Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][NH2:3].[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1[C:12](SC)=[N:13][C:14]([C:16]1[C:20]([CH3:21])=[CH:19][S:18][CH:17]=1)=O>C1(C)C=CC=CC=1>[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1[C:12]1[N:13]=[C:14]([C:16]2[C:20]([CH3:21])=[CH:19][S:18][CH:17]=2)[N:2]([CH3:1])[N:3]=1
Reactant: CNN
Reactant: CSC(=NC(=O)c1cscc1C)c1c(F)cccc1Cl
Solvent: Cc1ccccc1
Product: Cc1cscc1-c1nc(-c2c(F)cccc2Cl)nn1C
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 83.1 %

Procedure:
A solution of methylhydrazine (2.02 mL, 1.75 g, 38 mmol) in toluene (5 mL) was added at a rapid dropwise rate to a solution of methyl 2-chloro-6-fluoro-N-[(4-methylthien-3-yl)carbonyl]benzenecarbimidothioate (4.15 g, 12.7 mmol) in dry toluene (100 mL) at 55° C. The reaction was stirred at this temperature for 10 minutes and then left at room temperature for 14 hours. Another identical portion of methylhydrazine in toluene was added at room temperature and the reaction was heated at 80° C. for 3 hours and refluxed for an additional 3 hours. After cooling to room temperature, the reaction mixture was washed with water (100 mL), dilute hydrochloric acid (0.05 N, 2×100 mL) and brine (70 mL), dried over magnesium sulphate and concentrated under reduced pressure. The residue was recrystallised from ethyl acetate/hexane to give white cubes. The mother liquor was chromatographed (eluant, 30:9:1 hexane/methylene chloride/acetonitrile to afford the product (3.25 g, 84%): mp 153–155° C.; 1H NMR (CDCl3) δ 7.54 (d, 1H), 7.26–7.38 (m, 2H), 7.06–7.13 (m, 2H), 3.98 (s, 3H), 2.35 (d, 3H); 19F NMR (external reference)—110 ppm; EI/MS 307 m/e (M−1).
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:41]=[CH:40][N:14]3[C:15](=[O:39])[C:16]([C:25]4[N:29](CC5C=CC(OC)=CC=5)[N:28]=[N:27][N:26]=4)=[C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:41]=[CH:40][N:14]3[C:15](=[O:39])[C:16]([C:25]4[NH:29][N:28]=[N:27][N:26]=4)=[C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(Cn2nnnc2-c2c(N3CCOCC3)nc3cc(CCc4nc(C(C)C)cs4)ccn3c2=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC(C)c1csc(CCc2ccn3c(=O)c(-c4nnn[nH]4)c(N4CCOCC4)nc3c2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.6 %

Procedure:
The 8-[2-(4-isopropyl-1,3-thiazol-2-yl)ethyl]-2-morpholino-3-(1-p-methoxybenzyl-1,2,3,4-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (10 mg) obtained in (C) was dissolved in trifluoroacetic acid (1 ml) and added with anisole (50 ml), and then stirred at room temperature for 4 hours. After the solvent was evaporated, the residue was purified by silica gel column chromatography to obtain the title compound (7 mg) as yellow powder.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4](C(OCC)=O)[C:3]=1[C:17](=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1.[C:26](Cl)(=[O:29])[CH2:27][CH3:28]>C(OCC)(=O)C>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3]([C:17](=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)=[C:2]2[NH:1][C:26](=[O:29])[CH2:27][CH3:28]
Reactant: CCOC(=O)n1c(C(=O)c2cccc(Cl)c2)c(N)c2cc(Cl)ccc21
Reactant: CCC(=O)Cl
Solvent: CCOC(C)=O
Product: CCC(=O)Nc1c(C(=O)c2cccc(Cl)c2)[nH]c2ccc(Cl)cc12

