Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([NH:12][CH2:13][CH3:14])[CH3:11])=[CH:5][CH:4]=1.[O:15]=[C:16]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][N:17]1[CH2:23][CH:24]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:13]([N:12]([CH:10]([CH3:11])[CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH2:24][CH2:23][N:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:16]1=[O:15])[CH3:14]
Reactant: CCNC(C)Cc1ccc(OC)cc1
Reactant: O=CCN1CCCCCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCN(CCN1CCCCCC1=O)C(C)Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 91.9 %

Procedure:
A mixture of [2-(4-methoxyphenyl)-1-methylethyl]ethylamine (0.53 g, 2.75 mmole), (2-oxo-azepan-1-yl)acetaldehyde (0.5 g, 3.2 mmole), and sodium triacetoxyborohydride (0.88 g, 4.1 mmole) in 1,2-dichloroethane (15 mL) was stirred at room temperature for 60 hours. The mixture was concentrated, and the residue was partitioned between diethyl ether (50 mL) and saturated aqueous sodium bicarbonate (25 mL). The organic solution was extracted with 5% hydrochloric acid (20 mL), and the aqueous acidic phase was washed with diethyl ether and the pH was adjusted to 12 with 25% sodium hydroxide. The mixture was extracted with dichoromethane, and the organic phase was dried (sodium sulfate) and concentrated to give 1-(2-{ethyl-[2-(4-methoxyphenyl)-1-methylethyl]amino}ethyl)-azepan-2-one 11(0.84 g) as a viscous oil, which was converted to the dibenzoyl-L-tartrate salt, Anal.: Calcd. for C38H46N2O10: C, 66.07; H, 6.71; N, 4.06%; Found C, 64.69; H, 6.45; N 3.90%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([F:15])([F:14])[F:13])[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5]2.S(Cl)([Cl:24])(=O)=O>C1(C)C=CC=CC=1.C(N)(C)(C)C.S(Cl)(Cl)(=O)=O>[Cl:24][C:3]1[C:2]([OH:1])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:7]2[CH2:11][C:12]([F:15])([F:13])[F:14]
Reactant: CCOC(=O)c1cc2cc(O)ccc2n1CC(F)(F)F
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(C)(C)N
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2c(Cl)c(O)ccc2n1CC(F)(F)F
Reaction time: 0.02 h
Yield: 91.7 %

Procedure:
To a solution of ethyl 5-hydroxy-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxylate (0.7 g, 2.44 mmol) in toluene (30 mL) was added tert-butyl amine (0.014 g, 0.2 mmol) and the mixture was set in an oil bath preheated at 70° C. After 1 min, a solution of sulfuryl chloride (0.37 g, 2.49 mmol) in toluene (1 mL) was added. The reaction was followed by TLC (60% CH2Cl2-hexanes) and additional reagents were added accordingly. After 30 min, more tert-butylamine (0.014 g, 0.2 mmol) and sulfuryl chloride (0.06 g, 0.37 mmol) were added. After another 30 min additional tert-butylamine (0.014 g, 0.2 mmol) and sulfuryl chloride (0.019 g, 0.12 mmol) were added and heating was continued for 30 min. Upon cooling, the mixture was partitioned between EtOAc and 0.2N HCl. The organic phase was washed with 0.2N HCl and sat'd brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (10-80% CH2Cl2-hexanes gradient) to afford the title compound (0.72 g, 92% yield, 95% purity): MS (ES) m/z 322 (M+1).
Reaction SMILES: [F:1][CH:2]1[CH:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][NH:4][CH2:3]1.Br[C:15]1[CH:16]=[C:17]([C:21]2[N:25]([CH3:26])[C:24]3[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=3[N:22]=2)[CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][CH:2]1[CH:7]([N:8]2[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[CH2:6][CH2:5][N:4]([C:15]2[CH:16]=[C:17]([C:21]3[N:25]([CH3:26])[C:24]4[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=4[N:22]=3)[CH:18]=[CH:19][CH:20]=2)[CH2:3]1
Reactant: Cn1c(-c2cccc(Br)c2)nc2ccccc21
Reactant: FC1CNCCC1N1CCOCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Cn1c(-c2cccc(N3CCC(N4CCOCC4)C(F)C3)c2)nc2ccccc21

