Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[O:5][CH2:6][C:7]1([O:23][CH2:22][CH2:21][O:20]1)[CH2:8][CH2:9][C@@H:10]1[C@@H:17]2[C@@H:13]([O:14][C:15](=[O:18])[CH2:16]2)[CH2:12][C@H:11]1[OH:19].N1C=CN=C1.[Si:32](Cl)([C:45]([CH3:48])([CH3:47])[CH3:46])([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[Cl-].[NH4+]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[O:19]([C@@H:11]1[CH2:12][C@@H:13]2[O:14][C:15](=[O:18])[CH2:16][C@@H:17]2[C@H:10]1[CH2:9][CH2:8][C:7]1([O:23][CH2:22][CH2:21][O:20]1)[CH2:6][O:5][C:4]1[CH:24]=[CH:25][CH:26]=[C:2]([Cl:1])[CH:3]=1)[Si:32]([C:45]([CH3:48])([CH3:47])[CH3:46])([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=C1C[C@@H]2[C@@H](CCC3(COc4cccc(Cl)c4)OCCO3)[C@H](O)C[C@@H]2O1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CC(C)(C)[Si](O[C@@H]1C[C@@H]2OC(=O)C[C@@H]2[C@H]1CCC1(COc2cccc(Cl)c2)OCCO1)(c1ccccc1)c1ccccc1
Reaction time: 4.5 h
Yield: 81 %

Procedure:
To a solution of 10 (700 mg, 1.89 mmol), DMAP (58 mg, 0.48 mmol), and imidazole (192 mg, 2.82 mmol) in methylene chloride (11 mL) was added t-butyldiphenylsilyl chloride (670 mg, 2.45 mmol). After 4.5 h, saturated ammonium chloride (15 mL) was added, the phases were separated, the aqueous layer was extracted with methylene chloride (2×15 mL), the combined organic layers were dried (magnesium sulfate), filtered, concentrated, and chromatographed on a 22 cm tall×26 mm diameter silica gel column eluting with 40% ethyl acetate in hexane to afford 11 (951 mg, 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[CH:6]3[C:20](=[O:21])[NH:19][CH:18]=[N:17][CH:7]3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1>O1CCCC1.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[C:20](=[O:21])[NH:19][CH:18]=[N:17][C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:4]=2[CH:3]=1
Reactant: O=C1NC=NC2CN=C(c3ccccc3)c3cc(Cl)ccc3C12
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: O=c1[nH]cnc2c1-c1ccc(Cl)cc1C(c1ccccc1)=NC2

Procedure:
A mixture of 2.2 g (6.8 mmol) of 9-chloro-4a,11b-dihydro-7-phenyl-5H-pyrimido[4,5-d][2]benzazepin-1(2H)-one and 10 g (110 mmol) of activated manganese dioxide in 100 mL of tetrahydrofuran was refluxed for 18 hr. The mixture was cooled, the manganese dioxide was removed by filtration over celite and the filtrate was concentrated at reduced pressure. Purification of the residue by column chromatography (silica gel 10 g; eluents, 20% ether in methylene chloride followed by 50% ethyl acetate in methylene chloride) gave pale yellow prisms, mp 226°-229°.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@H:16]2[C@H:12]([N:13](S(C3C=CC=CC=3[N+]([O-])=O)(=O)=O)[C:14](=[O:17])[O:15]2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].C(N[C@H](C(O)=O)CS)(=O)C>CN(C=O)C>[Si:1]([O:8][C@H:9]1[C@H:16]2[C@H:12]([NH:13][C:14](=[O:17])[O:15]2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@@H]2[C@H]1OC(=O)N2S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: CC(=O)N[C@@H](CS)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@H]2NC(=O)O[C@H]21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of (3aR*,6R*,6aR*)-6-((tert-butyldimethylsilyl)oxy)-3-((2-nitrophenyl)sulfonyl)-hexahydro-2H-cyclopenta[d]oxazol-2-one (1.47 g, 3.32 mmol) and Cs2CO3 (2.164 g, 6.64 mmol) in DMF (25 mL) was added N-acetyl-L-cysteine (0.921 g, 5.65 mmol) and the reaction mixture was stirred for 16 h at RT. The reaction mixture was evaporated and the residue suspended in saturated NaHCO3 solution and extracted with EtOAc. Combined extracts were washed with brine, dried over MgSO4, filtered and concentrated. The title compound was obtained after purification by flash chromatography (heptane/EtOAc 90:10→50:50) as a yellow oil (0.84 g, 98%): TLC (heptane/EtOAc 1:1) Rf=0.28.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[C:7]3[CH2:8][C:9]([CH3:17])([CH3:16])[C:10](=[O:15])[C:11]4[NH:12][C:13]([CH:14]=1)=[C:5]2[C:6]=43.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[C:7]3[CH2:8][C:9]([CH3:17])([CH3:16])[CH:10]([OH:15])[C:11]4[NH:12][C:13]([CH:14]=1)=[C:5]2[C:6]=43
Reactant: CC1(C)CC2=NNC(=O)c3cc(F)cc4[nH]c(c2c34)C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC1(C)CC2=NNC(=O)c3cc(F)cc4[nH]c(c2c34)C1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 9.7 %

