Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].[CH2:5]([C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[CH2:6][CH3:7].[OH-].[K+]>C(O)C.O>[OH:4][CH2:3][CH2:2][O:20][C:17]1[CH:18]=[CH:19][C:14]([C@H:11]2[CH2:10][CH2:9][C@H:8]([CH2:5][CH2:6][CH3:7])[CH2:13][CH2:12]2)=[CH:15][CH:16]=1
Reactant: OCCBr
Reactant: CCC[C@H]1CC[C@H](c2ccc(O)cc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCC[C@H]1CC[C@H](c2ccc(OCCO)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Bromo-1-ethanol (5.0 g, 0.04 mol) and 4-(trans-4-propylcyclohexyl)phenol (4.4 g, 0.02 mol) were dissolved in ethanol (300 ml) and agitated at room temperature. To this solution was gradually dropwise added a solution of KOH (10 g) in water (20 ml), over 30 minutes, followed by stirring for 40 hours, distilling off about 200 ml of ethanol under reduced pressure, adding water (500 ml) to deposit solids, separating the solids from liquid, dissolving them in toluene (100 ml), filtering off insoluble matter, washing the toluene solution twice with 2N-NaOH, then three times with water, drying over anhydrous sodium sulfate, distilling off toluene and recrystallizing the resulting crystals from n-heptane to obtain the objective 1-(2-hydroxyethoxy)-4-(trans-4-propylcyclohexyl)benzene. Yield: 1.8 g (34%). C-S: 71.5° C. S-I: 81.4° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([F:11])[CH:5]=1.Cl.[CH3:14][NH:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([N:15]([CH3:16])[CH3:14])=[C:6]([F:11])[CH:5]=1
Reactant: COC(=O)c1ccc(F)c(F)c1
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(N(C)C)c(F)c1
Temperature: 55 °C
Reaction time: 5 h
Yield: 71 %

Procedure:
To a stirred solution of 38.7 g (225 mmol) 3.4-difluoro-benzoic acid methyl ester (Apollo) and 600 ml dimethylsulphoxid were added 22.3 g (270 mmol) dimethylamine hydrochloride and 65.4 g (473 mmol) potassium carbonate. The reaction mixture was stirred for 5 h at 55° C. in an autoclave and was reduced with high vacuum rotation evaporator at 65° C. The residue was diluted with dichloromethane, washed twice with water. The combined water phases were extracted with dichloromethane. The combined dichloromethane phases were washed with diluted sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. The oily crude product 3a was obtained in 71% yield (31.5 g, 160.0 mmol) and was used for the next step without purification.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[N:6]=1)(=O)=O.[I:25][C:26]1[N:27]=[CH:28][NH:29][CH:30]=1>>[I:25][C:26]1[N:27]=[CH:28][N:29]([C:5]2[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)[N:6]=2)[CH:30]=1
Reactant: CS(=O)(=O)c1nc(-c2cccc(C(F)(F)F)c2)cc(C(F)(F)F)n1
Reactant: Ic1c[nH]cn1
Product: FC(F)(F)c1cccc(-c2cc(C(F)(F)F)nc(-n3cnc(I)c3)n2)c1

Procedure:
The title compound was prepared 2-methanesulfonyl-4-trifluoromethyl-6-(3-trifluoromethyl-phenyl)-pyrimidine (example A.15) (1.1 g, 3 mmol) and commercially available 4-iodo-imidazole (0.70 g, 4 mmol) according to the general procedure IVa. Obtained as a white solid (0.96 g, 66%). MS (ISP) 485.2 [(M+H)+].
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][C:8]1[S:12][C:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:10][CH:9]=1)=[O:5])C>C(O)C>[C:16]([O:15][C:13]([C:11]1[S:12][C:8]([CH2:7][CH2:6][C:4]([OH:5])=[O:3])=[CH:9][CH:10]=1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: CCOC(=O)CCc1ccc(C(=O)OC(C)(C)C)s1
Solvent: CCO
Product: CC(C)(C)OC(=O)c1ccc(CCC(=O)O)s1
Yield: 88.8 %

