Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:13][C:14]2[C:23]([NH:24][S:25]([CH2:28][CH2:29][CH3:30])(=[O:27])=[O:26])=[N:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[C:9]([F:12])([F:11])[F:10])=[CH:4][N+:3]=1[O-].O.C(=O)([O-])[O-:34].[K+].[K+]>C(OC(=O)C)(=O)C>[F:10][C:9]([F:12])([F:11])[CH:8]([C:5]1[CH:4]=[N:3][C:2]([CH2:1][OH:34])=[CH:7][CH:6]=1)[O:13][C:14]1[C:23]([NH:24][S:25]([CH2:28][CH2:29][CH3:30])(=[O:27])=[O:26])=[N:22][C:21]2[C:16]([N:15]=1)=[CH:17][CH:18]=[CH:19][CH:20]=2
Reactant: CCCS(=O)(=O)Nc1nc2ccccc2nc1OC(c1ccc(C)[n+]([O-])c1)C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CCCS(=O)(=O)Nc1nc2ccccc2nc1OC(c1ccc(CO)nc1)C(F)(F)F
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 29.9 %

Procedure:
Compound B2 (103 mg, 0.226 mmol) obtained in Step 2 was suspended in acetic anhydride (1.0 mL) and the suspension was stirred at 100° C. for 1.5 hours. Water was added to the reaction mixture. Extraction with ethyl acetate, washing with saturated brine and drying over anhydrous sodium sulfate were performed. The solvent was evaporated under reduced pressure and the resulting residue was dissolved in methanol (2.0 mL). Potassium carbonate (93.7 mg, 0.678 mmol) was added and the mixture was stirred at room temperature for 30 minutes. The solvent was evaporated under reduced pressure, and a saturated aqueous ammonium chloride solution and water were added. Extraction with ethyl acetate, washing with saturated brine and drying over anhydrous sodium sulfate were performed. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) and further purified by preparative thin-layer chromatography (hexane/ethyl acetate=1/1) to give Compound 31 (30.8 mg, 30% yield).
Reaction SMILES: [OH:1][C:2]1[C:32]([O:33][CH3:34])=[C:31]([O:35][CH3:36])[CH:30]=[C:29]([CH3:37])[C:3]=1[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:5].[C:38]1(C)C=CC(S(O)(=O)=O)=CC=1.O>CO>[OH:1][C:2]1[C:32]([O:33][CH3:34])=[C:31]([O:35][CH3:36])[CH:30]=[C:29]([CH3:37])[C:3]=1[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:38])=[O:27])=[O:5]
Reactant: COc1cc(C)c(C(=O)CCCCCCCCCCCCCCCCCCCCC(=O)O)c(O)c1OC
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC(=O)CCCCCCCCCCCCCCCCCCCCC(=O)c1c(C)cc(OC)c(OC)c1O
Temperature: 25 °C

Procedure:
To a solution of 3 g of the above 21-(2-hydroxy-3,4-dimethoxy-6-methylbenzoyl)heneicosanoic acid in 10 ml of methanol is added p-toluenesulfonic acid (30 mg), followed by heating under reflux for 2 hours. After cooling to room temperature, water is added and the mixture is stirred at 0° C. to give colorless crystals of methyl 21-(2-hydroxy-3,4-dimethoxy-6-methylbenzoyl)heneicosanoate. m.p. 72°-72.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH2:13][N:12]([C@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])[C:11](=[O:22])[C:10]=2[F:23])[CH2:8][CH2:7]1)=[O:5])[CH3:2]>C(O)C.[Ni]>[CH2:1]([O:3][C:4]([C:6]1([C@H:9]2[CH2:13][N:12]([C@H:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH3:15])[C:11](=[O:22])[C@H:10]2[F:23])[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(C2=C(F)C(=O)N([C@@H](C)c3ccccc3)C2)CC1
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)C1([C@H]2CN([C@@H](C)c3ccccc3)C(=O)[C@H]2F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.7 %

