Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:13])[CH2:9][CH:10]([NH2:12])[CH3:11])=[CH:4][N:3]=1.CC1C=CC(C(CC(=O)C)=O)=CN=1.[Br-].[NH4+].N.B([O-])=O.[Na+]>C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH:9]=[C:10]([NH2:12])[CH3:11])=[CH:4][N:3]=1
Reactant: Cc1ccc(C(O)CC(C)N)cn1
Agent: CC(=O)CC(=O)c1ccc(C)nc1
Agent: N
Agent: O=B[O-]
Solvent: CCO
Product: CC(N)=CC(=O)c1ccc(C)nc1

Procedure:
1-(2-Methyl-5-pyridyl)-3-amino-n-butanol can be used as the starting material, is obtained as follows: 20.0 g of (6-methyl-nicotinoyl)-acetone, 200 ml of ethanol and 0.5 g of ammonium bromide are saturated with ammonia at 50° and heated at 50° for 15 hours whilst continuing to introduce ammonia. 8.5 g of sodium boranate are introduced in portions over the course of 1 hour into the solution, obtained above, of 1-(2-methyl-5-pyridyl)-3-amino-but-2-en-1-one of the formula ##EQU46## and the mixture is stirred for 7 hours at 70° . The solvent is distilled off in vacuo and the residue is taken up in 20% strength aqueous potassium hydroxide solution and pentanol-1. After working up in the usual manner, 19.2 g of crude 1-(2-methyl-5-pyridyl)-3-amino-n-butanol of the formula ##EQU47## are obtained from the pentanol solution as an oil which can be purified further by column chromatography.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:17][CH3:18])=[C:4]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C[O:20][C:21](=O)[C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([N:29]2[CH:33]=[C:32]([C:34]3[CH:35]=[N:36][N:37]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:38]=3[CH2:39][CH3:40])[N:31]=[CH:30]2)[CH:23]=1>>[CH2:39]([C:38]1[N:37]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[N:36]=[CH:35][C:34]=1[C:32]1[N:31]=[CH:30][N:29]([C:24]2[CH:23]=[C:22]([CH:27]=[CH:26][C:25]=2[CH3:28])[C:21]([NH:1][C:2]2[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:5]=[C:4]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:3]=2[O:17][CH3:18])=[O:20])[CH:33]=1)[CH3:40]
Reactant: CCc1c(-c2cn(-c3cc(C(=O)OC)ccc3C)cn2)cnn1-c1ccccc1
Reactant: COc1c(N)cc(C(F)(F)F)cc1NS(C)(=O)=O
Product: CCc1c(-c2cn(-c3cc(C(=O)Nc4cc(C(F)(F)F)cc(NS(C)(=O)=O)c4OC)ccc3C)cn2)cnn1-c1ccccc1

Procedure:
Example 159 was prepared from N-(3-amino-2-methoxy-5-trifluoromethyl-phenyl)-methanesulfonamide and 3-[4-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-4-methyl-benzoic acid methyl ester (Example 151) in the same manner as Example 151. ESI MS m/z 639 [C31H29F3N6O4S+H]+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[CH3:10][O:11][C:12](=[O:32])[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[C:21](Cl)[C:22]3[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[S:25][C:23]=3[N:24]=2)=[CH:15][CH:14]=1>>[CH3:10][O:11][C:12](=[O:32])[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[C:21]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[C:22]3[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[S:25][C:23]=3[N:24]=2)=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3cc([N+](=O)[O-])sc3n2)cc1
Reactant: NCc1ccc(F)cc1
Product: COC(=O)c1ccc(-c2nc(NCc3ccc(F)cc3)c3cc([N+](=O)[O-])sc3n2)cc1

