Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[N:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[N:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: CCCCCCCCCCCCOc1cccc(Br)n1
Product: CCCCCCCCCCCCOc1cccc(Nc2c(C)noc2-c2ccc(-c3ccc(C4(C(=O)OCC)CC4)cc3)cc2)n1

Procedure:
Prepared according to the procedure described in Example 290, Step 1, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-bromo-6-dodecyloxy-pyridine.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH2:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:12][N:13]([C:18]1[CH:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][CH:19]=1)[S:14]([CH3:17])(=[O:16])=[O:15]>>[NH2:11][C:9]1[N:10]=[C:3]2[C:2]([C:21]3[CH:20]=[CH:19][C:18]([N:13]([CH3:12])[S:14]([CH3:17])(=[O:15])=[O:16])=[CH:23][CH:22]=3)=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: CN(c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)S(C)(=O)=O
Reactant: Nc1nc2c(Br)cccn2n1
Product: CN(c1ccc(-c2cccn3nc(N)nc23)cc1)S(C)(=O)=O

Procedure:
To a suspension of N-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-methanesulfonamide (0.50 g, 1.7 mmol) and potassium carbonate (0.28 g, 2.0 mmol) in acetone (10 mL) was added methyl iodide (0.12 mL, 2.0 mmol). The mixture was stirred at room temperature for 18 hours under an atmosphere of nitrogen then diluted with dichloromethane (20 mL), filtered through a plug of diatomaceous earth, rinsed with dichloromethane and evaporated. The material was subjected to high vacuum for 18 hours. N-Methyl-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-methanesulfonamide was isolated as a yellow solid (0.50 g, 95%) and was used without further purification. 1H NMR (400 MHz, CDCl3, δ, ppm): 7.83 (d, J=7.9 Hz, 2H), 7.39 (d, J=7.8 Hz, 2H), 3.34 (s, 3H), 2.82 (s, 3H), 1.34 (s, 12H). MS=312 (MH)+. 62b) N-[4-(2-Amino-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-phenyl]-N-methyl-methanesulfonamide was prepared from 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (300.0 mg, 1.408 mmol) and N-methyl-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-methanesulfonamide (500.0 mg, 1.607 mmol) in a manner analogous to Step 2c. The reaction product was isolated as an off-white solid (0.33 g, 73%). MP=245-247° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.55 (d, J=5.8 Hz, 1H), 8.12 (d, J=7.5 Hz, 2H), 7.72 (d, J=7.1, 1H), 7.52 (d, J=7.2 Hz, 2H), 6.98 (t, J=6.2 Hz, 1H), 6.11 (s, 2H), 3.29 (s, 3H), 2.98 (s, 3H). MS=318 (MH)+. 62c) N-Methyl-N-(4-{2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-yl}-phenyl)-methanesulfonamide was prepared from N-[4-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-phenyl]-N-methyl-methanesulfonamide (75.0 mg, 0.236 mmol) and 1-(4-bromo-phenyl)-4-methyl-piperazine (70.0 mg, 0.274 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (26.0 mg, 0.0476 mmol) as the ligand in a manner analogous to Step 2d. The title compound was isolated as a tan solid (0.027 g, 23%). MP=205-206° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.41 (d, J=6.5 Hz, 1H), 8.04 (d, J=7.7 Hz, 2H), 7.57-7.46 (m, 5H), 6.99-6.91 (m, 3H), 6.66 (s, 1H), 3.38 (s, 3H), 3.19-3.14 (m, 4H), 2.90 (s, 3H), 2.62-2.57 (m, 4H), 2.36 (s, 3H). MS=492 (MH)+.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].O.[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11]([CH:13]=O)=O.[BH4-].[Na+].O>C(O)C>[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH:11]1[CH2:13][NH:4][CH2:1][CH2:2][NH:3]1
Reactant: O=CC(=O)c1cccs1
Reactant: NCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: c1csc(C2CNCCN2)c1
Reaction time: 1.5 h

