Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([O:22]CC)=O)[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH:26]1([NH2:30])[CH2:29][CH2:28][CH2:27]1>>[CH:26]1([NH:30][C:20]([C:14]2[C:15](=[O:19])[NH:16][C:17]3[C:12]([C:13]=2[OH:25])=[N:11][CH:10]=[C:9]([CH2:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH:18]=3)=[O:22])[CH2:29][CH2:28][CH2:27]1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Reactant: NC1CCC1
Product: O=C(NC1CCC1)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and cyclobutylamine employing methods similar to those described in Example 2 and was obtained as an off-white solid: 1H NMR (d6-DMSO) δ 11.90 (1H, br), 10.50 (1H, br), 8.33 (1H, br), 7.39 (1H, br s), 7.31 (2H, m), 7.15 (2H, t, J˜9 Hz), 4.42 (1H, m, J=8 Hz), 4.06 (2H, br s), 2.29 (2H, m), 1.95 (2H, m), 1.71 (2H, m); HRMS calcd for C20H18FN3O3+H+: 368.1410. Found: 368.1410.
Reaction SMILES: [C:1]([C:8]1NC=CN=1)([C:3]1[NH:4]C=CN=1)=O.[CH:13]1([N:17]2[CH2:23][CH2:22][C:21]3[CH:24]=[CH:25][C:26]([O:28][C:29]4[N:34]=[CH:33][C:32]([C:35]([OH:37])=O)=[CH:31][CH:30]=4)=[CH:27][C:20]=3[CH2:19][CH2:18]2)[CH2:16][CH2:15][CH2:14]1.C1(N)CC1>ClCCl>[CH:13]1([N:17]2[CH2:23][CH2:22][C:21]3[CH:24]=[CH:25][C:26]([O:28][C:29]4[N:34]=[CH:33][C:32]([C:35]([NH:4][CH:3]5[CH2:1][CH2:8]5)=[O:37])=[CH:31][CH:30]=4)=[CH:27][C:20]=3[CH2:19][CH2:18]2)[CH2:14][CH2:15][CH2:16]1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: O=C(O)c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1
Agent: NC1CC1
Solvent: ClCCl
Product: O=C(NC1CC1)c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Carbonyl diimidazole (142 mg, 0.88 mmol) was added to a stirred solution of 6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinecarboxylic acid (E196b) (150 mg, 0.44 mmol) in dichloromethane (5 ml). After stirring at room temperature for 3 hours, cyclopropylamine (0.15 ml, 2.2 mmol) was added and the mixture was allowed to stir for a further 18 hours. The reaction mixture was applied to a SCX ion cartridge (Varian bond-elute, 10 g) and washed with methanol and then a mixture of 0.880 ammonia:methanol (1:9). The combined basic fractions were concentrated in vacuo to afford the title compound (E196). MS (ES+) m/e 378 [M+H]+.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][S:41]([CH3:44])(=[O:43])=[O:42])=[CH:36][CH:35]=1)[C:4]([O:6][C@H:7]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH:25]([F:27])[F:26])=[C:20]([O:28][CH2:29][CH:30]2[CH2:32][CH2:31]2)[CH:19]=1)[CH2:8][C:9]1[C:14]([Cl:15])=[CH:13][N+:12]([O-:16])=[CH:11][C:10]=1[Cl:17])=[O:5].[CH3:45][S:46](Cl)(=[O:48])=[O:47]>C(Cl)Cl.N1C=CC=CC=1>[Cl:15][C:14]1[CH:13]=[N+:12]([O-:16])[CH:11]=[C:10]([Cl:17])[C:9]=1[CH2:8][C@@H:7]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH:25]([F:27])[F:26])=[C:20]([O:28][CH2:29][CH:30]2[CH2:32][CH2:31]2)[CH:19]=1)[O:6][C:4](=[O:5])[C@@H:3]([NH:2][S:46]([CH3:45])(=[O:48])=[O:47])[CH2:33][C:34]1[CH:35]=[CH:36][C:37]([O:40][S:41]([CH3:44])(=[O:42])=[O:43])=[CH:38][CH:39]=1
Reactant: CS(=O)(=O)Oc1ccc(C[C@H](N)C(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)N[C@@H](Cc1ccc(OS(C)(=O)=O)cc1)C(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.4 %

