Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[H-].[Na+].[CH3:9][Si:10]([CH2:13][CH2:14][O:15][CH2:16]Cl)([CH3:12])[CH3:11]>C1COCC1>[Br:1][C:2]1[N:3]=[CH:4][N:5]([CH2:16][O:15][CH2:14][CH2:13][Si:10]([CH3:12])([CH3:11])[CH3:9])[CH:6]=1
Reactant: Brc1c[nH]cn1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cnc(Br)c1
Reaction time: 0.5 h
Yield: 72.1 %

Procedure:
To a mixture of 4-bromo-1H-imidazole (1.0 g, 6.8 mmol) in THF (15 mL) was added NaH (327 mg, 8.16 mmol) at 0° C. The mixture was stirred at 0° C. to RT for 0.5 h. SEMCl (1.45 mL, 8.16 mmol) was added dropwise and the reaction mixture was stirred at RT for 2 h. The reaction mixture was quenched with water and extracted with DCM. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to give the crude product which was purified by silica gel chromotography (10-100% EtOAc/Heptane, then 0-15% MeOH/DCM) to afford 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (1.36 g, MS: 279.3 [M+H+]).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:20])[F:19])[C:8]([CH:22]=O)=[CH:7]2.[CH2:24]([NH2:33])[C:25]1[CH:32]=[CH:31][C:28]([O:29][CH3:30])=[CH:27][CH:26]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH3:30][O:29][C:28]1[CH:31]=[CH:32][C:25]([CH2:24][NH:33][CH2:22][C:8]2[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:18]([F:21])([F:20])[F:19])=[N:10][C:11]3[C:6]([CH:7]=2)=[CH:5][CH:4]=[CH:3][C:2]=3[CH3:1])=[CH:26][CH:27]=1
Reactant: Cc1cccc2cc(C=O)c(-c3ccccc3C(F)(F)F)nc12
Reactant: COc1ccc(CN)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: COc1ccc(CNCc2cc3cccc(C)c3nc2-c2ccccc2C(F)(F)F)cc1

Procedure:
Prepared according to Procedure F using 8-methyl-2-(2-(trifluoromethyl)phenyl)-quinoline-3-carbaldehyde (1 g, 3.17 mmol), DCE (16 mL), PMBNH2 (0.62 mL, 4.75 mmol, 1.5 eq), and NaBH(OAc)3 (2.0166 g, 9.52 mmol, 3 eq). After purification, N-(4-methoxybenzyl)(8-methyl-2-(2-(trifluoromethyl)phenyl)-quinolin-3-yl)methanamine was obtained as light yellow syrup. 1H NMR (DMSO-d6) δ ppm 8.48 (1 H, s), 7.87 (2 H, t, J=7.2 Hz), 7.64-7.77 (2 H, m), 7.48-7.62 (3 H, m), 7.14 (2 H, d, J=8.6 Hz), 6.81 (2 H, d, J=8.6 Hz), 3.71 (3 H, s), 3.44-3.62 (4 H, m), 2.61 (3 H, s), 2.54 (1 H, s). Mass Spectrum (ESI) m/e=437.2 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[CH3:10][S:11]([O-:13])=[O:12].[Na+].CS(C)=O>O>[CH3:10][S:11]([C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1)(=[O:13])=[O:12]
Reactant: CS(=O)[O-]
Reactant: N#Cc1ccc(Br)cn1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CS(=O)(=O)c1ccc(C#N)nc1
Yield: 87 %