Procedure:
4-(3-Fluoro-piperidin-4-yl)-morpholine (0.085 g, 0.45 mmol), 2-(3-Bromo-phenyl)-1-methyl-1H-benzoimidazole (described in method N, step a, b) (0.10 g, 0.35 mmol), and cesium carbonate (10.50 g, 32.2 mmol) were placed into a dry sealed 7 mL vial under nitrogen and dry toluene (0.4 mL) was added. At the same time Palladium acetate (0.016 g, 0.07 mmol), and BINAP (0.065 g, 0.10 mmol) were placed into another dry sealed 7 mL vial under nitrogen and diluted with dry toluene (0.8 mL) After about 20 minutes the resulting suspension was added to the vial containing the starting materials.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[C:8]1[CH:13]=[N:12][CH:11]=[C:10](Cl)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[Br-].[CH3:24][O:25][C:26]1[N:31]=[C:30]([Zn+])[CH:29]=[CH:28][CH:27]=1>>[C:1]([O:5][C:6](=[O:22])[N:7]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[C:8]1[CH:13]=[N:12][CH:11]=[C:10]([C:30]2[CH:29]=[CH:28][CH:27]=[C:26]([O:25][CH3:24])[N:31]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(c1ccc(Cl)cc1)c1cncc(Cl)n1
Reactant: COc1cccc([Zn+])n1
Agent: [Br-]
Product: COc1cccc(-c2cncc(N(C(=O)OC(C)(C)C)c3ccc(Cl)cc3)n2)n1

Procedure:
Was prepared according to Example 5 from (4-chloro-phenyl)-(6-chloro-pyrazin-2-yl)-carbamic acid tert-butyl ester and 6-methoxy-2-pyridylzinc bromide.
Reaction SMILES: [CH2:1]([N:3]([CH2:35][CH3:36])[CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[C:30]([C:31]([O:33]C)=[O:32])=[C:22]2[O:23][CH2:24][C:25]3[N:26]([CH:27]=[CH:28][CH:29]=3)[C:21]2=[CH:20][CH:19]=1)(=[O:16])=[O:15])[CH3:2].O.[OH-].[Li+].C(O)=O>O1CCOCC1.O.C(O)C.C1(C)C=CC=CC=1>[CH2:35]([N:3]([CH2:1][CH3:2])[CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[C:30]([C:31]([OH:33])=[O:32])=[C:22]2[O:23][CH2:24][C:25]3[N:26]([CH:27]=[CH:28][CH:29]=3)[C:21]2=[CH:20][CH:19]=1)(=[O:15])=[O:16])[CH3:36]
Reactant: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCc1cccn1-2
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O=CO
Solvent: O
Product: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)OCc1cccn1-2
Yield: 16.7 %

