Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][C:4]([NH:8][C:9](=[O:18])[O:10][CH2:11]C1C=CC=CC=1)([CH3:7])CO.[H-].[Na+].CC(O)=O>C1COCC1>[CH3:7][C:4]1([CH2:3][C:2]([F:1])([F:19])[F:20])[CH2:11][O:10][C:9](=[O:18])[NH:8]1
Reactant: CC(CO)(CC(F)(F)F)NC(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC1(CC(F)(F)F)COC(=O)N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.6 %

Procedure:
A solution of benzyl 4,4,4-trifluoro-1-hydroxy-2-methylbutan-2-ylcarbamate (830 mg, 2.85 mmol) in THF (55 ml) was cooled to 0° C., and 60% NaH in mineral oil (143 mg, 3.6 mmol) added in one portion. The suspension was stirred for 30 min, then warmed to RT and stirred for 24 h. AcOH (200 ul) added to quench the reaction, and the solution was concentrated in vacuo. The residue was purified by flash chromatography (5% to 20% CH3CN in DCM) to afford the title compound as a white solid (405 mg). 1H NMR (CDCl3, 400 MHz) δ 1.47 (s, 3H), 2.43-2.53 (m, 2H), 4.10 (d, J=8.8 Hz, 1H), 4.28 (d, J=8.8 Hz, 1H), 6.84 (s, 1H). 19F NMR (CDCl3, 376 MHz) δ −61.3 (t, J=10.9 Hz). 13C NMR (CDCl3, 100 MHz) δ 25.3, 43.0 (q, J=27.2 Hz), 55.0, 75.4, 125 (q, J=277.8 Hz), 158.7. LRMS (ESI/APCI): 184 [M+H]+, 225 [M+H+CH3CN]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[C:5]([NH2:10])[CH:4]=1.C(N(CC)CC)C.[C:18](Cl)(=O)[CH2:19][CH2:20][CH2:21][CH3:22].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C1C=CN=CC=1.C(OCC)(=O)C.C(O)C.C(O)(=O)C>[CH2:19]([C:18]1[NH:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[N:10]=1)[CH2:20][CH2:21][CH3:22]
Reactant: COc1ccc(N)c(N)c1
Reactant: CCCCC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCCc1nc2cc(OC)ccc2[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1.75 g of 4-methoxy-o-phenylenediamine, 2 mL of triethylamine and a catalytic amount of p-dimethylaminopyridine in 20 mL of methylene chrloride was cooled with ice. To the above solution was added 1.3 mL of valeryl chloride dropwise. The reaction mixture was stirred at room temperature for 2 hours and diluted with 100 mL of ethyl acetate, then washed with water and concentrated to give a crude product which was dissolved in 30 mL of absolute ethanol. After 2 mL of glacial acetic acid and a catalytic amount of p-toluenesulfonic acid were added to the above, the solution was refluxed for 18 hours. The reaction mixture was concentrated and the residue was purified by flash column chromatography on silica gel (100% EtOAc elution) to give 0.46 g of the desired product as a thick colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][O:7][C@@H:8]2[CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23]/[CH:24]=[C:25]1/[C:26]2[CH:39]=[C:38]([C:40]([OH:43])([CH3:42])[CH3:41])[CH:37]=[CH:36][C:27]=2[O:28][CH2:29][C:30]2[N:35]=[CH:34][CH:33]=[CH:32][C:31]/1=2>C(#N)C.O>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][O:7][CH:8]2[CH2:12][CH2:11][N:10]([CH2:22][CH2:23][CH:24]=[C:25]3[C:31]4[CH:32]=[CH:33][CH:34]=[N:35][C:30]=4[CH2:29][O:28][C:27]4[CH:36]=[CH:37][C:38]([C:40]([OH:43])([CH3:42])[CH3:41])=[CH:39][C:26]3=4)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(CO[C@@H]2CCNC2)cc1
Reactant: CC(C)(O)c1ccc2c(c1)/C(=C/CCBr)c1cccnc1CO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(O)c1ccc2c(c1)C(=CCCN1CCC(OCc3ccc(Cl)cc3)C1)c1cccnc1CO2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (R)-3-(4-chloro-benzyloxy)-pyrrolidine (0.88 mmol, 2.0 eq) in acetonitrile:water (4:1) was added potassium carbonate (0.88 mmol, 2.0 eqv) and (E)-2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol and the resulting mixture was stirred at room temperature for 24 h. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate, and dried over sodium sulfate. The crude product was purified by Reverse Phase HPLC. 1H-NMR (CDCl3) δ: 1.40 (6H, s), 1.15–1.35 (1H, m), 1.85–2.05 (1H, m), 2.20–2.40 (1H, m), 2.35–2.65 (8H, m), 3.90–4.10 (1H, m), 4.30–4.50 (2H, d), 5.10–5.30 (2H, br, s), 6.05 (1H, t), 6.50 (1H, dd), 7.10–7.50 (4H, m), 7.70 (1H, dd), 8.50 (1H, dd). ESI-MS m/z: 505 (M+1), UV retention time: 1.52 min.
