Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[N:12]([CH2:15][C@H:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[CH:26][C:25]([S:28][CH3:29])=[C:24]([F:30])[CH:23]=2)[CH2:17]1)=[N+:13]=[N-:14]>C(Cl)Cl>[N:12]([CH2:15][C@H:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:29])=[O:6])=[C:24]([F:30])[CH:23]=2)[CH2:17]1)=[N+:13]=[N-:14]
Reactant: CSc1ccc(N2C[C@@H](CN=[N+]=[N-])OC2=O)cc1F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1ccc(N2C[C@@H](CN=[N+]=[N-])OC2=O)cc1F
Temperature: 25 °C
Yield: 94.7 %

Procedure:
m-Chloroperoxybenzoic acid (77%, 0.079 g, 0.354 mmol) was added portionwise with stirring to a solution of 5-(S)-azidomethyl-3-[4′-methylthio-3′-fluorophenyl]oxazolidine-2-one (0.100 g, 0.354 mmol) in DCM (4 ml) at 0° C. The mixture was allowed to warm up to r.t. over 2 h. The mixture was washed with aq. saturated sodium bicarbonate, brine, dried (MgSO4), and evaporated to give product as a white solid (0.100 g, 95%). MS (m/z): [M+H]+=299.
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:21])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[O:32])[CH:27]=[CH:28][CH:29]=1>>[C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:21][C:31]([NH:30][C:26]4[CH:27]=[CH:28][CH:29]=[C:24]([O:23][CH3:22])[CH:25]=4)=[O:32])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: COc1cccc(N=C=O)c1
Product: COc1cccc(NC(=O)Nc2ccc3nc(N[C@@H]4CCc5ccccc54)ccc3c2)c1

Procedure:
The title compound, MS: m/e=425.7 (M+H+), was prepared in accordance with the general method 4 of example 16 from (R)—N2-indan-1-yl-quinoline-2,6-diamine and 3-methoxyphenyl-isocyanate.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:23])=[C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:8]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:9]2=[O:12])=[CH:4][CH:3]=1.[CH2:24](O)[CH2:25][CH2:26][CH3:27].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH2:24]([O:23][C:6]1[C:5]2[C:10](=[CH:11][C:2]([F:1])=[CH:3][CH:4]=2)[C:9](=[O:12])[N:8]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:7]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:25][CH2:26][CH3:27]
Reactant: CCCCO
Reactant: CCOC(=O)c1c(O)c2ccc(F)cc2c(=O)n1CC(C)(C)C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCCCOc1c(C(=O)OCC)n(CC(C)(C)C)c(=O)c2cc(F)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.1 %

Procedure:
To a solution of ethyl 7-fluoro-4-hydroxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (5.12 g, 31.9%) (from Example 1(1), 3.21 g, 10 mmol), 1-butanol (1.4 ml, 15 mmol) and tributylphosphine (5.0 ml, 20 mmol) in tetrahydrofuran (30 ml) was added 1,1′-(azodicarbonyl)dipiperidine (5.05. g, 20 mmol) and the mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated, under reduced pressure and the residue was purified by silica gel column chromatography to give ethyl 4-butoxy-7-fluoro-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (3.55 g, 94.2%) as an oil.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[C:8]2[O:13][CH2:14][C:15]([OH:17])=O.C(Cl)(=O)C(Cl)=O.[CH:26]1[C:31]([NH2:32])=[CH:30][CH:29]=[C:28]([S:33]([NH:36][C:37]2[S:41][CH:40]=[CH:39][N:38]=2)(=[O:35])=[O:34])[CH:27]=1.N1C=CC=CC=1>C(Cl)Cl>[S:41]1[CH:40]=[CH:39][N:38]=[C:37]1[NH:36][S:33]([C:28]1[CH:27]=[CH:26][C:31]([NH:32][C:15](=[O:17])[CH2:14][O:13][C:8]2[C:7]3[C:12](=[C:3]([C:2]([F:1])([F:19])[F:18])[CH:4]=[CH:5][CH:6]=3)[N:11]=[CH:10][CH:9]=2)=[CH:30][CH:29]=1)(=[O:35])=[O:34]
Reactant: O=C(O)COc1ccnc2c(C(F)(F)F)cccc12
Reactant: Nc1ccc(S(=O)(=O)Nc2nccs2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(COc1ccnc2c(C(F)(F)F)cccc12)Nc1ccc(S(=O)(=O)Nc2nccs2)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 69.5 %

