Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC2SC3C(=CC=CC=3)NC=2C=1.O.[C:18]1([CH3:45])[CH:23]=[CH:22][C:21]([C:24]([C@@:26]([C:42]([OH:44])=[O:43])([OH:41])[C@@:27]([C:32]([C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=2)=[O:33])([OH:31])[C:28]([OH:30])=[O:29])=[O:25])=[CH:20][CH:19]=1>C(O)C>[C:18]1([CH3:45])[CH:23]=[CH:22][C:21]([C:24]([C:26]([C:42]([OH:44])=[O:43])([OH:41])[C:27]([C:32]([C:34]2[CH:35]=[CH:36][C:37]([CH3:40])=[CH:38][CH:39]=2)=[O:33])([OH:31])[C:28]([OH:30])=[O:29])=[O:25])=[CH:20][CH:19]=1
Reactant: Cc1ccc(C(=O)[C@](O)(C(=O)O)[C@@](O)(C(=O)O)C(=O)c2ccc(C)cc2)cc1
Agent: COc1ccc2c(c1)Nc1ccccc1S2
Solvent: O
Solvent: CCO
Product: Cc1ccc(C(=O)C(O)(C(=O)O)C(O)(C(=O)O)C(=O)c2ccc(C)cc2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 134.5 %

Procedure:
(±)-10-(3 Dimethy]amino-2-methylpropyl)-2-methoxyphenothiazine (16.5 g; 0.05 mole), (-)-di(p-toluoyl)-L-tartaric acid monohydrate (10.15 g; 0.025 mole) and ethanol (75 cc) are introduced into a 250-cc three-necked round-bottomed flask equipped with a mechanical stirrer, a condenser and a nitrogen inlet. The stirred mixture is heated to 60° C. until a homogeneous solution is obtained. The mixture is cooled to 50° C. and crystallization is then seeded by adding a few crystals of the neutral salt of (-)-di(p-toluoyl)tartaric acid and the dextrorotatory base. While stirring is maintained, the mixture is kept for 1 hour at 50° C., cooled to 20° C. in the course of 2 hours, and maintained at 20° C. for 1 hour. The crystals obtained are separated by filtration, washed with ethanol (2×30 cc) and then dried. The neutral salt (12.99 g) of (-)-di(p-toluoyl)tartaric acid and dextrorotatory 10-(3-dimethylamino-2-methylpropyl) -2-methoxyphenothiazine is thereby obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2/[C:10](=[CH:18]/[C:19]2[NH:20][CH:21]=[CH:22][CH:23]=2)/[C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.[C:31]1([S:37]([C:40]2[CH:41]=[C:42]([S:45](Cl)(=[O:47])=[O:46])[S:43][CH:44]=2)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>COCCOC>[O:17]=[C:11]1[NH:12][C:13]2[C:9](/[C:10]/1=[CH:18]/[C:19]1[NH:20][CH:21]=[CH:22][CH:23]=1)=[C:8]([C:4]1[CH:3]=[C:2]([NH:1][S:45]([C:42]3[S:43][CH:44]=[C:40]([S:37]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)(=[O:39])=[O:38])[CH:41]=3)(=[O:46])=[O:47])[CH:7]=[CH:6][CH:5]=1)[CH:16]=[CH:15][CH:14]=2
Reactant: Nc1cccc(-c2cccc3c2/C(=C/c2ccc[nH]2)C(=O)N3)c1
Reactant: O=S(=O)(Cl)c1cc(S(=O)(=O)c2ccccc2)cs1
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: O=C1Nc2cccc(-c3cccc(NS(=O)(=O)c4cc(S(=O)(=O)c5ccccc5)cs4)c3)c2/C1=C/c1ccc[nH]1
Temperature: 25 °C
Reaction time: 15 h
Yield: 35.7 %

