Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([N:9]2[C:14]([CH3:15])=[CH:13][C:12]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])=[CH:11][C:10]2=[O:26])[CH:6]=[CH:7][CH:8]=1.[CH3:27][NH:28][CH3:29]>CO>[F:25][C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=1[CH2:17][O:16][C:12]1[CH:13]=[C:14]([CH3:15])[N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][N:28]([CH3:29])[CH3:27])[CH:4]=2)[C:10](=[O:26])[CH:11]=1
Reactant: Cc1cc(OCc2ccc(F)cc2F)cc(=O)n1-c1cccc(CCl)c1
Reactant: CNC
Solvent: CO
Product: Cc1cc(OCc2ccc(F)cc2F)cc(=O)n1-c1cccc(CN(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
1-[3-(chloromethyl)phenyl]-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one (from step 1 of the synthesis of EXAMPLE 293) (0.500 g, 1.330 mmol) was suspended in a stock solution of N,N-dimethylamine in methanol (2.0 mL, 2.0 M) and stirred overnight at room temperature. Reaction was concentrated and the residue partitioned between H2O (25 mL) and ethyl acetate (25 mL). The aqueous layer was further extracted with ethyl acetate (2×30 ml), and the combined organics were washed with brine (30 mL), dried over MgSO4, and concentrated to afford an off-white solid (0.508 g, 99%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)C.C1COCC1.[Pd]>[F:32][C:29]([F:30])([F:31])[C:26]1[CH:27]=[CH:28][C:23]([CH2:22][CH2:21][N:18]2[CH2:17][CH2:16][N:15]([C:12]3[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=3)[CH2:20][CH2:19]2)=[CH:24][CH:25]=1
Reactant: FC(F)(F)c1ccc(CCN2CCN(c3ccc(OCc4ccccc4)cc3)CC2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Oc1ccc(N2CCN(CCc3ccc(C(F)(F)F)cc3)CC2)cc1
Temperature: 55 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
1-(4-Benzyloxyphenyl)-4-[2-(4-trifluoromethylphenyl)ethyl]piperazine (0.94 g) was dissolved in ethanol (19 ml) and THF (19 ml). 10% palladium on carbon (94 mg) was added to the mixture and stirred at 50 to 60° C. under a hydrogen atmosphere for 8 hours. After being cooled to room temperature, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to afford the title compound as a gray powder (0.72 g).
Reaction SMILES: COC([C:5]1([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10](=[O:11])[CH2:9][CH2:8][N:7]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:6]1)=O.[OH-].[Na+]>Cl.CO>[CH2:12]([N:7]1[CH2:8][CH2:9][C:10](=[O:11])[CH:5]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:6]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)C1(Cc2ccccc2)CN(Cc2ccccc2)CCC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1CCN(Cc2ccccc2)CC1Cc1ccccc1
Reaction time: 48 h

Procedure:
1,3-Dibenzyl-4-oxo-piperidine-3-carboxylic acid methyl ester, (2, R1B=H, Z=benzyl) (17.52 g, 51.92 mmol) was suspended in 150 mL of 6N HCl:MeOH (5:1) and the mixture was heated to reflux temperature with stirring for 48 h. After cooling the mixture was basified to pH 10 with 6N NaOH and extracted with 3×200 mL dichloromethane. The combined organics were dried (MgSO4) and concentrated to give 11.60 g of the title compound as a colorless oil, 80%. LC-MS: RT=0.38 min. (M+H)+ 280.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])([CH3:14])[CH2:10][CH2:9]1)=O)(C)(C)C.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>C(OCC)(=O)C.Cl.C(OCC)(=O)C>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[O:16][CH2:15][C:11]1([CH3:14])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC1(COc2ccccc2Cl)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC1(COc2ccccc2Cl)CCNCC1
Reaction time: 2.5 h
Yield: 91.2 %

