Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:14]=[CH:13][C:7]2[C:8](=[O:12])[CH:9]=[CH:10][O:11][C:6]=2[C:5]=1[CH2:15][CH:16]=[CH2:17].[CH3:18][O:19][C:20](=[O:44])[CH2:21][CH2:22][C:23]1[C:28]([O:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]I.C(OCC)(=O)C>CN(C)C=O>[CH3:18][O:19][C:20](=[O:44])[CH2:21][CH2:22][C:23]1[C:24]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][O:3][C:4]2[CH:14]=[CH:13][C:7]3[C:8](=[O:12])[CH:9]=[CH:10][O:11][C:6]=3[C:5]=2[CH2:15][CH:16]=[CH2:17])=[CH:25][CH:26]=[CH:27][C:28]=1[O:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34]
Reactant: C=CCc1c(O)ccc2c(=O)ccoc12
Reactant: COC(=O)CCCOc1cccc(CCCCCCI)c1CCC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCc1c(OCCCCCCc2cccc(OCCCC(=O)OC)c2CCC(=O)OC)ccc2c(=O)ccoc12
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 79 %

Procedure:
To a slurry of 202 mg(5.05 mmol) of 60% sodium hydride-mineral oil dispersion (pre-washed with penlane) in 3 mL of anhydrous N,N-dimethylformamide was added a solution of 0.77 g (3.81 mmol) of 7-hydroxy-8-(2-propenyl)-4H-1-benzopyran-4-one in 12 mL of anhydrous N,N-dimethylformamide, over a 1 min period. The mixture was stirred at room temperature for 15 min whereupon a solution of 2.1 g (4.29 mmol) of 2-(6-iodohexyl)-6-(4-methoxy-4-oxobutoxy)benzenepropanoic acid methyl ester (example 17) in 15 mL of anhydrous N,N-dimethylformamide was added over a 1 min period. The resulting mixture was stirred at room temperature for 3 hr before being treated with ice-water, and worked-up with ethyl acetate in the usual manner. The oily product was chromatographed on silica gel, eluting with hexane-ethyl acetate mixtures. There was obtained 1.7 g (79.1%) of the title compound as a yellow oil.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[CH3:13][C@@H:14]1[S:20][C@@H:19]([C:21]([OH:23])=O)[CH2:18][C:17]2[CH:24]=[C:25]3[O:30][CH2:29][O:28][C:26]3=[CH:27][C:16]=2[C:15]1=[O:31].[NH2:32][C:33]1[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][CH:34]=1.ON1C2C=CC=CC=2N=N1>ClCCl.CN(C)C=O.O>[CH2:43]([O:42][P:38]([CH2:37][C:36]1[CH:35]=[CH:34][C:33]([NH:32][C:21]([C@H:19]2[CH2:18][C:17]3[CH:24]=[C:25]4[O:30][CH2:29][O:28][C:26]4=[CH:27][C:16]=3[C:15](=[O:31])[C@H:14]([CH3:13])[S:20]2)=[O:23])=[CH:47][CH:46]=1)([O:39][CH2:40][CH3:41])=[O:45])[CH3:44]
Reactant: CCOP(=O)(Cc1ccc(N)cc1)OCC
Reactant: C[C@@H]1S[C@@H](C(=O)O)Cc2cc3c(cc2C1=O)OCO3
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(Cc1ccc(NC(=O)[C@H]2Cc3cc4c(cc3C(=O)[C@H](C)S2)OCO4)cc1)OCC
Temperature: 25 °C
Reaction time: 15 h
Yield: 43.6 %

