Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH2:61][CH:62]=[CH:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1.FC(F)(F)S(O)(=O)=O>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:61][CH:62]=[CH:63][C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2]
Reactant: N=C(OCC=Cc1ccccc1)C(Cl)(Cl)Cl
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: O=S(=O)(O)C(F)(F)F
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC=Cc4ccccc4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (50 mg in 1.5 ml 33% methylene chloride in cyclohexane), cinnamyl trichloroacetimidate (26 μl neat) was added and the reagents allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (2 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 15 minutes the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×5 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by preparative TLC on silica gel (ethyl acetate:hexane (1:1)+1% methanol) gave the title compound (10 mg).
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25](O)=[O:26])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:28][C:29]1[CH:30]=[C:31]([C:35]([NH:37][NH2:38])=O)[CH:32]=[CH:33][CH:34]=1>>[Cl:28][C:29]1[CH:30]=[C:31]([C:35]2[O:26][C:25]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[O:8])[CH2:10]3)=[N:38][N:37]=2)[CH:32]=[CH:33][CH:34]=1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: NNC(=O)c1cccc(Cl)c1
Product: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nnc(-c3cccc(Cl)c3)o2)C1

Procedure:
200 mg (0.518 mmol) of the compound from Example 49A and 97 mg (0.569 mmol) of 3-chlorobenzenecarbohydrazide were reacted according to the General Method 4. Yield: 13 mg (11% of theory).
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.C1(C)C(S(O)(=O)=O)=CC=CC=1.O>C1C=CC=CC=1>[O:11]1[CH2:12][CH2:13][N:8]([C:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=2)[CH2:9][CH2:10]1
Reactant: O=C1CCCCC1
Reactant: C1COCCN1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: c1ccccc1
Solvent: O
Product: C1=C(N2CCOCC2)CCCC1

Procedure:
295g of cyclohexanone and 261 g of morpholine are dissolved in 800ml of benzene. After the whole has been dissolved, 1.5g of p. toluene sulphonic acid are added and the mixture is heated under reflux. The water formed is extracted continuously by azeotropic distillation. After 20 hours reflux, the remaining solvent is distilled off and the oily residue is recovered. 379 g of the enamine are so obtained, boiling under 2mm at 115° to 117°. The yield amounts to 76%.
Reaction SMILES: [CH2:1]=[CH:2][CH3:3].[Cl:4][C:5]1[C:14]([CH:15]=[N:16][OH:17])=[C:13]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8].C([O-])(=O)C.[Na+].Cl[O-].[Na+]>ClCCl>[Cl:4][C:5]1[C:14]([C:15]2[CH2:1][CH:2]([CH3:3])[O:17][N:16]=2)=[C:13]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: C=CC
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C=NO)c1Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(S(C)(=O)=O)c(C2=NOC(C)C2)c1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 89 %

Procedure:
At room temperature, propene was introduced into a solution of 15.0 g (52 mmol) of methyl 2-chloro-3-hydroxyiminomethyl-4-methylsulfonylbenzoate and 200 ml of dichloromethane for 30 minutes. After the addition of 1.6 g of sodium acetate, 42.8 ml of sodium hypochlorite solution were added dropwise, with the simultaneous introduction of propene. At room temperature, propene was subsequently introduced into the mixture for a further 15 minutes. The mixture was heated for 3 hours under reflux and then stirred for 12 hours at room temperature, propene was introduced once more under reflux for 5 hours and the mixture was stirred at room temperature for another 12 hours. The phases were separated and the organic phase was washed with water, dried and concentrated. 15.5 g (89% of theory) of methyl 2-chloro-(5-methyl-4,5-dihydroisoxazol-3-yl)-4-methylsulfonylbenzoate were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[NH:11][C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[F:20][C:21]1[CH:22]=[C:23]([S:27](Cl)(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1>N1C=CC=CC=1>[F:20][C:21]1[CH:22]=[C:23]([S:27]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][N:6]=[C:5]3[NH:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1
Reactant: Nc1ccc2[nH]nc(NC(=O)c3ccccc3)c2c1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Solvent: c1ccncc1
Product: O=C(Nc1n[nH]c2ccc(NS(=O)(=O)c3cccc(F)c3)cc12)c1ccccc1
Yield: 82 %

