Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([O:14]CC)=O)[N:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([Mg]Br)=[CH:20][C:19]=1[O:26][CH3:27].CC1CCCO1.[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([C:21]2[CH:22]=[CH:23][C:18]([F:17])=[C:19]([O:26][CH3:27])[CH:20]=2)=[O:14])[N:3]=1
Reactant: CCOC(=O)c1nc(Cl)c2ccccc2n1
Reactant: COc1cc([Mg]Br)ccc1F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC1CCCO1
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2nc(Cl)c3ccccc3n2)ccc1F
Temperature: -35 °C
Reaction time: 3 h
Yield: 62.4 %

Procedure:
To a stirred mixture of ethyl 4-chloroquinazoline-2-carboxylate (500 mg, 2.11 mmol) in THF (17 mL) at −40° C. was added dropwise 1 M 4-fluoro-3-methoxyphenylmagnesium bromide/2-methyltetrahydrofuran (2.53 mL, 2.53 mmol). The reaction mixture was stirred at −30 to −40° C. for 3 h. Additional 1 M 4-fluoro-3-methoxyphenylmagnesium bromide/2-methyltetrahydrofuran (1.05 mL, 1.05 mmol) was added and stirring was continued at −30 to −40° C. for an additional 1.5 h. To the mixture was added saturated aq ammonium chloride (25 mL) and the mixture was allowed to warm to rt. The mixture was extracted with EtOAc (2×) and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was triturated with diethyl ether and the resulting solid was collected by filtration and dried to afford (4-chloroquinazolin-2-yl)(4-fluoro-3-methoxyphenyl)methanone as a colorless solid (417 mg, 62%). 1H NMR (300 MHz, DMSO-d6) δ ppm 3.92 (s, 3H), 7.42 (dd, J=11.1, 8.7 Hz, 1H), 7.64 (m, 1H), 7.85 (d, J=8.4 Hz, 1H), 8.04 (m, 1H), 8.23-8.25 (m, 2H), 8.43 (d, J=8.4 Hz, 1H); LC-MS (ESI) m/z 317 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([Br:13])[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.[CH3:14][S:15]([O-:17])=[O:16].[Na+]>CN(C=O)C>[Br:13][C:11]1[CH:12]=[C:3]([CH2:2][S:15]([CH3:14])(=[O:17])=[O:16])[CH:4]=[C:5]2[C:10]=1[N:9]=[CH:8][CH:7]=[CH:6]2
Reactant: BrCc1cc(Br)c2ncccc2c1
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)Cc1cc(Br)c2ncccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-bromomethyl-8-bromoquinoline (1.0 eq.) described in International Patent Publication WO 94/22852 in DMF, was added sodium methanesulfinate (1.4 eq.). After stirring overnight at rt, the mixture was quenched with H2O, stirred for 1 h. The resulting precipitate was isolated by filtration and washed with Et2O to afford the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].[CH3:27][C@H:28]1[O:33][CH2:32][CH2:31][NH:30][C@@H:29]1[C:34]([OH:36])=[O:35]>>[Cl:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[NH:8][C:3]([CH2:2][N:30]2[CH2:31][CH2:32][O:33][C@H:28]([CH3:27])[C@H:29]2[C:34]([OH:36])=[O:35])=[C:4]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Reactant: C[C@H]1OCCN[C@@H]1C(=O)O
Product: CCOC(=O)C1=C(CN2CCO[C@H](C)[C@H]2C(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Yield: 60.4 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.87 g, 1.9 mmol) was reacted with (2R,3S)-2-methyl morpholine-3-carboxylic acid (0.28 g, 1.9 mmol) according to the procedure as described in Example 34, Step D to give the title compound as a yellow solid (0.6 g, 60%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])=[C:5]([Br:7])[N:6]=1.C([Li])CCC.O>C(OCC)C>[Br:7][C:5]1[N:6]=[CH:2][S:3][C:4]=1[CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:11])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)OCc1sc(Br)nc1Br
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1scnc1Br
Temperature: -78 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
To a −78° C. solution of 2,4-dibromo-5-{[(tert-butyldimethylsilyl)oxy]methyl}-1,3-thiazole (2.44 g, 6.3 mmol) in anhydrous diethyl ether (120 mL) was added a solution of n-butyl lithium (2.5M in hexanes, 2.5 mL, 6.3 mmol). The reaction mixture was stirred at −78° C. for 1 hour. Water (75 mL) was added, and the mixture was warmed to room temperature then extracted with EtOAc (3×75 mL). The organic extracts were combined, dried over MgSO4, filtered, evaporated, and dried in vacuo, affording 4-bromo-5-{[(tert-butyldimethylsilyl)oxy]methyl}-1,3-thiazole (1.77 g, 90%). The product was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[O:8])=[CH:5][NH:4][N:3]=1.CN(C)[CH:16]=[CH:17][C:18]([C:20]1[CH:21]=[C:22]([N:26]([CH3:30])[C:27](=[O:29])[CH3:28])[CH:23]=[CH:24][CH:25]=1)=O>C(O)(=O)C>[CH3:30][N:26]([C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:18]2[N:3]3[N:4]=[CH:5][C:6]([C:7]([C:9]4[S:10][CH:11]=[CH:12][CH:13]=4)=[O:8])=[C:2]3[N:1]=[CH:16][CH:17]=2)[CH:21]=1)[C:27](=[O:29])[CH3:28]
Reactant: CC(=O)N(C)c1cccc(C(=O)C=CN(C)C)c1
Reactant: Nc1n[nH]cc1C(=O)c1cccs1
Solvent: CC(=O)O
Product: CC(=O)N(C)c1cccc(-c2ccnc3c(C(=O)c4cccs4)cnn23)c1
Temperature: 25 °C