Procedure:
The title compound was prepared according to the procedure described in Example 2 (Method A) from 3-amino-5-chloro-2-(3-chlorobenzoyl)-1-(ethoxycarbonyl)indole (step 1) and propionyl chloride. m.p.: 206.5-207.5° C. (ethyl acetate) 1H-NMR (CDCl3) δ: 9.78 (1H, br s), 8.31 (1H, s), 8.28 (1H, br s), 7.78 (1H, s), 7.70-7.59 (2H, m), 7.51 (1H, t, J=8 Hz), 7.34 (1H, dd, J=8, 1.5 Hz), 7.25 (1H, d, J=8 Hz), 2.51 (2H, q, J=7 Hz), 1.30 (3H, t, J=7 Hz)
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][C:12]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH:29]=2)O1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH:29]=2)=[CH:13][C:12]=1[CH3:18])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Cc1cc(Br)ccc1NC(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)ccc1NC(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
A suspension of benzyl(4-bromo-2-methylphenyl)carbamate (I51) (1.00 g, 3.12 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (37) (1.16 g, 3.74 mmol), PdCl2(dppf)-DCM complex (310 mg, 0.374 mmol) and potassium carbonate (1.29 g, 9.36 mmol) in DMF (30 mL) was stirred under nitrogen at 80° C. for 16 hours. The volatiles were evaporated under reduced pressure and the residue adsorbed onto silica gel. Chromatography on silica gel (0-30% ethyl acetate/petroleum benzine 40-60° C.) gave the title compound (I52) (949 mg, 72%) as a yellow liquid; 1H NMR (400 MHz, CDCl3) δ 7.83-7.70 (m, 1H), 7.41-7.34 (m, 5H), 7.21 (dd, J=8.5, 1.9 Hz, 1H), 7.16 (d, J=1.8 Hz, 1H), 6.56 (s, 1H), 5.97 (s, 1H), 5.20 (s, 2H), 4.05 (d, J=2.9 Hz, 2H), 3.61 (t, J=5.7 Hz, 2H), 2.48 (d, J=1.5 Hz, 2H), 2.23 (s, 3H), 1.50 (d, J=2.6 Hz, 9H).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[C:29]([O:33][C:34](=[O:37])[CH2:35][NH2:36])([CH3:32])([CH3:31])[CH3:30].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[C:29]([O:33][C:34](=[O:37])[CH2:35][NH:36][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:28])([F:26])[F:27])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12])([CH3:32])([CH3:31])[CH3:30]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CC(C)(C)OC(=O)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCC(=O)OC(C)(C)C)ccc21
Yield: 78.3 %

Procedure:
{[1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-acetic acid tert-butyl ester (41 mg) was prepared by following General Procedure F using 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid (41 mg), glycine-tert-butyl ester (44 mg), HBTU (38 mg), and DIEA (0.1 ml). LC/MS: m/z 523. 1H NMR (DMSO-d6, 400 MHz): δ 8.76 (t, 1H), 8.20 (br, 1H), 8.12 (m, 1H), 8.05 (s, 1H), 7.88 (d, 1H), 7.73 (d, 1H), 7.46 (d, 1H), 7.31 (d, 1H), 3.90 (d, 2H), 3.65 (s, 3H), and 1.42 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=2[CH:13]=1.Cl[C:15]1[N:20]=[C:19]([NH:21][C:22]2[C:27]([O:28][CH:29]3[CH2:33][CH2:32][O:31][CH2:30]3)=[CH:26][CH:25]=[CH:24][C:23]=2[F:34])[C:18]([Cl:35])=[CH:17][N:16]=1>>[Cl:35][C:18]1[C:19]([NH:21][C:22]2[C:27]([O:28][CH:29]3[CH2:33][CH2:32][O:31][CH2:30]3)=[CH:26][CH:25]=[CH:24][C:23]=2[F:34])=[N:20][C:15]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=3[CH:13]=2)=[N:16][CH:17]=1
Reactant: Nc1ccc2c(c1)NC(=O)CCC2
Reactant: Fc1cccc(OC2CCOC2)c1Nc1nc(Cl)ncc1Cl
Product: O=C1CCCc2ccc(Nc3ncc(Cl)c(Nc4c(F)cccc4OC4CCOC4)n3)cc2N1

