Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([CH3:14])=[C:12]([C:15]([OH:17])=O)[N:11]=[N:10]1.C(Cl)(=O)C(Cl)=O.CN(C=O)C.[NH2:29][C:30]1[C:31](=[O:44])[N:32]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[F:43])[N:33]([CH3:36])[C:34]=1[CH3:35].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([CH3:14])=[C:12]([C:15]([NH:29][C:30]2[C:31](=[O:44])[N:32]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[F:43])[N:33]([CH3:36])[C:34]=2[CH3:35])=[O:17])[N:11]=[N:10]1
Reactant: Cc1c(C(=O)O)nnn1-c1ccc(Cl)cc1Cl
Reactant: Cc1c(N)c(=O)n(-c2ccccc2F)n1C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Nc2c(C)n(C)n(-c3ccccc3F)c2=O)nnn1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-(2,4-dichlorophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid (100 mg, 0.368 mmol), oxalyl chloride (0.048 ml, 0.551 mmol) and DMF (0.057 ml, 0.735 mmol) in DCM (5 ml) was stirred at RT for 15 mins. 4-Amino-2-(2-fluorophenyl)-1,5-dimethyl-1H-pyrazol-3(2H)-one (Intermediate B) (89 mg, 0.404 mmol) was added followed by triethylamine (0.154 ml, 1.103 mmol) and the mixture was stirred at RT for 30 mins. The resulting mixture was diluted with DCM, washed with 0.1M HCl(aq) and sat. NaHCO3(aq) and the organic extracts were passed through a phase separating cartridge and concentrated under reduced pressure. The resultant brown oil was absorbed onto silica and purified by chromatography eluting with 0-10% MeOH in TBME. The product fractions were combined and concentrated under reduced pressure to give a pale pink solid which was triturated with diethylether. The resulting solid was collected by filtration and dried in the vacuum oven to give the title compound as a pale pink solid.
Reaction SMILES: CC1(C)CCC2C(=CC=CC=2)N1.[CH2:13]([C:15]1([CH2:25][CH3:26])[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16]1)[CH3:14]>CCOC(C)=O.[Pd]>[CH2:25]([C:15]1([CH2:13][CH3:14])[CH2:24][CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16]1)[CH3:26]
Reactant: CCC1(CC)C=Cc2ccccc2N1
Agent: [Pd]
Agent: CC1(C)CCc2ccccc2N1
Solvent: CCOC(C)=O
Product: CCC1(CC)CCc2ccccc2N1
Yield: 70.4 %

Procedure:
This compound was prepared in a manner similar to that described for 1,2,3,4-tetrahydro-2,2-dimethylquinoline (structure 18 of Scheme III, where R1=R2=Me) from 2,2-diethyl-1,2-dihydroquinoline (1.46 g, 7.80 mmol) and 10% Pd/C (146 mg, 10% by weight) in EtOAc (18.7 mL) to afford 1.04 g (70%) 2,2-diethyl-1,2,3,4-tetrahydroquinoline after flash chromatography (hexanes:EtOAc, 97:3). Data for 2,2-diethyl-1,2,3,4-tetrahydroquinoline: Rf 0.43 (24:1 hexanes:ethyl acetate); 1H NMR (400 MHz, CDCl3) 6.90-7.00 (m, 2H), 6.57 (td, J=7.3, 1.0, 1H), 6.46 (dd, J=8.4, 1.0, 1H), 3.63 (broad s, 1H), 2.72 (t, J=6.7, 2H), 1.69 (t, J=6.7, 2H), 1.38-1.53 (m, 4H), 0.86 (t,J=7.4, 6H).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C(=NC1CCCCC1)C.[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)=[C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])C=O)=[CH:21][CH:20]=1.[O:40]1C[CH2:43][CH2:42][CH2:41]1>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([C:33]2[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=2)=[C:26]([C:29]([CH3:31])([CH3:32])[CH3:30])[CH:43]=[CH:42][CH:41]=[O:40])=[CH:21][CH:20]=1
Reactant: C1CCOC1
Reactant: CC(C)(C)C(C=O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: CC(C)[N-]C(C)C
Agent: CC=NC1CCCCC1
Agent: [Li+]
Product: CC(C)(C)C(C=CC=O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: -50 °C
Reaction time: 0.5 h