Procedure:
A solution of ethylenediamine (4.1 g, 0.068 mol) in ethanol (25 ml) is added dropwise to a solution of 2-thienylglyoxal hydrate [prepared by the procedure of F. Kipnis and J. Ornfelt, J. Amer. Chem. Soc. 68, 2734 (1946)] (10.0 g, 0.063 mol) in ethanol (250 ml) at 0° C. under an atmosphere of dry nitrogen. The cooling bath is removed and the reaction mixture stirred for an additional 1.5 h. Sodium borohydride (4.5 g, 0.126 mol) is added all at once, and a cooling bath used to control the exothermic reaction. Stirring is continued for an additional 18 h. Water (25 ml) is added, and the ethanol removed under reduced pressure. The remaining aqueous solution is extracted with methylene chloride (3×100 ml) and the extracts dried with potassium carbonate. Removal of the solvent under reduced pressure gives 2-(2-thienyl)piperazine as an off-white solid. An analytical sample is obtained by addition of an ethereal solution of the base to an ethereal solution of oxalic acid dihydrate. The resulting precipitate is washed with diethyl ether and methanol, and the free base (m.p. 81°-83° C.) is obtained with a saturated solution of potassium carbonate.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:6].[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28]([CH:30]3[CH2:32][CH2:31]3)=[O:29])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1>>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([C:5](=[O:6])[CH2:4][CH2:3][CH2:2][N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:22]=[C:23]([NH:27][C:28]([CH:30]4[CH2:31][CH2:32]4)=[O:29])[CH:24]=[CH:25][CH:26]=3)[CH2:17][CH2:16]2)=[CH:8][CH:9]=1
Reactant: O=C(Nc1cccc(C2CCNCC2)c1)C1CC1
Reactant: COc1ccc(C(=O)CCCCl)cc1
Product: COc1ccc(C(=O)CCCN2CCC(c3cccc(NC(=O)C4CC4)c3)CC2)cc1

Procedure:
Prepared by Procedure K and Scheme B1 using 4-chloro-1-(4-methoxyphenyl)-1-butanone and N-[3-(4-piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e: 421.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH:5]([C:15]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)=O)[CH2:6][C:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].[CH3:28][Si:29]([CH3:38])([CH3:37])[CH2:30][CH2:31][O:32][C:33]([NH:35][NH2:36])=[O:34].O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:36]([NH:35][C:33]([O:32][CH2:31][CH2:30][Si:29]([CH3:38])([CH3:37])[CH3:28])=[O:34])[C:15]=1[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)=[O:27])[CH3:2]
Reactant: C[Si](C)(C)CCOC(=O)NN
Reactant: CCOC(=O)C(CC(=O)c1ccccc1)C(=O)c1cccc2ccccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1cc(-c2ccccc2)n(NC(=O)OCC[Si](C)(C)C)c1-c1cccc2ccccc12
Temperature: 25 °C
Yield: 95.9 %

Procedure:
A solution of 2-(Naphthalene-1-carbonyl)-4-oxo-4-phenyl-butyric acid ethyl ester (1 g, 2.77 mmol) in toluene (6.5 mL) was treated with Hydrazinecarboxylic acid 2-trimethylsilanyl-ethyl ester (599 mg, 3.34 mmol) and p-toluene sulfonic acid (33 mg). The resulting solution was heated to reflux, with the azeotropic removal of water (Dean Stark trap), under Ar for 6 h, cooled to rt and concentrated in vacuo to afford 2-Naphthalen-1-yl-5-phenyl-1-(2-trimethylsilanyl-ethoxycarbonylamino)-1H-pyrrole-3-carboxylic acid ethyl ester (1.33 g), which was not purified, but used immediately in the next reaction.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][SH:10])=[CH:7][CH:6]=1.[C:13]([O:17][C:18]([N:20]1[CH2:24][C@H:23](OS(C)(=O)=O)[CH2:22][C@H:21]1[C:30](=[O:32])[NH2:31])=[O:19])([CH3:16])([CH3:15])[CH3:14].[Cl-].[Na+]>CN(C)C=O>[C:13]([O:17][C:18]([N:20]1[CH2:24][C@H:23]([S:10][CH2:9][C:8]2[CH:11]=[CH:12][C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)[CH2:22][C@H:21]1[C:30](=[O:32])[NH2:31])=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1C(N)=O
Reactant: COc1ccc(CS)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CS[C@@H]2C[C@@H](C(N)=O)N(C(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.3 %

