Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:12]=1[CH2:13]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:12]=1[CH2:13][O:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=1
Reactant: OCc1ccc(O)cc1
Reactant: Clc1cccc(Cl)c1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: OCc1ccc(OCc2c(Cl)cccc2Cl)cc1
Temperature: 25 °C
Yield: 100710.4 %

Procedure:
A solution of 4-(hydroxymethyl)phenol (38.0 g, 0.31 mmol) and 2,6-dichlorobenzyl bromide (73.4 g, 0.31 mmol) in DMF (500 ml) was treated with caesium carbonate (100 g, 0.31 mmol) and heated to 60° for 16 h. The mixture was cooled to room temperature and the solvent evaporated in vacuo. The residue was partitioned between EtOAc (250 ml) and water (250 ml), the aqueous layer was separated and extracted with EtOAc (250 ml) and the combined organic layers washed with 10% hydrochloric acid (100 ml), NaHCO3 solution (100 ml) and brine (200 ml), dried (MgSO4) and the solvent evaporated in vacuo to give the title compound as a brown oil (88.4 g) which was used without further purification. δH (CDCl3) 7.38-7.21 (5H, m, ArH), 7.02 (2H, d, J 8.7 Hz, ArH), 5.28 (2H, s, CH2OAr) and 4.63 (2H, s, CH2OH).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:28][CH:27]=2)[C:8]2[C:13]([C:14]=1I)=[CH:12][C:11]([C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2].C([Mg]Cl)(C)C.[Li+].[Cl-].[C:45](=[O:47])=[O:46]>C1COCC1>[CH3:2][CH2:1][O:3][C:4]([C:6]1[N:7]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:28][CH:27]=2)[C:8]2[C:13]([C:14]=1[C:45]([OH:47])=[O:46])=[CH:12][C:11]([C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1)=[CH:10][CH:9]=2)=[O:5]
Reactant: O=C=O
Reactant: CCOC(=O)c1c(I)c2cc(-c3ccc(C(F)(F)F)cc3)ccc2n1-c1ccc(OC2CCCC2)cc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C(=O)O)c2cc(-c3ccc(C(F)(F)F)cc3)ccc2n1-c1ccc(OC2CCCC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1-(4-Cyclopentyloxyphenyl)-3-iodo-5-(4-trifluoromethylphenyl)indole-2-carboxylic acid ethyl ester (310 mg, 0.5 mmol; see step (c) above) in THF (2 mL) was added dropwise to i-PrMgCl.LiCl (1.0 M in THF, 500 μL, 0.5 mmol) at −40° C. After 15 min at −40° C., a stream of dry CO2 was passed through the mixture for 5 min and the mixture was allowed to warm to rt. The mixture was partitioned between EtOAc (10 mL) and NH4Cl (aq, sat). The phases were separated and the aqueous layer was extracted with EtOAc. The combined organic phases were washed with H2O and brine, dried (Na2SO4) concentrated and purified by chromatography, followed by recrystallisation from EtOAc/petroleum ether to give the title compound. Yield 70 mg (26%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([NH2:45])[CH:34]=[CH:35][C:36]=1[O:37][CH2:38][CH2:39][N:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([NH:45][C:33]1[CH:34]=[CH:35][C:36]([O:37][CH2:38][CH2:39][N:40]2[CH2:41][CH2:42][CH2:43][CH2:44]2)=[C:31]([O:30][CH3:29])[CH:32]=1)=[O:9]
Reactant: COc1cc(N)ccc1OCCN1CCCC1
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(NC(=O)c2cc(Cl)ccc2[N+](=O)[O-])ccc1OCCN1CCCC1
Reaction time: 1 h