Procedure:
Lithium diisopropylamide (5.4 mL of 1.84M solution, 10 mmol) was added to N-ethylidenecyclohexanamine (5 mL of 2M solution, 10 mmol) in tetrahydrofuran at -20° C. After stirring for 30 minutes and further cooling to -50° C., 3,3-bis(4-fluorophenyl)-2-(1,1-dimethylethyl)propenal (0.9 g, 3.0 mmol) was added and the solution stirred for 4 hours during which time the temperature was allowed to rise to -20° C. The solution was quenched with 2N hydrochloric acid and the mixture extracted with diethyl ether. The extracts were dried and concentrated in vacuo. The residue was stirred for 18 hours with a mixture of 50 mL benzene, 15 mL of water and 35 mL of acetic acid. The mixture was diluted to 200 mL with water. The organic layer was separated, washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica eluting with 1% ethyl acetate in hexane to give 0.5 g of the title compound; m.p. =87°-89° C.
Reaction SMILES: [CH:1]1([N:7]([C:11](Cl)=[O:12])[C:8](Cl)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.I.[CH3:15][S:16][C:17](=[NH:23])[NH:18][N:19]=[C:20]([CH3:22])[CH3:21]>C(N(CC)CC)C>[CH:1]1([N:7]2[C:11](=[O:12])[NH:23][CH:17]([S:16][CH3:15])[N:18]([N:19]=[C:20]([CH3:22])[CH3:21])[C:8]2=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)N(C(=O)Cl)C1CCCCC1
Reactant: CSC(=N)NN=C(C)C
Agent: I
Solvent: CCN(CC)CC
Product: CSC1NC(=O)N(C2CCCCC2)C(=O)N1N=C(C)C

Procedure:
Analogously to Example 1, N-cyclohexyl-bis-(chloro-carbonyl)-amine (prepared analogously to Snythesis 1970, pages 542-543; boiling point 80°-82° C/0.3 mm Hg) and acetone-S-methylisothiosemicarbazone hydroiodide, with addition of triethylamine, yielded 1-cyclohexyl-3-isopropylideneamino-4-methylmercaptotetrahydro- 1,3,5-triazine-2,6-dione as a pale yellow powder of melting point 111°-112° C.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH:6]=O.[CH3:17][C:18]([S@@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19].O>C(Cl)Cl>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH:6]=[N:23][S@:21]([C:18]([CH3:20])([CH3:19])[CH3:17])=[O:22]
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)(C)[S@@](N)=O
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[S@](=O)N=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 83.9 %

Procedure:
To a mixture of 3,5-bis(trifluoromethyl)benzaldehyde (5 g, 20.7 mmol) and (S)-2-methylpropane-2-sulfinamide (3 g, 24.8 mmol) in DCM (50 ml) at 0° C., was drop wise added Ti(O-iPr)4 (5.9 g, 24.8 mmol) under N2 atmosphere. After stirring for 20 h at room temperature, the reaction mixture was poured into water (100 mL) with vigorous stirring. The precipitate was filtered and the filtrate was extracted with DCM (2×150 mL). The combined organic layers were washed with brine (80 mL), dried over anhydrous MgSO4, and then concentrated. The residue was purified by silica gel chromatography (PE/EtOAc=5/1 to 2/1) to give the title compound (6 g, yield: 84%); m/z (ES+): 346 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]([CH3:14])([CH3:13])[C:11]#N)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].CC(C[AlH]CC(C)C)C.Cl.C1C[O:28]CC1>>[Br:1][C:2]1[CH:3]=[C:4]([C:10]([CH3:14])([CH3:13])[CH:11]=[O:28])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C(C)(C)C#N)cc1Br
Reactant: C1CCOC1
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Product: COc1ccc(C(C)(C)C=O)cc1Br
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-(3-bromo-4-methoxy-phenyl)-2-methyl-propionitrile (12.71 g, 0.050 mol) in dry THF (100 mL) was cooled to −10° C. under argon. DIBALH (1M in THF, 100 mL, 0.10 mol) was added keeping the temperature below 0° C. The mixture was stirred for 30 min/0° C. and then 2 h/25° C. The clear solution was carefully poured into icecold hydrochloric acid (2M, 100 mL). The THF was removed under reduced pressure to give clear oil. The oil was destilled (b.p. 114-130° C./4.3×10−3 mbar) Yield: 7.40 g (58%). GCMS: >99%
Reaction SMILES: BrBr.[C:3]([O-:6])(=[O:5])[CH3:4].[K+].[CH2:8]=[CH:9][CH:10]=[CH2:11]>C(O)(=O)C>[C:3]([O:6][C:9]([CH3:8])=[C:10]([O:6][C:3](=[O:5])[CH3:4])[CH3:11])(=[O:5])[CH3:4]
Reactant: CC(=O)[O-]
Reactant: C=CC=C
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: CC(=O)OC(C)=C(C)OC(C)=O
Temperature: 123 °C

