Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[CH:17]([F:19])[F:18])[N:5]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:3]=1.[C:26]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)(=[O:28])[CH3:27].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[C:26]([N:29]1[CH2:34][CH2:33][N:32]([C:2]2[N:3]=[C:4]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:5]=[C:6]([N:8]3[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=4[N:10]=[C:9]3[CH:17]([F:18])[F:19])[N:7]=2)[CH2:31][CH2:30]1)(=[O:28])[CH3:27]
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: CC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4ccccc43)n2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
A mixture of 6-chloro-2-(2-difluoromethylbenzimidazol-1-yl)-4-morpholino-1,3,5-triazine (3.66 g, 10 mmol), 1-acetylpiperazine (1.40 g, 11 mmol), potassium carbonate (1.38 g, 10 mmol) and DMF (30 ml) was stirred at room temperature for 16 hours. The reaction mixture was poured into water, and extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, concentrated under vacuum, and the residue was purified by silica gel column to obtain 4-(4-acetylpiperazin-1-yl)-2-(2-difluoromethylbenzimidazol-1-yl)-6-morpholino-1,3,5-triazine (4.08 g, 9.0 mmol) in a yield of 90% as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12](=[O:17])N(OC)C)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][Mg]Br>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([C:12](=[O:17])[CH3:18])[CH2:11]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)C1CN(C(=O)OC(C)(C)C)C1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)C1CN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 65.4 %

Procedure:
To a solution of 3-(methoxy-methyl-carbamoyl)-azetidine-1-carboxylic acid tert-butyl ester (6.0 g, 24.56 mmol) in THF (15 mL) at −78° C. was added a solution of methymagnesium bromide (3M in toluene, 12.3 mL, 36.9 mmol). The reaction mixture was stirred at −78° C. for 1 h. The reaction mixture was warmed to ambient temperature gradually and stirred for 1 h. The reaction was quenched by the addition of aqueous KHSO4 solution (20 mL). The aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 10% EtOAc in petroleum ether) to give 3-acetyl-azetidine-1-carboxylic acid tert-butyl ester (3.2 g, 65.4%). 1H NMR (DMSO-d6, 400 MHz): δ 3.88 (m, 4H), 3.53 (m, 1H), 2.08 (s, 3H), 1.34 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]([CH3:20])([NH:6][S:7]([C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]=[CH:17][CH:16]=[CH:15]2)(=[O:9])=[O:8])[CH3:5].[CH3:22]I.O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:21])[C:4]([CH3:5])([N:6]([CH3:22])[S:7]([C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]=[CH:17][CH:16]=[CH:15]2)(=[O:9])=[O:8])[CH3:20]
Reactant: COC(=O)C(C)(C)NS(=O)(=O)c1cccc2cccnc12
Reactant: CI
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(C)(C)N(C)S(=O)(=O)c1cccc2cccnc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 95.1 %

Procedure:
methyl-2-methyl-2-(quinoline-8-sulfonamido)propanoate (699 mg, 2.26 mmol) was dissolved in DMF (10 ml), added with MeI (0.49 ml, 7.93 mmol) at 0° C., and stirred at room temperature for 12 hours. The resultant solution was added with H2O and extracted with EA (×2). The organic solution was washed with H2O, dried with MgSO4, and filtered. Through vacuum distillation, the solvent was removed. The resultant mixture was purified with column chromatography so as to obtain methyl-2-methyl-2-(N-methylquinoline-8-sulfonamido)propanoate (694 mg, 2.15 mmol, 95%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N:11]=[C:10]([C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])[CH2:9]2)=[CH:6][CH:7]=1.[C:27]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)(=[O:29])[CH3:28].C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[N:12]1[CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:34]3[CH:33]=[CH:32][CH:31]=[C:30]([C:27](=[O:29])[CH3:28])[CH:35]=3)=[CH:3][N:4]=2)[CH2:9][C:10]([C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])=[N:11]1
Reactant: CC(=O)c1cccc(B(O)O)c1
Reactant: FC(F)(F)C(F)(F)C1=NN(c2ccccc2Cl)C(c2ccc(Br)cn2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(=O)c1cccc(-c2ccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccccc3Cl)nc2)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 20.2 %

