Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6](=[N:8][OH:9])[NH2:7].[Cl:15][C:16]1[CH:20]=[CH:19][S:18][C:17]=1[C:21](Cl)=O>>[Cl:15][C:16]1[CH:20]=[CH:19][S:18][C:17]=1[C:21]1[O:9][N:8]=[C:6]([C:5]2[CH:10]=[CH:11][CH:12]=[C:3]([C:2]([F:13])([F:14])[F:1])[CH:4]=2)[N:7]=1
Reactant: O=C(Cl)c1sccc1Cl
Reactant: NC(=NO)c1cccc(C(F)(F)F)c1
Product: FC(F)(F)c1cccc(-c2noc(-c3sccc3Cl)n2)c1

Procedure:
The title compound was prepared from 3-trifluoromethyl-benzamidoxime (70.3 mg, 0.344 mmol) and 3-chloro-thiophene-2-carbonyl chloride (62 mg, 0.343 mmol), similar to Example 16, and yielded 81.6 mg (72%) as an off-white solid. 1H NMR (CDCl3): 8.44 (s, 1H), 8.36 (d, J=7.69 Hz, 1H), 7.80 (d, J=8.51 Hz, 1H), 7.67 (d, J=7.96 Hz, 1H), 7.64 (d, J=5.21 Hz, 1H), 7.15 (d, J=5.22 Hz, 1H).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25])[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:64][CH2:65][CH2:66][NH:67][C:68](=[O:74])[O:69][C:70]([CH3:73])([CH3:72])[CH3:71]>CN(C=O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:64][CH2:65][CH2:66][NH:67][C:68]([O:69][C:70]([CH3:71])([CH3:73])[CH3:72])=[O:74])=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24](=[O:25])[O:26][CH:27]([CH3:28])[CH3:29])[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)NCCNC(=O)OC(C)(C)C)cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 86 %

Procedure:
To a flask charged with 4-((2S,4R)-1-acetyl-4-((isopropoxycarbonyl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoic acid (for a preparation see Intermediate 48) (82 mg, 0.2 mmol) and HATU (0.091 g, 0.240 mmol) was added DMF (2 mL) and the mixture treated with DIPEA (0.105 mL, 0.600 mmol) at room temperature. After 5 min, 1,1-dimethylethyl (2-aminoethyl)carbamate (0.047 mL, 0.300 mmol) was added and the mixture stirred at room temperature for 1 h. The reaction mixture was partitioned between EtOAc and water. The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by chromatography eluting with a MeOH/DCM gradient to give 1-methylethyl {(2S,4R)-1-acetyl-6-[4-({[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)ethyl]amino}carbonyl)phenyl]-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl}carbamate (95 mg, 0.172 mmol, 86% yield) as a pale brown foam. LCMS (HpH, 2 min), Rt=1.02 min, MH+=553.
Reaction SMILES: C1C2C(COC([N:18]3[CH2:23][C@@H:22]([C:24](=[O:44])[N:25]([CH:41]4[CH2:43][CH2:42]4)[CH2:26][C:27]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:28]=4)[CH2:21][C@@H:20]([NH2:45])[CH2:19]3)=O)C3C(=CC=CC=3)C=2C=CC=1.ClC(Cl)C.[CH2:50]([N:57]=[C:58]=[O:59])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>>[CH:41]1([N:25]([CH2:26][C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:28]=2)[C:24]([C@H:22]2[CH2:21][C@@H:20]([NH:45][C:58]([NH:57][CH2:50][C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)=[O:59])[CH2:19][NH:18][CH2:23]2)=[O:44])[CH2:43][CH2:42]1
Reactant: COCCCn1cc(CN(C(=O)[C@H]2C[C@@H](N)CN(C(=O)OCC3c4ccccc4-c4ccccc43)C2)C2CC2)c2ccccc21
Reactant: O=C=NCc1ccccc1
Solvent: CC(Cl)Cl
Product: COCCCn1cc(CN(C(=O)[C@@H]2CNC[C@H](NC(=O)NCc3ccccc3)C2)C2CC2)c2ccccc21
Temperature: 50 °C
Reaction time: 14 h

