Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10](B2OC(C)(C)C(C)(C)O2)=[CH:9][N:8]=1)=[O:5])[CH3:2].I[C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]([CH2:33][CH2:34][O:35][CH3:36])[CH:28]=[C:27]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:26]2=[O:42].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.[Pd].C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([NH:3][C:4](=[O:5])[NH:6][C:7]1[N:8]=[CH:9][C:10]([C:23]2[CH:24]=[C:25]3[C:30](=[CH:31][CH:32]=2)[N:29]([CH2:33][CH2:34][O:35][CH3:36])[CH:28]=[C:27]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:26]3=[O:42])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CCOC(=O)c1cn(CCOC)c2ccc(I)cc2c1=O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CCNC(=O)Nc1ccc(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3CCOC)cn1
Temperature: 110 °C

Procedure:
A mixture of N-ethyl-N′-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)urea (Intermediate 1, 80 mg, 0.27 mmol), ethyl 6-iodo-1-(2-methoxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (WO2006010733, 100 mg, 0.25 mmol), cesium carbonate (90 mg, 0.27 mmol), and Tetrakisphenylphosphine palladium (28.9 mg, 0.02 mmol) in dioxane (4 mL) and water (1 mL) was degassed with nitrogen for 30 minutes. The reaction mixture was then heated in a microwave for 1 h at 110° C. The reaction mixture was cooled to room temperature and filtered, then placed on high vacuum to remove residual solvent (59 mg). MS (ESP): 439 (M+H+) for C23H26N4O5; NMR: 9.34 (s, 1H), 8.61 (m, 2H), 8.45 (m, 1H), 8.10 (m, 1H), 8.09 (m, 2H), 7.54 (m, 1H), 4.62 (m, 2H), 4.25 (m, 2H), 3.71 (m, 2H), 3.57 (s, 3H), 3.21 (m, 2H), 1.30 (t, J=7 Hz, 3H), 1.11 (t, J=8 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6](=[O:12])[NH:7][CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[F:15][C:16]1[CH:17]=[C:18]([CH:22]([NH2:30])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=2)[CH:19]=[CH:20][CH:21]=1>>[F:15][C:16]1[CH:17]=[C:18]([CH:22]([NH:30][C:9]([CH2:8][NH:7][C:6](=[O:12])[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:14][CH:13]=2)=[O:11])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: O=C(O)CNC(=O)c1ccc(F)cc1
Reactant: NC(c1cccc(F)c1)c1cccc(F)c1
Product: O=C(CNC(=O)c1ccc(F)cc1)NC(c1cccc(F)c1)c1cccc(F)c1

Procedure:
Prepared in analogy to example 1.1 from 4-fluoro-hippuric acid (CA [366-79-0]) and C,C-bis-(3-fluoro-phenyl)-methylamine (CA [261925-16-0]).
Reaction SMILES: C[O:2][C:3]([C@@:5]1([CH3:25])[C@@H:9]([O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH2:8][CH2:7][N:6]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=O.[Li+].[B-](CC)(CC)CC>C1COCC1>[C:21]([O:20][C:18]([N:6]1[CH2:7][CH2:8][C@H:9]([O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[C@@:5]1([CH2:3][OH:2])[CH3:25])=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: COC(=O)[C@@]1(C)[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Agent: CC[B-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](O[Si](C)(C)C(C)(C)C)[C@]1(C)CO
Temperature: -78 °C
Reaction time: 60 h
Yield: 24.4 %

