Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([CH:26]=[CH2:27])[C@H:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[OH:25])[C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:35](OC(=O)C)(=[O:37])[CH3:36].[C:42](OCC)(=[O:44])[CH3:43]>C1COCC1.C(Cl)Cl>[C:35]([O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][N:17]([C@H:9]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[C@@H:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH:26]=[CH2:27])[C:42](=[O:44])[CH3:43])(=[O:37])[CH3:36]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(C)=O
Reactant: C=C[C@H](c1cccc(Cl)c1)[C@H](NCc1ccccc1O)c1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C[C@H](c1cccc(Cl)c1)[C@@H](c1ccc(Cl)cc1)N(Cc1ccccc1OC(C)=O)C(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.1 g (2.76 mmol) of 2-(((1S,2R)-2-(3-chlorophenyl)-1-(4-chlorophenyl)but-3-enylamino)methyl)phenol (Example 115, Step B) and triethylamine (0.85 mL, 6.08 mmol) in a mixture of THF (5.0 mL) and DCM (5.0 mL) was added acetic anhydride (0.55 mL, 5.80 mmol) at 0° C. The temperature of the reaction was slowly allowed to rise to room temperature and the mixture was stirred at ambient temperature overnight. When LCMS indicated completion of the reaction, 100 ml of ethyl acetate was added and the combined organics were washed consecutively with water (30 ml), citric acid (30 ml, 1M), NaHCO3 solution (30 ml) and sat. NaCl solution (30 ml), dried over MgSO4, filtered and the filtrate was concentrated to give the title compound. The crude product was used without further purification.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([C:34](OC)=[O:35])=[N:14][C:15]=2[NH:19][CH2:20][CH:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[NH2:38][CH2:39][CH2:40][N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>C(OCC)C>[OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([C:34]([NH:38][CH2:39][CH2:40][N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1)=[O:35])=[N:14][C:15]=2[NH:19][CH2:20][CH:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Reactant: NCCN1CCOCC1
Solvent: CCOCC
Product: O=C(NCCN1CCOCC1)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 120 °C

Procedure:
A mixture of methyl 9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)-tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9H-purine-2-carboxylate (Preparation 18) (92 mg, 0.18 mmol) and N-(2-aminoethyl)morpholine (0.25 ml, 1.9 mmol) were heated at 120° C. under a nitrogen atmosphere for 75 minutes. The reaction mixture was allowed to cool to room temperature and diethyl ether (2 ml) added to precipitate the title compound as a white solid which was filtered off and dried (68 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[CH:46][CH:45]=[CH:44][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:13][CH:12]=1.[F:48][C:49]1[C:50]([OH:61])=[C:51]([CH2:55][CH2:56][NH:57][C:58](=[O:60])[CH3:59])[CH:52]=[CH:53][CH:54]=1>>[C:58]([NH:57][CH2:56][CH2:55][C:51]1[CH:52]=[CH:53][CH:54]=[C:49]([F:48])[C:50]=1[O:61][CH2:32][CH2:31][O:30][CH:18]1[CH:17]([C:14]2[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][C:4]3[CH:44]=[CH:45][CH:46]=[CH:47][C:3]=3[O:2][CH3:1])=[CH:16][CH:15]=2)[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:19]1)(=[O:60])[CH3:59]
Reactant: CC(=O)NCCc1cccc(F)c1O
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2c(F)cccc2CCNC(C)=O)cc1

