Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][NH2:3].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[O:21][CH:20]=[CH:19][C:18]3=O)=[O:13])=[CH:7][CH:6]=1>N1C=CC=CC=1>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH:14][C:15]2[CH:24]=[CH:23][C:22]([OH:21])=[C:17]([C:18]3[N:2]([CH3:1])[N:3]=[CH:20][CH:19]=3)[CH:16]=2)=[O:13])=[CH:7][CH:6]=1
Reactant: CNN
Reactant: O=C(Nc1ccc(Cl)cc1)Nc1ccc2occc(=O)c2c1
Solvent: c1ccncc1
Product: Cn1nccc1-c1cc(NC(=O)Nc2ccc(Cl)cc2)ccc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.7 %

Procedure:
To a cooled and stirred solution of methyl hydrazine (1.46 g, 31.6 mmol) in pyridine was added slurry of 1-(4-Chloro-phenyl)-3-(4-oxo-4H-chromen-6-yl)-urea (2.5 g, 7.9 mmol) in pyridine over a period of 10 mins. The reaction mixture was left at this temperature for another 2 hrs and then warmed to room temperature slowly. After 6 hrs the reaction mixture turned clear. The reaction was stirred at this temperature for 18 hrs and pyridine was evaporated. The dark colored residue was dissolved in DMSO and purified using Varian Prep. HPLC system. (The two regioisomers were separated. The fractions containing Compound 119 were dried in vacuo to produce a colorless powder (1.78 g, 47%) 1-(4-Chloro-phenyl)-3-[4-hydroxy-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea. LCMS m/z (%)=343 (M+H, 35Cl 100), 345 (M+H, 37Cl, 32.5). 1H NMR (400 MHz, DMSO-d6) δ: 9.59 (bs, 1H), 8.72 (bs, 1H), 8.48 (bs, 1H), 7.43-7.46 (dd, J=6.8, 2.07 Hz, 2H), 7.41 (d, J=1.83 Hz, 1H), 7.28-7.30 (dd, J=7.13, 2.09 Hz, 2H), 7.26 (d, J=2.72 Hz, 1H), 6.88-6.90 (d, J=9.36 Hz, 1H), 6.21 (d, J=1.84 Hz, 1H), 3.67 (s, 3H).
Reaction SMILES: [C:1]([Si:5]([CH3:37])([CH3:36])[O:6][CH:7]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:21]2[S:25][C:24]([S:26]([NH2:29])(=[O:28])=[O:27])=[C:23]([CH3:30])[CH:22]=2)([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:12][C:11]=1[CH3:31])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.[C:49](O)(=[O:51])[CH3:50]>CN(C1C=CN=CC=1)C.ClCCl>[C:49]([NH:29][S:26]([C:24]1[S:25][C:21]([C:16]([C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH:7]([O:6][Si:5]([C:1]([CH3:2])([CH3:3])[CH3:4])([CH3:36])[CH3:37])[C:32]([CH3:35])([CH3:34])[CH3:33])=[C:11]([CH3:31])[CH:12]=2)([CH2:17][CH3:18])[CH2:19][CH3:20])=[CH:22][C:23]=1[CH3:30])(=[O:28])=[O:27])(=[O:51])[CH3:50]
Reactant: CC(=O)O
Reactant: CCC(CC)(c1ccc(OCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1cc(C)c(S(N)(=O)=O)s1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC(CC)(c1ccc(OCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1cc(C)c(S(=O)(=O)NC(C)=O)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
A mixture of 5-(1-{4-[2-(tert-Butyl-dimethyl-silanyloxy)-3,3-dimethyl-butoxy]-3-methyl-phenyl}-1-ethyl-propyl)-3-methyl-thiophene-2-sulfonic acid amide (227 mg, 0.4 mmol), EDCI (92 mg, 0.48 mmol), acetic acid (27 μL, 0.48 mmol) and DMAP (50 mg) in dichloromethane (10 ml) is stirred at RT overnight. The reaction is diluted with dichloromethane and washed with 1N HCl. The organic phase is concentrated and chromatographed (Hex to 20% EtOAc/Hex) to give the title compound (240 mg, 98%). 1H NMR (CDC3) δ 7.99 (s, 1H), 7.02 (d 1H, J=8.8 Hz), 6.96 (s, 1H), 6.69 (d, 1H, J=8.8 Hz), 6.59 (s, 1H), 3.98 (dd, 1H, J=3.4, 9.8 Hz), 3.85 (dd, 1H, J=5.8, 9.8 Hz), 3.67 (dd, 1H, J=3.4, 5.8 Hz), 2.43 (s, 3H), 2.20 (s, 3H), 2.13 9s, 3H), 2.06 (q, 4H), 0.96 (s, 9H), 0.89 (s, 9H), 0.70 (t, 6H), 0.11 (s, 3H), 0.05 (s, 3H);
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]([NH:21]C=O)(C(OCC)=O)[CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)C.[OH-].[Na+].O>C(O)(=O)C>[NH2:21][C@H:5]([C:4]([OH:24])=[O:3])[CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1
Reactant: CCOC(=O)C(Cc1c[nH]c2ccccc12)(NC=O)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reaction time: 8 h
Yield: 100.8 %

