Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]2=[C:15]3[N:10]([CH2:11][CH2:12][CH2:13]2)[CH2:9][CH2:8][CH2:7][C:6]3=[CH:5][C:4]=1[CH:16]=[CH:17][C:18]1[S:22][C:21]([CH:23]=O)=[CH:20][CH:19]=1.[C:25]([C:27]1[C:28](=[C:38]([C:41]#[N:42])[C:39]#[N:40])[O:29][C:30]([CH3:37])([C:33]([F:36])([F:35])[F:34])[C:31]=1[CH3:32])#[N:26]>C(O)C.O1CCCC1>[C:25]([C:27]1[C:28](=[C:38]([C:39]#[N:40])[C:41]#[N:42])[O:29][C:30]([CH3:37])([C:33]([F:36])([F:34])[F:35])[C:31]=1[CH:32]=[CH:23][C:21]1[S:22][C:18]([CH:17]=[CH:16][C:4]2[CH:5]=[C:6]3[C:15]4[N:10]([CH2:9][CH2:8][CH2:7]3)[CH2:11][CH2:12][CH2:13][C:14]=4[C:3]=2[O:2][CH3:1])=[CH:19][CH:20]=1)#[N:26]
Reactant: COc1c(C=Cc2ccc(C=O)s2)cc2c3c1CCCN3CCC2
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C(F)(F)F
Solvent: CCO
Solvent: C1CCOC1
Product: COc1c(C=Cc2ccc(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(C)C(F)(F)F)s2)cc2c3c1CCCN3CCC2
Temperature: 60 °C
Yield: 77.4 %

Procedure:
In 5 ml of ethanol and 1.5 ml of tetrahydrofuran were dissolved 135 mg (0.40 mmol) of 5-[2-(8-methoxy-2,3,6,7-tetrahydro-1H,5H-benzo[ij]quinolizine-9-yl)vinyl]thiophene-2-carboaldehyde and 110 mg (0.43 mmol) of 2-(3-cyano-4,5-dimethyl-5-trifluoromethyl-2(5H)-furanylidene)propanedinitrile. The mixture was stirred with heating at 60° C. for 3.5 hours. The solvent was evaporated off and the residue was washed with ethanol. The residue was purified by silica gel column chromatography and washed with methanol to give 178 mg of a dark brown crystal (yield: 78.1%; mp: 159-161° C.)
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[N:17]=[CH:16][CH:15]=2)[CH:10]([CH3:25])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.[F:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]=C=O)=[CH:36][CH:35]=1>C(Cl)Cl>[Cl:24][C:20]1[CH:19]=[C:18]2[C:23]([C:14]([N:11]3[CH2:12][CH2:13][N:8]([C:6]([NH:40][C:37]4[CH:38]=[CH:39][C:34]([F:33])=[CH:35][CH:36]=4)=[O:5])[CH2:9][CH:10]3[CH3:25])=[CH:15][CH:16]=[N:17]2)=[CH:22][CH:21]=1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1c1ccnc2cc(Cl)ccc12
Reactant: O=C=Nc1ccc(F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1CN(C(=O)Nc2ccc(F)cc2)CCN1c1ccnc2cc(Cl)ccc12

Procedure:
4-[4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl]-7-chloroquinoline (0.30 g, 0.8 mmol) is deprotected with TFA in CH2Cl2 and transformed after being washed with base into the product according to method C using 4-fluorophenyl isocyanate (61 μL, 0.54 mmol) to give the title product a colorless solid.
Reaction SMILES: [CH3:1][CH2:2][C@@:3]1([OH:27])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:16](=[CH:17][C:4]1=2)[C:15]1[NH:18][C:19]2[C:25](=[CH:26][C:14]=1[CH2:13]3)[CH:24]=[CH:23][C:21](=O)[CH:20]=2)=[O:11].C[OH:29].C(Cl)(Cl)Cl>FC(F)(F)C(O)=O>[CH3:1][CH2:2][C@@:3]1([OH:27])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:16](=[CH:17][C:4]1=2)[C:15]1[N:18]=[C:19]2[C:25]([CH:24]=[C:23]([OH:29])[CH:21]=[CH:20]2)=[CH:26][C:14]=1[CH2:13]3)=[O:11]
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3ccc(=O)cc-3[nH]c2-1
Reactant: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3cc(O)ccc3nc2-1