Procedure:
Analogously to Method G. 0.45 g of tert-butyl 4-{4-[3-(2-methoxybenyloxy)propoxy]phenyl}-3-[2-(toluene-4-sulphonyloxy)ethoxy]piperidine-1-carboxylate (Example 14b) and 0.26 g of N-[2(3-fluoro-2-hydroxyphenyl)ethyl]acetamide are reacted. The title compound is obtained as a yellow oil. Rf=0.42 (EtOAc); Rt=5.65.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][C:4]=1[O:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16].[BH4-].[Na+].O>C1COCC1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][C:4]=1[O:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16]
Reactant: COCCCOc1cc(C=O)ccc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCCCOc1cc(CO)ccc1OC
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of the title A compound, 4-methoxy-3-(3-methoxy-propoxy)-benzaldehyde (2.02 g, 8.9 mmol) in 60 mL of THF is added portion wise sodium borohydride (0.74 g, 18.73 mmol) at 0° C. The reaction mixture is stirred for 6 hours at room temperature. After addition of H2O, the aqueous layer is extracted twice with ethyl acetate. The combined organic extracts are dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the title compound as a colorless oil: TLC, Rf (hexane/AcOEt 1/1)=0.34.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=4[CH3:30])[C:24](O)=[O:25])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[CH3:31][N:32]1[CH:36]=[CH:35][C:34]([C:37]2([NH2:40])[CH2:39][CH2:38]2)=[N:33]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([C:24](=[O:25])[NH:40][C:37]5([C:34]6[CH:35]=[CH:36][N:32]([CH3:31])[N:33]=6)[CH2:39][CH2:38]5)[CH:27]=[CH:28][C:29]=4[CH3:30])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: Cn1ccc(C2(N)CC2)n1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ccn(C)n5)CC4)ccc3C)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.15 g, 0.37 mmol, 1 eq), 1-(1-methyl-1H-pyrazol-3-yl)cyclopropanamine (0.061 g, 0.44 mmol, 1.2 eq), HOBT (0.057 g, 0.42 mmol, 1.7 eq), EDC.HCl (0.086 g, 0.44 mmol, 1.8 eq) in DCM at ambient temperature under nitrogen was added diisopropylehtylamine (0.16 g, 1.2 mmol, 5.0 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was further purified by column chromatography (neutral alumina) using 0.5% Methanol/DCM and finally by preparative HPLC. Yield: 0.06 g (40%)1H NMR (400 MHz, DMSO-d6): δ 1.12-1.16 (m, 2H), 1.20-1.23 (m, 2H), 2.29 (s, 3H), 2.82-2.83 (d, 3H, J=4.64 Hz), 3.37 (s, 3H), 5.9-6.0 (d, 1H, J=2.12 Hz), 7.39-7.48 (m, 5H), 7.58 (d, 1H, J=1.68 Hz), 7.75-7.77 (d, 1H, J=9.7 Hz), 7.81-7.83 (t, 2H, J=2.87 Hz), 7.98-8.46 (m, 2H), 8.47-8.48 (d, 1H, J=4.52 Hz), 9.14 (s, 1H). LCMS: (ES+) m/z=523.2 (M+H). LCMS Method: Column-Ascentis Express C18 (5×2.1 mm-2.7 μm) Mphase A: 2% MeCN-98% H2O-10 mM NH4COOH Mphase B: 98% MeCN-2% H2O-10 mM NH4COOH Flow: 1 ML/Min
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[CH:22]=[CH:21][NH:20][C:19](=[O:23])[CH:18]=3)[CH2:12][CH2:11]2)=[N:8][CH:9]=1)[CH2:2][CH3:3].C(C1[CH:27]=[N:28]C(N2CCC(OC3C=CNC(=O)C=3)CC2)=NC=1)C.[F:46][C:47]1[CH:52]=[CH:51][C:50](S(C)(=O)=O)=[CH:49][C:48]=1[F:57]>>[F:57][C:48]1[C:49]([N:20]2[CH:21]=[CH:22][C:17]([O:16][CH:13]3[CH2:14][CH2:15][N:10]([C:7]4[N:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][N:6]=4)[CH2:11][CH2:12]3)=[CH:18][C:19]2=[O:23])=[C:50]([CH:51]=[CH:52][C:47]=1[F:46])[C:27]#[N:28]
Reactant: CS(=O)(=O)c1ccc(F)c(F)c1
Reactant: CCCc1cnc(N2CCC(Oc3cc[nH]c(=O)c3)CC2)nc1
Reactant: CCc1cnc(N2CCC(Oc3cc[nH]c(=O)c3)CC2)nc1
Product: CCCc1cnc(N2CCC(Oc3ccn(-c4c(C#N)ccc(F)c4F)c(=O)c3)CC2)nc1