Procedure:
5-Chloro-2-nitrobenzoic acid [Aldrich] (600 mg, 3 mmol) was suspended in dichloromethane (5 ml) and treated with oxalyl chloride (2 ml) and DMF (1 drop). On stirring, an immediate effervescence occurred which ceased after 1 hour. The solvent was removed in vacuo and the residue dissolved in dichloromethane (10 ml) and treated successively with DIEA resin (3.1 mmol/g, 1.95 g) and 3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (650 mg, 3 mmol). The mixture was stirred at RT for 16 hours then filtered, evaporated, and the residue purified by flash chromatography (methanol-dichloromethane-aqueous ammonia) to afford 5-chloro-N-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-2-nitro-benzamide as a yellow foam;
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[C:4]([NH:6][C@H:7]1[CH2:21][C@H:20]2[C@@H:10]([CH2:11][C:12]3[C:22]4[C:15](=[CH:16][CH:17]=[CH:18][C:19]2=4)[NH:14][C:13]=3[I:23])[N:9]([CH3:24])[CH2:8]1)=[O:5])[CH3:2].[C:27](Cl)(=[O:29])[CH3:28].[OH-].[K+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:25]([N:3]([CH2:1][CH3:2])[C:4]([NH:6][C@H:7]1[CH2:21][C@H:20]2[C@@H:10]([CH2:11][C:12]3[C:22]4[C:15](=[CH:16][CH:17]=[CH:18][C:19]2=4)[N:14]([C:27](=[O:29])[CH3:28])[C:13]=3[I:23])[N:9]([CH3:24])[CH2:8]1)=[O:5])[CH3:26]
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4[nH]c(I)c(c34)C[C@H]2N(C)C1
Reactant: CC(=O)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Solvent: ClCCl
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4c3c(c(I)n4C(C)=O)C[C@H]2N(C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.05 g of 1,1-diethyl-3-(2-iodo-6-methyl-8α-ergolinyl)urea is stirred for 3 hours at room temperature in 90 ml of methylene chloride with 115 mg of tetrabutylammonium hydrogen sulfate, 0.18 ml of acetyl chloride and 139 mg of pulverized potassium hydroxide pellets. After suctioning off over kieselguhr, the mixture is once again combined with the same amounts of acetyl chloride, pulverized potassium hydroxide and tetrabutylammonium hydrogen sulfate and stirred for one hour at room temperature. After combining with ice water, the mixture is neutralized with sodium bicarbonate and extracted by shaking. The organic phase is dried, filtered, and concentrated. The residue is chromatographed over silica gel with methylene chloride:ethanol=10:1 as the eluent, thus obtaining 500 mg of 1,1-diethyl-3-(2-iodo-1-acetyl-6-methyl-8α-ergolinyl)urea as an oil. [α]D =+40° (c=0.2 pyridine).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([C:9]1[CH:14]=[CH:13][C:12]([CH:15](OCC2CCCC2)[C:16]2[N:21]=[C:20]([O:22]C)[C:19]([Cl:24])=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)([CH3:8])([CH3:7])[CH3:6].O.[CH:33]1([SH:38])[CH2:37][CH2:36][CH2:35][CH2:34]1>>[C:5]([C:9]1[CH:10]=[CH:11][C:12]([CH:15]([S:38][CH:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)[C:16]2[NH:21][C:20](=[O:22])[C:19]([Cl:24])=[CH:18][CH:17]=2)=[CH:13][CH:14]=1)([CH3:6])([CH3:7])[CH3:8]
Reactant: COc1nc(C(OCC2CCCC2)c2ccc(C(C)(C)C)cc2)ccc1Cl
Reactant: SC1CCCC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: CC(C)(C)c1ccc(C(SC2CCCC2)c2ccc(Cl)c(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 25 %

Procedure:
Aluminum chloride (66 mg) was added to a solution of 6-[(4-tert-butylphenyl)(cyclopentylmethoxy)methyl]-3-chloro-2-methoxypyridine (64 mg) in cyclopentanethiol (1 mL) under ice-cooling, and then the mixture was stirred at 40° C. for two hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and filtered, after which the solvent was evaporated under reduced pressure. The residue was purified by preparative TLC (hexane:ethyl acetate=1:10) to give the title compound as a pale yellow solid (15 mg, 25%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([CH3:11])=[CH:4][C:3]=1[C:12]1[NH:13][CH:14]=[CH:15][N:16]=1.[H-].[Na+].I[CH3:20]>CN(C=O)C>[CH3:11][C:5]1[CH:4]=[C:3]([C:12]2[N:13]([CH3:20])[CH:14]=[CH:15][N:16]=2)[C:2]([CH3:1])=[CH:7][C:6]=1[NH2:8]
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1-c1ncc[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2nccn2C)c(C)cc1N
Reaction time: 0.25 h