Procedure:
A mixture of 40 g (0.12 mol) of the compound of Example 6 and 24.0 g (0.60 mol) of sodium hydroxide in 240 ml. of water was heated at reflux for 18 hours. 48 ml of glacial acetic acid was added to the solution and heating was continued for an additional 8 hours. The suspension was allowed to stand at 0° overnight and the white precipitate was collected, washed with icecold water and dried to yield 24.7 g (100%) of crude product. Recrystallization from 80% aqueous acetic acid afforded, after drying at 100°/0.05 mmHg, 21.2 g (86%) of white crystals, m.p. 292° (dec.) (lit. m.p. 293°) which was identical with an authentic sample.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([O:45]C2CCCCO2)[CH2:9][N:10]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:34]=[C:33]4[C:29]([C:30]([C:38]([NH:40][S:41]([CH3:44])(=[O:43])=[O:42])=[O:39])=[CH:31][N:32]4[CH:35]([CH3:37])[CH3:36])=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)C(=O)OC(C)(C)C)[CH:5]=[CH:6][CH:7]=1>CO.Cl.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([OH:45])[CH2:9][NH:10][CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:34]=[C:33]4[C:29]([C:30]([C:38]([NH:40][S:41]([CH3:44])(=[O:42])=[O:43])=[O:39])=[CH:31][N:32]4[CH:35]([CH3:37])[CH3:36])=[CH:28][CH:27]=3)=[CH:24][CH:25]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)n1cc(C(=O)NS(C)(=O)=O)c2ccc(-c3ccc(CCN(C[C@H](OC4CCCCO4)c4cccc(Cl)c4)C(=O)OC(C)(C)C)cc3)cc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)n1cc(C(=O)NS(C)(=O)=O)c2ccc(-c3ccc(CCNC[C@H](O)c4cccc(Cl)c4)cc3)cc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 153.4 %

Procedure:
A mixture of tert-butyl [(2R)-2-(3-chlorophenyl)-2-(tetrahydro-2H-pyran-2-yloxy)ethyl][2-[4-[1-isopropyl-3-[[(methylsulfonyl)amino]carbonyl]-1H-indol-6-yl]phenyl]-ethyl]carbamate (132 mg), 10% hydrogen chloride in methanol (2 ml) and 4N hydrogen chloride in 1,4-dioxane (2 ml) was stirred at room temperature for 12 hours. The resulting mixture was evaporated under reduced pressure. The residue was purified by reverse phase column chromatography followed by treatment of 1N hydrochloric acid to give 6-[4-[2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]phenyl]-1-isopropyl-N-(methylsulfonyl)-1H-indole-3-carboxamide hydrochloride (81 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:27][CH2:28][C:29]([NH:31][CH2:32][CH2:33][O:34]C)=[O:30])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:36].B(Br)(Br)Br.O>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:27][CH2:28][C:29]([NH:31][CH2:32][CH2:33][OH:34])=[O:30])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:36]
Reactant: COCCNC(=O)CNc1nc(-c2ccc(F)cc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Cc1cc(F)ccc1-c1nc(NCC(=O)NCCO)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reaction time: 2 h
Yield: 62.1 %

