C:24]([OH:28])[C:25]([CH3:27])=[CH:26][C:20]=1[F:19])#[N:14]
Reactant: COc1cc2nccc(Cl)c2cc1C#N
Reactant: Cc1cc(F)c(N)cc1O
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Product: COc1cc2nccc(Nc3cc(O)c(C)cc3F)c2cc1C#N
Yield: 48.9 %

Procedure:
A mixture of 4-chloro-6-cyano-7-methoxyquinoline hydrochloride (500 mg, 2 mmol), (prepared by an analogous procedure to that described for the starting material in Example 1 but using methanol instead of 2-methoxyethanol), and 2-fluoro-5-hydroxy-4-methylaniline (141 mg, 1 mmol), (prepared as described for the starting material in Example 1), in isopropanol (10 ml) was heated at reflux for 4 hours. The mixture was allowed to cool, the solid product was collected by filtration, washed with acetone and dried to give 6-cyano-4-(2-fluoro-5-hydroxy-4-methylanilino)-7-methoxyquinoline hydrochloride (176 mg, 54%) as a light brown solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.F[C:12]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:13]=1[C:14]#[N:15]>CN(C=O)C>[CH2:3]([O:10][C:12]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:13]=1[C:14]#[N:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCc1ccccc1
Reactant: N#Cc1cc(F)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cc(F)ccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
In a 12 L, 4-neck round bottom flask equipped with a mechanic stirrer and temperature probe, a suspension of sodium hydride (74 g, 1.82 mol) in DMF (1.95 L) was added benzyl alcohol (142 g, 1.3 mol) through a dropping funnel slowly over 30 minutes in an ice bath under nitrogen. The mixture was stirred in an ice bath (0° C.) for 120 minutes, a solution of 2,5-difluorobenzonitrile (180 g, 1.3 mol) in DMF (650 mL) was added through a dropping funnel over 35 minutes. The resulting mixture was warmed up to room temperature. After 2 hours, the mixture was cooled in an ice bath (4° C.) and quenched with saturated NH4Cl (130 mL) followed by the addition of water (2.6 L×3). The slurry was stirred at room temperature overnight and the precipitate was filtered and washed with water (650 mL×3). The solid was dried in vacuum for 2 days to give 292 g (99.3%) of the desired compound. 1H NMR (400 MHz, DMSO-d6) δ 7.78 (dd, 1H, J=3.2 Hz, J=8.2 Hz), 7.5-7.76 (m, 1H), 7.35-7.48 (m, 6H), 5.28 (s, 2H).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:50]=[CH:49][C:10]([CH2:11][N:12]([C:31]2[CH:40]=[CH:39][C:38]3[C:33](=[CH:34][CH:35]=[C:36]([O:41]CC4C=CC=CC=4)[CH:37]=3)[CH:32]=2)[C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)[CH:15]=2)=[CH:9][CH:8]=1>C1(OC)C=CC=CC=1.CO>[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][N:12]([C:31]2[CH:40]=[CH:39][C:38]3[C:33](=[CH:34][CH:35]=[C:36]([OH:41])[CH:37]=3)[CH:32]=2)[C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)[CH:15]=2)=[CH:49][CH:50]=1
Reactant: COc1ccc(CN(C(=O)c2ccc(OC)c(-c3cccc(OC)c3)c2)c2ccc3cc(OCc4ccccc4)ccc3c2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1
Solvent: CO
Product: COc1ccc(CN(C(=O)c2ccc(OC)c(-c3cccc(OC)c3)c2)c2ccc3cc(O)ccc3c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.2 %