Procedure:
A 5-liter round-bottom flask was fitted with a heating mantle, stirrer, reflux condenser, thermowell, gas inputs and a burette for bromine addition via an electrically heated vaporizer. To the flask was charged 416.8 grams of glacial acetic acid and 98.2 grams potassium acetate. Nitrogen diluent was passed through the vaporizer and above the surface of the liquid at about 1.5 liters per hr. while the contents of the flask were heated to about 123° C. Butadiene was added at a rate of about 4 liters/hr in the vapor phase above the liquid level of the flask. Bromine was slowly added at a rate of about 3 milliliters per hour into the stream of nitrogen diluent, vaporized in the vaporizer and contacted with butadiene in the vapor phase above the liquid level of the flask. The reaction product of bromine and butadiene liquified in the condenser and dropped back into the rapidly stirred liquid phase of potassium acetate and acetic acid whereupon the dibromobutene-2 reacted with potassium acetate to form diacetoxy-2-butene. A total of 63.7 grams of bromine was added in the above-described manner over a five hour period. The temperature of the liquid layer within the flask was maintained about 122° to 126° C. during the reaction. After the addition of bromine was complete, the liquid layer was stirred for about one hour and cooled to ambient room temperature. At this point the products can be separated by distillation. A more rapid means of product analysis is by gas-liquid chromatography (GLC) using a 3.048 m (10 ft) chromatographic column filled with CS-10 packing (Cyanosilicon, Analabs, Inc.) and programed between 150° C. to 220° C. at a rate of 20° C./minute. Approximately 508 grams of effluent was mixed with 35 grams of an internal standard, hexyl acetate, and the stirring stopped to allow all undissolved salts (mainly potassium bromide) to settle. An aliquot sample of the liquid phase was analyzed by GLC as shown:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[C:5]3[CH:16]=[CH:15][S:14][C:6]=3[NH:7][C:8](=[O:13])[C:9]=2[CH:10]=[CH:11][CH:12]=1.[Cl-:17].[CH3:18][N+:19](=[CH2:21])[CH3:20]>CN(C=O)C.CC#N>[ClH:17].[CH3:18][N:19]([CH2:21][C:15]1[S:14][C:6]2[NH:7][C:8](=[O:13])[C:9]3[CH:10]=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[C:4]=3[C:5]=2[CH:16]=1)[CH3:20]
Reactant: C=[N+](C)C
Reactant: [Cl-]
Reactant: COc1cccc2c(=O)[nH]c3sccc3c12
Solvent: CC#N
Solvent: CN(C)C=O
Product: COc1cccc2c(=O)[nH]c3sc(CN(C)C)cc3c12
Product: Cl
Yield: 83 %

