Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:3]1.Br[CH2:24][CH2:25][CH2:26][F:27].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>C(OCC)C.CN(C)C=O>[F:27][CH2:26][CH2:25][CH2:24][N:19]1[CH2:18][CH2:17][N:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:4]2[CH2:3][C:2]([CH3:22])([CH3:1])[CH2:7][C:6]([CH3:8])([CH3:9])[CH2:5]2)[CH2:21][CH2:20]1
Reactant: FCCCBr
Reactant: CC1(C)CC(c2ccccc2N2CCNCC2)CC(C)(C)C1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC1(C)CC(c2ccccc2N2CCN(CCCF)CC2)CC(C)(C)C1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of 1-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine (30 mg, 0.1 mmol) produced in Example (8b), 1-bromo-3-fluoropropane (18.0 mg, 0.125 mmol), sodium iodide (1.5 mg, 0.01 mmol), potassium carbonate (20.8 mg, 0.15 mmol) and dimethylformamide (1 mL) was stirred for 2 hours at an external temperature of 80° C. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with diethyl ether. The solvent was distilled off by nitrogen stream to the separated organic layer. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/beptane) to give 1-(3-fluoropropyl)-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine.
Reaction SMILES: CC(C)([O-])C.[K+].C(O)(C)(C)C.[C:12]1([C:18]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[C:22]3[N:29]=[CH:30][N:31]=[CH:32][C:21]=3[CH2:20][N:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[N:33](OCCC(C)C)=[O:34]>O1CCCC1>[N:33](=[C:20]1[C:21]2[CH:32]=[N:31][CH:30]=[N:29][C:22]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:18]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[N:19]1)[OH:34]
Reactant: c1ccc(C2=NCc3cncnc3-c3ccccc32)cc1
Reactant: CC(C)CCON=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: ON=c1nc(-c2ccccc2)c2ccccc2c2ncncc12
Temperature: -20 °C
Reaction time: 2 h

Procedure:
To a suspension of potassium tert-butoxide (24.9 g, 222 mmole) in 600 ml of dry tetrahydrofuran is added 200 ml of dry tert-butylalcohol at -20° C. under nitrogen. To this solution is then added, via addition funnel, 7-phenyl-5H-pyrimido[5,4-d][2]-benzazepine (25 g) in 260 ml of tetrahydrofuran. The resulting solution is stirred for about 2 hours at -20° C. and treated with 17.4 ml (130 mmole) of isoamyl nitrite. The reaction mixture is warmed to 0° C. over approximately 15 minutes and quenched with the addition of 60 ml of cold water and 20 ml of glacial acetic acid. All solvents are removed under reduced pressure and the residue is partitioned between ethyl acetate (600 ml) and brine (100 ml). The phases are separated and the organic extracts are dried (Na2SO4), concentrated, and triturated with ether.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]=[C:10]1[N:11]=[C:12]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:13][C:14](=[O:32])/[C:15]/1=[CH:16]/[C:17](/[C:20]([C:22]1[N:30]2[C:25]([CH:26]=[CH:27][CH:28]=[CH:29]2)=[CH:24][C:23]=1[CH3:31])=[O:21])=[CH:18]\[CH3:19]>C(Cl)Cl.CN1C(=O)CCC1>[Br:1][C:24]1[C:23]([CH3:31])=[C:22]([C:20](/[C:17](=[CH:18]/[CH3:19])/[CH:16]=[C:15]2\[C:10](=[CH2:9])[N:11]=[C:12]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[O:13][C:14]\2=[O:32])=[O:21])[N:30]2[C:25]=1[CH:26]=[CH:27][CH:28]=[CH:29]2
Reactant: C=c1nc(-c2ccccc2)oc(=O)/c1=C/C(=C\C)C(=O)c1c(C)cc2ccccn12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: C=c1nc(-c2ccccc2)oc(=O)/c1=C/C(=C\C)C(=O)c1c(C)c(Br)c2ccccn12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81.6 %

