Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C@:11]([OH:17])([CH3:16])[C:12]([F:15])([F:14])[F:13].[C:19]1([N:25]=[C:26]=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(OCC)C>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:26]([NH:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:27])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C@:11]([OH:17])([CH3:16])[C:12]([F:13])([F:15])[F:14]
Reactant: C[C@@](O)(C(=O)Nc1ccc(N)cc1Cl)C(F)(F)F
Reactant: O=C=Nc1ccccc1
Solvent: CCOCC
Product: C[C@@](O)(C(=O)Nc1ccc(NC(=O)Nc2ccccc2)cc1Cl)C(F)(F)F
Reaction time: 22 h

Procedure:
A mixture of (R)-N-[2-chloro-4-aminophenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 208) (0.198 g) and phenyl isocyanate (0.09 ml) in diethyl ether (10 ml) was stirred for 22 hours then evaporated to dryness. The residue was partitioned between water (25 ml) and ethyl acetate (50 ml). The organic phase was washed with brine (25 ml), dried and concentrated by evaporation to give the title compound (170 mg) as a foam. NMR: 1.66 (s, 3H), 7.04 (t, 1H), 7.35 (m, 3H), 7.52 (d, 1H), 7.1 (s, 1H), 7.86 (m, 2H), 8.77 (s, 1H), 8.92 (s, 1H), 9.63 (s, 1H); MS (ESP−): 400.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:11])=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(O)(=O)C.C([BH3-])#N.[Na+].[CH:20]1([CH:23]=O)[CH2:22][CH2:21]1>C(O)C>[Cl:1][C:2]1[C:3]([NH:11][CH2:23][CH:20]2[CH2:22][CH2:21]2)=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1c(Cl)cnc2[nH]ccc12
Reactant: O=CC1CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: Clc1cnc2[nH]ccc2c1NCC1CC1
Temperature: 25 °C
Yield: 68.9 %

Procedure:
In a round bottom flask, 5-chloro-1H-pyrrolo[2,3-b]pyridin-4-ylamine (22, 0.21 g, 1.25 mmol) is combined with 3.5 mL of ethanol, acetic acid (0.38 g, 6.25 mmol), silica bound sodium cyanoborohydride (1.1 g, 1.02 mmol), and cyclopropanecarbaldehyde (23, 0.26 g, 4 mmol). The reaction mixture was stirred over night at room temperature, heated up to 145° C. until the reaction was complete, filtered, concentrated, and purified by flash chromatography to provide compound as a solid (24, 0.191 g; yield=69%).
Reaction SMILES: [CH:1]1[CH:8]=[CH:7][C:5](=[O:6])[C:4]([OH:9])=[CH:3][CH:2]=1.[OH-].[Cu+2:11].[OH-].CO.C(Cl)(Cl)Cl>O>[CH:1]1[CH:8]=[CH:7][C:5](=[O:6])[C:4]([OH:9])=[CH:3][CH:2]=1.[Cu:11]
Reactant: [Cu+2]
Agent: O=c1cccccc1O
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O
Product: [Cu]
Temperature: 80 °C

Procedure:
To a solution of tropolone (244 mg) in water is added a suspension of copper (II) hydroxide (98 mg) in water. The mixture is heated at 80° C. and methanol-chloroform is added thereto until the mixture becomes homogeneous. The solution is concentrated under reduced pressure. The depositing green crystals are collected by filtration and dissolved in hot chloroform. After removing impurities by filtration, to the filtrate is added methanol. The solution is cooled with ice. The precipitating green needles are recovered by filtration to give tropolone copper complex (203 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](CC#N)[C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:7]=1.[CH2:18]([OH:20])[CH3:19].[OH-:21].[K+]>O>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:19][C:18]([OH:21])=[O:20])[C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CCO
Reactant: Cc1ccc(Sc2ccccc2)c(CC#N)c1
Reactant: [OH-]
Agent: [K+]
Solvent: O
Product: Cc1ccc(Sc2ccccc2)c(CC(=O)O)c1