Procedure:
The reaction procedure as above wherein 4-fluorobenzylamine is reacted with 4-(4-chloro-6-nitro-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(4-fluorobenzylamino)-6-nitro-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: C([O:3][C:4]([NH:6][N:7]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:8]1[C:18]([O:20]C)=O)=O)C.[OH-].[NH4+:23]>>[C:12]1([C:9]2[CH:10]=[CH:11][N:7]3[C:8]=2[C:18](=[O:20])[NH:23][C:4](=[O:3])[NH:6]3)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)Nn1ccc(-c2ccccc2)c1C(=O)OC
Reactant: [NH4+]
Agent: [OH-]
Product: O=c1[nH]c(=O)c2c(-c3ccccc3)ccn2[nH]1
Temperature: 110 °C
Reaction time: 30 h
Yield: 38 %

Procedure:
Methyl 1-((ethoxycarbonyl)amino)-3-phenyl-1H-pyrrole-2-carboxylate (1.00 g, 3.47 mmol) was taken in a pressure tube and ammonium hydroxide (30%, 67.5 mL, 1.73 mol) was added and sealed. The reaction mixture was stirred at 110° C. for 30 h and transferred to a round bottomed flask and concentrated under reduced pressure. Toluene was added to it and azeotroped to remove trace amount of water (3 times). Then residue obtained was triturated with ethyl acetate (50×2 mL) to afford 5-phenylpyrrolo[2,1-f][1,2,4]triazine-2,4(1H,3H)-dione (0.300 g, 38.1%). LCMS Condition B-39: retention time 1.49 min, [M+1]=228.0.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:13][CH2:14][CH3:15])(=[O:12])[CH2:10][CH3:11]>>[C:2]1([CH:1]([OH:8])[CH:10]([CH3:11])[C:9]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC
Reactant: O=Cc1ccccc1
Product: CCOC(=O)C(C)C(O)c1ccccc1
Temperature: -78 °C
Reaction time: 0 h
Yield: 72 %

Procedure:
50 mmol (5.10 ml) of benzaldehyde are added at -78° C. to the manganous enolate of ethyl propionate, prepared as indicated above. After stirring for 10 seconds at -78° C., the reaction medium is hydrolyzed by the dropwise addition of a saturated solution of (NH4)2SO4. After decantation, filtration on hyflo-supercel and evaporation of the solvents under vacuum, ethyl 3-phenyl-3-hydroxy-2-methylpropionate is isolated by low pressure liquid chromatography on 15 μm silica gel using cyclohexane/ethyle acetate (90/10) as the eluent. Yield=72%. Erythro/threo=61/39.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:14]=[CH:13][N:12]=[C:11]2[C:7]=1[N:8]=[CH:9][N:10]2C1CCCCO1)=[CH2:5])C.O.[Br:22]N1C(=O)CCC1=O>O1CCCC1>[Br:22][CH2:3][C:4]([C:6]1[N:14]=[CH:13][N:12]=[C:11]2[C:7]=1[N:8]=[CH:9][NH:10]2)=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(OCC)c1ncnc2c1ncn2C1CCCCO1
Solvent: C1CCOC1
Solvent: O
Product: O=C(CBr)c1ncnc2[nH]cnc12
Reaction time: 0.25 h
Yield: 82.4 %