Procedure:
To a solution of 2-(2,5-dimethyl-4-nitrophenyl)-1H-imidazole (50 mg, 0.23 mmol) in DMF (2 mL) was added NaH (11 mg, 0.46 mmol) at 0° C. After stirring for 15 min, iodomethane (65 mg, 0.46 mmol) was added dropwise. The mixture was stirred at 0° C. for 1 hr, and quenched by adding saturated ammonium chloride aqueous solution. The mixture was extracted with ethyl acetate (3×15 mL). The organic layer was washed with brine and dried over sodium sulfate. After concentration, the residue was dissolved in methanol (10 mL). To the solution was added Pd/C (10%). The reaction mixture was degassed and purged with H2 for several times and stirred under 1 atm. hydrogen gas overnight. The mixture was filtered and concentrated to afford 2,5-dimethyl-4-(1-methyl-1H-imidazol-2-yl)aniline. ESMS m/z 202 (M+H+).
Reaction SMILES: [Cl:1][C:2]([Cl:8])([Cl:7])[C:3](=N)OC.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[C:22]([NH2:23])=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:12][C:11]=1[F:24]>C(O)(=O)C>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:22]3[N:23]=[C:3]2[C:2]([Cl:8])([Cl:7])[Cl:1])=[CH:12][C:11]=1[F:24]
Reactant: Nc1cccnc1Nc1ccc(Cl)c(F)c1
Reactant: COC(=N)C(Cl)(Cl)Cl
Solvent: CC(=O)O
Product: Fc1cc(-n2c(C(Cl)(Cl)Cl)nc3cccnc32)ccc1Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Methyl 2,2,2-trichloroethanimidoate (0.743 mL, 6.00 mmol) was added to a solution of N2-(4-chloro-3-fluorophenyl)pyridine-2,3-diamine (C12) (951 mg, 4.00 mmol) in acetic acid (4 mL), and the reaction mixture was stirred at room temperature for 5 hours. After concentration in vacuo, the residue was purified via chromatography on silica gel (Gradient: 5% to 100% ethyl acetate in heptane) to afford the product as a white solid. Yield: 1.04 g, 2.85 mmol, 71%. LCMS m/z 366.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.49 (dd, J=4.7, 1.5 Hz, 1H), 8.27 (dd, J=8.1, 1.5 Hz, 1H), 7.64 (ddd, J=8.5, 7.8, 0.3 Hz, 1H), 7.42 (dd, J=8.1, 4.7 Hz, 1H), 7.39 (ddd, J=8.8, 2.4, 0.2 Hz, 1H), 7.32 (ddd, J=8.5, 2.4, 1.3 Hz, 1H).
Reaction SMILES: C([O:8][C:9]1[C:14]([N+:15]([O-])=O)=[CH:13][N:12]=[C:11]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:21])[N:10]=1)C1C=CC=CC=1.[F:30][C:31]1([F:46])[CH2:33][C@@H:32]1[CH2:34][O:35][C:36]1[CH:37]=[C:38]([F:45])[C:39]([C:42](O)=[O:43])=[N:40][CH:41]=1>>[F:46][C:31]1([F:30])[CH2:33][C@@H:32]1[CH2:34][O:35][C:36]1[CH:37]=[C:38]([F:45])[C:39]([C:42]([NH:15][C:14]2[C:9]([OH:8])=[N:10][C:11]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])[CH3:21])=[N:12][CH:13]=2)=[O:43])=[N:40][CH:41]=1
Reactant: O=C(O)c1ncc(OC[C@H]2CC2(F)F)cc1F
Reactant: C[C@@H](COc1ncc([N+](=O)[O-])c(OCc2ccccc2)n1)NC(=O)OC(C)(C)C
Product: C[C@@H](COc1ncc(NC(=O)c2ncc(OC[C@H]3CC3(F)F)cc2F)c(O)n1)NC(=O)OC(C)(C)C

Procedure:
Using tert-butyl ((2S)-1-((4-(benzyloxy)-5-nitropyrimidin-2-yl)oxy)propan-2-yl)carbamate and 5-(((1R)-2,2-difluorocyclopropyl)methoxy)-3-fluoropyridine-2-carboxylic acid, and in the same manner as in Step A of Example 4 and Step D of Example 83, the title compound was obtained.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([CH:9]3[CH2:11][CH:10]3[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:5]=2[CH2:18][O:19][CH:20]2[CH2:26][CH:25]3[N:27]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:22]([CH2:23][CH2:24]3)[CH2:21]2)[CH2:3][CH2:2]1.Cl[C:36]1[S:37][C:38]2[CH:44]=[C:43]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH:42]=[CH:41][C:39]=2[N:40]=1>>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([CH:9]3[CH2:11][CH:10]3[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:5]=2[CH2:18][O:19][CH:20]2[CH2:21][CH:22]3[N:27]([C:36]4[S:37][C:38]5[CH:44]=[C:43]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH:42]=[CH:41][C:39]=5[N:40]=4)[CH:25]([CH2:24][CH2:23]3)[CH2:26]2)[CH2:3][CH2:2]1.[CH:1]1([C:4]2[O:8][N:7]=[C:6]([CH:9]3[CH2:11][CH:10]3[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:5]=2[CH2:18][O:19][CH:20]2[CH2:26][CH:25]3[N:27]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:22]([CH2:23][CH2:24]3)[CH2:21]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1ccc2nc(Cl)sc2c1
Agent: CC(C)(C)OC(=O)N1C2CCC1CC(OCc1c(C3CC3c3ccccc3)noc1C1CC1)C2
Product: CCOC(=O)c1ccc2nc(N3C4CCC3CC(OCc3c(C5CC5c5ccccc5)noc3C3CC3)C4)sc2c1