Procedure:
N-[5-(3-Fluorobenzenesulfonylamino)-1H-indazol-3-yl]benzamide can be obtained as described in Example 2 from 0.45 g of N-(5-amino-1H-indazol-3-yl)benzamide, 10 ml of pyridine and 0.35 g of 3-fluorobenzenesulfonyl chloride. 0.6 g of N-[5-(3-fluorobenzenesulfonylamino)-1H-indazol-3-yl]-benzamide is thus obtained in the form of a white solid melting at 225° C. (analysis C20H15FN4O3S: % calculated C, 58.53; H, 3.68; F, 4.63; N, 13.65; O, 11.69; S, 7.81. % found C, 58.38; H, 3.42; N, 13.56; S, 7.44).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>O>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCCCC2)c(F)c1
Temperature: 25 °C

Procedure:
3,4-Difluoronitrobenzene (1.4 mL, 2.01 g, 12.7 mmol) in piperidine (4 mL, 40.4 mmol) was heated in a sealed tube at 130° C. for 2 hours. The mixture was allowed to cool to room temperature and poured into H2O (150 mL). The title compound was separated by pipette. 1H NMR (300 MHz, DMSO-d6) δ 7.95–8.01 (m, 2H), 7.11–7.18 (m, 1H), 3.26–3.29 (m, 4H), 1.62–1.68 (m, 6H); MS (ESI+) m/z 225 (M+H)+.
Reaction SMILES: [F:1][C@:2]12[C@@H:22]([OH:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][C@@H:14]([O:26][CH2:27][CH2:28][O:29]C4CCCCO4)[C@:15]3([OH:25])[C:16](=[O:19])[CH2:17][OH:18])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:37])[CH2:4][CH2:5][C:6](=[O:36])[CH:7]=1>C(O)(=O)C.O>[F:1][C@:2]12[C@@H:22]([OH:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][C@@H:14]([O:26][CH2:27][CH2:28][OH:29])[C@:15]3([OH:25])[C:16](=[O:19])[CH2:17][OH:18])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:37])[CH2:4][CH2:5][C:6](=[O:36])[CH:7]=1
Reactant: C[C@]12CCC(=O)C=C1CC[C@H]1[C@@H]3C[C@@H](OCCOC4CCCCO4)[C@](O)(C(=O)CO)[C@@]3(C)C[C@H](O)[C@@]12F
Solvent: O
Solvent: CC(=O)O
Product: C[C@]12CCC(=O)C=C1CC[C@H]1[C@@H]3C[C@@H](OCCO)[C@](O)(C(=O)CO)[C@@]3(C)C[C@H](O)[C@@]12F
Yield: 65 %

Procedure:
A solution of 4.4 g of 9-fluoro-11β,17,21-trihydroxy-16α-[2-(tetrahydropyran-2-yloxy)ethoxy]pregn-4-ene-3,20-dione, 21-acetate in 60 ml each of acetic acid and water is stirred for 4 hours and the bulk of the solvent removed in vacuo. The residue is dissolved in chloroform and washed with 5% sodium bicarbonate solution. Drying and solvent removal gives an oil which crystallizes from acetone-hexane to give 2.4 g of 9-fluoro-11β,17,21-trihydroxy-16α-(2-hydroxyethoxy)pregn-4-ene-3,20-dione, 21-acetate, melting point 162°-165°C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:13][CH2:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[NH:9][C:8]2=[O:18])[CH2:3][CH2:2]1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:33]=[C:34]([C:37]([F:40])([F:39])[F:38])[C:35]=1[OH:36])[CH2:23][C@@H:24]([CH2:29][C:30]([O-])=[O:31])[C:25]([O:27][CH3:28])=[O:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[Cl:19][C:20]1[CH:21]=[C:22]([CH:33]=[C:34]([C:37]([F:38])([F:39])[F:40])[C:35]=1[OH:36])[CH2:23][C@@H:24]([CH2:29][C:30](=[O:31])[N:1]1[CH2:2][CH2:3][CH:4]([N:7]2[CH2:13][CH2:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[NH:9][C:8]2=[O:18])[CH2:5][CH2:6]1)[C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)[C@H](CC(=O)[O-])Cc1cc(Cl)c(O)c(C(F)(F)F)c1
Reactant: O=C1Nc2ccccc2CCN1C1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1)Cc1cc(Cl)c(O)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.65 g (4.84 mmol) 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one were added to a mixture of 1.19 g (4.85 mmol) 1-methyl(S)-2-(3-chloro-4-hydroxy-5-trifluoromethyl-benzyl)-succinate, 1.56 g (4.85 mmol) TBTU, 0.73 mL (5.00 mmol) triethylamine, in 30 mL DMF and the reaction mixture was stirred overnight at RT. The reaction solution was evaporated down i.vac., the residue was taken up in 200 mL EtOAc, the organic phase was washed with 10% citric acid and saturated Na2CO3 solution and dried over Na2SO4. After the desiccant and solvent had been eliminated the desired product was obtained.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=[O:7].[N+](=[CH2:11])=[N-].C(O)(=O)C>C(OCC)C>[CH3:11][O:7][C:6]([C:2]1[NH:1][CH:5]=[CH:4][CH:3]=1)=[O:8]
Reactant: C=[N+]=[N-]
Reactant: O=C(O)c1ccc[nH]1
Solvent: CCOCC
Solvent: CC(=O)O
Product: COC(=O)c1ccc[nH]1
Yield: 88.8 %