Procedure:
A solution of 6-(1-ethoxyvinyl)-9-tetrahydro-2H-pyran-2-yl-9H-purine (430 mg, 1.57 mmols), being prepared as described in Tetrahedron, 53 (6), 2291-2302, (1997), in tetrahydrofuran (24 ml) and water (1.5 ml) was treated with N-bromo-succinimide (NBS, 280 mg, 1.57 mmols) and kept at room temperature for 15 minutes. The solution was evaporated under reduced pressure, taken up with water and filtered to obtain the title compound (312 mg, Y=82%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCCC)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1.[NH:33]1[CH2:38][CH2:37][S:36](=[O:40])(=[O:39])[CH2:35][CH2:34]1>>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:33]5[CH2:38][CH2:37][S:36](=[O:40])(=[O:39])[CH2:35][CH2:34]5)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:30])[F:31])[CH:3]=1
Reactant: CCCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: O=S1(=O)CCNCC1
Product: O=C1N=C(N2CCS(=O)(=O)CC2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(1,1-dioxidothiomorpholin-4-yl)-thiazol-4-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-one and thiomorpholine 1,1-dioxide following General Procedure B.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH:8][N:9]=[C:10]([C:13]#[N:14])[C:11]#[N:12])[CH:5]=[CH:6][CH:7]=1.IC1C=C(C=CC=1)N.C(#N)CC#N.O.[NH2:29][NH2:30]>>[NH2:14][C:13]1[C:10](=[N:9][NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([I:1])[CH:3]=2)[C:11]([NH2:12])=[N:30][N:29]=1
Reactant: NN
Reactant: N#CC(C#N)=NNc1cccc(I)c1
Agent: Nc1cccc(I)c1
Solvent: O
Solvent: N#CCC#N
Product: NC1=NN=C(N)C1=NNc1cccc(I)c1
Yield: 74 %

Procedure:
This compound was prepared using 148 mg (0.5 mmol) of 2-[(3-iodophenyl)hydrazono]-malononitrile, which was derived from 3-iodoaniline (219 mg, 1.0 mmol) and malononitrile (1.5 mmol) as described in Example 8, and hydrazine hydrate. The hydrazine hydrate was added to the solution at a temperature of 75° C. despite the fact that the starting material had not fully dissolved. The solution cleared briefly and then a precipitate formed. The resulting solid was isolated by filtration, washed with ethanol, and dried to yield 122 mg (74%) of the title compound as a mustard coloured solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]2[CH:18]([C:19]3[O:20][C:21]([S:24][C:25]4[NH:29][C:28]5[CH:30]=[C:31]([Cl:35])[C:32]([F:34])=[CH:33][C:27]=5[N:26]=4)=[CH:22][CH:23]=3)[C:17]3[C:16](=[O:36])[CH2:15][N:14](OC(C)(C)C)[CH2:13][C:12]=3[NH:11][C:10]=12)=[O:5])[CH3:2].Cl>O1CCOCC1>[ClH:35].[CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]2[CH:18]([C:19]3[O:20][C:21]([S:24][C:25]4[NH:29][C:28]5[CH:30]=[C:31]([Cl:35])[C:32]([F:34])=[CH:33][C:27]=5[N:26]=4)=[CH:22][CH:23]=3)[C:17]3[C:16](=[O:36])[CH2:15][NH:14][CH2:13][C:12]=3[NH:11][C:10]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]cc2c1NC1=C(C(=O)CN(OC(C)(C)C)C1)C2c1ccc(Sc2nc3cc(F)c(Cl)cc3[nH]2)o1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1[nH]cc2c1NC1=C(C(=O)CNC1)C2c1ccc(Sc2nc3cc(F)c(Cl)cc3[nH]2)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 183.1 %