Procedure:
Ethyl 2-(3-((5-cyclopropyl-3-(2-phenylcyclopropyl)isoxazol-4-yl)methoxy)-8-azabicyclo[3.2.1]octan-8-yl)benzo[d]thiazole-6-carboxylate (10A) was prepared from tert-butyl 3-((5-cyclopropyl-3-(2-phenylcyclopropyl)isoxazol-4-yl)methoxy)-8-azabicyclo[3.2.1]octane-8-carboxylate and ethyl 2-chlorobenzothiazole-6-carboxylate following the procedure described in the preparation of Example 7. The crude product was purified by silica gel column chromatography with hexane-EtOAc 20% isocratic as eluant to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]2[S:6][CH:7]=[C:8]([C:9](=[CH:14][O:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])[C:4]=2[CH:3]=1.[Br:19]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:1][C:2]1[CH:18]=[CH:17][C:5]2[S:6][CH:7]=[C:8]([C:9](=[CH:14][O:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])[C:4]=2[CH:3]=1
Reactant: COC=C(C(=O)OC)c1csc2ccc(C)cc12
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC=C(C(=O)OC)c1csc2ccc(CBr)cc12
Temperature: 25 °C

Procedure:
A mixture of 71 g of methyl α-(5-methyl-3-benzo[b]thienyl)-β-methoxyacrylate (see Example 1 ), 57.8 g of N-bromosuccinimide, 1.1 g of azodiisobutyronitrile and 720 ml of carbon tetrachloride is refluxed for 75 minutes. The mixture is cooled to room temperature and filtered, and the filtrate is then concentrated under reduced pressure, and the yellow oil which remains is purified by chromatography on silica gel using diethyl ether/n-hexane (1:1). The crude product is crystallized from methylene chloride/n-hexane, and methyl α-(5-bromomethyl-3-benzo[b]thienyl)-β-methoxyacrylate is obtained in this manner as pale yellow crystals, m.p. 124°-125° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:7].C([Li])CCC.Cl[CH2:14][C:15]1[N:24]=[C:23]([N:25]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[CH3:26])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=1>C1COCC1>[CH3:34][O:33][C:30]1[CH:29]=[CH:28][C:27]([N:25]([CH3:26])[C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=[C:15]([CH2:14][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][C:2]3=[O:7])[N:24]=2)=[CH:32][CH:31]=1
Reactant: O=C1CCCCN1
Reactant: COc1ccc(N(C)c2nc(CCl)nc3ccccc23)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(N(C)c2nc(CN3CCCCC3=O)nc3ccccc23)cc1
Temperature: 25 °C
Yield: 82.2 %

Procedure:
To 2-piperidone (149 mg, 1.5 mmol) in THF (1 mL) at 0° C. was added n-butyllithium (2.5 M, 0.60 mL, 1.5 mmol) followed by a solution of (2-chloromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (150 mg, 0.43 mmol) in THF (1.5 mL). The reaction was heated to reflux for 2 h, cooled to room temperature, quenched with H2O and diluted with ether. The aqueous phase was extracted with ether (3×10 mL) The combined organic phases were washed with brine, dried (MgSO4), concentrated and purified by gradient MPLC (SiO2, 0-20% MeOH/CH2Cl2 with 0.1% NH4OH) to give 133 mg (82%) of the title compound as a yellow oil. 1H NMR (MeOH-d4) δ 7.73 (d, 1H), 7.52 (dd, 1H), 7.71 (d, 2H), 6.98-6.96 (m, 2H), 6.90 (d, 2H), 4.82 (s, 2H), 3.84 (s, 3H), 3.55 (s, 3H), 3.52 (m, 2H), 2.53 (m, 2H), 1.92-1.88 (m, 4H); LC-MS (ESI+; 377 ([M+H]+)).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18]([F:23])=[C:17]([F:24])[C:16]=3F)=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].[O:28]1[CH2:33][CH2:32][CH:31]([OH:34])[CH2:30][CH2:29]1.Cl>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18]([F:23])=[C:17]([F:24])[C:16]=3[O:34][CH:31]2[CH2:32][CH2:33][O:28][CH2:29][CH2:30]2)=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)c(F)c(F)cc2c1O
Reactant: OC1CCOCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2c(OC3CCOCC3)c(F)c(F)cc2c1O
Temperature: 140 °C