Procedure:
A suspension of methyl 7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-4H-benzo[b]pyrrolo[1,2-d][1,4]oxazine-6-carboxylate (Intermediate 15, 0.074 g) and lithium hydroxide monohydrate (0.060 g) in dioxane (2 mL) and water (0.5 mL) was irradiated in the microwave at 130° C. for 45 minutes. After cooling, the mixture was acidified to pH3 with formic acid, diluted with ethanol and toluene and concentrated in vacuo. The residue was triturated with a solution of methanol in DCM (10%) and the solid was filtered off and washed with DCM. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-6%. The resultant solid was triturated with a mixture of ethyl acetate and ether and the solid obtained was dried in vacuo at 60° C. overnight to give 7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-4H-benzo[b]pyrrolo[1,2-d][1,4]oxazine-6-carboxylic acid (0.012 g) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].N1C=CC=CC=1.[Cl:24][C:25]1[CH:26]=[C:27]([S:32](Cl)(=[O:34])=[O:33])[CH:28]=[CH:29][C:30]=1[Cl:31].O>C(Cl)Cl>[Cl:24][C:25]1[CH:26]=[C:27]([S:32]([NH:1][C:2]2[S:6][C:5]3[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=3[C:3]=2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])(=[O:33])=[O:34])[CH:28]=[CH:29][C:30]=1[Cl:31]
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CCCC2
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)OC(=O)c1c(NS(=O)(=O)c2ccc(Cl)c(Cl)c2)sc2c1CCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (12.26 g, 48.4 mmol) was dissolved in DCM (150 ml), and pyridine (6.0 ml, 74 mmol) was added thereto. A solution of 3,4-dichlorobenzenesulfonyl chloride (8.4 ml, 54 mmol) was then added, and the mixture was heated for 17 h under reflux and then cooled to room temperature. Water was added (100 ml), and stirring was carried out overnight at room temperature. The phases were then separated (pH organic phase≈2), washed with saturated NaHCO3 solution, dried (sodium sulfate) and concentrated in vacuo.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].C(N(CC)CC)C.[C:19]([C:21]1[CH:22]=[C:23]([S:27](Cl)(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1)#[N:20]>O1CCOCC1>[C:19]([C:21]1[CH:22]=[C:23]([S:27]([NH:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:10])[CH3:9])(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1)#[N:20]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1cccc(C#N)c1
Reaction time: 8 h
Yield: 100 %

Procedure:
To a stirring mixture consisting of tert-butyl 2-aminoethylcarbamate (Sigma-Aldrich, 832 mg), triethylamine (1.44 mL), and 1,4-dioxane (25 mL) was added 3-cyanobenzene-1-sulfonyl chloride (Compound 14, Sigma-Aldrich, 942 mg) and the mixture was stirred overnight. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and 5% aqueous potassium hydrogen sulfate. The organic phase was washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford the title intermediate (1.52 g), which was carried on without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:16][CH2:17][C:18]1([OH:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[OH:24][C:18]1([CH2:17][NH:16][C:8]([C:5]2[CH:4]=[C:3]([O:11][CH2:12][CH:13]3[CH2:15][CH2:14]3)[C:2]([Cl:1])=[CH:7][N:6]=2)=[O:10])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: NCC1(O)CCCCC1
Reactant: O=C(O)c1cc(OCC2CC2)c(Cl)cn1
Product: O=C(NCC1(O)CCCCC1)c1cc(OCC2CC2)c(Cl)cn1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid and 1-(aminomethyl)-cyclohexanol (CAN 4000-72-0) as starting materials and isolated (19.2 mg, 57%) as white solid; MS (ESI, m/z): 339.1 (MH+).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[C:17]([O:19][CH3:20])=[O:18])(=O)=O.C(N(CC)CC)C.[C:30]1([PH:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:37]1([P:36]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[C:17]([O:19][CH3:20])=[O:18])[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: c1ccc(Pc2ccccc2)cc1
Reactant: COC(=O)c1c(OS(=O)(=O)C(F)(F)F)ccc2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1c(P(c2ccccc2)c2ccccc2)ccc2ccccc12

Procedure:
A stirred solution of methyl 2-trifluoromethanesulfonyloxy-1-naphthoate (52.7 g, 158 mmol, 1 eq), triethylamine (26.5 ml, 190 mmol, 1.2 eq) and palladium acetate (0.15 g, 0.7 mmol, 0.004 eq) in acetonitrile (600 ml) was sparged with nitrogen for 30 minutes. Diphenylphosphine (29.4 g, 158 mmol, 1 eq) was added instantly giving a red coloration. The solution was heated at reflux under nitrogen for 17 hours. The blood-red solution was allowed to cool and concentrated under reduced pressure to approximately half its original volume. Methanol (50 ml) was added and the mixture concentrated a little more under reduced pressure. The product crystallised from this mixture and was collected by filtration and washed with ice-cold methanol (200 ml) and dried under vacuum at ambient temperature; 31p NMR (162 mHz; CDCl3): δ−7.8. Yield 54.1 g, 92%
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[H][H]>[Ni].C(O)C>[CH2:9]([O:8][C:6]([CH:5]1[CH2:11][CH2:12][CH:2]([OH:1])[CH2:3][CH2:4]1)=[O:7])[CH3:10]
Reactant: [H][H]
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)C1CCC(O)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 79.1 %