Procedure:
A solution of 6-tert-butyloxy-9-[5-(6-chloro-5-fluoro-1H-benzimidazol-2-ylsulfanyl)-furan-2-yl]-8-oxo-2,4,5,7,8,9-hexahydro-pyrrolo[3,4-b]-1,7-naphthyridine-3-carboxylic acid ethyl ester (0.376 g, 0.60 mmol) in dioxane (20 ml) is combined with 4 N HCl in dioxane (2.17 ml) and the mixture is stirred at room temperature for 16 hours. The formed insoluble material is collected by filtration, washed with dioxane (40 ml), pentane (40 ml), diisopropylether (40 ml) and dried under vacuum to yield 310 mg of 9-[5-(6-chloro-5-fluoro-1H-benzimidazol-2-ylsulfanyl)-furan-2-yl]-8-oxo-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4-b]-1,7-naphthyridine-3-carboxylic acid ethyl ester hydrochloride as a light brown powder. Yield=92%. Analytical LC/MS (method B): m/z=528 (positive ion mode, [M+H]+, 1 Cl present), m/z=526 (negative ion mode [M−H]−, 1 Cl present)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:21]2[C:33]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:27]3[C:22]2=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:5]=[C:6]([N:8]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:7]=1.[Br:34][C:35]1[CH:36]=[CH:37][C:38]2[NH:39][C:40]3[C:45]([C:46]=2[CH:47]=1)=[CH:44][CH:43]=[CH:42][CH:41]=3.C(=O)([O-])[O-].[K+].[K+].C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1>ClC1C=CC=CC=1Cl.[Cu]>[Br:34][C:35]1[CH:36]=[CH:37][C:38]2[N:39]([C:2]3[CH:7]=[C:6]([N:8]4[C:20]5[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=5[C:14]5[C:9]4=[CH:10][CH:11]=[CH:12][CH:13]=5)[CH:5]=[C:4]([N:21]4[C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=5[C:28]5[C:33]4=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH:3]=3)[C:40]3[C:45]([C:46]=2[CH:47]=1)=[CH:44][CH:43]=[CH:42][CH:41]=3
Reactant: Brc1cc(-n2c3ccccc3c3ccccc32)cc(-n2c3ccccc3c3ccccc32)c1
Reactant: Brc1ccc2[nH]c3ccccc3c2c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Clc1ccccc1Cl
Product: Brc1ccc2c(c1)c1ccccc1n2-c1cc(-n2c3ccccc3c3ccccc32)cc(-n2c3ccccc3c3ccccc32)c1
Temperature: 100 °C

Procedure:
1.00 g of 9,9′-(5-bromo-1,3-phenylene)bis(9H-carbazole), 0.65 g of 3-bromo-9H-carbazole, 1.13 g of potassium carbonate, 0.26 g of copper powder and 0.05 g of dibenzo-18-crown-6 were dissolved in 20 mL of o-dichlorobenzene, and the resulting solution was refluxed at a steady 100° C. After completion of the reaction, the reaction mixture was extracted with dichloromethane and distilled water, and the solvent was dried. The resulting solid was filtered and purified, yielding 9,9′-(5-(3-bromo-9H-carbazol-9-yl)-1,3-phenylene)bis(9H-carbazole) as an intermediate.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@H:6]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH2:5]2.[H-].[Na+].Br[CH2:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[C:24]#[N:25]>CN(C=O)C>[C:24]([C:23]1[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=1[CH2:21][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@H:6]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH2:5]2)#[N:25]
Reactant: N#Cc1ccccc1CBr
Reactant: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(O)cc2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(OCc3ccccc3C#N)cc2C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49 %

Procedure:
A mixture of (S)-N-(5-hydroxy-2,3-dihydro-1H-inden-2-yl)propane-2-sulfonamide (0.098 mmol, 25 mg) and NaH (0.196 mmol, 4.70 mg) in DMF (1 mL) was stirred at room temp for 15 min. 2-(bromomethyl)benzonitrile (0.098 mmol, 19.20 mg) in DMF (1 mL) was added and the reaction mixture heated at 120° C. for 600 s in a Smith Synthesiser microwave. The reaction mixture was filtered through a Whatman filter and purified by preparative HPLC to give desired product (17.8 mg, 49.1%). MS (ESI): m/z [M−H]− 369.2
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCCCC.[H-].[Na+].F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1>CS(C)=O>[CH2:1]([O:8][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)cc1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 91.3 %