Procedure:
After dissolving 810 mg of 1-(tert-butoxycarbonyl)-4-(2-chlorophenoxymethyl)-4-methylpiperidine in 3 ml of ethyl acetate, 3 ml of 4N hydrogen chloride/ethyl acetate was added and the mixture was allowed to stand at room temperature for 2.5 hours. A sodium carbonate solution was added to the reaction solution, and extraction was performed with dichloromethane. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound (521 mg, 91% yield).
Reaction SMILES: O=[C:2]([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:10][C:11]([F:20])([F:19])[C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH2:15].C(O)(=O)C>C1(C)C=CC=CC=1>[F:10][C:11]([F:19])([F:20])[C:12]1[CH:13]=[C:14]([NH:15]/[C:2](/[CH3:9])=[CH:3]/[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:16]=[CH:17][CH:18]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)CC(C)=O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)/C=C(\C)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
4.0 g (31 mmol) Ethyl 3-oxobutanoate, 5.0 g (31 mmol) 3-trifluoromethylaniline, and 1.86 g (31 mmol) acetic acid are dissolved in 50 ml toluene. The reaction mixture is refluxed overnight with a Dean-Stark trap to remove water. After cooling down to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica with cyclohexane/ethylacetate mixtures as eluent.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH:4]([NH:15][CH2:16][C:17]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:31])=[CH:18][C:19]([O:21]CC)=O)[CH2:5][CH:6]([C:11]([F:14])([F:13])[F:12])[C:7]([F:10])([F:9])[F:8]>C(#N)C>[CH3:1][O:2][C:3](=[O:32])[CH:4]([N:15]1[CH2:16][C:17]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])=[CH:18][C:19]1=[O:21])[CH2:5][CH:6]([C:11]([F:12])([F:13])[F:14])[C:7]([F:10])([F:9])[F:8]
Reactant: CCOC(=O)C=C(CNC(CC(C(F)(F)F)C(F)(F)F)C(=O)OC)Oc1ccccc1Cl
Solvent: CC#N
Product: COC(=O)C(CC(C(F)(F)F)C(F)(F)F)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 180 °C
Yield: 40.2 %

Procedure:
A solution of 2-[2-(2-chloro-phenoxy)-3-ethoxycarbonyl-allylamino]-5,5,5-trifluoro-4-trifluoromethyl-pentanoic acid methyl ester (144 mg, 0.29 mmol) in acetonitrile (2 mL) was placed in a sealed microwave reaction tube and heated in a microwave reactor at 180° C. for 3 h. The mixture was cooled to room temperature and concentrated in vacuo with silica gel (1.2 g). Purification by Biotage flash chromatography (AnaLogix 25 g column, 16% ethyl acetate/hexanes to 33% ethyl acetate/hexanes) afforded 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-5,5,5-trifluoro-4-trifluoromethyl-pentanoic acid methyl ester (52 mg, 7% over two steps) as an amber oil: HR-ES-MS m/z calculated for C17H14NO4ClF6 [M+H]+ 446.0589, observed 446.0588.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[NH:22]([C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:30](=[O:35])[CH2:29]2)[C:23]([CH3:25])=[O:24]>>[CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=[C:29]1[C:28]2[C:32](=[CH:33][CH:34]=[C:26]([NH:22][C:23](=[O:24])[CH3:25])[CH:27]=2)[NH:31][C:30]1=[O:35]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Reactant: CC(=O)Nc1ccc2c(c1)CC(=O)N2
Product: CC(=O)Nc1ccc2c(c1)C(=Cc1[nH]c3c(c1C)C(=O)N(CCN1CCCCC1)CC3)C(=O)N2
Yield: 69.7 %

Procedure:
The title compound was prepared under the same conditions as described in Example 25 with 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 5-acetamino-1,3-dihydro-indol-2-one as starting materials to give N-{3-[3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-5-yl}-acetamide (55 mg, 69.7%) as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH:12]2[C:17]([C:18]([O:20][CH2:21]C)=[O:19])=[CH:16][CH2:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])=[C:4]([F:23])[CH:3]=1>CO.S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH:12]2[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH2:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])=[C:4]([F:23])[CH:3]=1
Reactant: CCOC(=O)C1=CCCCC1S(=O)(=O)Nc1ccc(Cl)cc1F
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)C1=CCCCC1S(=O)(=O)Nc1ccc(Cl)cc1F
Yield: 24.1 %

