Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[S:4][C:5]([C:8]([OH:10])=O)=[CH:6][N:7]=1.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[NH2:34][C@H:35]([CH2:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[CH:47][CH:46]=1)[CH2:36][C@@H:37]([CH3:43])[C:38]([O:40][CH2:41][CH3:42])=[O:39]>CN(C=O)C>[C:48]1([C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH:47]=[CH:46][C:45]([CH2:44][C@@H:35]([NH:34][C:8]([C:5]2[S:4][C:3]([O:2][CH3:1])=[N:7][CH:6]=2)=[O:10])[CH2:36][C@@H:37]([CH3:43])[C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:50][CH:49]=1
Reactant: COc1ncc(C(=O)O)s1
Reactant: CCOC(=O)[C@H](C)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnc(OC)s1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-methoxythiazole-5-carboxylic acid (101 mg, 0.64 mmol) in DMF (6 mL) is added HOAt (107 mg, 0.58 mmol), EDCl (133 mg, 0.69 mmol), and TEA (0.48 mL, 3.47 mmol). The crude is stirred at room temperature for 15 mins. To this crude is added (2R,4S)-ethyl 4-amino-5-(biphenyl-4-yl)-2-methylpentanoate hydrochloride salt. The crude is stirred at room temperature for overnight. The crude is quenched with 1 N HCl and water, diluted in EtOAc. The organic layer is washed with brine, dried over MgSO4, filtered, and concentrated. The residue is purified via flash column chromatography using 30% EtOAc/heptane to 70% EtOAc/heptane to give (2R,4S)-ethyl 5-(biphenyl-4-yl)-4-(2-methoxythiazole-5-carboxamido)-2-methylpentanoate (170 mg). HPLC retention time 1.94 minutes (condition A); MS 453.3 (M+1); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.18 (d, J=7.1 Hz, 3H), 1.23 (t, J=7.1 Hz, 3H), 1.71 (ddd, J=14.0, 9.9, 3.9 Hz, 1H), 1.88-2.04 (m, 1H), 2.56-2.73 (m, 1H), 2.78-2.96 (m, 1H), 2.96-3.09 (m, 1H), 4.09 (s, 3H), 4.09-4.18 (m, 2H), 4.30-4.47 (m, 1H), 6.15 (d, J=8.1 Hz, 1H), 7.27 (d, J=6.8 Hz, 2H), 7.29-7.36 (m, 1H), 7.42 (t, J=7.6 Hz, 2H), 7.49 (s, 1H), 7.53 (d, J=8.1 Hz, 2H), 7.57 (d, J=7.3 Hz, 2H).
Reaction SMILES: [C:1](=[O:5])([O:3][CH3:4])[NH2:2].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([N:16]=[C:17]=[O:18])(=[O:15])=[O:14])=[CH:9][CH:8]=1>C1(C)C=CC=CC=1>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([S:13]([NH:16][C:17]([NH:2][C:1]([O:3][CH3:4])=[O:5])=[O:18])(=[O:14])=[O:15])=[CH:11][CH:12]=1
Reactant: COC(N)=O
Reactant: O=C=NS(=O)(=O)c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: COC(=O)NC(=O)NS(=O)(=O)c1ccc(Cl)cc1
Yield: 95.3 %

Procedure:
Methyl carbamate (43.0 grams, 0.57 moles) was stirred in 500 milliliters of dry toluene. 4-chlorobenzenesulfonyl isocyanate (125 grams, 0.57 moles) was added dropwise. An exothermic reaction occurred. The reaction mixture was kept at 80° C. for 11/2hours. It was then cooled and the percipitate removed by filtration. The filtered material was washed with toluene and dried. There was obtained 159 grams of the title product, m.p. 174°-175° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=2)=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[S:28])=[CH:22][C:21]=1[C:29]([F:32])([F:31])[F:30]>>[CH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][C:9]=1[S:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[C:21]([C:29]([F:32])([F:30])[F:31])[CH:22]=2)=[S:28])=[CH:3][CH:4]=1
Reactant: Nc1ccc(Sc2ccc3ccccc3c2)cc1
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Product: FC(F)(F)c1cc(NC(=S)Nc2ccc(Sc3ccc4ccccc4c3)cc2)ccc1Cl
Yield: 34.1 %