Procedure:
A solution of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.39 g) in dichloromethane (7 ml) was added to a solution of (2R,4S)-(−)-1,2,4,5-tetrahydro-4-methyl-7,8-methylenedioxy-5-oxo-3-benzothiepin-2-carboxylic acid (0.47 g) and diethyl 4-aminobenzylphosphonate (0.41 g) in N,N-dimethylformamide (DMF) (7 ml) at 0° C., followed by the addition of 1-hydroxybenzo-triazole (HOBt) (0.28 g). This mixture was stirred at 0° C. for 1 hour and at room temperature (25° C.) for 15 hours, after which it was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (using MgSO4), after which the solvent was distilled off; the residual crystals were collected by filtration, followed by recrystallization from ethyl acetate-hexane and then recrystalized from methanol-hexane to yield (2R,4S)-(−)-N-[4-(diethoxyphosphorylmethyl)phenyl]-1,2,4,5-tetrahydro-4-methyl-7,8-methylenedioxy-5-oxo-3-benzo-thiepin-2-carboxamide (0.37 g, 44%). Colorless Prisms.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:11]1[N:16]2[N:17]=[C:18]([NH2:20])[N:19]=[C:15]2[CH:14]=[CH:13][CH:12]=1>C1COCC1>[CH:1]1([O:7][C:11]2[N:16]3[N:17]=[C:18]([NH2:20])[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1nc2cccc(Cl)n2n1
Reactant: OC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1nc2cccc(OC3CCCCC3)n2n1
Temperature: 0 °C
Yield: 80.1 %

Procedure:
Cyclohexanol (1.68 mL; 15.84 mmol; 5.0 eq.) was added to a suspension of NaH (152 mg; 3.80 mmol; 1.2 eq.) in THF (6.0 mL) and maintained under inert atmosphere at 0° C. The reaction mixture was brought back to rt and stirred for 1 h before the addition of 5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A4), 534 mg; 3.17 mmol; 1.0 eq.). Reaction mixture was then heated at reflux for 3 h after which time it was quenched by addition of water. It was then extracted with EtOAc, washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel (DCM/MeOH, 95:5 to 10:90) gave the title compound as a white solid (590 mg, 80%). HPLC, Rt: 2.18 min. (purity 90.1%). LC/MS, M+(ESI): 233.0.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2Br)[CH:5]=[CH:4]1)[CH3:2].[Li]C(C)(C)C.CCCCC.C(=O)=O.[C:26](OC)(=[O:31])[C:27]([O:29][CH3:30])=[O:28]>C1COCC1.CCOC(C)=O>[CH3:30][O:29][C:27](=[O:28])[C:26]([C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[N:3]([CH2:1][CH3:2])[CH:4]=[CH:5]2)=[O:31]
Reactant: CCn1ccc2cccc(Br)c21
Reactant: COC(=O)C(=O)OC
Agent: O=C=O
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCn1ccc2cccc(C(=O)C(=O)OC)c21
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 82.8 %

Procedure:
A solution of 1-ethyl-7-bromoindole (2.1 g, 9.4 mmol) in THF (50 mL) was cooled to −78° C. and a 1.7 M solution of tBuLi in pentane (13.8 mL, 23.5 mmol) was added dropwise over 10 min. After 15 min, the resultant brown solution was transferred over 30 min via a cannula cooled with dry ice to a solution of dimethyl oxalate (3.88 g, 32.9 mmol) in THF (40 mL) maintained at −78° C. After 15 min, the mixture was allowed to warm to room temperature and stirred 4 h. The brown solution was treated with pH 7.0 buffer, poured into EtOAc and the EtOAc washed with pH 7.0 buffer, saturated aq NaHCO3, brine, dried (MgSO4) and concentrated to a brown oil. Flash chromatography (20% EtOAc/hexanes) afforded the title compound (1.8 g, 83%) as a yellow oil, which was used without further purification. 1H NMR (400 MHz, DMSO-d6) 7.9 (d, J=8, 1H), 7.55 (m, 2H), 7.2 (dd, J=8, 8 Hz, 1H), 6.66 (d, J=3 Hz, 1H), 4.25 (q, J=7 Hz, 2H), 3.94 (t, J=7 Hz, 3H). MS (electrospray, m/z) 232 (M++1).
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[NH:14])[NH:12][OH:13])=[CH:7][C:6]=1[Cl:15].[C:21](Cl)(=[O:23])[CH3:22].N1C=CC=[CH:27][CH:26]=1>Cl>[Cl:20][C:17]1[CH:18]=[CH:19][C:2]([NH:1][C:21](=[O:23])[CH3:22])=[C:3]([O:4][C:5]2[CH:10]=[CH:9][C:8]([C:11]3[N:14]=[C:26]([CH3:27])[O:13][N:12]=3)=[CH:7][C:6]=2[Cl:15])[CH:16]=1
Reactant: CC(=O)Cl
Reactant: N=C(NO)c1ccc(Oc2cc(Cl)ccc2N)c(Cl)c1
Reactant: c1ccncc1
Agent: Cl
Product: CC(=O)Nc1ccc(Cl)cc1Oc1ccc(-c2noc(C)n2)cc1Cl
Temperature: 25 °C