Procedure:
A mixture of (3R*,5S*)-3-amino-5-{cyclopropyl-[1-(3-methoxy-propyl)-1H-indol-3-ylmethyl]-carbamoyl}-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (91 mg, 0.15 mmol), dichloroethane (2 mL) and benzyl isocyanate (18.4 μL, 0.15 mmol) is shaken for 14 h at 50° C. A second portion of benzyl isocyanate (9.2 μL, 0.075 mmol) is added and shaking is continued for 5 h at 60° C. The mixture is evaporated in vacuo. The crude product is stirred with a solution of CH2Cl2/piperidine 4:1 (5 mL) for 2 h, the mixture is evaporated and the residue purified by preparative HPLC (C18 column, 10-100% CH3CN+0.1% TFA/H2O+0.1% TFA, 20 min, flow 20 mL/min). The combined pure fractions are treated with K2CO3, CH3CN is removed in vacuo and the residual aqueous phase extracted three times with CH2Cl2. The combined organic layers are dried (Na2SO4) and evaporated to afford the title compound as a yellow resin. MS: 518.3 [M+H]+; tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, flow 1.5 ml/min): 5.05 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[N:18]=[C:17]4[C:13]([NH:14][C:15](=[O:29])[N:16]4[C@H:19]4[CH2:24][CH2:23][C@H:22]([C:25]([O:27]C)=[O:26])[CH2:21][CH2:20]4)=[CH:12][N:11]=3)[C:6]=2[CH:30]=1.[OH-].[K+].C(O)(C(F)(F)F)=O>C1COCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[N:18]=[C:17]4[C:13]([NH:14][C:15](=[O:29])[N:16]4[C@H:19]4[CH2:24][CH2:23][C@H:22]([C:25]([OH:27])=[O:26])[CH2:21][CH2:20]4)=[CH:12][N:11]=3)[C:6]=2[CH:30]=1
Reactant: COC(=O)[C@H]1CC[C@H](n2c(=O)[nH]c3cnc(-n4cnc5ccc(F)cc54)nc32)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]c2cnc(-n3cnc4ccc(F)cc43)nc2n1[C@H]1CC[C@H](C(=O)O)CC1
Temperature: 50 °C

Procedure:
A solution of trans-methyl 4-(2-(6-fluoro-1H-benzo[d]imidazol-1-yl)-8-oxo-7,8-dihydropurin-9-yl)cyclohexanecarboxylate (5 mg) in THF was treated with an aqueous solution of KOH (35 mg) in 2 mL of water. The mixture was heated at 50° C. for 12 hours. The mixture was acidified with TFA and concentrated. Silica gel chromatography (60:30:10 DCM:EtOAc:MeOH) provided 4.3 mg of the title compound. 1H-NMR (300 MHz, CDCl3) δ 9.0 (s, 1H), 8.3 (dd, 1H), 8.1 (s, 1H), 7.7 (dd, 1H), 7.1 (td, 1H), 4.3 (m, 1H), 2.4 (m, 3H), 2.2 (m, 2H), 1.9 (m, 2H), 1.6 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][N:3]=1.[CH3:13][C:14]([S-:17])([CH3:16])[CH3:15].[Na+].C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.FC(F)(F)S(O[Sc](OS(C(F)(F)F)(=O)=O)OS(C(F)(F)F)(=O)=O)(=O)=O>[C:14]([S:17][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][N:3]=1)([CH3:16])([CH3:15])[CH3:13]
Reactant: CC(C)(C)[S-]
Reactant: O=c1[nH]nc(Cl)c2ccccc12
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O[Sc](OS(=O)(=O)C(F)(F)F)OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [K+]
Solvent: CCOC(C)=O
Product: CC(C)(C)Sc1n[nH]c(=O)c2ccccc12
Temperature: 160 °C
Yield: 20 %