Procedure:
To compound 3B (0.519 g, 1.39 mmol) in THF (10 mL) at −78° C. was added a 1 M solution of Super-Hydride® in THF (9.73 mL, 9.73 mmol). The cold bath was removed and the reaction was stirred for 2.5 days. The reaction was cooled to −78° C., additional 1 M Super-Hydride® in THF (4.00 mL, 4.00 mmol) was added, and reaction was stirred overnight at rt. The reaction was poured into a 1-L Erlenmeyer flask and was carefully quenched with ice while stirring and then diluted with EtOAc. The layers were separated and the organic layer washed with 1 M H3PO4, saturated aqueous NaHCO3 and brine, dried (MgSO4), filtered and concentrated. The residue was purified via flash chromatography eluting with 20-50% EtOAc/hexane to obtain compound 3C (117 mg) as a clear oil.
Reaction SMILES: [CH3:1][C:2]12[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]4[NH:16][CH:17]=[C:9]([C:10]=34)[CH2:8][CH:3]1[NH:4][CH2:5][CH2:6][O:7]2.C(=O)([O-])[O-].[K+].[K+].I[CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(OCC)(=O)C>CN(C=O)C>[CH3:1][C:2]12[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]4[NH:16][CH:17]=[C:9]([C:10]=34)[CH2:8][CH:3]1[N:4]([CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:5][CH2:6][O:7]2
Reactant: CC12OCCNC1Cc1c[nH]c3cccc2c13
Reactant: ICCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC12OCCN(CCOc3ccccc3)C1Cc1c[nH]c3cccc2c13
Temperature: 60 °C
Yield: 45.8 %

Procedure:
To a solution of 4,6,6a,8,9,10a-hexahydro-10a-methyl-7H-indolo[3,4-gh][1.4]benzoxazine (85 mg, 0.37 mmol) in DMF (5 ml) were added potassium carbonate (255 mg, 1.9 mmol) and 1-iodo-2-phenoxyethane (99 mg, 0.4 mmol). The mixture was heated at 60° C for 24 hours. After completion of the reaction, the reaction mixture was added to a mixture of ice water and ethyl acetate. The organic layer was separated, washed with a saturated aqueous saline solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to a silica gel column chromatography, eluting with n-hexane-ethyl acetate (2:1), to afford 59 mg (46%) of the title compound as an amorphous crystalline product.
Reaction SMILES: [CH2:1]([N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14])[CH:2]=[CH2:3].[F:15][C:16]1[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=1>C(#N)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:3]/[CH:2]=[CH:1]/[N:4]2[C:8](=[O:9])[C:7]3[C:6](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:5]2=[O:14])=[CH:18][CH:17]=1
Reactant: C=CCN1C(=O)c2ccccc2C1=O
Reactant: Fc1ccc(I)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1/C=C/Cc1ccc(F)cc1
Reaction time: 18 h

Procedure:
N-Allylphthalimide (13.9 g, 74.3 mmol), 1-fluoro-4-iodobenzene (15.0 g, 67.6 mmol) triethylamine (15.0 g, 148 mmol) and Pd(OAc)2 (152 mg) were heated at 104° in a glass bomb with shaking for 18 h under an inert atmosphere. The reaction mixture was dissolved in hot acetonitrile. The catalyst was removed by filtration and the filtrate cooled to 0°. The precipitated white solid product was filtered off and dried under vacuum. This title material (12.55 g) was used without further purification.
Reaction SMILES: C(C1C=CC2N(C=CN=2)C=1)(OCC)=O.[C:15]([N:19]1[C:23]([NH2:24])=[C:22]([C:25]([NH2:27])=[O:26])[C:21]([CH2:28][C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)=[N:20]1)([CH3:18])([CH3:17])[CH3:16].[CH:35]1([N:40]2[C:44](N)=[C:43](C(N)=O)[C:42]([CH2:49]C)=N2)[CH2:39]CCC1>>[C:15]([N:19]1[C:23]2=[N:24][C:49]([C:42]3[CH:39]=[CH:35][N:40]=[CH:44][CH:43]=3)=[N:27][C:25](=[O:26])[C:22]2=[C:21]([CH2:28][C:29]2[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=2)[NH:20]1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Reactant: CC(C)(C)n1nc(Cc2ccncc2)c(C(N)=O)c1N
Agent: CCOC(=O)c1ccc2nccn2c1
Product: CC(C)(C)n1[nH]c(Cc2ccncc2)c2c(=O)nc(-c3ccncc3)nc1-2
Yield: 84 %