Procedure:
To a soln of the product of Example 205 (50 mg, 0.1 mmol), in dichloromethane (2 mL) was added 1 M boron tribromide in dichloromethane (0.5 mL, 0.5 mmol). The mixture was stirred at 23° for 2 h, H2O was added, extracted with EtOAc. The organic layer was dried (Na2SO4) and concentrated to give the crude material. Recrystallization from dichloromethane and hexane afforded the title product (30 mg, 62%). LC-MS: 484.2 (MH+, m/z), 1.59 (Rt, min).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][C:11]([NH2:13])=[O:12])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[N+:14]([CH:17]=[CH:18][CH3:19])([O-:16])=[O:15]>>[CH3:19][CH:18]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([CH2:10][C:11]([NH2:13])=[O:12])[CH:5]=2)[NH:1][CH:2]=1)[CH2:17][N+:14]([O-:16])=[O:15]
Reactant: CC=C[N+](=O)[O-]
Reactant: NC(=O)Cc1ccc2[nH]ccc2c1
Product: CC(C[N+](=O)[O-])c1c[nH]c2ccc(CC(N)=O)cc12
Reaction time: 24 h

Procedure:
A mixture of 1H-indole-5-acetamide (0.41 g) and 1-nitropropene (0.23 g) was heated at 80° for 24 h and then left at ambient temperature for another 24 h. Chromatography of the thick oil on silica (Merck 7734, 35 g) eluting with ethyl acetate gave a mixture of the title compound and starting material (4:1, 0.26 g) which was used in the next stage without further purification.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9][CH2:8]1)C.O.[OH-].[Li+]>CO.O>[C:17]([O:16][C:14]([NH:13][C@H:10]1[CH2:11][CH2:12][C@H:7]([O:6][CH2:5][C:4]([OH:21])=[O:3])[CH2:8][CH2:9]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: CCOC(=O)CO[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](OCC(=O)O)CC1
Temperature: 25 °C
Reaction time: 2.25 h

Procedure:
A solution of trans (4-tert-butoxycarbonylamino-cyclohexyloxy)-acetic acid ethyl ester (720 mg, 2.40 mmol) in methanol (18 mL) and water (6 mL) as treated with lithium hydroxide monohydrate (210 mg, 5.00 mmol) and stirred at ambient temperature for 2.25 hours. Methanol was removed under vacuum and the residue partitioned between ethyl acetate and 1M HCl. The phases were separated and the aqueous phase extracted into ethyl acetate (2×). The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated under vacuum to afford 600 mg (92%) of trans (4-tert-butoxycarbonylamino-cyclohexyloxy)-acetic acid as a white solid. LCMS (Method Q, ESI): RT=2.96 min, m+H=296.0; 1H NMR (400 MHz, CDCl3) δ: 4.38 (br s, 1H), 4.12 (s, 2H), 3.41 (m, 2H), 2.04 (m, 4H), 1.44 (m, 11H), 1.15 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]([OH:7])[CH:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[CH2:12][CH2:13]2)=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccc(Cl)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(C(O)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.8 %