Procedure:
5-Bromo-2-cyanopyridine (38.0 kg 1.0 mol eq, limiting reagent) and sodium methane sulfinate (29.68 kg, 1.4 mol eq) were charged followed by DMSO (228 L, 6 rel vol). The reaction was heated to 100° C.-105° C. and stirred until reaction complete as judged by HPLC analysis. After cooling, the reaction mixture was added to preheated water (356 L, 9.4 rel vol). After cooling and stirring, the product was isolated by filtration. The solid was washed with water (456 L, 12 rel vol) and dried to constant weight to yield the title compound (33 kg, 18.1 mol, 87%).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[C:7]([CH:17]1[CH2:19][CH2:18]1)=[CH:6]2)#[N:2].[F:24][C:25]([F:36])([F:35])[C:26]1[N:31]=[C:30]([C:32](O)=O)[CH:29]=[CH:28][CH:27]=1>>[CH:17]1([C:7]2[N:8]([CH2:12][C:13]3[N:16]=[C:32]([C:30]4[CH:29]=[CH:28][CH:27]=[C:26]([C:25]([F:35])([F:24])[F:36])[N:31]=4)[O:15][N:14]=3)[C:9]3[C:5]([CH:6]=2)=[C:4]([C:20]([F:22])([F:23])[F:21])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)[CH2:19][CH2:18]1
Reactant: N#Cc1ccc2c(cc(C3CC3)n2CC(=N)NO)c1C(F)(F)F
Reactant: O=C(O)c1cccc(C(F)(F)F)n1
Product: N#Cc1ccc2c(cc(C3CC3)n2Cc2noc(-c3cccc(C(F)(F)F)n3)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 72 from 2-[5-cyano-2-cyclopropyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 364B) and 6-(trifluoromethyl)-2-pyridinecarboxylic acid: MS (ES) m/z 478 (M+1).
Reaction SMILES: [F:1][CH:2]([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:9].[Br:11]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl.ClCCl>[Br:11][CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH:2]([F:10])[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccccc1C(F)F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: FC(F)c1ccccc1CBr
Temperature: 25 °C

Procedure:
To a solution of 1-(difluoromethyl)-2-methylbenzene (2.90 g, 20.4 mmol) in carbon tetrachloride (50 mL) was added N-bromosuccinimide (3.63 g, 20.4 mmol) and 2,2′-azobis(2-methylpropionitrile) (0.167 g, 1.02 mmol). The mixture was heated at reflux for 16 h. Further 2,2′-azobis(2-methylpropionitrile) (0.167 g, 1.02 mmol) was added, the mixture was heated at reflux for 4 h, allowed to cool to ambient temperature, diluted with dichloromethane (175 mL) and washed with water (2×175 mL) and saturated sodium bicarbonate (150 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo. The resultant residue was purified by column chromatography and eluted with a 0% to 10% gradient of ethyl acetate in dichloromethane to afford 1-(bromomethyl)-2-(difluoromethyl)benzene as a yellow solid: 1H NMR (300 MHz, CDCl3) δ7.58-7.56 (m, 1H), 7.43-7.37 (m, 3H), 6.95 (t, 55.2 Hz, 1H), 4.59 (s, 2H).
Reaction SMILES: C(O[C:6]1[C:11]2[N:12]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[C:27]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:28][CH:29]=[CH:30][CH:31]=4)=[CH:22][CH:21]=3)[C:13]([CH2:15][CH2:16]CC)=[N:14][C:10]=2[C:9](C)=[CH:8][CH:7]=1)CCC>C(Cl)Cl.C(O)C>[CH2:15]([C:13]1[N:12]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]3[C:27]([C:32]([O:34][C:35]([CH3:38])([CH3:36])[CH3:37])=[O:33])=[CH:28][CH:29]=[CH:30][CH:31]=3)=[CH:24][CH:25]=2)[C:11]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[N:14]=1)[CH3:16]
Reactant: CCCCOc1ccc(C)c2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)OC(C)(C)C)cc3)c12
Solvent: ClCCl
Solvent: CCO
Product: CCc1nc2ccccc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1

Procedure:
tert.butyl 4'-[(7-n-butoxy-2-n-butyl-4-methyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate oil, Rf value: 0.55 (Silica gel: methylene chloride/ethanol=19:1)
Reaction SMILES: [C:1](=[O:19])([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[C:10]([OH:18])[CH:9]=1)[O:2][C:3]([CH3:6])([CH3:5])[CH3:4].[CH3:20][O:21][CH2:22][CH2:23]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:1](=[O:19])([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[C:10]([O:18][CH2:23][CH2:22][O:21][CH3:20])[CH:9]=1)[O:2][C:3]([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)OC(=O)Oc1ccc(C(C)(C)C)c(O)c1
Reactant: COCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCCOc1cc(OC(=O)OC(C)(C)C)ccc1C(C)(C)C
Temperature: 50 °C
Reaction time: 3 h
Yield: 70.9 %