Procedure:
Following a procedure substantially similar to that described in Example 16, part c, but substituting ethyl isonicotinate for 6-carboethoxyimidazo[1,2-a]pyridine and 1-tertbutyl-3-(4-pyridylmethyl)-5-amino-1H-pyrazole-4-carboxamide for 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide there was obtained 1-tert-butyl-3-(4-pyridylmethyl)-6-(4-pyridyl)-pyrazolo[3,4-d]pyrimidin-4-one in 84% yield as a white powder, m.p. 233°-235° C.
Reaction SMILES: Cl[C:2]1[C:3]([N:8]2[CH2:13][CH:12]=[C:11]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24])=[CH:19][CH:18]=3)=[O:15])[C@@H:10]([CH3:30])[CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.N.[CH3:32]O>>[CH3:30][C@@H:10]1[C:11]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[O:15])=[CH:12][CH2:13][N:8]([C:3]2[C:2]([CH3:32])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH2:9]1
Reactant: C[C@H]1CN(c2ncccc2Cl)CC=C1C(=O)Nc1ccc(S(=O)(=O)C(F)(F)F)cc1
Reactant: CO
Agent: N
Product: Cc1cccnc1N1CC=C(C(=O)Nc2ccc(S(=O)(=O)C(F)(F)F)cc2)[C@@H](C)C1
Yield: 54 %

Procedure:
The title compound (51 mg, 54%) was prepared using similar procedure as described in Example 3, substituting the product from Example 5 for the product from Example 1G. 1H NMR (300 MHz, CDCl3) δ 8.19-8.17 (m, 1H), 8.00 (d, 2H, J=9.2 Hz), 7.90 (d, 2H, J=9.2 Hz), 7.86 (br s, 1H), 7.47-7.43 (m, 1H), 6.91 (dd, 1H, J=7.1, 4.8 Hz), 6.68 (dd, 1H, J=3.4, 3.4 Hz), 3.94 (app t, 2H, J=2.4 Hz), 3.23 (app d, 2H, J=4.1 Hz), 3.10-2.99 (m, 1H), 2.35 (s, 3H), 1.27 (d, 3H, J=7.1 Hz); MS (DCI/NH3) m/e 440 (M+H)+; [α]23D −38.0° (c 0.25, CH3OH).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][NH:11][CH:12]=2)=[CH:4][CH:3]=1.[C:13]1([N:19]=[CH:20]OCC)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CC(C)=O>[C:13]1([NH:19][CH:20]=[N:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[N:9]=[CH:10][NH:11][CH:12]=3)=[CH:6][CH:7]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccc(-c2c[nH]cn2)cc1
Reactant: CCOC=Nc1ccccc1
Solvent: CC(C)=O
Product: C(=Nc1ccc(-c2c[nH]cn2)cc1)Nc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.9 %

Procedure:
Five grams of 4-(4-aminophenyl)-1-H-imidazole were added to a solution of 4.6 gm of ethyl N-phenyl-formimidate [Org. Synth., 35, 65 (1965)] in 25 ml of acetone. After stirring for four hours at room temperature, the solid that separated was filtered and dried under vacuum. The product was treated with acetone and acidified with glacial acetic acid. N-Phenyl-N'-[4-(imidazol-4-yl]-formamidine crystallized as acetate salt which was filtered to give 4.6 gm of the desired product.
Reaction SMILES: [C:1]([C:3]1[CH:26]=[CH:25][C:6]([O:7][C@H:8]2[CH2:13][CH2:12][C@H:11]([C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]3)=[O:15])[CH2:10][CH2:9]2)=[CH:5][CH:4]=1)#[N:2].Cl.[NH2:28][OH:29].C(N(CC)CC)C>C(O)C>[OH:29][NH:28][C:1](=[NH:2])[C:3]1[CH:4]=[CH:5][C:6]([O:7][C@H:8]2[CH2:13][CH2:12][C@H:11]([C:14]([N:16]3[CH2:17][CH2:18][N:19]([CH:22]([CH3:23])[CH3:24])[CH2:20][CH2:21]3)=[O:15])[CH2:10][CH2:9]2)=[CH:25][CH:26]=1
Reactant: CC(C)N1CCN(C(=O)[C@H]2CC[C@H](Oc3ccc(C#N)cc3)CC2)CC1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)N1CCN(C(=O)[C@H]2CC[C@H](Oc3ccc(C(=N)NO)cc3)CC2)CC1