Procedure:
9-Methoxythieno[2,3-c]isoquinolin-5(4H)-one (Pellicciari, R., et al., Farmaco, 2003, 58, 851-858) (0.20 g, 0.86 mmol), was dissolved in a mixture of dry DMF (1 ml) and dry MeCN (2 ml) and treated with N,N-dimethyl(methylene)ammonium chloride (1.2 mmol) prepared according to a known procedure (Kinast, G. et al. Angew. Chem. Int. Ed. Engl. 1976, 15, 239-240. Bohme, H et al. Chem. Ber. 1960, 93, 1305). The reaction mixture was refluxed overnight. The formed solid was then filtered and washed with dry diethyl ether to give title compound (83% yield) as a solid. mp 264-265° C.
Reaction SMILES: Cl.C[O:3][C:4](=O)[C@H:5]([CH3:7])[NH2:6].[C:9]1([Mg]Br)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1COCC1>[NH2:6][C@@H:5]([CH3:7])[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[OH:3]
Reactant: COC(=O)[C@H](C)N
Reactant: Br[Mg]c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: C[C@H](N)C(O)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 7.2 %

Procedure:
L-Alanine methyl ester hydrochloride (9.9 g, 70.9 mmol) was added portionwise to a 1.0 M solution of phenylmagnesium bromide (78.0 g, 0.43 mol) in THF at 0° C. and then heated under reflux for 21 h. The reaction mixture was cooled to 0° C., quenched with dropwise addition of saturated NH4Cl, and stirred for 1 h. After collecting insoluble products through the Buchner funnel, organic products were extracted into AcOEt (3×100 ml). The combined organic extracts were dried over K2CO3/MgSO4, and concentrated under reduced pressure to obtain a crude product. Impurities were washed with dichloromethane over silica gel by means of dry-flash column chromatography, further elution with a mixture of AcOEt and petrol, ranging from 20% up to 100%, gave the title compound (10) (1.16 g, 9%) as a white solid. m.p. 100–101° C. (litii,v 100–102° C.). [α]D25=−85.59° (c, 0.0362 in CHCl3) (litii: −82.38° (c, 0.814 in CHCl3; litv: −85.9° (c, 2.77 in CHCl3). δH 0.94 (3H, d, 3J=6.30 Hz, CH3), 1.23 (2H, broad s, NH2), 4.15 (1H, q, 3J=6.30 Hz, CH—NH2), 4.25 (1H, broad s, OH), 7.10–7.66 (10H, m, Ar—H). δC 17.4 (CH3), 52.1 (CH—NH2), 78.7 (C—OH), 125.7, 126.1, 126.6, 126.9, 128.2 and 128.7 (o-, m- and p-Ar), 145.0 and 147.2 (α-Ar). Anal. Calcld. for C15H17NO: C 79.26; H 7.54; N 6.16. Found: C 79.30; H 7.66; N 6.27. ir 3432 (OH), 3389 (NH2). m/e (CI—NH3) 228 (MH+, 100%).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[C:9](=[O:25])[O:10][C:11]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[C:12]=2[C:13]=1[CH3:14])(=O)=O.[C:26]1([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CC(OC)(C)C.C(O)(C)C>[CH3:24][O:23][C:15]1[C:12]2[C:13]([CH3:14])=[C:8]([CH2:7][CH2:6][N:35]3[CH2:36][CH2:37][CH:32]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:33][CH2:34]3)[C:9](=[O:25])[O:10][C:11]=2[CH:18]=[C:17]([O:19][CH3:20])[C:16]=1[O:21][CH3:22]
Reactant: COc1cc2oc(=O)c(CCOS(C)(=O)=O)c(C)c2c(OC)c1OC
Reactant: c1ccc(C2CCNCC2)cc1
Solvent: COC(C)(C)C
Solvent: CC(C)O
Product: COc1cc2oc(=O)c(CCN3CCC(c4ccccc4)CC3)c(C)c2c(OC)c1OC
Yield: 27 %