Procedure:
A fifty liter flask is charged with 1.936 kg of (3-amino-1H-pyrazol-4-yl)-2-thienylmethanone, 2.450 kg of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-methylacetamide and 33.3 kg of acetic acid (Van Waters). The reaction mixture is heated at reflux for 6 hours. The reaction mixture is evaporated to a residue under reduced pressure while maintaining the temperature at approximately 45?C. The residue is dissolved in methylene chloride (8 L; Spectrum) then precipitated by the addition of 32 L of methyl-t-butyl ether. The solid is isolated by filtration and the cake washed with a small portion (3.6 L) of methyl-t-butyl ether (Van Waters). The solid is suspended in a mixture of hexanes (20 L) and ethyl acetate (20 L) and heated at reflux for 5 minutes. The mixture was allowed to cool to room temperature and the solid is isolated by filtration. The cake is washed with a small portion (6 L) of hexanes/ethyl acetate (1:1). The material is dissolved in hot methylene chloride (17 L) then the product is precipitated by the addition of hexanes (17 L). The mixture was allowed to cool to room temperature and the solid is collected by filtration. The solid may be further purified by crystallization from any one of a variety of known solvents and/or washing techniques.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1)[CH3:2].[Cl:15][C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O>>[CH2:1]([O:3][C:4](=[O:14])[C@@H:5]([O:3][CH2:1][CH3:2])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:14][CH2:4]/[CH:5]=[CH:6]/[C:7]2[CH:12]=[CH:11][C:10]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:16]=3[Cl:15])=[CH:9][CH:8]=2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)/C=C/c1ccc(Br)cc1
Reactant: OB(O)c1cccc(Cl)c1Cl
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C/c2ccc(-c3cccc(Cl)c3Cl)cc2)cc1)OCC

Procedure:
The title compound was prepared from (E)-3-(4-bromo-phenyl)-acrylic acid ethyl ester and 2,3-dichlorobenzene boronic acid by a sequence analogous to that described in example 52a-c.
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:12]N1C(=O)CCC1=O>ClCCl>[NH2:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([Br:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1c(F)cccc1C(=O)O
Solvent: ClCCl
Product: Nc1c(F)cc(Br)cc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.5 %