Procedure:
500 g of 3-methyl-6-(phenylthio)-phenylacetonitrile, 1.2 litres of ethanol, 470 g of potassium hydroxide and 500 ml of water are heated for 12 hours under reflux. Then the ethanol is evaporated off under reduced pressure. The residue is treated with water until completely dissolved and the neutral constituents are extracted with benzene. The aqueous solution is filtered with the addition of some dicalite and active carbon, cooled and adjusted to pH 3 with concentrated hydrochloric acid. The mixture is then extracted three times with 1 litre of chloroform each time and the extracts are washed with water, dried over calcium chloride, filtered and concentrated under reduced pressure. The crude 3-methyl-6-(phenylthio)-phenylacetic acid obtained is recrystallised from benzene/hexane; melting point 132°-135° C.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]#[N:27])[N:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:12]([O:19][C:20]1[N:21]=[C:22]([C:26]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:27]=2)[CH:23]=[CH:24][CH:25]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccccc1S
Reactant: N#Cc1cccc(OCc2ccccc2)n1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=c1nc(-c2cccc(OCc3ccccc3)n2)sc2ccccc12
Yield: 25.3 %

Procedure:
A mixture of methyl thiosalicylate (0.40 g, 2.4 mmol), 2-benzyloxy-6-cyanopyridine (0.50 g, 2.4 mmol), triethylamine (0.50 ml, 3.6 mmol) and toluene (30 ml) was refluxed for 48 hrs as described in Example 1. The reaction mixture was concentrated under reduced pressure and recrystallized from ethanol to give the titled compound (0.21 g, 26%) as crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](=O)[CH2:10][NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.[C:26]([O:30][NH2:31])([CH3:29])([CH3:28])[CH3:27].N1C=CC=CC=1>C(O)C>[Cl:1][C:2]1[C:3]([C:9](=[N:31][O:30][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:10][NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(NCC(=O)c1ncc(Cl)cc1Cl)c1ccccc1C(F)(F)F
Reactant: CC(C)(C)ON
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CC(C)(C)ON=C(CNC(=O)c1ccccc1C(F)(F)F)c1ncc(Cl)cc1Cl
Temperature: 70 °C
Reaction time: 18 h
Yield: 87.1 %

Procedure:
To a solution of 200 mg of the N-[2-(3,5-dichloropyridin-2-yl)-2-oxoethyl]-2-(trifluoromethyl)benzamide prepared in Step 3 in Synthetic Example 10 and 199 mg of O-(tert-butyl)hydroxylamine hydrochloride in 2.6 ml of ethanol, 167 mg of pyridine was added, and the mixture was stirred at 70° C. for 18 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, the resulting residue was mixed with 2 ml of water and extracted with ethyl acetate (2 ml×2), the resulting organic layers were combined, dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 5:95 to 50:50) as the eluent to obtain 207 mg of the desired product as a colorless resinous substance.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)([O:14][CH3:15])[C:10](=[O:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][Mg]Br>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:16]2[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=2)([O:14][CH3:15])[C:10]([OH:23])([CH3:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC1(c2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)CC1=O
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: COC1(c2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)CC1(C)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.8 %

Procedure:
To a solution of 4-(4-chloro-phenyl)-4-methoxy-3-oxo-piperidine-1-carboxylic acid tert-butyl ester (470 mg, 1.38 mmol) in anhydrous tetrahydrofuran (10 mL) at 0° C. was added methylmagnesium bromide (1.4 M in diethyl ether, 2.96 mL, 4.15 mmol) and the resulting mixture was stirred at that temperature for 3 h. Excess organomagnesium was quenched by the addition of saturated aqueous ammonium chloride and the reaction was allowed to warm to rt. To the biphasic mixture was added water and ethyl acetate. The phases were separated and the organic phase washed with brine, dried over magnesium sulfate, filtered, dried and concentrated to afford a crude residue which was purified by silica gel chromatography (100% methylene chloride-97.5% methylene chloride/2.5% methanol gradient) to afford pure 4-(4-chloro-phenyl)-3-hydroxy-4-methoxy-3-methyl-piperidine-1-carboxylic acid tert-butyl ester (269 mg, 58%).
Reaction SMILES: [C:1]([NH:5][S:6]([CH2:9][CH2:10][CH2:11][CH2:12][OH:13])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:14](OC(=O)C)(=[O:16])[CH3:15]>N1C=CC=CC=1>[C:1]([NH:5][S:6]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14](=[O:16])[CH3:15])(=[O:7])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)NS(=O)(=O)CCCCO
Solvent: c1ccncc1
Product: CC(=O)OCCCCS(=O)(=O)NC(C)(C)C
Reaction time: 1 h

