Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[S:8][CH:9]=[CH:10][C:11]=1[CH3:12].[CH:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[NH4+]>C1COCC1>[CH3:12][C:11]1[CH:10]=[C:9]([CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[OH:20])[S:8][C:7]=1[CH3:6]
Reactant: Cc1ccsc1C
Reactant: O=Cc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc(C(O)c2ccccc2)sc1C
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 79.8 %

Procedure:
n-Butyl lithium (19.6 ml, 49.1 mmol, 2.5 N in hexanes) was added dropwise to a stirred solution of 2,3-dimethyl-thiophene (5.0 g, 44.6 mmol) in THF (100 mL) at −78° C. under a dry nitrogen atmosphere. The solution was warmed to 0° C. for 30 min and recooled to −78° C. whereupon benzaldehyde (5.0 mL, 49.1 mmol ) was added. After an additional 45 minutes, sat. aq. ammonium chloride was added and the reaction mixture was partitioned between water and ether. The ether phase was washed with brine and concentrated. The resultant oil was triturated with pet. ether to provide the title compound as a white solid (7.77 g, 80%): mp 80-81° C.: NMR (CDCl3); δ7.45 (ddd, J=8, 1, 1 Hz, 2H), 7.37 (ddd, J=8, 8, 1 Hz, 2H), 7.3 (m, 1H), 6.57 (s, 1H), 6.93 (s, 1H, OH), 2.29 (s, 3H), 2.05 (s, 3H); MS (EI) (M+) 218 (45%, MI): Anal. Calc. for C13H14OS: C, 71.52; H, 6.46; N, 0.00. Found: C, 71.41; H, 6.42; N, 0.09.
Reaction SMILES: [I:1][C:2]1[N:11]=[CH:10][C:9]2[CH2:8][CH2:7][C:6]3[C:12]([C:16]([O:18]CC)=O)=[N:13][N:14]([CH3:15])[C:5]=3[C:4]=2[N:3]=1.O.[NH4+:22]>CO>[I:1][C:2]1[N:11]=[CH:10][C:9]2[CH2:8][CH2:7][C:6]3[C:12]([C:16]([NH2:22])=[O:18])=[N:13][N:14]([CH3:15])[C:5]=3[C:4]=2[N:3]=1
Reactant: CCOC(=O)c1nn(C)c2c1CCc1cnc(I)nc1-2
Reactant: [NH4+]
Solvent: O
Solvent: CO
Product: Cn1nc(C(N)=O)c2c1-c1nc(I)ncc1CC2
Temperature: 60 °C
Reaction time: 4 h
Yield: 54 %

Procedure:
1.0 g (2.6 mmol) of ethyl 8-iodo-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate were dissolved in a mixture of 100 mL of methanol and 100 mL of ammonium hydrate 33%. The solution was stirred in a close bottle at 60° C. for 4 hours. The resulting precipitate was collected giving 0.5 g (54% yield) of the title compound.
Reaction SMILES: [H-].[Na+].CCCCCC.[CH3:9][O:10][C:11]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:12]=1[NH2:13].[Br:21][CH2:22][C:23](Br)=[O:24]>C1COCC1>[Br:21][CH2:22][C:23]([NH:13][C:12]1[C:14]([N+:18]([O-:20])=[O:19])=[CH:15][CH:16]=[CH:17][C:11]=1[O:10][CH3:9])=[O:24]
Reactant: COc1cccc([N+](=O)[O-])c1N
Reactant: O=C(Br)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cccc([N+](=O)[O-])c1NC(=O)CBr
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.6 %

Procedure:
To a flask was added sodium hydride (60% dispersion in mineral oil, 610 mg, 15 mmol) and hexane (2 mL) at 0° C. The supernatant liquid was decanted and the residue was dried under reduced pressure. To this was added THF (20 mL) and a solution of 2-methoxy-6-nitroaniline (2 g, 12 mmol, Kubo, K. et al. J. Med. Chem. 1993, 36, 1772-1784) in THF (20 mL) at 0° C. and stirred at rt for 2 h. To this mixture was added bromoacetyl bromide (1.2 mL, 14 mmol) at 0° C. and stirred at rt for 3 h. Then the reaction mixture was quenched by addition of water (100 mL) and extracted with ethyl acetate (100 mL×2). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (2/1-1/1) to afford 2.9 g (85%) of the title compound.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[C@@H:9](O)[CH2:8][N:7]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:6]1)=[N+:2]=[N-:3].N12CCCN=C1CCCCC2.[F:32]C(F)(S(F)(=O)=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F>C1(C)C=CC=CC=1>[N:1]([CH2:4][C@@H:5]1[C@H:9]([F:32])[CH2:8][N:7]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:6]1)=[N+:2]=[N-:3]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: [N-]=[N+]=NC[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1O
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: [N-]=[N+]=NC[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1F
Reaction time: 1 h

