Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([C:10]2[CH2:11][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:14][CH:15]=2)[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[N:3]=1.C(N(CC)CC)C.Cl[C:47](Cl)([O:49]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][O:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[C:4]2[CH:5]=[C:6]([C:10]3[CH2:11][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:14][CH:15]=3)[C:7]3[CH2:8][O:9][C:47](=[O:49])[NH:1][C:2]=3[N:3]=2)=[CH:36][CH:35]=1
Reactant: COc1ccc(COc2ccccc2-c2cc(C3=CCCN(C(=O)OC(C)(C)C)C3)c(CO)c(N)n2)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(COc2ccccc2-c2cc(C3=CCCN(C(=O)OC(C)(C)C)C3)c3c(n2)NC(=O)OC3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a cooled (0° C.) solution of tert-butyl 2′-amino-3′-(hydroxymethyl)-6′-{2-[(4-methoxybenzyl)oxy]phenyl }-5,6-dihydro-3,4′-bipyridine-1(2H)-carboxylate (25.0 mg, 0.05 mmol), which was obtained in the step (2) of Example 11-4, and triethylamine (0.02 mL, 0.14 mmol) in THF (3.0 mL) was added a solution of triphosgene (5.7 mg, 0.02 mmol) in THF (3.0 mL), and the stirring was continued for 30 min. The reaction mixture was allowed to warm to room temperature. The reaction was cooled to 0° C. and then quenched by an addition of saturated aqueous NaHCO3 solution, extracted with ethyl acetate. The separated organic phase was washed with brine, dried over MgSO4, filtered and evaporated. The crude product was purified by preparative silica gel TLC (10% acetone in chloroform) to give tertbutyl 5-(7-{2-[(4-methoxybenzyl)oxy]phenyl}-2-oxo-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-5-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate as a white solid. (21.7 mg, yield 83%)
Reaction SMILES: [CH3:1][C:2]([CH3:23])([C:4](=[O:22])[CH:5]([N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)[CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:3]>O1CCOCC1>[CH3:3][C:2]([CH3:23])([C@@H:4]([OH:22])[C@@H:5]([N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)[CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:1]
Reactant: CC(C)(C)C(=O)C(CCCCOc1ccccc1)n1cncn1
Solvent: C1COCCO1
Product: CC(C)(C)[C@@H](O)[C@H](CCCCOc1ccccc1)n1cncn1
Reaction time: 62 h
Yield: 97.2 %

Procedure:
280 g of 2,2-dimethyl-4-(1,2,4-triazol-1-yl)-8-phenoxyoctan-3-one were dissolved in 1.8 liters of dioxane, 10 g of RuO(OH)x were added, and hydrogenation was then carried out in an autoclave for 62 hours under a hydrogen pressure of 25 bar and at 125°. The hydrogenation catalyst was filtered off and the solvent distilled off to give 274 g of residue; according to NMR analysis, this residue contained, in addition to 5% of the starting ketone, the compound No. 1 (R*,S*) and its diastereomer (R*,R*) in a ratio of 7:3. It was possible to isolate the compound No. 1 from the mixture by crystallization from diisopropyl ether.
Reaction SMILES: [C:1]([C:5]1[O:9][C:8]([C:10]2[C:11]([NH2:28])=[N:12][CH:13]=[C:14]([C:16]3[N:20]([CH3:21])[N:19]=[C:18]([CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[N:17]=3)[N:15]=2)=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.[OH:38][C@H:39]([CH3:44])[CH2:40][C:41](O)=[O:42]>CN(C)C=O.C(#N)C>[NH2:28][C:11]1[N:12]=[CH:13][C:14]([C:16]2[N:20]([CH3:21])[N:19]=[C:18]([CH:22]3[CH2:23][CH2:24][N:25]([C:41](=[O:42])[CH2:40][C@H:39]([OH:38])[CH3:44])[CH2:26][CH2:27]3)[N:17]=2)=[N:15][C:10]=1[C:8]1[O:9][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[N:6][N:7]=1
Reactant: C[C@@H](O)CC(=O)O
Reactant: Cn1nc(C2CCNCC2)nc1-c1cnc(N)c(-c2nnc(C(C)(C)C)o2)n1
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)CC(=O)N1CCC(c2nc(-c3cnc(N)c(-c4nnc(C(C)(C)C)o4)n3)n(C)n2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.2 %

