Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:11][O-:12].[Na+]>>[Cl:10][C:8]1[CH:7]=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([O:12][CH3:11])[N:9]=1
Reactant: C[O-]
Reactant: O=Cc1ccc(Cl)nc1Cl
Agent: [Na+]
Product: COc1nc(Cl)ccc1C=O
Temperature: 55 °C
Reaction time: 3 h
Yield: 71.3 %

Procedure:
2,6-Dichloronicotinaldehyde (1 g, 5.68 mmol) was diluted with sodium methoxide (11.4 mL, 5.68 mmol) (solution in methanol) and heated to 55° C. After stirring for 3 hours, the reaction was loaded directly onto a silica gel column and eluted with 5% ethyl acetate/hexanes to 50% ethyl acetate/hexanes to yield 6-chloro-2-methoxynicotinaldehyde (0.695 g, 4.05 mmol, 71.3% yield).
Reaction SMILES: [NH2:1][C:2]1[C:11]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=3[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=O)[CH:8]=2)[N:3]=1.[Cl-].[OH:34][NH3+:35]>CO.N1C=CC=CC=1>[NH2:1][C:2]1[C:11]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=3[C:25]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[N:35][OH:34])[CH:8]=2)[N:3]=1
Reactant: [NH3+]O
Reactant: Cc1cccc(C(=O)c2ccccc2)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Agent: [Cl-]
Solvent: CO
Solvent: c1ccncc1
Product: Cc1cccc(C(=NO)c2ccccc2)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Temperature: 25 °C

Procedure:
To a solution of (2-(2-amino-3-morpholinoquinolin-6-yl)-3-methylphenyl)(phenyl)methanone (0.090 g, 0.213 mmol, prepared as Example 15, Step 1) in MeOH (4.0 mL) was added hydroxyammonium chloride (0.044 mL, 1.063 mmol) followed by 3 drops of pyridine. The reaction mixture was brought up to reflux for 41 h until the conversion was completed, determined by LCMS. The reaction mixture was cooled to RT and purified on HPLC (10-100% MeCN/H2O with 0.1% TFA) to afford (2-(2-amino-3-morpholinoquinolin-6-yl)-3-methylphenyl)(phenyl)methanone oxime as a off-white solid. MS (ESI, pos. ion) m/z: 439 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18].C([O-])(=O)C.[NH4+].[N+:26]([CH3:29])([O-:28])=[O:27]>CC(O)=O>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10](/[CH:11]=[CH:29]/[N+:26]([O-:28])=[O:27])=[CH:9][CH:8]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18]
Reactant: O=Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])/C=C/c1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 120 °C
Yield: 99.1 %

Procedure:
To the mixture of 4-(4-chloro-3-(trifluoromethyl)phenoxy)benzaldehyde (600 mg, 1.996 mmol), ammonium acetate (77 mg, 0.998 mmol) in AcOH (5 mL) was added nitromethane (0.323 mL, 5.99 mmol). It was heated at 120° C. for 3 h, then concentrated in vacuo. The residue was dissolved in DCM (30 ml), washed with saturated NaHCO3 aqueous solution (20 ml×2), and brine. The organic phase was collected, dried over Na2SO4, filtered, concentrated to provide the title compound as a brown solid (680 mg, 66.4% yield), which was used without further purification. LCMS: rt=4.17 min, [M+H+]=344.1
Reaction SMILES: C[O:2][C:3]([C:5]1[C:29]([O:30][CH2:31][CH3:32])=[CH:28][C:8]2[NH:9][C:10]([C:12]3[C:16]([NH:17][C:18](=[O:27])[C:19]4[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=4[F:26])=[CH:15][NH:14][N:13]=3)=[N:11][C:7]=2[CH:6]=1)=[O:4]>CO>[F:26][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([F:25])[C:19]=1[C:18]([NH:17][C:16]1[C:12]([C:10]2[NH:9][C:8]3[CH:28]=[C:29]([O:30][CH2:31][CH3:32])[C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=3[N:11]=2)=[N:13][NH:14][CH:15]=1)=[O:27]
Reactant: CCOc1cc2[nH]c(-c3n[nH]cc3NC(=O)c3c(F)cccc3F)nc2cc1C(=O)OC
Solvent: CO
Product: CCOc1cc2[nH]c(-c3n[nH]cc3NC(=O)c3c(F)cccc3F)nc2cc1C(=O)O
Temperature: 25 °C
Reaction time: 14 h
Yield: 82.6 %