Reaction SMILES: [CH:1]([S:3]([CH3:6])(=[O:5])=[O:4])=[CH2:2].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[NH2:36][C:37]1[C:46]2[N:47]=[CH:48][N:49]([CH2:50][C:51]([CH3:54])([OH:53])[CH3:52])[C:45]=2[C:44]2[CH:43]=[CH:42][C:41](Br)=[CH:40][C:39]=2[N:38]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[NH2:36][C:37]1[C:46]2[N:47]=[CH:48][N:49]([CH2:50][C:51]([CH3:54])([OH:53])[CH3:52])[C:45]=2[C:44]2[CH:43]=[CH:42][C:41]([CH:2]=[CH:1][S:3]([CH3:6])(=[O:5])=[O:4])=[CH:40][C:39]=2[N:38]=1
Reactant: C=CS(C)(=O)=O
Reactant: CC(C)(O)Cn1cnc2c(N)nc3cc(Br)ccc3c21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(O)Cn1cnc2c(N)nc3cc(C=CS(C)(=O)=O)ccc3c21
Temperature: 120 °C
Yield: 44.1 %

Procedure:
A thick walled glass tube, equipped with a stir bar, was charged with palladium (II) acetate (15 mg, 0.07 mmol), acetonitrile (50 mL), methyl vinyl sulfone (268 mg, 2.52 mmol), triethylamine (1.00 mL, 7.17 mmol), tri-o-tolylphosphine (45 mg, 0.21 mmol) and 1-(4-amino-7-bromo-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (800 mg, 2.39 mmol). The reaction mixture was purged with nitrogen and the tube was sealed and heated at 120° C. in an oil bath. The reaction was maintained at 120° C. for 12 hours, cooled to ambient temperature, and then concentrated under reduced pressure to yield a dark brown oil. The oil was partitioned between chloroform (75 mL) and a solution comprised of a 1:1 combination of 10% aqueous potassium carbonate and 10% sodium hydroxide. A precipitate formed. The mixture was filtered and the recovered solid was purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with 20% methanol in dichloromethane. The filtrate was also concentrated and the residue purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with a 0-8% gradient of methanol in dichloromethane). The two lots of purified product were combined to provide 380 mg of 1-{4-amino-7-[2-(methylsulfonyl)ethenyl]-1H-imidazo[4,5-c]quinolin-1-yl}-2-methylpropan-2-ol as a pale yellow solid. MS (APCI) m/z 361 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:30]=[C:31](F)[CH:32]=1)[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:29])=[C:12]([NH:14][C:15](=[O:28])[C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[CH:18][CH:17]=2)[CH:13]=1)=[O:6].[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:30]=[C:31]([N:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[CH:32]=1)[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:29])=[C:12]([NH:14][C:15](=[O:28])[C:16]2[CH:17]=[CH:18][C:19]([CH2:22][N:23]([CH2:24][CH3:25])[CH2:26][CH3:27])=[CH:20][CH:21]=2)[CH:13]=1)=[O:6]
Reactant: CCN(CC)Cc1ccc(C(=O)Nc2cc(NC(=O)c3cc(F)cc(F)c3)ccc2C)cc1
Reactant: C1CCNCC1
Product: CCN(CC)Cc1ccc(C(=O)Nc2cc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)ccc2C)cc1
Yield: 83 %

Procedure:
Using an analogous procedure to that described in Example 67 except that the reaction mixture was heated to 100° C. for 16 hours rather than for 6 days, N-[5-(3,5-difluorobenzamido)-2-methylphenyl]-4-diethylaminomethylbenzamide was reacted with piperidine. There was thus obtained the title compound in 83% yield; NMR Spectrum: (DMSOd6) 0.98 (t, 6H), 1.3-1.7 (m, 8H), 2.2 (s, 3H), 2.4-2.5 (m, 2H), 3.2-3.4 (m, 4H), 6.85-6.95 (m, 1H), 7.0-7.1 (m, 1H), 7.2-7.3 (m, 2H), 7.45 (d, 2H), 7.5-7.6 (m, 1H), 7.8 (m, 1H), 7.9 (d, 2H), 9.8 (s, 1H), 10.13 (broad s, 1H); Mass Spectrum: M+H+ 517.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[C:11]([C:15](=O)[CH3:16])[CH:12]=[N:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:18].[NH2:19][OH:20].C(=O)([O-])[O-].[K+].[K+]>>[ClH:18].[C:1]1([C:7]#[C:8][C:9]2[CH:10]=[C:11]([C:15](=[N:19][OH:20])[CH3:16])[CH:12]=[N:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: CC(=O)c1cncc(C#Cc2ccccc2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=NO)c1cncc(C#Cc2ccccc2)c1

