Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]1.[F:32][C:33]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[C:35]([F:48])[C:34]=1[OH:49]>>[F:32][C:33]1[CH:38]=[C:37]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[C:5]3[NH:17][C@H:18]2[CH2:19][CH2:20][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:28])[CH3:29])[CH2:22][CH2:23]2)[CH:36]=[C:35]([F:48])[C:34]=1[OH:49]
Reactant: CC(C)C(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Reactant: CC1(C)OB(c2cc(F)c(O)c(F)c2)OC1(C)C
Product: CC(C)C(=O)c1cnc2ccc(-c3cc(F)c(O)c(F)c3)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1

Procedure:
Following general procedure D, tert-butyl trans-4-(6-bromo-3-isobutyrylquinolin-4-ylamino)cyclohexylcarbamate (49 mg, 0.100 mmol) was reacted with 2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (58 mg, 0.227 mmol) to afford the crude product (64 mg) as an off-white solid: ESI MS m/z 540 [C30H35F2N3O4+H]+.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([C:9]1[CH:18]=[CH:17][C:12]2[NH:13][CH2:14][CH2:15][S:16][C:11]=2[CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[C:21]([CH2:25][C:26](OCC)=[O:27])(=[O:24])[CH2:22][CH3:23]>>[O:27]=[C:26]([SH:16]1[C:11]2[CH:10]=[C:9]([C:3]([OH:8])([C:4]([F:7])([F:6])[F:5])[C:2]([F:1])([F:19])[F:20])[CH:18]=[CH:17][C:12]=2[NH:13][CH2:14][CH2:15]1)[CH2:25][C:21](=[O:24])[CH2:22][CH3:23]
Reactant: OC(c1ccc2c(c1)SCCN2)(C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)CC(=O)CC
Product: CCC(=O)CC(=O)[SH]1CCNc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc21

Procedure:
A stirred mixture of 3,4-dihydro-7-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-2H-1,4-benzothiazine and ethyl propionylacetate can be heated in an oil bath to give 3,4-dihydro-1-(1,3-dioxopentyl)-7-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-2H-1,4-benzothiazine.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=1[O:18][CH2:19][CH:20]1[CH2:22][O:21]1)#[N:5]>O1CCCC1>[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=1[O:18][CH2:19][CH:20]([OH:21])[CH2:22][N:2]([CH3:3])[CH3:1])#[N:5]
Reactant: CNC
Reactant: N#Cc1ccccc1CCCCc1ccccc1OCC1CO1
Solvent: C1CCOC1
Product: CN(C)CC(O)COc1ccccc1CCCCc1ccccc1C#N
Yield: 73 %

Procedure:
2 ml of 50% by volume aqueous dimethylamine were added to a solution of 319 mg of 2-{2-[4-(2-cyanophenyl)butyl]phenoxymethyl}oxirane [prepared as described in step (a) above] in 10 ml of tetrahydrofuran, and the resulting mixture was reacted and worked-up in a similar manner to that described in Example 1(b). The resulting crude product was then purified by column chromatography through silica gel, using a 10:1 by volume mixture of methylene chloride and methanol as the eluent, to give 267 mg (yield 73%) of the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[CH:13][C:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.C1(P([N:47]=[N+:48]=[N-:49])(C2C=CC=CC=2)=O)C=CC=CC=1>C(O)(C)C>[F:1][C:2]([F:25])([F:24])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[CH:13][C:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:47]=[N+:48]=[N-:49])=[O:20])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1
Reactant: O=C(O)c1ccc(-c2ccn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: [N-]=[N+]=NC(=O)c1ccc(-c2ccn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.2 %

