Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:14][O:15][C:16](=[O:29])[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26]>ClCCl>[CH3:14][O:15][C:16](=[O:29])[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](=[O:26])(=[O:27])[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C=Cc1ccccc1S(=O)(=O)Cl
Reactant: Nc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C=Cc1ccccc1S(=O)(=O)Nc1ccccc1
Yield: 60.5 %

Procedure:
To a mixture of aniline (0.33 g, 3.53 mmol) and pyridine (1 ml) a solution of 3-(2-chlorosulfonylphenyl)acrylic acid methyl ester (33) (0.45 g, 1.72 mmol) in dichloromethane (3 ml) was added and the resultant solution was stirred at 50° C. for 1 hour. The reaction mixture was evaporated and the residue was partitioned between ethyl acetate and 10% HCl. The organic layer was washed successively with water, saturated NaCl and dried (Na2SO4). The solvent was removed and the residue was chromatographed on silica gel with ethyl acetate-chloroform (1:7, v/v) as eluent. The obtained product was washed with diethyl ether to give the title compound (0.33 g, 60%). 1H NMR (CDCl3, HMDSO), δ: 3.86 (3H, s); 6.27 (1H, d, J=16.0 Hz); 6.69 (1H, br s); 6.87–7.67 (8H, m); 7.94–8.13 (1H, m); 8.49 (1H, d, J=16.0 Hz).
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17].[N:19]#[C:20]Br.[OH-].[Na+]>CCO>[C:1]1([CH3:18])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:8][CH2:9][N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[C:20]1=[NH:19]
Reactant: N#CBr
Reactant: Cc1ccccc1NCCNc1ccccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccccc1N1CCN(c2ccccc2C)C1=N
Reaction time: 1 h
Yield: 92.6 %

Procedure:
N,N' Bistolyl ethylene diamine (105.8 mg, 0.44 mmol) was taken up in EtOH (3 mL) to provide a light purple solution. This solution was then placed in a one-necked round-bottom flask (25 mL) equipped with magnetic stirbar and reflux condenser. To this solution, cyanogen bromide (50 mg, 0.47 mmol) in ethanol (2 mL) was added in a single portion. The resultant reaction mixture was stirred for 1 h. It was noted that the solution turned clear. The solution was then brought to reflux and maintained at that temperature for 16 h. The reflux condenser was then removed, allowing the solvent to evaporate. The reaction mixture was then fused at 150° C. for 30 min to provide a brown solid. This solid was immediately taken up in ethanol (4 mL) and placed into a centrifuge tube. To this solution 1N NaOH was added (8 mL) to provide a "whispy" tan precipitate. After several failed attempts to pellet the precipitate, the solution was simply extracted with chloroform (20 mL). The chloroform was concentrated to dryness to provide a clear oil (108.1 mg, 92.6%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[OH:19].Br[CH2:21][CH2:22][CH2:23][C:24]#[N:25].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:14]1([C:7]2([CH3:13])[CH2:6][C:5]3[C:9](=[C:10]([Cl:11])[C:2]([Cl:1])=[C:3]([O:19][CH2:21][CH2:22][CH2:23][C:24]#[N:25])[CH:4]=3)[C:8]2=[O:12])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: N#CCCCBr
Reactant: CC1(C2CCCC2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C2CCCC2)Cc2cc(OCCCC#N)c(Cl)c(Cl)c2C1=O
Reaction time: 4 h

Procedure:
A mixture of 6,7-dichloro-2-cyclopentyl-5-hydroxy-2-methyl-2,3-dihydro-1H-inden-1-one (6.0 g, 20 mmole), 4-bromobutanenitrile (3.28 g, 22 mmole), and potassium carbonate (3.1 g, 22 mmole) in dimethylformamide (50 ml) was stirred at 60°-65° for four hours. The reaction mixture was poured into water and extracted with diethyl ether. The organic layer was washed successively with water and brine, dried over magnesium sulfate, and concentrated in vacuo to a solid residue (4.7 g). Recrystallization from butyl chloride-hexane afforded the analytically pure title compound, m.p. ca. 112°.
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[C:4]2[C:9]([C:10]=1[C:11](Cl)=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[Cl:1][C:2]1[N:3]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[C:4]2[C:9]([C:10]=1[C:11]([N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: C1COCCN1
Reactant: COc1cccc(-n2c(Cl)c(C(=O)Cl)c3ccccc32)c1
Product: COc1cccc(-n2c(Cl)c(C(=O)N3CCOCC3)c3ccccc32)c1