Procedure:
Example 252 was prepared according to procedures described in Example 248 substituting 4-(1-(5-propylpyrimidin-2-yl)piperidin-4-yloxy)pyridin-2(1H)-one (prepared according to procedures described in Example 173 Step C) for 4-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yloxy)pyridin-2(1H)-one and substituting 2,3,4-trifluorobenzonitrile (Oakwood) for 1,2-difluoro-4-(methylsulfonyl)benzene. 1H NMR (400 MHz, CDCl3) δ ppm 8.10 (s, 2H), 7.43-7.60 (m, 1H), 7.27-7.43 (m, 1H), 7.02 (d, J=7.78 Hz, 1 H), 6.05 (dd, J=7.65, 2.64 Hz, 1 H), 5.96 (d, J=2.51 Hz, 1H), 4.43-4.60 (m, 1 H), 4.08-4.24 (m, 2 H), 3.49-3.66 (m, 2H), 2.34 (t, J=7.53 Hz, 2 H), 1.99-2.08 (m, 2 H), 1.71-1.88 (m, 2 H), 1.43-1.59 (m, 2 H), 0.87 (t, J=7.28 Hz, 3 H). MS (ESI) 452 (M+H).
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][N:6]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]2)=[O:2].[BH4-].[Na+].O.C(OCC)(=O)C>CO>[OH:2][CH2:1][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][N:6]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]2
Reactant: CC(C)(C)OC(=O)N1Cc2cccc(C=O)c2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1Cc2cccc(CO)c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.4 %

Procedure:
To a solution of 350 mg of tert-butyl 4-formyl-1,3-dihydro-2H-isoindole-2-carboxylate in 11 mL of methanol was added 134 mg of sodium borohydride under ice-cooling, followed by stirring at room temperature overnight. To the reaction mixture were added water and ethyl acetate and the aqueous layer was separated. The obtained organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 213 mg of tert-butyl 4-(hydroxymethyl)-1,3-dihydro-2H-isoindole-2-carboxylate as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][N:9]=[C:10]([C:15](=[N:17][O:18][CH3:19])[CH3:16])[C:11]([O:13]C)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O>CO>[CH2:1]([O:8][N:9]=[C:10]([C:15](=[N:17][O:18][CH3:19])[CH3:16])[C:11]([OH:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CON=C(C)C(=NOCc1ccccc1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CON=C(C)C(=NOCc1ccccc1)C(=O)O
Yield: 99.7 %

Procedure:
To a solution of 3.2 g (12.1 mmol) of methyl 2-benzyloxyimino-3-methoxyiminobutyrate in 50 ml of methanol, 1.01 g (24.2 mmol) of sodium hydroxide and 10 ml of water were added and the mixture was heated under reflux for 24 hours. After distilling the solvent off under reduced pressure and adding 50 ml of water, the mixture was washed with 50 ml of diethylether. The aqueous layer was made acidic by adding a concentrated hydrochloric acid, and then the mixture was extracted three times with 50 ml of diethylether. After washing with water and with a saturated aqueous sodium chloride, the organic layer was dried over with anhydrous magnesium sulfate and the solvent was distilled off to obtain 3.02 g (yield: 100% ) of 2-benzyloxyimino-3-methoxyiminobutyric acid as a white solid.
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([CH3:18])=[CH:12]2)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:19]([O:21]C1C=C2C(=CC=1)NC(C)=C2C=O)C>>[C:1]([NH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([CH3:18])=[C:12]2[CH:19]=[O:21])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CCOc1ccc2[nH]c(C)c(C=O)c2c1
Reactant: Cc1cc2cc(NC(=O)OC(C)(C)C)ccc2[nH]1
Product: Cc1[nH]c2ccc(NC(=O)OC(C)(C)C)cc2c1C=O
Reaction time: 4 h
Yield: 36 %