Procedure:
A solution of 2-amino-3-fluorobenzoic acid (10.85 g, 70 mmol) in dichloromethane (175 mL) was added N-bromosuccinimide (12.46 g, 70 mmol), and the mixture was stirred at RT for 2 h. LCMS showed the reaction was completed. The precipitate was filtered and washed with dichloromethane (100 mL*3) to give the title compound (12.7 g, 78%) as a grey solid, which was directly used in the next step without further purification. MS (ES+) C7H5BrFNO2 requires: 233, 235. Found: 232, 234 [M−H]−.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:20]=[O:21])[CH:16]=[N:17][C:18]=1[CH3:19].[CH2:22](O)[CH2:23][OH:24].C1(C)C=CC=CC=1>O>[Cl:12][C:13]1[C:18]([CH3:19])=[N:17][CH:16]=[C:15]([CH:20]2[O:24][CH2:23][CH2:22][O:21]2)[CH:14]=1
Reactant: OCCO
Reactant: Cc1ncc(C=O)cc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ncc(C2OCCO2)cc1Cl
Yield: 86 %

Procedure:
p-Toluenesulfonic acid (5.53 mg, 0.032 mmol) was added to a mixture of 5-chloro-6-methyl-3-pyridinecarbaldehyde (for a synthesis see WO20006/137485 A1 Example 256) (250 mg, 1.607 mmol), ethylene glycol (179 μl, 3.21 mmol), and toluene (8 ml) and the mixture was heated under reflux as water was azeotropically removed (Dean-Stark). The progression was monitored by TLC (50% hexane:EtOAc) and HPLC. More ethylene glycol (180 μl) and TsOH (3 mg) were added and after 46 hr full conversion was observed by HPLC. 10% Na2CO3 and EtOAc were added. Extraction, drying (MgSO4), and filtration afforded 3-chloro-5-(1,3-dioxolan-2-yl)-2-methylpyridine (274.3 mg, 86%) pure enough to be used in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:33]([C:35]1[CH:40]=[CH:39][C:38]([N:41]=[C:42]=[O:43])=[CH:37][CH:36]=1)#[N:34]>ClCCl>[C:33]([C:35]1[CH:36]=[CH:37][C:38]([NH:41][C:42]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:6]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH2:13]2)=[O:43])=[CH:39][CH:40]=1)#[N:34]
Reactant: N#Cc1ccc(N=C=O)cc1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.2 %

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (50 mg, 0.13 mmol) (from Example 25a supra) in dichloromethane (3 mL) was added triethylamine (33.6 mg, 0.33 mmol) (Aldrich), followed by the addition of 1-cyano-4-isocyanato-benzene (23.0 mg, 0.16 mmol) (Aldrich). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layer was washed with water, brine, dried over MgSO4 and concentrated. The residue was purified by chromatography to give rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid (4-cyano-phenyl)-amide as a white solid (Yield 40 mg, 58%).
Reaction SMILES: S(=O)(=O)(O)O.Cl.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14]N)=[CH:10][C:9]=1[F:16].[CH3:17][N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C:19]1=O>O1CCOCC1>[Cl:7][C:8]1[C:9]([F:16])=[CH:10][C:11]2[NH:14][C:21]3[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][C:20]=3[C:12]=2[CH:13]=1
Reactant: CN1CCCCC1=O
Reactant: NNc1ccc(Cl)c(F)c1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: CN1CCc2[nH]c3cc(F)c(Cl)cc3c2C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Sulfuric acid is added to a solution of 4-chloro-3-fluorophenyl hydrazine hydrochloride (1 equiv.) in dioxane, and stirred for 5 min. at RT. N-Methyl piperidone (0.76-1.4 equiv.) is added and the mixture is heated at 80° C. for 3 h. After completion, as monitored by TLC, the reaction mixture is concentrated under reduced pressure and basified to pH 10 using 10% aqueous KOH solution, extracted with EtOAc, dried over anhydrous sodium sulfate and concentrated under reduced pressure using rotary evaporator to give a mixture or regioisomeric products. For this Example, silica gel chromatography separates the title compound from the other regioisomer (Compound 4) obtained in Example 10.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([Cl:20])[CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>ClC(Cl)(Cl)Cl>[Cl:20][C:15]1[CH:14]=[C:13]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:18]=[CH:17][C:16]=1[CH2:19][Br:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(C)(C)C)cc1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1ccc(CBr)c(Cl)c1