Procedure:
A mixture of 0.15 g (0.42 mmol) of trans-[4-(4-cyano-phenoxy)-cyclohexyl]-(4-isopropyl-piperazin-1-yl)-methanone, 0.118 g (1.69 mmol) of hydroxylamine hydrochloride, 0.24 ml (1.73 mmol) of triethylamine in 3 ml ethanol was refluxed for 1 hr. The mixture was evaporated to dryness to yield 0.34 g (84% yields, about 40% purity) of the titled compound. MS (m/e): 389.3 (MH+).
Reaction SMILES: Cl[CH2:2][CH:3]([NH:22][C:23](=[O:32])[C:24]1[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=1[F:31])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH:19]([F:21])[F:20])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[OH-].[Na+]>C(O)(C)C.O>[F:20][CH:19]([F:21])[S:16]([C:13]1[CH:14]=[CH:15][C:10]([C:7]2[CH:8]=[CH:9][C:4]([CH:3]3[CH2:2][O:32][C:23]([C:24]4[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=4[F:31])=[N:22]3)=[CH:5][CH:6]=2)=[CH:11][CH:12]=1)(=[O:18])=[O:17]
Reactant: O=C(NC(CCl)c1ccc(-c2ccc(S(=O)(=O)C(F)F)cc2)cc1)c1c(F)cccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: O=S(=O)(c1ccc(-c2ccc(C3COC(c4c(F)cccc4F)=N3)cc2)cc1)C(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.3 %

Procedure:
To a slurry of 9.18 g (18.9 mmol) of N-[2-chloro-1-[4'-[(difluoromethyl) -sulfonyl][1,1'-biphenyl]-4-yl]ethyl]-2,6-difluorobenzamide in 70 mL of isopropanol was added a solution of 1.8 g (22.5 mmol) of aqueous 50% NaOH at 25-30° C. The mixture was allowed to stir for 30 minutes at ambient temperature, diluted with 40 mL of water, and filtered. The solid product was washed with 20 mL of 50% aqueous isopropanol and suction-dried to afford 7.5 g (88%) of 4-[4'-[(difluoromethyl)sulfonyl][1,1'-biphenyl]-4-yl]-2-(2,6-difluorophenyl)-4,5-dihydrooxazole, m.p. 107-111° C. An analytical sample was prepared by recrystallization from isopropanol, m.p. 109-111° C. IR(KBr): 1669, 1622, 1593, 1485, 1469, 1395, 1345, 1300, 1285, 1240, 1168, 1161, 1114, 1081, 1053, 1041, 1012, 822, 793 cm-1. UV(CH2Cl2): λmax =279 nm (ε=25.9×103). 1H-NMR (benzene-d6): δ3.9 (t, 1H), 4.25 (dd, 1H), 5.15 (dd, 1H), (dq, 2H), 5.68 (m, 1H), 6.22 (t, 1H, J=53 Hz), 6.7 (br d, 1H), 7.0 (t, 2H, J=9 Hz), 7.41 (m, 1H), 7.53 (d, 2H), 7.65 (d, 2H), 7.83 (d, 2H), 8.05 (d, 2H). 13C-NMR (CDCl3): δ69.9, 74.6, 107.1 (dd, JCF =2, 23 Hz), 114.8, 127.6, 127.9, 128.1, 131.2, 132.2. 19F-NMR (CDCl3): δ-112.1 (t, JHF =7.3 Hz), -121.8 (d, JHF =53 Hz).
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][CH:10]([OH:12])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C.C(O)(=O)C>[CH2:21]([O:12][CH:10]1[CH2:11][N:8]([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:9]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: c1ccc(COC2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 24.3 %