Procedure:
Prepared in the same manner as described in EXAMPLE 6, using 1-(5-phenylethynyl-pyridin-3-yl)-ethanone, (prepared as described in EXAMPLE 166), (0.22 g, 0.97 mmol), hydroxylamine hydrochloride (0.54 g, 7.78 mmol) and potassium carbonate (0.67 g, 4.86 mmol) to give the free base of the title compound. Convert the free base to the hydrochloride salt as described in EXAMPLE 163 to give the title compound (0.112 g, 42%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[N:25]([C:26]2[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=2[F:33])[C:13]2[N:14]=[C:15]([NH:18][C@@H:19]([CH3:24])[C:20]([OH:23])([CH3:22])[CH3:21])[N:16]=[CH:17][C:12]=2[CH:11]=1)=[O:9].[BH4-].[Na+].[Cl-].[NH4+]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:9])[C:10]1[N:25]([C:26]2[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=2[F:33])[C:13]2[N:14]=[C:15]([NH:18][CH:19]([CH3:24])[C:20]([CH3:22])([OH:23])[CH3:21])[N:16]=[CH:17][C:12]=2[CH:11]=1
Reactant: C[C@H](Nc1ncc2cc(C(=O)c3ccccc3Cl)n(-c3c(F)cccc3F)c2n1)C(C)(C)O
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CC(Nc1ncc2cc(C(O)c3ccccc3Cl)n(-c3c(F)cccc3F)c2n1)C(C)(C)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-(2-chloro-phenyl)-[7-(2,6-difluoro-phenyl)-2-(2-hydroxy-1,2-dimethyl-propylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-methanone, 8, (1.0 g, 2.1 mmol) in ethanol (2.4 mL) is added sodium borohydride (0.3 g, 8.5 mmol) and the mixture stirred overnight at room temperature. Aqueous ammonium chloride solution is then added and the mixture is extracted with EtOAc several times and the organic phases combined washed with water, brine, dried (MgSO4), filtered and concentrated in vacuo. The resulting residue is purified over silica (50% EtOAc/hexanes, then 100% EtOAc) to afford 470 mg of the desired product as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 8.37 (s, 1H), 7.44-7.36 (m, 2H), 7.22-7.17 (m, 3H), 7.08 (t, J=8.8 Hz, 2H), 6.95 (dd, J=8.4, 8.0 Hz, 1H), 6.32 (d, J=13.2 Hz, 1H), 6.00 (s, 1H), 3.81 (m, 1H), 1.12-1.08 (m, 9H); HRMS calcd for C24H23ClF2N4O2 (M+H)+ 473.1556, found 473.1542.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][CH:10]=[C:9]([C:12]([OH:14])=O)[C:8]=2[CH:15]=1)([O-:3])=[O:2].S(Cl)(Cl)=O.CN(C=O)C.[CH2:25]([NH:28][CH2:29][CH2:30][CH3:31])[CH2:26][CH3:27]>ClC(Cl)(Cl)C.ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][CH:10]=[C:9]([C:12]([N:28]([CH2:29][CH2:30][CH3:31])[CH2:25][CH2:26][CH3:27])=[O:14])[C:8]=2[CH:15]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1csc2ccc([N+](=O)[O-])cc12
Reactant: CCCNCCC
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCCN(CCC)C(=O)c1csc2ccc([N+](=O)[O-])cc12
Temperature: 30 °C

Procedure:
45 g of 5-nitro-3-benzothiophencarboxylic acid were suspended in 150 ml of 1,1,1-trichloroethane. 100 ml of thionyl chloride and 0.5 ml of DMF were added. The mixture was refluxed for 2 hours resulting in a clear solution. The solvents were evaporated and remaining thionyl chloride was removed by evaporation twice with toluene. The crystalline product thus obtained was added in small portions to a solution of 60 g of dipropylamine in 500 ml of dichloromethane below 10° C. The mixture was heated to 30° C. and eluted through 200 g of silica gel with 1500 ml of a mixture (1:1) of dichloromethane and ethyl acetate. The organic phase was washed with water, dried (MgSO4) and evaporated. 200 ml of n-heptane were added and the crystalline product filtered off. Yield: 56 g. M.P. 100° C.