Procedure:
A mixture of 2-[4-(2,6-difluoro-benzoylamino)-1H-pyrazol-3-yl]-6-ethoxy-1H-benzimidazole-5-carboxylic acid methyl ester (90 mg) in MeOH-2M aqueous NaOH (1:1, 10 mL) was stirred at r.t. for 14 h. The MeOH was removed in vacuo and water (30 mL) added. The mixture was taken to pH=3 using 2M aqueous HCl and then extracted with EtOAc (×3). The combined organic extracts were reduced in vacuo and dried through azeotrope with toluene to give the title compound (72 mg) as a gray solid. (LC/MS: Rt 2.70, [M+H]+ 428.04).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:14])O[C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:15][O:16][CH2:17][CH2:18][NH2:19]>C(O)(=O)C>[Cl:1][C:2]1[C:3](=[O:14])[N:19]([CH2:18][CH2:17][O:16][CH3:15])[C:5](=[O:13])[C:6]=1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COCCN
Reactant: O=C1OC(=O)C(c2ccccc2)=C1Cl
Solvent: CC(=O)O
Product: COCCN1C(=O)C(Cl)=C(c2ccccc2)C1=O

Procedure:
A solution of 3-chloro-4-phenylfuran-2,5-dione (0.20 mmol, 42 mg) and 2-methoxyethylamine (0.20 mmol, 15 mg) in glacial acetic acid (1 mL) was heated in a microwave reactor at 120° C. for two min. After cooling, the solvent was evaporated at reduced pressure. The crude product was used without purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH2:6].I[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[N:16][N:17]([CH:19]3[CH2:25][CH2:24][C:23]4[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=4[N:21]([CH2:30][C:31]([F:34])([F:33])[F:32])[C:20]3=[O:35])[CH:18]=2)=[CH:10][C:9]=1[O:36][CH3:37].CC(C)([O-])C.[K+].C1COCC1.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>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:37][O:36][C:9]1[CH:10]=[C:11]([C:14]2[N:15]=[N:16][N:17]([CH:19]3[CH2:25][CH2:24][C:23]4[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=4[N:21]([CH2:30][C:31]([F:34])([F:33])[F:32])[C:20]3=[O:35])[CH:18]=2)[CH:12]=[CH:13][C:8]=1[NH:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1
Reactant: Nc1nccs1
Reactant: COc1cc(-c2cn(C3CCc4ccccc4N(CC(F)(F)F)C3=O)nn2)ccc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc(-c2cn(C3CCc4ccccc4N(CC(F)(F)F)C3=O)nn2)ccc1Nc1nccs1

Procedure:
A suspension of 1,3-thiazol-2-amine (5.54 mg, 0.055 mmol 3-[4-(4-iodo-3-methoxyphenyl)-1H-1,2,3-triazol-1-yl]-1-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (20 mg, 0.037 mmol), potassium tert-butoxide 1M in THF (36.9 μL, 0.037 mmol), BINAP (4.59 mg, 0.008 mmol), and palladium acetate (1.66 mg, 0.008 mmol) were combined in a μwave vial and dissolved in DMF (738 μl). The reaction was microwaved at 180° C. for 5 minutes. The reaction mixture was filtered, and the solvent was removed in vacuo. Analytically pure material was obtained by purification by preparative HPLC Reverse phase (C-18), eluting with acetonitrile/water+0.05% Formic Acid. Lyophilisation afforded 3-{4-[3-methoxy-4-(1,3-thiazol-2-ylamino)phenyl]-1H-1,2,3-triazol-1-yl}-1-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]#[N:12])[CH:8]=2)[NH:3]1.Cl[C:14]1[N:19]=[C:18]2[CH2:20][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][C:17]2=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCCC1>[C:11]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2](=[O:1])[CH:10]2[C:14]1[N:19]=[C:18]2[CH2:20][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][C:17]2=[CH:16][CH:15]=1)#[N:12]
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(Cl)nc2C1
Reactant: N#Cc1ccc2c(c1)CC(=O)N2
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1Cc2ccc(C3C(=O)Nc4ccc(C#N)cc43)nc2C1
Temperature: 100 °C
Yield: 40 %