Procedure:
A crude product (1.17 g) of N-tert-butyl-4-hydroxybutanesulfonamide was dissolved in pyridine (3.0 ml) and acetic anhydride (1.5 ml) was added, and the mixture was left standing at room temperature for 1 hr. The reaction mixture was concentrated to dryness under reduced pressure and the residue was partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was washed once with water and once with saturated brine, dried over magnesium sulfate and concentrated to dryness under reduced pressure to give N-tert-butyl-4-acetoxybutanesulfonamide (425 mg) as a pale-yellow oil.
Reaction SMILES: [C:1]([CH2:3][CH2:4][NH:5][C:6](=[O:32])[C@@H:7]([NH:12][C:13]([N:15]1[C:19]2[CH2:20][CH2:21][O:22][CH2:23][C:18]=2[C:17]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[C:26]([F:31])[CH:25]=2)=[N:16]1)=[O:14])[C:8]([CH3:11])([CH3:10])[CH3:9])#[N:2].[NH2:33][CH2:34][C:35]1[CH:40]=NC(C)=CN=1>>[F:31][C:26]1[CH:25]=[C:24]([C:17]2[C:18]3[CH2:23][O:22][CH2:21][CH2:20][C:19]=3[N:15]([C:13]([NH:12][C@@H:7]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:6]([NH:5][CH2:4][C:3]3[CH:1]=[N:2][C:35]([CH3:40])=[CH:34][N:33]=3)=[O:32])=[O:14])[N:16]=2)[CH:29]=[CH:28][C:27]=1[F:30]
Reactant: Cc1cnc(CN)cn1
Reactant: CC(C)(C)[C@H](NC(=O)n1nc(-c2ccc(F)c(F)c2)c2c1CCOC2)C(=O)NCCC#N
Product: Cc1cnc(CNC(=O)[C@@H](NC(=O)n2nc(-c3ccc(F)c(F)c3)c3c2CCOC3)C(C)(C)C)cn1

Procedure:
Compound 106 was prepared by the procedure described for the synthesis of compound 104 by replacing 2-cyanoethylamine with 2-aminomethyl-5-methylpyrazine. LCMS (+ESI) m/z=499.3 [M+H]+. 1H NMR (CDCl3) δ 8.48 (s, 1H), 8.35 (s, 1H), 7.92 (d, J=9.4 Hz, 1H), 7.47-7.52 (m, 1H), 7.28-7.32 (m, 1H), 7.19-7.27 (m, 1H), 6.98 (br, 1H), 4.82 (s, 2H), 4.57-4.62 (m, 2H), 4.30 (d, J=10.4 Hz, 1H), 3.93 (t, J=5.4 Hz, 2H), 3.18 (br, 2H), 2.80 (s, 3H), 1.11 (s, 9H).
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[S:26][CH2:27][CH2:28][O:29]C2CCCCO2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.O>O1CCCC1.CO>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[S:26][CH2:27][CH2:28][OH:29])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3SCCOC3CCCCO3)[nH]c2c1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3SCCO)[nH]c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
To a solution of methyl 3-cyclohexyl-2-{2-[2-(tetrahydropyran-2-yloxy)ethylsulfanyl]phenyl}-1H-indole-6-carboxylate (1.38 g, 2.81 mmol) in tetrahydrofuran (4 ml) and methanol (4 ml) was added 6N hydrochloric acid (4 ml), and the mixture was stirred at room temperature for 30 min. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane:ethyl acetate=2:1-1:1) to give methyl 3-cyclohexyl-2-[2-(2-hydroxyethylsulfanyl)phenyl]-1H-indole-6-carboxylate (1.00 g, yield 87.5%).
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.F[C:28]1[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][C:29]=1[C:30]#[N:31]>>[C:30]([C:29]1[CH:32]=[C:33]([O:36][C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:35][C:28]=1[O:25][C:19]1[CH:20]=[CH:21][C:22]([F:24])=[C:23]2[C:18]=1[CH2:17][CH2:16][C@H:15]2[O:14][C:12]1[CH:11]=[CH:10][C:9]2[C@H:5]([CH2:4][C:3]([OH:26])=[O:2])[CH2:6][O:7][C:8]=2[CH:13]=1)#[N:31]
Reactant: N#Cc1cc(OC(F)(F)F)ccc1F
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Product: N#Cc1cc(OC(F)(F)F)ccc1Oc1ccc(F)c2c1CC[C@H]2Oc1ccc2c(c1)OC[C@H]2CC(=O)O