Procedure:
Naturally available mixture of 10 and 11-hydroxy camptothecin (1.0 g) is dissolved in anhydrous trifluoroacetic acid (5 ml) and anhydrous methanol (10 ml) to form a homogeneous solution of the quaternized components of the mixture. The homogeneous solution is then absorbed over enough silica gel (60 A; 60-230 mesh) to form a thick slurry. This slurry is dried by evaporating methanol and excess acid in vacuo on a rotary evaporator, leaving a powdery mass. The powder is then loaded over a pre-equilibrated silica gel column using chloroform. The column is washed using 1000 ml of a solvent mixture of 80% chloroform-20% methanol to remove non polar impurities, occluded trifluoroacetic acid and 11-hydroxcamptothecin (fraction A). Elution is then continued with chloroform-methanol-triethyl amine (in the approximate ratio of 1:1:0.01) and the band migrating away from the origin is collected using this eluent (Fraction B). Fractions A and B are evaporated separately and analyzed. Fraction B corresponds to the 10-hydroxy camptothecin isolate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:6]([OH:8])=[O:7].S(Cl)(Cl)=O.[CH2:19](O)[CH3:20]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:6]([O:8][CH2:19][CH3:20])=[O:7]
Reactant: CCO
Reactant: COc1cc(C(=O)O)cc([N+](=O)[O-])c1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cc(OC)cc([N+](=O)[O-])c1
Yield: 85.6 %

Procedure:
The compound (5.33 g, 27.0 mmol) prepared in step 1 was dissolved in absolute ethanol (55.0 ml), added dropwise with thionyl chloride (2.96 ml, 40.55 mmol) at 0° C. The resulting mixture was refluxed for 6 hours. After completion, the reaction mixture was concentrated under reduced pressure and mixed with sodium bicarbonate aqueous solution. The mixture was extracted with dichloromethan, dried over anhydrous magnesium sulfate, and concentrated to dryness. The residue was then purified by flash column chromatography (dichloromethane:hexane=4:1) to obtain the title compound (5.1 g, yield: 85.6%, ivory solid).
Reaction SMILES: C([CH:3]([CH2:19][C:20]([OH:22])=[O:21])[N:4]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:5][C:6]1C=CC=CC=1)C.[ClH:23].[H][H]>[Pd].C(O)C>[ClH:23].[CH2:5]([N:4]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:3][CH2:19][C:20]([OH:22])=[O:21])[CH3:6]
Reactant: CCOC(=O)CCN(Cc1ccccc1)C(CC)CC(=O)O
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CCN(CC)CCC(=O)O

Procedure:
A mixture of 192.8 parts of ethyl N-[2(ethoxycarbonyl)-ethyl]-N-(phenylmethyl)-β-alanine and 280 parts of absolute ethanol is stirred in an hydrogenation vessel. Then there are added 45 parts of hydrochloric acid solution. After cooling, 10 parts of palladium-on-charcoal catalyst 5% are added and the whole is shaken at room temperature while one equivalent of hydrogen is taken up. The catalyst is filtered off and the filtrate is evaporated, yielding ethyl N-[2-(ethoxycarbonyl)ethyl]-β-alanine hydrochloride as an oily residue.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:18]4[CH:20]=[C:21]([NH:24][C:25](=[O:33])[C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[Cl:32])[CH:22]=[CH:23][C:17]=4[CH2:16][CH2:15][C:14]=3[C:13]([C:34]([NH2:36])=[O:35])=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[C:44](OC(=O)C)(=[O:46])[CH3:45]>C1COCC1.CN(C1C=CN=CC=1)C>[C:44]([NH:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:18]4[CH:20]=[C:21]([NH:24][C:25](=[O:33])[C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[Cl:32])[CH:22]=[CH:23][C:17]=4[CH2:16][CH2:15][C:14]=3[C:13]([C:34]([NH2:36])=[O:35])=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3])(=[O:46])[CH3:45]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)c1nn(-c2ccc(S(N)(=O)=O)cc2)c2c1CCc1ccc(NC(=O)c3ccccc3Cl)cc1-2
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NS(=O)(=O)c1ccc(-n2nc(C(N)=O)c3c2-c2cc(NC(=O)c4ccccc4Cl)ccc2CC3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.2 %

