Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[C:5](=[O:10])[NH:6][CH:7]=[CH:8][CH:9]=1)[CH2:2][CH3:3].CC(C)([O-])C.[K+].F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:19]=1[O:27][CH3:28].O>CN(C=O)C>[CH3:28][O:27][C:19]1[CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=[CH:23][C:18]=1[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH2:1][CH2:2][CH3:3])[C:5]1=[O:10]
Reactant: COc1cc([N+](=O)[O-])ccc1F
Reactant: CCCc1ccc[nH]c1=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1cccn(-c2ccc([N+](=O)[O-])cc2OC)c1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
500 mg (3.65 mmol) of the product from example 51A are dissolved in 7.3 ml of DMF and cooled to 0° C. To this are added 613 mg (5.47 mmol) of potassium tert-butoxide, and the mixture is left to stir at RT for 30 min. Then 624 mg (3.65 mmol) of 1-fluoro-2-methoxy-4-nitrobenzene are added. The mixture is stirred at RT for 6 h, water is added and the mixture is extracted four times with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated. Purification is effected by preparative HPLC. The resulting product fraction is purified further by chromatography on silica gel (eluent: dichloromethane, then 10:1 dichloromethane/methanol). This affords 158 mg (15% of theory) of the desired compound as a solid.
Reaction SMILES: [CH:1]1[C:11]2[C:10](=[O:12])[C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:18]1(C)C=CC=CC=1.[Cl-].[NH4+]>>[OH:12][C:10]1([CH3:18])[C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=2[C:7](=[O:17])[NH:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]1=2
Reactant: O=c1[nH]c2ccccc2c(=O)c2ccccc12
Reactant: Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Product: CC1(O)c2ccccc2NC(=O)c2ccccc21
Reaction time: 0.17 h
Yield: 98 %

Procedure:
To a suspension of 5H-dibenzo[b,e]azepine-6,11-dione (2) (50 g, 0.22 mol) in toluene (800 mL) methyl magnesium iodide (3 M in Et2O, 200 mL, 0.6 mol) was added. The reaction mixture was heated under reflux for 6 h, then poured into aqueous ammonium chloride and stirred for 10 minutes. The product was filtered off and dried to give 11-hydroxy-11-methyl-5,11-dihydro-dibenzo[b,e]azepin-6-one (3) as a white solid (51.6 g, 96%). Data: (m/z)=240 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]([NH:14][CH3:15])=[O:13])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:10])[CH3:9].CN(C)[CH:18]=[O:19].[C:21]1(C)C=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1>[F:1][C:2]1[CH:3]=[C:4]([N:11]2[C:12](=[O:13])[N:14]([CH3:21])[CH2:15][O:19][CH2:18]2)[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:9])[CH3:10]
Reactant: Cc1ccccc1
Reactant: CN(C)C=O
Reactant: CNC(=O)Nc1ccc(C(C)C)c(F)c1
Agent: *CO*
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)c1ccc(N2COCN(C)C2=O)cc1F
Temperature: 80 °C
Yield: 82 %

Procedure:
N-(3-Fluoro-4-isopropyl-phenyl)-N'-methyl-urea (one mol=210 g.) and polyoxymethylene (1 mol=90 g.) are dissolved in toluene (800 cc.) in the presence of para-toluenesulphonic acid (0.3 mol=51.6 g.) as a catalyst and of dimethylformamide (0.3 mol=22 g.), and the mixture is heated for 15 minutes at 80° C. After having washed the solution with water and then concentrated it, 3-(3-fluoro-4-isopropyl-phenyl)-5-methyltetrahydro-1,3,5-oxadiazin-4-one is obtained in the form of an oil which is purified by dissolving in hot hexane and recrystallising.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[N:8]=[N:9][N:10]=[C:6]2[C:5]2[N:11]=[C:12]([CH2:29][CH2:30][CH3:31])[N:13]([CH2:14][CH2:15][CH2:16][S:17]([C:20]3[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C:4]=2[C:3]=1[CH3:32].C(Cl)(=O)C(Cl)=O.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>ClCCl>[CH3:1][C:2]1[N:7]2[N:8]=[N:9][N:10]=[C:6]2[C:5]2[N:11]=[C:12]([CH2:29][CH2:30][CH3:31])[N:13]([CH2:14][CH2:15][CH2:16][S:17]([C:20]3[CH:28]=[CH:27][C:23]([C:24]([N:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)=[O:26])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C:4]=2[C:3]=1[CH3:32]
Reactant: C1COCCN1
Reactant: CCCc1nc2c(c(C)c(C)n3nnnc23)n1CCCS(=O)(=O)c1ccc(C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CCCc1nc2c(c(C)c(C)n3nnnc23)n1CCCS(=O)(=O)c1ccc(C(=O)N2CCOCC2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 29.1 %