Procedure:
To a solution of 4-(1-ethoxycarbonylcyclopropyl)-3-fluoro-1-[1-(S)-phenylethyl]-3-pyrrolin-2-one (587 mg, 1.85 mmol) in ethanol (5 ml) was added Raney nickel (R-100, 2 ml). Under a hydrogen atmosphere of 5 kg/cm2, the mixture was stirred at room temperature for 1 hour. Next, Raney nickel (R-100, 3 ml) was further added and stirring was continued under the same conditions for 2.5 hours. After eliminating the catalyst by filtering through celite (washed with ethanol), the filtrate was concentrated under reduced pressure. The residue was subjected to flash silica gel column chromatography (eluent:n-hexane:ethyl acetate=3:1) to obtain 382 mg (64.6%) of the title compound as a colorless oily substance. The 1H-NMR data of this compound agreed with the data of the compound obtained in Referential Example 10-2.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([NH2:6])=[C:4]([CH3:10])[CH:3]=1.[Li]CCCC.Cl[Si:17]([CH:20]1[C:24]2[S:25][CH:26]=[CH:27][C:23]=2[C:22]([CH3:28])=[C:21]1[CH3:29])([CH3:19])[CH3:18]>C1COCC1>[Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([NH:6][Si:17]([CH:20]2[C:24]3[S:25][CH:26]=[CH:27][C:23]=3[C:22]([CH3:28])=[C:21]2[CH3:29])([CH3:18])[CH3:19])=[C:4]([CH3:10])[CH:3]=1
Reactant: CC1=C(C)C([Si](C)(C)Cl)c2sccc21
Reactant: Cc1cc(Br)cc(C)c1N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1=C(C)C([Si](C)(C)Nc2c(C)cc(Br)cc2C)c2sccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under an argon atmosphere, to a solution of 12.4 g (61.9 mmol) of 4-bromo-2,6-dimethylaniline in 300 ml of THF, 16.5 ml of 2.5 M (41.2 mmol) nBuLi in hexanes was added at −80° C. This mixture was warmed for ca. 2 hour to ambient temperature. Then, the resulting solution was added dropwise over ca. 1 hour, while vigorously stirring, to a solution of 10.0 g (41.2 mmol) of chloro(4,5-dimethyl-6H-cyclopenta[b]thien-6-yl)dimethylsilane in 50 ml of THF. The resulting mixture was stirred overnight at ambient temperature, and then, evaporated to dryness. To the residue, 150 ml of toluene was added. This mixture was filtered through a glass frit (G4). The filtrate was evaporated to dryness. Fractional distillation gave a yellow liquid, bp 154-156° C./0.05 mm Hg. The product crystallizes slowly at ambient temperature. Yield 8.36 g (50%).
Reaction SMILES: [NH:1]([CH:3]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1)[NH2:2].C(O)(=O)C.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([OH:32])=[C:23]([C:25](=O)/[CH:26]=[CH:27]/N(C)C)[CH:24]=1>C(O)C>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([OH:32])=[C:23]([C:25]2[N:1]([CH:3]3[CH2:4][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6]3)[N:2]=[CH:27][CH:26]=2)[CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CC(NN)C1
Reactant: CN(C)/C=C/C(=O)c1cc(Cl)ccc1O
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CC(n2nccc2-c2cc(Cl)ccc2O)C1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
Tert-butyl 3-hydrazinoazetidine-1-carboxylate, (Preparation 696, 88.37 g, 0.4247 mol) was dissolved in ethanol (883.7 mL) and the solution was cooled to 0° C. in an ice bath. Acetic acid (97.36 mL, 1.70 mol) was added followed by (2E)-1-(5-chloro-2-hydroxyphenyl)-3-(dimethylamino)prop-2-en-1-one, (Preparation 852, 95.86 g, 0.4247 mol) and the resulting slurry was allowed to warm to room temperature then stirred at room temperature for 2 days. The resulting suspension was cooled to 0° C. and the solid was filtered off, washed with cold ethanol (2×40 mL) and dried to give the title compound as a white granular solid, (83.23 g).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.C([O:16][N:17]=O)CCC>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[N:17][OH:16])[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: O=C1CCc2ccc(Br)cc21
Reactant: CCCCON=O
Product: O=C1C(=NO)Cc2ccc(Br)cc21