Procedure:
1.75 g (9.85 mmol) of N-bromosuccinimide and 10.8 mg (0.006 mmol) of 2,2′-azobis-2-methylpropanenitrile are added to a solution of 2 g (10.95 mmol) of 4-tert-butyl-2-chloro-1-methylbenzene in 10 ml of tetrachloromethane, and the mixtures is stirred under reflux for 4 hours. After cooling, the mixture is concentrated. The residue is purified by flash chromatography on silica gel (mobile phase, cyclohexane). 2.1 g (38% of theory) of the title compound are obtained with a purity of 52%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]([NH2:13])=[S:12])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Br[CH2:15][C:16](=O)[C:17]([O:19]CC)=[O:18]>C(O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[S:12][CH:15]=[C:16]([C:17]([OH:19])=[O:18])[N:13]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(=S)Nc1ccc2[nH]ccc2c1
Solvent: CCO
Product: O=C(O)c1csc(Nc2ccc3[nH]ccc3c2)n1

Procedure:
A solution of 5-aminoindole (8 g, 60.6 mmol) in acetone (150 mL) was reacted with benzoylisothiocyanate (9.88 g, 60. mmol) at RT for about 4 h. The resulting solid was filtered and treated with 2 N NaOH in THF (120 mL). The mixture was refluxed for about 6 h and allowed to warm to RT. The solvent was evaporated off under vacuum. The residue was diluted with water (20 mL) and neutralized to pH 7 with 1N HCl. The resulting solid was filtered and dried under vacuum to afford 5-indolylthiourea (55-2). 5-Indolyl thiourea (0.01 mol) and ethyl bromopyruvate (0.011 mol) were dissolved in 3 mL ethanol and held at reflux for 2 h. The reaction was cooled, the crystalline ethyl 2-(1H-indol-5-ylamino)thiazole-4-carboxylate (55-3) was collected by filtration and washed with ethanol. Refluxing the mixture of ethyl esters with the NaOH-ethanol solution gave 2-(1H-indol-5-ylamino)thiazole-4-carboxylic acid (55-4) which was used directly in next steps. To a mixture of the crude acid (2.5 mmol), EDCI (2.9 mmol), HOBt (2.6 mmol) and NMM (5.3 mmol) in CH2Cl2 (30 mL) was added HNCH3OCH3HCl salt (2.6 mmol) and stirring continued at RT for overnight. The reaction mixture was diluted with CH2Cl2 (20 mL) and sequentially washed with water, satd. NaHCO3, brine and dried over MgSO4. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography to obtain pure compound 2-(1H-indol-5-ylamino)-N-methoxy-N-methylthiazole-4-carboxamide (55-5) (45.6% yield for overall 5 steps). At −78° C., to a solution of 5-bromo-1,2,3-trimethoxybenzene (1.235 g, 5.0 mmol) in 30 mL THF was charged n-BuLi in hexane (2.5 N, 2.4 mL, 6 mmol) under Ar2 protection and stirred for 10 min Weinreb amide (1 mmol) in 10 ml, THF was added to lithium reagent and allowed to stir at RT for 2 h. The reaction mixture was quenched with satd. NH4Cl, extracted with ethyl ether, dried with MgSO4. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography to obtain pure compound 55 (51.7% yield). 1H NMR (300 MHz, CDCl3) δ 8.29 (br, 1H), 7.68 (d, 1H), 7.46 (s, 2H), 7.39 (s, 1H), 7.36 (s, 1H), 7.28˜7.26 (m, 1H), 7.15˜7.12 (m, 1H), 6.55 (m, 1H), 3.93 (s, 3H), 3.89 (s, 6H). MS (ESI) m/z 432.1 (M+Na)+, 408.0 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([CH3:21])[CH:15]=3)[CH:11]=[C:10]([C:22]([F:25])([F:24])[F:23])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[CH:11]=[C:10]([C:22]([F:25])([F:24])[F:23])[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([C:30]4[CH:31]=[CH:32][C:27]([NH2:26])=[N:28][CH:29]=4)[CH:7]=[CH:6][CH:5]=3)[N:13]=2)=[CH:15][C:16]=1[CH3:21]
Reactant: Cc1cc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)ccc1Cl
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Cc1cc(-c2cc(C(F)(F)F)nc(-c3cccc(-c4ccc(N)nc4)c3)n2)ccc1Cl