Procedure:
The subtitle compound was prepared using the product from step i) (0.94 g) which was dissolved in pyridine (10 ml) and treated with acetyl chloride (0.22 ml) at 0 C. This was then allowed to warm to room temperature. The mixture was heated at reflux for 3 hours, diluted with 2M HCl, extracted with ethyl acetate, dried and concentrated under reduced pressure to an oil. The residue was purified by chromatography on silica eluting with diethyl ether/isohexane 3:1, yield 0.50 g.
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][C:4]([NH:7][C:8]([NH:10][C:11]([NH2:13])=[NH:12])=[NH:9])=[CH:3][CH:2]=1.[Br:15]Br.S(=O)(O)[O-].[Na+]>O>[Br:15][C:5]1[CH:6]=[C:1]([CH3:14])[CH:2]=[CH:3][C:4]=1[NH:7][C:8]([NH:10][C:11]([NH2:13])=[NH:12])=[NH:9]
Reactant: Cc1ccc(NC(=N)NC(=N)N)cc1
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Product: Cc1ccc(NC(=N)NC(=N)N)c(Br)c1

Procedure:
To a slurry of 10 g. (0.0523 mole) of 1-(p-tolyl)biguanide in 175 ml of water is added dropwise 8.4 g. (0.053 mole) of bromine over a period of 3 hours. The reaction mixture is cooled and the unreacted bromine discharged with sodium bisulfite. The mixture is made strongly alkaline and extracted into ether. The ether layer is dried over Na2SO4, charcoaled, filtered and evaporated to obtain 1-(2-bromo-4-methylphenyl)biguanide.
Reaction SMILES: [Li]CCCC.Br[C:7]1[C:15]2[N:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[N:13]=[CH:12][C:11]=2[CH:10]=[C:9]2[C:23]3([CH2:37][CH3:38])[CH2:31][CH2:30][C:29]([C:33]([F:36])([F:35])[F:34])([OH:32])[CH2:28][CH:24]3[CH2:25][CH2:26][O:27][C:8]=12.C1COCC1>CO>[CH2:37]([C@:23]12[CH2:31][CH2:30][C@:29]([C:33]([F:35])([F:36])[F:34])([OH:32])[CH2:28][C@@H:24]1[CH2:25][CH2:26][O:27][C:8]1[C:9]2=[CH:10][C:11]2[CH:12]=[N:13][N:14]([C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[C:15]=2[CH:7]=1)[CH3:38].[CH2:37]([C@@:23]12[CH2:31][CH2:30][C@@:29]([C:33]([F:35])([F:36])[F:34])([OH:32])[CH2:28][C@H:24]1[CH2:25][CH2:26][O:27][C:8]1[C:9]2=[CH:10][C:11]2[CH:12]=[N:13][N:14]([C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[C:15]=2[CH:7]=1)[CH3:38]
Reactant: CCC12CCC(O)(C(F)(F)F)CC1CCOc1c2cc2cnn(-c3ccc(F)cc3)c2c1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CO
Product: CC[C@@]12CC[C@](O)(C(F)(F)F)C[C@H]1CCOc1cc3c(cnn3-c3ccc(F)cc3)cc12
Product: CC[C@]12CC[C@@](O)(C(F)(F)F)C[C@@H]1CCOc1cc3c(cnn3-c3ccc(F)cc3)cc12
Reaction time: 0.75 h