Procedure:
To a solution of 1-diphenylmethylazetidin-3-ol (300 mg, 1.3 mmol) in DMF (2.6 mL) at 0° C. under nitrogen was added NaH (60% in oil, 56 mg, 1.4 mmol). The suspension was stirred for 0.5 h at 0° C. then treated with benzyl bromide (236 μL, 2.0 mmol). The mixture was allowed to warm to room temperature then heated to 80° C. overnight. The reaction mixture was cooled, acetic acid (20 drops) was added and the mixture concentrated under reduced pressure. The crude material was purified on column chromatography (eluent: Pentane/EtOAc, 95/5 to 70/30) to give the product (104 mg, 24%) as an orange oil.
Reaction SMILES: Cl[C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[CH:23]1([CH2:26][NH:27][C:28](=[O:45])[C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[C:31](B3OC(C)(C)C(C)(C)O3)[CH:30]=2)[CH2:25][CH2:24]1>>[CH:23]1([CH2:26][NH:27][C:28]([C:29]2[CH:30]=[CH:31][C:32]([CH3:35])=[C:33]([C:2]3[CH:22]=[CH:21][C:5]([C:6]([NH:8][CH2:9][C:10]4[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:11]=4)=[O:7])=[CH:4][N:3]=3)[CH:34]=2)=[O:45])[CH2:25][CH2:24]1
Reactant: CS(=O)(=O)Nc1cccc(CNC(=O)c2ccc(Cl)nc2)c1
Reactant: Cc1ccc(C(=O)NCC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Product: Cc1ccc(C(=O)NCC2CC2)cc1-c1ccc(C(=O)NCc2cccc(NS(C)(=O)=O)c2)cn1

Procedure:
6-(5-Cyclopropylmethylcarbamoyl-2-methyl-phenyl)-N-(3-methylsulphonylaminobenzyl)-nicotinamide was prepared from 6-chloro-N-(3-methylsulphonylaminobenzyl)nicotinamide (Intermediate 4) and N-cyclopropylmethyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 10) using General Method B. LCMS: retention time 2.88 min, MH+ 493. NMR: δH [2H6]-DMSO 9.34,(1H, t), 9.16,(1H, d), 8.96,(1H, b), 8.62,(1H, t), 8.35,(1H, dd), 7.94,(1H, s), 7.85,(1H, d), 7.75,(1H, d), 7.43,(1H, d), 7.31,(1H, t), 7.21,(1H, s), 7.11,(2H, m), 4.52,(2H, d), 3.14,(2H, t), 2.99,(3H, s), 2.39,(3H, s), 1.03,(1H, m), 0.43,(2H, m), 0.23,(2H, m).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:19][C:20]([S@:23]([NH2:25])=[O:24])([CH3:22])[CH3:21].ClCCl.C(=O)(O)[O-].[Na+]>[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC.[Ti].CO>[CH3:19][C:20]([S@:23](/[N:25]=[CH:15]/[C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:18])([F:17])[F:1])=[CH:4][CH:5]=2)=[CH:10][CH:11]=1)=[O:24])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[S@](N)=O
Reactant: O=Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: [Ti+4]
Agent: [Ti]
Agent: CC[O-]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)[S@@](=O)/N=C/c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reaction time: 0.5 h
Yield: 83.9 %

Procedure:
A round bottom flask equipped with a condenser was charged with 4′-(trifluoromethyl)biphenyl-4-carbaldehyde (20.0 g, 79.9 mmol), (R)-(+)-2-methylpropane-2-sulfinamide (9.69 g, 79.9 mmol) and dichloromethane (400 mL). Titanium(IV) ethoxide (33.2 mL, 160 mmol) was then added, and the mixture was heated to reflux for 3 hours. Methanol (50 mL) and saturated sodium bicarbonate (10 mL) were then added to the reaction, causing the titanium salts to precipitate. This mixture was stirred for 30 minutes and then filtered, rinsing with ethyl acetate. Sodium sulfate was added to the filtrate to remove the water and then filtered a second time. The solvent was removed under reduced pressure to afford (R,E)-2-methyl-N-((4′-(trifluoromethyl)biphenyl-4-yl)methylene)propane-2-sulfinamide (23.7 g, 84%) as a white solid. 1H NMR (400 MHz, CDCl3, δ): 1.30 (s, 9H) 7.70-7.74 (m, 2H) 7.74 (s, 4H) 7.95-7.99 (m, 2H) 8.66 (s, 1H). MS (M+1): 354.1.
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[N:20][C:19]([CH3:22])=[CH:18][N:17]=2)=[O:14])=[CH:6][C:5]=1[C:23]([F:26])([F:25])[F:24].CO.O.[OH-].[Li+]>O>[CH3:11][O:10][C:8]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[N:20][C:19]([CH3:22])=[CH:18][N:17]=2)=[O:14])=[CH:6][C:5]([C:23]([F:26])([F:24])[F:25])=[C:4]([CH:9]=1)[C:3]([OH:27])=[O:2]
Reactant: COC(=O)c1cc(OC)c(NC(=O)Nc2cnc(C)cn2)cc1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(C(=O)O)c(C(F)(F)F)cc1NC(=O)Nc1cnc(C)cn1
Temperature: 85 °C
Reaction time: 8 h
Yield: 64.9 %