Procedure:
In an autoclave made of stainless steel having a volume of 1 liter were placed 142 g (0.86 mole) of ethyl para-hydroxybenzoate, 10 g of Raney Ni catalyst (activity W-7) and 400 ml of ethanol, and reacted with stirring at a pressure of hydrogen of 100 kg/cm2 and a reaction temperature of 150° C. for 20 hours. After the autoclave was allowed to cool to room temperature, the hydrogen in the vessel was released, and the Raney Ni catalyst was then removed by suction filtration. The filtrate was concentrated by means of a rotary evaporator and then distilled under reduced pressure to obtain 117 g (0.68 mole, yield 79%) of 4-ethoxycarbonylcyclohexanol having a boiling point of 98° to 104° C./4 mmHg.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][C:4]([CH3:9])([CH3:8])[C:5](O)=[O:6].O=S(Cl)Cl.[F:16][C:17]1[CH:18]=[C:19]([C@@:30]([C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=2)([NH2:38])[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:20]=[C:21]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])[CH:22]=1>ClCCCl>[F:1][C:2]([F:11])([F:10])[CH2:3][C:4]([CH3:9])([CH3:8])[C:5]([NH:38][C@@:30]([C:19]1[CH:20]=[C:21]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])[CH:22]=[C:17]([F:16])[CH:18]=1)([C:39]1[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=1)[CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:6]
Reactant: N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Reactant: CC(C)(CC(F)(F)F)C(=O)O
Solvent: O=S(Cl)Cl
Solvent: ClCCCl
Product: CC(C)(CC(F)(F)F)C(=O)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Temperature: 25 °C
Yield: 24 %

Procedure:
To a solution of 4,4,4-trifluoro-2,2-dimethylbutanoic acid (30 mg, 0.176 mmol) in DCE (1 mL) was added SOCl2 (21 mg, 0.176 mmol) and the resulting mixture was refluxed for 2 h. After cooling to room temperature, TEA was added (82 uL, 0.59 mmol), followed by the addition of (R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethanamine, prepared as described in Procedure 3, 4, 5 and 6, (25 mg, 0.059 mmol). The reaction mixture was heated to reflux overnight, concentrated and the residue was purified by preparative HPLC (Axia column, 30×100 mm, 40 mL/min, 40-100% ACN/H2O/0.1% TFA over 12 min) to give (R)-4,4,4-trifluoro-N-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2,2-dimethylbutanamide (Example 266) as a brownish oil (8 mg, 24% yield). LCMS: RT=2.13 min [M+H] 578.3 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); 1H NMR (400 MHz, CDCl3) ppm 1.28 (s, 6H), 2.21-2.51 (m, 2H), 3.77 (ABqt, J=13 Hz, 2H), 5.83 (t, J=53 Hz, 1H), 6.37 (s, 1H), 6.65-6.74 (m, 2H), 6.75-6.95 (m, 3H), 6.94-7.09 (m, 4H), 7.09-7.31 (m, 3H).
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=4)[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.C([N:48]1[CH:52]=[C:51]([CH2:53][CH2:54][NH2:55])[N:50]=[CH:49]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>>[NH:48]1[CH:52]=[C:51]([CH2:53][CH2:54][NH:55][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([C:8]3[C:16]4[C:11](=[CH:12][N:13]=[C:14]([C:17]5[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=5)[CH:15]=4)[NH:10][N:9]=3)[N:7]=2)[N:50]=[CH:49]1
Reactant: Cn1cc(-c2cc3c(-c4cccc(F)n4)nn(C4CCCCO4)c3cn2)cn1
Reactant: NCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Product: Cn1cc(-c2cc3c(-c4cccc(NCCc5c[nH]cn5)n4)n[nH]c3cn2)cn1
Yield: 37.6 %