Procedure:
To 4-(1-(4-(trifluoromethoxy)phenyl)-1H-pyrazol-3-yl)benzoic acid (0.58 g, 1.67 mmol) in isopropanol (10.7 mL) was added triethylamine (0.30 mL, 2.17 mmol) and diphenylphosphoryl azide (0.47 mL, 2.17 mmol) and the reaction was stirred at room temperature for 16 hours. The orange precipitate that had formed was filtered through a fritted glass funnel, rinsed with isopropanol, and dried in a vacuum oven to provide 4-(1-(4-(trifluoromethoxy)phenyl)-1H-pyrazol-3-yl)benzoyl azide as an orange solid (188 mg, 30%): 1H NMR (400 MHz, DMSO-d6) δ 8.69 (d, J=2.6 Hz, 1H), 8.17-8.11 (m, 2H), 8.09-8.04 (m, 4H), 7.57 (d, J=8.4 Hz, 2H), 7.24 (d, J=2.6 Hz, 1H); 19F NMR (376 MHz, DMSO-d6) δ −56.97; ESIMS m/z 374 ([M+H]+).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:29])[N:10]2[CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([NH:21]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[CH:5][CH:4]=1)#[N:2].FC(F)(F)C(O)=O>ClCCl>[NH2:21][CH:18]1[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][N:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([C:1]#[N:2])[CH:12]=3)[CH:7]=[CH:8][C:9]2=[O:29])[CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3ccc(C#N)cc32)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc2ccc(=O)n(CCN3CCC(N)CC3)c2c1

Procedure:
A solution of tert-butyl {1-[2-(7-cyano-2-oxoquinolin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 15) (6.57 g, 16.57 mmol) in dichloromethane (100 mL) was treated with trifluoroacetic acid (40 mL) at 0° C. for 30 minutes. The solvent was removed under reduced pressure and the residue codistilled once with dichloromethane, then taken up in dichloromethane (200 mL) and washed with saturated sodium hydrogencarbonate solution (50 mL, pH adjusted to 10 with sodium hydroxide). The aqueous phase was back-extracted three times with dichloromethane (3×100 mL) and dried over sodium sulfate. The solvent was removed under reduced pressure to give the product as off-white solid, 5 g, mp 138° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH2:17][NH:16][CH2:15][CH2:14]3)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[O:21]1[CH2:24][C:23](=O)[CH2:22]1.[BH3-]C#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH2:17][N:16]([CH:23]2[CH2:24][O:21][CH2:22]2)[CH2:15][CH2:14]3)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: Cn1cc(Br)cc(Nc2ccc3c(c2)CCNC3)c1=O
Reactant: O=C1COC1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: Cn1cc(Br)cc(Nc2ccc3c(c2)CCN(C2COC2)C3)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.2 %

Procedure:
A mixture of 258b (1.7 g, 5 mmol), oxetan-3-one (1.8 g, 25 mmol), NaBH3CN (1 g, 15 mmol) and zinc chloride (3.4 g, 25 mmol) in methanol (50 mL) was stirred for 4 hours at room temperature. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography eluting with 25:1 dichloromethane/methanol to give 258c (1.8 g, 92%). LC/MS: m/z 391 (M+H)+
Reaction SMILES: C(O/[CH:4]=[CH:5]/[C:6]1[C:7]([C:14]([O:16]C)=O)=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)C.[NH3:18]>CO.C1(C)C=CC=CC=1>[CH3:13][S:12][C:9]1[N:10]=[CH:11][C:6]2[CH:5]=[CH:4][NH:18][C:14](=[O:16])[C:7]=2[N:8]=1
Reactant: N
Reactant: CCO/C=C/c1cnc(SC)nc1C(=O)OC
Solvent: Cc1ccccc1
Solvent: CO
Product: CSc1ncc2cc[nH]c(=O)c2n1
Temperature: 85 °C
Yield: 84 %

Procedure:
(E)-Methyl 5-(2-ethoxyvinyl)-2-(methylthio)pyrimidine-4-carboxylate (Preparation 31, 2.30 g, 9.04 mmol) was treated with ammonia in methanol 7M (45 mL) and heated to 85° C. for 18 hours in a capped vial. The solvent was removed under reduced pressure, and the resulting solid was treated with TsOH monohydrate (175 mg, 0.92 mmol), suspended in toluene (50 mL) and heated to 90° C. for 2 hours. The mixture was concentrated and the residue was purified by silica gel column chromatography eluting with 0 to 5% MeOH in DCM to give the title compound (1.47 g, 84%).
Reaction SMILES: [C:1]1([CH:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:16]([O:23][CH2:24][CH2:25]Cl)=[CH:17][CH:18]=[CH:19][C:20]=53)=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].[CH3:35][NH:36][CH3:37].C1COCC1>CN(C=O)C>[CH3:35][N:36]([CH3:37])[CH2:25][CH2:24][O:23][C:16]1[C:15]2[C:14]3[C:22]4=[C:10]([O:9][CH2:8][CH:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[N:21]4[C:20]=2[CH:19]=[CH:18][CH:17]=1)[CH:11]=[CH:12][CH:13]=3
Reactant: CNC
Reactant: ClCCOc1cccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN(C)CCOc1cccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Temperature: 25 °C
Reaction time: 48 h
Yield: 8 %