Procedure:
(8-Trifluoromethylquinolin-4-yloxy)-acetic acid (0.50 g, 1.84 mmol) was suspended in 20 mL DCM with rapid stirring. At rt, oxalyl chloride (0.19 mL, 1.2 equiv) was added dropwise and stirring continued for 4 h. Solvent and excess oxalyl chloride were removed in vacuo, the white residue was re-suspended in DCM, and the mixture cooled to 0° C. N′-(2-thiazolyl)sulfanilamide (0.47 g, 1.0 equiv) was added followed by pyridine (0.30 mL, 2.0 equiv). The mixture was allowed to warm to rt overnight. The solid was collected and rinsed with fresh DCM. Further purification was effected by suspending the solid in 20 mL methanol, stirring vigorously for 4 h, and filtration. After drying under vacuum, white solid 0.65 g (69%) was obtained. 1H-NMR (DMSO-d6) 5.11 (s, 2H), 6.79 (d, J=4.8 Hz, 1H), 7.12 (d, J=5.2 Hz, 1H), 7.22 (d, J=4.8 Hz, 1H), 7.71 (t, J=8.0 Hz, 1H), 8.17 (d, J=8.0 Hz, 1H), 8.55 (d, J=8.0 Hz, 1H), 8.85 (d, J=5.2 Hz, 1H); 13C-NMR (DMSO-d6) 68.0, 103.6, 108.8, 120.0, 122.0, 124.8 (q, J=270 Hz), 125.1, 125.4, 126.4 (q, J=33 Hz), 127.7, 127.8, 129.2, 137.7, 142.1, 145.6, 153.2, 161.2, 166.5, 169.4 LC/MS (10-99%) M/Z: M+1 obs=509.5; tR=3.13 min.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[N:10][CH:9]=[C:8]([CH:12]=[CH2:13])[N:7]=1)([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]1[CH:28]=[CH:27][CH:26]=[CH:25][C:16]=1[O:17][CH2:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C(O)C>[C:1]([O:5][C:6]1[CH:11]=[N:10][CH:9]=[C:8]([CH2:12][CH2:13][N:22]2[CH2:21][CH2:20][CH:19]([CH2:18][O:17][C:16]3[CH:25]=[CH:26][CH:27]=[CH:28][C:15]=3[F:14])[CH2:24][CH2:23]2)[N:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=Cc1cncc(OC(C)(C)C)n1
Reactant: Fc1ccccc1OCC1CCNCC1
Solvent: CCO
Product: CC(C)(C)Oc1cncc(CCN2CCC(COc3ccccc3F)CC2)n1
Yield: 11.8 %

Procedure:
After dissolving 262 mg of 2-tert-butoxy-6-vinylpyrazine and 401 mg of 4-(2-fluorophenoxymethyl)piperidine [CAS No. 63608-34-4] in 3 ml of ethanol, the mixture was stirred for 2 days at 80° C. The reaction solution was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (67 mg, 12% yield).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]([O:20][CH3:21])([CH3:19])[CH3:18])[CH2:12][CH2:11]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.O.[Pd]>[CH3:21][O:20][C:17]([CH3:19])([CH3:18])[CH2:16][N:13]1[CH2:14][CH2:15][CH:10]([CH2:9][NH2:8])[CH2:11][CH2:12]1
Reactant: COC(C)(C)CN1CCC(CN(Cc2ccccc2)Cc2ccccc2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: COC(C)(C)CN1CCC(CN)CC1
Temperature: 80 °C
Yield: 74.2 %

Procedure:
To a solution of N,N-dibenzyl-N-{[1-(2-methoxy-2-methylpropyl)piperidin-4-yl]methyl}amine (EXAMPLE 4, Step 5, 756 mg, 1.85 mmol) and ammonium formate (583 mg, 9.24 mmol) in methanol (40 mL) and water (15 mL) was added 10% palladium on carbon (185 mg) at ambient temperature. The mixture was heated at 80° C. for 6 h. After cooling, the mixture was filtered through a pad of Celite and the filtrate was concentrated in vacuo. The obtained residue was partitioned between dichlorometane and aqueous ammonia. After extraction with dichloromethane, the combined organic extract was dried over magnesium sulfate and concentrated to give 275 mg (66%) of the title compound as a pale yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:18]([NH2:21])(=[O:20])=[O:19])[CH:7]=[N:8][C:9]=1[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]([S:18]([NH2:21])(=[O:20])=[O:19])[CH:7]=[N:8][C:9]=1[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: NS(=O)(=O)c1cnc(NCC2CCOCC2)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(S(N)(=O)=O)cnc1NCC1CCOCC1
Reaction time: 8 h