Procedure:
This compound was prepared from 2-chloro-1(3-methoxyphenyl)-indole-3-carboxylic acid chloride and morpholine to yield 2-chloro-1-(3-methoxyphenyl)-indole 3-carboxylic acid morpholide which was reacted with N-methyl-piperazine according to Example 42. The yield of amorphous product was 85% of the theoretical yield; the amorpheus hydrochloride had a decomposition point above 160° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([CH3:3])=[CH2:2].C1(=O)O[CH2:14][CH2:13][O:12]1.O.O.[F-].[K+]>CN(C)C=O>[CH3:2][C:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:14][CH2:13][OH:12])=[CH:6][CH:5]=1)=[CH2:3]
Reactant: O=C1OCCO1
Reactant: C=C(C)c1ccc(O)cc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)c1ccc(OCCO)cc1
Temperature: 150 °C
Yield: 69 %

Procedure:
A mixture of 20 g p-isopropenylphenol, 1.1 equivalents ethylene carbonate, 0.02 equivalent potassium fluoride dihydrate, and 200 ml N,N-dimethylformamide (DMF) was heated at about 150° C. for about 1.5 hours. After removal of DMF under reduced pressure, the crude product was distilled. 2-(4-(1-Methylethenyl)phenoxy)ethanol, bp 143° C./7 torr, was obtained as a white solid in 69% yield.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)=O.[C:10]([CH2:12][C:13]([NH2:15])=[S:14])#[N:11]>>[S:6]1[CH:7]=[CH:8][CH:9]=[C:5]1[C:3]1[N:15]=[C:13]([CH2:12][C:10]#[N:11])[S:14][CH:2]=1
Reactant: N#CCC(N)=S
Reactant: O=C(CBr)c1cccs1
Product: N#CCc1nc(-c2cccs2)cs1
Yield: 49 %

Procedure:
This compound was synthesized from 2-bromo-1-(thiophen-2-yl)ethanone and 2-cyanothioacetamide as described in example 1 step 1 (0.25 g, yield 49%): 1H NMR (400 MHz, CDCl3) δ 7.47 (d, J=3.4 Hz, 1H), 7.36 (s, 1H), 7.33 (d, J=5.1 Hz, 1H), 7.09 (t, J=4.2 Hz, 1H), 4.17 (s, 2H). MS (ESI) m/z: Calculated for C9H6N2S2: 206.00. found: 207.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:29]([NH2:30])=[N:28][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[N:15]=[CH:16][C:11]=2[CH:10]=1.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:38]=[CH:37][C:36]([N:39]=[C:40]=[O:41])=[CH:35][CH:34]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:29]([NH:30][C:40]([NH:39][C:36]2[CH:35]=[CH:34][C:33]([C:32]([F:31])([F:42])[F:43])=[CH:38][CH:37]=2)=[O:41])=[N:28][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: CN1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(N)nc3n2)CC1
Product: CN1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(NC(=O)Nc4ccc(C(F)(F)F)cc4)nc3n2)CC1

Procedure:
6-(2, 6-Dichlorophenyl)-N2 -[3-(4-methyl-piperazin-1-yl)-propyl]-pyrido[2,3-d]pyrimidine-2,7-diamine from Example 36 was reacted with trifluoro-p-tolyl isocyanate according to the general procedure of Example 37. Chromatography, eluting first with ethyl acetate:methyl alcohol:triethylamine (90:10:1) then switching to ethyl acetate:ethanol:triethylamine (9:2:1) gave 0.8650 g of the title compound 1-{6-(2,6-dichlorophenyl)-2-[3-(4-methyl-piperazin-1-yl)-propylamino]-pyrido[2,3-d]pyrimidin-7-yl}-3-(4-trifluoromethyl-phenyl)-urea, ESMS (20/80 MeOH/CH3CN +0.1% AcOH): M+ +H=633; mp 145.5-151° C.
Reaction SMILES: [CH3:1][C:2]([C:12]1[C:20]2[O:19][CH2:18][CH2:17][C:16]=2[CH:15]=[C:14]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:13]=1)([CH3:11])[CH2:3][C:4]1([C:7]([F:10])([F:9])[F:8])[CH2:6][O:5]1.[NH:25]1[C:33]2[CH2:32][CH2:31][CH2:30][C:29](=[O:34])[C:28]=2[CH:27]=[CH:26]1.[O-]CC.[Na+]>C(O)C.C(OCC)(=O)C>[OH:5][C:4]([C:7]([F:9])([F:8])[F:10])([CH2:3][C:2]([C:12]1[C:20]2[O:19][CH2:18][CH2:17][C:16]=2[CH:15]=[C:14]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:13]=1)([CH3:11])[CH3:1])[CH2:6][N:25]1[C:33]2[CH2:32][CH2:31][CH2:30][C:29](=[O:34])[C:28]=2[CH:27]=[CH:26]1
Reactant: O=C1CCCc2[nH]ccc21
Reactant: CC(C)(CC1(C(F)(F)F)CO1)c1cc(S(C)(=O)=O)cc2c1OCC2
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(CC(O)(Cn1ccc2c1CCCC2=O)C(F)(F)F)c1cc(S(C)(=O)=O)cc2c1OCC2
Temperature: 85 °C
Yield: 48.5 %