Procedure:
tert-Butyl 4-(4-chlorobenzoyl)piperidine-1-carboxylate (3.63 g, 11.2 mmol) was dissolved in ethanol (100 mL) then sodium tetrahydroborate (424 mg, 112 mmol) was added to this solution. The reaction mixture was stirred at room temperature for 3 h. LC-MS analysis of the reaction mixture showed no more starting material. The crude reaction mixture was concentrated and the residue was diluted with EtOAc (100 mL) and washed with water (2×50 mL) and brine (50 mL). The organic layer was dried over Na2SO4, filtered and concentrated to yield tert-butyl 4-((4-chlorophenyl)(hydroxy)methyl)piperidine-1-carboxylate (3.46 g, 94%), which was used in the next step directly. m/z: 326 (MH+).
Reaction SMILES: [CH:1]1([C:4]2[N:5](COCC[Si](C)(C)C)[C:6]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:27][CH3:28])[N:22]=3)=[C:7]([C:9]3[C:10]([F:20])=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=3)[N:8]=2)[CH2:3][CH2:2]1.Cl>CCO>[CH:1]1([C:4]2[NH:5][C:6]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:27][CH3:28])[N:22]=3)=[C:7]([C:9]3[C:10]([F:20])=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[CH:12]=[CH:13][CH:14]=3)[N:8]=2)[CH2:2][CH2:3]1
Reactant: CNc1nccc(-c2c(-c3cccc(NS(C)(=O)=O)c3F)nc(C3CC3)n2COCC[Si](C)(C)C)n1
Agent: Cl
Solvent: CCO
Product: CNc1nccc(-c2[nH]c(C3CC3)nc2-c2cccc(NS(C)(=O)=O)c2F)n1
Temperature: 60 °C
Yield: 40.8 %

Procedure:
A solution of N-(3-(2-cyclopropyl-5-(2-(methylamino)pyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-2-fluorophenyl)methanesulfonamide (78 mg, 0.14 mmol) in EtOH (2 mL) was treated with aqueous 6.0 N HCl solution and the resulting reaction was heated at 60° C. for 1 hour. LCMS indicated complete reaction, and the reaction was allowed to cool to room temperature. The volatiles were removed in vacuo, and the resulting residue was dissolved in DMSO and purified by reverse phase HPLC. Product fractions were combined, neutralized with saturated aqueous NaHCO3 solution (pH=6), and extracted with DCM (2×). The combined organic portions were dried (Na2SO4), and concentrated. The resulting free base (3A-1) was dissolved in ACN, treated with aqueous 1.0 N HCl solution, frozen, and lyophilized to provide N-(3-(2-cyclopropyl-5-(2-(methylamino)pyrimidin-4-yl)-1H-imidazol-4-yl)-2-fluorophenyl)methanesulfonamide (23 mg) as the HCl salt (3A-2): LCMS (m/z) 402.9, (MH+), tR=0.44 minute; 1H NMR (300 MHz, CD3CO2D) δ 1.26-1.38 (m, 2H) 1.37-1.52 (m, 2H) 2.41-2.60 (m, 1H) 2.84 (br s, 3H) 3.12 (s, 3H) 7.03 (d, J=6.5 Hz, 1H) 7.29-7.41 (m, 1H) 7.44-7.59 (m, 1H) 7.69-7.84 (m, 1H) 8.29 (d, J=6.5 Hz, 1H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH:11]([OH:14])[CH2:12][NH2:13].Cl.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C:17]1=O.C([BH3-])#N.[Na+]>C(O)C>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH:11]([OH:14])[CH2:12][NH:13][CH:19]1[CH2:20][CH2:21][NH:16][CH2:17][CH2:18]1
Reactant: NCC(O)C1COc2ccccc2O1
Reactant: O=C1CCCCN1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: OC(CNC1CCNCC1)C1COc2ccccc2O1
Reaction time: 16 h