Procedure:
N-((4-Chlorophenyl)methyl)-4-hydroxy-6,7,8-trifluoro-3-quinolinecarboxamide (366 mg) from Example No. 15 and sodium hydride (60% dispersion, 40 mg) are dissolved in DMF (10 mL) and to the mixture is added tetrahydro-2H-pyran-4-ol (114 μL). Additional sodium hydride (60 mg) is added and the mixture is heated at 140° C. for 1 h. The reaction mixture is allowed to cool to rt, poured into water (30 mL), acidified with 1 N hydrochloric acid (20 mL), and extracted with ethyl acetate (3×25 mL). The organic layer is washed with brine (10 mL), dried (MgSO4), and concentrated. The resulting solid is triturated with heptane (10 mL) and filtered to afford 153 mg of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[N+:15]([O-])=O>C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:4][C:3]=1[NH2:15]
Reactant: O=[N+]([O-])c1ccc(Cc2ccccc2)cc1Cl
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(Cc2ccccc2)cc1Cl
Reaction time: 10 h
Yield: 44.9 %

Procedure:
A solution of 2-chloro-4-benzylnitrobenzene (Method 29) (0.60 g) in ethyl acetate was treated with 10% Pd/C (0.06 g) under argon. The mixture was then stirred under a hydrogen atmosphere for 10 hours. The mixture was filtered under argon and extracted with aqueous hydrochloric acid (50% v/v, 50 ml). The aqueous layer was separated, basified with 2M aqueous NaOH and extracted with ethyl acetate to give the title compound as an oil (0.237 g). NMR: 3.6 (s, 2H), 5.1 (brs, 2H), 6.7 (d, 1H), 6.9 (dd, 1H), 7.0(d, 1H), 7.1-7.3 (m, 5H), MS (CI): 218 (M+).
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[F:20])#[CH:12].N>>[F:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[C:11]1[O:1][N:2]=[C:3]([C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:12]=1
Reactant: ON=C(Cl)c1cccnc1
Reactant: C#Cc1ccc(F)cc1F
Agent: N
Product: Fc1ccc(-c2cc(-c3cccnc3)no2)c(F)c1

Procedure:
The titled compound was prepared as the hydrochloride salt according to Method CB using the product of Example 1A (78 mg, 0.5 mmol) and 1-ethynyl-2,4-difluorobenzene (Aldrich, 69 mg, 0.5 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.29-7.43 (m, 1H), 7.53-7.65 (m, 2H), 7.69 (dd, J=7.5, 4.7 Hz, 1H), 8.08 (td, J=8.7, 6.3 Hz, 1H), 8.48 (dt, J=7.9, 2.0 Hz, 1H), 8.78 (dd, J=4.9, 1.5 Hz, 1H), 9.23 (d, J=1.7 Hz, 1H) ppm; MS (DCI/NH3) m/z 259 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[OH-].[NH4+:14].[OH-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH2:14])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(S(N)(=O)=O)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
With stirring 96.47 g (0.467 m) of the 4-methoxybenzenesulfonyl chloride obtained in part A above was slowly added to a slurry of 175.0 ml of concentrated ammonium hydroxide and 175.0 g of ice keeping the temperature under -5° C. during the addition. Slowly the resulting mixture was heated to approximately 70° C. over approximately two and one half hours. The resulting slurry was cooled and maintained at approximately 10° C. for about forty minutes. The solid was collected by filtration, washed three times with 50.0 ml of ice water and dried on the filter to obtain 97.37 g of water-wet 4-methoxybenzenesulfonamide. This product was suspended in 664.0 ml of water and 22.0 ml of 50 percent aqueous sodium hydroxide and 3.75 g of decolorizing carbon was added. After approximately forty-five minutes, the carbon was collected by filtration and washed twice with 50.0 ml of water. The filtrate and 50.0 ml or rinse water was adjusted to approximately pH 3 with the addition of approximately 33.0 ml of concentrated hydrochloric acid. The resulting slurry was cooled to approximately 5° C., stirred approximately two hours and the solid was collected by filtration, washed three times each with 50.0 ml of ice water and dried in vacuo to obtain 70.93 g of 4-methoxybenzenesulfonamide, a shiny white solid which melted at 111.5°-112.50° C. The nuclear magnetic resonance spectrum was concordant with the assisgned structure.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-])=O.[ClH:14].[H][H]>[Pd].O>[OH2:1].[ClH:14].[NH2:11][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[OH:1])[C:6]([OH:8])=[O:7]
Reactant: [H][H]
Reactant: O=C(O)c1ccc(O)c([N+](=O)[O-])c1
Agent: [Pd]
Agent: Cl
Solvent: O
Product: Nc1cc(C(=O)O)ccc1O
Temperature: 95 °C