Procedure:
8-{5-Chloro-4-[2-fluoro-6-(tetrahydro-furan-3-yloxy)-phenylamino]-pyrimidin-2-ylamino}-1,3,4,5-tetrahydro-1-benzazepin-2-one was prepared from 8-Amino-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and (2,5-Dichloro-pyrimidin-4-yl)-[2-fluoro-6-(tetrahydro-furan-3-yloxy)-phenyl]-amine in an analogous manner to Example 1221d. Title compound was isolated as a white solid (66 mg, 51%). LCMS 485.09 (M+H), HPLC purity 99%. 1H-NMR (CDCl3, 400 MHz) δ 11.99 (s, 1H), 7.92 (s, 1H), 7.52-7.49 (m, 1H), 7.41 (s, 1H), 7.23 (s, 1H), 7.11-7.06 (m, 2H), 7.01 (s, 1H), 6.93 (dd, J=9.3 Hz, 1H), 6.81 (d, J=8.3 Hz, 1H), 4.96 (s, 1H), 3.90-3.86 m, 4H), 2.74-2.70 (m, 4H), 2.35-2.29 (m, 3H), 2.28-2.21 (m, 3H), 2.09-2.06 (m, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[NH:13][N:12]=[C:11]([CH:14]3[CH2:16][CH2:15]3)[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[CH2:27][NH2:28])[NH:20][CH:19]=1.CCN(C(C)C)C(C)C>CC(O)C>[CH:14]1([C:11]2[NH:12][N:13]=[C:9]([NH:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:28][CH2:27][C:25]4[CH:24]=[CH:23][CH:22]=[C:21]5[C:26]=4[C:18]([CH3:17])=[CH:19][NH:20]5)[N:7]=3)[CH:10]=2)[CH2:16][CH2:15]1
Reactant: Clc1nccc(Nc2cc(C3CC3)n[nH]2)n1
Reactant: Cc1c[nH]c2cccc(CN)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1c[nH]c2cccc(CNc3nccc(Nc4cc(C5CC5)[nH]n4)n3)c12
Temperature: 120 °C

Procedure:
A tube was charged with 53 (200 mg, 0.85 mmol), 234 (181 mg, 1.13 mmol), DIPEA (0.2 mL) and IPA (2 mL), degassed, sealed and heated at 120° C. overnight. The solvent was concentrated to dryness in vacuo. The residue was purified by preparative HPLC to afford 80 mg (26%) of I-92 as white solid.
Reaction SMILES: [OH-].[Na+].C([O:6][C:7](=[O:33])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[C:15]2[C:20]([O:21][C:22]3[C:27]=1[CH:26]=[CH:25][C:24](=[O:28])[CH:23]=3)=[CH:19][C:18]([O:29][CH2:30][CH:31]=[CH2:32])=[CH:17][CH:16]=2)C=C>CO>[OH:28][C:24]1[CH:25]=[CH:26][C:27]2[C:14]3([C:9]4[C:8](=[CH:13][CH:12]=[CH:11][CH:10]=4)[C:7](=[O:6])[O:33]3)[C:15]3[C:20]([O:21][C:22]=2[CH:23]=1)=[CH:19][C:18]([O:29][CH2:30][CH:31]=[CH2:32])=[CH:17][CH:16]=3
Reactant: C=CCOC(=O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(OCC=C)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=CCOc1ccc2c(c1)Oc1cc(O)ccc1C21OC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.7 %

Procedure:
NaOH (20 mL, 1.0 M, 20.0 mmol) was added to a solution of 17 (0.40 g, 0.97 mmol) in methanol (60 mL). The resulting mixture was stirred for 2 h at room temperature. The mixture was concentrated, diluted with ethyl acetate, washed with 10% NaHCO3, brine, dried with anhydrous Na2SO4, and evaporated. The residue was purified by column chromatography (ethyl acetate/hexane=1:1) to give 18 as a yellow solid (0.23 g, 65%). TLC (ethyl acetate/hexane, 3:1): Rf=0.6. mp 204° C. 1H NMR (CDCl3/CD3OD, 500 MHz) δ 4.58 (d, J=5.0 Hz, 2H, CH2), 5.32 (d, J=10.5 Hz, 1H, CH), 5.43 (d, J=17.5 Hz, 1H, CH), 6.04 (m, 1H, CH), 6.62 (m, 4H), 6.74 (s, 1H), 6.80 (s, 1H), 7.20 (d, J=7.5 Hz, 1H), 7.65 (t, J=7.5 Hz, 1H), 7.71 (t, J=7.5 Hz, 1H), 8.01 (d, J=7.5 Hz, 1H). 13C NMR (CDCl3/CD3OD, 125 MHz) δ 69.00, 101.71, 102.73, 109.90, 111.21, 111.94, 112.42, 117.89, 124.04, 124.80, 126.69, 128.88, 128.95, 129.72, 132.51, 135.16, 152.56, 160.28, 170.26. ESIMS calcd for C23H17O5 [M+H]+ 373.1. Found 373.2.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][C:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][CH:6]=1.[NH:14]1[CH2:19][CH2:18][CH:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:16][CH2:15]1>C(O)(C)C>[O:7]1[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:5]([CH2:4][CH:2]([OH:1])[CH2:3][N:14]2[CH2:15][CH2:16][CH:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[CH2:18][CH2:19]2)=[CH:6]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: c1ccc2c(CC3CO3)coc2c1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)NC1CCN(CC(O)Cc2coc3ccccc23)CC1