Procedure:
330 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) were added, whilst ice-cooling, to a solution of 1.18 g of p-methoxybenzyl mercaptan in 25 ml of dry dimethylformamide, and the mixture was stirred at room temperature for 30 minutes. At the end of this time, 2.14 g of (2S, 4R)-1-(t-butoxycarbonyl)-2-carbamoyl-4-methanesulfonyloxypyrrolidine [prepared as described in step (3) above] were added to the mixture, which was then stirred at room temperature for 3 hours. The reaction mixture was then poured into an aqueous solution of sodium chloride and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by chromatography through silica gel (eluted with a 2:3 by volume mixture of cyclohexane and ethyl acetate) to afford 1.94 g of the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C@@H:4]([NH:9][C:10](=[O:24])[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[NH2:26][CH2:27][C@@H:28]([C:30]1[CH:31]=[CH:32][C:33]([OH:41])=[C:34]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH:35]=1)[OH:29]>>[CH3:1][O:2][C:3](=[O:25])[C@@H:4]([NH:9][C:10](=[O:24])[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][CH:20]([NH:26][CH2:27][CH:28]([OH:29])[C:30]3[CH:31]=[CH:32][C:33]([OH:41])=[C:34]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH:35]=3)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)c1ccc(N2CCC(=O)CC2)cc1
Product: COC(=O)[C@H](CC(C)C)NC(=O)c1ccc(N2CCC(NCC(O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1

Procedure:
The title compound was prepared from methyl 4-methyl-2-[(2S)-4-(4-oxo-piperidin-1-yl)-benzylamino]-pentanoic acid methyl ester (which was obtained in Example 166) and N-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) according to the procedure of Example 180 as a white solid; mp>90° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 0.86 (d, J=6.4 Hz, 3 H), 0.92 (d, J=6.4 Hz, 3 H), 1.20–1.40 (m, 2 H), 1.50–1.95 (m, 5 H), 2.55–2.92 (m, 5 H), 2.91 (s, 3 H), 3.62 (s, 3 H), 3.70–3.85 (m, 2 H), 4.40–4.55 (m, 2 H), 6.82 (d, J=8.2 Hz, 1 H), 6.93 (d, J=8.9 Hz, 2 H), 7.00 (dd, J=8.2, 2.0 Hz, 2 H), 7.18 (d, J=2.0 Hz, 1 H), 7.75 (d, J=8.9 Hz, 2 H), 8.34 (d, J=7.7 Hz, 1 H); MS (ES) m/z: 577.3 (MH+); HRMS Calcd. for C28H41N4O7S (MH+): 577.2690. Found: 577.2682.
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[C:17]1([CH3:28])[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25](O)=[O:26])=[CH:19][CH:18]=1>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[C:14]([NH:16][C:25](=[O:26])/[CH:24]=[CH:23]/[C:20]3[CH:21]=[CH:22][C:17]([CH3:28])=[CH:18][CH:19]=3)[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: CC(F)(F)c1ccc(Cn2cc(N)cn2)o1
Reactant: Cc1ccc(/C=C/C(=O)O)cc1
Product: Cc1ccc(/C=C/C(=O)Nc2cnn(Cc3ccc(C(C)(F)F)o3)c2)cc1

Procedure:
Following general procedure B, starting from 1-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-p-tolyl-acrylic acid. LC-MS-conditions 05b: tR=1.10 min; [M+H]+=372.18.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[F:20])[C:9]([O:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:26][O-:27].[Na+].Cl>C1COCC1.CO>[F:20][C:13]1[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:12]=1[C:10]1[C:9]([O:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([O:27][CH3:26])[N:11]=1
Reactant: C[O-]
Reactant: COC(=O)c1cc(OCC(C)C)c(-c2cc(OC)ccc2F)nc1Cl
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc(OCC(C)C)c(-c2cc(OC)ccc2F)nc1OC
Temperature: 60 °C
Reaction time: 48 h