Procedure:
Benzyl alcohol (2.22 g, 20 mmol) was added to a slurry of hexane-washed NaH (60% oil suspension, 820 mg, 20.5 mmol) in DMSO (20 mL), stirred under nitrogen at 20° C., producing strong gas evolution. After 30 minutes, 1-fluoro-4-nitrobenzene (2.826 g, 20 mmol) was added dropwise to the light grey slurry. The reaction mixture became a bright orange red and quite strongly exothermic, and a lot of gas was evolved. After 2 hours, the reaction mixture was poured onto ice-water (200 mL), and the solid was collected by Buchner filtration, rinsed with water (2×50 mL), and air dried to give 1-benzyloxy-4-nitrobenzene (4.188 g, 91.3%) as canary yellow crystals. 1H NMR (DMSO-d6): δ8.16 (2 H, AA'BB', J=9.3 Hz), 7.47 (2 H, d, J=7.1 Hz), 7.41 (2 H, t, J=7.3 Hz), 7.36 (1 H, t, J=7.1 Hz), 7.23 (2 H, AA'BB', J=9.1 Hz), 5.26 (2 H, s).
Reaction SMILES: [CH:1]([CH:3]=[CH2:4])=[O:2].[CH:5]([C:8]([CH2:10][CH3:11])=[O:9])([CH3:7])[CH3:6].[C:12]1([CH3:22])[CH:17]=C[C:15](S(O)(=O)=O)=[CH:14][CH:13]=1>O>[CH:1]([CH:3]=[CH2:4])=[O:2].[CH:5]([C:8]([CH2:10][CH3:11])=[O:9])([CH3:7])[CH3:6].[CH3:4][C:3]1[C:1](=[O:2])[C:12]([CH3:22])([CH3:17])[CH2:13][CH2:14][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C=CC=O
Agent: CCC(=O)C(C)C
Solvent: O
Product: CC1=CCCC(C)(C)C1=O
Reaction time: 3 h

Procedure:
30 g of acrolein (boiling point about 105° C) are added dropwise in the course of 60 minutes to 150 g of ethyl isopropyl ketone and 2 g of p-toluenesulfonic acid, under reflux. The water formed is removed. After 3 hours, the unconverted starting materials are distilled off through a short column under atmospheric pressure at from 40° to 112° C. The reaction mixture ist then kept for 1 hour at an internal temperature of 200° C and is thereafter distilled under reduced pressure. 7 g of water, 3 g of acrolein, 122 g of ethyl isopropyl ketone, 22 g of 2,6,6-trimethyl-cyclohex-2-en-1-one (free from isomers) and 28 g of residue are obtained. This amounts to a yield of 57%, based on ethyl isopropyl ketone employed.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)OCC[O:3]1>Cl>[N:10]1([CH2:9][CH2:8][CH2:7][C:2](=[O:3])[CH3:1])[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: CC1(CCCn2ccnc2)OCCO1
Agent: Cl
Product: CC(=O)CCCn1ccnc1

Procedure:
A solution of 48.4 g of 1-[3-(2-methyl-1,3-dioxolan-2-yl)-propyl]-1H-imidazole in 615 ml of 1M hydrochloric acid was stirred overnight. The reaction mixture was concentrated to half volume under reduced pressure and the solution was made basic with sodium hydroxide and extracted with dichloromethane. The combined organic layers were dried over potassium carbonate and the residue obtained after concentration was distilled to yield 30.17 g (77%), bp 110°-121° C./0.1 min. A sample was further purified on silica gel thick layer plates eluting with 9% methanol-dichloromethane to give an analytical sample of 5-(1H-imidazol-1-yl)-2-pentanone.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].C(=O)([O-])[O-].[K+].[K+].C[N:16]([CH:18]=O)C>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])=[C:4]([C:18]#[N:16])[C:3]=1[C:18]#[N:16]
Reactant: Cc1ccccc1S
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccccc1Sc1ccc(Sc2ccccc2C)c(C#N)c1C#N
Yield: 42 %