Procedure:
To a tetrahydrofuran (THF) (3 ml) solution of tert-butyl 4-tert-butyl-3-hydroxyphenyl carbonate (J. Org. Chem. 2001, 66, 3435) (266 mg, 1.0 mmol), 2-methoxy-ethanol (83 μL, 1.1 mmol) and triphenylphosphine (275 mg, 1.1 mmol) were added diethyl azodicarboxylate (DEAD) (165 μl, 1.1 mmol) and the mixture was stirred for 3 hours at 50° C. The solvent was removed under reduced pressure to give a residue, which was applied to a silica gel chromatography column and eluted with ethyl acetate/hexane=1/19 to furnish 0.23 g (71% yield) of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[CH:13]=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[S:18]1[CH2:22][C:21](=[O:23])[NH:20][C:19]1=[O:24].N1CCCCC1>CCO>[CH3:1][C:2]1([CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[CH:13]=[C:22]2[S:18][C:19](=[O:24])[NH:20][C:21]2=[O:23])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CC1(COc2cccc(C=O)c2)CCCCC1
Reactant: O=C1CSC(=O)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: CC1(COc2cccc(C=C3SC(=O)NC3=O)c2)CCCCC1
Yield: 67 %

Procedure:
A mixture consisting of compound v (0.5 mmol), 2,4-thiazolidinedione (0.6 mmol) and catalytic amounts of piperidine was refluxed in EtOH (5 mL) for 24 h and then concentrated. The oily product was dissolved in ethyl acetate, poured into water and acidified with AcOH. The solution was extracted with ethyl acetate, dried and concentrated. The residue was purified by silica gel chromatography, providing compound 1 in 67% yield. 1H NMR (300 MHz, CDCl3) δ 1.04 (s, 3H), 1.46-1.56 (m, 10H), 3.69 (s, 2H), 6.78-7.28 (m, 2H), 7.08 (d, J=8.40 Hz, 1H), 7.39 (dt, J=2.10, 8.40 Hz, 1H), 7.84 (s, 1H), 8.21-8.78 (br, 1H); HRMS exact mass of (M+Na)+, 354.1140 amu; observed mass of (M+Na)+, 354.113 amu.
Reaction SMILES: N[C:2](N)=[S:3].BrC[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1.[OH-].[K+].Cl>C(O)C.O>[SH:3][CH2:2][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1
Reactant: NC(N)=S
Reactant: BrCc1ccc2ccccc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: SCc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 91.9 %

Procedure:
Utilizing the procedure of G. G. Urquhart, J. W. Gates and R. Conner, Org. Syn. Coll. Vol. 3, p. 363, thiourea (6.89 g, 90.5 mmol) was added to a solution of 2-(bromomethyl)naphthalene (20.6 g, 90.5 mmol) in anhydrous ethanol (100 mL) and then heated at reflux. After 17 h, the reaction solution was concentrated to an oil. The oil was dissolved in a solution of potassium hydroxide (11.2 g, 199 mmol) in water (100 mL) and heated at reflux for 2 h. The solution was then cooled to 25° C. and treated with aqueous hydrochloric acid (2.0N). The resulting aqueous mixture was extracted with ethyl acetate (3×). The combined ethyl acetate extracts were dried over magnesium sulfate, filtered and evaporated to give yellow crystals (14.5 g, 91.9% yield).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16].[CH3:17][C:18]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:23])[CH2:19][C:20](O)=[O:21]>>[C:12]([C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:16])[N:2]([NH:1][C:20](=[O:21])[CH2:19][C:18]([CH3:17])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH3:23])[N:11]=1)([CH3:13])([CH3:15])[CH3:14]
Reactant: CC(C)(CC(=O)O)c1ccccc1
Reactant: CC(C)(C)c1nn(N)c(=O)c2ccccc12
Product: CC(C)(C)c1nn(NC(=O)CC(C)(C)c2ccccc2)c(=O)c2ccccc12