Procedure:
4-((S)-2-((S)-2-amino-3-(4-(methylsulfonyloxy)phenyl)propanoyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide hydrochloride (30 mg, 0.05 mmol) was dissolved in DCM (2 ml) and pyridine (100 μl), then methanesulfonyl chloride (7 mg, 0.06 mmol) was added. The mixture was stirred at RT for 2 h, then was washed with HCl 1N (2×). The crude was purified by semi-preparative HPLC to give 29 mg of the final compound (Yield: 80%)
Reaction SMILES: [CH:1]([S:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]([C:16]([OH:18])=[O:17])[S:14][CH:15]=2)=[CH:7][CH:6]=1)([CH3:3])C.[CH2:19](SC1C=CC(B(O)O)=CC=1)CC>>[CH2:1]([S:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]=[C:13]([C:16]([OH:18])=[O:17])[S:14][CH:15]=2)=[CH:9][CH:10]=1)[CH2:3][CH3:19]
Reactant: CCCSc1ccc(B(O)O)cc1
Reactant: CC(C)Sc1ccc(-c2csc(C(=O)O)c2)cc1
Product: CCCSc1ccc(-c2csc(C(=O)O)c2)cc1

Procedure:
The title compound was prepared in a similar manner as described in the preparation of 4-(4-(isopropylthio)phenyl)thiophene-2-carboxylic acid (compound 73, example 12), except commercially available 4-(propylthio)phenylboronic acid was used in the place of 4-(isopropylthio)phenylboronic acid.
Reaction SMILES: [CH2:1]([C:3]1([CH3:22])[CH:8]([CH3:9])[CH:7]([NH:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][C:5]([CH2:20][CH3:21])([CH3:19])[NH:4]1)[CH3:2].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>S1(=O)(=O)CCCC1.C1(C)C=CC=CC=1>[CH2:23]([N:4]1[C:5]([CH2:20][CH3:21])([CH3:19])[CH2:6][CH:7]([NH:10][C:11](=[O:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:8]([CH3:9])[C:3]1([CH2:1][CH3:2])[CH3:22])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCC1(C)CC(NC(=O)c2ccccc2)C(C)C(C)(CC)N1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Solvent: Cc1ccccc1
Product: CCC1(C)CC(NC(=O)c2ccccc2)C(C)C(C)(CC)N1Cc1ccccc1
Temperature: 25 °C

Procedure:
20 g of 2,6-diethyl-2,3,6-trimethyl-4-benzamidopiperidine (compound no. 9), 12.5 g of benzylbromide, 1 g of potassium iodide and 20 g of potassium carbonate are stirred in 200 ml of tetrahydrothiophene dioxide (sulpholane) at 110° C. for 4 days. Thereafter the reaction mixture is diluted with 200 ml of toluene, cooled to room temperature and purified by filtration. The filtrate is washed four times with about 200 ml of water, the toluene phase is dried over sodium sulfate and evaporated under vacuum. Crystallization of the residue from acetic acid ethyl ester yields 1-benzyl-2,6-diethyl-2,3,6-trimethyl-4-benzamidopiperidine (compound no. 48); m.p. 234°-236° C.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[CH:11][NH:10][C:9]=2[C:8](=[O:14])[NH:7]/[C:6]/1=[N:15]\[NH2:16])[CH2:2][CH2:3][CH3:4].[CH:17]([O-])([O-])OCC>>[CH2:1]([N:5]1[C:13]2[N:12]=[CH:11][NH:10][C:9]=2[C:8](=[O:14])[N:7]2[CH:17]=[N:16][N:15]=[C:6]12)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1/c(=N/N)[nH]c(=O)c2[nH]cnc21
Reactant: CCOC([O-])[O-]
Product: CCCCn1c2nc[nH]c2c(=O)n2cnnc12
Temperature: 100 °C
Yield: 71.8 %