Procedure:
2-(1H-Benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (201 mg, 0.63 mmol) was added to a stirred suspension of 3-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-(1-methyl-3-(piperidin-4-yl)-1H-1,2,4-triazol-5-yl)pyrazin-2-amine (200 mg, 0.52 mmol, described in Example 1), N-ethyl-N-isopropylpropan-2-amine (0.273 mL, 1.56 mmol) and (R)-3-hydroxybutanoic acid (65.2 mg, 0.63 mmol) in N,N-dimethylformamide (3 mL). The resulting suspension was stirred at room temperature for 2 hours. The resulting mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 30 mm diameter, 150 mm length, flow rate of 60 ml/minute) using an isocratic mixture of 31% acetonitrile in water (containing ammonium carbonate (2 g/L). The fractions containing the desired compound were evaporated to dryness to afford a pale yellow solid. This solid was stirred in acetonitrile (3 mL) at room temperature. The resulting solid was filtered, washed with cold acetonitrile and dried to afford the title compound (125 mg, 51.0%) as a pale yellow solid.
Reaction SMILES: [C:1]1(B(O)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:19])=[O:18])=[CH:13][C:12]=1Br>>[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:19])=[O:18])=[CH:13][C:12]=1[C:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: OB(O)C1=CCCCC1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(N)c(Br)c1
Product: CC(C)(C)NS(=O)(=O)c1ccc(N)c(C2=CCCCC2)c1
Yield: 70.5 %

Procedure:
4-Amino-N-tert-butyl-3-cyclohex-1-enyl-benzenesulfonamide was prepared according to the Suzuki coupling procedure of Example 44, step (b) using cyclohex-1-enyl boronic acid (63 mg, 0.50 mmol) and 4-amino-3-bromo-N-tert-butyl-benzenesulfonamide (123 mg, 0.400 mmol, as prepared above) to obtain 4-amino-N-tert-butyl-3-cyclohex-1-enyl-benzenesulfonamide (87 mg, 70%) after purification on silica (30% EtOAc/hexanes). Mass spectrum (ESI, m/z): Calcd. for C16H24N2O2S, 309.1 (M+H), found 309.1
Reaction SMILES: Br[C:2]1[C:11]([F:12])=[C:10]2[C:5]([C:6](=[O:21])[C:7]([C:16]([O:18]CC)=[O:17])=[CH:8][N:9]2[CH:13]2[CH2:15][CH2:14]2)=[C:4]([F:22])[C:3]=1[F:23].[CH3:24][C:25]1[CH:30]=[C:29]([Sn](C)(C)C)[CH:28]=[C:27]([CH3:35])[N:26]=1.CN(C)P(N(C)C)(N(C)C)=O>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[CH:13]1([N:9]2[C:10]3[C:5](=[C:4]([F:22])[C:3]([F:23])=[C:2]([C:30]4[C:25]([CH3:24])=[N:26][C:27]([CH3:35])=[CH:28][CH:29]=4)[C:11]=3[F:12])[C:6](=[O:21])[C:7]([C:16]([OH:18])=[O:17])=[CH:8]2)[CH2:15][CH2:14]1
Reactant: Cc1cc([Sn](C)(C)C)cc(C)n1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(Br)c(F)c(F)c2c1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Cc1ccc(-c2c(F)c(F)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)c(C)n1
Yield: 57.4 %

Procedure:
A mixture of 2.8 g ethyl 7-bromo-1-cyclopropyl-5,6,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, 2.2 g 2,6-dimethyl-4-(trimethylstannyl)pyridine (Example 1, part g), 2 ml hexamethylphosphoramide, 320 mg dichlorobis(triphenylphosphine)palladium and 50 ml dioxane was stirred and heated under reflux in an argon atmosphere for 24 hours. The reaction mixture was concentrated to dryness and the residue was treated with 100 ml of 1N hydrochloric acid and heated at reflux for 2 hours. The latter mixture was filtered and the filtrate concentrated to dryness. The residue was dissolved in 50 ml 5% aqueous potassium carbonate, decolorized with charcoal and filtered. The filtrate was acidified with concentrated hydrochloric acid, sodium acetate added, and the resulting precipitate was collected, dried and recrystallized from ethanol to give 1.6 g 1-cyclopropyl-7-(2,6-dimethylpyridinyl)-5,6,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid as a cream-colored solid, m.p. 264°-266° C.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9][C:8]=2[C:7]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[N:6]1)[CH2:2][CH2:3][CH3:4].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH:27]=O>>[CH2:1]([N:5]1[C:14]2[CH2:13][CH2:12][N:11]([CH2:27][C:26]3[CH:29]=[CH:30][C:31]([O:32][CH3:33])=[C:24]([O:23][CH3:22])[CH:25]=3)[CH2:10][CH2:9][C:8]=2[C:7]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[N:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccc(C=O)cc1OC
Reactant: CCCCn1nc(-c2ccc(Cl)cc2)c2c1CCNCC2
Product: CCCCn1nc(-c2ccc(Cl)cc2)c2c1CCN(Cc1ccc(OC)c(OC)c1)CC2
Yield: 38.2 %