Reaction SMILES: CO.[O:3]1CCCC1.[CH3:8][C:9]1[C:21]2[C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([S:23][CH3:24])[CH:18]=3)[NH:13][C:12]=2[N:11]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[N:10]=1.I([O-])(=O)(=O)=O.[Na+]>O>[CH3:8][C:9]1[C:21]2[C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([S:23]([CH3:24])=[O:3])[CH:18]=3)[NH:13][C:12]=2[N:11]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[N:10]=1
Reactant: CSc1ccc2[nH]c3c(c(C)nn3-c3ccccn3)c(=O)c2c1
Reactant: C1CCOC1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CO
Product: Cc1nn(-c2ccccn2)c2[nH]c3ccc(S(C)=O)cc3c(=O)c12
Temperature: 25 °C
Yield: 61 %

Procedure:
A solution in a mixed solvent of methanol (40 mL), tetrahydrofuran (10 mL) and water (10 mL) of 3-methyl-6-(methylsulfanyl)-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one (1.00 g, 3.10 mmol) and sodium periodate (0.66 g, 3.10 mmol) was heated under reflux for 2 hours. The solution was allowed to cool to room temperature, and concentrated under reduced pressure. The residue was poured into water, and the organic matter was extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (chloroform to chloroform:methanol=98:2) to give the title compound (0.63 g, 61% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2.[CH3:13][O:14][C:15]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[CH:20][C:16]=1[C:17](Cl)=[O:18]>>[CH3:13][O:14][C:15]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[CH:20][C:16]=1[C:17]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2)=[O:18]
Reactant: CN1CCc2c(N)cccc2C1
Reactant: COc1cc(OC)c(C(=O)Cl)cc1OC
Product: COc1cc(OC)c(C(=O)Nc2cccc3c2CCN(C)C3)cc1OC

Procedure:
5-Amino-2-methyl-1,2,3,4-tetrahydroisoquinoline was reacted with 2,4,5-trimethoxybenzoyl chloride according to the procedure of Example 19 to yield 5-(2,4,5-trimethoxybenzamido)-2-methyl-1,2,3,4-tetrahydroisoquinoline; m.p. 159°-160.5° C. after purification from ethanol.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][CH:33]=1)[CH2:6][NH:7][C:8](=[O:30])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[CH:18]=[CH:17][C:16]=2[N+:27]([O-])=O)[CH:10]=1>CO.[Pd]>[F:34][C:2]([F:1])([F:35])[C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][CH:33]=1)[CH2:6][NH:7][C:8](=[O:30])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([O:21][CH2:22][C:23]([F:25])([F:24])[F:26])[CH:18]=[CH:17][C:16]=2[NH2:27])[CH:10]=1
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(OCC(F)(F)F)ccc2[N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(OCC(F)(F)F)cc1-c1cc(C(=O)NCc2cccc(C(F)(F)F)c2)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(2-nitro-5-(2,2,2-trifluoroethoxy)phenyl)isonicotinamide (200 mg, 0.40 mmol, 1.00 equiv) in methanol (5 mL). The solution was treated with Pd/C (0.2 g), and stirred under an atmosphere of hydrogen for 2 h at room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 200 mg (crude) of N-(3-(trifluoromethyl)benzyl)-2-(2-amino-5-(2,2,2-trifluoroethoxy)phenyl)isonicotinamide as a yellow solid.