Procedure:
n-BuLi (1.6 M solution in hexanes, 0.900 mL, 1.440 mmol) was added dropwise to a solution of 3R,4aR,12bR)-8-bromo-12b-ethyl-9-(4-fluorophenyl)-3-(trifluoromethyl)-2,3,4,4a,5,6,9,12b-octahydro-1H-benzo[4,5]oxepino[3,2-f]indazol-3-ol; compound with 3S,4aS,12bS)-8-bromo-12b-ethyl-9-(4-fluorophenyl)-3-(trifluoromethyl)-2,3,4,4a,5,6,9,12b-octahydro-1H-benzo[4,5]oxepino[3,2-f]indazol-3-ol (108, R1=4-Fluorophenyl, R2=Ethyl, R3=Trifluoromethyl) (0.364 g, 0.690 mmol) and THF (10.0 mL) under a nitrogen atmosphere at about −78° C. After about 45 min, n-BuLi (1.6 M solution in hexanes, 0.100 mL, 0.160 mmol) was added dropwise over about 2 min. After about 30 min, MeOH (0.4 mL) was added dropwise. The cold bath was removed. Sat. aq. NH4Cl (20 mL), water (5 mL) and EtOAc (20 mL) were added. The layers were separated and the organics were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified on silica gel (40 g) using a gradient of 0-2% EtOAc in DCM. The fractions containing the product were combined and concentrated under reduced pressure to afford (3R,4aR,12bR)-12b-ethyl-9-(4-fluorophenyl)-3-(trifluoromethyl)-2,3,4,4a,5,6,9,12b-octahydro-1H-benzo[4,5]oxepino[3,2-f]indazol-3-ol; compound with (3S,4aS,12bS)-12b-ethyl-9-(4-fluorophenyl)-3-(trifluoromethyl)-2,3,4,4a,5,6,9,12b-octahydro-1H-benzo[4,5]oxepino[3,2-f]indazol-3-ol (109, R1=4-Fluorophenyl, R2=Ethyl, R3=Trifluoromethyl) (0.273 g, 88% yield) of an ivory solid. LC/MS, method 2, Rt=2.77 min, MS m/z 449 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.27 (d, J=1.0 Hz, 1H), 7.82-7.74 (m, 3H), 7.44-7.36 (m, 2H), 7.31 (d, J=0.9 Hz, 1H), 5.91 (s, 1H), 4.45-4.34 (m, 1H), 3.60-3.47 (m, 1H), 2.40-2.25 (m, 1H), 2.23-1.49 (m, 10H), 0.38 (t, J=7.4 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=O.[CH2:11]1[C:16](=O)[CH2:15][C:13](=[O:14])[CH2:12]1.[NH2:18][C:19]1[N:23]([CH3:24])[NH:22][C:21](=[O:25])[CH:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]2[C:20]3[C:21](=[O:25])[NH:22][N:23]([CH3:24])[C:19]=3[NH:18][C:16]3[CH2:11][CH2:12][C:13](=[O:14])[C:15]2=3)[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: O=C1CCC(=O)C1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: Cn1[nH]c(=O)cc1N
Product: Cn1[nH]c(=O)c2c1NC1=C(C(=O)CC1)C2c1ccc(Cl)c(Cl)c1
Yield: 68.5 %

Procedure:
3,4-Dichlorobenzaldehyde (0.17 g, 1.0 mmol), 1,3-cyclopentadione (0.1 g, 1.0 mmol), and 5-amino-1-methyl-1,2-dihydropyrazol-3-one (0.11 g, 1.0 mmol) were processed as described in Example 1 to provide 0.24 g of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.28 (t, 2H), 2.68 (m, 2H), 3.5 (s, 3H), 4.7 (s, 1H), 7.13 (dd, 1H), 7.33 (d, 1H), 7.49 (d, 1H), 9.58 (s, 1H), 10.45 (s, 1H); MS (ESI−) m/z 348 (M−H)−; Anal. calcd for C16H13N3Cl2O2: C, 54.71; H, 4.32; N, 11.26. Found: C, 54.37; H, 4.40; N, 10.80.
Reaction SMILES: [CH:1]1([N:7]([C@H:21]2C[CH2:25][C@H:24](COC)[CH2:23][CH2:22]2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15]CC(O)=O)=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(N[C@H]2C[C@H]([CH2:42][O:43][CH3:44])CC2)CCCCC1.C([O:47][C:48](=[O:58])[CH:49](SC1SC(N)=NC=1)[CH3:50])C>>[CH:21]1([N:7]([C@H:1]2[CH2:2][CH2:3][C@H:4]([CH2:42][O:43][CH3:44])[CH2:5][CH2:6]2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:50][CH2:49][C:48]([OH:47])=[O:58])=[CH:13][N:14]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CCOC(=O)C(C)Sc1cnc(N)s1
Reactant: COC[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCCCC2)CC1
Reactant: COC[C@@H]1CC[C@@H](NC2CCCCC2)C1
Product: COC[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCCC(=O)O)s2)C2CCCC2)CC1