Procedure:
Similar procedure as described in example 9B was used, starting from 6-Bromo-indan-1-one and n-butylnitrite to give 6-Bromo-indan-1,2-dione 2-oxime. LC-MS: m/e 240 (MH+).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1I)[CH:2]=[CH2:3].C(N(CC)CC)C.C(=O)=O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCOCC>[CH3:3][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:1]=1
Reactant: C=CCNc1ccccc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C=O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Cc1c[nH]c2ccccc12
Reaction time: 64 h
Yield: 37 %

Procedure:
Di(1H,2H,2H-perfluorooctyl)phenylphosphine (80 mg, 0.1 mmol), palladium (II) acetate (11 mg, 0.05 mmol), N-allyl-2-iodoaniline (259 mg, 1 mmol) and triethylamine (0.15 ml, 1.1 mmol) were placed in a 10 ml stainless steel cell. The cell was sealed and pressurised to approximately 5520 kPa (800 psi) (i.e. full of carbon dioxide). The cell was then heated to 100 C. for 64 hrs and then allowed to cool. When the pressure had dropped below 13800 kPa (2000 psi), the cell was vented into ether (100 ml), the cell was opened once atmospheric pressure was reached and washed out with dichloromethane (20 ml). The organic fractions were combined and concentrated in vacuo to give the crude product. The product was purified by flash column chromatography on silica gel, eluting with 20% ether in hexane to give a white crystalline solid (49 mg, 0.37 mmol, 37%); δH (250 MHz; CDCl3) 7.85 (1H, br, NH), 7.63 (1H, m, H7), 7.34 (1H, m, H4), 7.15-7.26 (2H, m, H5 and H6), 6.97 (1H, s, NHCH), 2.38 (3H, s, Me).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[NH:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=1)([O-:3])=[O:2].O.[F:15][C:16]([F:20])([F:19])[CH:17]=O.[BH3-]C#N.[Na+]>>[N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[N:8]([CH2:17][C:16]([F:20])([F:19])[F:15])[CH2:9][CH2:10][O:11][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=CC(F)(F)F
Reactant: O=[N+]([O-])c1ccc2c(c1)OCCN2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ccc2c(c1)OCCN2CC(F)(F)F
Yield: 90.8 %

Procedure:
This compound was prepared by General Method 7 from 3,4-dihydro-7-nitro-2H-1,4-benzoxazine (EXAMPLE 1) (388 mg, 2.1 mmol), 2,2,2-trifluoroacetaldehyde monohydrate (2.51 g, 21.6 mmol) and NaBH3CN (656 mg, 10.4 mmol) to afford 500 mg (88%) of 3,4-dihydro-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine, a yellow solid. Data for 3,4-dihydro-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine: Rf 0.59 (3:2 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3) δ 7.81 (dd, 1H, J=8.8, 2.6), 7.72 (d, 1H, J=2.6), 6.72 (d, 1H, J=9.1), 4.27 (t, 2H, J=4.5), 3.94 (2H, J=8.6), 3.61 (t, 2H, J=4.5).
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH2:12][CH2:13][CH3:14])=[N:6][NH:7][C:8]=1[C:9]([NH2:11])=[O:10])([O-])=O.[BH4-].[Na+].O>CO.[Pd]>[NH2:1][C:4]1[C:5]([CH2:12][CH2:13][CH3:14])=[N:6][NH:7][C:8]=1[C:9]([NH2:11])=[O:10]
Reactant: CCCc1n[nH]c(C(N)=O)c1[N+](=O)[O-]
Agent: [Pd]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCc1n[nH]c(C(N)=O)c1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.3 %