Reaction SMILES: [N:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH:4]=[N:3][C:2]=1[C:14]([NH:16][NH2:17])=[O:15].[N:18]([O-])=O.[Na+].N([O-])=O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C.O>[N:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH:4]=[N:3][C:2]=1[C:14]([N:16]=[N+:17]=[N-:18])=[O:15]
Reactant: O=N[O-]
Reactant: NNC(=O)c1ncc2[nH]c3ccccc3c2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: [N-]=[N+]=NC(=O)c1ncc2[nH]c3ccccc3c2n1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Under heating, 0.3 g of 5H-pyrimido[5,4-b]indole-2-carboxylic acid hydrazide (Example 5) is dissolved in a mixture of 6 ml of glacial acetic acid and 2.4 ml of water. Then, a solution of 0.33 g of sodium nitrite in 1 ml of water is added gradually thereto at 0° C. After adding the nitrite, the mixture is stirred for another 4 hours at 0° C., thereafter rendered alkaline with sodium carbonate solution, and the thus-crystallized 5H-pyrimido[5,4-b]indole-2-carboxylic acid azide is vacuum-filtered. The yield is 0.3 g.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([NH2:11])[C:6](=[CH:9][CH:10]=1)[C:7]#[N:8].[S:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1>[N+](C1C=CC=CC=1)([O-])=O.[Cl-].[Zn+2].[Cl-]>[NH2:8][C:7]1[C:6]2[CH:9]=[CH:10][C:3]([C:2]([F:12])([F:13])[F:1])=[CH:4][C:5]=2[N:11]=[C:17]2[CH2:18][CH2:19][S:14][CH2:15][C:16]=12
Reactant: N#Cc1ccc(C(F)(F)F)cc1N
Reactant: O=C1CCSCC1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O=[N+]([O-])c1ccccc1
Product: Nc1c2c(nc3cc(C(F)(F)F)ccc13)CCSC2
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 54.7 %

Procedure:
To a solution of 4-trifluoromethyl anthranilonitrile (12.2 g) in 50 ml of nitrobenzene was added freshly fused and pulverized zinc chloride (13.4 g). This was stirred at 50° C. for 1.5 hours after which was added tetrahydrothiopyran-4-one (9.9 g). The reaction mixture was stirred at 130° C. for 2 hours and allowed to cool, and the resulting complex was filtered and rinsed with ethyl ether. The solid was partitioned between 2-butanone (MEK) and NH4OH and the aqueous phase was extracted with MEK (2x). The organics were washed with water, dried (saturated NaCl, MgSO4) and concentrated to give 10.2 g of a yellow powder m.p. 253°-259° C. d. A 3.7 g portion was recrystallized from methanol/water to give 3.0 g of an off-white powder, m.p. 258°-262° C. d.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][N:5]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:4][C@H:3]1[OH:13].C(=O)([O-])[O-].[K+].[K+].[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1.O>O1CCOCC1>[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:1][C@H:2]2[C@H:3]([OH:13])[CH2:4][N:5]([CH:7]3[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]3)[CH2:6]2)=[O:26])=[CH:23][CH:22]=1
Reactant: N[C@@H]1CN(C2CCCCC2)C[C@H]1O
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(N[C@@H]1CN(C2CCCCC2)C[C@H]1O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 36.8 g of trans-4-amino-1-cyclohexyl-3-pyrrolidinol in 600 ml of p-dioxane was mixed with 40 g of powdered anhydrous potassium carbonate and stirred while 35.0 g of p-chlorobenzoyl chloride in 100 ml of p-dioxane was added dropwise. The mixture was stirred at room temperature for 2 hrs, then heated at reflux for 2 hrs. While still hot, 10 ml of water was added to make the precipitate granular; the mixture was filtered and the dioxane reduced to one-half volume. This solution was poured into one liter of water. The precipitate was collected and recrystallized from acetone. Yield was 60.5 g (94%), m.p. 193°-195° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:38])/[C:5](=[CH:9]/[C:10]1[C:18]2[C:13](=[CH:14][N:15]=[C:16]([C:19]3[C:24]([CH2:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=3[CH2:27][CH3:28])[CH:17]=2)[N:12]([C:29]2[CH:34]=[CH:33][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:31][CH:30]=2)[CH:11]=1)/[CH2:6][CH2:7][CH3:8])[CH3:2]>[Pd].CCO>[CH2:1]([O:3][C:4](=[O:38])[CH:5]([CH2:9][C:10]1[C:18]2[C:13](=[CH:14][N:15]=[C:16]([C:19]3[C:24]([CH2:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=3[CH2:27][CH3:28])[CH:17]=2)[N:12]([C:29]2[CH:34]=[CH:33][C:32]([CH:35]([CH3:36])[CH3:37])=[CH:31][CH:30]=2)[CH:11]=1)[CH2:6][CH2:7][CH3:8])[CH3:2]