Procedure:
5-(3-Bromo-pyridin-6-yl)-1-(2-chloro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (20.0 mg, 0.04 mmol) prepared in Step 4 of Preparation 3, 3-acetylphenylboronic acid (11.0 mg, 0.07 mmol), Pd(PPh3)4 (2.0 mg, cat.) and a 2N sodium carbonate solution (210.0 uL) were added to a mixed solvent of ethanol (210.0 uL) and toluene (310.0 uL). The reaction mixture was stirred at 80° C. for 1 hour and then filtered through celite pad. A saturated solution of ammonium chloride was added to the filtrate, which was then extracted with ethyl acetate three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/6) to give 4.0 mg of the titled compound as a white liquid.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][N:9]1[N:13]=[N:12][C:11]([C:14]2[CH:40]=[CH:39][C:17]([O:18][C:19]3[C:33]([CH:34]4[CH2:38][CH2:37][CH2:36][NH:35]4)=[CH:32][C:22]4[NH:23][C:24]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=5)=[N:25][C:21]=4[CH:20]=3)=[CH:16][CH:15]=2)=[N:10]1>C(Cl)(Cl)Cl>[C:1]([N:35]1[CH2:36][CH2:37][CH2:38][CH:34]1[C:33]1[C:19]([O:18][C:17]2[CH:16]=[CH:15][C:14]([C:11]3[N:12]=[N:13][N:9]([CH3:8])[N:10]=3)=[CH:40][CH:39]=2)=[CH:20][C:21]2[N:25]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[NH:23][C:22]=2[CH:32]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: Cn1nnc(-c2ccc(Oc3cc4nc(-c5ccccn5)[nH]c4cc3C3CCCN3)cc2)n1
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCCC1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc(-c2nnn(C)n2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
0.007 ml of acetic anhydride was added to a chloroform (1 ml) solution of 30.9 mg of 5-(4-(2-methyl-2H-tetrazol-5-yl)phenoxy)-2-pyridin-2-yl-6-pyrrolidin-2-yl-1H-benzimidazole enantiomer B obtained in Example 542, and the reaction liquid was stirred at room temperature for 10 minutes. The reaction solvent was evaporated away under reduced pressure, and the resulting residue was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol=10/1) to obtain one chiral form of the entitled compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([OH:11])=[C:4]([CH3:12])[CH:3]=1.[H][H]>C(O)C.[Ni]>[ClH:1].[CH3:12][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([NH2:8])=[CH:6][C:5]=1[OH:11]
Reactant: Cc1cc(Cl)c([N+](=O)[O-])cc1O
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: Cc1cc(Cl)c(N)cc1O
Product: Cl

Procedure:
5 g of 4-chloro-2-methyl-5-nitrophenol were dissolved in 200 ml of ethanol and, after addition of 0.5 g of Raney nickel, the resulting solution was catalytically hydrogenated. When the uptake of hydrogen stopped, the catalyst was separated off by filtration and the filtrate acidified with dilute hydrochloric acid. Concentration to dryness produced light beige crystals melting at 198° C. (with decomposition).
Reaction SMILES: CC(C)=O.CN.[C:7](Cl)(=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[CH2:27]([N:29](CC)CC)C>O>[CH3:27][NH:29][C:7](=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: CCN(CC)CC
Agent: CN
Solvent: O
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCCC(=O)NC
Temperature: 0 °C