Procedure:
Prepared in an similar manner to {2-[3-cyclohexyl-3-(trans-4-methoxymethyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid via cyclohexyl-(trans-4-methoxymethyl-cyclopentyl)-amine and (2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:35])=[C:21]([NH:25][S:26]([C:29]3[CH:33]=[CH:32][N:31]([CH3:34])[N:30]=3)(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[NH4+:37]>>[ClH:1].[NH2:37][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:35])=[C:21]([NH:25][S:26]([C:29]3[CH:33]=[CH:32][N:31]([CH3:34])[N:30]=3)(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1
Reactant: [NH4+]
Reactant: Cn1ccc(S(=O)(=O)Nc2cccc(-c3nc(C4CCOCC4)sc3-c3ccnc(Cl)n3)c2F)n1
Agent: [OH-]
Product: Cl
Product: Cn1ccc(S(=O)(=O)Nc2cccc(-c3nc(C4CCOCC4)sc3-c3ccnc(N)n3)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in Example 282 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-1-methyl-1H-pyrazole-3-sulfonamide (640 mg, 1.19 mmol) and ammonium hydroxide (15 ml), the title compound was obtained as a white solid (340 mg, 51.5%). 1HNMR (MEOD-d4): δ ppm 7.93-7.95 (d, J=6.0 Hz, 1H), 7.59-7.59 (d, J=2.0 Hz, 1H), 7.46-7.50 (dd, J1=7.8 Hz, J2=1.6 Hz, 1H), 7.24-7.28 (dd, J1=6.8 Hz, J2=1.6 Hz, 1H), 7.15-7.18 (t, J=7.8 Hz, 1H), 6.54-6.55 (d, J=2.4 Hz, 1H), 6.32-6.34 (d, J=6.0 Hz, 1H), 3.92-3.96 (dd, J1=11.6 Hz, J2=2.4 Hz, 1H), 3.80 (s, 3H), 3.45-3.51 (dd, J1=11.6 Hz, J2=2.0 Hz, 2H), 3.21-3.28 (m, 1H), 1.96-2.00 (dd, J1=12.8 Hz, J2=2.4 Hz, 2H), 1.75-1.85 (dd, J1=12.2 Hz, J2=4.4 Hz, 2H); MS: 516 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:19][CH2:18][C:5]2[N:6]([CH2:14][C:15](O)=[O:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.CCN=C=NCCCN(C)C.[F:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1>>[F:31][C:32]1[CH:38]=[CH:37][C:35]([NH:36][C:15](=[O:16])[CH2:14][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:19][CH2:18][C:5]2=3)=[CH:34][CH:33]=1
Reactant: Nc1ccc(F)cc1
Reactant: Cc1ccc2c(c1)c1c(n2CC(=O)O)CCN(C)C1
Agent: CCN=C=NCCCN(C)C
Product: Cc1ccc2c(c1)c1c(n2CC(=O)Nc2ccc(F)cc2)CCN(C)C1
Reaction time: 16 h