Procedure:
To a mixture of 2-chloroethyl 1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl ether (0.248 g, 0.68 mmol) in dry DMF (10 mL) is added potassium carbonate (0.376 g, 2.7 mmol), sodium iodide (0.101 g, 0.68 mmol), and 2M dimethylamine in THF (0.68 mL, 1.36 mmol). The mixture is stirred for 48 h at room temperature. The mixture is then partitioned between water and Et2O. The organic layer is washed three times with water (100 mL), dried over anhydrous sodium sulfate and concentrated. Column chromatography (50 mL silica) using CH2Cl2 followed by CH3OH/CH2Cl2 (95/5) as eluent and then drying of the appropriate fractions under house vacuum gave 0.020 g (8%) of N,N-dimethyl-2-[(1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]-1-ethanamine; mp 117-118° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH:17]=O)=[O:16])=[CH:11][C:10]=1[CH2:19][OH:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C1C=CC(CCN)=CC=1)(OC)=O.[C:34]([C:38]1[CH:43]=[CH:42][C:41]([CH2:44][C:45]([CH3:48])([CH3:47])[NH2:46])=[CH:40][CH:39]=1)([O:36][CH3:37])=[O:35]>>[C:34]([C:38]1[CH:43]=[CH:42][C:41]([CH2:44][C:45]([NH:46][CH2:17][CH:15]([OH:16])[C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:10]([CH2:19][OH:20])[CH:11]=2)([CH3:47])[CH3:48])=[CH:40][CH:39]=1)([O:36][CH3:37])=[O:35]
Reactant: COC(=O)c1ccc(CC(C)(C)N)cc1
Reactant: O=CC(=O)c1ccc(OCc2ccccc2)c(CO)c1
Agent: COC(=O)c1ccc(CCN)cc1
Product: COC(=O)c1ccc(CC(C)(C)NCC(O)c2ccc(OCc3ccccc3)c(CO)c2)cc1

Procedure:
The title compound was prepared by the process of Example 25, replacing phenyl glyoxal by 4-benzyloxy-3-hydroxymethylphenyl glyoxal and 2-(4-carbomethoxyphenyl)ethanamine by 2-(4-carbomethoxyphenyl)-1,1-dimethylethanamine. τ(d6DMSO) 9.06 (6H, s), 7.10-7.60 (5H, m), 6.20 (3H, s), 5.39 (2H, s), 5.00 (1H, m), 4.88 (2H, s), 3.04 (2H, d, J=8 Hz), 2.40-3.00 (10H, m), 2.12 (2H, d, J=8 Hz).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH2:18][N:19]1[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[N:21]=[C:20]1[NH2:28].CC1C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+]>O.C(O)(=O)C.C(O)C.CC1C=CC=CC=1>[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH2:18][N:19]1[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[N:21]=[C:20]1[NH:28][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: Nc1nc2cccnc2n1Cc1ccco1
Reactant: CCOC(=O)N1CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)N1CCC(Nc2nc3cccnc3n2Cc2ccco2)CC1
Temperature: 50 °C
Reaction time: 96 h

Procedure:
A mixture of 22.2 parts of ethyl 4-oxo-1-piperidinecarboxylate, 21.4 parts of 3-(2-furanylmethyl)-3H-imidazo[4,5-b]pyridin-2-amine, 360 parts of methylbenzene and 0.1 parts of 4-methylbenzenesulfonic acid was stirred for 4 days at reflux temperature using a water separator. After cooling to 50° C., 64 parts of ethanol were added and 3.8 parts of sodium tetrahydroborate were added portionwise to the reaction mixture. Upon completion, stirring was continued for 2 hours at 50° C. After cooling, the mixture was decomposed with 3.5 parts of acetic acid. Water was added to the mixture while stirring and the layers were separated. The aqueous layer was extracted with methylbenzene. The combined methylbenzene layers were dried, filtered and evaporated, yielded ethyl 4-[[3-(2-furanylmethyl)-3H-imidazo[4,5-b]pyridin-2-yl]amino]-1-piperidinecarboxylate as an oily residue (compound 56).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.O=[C:12]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[N:1]1([CH:16]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: c1ccc2c(c1)CCCN2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(N2CCCc3ccccc32)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.7 %