Procedure:
2-(4-Aminophenylthio)naphthalene (4.2 mmoles, 1.06 g) and 4-chloro-3-trifluoromethylphenylisothiocyanate (4.2 mmoles, 0.93 g) were reacted according to procedure A to yield of the title compound 0.7 g, 34%. Mass Spec (FD) 489. Calculated for C24H16ClF3 N2S2 : C, ; H, N, . Found: C, ; H, ; N, .
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])[CH3:2].[NH2:13][C:14]1[C:22]([O:23][CH3:24])=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([NH2:18])=[O:17]>N1C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH:13][C:14]1[C:22]([O:23][CH3:24])=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([NH2:18])=[O:17])=[O:7])[CH3:2]
Reactant: COc1cccc(C(N)=O)c1N
Reactant: CCOc1ccccc1C(=O)Cl
Solvent: c1ccncc1
Product: CCOc1ccccc1C(=O)Nc1c(OC)cccc1C(N)=O
Reaction time: 20 h
Yield: 54.3 %

Procedure:
2-Ethoxybenzoyl chloride (8.9 g, 0.048 mol) was added dropwise to a stirred solution of 2-amino-3-methoxybenzamide (4.0 g, 0.024 mol) in pyridine (35 ml) under a nitrogen atmosphere at 0° C. After 20 hours at room temperature, the solvent was removed by evaporation under vacuum, the residue dissolved in dichloromethane (100 ml) and the solution washed successively with 2N hydrochloric acid (2×100 ml) and saturated aqueous sodium hydrogen carbonate solution (2×100 ml). The organic phase was dried (MgSO4) and evaporated under vacuum, then the resulting oil chromatographed on silica gel (40 g), eluting with a mixture of methanol in-dichloromethane (2%), to give the title compound as a colourless solid (4.1 g, 54%), m.p. 177-179° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]3[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C(OCC)(=O)C.O>C(OCC)(=O)C>[CH:21]1([C:18]2[CH:19]=[CH:20][C:15]([O:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:16][CH:17]=2)[CH2:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C3CC3)cc2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: c1cc(C2CC2)ccc1OC1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 1-Boc-4-(4-bromophenoxy)piperidine (5 g), dichlorobis(tricyclohexylphosphine)palladium(II) (725 mg), tripotassium phosphate (14.9 g) and cyclopropylboronic acid (1.81 g) was added toluene (70 mL), and the mixture was stirred with heating under reflux for 7 hr. The reaction mixture was cooled, water was added, and the insoluble material was collected by filtration. The filtrate was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography to give 4-(4-cyclopropylphenoxy)piperidine-1-carboxylic acid tert-butyl ester. The obtained 4-(4-cyclopropylphenoxy)piperidine-1-carboxylic acid tert-butyl ester was dissolved in ethyl acetate (3 mL), 4N hydrogen chloride/ethyl acetate (7 mL) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was washed with ethyl acetate. To the obtained aqueous layer was added 1N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated to give 4-(4-cyclopropylphenoxy)piperidine (2.49 g). Using the obtained 4-(4-cyclopropylphenoxy)piperidine (1.4 g) and 6-bromonicotinic acid (1.2 g) and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (2.4 g) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([C:37]([O:39]C)=[O:38])=[C:9]([CH2:24][N:25]3[CH2:30][CH2:29][CH:28]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)[CH2:27][CH2:26]3)[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)=[N:11]2)=[CH:6][C:5]=1[S:41]([CH:44]([CH3:46])[CH3:45])(=[O:43])=[O:42])[CH3:2].[OH-].[K+]>CO.O>[CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([C:37]([OH:39])=[O:38])=[C:9]([CH2:24][N:25]3[CH2:26][CH2:27][CH:28]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)[CH2:29][CH2:30]3)[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=3)=[N:11]2)=[CH:6][C:5]=1[S:41]([CH:44]([CH3:45])[CH3:46])(=[O:43])=[O:42])[CH3:2]
Reactant: CCOc1cc2nc(-c3cccc(C(F)(F)F)c3)c(CN3CCC(N4CCOCC4)CC3)c(C(=O)OC)c2cc1S(=O)(=O)C(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCOc1cc2nc(-c3cccc(C(F)(F)F)c3)c(CN3CCC(N4CCOCC4)CC3)c(C(=O)O)c2cc1S(=O)(=O)C(C)C
Temperature: 25 °C
Yield: 102.1 %