Procedure:
Process B; starting materials: 3-[2-(methanesulphonyloxy)ethyl]-5,6,7-trimethoxy-4-methyl-2H-1-benzopyran-2-one (Example 34) and 4-phenylpiperidine; yield 27%; m.p. 117°-118° C. (from TBME/isopropanol).
Reaction SMILES: C([O:3][C:4](=[O:46])[CH:5]([N:24]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:25]([C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:29][CH:28]=1)=[O:26])[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([C:19]([O:21]CC)=[O:20])([CH3:18])[CH3:17])=[CH:11][CH:10]=1)C.[OH-].[Na+].Cl>O1CCOCC1>[CH2:39]([N:24]([C:25]([C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[CH:29][CH:28]=1)=[O:26])[CH:5]([CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([C:19]([OH:21])=[O:20])([CH3:18])[CH3:17])=[CH:11][CH:10]=1)[C:4]([OH:46])=[O:3])[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: CCOC(=O)C(CCOc1ccc(OC(C)(C)C(=O)OCC)cc1)N(Cc1ccccc1)C(=O)c1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(Oc1ccc(OCCC(C(=O)O)N(Cc2ccccc2)C(=O)c2ccc(-c3ccccc3)cc2)cc1)C(=O)O
Temperature: 60 °C
Yield: 110.5 %

Procedure:
A sample of 2-[benzyl-(biphenyl-4-carbonyl)-amino]-4-[4-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenoxy]-butyric acid ethyl ester (687 mg, 1.10 mmol) was dissolved in 5 mL of dioxane followed by addition of 5.0 N NaOH (2.3 mL, 11.6 mmol). The mixture was magnetically stirred and heated at 60° C. for 7 hours. The reaction mixture was allowed to cool to room temperature followed by addition of 1.0 N HCl (12 mL, 12 mmol) then partitioned by addition of methylene chloride (50 mL). The organic phase was separated, dried over sodium chloride and concentrated under reduced pressure to yield 690 mg (˜100%) of a glassy solid. HPLC RT1=2.24 min; 1H NMR (400 MHz, CDCl3) δ 12.82 (broad s, 2H), 7.70-7.75 (m, 4H), 7.45-7.17 (m, 10H), 6.75-6.48 (m, 4H), 2.24-2.00 (m, 2H), 1.39 (s, 6H); MS (EI) 568.31 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[C:6]([CH2:9][CH3:10])[N:5]=[CH:4][N:3]=1.[NH2:11][CH:12]1[CH2:17][O:16][CH:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][CH2:13]1.C1(C2CCC(O)CO2)C=CC=CC=1.C(N(CC)CC)C>O>[Cl:8][C:7]1[C:2]([NH:11][CH:12]2[CH2:17][O:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)=[N:3][CH:4]=[N:5][C:6]=1[CH2:9][CH3:10]
Reactant: NC1CCC(c2ccccc2)OC1
Reactant: CCc1ncnc(Cl)c1Cl
Agent: OC1CCC(c2ccccc2)OC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCc1ncnc(NC2CCC(c3ccccc3)OC2)c1Cl
Temperature: 85 °C

Procedure:
2.4 g (13.5 mmol) of 4,5-dichloro-6-ethylpyrimidine, 2.4 g (13.5 mmol) of 5-amino-2-phenyltetrahydropyran (prepared from 2-phenyltetrahydropyran-5-ol (cf. U.S. Pat. No. 4,388,104) analogously to the routes described in Example A) and 3 ml (21 mmol) of triethylamine were heated for 12 hours at 85° C. After cooling, the mixture was diluted with water and extracted with ether, and the organic phase was washed with saturated NaCl solution. After drying and concentrating, the residue was purified by column chromatography using petroleum ether/ethyl acetate (9:1, 8:2). This gave 0.65 g (15% of theory) of the trans isomer as a colorless oil and 2.17 g (51% of theory) of the cis isomer as a colorless oil.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:28][CH2:27][CH:26]3[C:21]([C:22]4[CH:32]=[N:31][CH:30]=[CH:29][C:23]=4[CH2:24][CH2:25]3)=[N:20]2)=[CH:15][CH:14]=1>ClCCl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:28][CH2:27][CH:26]3[C:21]([C:22]4[CH:32]=[N+:31]([O-:6])[CH:30]=[CH:29][C:23]=4[CH2:24][CH2:25]3)=[N:20]2)=[CH:15][CH:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Clc1ccc(N2CCC3CCc4ccncc4C3=N2)cc1
Solvent: ClCCl
Product: [O-][n+]1ccc2c(c1)C1=NN(c3ccc(Cl)cc3)CCC1CC2
Yield: 72.1 %