Procedure:
N-Bromosuccinimide (10.64 g; 59.8 mmol) is added portionwise to a solution of (5E)-4-methylidene-5-{(2E)-2-[(2-methylindolizin-3-yl)carbonyl]but-2-en-1-ylidene}-2-phenyl-4,5-dihydro-6H-1,3-oxazin-6-one (22.8 g; 59.8 mmol) in 350 mL of DCM and 105 mL of NMP. After 10 min of stirring at ambient temperature, the yellow precipitate formed is filtered off, washed with DCM and dried under vacuum to give 23.2 g (85%) of the yellow powder.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:20])[CH3:19])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[CH:29]1[CH2:34][C:33](=[O:35])[NH:32][C:31]([CH3:36])=[C:30]1[C:37](O)=[O:38]>>[C:18]([NH:17][C:13]1[CH:12]=[C:11]([CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:37]([C:30]3[CH:29]([C:23]4[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:22]=4[F:21])[CH2:34][C:33](=[O:35])[NH:32][C:31]=3[CH3:36])=[O:38])[CH2:6][CH2:7]2)[CH:16]=[CH:15][CH:14]=1)(=[O:20])[CH3:19]
Reactant: CC1=C(C(=O)O)C(c2ccc(F)cc2F)CC(=O)N1
Reactant: CC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CC(=O)Nc1cccc(C2CCN(CCCNC(=O)C3=C(C)NC(=O)CC3c3ccc(F)cc3F)CC2)c1

Procedure:
Prepared by Procedure AC and Scheme AM using N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}acetamide and 4-(2,4-difluorophenyl)-2-methyl-6-oxo-1,4,5,6-tetrahydro-3-pyridinecarboxylic acid: ESMS m/e: 525.2 (M+H)+.
Reaction SMILES: [BH4-].[Na+].[I-].[CH2:4]([O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][C:13]1[C:14]([C:18]2[CH:19]=[N+:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[N:15][S:16][N:17]=1)[CH3:5]>C(O)C>[CH2:4]([O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][C:13]1[C:14]([C:18]2[CH2:19][N:20]([CH3:24])[CH2:21][CH2:22][CH:23]=2)=[N:15][S:16][N:17]=1)[CH3:5]
Reactant: CCOCCOCCOc1nsnc1-c1ccc[n+](C)c1
Agent: [BH4-]
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Product: CCOCCOCCOc1nsnc1C1=CCCN(C)C1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
Sodium borohydride (230 mg, 6 mmol) was added to a solution of 3-(4-(2-(2-ethoxyethoxy)ethoxy)-1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodide (3 mmol) in ethanol (99.9%, 20 ml) and the reaction mixture was stirred at -10° C. for 1 h. After evaporation the residue was dissolved in water and extracted with ethyl acetate. The dried organic phases were evaporated and the residue purified by column chromatography (SiO2, eluent: ethyl acetate/methanol (4:1)). The title compound was crystallized as the oxalate salt from acetone to yield 290 mg. (M.p. 115°-116° C.; M+ : 313; Compound 43).
Reaction SMILES: [C:1]([O:9][CH:10]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25]C(N)=S>CN(C)C=O>[C:2]1([C:1]2[O:9][C:10]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:25]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OC(C(=O)c1ccccc1)c1ccccc1)c1ccccc1
Reactant: NC(N)=S
Solvent: CN(C)C=O
Product: c1ccc(-c2nc(-c3ccccc3)c(-c3ccccc3)o2)cc1
Temperature: 160 °C
Reaction time: 7 h

Procedure:
1 g of desyl benzoate and 0.5 g of thiourea (2 eq.) are added to 10 ml of dimethylformamide in a reactor. The solution is left stirring at 160° C. for 7 hours.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([OH:15])=O)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.CN(C)C=O.[CH3:21][O:22][C:23]1[CH:35]=[CH:34][CH:33]=[CH:32][C:24]=1[CH2:25][C:26]1[S:30][C:29]([NH2:31])=[N:28][CH:27]=1.C(N(CC)CC)C>S(Cl)(Cl)=O.O1CCOCC1>[CH3:21][O:22][C:23]1[CH:35]=[CH:34][CH:33]=[CH:32][C:24]=1[CH2:25][C:26]1[S:30][C:29]([NH:31][C:13]([C:10]2([C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)[CH2:11][CH2:12]2)=[O:15])=[N:28][CH:27]=1
Reactant: COc1ccccc1Cc1cnc(N)s1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccccc1Cc1cnc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)s1
Reaction time: 0.5 h
Yield: 54.2 %