Procedure:
To a solution of 8-fluoro-2,2-dimethyl-2,3-dihydro-[1,2]diazepino[3,4,5,6-def]carbazole-1,6(5H, 10H)-dione (50 mg, 0.18 mmol) in 10 mL of MeOH, was added NaBH4 (0.18 mmol) at 0° C. The mixture was stirred for additional 30 min. The solution was poured into ice water, and extracted with EtOAc (5mL×3). The organic layers were combined, washed with H2O (5mL×3) and brine (5mL×3), dried over Na2SO4, and filtered. The filtrate was concentrated, and the residue was chromatographed to give the crude product which was then purified on Pre-HPLC to give the product (5 mg) as a yellow solid. 1H NMR (DMSO-d6) δ 11.9 (s, 1H), 10.1 (s, 1H), 7.23 (dd, 1H, J=9.2, 2.0 Hz), 7.17 (dd, 1H, J=10.8, 2.4 Hz), 5.68 (d, 1H, J=6.0 Hz), 5.49 (d, 1H, J=6.0 Hz), 2.31 (s, 2H), 1.00 (s, 3H), and 0.88 (s, 3H). MS (ESI) m/e [M+1]+ 288.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:22])[C:5]2[C:10]([CH2:11][CH2:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=3)=[CH:9][NH:8][C:6]=2[N:7]=1.[OH-].[Na+:24].Cl>O>[Na+:24].[NH2:1][C:2]1[NH:3][C:4](=[O:22])[C:5]2[C:10]([CH2:11][CH2:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([O-:19])=[O:18])=[CH:15][CH:14]=3)=[CH:9][NH:8][C:6]=2[N:7]=1
Reactant: Nc1nc2[nH]cc(CCc3ccc(C(=O)O)cc3)c2c(=O)[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1nc2[nH]cc(CCc3ccc(C(=O)[O-])cc3)c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A flask was charged with 4-[2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidine-5-yl)ethyl] benzoic acid (5.0 g; 93.85% purity HPLC) and water (30 ml), the pH was corrected to about 13 with a 2M sodium hydroxide solution in water, and complete dissolution was observed. The pH was then corrected to about 9 with a 1M hydrochloric acid solution in water, and abundant solid formation was observed. The resulting suspension was stirred at about 25° C. for 1 hour, the solid was collected by filtration and dried in an oven under vacuum to afford 4-[2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidine-5-yl)ethyl] benzoic acid sodium salt as a white solid in 99.6% purity (HPLC).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C(C)=CC=CC=1>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: COc1cccc(-c2ccccc2)c1
Temperature: 130 °C

Procedure:
190 mg 3-bromoanisole, 183 mg phenyl boronic acid and 275 mg potassium carbonate are mixed in 2 ml xylene. To this is added 27 mg of the catalyst from example 5a (corresponds to 0.5 mol % palladium). The reaction mixture is stirred and heated, under an atmosphere of nitrogen, to a temperature of 130° C. for a period of 2 hours. A GC analysis showed that all starting material is consumed and 3-methoxy biphenyl is formed selectively (100% conversion).
Reaction SMILES: C[S-].[Na+].C[S:5][C:6]1[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>CN(C)P(N(C)C)(N(C)C)=O>[C:9]1([NH:8][C:7]2[CH:15]=[CH:16][CH:17]=[CH:18][C:6]=2[SH:5])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CSc1ccccc1Nc1ccccc1
Agent: C[S-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Sc1ccccc1Nc1ccccc1
Temperature: 140 °C