Procedure:
To a solution of ethyl 6-[N-(4-chloro-2-fluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate obtained in Example 1 (Compound 1, 250 mg) in methanol (5 ml), concentrated sulfuric acid (0.2 ml) was added and the mixture was stirred under reflux for 8 days hours. The reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate (30 ml) and washed with water (30 ml). The ethyl acetate layer was washed with water (30 ml×2) and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was ,subjected to silica gel chromatography (eluent: ethyl acetate/hexane=1/4) and desired fractions were concentrated under reduced pressure. The residue was purified by an ODS column chromatography (eluent: methanol/water=4/1) and then crystallized from diisopropyl ether to yield methyl 6-[N-(4-chloro-2-fluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate (Compound 24, 58 mg) as colorless prism-like crystals.
Reaction SMILES: Cl[S:2]([C:5]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:6]=1[CH2:7][O:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1)(=[O:4])=[O:3].[NH2:26][C:27]1[C:36]([C:37]([O:39][CH3:40])=[O:38])=[C:35]2[C:30]([C@H:31]3[CH2:41][C@H:32]3[CH2:33][O:34]2)=[CH:29][CH:28]=1>C(Cl)Cl>[F:25][C:22]1[CH:23]=[CH:24][C:5]([S:2](=[O:4])(=[O:3])[NH:26][C:27]2[CH:28]=[CH:29][C:30]3[C@H:31]4[CH2:41][C@H:32]4[CH2:33][O:34][C:35]=3[C:36]=2[C:37]([O:39][CH3:40])=[O:38])=[C:6]([CH:21]=1)[CH2:7][O:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](OCc2cc(F)ccc2S(=O)(=O)Cl)C1
Reactant: COC(=O)c1c(N)ccc2c1OC[C@@H]1C[C@H]21
Solvent: ClCCl
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2CO[C@H]2CCN(C(=O)OC(C)(C)C)C2)ccc2c1OC[C@@H]1C[C@H]21
Reaction time: 120 h
Yield: 99.5 %