Procedure:
1-Benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid (1.87 g, 9.08 mmol) was dissolved in thionyl chloride (5 mL) under nitrogen for 30 minutes. A catalytic amount of N,N-dimethylformamide was added and stirring continued for an additional 30 minutes. The excess thionyl chloride was evaporated and the resulting residue was dissolved in 1,4 dioxane (15 mL). This solution was slowly added under nitrogen to 5-(2-methoxy-benzyl)-thiazol-2-ylamine (2.00 g, 9.08 mmol) dissolved in 1,4 dioxane (20 mL) containing triethylamine (3.5 mL, 25 mmol). The solution was allowed to stir for 2 hours. The reaction mixture was filtered, the precipitate was washed three times with 1,4 dioxane (20 mL), and the combined filtrate was evaporated to dryness and purified by column chromatography on silica gel using a gradient of 0-30% ethyl acetate in hexanes. The pure fractions were combined and evaporated to dryness to yield an off-white solid. The product was recrystallized twice from ethyl acetate/hexanes to yield the pure product (2.01 g, 4.92 mmol, 54.2%). ESI-MS m/z calc. 408.11. found 409.3 (M+1)+. Retention time of 3.48 minutes. 1H NMR (400 MHz, DMSO-d6) δ 1.11 (m, 2H), 1.43 (m, 2H), 3.80 (s, 3H), 3.97 (s, 2H), 6.01 (s, 2H), 6.87 (m, 3H), 6.98 (m, 2H), 7.16 (m, 2H), 7.22 (m, 1H), 10.76 (s, 1H).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1CCN2C(=NCCC2)CC1.[CH3:19][N:20]([CH3:49])[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[N:35]=[C:34]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][C@@H:37]3[CH3:42])[CH:33]=[C:32]([CH2:43]OS(C)(=O)=O)[N:31]=2)=[CH:26][CH:25]=1)=[O:22]>C(#N)C>[CH3:19][N:20]([CH3:49])[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[N:35]=[C:34]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][C@@H:37]3[CH3:42])[CH:33]=[C:32]([CH2:43][S:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:31]=2)=[CH:26][CH:25]=1)=[O:22]
Reactant: Sc1ccccc1
Reactant: C[C@H]1COCCN1c1cc(COS(C)(=O)=O)nc(-c2ccc(NC(=O)N(C)C)cc2)n1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C[C@H]1COCCN1c1cc(CSc2ccccc2)nc(-c2ccc(NC(=O)N(C)C)cc2)n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Thiophenol (0.062 mL) was dissolved in acetonitrile (5 mL). DBU (0.141 mL) was then added to the solution and was allowed to stir at RT for 5 minutes. 1,1-Dimethyl-3-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(methylsulfonyloxymethyl)pyrimidin-2-yl]phenyl]urea (154 mg) was suspended in acetonitrile (5 mL) and added to the thiol. The reaction was left to stir at RT of 1 hour then concentrated in vacuo to give the desired material which was used without further purification.
Reaction SMILES: C(O[CH:5]1[O:22][C@@H:21]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[C@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)C.[BrH:28].CC(O)=O.C(OCC)(=O)C.C1(C)C=CC=CC=1>ClCCl>[C:8]([O:7][C@@H:6]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:21]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:22][C@H:5]1[Br:28])(=[O:10])[CH3:9]
Reactant: Br
Reactant: CC(=O)OC[C@@H]1OC(OC(C)=O)[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(=O)OC[C@@H]1O[C@@H](Br)[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1,2,3,4,6-penta-O-acetyl-L-mannopyranose (1) (21.04 g) was dissolved in dehydrated dichloromethane (150 ml), and the resulting solution was cooled in ice. 30% HBr/AcOH (27.5 ml) was added dropwise thereto over about 10 minutes, and after completion of the dropwise addition, the ice bath was removed, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. Toluene was added to the resulting residue, and an azeotropic distillation procedure was performed twice. Ethyl acetate was added to the residue to dissolve the residue, and the resulting solution was washed sequentially with saturated NaHCO3 solution, water, and saturated saline. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was dried well under reduced pressure, whereby a target product was obtained (crude yield: 21.45 g (which exceeded the theoretical yield because ethyl acetate and toluene were contained, and therefore, the molar amount thereof was taken as 49.96 mmol, and the subsequent reaction was performed)).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=O)[C:13](=[N:21]O)[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:8][CH:7]=1)(=[O:3])[CH3:2].[N+:24]([C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1)([O-:26])=[O:25]>>[C:1]([O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[NH:32][C:31]([C:30]3[CH:29]=[CH:28][C:27]([N+:24]([O-:26])=[O:25])=[CH:34][CH:33]=3)=[N:21][C:13]=2[C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])=[CH:10][CH:11]=1)(=[O:3])[CH3:2]
Reactant: NCc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)OCc1ccc(C(=O)C(=NO)C(=O)OC(C)(C)C)cc1
Product: CC(=O)OCc1ccc(-c2[nH]c(-c3ccc([N+](=O)[O-])cc3)nc2C(=O)OC(C)(C)C)cc1
Yield: 15.3 %