Procedure:
The t-butyl 5-(2-ethoxycarbonylethyl)-2-thiophenecarboxylate (7.6 g, 26.8 mmol) prepared in the Preparative Example 15 was partially hydrolyzed in an ethanol/1N sodium hydroxide mixture at room temperature to give 6.1 g of 3-(5-t-butoxycarbonylthiophen-2-yl)propionic acid. This acid was dissolved in anhydrous tetrahydrofuran and the obtained solution was dropped into a solution of borane in tetra-hydrofuran, which had been preliminarily prepared from sodium borohydride (3.37 g, 89 ml) and trifluoroborane-diethyl ether complex (16.9 g, 119 mmol), under cooling with ice in about 30 minutes. The obtained mixture was stirred for 30 minutes, followed by the gradual dropwise addition of methanol. After the generation of hydrogen gas had discontinued, the reaction mixture was filtered and the filtrate was evaporated to dryness. Methanol was added to the residue to remove the boron compound by azeotropic distillation. The residue was dissolved in diethyl ether and the obtained solution was washed with a dilute hydrochloric acid and an aqueous solution of common salt, dehydrated and distilled to remove the solvent. The residue was evaporated to dryness in a vacuum to give 6.0 g of the compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:30])[NH:8][C:9]2[C:14]([C:15]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)=[O:23])[CH2:18][CH2:17]1)=[CH:13][C:12]([F:29])=[CH:11][N:10]=2)=[O:5])[CH3:2].Br[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:34]>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:30])[N:8]([CH2:32][C:33](=[O:34])[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:9]2[C:14]([C:15]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)=[O:23])[CH2:18][CH2:17]1)=[CH:13][C:12]([F:29])=[CH:11][N:10]=2)=[O:5])[CH3:2]
Reactant: O=C(CBr)c1ccccc1
Reactant: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2cc(F)cnc2[nH]c1=O
Product: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2cc(F)cnc2n(CC(=O)c2ccccc2)c1=O

Procedure:
This compound was prepared from 6-fluoro-2-oxo-4-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (80) and 2-bromoacetophenone according to General Procedure B. Yield 293 mg (38%), MP 262° C.; 1H-NMR (DMSO-d6): δ 1.29 (t, J=7.2 Hz, 3H), 3.19 (m, 4H), 3.92 (m, 4H), 4.32 (q, J=7.2 Hz, 2H), 5.88 (s, 2H), 7.16 (dd, J=3.6, 4.8 Hz, 1H), 7.47 (dd, J=1.2, 3.6 Hz, 1H), 7.61 (m, 2H), 7.72 (m, 1H), 7.81 (d, J=4.8 Hz, 1H), 8.11 (m, 2H), 8.18 (dd, J=2.8, 8.8 Hz, 1H), 8.65 (d, J=2.8 Hz, 1H); EIMS: 549 (M+1). Anal. (C28H25FN4O5S) C, H, N.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:9]([NH:11][CH3:12])=[O:10])[CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]1[S:21][C:22]([C:28]2[C:33]([F:34])=[CH:32][C:31]([C:35]([OH:38])([CH3:37])[CH3:36])=[CH:30][C:29]=2[F:39])=[CH:23][C:24]=1[C:25]([NH2:27])=[O:26]>>[F:39][C:29]1[CH:30]=[C:31]([C:35]([OH:38])([CH3:37])[CH3:36])[CH:32]=[C:33]([F:34])[C:28]=1[C:22]1[S:21][C:20]([NH:19][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([CH:8]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[C:9]([NH:11][CH3:12])=[O:10])[N:7]=2)=[C:24]([C:25]([NH2:27])=[O:26])[CH:23]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: CNC(=O)C(c1cccc(Br)n1)N1CCOCC1
Product: CNC(=O)C(c1cccc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)n1)N1CCOCC1