Procedure:
A solution of tert-butyl (S)-3-(2-chlorosulfonyl-5-fluorobenzyloxy)pyrrolidine-1-carboxylate (Intermediate 215, 0.295 g) in DCM (2 mL) was added to a solution of methyl (1aR,7bS)-5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 42A, 0.11 g) in DCM (2 mL) and the mixture was left at room temperature for 5 days. The mixture was diluted with DCM, washed with 1M hydrochloric acid and filtered through a phase separator. The filtrate was evaporated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-30% to give tert-butyl (S)-3-[5-fluoro-2-((1aR,7bS)-4-methoxycarbonyl-1,1a,2,7b-tetrahydrocyclopropa-[c]chromen-5-ylsulfamoyl)benzyloxy]pyrrolidine-1-carboxylate (0.288 g) as a white foam.
Reaction SMILES: Br[CH2:2][CH2:3][C:4](Br)=[O:5].[CH2:7]([O:9][C:10](=[O:45])[CH2:11][CH2:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]([C:23](=[O:44])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([NH:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[CH3:41])=[O:33])=[C:27]([O:42][CH3:43])[CH:26]=1)[CH2:18][CH2:17][NH:16]2)[CH3:8].C(N(CC)CC)C.O>O1CCCC1>[C:4]([N:16]1[C:15]2[C:20](=[CH:21][CH:22]=[C:13]([CH2:12][CH2:11][C:10]([O:9][CH2:7][CH3:8])=[O:45])[CH:14]=2)[N:19]([C:23](=[O:44])[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32]([NH:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[CH3:41])=[O:33])=[C:27]([O:42][CH3:43])[CH:26]=2)[CH2:18][CH2:17]1)(=[O:5])[CH:3]=[CH2:2]
Reactant: O=C(Br)CCBr
Reactant: CCOC(=O)CCc1ccc2c(c1)NCCN2C(=O)Cc1ccc(NC(=O)Nc2ccccc2C)c(OC)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: C=CC(=O)N1CCN(C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)c2ccc(CCC(=O)OCC)cc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-Bromo propionyl bromide (262 μl) was added to a stirred suspension of 3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-1,2,3,4-tetrahydro-quinoxalin-6-yl)-propionic acid ethyl ester (0.229 g, Reference Example 1) and triethylamine (680 μl) in tetrahydrofuran (10 ml) cooled to 0° C. under argon atmosphere. After stirring at 0° C. for 1 hour then at 20° C. overnight the mixture was treated with 3-bromo propionyl bromide (90 μl) and stirring was continued for 2 hours at 21° C. The reaction mixture was treated with water (25 ml) and after stirring for 15 minutes at 20° C. the mixture was extracted three times with ethyl acetate (25 ml). The combined extracts were washed with saturated aqueous sodium bicarbonate (10 ml), then washed four times with water (10 ml), then dried over magnesium sulfate and then evaporated to dryness under reduced pressure (40° C., 40 mbar). The residue (1.7 g) was subjected to flash chromatography on silica (50 g, 0.040-0.063 mm particle size) eluting with a mixture of cyclohexane and ethyl acetate (1:1, v/v) to give the title compound as a yellow foam (550 mg). TLC: RF=30/72, silica, eluting with a mixture of dichloromethane and methanol (9:1, v/v). 1H NMR [400 MHz, (CD3)2SO, at a temperature of 373° K.]: δ1.20 (t, J=7 Hz, 3H); 2.28 (s,, 3H); 2.64 (t, J=7.5 Hz, 2H); 2.91 (t, J=7.5 Hz, 2H); 3.81 (s, 3H); 3.84 (s, 2H); 3.87 (m, 2H); 3.93 (m, 2H); 4.11 (q, J=7 Hz, 2H); 5.68 (dd, J=10.5 and 2 Hz, 1H); 6.21 (dd, J=17 and 2 Hz, 1H); 6.38 (dd, J=17 and 10.5 Hz, 1H); 6.58 (broad d, J=8 Hz, 1H); 6.75 (broad s, 1H); 6.99 (broad t, J=7.5 Hz, 1H); from 7.10 to 7.25 (m, 4H); 7.57 (d, J=8.5 Hz, 1H); 7.69 (broad d, J=8 Hz, 1H); 7.92 (d, J=8.5 Hz, 1H); 8.18 (broad s, 1H); 8.28 (broad s, 1H). MS (EI): 584 (M+).
Reaction SMILES: O.[OH-].[Li+].[NH:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:5][C:6]([N:8]([CH2:10][C:11]([O:13]C)=[O:12])[CH3:9])=[O:7].Cl>C1COCC1.CO.O>[NH:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:5][C:6]([N:8]([CH2:10][C:11]([OH:13])=[O:12])[CH3:9])=[O:7]
Reactant: COC(=O)CN(C)C(=O)CNC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CN(CC(=O)O)C(=O)CNC(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 100.2 %

Procedure:
Lithium hydroxide monohydrate (598 mg, 14.3 mmol) was added to a solution of 200 (1.22 g, 4.7 mmol) in 20 mL of THF—CH3OH—H2O (3:1:1) at 25° C. and the resulting reaction mixture was stirred for 3 h. The reaction mixture was poured onto 3M aqueous HCl (10 mL) and extracted with EtOAc (3×20 mL). The combined organic phases were dried (Na2SO4), filtered and concentrated in vacuo to give 300 (1.16 g, 1.16 g theoretical, 100%) as a colorless oil. This acid was identical to authentic material14 and was used directly in the next step without further purification: 1H NMR (CDCl3, 400 MHz)14 5.76 and 5.66 (two br s, 1H), 4.11, 4.00, and 3.91 (three s, 4H), 2.99 and 2.95 (two s, 3H), 1.38 (s, 9H); IR (neat)max 3348, 2979, 2937, 1717, 1654, 1691, 1409, 1368, 1287, 1252, 1167, 1053, 1030, 954, 866, 782, 736 cm−1.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[NH2:21][C:22]1[C:27]([C:28]#[N:29])=[CH:26][C:25]([CH2:30][CH2:31][NH:32][CH3:33])=[CH:24][C:23]=1[Cl:34]>>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][N:32]([CH3:33])[CH2:31][CH2:30][C:25]3[CH:26]=[C:27]([C:28]#[N:29])[C:22]([NH2:21])=[C:23]([Cl:34])[CH:24]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: CNCCc1cc(Cl)c(N)c(C#N)c1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCc1cc(Cl)c(N)c(C#N)c1)CC2