Procedure:
A mixture of 4-chlorophthalazin-1(2H)-one (200 mg, 1.11 mmol), sodium 2-methylpropane-2-thiolate (248 mg, 2.22 mmol), tris(trifluoromethylsulfonyloxy)scandium (54.5 mg, 0.11 mmol) and K2CO3 (308 mg, 2.22 mmol) was heated at 160° C. under microwave condition for 30 minutes. The mixture was diluted with EtOAc and washed with saturated aqueous NaHCO3, dried (Na2SO4), filtered, and chromatographed (0-30% EtOAc/DCM) to give 52 mg (20%) of the title compound as a white solid: MS (DCI) 235 (M+H).
Reaction SMILES: Cl.CN([CH2:5][C:6]1[C:7](=[O:13])[NH:8][C:9](=[O:12])[NH:10][CH:11]=1)C.[NH2:14][C:15]1[C:16]([CH3:25])=[CH:17][CH:18]=[C:19]2[C:24]=1[N:23]=[CH:22][CH:21]=[CH:20]2>C(O)CO>[NH2:14][C:15]1[C:16]([CH3:25])=[CH:17][C:18]([CH2:5][C:6]2[C:7](=[O:13])[NH:8][C:9](=[O:12])[NH:10][CH:11]=2)=[C:19]2[C:24]=1[N:23]=[CH:22][CH:21]=[CH:20]2
Reactant: Cc1ccc2cccnc2c1N
Reactant: CN(C)Cc1c[nH]c(=O)[nH]c1=O
Agent: Cl
Solvent: OCCO
Product: Cc1cc(Cc2c[nH]c(=O)[nH]c2=O)c2cccnc2c1N
Yield: 77.7 %

Procedure:
A mixture of 8.36 g (0.0406 mole) of 5-[(dimethylamino)methyl]uracil hydrochloride (B. Roth, J. Z. Strelitz, and B. S. Rauckman, J. Med. Chem. 23, 379 (1980) and 6.43 g (0.0406 mole) of 8-amino-7-methylquinoline (R. Long and K. Schofield, J. Chem. Soc. 1953, 2350) in 60 ml of ethylene glycol under nitrogen was heated at 135° for 4 hours. The mixture was cooled and the precipitated solid was collected, washed with ethanol and ether and dried. This crude product was purified by suspension in 550 ml of boiling ethanol and collection of the insoluble product. Yield, 8.90 g of the title compound (78%) m.p. 302°-305° (dec.). Anal. Calcd for C21H20N4 : C, 76.89; H, 6.14; N, 17.06. Found: C, 76.82; H, 6.17; N, 17.04.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19]Cl)[CH2:13][CH2:12]2)[CH:8]=[C:7]([CH:21]2[CH2:24][CH2:23][CH2:22]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:25][N:26]1[C:30]([SH:31])=[N:29][N:28]=[N:27]1.[OH-].[Li+].[I-].[K+]>CN(C)C=O>[C:1]([C:5]1[N:6]=[C:7]([CH:21]2[CH2:24][CH2:23][CH2:22]2)[CH:8]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][S:31][C:30]3[N:26]([CH3:25])[N:27]=[N:28][N:29]=3)[CH2:13][CH2:12]2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCl)CC2)n1
Reactant: Cn1nnnc1S
Agent: [I-]
Agent: [K+]
Agent: [Li+]
Solvent: CN(C)C=O
Product: Cn1nnnc1SCCCN1CCN(c2cc(C3CCC3)nc(C(C)(C)C)n2)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 49.1 %

