Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[N:23][C:24]=3[NH2:26])[N:19]([C@H:27]3[CH2:32][CH2:31][C@H:30]([N:33]4[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]4)[CH2:29][CH2:28]3)[N:18]=2)=[CH:13][C:12]=1[Cl:40]>C(O)C>[NH2:26][C:24]1[N:23]=[CH:22][N:21]=[C:20]2[N:19]([C@H:27]3[CH2:32][CH2:31][C@H:30]([N:33]4[CH2:34][CH2:35][N:36]([CH3:39])[CH2:37][CH2:38]4)[CH2:29][CH2:28]3)[N:18]=[C:17]([C:14]3[CH:15]=[CH:16][C:11]([N:10]=[CH:1][C:2]4[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=4[OH:4])=[C:12]([Cl:40])[CH:13]=3)[C:25]=12
Reactant: O=Cc1ccccc1O
Reactant: CN1CCN([C@H]2CC[C@H](n3nc(-c4ccc(N)c(Cl)c4)c4c(N)ncnc43)CC2)CC1
Solvent: CCO
Product: CN1CCN([C@H]2CC[C@H](n3nc(-c4ccc(N=Cc5ccccc5O)c(Cl)c4)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Salicylaldehyde (0.033 g, 0.000274 mol) and trans-3-(4-amino-3-chlorophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.115 g, 0.000261 mol) were combined in absolute ethanol and stirred at ambient temperature for 48 hours. The reaction mixture was concentrated under reduced pressure and the residue dried overnight to yield trans-2-[(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-chlorophenyl)imino]methylphenol which was used without further purification. Trimethylsulfoxonium iodide (0.110 g, 0.0005 mol) was dissolved in anhydrous dimethylsulfoxide (2 mL) and 60% dispersion of sodium hydride in paraffine (0.02 g, 0005 mol) was added at once. After 10 min., the solution of trans-2-[(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-chlorophenyl)imino]methylphenol in anhydrous dimethylsulfoxide (2 mL) was added and the resulting mixture was stirred at ambient temperature under an atmosphere of nitrogen for 2.5 hours. The solution was poured into ice-cold water (50 mL) and extracted with dichloromethane (2×40 mL). The combined organic extracts were dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC (Hypersil C18, 8 μm, 25 cm; 10-60% acetonitrile-0.1M ammonium acetate over 25 min, 21 mL/min) to yield trans-3-[3-chloro-4-(2,3-dihydrobenzo[b]furan-3-ylamino)phenyl]-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine acetate (0.044 g, 0.000071 mol) as a white solid.
Reaction SMILES: [ClH:1].[N:2]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH:6]=[N:5][CH:4]=[N:3]1.[N:15]([O-])=O.[Na+].S([O-])([O-])=O.[Na+].[Na+]>O.Cl>[ClH:1].[N:2]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][NH2:15])=[CH:10][CH:9]=2)[CH:6]=[N:5][CH:4]=[N:3]1
Reactant: O=N[O-]
Reactant: Nc1ccc(Cn2cncn2)cc1
Agent: Cl
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: NNc1ccc(Cn2cncn2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1.5 g (7.1 mmoles) of 4-(1,2,4-triazol-1-ylmethyl)phenylamine hydrochloride in 3.75 ml of water and 6.3 ml of concentrated HCl, cooled to 0° C., was added slowly a solution of 0.5 g (7.2 mmoles) of sodium nitrite in 2.6 ml of water, keeping the temperature below 0° C. The mixture was stirred at this temperature for 15 minutes. Once this time had elapsed the solution of the diazonium salt was added rapidly to a solution of 5.37 g (42.6 mmoles) of sodium sulphite in 19 ml of water precooled to 0° C. under nitrogen atmosphere. The red solution was stirred at 0° C. for 10 minutes and then left to reach 65° C. in 1 hour. It was stirred at 65° C. for 30 minutes, and 5 ml of concentrated HCl were then added. The mixture was stirred at the same temperature under nitrogen atmosphere for 3 hours and then left to cool to room temperature.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH:5]=[CH:6][C:7](=[O:23])[NH:8][CH2:9][C:10]1[CH:19]=[C:18]([Br:20])[CH:17]=[C:16]2[C:11]=1[NH:12][C:13](=[O:22])[C:14](=[O:21])[NH:15]2)C.O.[OH-].[Li+].O>O1CCCC1.O>[Br:20][C:18]1[CH:17]=[C:16]2[C:11]([NH:12][C:13](=[O:22])[C:14](=[O:21])[NH:15]2)=[C:10]([CH2:9][NH:8][C:7]([CH:6]=[CH:5][C:4]([OH:24])=[O:3])=[O:23])[CH:19]=1
Reactant: CCOC(=O)C=CC(=O)NCc1cc(Br)cc2[nH]c(=O)c(=O)[nH]c12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C=CC(=O)NCc1cc(Br)cc2[nH]c(=O)c(=O)[nH]c12
Reaction time: 18 h