Procedure:
Fifty g of [2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]amine and 85 g of piperidone HCl (ALDRICH) are dissolved in 1000 ml of ethanol. Sodium cyanoborohydride (75 g) is added, and after stirring at ambient conditions overnight (about 16 hr) the mixture is cooled and evaporated. The product is recovered by extraction with methylene chloride to yield 4-{[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]amino}piperidine. This material is of sufficient purity to use in this invention.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:15][C@H:14]([CH2:16][OH:17])[C@H:13]([OH:18])[C@@H:12]2[OH:19])=[C:4]([NH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[N:3]=1.O.[NH2:27][NH2:28]>>[NH:27]([C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[C@H:12]([OH:19])[C@H:13]([OH:18])[C@@H:14]([CH2:16][OH:17])[O:15]2)=[C:4]([NH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[N:3]=1)[NH2:28]
Reactant: NN
Reactant: OC[C@H]1O[C@@H](n2cnc3c(NC4CCCC4)nc(Cl)nc32)[C@@H](O)[C@H]1O
Solvent: O
Product: NNc1nc(NC2CCCC2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(4S,2R,3R,5R) 5-[2-chloro-6-(cyclopentylamino)purin-9-yl]-2-(hydroxymethyl)oxolane-3,4-diol, a compound of formula (2) as prepared in Example 1A, was suspended in hydrazine hydrate (5 mL), and the mixture was allowed to stir at room temperature for 24 hours. The hydrazine was removed by filtration and the residue triturated with ethanol and filtered, to afford (4S,2R,3R,5R)-2-[2-hydrazino-6-(cyclopentylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol, a compound of formula (3), as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[N:19]1([C:25]2[CH:26]=[CH:27][CH:28]=[C:29]3[C:34]=2[N:33]=[CH:32][CH:31]=[CH:30]3)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[F:1][C:2]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][CH:15]([N:22]3[CH2:23][CH2:24][N:19]([C:25]4[CH:26]=[CH:27][CH:28]=[C:29]5[C:34]=4[N:33]=[CH:32][CH:31]=[CH:30]5)[CH2:20][CH2:21]3)[CH2:14][CH2:13]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=C1CCN(c2ccc(F)c3cccnc23)CC1
Reactant: c1cnc2c(N3CCNCC3)cccc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: Fc1ccc(N2CCC(N3CCN(c4cccc5cccnc45)CC3)CC2)c2ncccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 138.3 %

Procedure:
To a solution of 0.120 g of 1-(5-fluoro-quinolin-8-yl)-piperidin-4-one (Step 3, 0.22 g) and 8-piperazin-1-ylquinoline (Oruz, et al., J. Med. Chem. 45:4128 (2002), 0.19 g) was added of 0.19 g sodium triacetoxyborohydride and 0.1 mL acetic acid. The reaction was stirred at room temperature overnight. It was quenched with 1N NaOH, and the product was extracted with CH2Cl2. The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 75 ml of silica gel using 100% Ethyl acetate, to give 0.30 g of the desired product. Mp: 224° C.; MS (ES) m/z (relative intensity): 442 (M++−H, 100).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[I:12]I>C(O)C.[N+]([O-])([O-])=O.[Ag+]>[I:12][C:7]1[CH:8]=[C:2]([CH3:1])[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]=1[NH2:6]
Reactant: II
Reactant: Cc1ccc(N)c([N+](=O)[O-])c1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CCO
Product: Cc1cc(I)c(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
4-Methyl-2-nitroaniline (20 g, 131.5 mmol) was dissolved in ethanol (300 ml), silver nitrate (27 g, 157.7 mmol) and iodine (40 g, 157.7 mmol) were added, and the mixture was stirred for 8 h at room temperature. After completion of the reaction, the reaction mixture was filtered through celite, washed with ethyl acetate (100 ml) and concentrated. Water was added, and the mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate to give 2-iodo-4-methyl-6-nitro-phenylamine (29 g, Yield 69%).
Reaction SMILES: [NH2:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([S:10](=[O:13])(=[O:12])[NH2:11])=[CH:5][C:3]=1[NH2:4].[C:14](O)(=O)[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>Cl>[Cl:9][C:7]1[C:6]([S:10](=[O:12])(=[O:13])[NH2:11])=[CH:5][C:3]2[NH:4][C:14]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:1][C:2]=2[CH:8]=1
Reactant: Nc1cc(Cl)c(S(N)(=O)=O)cc1N
Reactant: O=C(O)CCc1ccccc1
Agent: Cl
Product: NS(=O)(=O)c1cc2[nH]c(CCc3ccccc3)nc2cc1Cl
Reaction time: 0.08 h