Procedure:
A 250 mL round bottom flask was charged with sodium methanethiolate (5.18 g, 73.8 mmol), 2-(methylthio)-N-phenylaniline (13.25 g, 61.5 mmol) and hexamethyiphosphoramide (HMPA) (100 mL). The reaction mixture was heated up to 140° C. for 7 hours. The reaction was cooled to room temperature and 100 mL of 1N HCl was added. The reaction mixture was extracted with 3×100 mL ethyl acetate, the organic portion was washed with 3×50 mL brine, dried over sodium sulfate and evaporated to yield the desired compound. (12 g, 97%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](CC(O)=O)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].Cl.[CH3:22][CH2:23][O:24]CC>>[CH3:10][O:9][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[CH2:22][CH2:23][OH:24]
Reactant: CCOCC
Reactant: COc1cc(CC(=O)O)cc(OC)c1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Product: COc1cccc(OC)c1CCO
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of (3,5-dimethoxy)phenylacetic acid (3 g) in Et2O (100 mL) was cooled to 0° C. and LiAlH4 (1M in Et2O, 16.8 mL) was added. The mixture was warmed to room temperature and stirred for 5 h, whereupon the pH was adjusted to 5 using HCl (1 M). The mixture was washed with H2O/EtOAc and the organic layer was separated. The aqueous layer was extracted with EtOAc. The combined organic layers were dried (MgSO4) and concentrated in vacuo to give 3,5-dimethoxy-4-(2-hydroxyethyl)benzene (2.8 g) as a crude product.
Reaction SMILES: [CH2:1]([C:3]([OH:36])([CH2:34][CH3:35])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH2:31][CH3:32])([C:15]2[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[C:17]([CH3:30])[CH:16]=2)[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:33])[CH3:2].[CH3:37][O:38][C:39](=[O:48])[CH2:40][C:41]1[CH:42]=[N:43][CH:44]=[C:45](Br)[CH:46]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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.O>[CH3:37][O:38][C:39](=[O:48])[CH2:40][C:41]1[CH:42]=[N:43][CH:44]=[C:45]([C:18]2[CH:19]=[CH:20][C:15]([C:12]([CH2:13][CH3:14])([C:9]3[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([CH2:34][CH3:35])([OH:36])[CH2:1][CH3:2])=[C:7]([CH3:33])[CH:8]=3)[CH2:31][CH3:32])=[CH:16][C:17]=2[CH3:30])[CH:46]=1
Reactant: CCC(O)(CC)CCc1ccc(C(CC)(CC)c2ccc(B3OC(C)(C)C(C)(C)O3)c(C)c2)cc1C
Reactant: COC(=O)Cc1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCC(O)(CC)CCc1ccc(C(CC)(CC)c2ccc(-c3cncc(CC(=O)OC)c3)c(C)c2)cc1C
Temperature: 89.5 °C
Reaction time: 3 h
Yield: 92.1 %

Procedure:
Degassed N,N-dimethylformamide (0.37 mL) was added to 3-ethyl-1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-pentan-3-ol (Example 29; 30.6 mg, 0.0621 mmol), (5-bromo-pyridin-3-yl)acetic acid methyl ester (Example 24-(2); 21.1 mg, 0.0917 mmol), tetrakis(triphenylphosphine)palladium (0) (9.0 mg, 0.0078 mmol) and potassium phosphate (29.4 mg, 0.138 mmol). After replacement with nitrogen, the mixture was heated while stirring at an external temperature of 85 to 94° C. for three hours. Water was added to the reaction mixture, followed by extraction with diethyl ether. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=1/1) to give the title compound (29.5 mg, 92%).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[CH:5][C:6]([S:9](Cl)(=[O:11])=[O:10])=[N:7][CH:8]=1.[OH-].[NH4+:14]>>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([NH2:14])(=[O:11])=[O:10])=[N:7][CH:8]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cn1
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Product: NS(=O)(=O)c1ccc(Br)cn1
Temperature: 70 °C