Procedure:
To 500 cc of acetone was added 15.5 g of methylamine to form a mixture. 60.0 g of stearoyl chloride was drop-wise added to the mixture, while the mixture was stirred and cooled using ice water. The addition was conducted at a temperature of not higher than 20° C. Further, 20.2 g of triethylamine was dropwise added to the mixture at a temperature of not higher than 20° C. After the addition was complete, the mixture was allowed to react for 3 hours. The reaction mixture was then poured into water and the aqueous mixture was filtered to collect produced crystals, and the crystals were recrystallized from a mixed solvent of ethyl acetate and methanol to give a white crystalline product of N-methylstearic amide (Amide compound No. 1 mentioned above).
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([C:9]1[CH:14]=[C:13]([CH2:15][CH2:16][C:17]#[N:18])[CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[CH:23][C:22]([O:25]C)=[C:21]([CH2:27][CH:28]([CH3:30])[CH3:29])[CH:20]=1)[CH:6]([CH3:8])[CH3:7].O>C(Cl)Cl>[OH:25][C:22]1[CH:23]=[CH:24][C:19]([C:10]2[CH:11]=[CH:12][C:13]([CH2:15][CH2:16][C:17]#[N:18])=[CH:14][C:9]=2[CH2:5][CH:6]([CH3:7])[CH3:8])=[CH:20][C:21]=1[CH2:27][CH:28]([CH3:30])[CH3:29]
Reactant: COc1ccc(-c2ccc(CCC#N)cc2CC(C)C)cc1CC(C)C
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CC(C)Cc1cc(-c2ccc(CCC#N)cc2CC(C)C)ccc1O
Temperature: 0 °C
Reaction time: 3 h
Yield: 65.8 %

Procedure:
2.37 ml (2.37 mmol, 3.00 eq.) of a 1 M solution of BBr3 in CH2Cl2 was added to a solution of 275.6 mg (0.79 mmol) 3-(2,3′-Diisobutyl-4′-methoxy-biphenyl-4-yl)propionitrile (73) in 25 ml dry CH2Cl2 at 0° C. via syringe. After that the solution was stirred for 3 h at 0° C. and then for 10 h at r.t. The reaction mixture was then added to water and extracted with CH2Cl2. The comb. org. fractions were dried over MgSO4 and evaporated. Column chromatography (hexanes/EtOAc (2+1)) yielded 174.9 mg (0.52 mmol, 65.99%) 3-(4′-Hydroxy-2,3′-diisobutyl-biphenyl-4-yl)-propionitrile (74) as an oily white solid. Rf (hexanes/EtOAc (2+1)) =0.38. 1H-NMR (500 MHz, CDCl3): δ=0.69 (d, 6H, J=6.62 Hz, 2*CH3), 0.92 (d, 6H, J=6.62 Hz, 2*CH3), 1.63 (m, 1H, CH), 1.93 (m, 1H, CH), 2.45 (d, 2H, J=7.25 Hz, CH2), 2.47 (d, 2H, J=7.25 Hz, CH2), 2.62 (t, 2H, J=7.41 Hz, CH2CH2CN), 2.94 (t, 2H, J=7.41 Hz, CH2CH2CN), 4.60 (s, br., 1H, OH), 6.75 (d, 1H, J=8.36 Hz), 6.92-6.96 (m, 2H), 7.01-7.06 (m, 2H), 7.11 (d, 1H, J=7.57 Hz). MS (EI): m/z=336 (24), 335 (100), 292 (18), 251 (10), 236 (35), 209 (12), 196 (10), 195 (48), 178 (10), 165 (10). HR-MS (EI): Calcd. for C23H29NO: 335.224914. Found: 335.225330.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([CH:21]=O)=[CH:13][CH:12]=2)[CH:3]=1.CN.[C:25]([BH3-])#[N:26].[Na+].[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33]>C(O)(=O)C.CO>[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([CH2:21][NH:26][CH3:25])=[CH:13][CH:12]=2)[CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1Oc1ccc(C=O)c2ccccc12
Reactant: [BH3-]C#N
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CNCc1ccc(Oc2cc(Cl)ccc2C#N)c2ccccc12
Yield: 74.7 %