Procedure:
A solution of 4-nitro-3-n-propylpyrazole-5-carboxamide (198 mg, 1.0 mmol) in methanol (5 ml) was added dropwise to a mixture of sodium borohydride (113 mg, 2.97 mmol), 10% palladium on carbon (5 mg) and water (3 ml). The mixture was stirred at room temperature for 3 hours, filtered and the solvent removed by evaporation under vacuum. Crystallisation of the residue from ethyl acetate-methanol gave the title compound as an off-white solid (61 mg, 36%), m.p. 196°-201° C. Rf 0.4 (silica; dichloromethane, methanol, ammonium hydroxide; 90:10:1). Found: C,48.96; H,6.98; N,32.08. C7H12N4O requires C,49.98; H,7.19; N,33.31%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:25]=[CH:24][N:23]=[C:22]([C:26]([OH:28])=O)[C:21]=4[CH3:29])[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:30]=1.[F:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[NH:37][CH2:36][CH2:35]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[F:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[N:37]([C:26]([C:22]1[N:23]=[CH:24][N:25]=[C:20]([N:17]3[CH2:18][CH2:19][CH:14]([N:10]4[CH2:9][CH2:8][C:7]5[CH:30]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=5[NH:12][C:11]4=[O:13])[CH2:15][CH2:16]3)[C:21]=1[CH3:29])=[O:28])[CH2:36][CH2:35]2
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3ncnc(C(=O)O)c3C)CC1)C(=O)N2
Reactant: Fc1ccc2c(c1)CCN2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3ncnc(C(=O)N4CCc5cc(F)ccc54)c3C)CC1)C(=O)N2

Procedure:
70 mg (0.17 mmol) 6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-5-methyl-pyrimidine-4-carboxylic acid, 26.1 mg (0.19 mmol) 5-fluoroindoline, 61 mg (0.19 mmol) TBTU and 0.027 mL (0.19 mmol) TEA were stirred in 1 mL DMF for 3 h at RT. The reaction mixture was purified by HPLC-MS. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:13])[C:10]=1[O:11]C)[C:5]([OH:7])=O.[NH2:14][C:15]1[CH:20]=[C:19]([O:21]C)[CH:18]=[C:17]([Br:23])[C:16]=1O>>[Br:23][C:17]1[C:16]2[O:7][C:5]([C:4]3[CH:8]=[C:9]([F:13])[C:10]([OH:11])=[C:2]([F:1])[CH:3]=3)=[N:14][C:15]=2[CH:20]=[C:19]([OH:21])[CH:18]=1
Reactant: COc1c(F)cc(C(=O)O)cc1F
Reactant: COc1cc(N)c(O)c(Br)c1
Product: Oc1cc(Br)c2oc(-c3cc(F)c(O)c(F)c3)nc2c1

Procedure:
The title compound was prepared in substantially the same manner as described in Example 21, from 3,5-difluoro-4-methoxybenzoic acid, and 2-amino-6-bromo-4-methoxyphenol, and was obtained as a white solid, m.p. 270-272° C.; MS m/e 340 (M−H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[N:13][C:12]2[NH:11][C:10]3[CH2:9][CH2:8][N:7]4[CH2:15][CH2:16][CH2:17][CH:6]4[C:5]=3[C:4]=2[CH:3]=1.[H-].[Na+].[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2([CH3:30])[CH2:29][O:28]2)=[CH:23][CH:22]=1>CN(C=O)C>[F:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]([OH:28])([CH3:29])[CH2:30][N:11]2[C:10]3[CH2:9][CH2:8][N:7]4[CH2:15][CH2:16][CH2:17][CH:6]4[C:5]=3[C:4]3[CH:3]=[C:2]([CH3:1])[CH:14]=[N:13][C:12]2=3)=[CH:25][CH:26]=1
Reactant: CC1(c2ccc(F)cc2)CO1
Reactant: Cc1cnc2[nH]c3c(c2c1)C1CCCN1CC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cnc2c(c1)c1c(n2CC(C)(O)c2ccc(F)cc2)CCN2CCCC12
Reaction time: 0.17 h
Yield: 45.7 %