Reactant: CCC/C(=C\c1cn(-c2ccc(C(C)C)cc2)c2cnc(-c3c(CC)cccc3CC)cc12)C(=O)OCC
Agent: [Pd]
Solvent: CCO
Product: CCCC(Cc1cn(-c2ccc(C(C)C)cc2)c2cnc(-c3c(CC)cccc3CC)cc12)C(=O)OCC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of (2-[1-[5-(2,6-diethyl-phenyl)-1-(4-isopropyl-phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-meth-(E)-ylidene]-pentanoic acid ethyl ester (120 mg, 0.23 mmol), 10% Pd/C (20 mg), and EtOH (4 mL) is stirred under hydrogen (1 atm) for 18 h at room temperature. The mixture is filtered over celite and concentrated under reduced pressure to afford 2-[5-(2,6-diethyl-phenyl)-1-(4-isopropyl-phenyl)-1H-pyrrolo[2,3-c]pyridin-3-ylmethyl]-pentanoic acid ethyl ester as colorless oil.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[CH3:21][N:22]1[C:34]2[CH:33]=[CH:32][C:31]([CH:35]=O)=[CH:30][C:29]=2[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2>>[CH3:20][O:19][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:35][C:31]2[CH:32]=[CH:33][C:34]3[N:22]([CH3:21])[C:23]4[C:28]([C:29]=3[CH:30]=2)=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: Cn1c2ccccc2c2cc(C=O)ccc21
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1ccc2c(c1)c1ccccc1n2C

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with commercially available 9-methyl-9H-carbazole-3-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions I): tR=1.49 min.; [M+H]+: 443.14 g/mol.
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17]C(=O)C)[CH2:14][C@H:13]2[C:21](=[O:23])[NH2:22])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[Na+].Cl>CO>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([SH:17])[CH2:14][C@H:13]2[C:21](=[O:23])[NH2:22])=[O:11])=[CH:24][CH:25]=1)([O-:3])=[O:2]
Reactant: CC(=O)S[C@H]1C[C@@H](C(N)=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC(=O)[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.25 h

Procedure:
950 mg of (2S,4S)-1-(p-nitrobenzyloxycarbonyl)-2-carbamoyl-4-acetylthiopyrrolidine was dissolved in 95 ml of methanol, and 2.59 ml of a 1N aqueous solution of sodium hydroxide was added thereto at room temperature in an argon stream, followed by stirring at that temperature for 15 minutes. The reaction mixture was neutralized with 2.59 ml of a 1N aqueous solution of hydrochloric acid and distilled off under reduced pressure to remove the methanol. The thus precipitated crystals were filtered and washed with water to obtain (2S,4S)-1-(p-nitrobenzyloxycarbonyl)-2-carbamoyl-4-mercaptopyrrolidine.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([C@@H:23]5[CH2:28][CH2:27][NH:26][CH2:25][C@H:24]5[OH:29])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1.[CH2:37]=O>>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([C@@H:23]5[CH2:28][CH2:27][N:26]([CH3:37])[CH2:25][C@H:24]5[OH:29])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1[C@@H]1CCNC[C@H]1O
Reactant: C=O
Product: CN1CC[C@@H](N2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)[C@H](O)C1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[trans-3-hydroxy-1-methylpiperidin-4-yl]-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[trans-3-hydroxypiperidin-4-yl]-1,3-thiazolidine-2,4-dione (Example 270) and formaldehyde following General Procedure R.