Procedure:
A solution of (Z)-4-(3-aminophenyl)-1,3-dihydro-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (60 mg, 0.200 mmol) (from Example 4 supra), Et3N (28 μL , 0.201 mmol), and 4-benzenesulfonylthiophene-2-sulfonyl chloride (64.6 mg, 0.200 mmol) (Lancaster) in 7 mL of 1,2-dimethoxyethane (Fisher Scientific) was heated at reflux for 1 h. The reaction mixture was allowed to cool and then stirred at room temperature for 15 h. The reaction mixture was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 45% ethyl acetate-hexanes elution) provided pure (Z)-N-[3-[2,3-dihydro-2-oxo-3-[(1H-pyrrol-2-yl)methylene]-1H-indol-4-yl]phenyl]-4-(phenylsulfonyl)-2-thiophenesulfonamide (yield: 42 mg, 36%) as a yellow solid (mp 132-134° C.) (solid to gel).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([NH:11][C:12]1[N:17]=[CH:16][C:15]([C:18]([OH:20])=O)=[CH:14][CH:13]=1)=[O:10].S(Cl)([Cl:23])=O>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([NH:11][C:12]1[N:17]=[CH:16][C:15]([C:18]([Cl:23])=[O:20])=[CH:14][CH:13]=1)=[O:10]
Reactant: Cc1ccccc1CC(=O)Nc1ccc(C(=O)O)cn1
Reactant: O=S(Cl)Cl
Product: Cc1ccccc1CC(=O)Nc1ccc(C(=O)Cl)cn1

Procedure:
A mixture of 4.5 g of 6-[(2-methylbenzeneacetyl)amino]pyridine-3-carboxylic acid and 17 ml of thionyl chloride is heated on a steam bath for 1/2 hour. An additional 815 ml of thionyl chloride is added and the mixture refluxed for 0.5 hour. The volatiles are removed under vacuum and toluene (20 ml) added (twice) and the solvent removed under vacuum to give 5.3 g of a dark colored solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH2:21][CH:22]1[O:26][CH2:25][CH2:24][O:23]1>CN(C=O)C.C(OCC)(=O)C>[OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([O:9][CH2:19][CH2:20][CH2:21][CH:22]2[O:26][CH2:25][CH2:24][O:23]2)=[O:8])=[CH:10][CH:11]=1
Reactant: BrCCCC1OCCO1
Reactant: O=C(O)c1ccc(CO)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(OCCCC1OCCO1)c1ccc(CO)cc1
Temperature: 80 °C
Yield: 48.1 %