Procedure:
9-Methyl-2,3,4,5,6,10c-hexahydro-1H-3a,6,7-triaza-cyclopenta[c]fluorene (700 mg, 3.0 mmol) was dissolved in DMF (7 mL) and sodium hydride (360 mg, 9.0 mmol) was added portionwise at 0° C. and stirred for 10 min. 2-(4-Fluoro-phenyl)-2-methyl-oxirane (720 mg, 4.8 mmol) in 3 mL DMF was added dropwise into the reaction mixture and the mixture was stirred at RT for 18 h. The reaction mixture was quenched with ice cooled water and extracted with EtOAc (3×100 mL). The combined organic layer was washed with water (4×75 mL), dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by passing through a column of silica gel (100-200 mesh), using the eluent 5% MeOH in DCM to obtain 520 mg of 2-(4-fluoro-phenyl)-1-(9-methyl-1,2,3,4,5,10c-hexahydro-3a,6,7-triaza cyclopenta[c]fluoren-6-yl)-propan-2-ol. 1H NMR (CDCl3, freebase) δ (ppm): 8.02 (s, 1H), 7.54 (s, 1H), 7.43 s (OH), 7.37 (t, 2H), 6.93 (t, 2H), 4.37 (d, 1H), 4.22 (d, 1H), 4.04 (t, 1H), 3.23 (dd, 1H), 2.9 (m, 1H), 2.7 (m, 2H), 2.5 (m, 2H), 2.42 (s, 3H), 2.3 (m, 1H), 1.84 (m, 3H), 1.6 (s, 3H). Separation by chiral HPLC provided diastereomers II-149a-d.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[CH:10]=[C:11]([C:22]([O:24]CC)=[O:23])[CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[CH:14]=2)=[O:8])[CH2:3]1.[OH-].[Li+].CO>O>[OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[CH:10]=[C:11]([C:22]([OH:24])=[O:23])[CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[CH:14]=2)=[O:8])[CH2:3]1
Reactant: CCOC(=O)c1cc(C(=O)N2CC[C@@H](O)C2)cc(-c2ccc(C)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)N3CC[C@@H](O)C3)c2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of (R)-ethyl 5-(3-hydroxypyrrolidine-1-carbonyl)-4′-methylbiphenyl-3-carboxylate (1.25 g, 3.54 mmol), lithium hydroxide (0.42 g, 18 mmol), methanol (50 mL), and water (5 mL) was stirred at rt for 4 h. LC-MS indicated completion of the reaction. The volatiles were removed in vacuo and the residue was treated with water and acidified with 1N aq. HCl to pH 2-3 and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated to afford a white foam. LC-MS: 326.3 [M+1]+; 1H NMR (400 MHz, CD3OD): 8.33 (m, 1H), 8.11 and 8.10 (t, 1H, J=1.6 Hz), 7.98 and 7.97 (t, 1H, J=1.6 Hz), 7.57 (d, 2H, J=7.6 Hz), 7.30 (d, 2H, J=8.0 Hz), 4.51 and 4.38 (m, 1H), 3.85-3.35 (m, 4H), 2.39 (s, 3H), 2.20-1.90 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[Cl:16].[N+:17]([O-])([OH:19])=[O:18]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([N+:17]([O-:19])=[O:18])=[CH:11][C:10]=1[Cl:16]
Reactant: Fc1ccc(Cl)c(Oc2ccncc2Br)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(Cl)c(Oc2ccncc2Br)cc1F
Temperature: 25 °C
Yield: 91.5 %