Procedure:
This compound was prepared from 412 (615 mg, 2.24 mmol) in a manner similar to that for 409a except for after the drop-wise addition of substituted indole, the solution was stirred for 4 h to provide an orange precipitate. The precipitate was further purified by chromatography (isocratic 5% MeOH/DCM) to yield a white solid (250 mg, 36%): mp 201-203° C. TLC Rf 0.33 (75% EtOAc/hexanes). 1H NMR (600 MHz, d6-DMSO) δ 9.70 (s, 1H), 8.08 (s, 1H), 7.26-7.24 (m, 2H), 2.69 (s, 3H), 1.52 (s, 9H). 13C NMR (150 MHz, d6-DMSO) δ 184.4, 153.4, 149.4, 134.5, 131.6, 125.9, 115.6, 113.9, 111.4, 110.3, 79.0, 28.5, 11.7. Elemental analysis calculated for C15H18N2O3.0.125H2O: C, 65.14; H, 6.65; N, 10.13. Found: C, 64.82; H, 6.81; N, 10.14. HRMS ESI calculated for C15H18N2O3 (M+H)+ 275.1390; (M+Na)+ 297.1210. Found (M+H)+ 275.1393; (M+Na)+ 297.1210.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([CH3:24])=[CH:21][CH:22]=3)[N:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].C(OC(N1CCNCC1)=O)(C)(C)C.[F:45][C:46]1[CH:51]=[CH:50][C:49]([N:52]=C=O)=[CH:48][CH:47]=1>C(Cl)Cl.C(N(CC)CC)C>[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].[F:45][C:46]1[CH:51]=[CH:50][C:49]([NH:52][C:6]([N:8]2[CH2:9][CH2:10][N:11]([C:14]3[C:23]4[C:18](=[CH:19][C:20]([CH3:24])=[CH:21][CH:22]=4)[N:17]=[CH:16][CH:15]=3)[CH2:12][CH2:13]2)=[O:5])=[CH:48][CH:47]=1
Reactant: Cc1ccc2c(N3CCN(C(=O)OC(C)(C)C)CC3)ccnc2c1
Reactant: O=C=Nc1ccc(F)cc1
Agent: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc2c(N3CCN(C(=O)Nc4ccc(F)cc4)CC3)ccnc2c1

Procedure:
4-Chloro-7-methylquinoline [obtained from 3-toluidine following the protocol of Krogstad et. al. (De, D., Byers L. D., Krogstad, D. J. J. Heterocyclic Chem. 1997, 34, 315; 1H NMR ([D]6-DMSO), δ 2.55 (s, 3H), 7.60 (m, 1H), 7.75 (d, 1H), 7.90 (s, 1H), 8.10 (d, 1H), 8.80 (d, 1H)) (0.80 g, 4.5 mmol) and 1-tert-butoxycarbonylpiperazine (3.35 g, 18 mmol) are reacted according to method A yielding 475 mg of 4-[4-(tert-butoxycarbonyl)piperazin-1-yl]-7-methylquinoline. After cleaving the Boc group with trifluoroacetic acid (1.8 mL) in CH2Cl2 (1.8 mL), the piperazine is treated with 4-fluorophenyl isocyanate and triethylamine (0.245 mL) according to method C yielding the title product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[NH2:6].C(N(CC)CC)C.Cl[C:22](=[O:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24].Cl>ClCCl>[CH3:13][O:12][C:8]1[CH:7]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:9]=1[O:10][CH3:11])[NH:6][C:22](=[O:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: CCOC(=O)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(=O)Nc1cc(OC)c(OC)c(OC)c1
Reaction time: 2 h

Procedure:
3,4,5-Trimethoxyaniline (3.0 g) and triethylamine (4.5 mL) were dissolved in dichloromethane (10 mL), ethyl chloroglyoxylate (1.89 mL) was added dropwise to the solution under ice cooling, and the mixture was stirred for 2 hours. 1 M Hydrochloric acid was added to the reaction mixture to conduct extraction with dichloromethane. The resultant organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14](O)=[O:15])[C:9]2=[O:17])=[CH:4][CH:3]=1.FC1C=CC(C2(C3C=CC(F)=CC=3)CCCN(CC(O)=O)C2=O)=CC=1.[F:50][C:51]([F:63])([F:62])[C:52]1[CH:61]=[C:60]2[C:55]([CH2:56][CH2:57][NH:58][CH2:59]2)=[CH:54][CH:53]=1.C1(C2(C3C=CC=CC=3)CCNC2)C=CC=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14](=[O:15])[N:58]3[CH2:57][CH2:56][C:55]4[C:60](=[CH:61][C:52]([C:51]([F:50])([F:63])[F:62])=[CH:53][CH:54]=4)[CH2:59]3)[C:9]2=[O:17])=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1ccc2c(c1)CNCC2
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: O=C(O)CN1CCCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: c1ccc(C2(c3ccccc3)CCNC2)cc1
Product: O=C(CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O)N1CCc2ccc(C(F)(F)F)cc2C1