Procedure:
To a suspension of 7-[1,1-dimethyl-2-(2-trifluoromethyloxiranyl)ethyl]-5-methanesulfonyl-2,3-dihydrobenzofuran (101 mg, 0.33 mmol) and 1,5,6,7-tetrahydroindol-4-one (74.9 mg, 0.56 mmol) in 0.75 mL of anhydrous ethanol was added sodium ethoxide (21 wt. % solution in ethanol, 103 μL). After heating at 85° C. for 16 hours, the reaction mixture was diluted with ethyl acetate, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography with silica gel (eluted with 50% to 60% ethyl acetate-hexanes) to give 80.0 mg (58% yield) of the title compound as a white solid, m.p. 207° C.-208° C.
Reaction SMILES: [C:1]([C:3]1[C:12]([CH2:13][CH2:14][CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])=[CH:11][C:10]2[C:9]([CH3:25])([CH3:24])[CH2:8][CH2:7][C:6]([CH3:27])([CH3:26])[C:5]=2[CH:4]=1)#N.[H-].C([Al+]CC(C)C)C(C)C.C(O)(=[O:40])C.O>ClCCl>[CH:1]([C:3]1[C:12]([CH2:13][CH2:14][CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])=[CH:11][C:10]2[C:9]([CH3:25])([CH3:24])[CH2:8][CH2:7][C:6]([CH3:27])([CH3:26])[C:5]=2[CH:4]=1)=[O:40]
Reactant: CC1(C)CCC(C)(C)c2cc(CCCO[Si](C)(C)C(C)(C)C)c(C#N)cc21
Reactant: CC(=O)O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2cc(CCCO[Si](C)(C)C(C)(C)C)c(C=O)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 53 %

Procedure:
To a solution of 4.6 g (11.9 mmol) of 2-cyano-3-(3-t-butyldimethylsiloxypropyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene.in 40 mL of dichloromethane at −78° C. was added 17.9 mL (17.9 mmol) of diisobutylaluminum hydride (1.0 M in toluene). The reaction mixture was stirred and allowed to slowly warm to room temperature. After 16 hours, acetic acid was added dropwise, followed by addition of water and dichloromethane. The organic fraction was separated, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (gradient elution: 4-25% ethyl acetate/hexane) to afford 2.48 g (53%) of 2-formyl -3-(3-t-butyldimethylsiloxypropyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene. M+=389).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3([N:18]4[CH2:23][CH2:22][C:21]([CH2:30][C:31]([CH3:33])=[CH2:32])([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[O:20][C:19]4=[O:34])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1.[C:35]([O-])([O-])=O.[K+].[K+].IC>C(#N)C>[CH3:35][N:4]1[CH:5]=[CH:6][C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3([N:18]4[CH2:23][CH2:22][C:21]([CH2:30][C:31]([CH3:33])=[CH2:32])([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[O:20][C:19]4=[O:34])[CH2:16][CH2:17]3)=[CH:11][CH:10]=2)=[CH:8][C:3]1=[O:2]
Reactant: O=C([O-])[O-]
Reactant: C=C(C)CC1(c2ccccc2)CCN(C2(c3ccc(-c4ccnc(OC)c4)cc3)CC2)C(=O)O1
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: C=C(C)CC1(c2ccccc2)CCN(C2(c3ccc(-c4ccn(C)c(=O)c4)cc3)CC2)C(=O)O1
Temperature: 90 °C
Yield: 83.4 %