Procedure:
A solution of 2.9 g of 3-(2-oxiranylmethyl)benzofuran, 4 g of tert-butyl 4-piperidyl-carbamate and 35 ml of isopropanol is heated at 80° C. for 5 hours. After evaporation to dryness, chromatography over silica gel enables the expected product to be isolated.
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]([CH2:18][CH2:19][C:20]#[N:21])[CH2:6][CH2:7][CH2:8][N:9]([CH2:14][CH2:15][C:16]#[N:17])[CH2:10][CH2:11][C:12]#[N:13])#[N:2].[H][H]>O1CCOCC1>[NH2:13][CH2:12][CH2:11][CH2:10][N:9]([CH2:14][CH2:15][CH2:16][NH2:17])[CH2:8][CH2:7][CH2:6][N:5]([CH2:18][CH2:19][CH2:20][NH2:21])[CH2:4][CH2:3][CH2:1][NH2:2]
Reactant: N#CCCN(CCC#N)CCCN(CCC#N)CCC#N
Reactant: [H][H]
Solvent: C1COCCO1
Product: NCCCN(CCCN)CCCN(CCCN)CCCN
Yield: 87.7 %

Procedure:
20.05 g of N,N,N′,N′-tetrakis(2-cyanoethyl)-1,3-propanediamine, 2.01 g of Raney Co and 100 mL of 1,4-dioxane were charged in an autoclave and a hydrogenation reaction was carried out at an initial hydrogen pressure of 9.0 MPa at 150° C. for 3 hours. After the catalyst was removed by filtration, the obtained filtrate was concentrated to dryness to give 18.57 g of the title compound as a pale yellow oil.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[C:6]([CH:12]([O:14][CH2:15][C:16]3([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[CH3:13])[CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[N:3]=1.[CH:44]1(B(O)O)[CH2:46][CH2:45]1>O1CCCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[C:6]([CH:12]([O:14][CH2:15][C:16]3([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[CH3:13])[CH:7]=1)[N:4]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[N:3]=[C:2]2[CH:44]1[CH2:46][CH2:45]1
Reactant: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2c(Br)nn(COCC[Si](C)(C)C)c12
Reactant: OB(O)C1CC1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2c(C3CC3)nn(COCC[Si](C)(C)C)c12
Temperature: 100 °C

Procedure:
(±)-tert-Butyl 4-((1-(3-bromo-5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (100 mg, 0.14 mmol), cyclopropylboronic acid (18.5 mg, 0.22 mmol), and tetrakis(triphenylphosphine) palladium(0) (16.6 mg, 0.01 mmol) were combined in dry tetrahydrofuran (3 mL) in a microwave tube and sealed. The mixture was flushed with nitrogen then 0.5 mL of a 1 N potassium hydroxide aqueous solution was introduced. The mixture was heated at 100° C. for 1 h via microwave. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed with water (2×), then brine (2×), dried over sodium sulfate, and concentrated. Flash chromatography on silica gel (15% ethyl acetate/hexanes) gave 65 mg (69%). 1H-NMR (CDCl3, 500 MHz) δ 7.58 (d, J=1.8 Hz, 1H), 7.21-7.23 (m, 2H), 6.97-7.01 (m, 3H), 5.50 (qAB, JAB=11.9 Hz, 2H), 5.00 (q, J=6.4 Hz, 1H), 3.69 (m, 2H), 3.33-3.45 (m, 2H), 3.19-3.27 (m, 2H), 3.01-3.06 (m, 2H), 2.01-2.14 (m, 3H), 1.79-1.89 (m, 2H), 1.43 (s, 9H), 1.41 (m, 3H), 0.96-1.01 (m, 4H), 0.67-0.83 (m, 2H), 0.09 (s, 9H). Mass spec.: 658.67 (MH)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].ClC1C=CC(O[CH2:20][C:21]#[N:22])=CC=1.CC(C)([O-])C.[K+].Cl>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([F:11])([F:12])[F:13])=[CH:8][C:9]=1[CH2:20][C:21]#[N:22])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(C(F)(F)F)cc1
Reactant: N#CCOc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCc1cc(C(F)(F)F)ccc1[N+](=O)[O-]
Temperature: -10 °C