Procedure:
144 mg (0.36 mmol) of 3-[(7-bromo-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-ylmethyl)-carbamoyl]-acrylic acid ethyl ester (Example 10) and 76 mg of lithium hydroxide hydrate are dissolved in 18 ml of tetrahydrofuran/water (2:1) and the solution is stirred for 18 hours. 50 ml of water are added, the tetrahydrofuran is concentrated by evaporation and the solution is acidified with 1 N hydrochloric acid. The solid is filtered off, washed with water and dried.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])O[C:10]=1[C:17]([NH:19][CH:20]1[CH2:23][CH2:22][CH2:21]1)=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][NH2:25]>CO>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])[N:25]([CH3:24])[C:10]=1[C:17]([NH:19][CH:20]1[CH2:23][CH2:22][CH2:21]1)=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN
Reactant: Cc1cc(=O)c(OCc2ccccc2)c(C(=O)NC2CCC2)o1
Solvent: CO
Product: Cc1cc(=O)c(OCc2ccccc2)c(C(=O)NC2CCC2)n1C
Temperature: 72.5 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
To a solution of the compound from example 4 (2.616 g, 8.35 mmol, 1.0 equiv) in methanol (10 ml) was quickly added methylamine (2M in methanol, 20 ml, 40 mmol, 4.79 equiv). The sealed tube was stirred overnight at 70-75° C. The resulting brown solution was evaporated to dryness and purified by chromatography (EtOAc, then 1:4 MeOH/EtOAc) provided the titled compound (1.70 g, 62.24%) as a white solid. M.p. 221.3-222.4° C.; 1H-NMR (DMSO-d6, 400 MHz) δ 1.65-1.69 (m, 2H, cyclobutyl H), 1.90-1.95 (m, 2H, cyclobutyl H), 2.14-2.21 (m, 2H, cyclobutyl H), 2.31 (s, 3H, CH3), 3.42 (s, 3H, NCH3), 4.34-4.30 (m, 1H, CH), 5.05 (s, 2H, OCH2Ph), 6.22 (s, 1H, CH), 7.39-7.30 (m, 5H, ArH), 9.08-9.06 (d, 1H, J=7.08 Hz, NH); MS (m/z) 327 (M++1), 230, 166, 91.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[N:26]=[C:27]=[S:28].C1(C)C=CC=CC=1>CCOCC>[Cl:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([F:16])[C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:27]([NH:26][C:20]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:19]=2[CH3:18])=[S:28])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cc(Cl)ccc1N=C=S
Reactant: Nc1ncccc1OCc1c(F)cccc1Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Cc1cc(Cl)ccc1NC(=S)Nc1ncccc1OCc1c(F)cccc1Cl

Procedure:
A mixture of 2-amino-3-(2-chloro-6-fluorobenzyloxy)pyridine (2 g, 0.008 mol), (2-methyl-4-chlorophenyl isothiocyanate (1.76 g, 0.0096 mol) and toluene (10 ml) was heated under reflux for 5 hours, then cooled and diluted with ether to induce crystallisation of the product. Yield 2.72g (77%), m.p. 176°-177 ° C.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:5]=[C:6](/[CH:9]=[CH:10]/[C:11]2[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[CH:13][C:12]=2[CH3:20])[S:7][CH:8]=1)[CH3:3].O.O.[Sn](Cl)Cl.C(O)C>[OH-].[Na+]>[CH3:20][C:12]1[CH:13]=[CH:14][C:15]([NH2:17])=[CH:16][C:11]=1/[CH:10]=[CH:9]/[C:6]1[S:7][CH:8]=[C:4]([CH:2]([CH3:3])[CH3:1])[N:5]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1/C=C/c1nc(C(C)C)cs1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(N)cc1/C=C/c1nc(C(C)C)cs1
Yield: 111.6 %