Procedure:
The mixture of (2E)-3-butyl-3,7-dihydro-1H-purine-2,6-dione 2-hydrazone (200 mg, 0.0009 mol) in Ethyl orthoformate (5 mL, 0.03 mol) was heated at 100° C. overnight. After cooling to room temperature, the reaction mixture was filtrated and dried to give the desired product (150 mg, 71.8%). LCMS calculated for C10H13N6O (M+H): 233.1; found: 233.1.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:6])=[CH:3]\[C:4]#[N:5].[Cl:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([Cl:18])[C:9]=1[NH:19]N.S(=O)(=O)(O)O>C(O)C>[NH2:5][C:4]1[N:19]([C:9]2[C:10]([Cl:18])=[CH:11][C:12]([C:14]([F:17])([F:15])[F:16])=[CH:13][C:8]=2[Cl:7])[N:1]=[C:2]([CH3:6])[CH:3]=1
Reactant: C/C(N)=C/C#N
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: O=S(=O)(O)O
Solvent: CCO
Product: Cc1cc(N)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-Aminocrotononitrile (5.0 g) was added to a stirred solution of 2,6-dichloro-4-trifluoromethylphenylhydrazine (15.0 g) in ethanol (100 ml), then the resulting solution treated with concentrated sulphuric acid (1.0 ml) to produce a white solid precipitate. The mixture was heated under reflux for 6 hours, allowed to cool and stirred for a further 18 hours at room temperature; this cycle was repeated, then more concentrated sulphuric acid (4 ml) added. The reaction mixture was heated at 60° C. for 8 hours, allowed to cool, stirred at room temperature for 18 hours and evaporated under reduced pressure. The resulting orange oil was partitioned between dichloromethane (100 ml) and water (100 ml), then the organic phase dried, allowed to stand at room temperature for 18 hours and filtered to remove some white solid material. The filtrate was evaporated under reduced pressure to give an orange oil which was triturated with hot hexane. On cooling, the hexane solution deposited a yellow oil which slowly crystallised to furnish the title compound as a white solid, m.p. 80-83° C. Found: C, 42.73; H, 2.62; N, 13.58. C11H8Cl2F3N3 requires 42.61; H, 2.60; N, 13.55%. δ(CDCl3): 2.25 (s,3H), 3.48 (br.s,2H), 5.52 (s,1H), 7.70 (s,2H). MS (thermospray): M/Z [M] 310.0; C11H8Cl2F3N3 requires 310.12.
Reaction SMILES: [CH3:1][C:2]12[CH2:37][CH:5]([C:6]3([CH3:36])[C:10]1([CH3:11])[C:9]1[CH:12]=[C:13]([C:16](=[O:35])[CH2:17][O:18][C:19]4[CH:34]=[CH:33][C:22]([C:23]([O:25]CC5C=CC=CC=5)=[O:24])=[CH:21][CH:20]=4)[CH:14]=[CH:15][C:8]=1[O:7]3)[CH2:4][CH2:3]2.[H][H]>O1CCOCC1.[Pd]>[CH3:1][C:2]12[CH2:37][CH:5]([C:6]3([CH3:36])[C:10]1([CH3:11])[C:9]1[CH:12]=[C:13]([CH:16]([OH:35])[CH2:17][O:18][C:19]4[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:33][CH:34]=4)[CH:14]=[CH:15][C:8]=1[O:7]3)[CH2:4][CH2:3]2
Reactant: [H][H]
Reactant: CC12CCC(C1)C1(C)Oc3ccc(C(=O)COc4ccc(C(=O)OCc5ccccc5)cc4)cc3C21C
Agent: [Pd]
Solvent: C1COCCO1
Product: CC12CCC(C1)C1(C)Oc3ccc(C(O)COc4ccc(C(=O)O)cc4)cc3C21C