Procedure:
The title compound (8 mg) was prepared from 1-butyl-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene (Example 67, 14 mg) using 3,4-dimethoxy-benzaldehyde (0.2 mmol) in place of formaldehyde. MS (ESI): exact mass calculated for C26H32ClN3O2, 453.22; found, m/z 454.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.38 (d, J=8.4 Hz, 2H), 7.28 (d, J=8.4 Hz, 2H), 7.20 (s, 1H), 6.91-6.90 (br m, 1H), 6.81 (d, J=8.2 Hz, 1H), 6.75 (d, J=8.2 Hz, 1H), 3.98 (t, J=7.3 Hz, 2H), 3.82 (d, J=7.0 Hz, 6H), 3.66 (s, 2H), 2.78-2.72 (br m, 8H), 1.67 (m, 2H), 1.27 (m, 2H), 0.86 (t, J=7.3 Hz, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:12](OC)=[O:13])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Li+]>O1CCCC1>[OH:13][CH2:12][C:9]1([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:10][CH2:11]1
Reactant: COC(=O)C1(NC(=O)OC(C)(C)C)CC1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(CO)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.3 %

Procedure:
To a cooled solution of methyl 1-[(tert-butoxycarbonyl)amino]cyclopropanecarboxylate (1.2 g, 5.6 mmol) in tetrahydrofuran (10 mL) at 0° C. was added dropwise a solution of lithium borohydride (244 mg, 11.2 mmol) in tetrahydrofuran (10 mL) The reaction mixture was allowed to warm to room temperature and stirred at this temperature overnight. The reaction was quenched by addition of water (10 mL) and the resulting mixture was extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated in vacuo to afford 0.8 g of the product (yield was 76.2%).
Reaction SMILES: [C:1]1([C:6]2[CH:7]=[CH:8][C:9]([N+:20]([O-])=O)=[C:10]([NH:12][C:13](=[O:19])[N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[CH:11]=2)[CH2:5][CH2:4][CH2:3][CH:2]=1.C([O-])=O.[NH4+]>CO.[Zn]>[NH2:20][C:9]1[CH:8]=[CH:7][C:6]([C:1]2[CH2:5][CH2:4][CH2:3][CH:2]=2)=[CH:11][C:10]=1[NH:12][C:13](=[O:19])[N:14]([CH3:18])[CH2:15][CH2:16][CH3:17]
Reactant: CCCN(C)C(=O)Nc1cc(C2=CCCC2)ccc1[N+](=O)[O-]
Agent: O=C[O-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: CCCN(C)C(=O)Nc1cc(C2=CCCC2)ccc1N
Reaction time: 2 h
Yield: 78.4 %

Procedure:
To a stirred solution 3-(5-(cyclopent-1-en-1-yl)-2-nitrophenyl)-1-methyl-1-propyl urea (0.17 g, 0.56 mmol, 1.0 equiv.) in MeOH were added Zn (0.18 g, 2.80 mmol, 5.0 equiv.) and HCOONH4 (0.28 d, 4.48 mmol, 8.0 equiv.) at room temperature. The reaction was stirred for 2 h then filtered through celite. The organic layer was concentrated and the crude residue was purified by column chromatography (silica gel, 5% MeOH/CH2Cl2) to afford 3-(2-amino-5-(cyclopent-1-en-1-yl)phenyl)-1-methyl-1-propylurea (0.12 g, 78% yield). ESI+ MS: m/z 274 ([M+H]+), 1H NMR (500 MHz, d6-DMSO): δ 7.61 (s, 1H), 7.08 (d, J=1.5 Hz, 1H), 7.01 (dd, J=8.0, 1.5 Hz, 1H), 6.66 (d, J=8.0 Hz, 1H), 5.94-8.90 (m, 1H), 4.77 (s, 2H), 3.24 (t, J=7.5 Hz, 2H), 2.92 (s, 3H), 2.58-2.52 (m, 2H), 2.46-2.40 (m, 2H), 1.95-1.86 (m, 2H), 1.52 (next, J=7.5 Hz, 2H), 0.86 (t, J=7.5 Hz, 3H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][O:21][C:22](=[O:34])[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][N:30]=[N+]=[N-])=[CH:25][C:24]=1[Cl:33]>O1CCCC1.O>[CH3:20][O:21][C:22](=[O:34])[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][NH2:30])=[CH:25][C:24]=1[Cl:33]
Reactant: COC(=O)c1ccc(CN=[N+]=[N-])cc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CN)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.8 %