Procedure:
The title compound was prepared as described for Example 1.2 using 2-oxoindoline-5-carbonitrile (200 mg, 1.265 mmol), tert-butyl 2-chloro-5H-pyrrolo[3,4-b]pyridine-6(7H)-carboxylate (387 mg, 1.517 mmol), K2CO3 (350 mg, 2.53 mmol), X-PHOS (48.2 mg, 0.101 mmol), Pd2(dba)3 (23.16 mg, 0.025 mmol), and tetrahydrofuran (4 mL). The reaction mixture was heated in a microwave oven at 100° C. for 90 min. After cooling to RT the mixture was filtered and the yellow residue was washed with tetrahydrofuran (10 mL) and water (10 mL). The solid was dried under reduced pressure. Amount 193 mg. Yield 40%.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:10])[NH:8][N:9]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].CN[C@@H]1CCCC[C@H]1NC.I[C:28]1[N:32]([CH2:33][CH2:34][O:35][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][O:37]2)[CH:31]=[N:30][CH:29]=1>[Cu]I.O.C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([NH2:10])[N:8]([C:29]2[N:30]=[CH:31][N:32]([CH2:33][CH2:34][O:35][CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][O:37]3)[CH:28]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Ic1cncn1CCOC1CCCCO1
Reactant: CC(C)(C)c1cc(N)[nH]n1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)c1cc(N)n(-c2cn(CCOC3CCCCO3)cn2)n1
Temperature: 150 °C

Procedure:
To a mixture of Intermediate 119a (1.50 g, 4.66 mmol), 5-tert-butyl-2H-pyrazol-3-ylamine (648 mg, 4.66 mmol), copper(I)iodide (44 mg, 0.23 mmol) and K2CO3 (1.35 g, 9.78 mmol) was added a solution of toluene (10 mL), previously degassed by using a stream of argon. (R,R)-(−)-N,N′-Dimethyl-1,2-cyclohexanediamine (147 μL, 0.93 mmol) was then added and the reaction mixture was heated at 150° C. for 3 h under microwave irradiation. The crude reaction mixture was poured into water and extracted with EtOAc (×3). The combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-100% EtOAc in cyclohexane, to give a product consisting of the title compound (550 mg) in mixture with the un-reacted 5-iodo-1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-imidazole isomer. LCMS (Method 4): Rt 2.32 min, m/z 334 [MH+].
Reaction SMILES: [NH:1]1[C:5]([SH:6])=[N:4][N:3]=[N:2]1.C(N(CC)CC)C.[CH:14](Br)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C.O>[CH:14]([S:6][C:5]1[NH:4][N:3]=[N:2][N:1]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Sc1nnn[nH]1
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: c1ccc(C(Sc2nnn[nH]2)c2ccccc2)cc1
Reaction time: 6.5 h
Yield: 41 %