Procedure:
To a stirred solution of 4-hydroxymethylbenzoic acid (3.33 g, 21.9 mmol) in DMF (100 mL), was added potassium carbonate (5.67 g, 41.04 mmol) followed by 2-(3-bromopropyl)-1,3-dioxolane (3.0 g, 19.9 mmol). The resulting mixture was heated at 80° C. for 16 hours. The reaction mixture was diluted with ethyl acetate and washed sequentially with water and twice with brine. The organic phase was dried with anhydrous magnesium sulfate, and filtered, and the filtrate evaporated at reduced pressure. The crude material was purified by silica gel chromatography eluting with 100% iso-hexane to 100% ethyl acetate in iso-hexane to afford the title compound as a colourless oil (2.55 g, 48%).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][C:27](O)=[O:28]>>[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][C:27]([NH:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18])=[O:28]
Reactant: O=C(O)Cc1ccccc1Cl
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Product: O=C(Cc1ccccc1Cl)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 2-(2-chlorophenyl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.32 (d, J=8.4 Hz, 1H), 8.02-8.05 (m, 1H), 7.97-8.01 (m, 1H), 7.89-7.93 (m, 1H), 7.46-7.54 (m, 2H), 7.31-7.36 (m, 2H), 3.82-3.83 (m, 6H), 3.09-3.12 (m, 4H); MS (ESI−) M/Z 397 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:27]([N:34]1[CH2:39][CH2:38][N:37]([CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:36][CH:35]1[CH2:47]Cl)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:47][CH:35]2[CH2:36][N:37]([CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:38][CH2:39][N:34]2[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:4][CH:3]=1
Reactant: ClCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12
Product: O=C(c1cn(CC2CN(Cc3ccccc3)CCN2Cc2ccccc2)c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine] (prepared according to example 69 above) with 1,4-dibenzyl-2-chloromethyl-piperazine (described in Journal of Medicinal Chemistry (1999), 42(9), 1587-1603) gave the title compound.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[OH:17].[CH2:18]=O>C(O)(C)C>[CH3:1][C:2]1[NH:3][CH:4]=[C:5]([CH2:18][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][C:8]=2[OH:17])[N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: Oc1ccc2ccccc2c1
Reactant: C=O
Solvent: CC(C)O
Product: Cc1nc(Cc2c(O)ccc3ccccc23)c[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To a solution of 2-methylimidazole (82.1 g, 1 mole) and 2-naphthol (144.0 g, 1 mole) in isopropanol (400.0 g), formaline (37% aqueous solution, 1 mole of CH2O) is added over a period of 30 minutes at room temperature. Thereafter, the reaction mixture is agitated for 30 minutes at room temperature, followed by agitation at 80°-84° C. for four hours. The mixture is then cooled and filtered. The filtrate is triturated and dried in vacuo at 60° C. The product (a white powder) is obtained in a yield of 92% with a melting point of 207° C., as determined by Differential Scanning Calorimetry (DSC).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28]([OH:30])=O)[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[NH2:33][C@H:34]([C:42]([NH2:44])=[O:43])[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[C:42]([CH:34]([NH:33][C:28]([C:23]1[CH:24]=[N:25][C:26]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]1[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:31])([F:32])[F:1])=[CH:4][CH:5]=3)=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:16])[CH:27]=2)=[O:30])[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(=[O:43])[NH2:44]
Reactant: NC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)C(Cc1ccccc1)NC(=O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.1 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (100 mg, 0.23 mmol) was combined with phenylalaninamide (38 mg, 0.23 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53 mg, 0.27 mmol), 1-hydroxybenzotriazole (34 mg, 0.25 mmol), and triethylamine (0.13 ml, 0.92 mmol) in 1.5 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was diluted with 50 ml of dichloromethane, and the organic phase washed sequentially with water, and brine, and then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide a residue. This material was purified by preparative thin-layer-chromatography on silica eluting with ethyl acetate. The product containing band was collected and eluted with 5% methanol in ethyl acetate to afford 47 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:17][C:18]([OH:20])=O)[C:5]2[C:6]([CH:16]=1)=[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:8][N:9]=2.[C:21]1([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:17][C:18](=[O:20])[N:30]2[CH2:31][CH2:32][N:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:28][CH2:29]2)[C:5]2[C:6]([CH:16]=1)=[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:8][N:9]=2
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C(O)Cc1cc(Cl)cc2c(-c3ccccc3)onc12
Product: O=C(Cc1cc(Cl)cc2c(-c3ccccc3)onc12)N1CCN(c2ccccc2)CC1

Procedure:
The title compound is prepared by reacting the acid chloride of 5-chloro-3-phenyl-2,1-benzisoxazole-7-acetic acid with N-phenyl-piperazine in an aprotic solvent and washing the reaction mixture with sodium bicarbonate solution.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[N:10]=[C:9]([CH:11]2[CH2:15][CH2:14][CH2:13][O:12]2)[C:8]([F:16])=[C:7]([NH:17]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=1)C.OS(O)(=O)=O.CC#N>O>[NH2:17][C:7]1[C:8]([F:16])=[C:9]([CH:11]2[CH2:15][CH2:14][CH2:13][O:12]2)[N:10]=[C:5]([CH:4]=[O:3])[CH:6]=1
Reactant: CCOC(OCC)c1cc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)c(C2CCCO2)n1
Agent: O=S(=O)(O)O
Solvent: CC#N
Solvent: O
Product: Nc1cc(C=O)nc(C2CCCO2)c1F
Yield: 95.7 %