Procedure:
0.5 g of 2-tert-Butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-cyclobutyl-pyrimidine (1.42 mmol) were dissolved in 15 ml of dimethylformamide. 0.18 g of 1-methyl-1H-tetrazole-5-thiol (1.56 mmol), 0.09 g of lithium hydroxide (3.76 mmol) and a spatula tip of potassium iodide were added. The mixture was stirred for 2 h at 60° C. After cooling to room temperature, the reaction mixture was partitioned between water and ethyl acetate. The ethyl acetate layer was dried over magnesium sulfate, filtered, and the solvent evaporated under vacuum. The resulting crude product was purified by column chromatography on silica gel using dichloromethane-methanol (1-5%). Fractions containing the product were combined and the solvent was evaporated under vacuum. The residue was treated with acetonitril, the solvent evaporated, whereby 0.3 g of the title compound were obtained as an oily residue.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:26]3[C:34]4[C:29](=[CH:30][C:31](Br)=[CH:32][CH:33]=4)[N:28]([CH3:36])[CH:27]=3)[C:11]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[O:24][CH3:25])(=[O:16])=[O:15])=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH:37]([O:39]CC)=[CH2:38].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:37]([C:31]1[CH:30]=[C:29]2[C:34]([C:26]([CH:10]([C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)[C:11]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[O:24][CH3:25])(=[O:16])=[O:15])=[O:12])=[CH:27][N:28]2[CH3:36])=[CH:33][CH:32]=1)(=[O:39])[CH3:38]
Reactant: COc1cc(C)ccc1S(=O)(=O)NC(=O)C(c1ccc2c(c1)OCO2)c1cn(C)c2cc(Br)ccc12
Reactant: C=COCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1cc(C)ccc1S(=O)(=O)NC(=O)C(c1ccc2c(c1)OCO2)c1cn(C)c2cc(C(C)=O)ccc12
Reaction time: 0.75 h

Procedure:
A mixture of 3-{1-(1,3-benzodioxol-5-yl)-2-[(2-methoxy-4-methylphenyl)sulfonamido]-2-oxoethyl}-6-bromo-1-methyl-1H-indole (from Example 85, 300 mg, 0.53 mmol), ethyl vinyl ether (0.063 ml), palladium(II)acetate (6 mg), tri-o-tolylphosphine (13 mg) and triethylamine (0.1 ml) in acetonitrile (5 ml) was heated at reflux for 18 hours under a nitrogen atmosphere. After cooling, the solvent was evaporated in vacuo and the residue was stirred with 2N hydrochloric acid (~6 ml) for 45 minutes. The mixture was twice extracted with ethyl acetate, and then washed with water, and brine. The organic layer was dried (magnesium sulphate) and the solvents were evaporated in vacuo. The residue was flash chromatographed using a gradient elution of a mixture of 90% hexane and 10% ethyl acetate, through to 40% hexane and 60% ethyl acetate, to give the title compound (80 mg).
Reaction SMILES: C(OC([N:8]1[CH2:17][C:16]2[CH:15]=[N:14][C:13]3[NH:18][N:19]=[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][NH:28]C(OC(C)(C)C)=O)[CH:22]=4)[C:12]=3[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[C:20]1([C:21]2[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=2)[CH2:27][NH2:28])[C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][C:16]=3[CH:15]=[N:14][C:13]=2[NH:18][N:19]=1.[C:38]([OH:40])([C:37]([F:42])([F:41])[F:36])=[O:39]
Reactant: CC(C)(C)OC(=O)NCc1cccc(-c2n[nH]c3ncc4c(c23)CCN(C(=O)OC(C)(C)C)C4)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1cccc(-c2n[nH]c3ncc4c(c23)CCNC4)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-[3-(tert-butoxycarbonylamino-methyl)-phenyl]-3,6,8,9-tetrahydro-pyrazolo[3,4-c][2,7]naphthyridine-7-carboxylic acid tert-butyl ester (0.07 g, 0.14 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL). The mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and purified by reverse phase HPLC to give the desired product, 3-(6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridin-1-yl)-benzylamine as a bis TFA salt and as a white solid (0.046 g, 62%). 1H NMR (400 MHz, DMSO-d6) δ13.98 (s, 1H), 9.27 (brs, 2H), 8.45 (s, 1H), 8.30 (brs, 2H), 7.70 (s, 1H), 7.58 (m, 3H), 4.44 (s, 2H), 4.14 (m, 2H), 3.31 (m, 2H), 3.01 (m, 2H); LC-Mass: m/e 480.73 (M+H).
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].[C:32]([O:40][CH2:41][N:42]1[C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=2[N:44]([CH2:51][CH2:52][CH2:53]Cl)[C:43]1=[O:55])(=[O:39])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC.CO.ClCCl>[C:32]([O:40][CH2:41][N:42]1[C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=2[N:44]([CH2:51][CH2:52][CH2:53][N:9]2[CH2:10][CH2:11][C:6]3([N:5]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH2:4][N:3]([CH2:18][C:19]4[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=4)[C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[C:2]3=[O:1])[CH2:7][CH2:8]2)[C:43]1=[O:55])(=[O:39])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCCC(=O)OCn1c(=O)n(CCCCl)c2ccccc21
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCNCC3)C2=O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: CCC(C)=O
Solvent: ClCCl
Product: CCCCCCC(=O)OCn1c(=O)n(CCCN2CCC3(CC2)C(=O)N(Cc2cccc(C(=O)OC(C)(C)C)c2)CN3c2ccccc2)c2ccccc21
Yield: 85.8 %