Procedure:
Method 4 General Experimental: Pyrrole-2-carboxylic acid (90.0 mmol, 10.0 g) in diethyl ether (200 ml) was treated with diazomethane (270 mmol, generated from N-nitroso-N-methyl urea), then back titrated with acetic acid until the yellow color dissipated. The solution was washed with saturated aqueous sodium bicarbonate (3×20 ml) and brine (3×20 ml), then concentrated under reduced pressure to provide 10 g (88%) of pyrrole-2-carboxylic acid methyl ester. 1H NMR (CDCl3) δ9.14 (1H, s), 6.98-6.65 (1H, m), 6.94-6.91 (1H, m), 6.29-6.26 (1H, m), 3.86 (3H, s).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C@H:16]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:17]([N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:18].[CH:28]([C:30]1[CH:35]=[CH:34][N:33]=[C:32]2[N:36]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH:37]=[C:38]([C:39]([O:41][CH3:42])=[O:40])[C:31]=12)=O>ClCCCl.C(O)(=O)C>[CH3:26][CH:25]([CH3:27])[CH2:24][C@@H:16]([NH:15][CH2:28][C:30]1[CH:35]=[CH:34][N:33]=[C:32]2[N:36]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH:37]=[C:38]([C:39]([O:41][CH3:42])=[O:40])[C:31]=12)[C:17](=[O:18])[N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CC(C)C[C@@H](N)C(=O)N1CCCC1
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(C=O)c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(CN[C@H](CC(C)C)C(=O)N3CCCC3)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 102.9 %

Procedure:
A mixture of sodium triacetoxyborohydride (139 mg, 0.657 mmol) and (R)-2-amino-4-methyl-1-(pyrrolidin-1-yl)pentan-1-one (91 mg, 0.493 mmol) in DCE (2 mL) was stirred at room temperature for 30 min. The reaction mixture was cooled to 0° C. A solution of 1-tert-butyl 3-methyl 4-formyl-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate (100 mg, 0.329 mmol) in DCE (2 mL) was added, followed by acetic acid (1 drop). The reaction was stirred at 0° C. for 30 min and then at room temperature for 3 h. Purification by silica column chromatography (EtOAc/DCM, 0-10%) afforded the title compound as a yellow oil (160 mg, 93%). [M+H] calc'd for C25H36N4O5, 473; found, 473.7.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:30][NH:31][C:32](=[O:37])[C:33]([F:36])([F:35])[F:34])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:42]>CN(C=O)C>[C:1]([O:5][C:6](=[O:38])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:30][N:31]([CH3:42])[C:32](=[O:37])[C:33]([F:34])([F:35])[F:36])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCC(=O)OC(C)(C)C)c(CNC(=O)C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCC(=O)OC(C)(C)C)c(CN(C)C(=O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 72.5 %

Procedure:
A solution of 3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-2-[(2,2,2-trifluoro-acetylamino)-methyl]-phenyl}-propionic acid tert-butyl ester (151 mg, 0.28 mmol) in dry DMF (10 mL) was cooled in an ice bath and treated with NaH (22 mg, 0.55 mmol, 60% oil dispersion). After the reaction mixture was stirred for 25 min, iodomethane (0.15 mL, 3.0 mmol) was added, and the reaction was allowed to warm to ambient temperature gradually. After 4 h, more iodomethane (0.10 mL, 2 mmol) was added. The mixture was stirred overnight and was partitioned between EtOAc and aqueous LiCl solution. The organic layer was washed with brine, dried (Na2SO4), and concentrated. The residue was purified by silica gel radial chromatography (CH2Cl2/EtOAc 100/0 to 95/5) to give the title compound (111 mg, 73%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].C(O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([NH2:20])=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2)CC1