Procedure:
To a cold (−10° C.) solution of 3-bromo-4-(2-chloro-5-fluorophenoxy)pyridine (1.98 g, 6.54 mmol) in conc. sulfuric acid (5 ml) was added nitric acid (0.55 ml, 8.69 mmol). The resultant mixture was stirred at the same temp for 20 minutes and was then allowed to warm to ambient temp for 30 min. The reaction mixture was treated with crushed ice, stirred, filtered, washed and dried to provide 3-bromo-4-(2-chloro-5-fluoro-4-nitrophenoxy)pyridine, (2.08 g, 91% yield) as orange yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.62 (m, 2H), 7.81 (d, J=8 Hz, 1H), 7.23 (d, J=2.5 Hz, 1H); MS (ESI) m/z: 348.9 (M+1H+).
Reaction SMILES: [OH:1][CH2:2]C(CO)OCN1C=C(C=C)C(=O)NC1=O.BrN1C(=O)CCC1=O.[OH:26][CH2:27][CH2:28][O:29][CH2:30][N:31]1[CH:38]=[C:37]([CH:39]([N:42]=[N+:43]=[N-:44])[CH2:40][Br:41])[C:35](=[O:36])[NH:34][C:32]1=[O:33]>C(Cl)(Cl)Cl.CO>[OH:26][CH2:27][CH:28]([CH2:2][OH:1])[O:29][CH2:30][N:31]1[CH:38]=[C:37]([CH:39]([N:42]=[N+:43]=[N-:44])[CH2:40][Br:41])[C:35](=[O:36])[NH:34][C:32]1=[O:33]
Reactant: C=Cc1cn(COC(CO)CO)c(=O)[nH]c1=O
Reactant: [N-]=[N+]=NC(CBr)c1cn(COCCO)c(=O)[nH]c1=O
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: CO
Product: [N-]=[N+]=NC(CBr)c1cn(COC(CO)CO)c(=O)[nH]c1=O
Yield: 31.4 %

Procedure:
Reaction of 9a with N-bromosuccinimide, using the procedure outlined for the preparation of 2a, and purification of the product by silica gel column chromatography using chloroform-methanol (92:8, v/v) as eluent provided 10a as a syrup (92 mg, 31.4%).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][O:3][CH2:4][CH2:5][OH:6].[H-].[Na+].[Cl-].[CH3:11][SiH:12]([CH3:17])[C:13]([CH3:16])([CH3:15])[CH3:14]>O1CCCC1>[CH3:14][C:13]([Si:12]([CH3:17])([CH3:11])[O:7][CH2:1][CH2:2][O:3][CH2:4][CH2:5][OH:6])([CH3:16])[CH3:15]
Reactant: OCCOCCO
Reactant: C[SiH](C)C(C)(C)C
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCOCCO
Reaction time: 0.75 h
Yield: 97.9 %

Procedure:
20 g of diethyleneglycol is added to 9.05 g of sodium hydride in 320 cm3 of tetrahydrofuran, the reaction medium is agitated for 45 minutes, 28.3 g of dimethylterbutylsilane chloride is added, agitation is carried out for 3 hours while leaving the temperature to return to ambient. Extraction is carried out with ether, followed by washing with an aqueous solution of sodium bicarbonate, with salt water, drying and evaporating the solvent. 40.25 g of expected product is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]2[O:15][CH3:16])=[O:7])=[C:4]([O:20][CH3:21])[CH:3]=1.CS(O[CH2:27][C:28]1[CH:33]=[N:32][CH:31]=[CH:30][N:29]=1)(=O)=O.C(=O)([O-])O.[Na+]>CC(=O)C>[NH2:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH2:27][C:28]3[CH:33]=[N:32][CH:31]=[CH:30][N:29]=3)[CH2:11][C@H:10]2[O:15][CH3:16])=[O:7])=[C:4]([O:20][CH3:21])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCNC[C@H]1OC
Reactant: CS(=O)(=O)OCc1cnccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(Cc2cnccn2)C[C@H]1OC

Procedure:
4.7 Parts of cis-4-amino-5-chloro-2-methoxy-N-(3-methoxy-4-piperidinyl)benzamide were dissolved in 160 parts of 2-propanone. Then there were added successively 3.2 parts of [(2-pyrazinyl)methyl] methanesulfonate (ester) and 1.7 parts of sodium hydrogen carbonate. The whole was stirred and refluxed for 18 hours while nitrogen gas was introduced. The precipitated product was filtered off and the filtrate was evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized twice from acetonitrile, yielding 1.16 parts of cis-4-amino-5-chloro-2-methoxy-N-[3-methoxy-1-(2-pyrazinylmethyl)-4-piperidiny]benzamide; mp. 203.5° C. (compound 144).
Reaction SMILES: [C:1]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([N+:14]([O-])=O)=[CH:11][CH:12]=2)[NH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Ni]>[C:1]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[NH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1c[nH]c2cc([N+](=O)[O-])ccc12
Agent: [Ni]
Solvent: CCO
Product: CC(C)(C)c1c[nH]c2cc(N)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.5 %