Procedure:
4-Chloro-2-(4-formylnaphthalen-1-yloxy)benzonitrile (0.34 g, 1.1 mmol), methylamine (2M in methanol, 2.0 mL, 4.0 mmol) and sodium cyanoborohydride (80 mg, 1.3 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (30 mL) for 18 h. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and fumaric acid (0.12 g, 1.0 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with ethyl acetate overnight, collected by filtration, and dried to give 4-chloro-2-[4-(methylaminomethyl)naphthalen-1-yloxy]benzonitrile fumarate (328 mg, 68%) as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:8]([OH:10])=[O:9])[S:5][C:6]=1[CH3:7].C(Cl)Cl.C(Cl)(=O)C(Cl)=O.[CH:20]1([NH:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(O)C.O>[CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH3:7].[CH:27]1([NH:26][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1.[S:5]1[CH:6]=[CH:2][CH:1]=[C:4]1[C:8]([OH:10])=[O:9]
Reactant: Cc1nc(C(=O)O)sc1C
Agent: C1CCC(NC2CCCCC2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: Cc1ncsc1C
Product: O=C(O)c1cccs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a slurry of 19.0 g. (0.121 mole) of 4,5-dimethylthiazole-2-carboxylic acid in 250 ml. of dry methylene chloride was added over 1 hour 10.3 ml. (0.121 mole) of oxalyl chloride. The reaction mixture was stirred at room temperature for 1 hour and was refluxed for 2 hours. The small amount of insoluble material was removed by filtration and the filtrate was concentrated under reduced pressure to a yellow oil. Infrared spectrum indicated this to be the desired acid chloride. This was added dropwise to a stirred and cooled solution of 26.4 g. (0.24 mole) of hydrated sodium sulfhydrate in 275 ml. of ethanol and 30 ml. of water at such a rate as to keep the temperature of the mixture at 10°-15°. After the addition was completed, the reaction mixture was stirred for 40 minutes at 5°-10°. Then most of the ethanol was removed under reduced pressure and the residue was dissolved in 150 ml. of water. The pH of the solution was lowered to 2.5 with 6N hydrochloric acid and was maintained there, while the mixture was extracted with 5 × 100 ml. of ethyl acetate. The extracts were combined, washed with ice water, dried over magnesium sulfate, filtered and evaporated to dryness to give 10.6 g. of a reddish solid. It was dissolved in 200 ml. of hot ethanol and 7.5 ml. of dicyclohexylamine were added. Bright yellow crystals resulted. The mixture was cooled at 5° for 1 hour. Then the precipitate was removed by filtration, washed with ether and dried under high vacuum to give 11.75 g. (27%) of a yellow solid. NMR spectrum was consistent with the desired material.
Reaction SMILES: C[N:2]1CCN(C2C=CC(NC3C4N(N=CN=4)C(C4C=C(C(N)=O)SC=4)=CN=3)=CC=2)CC1.Br[C:33]1[N:38]2[N:39]=[CH:40][N:41]=[C:37]2[C:36]([NH:42][C:43]2[CH:58]=[CH:57][C:46]([C:47]([NH:49][CH2:50][C:51]3[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=3)=[O:48])=[CH:45][CH:44]=2)=[N:35][CH:34]=1.[CH3:59][O:60][C:61]1[CH:66]=[C:65](B(O)O)[CH:64]=[CH:63][N:62]=1>C([O-])([O-])=O.[K+].[K+].O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH3:2].[CH3:59][O:60][C:61]1[CH:66]=[C:65]([C:33]2[N:38]3[N:39]=[CH:40][N:41]=[C:37]3[C:36]([NH:42][C:43]3[CH:58]=[CH:57][C:46]([C:47]([NH:49][CH2:50][C:51]4[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=4)=[O:48])=[CH:45][CH:44]=3)=[N:35][CH:34]=2)[CH:64]=[CH:63][N:62]=1
Reactant: CN1CCN(c2ccc(Nc3ncc(-c4csc(C(N)=O)c4)n4ncnc34)cc2)CC1
Reactant: COc1cc(B(O)O)ccn1
Reactant: O=C(NCc1cccnc1)c1ccc(Nc2ncc(Br)n3ncnc23)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1cc(-c2cnc(Nc3ccc(C(=O)NCc4cccnc4)cc3)c3ncnn23)ccn1
Product: N
Yield: 73 %