Procedure:
This compound was prepared analogous to Example 5(b) from 1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl]-3-chloro-propane and 2-(4-amino-3-chloro-5-cyano-phenyl)-N-methyl-ethylamine.
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[Cl:17][C:18]1[C:19]([C:26]#[N:27])=[N:20][CH:21]=[C:22]([CH2:24][OH:25])[CH:23]=1.[C:28]1(O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CCOC(C)=O>[Cl:17][C:18]1[C:19]([C:26]#[N:27])=[N:20][CH:21]=[C:22]([CH2:24][O:25][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:23]=1
Reactant: Oc1ccccc1
Reactant: N#Cc1ncc(CO)cc1Cl
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1ncc(COc2ccccc2)cc1Cl
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 80.8 %

Procedure:
Di-tert-butyl azodicarboxylate (174 mg, 0.76 mmol) was added to a stirred solution of 3-chloro-5-hydroxymethyl-pyridine-2-carbonitrile (71 mg, 0.42 mmol), phenol (79 mg, 0.84 mmol) and triphenylphosphine (199 mg, 0.76 mmol) in anhydrous THF (3.3 mL) at 0° C. The mixture was stirred at 120° C. for 30 minutes under microwave irradiation. Then, the mixture was diluted with EtOAc and washed with a saturated solution of NaHCO3 and brine. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; EtOAc in DCM 0/100 to 20/80). The desired fractions were collected and the solvents evaporated in vacuo to yield 3-chloro-5-phenoxymethyl-pyridine-2-carbonitrile (83 mg, 80%) as a white solid.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][C:14]3=[N:17]O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H][H]>C(O)C.[C].[Pd]>[N:1]1([C:7]2[CH:16]=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH:14]3[NH2:17])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: ON=C1CCCc2ccc(N3CCOCC3)cc21
Agent: [Pd]
Solvent: CCO
Product: NC1CCCc2ccc(N3CCOCC3)cc21
Yield: 30.4 %

Procedure:
A solution of crude 7-morpholin-4-yl-3,4-dihydro-2H-naphthalen-1-one oxime (384 mg) and 10% palladium-carbon (water content: 48%, 350 mg) in ethanol (10 mL) was stirred in a hydrogen atmosphere (0.4 Mpa) at room temperature for 8 hours. The reaction solution was filtered on a celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane-ethyl acetate system->ethyl acetate-methanol system) to obtain 110 mg of the title compound. The physical properties of the compound are as follows.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=[O:14])=[C:8]([F:16])[CH:7]=1.[CH3:17]O>>[CH3:17][O:14][C:13](=[O:15])[CH2:12][C:9]1[CH:10]=[CH:11][C:6]([Cl:5])=[CH:7][C:8]=1[F:16]
Reactant: CO
Reactant: O=C(O)Cc1ccc(Cl)cc1F
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
Thionyl chloride (0.94 mL, 0.0129 mol) was added dropwise to a solution of (4-chloro-2-fluoro-phenyl)acetic acid (2.03 g, 0.0108 mol) in methanol (100 mL) at 0° C., and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel chromatography (n-hexane/ethyl acetate=1/0 to 3/1) to give the title compound (2.11 g, 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]2[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=2)=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]1([OH:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:5].[CH3:26][O:27][CH2:28][CH:29]1[CH2:31][O:30]1>CN(C)C=O>[Cl:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]2[CH:24]=[C:23]([CH3:25])[N:22]([CH2:31][CH:29]([OH:30])[CH2:28][O:27][CH3:26])[N:21]=2)=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]1([OH:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:5]
Reactant: Cc1cc(-c2ccc(Cl)c(C(=O)NCC3(O)CCCCCC3)c2)n[nH]1
Reactant: COCC1CO1
Solvent: CN(C)C=O
Product: COCC(O)Cn1nc(-c2ccc(Cl)c(C(=O)NCC3(O)CCCCCC3)c2)cc1C