Procedure:
4.41 g (8.9 mmol) of the benzyl ester obtained in Step (a) of Example 12 in 90 ml of dioxane were hydrogenated in the presence of 660 mg of palladium (10%) on charcoal at a hydrogen pressure of 7 bars at room temperature for 3 hours. After filtration of the reaction medium through Celite, evaporation and chromatography on silica in the eluent CH2Cl2 /methanol (9:1), 1.60 g (63%) of the expected compound, melting at 123.20° C., was isolated.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[C:4]([O:11][CH3:12])[CH:3]=1.[N:13]1([CH2:18][CH2:19][NH2:20])[CH2:17][CH2:16][CH2:15][CH2:14]1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([NH:20][CH2:19][CH2:18][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:7]=[CH:6][C:5]=1[NH2:8]
Reactant: NCCN1CCCC1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COc1cc(NCCN2CCCC2)ccc1N
Temperature: 80 °C
Yield: 1.5 %

Procedure:
To a stirred solution of 4-fluoro-2-methoxy-1-nitro-benzene (Fluorochem; 2.57 g; 15 mmol) in DMA was 2-pyrrolidin-1-ylethanamine (Aldrich; 1.88 g, 16.5 mmol) followed by DIPEA (2.97 mL, 18 mmol). The mixture was heated at 80° C. for 20 hours, then cooled to room temp. The mixture was concentrated in vacuo, dissolved in DCM and purified by SCX (50 g SCX 2 column). The product was eluted from the column with 7N ammonia in methanol, concentrated in vacuo to give the title compound (53 mg) which was dissolved in Methanol as a 0.05 mmol solution and reduced using an H-cube hydrogenator. 10% Pd/C catalyst, 1 bar hydrogen (full hydrogen setting), 3 mL/min flow-rate at 50° C. The resultant solution was concentrated in vacuo, and the resultant material purified by column chromatography, eluting with 0-10% ammonia/methanol in DCM, to give the title compound as a solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[F:8].Cl.[CH3:15]O>>[CH3:15][O:12][C:11](=[O:13])[CH2:10][NH:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=1
Reactant: O=C(O)CNc1ccc(F)c(F)c1
Reactant: CO
Agent: Cl
Product: COC(=O)CNc1ccc(F)c(F)c1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
Through a suspension of 3,4-difluorophenylglycine (2.00 g, 10.7 mmol) in methanol (100 mL) was passed gaseous hydrochloric acid for 40 min while cooling with an ice-bath to keep ambient temperature. The resulting solution was stirred for 1 h at 5° C. and for 30 min at ambient temperature. Nitrogene was passed through the reaction mixture for 120 min. Concentration afforded the title compound (2.52 g, 99%) as a white solid. MS m/e: 202.2 [M−HCl+H]+).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)[N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:37]=1[O:38][CH2:39][CH2:40][O:41][CH3:42])[N:34]=[CH:33][N:32]=[C:31]2[O:43][C:44]1[CH:45]=[C:46]([CH:48]=[CH:49][CH:50]=1)[NH2:47].C(N(C(C)C)CC)(C)C>CN(C1C=CN=CC=1)C>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:47][C:46]2[CH:48]=[CH:49][CH:50]=[C:44]([O:43][C:31]3[C:30]4[C:35](=[CH:36][C:37]([O:38][CH2:39][CH2:40][O:41][CH3:42])=[C:28]([O:27][CH3:26])[CH:29]=4)[N:34]=[CH:33][N:32]=3)[CH:45]=2)=[O:19])[N:7]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COCCOc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: COCCOc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccccc4)c3)c2cc1OC