Procedure:
A mixture of 4-(4-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (3 g, 9.76 mmol) and 10% palladium on carbon (300 mg) in 50 mL ethanol and 20 mL ethyl acetate was hydrogenated at room temperature under a 50 psi hydrogen atmosphere for 2 hrs. The reaction mixture was filtered through a plug of Celite and evaporated under reduced pressure to give 4-(4-amino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester that was used in the in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18]CC4C=CC=CC=4)[CH:14]=3)[CH:9]2[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][N:37]3[CH3:42])=[CH:29][CH:28]=2)=[CH:4][CH:3]=1>C(Cl)Cl.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=3)[CH:9]2[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][N:37]3[CH3:42])=[CH:29][CH:28]=2)=[CH:4][CH:3]=1
Reactant: CN1CCCCC1CCOc1ccc(CC2c3ccc(OCc4ccccc4)cc3CCN2c2ccc(F)cc2)cc1
Solvent: ClCCl
Solvent: CO
Product: CN1CCCCC1CCOc1ccc(CC2c3ccc(O)cc3CCN2c2ccc(F)cc2)cc1
Yield: 13.9 %

Procedure:
The title compound was prepared as described in Example 44. G, using 2-(4-fluorophenyl)-1-(4-[2-(1-methyl(2-piperidyl))ethoxy]benzyl)-6-(phenylmethoxy)-1,2,3,4-tetrahydroisoquinoline (0.043 g, 0.076 mmol). The product was purified by radial chromatography (100% CH2Cl2, then CH2Cl2/MeOH, 95:5) to yield the title compound (0.005 g, 14% yield): ES-MS (m/z) 475 [M+H]+.
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]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[N:20][C:21]([N:24]2[CH2:29][CH2:28][CH2:27][CH:26]([NH:30]C(=O)OC(C)(C)C)[CH2:25]2)=[N:22][CH:23]=1.[Cl:38][C:39]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[C:41]([O:54][CH3:55])[C:40]=1[OH:56]>>[NH2:30][CH:26]1[CH2:27][CH2:28][CH2:29][N:24]([C:21]2[N:20]=[CH:19][C:18]([NH:17][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([C:43]5[CH:42]=[C:41]([O:54][CH3:55])[C:40]([OH:56])=[C:39]([Cl:38])[CH:44]=5)[CH:3]=4)[N:8]=[CH:7][C:6]=3[C:12]([CH:14]3[CH2:15][CH2:16]3)=[O:13])=[CH:23][N:22]=2)[CH2:25]1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Reactant: CC(C)(C)OC(=O)NC1CCCN(c2ncc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Product: COc1cc(-c2ccc3ncc(C(=O)C4CC4)c(Nc4cnc(N5CCCC(N)C5)nc4)c3c2)cc(Cl)c1O
Yield: 11.3 %

Procedure:
Following general procedure D, tert-butyl 1-(5-(6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino)pyrimidin-2-yl)piperidin-3-ylcarbamate (150 mg, 0.26 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (111 mg, 0.39 mmol) to obtain the protected intermediate which was subjected to general procedure A-2 to afford the desired product (16 mg, 11% over 2 steps) as an orange-yellow solid: 1H NMR (500 MHz, MeOD+TFA-d) δ 9.35 (br s, 1H), 8.45 (s, 2H), 8.29 (dd, J=8.8, 1.9 Hz, 1H), 8.26-8.15 (br s, 1H), 8.03 (d, J=8.8 Hz, 1H), 7.07 (br s, 1H), 6.96 (br s, 1H), 4.76 (d, J=12.9 Hz, 1H), 4.45 (br s, 1H), 3.37-3.31 (m, 1H), 2.82 (br s, 1H), 2.23-2.16 (m, 1H), 1.96-1.85 (m, 1H), 1.78-1.68 (m, 1H), 1.68-1.56 (m, 1H), 1.22-1.16 (m, 4H); ESI MS m/z 545 [C29H29ClN6O3+H]+; HPLC 98.5% (AUC), tR=10.69 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[C:19]([O:23][C:24](=[O:32])[NH:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24](=[O:32])[NH:25][CH:26]1[CH2:31][CH2:30][N:29]([C:12](=[O:14])[C:11]2[CH:15]=[CH:16][N:17]=[CH:18][C:10]=2[NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])[CH2:28][CH2:27]1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)c2ccncc2Nc2ccc(I)cc2F)CC1