Procedure:
Following the procedures as described in Example 189, 3-(6-fluoropyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine and 2-(1-trityl-1H-imidazol-4-yl)-ethylamine were reacted. The product was deprotected to give 217 as a white solid (37.6% over two steps). 1H NMR (400 MHz, DMSO) δ 9.01 (s, 1H), 8.62 (s, 1H), 8.26 (s, 1H), 8.03 (s, 1H), 7.88 (s, 1H), 7.56 (s, 1H), 7.49 (d, J=8.1 Hz, 1H), 7.34 (d, J=7.4 Hz, 1H), 6.86 (s, 1H), 6.80 (s, 1H), 6.49 (d, J=8.3 Hz, 1H), 3.88 (s, 3H), 3.78-3.70 (m, 2H), 2.92 (t, J=7.5 Hz, 2H), 2.54 (s, 1H). LC/MS: m/z 386.1 [M+1]
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)[CH:5]=[CH:6][C:7]=1[CH2:8][OH:9].Cl.[Cl:21][C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[N:29]1[C:33]([CH2:34][NH2:35])=[CH:32][C:31]([C:36]([F:39])([F:38])[F:37])=[N:30]1>C(Cl)Cl.O>[Cl:21][C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[N:29]1[C:33]([CH2:34][NH:35][C:11]([NH:10][C:4]2[CH:5]=[CH:6][C:7]([CH2:8][OH:9])=[C:2]([F:1])[CH:3]=2)=[O:19])=[CH:32][C:31]([C:36]([F:38])([F:39])[F:37])=[N:30]1
Reactant: NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1Cl
Reactant: O=C(Nc1ccc(CO)c(F)c1)Oc1ccccc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: O=C(NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1Cl)Nc1ccc(CO)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 23.3 %

Procedure:
To a stirred solution of phenyl 3-fluoro-4-(hydroxymethyl)phenylcarbamate (0.175 g, 0.63 mmol, 1.0 eq) in DCM (5 mL) was added TEA (0.25 mL, 1.9 mmol, 3.0 eq.) followed by compound (1-(2,3-dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine hydrochloride (0.218 mg, 0.63 mmol, 1.0 eq.) at RT and stirred for 16 h at RT. The reaction mixture was diluted with water (10 mL) and extracted into DCM (25 mL). The organic layer was washed with brine (10 mL), dried over (Na2SO4) and the solvent evaporated under vacuum. The resulting residue was purified by CC using EtOAc/PE (1:1) as eluent to get 1-((1-(2,3-dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(3-fluoro-4-(hydroxymethyl)phenyl)urea (70 mg; 23%) as white solid (TLC system: EtOAc, Rf: 0.55).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([O:12][CH3:13])=[O:11])[CH:3]=[CH:2]1.Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1.[H-].[Na+]>CN(C=O)C>[F:23][C:22]([F:24])([F:25])[C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][C:8]=3[C:10]([O:12][CH3:13])=[O:11])[CH:3]=[CH:2]2)=[CH:17][CH:18]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: COC(=O)c1cccc2cc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2ccn(Cc3ccc(C(F)(F)F)cc3)c12
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Methyl 1H-indole-7-carboxylate (47.8 g, 273 mmol) and 1-(bromomethyl)-4-(trifluoromethyl)benzene (81 g, 341 mmol) were dissolved in DMF (1.3 L) at 0° C. 60% w/w NaH (12 g, 300 mmol) was added portion wise. The ice bath was removed and the mixture stirred at 0° C. for 3 hours, then overnight at RT. The reaction mixture was quenched with 3 L of NH4Cl(sat.) and the aqueous layer was extracted 3 times with 1 L of ether. The organic layers were combined, washed with water and brine. The compound was purified by flash chromatography on silica gel. 1H NMR (500 MHz, DMSO-d6): δ 8.90 (d, 1H), 7.70 (s, 1H), 7.60 (d, 2H), 7.40 (d, 1H), 7.10 (t, 1H), 7.00 (d, 2H), 6.70 (d, 1H), 5.70 (s, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][C@:11]([CH:17]([CH3:19])[CH3:18])([C:14]([OH:16])=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:20]1([C:26]2([OH:32])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]1[CH2:13][CH2:12][C@@:11]([C:14]([N:29]2[CH2:30][CH2:31][C:26]([OH:32])([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:27][CH2:28]2)=[O:16])([CH:17]([CH3:19])[CH3:18])[CH2:10]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: CC(C)[C@]1(C(=O)O)CC[C@@H](NC(=O)OC(C)(C)C)C1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[C@]1(C(=O)N2CCC(O)(c3ccccc3)CC2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1S,3R)-3-[(tert-butoxycarbonyl)amino]-1-isopropylcyclopentane-carboxylic acid (200 mg, 0.7 mmol), 4-phenylpiperidin-4-ol (140 mg, 0.81 mmol), and triethylamine (0.15 g, 1.5 mmol) in methylene chloride (4 mL) was added (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (0.42 g, 0.81 mmol). After being stirred overnight at room temperature, the reaction was quenched by addition of a saturated NaHCO3 solution. The resulting solution was extracted with methylene chloride three times. The combined extracts were dried (MgSO4), filtered, and concentrated. The crude was carried on to the next step without purification. MS calculated for C25H38N2O4: (M+H) 431; found 431.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([N:12]1[C:16]3[CH:17]=[CH:18][C:19]([O:21]C)=[CH:20][C:15]=3[N:14]=[CH:13]1)[CH:8]=[CH:7]2.[OH-].[Na+].Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([N:12]1[C:16]3[CH:17]=[CH:18][C:19]([OH:21])=[CH:20][C:15]=3[N:14]=[CH:13]1)[CH:8]=[CH:7]2
Reactant: COc1ccc2c(c1)ncn2-c1ccc2cccc(Cl)c2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Oc1ccc2c(c1)ncn2-c1ccc2cccc(Cl)c2n1
Temperature: -78 °C
Reaction time: 22 h