Procedure:
A solution of 1,2,3,4-tetrahydroquinoline (1.0 mL, 7.94 mmol) in 30 mL 1,2-dichloroethane was treated with tert-butyl 3-oxopyrrolidine-1-carboxylate (2.94 g, 15.87 mmol) followed by sodium triacetoxyborohydride (8.4 g, 39.68 mmol) then acetic acid (2.25 mL). The suspension was stirred at room temperature for 1 day. After this time, the mixture was cooled to 0° C., quenched with 20 mL 1N NaOH and stirred for 20 minutes. The suspension was extracted with 2×100 mL CH2Cl2. The organic layer was rinsed with brine, dried over MgSO4, filtered and concentrated to give a yellow residue which was subjected to flash chromatography on silica gel using 15% EtOAc/Hexanes to give a viscous oil (1.89 g, 78.8%). 1H-NMR (CDCl3) δ 7.07 (pseudo t, J=7.2 Hz, 1H), 6.97 (d, J=7.2 Hz, 1H), 6.69 (d, J=8.1 Hz, 1H), 6.62 (pseudo t, J=7.5 Hz, 1H), 4.44-4.40 (m, 1H), 3.63-3.20 (m, 6H), 2.75 (t, J=6.3 Hz, 2H), 2.13-2.08 (m, 2H), 1.94-1.90 (m, 2H), 1.48 (s, 9H). MS (ESI): 303.2 (M+1).
Reaction SMILES: C[N:2](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]2[CH:42]=[C:41]3[C:36]([C:37]([OH:55])=[C:38]([C:48]([NH:50][CH2:51][CH2:52][O:53][CH3:54])=[O:49])[C:39](=[O:47])[N:40]3[CH2:43][C:44]([OH:46])=O)=[N:35][CH:34]=2)=[CH:28][CH:27]=1.[OH-].[NH4+]>CN(C=O)C.O>[NH2:2][C:44](=[O:46])[CH2:43][N:40]1[C:41]2[C:36](=[N:35][CH:34]=[C:33]([CH2:32][C:29]3[CH:28]=[CH:27][C:26]([F:25])=[CH:31][CH:30]=3)[CH:42]=2)[C:37]([OH:55])=[C:38]([C:48]([NH:50][CH2:51][CH2:52][O:53][CH3:54])=[O:49])[C:39]1=[O:47]
Reactant: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)O)c1=O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(N)=O)c1=O
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A solution of HATU (1.14 g, 3 mmol) in DMF (4 mL) was added in portions to a stirred suspension of [7-[(4-fluorophenyl)methyl]-4-hydroxy-3-({[2-(methyloxy)ethyl]amino}carbonyl)-2-oxo-1,5-naphthyridine-1(2H)-yl]acetic acid (1 g, 2.3 mmol) in 29% ammonium hydroxide (0.4 mL, 2.9 mmol), TEA (0.4 mL, 2.9 mmol) and DMF (4 mL) at 60° C. The mixture was stirred 40 min at rt and additional HATU (350 mg, 0.92 mmol), 29% ammonium hydroxide (0.15 mL, 1 mmol) and DMF (3 mL) were added. Stirring was continued 20 min and the suspension was diluted with water and filtered. The filter cake was washed with water and EtOH; then dried in a vacuum oven to afford the product as a white solid: 1H NMR (d6-DMSO) δ 10.25 (1H, t, J=5 Hz), 8.52 (1H, d, J=1 Hz), 7.83 (1H, s), 7.64 (1H, br s), 7.33 (2H, dd, J=8.6, 5.7 Hz), 7.27 (1H, br s), 7.11 (2H, t, J=8.6 Hz), 4.83 (2H, s), 4.11 (2H, s), 3.50 (4H, m), 3.28 (3H, s); HRMS calcd for C21H21FN4O5+H+: 429.1574. Found: 429.1575.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C@@H:14]1[CH2:31][C:30]2[C@H:25]([CH2:26][CH2:27][C:28](=[O:32])[CH:29]=2)[C@@H:24]2[C@@H:15]1[C@H:16]1[C@@:20]([CH2:22][CH2:23]2)([CH3:21])[C:19](=[O:33])[CH2:18][CH2:17]1)(C(C)(C)C)(C)C.C(O)(=O)C>CO.O>[OH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C@@H:14]1[CH2:31][C:30]2[C@H:25]([CH2:26][CH2:27][C:28](=[O:32])[CH:29]=2)[C@@H:24]2[C@@H:15]1[C@H:16]1[C@@:20]([CH2:22][CH2:23]2)([CH3:21])[C:19](=[O:33])[CH2:18][CH2:17]1
Reactant: CC(C)(C)[Si](C)(C)OCCCCC[C@@H]1CC2=CC(=O)CC[C@@H]2[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: C[C@]12CC[C@H]3[C@@H]([C@H](CCCCCO)CC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Yield: 99 %