Procedure:
To a mixture of 1H-tetrazole-5-thiol (27.5 g) and triethylamine (59.9 g) in tetrahydrofuran (550 ml) was added benzhydryl bromide (66.6 g) and then the mixture was refluxed with stirring for 6.5 hours. After the addition of water and ethyl acetate to the reaction mixture, the pH was adjusted to 9.0 with 2 N aqueous solution of sodium hydroxide. The aqueous layer was separated and washed with ethyl acetate. After the addition of ethyl acetate to the washed aqueous layer, the mixture was adjusted to pH 2.0 with 10% hydrochloric acid. The ethyl acetate layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then evaporated. The residue was pulverized in a mixture of isopropyl ether and n-hexane, collected by filtration, washed with a mixture of isopropyl ether and n-hexane and then dried to give 5-benzhydrylthio-1H-tetrazole (29.62 g), mp 132° to 134° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C@@H:5]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][OH:7].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:26][S:27]([O:7][CH2:6][C@H:5]([NH:8][C:9]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:18])[CH2:4][CH2:3][CH2:2][O:1][S:27]([CH3:26])(=[O:29])=[O:28])(=[O:29])=[O:28]
Reactant: O=C(N[C@@H](CO)CCCO)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCC[C@H](COS(C)(=O)=O)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of benzyl (1R)-4-hydroxy-1-(hydroxymethyl)butylcarbamate (1.5 g) in DCM (60 ml) was treated with triethylamine (3.3 ml) and stirred at room temperature for 10 min. Methanesulphonyl chloride (1.34 ml) was then added dropwise and the resultant mixture stirred at 0° C. for 75 min. Sodium bicarbonate solution was added and the reaction mixture allowed to reach room temperature over 1 h. The organic layer was separated, washed with brine, dried (over magnesium sulphate) and concentrated under reduced pressure to give a yellow oil. The oil was purified using Biotage™ chromatography (eluting with hexane:ethyl acetate 1:2, 1:3) to give the title compound (1.924 g) as a yellow oil
Reaction SMILES: Cl.[C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13]([C:15]2[CH:19]=[C:18]([CH3:20])[N:17]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[C:16]=2[CH3:28])=[O:14])=[CH:7][CH:6]=1)(=[NH:4])[NH2:3].C(=O)([O-])[O-].[K+].[K+].Cl[C:36]([O:38][CH2:39][CH3:40])=[O:37]>O.O1CCCC1>[NH2:4]/[C:2](=[N:3]\[C:36](=[O:37])[O:38][CH2:39][CH3:40])/[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13]([C:15]2[CH:19]=[C:18]([CH3:20])[N:17]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[C:16]=2[CH3:28])=[O:14])=[CH:7][CH:6]=1
Reactant: Cc1cc(C(=O)NCc2ccc(C(=N)N)cc2)c(C)n1-c1ccc(F)cc1
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/N=C(\N)c1ccc(CNC(=O)c2cc(C)n(-c3ccc(F)cc3)c2C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
130 mg of N-[(4-carbamimidoylphenyl)methyl]-1-(4-fluorophenyl)-2,5-dimethyl-pyrrole-3-carboxamide hydrochloride and 130 mg of potassium carbonate were dissolved in 1.6 ml of water and 8 ml of tetrahydrofuran. The mixture was stirred at room temperature, and 0.031 ml of ethyl chloroformate (Sigma-Aldrich) added. Stirring was continued for 1 h, following which the organic layer is removed, and dried in vacuo to obtain the synthetic target. The mass of the compound was verified using LC/MS/MS.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[CH:4][CH:3]=1.[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH2:10]([NH:9][C:5]1[C:6]([NH2:8])=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccc(Cl)nc1N
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Nc1nc(Cl)ccc1NCc1ccccc1
Reaction time: 0.5 h

Procedure:
A mixture of 6-chloro-2,3-diaminopyridine (2.00 g, 13.9 mmol, Combi-Blocks) and benzaldehyde (1.48 g, 13.9 mmol, Aldrich) in 1,2-dichloroethane (50 mL) was treated with acetic acid (0.2 mL, 3 mmol) and the mixture was allowed to stir for 30 minutes. Na(OAc)3BH (8.8 g, 42 mmol) was added and the reaction was stirred overnight. The reaction was quenched with water, then poured into saturated NaHCO3 solution. The product was extracted with three portions of DCM, and the combined extracts were washed with saturated NaHCO3 solution and brine, dried over sodium sulfate, filtered and concentrated. Flash chromatography, eluting with a gradient from 0-75% EtOAc in hexanes was used to afford purified product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)[C:10]1[CH2:9][CH2:8][CH:7]([NH2:23])[CH2:6][C:5]2=1.Cl.[CH3:25][N:26]([CH3:30])[C:27](Cl)=[O:28].C(N(CC)CC)C>CN1CCCC1=O.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)[C:10]1[CH2:9][CH2:8][CH:7]([NH:23][C:27](=[O:28])[N:26]([CH3:30])[CH3:25])[CH2:6][C:5]2=1
Reactant: NC1CCc2c(c3cc(Br)ccc3n2Cc2cccc(F)c2)C1
Reactant: CN(C)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: CN(C)C(=O)NC1CCc2c(c3cc(Br)ccc3n2Cc2cccc(F)c2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
Mix 6-bromo-9-(3-fluoro-benzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-ylamine.HCl (Preparation 51) (200 mg, 0.49 mmol), N,N-dimethylcarbamoyl chloride (54 μL, 63 mg, 0.59 mmol), triethylamine (205 μL, 149 mg, 1.47 mmol), CH2Cl2 (6 mL), and N-methylpyrrolidinone (2 mL). Stir at room temperature for 18 h, then add more N,N-dimethylcarbamoyl chloride (54 μL, 63 mg, 0.59 mmol). Stir at room temperature for 60 h, then evaporate the solvents. Dilute the residue with EtOAc (80 mL) and wash the organic solution with HCl (<1N in water, 40 mL) and aqueous NaHCO3. Dry (MgSO4), filter, and concentrate the organic portion to obtain 308 mg crude product as a brown oil. Purify on silica gel (12 g), eluting with 80-100% EtOAc/hexanes to afford 164 mg (75%) of the title compound as a white foam. MS (ES): 444, 446 (M+1); HPLC: Rt=3.27 min, (92%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[CH:10][C:11]2[N:12]([C:14]([C:17](OCC)=[O:18])=[N:15][N:16]=2)[N:13]=1.[F:29][C:30]([F:40])([F:39])[C:31]1[CH:36]=[CH:35][C:34]([CH2:37][NH2:38])=[CH:33][CH:32]=1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[CH:10][C:11]2[N:12]([C:14]([C:17]([NH:38][CH2:37][C:34]3[CH:33]=[CH:32][C:31]([C:30]([F:29])([F:39])[F:40])=[CH:36][CH:35]=3)=[O:18])=[N:15][N:16]=2)[N:13]=1
Reactant: CCOC(=O)c1nnc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Reactant: NCc1ccc(C(F)(F)F)cc1
Solvent: CO
Product: O=C(NCc1ccc(C(F)(F)F)cc1)c1nnc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Yield: 40.6 %