Procedure:
tert-Butyl 3-(4-acetoxymethylphenyl)-2-hydroxyimino-3-oxopropionate (33.9 g) and 4-nitrobenzylamine (19.3 g) were reacted and treated in the same manner as in Starting Material Synthetic Example 1 to give tert-butyl 5-(4-acetoxymethylphenyl)-2-(4-nitrophenyl)-imidazole-4-carboxylate (7.07 g), melting point 178-180° C. (decomposition).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:13][CH2:12][CH2:11][N:10]([CH3:14])[CH2:9]2)=[CH:4][CH:3]=1.[N:15]1[N:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]2=[C:17]([CH2:24][CH:25]=O)[CH:16]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.C(OCC)(=O)C.C(O)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][N:10]([CH3:14])[CH2:11][CH2:12][N:13]2[CH2:25][CH2:24][C:17]2[CH:16]=[N:15][N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=23)=[CH:6][CH:7]=1
Reactant: O=CCc1cnn2ccccc12
Reactant: CN1CCNC(c2ccc(Br)cc2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CN1CCN(CCc2cnn3ccccc23)C(c2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 50.2 %

Procedure:
To a solution of 3-(4-bromo-phenyl)-1-methyl-piperazine (1.0 g, 3.92 mmol), pyrazolo[1,5-a]pyridin-3-yl-acetaldehyde (753 mg, 4.70 mmol) and acetic acid (1.2 mg) in tetrahydrofuran (15 mL) was added sodium triacetoxyborohydride (1.92 g, 8.62 mmol) and the resulting mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with ethyl acetate, washed with a saturated aqueous sodium bicarbonate solution, a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated in vacuo. Purification via flash silica gel column chromatography (heptane/ethyl acetate) gave 3-{2-[2-(4-bromo-phenyl)-4-methyl-piperazin-1-yl]-ethyl}-pyrazolo[1,5-a]pyridine (786 mg, 50% yield). LCMS (m/z): 401.00 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:14]2[CH:15]=[C:16]([CH2:24][CH3:25])[C:17]3[O:21][CH:20]=[C:19]([CH3:22])[C:18]=3[CH:23]=2)[C:11](O)=[O:12])=[CH:5][CH:4]=1)#[N:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[S:38]([NH2:42])([NH2:41])(=[O:40])=[O:39].CCCCCCC=CCCC>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][CH:10]([C:14]2[CH:15]=[C:16]([CH2:24][CH3:25])[C:17]3[O:21][CH:20]=[C:19]([CH3:22])[C:18]=3[CH:23]=2)[C:11]([NH:41][S:38]([NH2:42])(=[O:40])=[O:39])=[O:12])=[CH:7][CH:8]=1)#[N:2]
Reactant: CCc1cc(C(Nc2ccc(C#N)cc2)C(=O)O)cc2c(C)coc12
Reactant: NS(N)(=O)=O
Agent: CCCC=CCCCCCC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCc1cc(C(Nc2ccc(C#N)cc2)C(=O)NS(N)(=O)=O)cc2c(C)coc12
Reaction time: 1 h
Yield: 69.5 %

Procedure:
2-(4-Cyanophenylamino)-2-(7-ethyl-3-methylbenzofuran-5-yl)acetic acid 6 (5.45 g, 16.4 mmoles), carbonyldiimidazole (CDI, 5.28 g 32.6 mmoles) were combined under a nitrogen atmosphere and THF (50 ml) added. The reaction was stirred for 1 h. Sulfamide (4.7 g, 49 mmoles) was added to the reaction followed by drop wise addition of 1,8-diazabiocyclo[5.4.0]undec-7-ene (DBU, 7.3 ml, 49 mmoles). The reaction was then stirred an additional 2 hours at room temperature and the solvent removed in vacuo. The residue was taken up in ethyl acetate (ca. 150 ml) and washed with aqueous 2 N HCl. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to a yellow foam. The crude product was then purified on a silica flash column eluted with 40% ethyl acetate/60% hexane to provide 2-(4-cyanophenylamino)-2-(7-ethyl-3-methylbenzofuran-5-yl)acetylsulfamide 7 (4.7 g).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:13][CH2:14][CH2:15][CH2:16][CH:17]([O:20][CH3:21])[O:18][CH3:19])=[C:7]([NH2:12])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.C(O[CH:25](OCC)[CH2:26][CH2:27][CH2:28]NC1C2C(=CC=CC=2)N=C(N)C=1)C.C(OC)(OC)(OC)CCC.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH+]1C=CC=CC=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:13]([CH2:14][CH2:15][CH2:16][CH:17]([O:20][CH3:21])[O:18][CH3:19])[C:25]([CH2:26][CH2:27][CH3:28])=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1
Reactant: CCOC(CCCNc1cc(N)nc2ccccc12)OCC
Reactant: COC(CCCNc1c(N)cnc2cc(Br)ccc12)OC
Agent: CCCC(OC)(OC)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Product: CCCc1nc2cnc3cc(Br)ccc3c2n1CCCC(OC)OC
Reaction time: 8 h