Procedure:
A mixture of 3-(1-(4-(2-methoxypyridin-4-yl)phenyl)cyclopropyl)-6-(2-methylallyl)-6-phenyl-1,3-oxazinan-2-one (26.5 mg, 0.058 mmol), K2CO3 (16 mg, 2 equiv), iodomethane (250 μL, excess) and acetonitrile (3 mL) was heated at 90° C. for 1.5 h in the microwave oven. LC-MS found the reaction was complete. The mixture was filtered, concentrated, acidified with 5% aq HCl and purified by prep HPLC to afford the title compound (22 mg, 83%). LC-MS Method 1 tR=1.68 min, m/z=455.
Reaction SMILES: O=[C:2]1[C:11]2[CH2:12][CH2:13]O[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([O:15][C:16]([F:19])([F:18])[F:17])[C:4]=2[NH:3]1.[CH3:20][C:21]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:22]=1[NH2:23]>C(O)COCCO.[Cl-].[Na+].O>[CH3:20][C:21]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:22]=1[N:23]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([O:15][C:16]([F:19])([F:18])[F:17])[C:4]=3[N:3]=[C:2]([NH:3][CH2:4][CH2:5][OH:15])[C:11]=2[CH2:12][CH2:13]1
Reactant: COc1ccc(N)c(C)c1
Reactant: O=c1[nH]c2c(OC(F)(F)F)cccc2c2c1CCO2
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: OCCOCCO
Product: COc1ccc(N2CCc3c(NCCO)nc4c(OC(F)(F)F)cccc4c32)c(C)c1
Temperature: 250 °C
Yield: 160.3 %

Procedure:
4-Oxo-6-trifluoromethoxy-2,3,4,5-tetrahydrofuro[3,2-c]quinoline(5.0 g, 19 mmol) was dissolved in diethylene glycol(30 ml) and 2-methyl-4-methoxyaniline(6.1 ml, 46 mmol) was added. The reaction mixture was refluxed at 250° C. for 15 hours, diluted in brine(20 ml), and the aqueous layer was extracted with dichloromethane(15 ml) for 3 times. The organic layer was washed with water(15 ml) for 3 times, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified with ethyl acetate as eluent by silica gel chromatography to obtain 6.6 g of desired compound as solid in 91% of yield.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[C:4]([Cl:14])[N:3]=1.[NH2:15][C:16]1[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[CH:18][N:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>C(OCC)(=O)C.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:14][C:4]1[N:3]=[C:2]([NH:15][C:16]2[CH:21]=[C:20]([CH:19]=[CH:18][N:17]=2)[C:22]#[N:23])[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=1
Reactant: Clc1cc(C2CCOCC2)cc(Cl)n1
Reactant: N#Cc1ccnc(N)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: N#Cc1ccnc(Nc2cc(C3CCOCC3)cc(Cl)n2)c1
Temperature: 80 °C
Yield: 54.5 %

Procedure:
To a 25 mL round-bottomed flask charged with 2,6-dichloro-4-(tetrahydro-2H-pyran-4-yl)pyridine (1.20 g, 5.20 mmol, 1.00 equiv), 2-aminopyridine-4-carbonitrile (620 mg, 5.20 mmol, 1.00 equiv), cesium carbonate (2.40 g, 7.20 mmol, 1.40 equiv), 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (170 mg, 0.260 mmol, 0.0500 equiv), and tris(dibenzylidineacetone)dipalladium(0) (120 mg 0.130 mmol, 0.0250 equiv) was added 1,4-dioxane (10 mL) under nitrogen atmosphere. The reaction was then heated to 80° C. for 16 h after which the mixture was cooled to room temperature, diluted with ethyl acetate (15 mL) and washed with water (2×15 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. Purification by flash column chromatography (40:60 ethyl acetate/heptane) afforded the desired product as a yellow solid (892 mg, 51% yield). 1H NMR (400 MHz, DMSO-d6), δ: 10.38 (s, 1H), 8.49 (d, J=5.3 Hz, 1H), 7.94 (s, 1H), 7.63 (s, 1H), 7.34-7.23 (dd, J=4.0, 2.0 Hz, 1H), 6.98 (d, J=1.1 Hz, 1H), 3.95 (dd, J=11.9, 4.0 Hz, 2H), 3.44 (td, J=11.9, 2.4 Hz, 2H), 2.82 (tt, J=12.0, 3.6 Hz, 1H), 1.77-1.70 (m, 2H), 1.69-1.61 (m, 2H).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=2)[NH:12][CH:11]=[C:10]3[CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:25][N:26]1[CH:30]=[C:29]([S:31](Cl)(=[O:33])=[O:32])[N:28]=[CH:27]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:25][N:26]1[CH:30]=[C:29]([S:31]([N:22]2[CH2:23][CH2:24][CH:19]([C:10]3[C:9]4[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=[C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[CH:8]=4)[NH:12][CH:11]=3)[CH2:20][CH2:21]2)(=[O:33])=[O:32])[N:28]=[CH:27]1
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)c[nH]c12
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cnc(S(=O)(=O)N2CCC(c3c[nH]c4c(C(N)=O)cc(-c5ccccc5)cc34)CC2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 40.4 %