Procedure:
tert-Butyl 3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.200 g, 0.474 mmol), (3-(3-chloropropyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl heptanoate (0.17 g, 0.474 mmol), sodium iodide (0.021 g, 0.142 mmol), and potassium carbonate (0.0983 g, 0.711 mmol) in 2-butanone (5 mL) were heated at 78° C. for 4 hours. The reaction was diluted with 10% methanol/dichloromethane, filtered, and evaporated. The residue was purified by PTLC (50% ethyl acetate/hexanes) to give product as foam (0.30 g, 86%); NMR (DMSO-d6); δ0.78 (t, J=6.4 Hz, 3H); 1.16 (m, 6H); 1.44-1.48 (m, 2H); 1.51 (s, 9H); 1.60 (m, 2H); 1.84-1.87 (m, 2H); 2.28 (t, J=6.8 Hz, 2H); 2.35 (m, 2H); 2.51-2.59 (m, 2H); 2.65-2.71 (m, 4H); 3.93 (t, J=6.8 Hz, 2H); 4.58 (s, 2H); 4.61 (s, 2H); 5.88 (s, 2H); 6.77 (t, J=7.2 Hz, 1H); 6.85 (d, J=8 Hz, 2H); 7.06-7.10 (m, 2H); 7.22 (t, J=8.4 Hz, 2H); 7.26-7.32 (m, 2H); 7.48-7.54 (m, 2H); 7.79 (s, 1H); 7.82-7.84 (m, 1H); MS for C43H55N5O6 m/z 738 (M+H)+.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([O:13][C:14](=[O:16])[CH3:15])=[C:7]([CH3:17])[C:6]=1[CH2:18][CH2:19][C@:20]([O:24]C(C1C(C(O)=O)=CC=CC=1)=O)([C:22]#[CH:23])[CH3:21])(=[O:3])[CH3:2].Cl>CO.[OH-].[Na+]>[C:1]([O:4][C:5]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([O:13][C:14](=[O:16])[CH3:15])=[C:7]([CH3:17])[C:6]=1[CH2:18][CH2:19][C@:20]([CH3:21])([OH:24])[C:22]#[CH:23])(=[O:3])[CH3:2]
Reactant: C#C[C@](C)(CCc1c(C)c(OC(C)=O)c(C)c(C)c1OC(C)=O)OC(=O)c1ccccc1C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C#C[C@@](C)(O)CCc1c(C)c(OC(C)=O)c(C)c(C)c1OC(C)=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 27.4 %