Procedure:
To a stirring solution of 1-[4-(aminosulfonyl)phenyl]-8-[(2-chlorobenzoyl)amino]-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide (2967 mg, 5.7 mmol) in THF (120 mL) was added DMAP (348 mg, 2.8 mmol), then tri-ethyl amine (0.95 mL, 6.8 mmol), followed by acetic anhydride (1.62 mL, 17.1 mmol). The reaction mixture was stirred at room temperature for overnight and then concentrated. To the residue was added 5% aq. NaHCO3 (100 mL). All compounds were dissolved. The aq. Layer was washed with EA (100 mL×2), CH2Cl2 (100 mL). The aq. layer was separated. To the aq. Layer was added 1N HCl to pH=6. A white precipitate was formed. It was filtered and washed with ether to give a white solid. The solid was dried under reduced pressure at 45° C. to give 1-{4-[(acetylamino)sulfonyl]phenyl}-8-[(2-chlorobenzoyl)amino]-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide (2255.4 mg, 70%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([OH:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2].Cl[CH2:17][C:18]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:17][C:18](=[O:19])[N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCN(CC)C(=O)CCl
Reactant: CCOC(=O)c1cc2cc(O)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(OCC(=O)N(CC)CC)ccc2[nH]1
Temperature: 25 °C
Reaction time: 6 h
Yield: 32.7 %

Procedure:
A mixture of 5-hydroxy-1H-indole-2-carboxylic acid ethyl ester (1 g, 5 mmol), 2-chloro-N,N-diethylacetamide (1 mL, 7.5 mmol) and cesium carbonate (5 g, 15 mmol) in dimethylformamide (10 mL) was stirred at room temperature for 6 hours. The reaction was diluted with ethyl acetate (160 mL), washed with water (5×50 mL) and brine, dried and concentrated. The residue was recrystallized from ethyl acetate and hexane to give 0.52 g of 5-diethylcarbamoylmethoxy-1H-indole-2-carboxylic acid ethyl ester as an off-white solid.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4](S(O)(=O)=O)=[CH:3][CH:2]=1.C(=O)(O)[O-].[Na+].O.[C:18]1(C)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH:1]([C:2]1[CH2:11][C:1]2[C:6]([CH:3]=1)=[C:5]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH:4]=[CH:3][CH:2]=2)([CH3:11])[CH3:6]
Reactant: Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(C)C1=Cc2c(cccc2-c2ccccc2)C1
Reaction time: 8 h

Procedure:
The crude mix of isomeric alcohols was dissolved in toluene (150 ml) to which p-toluene sulfonic acid (0.5 g) was added. The solution was refluxed in a flask equipped with a Dean-Stark trap for 1.5 h then cooled. Solid sodium bicarbonate was added and the mixture was stored overnight in a refrigerator. The next morning water (100 ml) was added and the organic layer was separated, dried over Na2SO4, and stripped under reduced pressure. The product, 2-isopropyl-4-phenylindene (10.4 g) was obtained as a brown oil. Analysis by GC indicated a purity of >96 area percent. This material was stored cold under an inert atmosphere until ready for further conversion.
Reaction SMILES: Br[CH2:2][C:3](=O)/[C:4](=[N:10]/[O:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([CH3:18])[CH2:14][CH2:13]1)/[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:20][C:21]([NH2:23])=[S:22]>>[NH2:23][C:21]1[S:22][CH:2]=[C:3](/[C:4](=[N:10]/[O:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([CH3:18])[CH2:14][CH2:13]2)/[C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:20]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)/C(=N\O[C@H]1CC[C@H](C)CC1)C(=O)CBr
Product: CCOC(=O)/C(=N\O[C@H]1CC[C@H](C)CC1)c1csc(N)n1

Procedure:
Ethyl 4-bromo-(Z)-2-(trans-4-methylcyclohexyloxyimino)-3-oxobutyrate (1.46 g) was treated with thiourea as described in Example 4d. Crystallisation from cyclohexane gave the title compound as a cream solid (0.80 g, 58%), m.p. 133°-5° C. [Found: M+, 311.1300, C14H21N3O3S requires M, 311.13O3 ]. νmax (KBr) 3447, 3119, 2940, 1723, 1616, 1538 cm-1, δH (CDCl3) 0.89 (3H, d), 0.98 (2H, m), 1.36 (6H, t+m), 1.72 (2H, m), 2.11 (2H, m), 4.16 (1H, m), 4.39 (2H, q), 5.44 (2H, s, exch. D2O) 6.68 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]2[NH:16][C@@H:15]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:14][S:13]2)=[C:7]([CH3:21])[CH:6]=1)=[O:4].[CH2:22](Br)[CH:23]([CH3:25])[CH3:24]>>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]2[N:16]([CH2:22][CH:23]([CH3:25])[CH3:24])[C@@H:15]([CH2:17][CH:18]([CH3:19])[CH3:20])[CH2:14][S:13]2)=[C:7]([CH3:21])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(N=C2N[C@@H](CC(C)C)CS2)c(C)c1
Reactant: CC(C)CBr
Product: COC(=O)c1ccc(N=C2SC[C@H](CC(C)C)N2CC(C)C)c(C)c1