Procedure:
The procedure for Example 138B was used to react phenyl 3-tert-butyl-1-phenyl-1H-pyrazol-5-ylcarbamate described in Example 154A (151 mg, 0.45 mmol) with 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example 117B (103 mg, 0.30 mmol). To this solution was added diisopropylethyl amine (80 μL, 0.45 mmol) and DMAP (4 mg, 0.03 mmol). After heating for 2 hours the reaction was concentrated to dryness. The resulting solid was chromatographed using silica gel (eluting with an ethyl acetate/hexane gradient 0-85%). The main peak was concentrated to give 59 mg. 1H (DMSO-d6) 9.23 (s, 1H), 8.54 (s, 1H), 8.47 (s, 1H), 7.55 (m, 6H), 7.40 (m, 3H), 7.18 (s, 1H), 6.95 (m, 1H), 6.35 (s, 1H), 4.34 (m, 2H), 3.98 (s, 3H), 3.77 (m, 2H), 3.34 (s, 3H), 1.25 (s, 9H). LCMS (ESI) m/z 583 (M+H)
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[N:8]([CH:9]2[CH2:15][CH:14]3[N:16]([CH2:17][CH2:18][C:19]4([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[C:7]2[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=2[N:5]=1.C(N(CC)CC)C.[O:42]1[CH:46]=[CH:45][CH:44]=[C:43]1[C:47](Cl)=[O:48]>ClCCl>[O:42]1[CH:46]=[CH:45][CH:44]=[C:43]1[C:47]([N:22]1[CH2:21][CH2:20][C:19]([CH2:18][CH2:17][N:16]2[C@H:14]3[CH2:13][CH2:12][C@@H:11]2[CH2:10][CH:9]([N:8]2[C:7]4[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=4[N:5]=[C:4]2[CH3:3])[CH2:15]3)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:24][CH2:23]1)=[O:48]
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCNCC1
Reactant: O=C(Cl)c1ccco1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2ccccc2)CCN(C(=O)c2ccco2)CC1
Reaction time: 0.5 h
Yield: 49.9 %

Procedure:
To a stirred solution of endo 2-methyl-1-{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole dihydrochloride II (0.35 g, 0.69 mmol) in dichloromethane (7 mL) and triethylamine (0.209 g, 2.07 mmol) was added 2-furoyl chloride (0.094 g, 0.72 mmol) at 0° C. The ice bath was then removed and the mixture allowed to stir for 30 min. The solvents were then removed in vacuo and the solid was added ethyl acetate and water. The insoluble precipitate was then filtered off and subsequently characterized as the desired product 19. Additional 0.18 g of the desired product 19 was obtained by extracting the organic layer with water (3×), drying with magnesium sulfate and evaporating solvents in vacuo. Following the SFC purification, on a portion of crude 19, 60 mg of the desired product 1-((1R,5S)-8-{2-[1-(2-furoyl)-4-phenylpiperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole 19 was obtained (calculated yield 86%). 1H NMR (400 MHz, CD3OD) δ 7.57 (1H, dist. d, J=1.1 Hz), 7.47 (1H, d, J=7.1 Hz), 7.43-7.29 (5H, m), 7.26-7.09 (3H, m), 6.89 (1H, d, J=3.6 Hz), 6.48 (1H, dd, J=1.8, 3.6 Hz), 4.08 (2H, m), 3.84 (2H, m), 2.60 (5H, m), 2.42 (3H, s), 2.30 (2H, m), 2.20 (2H, m), 2.05 (7H, m), 1.83 (2H, m). HRMS m/z (M+H)+Calc 523.3062; (M+H)+Obs 523.3073.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.Br[CH2:14][C:15]#[N:16]>>[N:10]1([CH2:14][C:15]#[N:16])[CH2:9][CH2:8][CH:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH2:12][CH2:11]1
Reactant: N#CCBr
Reactant: c1cc(C2CCNCC2)ccn1
Product: N#CCN1CCC(c2ccncc2)CC1