Procedure:
3-Chloroperoxybenzoic acid (60%) (35 mg) was added to a solution of 2-(4-Chlorophenyl)-2,3,4,4a,5,6-hexahydropyrido[4,3-h]cinnoline (example 17, 25 mg) in dichloromethane (5 ml) at 25° C. After 4 hours the reaction was diluted with dichloromethane and sequentially washed with an aqueous solution of sodium metabisulfite, saturated sodium bicarbonate solution, brine, dried and evaporated. Purification by chromatography, eluting with ethyl acetate/methanol (4:1) afforded the title compound (19 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1O)([O-:3])=[O:2].[C:14]([O-:17])([O-])=O.[K+].[K+].ICCCCC[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]C>CC(N(C)C)=O>[N+:10]([CH:8]([CH2:9][CH:4]([N+:1]([O-:3])=[O:2])[CH2:5][CH2:6][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH3:26])[CH2:7][O:17][C:14]1[CH:8]=[CH:9][CH:4]=[CH:5][CH:6]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccc(O)c([N+](=O)[O-])c1
Reactant: O=C([O-])[O-]
Reactant: CCCCCCCCCCCCCCCCCCI
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCCCCCCCCCCCCCC(CC(COc1ccccc1)[N+](=O)[O-])[N+](=O)[O-]
Yield: 72 %

Procedure:
To a 250 ml reactor equipped with an agitator and nitrogen-inlet, nitrogen gas was slowly influxed as 2,4-dinitrophenol (7.36 g, 0.04 mole) was dissolved in 50 ml of the reacting solvent of dimethylacetamide. While influxing nitrogen gas, K2CO3 (6.99 g, 0.05 mole), 1-iodooctadecane (19 g, 0.05 mole) was slowly added and refluxed for 48 hours. The mixture was precipitated in excess distilled water. Thereafter, the solid material so filtered was recrystalized to obtain 2,4-dinitro-octadecanoxy-benzene (DN-L-18O) with the yield of 72%.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].C([O-])([O-])=O.[K+].[K+].F[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=1[F:22]>CN(C=O)C.O>[F:22][C:14]1[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=1[O:5][CH2:4][CH2:3][O:2][CH3:1]
Reactant: COCCO
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1ccc([N+](=O)[O-])cc1F
Temperature: 70 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
To a stirred suspension of methyl glycol (2.2 mL, 28.28 mmol, 1.5 eq.) and K2CO3 (7.8 g, 56.60 mmol, 3.0 eq.) in DMF (20 mL) was added 1,2-difluoro-4-nitrobenzene (3.0 g, 18.85 mmol, 1.0 eq.) and the mixture was stirred for 16 h at 70° C. The reaction mixture was cooled and diluted with water (30 mL) and extracted with ethyl acetate (40 mL). The organic layer was separated and washed with water (50 mL), brine (50 mL), and dried over sodium sulfate and the solvent evaporated under vacuum. The crude product was washed with n-pentane (30 mL) to obtain 2-fluoro-1-(2-methoxyethoxy)-4-nitrobenzene (3 g, 74%, as solid; TLC system: EtOAc/PE (1:9), Rf: 0.2).
Reaction SMILES: C1COCC1.[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:17]=[C:18]([Br:22])[CH:19]=[CH:20][CH:21]=2)=[CH:11][CH:10]=1)([O-])=O.[BH4-].[K+]>CO>[NH2:6][C:9]1[CH:10]=[CH:11][C:12]([S:15][C:16]2[CH:17]=[C:18]([Br:22])[CH:19]=[CH:20][CH:21]=2)=[CH:13][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(Sc2cccc(Br)c2)cc1
Agent: [BH4-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(Sc2cccc(Br)c2)cc1
Temperature: 20 °C
Reaction time: 0.33 h
Yield: 100.9 %