Procedure:
Add triphenylphosphine (30.3 g, 115 mmol) to crude 4-azidomethyl-2-chloro-benzoic acid methyl ester (5.8 g, 25.7 mmol) in tetrahydrofuran (152 mL) and water (4.6 mL). Stir the reaction mixture at room temperature overnight. Concentrate the reaction mixture and partition the residue between 1N hydrochloric acid and ethyl acetate. Separate the organic layer and wash the organic layer with water. Combine the aqueous layers, wash with ethyl acetate, and then neutralize with 1N sodium hydroxide. Extract the resulting aqueous mixture with ethyl acetate (3×). Combine the organic layers, wash with brine, dry over sodium sulfate, and concentrate to provide the crude title compound (2.2 g, 11.0 mmol). MS (m/z): 200 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:23]([O:25]CC)=[O:24])=[CH:21][N:22]=3)[CH2:14][C@H:13]2[O:28][CH2:29][CH2:30][CH3:31])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+].CO>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:23]([OH:25])=[O:24])=[CH:21][N:22]=3)[CH2:14][C@H:13]2[O:28][CH2:29][CH2:30][CH3:31])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCCO[C@@H]1CN(c2ncc(C(=O)OCC)s2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCO[C@@H]1CN(c2ncc(C(=O)O)s2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 84.4 %

Procedure:
The same operation as in Example (91d) was performed using ethyl cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-propoxypiperidin-1-yl)-1,3-thiazole-5-carboxylate obtained in Example (126b) (0.27 g, 0.59 mmol), 2 N lithium hydroxide (5 mL, 10 mmol), methanol (5 mL) and THF (5 mL), to obtain 0.22 g of the title compound as a colorless solid (87%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[C:15](Br)[CH:16]=[C:11]2[C:10]([C:18](=[O:27])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[S:34]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35]1.C1COCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([C:36]3[CH:37]=[CH:38][S:34][CH:35]=3)[CH:16]=[C:11]2[C:10]([C:18](=[O:27])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cccc(C(=O)c2cn(C(=O)OC(C)(C)C)c3ncc(Br)cc23)c1
Reactant: OB(O)c1ccsc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(C(=O)c2cn(C(=O)OC(C)(C)C)c3ncc(-c4ccsc4)cc23)c1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Azaindole 26 (33 mg, 0.00076 mol), Potassium carbonate (44 mg, 0.00032 mol), 3-thiophene boronic acid (20 mg, 0.0002 mol), THF (7 mL), water (1.5 mL), and tetrakis(triphenylphosphine)palladium (0) (5 mg, 0.000004 mol) were added to a round bottom flask. The reaction mixture was stirred under nitrogen at 70° C. for overnight. The solvent was removed and the resulting residue was dissolved in EtOAc, washed with brine, dried over MgSO4 and concentrated. The desired product was purified by silica gel flash chromatography using a 90:10 Hexane/ETOAc solvent system. The product 27 was identified by LC/MS and H1-NMR. LRMS (ESI+): (M+H+)+ 436.5
Reaction SMILES: C(N(CC)C(C)C)(C)C.[S:10](Cl)([CH3:13])(=[O:12])=[O:11].[C:15]([O:19][C:20]([N:22]1[CH2:26][C@H:25]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH2:24][C@H:23]1[CH2:35][OH:36])=[O:21])([CH3:18])([CH3:17])[CH3:16].[Cl-].[NH4+]>C(Cl)Cl>[C:15]([O:19][C:20]([N:22]1[CH2:26][C@H:25]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH2:24][C@H:23]1[CH2:35][O:36][S:10]([CH3:13])(=[O:12])=[O:11])=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CO
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1COS(C)(=O)=O
Reaction time: 0.5 h