Procedure:
A modification of the general method of Part B of Example 6 was followed using 7-bromo-N4-(4,4-dimethoxybutyl)quinoline-3,4 diamine (59.3 g, 167.39 mmol) in lieu of N4-(4,4-diethoxybutyl)quinoline-2,4 diamine. The reaction was incomplete after running overnight. Trimethyl orthobutyrate (5 mL) was added to the reaction mixture and heated to reflux for an additional 2 hours, upon which an additional amount of trimethyl orthobutyrate (5 mL) and pyridinium tosylate (5 mL) were added. After 2 hours of heating to reflux, the mixture was concentrated under reduced pressure, diluted in dichloromethane (300 mL) and methanol (45 mL), washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, and the mixture was concentrated under reduced pressure to afford 57.0 g of 7-bromo-1-(4,4-dimethoxybutyl)-2-propyl-1H-imidazo[4,5-c]quinoline as a brown solid.
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[CH3:7][N:8]([CH3:41])[C:9]([C:11]1[CH:12]=[C:13]([S:17][C:18]2[CH:27]=[C:26]3[C:21]([C:22]([NH:31][C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=4)=[C:23]([C:28]([NH2:30])=[O:29])[CH:24]=[N:25]3)=[CH:20][C:19]=2[I:40])[CH:14]=[CH:15][CH:16]=1)=[O:10]>CN(C)C=O>[CH3:41][N:8]([CH3:7])[C:9]([C:11]1[CH:12]=[C:13]([S:17]([C:18]2[CH:27]=[C:26]3[C:21]([C:22]([NH:31][C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=4)=[C:23]([C:28]([NH2:30])=[O:29])[CH:24]=[N:25]3)=[CH:20][C:19]=2[I:40])=[O:1])[CH:14]=[CH:15][CH:16]=1)=[O:10]
Reactant: O=S([O-])OO
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3cc(Sc4cccc(C(=O)N(C)C)c4)c(I)cc23)c1
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(Nc2c(C(N)=O)cnc3cc(S(=O)c4cccc(C(=O)N(C)C)c4)c(I)cc23)c1
Temperature: 25 °C
Reaction time: 21 h
Yield: 121.7 %

Procedure:
Oxone (0.5 g) was added portionwise to a stirred solution of Intermediate 64 (0.12 g) in N,N-dimethylformamide (5 ml). The solution was stirred at room temperature under nitrogen for 21 h. More oxone (0.5 g) was added and the mixture was stirred for a further 3 h, quenched with a solution of sodium sulphite (1.5 g) in water (15 ml), diluted with water (50 ml) and extracted with ethyl acetate (3×50 ml). The combined organic extracts were dried over magnesium sulphate and concentrated in vacuo to give the title compound as a yellow solid (0.15 g).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:11]([C:12](=[S:14])[NH2:13])[N:10]=[C:9]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])[S:8]1)=[N+:2]=[N-:3].[CH2:29](Cl)Cl.CI>CO>[N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:11]([C:12]([S:14][CH3:29])=[NH:13])[N:10]=[C:9]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])[S:8]1)=[N+:2]=[N-:3]
Reactant: ClCCl
Reactant: [N-]=[N+]=NCCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1C(N)=S
Solvent: CI
Solvent: CO
Product: CSC(=N)N1N=C(c2cc(F)ccc2F)SC1(CCCN=[N+]=[N-])c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carbothioamide (0.120 g, 0.29 mmol) in 2 mL of a 4:1 mixture of DCM:MeOH was added methyl iodide (0.022 mL, 0.34 mmol). After stirring for 16 hours at room temperature, methyl iodide (0.050 mL) was added and the mixture stirred for a further 4 hours then concentrated in vacuo. The residue was partitioned between saturated NaHCO3 (10 mL) and EtOAc (10 mL) and the aqueous layer was extracted with EtOAc (2×10 mL). The combined organic phases were washed with brine (10 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (10-20% ethyl acetate/hexanes) to afford the desired product, 0.124 g, 59%.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13](Br)[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH:20]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)=[O:21].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]12([C:11]3[CH:12]=[C:13]([C:25]4[CH:26]=[CH:27][C:22]([CH:20]=[O:21])=[CH:23][CH:24]=4)[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: COc1ccc(Br)cc1C12CC3CC(CC(C3)C1)C2
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: COc1ccc(-c2ccc(C=O)cc2)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Yield: 34 %