Procedure:
This compound may be prepared using methods as described for Compound 6, step 4 using 4-(5-bromo-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino)-N-pyridin-3-ylmethyl-benzamide (120 mg, 0.28 mmol), 2-methoxypyridine-4-boronic acid (87 mg, 0.57 mmol) and Pd(PPh3)4 (81 mg, 0.07 mmol) in 1.5M K2CO3 (aq) (1.6 mL) and dioxane (2.9 mL). The crude material is purified by silica gel column chromatography eluting with DCM followed by 99:1 then 97:3 then 95:5 DCM:NH3 (7M in MeOH) to afford the title compound as a white solid (92.6 mg, 73%).
Reaction SMILES: C([CH:6]([C:40]1[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=1)[CH:7]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH:33]([F:35])[F:34])=[C:28]([O:36][CH:37]([F:39])[F:38])[CH:27]=1)[C:8]1[CH:9]=[N:10][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)=[CH:12][CH:13]=1)(OCC)=O.C1COCC1.[Li+].[OH-].Cl>O.CO>[F:39][CH:37]([F:38])[O:36][C:28]1[CH:27]=[C:26]([CH:7]([C:8]2[CH:9]=[N:10][C:11]([O:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)=[CH:12][CH:13]=2)[CH2:6][C:40]2[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=2)[CH:31]=[CH:30][C:29]=1[O:32][CH:33]([F:35])[F:34]
Reactant: CCOC(=O)C(c1ccncc1)C(c1ccc(Oc2ccc(OC(F)(F)F)cc2)nc1)c1ccc(OC(F)F)c(OC(F)F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: FC(F)Oc1ccc(C(Cc2ccncc2)c2ccc(Oc3ccc(OC(F)(F)F)cc3)nc2)cc1OC(F)F
Temperature: 65 °C
Reaction time: 1.5 h

Procedure:
To a solution of the crude ester from Step 4 above in 25 mL of a 3:1:1 mixture of THF:MeOH:water, was added 5.1 mL (10.3 mmol) of a 2 N solution of LiOH. The resulting solution was stirred at 65° C. for 1.5 h, cooled down to room temperature followed by the addition of 10 mL of a 1.0 N HCl solution. The resulting mixture was rotovaped down to evaporate MeOH and the aqueous residue was diluted with ethyl acetate. The organic layer was washed with water and brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (50% Ethyl acetate/hexane) to afford the desired pyridine as an oil (380 mg, 68% from Step 2).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:11]2[CH2:16][CH2:15][C@:14]([CH3:23])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:13][C:12]2=[O:24])[CH2:9][CH3:10])=[CH:4][CH:3]=1.I[C:26]1[CH:31]=[CH:30][N:29]([CH3:32])[C:28](=[O:33])[CH:27]=1>>[CH3:23][C@@:14]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:13][C:12](=[O:24])[N:11]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:26]3[CH:31]=[CH:30][N:29]([CH3:32])[C:28](=[O:33])[CH:27]=3)=[CH:3][CH:4]=2)[CH2:9][CH3:10])[CH2:16][CH2:15]1
Reactant: CC[C@@H](c1ccc(Br)cc1)N1CC[C@](C)(c2ccccc2)OC1=O
Reactant: Cn1ccc(I)cc1=O
Product: CC[C@@H](c1ccc(-c2ccn(C)c(=O)c2)cc1)N1CC[C@](C)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)propyl)-6-methyl-6-phenyl-1,3-oxazinan-2-one following procedures analogous to those described in Example 32 Method 2 Steps 3 and 4 using 4-iodo-1-methylpyridin-2(1H)-one in Step 4. LC-MS Method 1 tR=1.55 min, m/z=417 (M+1); 1H NMR (CDCl3) 7.41 (1H, d, J=7.03 Hz), 7.33 (2H, d, J=8.20 Hz), 7.29-7.19 (5H, m), 7.10 (1H, d, J=8.20), 6.95 (1H, d=1.76), 6.55 (1H, dd, J=2, 7.03 Hz), 5.51 (1H, q, J=6.49, 9.66 Hz), 3.65 (3H, s), 3.00-2.95 (1H, m), 2.44-2.36 (1H, m), 2.33-2.15 (2H, m), 2.06-1.86 (2H, m), 1.64 (3H, s), 1.02 (3H, t, J=7.32 Hz).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].Cl.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH:24]([CH3:25])[CH:23]2[NH2:26])=[CH:18][CH:17]=1.C(N(CC)CC)C>C1COCC1>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C@H:22]2[C@H:24]([CH3:25])[C@H:23]2[NH:26][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=2[C:2]([F:13])([F:12])[F:1])=[CH:20][CH:21]=1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: CC1C(N)C1c1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@@H]1[C@@H](NC(=O)c2ccccc2C(F)(F)F)[C@H]1c1ccc(Cl)cc1
Yield: 33.3 %