Procedure:
Process B: (3R,4R)-3-Azidomethyl-1-benzyloxycarbonyl-4-hydroxypyrrolidine (1.79 g) was dissolved in toluene (56 mL). While this solution was chilled in an ice water bath, 1,8-diazabicyclo[5.4.0]undec-7-ene (2.03 mL) was added, followed by dropwise addition of perfluoro-1-octanesulfonyl fluoride (2.80 mL) and stirring for 1 hour. The insoluble material in the reaction mixture was filtered and washed with toluene. The filtrate and the washings were combined and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: hexane: ethyl acetate=2:1) to give (3R,4S)-3-azidomethyl-1-benzyloxycarbonyl-4-fluoropyrrolidine as a pale brown syrup (1.58 g). This compound was identical to the compound obtained by Process A.
Reaction SMILES: C([O:8][NH:9][C:10](=[O:37])[C:11]1[C:16]([O:17]CC2C=CC=CC=2)=[C:15]([CH2:25][OH:26])[C:14]([CH2:27][NH:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[CH:13][N:12]=1)C1C=CC=CC=1.[CH3:38]O>[Pd]>[F:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][NH:28][CH2:27][C:14]2[C:15]([CH2:25][O:26][CH3:38])=[C:16]([OH:17])[C:11]([C:10]([NH:9][OH:8])=[O:37])=[N:12][CH:13]=2)=[CH:31][CH:32]=1
Reactant: O=C(NOCc1ccccc1)c1ncc(CNCc2ccc(F)cc2)c(CO)c1OCc1ccccc1
Reactant: CO
Agent: [Pd]
Product: COCc1c(CNCc2ccc(F)cc2)cnc(C(=O)NO)c1O
Yield: 75 %

Procedure:
Compound 9a (0.013 g, 0.019 mmol, 1 eq) and 10% Pd/C catalyst (5 mg) were stirred in 4 mL of methanol under an atmosphere of hydrogen for 12 hrs. The catalyst was filtered and reaction mixture was concentrated under vacuum yielding 0.006 g of 5-((4-fluorobenzylamino)methyl)-N,3-dihydroxy-4-(methoxymethyl)picolinamide) (75% yield) as a white solid; MS-ESI m/z 322 [MH]+.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[S:4][C:3]=1[C:15]([NH2:17])=[O:16].C[Si]([N:22]=[C:23]=[O:24])(C)C>>[NH2:22][C:23]([NH:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=2)[S:4][C:3]=1[C:15]([NH2:17])=[O:16])=[O:24]
Reactant: COc1ccc(-c2cc(N)c(C(N)=O)s2)cc1
Reactant: C[Si](C)(C)N=C=O
Product: COc1ccc(-c2cc(NC(N)=O)c(C(N)=O)s2)cc1

Procedure:
Prepared by the method of Example 1 from 3-amino-5-(4-methoxyphenyl)-2-thiophenecarboxamide and trimethylsilylisocyanate.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12](=O)[CH3:13])=[CH:2]1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:21].[Na+]>CO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH:12]([NH2:21])[CH3:13])=[CH:2]1
Reactant: CC(=O)CCc1c[nH]c2ccccc12
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(N)CCc1c[nH]c2ccccc12
Reaction time: 64 h
Yield: 62.3 %