Procedure:
2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)acetic acid (CD58) was mixed with EDCI and 4-fluoroaniline and the reaction mixture was stirred for 16 h to obtain N-(4-fluorophenyl)-2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)acetamide after purification on neutral alumina chromatography eluting with methanol-dichloromethane gradient. The free base was converted into its oxalate salt by treatment of oxalic acid (1 equiv) in anhydrous THF.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8](Cl)=[O:9].[NH2:11][C:12]1[CH:13]=[C:14]([CH:27]=[CH:28][CH:29]=1)[C:15]([C:17]1[CH:25]=[C:24]2[C:20]([CH2:21][C:22](=[O:26])[NH:23]2)=[CH:19][CH:18]=1)=[O:16]>C1COCC1>[O:26]=[C:22]1[CH2:21][C:20]2[C:24](=[CH:25][C:17]([C:15]([C:14]3[CH:13]=[C:12]([NH:11][C:8]([C:3]4[CH:4]=[N:5][N:6]([CH3:7])[C:2]=4[Cl:1])=[O:9])[CH:29]=[CH:28][CH:27]=3)=[O:16])=[CH:18][CH:19]=2)[NH:23]1
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Reactant: Cn1ncc(C(=O)Cl)c1Cl
Solvent: C1CCOC1
Product: Cn1ncc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4)c2)c1Cl
Temperature: 25 °C
Yield: 71.4 %

Procedure:
A dry flask was charged with 5-Chloro-1-methyl-1H-pyrazole-4-carbonyl chloride (0.200 g, 1.1 mmol) was dissolved in THF (10 mL). 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 0.178 g, 0.706 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux for overnight. The reaction mixture was then allowed to cool to room temperature. The room temperature reaction mixture was filtered. The solid residue was washed with 0° C. THF (10 mL) to afford the 5-Chloro-1-methyl-1H-pyrazole-4-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide as a solid (0.199 g, 0.504 mmol, 71%).
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][CH2:24][NH2:25]>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:25][CH2:24][CH2:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[O:16][CH3:15])#[N:2]
Reactant: COc1ccccc1CCN
Reactant: CC(C)OC(=NC#N)c1cccnc1
Solvent: CO
Product: COc1ccccc1CCN=C(NC#N)c1cccnc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 69.2 %

Procedure:
Isopropyl N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 ml), and 2-(2-methoxyphenyl)ethylamine (0.44 g, 2.9 mmol) was added. The mixture was stirred at room temperature for 6 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue thus obtained was subjected to chromatography on a silica gel column (WAKO GEL C-200, 30 g) eluting with chloroform methanol (100:1). The eluted fractions were concentrated under reduced pressure, and the concentrated residue thus obtained was crystallized from chloroform-hexane to give the title compound (0.50 g, 1.8 mmol, yield: 68%) as colorless crystals.
Reaction SMILES: [CH3:1][N:2]([C:17]([O:19][C@@H:20]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])=[O:18])[CH2:3][CH2:4][C:5]([O:7]CC(C1C=CC=CC=1)=O)=[O:6]>C(O)(=O)C.[Zn]>[CH3:1][N:2]([C:17]([O:19][C@@H:20]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])=[O:18])[CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: CN(CCC(=O)OCC(=O)c1ccccc1)C(=O)O[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: [Zn]
Solvent: CC(=O)O
Product: CN(CCC(=O)O)C(=O)O[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 70.9 %

Procedure:
To a solution of benzyl 2(S)-[N-methyl-N-(2-phenacyloxycarbonylethyl)aminocarbonyloxy]-3-phenylpropionate (1.0 g) in acetic acid (10 ml) was added zinc dust (1.0 g) portionwise at ambient temperature. After being stirred for 2 hours, zinc dust (0.2 g) was added thereto. The reaction mixture was stirred overnight at the same temperature and filtered, and the filtrate was evaporated in vacuo. The residue was dissolved in ethyl acetate (30 ml) and 0.5N hydrochloric acid (30 ml). The organic layer was extracted with 1N sodium hydroxide solution (20 ml×3). The combined aqueous extract was acidified to pH 2 with 1N hydrochloric acid and extracted with chloroform (50 ml ×3). The extract was washed with brine and dried over magnesium sulfate. Evaporation of the solvent gave benzyl 2(S)-[N-methyl-N-(2-carboxyethyl)aminocarbonyloxy]-3-phenylpropionate (543 mg) as an oil.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])#[N:2].[H][H]>C(O)C.[Pd]>[C:1]([CH2:3][C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])#[N:2]
Reactant: CCOC(=O)C=Cc1ccccc1CC#N
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccccc1CC#N