Procedure:
A solution of ethyl 6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazine-3-carboxylate (41 mg, 0.10 mmol) and (4-(trifluoromethyl)phenyl) methanamine (29 μL, 0.2 mmol) in methanol (0.5 mL) was stirred at room temperature for 16 h. Analysis by HPLC/MS indicated the staring material had been consumed. The resulting suspension was filtered, the collected solid was washed with hexanes (5 mL×2), dried in air to afford 22 mg (41%) of the title compound as a white solid. HPLC/MS (method A): retention time =3.93 min, (M+H)+=542.2.
Reaction SMILES: [Si]([O:18][CH2:19][C@H:20]1[S:24][CH:23]([N:25]2[CH:33]=[N:32][C:31]3[C:26]2=[N:27][C:28]([Cl:35])=[N:29][C:30]=3[NH2:34])[CH2:22][CH2:21]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CC(O)=O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CO>C1COCC1.N1C=CC=CC=1>[CH:23]1([N:25]2[CH:33]=[N:32][C:31]3[C:26]2=[N:27][C:28]([Cl:35])=[N:29][C:30]=3[NH2:34])[S:24][C@H:20]([CH2:19][OH:18])[CH2:21][CH2:22]1
Reactant: CC(C)(C)[Si](OC[C@@H]1CCC(n2cnc3c(N)nc(Cl)nc32)S1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: Nc1nc(Cl)nc2c1ncn2C1CC[C@@H](CO)S1
Reaction time: 1 h
Yield: 70 %

Procedure:
To a solution of 15 (100 mg, 0.19 mmol) in 5 mL of THF was added CH3COOH (14 μL, 0.24 mmol) and 1M solution of tetrabutylammonium fluoride in MeOH (0.4 mL, 0.4 mmol) followed by stirring for 1 hour. One drop of pyridine was added and then solvent was evaporated in vacuo. The residue was purified by preparative TLC using 90:10 CHCl3 -MeOH as eluant to afford crude 18 which was crystallized by EtOH to give pure 18 (38 mg, 70%); mp. 125°-127° C.; FAB MS 286 (M+H)+ ; 1H NMR (DMSO-d6) δ 8.45 (s, 1, H-2), 7.80 (brs, 2, NH2), 6.10 (m, 1, i'-H), 5.12 (m, 1, 5'-OH), 3.75 (m, 1, 4'-H), 3.61 (m, 2, 5'-H), 2.40 (m, 2, 2'-H), 2.15 (m, 1, 3'-H), 2.0 (m, 1, 3'-H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]([N:11]1[C:15]2[CH:16]=[C:17]([C:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=3)[CH:18]=[CH:19][C:14]=2[N:13]=[CH:12]1)[CH3:10].[C:26]1(=O)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C>[CH:26]1([N:23]2[CH2:22][CH:21]=[C:20]([C:17]3[CH:18]=[CH:19][C:14]4[N:13]=[CH:12][N:11]([C@@H:9]([C:3]5[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=5[Cl:1])[CH3:10])[C:15]=4[CH:16]=3)[CH2:25][CH2:24]2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: C[C@H](c1ccc(Cl)cc1Cl)n1cnc2ccc(C3=CCNCC3)cc21
Reactant: O=C1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: C[C@H](c1ccc(Cl)cc1Cl)n1cnc2ccc(C3=CCN(C4CCCCC4)CC3)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 24.6 %