Procedure:
To a solution of 4-(1H-indol-3-yl)-butan-2-one (1.0 g, 5.3 mmol) in methanol (20 mL is added ammonium acetate (4.45 g, 57.73 mmol) and sodium cyanoborohydride (0.37 g, 5.9 mmol) at room temperature. The resulting mixture is allowed to stir for 64 hours at the same temperature. The reaction mixture is quenched by addition of 1 N hydrochloric acid and adjusted to pH ˜2. The mixture is concentrated and extracted with dichloromethane (50 mL). Then the aqueous phase is adjusted to pH ˜12 using 4 N aqueous sodium hydroxide and extracted with dichloromethane (3×50 mL). The combined organic phases are dried with sodium sulfate and concentrated in vacuo. The resulting residue is subjected to flash column chromatography (5%-30% methanol in dichloromethane) to afford 3-(1H-indol-3-yl)-1-methyl-propylamine (622 mg, 62%) as an oil.
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([CH3:12])[C:9]([Cl:11])=[CH:10][C:4]=2[N:3]=1.[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Cl:26])[C:19]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[Cl:11][C:9]1[C:8]([CH3:12])=[CH:7][C:5]2[N:6]=[C:2]([N:23]3[CH2:24][CH2:25][N:20]([C:19]4[C:18]([Cl:26])=[CH:17][N:16]=[CH:15][C:14]=4[Cl:13])[CH2:21][CH2:22]3)[NH:3][C:4]=2[CH:10]=1
Reactant: Cc1cc2[nH]c(Cl)nc2cc1Cl
Reactant: Clc1cncc(Cl)c1N1CCNCC1
Product: Cc1cc2nc(N3CCN(c4c(Cl)cncc4Cl)CC3)[nH]c2cc1Cl

Procedure:
The benzoimidazole from step (b) above (0.201 g, 1 mmol) and 1-(3,5-dichloropyridin-4-yl)piperazine (0.462 g, 2 mmol, Maybridge) reacted under the conditions of Example 1d to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 396 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[NH2:13][CH2:14][CH:15]1[O:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]1.C(N(C(C)C)C(C)C)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([S:9](=[O:11])(=[O:10])[NH2:12])[CH:5]=[CH:6][C:7]=1[NH:13][CH2:14][CH:15]1[O:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCOC(CN)C1
Reactant: NS(=O)(=O)c1ccc(F)c(Cl)c1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCOC(CNc2ccc(S(N)(=O)=O)cc2Cl)C1

Procedure:
A solution of 3-chloro-4-fluorobenzenesulfonamide (1.0 g), tert-butyl 2-(aminomethyl)morpholine-4-carboxylate (1.135 g) and N-ethyl-N-isopropylpropan-2-amine (1.246 mL) in dimethylsulfoxide (15 mL) was stirred at 115° C. for 72 hours. The mixture was concentrated, and the residue was purified on a silica gel column eluting with 60% ethyl acetate to provide the title compound.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13](F)[C:12]([O:16][CH3:17])=[CH:11][C:10]=1[C:18](=[O:20])[CH3:19])C1C=CC=CC=1.[CH2:21]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:21]([N:28]1[CH2:33][CH2:32][N:31]([C:13]2[C:12]([O:16][CH3:17])=[CH:11][C:10]([C:18](=[O:20])[CH3:19])=[C:9]([OH:8])[CH:14]=2)[CH2:30][CH2:29]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: COc1cc(C(C)=O)c(OCc2ccccc2)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C(C)=O)c(O)cc1N1CCN(Cc2ccccc2)CC1
Temperature: 135 °C
Yield: 85.3 %

Procedure:
To a solution of 1-(2-Benzyloxy-4-fluoro-5-methoxy-phenyl)-ethanone (4.25 g, 15.5 mmol) in 3 mL DMF was added 1-benzyl-piperazine (5.4 mo, 30.9 mmol) and potassium carbonate (4.28 g, 30.9 mmol). The reaction mixture was heated under nitrogen to 130-140° C. for 18 hours. The reaction mixture was cooled to room temperature, poured into ice water, and extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered, and evaporated under reduced pressure. The resulting residue was purified by flash chromatography on silica gel (hexanes:ethyl acetate 8.5:1.5) to yield 4.5 g (73%) of 1-[4-(4-Benzyl-piperazin-1-yl)-2-hydroxy-5-methoxy-phenyl]-ethanone as a solid. MP=90-92° C.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[CH3:36][NH:37][C:38]([C:40]1([C:43]2[CH:48]=[CH:47][C:46](Br)=[CH:45][N:44]=2)[CH2:42][CH2:41]1)=[O:39]>>[CH3:36][NH:37][C:38]([C:40]1([C:43]2[CH:48]=[CH:47][C:46]([C:16]3[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]4[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[O:9][C:8]4=[O:10])[CH3:12])=[CH:18][CH:17]=3)=[CH:45][N:44]=2)[CH2:42][CH2:41]1)=[O:39]
Reactant: CNC(=O)C1(c2ccc(Br)cn2)CC1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: CNC(=O)C1(c2ccc(-c3ccc([C@H](C)N4CC[C@](CC(C)(C)O)(c5ccccc5)OC4=O)cc3)cn2)CC1
Yield: 91 %