Procedure:
2-Methylthiophenol (10.60 g, 85.5 mmol), potassium carbonate (11.82 g, 82.0 mmol) and ditosylated dicyanohydroquinone (20.00 g, 42.7 mmol) in DMF (75 mL) were reacted as described above. The mixture was isolated as described above to give a yellow oil. The material was purified by flash column chromatography (eluting 10% ethyl acetate:isohexane) to give the title compound as a yellow solid (8.85 g, 23.8 mmol, 42%). [Found: C, 70.7%; H, 4.6%; N, 7.5%; S, 17.2%; C22H16N2S2 requires C, 70.9%; H, 4.3%; N, 7.5%; S, 17.2%]; MS (EI+) 372 (M+, 100%), 357 (M-CH3, 8), 339 (20).
Reaction SMILES: [N:1]1([CH2:10][C:11]([C:13]2[CH:14]=[C:15]([C:19]3[CH:23]=[C:22]([CH2:24][CH:25]([CH3:27])[CH3:26])[S:21][C:20]=3[S:28]([NH:31]C(C)(C)C)(=[O:30])=[O:29])[CH:16]=[CH:17][CH:18]=2)=[O:12])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.B(Cl)(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+].Cl[C:47]([O:49][CH2:50][CH2:51][CH2:52][CH3:53])=[O:48]>C(Cl)Cl.O>[CH2:50]([O:49][C:47]([NH:31][S:28]([C:20]1[S:21][C:22]([CH2:24][CH:25]([CH3:27])[CH3:26])=[CH:23][C:19]=1[C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:11](=[O:12])[CH2:10][N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[CH:2]2)[CH:14]=1)(=[O:29])=[O:30])=[O:48])[CH2:51][CH2:52][CH3:53]
Reactant: CCCCOC(=O)Cl
Reactant: CC(C)Cc1cc(-c2cccc(C(=O)Cn3cnc4ccccc43)c2)c(S(=O)(=O)NC(C)(C)C)s1
Agent: ClB(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCCCOC(=O)NS(=O)(=O)c1sc(CC(C)C)cc1-c1cccc(C(=O)Cn2cnc3ccccc32)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of 3-[3-(2-Benzoimidazol-1-ylacetyl)phenyl]-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (67.3 mg, 0.151 mmol; see step (b)) in CH2Cl2 (1 mL) was added BCl3 (0.3 mL, 1.0 M in hexane) and the reaction mixture was stirred for 1 h at ambient temperature. The reaction mixture was concentrated in vacuo. CH2Cl2 (30 mL) was added to the residue and this was washed with water. The organic phase was dried (over anhydrous MgSO4), concentrated in vacuo. To the crude product dissolved in CH2Cl2 (5 mL) was added Na2CO3 (72 mg, 0.680 mmol), water (2 mL) and butyl chloroformate (24.9 μL, 0.196 mmol), and the reaction mixture was stirred for 2 h at ambient temperature. The reaction mixture was diluted with CH2Cl2 (30 mL) and washed with citric acid (10% aq), brine and water, dried (over anhydrous MgSO4), concentrated in vacuo, and the residue purified by flash chromatography using MeOH:CH2Cl2 (6:94) as eluent to give the title compound in 90% yield, over two steps, (66.2 mg, 0.135 mmol).
Reaction SMILES: C(O)(=O)C(O)=O.[O-]S([O-])(=O)=O.[Na+].[Na+].[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1.[OH:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1.[OH-].[Na+]>CC(C)=O.O>[O:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]1[O:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1
Reactant: C1=COCCC1
Reactant: OCCc1ccc(O)cc1
Agent: O=C(O)C(=O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Oc1ccc(CCOC2CCCCO2)cc1
Reaction time: 3 h