Procedure:
To a stirred solution of the crude (R)-1-(1-(2,4-dichlorophenyl)ethyl)-6-(1,2,3,6-tetrahydropyridin-4-yl)-1H-benzo[d]imidazole (prepared from Example 4 step d, 0.047 g, 0.13 mmol) and cyclohexanone (0.0.038 g, 0.38 mmol) in dichloromethane (1 mL) was added sodium triacetoxyborohydride (NaBH(OAc)3, 0.11 g, 0.52 mmol) and acetic acid (3 drops). The reaction mixture was stirred at room temperature for 18 h, and quenched with saturated aqueous sodium bicarbonate. The mixture was extracted with dichloromethane (2×15 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The resulting crude material was purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give a white solid (0.015 g, 0.032 mmol, 25%). 1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1 H), 7.69 (d, J=8.4 Hz, 1 H), 7.44 (d, J=2.4 Hz, 1 H), 7.32 (dd, J=1.2, 8.4 Hz, 1 H), 7.12 (dd, J=2.4, 8.4 Hz, 1 H), 7.06 (s, 1 H), 6.82 (d, J=8.4 Hz, 1 H), 5.99-5.94 (m, 2 H), 3.30 (d, J=2.8 Hz, 2 H), 2.81-2.78 (m, 2 H), 2.58-2.48 (m, 2 H), 2.38-2.36 (m, 1 H), 1.97 (d, J=6.8 Hz, 3 H), 1.94-1.82 (m, 4 H), 1.67-1.64 (m, 1 H), 1.31-1.26 (m, 4 H), 1.15-1.11 (m, 1 H); MS: (ES) m/z calculated for C26H30Cl2N3 [M+H]+ 454.2, found 453.
Reaction SMILES: [Br:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[O:11][CH3:12].C([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C.C(O)C.O.[Fe]>[Br:1][C:2]1[C:3]([O:11][CH3:12])=[CH:4][CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: COc1cccc([N+](=O)[O-])c1Br
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: COc1cccc(N)c1Br
Yield: 90.7 %

Procedure:
2-Bromo-3-nitroanisole B3 (1.00 g; 4.31 mmol) was dissolved in glacial acetic acid (11.0 mL) and ethanol (11.0 mL). To this solution was added iron powder (0.98 g; 17.5 mmol). The mixture was stirred at reflux for 3.5 h and worked up. The reaction mixture was diluted with water (35 mL), neutralized with solid Na2CO3 and the product extracted with CH2Cl2 (3×50 mL). The extracts were dried (Na2SO4), filtered and concentrated in vacuo to afford the crude product, 2-bromo-3 methoxyaniline B4 (91%; 0.79 g) as a pale yellow oil.
Reaction SMILES: C([O:3][C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:23])[CH3:22])=[C:17]([OH:24])[C:16]=2[CH2:25][CH2:26][CH3:27])=[CH:7][CH:6]=1)C>CO.[OH-].[Na+]>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][CH2:12][O:11][C:8]2[CH:9]=[CH:10][C:5]([C:4]([OH:28])=[O:3])=[CH:6][CH:7]=2)=[C:16]([CH2:25][CH2:26][CH3:27])[C:17]=1[OH:24])(=[O:23])[CH3:22]
Reactant: CCCc1c(OCCOc2ccc(C(=O)OCC)cc2)ccc(C(C)=O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c(OCCOc2ccc(C(=O)O)cc2)ccc(C(C)=O)c1O
Yield: 89.9 %

Procedure:
A solution of 1.44 g of 4-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]-benzoic acid ethyl ester in 18 ml of methanol and 18ml of 1N sodium hydroxide was stirred at reflux for 25 minutes. The methanol was removed in vacuo and the aqueous solution was diluted with water. The pH of solution was adjusted to 2.0 with 3N hydrochloric acid. The precipitate was extracted with methanol. The extract was washed with water, dried (over magnesium sulfate) and concentrated in vacuo to a solid which was treated with ether filtered to give 1.2 g , m.p. 175-176° (90%) of 4-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]-benzoic acid, the title compound.