Procedure:
A solution of 125.4 g of 7α-(5-tert-butyl-dimethylsilyloxypentyl)-estr-4-ene-3,17-dione in 625 ml of methanol and 347 ml of water is stirred with 694 ml of glacial acetic acid for 2.5 hours at 50° C. After concentration by evaporation at 60° C. in a vacuum, 94.1 g of crude 7α-(5-hydroxypentyl)-estr-4-ene-3,17-dione is obtained as an oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[CH2:18][Mg]Br>C(OCC)C>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH2:18][C:17]2[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=2[F:15])([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Fc1ccccc1C[Mg]Br
Solvent: CCOCC
Product: OC1(Cc2ccccc2F)CCN(Cc2ccccc2)CC1
Temperature: -4 °C
Reaction time: 0.33 h
Yield: 56.7 %

Procedure:
1-Benzyl-4-piperidone (10 g, 53 mmol) in diethyl ether (80 ml) was added dropwise to a cooled (-4° C.), stirred mixture of 2-fluorobenzyl magnesium bromide (prepared from magnesium and 2-fluorobenzyl bromide (9.56 ml, 80 mmol) in diethyl ether (65 ml)) under an atmosphere of nitrogen. The reaction mixture was stirred whilst warming to room temperature (30 minutes) then at room temperature for 20 minutes. The reaction mixture was quenched with 2M hydrochloric acid (100 ml). The aqueous was separated and washed with diethyl ether (100 ml). The aqueous was basified with 2M sodium hydroxide solution then exhaustively extracted with dichloromethane. The combined organics were dried (sodium sulphate) then evaporated to give crude 1-benzyl-4-(2-fluorobenzyl)-4-hydroxypiperidine as a gum (9.0 g). This crude product in methanol (100 ml) was treated with formic acid (6 ml), ammonium formate (9.5 g, 0.15 mol) and 10% palladium on carbon (900 mg). The mixture was stirred whilst heating at reflux for 4 hours, cooled, filtered then evaporated to afford 4-(2-fluorobenzyl)-4-hydroxypiperidine as a gum (3.4 g); m/z (ES) 210 (M+ +1). This amine (3.35 g, 16 mmol) in dichloromethane (75 ml) was treated with di-t-butyldicarbonate (3.5 g, 16 mmol) and stirred at ambient temperature for 18 hours, washed with aqueous 10% citric acid, dried (potassium carbonate), evaporated to give a gum which was purified by column chromatography on silica using ethyl acetate/n-hexane (1:1) to afford the title compound as a colourless, viscous gum (3.62 g, 73%). δH (360 MHz, CDCl3) 1.46 (9H, s, (CH3)3C), 1.48 (2H, d, J=13 Hz, 2×CH), 1.63 (2H, ddd, J1 =5, J2 =13, J3 =17 Hz, 2×CH), 2.82 (2H, d, J=1 Hz, CH2Ph), 3.11 (2H, ddd, J1 =3, J2 =J3 =13 Hz, 2×CH), 3.84 (2H, d, J=13 Hz, 2×CH), 7.02-7.27 (4H, m, C6H4); m/z (ES) 310 (M+ +1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)[N:11]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)[N:11]=1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: Oc1cccc(F)c1
Product: COc1ccc2c(Oc3cccc(F)c3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 10 was used, starting from 3-fluoro-phenol and (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(3-Fluoro-phenoxy)-6-methoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 365(MH+).
Reaction SMILES: [N+:1](/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O-:3])=[O:2]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh].C1C=CC=CC=1>[C:6]1([CH2:5][CH2:4][N+:1]([O-:3])=[O:2])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=[N+]([O-])/C=C/c1ccccc1
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: O=[N+]([O-])CCc1ccccc1
Reaction time: 14 h