Procedure:
The title compound was synthesized from 2-(6-bromopyridin-2-yl)-N-methyl-2-morpholin-4-ylacetamide (120 mg, 0.38 mmol) and 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (125 mg, 0.40 mmol) according to the procedure described in Example 1.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][NH2:12].Cl[CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH:20]=[CH:21][C:22](=[O:28])[NH:23]2.C(N(C(C)C)CC)(C)C.[I-].[Na+]>CN(C=O)C>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][NH:12][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH:20]=[CH:21][C:22](=[O:28])[NH:23]2
Reactant: O=c1ccc2c(OCCCCl)cccc2[nH]1
Reactant: NCC1COc2ccccc2O1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=c1ccc2c(OCCCNCC3COc4ccccc4O3)cccc2[nH]1
Temperature: 80 °C
Yield: 11 %

Procedure:
2,3-Dihydro-1,4-benzodioxin-2-methanamine (0.56 g, 4.0 mmole), 5-(3-chloropropoxy)carbostyril (0.70 g, 3.1 mmole), diisopropylethylamine (0.65 g, 5.0 mmole) and sodium iodide (1.0 g, 6.5 mmole) were combined in 50 ml of DMF and heated at 80° C. for 24 hours under a nitrogen atmosphere. The solvent was then removed and replaced with 250 ml of dichloromethane. The mixture was washed with an equal volume of saturated aqueous sodium bicarbonate, with saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated in vacuum. The residue was column chromatographed on 50 g of silica gel with a gradient elution commencing with chloroform and ending with 2% methanol in chloroform. The product-containing fractions were combined and concentrated in vacuum and the residue crystallized from isopropanol with the addition of 4N isopropanolic HCl to give 125 mg of title compound as a tan solid, monohydrochloride, quarter hydrate, m.p. 242°-244° C.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[CH3:18][O:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22]Br>>[CH3:18][O:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][N:12]1[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2
Reactant: COc1ccccc1CBr
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Product: COc1ccccc1CN1N(C2C3CC4CC(C3)CC2C4)C(=O)C1(C)C

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 2-methoxybenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>>[Br:8][C:6]1[CH:7]=[C:2]([NH:1][S:17]([C:14]2[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=2)(=[O:19])=[O:18])[CH:3]=[C:4]([OH:9])[CH:5]=1
Reactant: Nc1cc(O)cc(Br)c1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Product: O=S(=O)(Nc1cc(O)cc(Br)c1)c1ccc(F)cc1
Yield: 104.6 %

Procedure:
3-Amino-5-bromophenol (300 mg, 1.4 mmol, prepared according to WO 2011119704 A1 20110929) was treated with 4-fluorobenzene-1-sulfonyl chloride (326 mg, 1.68 mmol) according to the method described in Preparation 15b to give 507 mg (99% yield) of the title compound as an oil. Purity 70%.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([NH:11]C(=O)OC(C)(C)C)=[N:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([NH2:11])=[N:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(C)(C)C)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)c1ccc(N)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a 0° C. solution of Example 59A (1.0 g, 40 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (3. mL, 40 mmol). The reaction mixture was stirred at ambient temperature for 3 hours then concentrated under reduced pressure. The residue was diluted with ethyl acetate (100 mL) and washed with saturated aqueous NaHCO3. The layers were separated and the aqueous phase was extracted with ethyl acetate (5×100 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide the title compound. MS (ESI+) m/z 151 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[Cl:9].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C1COCC1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:18]([CH3:17])(=[O:20])=[O:19])=[CH:4][C:3]=1[Cl:9]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(Br)c(Cl)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1ccc(Br)c(Cl)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 21.1 %