Procedure:
The title compound was prepared using the procedure described in Example 172 substituting 2-(3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid from Example 58D for 2-(3,3-bis(4-fluorophenyl)-2-oxopiperidin-1-yl)acetic acid and 7-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline for 3,3-diphenylpyrrolidine. 1H NMR (300 MHz, CDCl3) δ ppm 7.51-7.35 (m, 2H), 7.36-7.21 (m, 5H), 6.98 (td, J=5.3, 8.6, 4H), 4.70 (d, J=35.4, 2H), 4.27 (s, 2H), 3.83 (t, J=6.0, 1H), 3.68 (t, J=5.9, 1H), 3.53 (t, J=6.5, 2H), 2.88 (dd, J=8.0, 13.3, 2H), 2.81-2.73 (m, 2H); MS (DCI) m/z 515.1 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11](=O)[CH3:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:16]([C:18]1[CH:23]=[CH:22][C:21]([NH:24][NH2:25])=[CH:20][CH:19]=1)#[N:17]>>[CH3:12][C:11](=[N:25][NH:24][C:21]1[CH:22]=[CH:23][C:18]([C:16]#[N:17])=[CH:19][CH:20]=1)[CH2:10][O:9][C:8]1[CH:14]=[CH:15][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=1
Reactant: CC(=O)COc1ccc(S(C)(=O)=O)cc1
Reactant: N#Cc1ccc(NN)cc1
Product: CC(COc1ccc(S(C)(=O)=O)cc1)=NNc1ccc(C#N)cc1

Procedure:
The sub-title compound was prepared by the method of example 20 step (ii), using the product from example 20 step (i) (700 mg) and 4-cyanophenylhydrazine (400 mg). Yield 900 mg.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]2[C:17]([C:18]#[N:19])=[CH:16][O:15][CH:14]3[C:20]4[C:24](=[CH:25][CH:26]=[C:13]23)[N:23]=[CH:22][CH:21]=4)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9].Br[CH2:28][CH3:29].C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]2[C:17]([C:18]#[N:19])=[CH:16][O:15][C:14]3[C:20]4[CH:21]=[CH:22][N:23]([CH2:28][CH3:29])[C:24]=4[CH:25]=[CH:26][C:13]2=3)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9]
Reactant: CCBr
Reactant: COc1cc(C2C(C#N)=COC3C4=CC=NC4=CC=C32)cc(Br)c1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCn1ccc2c3c(ccc21)C(c1cc(Br)c(OC)c(OC)c1)C(C#N)=CO3
Temperature: 60 °C
Reaction time: 22 h
Yield: 50.4 %