Procedure:
To 40 ml of 4 N hydrochloric acid containing 9.4 g of 2-amino-4-chloro-5-sulfamylaniline was added 9.5 g of hydrocinnamic acid and the mixture refluxed for 6 hours. The dark reaction mixture was concentrated in vacuo to a semi-solid which was then added with stirring to 200 ml of 38% ammonium hydroxide. After stirring for thirty minutes, the solid was collected by filtration and then suspended in 200 ml of water at 50° C. Upon stirring for thirty minutes, the product was collected by filtration, dissolved in methanol, and the solution treated with charcoal and boiled for five minutes. The suspension was cooled, filtered through Celite, and concentrated in vacuo to yield pink crystals. Recrystallization from acetonitrile provided 2.6 g of off-white crystals, mp 226°-228°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:21](=[O:25])[NH:22][C:23](=[O:24])[C:19]=2[C:18]2[C:17]3[CH:16]=[C:15]([O:26][CH3:27])[CH:14]=[CH:13][C:12]=3[NH:11][C:10]=2[CH:9]=1.C(=O)(O)[O-].[K+].[C:33](OCC)(=[O:35])[CH3:34]>C(OC(=O)C)(=O)C.Cl(O)(=O)(=O)=O>[C:33]([N:11]1[C:10]2[CH:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:20]3[C:21](=[O:25])[NH:22][C:23](=[O:24])[C:19]=3[C:18]=2[C:17]2[CH:16]=[C:15]([O:26][CH3:27])[CH:14]=[CH:13][C:12]1=2)(=[O:35])[CH3:34]
Reactant: CCOC(C)=O
Reactant: COc1ccc2[nH]c3cc(-c4ccccc4Cl)c4c(c3c2c1)C(=O)NC4=O
Agent: O=C([O-])O
Agent: [K+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)=O
Product: COc1ccc2c(c1)c1c3c(c(-c4ccccc4Cl)cc1n2C(C)=O)C(=O)NC3=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a solution of carbazole (33) (45 mg, 0.12 mmol) prepared as described in example 79 in acetic anhydride (4.0 mL) was added 35% perchloric acid (2 drops). The resulting solution was stirred at room temperature for 30 minutes before being poured onto ice water, basified by the addition of solid potassium bicarbonate and extraction with ethyl acetate. The organic phase was dried, the drying agent was removed and the solution was concentrated to dryness. Chromatography on silica eluting with ethyl acetate/hexane (2:3), followed by trituration from ethyl acetate gave acetamide (338) (40 mg, 80%) as a pale yellow powder, mp 277–280° C. 1H NMR δ [(CD3)2SO] 11.46 (br s, 1H), 8.74 (d, J=2.8 Hz, 1H), 8.53 (s, 1H), 8.17 (d, J=9.2 Hz, 1H), 7.60 (m, 1H), 7.54–7.47 (m, 3H), 7.32 (dd, J=9.2, 2.8 Hz, 1H), 3.93 (s, 3H), 2.91 (s, 3H). Found: C, 65.50; H, 3.49; N, 6.61. C23H15ClN2O4.1/4H2O requires: C, 65.26; H, 3.69; N, 6.62.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:14][C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)=[O:16]>CC(C)=O>[O:4]1[CH2:5][CH2:6][N:1]([CH2:14][C:15]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=2)=[O:16])[CH2:2][CH2:3]1
Reactant: O=C(CBr)Nc1ccc([N+](=O)[O-])cc1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(CN1CCOCC1)Nc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.6 g (30 mmol) of morpholine and 4.2 g (30 mmol) of potassium carbonate are suspended in 120 ml of acetone. 5.3 g (20 mmol) of N-bromoacetyl-4-nitro-aniline, dissolved in 80 ml of acetone, are added dropwise over a period of 20 minutes and then stirred for 2 hours at ambient temperature. The precipitate is filtered off and the solvent is eliminated in vacuo. The residue is suspended with water. The precipitate is suction filtered and dried in a drying cupboard.
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:13][CH3:14])=[CH:6][C:7]([CH3:12])=[C:8]([CH:11]=1)[CH:9]=O)([CH3:3])[CH3:2].[CH3:15][C:16]1[C:24]([Cl:25])=[CH:23][CH:22]=[C:21]2[C:17]=1[CH2:18][C:19](=[O:26])[NH:20]2>>[Cl:25][C:24]1[C:16]([CH3:15])=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:26])[C:18]2=[CH:9][C:8]1[CH:11]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]([O:13][CH3:14])=[CH:6][C:7]=1[CH3:12]
Reactant: COc1cc(C)c(C=O)cc1C(C)C
Reactant: Cc1c(Cl)ccc2c1CC(=O)N2
Product: COc1cc(C)c(C=C2C(=O)Nc3ccc(Cl)c(C)c32)cc1C(C)C