Procedure:
A solution of 600 mg (1.25 mmol) of (S)-(+)-1,2-benzenedicarboxylic acid[3-[2,5-bis(acetyloxy)-3,4,6-trimethylphenyl]-1-ethynyl-1-methylpropyl]ester (Example 9) in 10 mL of methanol and 10 mL of 1.0N NaOH was degassed with argon, and heated under reflux for 1.0 h. It was cooled to 0° C. and treated with 100 mL of cold 1.0N HCl. It was then extracted with ether (3×100 mL). The extracts were combined, washed with saturated sodium bicarbonate solution (3×100 mL) dried over MgSO4, and filtered. Dry pyridine (1 mL) was added to the filtrate which was concentrated to near dryness at reduced pressure. The residue was cooled to 0° C. and treated with 3 mL of dry pyridine and 3 mL of acetic anhydride. The resultant solution was kept under argon at 0° C. for 3.0 h, then taken into 100 mL of cold 1N HCl. It was then extracted with ether (3×100 mL). The ether extracts were combined, washed with cold 1.0N HCl (2×100 mL), saturated sodium bicarbonate solution (3×100), brine (1×100 mL), and dried over MgSO4. The crude product (369 mg) was crystallized twice from ether-hexane (1:2) to give (S)-(+)-5-[2,5-bis(acetyloxy)-3,4,6-trimethylphenyl]-3-methyl-1-pentyn-3-ol as a white solid (114 mg): mp 96°-102° C., [α]D25 +14.30° (c 0.965, ethanol); [α]D25 +17.17° (CHCl3).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([CH:19]=[N:20][OH:21])[C:3]=1[S:22]([CH3:24])=[O:23].[OH:25]O>O>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([CH:19]=[N:20][OH:21])[C:3]=1[S:22]([CH3:24])(=[O:25])=[O:23]
Reactant: CS(=O)c1c(C=NO)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Reactant: OO
Solvent: O
Product: CS(=O)(=O)c1c(C=NO)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Temperature: 20 °C
Reaction time: 8 h
Yield: 64.8 %

Procedure:
A mixture of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboxaldehyde oxime (1.38 g), 30% hydrogen peroxide (1.38 ml) sodium tungstate dihydrate (0.17 g) in methanouacetic acid was stirred at 20° C. overnight, then at 50° C. for 4 hours, and again at 20° C. overnight. Water was added and the solid filtered, water-washed and dried to give 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfonyl-1H-pyrazole-3-carboxaldehyde oxime (0.93 g) m.p.209.5-211° C. (decomposition). Compound 16.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([OH:27])=[C:5]([C:23]([O:25]C)=[O:24])[C:6](=[O:22])[NH:7][C:8]=1[C:9]1[CH:17]=[CH:16][C:15]2[N:14]3[CH2:18][CH2:19][C:20](=O)[C:13]3=[CH:12][C:11]=2[CH:10]=1)[CH3:2].[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[Li+].[I-].Cl>ClCCCl.CC(O)=O>[CH2:1]([C:3]1[C:4]([OH:27])=[C:5]([C:23]([OH:25])=[O:24])[C:6](=[O:22])[NH:7][C:8]=1[C:9]1[CH:17]=[CH:16][C:15]2[N:14]3[CH2:18][CH2:19][CH:20]([N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)[C:13]3=[CH:12][C:11]=2[CH:10]=1)[CH3:2]
Reactant: CCc1c(-c2ccc3c(c2)cc2n3CCC2=O)[nH]c(=O)c(C(=O)OC)c1O
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [I-]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCc1c(-c2ccc3c(c2)cc2n3CCC2N2CCCC2)[nH]c(=O)c(C(=O)O)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.6 %