Procedure:
The methyl ester of the title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-fluoro-5-trifluoromethoxy-benzonitrile following a procedure analogous to that described for Intermediate 12. The title compound is obtained after saponification of the methyl ester as described for Example 1. LC (method 2): tR=1.16 min; Mass spectrum (ESI+): m/z=530 [M+H]+.
Reaction SMILES: [C:1]1([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:26][C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=1>CN(C=O)C>[CH2:13]([N:12]([CH2:16][CH2:17][CH3:18])[CH2:11][CH2:10][CH2:9][CH2:8][N:7]([CH2:26][C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:14][CH3:15]
Reactant: CCCN(CCC)CCCCNc1ccccc1
Reactant: N#Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCN(CCC)CCCCN(Cc1ccc(C#N)cc1)c1ccccc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 39.8 %

Procedure:
The compound (152.5 mg) obtained in Example 24-1 was dissolved in anhydrous DMF (6.1 ml) and added with cesium carbonate (299.0 mg) and 4-bromomethyl-benzonitrile (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (184.0 mg). The whole was stirred overnight at 60° C. and then stirred at 80° C. for additional 24 hours. After completion of the reaction, the solvent was distilled off. The resultant was added with water, subjected to extraction with chloroform, and dried with magnesium sulfate. The solvent was distilled off. The residue was purified through silica gel column chromatography (hexane/ethyl acetate), thereby obtaining the subject compound (88.8 mg) as a colorless oily substance.
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][O:14][C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])[CH2:8][CH2:7]1)=O)C.[OH-].[K+].C(O)CO>O>[C:23]1([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([O:14][CH2:13][CH2:12][N:9]2[CH2:8][CH2:7][NH:6][CH2:11][CH2:10]2)[CH3:16])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)N1CCN(CCOC(C)(c2ccccc2)c2ccccc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: CC(OCCN1CCNCC1)(c1ccccc1)c1ccccc1
Yield: 71.1 %