Procedure:
To a solution of Intermediate 62A (0.843 g, 4.08 mmol) in THF (20.41 mL) was added triethylamine (5.69 mL, 40.8 mmol) followed by methanesulfonyl chloride (0.414 mL, 5.31 mmol). The reaction mixture was allowed to stir at room temperature for 3 days, then quenched with a saturated aqueous solution of NaHCO3 and diluted with EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (2×). The organic phases were combined, dried over Na2SO4, filtered, and concentrated to afford the title compound (245 mg, 0.861 mmol, 21.09% yield) as a white solid. HPLC Ret timej: 1.32 min. MS (ES): m/z=284.2 [M+H]−. Intermediate 62 was used in the synthesis of Example 212.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]([C:19]([OH:21])=O)=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:22][C:23]([CH3:28])([CH3:27])[CH2:24][CH2:25][NH2:26]>>[CH3:22][C:23]([CH3:28])([CH3:27])[CH2:24][CH2:25][NH:26][C:19]([C:12]1[C:13]([C:15]([F:18])([F:17])[F:16])=[N:14][C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[N:10][CH:11]=1)=[O:21]
Reactant: CC(C)(C)CCN
Reactant: O=C(O)c1cnc(Nc2cccc(Cl)c2)nc1C(F)(F)F
Product: CC(C)(C)CCNC(=O)c1cnc(Nc2cccc(Cl)c2)nc1C(F)(F)F
Yield: 50.7 %

Procedure:
In a manner similar to Reference Example 1 (c) 2-(3-chlorophenylamino)-4-trifluoromethyl-pyrimidine-5-carboxylic acid (50 mg) and 3,3-dimethylbutylamine (17 mg, ex Aldrich) afforded the title compound (32 mg).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH:20]([C:21]([OH:23])=O)[CH2:19][C:18]2[CH:17]=[C:16]3[C:11]([O:12][C@@H:13]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=5)=[CH:27][CH:26]=4)[C:14](=[O:24])[NH:15]3)=[CH:10][C:9]=2[CH2:8]1)=[O:6])([CH3:3])[CH3:2].Cl.[CH3:42][O:43][C:44](=[O:60])[C@@H:45]([NH2:59])[CH2:46][C:47]1[CH:52]=[CH:51][C:50]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[CH:49][CH:48]=1>>[CH:1]([O:4][C:5]([N:7]1[CH:20]([C:21](=[O:23])[NH:59][C@H:45]([C:44]([O:43][CH3:42])=[O:60])[CH2:46][C:47]2[CH:52]=[CH:51][C:50]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)=[CH:49][CH:48]=2)[CH2:19][C:18]2[CH:17]=[C:16]3[C:11]([O:12][C@@H:13]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=5)=[CH:27][CH:26]=4)[C:14](=[O:24])[NH:15]3)=[CH:10][C:9]=2[CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccccc2)cc1
Reactant: CC(C)OC(=O)N1Cc2cc3c(cc2CC1C(=O)O)NC(=O)[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1C(=O)OC(C)C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)C(=O)N3

Procedure:
(S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylic acid 6-isopropyl ester (120 mg) was coupled with (S)-2-amino-3-biphenyl-4-yl-propionic acid methyl ester hydrochloride according to general procedure A to provide (S)-7-((S)-2-biphenyl-4-yl-1-methoxycarbonyl-ethylcarbamoyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylic acid isopropyl ester (151 mg, LC/MS: m/z 825).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][N:20]3[S:23]([C:26]3[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=3)(=[O:25])=[O:24])=[CH:16][CH:15]=2)=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:35]1C=C(S(Cl)(=O)=O)C=C(Cl)C=1>>[CH3:35][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][N:20]3[S:23]([C:26]3[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=3)(=[O:25])=[O:24])=[CH:16][CH:15]=2)=[O:13])=[CH:10][C:2]=1[Cl:1]
Reactant: O=C(Nc1ccc(C(=O)O)c(Cl)c1)c1ccc2c(c1)N(S(=O)(=O)c1cc(Cl)cc(Cl)c1)CC2
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Product: COC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(Cl)cc(Cl)c2)CC3)cc1Cl

Procedure:
2-Chloro-4-{[1-(3,5-dichloro-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid, m/z (ES+): 525.21 (M+H+.), was prepared in analogy to example 1, steps 1 to 5. Step 4 was performed using 3,5-dichloro-benzenesulfonyl chloride and yielded 2-chloro-4-{[1-(3,5-dichloro-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid methyl ester, which was hydrolyzed in step 5.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH3:12])=[C:10]([CH:13]=[S:14](=[O:16])=[O:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[C:11]([CH2:12][Br:17])=[C:10]([CH:13]=[S:14](=[O:16])=[O:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C=S(=O)=O)c(C)c1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(C=S(=O)=O)c(CBr)c1Cl