Procedure:
To 5-phenyl-3-(4-piperidinyl)-1H-indole-7-carboxamide (40 mg, 0.12 mmol) in methylene chloride (5 mL) at 0° C., 1-methyl-1H-imidazole-4-sulfonyl chloride (27.1 mg, 0.14 mmol) and triethylamine (0.07 mL, 0.50 mmol) were added. The reaction mixture was stirred at 0° C. for 30 min. Then the reaction mixture was partitioned between methylene chloride and water, the aqueous layer was extracted with methylene chloride (25 mL×2) and combined organic phase was dried with Mg2SO4 and concentrated by reduce pressure, and purified by Gilson HPLC (reverse phase, eluting with CH3CN/Water, 0.1% TFA, 10/90, v/v, over 15 min) to give the title compound (22.5 mg, 39%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[C:6]([SH:12])=[N:5][N:4]=1.I[CH2:14][CH3:15].C(N(CC)CC)C>C(O)C>[CH2:14]([S:12][C:6]1[N:7]([CH2:8][CH:9]([CH3:10])[CH3:11])[C:3]([CH2:2][OH:1])=[N:4][N:5]=1)[CH3:15]
Reactant: CCI
Reactant: CC(C)Cn1c(S)nnc1CO
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCSc1nnc(CO)n1CC(C)C
Yield: 87 %

Procedure:
A solution of 3-hydroxymethyl-4-isobutyl-5-mercapto-4H-1,2,4-triazole (1.0 g), iodoethane (1.0 g) and triethylamine (1.1 ml) in ethanol (10 ml) was stirred for 2 days at 70° C. The solvent was removed under reduced pressure, and the obtained residue was purified by column chromatography (ethanol:ethyl acetate 1:9→1:5), to give 5-ethylthio-3-hydroxymethyl-4-isobutyl-4H-1,2,4-triazole (1.0 g) as pale yellow oil.
Reaction SMILES: [Se](=O)=[O:2].[C:4]([O:9][C:10]([NH:12][C:13]1[S:14][CH:15]=[C:16]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:17]=1)=[O:11])([CH2:7][CH3:8])([CH3:6])[CH3:5]>O1CCOCC1.O>[C:4]([O:9][C:10]([NH:12][C:13]1[S:14][CH:15]=[C:16]([C:18](=[O:2])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:17]=1)=[O:11])([CH2:7][CH3:8])([CH3:6])[CH3:5]
Reactant: O=[Se]=O
Reactant: CCOC(=O)Cc1csc(NC(=O)OC(C)(C)CC)n1
Agent: CCOC(=O)Cc1csc(=NC(=O)OC(C)(C)CC)[nH]1
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)C(=O)c1csc(NC(=O)OC(C)(C)CC)n1

Procedure:
To a solution of selenium dioxide (0.11 g.) in a mixture of dioxane (2.5 ml.) and water (0.1 ml.) was added a mixture of ethyl 2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)acetate, which can be represented as ethyl 2-(tert-pentyloxycarbonylimino-2,3-dihydro-1,3-thiazol-4-yl)acetate, (0.3 g.) and dioxane (2.5 ml.) at 110° C. with stirring. The mixture was stirred for 30 minutes at the same temperature, and selenium dioxide (0.055 g.) was further added thereto and then the mixture was stirred for 1.5 hours at the same temperature. After the reaction, the reaction liquid is separated by decantation, and the residue was washed with a small amount of dioxane. The reaction liquid and washing are combined together, and then the solvents were distilled off. The residue was dissolved in ethyl acetate. The solution was washed with water and dried and then the solvent was distilled off to give brown oil of ethyl 2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)glyoxylate, which can be represented as ethyl 2-(tert-pentyloxycarbonylimino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylate, (0.22 g.).
Reaction SMILES: [OH:1][C:2]([CH3:28])([CH:9]=[CH:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[CH:15][CH:14]=1)[CH2:3][C:4]([O:6]CC)=[O:5].[OH-].[Na+].[Br:31]Br.C(=O)([O-])O.[Na+]>CO>[OH:1][C:2]1([CH3:28])[CH:9]([Br:31])[CH:10]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[CH:15][CH:14]=2)[O:6][C:4](=[O:5])[CH2:3]1
Reactant: BrBr
Reactant: CCOC(=O)CC(C)(O)C=CCCc1ccc(OCc2ccc(F)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(O)CC(=O)OC(CCc2ccc(OCc3ccc(F)cc3)cc2)C1Br