Procedure:
To a 4 mL vial equipped with a magnetic stir bar were added 5-bromopyridine-2-sulfonyl chloride hydrochloride (250 mg, 0.853 mmol) and ammonium hydroxide (1329 μL, 34.1 mmol) to give a white suspension, which was heated to 70° C. in a sand bath overnight. The solvent was subsequently evaporated to give the title compound, which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24]CC4C=CC=CC=4)=[C:20]([F:32])[CH:19]=3)[CH:15]=[CH:14][N:13]=2)=[CH:6][CH:5]=1>CCOC(C)=O.[Pd]>[F:32][C:20]1[CH:19]=[C:18]([C:16]2[CH:15]=[CH:14][N:13]=[C:12]([NH:11][CH2:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([O:2][CH3:1])=[O:33])=[CH:5][CH:6]=3)[N:17]=2)[CH:23]=[CH:22][C:21]=1[OH:24]
Reactant: COC(=O)c1ccc(CNc2nccc(-c3ccc(OCc4ccccc4)c(F)c3)n2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CNc2nccc(-c3ccc(O)c(F)c3)n2)cc1
Reaction time: 120 h
Yield: 59.3 %

Procedure:
To a degassed solution of 38 (950 mg, 2.14 mmol) in EtOAc (100 mL) at room temperature under N2 was added 10% Pd/C (220 mg, 0.21 mmol). The mixture was hydrogenated for 5 days (1 atm, balloon), filtered through a celite pad, rinsed with MeOH and EtOAc and the filtrate was concentrated to afford the title compound 39 (450 mg, 1.27 mmol, 59% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[F:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)=[CH:4][CH:3]=1.Br.[OH:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[CH2:29][NH:30][CH2:31]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[OH:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[CH2:29][N:30]([C:15]1[C:16]([F:18])=[C:17]3[C:12]([C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9][N:8]3[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:13][C:14]=1[F:20])[CH2:31]2
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(F)c(F)cc2c1=O
Reactant: Oc1cccc2c1CNC2
Agent: Br
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(N3Cc4cccc(O)c4C3)c(F)cc2c1=O
Yield: 23.5 %

Procedure:
178 mg of 1-(4-fluorophenyl)-6,7,8-trifluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid, 130 mg of 4-hydroxyisoindoline hydrobromide, 137 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 56 mg of the target compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:29][CH3:30])=[C:16]([CH2:19][N:20]([CH3:28])[C:21]4([C:25]([NH2:27])=[O:26])[CH2:24][NH:23][CH2:22]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.C=O.[C:34](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.ClCCCl>[Cl:1][C:2]1[C:3]([F:31])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:29][CH3:30])=[C:16]([CH2:19][N:20]([CH3:28])[C:21]4([C:25]([NH2:27])=[O:26])[CH2:24][N:23]([CH3:34])[CH2:22]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(N)=O)CNC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(N)=O)CN(C)C1
Yield: 53 %