Procedure:
To a stirred suspension of 5-methoxy-4-[3-(5-methyl-pyrazin-2-yl)-ureido]-2-trifluoromethyl-benzoic acid methyl ester (257 mg, 0.67 mmol) in 6.7 mL 3:1 MeOH:H2O at room temperature under nitrogen was added lithium hydroxide monohydrate (281 mg, 6.7 mmol) and the mixture was heated to 85° C. After stirring overnight the reaction was cooled to room temperature, MeOH was removed by rotovap and the residual suspension was neutralized with concentrated HCl to pH of approximately 5. The suspension was filtered and rinsed with H2O and the filter cake dried under high vacuum to give the acid as a white solid (161 mg, 61%). 1H-NMR (400 MHz, d6-DMSO) δ8.90 (br s, 1H), 8.63 (s, 1H), 8.22 (s, 1H), 7.38 (s, 1H), 4.00 (s, 3H), 2.42 (s, 3H). LRMS (esi, negative) m/e 369.0 (M−1).
Reaction SMILES: [Na].[NH2:2][N:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1=O.[C:14]1([C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O)CO>C(O)C>[C:20]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:21]=[CH:22][C:23]([C:24]2[N:25]=[C:4]3[C:5]4[C:10]([CH:11]=[CH:12][N:3]3[N:2]=2)=[CH:9][CH:8]=[CH:7][CH:6]=4)=[CH:26][CH:27]=1
Reactant: N#Cc1ccc(-c2ccccc2)cc1
Reactant: Nn1ccc2ccccc2c1=O
Agent: [Na]
Solvent: CCO
Solvent: OCCO
Product: c1ccc(-c2ccc(-c3nc4c5ccccc5ccn4n3)cc2)cc1
Temperature: 25 °C

Procedure:
A solution prepared from 0.075 g. of sodium dissolved in 20 ml of absolute ethanol was added to a suspension of 0.640 g. (0.004 mole) of 2-amino-isoquinoline-1(2H)-one and 0.720 g. (0.004 mole) of 4-phenyl-benzonitrile in 20 ml of absolute ethanol. The resulting mixture was refluxed for 30 minutes on an oil bath, then 15 ml. of ethylene glycol were added and the ethanol was distilled off by adjusting the temperature of the oil bath at about 150° C. After three hours the reaction mixture was cooled to room temperature whereby the title compound crystallized out. It was recovered by filtration and re-crystallized from a mixture of methylene chloride/diethyl ether=1/1. Yield 650 mg. M.p. 203°-5° C.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([OH:12])=[C:7]([CH3:13])[C:6]=1[CH3:14])(=[O:3])[CH3:2].Cl[CH2:16][CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][CH2:16][CH:17]=[CH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:7]([CH3:13])[C:6]=1[CH3:14])(=[O:3])[CH3:2]
Reactant: ClCC=Cc1ccccc1
Reactant: CC(=O)Oc1c(C)cc(O)c(C)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Oc1c(C)cc(OCC=Cc2ccccc2)c(C)c1C
Temperature: 60 °C
Reaction time: 2 h
Yield: 81.3 %

Procedure:
To a solution of 4-hydroxy-2,3,6-trimethylphenyl acetate (10.0 g, 51.5 mmol) in N,N-dimethylformamide (100 mL) was added 1-chloro-3-phenyl-2-propene (7.86 g, 51.5 mmol) and potassium carbonate (7.10 g, 51.5 mmol) and the mixture was stirred under an argon atmosphere at 60° C. for 2 hours. This reaction mixture was poured into water and extracted twice with ethyl acetate. The combined extract was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from methanol to obtain the title compound (13.0 g, yield 81%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=O)[N:2]=1.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.[CH3:47][O:48][C:49]([C:51]1[C:59]2[N:58]=[C:57]([NH2:60])[N:56]([CH2:61][C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)[C:55]=2[CH:54]=[CH:53][CH:52]=1)=[O:50]>CN(C=O)C>[CH3:47][O:48][C:49]([C:51]1[C:59]2[N:58]=[C:57]([NH:60][C:11]([C:3]3[N:2]=[CH:1][C:10]4[C:5]([CH:4]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)=[O:13])[N:56]([CH2:61][C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)[C:55]=2[CH:54]=[CH:53][CH:52]=1)=[O:50]
Reactant: COC(=O)c1cccc2c1nc(N)n2Cc1ccccc1
Reactant: O=C(O)c1cc2ccccc2cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1nc(NC(=O)c1cc3ccccc3cn1)n2Cc1ccccc1
Reaction time: 0.08 h
Yield: 57.3 %