Procedure:
Under a nitrogen atmosphere, a mixture of 4-[3-(5,6-dimethyl-8-propyl-7H-imidazo[4,5-c]tetrazolo[1,5-a]pyridin-7-yl)propane-1-sulfonyl]benzoic acid (2.26 g, 4.95 mmol) and dichloromethane (50 mL) was cooled to 0° C. Oxalyl chloride (0.95 mL, 10.9 mmol) was added dropwise, and the reaction was stirred for two hours at room temperature. To one-third of the solution was added morpholine (0.43 mL, 4.9 mmol), and the reaction was stirred under nitrogen overnight. Additional morpholine (1.0 mL, 11 mmol) was added, and the reaction was stirred for two hours. A white precipitate formed, which was isolated by filtration, washed with ethyl acetate and water, and then dried for two hours in a vacuum oven at 80° C. to provide 0.75 g of {4-[3-(5,6-dimethyl-8-propyl-7H-imidazo[4,5-c]tetrazolo[1,5-a]pyridin-7-yl)propane-1-sulfonyl]phenyl}morpholin-4-ylmethanone as a white solid.
Reaction SMILES: [CH2:1]([N:7]=[C:8]=[S:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH2:10][CH:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:12].[CH2:18](I)[CH3:19].[OH-].[Na+]>C1(C)C=CC=CC=1.C(O)C>[CH:11]([NH:10][C:8](=[N:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[S:9][CH2:18][CH3:19])([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:12]
Reactant: CCI
Reactant: CCCCCCN=C=S
Reactant: CCCCCC(C)N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCCCCN=C(NC(C)CCCCC)SCC

Procedure:
The equipment, procedure and reactants were the same as in Example 31 with the exception that 10.01 g (0.07 mole) of n-hexylisothiocyanate, 8.05 g (0.07 mole) 2-aminoheptane, 35 ml ethanol 2B, 11.7 g (0.075 mole) ethyl iodide, 200 ml of toluene and a one percent solution sodium hydroxide (0.08 mole) were used as reactants and reagents in the procedure. The reaction produced 19.6 g (98 weight percent of theory yield of a clear liquid having a nD30 of 1.4765. The product was identified as the title product by IR and NMR spectra analyses.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[OH:11][C:12]1([NH3+:15])[CH2:14][CH2:13]1.C(N(CC)CC)C>O1CCCC1>[OH:11][C:12]1([NH:15][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:14][CH2:13]1
Reactant: O=C(Cl)c1ccccc1
Reactant: [NH3+]C1(O)CC1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NC1(O)CC1)c1ccccc1

Procedure:
Benzoyl chloride (4.2 g, 30 mmol) is added to a suspension of 1-hydroxycyclopropylammonium chloride (2.67 g, 24.5 mmol) in dry tetrahydrofuran. Triethylamine (6.5 g, 65 mmol) is added dropwise with stirring and ice-cooling (1 hr). The precipitate is filtered off and washed with tetrahydrofuran. The filtrate obtained is evaporated in vacuo. The crystalline residue is recrystallised from chloroform yielding N-(1-hydroxycyclopropyl)-benzamide, mp 153°-155° (3.0 g, 69%); NMR=δCDCl 3=0.87-1.38 (m, 4H), 4.7 (br. s, 1H), 7.3-7.9 (m, 6H, incl. NH).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[CH2:3]1.[C:11](Cl)(=[O:27])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(N([CH2:34][CH3:35])CC)C>C(Cl)Cl>[C:11]([O:8][C:6]1[CH2:7][C:2]([CH3:10])([CH3:1])[CH2:3][C:4](=[O:9])[C:5]=1[C:2]1[CH:7]=[CH:6][C:34]([CH3:35])=[CH:4][CH:3]=1)(=[O:27])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCN(CC)CC
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: CC1(C)CC(=O)CC(=O)C1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC(=O)OC1=C(c2ccc(C)cc2)C(=O)CC(C)(C)C1
Yield: 67 %