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-(4-chloro-3-methylphenyl)-6-trifluoromethyl-pyrimidine (example E.41) (0.21 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as a white solid (0.13 g, 60%). MS (ISP) 441.1 [(M+H)+]; mp 168.5° C.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:13][N:12]=[C:11]2[N:21]([CH2:30][C:31]([OH:33])=[O:32])[N:22]=[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:10]=12.[CH2:34](OC(Cl)=O)[CH:35]([CH3:37])[CH3:36].[BH4-].[Na+]>C1COCC1.Cl>[Cl:8][C:9]1[C:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[N:13][N:12]=[C:11]2[N:21]([CH2:30][C:31]([O:33][CH2:34][CH:35]([CH3:37])[CH3:36])=[O:32])[N:22]=[C:23]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:10]=12
Reactant: O=C(O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Reactant: CC(C)COC(=O)Cl
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)COC(=O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Reaction time: 1 h
Yield: 6.2 %

Procedure:
Triethylamine (535 μL, 3.8 mmol) was added to 2-(4-chloro-3,5-diphenyl-1Hpyrazolo[3,4-c]pyridazin-1-yl)acetic acid (700 mg, 1.92 mmol) in THF (20 mL) at 0° C., followed by the addition of isobutylchloroformate (342 mg, 2.9 mmol). The reaction mixture was stirred for 1 h. Sodium borohydride (220 mg, 5.8 mmol) was then added portionwise and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with 0.5 M HCl and the aqueous layer was extracted twice with ethyl acetate. The combined organic phases were washed with water and brine, dried (phase separator), and concentrated in vacuo. The residue was purified by chromatography (silica gel, ethyl acetate/isohexane 0:1 to 1:0), to provide Compound 12 as a solid (50 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([N:23]3[CH2:28][CH2:27][C:26]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)([NH2:29])[CH2:25][CH2:24]3)=[O:22])[C:9]=2[CH3:36])=[CH:4][CH:3]=1.[CH3:37][S:38](Cl)(=[O:40])=[O:39].C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([N:23]3[CH2:24][CH2:25][C:26]([NH:29][S:38]([CH3:37])(=[O:40])=[O:39])([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH2:27][CH2:28]3)=[O:22])[C:9]=2[CH3:36])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1c(C(=O)N2CCC(N)(c3ccccc3)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1c(C(=O)N2CCC(NS(C)(=O)=O)(c3ccccc3)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Yield: 64.3 %

Procedure:
1-{[5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl]carbonyl}-4-phenylpiperidin-4-amine (1 eq, 36.5 mg, 0.068 mmol), methanesulfonyl chloride (2 eq, 0.01 mL, 0.135 mmol), and triethylamine (3 eq, 0.03 mL, 0.203 mmol) was stirred in tetrahydrofuran for 16 h. The reaction was concentrated in vacuo. The crude reaction material was then purified by silica gel column chromatography using 0-100% ethyl acetate/hexane to yield pure N-(1-{[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl]carbonyl}-4-phenylpiperidin-4-yl)methanesulfonamide (27 mg, 65%). 1H NMR (300 MHz, CHLOROFORM-d) d ppm 2.18 (d, J=4.52 Hz, 6H) 2.21-2.37 (m, 2H) 2.39-2.61 (m, 2H) 3.65 (t, J=10.69 Hz, 1H) 3.86 (t, J=10.93 Hz, 1H) 4.07-4.20 (m, 2H) 4.29 (d, J=13.75 Hz, 1H) 5.30 (s, 1H) 7.03-7.11 (m, 2H) 7.15-7.21 (m, 1H) 7.21-7.38 (m, 4H) 7.38-7.47 (m, 2H) 7.47-7.55 (m, 2H).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:4]([N:6]1[CH2:10][CH2:9][S:8][CH2:7]1)=[O:5].[Cl:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([C:28](O)=[O:29])=[CH:22]2>>[CH2:11]([C@H:3]([NH:2][C:28]([C:23]1[NH:24][C:25]2[C:21]([CH:22]=1)=[CH:20][C:19]([Cl:18])=[CH:27][CH:26]=2)=[O:29])[C:4](=[O:5])[N:6]1[CH2:10][CH2:9][S:8][CH2:7]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)N1CCSC1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: Cl
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)N1CCSC1)c1cc2cc(Cl)ccc2[nH]1