Procedure:
A stirred suspension of methyl 7-(ethyloxy)-6-[(1-methylethyl)sulfonyl]-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (1.3 g, 1.959 mmol) and potassium hydroxide (0.879 g, 15.67 mmol) in methanol (15 mL) and water (3.75 mL) was heated to reflux for 20 h. The mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The resulting yellow oil was partitioned between water and methylene chloride and cooled in an ice bath. The pH was adjusted to ⅚ with 2N HCl and the organic phase was separated. The aqueous phase was extracted twice more with methylene chloride. The combined organic extracts were washed with brine, dried, and concentrated to afford 7-(ethyloxy)-6-[(1-methylethyl)sulfonyl]-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (1.3 g, 97% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ8.81 (s, 1H), 8.01 (s, 1H), 7.86-7.94 (m, 2H), 7.75-7.82 (m, 1H), 7.67 (s, 1H), 4.37 (q, J=6.80 Hz, 2H), 4.10 (br. s., 2H), 3.84 (quin, J=6.80 Hz, 1H), 3.56 (br. s., 4H), 3.02 (d, J=11.08 Hz, 2H), 2.52-2.63 (m, 2H), 2.44 (br. s., 4H), 2.33 (br. s., 1H), 1.79 (d, J=12.34 Hz, 2H), 1.44 (t, J=6.92 Hz, 3H), 1.26-1.39 (m, 2H), 1.23 (s, 3H), 1.21 (s, 3H); MS (m/z) 650.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:12]2[CH:13]=[N:14][N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:23](=[O:25])[CH3:24])[CH2:19][CH2:18]3)[CH:16]=2)=[C:6]2[CH:10]=[C:9](Cl)[O:8][C:7]=12.O1CCOCC1.[F:32][C:33]1[CH:41]=[C:40]2[C:36]([C:37](B3OC(C)(C)C(C)(C)O3)=[CH:38][N:39]2[Si](C(C)C)(C(C)C)C(C)C)=[CH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:12]2[CH:13]=[N:14][N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:23](=[O:25])[CH3:24])[CH2:19][CH2:18]3)[CH:16]=2)=[C:6]2[CH:10]=[C:9]([C:37]3[C:36]4[C:40](=[CH:41][C:33]([F:32])=[CH:34][CH:35]=4)[NH:39][CH:38]=3)[O:8][C:7]=12
Reactant: CC(=O)N1CCC(n2cc(-c3cnc(N)c4oc(Cl)cc34)cn2)CC1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(B2OC(C)(C)C(C)(C)O2)c2ccc(F)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)N1CCC(n2cc(-c3cnc(N)c4oc(-c5c[nH]c6cc(F)ccc56)cc34)cn2)CC1
Temperature: 25 °C
Yield: 28 %

Procedure:
To a nitrogen degassed solution of 1-{4-[4-(7-amino-2-chloro-furo[2,3-c]pyridin-4-yl)-pyrazol-1-yl]-piperidin-1-yl}ethanone (0.050 g, 0.14 mmol) in 4:1 1,4-dioxane:water (10 mL) was added 6-fluoro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-triisopropylsilanyl-1H-indole (0.060 g, 0.143 mmol), potassium carbonate (0.047 g, 0.34 mmol), dichlorobis(triphenylphosphine)palladium (16 mg, 0.023 mmol). The mixture was heated at reflux for 3 h, then cooled to room temperature and concentrated. The residue was suspended in water and extracted with ethyl acetate (3×50 mL). The combined organic fractions were washed with water (15 mL), dried, and evaporated. Purification by flash chromatography (5% MeOH:DCM) afforded 18 mg (28%) of the title compound as a solid. 1H NMR (300 MHz, CDCl3): δ 1.99-2.14 (m, 2H), 2.17 (s, 3H), 2.24-2.34 (m, 2H), 2.81 (t, J=12 Hz, 1H), 3.29 (m, 1H), 4.02 (d, J=14.7 Hz, 1H), 4.40-4.48 (m, 1H), 4.78 (br. s, 2H), 4.78-4.82 (m, 1H), 6.97 (s, 1H), 7.07 (dt, J=9 Hz, 2.4 Hz, 1H), 7.16 (dd, J=9 Hz, 2.4 Hz, 1H), 7.70 (s, 1H), 7.78 (d, J=2.7 Hz, 1H), 7.87 (s, 1H), 7.92-7.97 (m, 2H), 8.94 (brs, 1H); MS (ESI): 459 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([O:27][CH3:28])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[CH2:29]([N:8]1[C:9](=[O:26])[C:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:6]=[C:7]1[O:27][CH3:28])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: BrCc1ccccc1
Reactant: CCCCc1nc(OC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(OC)n(Cc2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Yield: 50 %