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-ethyl}-1,3-oxazinan-2-one and 1-(5-bromo-pyridin-2-yl)-cyclopropanecarboxylic acid methylamide following a procedure analogous to that described in Example 1. Yield: 91% of theory; LC (method 1): tR=1.88 min; Mass spectrum (ESI+): m/z=528 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:9]=1[C:10]([O:12]C)=O)(=[O:7])=[O:6].[CH3:21][NH:22][CH3:23].CC(C)([O-])C.[K+]>C(O)(C)(C)C.CO>[CH3:21][N:22]([CH3:23])[C:10](=[O:12])[C:9]1[C:14]([N+:18]([O-:20])=[O:19])=[CH:15][CH:16]=[CH:17][C:8]=1[S:5]([NH:4][CH2:3][CH2:2][OH:1])(=[O:6])=[O:7]
Reactant: COC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)NCCO
Reactant: CNC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CO
Product: CN(C)C(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)NCCO
Reaction time: 96 h
Yield: 87.7 %

Procedure:
A solution of methyl 2-[N-(2-hydroxyethyl)aminosulfonyl]-6-nitrobenzoate (4.58 g, 15.1 mmol) in absolute MeoH (50 ml) was added to a solution of dimethylamine (6.8 g, 0.15 mol) and potassium tertbutoxide (0.68 ml of a 0.262 M solution in tertbutanol) in absolute MeOH (100 ml). After stirring at 20°-25° for 4 days, solvents were removed under reduced pressure. The residue was dissolved in EtOAc and washed with 0.5 N HCl followed by a saturated aqueous NaCl solution. The EtOAc extract was dried (Na2SO4), filtered and concentrated to give 4.2 g (88%) of product.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:31])[CH:3]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][C:40]([N:42]=[C:43]=[O:44])=[O:41])=[CH:35][CH:34]=1>O1CCCC1>[F:31][C:4]1[CH:3]=[C:2]([NH:1][C:43]([NH:42][C:40](=[O:41])[CH2:39][C:36]2[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=2)=[O:44])[CH:30]=[CH:29][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([CH:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)[CH2:18][CH2:17]2)=[O:15])[CH:8]=1
Reactant: CN1CCC(N2CCN(C(=O)Nc3cc(Oc4ccc(N)cc4F)ccn3)CC2)CC1
Reactant: O=C=NC(=O)Cc1ccc(F)cc1
Solvent: C1CCOC1
Product: CN1CCC(N2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)NC(=O)Cc5ccc(F)cc5)cc4F)ccn3)CC2)CC1
Reaction time: 72 h
Yield: 8.5 %

Procedure:
To a solution of 4-(4-amino-2-fluorophenoxy)-2-{[4-(1-methylpiperidin-4-yl)piperazin-1-yl]carbonylamino}pyridine (81.2 mg) in tetrahydrofuran (2.0 ml) was added a solution of 2-(4-fluorophenyl)acetyl isocyanate in tetrahydrofuran (0.25 M, 1.9 ml) at room temperature, followed by stirring for 3 days. The reaction mixture was concentrated under reduced pressure. The resultant residue was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate:methanol=97:3 to 95:5) to provide the titled compound (9.7 mg, 8.5%) as white powder.
Reaction SMILES: [Cl:1][C:2]1[C:7](F)=[C:6]([S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[NH:14][C:15](=[O:23])[C@:16]([OH:22])([CH3:21])[C:17]([F:20])([F:19])[F:18].[C:24]1([OH:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CN(C=O)C>[Cl:1][C:2]1[C:7]([O:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:6]([S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[NH:14][C:15](=[O:23])[C@:16]([OH:22])([CH3:21])[C:17]([F:20])([F:19])[F:18]
Reactant: Oc1ccccc1
Reactant: CCS(=O)(=O)c1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1Oc1ccccc1
Temperature: 150 °C
Yield: 19.8 %