Procedure:
A mixture of 4-Nitrobenzotrifluoride (25.0 g, 131 mmol) and 4-chlorophenoxyacetonitrile (24.1 g, 144 mmol) in dry DMF (200 mL) was added dropwise over 1 h to a stirred solution of potassium tert-butoxide (32.3 g, 288 mmol) in dry DMF (200 mL) at −10° C. After complete addition the resulting purple solution was maintained at −10° C. for 3 h then poured into a mixture of ice water (200 mL) and 5 N aqueous HCl (200 mL). The resulting mixture was extracted with dichloromethane (3×300 mL). The combined extracts were washed with 10% aqueous NaOH, 5 N HCl, brine, dried over sodium sulfate, and concentrated in vacuo to give the crude (2-nitro-5-trifluoromethylphenyl) acetonitrile. The crude (2-nitro-5-trifluoromethylphenyl) acetonitrile (24.6 g, 107 mmol) was dissolved in 9:1 EtOH:H2O (300 mL) and glacial acetic acid (3.0 mL). This mixture was hydrogenated over 10% Pd/C (10.0 g) at 50 psi for 16 h at room temperature. The reaction was filtered through celite and evaporated in vacuo. The residue was partitioned between saturated aqueous sodium carbonate and dichloromethane (2×200 mL) and the combined organic extract was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel column chromatography (hexanes/ethyl acetate, 20:1, 9:1, 5:1) to afford 12.9 g (65% yield) of 5-trifluoromethyl-1H-indole as a yellow solid: 1H NMR (400 MHz, CDCl3) 8.34, (1H, br s), 7.95 (1H, s), 7.45 (2H, m), 7.32 (1H, m), 6.65 (1H, m); MS m/e 184 (M−H)−. Anal calcd. for C9H6F3N.0.15 H2O: C, 57.55; H, 3.38; N, 7.46. Found: C, 57.25; H, 2.98; N, 7.29.
Reaction SMILES: C([SiH](CC)CC)C.B(F)(F)F.CCOCC.[CH3:17][O:18][C:19](=[O:51])[C:20]([CH3:50])([O:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH2:21][C:22]1[S:23][C:24]([CH:27](O)[CH2:28][CH2:29][C:30]2[N:31]=[C:32]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[O:33][C:34]=2[CH3:35])=[CH:25][CH:26]=1.B(F)(F)F>C(Cl)Cl>[CH3:17][O:18][C:19](=[O:51])[C:20]([CH3:50])([O:43][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)[CH2:21][C:22]1[S:23][C:24]([CH2:27][CH2:28][CH2:29][C:30]2[N:31]=[C:32]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[O:33][C:34]=2[CH3:35])=[CH:25][CH:26]=1
Reactant: COC(=O)C(C)(Cc1ccc(C(O)CCc2nc(-c3ccccc3)oc2C)s1)Oc1ccccc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)C(C)(Cc1ccc(CCCc2nc(-c3ccccc3)oc2C)s1)Oc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of triethylsilane (0.62 mL, 3.89 mmol) in CH2Cl2 (4 mL) at −20° C., boron trifluoride diethyl etherate (0.49 mL, 3.89 mmol) was added. A solution of 3-{5-[1-hydroxy-3-(5-methyl-2-phenyl-oxazol-4-yl)-propyl]-thiophen-2-yl}-2-methyl-2-phenoxy-propionic acid methyl ester (650 mg, 1.30 mmol) in CH2Cl2 (4 mL) was then added dropwise to the BF3 solution over 1 h, keeping the temperature at −15° C. The reaction was stirred at 0° C. for 2 h. The reaction was quenched with 1 N NaOH (approx. 3.6 mL) diluted with 1.8 mL of water and the pH was adjusted to pH 4.0 using 1 N HCl and 1 N NaOH. The organic layer was separated and the aqueous layer was further extracted with CH2Cl2 (2×30 mL). The combined organic layers were then washed with 0.1 N HCl (30 mL) and water (2×30 mL). Xylene (15 mL) and NaCl were added and the organics were concentrated to dryness to yield a yellow oil. The product was used in the next step without further purification: 1H NMR (400 MHz, CDCl3) δ 7.95 (d, 2H), 7.37 (m, 4H), 7.20 (m, 1H), 6.96 (t, 1H), 6.84 (d, 2H), 6.60 (dd, 2H), 3.72 (s, 3H), 3.41 (d, 1H), 3.30 (d, 1H), 2.78 (t, 2H), 2.50 (t, 2H), 2.24 (s, 3H), 2.00 (m, 2H), 1.43 (s, 3H); MS (EI) 476.2 (M+H)+.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:20][N:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[C:22]1[CH:30]=O>>[CH3:20][N:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[C:22]1[CH2:30][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5]1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: Cn1c(C=O)nc2ccccc21
Product: Cn1c(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)nc2ccccc21