Procedure:
A solution of 1.2 g of (E)-4-(1-methylethyl)-2-[2-(2-methyl-5-nitrophenyl)ethenyl]thiazole, 3.2 g of tin(II) chloride dihydrate and 50 ml of ethyl alcohol was heated to reflux for 2 hr. The reaction mixture was cooled in an ice bath and then diluted with 50 ml of 3N sodium hydroxide. This mixture was extracted with ethyl acetate, dried (MgSO4) and condensed in vacuo to yield 1.2 g of (E)-4-methyl-3-[2-[4-(1-methylethyl)-2-thiazolyl]ethenyl]benzenamine; m.p. 60°-61° C. from hexane.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][CH2:5]2.Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)[CH2:5]2
Reactant: Cc1ccc(CBr)cc1
Reactant: O=C1NCc2cc(Br)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccc(CN2Cc3cc(Br)ccc3C2=O)cc1
Yield: 79.1 %

Procedure:
5-Bromo-2,3-dihydro-isoindol-1-one (1.0 g, 4.72 mmol), 1-bromomethyl-4-methyl-benzene (1.14 g, 6.14 mmol) and cesium carbonate (3.08 g, 9.44 mmol) were suspended in anhydrous NMP (10 mL). The mixture was immersed in a 60° C. oil bath for 16.5 hours. The cooled reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over magnesium sulfate, filtered and concentrated. Column chromatography (20% to 40% ethyl acetate/hexanes) provided the title compound as a yellow solid (1.18 g, 79%). 1H NMR CDCl3: 7.76 (d, 1H), 7.62 (d, 1H), 7.55 (s, 1H), 4.76 (s, 2H), 4.24 (s, 2H), 2.35 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][N:9]([CH2:23][C:24]2[CH:41]=[CH:40][C:27]3[N:28]([CH2:38][CH3:39])[C:29](=[O:37])[C:30]([CH3:36])([CH3:35])[C:31](=[O:34])[N:32]([CH3:33])[C:26]=3[CH:25]=2)[CH2:10][CH2:11][N:12]2[CH:17]=[CH:16][C:15]3[O:18][C:19]([CH3:21])=[CH:20][C:14]=3[C:13]2=[O:22])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:42][N:43](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Zn].O>[CH2:38]([N:28]1[C:29](=[O:37])[C:30]([CH3:36])([CH3:35])[C:31](=[O:34])[N:32]([CH3:33])[C:26]2[CH:25]=[C:24]([CH2:23][N:9]([CH2:8][C:7]3[C:2]([C:42]#[N:43])=[N:3][CH:4]=[CH:5][CH:6]=3)[CH2:10][CH2:11][N:12]3[CH:17]=[CH:16][C:15]4[O:18][C:19]([CH3:21])=[CH:20][C:14]=4[C:13]3=[O:22])[CH:41]=[CH:40][C:27]1=2)[CH3:39]
Reactant: CN(C)C=O
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN(CCn3ccc4oc(C)cc4c3=O)Cc3cccnc3Cl)ccc21
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN(CCn3ccc4oc(C)cc4c3=O)Cc3cccnc3C#N)ccc21
Temperature: 95 °C

Procedure:
2-Chloro-3-({(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)pyridine (0.3 g), zinc cyanide(120 mg), tris(dibenzylideneacetone)dipalladium(24 mg), 1,1′-bis(diphenylphosphino)ferrocene(14 mg), and zinc powder(3.4 mg) were added to DMF(3 ml), and the mixture was heated at 95° C. for 3 hours. The reaction liquid was cooled to room temperature. Water was added to the reaction mixture and subjected to celite filtration. Extraction with ethyl acetate was performed. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: methanol=93:7). The purified product was condensed under reduced pressure, and the residue was recrystallized from ether to give the title compound(1.35 g) as a white powder.
Reaction SMILES: CS(C)=O.[CH3:5][N:6]([CH3:12])[C@H:7]1[CH2:11][CH2:10][NH:9][CH2:8]1.[C:13]([C:15]1[C:20]2[N:21]=[C:22]([C:24]([N:26]([CH2:28][CH3:29])[CH3:27])=[O:25])[O:23][C:19]=2[C:18](F)=[C:17]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:16]=1[CH3:37])#[N:14].C(N(CC)CC)C>[Cl-].[Na+].O>[C:13]([C:15]1[C:20]2[N:21]=[C:22]([C:24]([N:26]([CH2:28][CH3:29])[CH3:27])=[O:25])[O:23][C:19]=2[C:18]([N:9]2[CH2:10][CH2:11][C@H:7]([N:6]([CH3:12])[CH3:5])[CH2:8]2)=[C:17]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:16]=1[CH3:37])#[N:14]
Reactant: CN(C)[C@H]1CCNC1
Reactant: CCN(C)C(=O)c1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCN(C)C(=O)c1nc2c(C#N)c(C)c(-c3ccccc3)c(N3CC[C@H](N(C)C)C3)c2o1
Reaction time: 2.75 h
Yield: 52.2 %