Procedure:
The title compound is synthesized by coupling of 1,2,3,4,5,6-Hexahydro-[4,4′]bipyridinyl (commercially available from CHESS GmbH) and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a colorless oil; ES-MS: M+H=202.2: CtRet=2.41.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:6]=2[CH:21]=1.[Br:22][CH:23]([Br:27])[C:24](Cl)=O.C([O-])(=O)C.[Na+]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:24]([CH:23]([Br:27])[Br:22])=[N:13][N:12]=[C:10]3[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:6]=2[CH:21]=1
Reactant: NNC1=Nc2ccc(F)cc2C(c2ccccc2Cl)=NC1
Reactant: O=C(Cl)C(Br)Br
Agent: CC(=O)[O-]
Agent: [Na+]
Product: Fc1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(C(Br)Br)n1-2

Procedure:
In the manner given in Example 2, 7-fluoro-5-(o-chlorophenyl)-3H-1,4-benzodiazepin-2-yl hydrazine was reacted with dibromoacetyl chloride and after 1.5 hours with sodium acetate, then the mixture was refluxed to give 8-fluoro-1-(dibromomethyl)-6-(o-chlorophenyl)-4H-s-triazolo-[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1)#[N:2].[CH2:12]=[O:13].C(N(CC)CC)C>CC(C)=O>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][OH:13])[CH:4]=1)#[N:2]
Reactant: C=O
Reactant: N#Cc1c[nH]c2ccccc12
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: N#Cc1cn(CO)c2ccccc12
Temperature: 130 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
The mixture of 1.42 g of 3-cyano-1H-indole, 0.60 g of paraformaldehyde and 0.1 g of triethylamine was stirred at 130 ° C. for 1 hour. After the reaction mixture was cooled to room temperature, acetone was added to the reaction mixture. The mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.69 g of 3-cyano-1H-indole-1-ylmethanol.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9][C@H:8]1[CH2:17][CH2:18]OS(C)(=O)=O)=[O:6])[CH:2]=[CH2:3].[C:24]([C:26]1[N:27]=[CH:28][NH:29][CH:30]=1)#[N:25].CC(C)([O-])C.[K+]>>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:14])=[O:15])[CH2:9][C@H:8]1[CH2:17][CH2:18][N:29]1[CH:30]=[C:26]([C:24]#[N:25])[N:27]=[CH:28]1)=[O:6])[CH:2]=[CH2:3]
Reactant: N#Cc1c[nH]cn1
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CCOS(C)(=O)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CCn1cnc(C#N)c1
Yield: 39.4 %

Procedure:
(2R,4R)-1-Allyloxycarbonyl-4-methanesulfonyloxy-2-(2methanesulfonyloxyethyl)pyrrolidine (36.1 g) was reacted with 4-cyanoimidazole (10.0 g) and potassium t-butoxide (12.0 g) in substantially the same manner as Preparation 10-3) to give (2R,4R)-1-allyloxycarbonyl-2-[2-(4-cyanoimidazol-1-yl)ethyl]-4-methanesulfonyloxypyrrolidine (14.1 g) as a yellow paste.
Reaction SMILES: Cl.[CH2:2]([O:5][NH2:6])[CH:3]=[CH2:4].[OH-].[Na+].[C:9]([C:14]1[C:15](=[O:30])[CH2:16][CH:17]([C:21]2[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=2[CH3:29])[CH2:18][C:19]=1[OH:20])(=O)[CH2:10][CH2:11][CH3:12].C(O)C>O>[CH2:2]([O:5][N:6]=[C:9]([C:14]1[C:19](=[O:20])[CH2:18][CH:17]([C:21]2[C:22]([CH3:29])=[CH:23][C:24]([CH3:28])=[CH:25][C:26]=2[CH3:27])[CH2:16][C:15]=1[OH:30])[CH2:10][CH2:11][CH3:12])[CH:3]=[CH2:4]
Reactant: CCCC(=O)C1=C(O)CC(c2c(C)cc(C)cc2C)CC1=O
Reactant: C=CCON
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=CCON=C(CCC)C1=C(O)CC(c2c(C)cc(C)cc2C)CC1=O
Yield: 76.3 %