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 1-methylbenzimidazole-2-carbaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(1-methylbenzimidazol-2-yl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: F[C:2]1[N:7]=[C:6](F)[C:5]([F:9])=[C:4](F)[C:3]=1[F:11].[OH:12][C:13]1[N:17]([CH3:18])[N:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1.[C:23](=[O:26])([O-])[O-].[K+].[K+]>S1(CCCC1)(=O)=O.CCCCC.C(OCC)(=O)C>[F:9][C:5]1[C:6]([O:26][C:23]2[N:17]([CH3:13])[N:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[N:7][C:2]([O:12][C:13]2[N:17]([CH3:18])[N:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[C:3]([F:11])[C:4]=1[O:12][C:13]1[N:17]([CH3:18])[N:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1
Reactant: O=C([O-])[O-]
Reactant: Cn1nc(C(F)(F)F)cc1O
Reactant: Fc1nc(F)c(F)c(F)c1F
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Solvent: CCOC(C)=O
Solvent: CCCCC
Product: Cn1nc(C(F)(F)F)cc1Oc1nc(Oc2cc(C(F)(F)F)nn2C)c(F)c(Oc2cc(C(F)(F)F)nn2C)c1F
Temperature: 80 °C
Reaction time: 3 h
Yield: 64.4 %

Procedure:
A mixture of pentafluoropyridine (16.9 g, 0.1 mol), 5-hydroxy-1-methyl-3-trifluoromethylpyrazole (potassium salt, 62 g, 0.33 mol), and potassium carbonate (45.5 g, 0.33 mol) in anhydrous sulfolane (70 ml) is heated to 80° C. for 4 hours and then to 100° C. for 3 hours. The reaction mixture is diluted with pentane/ethyl acetate (1/1 by volume). After filtration through a bed of silica gel the filtrate is washed 8 times with water. The organic layer is dried with anhydrous magnesium sulfate and filtered over silica gel. Now the solvent is removed and the residue is washed with diisopropyl ether. After drying, colorless crystals (39.1 g, 64% yield) of melting point 119° C. are obtained.
Reaction SMILES: C1(COC2C(C3N([CH2:17][C:18]4[CH:23]=[CH:22][C:21](CCC(O)=O)=[CH:20][CH:19]=4)C4C=C(F)C(F)=CC=4N=3)=CC=CN=2)CC1.[F:35][C:36]1[C:61]([F:62])=[CH:60][C:39]2[NH:40][C:41]([C:43]3[CH:59]=[CH:58][CH:57]=[CH:56][C:44]=3[CH2:45][O:46][C:47]3[CH:54]=[CH:53][C:50]([C:51]#[N:52])=[C:49]([F:55])[CH:48]=3)=[N:42][C:38]=2[CH:37]=1.BrCC1CCCCC1>>[CH:18]1([CH2:17][N:42]2[C:38]3[CH:37]=[C:36]([F:35])[C:61]([F:62])=[CH:60][C:39]=3[N:40]=[C:41]2[C:43]2[CH:59]=[CH:58][CH:57]=[CH:56][C:44]=2[CH2:45][O:46][C:47]2[CH:54]=[CH:53][C:50]([C:51]#[N:52])=[C:49]([F:55])[CH:48]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: N#Cc1ccc(OCc2ccccc2-c2nc3cc(F)c(F)cc3[nH]2)cc1F
Reactant: O=C(O)CCc1ccc(Cn2c(-c3cccnc3OCC3CC3)nc3cc(F)c(F)cc32)cc1
Agent: BrCC1CCCCC1
Product: N#Cc1ccc(OCc2ccccc2-c2nc3cc(F)c(F)cc3n2CC2CCCCC2)cc1F

Procedure:
The title compound was prepared in analogy to Example 19, intermediate b, from 4-[2-(5,6-difluoro-1H-benzoimidazol-2-yl)-benzyloxy]-2-fluoro-benzonitrile and bromomethyl-cyclohexane (CAS Reg. No. 2550-36-9). Light yellow solid (58%). MS (Turbo Spray): m/z=476.1 (M+H).