Procedure:
(R)-N-[2-Chloro-3-fluoro-4-(ethylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 15; 0.308 g) was added to a stirred suspension of phenol (0.150 g) and anhydrous potassium carbonate (0.220 g) in anhydrous DMF (2 ml). The reaction mixture was heated to 150° C. under argon for 17 hours and allowed to cool to ambient temperature. EtOAc (50 ml) was added and the organic phase was washed with brine (4×50 ml), separated, dried and volatile material was removed by evaporation. The residue was purified on a 8 g silica Biotage cartridge eluting 40% EtOAc/isohexane to give the title compound (0.073 g) as a pale yellow foam. NMR (CDCl3): 1.18 (t, 3H), 1.69 (s, 3H), 3.23-3.30 (q, 2H), 3.48 (s, 1H), 6.78 (d, 2H), 7.02 (t, 1H), 7.24 (t, 2H), 7.97 (d, 1), 8.50 (d, 1H), 9.24 (brs, 1H); m/z: 450.
Reaction SMILES: [NH3:1].[Br:2][C:3]1[N:4]=[C:5](Br)[C:6]2[N:7]([N:9]=[C:10]([C:12]3[O:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH:8]=1>O1CCOCC1>[Br:2][C:3]1[N:4]=[C:5]([NH2:1])[C:6]2[N:7]([N:9]=[C:10]([C:12]3[O:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH:8]=1
Reactant: Brc1cn2nc(-c3ccco3)nc2c(Br)n1
Reactant: N
Solvent: C1COCCO1
Product: Nc1nc(Br)cn2nc(-c3ccco3)nc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 99 %

Procedure:
Anhydrous ammonia was bubbled over a one-hour period into a solution of 6,8-dibromo-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrazine (18.4 g, 0.054 mol) in dioxane (400 ml). The resulting mixture was stirred at room temperature for 2 days during which time the solution was twice recharged with ammonia by bubbling in for one hour. After concentration, diethyl ether (200 ml) was added and the resulted yellow slurry was stirred at room temperature for overnight. 6-Bromo-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamine was then collected and- dried (15 g, 99% yield). 1H NMR (300 MHz, CDCl3) δ 6.70 (dd, 1H), 7.10 (d, 1H), 7.8-8.0 (br m, 3H), 8.58 (s, 1H). MS: m/z: 280 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6](=[O:19])[CH:7]([C:9](=[O:18])[C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=3[Cl:17])[O:8][C:4]=2[CH:3]=1.S(OC)(O[CH3:26])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[Br:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([O:19][CH3:26])=[C:7]([C:9]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=3[Cl:17])=[O:18])[O:8][C:4]=2[CH:3]=1
Reactant: COS(=O)(=O)OC
Reactant: O=C(c1ccc(Cl)cc1Cl)C1Oc2cc(Br)ccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COc1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc(Br)ccc12
Yield: 27.8 %

Procedure:
To a solution of 6-Bromo-2-(2,4-dichloro-benzoyl)-benzofuran-3-one (3.30 g, 8.55 mmol) in acetone (50 mL) was added dimethyl sulfate (1.19 g, 9.40 mmol) and cesium carbonate (4.18 g, 12.82 mmol). The resulting mixture was heated at 50 deg for 6 hours is at which time the reaction mixture was concentrated via rotary evaporation. The resulting mixture was taken up in EtOAc and washed twice with water and one time with a saturated sodium carbonate solution. The organic portion was dried over MgSO4 and then filtered and concentrated. The resultant oil was purified via column chromatography (10% MeOH/Dichloromethane) to provide the title compound (950 mg, 28%). 1H-NMR (CDCl3): δ 8.03 (d, 1H), 7.65 (d, 1H), 7.46 (m, 2H), 7.35 (m, 2H), 2.46 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[C:16]([CH3:34])=[CH:17][N:18]([CH:31]([CH3:33])[CH3:32])[C:19]=2[CH:20]=[C:21]([C:23]2[CH:24]=[N:25][C:26]([CH:29]=O)=[CH:27][CH:28]=2)[CH:22]=1)=[O:13].[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1.S([O-])([O-])(=O)=O.[Na+].[Na+].[BH4-].[Na+]>C(Cl)Cl.CO>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[C:16]([CH3:34])=[CH:17][N:18]([CH:31]([CH3:33])[CH3:32])[C:19]=2[CH:20]=[C:21]([C:23]2[CH:24]=[N:25][C:26]([CH2:29][N:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)=[CH:27][CH:28]=2)[CH:22]=1)=[O:13]
Reactant: C1CCNC1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)nc3)cc3c2c(C)cn3C(C)C)c(=O)[nH]1
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN4CCCC4)nc3)cc3c2c(C)cn3C(C)C)c(=O)[nH]1
Temperature: 45 °C
Reaction time: 2 h