Procedure:
A mixture of EXAMPLE 364E (0.16 g) and 5% palladium on carbon (0.025 g) in ethanol (5 mL) was treated with a balloon of hydrogen. The reaction mixture was stirred overnight. The solid was filtered off. The filtrate was concentrated. The residue was purified by flash chromatography on silica gel to give the title compound.
Reaction SMILES: [NH2:1][NH2:2].O[C:4]1[C:5]([OH:10])=[N:6][CH:7]=[CH:8][CH:9]=1>COCCOC>[NH:1]([C:9]1[CH:8]=[CH:7][NH:6][C:5](=[O:10])[CH:4]=1)[NH2:2]
Reactant: NN
Reactant: Oc1cccnc1O
Solvent: COCCOC
Product: NNc1cc[nH]c(=O)c1
Temperature: 25 °C
Yield: 78 %

Procedure:
To a solution of hydrazine (8 mL) in DME (40 mL) was added dihydroxypyridine (2.00 g, 18 mmol) and the reaction heated at reflux overnight. The solution was cooled to rt, and the solids removed by filtration. The filtrate was concentrated and the resulting solid crystallized from hot EtOH to afford 4-hydrazinylpyridin-2(1H)-one (1.75 g, 78% yield). LC-MS (ESI) m/z 126 (M+H)+.
Reaction SMILES: C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.[CH3:26][O:27][C:28]1[N:33]=[CH:32][C:31]([NH:34][CH:35]=[C:36]([C:42](=[O:46])[CH:43]([CH3:45])[CH3:44])[C:37]([O:39]CC)=O)=[CH:30][CH:29]=1>>[OH:39][C:37]1[C:32]2[C:31](=[CH:30][CH:29]=[C:28]([O:27][CH3:26])[N:33]=2)[N:34]=[CH:35][C:36]=1[C:42](=[O:46])[CH:43]([CH3:44])[CH3:45]
Reactant: CCOC(=O)C(=CNc1ccc(OC)nc1)C(=O)C(C)C
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1ccc2ncc(C(=O)C(C)C)c(O)c2n1
Temperature: 25 °C
Reaction time: 0.62 h
Yield: 141.6 %

Procedure:
To a flask containing Dowtherm™ A (400 mL) at 250° C. was added ethyl 2-(((6-methoxypyridin-3-yl)amino)methylene)-4-methyl-3-oxopentanoate (11.5 g, 39.3 mmol) portion wise over 3 to 5 min and the reaction mixture was stirred for an additional 30 to 45 min. The reaction mixture was removed from the heat source, cooled to room temperature and diluted with hexanes to facilitate precipitation. The solids were filtered, washed with hexanes and dried under vacuum to afford the desired product (13.7 g, crude) as a yellow-brown solid: ESI MS m/z 247 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:21])[C:7](=[O:20])[C:8]([F:19])([F:18])[CH2:9][N:10]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[F:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26]>Cl.CC(O)C>[CH:13]1([N:10]2[CH2:9][C:8]([F:19])([F:18])[C:7](=[O:20])[N:6]([CH3:21])[C:5]3[CH:4]=[N:3][C:2]([NH:26][C:25]4[CH:27]=[CH:28][CH:29]=[C:23]([F:22])[CH:24]=4)=[N:12][C:11]2=3)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: Nc1cccc(F)c1
Agent: Cl
Solvent: CC(C)O
Product: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3cccc(F)c3)ncc21

Procedure:
2-Chloro-9-cyclopentyl-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[5,4-b][1,4]diazepin-6(7H)-one (100 mg, 0.32 mmol), 3-fluoroaniline (54 mg, 0.48 mmol), i-PrOH (2 mL) and conc. HCl (5 drops) were heated to 100° C. overnight to give the title compound. The final compound was purified by reverse phase HPLC and basified to give the free base (50 mg, 40%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.58-1.96 (m, 8H) 4.04 (t, J=14 Hz, 2H) 4.78 (m, 1H) 6.59-6.87 (m, 1H) 7.16-7.33 (m, 1H) 7.38 (d, J=8 Hz, 1H) 7.79 (d, J=12 Hz, 1H) 8.26 (s, 1H) 9.66 (br. s., 1H). [M+H] calc'd for C19H20F3N5O, 392. found 392.
Reaction SMILES: COCCOC.Cl[C:8]1[S:12][N:11]=[C:10]([S:13][CH3:14])[N:9]=1.[Cl:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:14][S:13][C:10]1[N:9]=[C:8]([C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:15])[S:12][N:11]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CSc1nsc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CSc1nsc(-c2ccccc2Cl)n1
Yield: 50.8 %