Procedure:
To a THF (15 mL) solution of 3-(p-nitrobenzenethioxy)bromobenzene (2.0 g, 6.4 mmol), prepared as in step 1, was added methanol (50 mL) and CuC1 (0.89 g, 99%, 9.0 mmol). The solution was cooled to ~10° C. in an icebath and solid potassium borohydride (1.13 g, 21 mmol) was added in small portions while maintaining the reaction temperature below 20° C. After complete addition of potassium borohydride the icebath was removed. The reaction was judged to be complete after 20 min and was quenched by adding water (40mL) while maintaining the reaction temperature under 20° C. The quenched reaction mixture was filtered through celite and partitioned between ether and water. After separating the layers the aqueous layer was extracted three times with ether. The combined organic layers were washed twice with brine and concentrated to 1/2 the original volume. The solution was treated with decolorizing carbon while drying over MgSO4, filtered through a celite pad, and concentrated in vacuo to give 3-(p-aminobenzenethioxy)bromobenzene (1.81 g, 101%) as a waxy red solid which was carried on without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:24](=[O:31])[NH:25][C:26]2[NH:27][CH:28]=[CH:29][N:30]=2)[C:5]2[N:9]=[C:8]([NH:10][C:11]([C:13]3[N:14]=[CH:15][C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[O:12])[NH:7][C:6]=2[CH:23]=1.[C:32]1([S:38](Cl)(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>N1C=CC=CC=1.C(Cl)Cl.[Cl-].[Na+].O>[C:32]1([S:38]([NH:1][C:2]2[CH:3]=[C:4]([C:24](=[O:31])[NH:25][C:26]3[NH:27][CH:28]=[CH:29][N:30]=3)[C:5]3[NH:9][C:8]([NH:10][C:11]([C:13]4[N:14]=[CH:15][C:16]5[C:21]([CH:22]=4)=[CH:20][CH:19]=[CH:18][CH:17]=5)=[O:12])=[N:7][C:6]=3[CH:23]=2)(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1cc(C(=O)Nc2ncc[nH]2)c2nc(NC(=O)c3cc4ccccc4cn3)[nH]c2c1
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1nc2cc(NS(=O)(=O)c3ccccc3)cc(C(=O)Nc3ncc[nH]3)c2[nH]1)c1cc2ccccc2cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.8 %

Procedure:
82 mg (0.2 mmol) of the isoquinoline-3-carboxylic acid [6-amino-4-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide (See Example 130) was dissolve in pyridine (0.6 mL). To this stirred solution at 0° C., 0.2 mmol of phenylsulfonyl chloride in 0.2 mL of DCM was added in one portion. The reaction mixture was stirred at r.t. for 2 h. Brine (5 mL) was added and stirred for 10 min. The resulting solid was collected, washed with water (3×2 mL) and ethyl acetate (3×3 mL) and dried to give 55 mg (50%) of isoquinoline-3-carboxylic acid [5-benzenesulfonylamino-7-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide as a solid. LCMS: 553 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]2[CH2:13][N:14]([C:16]3[CH:17]=[N:18][CH:19]=[C:20]([CH:24]=3)[C:21](O)=[O:22])[CH2:15][C@H:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1>>[Cl:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:21]([C:20]2[CH:24]=[C:16]([N:14]3[CH2:13][C@@H:11]4[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9][C@@H:10]4[CH2:15]3)[CH:17]=[N:18][CH:19]=2)=[O:22])=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=O)O)c3)C[C@@H]2C1
Reactant: Nc1ccc(Cl)cc1
Product: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=O)Nc4ccc(Cl)cc4)c3)C[C@@H]2C1

Procedure:
The product from Example 33B and 4-chloroaniline were processed as described in Example 33C to provide the title compound. MS (APCI) m/z 443 (M+H)+.