Procedure:
A mixture of 2-chloro-N-(1-hydroxy-cycloheptylmethyl)-5-(5-methyl-1H-pyrazol-3-yl)-benzamide (0.36 g, 1 mmol) and 2-methoxymethyl-oxirane (0.8 mL) was stirred in N,N-dimethylformamide (1.0 mL) at 90° C. for 12 h. The mixture was concentrated in vacuo. The residue was purified by reverse phase chromatography, followed by trituration (1:1:1 diethyl ether-dichloromethane-ethyl acetate) to afford the title compound (0.08 g). LCMS (m/z) 450.1 M+1
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:24](/B(O)O)=[CH:25]\[CH2:26][CH2:27][CH2:28][CH3:29].C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[CH2:1]([O:8][C:9]1[CH:14]=[C:13](/[CH:24]=[CH:25]/[CH2:26][CH2:27][CH2:28][CH3:29])[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CN(c2ccc(I)cc2OCc2ccccc2)S(=O)(=O)N1
Reactant: CCCC/C=C/B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCCC/C=C/c1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Temperature: 110 °C

Procedure:
A mixture of 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (200 mg, 0.45 mmol), trans-1-hexen-1-ylboronic acid (77 mg, 0.676 mmol), resin-bound PPh3Pd (692 mg, loading 0.13 mmol/g) and aqueous Na2CO3 (0.9 mL of a 2M solution) in DME (3 mL) is placed in a microwave vial and heated at 110° C. for 30 min. The mixture is filtered, diluted with EtOAc and washed with 1N HCl. The organic phase is dried over magnesium sulfate and the solvent removed under reduced pressure. The residue is purified by preparative HPLC to give the title compound.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:22][O:23][CH3:24])([CH2:19][O:20][CH3:21])[O:4][C:5]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:6]=2[C:7]=1[C:8](=[S:11])[NH:9][CH3:10].O1CCCC1.[BH4-].[Na+]>CO>[OH:1][CH:2]1[CH:7]([C:8](=[S:11])[NH:9][CH3:10])[C:6]2[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:5]=2[O:4][C:3]1([CH2:22][O:23][CH3:24])[CH2:19][O:20][CH3:21]
Reactant: CNC(=S)C1=C(O)C(COC)(COC)Oc2ccc([N+](=O)[O-])cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=S)C1c2cc([N+](=O)[O-])ccc2OC(COC)(COC)C1O
Yield: 36.8 %

Procedure:
To a mixture of 2.7 g of 3-hydroxy-2,2-bis(methoxymethyl)-N-methyl-6-nitro-2H-1-benzopyran-4-carbothioamide, 12 ml of tetrahydrofuran and 46 ml of methanol was added 1.1 g of sodium borohydride (NaBH4) with stirring under ice-cooling and stirred under ice-cooling for 2 hours and subsequently further stirred at room temperature for 24 hours. The reaction solution was vacuum-distilled, water was added therein and the resultant mixture was extracted with methylene chloride. An organic layer was washed with water and dried. The solvent was distilled to obtain 1.0 g of 3,4-dihydro-3-hydroxy-2,2-bis(methoxymethyl)-N-methyl-6-nitro-2H-1-benzopyran-4-carbothioamide. Subsequently, to 700 mg of the obtained benzopyran derivative were added 0.75 g of p-toluenesulfonyl chloride and 11 ml of pyridine. The resultant mixture was refluxed with heating for 30 minutes and the solvent was distilled. Ice water was added to the residue and it was acidified to be hydrochloric acid and extracted with methylene chloride. An organic layer was washed with water and dried and the solvent was distilled. The resultant residue was purified according to silica gel column chromatography (developing solution, MeOH:CH2Cl2 =5:95) to obtain 500 mg of 2,2-bis(methoxymethyl)-N-methyl-6-nitro-2H-1-benzopyran-4-carboxamide with a melting point of 147°-149° C.