Procedure:
5-Isopropyl-4-methoxy-2-methylbenzaldehyde was condensed with 4-methyl-5-chloro-2-oxindole to give 0.3 g of 5-chloro-3-(5-isopropyl-4-methoxy-2-methylbenzylidene)-4-methyl-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [CH2:1]([N:4]1[CH2:7][CH:6]([C:8]2[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=2)[CH2:5]1)[CH2:2][CH3:3].[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[S:20](Cl)(=[O:22])=[O:21]>>[CH2:1]([N:4]1[CH2:5][CH:6]([C:8]2[CH:9]=[CH:10][C:11]([NH:12][S:20]([C:16]3[S:15][CH:19]=[CH:18][CH:17]=3)(=[O:22])=[O:21])=[CH:13][CH:14]=2)[CH2:7]1)[CH2:2][CH3:3]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CCCN1CC(c2ccc(N)cc2)C1
Product: CCCN1CC(c2ccc(NS(=O)(=O)c3cccs3)cc2)C1

Procedure:
Following the same procedure as described in Example 1.7, 4-(1-propylazetidin-3-yl)aniline was coupled with thiophene-2-sulfonyl chloride to give the title compound.
Reaction SMILES: [C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].Br[CH2:13][CH2:14]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CCOCC>[C:3]([C:2]1([C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH2:14][CH2:13]1)(=[O:4])[CH3:5]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: CC(=O)C1(C(=O)OC(C)(C)C)CC1
Temperature: 55 °C

Procedure:
Step 1 A stirred suspension of tert-butyl acetoacetate (2.1 mL, 12.6 mmol), 1,2-dibromoethane (1.14 mL, 13.3 mmol) and potassium carbonate (3.49 g, 25.3 mmol) in acetone (50.6 mL) was heated to 55° C. over a weekend. Upon cooling the mixture was diluted with Et2O and washed with water (×2). The organic phase was dried (Na2SO4), filtered and concentrated. Biotage column (40+M) eluting with a gradient of 0% Et2O/petrol to 20% Et2O/petrol gave tert-butyl 1-acetylcyclopropane-1-carboxylate, 0.78 g, 29%. 1H NMR (400 MHz, CDCl3): 2.46 (3H, s), 1.51 (9H, s), 1.43-1.38 (4H, m).