Procedure:
(1S)-1-(Hydroxymethyl)-1-methylbutylamine was made from (L)-leucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 4-(Methoxycarbonyl)-2-methylphenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-3-methylbutanammonium chloride according to Method C1a to give (4S)-2-(4-(methoxycarbonyl)-2-methylphenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S)-2-(4-(methoxycarbonyl)-2-methylphenylimino)-3,4-diisobutyl-1,3-thiazolidine. The thiazolidine was saponified according to Method D6a, Step 1 to give (4S)-2-(4-carboxy-2-methylphenylimino)-3,4-diisobutyl-1,3-thiazolidine. The acid was coupled with ammonia as described in Method D6a, Step 2 to afford (4S)-2-(4-carbamoyl-2-methylphenylimino)-3,4-diisobutyl-1,3-thiazolidine.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH2:3][N:4]=[C:5]([NH2:17])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])[N:11]=1.[CH3:20][N:21]=[C:22]=[S:23].C(Cl)(Cl)Cl.CO.N>CO>[F:19][C:2]([F:1])([F:18])[CH2:3][N:4]=[C:5]([NH2:17])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:22]([NH:21][CH3:20])=[S:23])[N:11]=1
Reactant: NCCCCc1csc(NC(N)=NCC(F)(F)F)n1
Reactant: CN=C=S
Agent: N
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CNC(=S)NCCCCc1csc(NC(N)=NCC(F)(F)F)n1
Reaction time: 3 h

Procedure:
A mixture of 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(4-aminobutyl)thiazole (0.3 g.) and methyl isothiocyanate (0.18 g.) in methanol (6 ml.) was allowed to stand at room temperature for 3 hours. The residue obtained on evaporation of the solvent was subjected to preparative thin layer chromatography using chloroform/methanol/ammonia 90:10:0.5 v/v/v for development. The appropriate zone of the chromatogram was isolated and extracted with hot ethanol/chloroform 50:50 v/v (100 ml.). Evaporation of the solvent gave B 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[4-(3-methylthioureido)butyl]thiazole as a straw-coloured gum. The n.m.r. spectrum d6 dimethylsulphoxide using tetramethylsilane as internal standard included the following resonances (ε): 2.75 (3H, doublet), 4.04 (2H, multiplet) and 6.34 (1H, singlet). On addition of D2O the multiplet at ε 4.04 collapsed to a quartet.
Reaction SMILES: [CH2:1]([O:4][NH:5][C@@H:6]1[C:11]([C:12]([N:14]([CH3:16])[CH3:15])=[O:13])=[CH:10][C@@H:9]([CH2:17][O:18][CH3:19])[NH:8][CH2:7]1)[CH:2]=[CH2:3].CCN(C(C)C)C(C)C.Cl[C:30](Cl)([O:32]C(=O)OC(Cl)(Cl)Cl)Cl>C(#N)C>[CH2:1]([O:4][N:5]1[C:30](=[O:32])[N:8]2[CH2:7][C@H:6]1[C:11]([C:12]([N:14]([CH3:16])[CH3:15])=[O:13])=[CH:10][C@H:9]2[CH2:17][O:18][CH3:19])[CH:2]=[CH2:3]
Reactant: C=CCON[C@H]1CN[C@H](COC)C=C1C(=O)N(C)C
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C=CCON1C(=O)N2C[C@H]1C(C(=O)N(C)C)=C[C@H]2COC
Temperature: 25 °C
Reaction time: 8 h
Yield: 206.3 %

Procedure:
A solution of (3R,6S)-3-(allyloxyamino)-6-(methoxymethyl)-N,N-dimethyl-1,2,3,6-tetrahydropyridine-4-carboxamide (Intermediate 142, 725 mg, 2.69 mmol) and Hunig's Base (1.880 mL, 10.77 mmol) in acetonitrile (350 mL) was cooled to below 0° C. in an ice-salt bath and then a solution of triphosgene (320 mg, 1.08 mmol) in ACN (22 mL) was added at a rate of 0.1 mL/min. The reaction was stirred overnight at rt. Upon completion of the reaction, the solvents were removed and the crude mixture was redissolved in EtOAc, washed with sat. NaHCO3 and brine, dried over MgSO4, filtered and concentrated to obtain the desired product (658 mg, 83%) as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][CH:8]=[C:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][CH2:11][C:10]=12)=[O:5])[CH3:2].[Br:17]Br>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([Br:17])=[C:9]2[CH2:14][C:13]([CH3:15])([CH3:16])[CH2:12][CH2:11][C:10]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1scc2c1CCC(C)(C)C2
Reactant: BrBr
Solvent: CC(=O)O
Product: CCOC(=O)c1sc(Br)c2c1CCC(C)(C)C2
Temperature: 50 °C
Reaction time: 4 h
Yield: 81.3 %