Procedure:
To a solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(6-formylpyridin-3-yl)-1-isopropyl-3-methyl-1H-indole-4-carboxamide (100 mg, 0.219 mmol), in DCM (10 mL) and methanol (2 mL) was added pyrrolidine (0.035 mL, 0.438 mmol), followed by sodium sulfate (31.1 mg, 0.219 mmol). The reaction stirred at rt for 12 h, at which time sodium borohydride (16.57 mg, 0.438 mmol) was added and the reaction stirred rt for 2 h and 45° C. for 2 h. The reaction was quenched with water and extracted with EtOAc. The organic layer was evaporated. Purification by reverse phase Gilson HPLC (10-60% acetonitrile/water+0.1% TFA, YMC ODS-A C18 Column 75×30 mm ID S-5 um, 12 nM Column 7 minutes), followed by isolation and extraction with EtOAc/0.1 N NaOH provided N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-3-methyl-6-(6-(pyrrolidin-1-ylmethyl)pyridin-3-yl)-1H-indole-4-carboxamide, which was evaporated from the organic layer as a yellow foam solid (68 mg, 0.125 mmol, 57.0% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.48 (br. s., 1 H) 9.06 (d, J=2.02 Hz, 1 H) 8.30 (dd, J=8.08, 2.27 Hz, 1 H) 8.20 (t, J=5.18 Hz, 1 H) 7.94 (d, J=1.26 Hz, 1 H) 7.60 (d, J=8.08 Hz, 1 H) 7.40 (s, 1 H) 7.32 (s, 1 H) 5.88 (s, 1 H) 4.92-4.89 (m, 1 H) 4.59 (d, J=5.56 Hz, 2 H) 4.36 (d, J=5.05 Hz, 2 H) 3.34 (br. s., 4 H) 2.25 (s, 3 H) 2.17 (d, J=1.01 Hz, 3 H) 2.11 (s, 3 H) 1.99 (br.s., 4 H) 1.45 (d, J=6.57 Hz, 6 H). LCMS: [M+H]+=512.3.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[F:9].[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[CH2:12].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(N(CC)C(C)C)(C)C.CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:6][C:5]1[CH:7]=[CH:8][C:2](/[CH:12]=[CH:11]/[C:10]([O:14][CH2:15][CH3:16])=[O:13])=[C:3]([F:9])[CH:4]=1
Reactant: C=CC(=O)OCC
Reactant: Nc1ccc(Br)c(F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc(N)cc1F
Temperature: 110 °C
Reaction time: 5 h
Yield: 95.6 %

Procedure:
4-Bromo-3-fluoroaniline (13.3 g, 70.0 mmol), ethyl acrylate (9.48 mL, 87.5 mmol) and tris(2-methylphenyl)phosphine (8.52 g, 28.0 mmol) were dissolved in N,N-diisopropylethylamine (50 mL) and N,N-dimethylformamide (50 mL), palladium(II) acetate (0.786 g, 3.50 mmol) was added, and the mixture was stirred under an argon atmosphere at 110° C. for 5 hr. After cooling the reaction mixture, the solvent was evaporated under reduced pressure. Water and ethyl acetate were added to the residue, and the insoluble material was removed by filtering through celite. The organic layer in the filtrate was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20%-60% ethyl acetate/hexane) to give the title compound (14.0 g, yield 96%). A part thereof was recrystallized to give yellow prism crystals.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]1[CH:43]=[CH:42][C:11]([CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH3:24])[CH:19]=3)[C:14]=2[C:25]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][N:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)=[CH:29][CH:28]=2)=[O:26])=[CH:10][CH:9]=1>C1COCC1>[F:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH3:24])[CH:19]=3)[C:14]=2[CH:25]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][N:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)=[CH:29][CH:28]=2)[OH:26])=[CH:42][CH:43]=1
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(Cc3ccc(F)cc3)ccc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc2c(C(O)c3ccc(OCCN4CCCCC4)cc3)c(Cc3ccc(F)cc3)ccc2c1
Temperature: 25 °C

Procedure:
Add LAH solution (2 mL, 1M/THF) to a stirred solution of [2-(4-fluoro-benzyl)-6-methoxy-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone (380 mg) in THF (5 mL) at room temperature. Heat the mixture to reflux for 1 h, cool to r.t. and quench with aq. NaHCO3. Dilute the mixture with CH2Cl2 and wash with water and brine, dry over MgSO4, filter and concentrate to afford [2-(4-fluoro-benzyl)-6-methoxy-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanol. Use the product without further purification.