Procedure:
Using the procedure described in Example III and starting with 3.00 g (0.0130 mol) of 2-4'-methylphenyl)-5,5-dimethyl-1,3-cyclohexanedione, 2.69 g (0.0098 mol) of palmitoyl chloride, 2.63 g (0.0260 mol) of triethylamine, and 30 ml of methylene chloride, 3.1 g (67% yield) of a clear, colorless oil was obtained as the desired product.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[CH3:15][C:16]1[O:20][N:19]=[C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17]=1[C:27](Cl)=[O:28].C(N(CC)CC)C.C(OCC)(=O)C>ClCCl>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:27]([C:17]1[C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:19][O:20][C:16]=1[CH3:15])=[O:28]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: Cc1onc(-c2ccccc2)c1C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1onc(-c2ccccc2)c1C(=O)NCCc1c[nH]c2ccc(Cl)cc12
Yield: 23.5 %

Procedure:
This compound was obtained following Method B starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.0421 g, 0.179 mmol), 5-methyl-3-phenylisoxazole-4-carbonyl chloride (0.044 g; 0.179 mmol), and triethylamine (0.063 mL; 0.447 mmol) in dichloromethane (3 mL). Flash chromatography on silica gel eluting with 2 to 20% of ethyl acetate in dichloromethane gave 0.016 g (24%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-methyl-3-phenylisoxazole-4-carboxamide as a solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:29]=[CH:28][C:13]([O:14][CH:15]([C:19]2[CH:24]=[CH:23][C:22]3[O:25][CH2:26][O:27][C:21]=3[CH:20]=2)[C:16]([OH:18])=O)=[C:12]([CH2:30][CH2:31][CH3:32])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:45]([C:48]1[CH:53]=[CH:52][C:51]([S:54]([NH2:57])(=[O:56])=[O:55])=[CH:50][CH:49]=1)([CH3:47])[CH3:46].N12CCCN=C1CCCCC2>C1COCC1.CCOC(C)=O>[CH:45]([C:48]1[CH:49]=[CH:50][C:51]([S:54]([NH:57][C:16](=[O:18])[CH:15]([C:19]2[CH:24]=[CH:23][C:22]3[O:25][CH2:26][O:27][C:21]=3[CH:20]=2)[O:14][C:13]2[CH:28]=[CH:29][C:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:11][C:12]=2[CH2:30][CH2:31][CH3:32])(=[O:55])=[O:56])=[CH:52][CH:53]=1)([CH3:47])[CH3:46]
Reactant: CC(C)c1ccc(S(N)(=O)=O)cc1
Reactant: CCCc1cc(CO[Si](C)(C)C(C)(C)C)ccc1OC(C(=O)O)c1ccc2c(c1)OCO2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCCc1cc(CO[Si](C)(C)C(C)(C)C)ccc1OC(C(=O)NS(=O)(=O)c1ccc(C(C)C)cc1)c1ccc2c(c1)OCO2
Temperature: 25 °C
Yield: 69.4 %