Procedure:
Under nitrogen atmosphere, a dimethyl sulfoxide (1 ml) solution of (3S)-3-(dimethylamino)pyrrolidine (80 μl, 633 μmol) was added at 140 to 150° C. to a dimethyl sulfoxide (10 ml) solution of 4-cyano-N-ethyl-7-fluoro-N,5-dimethyl-6-phenyl-1,3-benzoxazole-2-carboxamide (I-285) (178 mg, 528 μmol) and triethylamine (96 μl, 686 μmol), followed by stirring at the same temperature for 165 minutes. After cooling, saturated brine was added to the reaction liquid, and the reaction liquid was extracted with ethyl acetate. Next, the combined organic layer was washed with saturated brine, then dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under the reduced pressure. The resulting residue was purified by preparative TLC (eluent, dichloromethane:methanol=10:1, v/v) to obtain the entitled compound (119 mg, 52%) as an amorphous substance.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.[H-].[Na+].Br[CH2:13][C:14]1[CH:15]=[CH:16][C:17]2[C:21]([Cl:22])=[C:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[S:19][C:18]=2[CH:28]=1>CN(C)C=O>[Cl:22][C:21]1[C:17]2[CH:16]=[CH:15][C:14]([CH2:13][N:3]3[C:4]4[CH:5]=[N:6][CH:7]=[CH:8][C:9]=4[N:1]=[CH:2]3)=[CH:28][C:18]=2[S:19][C:20]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: c1cc2[nH]cnc2cn1
Reactant: CCOC(=O)c1sc2cc(CBr)ccc2c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc2cc(Cn3cnc4ccncc43)ccc2c1Cl
Reaction time: 0.67 h
Yield: 14.3 %

Procedure:
1H-Imidazo[4,5-c]pyridine (536 mg, 4.5 mmol) was added in portions to a stirred suspension of sodium hydride (144 mg of 60% dispersion in mineral oil, 3.6 mmol) in anhydrous dimethylformamide (5 ml) at 0° C., under a nitrogen atmosphere. After 40 minutes, ethyl 6-bromomethyl-3-chlorobenzo[b]thiophene-2-carboxylate (Preparation 10, 1 g, 3 mmol) was added. After 20 hours the mixture was partitioned between ethyl acetate and water. The organic layer was separated and washed with more water, dried (magnesium sulfate), and evaporated under reduced pressure. The residue was flash chromatographed on silica gel using 5% methanol in dichloromethane as eluant The fractions containing the less polar product (first isomer eluted from the chromatography column) were evaporated under reduced pressure to give the title compound as a colourless solid (160 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH2:13][C:6]3=[C:5]([CH:14]=O)[C:4]=2[CH:3]=1.C([O-])(=O)C.[NH4+].[N+:21]([CH2:24][CH3:25])([O-:23])=[O:22]>CO>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH2:13][C:6]3=[C:5]([CH:14]=[C:24]([N+:21]([O-:23])=[O:22])[CH3:25])[C:4]=2[CH:3]=1
Reactant: O=Cc1c2n(c3ccc(Cl)cc13)CCC2
Reactant: CC[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(=Cc1c2n(c3ccc(Cl)cc13)CCC2)[N+](=O)[O-]
Temperature: 25 °C
Yield: 46 %

Procedure:
A stirred solution of 7-chloro-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxaldehyde (1.0 g, 4.6 mmol) and ammonium acetate (0.4 g, 5.2 mmol) in nitroethane (10 mL) was heated to 100° C. for 1 h, cooled to room temperature, diluted with methanol (30 mL), cooled to 0° C., and filtered. The filter-cake was recrystallised (toluene) to give the product as yellow needles (0.58 g, 46%): mp 162-1623° C.; Found: C, 60.68; H, 4.67; N, 9.98%. C14H13ClN2O2 requires: C, 60.77; H, 4.73; N, 10.12%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10].C([Li])CCC.CCCCCC.[CH3:25][C:26]1([CH3:33])[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]1>O1CCCC1>[OH:32][C:29]1([C:3]2[C:2]([NH:7][C:8](=[O:13])[C:9]([CH3:10])([CH3:12])[CH3:11])=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:30][CH2:31][C:26]([CH3:33])([CH3:25])[CH2:27][CH2:28]1
Reactant: CC(C)(C)C(=O)Nc1ccccn1
Reactant: CC1(C)CCC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1(C)CCC(O)(c2cccnc2NC(=O)C(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 56.6 %