Procedure:
A solution of 4′-[(4-butyl-2-methoxy-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.5 g), benzyl bromide (0.53 mL) and cesium carbonate (1.4 g) in N,N-dimethylformamide (15 mL) was stirred overnight. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.93 g, 50%) as a colorless liquid.
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH2:6][C:7]3[NH:12][C:11]4[N:13]=[CH:14][CH:15]=[CH:16][C:10]=4[C:8]=32)[CH2:3][CH2:2]1.[OH-].[K+].[F:19][C:20]([F:30])([F:29])[C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[CH2:28])=[CH:23][N:22]=1>CN1C(=O)CCC1.O>[F:30][C:20]([F:19])([F:29])[C:21]1[N:22]=[CH:23][C:24]([CH2:27][CH2:28][N:12]2[C:7]3[CH2:6][CH2:5][N:4]4[CH:9]([C:8]=3[C:10]3[CH:16]=[CH:15][CH:14]=[N:13][C:11]2=3)[CH2:1][CH2:2][CH2:3]4)=[CH:25][CH:26]=1
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Reactant: c1cnc2[nH]c3c(c2c1)C1CCCN1CC3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: FC(F)(F)c1ccc(CCn2c3c(c4cccnc42)C2CCCN2CC3)cn1
Reaction time: 24 h

Procedure:
A solution of 2,3,5,6,7,11c-hexahydro-1H-pyrido[3′,2′:4,5]pyrrolo[2,3-g]indolizine (120 mg, 0.565 mmol) and powdered KOH (221.5 mg, 3.955 mmol) in NMP (2 mL) was stirred at RT for 10 min. 2-(Trifluoromethyl)-5-vinylpyridine (195.5 mg, 1.13 mmol) was added into the reaction mixture and stiffing continued for 24 h at RT. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by silica gel flash chromatography to yield 7-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-2,3,5,6,7,11c-hexahydro-1H-pyrido[3′,2′:4,5]pyrrolo[2,3-g]indolizine;
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([NH:7][NH2:8])=[CH:3][CH:2]=1.Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]>>[C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([N:7]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH2:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(NN)cc1
Reactant: CCOC(=O)CBr
Product: CCOC(=O)CN(N)c1ccc(C)cc1

Procedure:
Method for the preparation of compound 19 [isopentyl 2-(2,6-dimethyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)acetate]: p-tolylhydrazine is alkylated with ethyl 2-bromoacetate to give the substituted phenylhydrazine, ethyl 2-(1-p-tolylhydrazinyl)acetate (III). The reaction of III with 4,4-dimethoxy-N-methylbutan-1-amine gives the indole derivative ethyl 2-(5-methyl-3-(2-(methylamino)ethyl)-1H-indol-1-yl)acetate (V). Effecting the indole to standard Pictet Spingler conditions with formaldehyde gives the 1-carboline intermediate (VI) ethyl 2-(2,6-dimethyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)acetate. Following treatment of VI with base the acid (VIII) 2-(2,6-dimethyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)acetic acid is obtained. The treatment of this acid with DCC or other standard coupling reagents with 3-methylbutan-1-ol gives compound 19 isopentyl 2-(2,6-dimethyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)acetate. After the successful synthesis of the compound, purification can be achieved using standard normal phase or reverse phase methods.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:16])[NH:9][C@H:10]1[CH2:14][CH2:13][NH:12][C:11]1=[O:15])([CH3:6])([CH3:5])[CH3:4].Br[CH2:18][C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[CH:24][N:25]=[C:26]2[Cl:29])=[CH:21][CH:20]=1>C1COCC1.CN(C=O)C.C1COCC1>[C:3]([O:7][C:8](=[O:16])[NH:9][C@H:10]1[CH2:14][CH2:13][N:12]([CH2:18][C:19]2[CH:28]=[C:27]3[C:22]([CH:23]=[CH:24][N:25]=[C:26]3[Cl:29])=[CH:21][CH:20]=2)[C:11]1=[O:15])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1=O
Reactant: Clc1nccc2ccc(CBr)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CCN(Cc2ccc3ccnc(Cl)c3c2)C1=O
Reaction time: 0.03 h
Yield: 81.3 %