Procedure:
N,N-Diisopropylethylamine (21.1 ml, 121 mmol) and mesyl chloride (4.67 ml, 60.3 mmol) were successively added to a solution of (2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-hydroxymethylpyrrolidine (10.2 g, 30.2 mmol; the compound of Reference Example 1-3) in European Laid Open Patent Application No. 449191) in methylene chloride (200 ml) in a nitrogen stream under cooling with ice and the resulting liquid mixture was stirred at the same temperature for 30 minutes. To this reaction solution, saturated aqueous ammonium chloride was added to terminate the reaction. The reaction mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain (2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-(mesyloxymethyl)pyrrolidine as the residue.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]3[CH:25]=[C:24]([OH:26])[C:23]([O:27][CH3:28])=[CH:22][C:19]=3[CH:20]=2)[N:15]=[CH:14][C:13]=1[C:29]#[N:30].C1(C)C=CC(S(O[CH2:41][CH2:42][CH2:43][Cl:44])(=O)=O)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:44][CH2:43][CH2:42][CH2:41][O:26][C:24]1[C:23]([O:27][CH3:28])=[CH:22][C:19]2[CH:20]=[C:21]3[C:16](=[CH:17][C:18]=2[CH:25]=1)[N:15]=[CH:14][C:13]([C:29]#[N:30])=[C:12]3[NH:11][C:3]1[CH:4]=[C:5]([O:9][CH3:10])[C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1]
Reactant: COc1cc2cc3c(Nc4cc(OC)c(Cl)cc4Cl)c(C#N)cnc3cc2cc1O
Reactant: Cc1ccc(S(=O)(=O)OCCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc(Nc2c(C#N)cnc3cc4cc(OCCCCl)c(OC)cc4cc23)c(Cl)cc1Cl
Yield: 23.3 %

Procedure:
Following the procedure of Example 16, 0.43 g (0.98 mmol) of 4-(2,4-dichloro-5-methoxyphenylamino)-8-hydroxy-7-methoxybenzo[g]quinoline-3-carbonitrile is reacted with 0.31 g (1.25 mmol) of 3-chloropropyl p-toluene sulfonate and 0.48 g of (1.47 mmol) of cesium carbonate, then an additional 0.05 g (0.2 mmol) of 3-chloropropyl p-toluene sulfonate and 0.07 g (0.2 mmol) of cesium carbonate in 6 mL of dry dimethyl formamide. The crude product is purified by silica gel flash chromatography, utilizing a 99.5:0.5 to 99:1 gradient of methylene chloride/methanol to give 0.118 g of 8-(3-chloropropoxy)-4-(2,4-dichloro-5-methoxyphenylamino)-7-methoxybenzo[g]quinoline-3-carbonitrile as a yellow solid, mp 220-223° C.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[OH:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2.N1C=CC=CC=1.C(Cl)Cl>O>[CH3:2][C:1]([O:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:3]
Reactant: CC(=O)Cl
Reactant: Oc1cnc2ccccc2c1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Oc1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1.35 ml of acetyl chloride are added dropwise to a mixture of 2.5g of 3-hydroxyquinoline (prepared by the method described by Mills and Watson in J.Chem. Soc., 97, 753 (1910)), 8.6 ml of pyridine and 50 ml of methylene chloride, while cooling with ice. After the reaction mixture has been stirred at room temperature for 10 minutes, 50 ml of water are added. Customary working up and purification of the crude product by FC over 50 g of silica gel (mobile phase C) gives 3-methylcarbonyloxyquinoline: Rf (A)=0.55; IR (CH2Cl2): 1770(s) cm-1.
Reaction SMILES: C([O:5][CH2:6][CH2:7][O:8][NH:9][C:10]([C:12]1[C:13]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([I:30])=[CH:26][C:25]=2[F:31])=[C:14]([F:22])[C:15](=[O:21])[N:16]2[C:20]=1[CH2:19][CH2:18][CH2:17]2)=[O:11])(C)(C)C>C(O)(C(F)(F)F)=O>[F:22][C:14]1[C:15](=[O:21])[N:16]2[C:20](=[C:12]([C:10]([NH:9][O:8][CH2:7][CH2:6][OH:5])=[O:11])[C:13]=1[NH:23][C:24]1[CH:29]=[CH:28][C:27]([I:30])=[CH:26][C:25]=1[F:31])[CH2:19][CH2:18][CH2:17]2
Reactant: CC(C)(C)OCCONC(=O)c1c(Nc2ccc(I)cc2F)c(F)c(=O)n2c1CCC2
Solvent: O=C(O)C(F)(F)F
Product: O=C(NOCCO)c1c(Nc2ccc(I)cc2F)c(F)c(=O)n2c1CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.2 %