Procedure:
tert-butyl(1-{3-[(2-fluoro-4-iodophenyl)amino]isonicotinoyl}piperidin-4-yl)carbamate was synthesized according to the procedure for General Method 1, outlined above, starting with 2.4 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 4.0 mmol of piperidin-4-yl-carbamic acid tert-butyl ester. LC/MS [9.47 min; 541 (M+1)]
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])[CH:10]=2)[N:5]=[CH:4][N:3]=1.CO[CH:20]=[C:21]([C:26]([O:28][CH3:29])=[O:27])[C:22]([O:24][CH3:25])=[O:23].O>CN(C)C=O>[CH3:16][CH:14]([CH3:15])[C:13]([NH:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[NH:1][CH:20]=[C:21]([C:26]([O:28][CH3:29])=[O:27])[C:22]([O:24][CH3:25])=[O:23])=[O:17]
Reactant: CC(C)C(=O)Nc1ccc2ncnc(N)c2c1
Reactant: COC=C(C(=O)OC)C(=O)OC
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(=CNc1ncnc2ccc(NC(=O)C(C)C)cc12)C(=O)OC
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 88.8 %

Procedure:
A mixture of 4-amino-6-(2-methylpropionamido)quinazoline (6.2 g) and dimethyl methoxymethylenepropanedioate (7.01 g) in N,N-dimethylformamide (25 ml) was stirred at 100° C. for 1.5 hours and cooled to room temperature. Water was added to the reaction mixture. The resulting solid was separated by filtration, washed with water and dried to give dimethyl [[6-(2-methylpropionamido)-4-quinazolinylamino]methylene]propanedioate (8.9 g). Recrystallization from ethyl acetate gave pure crystals melting at 212°-214° C.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([S:17]([O-:20])(=O)=[O:18])=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[K+].CN(C)C=O.S(Cl)([Cl:29])=O>>[C:1]([O:4][CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([S:17]([Cl:29])(=[O:20])=[O:18])=[CH:9][CH:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCc1ccc(S(=O)(=O)[O-])c2ccccc12
Reactant: O=S(Cl)Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCCc1ccc(S(=O)(=O)Cl)c2ccccc12
Temperature: 80 °C
Reaction time: 1 h
Yield: 80.4 %

Procedure:
Potassium 4-(2-acetoxy-ethyl)-naphthalene-1-sulfonate (102.3 g, 308 mmol) was added in portions over 15 minutes to a room temperature solution of dimethylformamide (2.4 mL, 31 mmol) in thionyl chloride (112 mL, 1.54 mol). The reaction mixture was gradually brought to 80° C. (oil bath temperature) over 30 minutes and heated at 80° C. for 90 minutes, then cooled to room temperature and stirred at room temperature for 60 minutes. The reaction mixture was partitioned between ice water (500 mL) and ethyl acetate (500 mL). The organic layer was washed with water (200 mL) and brine (200 mL), dried over magnesium sulfate, filtered, and evaporated under vacuum to a cream colored solid. The crude product was triturated with pet ether to afford 4-(2-acetoxy-ethyl)-naphthalene-1-sulfonyl chloride as a pale tan solid (77.47 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[CH:27]=[C:26]([CH3:28])[S:25][C:15]=2[N:16]=[C:17]([C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)[N:18]=1>>[N:20]1[CH:21]=[CH:22][N:23]=[CH:24][C:19]=1[C:17]1[N:18]=[C:13]([NH:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:14]2[CH:27]=[C:26]([CH3:28])[S:25][C:15]=2[N:16]=1
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: Cc1cc2c(Cl)nc(-c3cnccn3)nc2s1
Product: Cc1cc2c(NCc3cccc([N+](=O)[O-])c3)nc(-c3cnccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(pyrazin-2-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(3-nitrobenzylamino)-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5](=[O:35])[C@@H:6]([O:11][C@@H:12]([C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][O:33][CH3:34])[CH2:27][CH2:26]2)=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:7][CH:8]([CH3:10])[CH3:9])#[N:2].CO.CC(C)=[O:40]>>[C:1]([CH2:3][NH:4][C:5](=[O:35])[C@@H:6]([O:11][C@@H:12]([C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[CH2:30][CH2:29][N+:28]([CH2:31][CH2:32][O:33][CH3:34])([O-:40])[CH2:27][CH2:26]2)=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:7][CH:8]([CH3:10])[CH3:9])#[N:2]
Reactant: CC(C)=O
Reactant: COCCN1CCC(c2ccc([C@H](O[C@@H](CC(C)C)C(=O)NCC#N)c3ccccc3)cc2)CC1
Solvent: CO
Product: COCC[N+]1([O-])CCC(c2ccc([C@H](O[C@@H](CC(C)C)C(=O)NCC#N)c3ccccc3)cc2)CC1

Procedure:
Using the same procedure as described for example 40, (2S)-N-(cyanomethyl)-2-{[(R)-{4-[1-(2-methoxyethyl)piperidin-4-yl]phenyl}(phenyl)methyl]oxy}-4-methylpentanamide (75 mg, 0.157 mmol) was oxidized to give the title compound after chromatography with 50% methanol/acetone.