Procedure:
A mixture of 2.6 g (6.8 mmole) of 4-ethoxycarbonyl-1-[2-(1,1-diphenylethoxy)ethyl]piperazine [prepared as described in step (a) above], 3.0 g (5.3 mmole) of potassium hydroxide, 9 ml of water and 30 ml of ethylene glycol was stirred at 160° C. for 2 hours while the water formed was removed by evaporation. The reaction mixture was then poured into ice water, and the mixture was extracted with chloroform, after which it was washed with water. The solvent was then removed by evaporation under reduced pressure, to obtain 1.5 g (yield 71%) of the title compound as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[OH:32])[CH:9]1[CH2:18][CH2:17][CH2:16][C:15]2[N:14]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:12]=[CH:11][C:10]1=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][C:43]2[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:45][CH:44]=2)=[CH:37][CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([O:5][C:6]([N:8]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH2:34][C:35]1[CH:36]=[CH:37][C:38]([CH2:41][CH2:42][C:43]2[CH:48]=[CH:47][C:46]([C:49]([F:50])([F:51])[F:52])=[CH:45][CH:44]=2)=[CH:39][CH:40]=1)[CH:9]1[CH2:18][CH2:17][CH2:16][C:15]2[N:14]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:12]=[CH:11][C:10]1=2)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: FC(F)(F)c1ccc(CCc2ccc(CCl)cc2)cc1
Reactant: CCOC(=O)c1ccc2c(n1)CCCC2N(CCc1ccccc1O)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1ccc2c(n1)CCCC2N(CCc1ccccc1OCc1ccc(CCc2ccc(C(F)(F)F)cc2)cc1)C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
1 g (2.27 mmol) of ethyl 5-{(tert-butoxycarbonyl)[2-(2-hydroxyphenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylate (Enantiomer 2, Example 69A), 746 mg (2.50 mmol) of 1-(chloromethyl)-4-{2-[4-(trifluoromethyl)phenyl]ethyl}benzene and 784 mg (5.68 mmol) of potassium carbonate in 25 ml of acetonitrile were heated to 110° C. and stirred at this temperature overnight. After cooling, the reaction mixture was filtered, the filter cake was washed repeatedly with acetonitrile and the combined filtrates were concentrated to dryness on a rotary evaporator. The residue obtained was purified chromatographically on silica gel (mobile phase: cyclohexane/ethyl acetate 20:1→10:1). This gave 1110 mg (1.48 mmol, 65% of theory) of the target compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:18][CH2:19][CH2:20][Cl:21])=[C:7]([O:16][CH3:17])[CH:8]=2)[N:3]=1.CO[CH:24](OC)[N:25]([CH3:27])[CH3:26].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)C>C1(C)C=CC=CC=1>[Cl:21][CH2:20][CH2:19][O:18][C:6]1[CH:5]=[C:4]2[C:9]([CH:10]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[C:2](/[N:1]=[CH:24]/[N:25]([CH3:27])[CH3:26])=[N:3]2)=[CH:8][C:7]=1[O:16][CH3:17]
Reactant: COC(=O)c1cc2cc(OC)c(OCCCl)cc2nc1N
Reactant: COC(OC)N(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COC(=O)c1cc2cc(OC)c(OCCCl)cc2nc1/N=C/N(C)C
Temperature: 25 °C
Yield: 64.7 %

Procedure:
A mixture of methyl 2-amino-7-[2-chloroethoxy]-6-methoxy-3-quinolinecarboxylate (5.00 g, 16.09 mmol) and 5.10 g of dimethylformamide dimethylacetal in 75 mL of toluene containing 50 mg of p-toluenesulfonic acid is heated at reflux for 10 minutes then cooled to room temperature. Diethyl ether is added and the solids are collected by filtration to provide 3.81 g of methyl 7-(2-chloroethoxy)-2-{[(1E)-(dimethylamino)methylidene]amino}-6-methoxy-3-quinolinecarboxylate as a pale yellow solid, mp 108–110° C. MS 366.1, 368.1 (M+H)+ Analysis for C17H20ClN3O4.0.5H2O Calcd. C, 54.47; H, 5.65; N, 11.21. Found: C, 54.86; H, 5.62; N, 10.89.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][NH2:15])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([C:20]1[N:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:23]=[C:22]([CH:31]=O)[CH:21]=1)[CH:17]([CH3:19])[CH3:18]>>[CH2:16]([C:20]1[N:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:23]=[C:22]([CH2:31][NH:15][CH2:14][CH2:13][N:10]2[CH2:9][CH2:8][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:12][CH2:11]2)[CH:21]=1)[CH:17]([CH3:19])[CH3:18]
Reactant: NCCN1CCN(c2ccccc2)CC1
Reactant: CC(C)Cc1cc(C=O)nn1-c1ccccc1
Product: CC(C)Cc1cc(CNCCN2CCN(c3ccccc3)CC2)nn1-c1ccccc1
Yield: 56.2 %

Procedure:
Compound 7 was prepared using the same method as used in Example 1 except that 4-phenylpiperazin-1-ylethylamine and 5-iso-butyl-1-phenylpyrazole-3-carbaldehyde were used.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[CH3:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][NH2:22].C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>O>[CH3:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][NH:22][C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2[C:3]=1[N:11]=[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:9]=2
Reactant: Cc1ccccc1CN
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: Cc1nc(NCc2ccccc2C)c2nc(-c3ccccc3)cc-2[nH]1
Temperature: 140 °C
Reaction time: 1.5 h
Yield: 36.5 %