Procedure:
To a solution of 5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid ethyl ester (715 mg, 3.0 mmol) in acetic acid (5 mL), bromine (480 mg, 3.0 mmol) is slowly added at rt. Upon completion of the addition, the mixture is heated to 50° C. and stirred for 4 h. The reaction is quenched by adding 1 N aq. NaOH and the mixture is extracted with DCM (3×50 mL). The organic extracts are dried (Na2SO4), filtered and evaporated to provide crude 3-bromo-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid ethyl ester (774 mg) as a brown oil; 1H NMR (CDCl3): δ 4.27 (q, J=7.6 Hz, 2H), 2.97 (t, J=7.0 Hz, 2H), 2.26 8 s, 2H), 1.51 (t, J=7.0 Hz, 2H), 1.33 8t, J=7.6 Hz, 3H), 0.95 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:31]2[CH2:36][CH2:35][C:34]([CH3:38])([CH3:37])[CH2:33][CH2:32]2)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@@H:23](OS(C)(=O)=O)[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[N-:39]=[N+:40]=[N-:41].[Na+]>CN(C=O)C.C(OCC)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:31]2[CH2:36][CH2:35][C:34]([CH3:38])([CH3:37])[CH2:33][CH2:32]2)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([N:39]=[N+:40]=[N-:41])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1sc(C2CCC(C)(C)CC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@@H](OS(C)(=O)=O)CC1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)c1sc(C2CCC(C)(C)CC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](N=[N+]=[N-])CC1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
To a solution of 5-(4,4-dimethyl-cyclohexyl)-3-[(cis-4-methanesulfonyloxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (2.56 g, 4.50 mmol) in 30 ml of DMF was added sodium azide (1.5 g, 23 mmol). The reaction mixture was stirred for 48 h at 50° C. The mixture was diluted with diethyl ether and washed 3 time with water and 1 time with brine. The organic layer was dried with sodium sulfate, filtered and concentrated under reduce pressure. The residue was purified by silica gel column chromatography (20% ethyl acetate/hexane to 100% ethyl acetate followed by 10% MeOH/CH2Cl2) to give 3-[(trans-4-Azido-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-5-(4,4-dimethyl-cyclohexyl)-thiophene-2-carboxylic acid methyl ester (1.6 g, 69%).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][C:6]([NH2:8])=[O:7].[NH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.O>C1(C)C=CC=CC=1>[N:9]1([CH2:2][CH2:3][O:4][CH2:5][C:6]([NH2:8])=[O:7])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1
Reactant: C1CNCCN1
Reactant: NC(=O)COCCCl
Solvent: O
Solvent: Cc1ccccc1
Product: NC(=O)COCCN1CCNCC1
Yield: 39.5 %

Procedure:
A mixture of 13.15 g of (2-chloroethoxy)acetamide (0.1 mol) and 43 g of anhydrous piperazine (0.5 mol) in 250 ml of toluene is introduced into a round-bottomed flask fitted with a water-cooled condenser and a mechanical stirrer. The mixture is heated at the reflux temperature for 4 hours. The precipitate formed is filtered off while hot and the solvent of the filtrate is evaporated off under reduced pressure to dryness. The evaporation residue is purified by chromatography on silica gel (eluent: 14/5/1 (v/v/v) of dichloromethane/methanol/28% aqueous ammonia solution). 7.4 g of 2-[2-(1-piperazinyl)ethoxy]acetamide are obtained in the form of a yellow oil. Yield: 39% Mass spectrum: 188 (MH+), 99 (HN(C4H8)N+=CH2), 44 (CONH2).
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:17][C:18](=[O:22])[CH2:19][CH2:20][CH:21]=2)=[C:12]([OH:23])[CH:11]=1)([CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[BH4-].[Na+].[Cl-].[Na+].CCOCC>CO>[CH3:9][C:2]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:17][CH:18]([OH:22])[CH2:19][CH2:20][CH:21]=2)=[C:12]([OH:23])[CH:11]=1)([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC(C)(C)c1ccc(C2=CCCC(=O)C2)c(O)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: CCCCCCC(C)(C)c1ccc(C2=CCCC(O)C2)c(O)c1
Reaction time: 0.5 h