Procedure:
Using the procedure of Example 12, 6-(diethoxymethyl)-3-fluoro-2-(tetrahydrofuran-2-yl)-N-tritylpyridin-4-amine (4.21 g, 8 mmol), conc H2SO4 (1 mL), CH3CN (35 mL) and H2O (35 mL) gave 4-amino-5-fluoro-6-(tetrahydrofuran-2-yl)picolinaldehyde (1.61 g, 95%) as a white solid: mp 122-123° C.; 1H NMR (400 MHz, CDCl3) δ 9.90 (s, 1H), 7.28 (d, J=6.7 Hz, 1H), 5.26 (td, J=7.1, 1.7 Hz, 1H), 4.46 (br s, 2H), 4.17 (dt, J=7.9, 6.9 Hz, 1H), 3.98 (td, J=7.8, 5.6 Hz, 1H), 2.29 (m, 2H), 2.19 (m, 1H), 2.05 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 193.12, 148.75 (d, J=5.2 Hz), 148.60 (d, J=11.7 Hz), 148.53 (d, J=256.8 Hz), 142.02 (d, J=12.1 Hz), 108.33 (d, J=4.1 Hz), 75.70, 69.26, 30.78 (d, J=0.9 Hz), 26.28; 19F NMR (376 MHz, CDCl3) δ −144.90 (d, J=6.6 Hz); HRMS-ESI (m/z) [M+H]+ calcd for C10H11FN2O2, 210.0805. found, 210.0803.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]([CH3:18])[C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][CH:25]=[C:24]2[CH2:30][CH2:31][NH2:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][CH:25]=[C:24]2[CH2:30][CH2:31][NH:32][C:13](=[O:15])[C:12]1[CH:11]=[CH:10][C:9]([N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH3:18])=[CH:17][CH:16]=1
Reactant: CN(c1ccc(C(=O)O)cc1)c1cccc(F)c1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1ccc(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)cc1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28 %

Procedure:
A mixture of 4-((3-fluorophenyl)(methyl)amino)benzoic acid (0.100 g, 0.407 mmol), 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.094 g; 0.407 mmol), HATU (0.170 g; 0.448 mmol) and N,N-diisopropylethylamine (0.176 mL; 1.02 mmol) in DMF (5 mL), was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulfate, the organic layer was washed with sodium carbonate, brine, dried and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica (eluent 2 to 20% ethyl acetate in dichloromethane) to yield 0.048 g (28%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([Br:26])[CH:19]=2)(O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:6][CH:5]=1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>ClCCl.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([Br:26])[CH:19]=2)=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:6][CH:5]=1
Reactant: CCCCCCC(O)(c1ccc(C(=O)OC)cc1)c1ccc(OC)c(Br)c1
Agent: CC[SiH](CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCC=C(c1ccc(C(=O)OC)cc1)c1ccc(OC)c(Br)c1
Yield: 69.5 %

Procedure:
To a solution of 4-[1-(3-bromo-4-methoxy-phenyl)-1-hydroxy-heptyl]-benzoic acid methyl ester (572 mg, 1.31 mmol) in dichloromethane (10 mL) is added TFA (749 mg, 6.57 mmol). 5 min later, triethylsilane (763 mg, 6.57 mmol) is added dropwise. 5 h later, the reaction mixture is diluted with ethyl acetate, washed with 1N NaOH, water, brine, dried over sodium sulfate, concentrated and purified by column chromatography to give 4-[1-(3-bromo-4-methoxy-phenyl)-hept-1-enyl]-benzoic acid methyl ester (380 mg), which is hydrolyzed by 5N NaOH (1 mL) to afford the titled compound (380 mg).
Reaction SMILES: [OH-:1].[Na+].Cl.[NH2:4]O.[Cl:6][C:7]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:8]=1[CH:9]=O>O.C(O)C>[Cl:6][C:7]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:8]=1[CH:9]=[N:4][OH:1]
Reactant: NO
Reactant: [OH-]
Reactant: O=Cc1c(Cl)cccc1Cl
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: ON=Cc1c(Cl)cccc1Cl
Temperature: 90 °C
Yield: 99.6 %