Procedure:
Under a nitrogen atmosphere, to a solution of methyl 2-chloro-6-(2-fluoro-5-methoxyphenyl)-5-isobutoxynicotinate (248 mg) in THF (5.0 mL) was added a 28% solution of sodium methoxide in methanol (3.42 mL). The reaction mixture was stirred at room temperature for 1 hr and further at 60° C. for 48 hr. 6N Hydrochloric acid (0.44 mL) was added to the reaction mixture, and the resulting sodium chloride was filtered off. The solvent in the filtrate was evaporated under reduced pressure, and the residue was heated with conc. sulfuric acid (108 μL) and methanol (10 mL) under reflux for 3 hr. The reaction mixture was neutralized with sodium hydrogen carbonate, and the solvent in the reaction mixture was evaporated under reduced pressure and the residue was filtered. The solvent in the filtrate was evaporated under reduced pressure to give a crude product of the title compound (213 mg) as a yellow oil. This compound was used for the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl[C:20]([O:22][CH3:23])=[O:21]>C1COCC1>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][C:20](=[O:21])[O:22][CH3:23]
Reactant: COC(=O)Cl
Reactant: Nc1ccncc1Br
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)Nc1ccncc1Br
Reaction time: 0.5 h
Yield: 58.2 %

Procedure:
To a solution of compound 3-bromopyridin-4-amine (3 g, 17.4 mmol.) in 20 mL of anhydrous THF was added a solution of LiHMDS (1M in THF, 36.4 mL, 36.4 mmol) at 0° C. After stirring for 30 min, methyl chloroformate (2 g, 20.8 mmol) was added at 0° C. The reaction mixture was stirred at 0° C. for 2 hrs and then at r.t. overnight. The reaction was quenched with saturated aqueous ammonium chloride. The organic solvent was evaporated and the aqueous layer was extracted with ethyl acetate. The organic layers were dried over Na2SO4, concentrated. The crude product was purified by silica gel column chromatography (Petroleum ether:Ethyl acetate=1:2) to afford methyl 3-bromopyridin-4-ylcarbamate (2.34 g, 59%).
Reaction SMILES: [C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C@@H:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CSC.[BH3:23].B>C1(C)C=CC=CC=1>[C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)[OH:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[BH3:23]
Reactant: OC(c1ccccc1)(c1ccccc1)[C@@H]1CCCN1
Agent: B
Solvent: Cc1ccccc1
Solvent: CSC
Product: OC(c1ccccc1)(c1ccccc1)C1CCCN1
Temperature: 20 °C

Procedure:
A 250-mL three-necked flask fitted with a mechanical stirrer, nitrogen inlet tube, and teflon coated thermocouple probe, was charged with a solution of the free base product of Example 1 Step B (20.7 g, 81.7 mmol) in dry toluene (100 mL). To the stirred solution at 20° C. was added borane-dimethyl sulfide (10M, 10.0 mL, 100 mmol) over 5 minutes via syringe. The borane reacted immediately in an exothermic reaction (raising the internal temperature from 20° C. to 32° C.) forming a thick white precipitate. With continued stirring, the mixture was allowed to cool to room temperature (20° C.) over a 1 hour period. The mixture was filtered, and the product cake washed with dry toluene (25 mL). The product was dried in vacuo (20° C., 0.01 mBar) to constant weight. Yield 15.7 g (72%) of a white crystal line solid. m.p. 130°-132° C. (dec). 1H NMR (CDCl3 ) δ7.7-7.1 (m, 10 H, Ar-H), 5.15 (s, 1 H, --OH), 4.5 (br, 1 H, --NH), 4.2 (m, 1 H, C2-H), 3.25 (m, 2 H, C5-H2), 2.6 (m, 1 H, C4- H), 2.3 (m, 1 H, C4-H), 1.85 (m, 1 H, C3-H), 1.6 (m, 1 H, C3-H), 2.1-0.7 (br, 3 H, BH3). 13C NMR (CDCl3) δ145.8, 144.5 (C1', C1"), 129.1, 128.2 (C3', C5', C3", C5"), 127.4, 127.0 (C4', C4"), 125.2, 125.1 (C2', C6', C2", C6"), 76.5 (Cα), 69.6 (C2), 55.6 (C 5), 20.6 (C4), 19.9 (C3).
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:22][N:23]([CH3:32])[C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1.C([BH3-])#N.[Na+].C(O)C>C(OCC)(=O)C>[CH:12]1[C:8]2[CH:9]=[CH:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH:6]([CH:16]3[CH2:17][CH2:18][N:19]([CH2:28][C:27]4[CH:30]=[CH:31][C:24]([N:23]([CH3:32])[CH3:22])=[CH:25][CH:26]=4)[CH2:20][CH2:21]3)[C:7]=2[CH:15]=[CH:14][CH:13]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: C1=Cc2ccccc2C(C2CCNCC2)c2ccccc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CN(C)c1ccc(CN2CCC(C3c4ccccc4C=Cc4ccccc43)CC2)cc1
Yield: 17.6 %