Procedure:
To a solution of 3.30 g (7.21 mmol) of the crude product from Step C dissolved in 40 mL of anhydrous THF was added 1.75 g (10.8 mmol) of 1,1'-carbonyldiimidazole and the reaction mixture was magnetically stirred and heated at reflux for 10 minutes. The reaction was then cooled to room temperature, 2.15 g (10.8 mmol) of 4-iso-propylbenzenesulfonamide and 1.61 mL (10.8 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene were added and the reaction was stirred for an additional 30 minutes at room temperature. The mixture was then diluted with EtOAc (80 mL), washed with 10% aqueous citric acid, saturated aqueous NaCl, dried (MgSO4), filtered and evaporated. The residue was partially purified on a silica gel flash chromatography column eluted with CHCl3 --MeOH--NH4OH (92:8:0.5). The semi-purified material was combined and repurified on a second silica gel flash chromatography column eluted initially with 35% EtOAc-hexane, later with 50% EtOAc-hexane, and finally with 70% EtOAc-hexane. Combination of the purified fractions and evaporation afforded 3.20 g (69%) of the title compound as a yellow oil.
Reaction SMILES: C[C:2]([CH2:4][C:5]([CH3:8])([CH3:7])C)=C.[CH2:9]=C>>[CH3:9][C:4]([CH3:2])=[C:5]([CH3:7])[CH3:8].[CH3:8][CH:5]([C:4]([CH3:2])=[CH2:9])[CH3:7]
Reactant: C=C
Reactant: C=C(C)CC(C)(C)C
Product: C=C(C)C(C)C
Product: CC(C)=C(C)C

Procedure:
contacting diisobutylene and ethylene under disproportionation conditions in the presence of disproportionation catalyst to form a product mixture comprising 3,3-dimethylbutene-1(neohexene), 2,3-dimethylbutene-2, and 2,3-dimethylbutene-1 and
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N+]([O-])(O)=O.[C:11]1([NH:17][C:18]([NH2:20])=[NH:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:21][C:22]1[O:29]C(=O)[CH:26]([C:30]([CH3:32])=O)[C:24](=O)[CH:23]=1.Cl>CN(C)C=O>[NH:17]([C:18]1[N:20]=[C:30]([CH3:32])[CH:26]=[C:24]([CH2:23][C:22]([CH3:21])=[O:29])[N:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N=C(N)Nc1ccccc1
Reactant: CC(=O)C1C(=O)C=C(C)OC1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=[N+]([O-])O
Product: CC(=O)Cc1cc(C)nc(Nc2ccccc2)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 49.9 %

Procedure:
Into a 500 ml reaction flask equipped with a stirrer, a thermometer and a condenser, 200 ml of dimethylformamide, 13.8 g (0.1 mol) of potassium carbonate, 39.6 g (0.2 mol) of phenylguanidine nitrate and 33.6 g (0.2 mol) of dehydroacetic acid were charged, and the reaction was conducted at 140° C. for 3 hours. After completion of the reaction, the reaction solution was cooled and put into ice water. Then, the reaction solution was extracted with toluene and washed with water. Then, 21 g (0.2 mol) of concentrated hydrochloric acid was dropwise added thereto. Precipitated crystals were collected by filtration, washed with toluene, then neutralized with an aqueous sodium carbonate solution and again extracted with toluene. This toluene layer was washed with water and concentrated to obtain 24.1 g of 2-anilino-4-methyl-6-acetonyl-pyrimidine having a melting point of from 77° to 80° C. The yield was 50%.
Reaction SMILES: Br[C:2]1[C:3]([F:20])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]1([CH3:17])[CH2:16][CH2:15][CH2:14]1)[N:8]([CH3:18])[C:7]2=[O:19].[CH3:21][C@@H:22]1[C:26]2[NH:27][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:29][C:25]=2[C:24](=[O:39])[NH:23]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1>[F:20][C:3]1[C:2]([C:28]2[NH:27][C:26]3[C@@H:22]([CH3:21])[NH:23][C:24](=[O:39])[C:25]=3[CH:29]=2)=[C:11]2[C:6]([C:7](=[O:19])[N:8]([CH3:18])[C:9]([NH:12][C:13]3([CH3:17])[CH2:16][CH2:15][CH2:14]3)=[N:10]2)=[CH:5][CH:4]=1
Reactant: Cn1c(NC2(C)CCC2)nc2c(Br)c(F)ccc2c1=O
Reactant: C[C@H]1NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)[nH]c21
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H]1NC(=O)c2cc(-c3c(F)ccc4c(=O)n(C)c(NC5(C)CCC5)nc34)[nH]c21
Temperature: 80 °C
Yield: 17.3 %