Procedure:
To 25 ml of 1,2-dimethoxyethane were added 2.0 g of 5-chloro-3-methylthio-1,2,4-thiadiazole, 2.25 g of 3-chlorophenylboronic acid, 694 mg of tetrakistriphenylphosphine palladium and about 25 ml of a 2 M aqueous sodium carbonate solution, and the mixture was heated under reflux for 3 hours in a nitrogen atmosphere. Then, the reaction mixture was poured into water, and the mixture was extracted with t-butyl methyl ether. The organic layer was dried with anhydrous sodium sulfate, and the residue obtained by concentration was subjected to silica gel column chromatography to obtain 1.48 g of 3-methylthio-5-(2-chlorophenyl)-1,2,4-thiadiazole.
Reaction SMILES: [CH2:1]([S:10][C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1)[C:14]([OH:16])=[O:15])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].OO.C(O)(=[O:28])C>O>[CH2:1]([S:10]([C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([C:20]([F:23])([F:21])[F:22])[CH:19]=1)[C:14]([OH:16])=[O:15])=[O:28])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)O
Reactant: O=C(O)c1cc(SCC(=O)c2ccccc2)cc(C(F)(F)F)c1
Agent: OO
Solvent: O
Product: O=C(O)c1cc(S(=O)CC(=O)c2ccccc2)cc(C(F)(F)F)c1

Procedure:
A solution of 2.6 g. (7.5 m moles) of 3-phenacylthio-5-trifluoromethylbenzoic acid and .75 ml. of 30% hydrogen peroxide in 15 ml. of acetic acid is heated on a steam bath for 1 hour, after which the reaction mixture is cooled and diluted with water to the turbidity point. The crystalline product which forms on standing is filtered, 1.0 g., m.p. 148°-151° C., and finally recrystallized from acetone-isopropyl ether, 850 mg., m.p. 154°-155° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.CCN(CC)CC.[O:25](C(OC(C)(C)C)=O)[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=O>C1COCC1.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[C:26](=[O:25])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1cccc(Nc2ccnc(Cl)c2)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(c1cccc([N+](=O)[O-])c1)c1ccnc(Cl)c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 96.4 %

Procedure:
To a stirring solution of 2-Chloro-N-(3-nitrophenyl)pyridine-4-amine (2.70 g, 10.82 mmol) in THF (45 mL) was added Et3N (6.32 mL, 45.3 mmol). The mixture was cooled to 0° C., and DMAP (0.0135 g, 0.110 mmol) and BOC2O (2.84 g, 12.99 mmol) were added. The mixture was warmed to rt and stirred for 18 h. The mixture was quenched with ice and diluted with water. Extracted with EtOAc (3×200 mL), washed with brine and water, dried (MgSO4), and concentrated. A dark oil was afforded, which was passed through a pad of silica gel, eluting with 1:1 EtOAc/hexanes. Concentrated and dried under high vacuum to afford tert-Butyl 2-chloropyridin-4-yl(3-nitrophenyl)carbamate (3.65 g, 96.5% yield).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:13][CH2:12][N:11]2[CH:6]([CH2:7][CH2:8][CH2:9][CH2:10]2)[CH2:5]1.[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([C:23](Cl)=[O:24])=[CH:15]1>>[CH2:5]1[CH:6]2[N:11]([CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:12][CH2:13][CH:4]1[CH2:3][CH2:2][O:1][C:23]([C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:14][CH:15]=1)=[O:24]
Reactant: O=C(Cl)c1c[nH]c2ccccc12
Reactant: OCCC1CCN2CCCCC2C1
Product: O=C(OCCC1CCN2CCCCC2C1)c1c[nH]c2ccccc12

Procedure:
eq-2-(2-Hydroxyethyl)quinolizidine (D5) was reacted with indole-3-carboxylic acid chloride using the method of Example 1. The product was chromatographed on silica gel eluting with ethyl acetate/methanol (95:5). The resulting beige solid was recrystallised from ethyl acetate/petrol (60-80) to afford the title compound (E10) as a white solid mp 170°-172° C.
Reaction SMILES: [C:1]1([NH2:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Br:12]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:12][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]=1[NH2:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cccc2ccccc12
Solvent: CN(C)C=O
Solvent: O
Product: Nc1c(Br)ccc2ccccc12