Procedure:
2-Trifluoromethyl-benzoyl chloride (0.028 ml, 39.4 mg, 0.17 mmol) was added to a solution of racemic (1R,2R,3S)-2-(4-chlorophenyl)-3-methyl-cyclopropanamine hydrochloride (37.2 mg, 0.17 mmol), and triethylamine (43.4 mg) in THF at 0° C. with stirring, and stirred for 18 hours. The white solid of Et3NHCl was filtered off and the filtrate concentrated and chromatographed with diethyl ether/hexane to yield 20 mg of pure racemic N-[(1R,2R,3S)-2-(4-chlorophenyl)-3-methyl-cyclopropyl]-2-(trifluoromethyl)benzamide. M.p. 167-9
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[C:8]([NH:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH:14]([OH:18])[CH2:13]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[C:22]([F:35])[N:21]=1.C([O-])([O-])=O.[Na+].[Na+]>C(O)C.O.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:19][C:20]1[CH:25]=[C:24]([C:2]2[N:6]3[CH:7]=[C:8]([NH:11][CH:12]4[CH2:17][CH2:16][CH2:15][CH:14]([OH:18])[CH2:13]4)[CH:9]=[CH:10][C:5]3=[N:4][CH:3]=2)[CH:23]=[C:22]([F:35])[N:21]=1
Reactant: OC1CCCC(Nc2ccc3ncc(Br)n3c2)C1
Reactant: CC1(C)OB(c2cc(F)nc(Cl)c2)OC1(C)C
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OC1CCCC(Nc2ccc3ncc(-c4cc(F)nc(Cl)c4)n3c2)C1
Temperature: 95 °C

Procedure:
To a solution of 3-trans-RS/RS (3-bromo-imidazo[1,2-a]pyridin-6-ylamino)-cyclohexanol [intermediate J step 2] (1 eq, 0.1 g), 2-Chloro-6-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (1.05 eq,82 mg), Na2CO3 (2 eq, 68 mg) in ethanol (2 ml) and water (0.2 ml), under an inert atmosphere of argon is added bis(triphenylphosphine)palladium II chloride (0.1 eq, 0.96 mmol, 22 mg). The reaction mixture is heated at 95° C. for 16 hours. The mixture is diluted with H2O (50 ml) and extracted with EtOAc. The combined organic portions are washed with brine, dried (MgSO4) and concentrated in vacuo. The residue is purified by chromatography on silica eluting with 0-10% MeOH in EtOAc to afford the title compound; [M+H]+=360.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[C:6]([CH:9]=1)[CH2:7][OH:8].N1C=CN=C1.[C:24]([Si:28]([CH3:31])([CH3:30])Cl)([CH3:27])([CH3:26])[CH3:25].C(=O)([O-])O.[Na+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[C:6]([CH:9]=1)[CH2:7][O:8][Si:28]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:31])[CH3:30]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCCCCCCCOc1ccc(Br)cc1CO
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(Br)cc1CO[Si](C)(C)C(C)(C)C
Reaction time: 0.33 h
Yield: 102.5 %

Procedure:
To a solution of compound 35-2 (7.95 g) and imidazole (4.19 g) in N,N-dimethylformamide (35 ml) was added t-butyldimethylchlorosilane (4.45 g) under ice-cooling, and the mixture was stirred for 20 min under ice-cooling, and further at room temperature for 18 hr. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (11.1 g) as a pale-brown oil.