Procedure:
Sodium hydride (0.24 g, 6.05 mmol, 60% mineral oil dispersion) is added to a solution of [2-oxopyrrolidin-3(S)-yl]-carbamic acid tert-butyl ester (1.18 g, 5.89 mmol) in THF/DMF (62 mL, 9/1, v/v) at 0° C. The mixture is stirred for 2 minutes, then a solution of 7-bromomethyl-1-chloro-isoquinoline (1.4 g, 5.46 mmol) in THF (10 mL) is added dropwise via a cannula. The resulting yellow solution is stirred for 1 hour at 0° C. then at room temperature for 3 hours. The reaction mixture is quenched with saturated ammonium chloride solution, then diluted with EtOAc. The organic layer is washed with water and brine, then dried over MgSO4, filtered and concentrated. The residue is purified by column chromatography eluting with a gradient of 50% EtOAc/hexanes to 70% EtOAc/hexanes to give the product (1.67 g, 4.44 mmol) as a foamy white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([C:16](=O)[CH2:17][CH3:18])[C:12](=O)[CH2:13][CH3:14].Cl.[C:27]([CH2:32][NH:33][NH2:34])([O:29][CH2:30][CH3:31])=[O:28].C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[C:16]([CH2:17][CH3:18])=[N:34][N:33]([CH2:32][C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:12]=1[CH2:13][CH3:14]
Reactant: CCOC(=O)CNN
Reactant: CCC(=O)C(CCCCCCOc1ccc(OC)cc1Cl)C(=O)CC
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)Cn1nc(CC)c(CCCCCCOc2ccc(OC)cc2Cl)c1CC
Yield: 74.1 %

Procedure:
A mixture of 18.45 g of 4-[6-(2-chloro-4-methoxyphenoxy)hexyl]-3,5-heptanedione, 7.73 g of carbethoxymethylhydrazine hydrochloride and 5 g of triethylamine in 100 ml of absolute ethanol was heated at reflux for 8 hours. The product was isolated and distilled to give 16.7 g of ethyl 4-[6-(2-chloro-4-methoxyphenoxy)hexyl]-3,5-diethyl-1H-pyrazol-1-acetate as a pale yellow oil, b.p. 205°-210° C. (0.05 mm); MIC=6-12 microg/ml (herpes 1 and 2).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH2:21][NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:19])([CH3:18])[CH:12]=[C:11]3[CH3:20])=[C:4]([O:31][CH3:32])[CH:3]=1.C(N(CC)CC)C.[C:40](Cl)(=[O:43])[O:41][CH3:42]>C(Cl)Cl>[CH3:32][O:31][C:4]1[CH:3]=[C:2]([O:1][C:40]([O:41][CH3:42])=[O:43])[CH:7]=[CH:6][C:5]=1[C:8]1[C:9]([CH2:21][NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([CH3:19])([CH3:18])[CH:12]=[C:11]2[CH3:20]
Reactant: COC(=O)Cl
Reactant: COc1ccccc1NCc1c(-c2ccc(O)cc2OC)ccc2c1C(C)=CC(C)(C)N2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Oc1ccc(-c2ccc3c(c2CNc2ccccc2OC)C(C)=CC(C)(C)N3)c(OC)c1
Reaction time: 0.17 h
Yield: 57 %