Procedure:
To a solution of 0.031 g (0.18 mmol) of isoquinoline-3-carboxylic acid in DMF (1 mL) was added 0.085 g (0.22 mmol) of HBTU and 0.1 mL of DIEA. The mixture was stirred for 5 min, then added 0.04 g (0.18 mmol) of 2-amino-1-benzyl-1H-benzoimidazole-4-carboxylic acid methyl ester in one portion. The reaction mixture was stirred for 1 h. After usual workup, 45 mg (73%) of 1-benzyl-2-[(isoquinoline-3-carbonyl)-amino]-1H-benzoimidazole-4-carboxylic acid methyl ester was isolated after purification by column chromatography eluting with DCM/methanol (v/v from 15:1 to 10:1). LCMS: 437 (M+1)+; 1H NMR (DMSO-d6, 400 MHz): δ 12.8 (s, 1H), 9.41 (s, 1H), 8.92(s, 1H), 8.20 (d, 1H), 8.14 (d, 1H), 7.84 (t, 1H), 7.77 (m, 3H), 7.51 (d, 2H), 7.32 (m, 4H), 5.63 (s, 2H), 3.99 (s, 3H) ppm.
Reaction SMILES: [F:1][C@@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.[Si]([O:33][CH2:34][CH2:35][O:36][C:37]1[CH:42]=[C:41]([F:43])[C:40]([C:44]2[N:49]=[C:48]([C:50](O)=[O:51])[CH:47]=[CH:46][C:45]=2[F:53])=[C:39]([F:54])[CH:38]=1)(C(C)(C)C)(C)C>>[NH2:9][C@H:8]1[C@@H:2]([F:1])[CH2:3][O:4][C@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[NH:23][C:50](=[O:51])[C:48]2[CH:47]=[CH:46][C:45]([F:53])=[C:44]([C:40]3[C:41]([F:43])=[CH:42][C:37]([O:36][CH2:35][CH2:34][OH:33])=[CH:38][C:39]=3[F:54])[N:49]=2)[CH2:6][CH2:7]1
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1
Reactant: CC(C)(C)[Si](C)(C)OCCOc1cc(F)c(-c2nc(C(=O)O)ccc2F)c(F)c1
Product: Cn1ncc(NC(=O)c2ccc(F)c(-c3c(F)cc(OCCO)cc3F)n2)c1[C@@H]1CC[C@@H](N)[C@@H](F)CO1
Yield: 62 %

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3R,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 24), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 6-(4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2,6-difluorophenyl)-5-fluoropicolinic acid (see US2012/225062) gave 190 as a white solid (29 mg, 62%). 1H NMR (400 MHz, d6-DMSO) δ 10.59 (s, 1H), 8.40 (dd, J=8.6, 3.9 Hz, 1H), 8.27 (dd, J=8.6, 8.6 Hz, 1H), 8.10 (s, 1H), 7.15 (d, J=10.5 Hz, 2H), 5.09 (dd, J=8.4, 3.6 Hz, 1H), 4.86-4.83 (d, J=48 Hz, 1H), 4.28 (t, J=4.8 Hz, 2H), 4.12-3.92 (m, 2H), 3.92-3.86 (m, 5H), 3.70-3.38 (br s, 1H), 3.36-3.24 (m, 1H), 2.33-2.25 (m, 1H), 2.02-1.87 (m, 1H), 1.87-1.75 (m, 1H), 1.75-1.63 (m, 1H). Alkyl NH2 not observed. LCMS (ES+) m/z 524 (M+1).