Procedure:
To a solution of naphthalen-1-amine (10 g, 69.8 mmol) in N,N-dimethylformamide (50 mL) at 0° C. was added N-bromosuccinimide (12.4 g, 69.8 mmol) in N,N-dimethylformamide (50 mL). The reaction mixture stirred for 1 hour before the addition of water (400 mL). The product was extracted with ethyl acetate (3×200 mL), and the combined ethyl acetate washes were extracted with brine (3×50 mL). The ethyl acetate was concentrated, and the crude material was purified by flash chromatography (0-20% ethyl acetate/hexanes) to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.15-8.24 (m, 1 H) 7.73-7.82 (m, 1 H) 7.40-7.52 (m, 3 H) 7.07 (d, J=8.82 Hz, 1 H) 5.87 (s, 2 H); MS (APCI+) m/z 222.0 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][O:9][CH2:10][CH2:11][CH:12]([C:15]#[N:16])[C:13]#[N:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:20][CH2:21][CH:22]1[O:26][CH2:25][CH2:24][O:23]1>CS(C)=O>[O:23]1[CH2:24][CH2:25][O:26][CH:22]1[CH2:21][CH2:20][C:12]([CH2:11][CH2:10][O:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([C:13]#[N:14])[C:15]#[N:16]
Reactant: N#CC(C#N)CCOCCc1ccccc1
Reactant: BrCCC1OCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CC(C#N)(CCOCCc1ccccc1)CCC1OCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25 %

Procedure:
A solution of the compound from step b) (1.53 g) in dry dimethyl sulphoxide (20 ml) was added to a suspension of sodium hydride (prewashed with diethyl ether) in dimethyl sulphoxide (20 ml). The mixture was stirred for 2 hours at room temperature. 2-[2-Bromoethyl]-1,3-dioxolane (0.920 ml) was then added and the whole heated at 60° for a further 2 hours. The cooled mixture was then quenched with water, acidified with dilute aqueous hydrochloric acid and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried (MgSO4) and evaporated under reduced pressure to yield the crude final product. This material was purified by flash chromatography over silica using ethyl acetate in dichloromethane as eluant to yield a pure sample of the subtitled compound (0.56g, 25%).
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](S(C)(=O)=O)[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:31].C([N:34](CC)CC)C.N>CN1C(=O)CCC1.CCOC(C)=O>[NH2:34][C:16]1[N:17]=[C:18]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[CH3:26])[C:13]2[CH:12]=[CH:11][C:10](=[O:31])[N:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[C:14]=2[N:15]=1
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: CCN(CC)CC
Agent: N
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1cc(F)ccc1-c1nc(N)nc2c1ccc(=O)n2-c1c(F)cccc1F
Yield: 43 %

Procedure:
To a solution of the product of Example 48 (1.0 g, 2.2 mmol) and triethylamine (1 mL) in 2 mL of NMP was bubbled NH3 gas at 23° for 30 min. The mixture was diluted with EtOAc and washed with H2O to give the crude material. Purification by flash chromatography eluting with EtOAc/hexane/triethylamine (50/50/2, v/v/v), followed by recrystallization from dichloromethane and hexane, gave the title compound, (360 mg, 43%). LC-MS: 383.0 (MH+, m/z), 1.95 (Rt, min).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.CN([CH:17]=[O:18])C.P(Cl)(Cl)(Cl)=O.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:3]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([CH3:7])=[CH:5][C:6]=1[CH:17]=[O:18]
Reactant: Cc1ccc(C)n1-c1ccccc1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cc(C=O)c(C)n1-c1ccccc1
Temperature: 80 °C
Yield: 29.2 %