Procedure:
Compound 4a (730 mg, 1.33 mmol) was dissolved in TFA (4 mL) and stirred at r.t. for 1 hour. Purification by prep-HPLC gave 393 mg (60%) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.47 (br s, 1H) 8.06 (br s, 1H) 7.58 (dd, 1H, J=10.7, 1.6 Hz) 7.42 (d, 1H, J=8.8 Hz) 6.80 (td, 1H, J=8.7, 2.8 Hz) 4.01 (t, 2H, J=7.3 Hz) 3.77 (t, 2H, J=4.8 Hz) 3.45 (t, 2H, J=4.8 Hz), 3.18 (t, 2H, J=7.7 Hz) 2.11-2.16 (m, 2H). MS (ES) [m+H] calc'd for C17H16F2IN3O4, 492. found 492.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.C(N(C(C)C)CC)(C)C.[F:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:30]=1[N:29]=[C:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:27]([CH2:37][NH2:38])=[CH:26]2>C(O)CCC>[F:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:30]=1[N:29]=[C:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:27]([CH2:37][NH:38][C:2]1[N:10]=[CH:9][N:8]=[C:7]3[C:3]=1[NH:4][CH:5]=[N:6]3)=[CH:26]2
Reactant: NCc1cc2cccc(F)c2nc1-c1ccccc1
Reactant: Brc1ncnc2nc[nH]c12
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Fc1cccc2cc(CNc3ncnc4nc[nH]c34)c(-c3ccccc3)nc12
Temperature: 110 °C

Procedure:
To a reaction flask was added 6-bromopurine (19 mg, 95 μmol, 1.2 eq), diisopropylethylamine (42 μl, 238 μmol, 3 eq), (8-fluoro-2-phenylquinolin-3-yl)-methanamine (20 mg, 79 μmol, 1 eq), and n-butanol (0.75 mL). The reaction was heated to 110° C. for 8 h. The reaction was cooled to rt and the solvent was removed in vacuo. The compound was purified by reverse phase HPLC. The fractions were concentrated and freebased with sat. NaHCO3. The organic layer was extracted into DCM, dried over MgSO4, filtered, and concentrated to afford a white solid, N-((8-fluoro-2-phenylquinolin-3-yl)methyl)-7H-purin-6-amine. 1H NMR (400 MHz, CDCl3) δ ppm 8.35 (s, 1H), 8.31 (s, 1H), 7.90 (s, 1H), 7.68 (m, 2H), 7.45 (m, 6H), 6.78 (br s, 1H), 5.07 (br s, 2H). Mass Spectrum (ESI) m/e=370.9 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][C:3]=1[S:15](=[O:18])(=[O:17])[NH2:16].[C:19](Cl)(=O)C.C(O)(=O)C.C(=O)(O)[O-].[Na+]>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:14])[CH2:9][CH2:10][C:11]([O:13][CH3:19])=[O:12])=[CH:4][C:3]=1[S:15](=[O:17])(=[O:18])[NH2:16]
Reactant: NS(=O)(=O)c1cc(C(=O)CCC(=O)O)ccc1Cl
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: COC(=O)CCC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
27 g of 4-(4-chloro-3-sulfamoylphenyl)-4-oxobutanoic acid are dissolved in 200 ml of methanol, 1 g of acetyl chloride is added and the mixture is stirred at room temperature. After 24 hours, only small amounts of starting material can still be detected in the thin layer chromatogram. The solvent is driven off, the residue is treated with 200 ml of acetic acid/200 ml of water and, after the pH has been adjusted to 8 with saturated sodium bicarbonate solution, the mixture is stirred vigorously for 30 minutes. After separating off the organic phase and drying it over sodium sulfate, the solvent is distilled off and methyl 4-(4-chloro-3-sulfamoylphenyl)-4-oxobutanoate is obtained.