Procedure:
A solution of AlCl3 (203 mg, 1.52 mmol) in anhydrous anisole (750 μl) was added to 38 (191 mg, 0.31 mmol) in anhydrous anisole (750 μl) and the resulting solution was stirred at room temperature for 18 hours. The reaction was diluted with MeOH (750 μl) and the solvent was concentrated. The residue was purified via column chromatography (SiO2, 1:1 EtOAc:Hexanes) to give 39 as a light yellow amorphous solid (126 mg, 77%): 1H NMR (CDCl3, 500 MHz) δ 7.56 (m, 1H), 7.50 (d, J=8.7 Hz, 1H), 7.47 (dd, J=8.6, 2.3 Hz, 1H), 7.36 (d, J=2.0 Hz, 1H), 7.29 (d, J=2.2 Hz, 1H), 7.25 (m, 2H), 7.12-7.06 (m, 3H), 7.00 (dd, J=8.7, 2.1 Hz, 1H), 6.80 (m, 2H), 6.77 (m, 1H), 6.73 (d, J=8.7 Hz, 1H), 6.59-6.55 (m, 2H), 5.43 (s, 1H), 5.15 (s, 2H), 3.77 (s, 3H), 3.71 (s, 3H), 3.62 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 170.2, 159.3, 159.0, 157.6, 154.2, 139.7, 139.0, 133.1, 132.4, 130.5, 130.1, 130.1 (2C), 130.0, 129.5, 128.9, 128.9, 128.0, 127.5, 127.3, 125.9, 122.1, 118.7, 114.7, 114.0 (2C), 113.2, 110.4, 109.5, 55.7, 55.4, 55.3, 54.0; IR (film) νmax 3236, 2934, 2835, 1599, 1508, 1456, 1437, 1394, 1248, 1177, 1036 cm−1; HRMS (ESI+) m/z: [M+H]+ calcd for C33H29NO5, 520.2124. found, 520.2120.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[F:10][C:11]1[CH:30]=[CH:29][C:14]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:23]([NH2:28])=[N:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][CH:17]=2)=[C:13]([CH3:31])[CH:12]=1>C1COCC1>[F:10][C:11]1[CH:30]=[CH:29][C:14]([O:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[C:23]4=[N:28][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:24]4[CH:25]=[CH:26][CH:27]=3)=[CH:20][CH:21]=2)=[C:13]([CH3:31])[CH:12]=1
Reactant: O=S(=O)(Cl)CCCl
Reactant: Cc1cc(F)ccc1Oc1ccc(-c2cccnc2N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1Oc1ccc(C2=CC=CN3CCS(=O)(=O)N=C23)cc1
Reaction time: 0.08 h

Procedure:
To a suspension of NaH (60%, 241 mg) in THF (dry) (25 mL) was added 2-chloroethanesulfonyl chloride (0.380 ml) at 0° C. and the mixture was stirred for 5 min at the same temperature. A solution of 3-(4-(4-fluoro-2-methylphenoxy)phenyl)pyridin-2-amine (354 mg) in THF (dry) (40 mL) was added at 0° C. and the mixture was stirred at room temperature overnight. The mixture was quenched with water at 0° C. Water, EtOAc and THF were added and the extracted organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was washed with IPE/EtOAc, dried in vacuo to give the title compound (375 mg) as a slightly yellow solid. A part of this was recrystallized from MeCN/IPE.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH2:9]([O:11][C:12]([CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)=[O:13])[CH3:10].Br[CH2:28][CH2:29][CH2:30][O:31][CH3:32]>C1COCC1>[CH2:9]([O:11][C:12]([C:14]1([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:16][CH2:15]1)=[O:13])[CH3:10]
Reactant: COCCCBr
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(CCCOC)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 3 h

Procedure:
To a pre-cooled THF solution (200 ml) under an argon atmosphere was added at −5° C. LDA (2M in THF/heptane/ethylbenzene, 16.24 ml) then dropwise piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (4.4 g, 4.2 ml) in THF (50 ml). The mixture was stirred between −5° C. to 0° C. for 3 hour and 1-bromo-3-methoxypropane (4.97 g) was added slowly at 0° C. The mixture was then stirred overnight at RT, the solvent was evaporated off, the residue taken up in ethyl acetate and washed with water then brine. The layers were separated, the organic layer dried over sodium sulphate and then evaporated off to give the desired 4-(3-methoxy-propyl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester a light brown oil (6.058 g) oil that was used in next reaction step without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[N:8]=[CH:7][C:6]([C:9]2([OH:16])[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[NH:18]1[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[O:24])[CH2:19]1>>[CH3:1][N:2]([CH3:17])[C:3]1[N:8]=[CH:7][C:6]([C:9]2([OH:16])[CH2:14][CH2:13][CH:12]([N:18]3[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=4)=[O:24])[CH2:19]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: CN(C)c1ccc(C2(O)CCC(=O)CC2)cn1
Product: CN(C)c1ccc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cn1