Procedure:
Allyloxyamine hydrochloride (0.72 g) and then a solution of sodium hydroxide (0.25 g) in water (3 ml) were added to a stirred mixture of 2-butyryl-3-hydroxy-5-mesitylcyclohex-2-en-1-one (1.78 g; 5.9 mmole) and 95% ethanol. The progress of the reaction was monitored using thin layer chromatography on silica gel (eluant dichloromethane). On completion of the reaction the ethanol was removed by evaporation using a rotary evaporator and the residue was extracted with dichloromethane. The organic extract was washed with aqueous 5% hydrochloric acid and then with water and dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure using a rotary evaporator to give the product, 2-[1-(allyloxyimino)butyl]-3-hydroxy-5-mesitylcyclohex-2-en-1-one (1.6 g) as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][C:9]2[C:10]([CH:19]([CH3:21])[CH3:20])=[CH:11][C:12]([O:17][CH3:18])=[C:13]([CH:16]=2)[C:14]#[N:15])=[CH:6][N:5]=[C:4]([NH:22][CH2:23][CH3:24])[N:3]=1.[OH-:25].[Na+].Cl>CCO.O.O>[NH2:1][C:2]1[C:7]([O:8][C:9]2[C:10]([CH:19]([CH3:20])[CH3:21])=[CH:11][C:12]([O:17][CH3:18])=[C:13]([CH:16]=2)[C:14]([NH2:15])=[O:25])=[CH:6][N:5]=[C:4]([NH:22][CH2:23][CH3:24])[N:3]=1
Reactant: CCNc1ncc(Oc2cc(C#N)c(OC)cc2C(C)C)c(N)n1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCNc1ncc(Oc2cc(C(N)=O)c(OC)cc2C(C)C)c(N)n1
Temperature: 100 °C
Yield: 27.1 %

Procedure:
To a solution of 5-(4-Amino-2-ethylamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-benzonitrile (0.3 g, 0.92 mmol) in EtOH/H2O (1:1, 10 ml) was added a solution of NaOH (0.37 g, 9.17 mmol) in H2O (1 ml). The reaction mixture was heated at 100° C. for 24 hrs and neutralized with 3N HCl. Ethanol was removed in vacuo and the remaining aqueous solution was extracted into methylene chloride. The combined extract was washed with water, dried over Na2SO4, filtered and concentrated. Flash chromatography on silica gel (3 to 8% EtOAc in Hexanes) gave 5-(4-Amino-2-ethylamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-benzamide (0.086 g, 27%) as a white solid. (M+H)=346.
Reaction SMILES: [CH3:1][C:2]([CH3:37])([CH3:36])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([O:25][CH3:26])=[C:16]([CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])[CH:17]=2)[CH:7]=[CH:6][C:5]=1[C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:28]=1[F:35].[OH-].[Na+].Cl>CO.O>[CH3:1][C:2]([CH3:37])([CH3:36])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([O:25][CH3:26])=[C:16]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:17]=2)[CH:7]=[CH:6][C:5]=1[C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:28]=1[F:35]
Reactant: CCOC(=O)CCc1cc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)ccc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(F)c(-c2ccc(COc3ccc(OC)c(CCC(=O)O)c3)nc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 75.7 %

Procedure:
To a solution of ethyl 3-(5-((6-(2,2-dimethylpropyl)-5-(2-fluoro-5-methoxyphenyl)pyridin-2-yl)methoxy)-2-methoxyphenyl)propanoate (200 mg) in methanol (3.0 mL) was added a solution of sodium hydroxide (100 mg) in water (3.0 mL), and the mixture was stirred at room temperature for 15 hr. 2N Hydrochloric acid was added to the reaction mixture to adjust to pH<2, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (143 mg) as a white solid.