Procedure:
A suspension of 3-tert-butyl-6-nitro-1H-indole (3.0 g, 13.7 mmol) and Raney Ni (0.5 g) in ethanol was stirred at room temperature under H2 (1 atm) for 3 h. The catalyst was filtered off and the filtrate was concentrated to dryness. The residue was purified by column chromatography on silica gel (Pet.Ether./EtOAc 4:1) to give 3-tert-butyl-1H-indol-6-ylamine (B-11) (2.0 g, 77.3%) as a gray solid. 1H NMR (CDCl3): δ 7.58 (m, 2H), 6.73 (d,J=1.2 Hz, 1H), 6.66 (s, 1H), 6.57 (dd,J=0.8, 8.6 Hz, 1H), 3.60 (br s, 2H), 1.42 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[C:16]([CH3:24])[N:15]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH3:25]I.[H-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:13]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[C:16]([CH3:24])[N:15]=2)[CH3:25])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(Nc2nc(C)nc3ccccc23)cc(OC)c1OC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(N(C)c2nc(C)nc3ccccc23)cc(OC)c1OC

Procedure:
The title compound was prepared from (3,4,5-trimethoxy-phenyl)-(2-methyl-quinazolin-4-yl)-amine (232 mg, 0.71 mmol), methyl iodide (0.07 ml, 1.08 mmol), sodium hydride (43 mg, 1.08 mmol, 60% oil dispersion) in DMF similar to example 21 to give 65 mg (27%) of white solids. 1H NMR (CDCl3): 7.75 (d, J=8.4 Hz, 1H), 7.58-7.53 (m, 1H), 7.11-7.00 (m, 2H), 6.39 (s, 2H), 3.88 (s, 3H), 3.73 (s, 6H), 3.62 (s, 3H), 2.74 (s, 3H).
Reaction SMILES: [C:1]([NH:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[C:17]1[N:22]=[C:21]([CH:23]=O)[CH:20]=[CH:19][CH:18]=1)([CH3:4])([CH3:3])[CH3:2].[C:25]([NH2:29])([CH3:28])([CH3:27])[CH3:26].[BH3-]C#N.[Na+]>C(O)C>[C:1]([NH:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[C:17]1[N:22]=[C:21]([CH2:23][NH:29][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:20]=[CH:19][CH:18]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NCc1ccc2ccccc2c1-c1cccc(C=O)n1
Reactant: CC(C)(C)N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)NCc1cccc(-c2c(CNC(C)(C)C)ccc3ccccc23)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2.68 g (8.43 mmol) of 6-{2-[(tert-butylamino)methyl]-1-naphthyl}pyridine-2-carbaldehyde, 3.07 g (42.1 mmol) of tert-butylamine and 800 mg (12.7 mmol) of NaBH3CN and 100 ml of dry ethanol was stirred overnight at room temperature. The resulting mixture was evaporated to dryness, and the product was isolated by flash chromatography on silica gel 60 (40-63 um; ethyl acetate-triethylamine=20:1, vol.). Yield 1.61 g (51%) of white solid. Anal. calc. for C25H33N3: C, 79.95; H, 8.86; N, 11.19. Found: C, 80.11; H, 8.95; N, 10.95. 1H NMR (CDCl3): 8.87 (d, J=8.6 Hz, 1H, 4-H in naphthyl), 7.83 (m, 1H, 8-H in naphthyl), 7.77 (m, 1H, 4-H in Py), 7.63 (d, J=8.6 Hz, 1H, 3-H in naphthyl), 7.46 (m, 1H, 3-H in Py), 7.41 (m, 1H, 7-H in naphthyl), 7.31-7.34 (m, 2H, 5,6-H in naphthyl), 7.27 (m, 1H, 5-H in Py), 3.97 (m, 2H, NaphCH2N), 3.53 (s, 21-1, PyCH2N), 1.17 (s, 9H, PyCH2NHtBu), 0.96 (s, 9H, NaphCH2NH′Bu).