Procedure:
Sodium hydroxide 3N (3.14 L, 9.43 mol) is added dropwise to a stirred suspension of hydroxylamine hydrochloride (675.55 g, 9.43 mol) in 0.5 L of water at 0° C. To this mixture is added dropwise a suspension of 2,6-dichlorobenzaldehyde (1500 g, 8.57 mol) in 7.5 L of ethanol and the reaction is heated at 90° C. overnight. The mixture is cooled to room temperature and then, concentrated to dryness. The solid is triturated in a mixture of H2O/EtOH, 10:1 (4.4 L), filtered and dried under high vacuum at 45° C. overnight. 1621.78 g of title compound (99%) is obtained as a white solid. MS (m/e): 190 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]([CH3:17])([CH3:16])[CH2:14][NH2:15])[S:11][CH:12]=2)=[CH:4][CH:3]=1.[C:18]([C:20]1[CH:21]=[N:22][C:23]([CH3:29])=[C:24]([CH:28]=1)[C:25](O)=[O:26])#[N:19]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([C:13]([CH3:17])([CH3:16])[CH2:14][NH:15][C:25](=[O:26])[C:24]3[CH:28]=[C:20]([C:18]#[N:19])[CH:21]=[N:22][C:23]=3[CH3:29])[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: Cc1ncc(C#N)cc1C(=O)O
Reactant: CC(C)(CN)c1nc(-c2ccc(Cl)cc2)cs1
Product: Cc1ncc(C#N)cc1C(=O)NCC(C)(C)c1nc(-c2ccc(Cl)cc2)cs1
Yield: 46 %

Procedure:
This compound was synthesized from 2-(4-(4-chlorophenyl)thiazol-2-yl)-2-methylpropan-1-amine and 5-cyano-2-methylnicotinic acid as described in example 8 step 6 (200 mg, yield 46%). 1H NMR (300 MHz, CDCl3) δ 8.81 (m, 1H), 8.00-7.99 (m, 1H), 7.70-7.67 (m, 2H), 7.50-7.46 (m, 1H), 7.41-7.37 (m, 3H), 3.81-3.79 (d, J=5.7 Hz, 2H), 2.81 (s, 3H), 1.57 (s, 6H). MS (ESI) m/z: Calculated for C21H19ClN4OS: 410.10. found: 411.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH3:27][CH:28]([CH3:40])[CH2:29][C:30]([C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH2:37])=[CH:34][CH:33]=1)=[O:31]>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:37][CH2:36][C:35]1[CH:38]=[CH:39][C:32]([C:30](=[O:31])[CH2:29][CH:28]([CH3:27])[CH3:40])=[CH:33][CH:34]=1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: CC(C)CC(=O)c1ccc(CN)cc1
Product: CC(C)CC(=O)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Yield: 43.3 %

Procedure:
Use a method similar to the General Procedure 1-3, using 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (175 mg, 0.42 mmol) and 4-(3-methyl-butyryl)-benzylamine (160 mg, 0.8 mmol) to obtain the title compound as a yellow syrup (85 mg, 45%). MS (ES+) m/z: 467 (M+H)+.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=1)(=O)=O.[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.[K]>CN(C=O)C>[Br:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][CH2:7][CH2:6][N:20]1[C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]2[C:16]1=[O:26]
Reactant: CS(=O)(=O)OCCOc1cccc(Br)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCOc1cccc(Br)c1
Temperature: 60 °C
Reaction time: 14 h
Yield: 78.2 %