Procedure:
To a -18° C. solution of 17.5 g (50 mmol) of 3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-cyclohex-3-enone in 50 ml of methanol is added 1.9 g (50 mmol) of sodium borohydride. The reaction mixture is stirred for 30 minutes and then added to 250 ml of saturated sodium chloride-250 ml of ether. The ether extract is washed once with 250 ml of saturated sodium chloride, dried over magnesium sulfate and evaporated. The residue is purified via column chromatography on 400 g of silica gel eluted with 50% ether-pentane to yield the title compound.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][NH:8][C:7](=[O:11])[CH:6]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCOCC1>[C:1]([O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([O:11][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc[nH]c(=O)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(=O)Oc1ccnc(OC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 73 %

Procedure:
A 0.77 g quantity of 4-acetoxy-2-pyridone was suspended in 30 ml of dioxane. To the suspension were added 2.09 ml of triethylamine and 0.58 ml of benzoyl chloride and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was concentrated under reduced pressure and the residue was subjected to silica gel chromatography using, as an eluent, chloroform, giving 0.95 g of the title compound in a yield of 73%.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][C:18]([S:22]([NH:25][C:26]3[S:27][CH:28]=[CH:29][N:30]=3)(=[O:24])=[O:23])=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1.[NH:31]1[CH:35]=[CH:34][N:33]=[CH:32]1.CC(C)([O-])C.[K+].CN(C=O)C>C(OCC)(=O)C>[N:31]1([C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=2[C:12]2[C:21]3[C:16](=[CH:17][C:18]([S:22]([NH:25][C:26]4[S:27][CH:28]=[CH:29][N:30]=4)(=[O:23])=[O:24])=[CH:19][CH:20]=3)[CH:15]=[CH:14][N:13]=2)[CH:35]=[CH:34][N:33]=[CH:32]1
Reactant: O=S(=O)(Nc1nccs1)c1ccc2c(-c3ccc(C(F)(F)F)cc3F)nccc2c1
Reactant: c1c[nH]cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=S(=O)(Nc1nccs1)c1ccc2c(-c3ccc(C(F)(F)F)cc3-n3ccnc3)nccc2c1
Temperature: 150 °C

Procedure:
A microwave vial was charged with 1-(2-fluoro-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (0.090 g, 0.198 mmol), imidazole (0.054 g, 0.794 mmol), and potassium tert-butoxide (0.111 g, 0.992 mmol). DMF (0.992 ml) was added and the reaction was heated in a microwave reactor at 150° C. for one hour. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, then acidified with concentrated HCl solution and extracted twice with ethyl acetate. The aqueous layer was passed through an SCX ion exchange column (pre-wetted with methanol). The column was flushed several times with methanol, then the product was liberated by flushing the column several times with 2.0 M ammonia in methanol. The ammonia/methanol filtrate was combined with the previously isolated organic layers. The combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via silica gel column chromatography (12 g, gradient elution 0 to 10% MeOH:DCM) to afford 1-(2-(1H-imidazol-1-yl)-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm=12.90 (br. s., 1H), 8.66 (d, J=5.7 Hz, 1H), 8.50 (d, J=1.6 Hz, 1H), 8.13 (d, J=5.4 Hz, 1H), 8.08 (s, 1H), 8.03 (dd, J=1.2, 8.1 Hz, 1H), 7.88 (d, J=7.9 Hz, 1H), 7.79-7.73 (m, 1H), 7.70-7.63 (m, 1H), 7.48 (t, J=1.0 Hz, 1H), 7.26 (d, J=4.6 Hz, 1H), 6.89-6.81 (m, 2H), 6.62 (t, J=1.1 Hz, 1H). m/z (ESI) 502.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].Br[C:13]([CH3:20])([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>>[OH:1][C:2]1[CH:7]=[C:6]([O:8][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])([CH3:20])[CH3:19])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10]
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: CCOC(=O)C(C)(C)Br
Product: CCOC(=O)C(C)(C)Oc1ccc(C(C)=O)c(O)c1

Procedure:
This compound was synthesized from 2′,4′-dihydroxyacetophenone and ethyl bromoisobutyrate (1 eq) according to general method 4 described earlier.