Procedure:
The product from Example 62A and 3-methyl-3-phenylbutanoic acid were treated using a method similar to that described in Example 51 to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.21 (s, 1H), 8.35-8.39 (m, 2H), 7.93-7.99 (m, 1H), 7.84-7.90 (m, 1H), 7.43-7.47 (m, 2H), 7.24-7.39 (m, 2H), 7.15-7.21 (m, 1H), 2.59 (s, 2H), 1.47 (s, 6H), 1.46 (s, 9H); MS (ESI−) M/Z 376 (M−H)−.
Reaction SMILES: [CH:1](Cl)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]([C:19]1[N:20]=[CH:21][NH:22][C:23]=1[C:24]([O:26][CH3:27])=[O:25])=[O:18]>C(#N)C.C(N(CC)CC)C>[CH:1]([N:20]1[C:19]([C:17]([O:16][CH3:15])=[O:18])=[C:23]([C:24]([O:26][CH3:27])=[O:25])[N:22]=[CH:21]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1nc[nH]c1C(=O)OC
Reactant: ClC(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1ncn(C(c2ccccc2)c2ccccc2)c1C(=O)OC
Temperature: 80 °C

Procedure:
20.3 g of benzhydryl chloride were added dropwise to a suspension of 18.4 g (0.1 mol) of 4,5-dimethoxycarbonyl-imidazole in 60 cc of acetonitrile and 14 cc of triethylamine and the reaction mixture was heated for 8 hours at 80° C. The solvent was then removed under reduced pressure and triethylammonium chloride was separated by washing with water. 30 g (85% of the theory) of 1-benzhydryl-4,5-dimethoxycarbonyl-imidazole, m.p. 93° C., were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)([C:21]3[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=3)[OH:20])[CH:8]=2)[N:3]=1.[O:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[C:39](Cl)=[O:40]>C1COCC1>[Cl:18][C:14]1[CH:13]=[C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:27]4[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=4)([OH:20])[C:21]4[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=4)[CH:8]=3)[N:3]=[C:2]([NH:1][C:39]([C:35]3[O:34][CH:38]=[CH:37][CH:36]=3)=[O:40])[CH:11]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccco1
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(N)cc(-c3cccc(Cl)c3)c2c1
Solvent: C1CCOC1
Product: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(NC(=O)c3ccco3)cc(-c3cccc(Cl)c3)c2c1
Temperature: 60 °C

Procedure:
A mixture of (±)-2-amino-4-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-6-quinolinemethanol (0.00021 mol), described in International Patent Specification WO 00/39082, and 2-furancarbonyl chloride (0.00063 mol) in THF (1 ml) was heated for 5 hours at 60° C. The solvent was evaporated and the residue was purified by HPLC. The product fractions were collected and the solvent was evaporated, yielding (±)-N-[4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-2-quinolinyl]-2-furancarboxamide, MS (ESI) m/z: 569 571 573.
Reaction SMILES: [F:1][CH:2]([F:27])[O:3][CH:4]=[C:5]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)[C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([O:18][CH3:19])[CH:12]=1)=[O:7].CN(C)C=O.Cl[CH2:34][C:35]#[CH:36].[H-].[Na+]>O>[F:1][CH:2]([F:27])[O:3][CH:4]=[C:5]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)[C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:36][C:35]#[CH:34])=[C:13]([O:18][CH3:19])[CH:12]=1)=[O:7]
Reactant: C#CCCl
Reactant: COc1cc(CCNC(=O)C(=COC(F)F)c2ccc(C)cc2)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCOc1ccc(CCNC(=O)C(=COC(F)F)c2ccc(C)cc2)cc1OC
Yield: 43.8 %