Procedure:
To a mixture of 4-chloro-2-methyl-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1(e)) (85.0 mg, 0.35 mmol) and 2-methylbenzyl amine (Aldrich Chemical Company) (2.2 mL, 17.4 mmol) was added a solution of K2CO3 (0.35 g, 2.54 mmol) in H2O (2.5 mL). This mixture was stirred at 140° C. in a closed-capped Wheaton vial for 1.5 h. After cooling, CH2Cl2 (10 mL) and H2O (10 mL) were added. The organic solution was removed and the aqueous solution washed with CH2Cl2 (10 mL). The combined organic solutions were washed with saturated NaCl (15 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (3% MeOH:CHCl3 on silica gel) and then recrystallized from MeOH/CH2Cl2 to give 42 mg (35%) of the title compound as a white solid. Mp: 277-281° C. MS m/z: 329 (M+1). 1H NMR (DMSO-d6; 400 MHz): δ 2.38 (s, 3), 2.42 (s, 3), 4.69 (d, 2, J=4.8), 6.75 (s, 1), 6.98 (br t, 1), 7.19-7.25 (m, 3), 7.35-7.42 (m, 2), 7.49 (t, 2, J=7.8), 7.76 (d, 2, J=7.8), 11.27 (s, 1). Anal. Calcd for C21H20N4: C, 76.83; H, 6.10; N, 17.07. Found: C, 76.58; H, 6.20; N, 16.94.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[O:9][C@H:8]3[NH:13][C@H:14]([C:16]([O:18][C@@H:19]4[C@:28]5([OH:29])[C@@H:23]([C@H:24]([CH:31]([CH3:33])[CH3:32])[CH2:25][CH2:26][C@H:27]5[CH3:30])[CH:22]=[C:21]([CH3:34])[C@H:20]4[O:35]C(=O)C)=[O:17])[CH2:15][C@@:7]3([OH:39])[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl>CO.ClCCl>[Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[O:9][C@H:8]3[NH:13][C@H:14]([C:16]([O:18][C@@H:19]4[C@:28]5([OH:29])[C@@H:23]([C@H:24]([CH:31]([CH3:32])[CH3:33])[CH2:25][CH2:26][CH:27]5[CH3:30])[CH:22]=[C:21]([CH3:34])[CH:20]4[OH:35])=[O:17])[CH2:15][C@@:7]3([OH:39])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O[C@@H]1C(C)=C[C@@H]2[C@H](C(C)C)CC[C@@H](C)[C@]2(O)[C@H]1OC(=O)[C@@H]1C[C@@]2(O)c3cccc(Cl)c3N(C)O[C@H]2N1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CC1=C[C@@H]2[C@H](C(C)C)CCC(C)[C@]2(O)[C@@H](OC(=O)[C@@H]2C[C@@]3(O)c4cccc(Cl)c4N(C)O[C@H]3N2)C1O
Yield: 97.7 %

Procedure:
To a stirred suspension of (1S,2R,4aS,5S,8R,8aR)-2-(acetyloxy)-8a-hydroxy-5-isopropyl-3,8-dimethyl-1,2,4a,5,6,7,8,8a-octahydro-1-naphthalenyl-(2S,3aR,9bR)-6-chloro-9b-hydroxy-5-methyl-1,2,3,3a,5,9b-hexahydropyrrolo[2,3-c][2,1]benzoxazine-2-carboxylate (Example 1, 887 mg) in methanol (25 ml) was added a solution of concentrated hydrochloric acid (1 ml) in methanol (25 ml). After 4 days the reaction mixture was diluted with dichloromethane (150 ml) and washed with water (3×100 ml). The combined aqueous layers were washed with dichloromethane (25 ml). All the organic phases were combined, dried and concentrated to yield a yellow solid (802 mg). Purification was achieved by flash column chromatography on silica gel eluting with 1:1 ethyl acetate:hexane to give the product (604 mg).