Procedure:
To a solution of methyl 5-ethyl-4-hydroxy-2-oxo-6-(1-oxo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-7-yl)-1,2-dihydropyridine-3-carboxylate (0.13 g, 0.37 mmol) in DCE (3 mL) was added pyrrolidine (60 μL, 0.8 mmol) and AcOH (30 μL). After stirring at room temperature for 1 h, NaBH(OAc)3 (0.17 g, 0.8 mmol) was added and stirred for an additional 1 h. The reaction mixture was then concentrated and to the crude residue was added H2O. The resulting precipitate was filtered and dried over N2 stream. The crude solid was dissolved in EtOAc (3 mL) and LiI (0.2 g, 1.6 mmol) was added. The resulting suspension was heated to 60° C. for 1 h. The reaction mixture was then cooled to room temperature and acidified with 4M HCl (1 mL). The resulting precipitate was filtered and rinsed with Et2O to afford the title compound as an orange solid (25 mg, 20%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[C:15]2[CH:16](O)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:14]=2[CH:13]=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O.[Cl-].[Li+].C1CCN2C(=NCCC2)CC1>C(#N)C.O>[C:4]([Si:1]([O:8][CH2:9][C:10]1[C:15]2[CH:16]=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][C:14]=2[CH:13]=[CH:12][CH:11]=1)([CH3:3])[CH3:2])([CH3:7])([CH3:5])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc2c1C(O)CCCCC2
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)[Si](C)(C)OCc1cccc2c1C=CCCCC2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 4-[[[tert-butyl(dimethyl)silyl]oxy]methyl]-5,6,7,8,9,10-hexahydrobenzo[a]cycloocten-5-ol (17.90 g, 55.84 mmol), triethylamine (15.6 ml, 112 mmol) and 4-N,N-dimethylaminopyridine (0.68 g, 5.58 mmol) in acetonitrile (100 ml) was dropwise-added a solution of methanesulfonyl chloride (9.59 g, 83.8 mmol) in acetonitrile (10 ml) under ice-cooling. Lithium chloride (3.55 g, 83.8 mmol) was added thereto and the mixture was stirred at room temperature for 6 hrs. The reaction solution was poured into water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in N,N-dimethylformamide (80 ml). 1,8-Diazabicyclo[5.4.0]-7-undecene (16.7 ml, 112 mmol) was added and the mixture was stirred overnight at 80° C. The reaction solution was poured into water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane/ethyl acetate=15/1) to give the objective substance.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:20][CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:29]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)#[N:30]>>[CH:18]1([N:13]2[C:12]([C:34]3[CH:35]=[CH:36][C:31]([C:29]#[N:30])=[CH:32][CH:33]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH2:19][CH2:20]1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C3CC3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Product: N#Cc1ccc(-c2c3c(nn2C2CC2)CCNCC3)cc1
Yield: 69.5 %

Procedure:
The title compound (91 mg) was prepared according to Example 281 using 200 mg of 2-cyclopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 281, Step C) and 97 mg of 4-cyanophenylboronic acid. MS (ESI): exact mass calculated for C17H18N4, 278.15; found, m/z 279.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.94-7.92 (m, 2H), 7.71-7.70 (m, 2H), 4.66 (br s, 1H), 3.71-3.68 (m, 1H), 3.47 (br s, 1H), 3.39-3.19 (m, 4H), 3.01-2.88 (m, 2H), 0.96-0.90 (m, 4H).
Reaction SMILES: [CH3:1][N:2]1[CH2:23][CH2:22][C:5]2[N:6]([CH2:14][CH2:15][CH2:16][C:17](OCC)=[O:18])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH2:24]([NH2:26])[CH3:25]>>[CH2:24]([NH:26][C:17](=[O:18])[CH2:16][CH2:15][CH2:14][N:6]1[C:7]2[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=2[C:4]2[CH2:3][N:2]([CH3:1])[CH2:23][CH2:22][C:5]1=2)[CH3:25]
Reactant: CCN
Reactant: CCOC(=O)CCCn1c2c(c3cc(C)ccc31)CN(C)CC2
Product: CCNC(=O)CCCn1c2c(c3cc(C)ccc31)CN(C)CC2

Procedure:
Ethyl 4-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)butanoate (80 mg, 0.2 mmol) was stirred with ethylamine (0.8 ml) at 100-120° C. for 3-4 h to obtain 40 mg of N-ethyl-4-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)butanamide after purification on neutral alumina chromatography eluting with methanol-dichloromethane gradient.