Procedure:
To a 5-liter, 3-necked, round-bottom flask is added 160 g of 4-hydroxy-3-nitrobenzoic acid, 150 cc hydrogen chloride, 3 liter of distilled water and 25 g of 5 percent palladium on carbon. The reaction mixture is heated to 95° C. with vigorous stirring and hydrogen gas is passed into the reaction mixture. Upon completion, the reaction is cooled to room temperature under nitrogen gas and the catalyst is recovered by filtration. The resulting solution is poured into two 4-liter beakers and acidified with concentrated hydrochloric acid to a normality of 4 and allowed to cool to 0° C. The resulting solid is isolated by filtration and dried under vacuum to afford 176 g of crude 3-amino-4-hydroxybenzoic acid hydrochloride monohydrate with a melting point of 300° C. decomposition.
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:32]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@@H:17]([F:29])[CH2:16][O:15]2)[N:6]=1.[CH3:40][N:41]1[C:45]([CH3:46])=[C:44](B(O)O)[CH:43]=[N:42]1>>[NH2:32][C:4]1[S:3][C:2]([C:44]2[CH:43]=[N:42][N:41]([CH3:40])[C:45]=2[CH3:46])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:30])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@@H:17]([F:29])[CH2:16][O:15]1)=[O:31]
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1
Reactant: Cc1c(B(O)O)cnn1C
Product: Cc1c(-c2nc(C(=O)Nc3cnn(C)c3[C@@H]3CC[C@@H](N)[C@@H](F)CO3)c(N)s2)cnn1C

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6R)-5-(tert-butoxycarbonylamino)-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 88), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (1,5-dimethyl-1H-pyrazol-4-yl)boronic acid gave 255. 1H NMR (400 MHz, DMSO-d6) δ 9.15 (s, 1H), 7.84 (s, 1H), 7.65 (s, 1H), 7.25 (s, 2H), 4.96-4.76 (m, 2H), 4.16-3.89 (m, 2H), 3.79 (s, 3H), 3.72 (s, 3H), 3.29-3.15 (m, 1H), 2.56 (s, 3H), 2.11-2.00 (m, 1H), 1.90-1.71 (m, 4H), 1.66-1.58 (m, 1H). LCMS (ES+) m/z 449 (M+1).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4](=O)[C:5]([CH3:8])([CH3:7])[CH3:6].[S-:10][C:11]#[N:12].[K+]>O>[C:5]([C:4]1[N:12]=[C:11]([SH:10])[NH:2][CH:3]=1)([CH3:8])([CH3:7])[CH3:6]
Reactant: N#C[S-]
Reactant: CC(C)(C)C(=O)CN
Agent: Cl
Agent: [K+]
Solvent: O
Product: CC(C)(C)c1c[nH]c(S)n1

Procedure:
35.2 g. 1-Amino-3,3-dimethylbutan-2-one hydrochloride and 30 g. potassium thiocyanate in 50 ml. water was warmed on the steam bath for two hours. After cooling, the solid formed was collected, washed with water, dried and recrystallised from industrial methylated spirit to give 4-tert.butylimidazole-2-thiol, melting point 232°-234° C. A solution/suspension of this in industrial methylated spirit was added to a solution of 4.5 g. sodium hydroxide in 100 ml. water. 17.6 g. Ethyl iodide was added forming a lower layer and the mixture was shaken for two minutes whilst the ethyl iodide reacted and dispersed. After 20 minutes the alkali was neutralised by passing in carbon dioxide and the methylated spirit removed by evaporation. The solid was collected, washed with water, dried and on recrystallisation from toluene gave 2-ethylthio-4-tert.butylimidazole, melting point 116.5°-120° C.