Procedure:
6-(4-Hydroxy-2-methoxyphenyl)-5-(2-methoxyphenylaminomethyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 4-1, 20.0 mg, 0.0465 mmol) was dissolved in anhydrous methylene dichloride (1.0 mL), triethylamine (13 μL, 0.093 mmol) and methyl chlorocarbonate (3.6 μL, 0.047 mmol) were added thereto under ice cooling, and then the mixture was stirred for 10 minutes. The reaction mixture was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (12.9 mg) as a colorless amorphous product. (Yield 57%)
Reaction SMILES: [Br:1][C:2]1([Br:14])[CH2:4][C:3]1([Br:13])[CH2:5][CH2:6][O:7]C(OCC)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl>CO.O>[Br:1][C:2]1([Br:14])[CH2:4][C:3]1([Br:13])[CH2:5][CH2:6][OH:7]
Reactant: CCOC(C)OCCC1(Br)CC1(Br)Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CO
Product: OCCC1(Br)CC1(Br)Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
To a slurry of 16.5 g (0.0418 mol) of 1,1,2-tribromo-2-[2-(1-ethoxy-ethoxy)-ethyl]-cyclopropane in 145 ml methanol and 40 ml water, was added 0.306 g (0.00161 mol) p-toluene sulfonic acid monohydrate and 145 ml 6M hydrochloric acid. After stirring at room temperature for 1 hour, the solvent was removed from the reaction mixture in vacuo. To the residue, there was added ethyl acetate and water. The resulting mixture was transferred to a separatory funnel and the phases were separated. The isolated organic layer was washed with brine then dried over MgSO4 and filtered. The solvent was removed from the filtrate in vacuo to yield 11.9 g of 1,1,2-tribromo-2-(2-hydroxyethyl)cyclopropane as an oil.
Reaction SMILES: [O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@@H:9]3[CH2:10][CH2:11][C@@H:12]2[O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH2:7][C:6]2=[C:15]4[C:2]1=[CH:3][CH:4]=[C:5]2OCOC.O.[C:32]([OH:35])(=[O:34])[CH3:33]>>[C:32]([O:35][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[N:18]([CH3:19])[CH2:17][CH2:16][C@:14]45[C:15]=2[C:2]=1[O:1][C@H:13]4[C@@H:12]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[CH2:11][CH2:10][C@@H:9]35)(=[O:34])[CH3:33]
Reactant: CC(=O)O
Reactant: COCOc1ccc2c3c1C[C@@H]1[C@@H]4CC[C@H](Oc5ccccn5)[C@H](O2)[C@]34CCN1C
Solvent: O
Product: CC(=O)Oc1ccc2c3c1O[C@H]1[C@@H](Oc4ccccn4)CC[C@H]4[C@@H](C2)N(C)CC[C@@]341
Temperature: 100 °C
Reaction time: 6 h

Procedure:
4,5α-Epoxy-methoxymethoxy-17-methyl-6α-((2-pyridyl)-oxy)-morphinane (0.940 g, 2.3 mmol) is mixed with H2O (35 ml) and glacial acetic acid (35 ml) and stirred for 6 hours at 100° C. The mixture is then evaporated down at 40° C. using the Rotavapor and the residue obtained is purified by flash chromatography (90 g silica gel; CH2Cl2 /MeOH=4/1). The product is dissolved in H2O (7 ml) and glacial acetic acid (0.7 ml) and lyophilised.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][N:5]([S:7][C@@H:8]2[NH:11][C:10](=[O:12])[C@H:9]2[NH:13]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:4]=[N:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:45][CH2:46][C:47]([NH:49][C:50]1[S:51][CH:52]=[C:53]([C:55](=[N:59][O:60][CH3:61])[C:56]([OH:58])=O)[N:54]=1)=[O:48]>CC(C)=O>[Cl:45][CH2:46][C:47]([NH:49][C:50]1[S:51][CH:52]=[C:53]([C:55](=[N:59][O:60][CH3:61])[C:56]([NH:13][C@H:9]2[C@H:8]([S:7][N:5]3[CH2:6][N:2]([CH3:1])[N:3]=[N:4]3)[NH:11][C:10]2=[O:12])=[O:58])[N:54]=1)=[O:48]
Reactant: CN1CN(S[C@@H]2NC(=O)[C@H]2NC(c2ccccc2)(c2ccccc2)c2ccccc2)N=N1
Reactant: CON=C(C(=O)O)c1csc(NC(=O)CCl)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: CON=C(C(=O)N[C@@H]1C(=O)N[C@H]1SN1CN(C)N=N1)c1csc(NC(=O)CCl)n1
Yield: 55.9 %

Procedure:
Following the procedure of Reference Example 66B, solution of 1.12 g of (3R,4S)-4-(1-methyl-1H-tetrazol-4-yl)thio-3-tritylamino-2-oxoazetidine in 5 ml of acetone, 0.491 g of p-toluenesulfonic acid monohydrate and 0.788 g of 2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetic acid is treated to give 0.650 g of (3R,4S)-3-[2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetamido]-4-(1-methyl-1H-tetrazol-4-yl)thio-2-oxoazetidine.