Procedure:
To a solution of mesylate 16 (24.05 g, 81.5 mmol) in anhydrous DMF (160 ml) was added potassium phthalimide (15.53 g, 83.8 mmol) and the reaction mixture stirred at 60° C. for 14 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was diluted with hexanes-EtOAc (7:1, 150 ml) and water (150 ml) and the mixture shaken in separating funnel. A precipitate formed which was removed by filtration, washed excessively with water and hexane, then dried under vacuum to give N-(2-(3-bromophenoxy)ethyl)phthalimide (17) as white fluffy crystals (22.05 g, 78%). The organic layer of the filtrate was concentrated under reduced pressure and the residue was suspended in 10% EtOAc-hexanes. The solution was washed with water and the precipitate collected by filtration, washed with water then hexanes and dried under vacuum to give additional phthalimide 17 (5.65 g). Combined yield (21.18 g, 98%): 1H NMR (400 MHz, CDCl3) δ 7.86 (m, 2H), 7.73 (m, 2H), 7.03-7.12 (m, 3H), 6.80 (ddd, J=8.0, 2.5 and 1.4 Hz, 1H), 4.21 (t, J=6.9 Hz, 2H), 4.10 (t, J=6.0 Hz, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([C:25]4[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=4)=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[C:9]2[CH2:14][CH2:13][CH2:12][N:10]2[N:11]=1.[F:32][C:33]([F:44])([F:43])[CH2:34][O:35]S(C(F)(F)F)(=O)=O.[H-].[Na+]>CN(C=O)C>[F:32][C:33]([F:44])([F:43])[C:34]([OH:31])=[O:35].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([C:25]4[CH:26]=[CH:27][C:28]([O:31][CH2:34][C:33]([F:44])([F:43])[F:32])=[CH:29][CH:30]=4)=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[C:9]2[CH2:14][CH2:13][CH2:12][N:10]2[N:11]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: Oc1ccc(-c2ccc3c(-c4c(-c5ccccn5)nn5c4CCC5)ccnc3c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)COc1ccc(-c2ccc3c(-c4c(-c5ccccn5)nn5c4CCC5)ccnc3c2)cc1
Product: O=C(O)C(F)(F)F
Temperature: 70 °C

Procedure:
Into a 25 mL glass pressure tube fitted with Teflon screw cap and magnetic bar is placed 4-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)quinolin-7-yl]phenol (Example 7 before reverse phase HPLC purification); 0.100 g, 0.25 mmol), DMF (2 mL), trifluoro-methanesulfonic acid 2,2,2-trifluoroethyl ester (0.064 g 0.275 mmol), and 60% NaH (11 mg, 0.275 mmol). The cap is positioned, and mixture heated in oil bath at 70° C. for 16 h. The reaction is quenched with 15 mL water, giving 67 mg of precipitate as the title compound as a free base. The purified product, 36.4 mg (24%), is obtained by freeze drying appropriate fractions (based on MS analysis) from reverse phase HPLC using Waters Symmetry C18 column with a gradient of 10 to 70% B in A, where A is water containing 0.1% TFA and B is CH3CN containing 0.1% TFA.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]3[CH2:14][CH2:13][CH2:12][C:11]=13)[N:8]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:7]([CH3:23])([CH3:22])[C:6](=[O:24])[C:5]2([CH3:26])[CH3:25].[Mn]([O-])(=O)(=O)=[O:28].[K+]>CC(C)=O.C(O)(C)C.C(Cl)(Cl)Cl.[Fe](Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]3[CH2:14][CH2:13][C:12](=[O:28])[C:11]=13)[N:8]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[C:7]([CH3:23])([CH3:22])[C:6](=[O:24])[C:5]2([CH3:26])[CH3:25]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CC(C)(C)OC(=O)N1c2c(cc(Br)c3c2CCC3)C(C)(C)C(=O)C1(C)C
Agent: Cl[Fe](Cl)Cl
Agent: [K+]
Solvent: CC(C)=O
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1c2c(cc(Br)c3c2CCC3=O)C(C)(C)C(=O)C1(C)C
Temperature: 0 °C
Reaction time: 16 h
Yield: 31.4 %

Procedure:
To a solution of tert-butyl 6-bromo-2,2,4,4-tetramethyl-2,3,4,7,8,9-hexahydro-1H-cyclopenta[h]quinolin-3-one-1-carboxylate (2.1 g) obtained in Example 1, 8) in acetone (50 ml) was added potassium permanganate (7.9 g), and the mixture was cooled to 0° C. Iron trichloride (5.0 g) was added, and the mixture was stirred at 50° C. for 16 hr. The reaction solution was diluted with isopropanol (20 ml) and CHCl3 (20 ml), filtered through celite, and extracted with CHCl3. The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to normal phase chromatography (elution solvent hexane-ethyl acetate=3:1) to give the title compound (681 mg, 31%, Rf=0.29 [hexane:ethyl acetate=3:1]) and tert-butyl 6-bromo-2,2,4,4-tetramethyl-2,3,7,8-hexahydro-1H-cyclopenta[h]quinoline-3,9-dione-1-carboxylate (293 mg, 13%, Rf=0.33 [hexane:ethyl acetate=3:1]).