Procedure:
A mixture of 8-bromo-7-fluoro-3-methyl-2-((1-methylcyclobutyl)amino)quinazolin-4(3H)-one (502a, 120 mg, 0.353 mmol), (R)-6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (705, 237 mg, 0.705 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)-dichloropalladium (II) (12.49 mg, 0.018 mmol), and potassium phosphate (225 mg, 1.058 mmol) in 1,4-dioxane (2.82 mL)/water (0.70 mL) was sparged with nitrogen for 3 min at RT; the red reaction mixture was then heated to 80° C. for 45 min. The reaction mixture was diluted with EtOAc (100 mL), added to a separatory funnel, and washed with saturated aqueous NaHCO3 (2×100 mL); the organic layer was separated, dried over Na2SO4, and concentrated. The crude product was loaded onto the column and was purified via automated flash chromatography (silica gel) with 0-5% 2 M ammonia in MeOH/DCM to give (R)-7-fluoro-3-methyl-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-2((1-methylcyclobutyl)amino)quinazolin-4(3H)-one (502, 24 mg, 0.061 mmol, 17% yield) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.58 (s, 3H) 1.78 (s, 3H) 1.98-2.15 (m, 2H) 2.27-2.42 (m, 3H) 2.42-2.52 (m, 1H) 3.56 (s, 3H) 4.69 (q, J=6.65 Hz, 1H) 5.08 (s, 1H) 6.01 (s, 1H) 7.00 (dd, J=11.54, 8.80 Hz, 1H) 7.08 (d, J=4.11 Hz, 1H) 8.01 (dd, J=8.80, 6.06 Hz, 1H) 12.76 (br. s., 1H). 19F NMR (376 MHz, CDCl3) δ ppm −99.57 (s, 1F). MS (ESI, pos. ion) m/z: 369.0 (M+1).
Reaction SMILES: [NH2:1][C:2]1[NH:30][CH2:29][C:28]2[CH:31]=[C:32]([Cl:33])[C:25](=[C:26]([Cl:34])[CH:27]=2)[NH:24][C:23](=[O:35])[CH2:22][NH:21][CH2:20][CH2:19][CH2:18][CH:17]=[CH:16][CH2:15][O:14][C:13]2[CH:36]=[CH:37][C:10](=[CH:11][CH:12]=2)[C:9]2[C:5](=[C:6]([CH3:38])[S:7][N:8]=2)[C:4](=[O:39])[N:3]=1.[CH:40](=O)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(OC)(OC)OC>C(O)(=O)C>[NH2:1][C:2]1[NH:30][CH2:29][C:28]2[CH:27]=[C:26]([Cl:34])[C:25](=[C:32]([Cl:33])[CH:31]=2)[NH:24][C:23](=[O:35])[CH2:22][N:21]([CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:20][CH2:19][CH2:18][CH:17]=[CH:16][CH2:15][O:14][C:13]2[CH:12]=[CH:11][C:10](=[CH:37][CH:36]=2)[C:9]2[C:5](=[C:6]([CH3:38])[S:7][N:8]=2)[C:4](=[O:39])[N:3]=1
Reactant: Cc1snc2c1C(=O)N=C(N)NCc1cc(Cl)c(c(Cl)c1)NC(=O)CNCCCC=CCOc1ccc-2cc1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: COC(OC)OC
Product: Cc1snc2c1C(=O)N=C(N)NCc1cc(Cl)c(c(Cl)c1)NC(=O)CN(Cc1ccccc1)CCCC=CCOc1ccc-2cc1