Procedure:
To a solution of N-(pyridin-2-yl)pivalamide (1.1 g, 6 mmol) in tetrahydrofurane (30 mL) was added at −78° C. under nitrogen and stirring a solution of 1.6M n-butyllithium in hexane (7.88 mL, 12.6 mmol). The reaction is exotherm and it turns light yellow. The reaction was stirred for 15 minutes at −78° C. and then for 2 hours at 0° C. The reaction was cooled to −78° C. and 4,4-dimethylcyclohexanone (937 mg, 7.2 mmol) dissolved in tetrahydrofurane (5 mL) was added dropwise. The reaction was warmed to room temperature over night. The reaction was quenched with saturated aqueous ammonium chloride solution and extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using ethyl acetate as the eluent to yield the title compound as a white powder (1.034 g, 57%).
Reaction SMILES: [N+:1]([C:4]1[CH:34]=[CH:33][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[CH2:21][N:22]2C(=O)C3=CC=CC=C3C2=O)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].O.NN>ClCCl.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[CH2:21][NH2:22])=[O:11])=[CH:33][CH:34]=1)([O-:3])=[O:2]
Reactant: CC(=O)S[C@H]1C[C@@H](CN2C(=O)c3ccccc3C2=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: NN
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: NC[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Yield: 104.1 %

Procedure:
To a solution of (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-phthalimidomethyl-4-acetylthiopyrrolidine (4.92 g: 10.18 mmole) in a mixture of dichloromethane (15 ml) and methanol (75 ml), hydrazine hydrate (1.53 ml: 3 eq.) is added. The mixture is warmed to remove dichloromethane and heated to reflux for 1 hour and 10 minutes. The reaction mixture is concentrated in vacuo. The residue is diluted with dichloromethane and filtered. The filtrate is washed with water, dried over magnesium sulfate, and concentrated in vacuo to give crude (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-aminomethyl-4-mercaptopyrrolidine (3.3 g). Yield: Quantitative.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[C:10]2[CH:9]=[C:8]3[N:11]=[C:12]([NH:14][C:15](=[O:22])[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[NH:13][C:7]3=[CH:6][C:5]=2[N:4]([CH2:23][CH2:24][CH:25]=O)[C:3]1=[O:27].Cl.[C:30]([O:34][NH2:35])([CH3:33])([CH3:32])[CH3:31]>CO.O>[C:30]([O:34][N:35]=[CH:25][CH2:24][CH2:23][N:4]1[C:5]2[CH:6]=[C:7]3[NH:13][C:12]([NH:14][C:15](=[O:22])[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)=[N:11][C:8]3=[CH:9][C:10]=2[C:2]([CH3:28])([CH3:1])[C:3]1=[O:27])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)ON
Reactant: CC1(C)C(=O)N(CCC=O)c2cc3[nH]c(NC(=O)c4ccccc4)nc3cc21
Agent: Cl
Solvent: CO
Solvent: O
Product: CC(C)(C)ON=CCCN1C(=O)C(C)(C)c2cc3nc(NC(=O)c4ccccc4)[nH]c3cc21
Yield: 11.8 %

Procedure:
A solution of N-[7,7-dimethyl-6-oxo-5-(3-oxo-propyl)-3,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl]-benzamide (50 mg) and O-tert-butyl-hydroxylamine hydrochloride (117 mg; 0.93 mmol) in MeOH (10 ml) and water (1 ml) is stirred at RT for 18 h. After evaporating to dryness the crude material is purified by preparative RP-HPLC eluting with MeCN/water to give the desired compound (7 mg).
Reaction SMILES: [CH:1]([N:3]([CH:12]1[CH:17]([CH2:18][CH3:19])[CH2:16][CH2:15][CH2:14][CH:13]1[CH2:20][CH3:21])[C:4](=[CH:10]O)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=O.Cl.C([NH2:25])=O>>[CH2:20]([CH:13]1[CH2:14][CH2:15][CH2:16][CH:17]([CH2:18][CH3:19])[CH:12]1[N:3]1[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:10][N:25]=[CH:1]1)[CH3:21]
Reactant: CCOC(=O)C(=CO)N(C=O)C1C(CC)CCCC1CC
Reactant: NC=O
Agent: Cl
Product: CCOC(=O)c1cncn1C1C(CC)CCCC1CC
Yield: 55 %