Procedure:
To a pre-cooled (−78° C.) solution containing 8-chloro-2-(5-methoxy-1H-benzimidazol-1-yl)quinoline 138B (2.16 g, 7.0 mMol) in anhydrous DCM (28 mL) was added a 1.0 M solution of borontribromide in DCM (20.9 mL, 20.9 mMol). The cooling bath was removed and the reaction mixture stirred at ambient temperature under nitrogen for 22 hours. The reaction was quenched by the addition of aqueous 1 N NaOH to a pH of about 8.8. After stirring for about minutes, the suspended solids were removed by filtration. The solids were subsequently stirred briefly with 1 N NaOH (21 mL, 21 mMol) to hydrolyse remaining borate esters, and then neutralized by adding 1 N HCl (21 mL, 21 mMol). The solid precipitate was filtered off, stirred briefly with a small amount of warm EtOAc to remove traces of starting material, and re-filtered to give 1.91 g, mp>250° C., of the title product 138C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:23]=[O:24])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]21.[CH:25]([Mg]Cl)([CH3:27])[CH3:26]>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([OH:24])[CH:25]([CH3:27])[CH3:26])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)C(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 47.2 %

Procedure:
To a solution of 9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (150.0 mg, 0.394 mmol) in tetrahydrofuran (3.0 mL) was added i-propylmagnesium chloride (1.0 M solution in tetrahydrofuran, 0.59 mL, 0.591 mmol). The reaction mixture was stirred at 0° C. for 2 hrs. To the mixture was added i-propylmagnesium chloride (1.0 M solution in tetrahydrofuran, 0.59 mL, 0.591 mmol). The mixture was stirred at 0° C. for 1 hr. After cooling, the mixture was quenched with aqueous saturated ammonium chloride and extracted with ethyl acetate (×3). The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 10-60% ethyl acetate/n-hexane gradient mixture to give the title compound as a solid (78.8 mg, 0.186 mmol, 47%).