Procedure:
The cis/trans mixture of the title compound of 9-amino-14,32-dichloro-5-methyl-26-oxa-4-thia-3,8,10,16,19-pentaazatetracyclo[25.2.2.212,15.02,6]tritriaconta-1(29),2,5,8,12,14,23,27,30,32-decaene-7,17-dione (Example 4) (60 mg), benzaldehyde (24 mg), sodium triacetoxyborohydride (30 mg), trimethyl orthoformate (0.2 mL) and acetic acid (0.1 mL), in 2 mL of DMF was stirred at room temperature for 16 hrs. Ethyl acetate (10 mL) and saturated sodium bicarbonate solution (10 mL) were added. Layers were separated after the mixture was well shaken. The organic layer was dried over anhydrous magnesium sulfate and solvent was evaporated in vacuo to give a crude product, which was purified by preparative HPLC to give 27 mg of the title compound as an inseparable mixture of cis/trans isomers.
Reaction SMILES: [CH3:1]I.[NH2:3][N:4]1[C:9](=[O:10])[C:8]([CH:11]([CH2:13][CH3:14])[CH3:12])=[N:7][NH:6][C:5]1=[S:15].[OH-].[Na+]>O>[NH2:3][N:4]1[C:9](=[O:10])[C:8]([CH:11]([CH2:13][CH3:14])[CH3:12])=[N:7][N:6]=[C:5]1[S:15][CH3:1]
Reactant: CCC(C)c1n[nH]c(=S)n(N)c1=O
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCC(C)c1nnc(SC)n(N)c1=O
Yield: 96 %

Procedure:
66 ml of methyl iodide were added to a solution of 200 g of 4-amino-6-sec.-butyl-3-thioxo-1,2,4-triazin-5(2H,4H)-one in a solution of 40 g of sodium hydroxide in 1 liter of water, at 20° C, whilst stirring. When the slightly exothermic reaction had subsided, stirring was continued until the pH value reached 7 - 8 and the reaction product which had crystallized out was filtered off and washed with cold water. After drying, 205 g (96%) of 4-amino-6-sec.-butyl-3-methylthio-1,2,4-triazin-5(4H)-one were obtained, melting point 60° C (from carbon tetrachloride/petroleum ether).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:12]2[N:13]([N:17]=[C:18]([NH2:20])[N:19]=2)[CH:14]=[CH:15][CH:16]=1)(=[O:4])=[O:3].Br[C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:12]2[N:13]([N:17]=[C:18]([NH:20][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N:28]4[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]4)[CH:23]=3)[N:19]=2)[CH:14]=[CH:15][CH:16]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccccc1-c1cccn2nc(N)nc12
Reactant: CN1CCN(c2cccc(Br)c2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2cccc(Nc3nc4c(-c5ccccc5S(C)(=O)=O)cccn4n3)c2)CC1

Procedure:
[8-(2-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from 8-(2-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75.0 mg, 0.260 mmol) and 1-(3-bromo-phenyl)-4-methyl-piperazine (80.0 mg, 0.314 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (30.0 mg, 0.0549 mmol) as the ligand in a manner analogous to Step 2d and was isolated as a yellow foam (0.074 g, 62%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.49 m (d, J=6.6 Hz, 1H), 8.24 (d, J=7.9 Hz, 1H), 7.74 (t, J=6.8 Hz, 1H), 7.67 (t, J=7.8 Hz, 1H), 7.49 (d, J=7.3 Hz, 2H), 7.29-7.25 (m, 1H), 7.19 (t, J=7.8 Hz, 1H), 6.99 (t, J=6.9 Hz, 1H), 6.90 (d, J=7.9 Hz, 1H), 6.73 (s, 1H), 6.57 (d, J=8.2 Hz, 1H), 3.24-3.19 (m, 4H), 2.96 (s, 3H), 2.59-2.54 (m, 4H), 2.36 (s, 3H). MS=463 (MH)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][N:7](C(OC(C)(C)C)=O)[C@H:6]([C:16]2[NH:20][C:19]3[C:21]4[C:26]([CH:27]=[CH:28][C:18]=3[N:17]=2)=[CH:25][C:24]2[C:29]3[C:34]([CH2:35][O:36][C:23]=2[CH:22]=4)=[CH:33][C:32]([B:37]2[O:41][C:40]([CH3:43])([CH3:42])[C:39]([CH3:45])([CH3:44])[O:38]2)=[CH:31][CH:30]=3)[CH2:5]1.Cl>C(O)C>[CH3:1][O:2][CH2:3][CH:4]1[CH2:8][NH:7][CH:6]([C:16]2[NH:20][C:19]3[C:21]4[C:26]([CH:27]=[CH:28][C:18]=3[N:17]=2)=[CH:25][C:24]2[C:29]3[C:34]([CH2:35][O:36][C:23]=2[CH:22]=4)=[CH:33][C:32]([B:37]2[O:41][C:40]([CH3:43])([CH3:42])[C:39]([CH3:45])([CH3:44])[O:38]2)=[CH:31][CH:30]=3)[CH2:5]1
Reactant: COC[C@H]1C[C@@H](c2nc3ccc4cc5c(cc4c3[nH]2)OCc2cc(B3OC(C)(C)C(C)(C)O3)ccc2-5)N(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCO
Product: COCC1CNC(c2nc3ccc4cc5c(cc4c3[nH]2)OCc2cc(B3OC(C)(C)C(C)(C)O3)ccc2-5)C1
Reaction time: 2 h