Procedure:
1.00 gram (3.47 millimoles) of 4-(5H-dibenzo[a,d]cyclohepten-5-yl)piperidine, 0.52 gram (3.47 millimoles) of p-dimethylaminobenzaldehyde, 0.63 gram (10.0 millimoles) of sodium cyanoborohydride and 10 milliliters of ethanol were stirred together at room temperature for 24 hours. At the end of this period, the mixture was diluted with 150 milliliters of ethyl acetate and the ethyl acetate solution washed successively with two 50 milliliter portions of 15 percent aqueous sodium bisulfite, one 50 milliliter portion of saturated sodium bicarbonate, and one 100 milliliter portion of brine and then dried over magnesium sulfate. The solvent was vaporized from the dried solution in vacuo to obtain a yellow oil. The oil was flash chromatographed on silica gel with 50/50 ethyl acetate/hexane as eluant to obtain 250 milligrams of a colorless oil which crystallized on standing overnight. The product after recrystallization from acetonitrile had a melting point of 163°-165° C. Elemental analyses of the product were as follows:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=2)[C:5]([Cl:15])=[CH:4][N:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:28]1[CH2:33][O:32][CH:31]=[CH:30][CH2:29]1>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[N:11]([CH:31]3[CH2:30][CH2:29][CH2:28][CH2:33][O:32]3)[N:10]=2)[C:5]([Cl:15])=[CH:4][N:3]=1
Reactant: Cc1cc(Nc2nc(Cl)ncc2Cl)n[nH]1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Nc2nc(Cl)ncc2Cl)nn1C1CCCCO1
Reaction time: 8 h

Procedure:
To a mixture of 2,5-dichloro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (2.44 g, 10 mmol) and 4-toluenesulfonic acid monohydrate (1.9 g, 10 mmol) in THF (200 mL), was added DHP (4.25 g, 50 mmol). After stirring overnight, the reaction turned clear. After concentration, the residue was dissolved in ethyl acetate and washed with Na2CO3 saturated aqueous solution. The organic layer was then washed with brine, dried over sodium sulfate and concentrated in vacuo to afford 2,5-Dichloro-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyrimidin-4-amine as light yellow solid, which was used in subsequent reactions without further purification; ESMS m/z 244 (M−THP+H+); TLC Rf=0.6 (Silica; 1:1 ethyl acetate/hexanes; starting material Rf=0.2).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[O:9])=[C:6]([CH3:19])[CH:5]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:3]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1.CCN(CC)CC>CC#N>[F:18][C:14]1[CH:13]=[C:12]([CH2:11][NH:10][C:8]([C:7]2[C:2]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[N:3][C:4]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:5][C:6]=2[CH3:19])=[O:9])[CH:17]=[CH:16][CH:15]=1
Reactant: C1CCNC1
Reactant: Cc1cc(N2CCOCC2)nc(Cl)c1C(=O)NCc1cccc(F)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(N2CCOCC2)nc(N2CCCC2)c1C(=O)NCc1cccc(F)c1
Temperature: 140 °C
Yield: 58.6 %