Procedure:
Ethyl o-(cyanomethyl)cinnamate (75.1 g., 0.35 mole) is dissolved in ethanol (300 ml.) and hydrogenated at a pressure of 1 atmosphere and room temperature over 2.5 g. of a 5% palladium on charcoal catalyst. When the theoretical amount of hydrogen (0.35 mole) has been absorbed, the catalyst is filtered off and the ethanol removed by distillation at reduced pressure to yield ethyl o-(cyanomethyl)hydrocinnamate.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[NH2:22][CH:23]1[NH:27][CH:26]([CH3:28])[CH2:25][CH2:24]1>>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:27]2[CH:23]([NH2:22])[CH2:24][CH2:25][CH:26]2[CH3:28])[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:16][CH2:17]1
Reactant: CC1CCC(N)N1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Product: CC1CCC(N)N1c1c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c2c1F
Yield: 40 %

Procedure:
The condensation of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid with 5-amino-2-methyl-pyrrolidine in a similar manner as described in example 1 gave the titled product. Yield 40%, m.p 224–30° C., C18H20F2N4O3, m/z 379. (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:6]2[C:11]=1[N:10]([CH3:12])[C:9](=[O:13])[CH2:8][CH2:7]2.Br[C:24]1[C:33]2[CH2:32][CH2:31][CH2:30][CH:29]([NH:34][S:35]([CH2:38][CH3:39])(=[O:37])=[O:36])[C:28]=2[CH:27]=[N:26][CH:25]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:24]2[C:33]3[CH2:32][CH2:31][CH2:30][CH:29]([NH:34][S:35]([CH2:38][CH3:39])(=[O:37])=[O:36])[C:28]=3[CH:27]=[N:26][CH:25]=2)[CH:5]=[C:6]2[C:11]=1[N:10]([CH3:12])[C:9](=[O:13])[CH2:8][CH2:7]2
Reactant: CN1C(=O)CCc2cc(B3OC(C)(C)C(C)(C)O3)cc(Cl)c21
Reactant: CCS(=O)(=O)NC1CCCc2c(Br)cncc21
Product: CCS(=O)(=O)NC1CCCc2c(-c3cc(Cl)c4c(c3)CCC(=O)N4C)cncc21
Yield: 35 %

Procedure:
In analogy to the procedure described for the preparation of example 28, 8-chloro-1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (intermediate A-8) and (rac)-ethanesulfonic acid (4-bromo-5,6,7,8-tetrahydro-isoquinolin-8-yl)-amide (intermediate B-4) were used to give the title compound (47.2 mg, 35%) as a white solid. MS: 434.2 (M+H)+.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([C:12](Cl)=[O:13])[CH:9]=[N:10][CH:11]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.[NH2:15][C:16]1[CH:28]=[C:27]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:26]=[CH:25][C:17]=1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(=O)([O-])O.[Na+]>C(N(CC)CC)C.C(Cl)Cl>[O:29]([C:27]1[CH:26]=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])=[C:16]([NH:15][C:12]([C:8]2[CH:9]=[N:10][CH:11]=[C:6]([N:1]3[CH:5]=[CH:4][CH:3]=[CH:2]3)[CH:7]=2)=[O:13])[CH:28]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1N
Reactant: O=C(Cl)c1cncc(-n2cccc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1NC(=O)c1cncc(-n2cccc2)c1
Reaction time: 2 h

Procedure:
0.059 mL of triethylamine and 65 mg of 5-(1H-pyrrol-1-yl)pyridine-3-carbonyl chloride were added to 5.0 mL of methylene chloride solution containing 60 mg of tert-butyl 2-amino-4-phenoxybenzoate at room temperature sequentially and stirred at the same temperature for 2 hours, 0.029 mL of triethylamine and 22 mg of 5-(1H-pyrrol-1-yl)pyridine-3-carbonyl chloride were added to the reaction mixture at room temperature sequentially and stirred at the same temperature for 1 hour. 0.58 g aminomethylated polystyrene was added to the reaction mixture and stirred at room temperature overnight. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, the organic layer was separated, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate=4:1] to obtain tert-butyl 4-phenoxy-2-(5-(1H-pyrrol-1-yl)pyridine-3-carboxamido)benzoate.