Procedure:
To a well stirred solution of 2,5-dimethyl-1-phenyl-1H-pyrrole (7.65 g, 44.7 mmol) and DMF (3.6 g, 49.2 mmol) in 70 mL of dry toluene, phosphorus oxychloride (6.9 g, 44.7 mmol) was added in small portions. The mixture was heated to 80° C. for 3 hrs. The solution was allowed to cool to room temperature, then 100 mL of saturated aqueous Na2CO3 was added. The aqueous layer was extracted with EtOAc (100 mL×3). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure, the residue was purified by column chromatography (hexane:EtOAc=10:1) to give 2.6 g of 2,5-dimethyl-1-phenyl-1H-pyrrole-3-carbaldehyde (29%). MS [M++1]=200, LC-MS: tR=1.96 min.
Reaction SMILES: C([O:4][C:5]1(/[CH:18]=[CH:19]/[CH2:20][C:21]([F:24])([F:23])[F:22])[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)(=O)C.[OH-].[Na+].CC(=O)OCC>CO>[OH:4][C:5]1(/[CH:18]=[CH:19]/[CH2:20][C:21]([F:24])([F:22])[F:23])[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12])[CH2:9][CH2:10]1
Reactant: CC(=O)OC1(/C=C/CC(F)(F)F)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(O)(/C=C/CC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of (E)-tert-butyl 4-acetoxy-4-(4,4,4-trifluorobut-1-enyl)piperidine-1-carboxylate (200 mg, 0.57 mmol) in methanol (5 mL) was added 2M NaOH (2 mL, 4 mmol), the mixture was held stirring at r.t. for 16 hrs, when TLC (20% EA/PE) indicated completion of the reaction. The mixture was concentrated in vacuo, the residue was diluted with brine and extracted with EtOAc, and the organic layer was concentrated in vacuo to get the crude product, which was used directly for the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](O)=[C:6]([C:8](=[O:11])[CH2:9][CH3:10])[CH:7]=1.[O:13]1[CH2:18][CH2:17][CH2:16][C:15](=[O:19])[CH2:14]1.N1CCCC1>CO>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:19][C:15]1([CH2:16][CH2:17][CH2:18][O:13][CH2:14]1)[CH:9]([CH3:10])[C:8]2=[O:11]
Reactant: CCC(=O)c1cc(Br)ccc1O
Reactant: O=C1CCCOC1
Solvent: CO
Solvent: C1CCNC1
Product: CC1C(=O)c2cc(Br)ccc2OC12CCCOC2
Reaction time: 8 h
Yield: 7.7 %

Procedure:
A mixture of 1-(5-bromo-2-hydroxyphenyl)propan-1-one (5.7 g, 25 mol), dihydro-2H-pyran-3(4H)-one (5 g, 50 mmol) and pyrrolidine (3.4 g, 48 mmol) in methanol (80 mL) was stirred overnight. The reaction mixture was removed in vacuo, and H2O was added. The resulting solution was extracted with ethyl acetate. The ethyl acetate solution was dried over anhydrous Na2SO4, filtered, and evaporated to give 6-bromo-3-methyl-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-one (1.2 g, 16%). 1HNMR (CDCl3): 1.16-1.27 (m, 3H), 1.51-1.57 (m, 1H), 1.66-1.73 (m, 1H), 1.91-2.08 (m, 2H), 2.59-2.69 (m, 1H), 3.46-3.56 (m, 2H), 3.88-3.98 (m, 2H), 6.97 (m, 1H), 7.58 (m, 1H), 7.95 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7]C)=[O:6].O=[C:13]1[CH2:17][CH2:16][CH2:15][CH:14]1[C:18](OC)=[O:19].[O-]S([O-])(=O)=O.[Mg+2]>CO.Cl>[O:19]=[C:18]1[C:3]2[C:4]([C:5]([OH:7])=[O:6])=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:13]2[CH2:17][CH2:16][CH2:15][C:14]1=2
Reactant: COC(=O)C1CCCC1=O
Reactant: COC(=O)c1cccc(N)c1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CO
Product: O=C(O)c1cccc2[nH]c3c(c(=O)c12)CCC3
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To the solution of methyl 3-aminobenzoate (302 mg, 2.0 mmol) and methyl 2-oxocyclopentanecarboxylate (284 mg, 2.0 mmol) in MeOH (10 mL) were added MgSO4 (240 mg) and concentrated HCl (2 drops), the mixture was heated to 60° C. for 4.0 h. After cooling to room temperature, the solvent was evaporated in vacuum. The mixture was filtered and washed with EtOAc (15 mL), the solvent was evaporated and used for the next step without further purification. The crude mixture was dissolved in PPA (4.0 mL), and was stirred in 130° C. for 3 h. After cooling to the room temperature, water (20 mL) was added, and the mixture was extracted with EtOAc (50 mL×3). The organic layers were combined, dried over Na2SO4, and concentrated to afford the mixture, which was purified on Pre-HPLC to afford 9-oxo-2,3,4,9-tetrahydro-1H-cyclopenta[b]quinoline-8-carboxylic acid as a white solid. MS (ESI) m/e [M+1]+230.0