Procedure:
80 g (0.3 mol) of methyl 2-chloro-3-methyl-4-sulfonylmethylbenzoate in 11 of carbon tetrachloride are heated at 76° C. together with 54 g (0.31 mol) of N-bromosuccinimide and 1.5 g of azoisobutyronitrile for 6 h. The reaction mixture is filtered and freed from the solvent under reduced pressure. Yield: 104 g; m.p. 83-85° C.
Reaction SMILES: [NH:1]([C:8]1[N:9]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=[C:12](Cl)[N:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.Cl>O1CCOCC1>[NH:1]([C:8]1[N:9]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=[C:12]([N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[N:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNCC1
Reactant: O=c1cc(Nc2ccccc2)n(-c2ccccc2)c2nc(Cl)cc(C(F)(F)F)c12
Agent: Cl
Solvent: C1COCCO1
Product: O=c1cc(Nc2ccccc2)n(-c2ccccc2)c2nc(N3CCCCC3)cc(C(F)(F)F)c12
Temperature: 80 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a solution of 2-anilino-7-chloro-1-phenyl-5-(trifluoromethyl)-1,8-naphthyridin-4(1H)-one (100.0 mg, 0.241 mmol) in dioxane (2.5 mL) was added piperdine (40.9 mg, 0.481 mmol). The mixture was left to stir at 80° C. overnight. The mixture was cooled to room temperature, poured into 1N HCl (1 mL) and extracted with CH2Cl2. The organic extracts were combined, washed with saturated aqueous NaHCO3, dried over Na2SO4, and concentrated in vacuo. The residue was purified by Biotage silica gel chromatography (1:1 EtOAc:Hex) to provide 2-anilino-1-phenyl-7-(1-piperidinyl)-5-(trifluoromethyl)-1,8-naphthyridin-4(1H)-one (89.5 mg, 80%) as a pale yellow solid: LCMS RT: 2.76 min, MH+: 465.5.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:9]=[N:10][C:11]([Cl:14])=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].CN(C)CCN(C)C.C([Li])CCC.[C:29](=[O:31])=[O:30]>C(OCC)C.C1COCC1>[C:1]([O:5][C:6]([NH:7][C:8]1[C:13]([C:29]([OH:31])=[O:30])=[CH:12][C:11]([Cl:14])=[N:10][CH:9]=1)=[O:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)nc1
Reactant: O=C=O
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cnc(Cl)cc1C(=O)O
Temperature: -10 °C
Reaction time: 2 h

Procedure:
A solution of (6-chloro-pyridin-3-yl)-carbamic acid tert-butyl ester (4.19 g) in diethyl ether (150 mL) was cooled to −78° C. and N,N,N′,N′-tetramethylethylendiamine (6.60 g) was added. After slow addition of n-butyl lithium solution (1.32 M in hexane, 41.6 mL) over a time period of 10 minutes, the mixture was allowed to warm up to −10° C., stirred at this temperature for 2 hours and then was re-cooled to −78° C. The mixture was poured slowly into a stirred mixture of crushed dry ice in THF and stirred for 30 minutes. The mixture was concentrated on a rotary evaporator and water was added to the residue. The aqueous layer was washed 2× with MTB-ether and acidified with 6N hydrochloric acid to pH ˜3. The formed precipitate was filtered off, washed with water, ethyl acetate and dried in vacuum to afford 2.46 g of the title compound of the formula
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=1.[Cl:12]N1C(=O)CCC1=O>>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[C:5]([Cl:12])=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1ccnc(N)c1[N+](=O)[O-]
Product: Cc1c(Cl)cnc(N)c1[N+](=O)[O-]
Yield: 75.1 %