Procedure:
To a solution of 254 mg (0.7 mmol) 2-chloro-N-[(3-fluorophenyl)-methyl]-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide (synthesis is described in section a) of example 9) in MeCN (0.5 ml) were added 115 μl (1.4 mmol) pyrrolidine and 290 μl (2.1 mmol) NEt3. The RM was heated in the microwave to 120° C. for 30 min and subsequently to 140° C. for 45 min. Then the mixture was filtered through celite and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 2:1), followed by crystallization (hexane/EtOAc) provided 164 mg (0.41 mmol, 59%) N-[(3-Fluorophenyl)-methyl]-4-methyl-6-morpholin-4-yl-2-pyrrolidin-1-yl-pyridine-3-carboxylic acid amide (example 24). [M+H]+ 399.2.
Reaction SMILES: C([O:8][CH2:9][CH2:10][NH:11][C:12]1[N:17]=[C:16]([C:18]([N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:22][CH2:21]2)=[O:19])[C:15]([CH3:31])=[CH:14][C:13]=1[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=1)C1C=CC=CC=1.Cl.[H][H]>CO.[Pd]>[OH:8][CH2:9][CH2:10][NH:11][C:12]1[N:17]=[C:16]([C:18]([N:20]2[CH2:21][CH2:22][CH:23]([N:26]3[CH2:27][CH2:28][CH2:29][CH2:30]3)[CH2:24][CH2:25]2)=[O:19])[C:15]([CH3:31])=[CH:14][C:13]=1[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:39])([F:41])[F:40])[CH:33]=1
Reactant: [H][H]
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(NCCOCc2ccccc2)nc1C(=O)N1CCC(N2CCCC2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)c(NCCO)nc1C(=O)N1CCC(N2CCCC2)CC1
Yield: 76.4 %

Procedure:
A solution of 0.14 g (0.25 mmol) of [6-(2-benzyloxy-ethylamino)-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (intermediate 14) in 6.0 ml of MeOH was treated at RT with 0.49 ml (0.49 mmol) of hydrochloric acid (1.0 molar in MeOH), followed by 0.026 g (0.025 mmol) of Pd—C (10%). The reaction mixture was vigorously stirred in an atmosphere of hydrogen for 3 hours. After filtration through dicalite, the solvent was removed by evaporation, then the residue was dissolved in H2O/Na2CO3 and extracted twice with CH2Cl2; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 95:5) to give 0.091 g (77%) of the title compound as yellow amorphous solid. MS: 477.3 (MH+).
Reaction SMILES: Br[CH:2]1[CH2:11][CH2:10][CH2:9][C:8]2[N:7]=[CH:6][CH:5]=[N:4][C:3]1=2.[N-:12]=[N+:13]=[N-:14].[Na+].O>CN(C=O)C>[N:12]([CH:2]1[CH2:11][CH2:10][CH2:9][C:8]2[N:7]=[CH:6][CH:5]=[N:4][C:3]1=2)=[N+:13]=[N-:14]
Reactant: BrC1CCCc2nccnc21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC1CCCc2nccnc21
Temperature: 60 °C
Yield: 96.9 %

Procedure:
5-bromo-5,6,7,8-tetrahydroquinoxaline (2.75 g, 12.9 mmol) and sodium azide (1.68 g, 25.8 mmol) were dissolved in DMF (50 mL) under nitrogen atmosphere and the reaction mixture was warmed to 60° C. for 2 days. The mixture was cooled to room temperature and poured over water (500 mL), and was extracted with CH2Cl2 (3×300 mL). The organic extracts were washed with brine (2×200 mL), dried and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel using 1:1 EtOAc/hexanes to afford 2.19 g (97%) of 5-azido-5,6,7,8-tetrahydroquinoxaline as a yellow liquid: 1H NMR (CDCl3): δ 1.80-1.96 (m, 1H), 2.00-2.10 (m, 3H), 2.75-3.06 (m, 2H), 4.74 (t, 1H, J=6.5 Hz), 8.44 (d, 1H, J=3 Hz), 8.45 (d, 1H, J=3 Hz); 13C NMR (CDCl3): δ 18.6, 28.9, 31.7, 60.2, 142.6, 144.3, 150.3, 153.6.