Procedure:
A mixture of 3-(1-adamantyl)-4-methoxy-1-bromobenzene (1.000 g, 3.11 mmol, prepared in a similar manner as described by Charpentier, B. et al. in J. Med. Chem. 1995, 38, 4993–5006), 4-formylphenylboronic acid (0.559 g, 3.73 mmol) and potassium carbonate (1.719 g, 12.44 mmol) in 10.5 mL of DME and 1.5 mL of water was degassed with argon for 30 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.185 g, 0.16 mmol) was added and the mixture heated at reflux under argon overnight. The solution was cooled to room temperature, diluted with ethyl acetate (200 mL) and washed successively with water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified on silica gel (eluent: hexane:ethyl acetate, 95:5) to give 0.372 g of 4-[3-(1-adamantyl)-4-methoxyphenyl]benzaldehyde (34%). 1H NMR (300 MHz; CDCl3): δ 1.80 (s, 6H), [2.10 (brs), 216 (s), 9 H], 3.91 (s, 3H), 6.98 (d, J=8.4 Hz, 1H), 7.48 (dd, J1=8.4 Hz, J2=2.4 Hz, 1H), 7.51 (d, J=2.4 Hz, 1H), 7.73 (d, J=8.7 Hz, 2H), 7.93 (d, J=8.7 Hz, 2H), 10.04 (s, 1H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][C:11]1[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][C:12]=1[N+:19]([O-:21])=[O:20].[CH:22]([N:25]1[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]1)([CH3:24])[CH3:23]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][C:11]1[S:15][C:14]([C:16]([NH:31][CH:28]2[CH2:29][CH2:30][N:25]([CH:22]([CH3:24])[CH3:23])[CH2:26][CH2:27]2)=[O:18])=[CH:13][C:12]=1[N+:19]([O-:21])=[O:20]
Reactant: CC(C)N1CCC(N)CC1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2nc3ccccc3s2)s1
Product: CC(C)N1CCC(NC(=O)c2cc([N+](=O)[O-])c(Sc3nc4ccccc4s3)s2)CC1

Procedure:
Prepared according to the procedure described for example 44 from 5-(1,3-benzothiazol-2-ylsulfanyl)-4-nitro-thiophene-2-carboxylic acid as in step A of example 256 (34 mg, 0.1 mmol) and 1-isopropylpiperidin-4-amine (17.0 mg, 0.12 mmol). The title compound was obtained as a solid (6.5 mg, 15% yield). MS m/z: 463.09, 465.09 [M+H]+.
Reaction SMILES: [C:1]123C(=O)[O:10][C:8](=[O:9])[CH:2]1[CH2:3][CH:4]([CH2:7]2)[CH2:5][CH2:6]3>C(O)C(C)C>[CH2:8]([O:9][CH:3]1[CH:4]2[CH2:7][CH:1]([CH2:6][CH2:5]2)[CH:2]1[C:8]([OH:10])=[O:9])[CH:2]([CH3:3])[CH3:1]
Reactant: O=C1OC(=O)C23CCC(CC12)C3
Solvent: CC(C)CO
Product: CC(C)COC1C2CCC(C2)C1C(=O)O

Procedure:
33.2 g (0.2 mol) bicyclo[2.2.1]heptane dicarboxylic anhydride was charged to 300 ml isobutyl alcohol in a 1 L round bottom flask. The system was refluxed for 2 hours with magnetic stirring. The solvent was then removed by rotary evaporator. The system was then dried and grounded. The product was characterized using FTIR and GC-MS. The yield was quantitative.