Procedure:
Tert-butyl (2S,4S)-4-(methoxymethyl)-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′: 6,7]naphtho[1,2-d]imidazol-2-yl]pyrrolidine-1-carboxylate (310 mg, 0.507 mmol) was treated with 2 mL 1.25N HCl in ethanol and stirred at room temperature for 2h then at 50° C. for 2h. The reaction mixture was concentrated under reduced pressure to give a dark yellow solid that was directly in the next step.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[NH2:20][C@H:21]([CH:24]([CH3:26])[CH3:25])[CH2:22][OH:23].CCN(C(C)C)C(C)C>>[OH:23][CH2:22][C@H:21]([NH:20][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1)[CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)[C@@H](N)CO
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H](CO)NC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, (R)-2-amino-3-methyl-butan-1-ol and DIEA to give 2-((R)-1-hydroxymethyl-2-methyl-propylamino)-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 342 (MH+).
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[N:5]([C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:4]1.[N+:22]([O-])([OH:24])=[O:23]>C(Cl)Cl>[Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][C:14]([N+:22]([O-:24])=[O:23])=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[N:5]([C:16](=[O:21])[C:17]([F:20])([F:18])[F:19])[CH2:4]1
Reactant: O=[N+]([O-])O
Reactant: O=C(N1CC(CCl)c2c1ccc1ccccc21)C(F)(F)F
Solvent: ClCCl
Product: O=C(N1CC(CCl)c2c1ccc1cc([N+](=O)[O-])ccc21)C(F)(F)F
Temperature: 25 °C
Yield: 38.6 %

Procedure:
A stirred solution of 108 (5.24 g, 16.7 mmol) in dry CH2Cl2 (70 mL) was treated dropwise at 10° C. with fuming HNO3 (2.0 mL, 48 mmol) and then warmed to room temperature for 5 min. The mixture was diluted with CH2Cl2 (100 mL) and the resulting solution was washed with water, dried, filtered through a column of silica gel, then concentrated to 25 mL and diluted with EtOAc (25 mL). Following refrigeration the precipitate was collected and washed with EtOAc to give 1-(chloromethyl)-3-(trifluoroacetyl)-7-nitro-1,2-dihydro-3H-benzo[e]indole (131) (2.31 g, 39%) as a pale yellow solid: mp (CH2Cl2/iPr2O) 213-214° C.; 1H NMR [(CD3)2SO] δ 9.06 (s, 1H), 8.48 (d, J=9.0 Hz, 1H), 8.36 (d, J=9.1 Hz, 1H), 8.33-8.25 (m, 2H) 4.67-4.51 (m, 2H), 4.46 (br d, J=10.6 Hz, 1H), 4.17 (dd, J=11.3, 3.0 Hz, 1H), 4.07 (dd, J=11.3, 5.5 Hz, 1H). Anal. (C15H10ClF3N2O3) C, H, N.