Procedure:
2-Amino-3-(6-chloro-3-methoxy-7-methyl-2H-pyrazolo[4,3-b]pyridin-2-yl)-2-methylpropionitrile (26 mg) was prepared using a procedure similar to that described in Example 1, part b, except starting from 1-(6-chloro-3-methoxy-7-methyl-2H-pyrazolo[4,3-b]pyridin-2-yl)propan-2-one (78 mg). 1-(6-Chloro-3-methoxy-7-methyl-2H-pyrazolo[4,3-b]pyridin-2-yl)propan-2-one was prepared using a procedure similar to that described in Example 105 part a to d except using 5-chloro-4-methyl-3-nitropyridine-2-carboxaldehyde (1.3 g) in part a to yield [2-(tert-butyldimethylsilanyloxy)propyl]-(5-chloro-4-methyl-3-nitropyridin-2-yl-methyl)amine (1.4 g, 57%). 5-Chloro-4-methyl-3-nitro-pyridine-2-carboxaldehyde was prepared using a procedure similar to that described in Example 136 part a to c except starting from 2-amino-5-chloro-4-methyl-3-nitropyridine (32 g) in part a to generate 2-bromo-5-chloro-4-methyl-3-nitropyridine (25.2 g, 59%). Oxidative cleavage using a 4% solution of osmium tetroxide in water (1.5 mL) and sodium periodate (2.5 g) was carried out in a mixture of THF and water (10:1, 60 mL) in part c instead of ozonolysis following a procedure similar to that described in Example 61 to afford 5-chloro-4-methyl-3-nitropyridine-2-carboxaldehyde (1.3 g, 56%) from 5-chloro-4-methyl-3-nitro-2-vinylpyridine (2.3 g). 2-Amino-5-chloro-4-methyl-3-nitropyridine (4.6 g, 75%) was prepared using a procedure similar to that described in Example 38 part a except starting from 2-amino-4-methyl-3-nitropyridine (5 g) and using N-chlorosuccinimide (5.8 g) instead of N-bromosuccinimide.
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:12]2[C:13]([CH3:16])=[N:14][S:15][C:11]=2[CH:10]=1.[ClH:22]>C(#N)C.[Cu](Cl)Cl>[Cl:22][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:12]2[C:13]([CH3:16])=[N:14][S:15][C:11]=2[CH:10]=1
Reactant: Cl
Reactant: Cc1nsc2cc(N)c([N+](=O)[O-])cc12
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: Cc1nsc2cc(Cl)c([N+](=O)[O-])cc12
Temperature: 65 °C

Procedure:
A mixture of tert-butyl nitrite (3.30 mL, 0.0278 mol) and copper(II) chloride (2.98 g, 0.0222 mol) in acetonitrile is heated to 65° C., treated portionwise with 6-amino-3-methyl-5-nitro-1,2-benzisothiazole (3.88 g, 0.0185 mol), stirred at 65° C., cooled to room temperature, and poured into 20% hydrochloric acid. The resultant aqueous mixture is extracted with ethyl acetate. The organic extracts are combined, washed with 20% hydrochloric acid, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a solid. Flash column chromatography of the solid using silica gel and methylene chloride/hexanes solutions (1:1 and 3:1) gives the title product as a pale, yellow solid (2.54 g, mp 156-158° C.) which is identified by NMR spectral analyses.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=1)[NH:8][CH2:7][CH2:6]2.[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1>>[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:9]2[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=2)=[O:34])=[CH:31][CH:30]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COc1ccc2c(c1)CCNC2Cc1ccc(OCc2ccccc2)cc1
Product: COc1ccc2c(c1)CCN(C(=O)c1ccc(F)cc1)C2Cc1ccc(OCc2ccccc2)cc1
Yield: 81.6 %

Procedure:
The title compound was prepared as described in Example 24.A, using 6-methoxy-1-[4-(phenylmethoxy)benzyl]-1,2,3,4-tetrahydroisoquinoline (0.72 g, 2.0 mmol) and 4-fluorobenzoyl chloride (0.475 g, 3.0 mmol) to provide the title compound (0.786 g, 82% yield): ES-MS (m/z) 482 [M+H]+.