Procedure:
A mixture of 4-(3-bromo-4,5-dimethoxy-phenyl)-3-cyano-4H-indolo[4,5-b]pyran (50 mg, 0.122 mmol), bromoethane (50 μL, 0.670 mmol) and cesium carbonate (122 mg, 0.375 mmol) in anhydrous THF (2 mL) was stirred at 60° C. in a sealed tube. After 22 h, additional bromoethane (100 μL, 1.34 mmol) was added and the reaction was continued for additional 43 h. The reaction mixture was diluted with EtOAc (20 mL). The insoluble material was filtered, and washed with EtOAc (30 mL). The EtOAc solution were combined, washed with brine (2×5 mL), dried over MgSO4, and evaporated to yield a light yellow solid. The crude product was purified by column chromatography (silica gel, EtOAc:hexanes, 1:3) to yield 27 mg (51%) of the product as an off-white solid. 1H NMR (CDCl3) 7.44 (d, J=0.9 Hz, 1H), 7.14 (d, J=3.3 Hz, 1H), 7.07 (dd, J=0.6, 8.4 Hz, 1H), 6.96 (d, J=1.8 Hz, 1H), 6.77 (d, J=1.8 Hz, 1H), 6.70 (d, J=8.4 Hz, 1H), 6.59 (dd, J=0.9, 3.3 Hz, 1H), 4.81 (s, 1H), 4.15 (q, J=7.2 Hz, 2H), 3.84 (s, 3H), 3.83 (s, 3H), 1.46 (t, J =7.2 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[NH:11][C:10](=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].C(OP(Cl)(OCC)=O)C.[N+:35]([CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])#[C-:36]>C1COCC1>[CH2:41]([O:40][C:38]([C:37]1[N:35]=[CH:36][N:11]2[C:10]=1[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:14][C:13]1[CH:15]=[CH:16][CH:17]=[CH:18][C:12]2=1)=[O:39])[CH3:42]
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: CC(C)(C)OC(=O)N1CC(=O)Nc2ccccc2C1
Agent: CC(C)(C)[O-]
Agent: CCOP(=O)(Cl)OCC
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ncn2c1CN(C(=O)OC(C)(C)C)Cc1ccccc1-2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-carboxylic acid tert-butyl ester (10.0 g, 38.16 mmol) in dry THF (300 mL) at 0° C., was added potassium tert-butoxide (6.4 g, 56.76 mmol) under nitrogen atmosphere and the reaction mixture was stirred at this temperature for 30 min followed by dropwise addition of diethylchlorophosphate (11 mL, 76.3.3 mmol). The reaction mixture was stirred at 0° C. for 40 min. This solution was transferred via cannula to a suspension of potassium tert-butoxide (12.86 g, 114.56 mmol) and ethyl isocyanoacetate (11.66 mL, 102.65 mmol) in dry THF (150 mL), kept in a separate flask at 0° C. under nitrogen atmosphere. When the addition was complete, the reaction mixture was allowed to come to r.t. and stirred for 45 min. during which the reaction was complete as confirmed by TLC. Reaction mixture was cooled to 0° C. and quenched with 10% acetic acid solution and stirred for 20 min. The crude compound was extracted with ethylacetate. The organic layer was washed with water, separated, dried over Na2SO4 and concentrated in vacuo to afford the crude compound which was purified by column chromatography (neutral alumina using neutral alumina, 3:7 EtOAc:Pet.Ether) to afford a viscous gel which was further purified by crystallisation from diethyl ether and hexane to afford 4H,6H-2,5,10b-triaza-benzo[e]azulene-3,5-dicarboxylic acid 5-tert-butyl ester 3-ethyl ester a white solid (4.4 g, 33%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4](C)[C:3]=1N1CCCC2C(=O)N(C)NC1=2.[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[N:29]1[CH2:34][CH2:33][CH2:32][C:31]2[C:35](=[O:39])[N:36]([CH3:38])[NH:37][C:30]1=2>>[ClH:1].[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[N:29]1[CH2:34][CH2:33][CH2:32][C:31]2=[C:35]([O:39][CH:2]([CH2:7][CH2:6][CH3:8])[CH2:3][CH2:4][CH3:5])[N:36]([CH3:38])[N:37]=[C:30]12
Reactant: Cn1[nH]c2c(c1=O)CCCN2c1ccc(Cl)cc1Cl
Reactant: Cc1cc(C)c(N2CCCc3c2[nH]n(C)c3=O)c(Cl)c1
Product: CCCC(CCC)Oc1c2c(nn1C)N(c1ccc(Cl)cc1Cl)CCC2
Product: Cl

Procedure:
Example 12b was prepared according to the procedure described in Example 12a, except that 7-(2-chloro-4,6-dimethylphenyl)-2-methyl-1,2,4,5,6,7-hexahydropyrazolo[3,4-b]pyridin-3-one was replaced by 7-(2,4-dichlorophenyl)-2-methyl-1,2,4,5,6,7-hexahydropyrazolo[3,4-b]pyridin-3-one.
Reaction SMILES: Cl[C:2]1[C:3]([CH3:15])=[C:4]([CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12])[C:5]([OH:7])=[O:6].[NH3:16]>>[NH2:16][C:2]1[C:3]([CH3:15])=[C:4]([CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12])[C:5]([OH:7])=[O:6]
Reactant: N
Reactant: Cc1c(C(=O)O)ccc(S(C)(=O)=O)c1Cl
Product: Cc1c(C(=O)O)ccc(S(C)(=O)=O)c1N
Temperature: 180 °C

Procedure:
A mixture of 79.0 g (grams) (320 mmol (millimole)) of 3-chloro-2-methyl-4-methylsulfonylbenzoic acid, 1.0 g (12.6 mmol) of cupric oxide, and 500 mL (milliliter) of concentrated aqueous ammonia was heated at 180° C. for 17 hours in a stirred Parr reactor. The resulting dark mixture was concentrated by evaporation under reduced pressure. The residue was acidified with 2N aqueous hydrochloric acid and the resulting mixture was extracted with ethyl acetate. The extract was filtered and concentrated by evaporation under reduced pressure. The solid residue was mixed with hexane, recovered by filtration, and dried to obtain 50.0 g (68 percent of theory) of the title acid compound as a light tan powder melting at 197-198° C.