Procedure:
(S)-2-Amino-3-phenyl-1-thiazolidin-3-yl-propan-1-one hydrochloride (2.6 mmol) and 5-chloro-1H-indole-2-carboxylic acid (2.6 mmol) were coupled according to Procedure A (0-25° C. reaction temperature, 96 hour reaction time, washed with acid first then base). The crude product was triturated with 1:1 ether-hexanes and dried. Yield 966 mg, 91%; HPLC (60/40) 7.99 minutes (97%); PBMS 414/416 (MH+, 100%);
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)/[CH:10]=[CH:11]/[CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:4]([N+:19]([O-])=O)[CH:3]=1.C(O)(=O)C>CO.[Fe]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:9](/[CH:10]=[CH:11]/[CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:19][C:4]=2[CH:3]=1
Reactant: O=C(/C=C/C1CCOCC1)Nc1ccc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CO
Solvent: CC(=O)O
Product: Brc1ccc2[nH]c(/C=C/C3CCOCC3)nc2c1
Temperature: 85 °C

Procedure:
A solution of (E)-N-(4-bromo-2-nitro-phenyl)-3-(tetrahydro-pyran-4-yl)-acrylamide (1.26 g, 3.55 mmol, as prepared in the previous step) in 25 mL anhydrous MeOH was treated with glacial acetic acid (4 mL) and Fe powder (0.991 g, 0.0177 mol) and heated to 85° C. under a reflux condenser for 2 h. The resulting mixture was concentrated in vacuo, treated with saturated aqueous NaHCO3 (200 mL) and extracted thrice with 125 mL CH2Cl2. The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was triturated with CH2Cl2, and the resulting solid was filtered and air-dried. The mother liquor was purified on an 80-g Sepra Si 50 SPE column (Isco system: flow rate=30 mL/min; eluting with EtOAc/hexane, 40:60 v/v over 10 min and 40:60 to 100:0, v/v over 30 min to yield (E)-5-bromo-2-[2-(tetrahydro-pyran-4-yl)-vinyl]-1H-benzimidazole as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].C(O)(=O)C.S(Cl)([Cl:22])(=O)=O>O>[Cl:22][C:10]1[CH:9]=[C:5]([CH:4]=[C:3]([C:11]([F:12])([F:13])[F:14])[C:2]=1[OH:1])[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1ccc(O)c(C(F)(F)F)c1
Reactant: O=S(=O)(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cc(Cl)c(O)c(C(F)(F)F)c1
Temperature: 40 °C

Procedure:
A mixture of 11.7 g (57 mmol) 4-hydroxy-3-trifluoromethyl-benzoic acid and 40 ml acetic acid was combined dropwise with 5.15 ml (63 mmol) sulphurylchloride, with stirring at a bath temperature of 40° C., and stirred for 2 hours at 40° C. Then another 2.5 ml (31 mmol) sulphurylchloride were added and the mixture was stirred for 4 hours at 60° C. The reaction mixture was poured onto 300 ml of water and extracted with 200 ml EtOAc. The organic phase washed twice with 500 ml of water, dried and evaporated down under reduced pressure. The residue was stirred with 80 ml petroleum ether, the precipitate was suction filtered, washed with 20 ml petroleum ether and dried.