Procedure:
Oxalic acid (64 g, 0.5 mol), Na2SO4 (400 g) and distilled dihydropyran (600 mL) are added to a solution of 4-(2-hydroxyethyl)phenol (600 g, 4.3 mol) in acetone (3 l) and the mixture stirred for 3 hours. The resulting solution is added to water (4 l) containing 35% NaOH solution (500 mL), and washed with CH2Cl2 (2X). The mixture was stirred vigorously for one hour. The organic phase was washed with water (3×1 l) and evaporated to yield 4-(2-tetrahydropyran-2-yloxyethyl)phenol (9).
Reaction SMILES: Cl.[NH2:2][NH:3][C:4](=[NH:7])[NH:5][NH2:6].[Br:8][C:9]1[C:10]([O:18][CH2:19][CH3:20])=[C:11]([CH:14]=[C:15]([Br:17])[CH:16]=1)[CH:12]=O.Cl>O.C(O)C>[Br:8][C:9]1[C:10]([O:18][CH2:19][CH3:20])=[C:11]([CH:14]=[C:15]([Br:17])[CH:16]=1)[CH:12]=[N:2][NH:3][C:4]([NH:5][N:6]=[CH:12][C:11]1[CH:14]=[C:15]([Br:17])[CH:16]=[C:9]([Br:8])[C:10]=1[O:18][CH2:19][CH3:20])=[NH:7]
Reactant: N=C(NN)NN
Reactant: CCOc1c(Br)cc(Br)cc1C=O
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOc1c(Br)cc(Br)cc1C=NNC(=N)NN=Cc1cc(Br)cc(Br)c1OCC
Temperature: 20 °C

Procedure:
A mixture was prepared by dissolving 7.9 grams (0.063 mole) of diaminoguanidine, hydrochloride in 60 milliliters of lukewarm water and this mixture was added to a solution of 38.2 grams (0.125 mole) of 3,5-dibromo-2-ethoxybenzaldehyde dissolved in 500 milliliters of ethanol. To this mixture was added a solution of 8 milliliters of concentrated hydrochloric acid in 80 milliliters of ethanol. The mixture was heated at the reflux temperature for 10 minutes and thereafter cooled to 20° C. The solid 1,3-bis[(3,5-dibromo-2-ethoxybenzylidene)amino]guanidine, hydrochloride product was recovered by filtration under reduced pressure, washed with ethanol and dried. The product was recovered in a yield of 20 grams (45 percent of theoretical) and melted at 188°-190° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:3][C:4]=1[N+:10]([O-:12])=[O:11]
Reactant: C1COCCN1
Reactant: COc1ccc(Br)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: COc1ccc(N2CCOCC2)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 20 ml vial was charged 4-bromo-1-methoxy-2-nitrobenzene (0.3 g, 1.293 mmol), morpholine (0.338 ml, 3.88 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.059 g, 0.065 mmol), xantphos (0.037 g, 0.065 mmol) and sodium tert-butoxide (0.311 g, 3.23 mmol) in 1,4-dioxane (12.93 ml). The reaction mixture was heated at 100° C. on a hot plate for 2 hours. The solution was allowed to cool and stir overnight at room temperature. The mixture was concentrated and the residue was loaded onto a silica gel column. The compound was eluted using a gradient starting with 100% dichloromethane to 1:1 dichloromethane/methanol over 50 minutes to provide the title compound. MS (DCI(+)) m/e 239.0 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[O:17]1[CH2:19][C@@H:18]1[C@@H:20]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC(O)C>[CH2:7]([NH:6][C:5]1[CH:4]=[C:3]([CH:16]=[CH:15][CH:14]=1)[CH2:2][NH:1][CH2:19][C@@H:18]([OH:17])[C@@H:20]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NCc1cccc(NCc2ccccc2)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H]1CO1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CNCc1cccc(NCc2ccccc2)c1
Temperature: 90 °C
Yield: 53.1 %

Procedure:
1 ml anhydrous iPrOH was added to a flask charged with 3-(aminomethyl)-N-benzylaniline (0.057 g, 0.269 mmol, 1.3 eq) and tert-butyl (S)-1-((S)-oxiran-2-yl)-2-phenylethylcarbamate (0.054 g, 0.207 mmol, 1 eq) under Ar. The mixture was heated to reflux at 90° C. overnight. After cooling to room temperature the solvent was removed in vacuo. The residue was dissolved in EtOAc, washed with water (×3), brine (×1), and dried over Na2SO4. The inorganics were filtered off, and the solvent was removed in vacuo. Purification via flash chromatography yielded 0.0526 g (0.11 mmol, 53% yield) of the product.