Procedure:
The title compounds were prepared as white solids from reductive amination of 4-(6-dimethylamino-pyridin-3-yl)-4-hydroxy-cyclohexanone, as prepared in the previous step, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step E of Example 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][C:13](=[O:17])[NH:14]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:18]([O:20][C:21]([C:23]1[C:27]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[C:26]([CH:33]=O)[NH:25][C:24]=1[CH3:35])=[O:22])[CH3:19].C(CCC1C(C(OCC)=O)=C(C)NC=1)(O)=O>>[CH2:18]([O:20][C:21]([C:23]1[C:27]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[C:26]([CH:33]=[C:12]2[C:11]3[C:15](=[CH:16][C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[CH:9][CH:10]=3)[NH:14][C:13]2=[O:17])[NH:25][C:24]=1[CH3:35])=[O:22])[CH3:19]
Reactant: O=C1Cc2ccc(-c3ccc(F)cc3)cc2N1
Reactant: CCOC(=O)c1c(C)[nH]c(C=O)c1CCC(=O)O
Agent: CCOC(=O)c1c(CCC(=O)O)c[nH]c1C
Product: CCOC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cc(-c4ccc(F)cc4)ccc32)c1CCC(=O)O

Procedure:
6-(4-Fluorophenyl)-1,3-dihydroindol-2-one (60 mg, 0.26 mmol) was condensed with 4-(2-carboxyethyl)-5-formyl-2-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (65 mg), prepared by formylation of 4-(2-carboxyethyl)-3-ethoxycarbonyl-2-methylpyrrole (Bulter, A. R., and George, S. D. (1993) Tetrahedron 49: 7017-7026), to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[C:15]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=2)[NH2:27])[CH2:20][CH2:19]1)(=[O:17])[CH3:16].C(N(CC)CC)C>CN1C(=O)CCC1>[C:15]([N:18]1[CH2:19][CH2:20][N:21]([C:24]2[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=2)[NH:27][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[CH2:22][CH2:23]1)(=[O:17])[CH3:16]
Reactant: CC(=O)N1CCN(c2cccc(N)c2)CC1
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(Nc2cccc(N3CCN(C(C)=O)CC3)c2)c([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
To a solution of methyl 4-chloro-3-nitrobenzoate (2.0 g, 9.28 mmol) in anhydrous NMP (5 ml) was added 2d (2.03 g, 9.28 mmol) and triethylamine (1.3 ml, 9.28 mmol). The mixture was heated with stirring to 80° C. overnight. The cooled solution was poured into ice-water (50 ml) and the resulting mixture was extracted with ethyl acetate (3×10 ml). The combined organic extracts were washed with water, dried over sodium sulfate and evaporated to dryness. The residue was triturated with petroleum ether to yield methyl 4-(3-(1-acetylpiperazin-4-yl)anilino)-3-nitrobenzoate (3.14 g, 85%) as red crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[Br:12]Br.Br>C(O)(=O)C.O>[Br:12][CH:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=2)[C:7]1=[O:11]
Reactant: O=C1CCc2cc(Cl)ccc21
Reactant: BrBr
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: O=C1c2ccc(Cl)cc2CC1Br

Procedure:
5-Chloroindan-1-one is reacted with bromine in glacial acetic acid using a catalytic amount of 48% strength HBr solution in water at room temperature. 2-Bromo-5-chloroindan-1-one is obtained with a melting point of 94-96° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[N:4][C:5]([F:10])=[C:6]([Cl:9])[C:7]=1F.[C-:12]#[N:13].[Na+]>CN(C)C=O>[C:12]([C:7]1[C:2]([Cl:1])=[C:3]([F:11])[N:4]=[C:5]([F:10])[C:6]=1[Cl:9])#[N:13]
Reactant: Fc1nc(F)c(Cl)c(F)c1Cl
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(Cl)c(F)nc(F)c1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 23.9 %

Procedure:
To a mixture of 40.4 g (0.200 mole) of 3,5-dichloro-2,4,6-trifluoropyridine in 50 ml of dimethylformamide that had been cooled to 0° C. was added slowly 10 g (0.20 mole) of sodium cyanide. After addition was complete the reaction was stirred at 0° C. for two hours and at room temperature of two hours. The dimethylformamide was distilled from the reaction mixture under reduced pressure, and the black residue was mixed with 200 ml of water. This mixture was extracted with ethyl acetate. The extracts were combined, and the ethyl acetate was evaporated, leaving a black residue weighing approximately 15 g. This residue was distilled, yielding approximately 10 g of 4-cyano-3,5-dichloro-2,6-difluoropyridine as a white solid.