Procedure:
The hydrochloride salt of 3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]azetidine-3-carboxamide Example 74 (100 mg, 0.19 mmol) and formaldehyde (51 μl of a 37% wt aqueous solution, 0.63 mmol) were stirred at room temperature in 5% acetic acid in 1,2-dichloroethane (2 ml) in the presence of 3 A molecular sieves. Sodium triacetoxyborohydride (89 mg, 0.42 mmol) was added portionwise over 0.5 hours. After the final addition the reaction mixture was concentrated under reduced pressure. The resulting product was purified on preparative HPLC (standard basic conditions) to give the title product (50 mg, 53%) as a white powder; 1H NMR Spectrum: (CDCl3) 2.41 (s, 3H), 2.45 (s, 3H), 3.35 (brs, 2H), 3.65 (d, 2H), 3.96-4.01 (m, 5H), 5.33 (brs, 1H), 7.15 (m, 2H), 7.25 (s, 1H), 7.47 (brs, 1H), 7.77 (brs, 1H), 7.98 (s, 1H), 8.55 (brs, 1H), 8.74 (s, 1H); Mass Spectrum: (M+H)+ 459.
Reaction SMILES: [CH:1]1([C:5]2[N:9]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[C:23]#[N:24])=[CH:13][CH:12]=3)[C:8]3[CH:25]=[C:26]([C:30]4[N:34]([CH3:35])[C:33]5[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=5[N:31]=4)[CH:27]=[C:28]([CH3:29])[C:7]=3[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[N-:40]=[N+:41]=[N-:42].[Na+]>CN(C)C=O>[CH:1]1([C:5]2[N:9]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[C:23]4[NH:42][N:41]=[N:40][N:24]=4)=[CH:13][CH:12]=3)[C:8]3[CH:25]=[C:26]([C:30]4[N:34]([CH3:35])[C:33]5[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=5[N:31]=4)[CH:27]=[C:28]([CH3:29])[C:7]=3[N:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(-c2nc3ccccc3n2C)cc2c1nc(C1CCC1)n2Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2nc3ccccc3n2C)cc2c1nc(C1CCC1)n2Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 10 from 4'-[(2-cyclobutyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.Cl[C:9]1[C:13]2[CH:14]=[C:15]([CH:27]=[O:28])[C:16]([N:19]3[CH2:24][C@@H:23]([CH3:25])[O:22][C@H:21]([CH3:26])[CH2:20]3)=[C:17]([F:18])[C:12]=2[O:11][N:10]=1>CN(C=O)C.C(Cl)Cl>[CH3:26][C@@H:21]1[CH2:20][N:19]([C:16]2[C:15]([CH:27]=[O:28])=[CH:14][C:13]3[C:9]([N:3]4[CH:7]=[N:6][CH:5]=[N:4]4)=[N:10][O:11][C:12]=3[C:17]=2[F:18])[CH2:24][C@@H:23]([CH3:25])[O:22]1
Reactant: C[C@@H]1CN(c2c(C=O)cc3c(Cl)noc3c2F)C[C@@H](C)O1
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@@H]1CN(c2c(C=O)cc3c(-n4cncn4)noc3c2F)C[C@@H](C)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydride (60% dispersion) (0.288 g, 7.19 mmol) was added to a solution of 1H-1,2,4-triazole (0.530 g, 7.67 mmol) and 3-chloro-6-((2R,6R)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-5-carbaldehyde (Intermediate 535, 1.5 g, 4.80 mmol) in DMF (10 ml), and the mixture was stirred at room temperature overnight. The mixture was quenched with aqueous NH4Cl and diluted with water before being extracted with CH2Cl2 5 times. The combined extracts were dried (MgSO4) and concentrated to give a solid that was taken up in CH2Cl2. Insoluble solids were filtered off and rinsed with additional CH2Cl2. The solids were dried in vacuo and were consistent with desired product. The filtrate was concentrated and chromatographed on silica gel (100% CH2Cl2 followed by gradient elution to 50% EtOAc in CH2Cl2) to give additional desired product. Total of 866 mg.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH:10]2[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1.[H][H].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[F:3][C:4]1[CH:5]=[C:6]([CH:10]2[CH2:11][CH2:12][CH:13]([OH:16])[CH2:14][CH2:15]2)[CH:7]=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: O=C1CCC(c2cccc(F)c2)CC1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OC1CCC(c2cccc(F)c2)CC1
Temperature: 0 °C
Yield: 85.8 %

Procedure:
Sodium borohydride (9.8 g) and THF (100 ml) were put in a reaction vessel under a nitrogen atmosphere, and cooled to 0° C. The compound (19) (47.2 g) dissolved in THF (100 ml) was added dropwise thereto, with caution in the evolution of hydrogen gas, and the mixture was stirred for 3 hours. A saturated aqueous solution of ammonium chloride (400 ml) and ethyl acetate (400 ml) were added and mixed thereto. The mixture was then allowed to stand until it had separated into organic and aqueous phases, and an extractive operation to an organic phase was carried out. The organic phase was fractionated, and washed with brine, and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was purified with a fractional operation by means of column chromatography using a mixed solvent of toluene and ethyl acetate (toluene: ethyl acetate=10:1 by volume) as an eluent and silica gel as a stationary phase powder, and dried, giving 40.9 g of 4-(3-fluorophenyl)cyclohexanol (20). The yield based on the compound (19) was 85.7%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:18].[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][C:27](=[NH:31])OCC>C(O)C>[ClH:18].[F:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([F:16])[C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:27](=[NH:31])[CH2:26][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH3:19])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ncccc1OCc1c(F)cccc1F
Reactant: CCOC(=N)Cc1ccccc1C
Agent: Cl
Solvent: CCO
Product: Cc1ccccc1CC(=N)Nc1ncccc1OCc1c(F)cccc1F
Yield: 2.2 %