Procedure:
39.7 g (0.13 mol) of ethyl 2-(N-formyl-2,6-diethylcyclohexylamino)-3-hydroxy-acrylate, together with 240 ml of formamide and 24 ml of concentrated hydrochloric acid, were heated at 150° C. for 6 hours. After cooling, the mixture was extracted twice with diisopropyl ether, the organic phase was washed twice with water, dried over sodium sulfate and evaporated, and the residue was chromatographed over a silica gel column (mobile phase 7:3 petroleum ether (low-boiling)/ethyl acetate). 20.5 g (55% of theory) of ethyl 1-(2,6-diethylcyclohexyl)-imidazole-5-carboxylate was obtained as a colorless oil. Identification was effected by means of NMR spectroscopy.
Reaction SMILES: C([NH:8][C:9](=[O:22])[CH2:10][NH:11][C:12](=[O:21])[C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1C(O)=O)C1C=CC=CC=1.[ClH:23].[H][H]>C(O)(=O)C.[Pd]>[ClH:23].[NH:14]1[CH2:15][CH2:16][CH2:17][C@H:13]1[C:12]([NH:11][CH2:10][C:9]([NH2:8])=[O:22])=[O:21]
Reactant: O=C(CNC(=O)[C@@H]1CCCN1C(=O)O)NCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Product: NC(=O)CNC(=O)[C@@H]1CCCN1

Procedure:
A solution of 2-[(N-carboxy-L-prolyl)amino]acetamide N-benzyl ester (Ex. 9, 610 mg, 2 mmoles) in glacial acetic acid (8 ml) containing hydrogen chloride (2 mmoles) is agitated with palladium on charcoal (5%, 50 mg) in an atmosphere of hydrogen in the same manner as described in Example 6 until one molar equivalent of hydrogen has been consumed. Filtration, evaporation of the filtrate and drying of the residue under reduced pressure gives the title compound which is used as such in the subsequent step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:35])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]([S:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=1)(=[O:24])=[O:23])[CH2:17][C:18]([O:20][CH3:21])=[O:19].C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[Cl:15][C:13]1[CH:14]=[C:9]2[C:10](=[CH:11][CH:12]=1)[N:16]([S:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=1)(=[O:23])=[O:24])[CH:17]([C:18]([O:20][CH3:21])=[O:19])[C:8]2([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[OH:35]
Reactant: COC(=O)CN(c1ccc(Cl)cc1C(=O)c1ccccc1Cl)S(=O)(=O)c1ccc(OC)c(OC)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COC(=O)C1N(S(=O)(=O)c2ccc(OC)c(OC)c2)c2ccc(Cl)cc2C1(O)c1ccccc1Cl
Reaction time: 8 h

Procedure:
1.3 g of the compound obtained in step B are dissolved at 0° C. in 13 ml of DCM in the presence of 180 mg of DBU. After stirring overnight, the reaction medium is poured directly on to a silica column prepared in DCM and the mixture of compounds resulting from cyclization is thus separated by elution with DCM. Chromatography is then carried out on alumina using a DCM/isopropyl ether mixture (70/30, v/v) as the eluent. The cis isomer is thus isolated.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]#[N:8].[C:9]([OH:13])(=[O:12])[CH:10]=O.CC(C)([O-])C.[K+:19]>CO>[K+:19].[C:7]([C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[CH:10][C:9]([O-:13])=[O:12])#[N:8]
Reactant: N#CCc1cccs1
Reactant: O=CC(=O)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Product: N#CC(=CC(=O)[O-])c1cccs1
Temperature: 25 °C
Reaction time: 6 h
Yield: 70.3 %

Procedure:
To a stirring solution of thiophene-2-acetonitrile 20 (Aldrich, Milwaukee, Wis.) (80.6 g, 0.655 mol) in MeOH (1.3 L) was added glyoxylic acid (63.3 g, 0.688 mol). To the reaction solution was added portion-wise over 10 minutes potassium tert-butoxide (77.2 g, 0.688 mol). A nitrogen atmosphere was applied, and the solution was brought to reflux. After 6 h, the reaction was warmed to room temperature, filtered, and washed with copious amounts of MeOH. After drying under reduced pressure, 100 g of 21 as a white crystalline solid was obtained.