Procedure:
The carboxylic acid (900 mg) prepared by hydrolyzing 1.03 g of ethyl 3-hydroxy-3-methyl-7-[p-(p-fluorobenzyloxy)phenyl]-4-heptenoate with 4 N sodium hydroxide solution in methanol, was treated with 0.2 ml of bromine in an aqueous sodium hydrogen carbonate solution and the reaction mixture was worked up according to the method described in Example 1 (b). The product was recrystallized from a mixture of acetone and ethyl ether (1:10) to yield 1.2 g of the desired compound melting at 160°-163° C.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10]2[C:15]([Cl:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:10]3[C:15]([Cl:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: Cc1sc2nc(Cl)nc(NCc3ccccc3)c2c1Cl
Product: Cc1sc2nc(-n3cncn3)nc(NCc3ccccc3)c2c1Cl

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2,5-dichloro-6-methyl-4-benzylamino-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-5-chloro-6-methyl-4-benzylamino-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH:23]=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH:47][C:48]1C=C(C=C[C:55]=1O)C=O.C(Br)CCCCCCC/C=C\CCCCCCCC.OC1C=C(C=CC=1O)C(OCC)=O>>[CH2:1]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[C:23]([O:47][CH2:48][CH3:55])=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCCOc1ccc(C=O)cc1OCCCCCCCC/C=C\CCCCCCCC
Reactant: O=Cc1ccc(O)c(O)c1
Agent: CCCCCCCC/C=C\CCCCCCCCBr
Agent: CCOC(=O)c1ccc(O)c(O)c1
Product: CCCCCCCC/C=C\CCCCCCCCOc1ccc(C(=O)OCC)cc1OCCCCCCCC/C=C\CCCCCCCC

Procedure:
The first step was the synthesis of 3,4-di(oleyloxy)benzaldehyde 8a by the O-alkylation of 3,4-dihydroxy benzaldehyde 7a with oleyl bromide (Scheme 1 as shown in FIG. 3). Similarly, the bis-O-alkylation of ethyl 3,4-dihydroxybenzoate 7b with oleyl bromide was used to form ethyl 3,4-di(oleyloxy)benzoate 8b using the method of Safinya et al.,23,24 Subsequent cleavage of 8b with KOH was carried out to give the acid 8c (Scheme 1) followed by treatment with oxalyl chloride to give the desired acid chloride 8d.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][C@H:8]1[CH2:32]O)=[O:6])[CH:2]=[CH2:3].CS(C)=O.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.C(OP([CH2:59][C:60]([N:62]([CH3:64])[CH3:63])=[O:61])(OCC)=O)C.[H-].[Na+]>>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][C@H:8]1/[CH:32]=[CH:59]/[C:60]([N:62]([CH3:63])[CH3:64])=[O:61])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CO
Reactant: CCOP(=O)(CC(=O)N(C)C)OCC
Agent: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1/C=C/C(=O)N(C)C
Yield: 88.1 %

Procedure:
The same operation as in Reference Example 4-1) was carried out by using (2S,4S)-N-allyloxycarbonyl-2-hydroxymethyl-4-tritylthiopyrrolidine (the compound obtained in Reference Example 3-1); 2.00 g, 4.35 mmol), dimethyl sulfoxide (0.87 ml, 12.2 mmol), oxalyl chloride (0.56 ml, 6.5 mmol), triethylamine (3.03 ml, 21 8 mmol), 2-(diethylphosphono)-N,N-dimethylacetamide (1.17 g, 5.22 mmol) and 60% sodium hydride (174 mg, 4.35 mmol), followed by flash column chromatographic purification on silica gel (Wakogel® C-300, 40 ml, elution with hexane-ethyl acetate 1 1) to give the title compound (2.02 g, 88.1% yield)