Procedure:
A mixture of 2-amino-3-(2,6-difluorobenzyloxy)pyridine (4.72 g, 20 mmol) and ethyl 2methylphenylacetimidate hydrochloride (4.69 g, 22 mmol) in ethanol (80 ml) was heated under reflux for 2 hours. Evaporation of the solvent gave art oil which was purified by flash chromatography (chloroform/methanol) to obtain the product (0.18 g), m.p. 127°-135° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7].[CH3:11][CH:12]([CH3:19])[C:13](=O)[C:14](=[N:16][OH:17])[CH3:15].Cl.C(=O)([O-])O.[Na+]>C(O)(=O)C.COCCOC.COC(C)(C)C.O>[CH:12]([C:13]1[O:7][C:6]([C:5]2[CH:8]=[CH:9][CH:10]=[C:3]([O:2][CH3:1])[CH:4]=2)=[N+:16]([O-:17])[C:14]=1[CH3:15])([CH3:19])[CH3:11]
Reactant: CC(=NO)C(=O)C(C)C
Reactant: COc1cccc(C=O)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: COC(C)(C)C
Solvent: O
Product: COc1cccc(-c2oc(C(C)C)c(C)[n+]2[O-])c1
Temperature: 52.5 °C
Reaction time: 60 h

Procedure:
19.0 g (137 mmol) of 3-methoxybenzaldehyde were added to a solution of 18.0 g (137 mmol) of 4-methylpentane-2,3-dione 2-oxime in 30 g (99 mmol) of solution of hydrogen chloride in acetic acid (12%) and 30 g (164 mmol) of solution of hydrogen chloride in ethylene glycol dimethyl ether (20%). The reaction was stirred at 50-55° C. for 3 hours and at room temperature for 60 hours. Subsequently, 500 ml of water and 300 ml of tert-butyl methyl ether were added before a pH of 3-4 was established by adding sodium hydrogen carbonate. After phase separation, the aqueous phase was extracted twice with 100 ml each time of tert-butyl methyl ether. The combined organic phases were washed with 4×100 ml of water and concentrated fully under reduced pressure.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH2:16][O:17][CH3:18])[C:6]=2[CH:19]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C@@H:28]2[C@@H:33]3[CH2:34][C@@H:30]([CH:31]=[CH:32]3)[C@@H:29]2[C:35]([NH2:37])=[O:36])[C:24]([Cl:38])=[CH:23][N:22]=1>>[Cl:38][C:24]1[C:25]([NH:27][C@@H:28]2[C@@H:33]3[CH2:34][C@@H:30]([CH:31]=[CH:32]3)[C@@H:29]2[C:35]([NH2:37])=[O:36])=[N:26][C:21]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH2:16][O:17][CH3:18])[C:6]=3[CH:19]=2)=[N:22][CH:23]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Reactant: COCCN1C(=O)CCC(C)(C)c2ccc(N)cc21
Product: COCCN1C(=O)CCC(C)(C)c2ccc(Nc3ncc(Cl)c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)n3)cc21

Procedure:
The title compound was prepared with a procedure analogous to that used to prepare example 381 by combining 8-Amino-1-(2-methoxy-ethyl)-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide to yield an off-white solid (44%). LCMS: m/z=525.22 (M+H+), 1H NMR (400 MHz, CDCl3) δ 7.89 (d, 1H, J=5.8 Hz), 7.63 (m, 2H), 7.45 (d, 1H, J=4.3 Hz), 7.27 (m, 1H), 7.03 (m, 1H), 6.03 (m, 2H), 5.97 (m, 2H), 4.36 (m, 1H), 3.74 (m, 4H), 3.38 (d, 3H, J=5.6 Hz), 3.06 (bs, 1H), 2.89 (bs, 1H), 2.51 (m, 1H), 2.30 (m, 3H), 2.03 (m, 2H), 1.62 (m, 1H), 1.33 (bs, 6H).