Procedure:
Five hundred milligrams (500 mg) of 3-difluoromethoxy-N-[2-(4-hydroxy-3-methoxyphenyl)ethyl]-2-(4-methylphenyl)acrylamide (1.33 mmol), 5 ml of anhydrous N,N-dimethylformamide, 196 mg (2.65 mmol) of 3-chloropropyne and 60 mg (1.46 mmol) of 60% sodium hydride were stirred at room temperature for 2 hours. Water was added to to the reaction mixture, which was followed by extracted with ethyl acetate, washed with 5% hydrochrolic acid, saturated aqueous sodium bicarbonate solution and saturated brine subsequently, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=2:1) to give 242 mg of 3-difluoromethoxy-N-[2-{3-methoxy-4-(2-propynyloxy)phenyl}ethyl]-2-(4-methylphenyl)acrylamide (the present compound 1353).
Reaction SMILES: C[O-].[Na+].Cl.[N:5]1[CH:10]=[CH:9][C:8]([CH2:11]Cl)=[CH:7][CH:6]=1.[SH:13][CH2:14][C:15]([O:17][CH3:18])=[O:16]>CO>[N:5]1[CH:10]=[CH:9][C:8]([CH2:11][S:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:7][CH:6]=1
Reactant: ClCc1ccncc1
Reactant: COC(=O)CS
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)CSCc1ccncc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Sodium methoxide (2.16 g., 40 mmoles) is dissolved in 24 ml. of methanol, stirring under nitrogen, and the solution cooled in an ice bath. 4-Picolyl chloride hydrochloride (3.38 g., 20 mmoles), finely divided and suspended in approximately 20 ml. of methanol, is added dropwise over approximately 15 minutes. A solution of methyl 2-mercaptoacetate (2.12 g., 20 mmoles) in 4 ml. of methanol is then added over approximately 5 minutes. The reaction mixture is warmed slowly and left to stir under nitrogen for 14 hours at room temperature. The reaction is filtered with diatomaceous earth. Solids are repulped with an additional 75 ml. of methanol. The methanol filtrates are combined and concentrated to yield title product
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]([N:18]2[CH2:22][CH2:21][CH2:20][S:19]2(=[O:24])=[O:23])[CH:15]=[CH:14][C:13]=1[C:25]([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][C:34]=2[CH3:40])[CH2:29][CH2:28]1)=[O:26])(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[NH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]([N:18]2[CH2:22][CH2:21][CH2:20][S:19]2(=[O:23])=[O:24])[CH:15]=[CH:14][C:13]=1[C:25]([N:27]1[CH2:28][CH2:29][N:30]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][C:34]=2[CH3:40])[CH2:31][CH2:32]1)=[O:26]
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3OCCCNC(=O)OC(C)(C)C)CC2)c(C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3OCCCN)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.4 %

Procedure:
To a mixture of [4-(2,4-dimethylphenyl)piperazin-1-yl][4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-hydroxyphenyl]methanone (241 mg) described in Example 124, (3-bromopropyl)carbamic acid tert-butyl ester (200 mg) and cesium carbonate (548 mg) was added 2-butanone (4 mL), and the mixture was stirred with heating under reflux for 4 hr. Water was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the solvent was evaporated. The obtained residue was purified by column chromatography (ethyl acetate:hexane) to give (3-{2-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]-5-(1,1-dioxo-1λ6-isothiazolidin-2-yl)phenoxy}propyl)carbamic acid tert-butyl ester (221 mg). The obtained (3-{2-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]-5-(1,1-dioxo-1λ6-isothiazolidin-2-yl)phenoxy}propyl)carbamic acid tert-butyl ester (221 mg) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (0.46 mL) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into ice water, the mixture was neutralized with sodium hydrogen carbonate and extracted with chloroform, and the solvent was evaporated. The obtained residue was purified by NH-coated silica gel column chromatography (ethyl acetate:methanol) to give the title compound (74 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[N:10]2)=[CH:6][CH:5]=1)([O-])=O.C(O)C>[C].[Pd].O1CCCC1>[N:9]1([CH2:8][C:7]2[CH:18]=[CH:19][C:4]([NH2:1])=[CH:5][CH:6]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[N:10]1
Reactant: O=[N+]([O-])c1ccc(Cn2ncc3ccccc32)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1ccc(Cn2ncc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83 %

Procedure:
A mixture of 1-(4-nitrobenzyl)-1H-indazole (9.25 g), 10% palladium carbon (1 g), ethanol (100 ml) and tetrahydrofuran (100 ml) was stirred under a hydrogen atmosphere at room temperature for 4 hrs. Palladium carbon was removed from the reaction mixture by filtration, and the filtrate was concentrated. Recrystallization of the residue from acetone-hexane gave 4-(1H-indazol-1-ylmethyl)aniline (6.77 g, 83%) as colorless prism crystals. melting point: 110-111° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30](O)=[O:31])[C:25]=1[CH3:33])(=[O:12])=[O:11].[NH:34]1[CH2:39][CH2:38][CH:37]([OH:40])[CH2:36][CH2:35]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([N:34]2[CH2:39][CH2:38][CH:37]([OH:40])[CH2:36][CH2:35]2)=[O:31])[C:25]=1[CH3:33])(=[O:11])=[O:12]
Reactant: OC1CCNCC1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cccc(Cl)c4Cl)cc32)c(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cccc(Cl)c4Cl)cc32)c(C)c1C(=O)N1CCC(O)CC1