Procedure:
A mixture of (trans)-β-Nitrostyrene (50.0 g, 0.335 mol), tris(triphenylphosphine)rhodium(I) chloride (10.7 g) and benzene (500 mL) at 50° C. was shaken under hydrogen at 50 psi for 14 hours and allowed to cool. The solution was rotoevaporated, suspended in petroleum ether-ether (9:1), and gravity filtered through a plug of fluorisil (80 g)/silica gel (300 g). The filtrate was rotoevaporated to a pale yellow oil; yield (49.5 g, 98%).
Reaction SMILES: [F:1][CH2:2][C:3]([NH:5][C:6]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:7]=1[C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:12]=1[CH3:18])=[O:9])=O.B(F)(F)F.CCOCC>C(O)(=O)C>[F:1][CH2:2][C:3]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:12]=2[CH3:18])[C:8](=[O:9])[C:7]2[C:6](=[CH:22][CH:21]=[C:20]([N+:23]([O-:25])=[O:24])[CH:19]=2)[N:5]=1
Reactant: Cc1cccc(NC(=O)c2cc([N+](=O)[O-])ccc2NC(=O)CF)c1C
Agent: FB(F)F
Solvent: CCOCC
Solvent: CC(=O)O
Product: Cc1cccc(-n2c(CF)nc3ccc([N+](=O)[O-])cc3c2=O)c1C
Yield: 84.4 %

Procedure:
3.5 g of N-(2-fluoroacetamido-5-nitrobenzoyl)-2,3-dimethylaniline, 3.0 g of boron trifluoride etherate and 30 ml of acetic acid are treated in the same manner as described in Example 1-(2), whereby 2.8 g of 2-fluoromethyl-3-(2,3-dimethylphenyl)-6-nitro-4(3H)-quinazolinone are obtained as yellow prisms.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[CH:12][C:13]([NH:15][NH2:16])=[O:14].C(N(CC)CC)C.[C:24](C1NC=CN=1)(C1NC=CN=1)=[O:25]>O1CCCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[CH:12][C:13]1[O:14][C:24](=[O:25])[NH:16][N:15]=1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: NNC(=O)C=Cc1ccc2ccccc2c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=c1[nH]nc(C=Cc2ccc3ccccc3c2)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of 3-naphthalen-2-yl-acrylic acid hydrazide (1.0 g, 4.71 mmol, prepared as described in example 5) and triethylamine (0.64 g, 6.28 mmol) in dry tetrahydrofuran (15 ml) was added carbonyl diimidazole (1.02 g, 6.28 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h. The resulting reaction mixture was evaporated in vacuo and to the residue was added water (25 ml). The precipitate was filtered off and washed with water (2×10 ml) and diethyl ether (2×10 ml) and recrystallised from ethyl acetate (100 ml) affording after drying In vacuo at 50° C. 0.5 g (45%) of the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:25][CH:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:13](=O)[CH2:14][CH2:15][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C([O-])(=O)C.[NH4+:36].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([C:13]2[NH:36][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[CH:15][CH:14]=2)[CH2:25][CH:26]2[CH2:27][CH2:28][O:29][CH2:30][CH2:31]2)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCOCC2)C(=O)CCC(=O)c2ccccn2)cc1Cl
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(C(CC2CCOCC2)c2ccc(-c3ccccn3)[nH]2)cc1Cl
Temperature: 110 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
To a solution of 5-[3-chloro-4-(methylsulfonyl)phenyl]-1-(pyridin-2-yl)-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (1.13 g) in acetic acid (12.2 mL) was added ammonium acetate (3.01 g), and the mixture was stirred at 110° C. for 1 hr. After cooling to room temperature, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (855 mg, yield 79%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). MS: 445 (MH+).