Procedure:
5-[5-(2,3-Dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (100 mg, 0.2 mmol) was coupled with piperidin-4-ol (22 mg, 1.2 eq.) using HOBt (1.2 eq.), EDAC.HCl (1.2 eq.) and TEA (3 eq.) to give the titled compound.
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=[O:10])[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.[CH3:12][N:13]([CH3:26])[CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1.[OH-].[K+]>C(O)C>[CH3:26][N:13]([CH3:12])[CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([CH:22]=[C:11]2[CH2:1][CH2:2][C:3]3[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:9]2=[O:10])=[CH:24][CH:25]=1
Reactant: CN(C)CCCOc1ccc(C=O)cc1
Reactant: O=C1CCCc2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CN(C)CCCOc1ccc(C=C2CCc3ccccc3C2=O)cc1
Reaction time: 16 h
Yield: 75.9 %

Procedure:
A stirred solution of 50 g of α-tetralone and 70 g of 4-(3-dimethylaminopropoxy)benzaldehyde in 275 ml of ethanol is cooled to -20° C. and treated with 2.0 g of potassium hydroxide dissolved in 50 ml of ethanol. The cooling bath is removed and after standing for about 16 hours at room temperature the reaction mixture (some product has separated) is added to 1.2 liters of cold water. The material is extracted with 3:1 ether-dichloromethane (five 300 ml portions), the combined extracts are dried over magnesium sulfate, and the solvents are removed on a rotary evaporator to give a semi-solid residue. Crystallization of the residue from 300 ml of diisopropyl ether yields 86 g of product; melting point 86°-88° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([CH2:14][CH:15]2[CH2:19][CH2:18][N:17]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:16]2=[O:26])=[C:9]([Cl:27])[CH:8]=1)(=O)=O.[CH3:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(COC)OC>[CH:20]1([N:17]2[CH2:18][CH2:19][CH:15]([CH2:14][C:10]3[C:11]([Cl:13])=[CH:12][C:7]([C:34]4[CH:33]=[N:32][N:31]([CH3:30])[CH:35]=4)=[CH:8][C:9]=3[Cl:27])[C:16]2=[O:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C1C(Cc2c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc2Cl)CCN1C1CCCCC1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cn1cc(-c2cc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)cn1

Procedure:
Using the method of Example 81 and using 3,5-dichloro-4-((1-cyclohexyl-2-oxopyrrolidin-3-yl)methyl)phenyl trifluoromethanesulfonate (Example 240) (1.673 g, 3.53 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.2 g, 10.6 mmol), tetrakis(triphenylphosphine)palladium (0.408 g, 0.353 mmol), dimethoxyethane (16 mL) and sodium carbonate (2M, 6.2 mL) gives the title compound. Purify the crude material over silica gel (1/1 hexane in ethyl acetate to 1/3 hexane in ethyl acetate) to yield 0.873 g (61%) of the title compound: mass spectrum (m/z): 408(M+2).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13](F)[C:12]=1[N+:18]([O-:20])=[O:19].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[F:10][C:11]1[C:12]([N+:18]([O-:20])=[O:19])=[C:13]([NH:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:14]=[CH:15][CH:16]=1
Reactant: O=[N+]([O-])c1c(F)cccc1F
Reactant: CCOC(=O)CCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)CCNc1cccc(F)c1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
A round bottomed flask was charged with ethyl 3-aminopropanoate hydrochloride (1 g, 6.51 mmol), 1,3-difluoro-2-nitrobenzene (1.036 g, 6.51 mmol), potassium carbonate (2.70 g, 19.53 mmol), and a stirbar. THF (35 mL, 0.2 M) was added, and the mixture was stirred at 100° C. overnight. The mixture was concentrated with celite and purified by silica gel chromatography (eluting with hexanes/ethyl acetate) to yield ethyl 3-(3-fluoro-2-nitrophenylamino)propionate as a yellow amorphous solid (1.473 g, 5.75 mmol, 88%).