Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10](Cl)=[C:9]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[CH3:17][O:18][CH2:19][CH2:20][NH2:21]>>[Cl:1][C:2]1[C:10]([NH:21][CH2:20][CH2:19][O:18][CH3:17])=[C:9]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1Cl
Reactant: COCCN
Agent: Cl
Product: COCCNc1c(S(C)(=O)=O)ccc(C(=O)O)c1Cl
Reaction time: 96 h

Procedure:
A solution of 5.0 g (19 mmol) of 2,3-dichloro-4-methylsulfonylbenzoic acid in 50 mL of 60 percent aqueous 2-methoxyethylamine was heated at reflux with stirring for 4 days. The dark mixture was then acidified with aqueous hydrochloric acid and extracted with dichloromethane. The extract was dried over magnesium sulfate and concentrated by evaporation under reduced pressure to obtain 8 g of the title compound as an impure dark oil. A 5.7 g portion of the this was converted to the methyl ester by refluxing overnight in 100 mL of a 50:1 mixture of methanol and concentrated sulfuric acid. The volatiles were removed by evaporation under reduced pressure and the residue obtained was partitioned between diethyl ether and water. The ethereal phase was dried over magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was purified by flash column chromatography eluting with a mixture of ethyl acetate and hexane. The product fractions were then hydrolyzed by heating with stirring in 70 mL of a 5:2 mixture of methanol and 1N aqueous sodium hydroxide solution. The methanol was removed by evaporation under reduced pressure. The aqueous residue was washed with diethyl ether, acidified with concentrated hydrochloric acid and extracted with dichloromethane. The dichloromethane extract was dried over magnesium sulfate and concentrated by evaporation under reduced pressure to obtain 2.8 g the title compound as a light green solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)#[N:2].O[C@@H:11]1[CH2:16][CH2:15][C@H:14]([C:17]([O:19][CH3:20])=[O:18])[CH2:13][CH2:12]1.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][C@H:11]1[CH2:16][CH2:15][C@H:14]([C:17]([O:19][CH3:20])=[O:18])[CH2:13][CH2:12]1)#[N:2]
Reactant: N#Cc1cccc(O)c1
Reactant: COC(=O)[C@H]1CC[C@@H](O)CC1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: COC(=O)[C@H]1CC[C@H](Oc2cccc(C#N)c2)CC1

Procedure:
3-Cyanophenol (3.00 g, 25.2 mmol) and methyl cis-4-hydroxycyclohexanecarboxylate (2.66 g, 16.8 mmol) were dissolved in toluene (80 mL), and cyanomethylenetributylphosphorane (6.6 mL, 25.2 mmol) was added thereto, and then, the resulting mixture was heated to reflux under a nitrogen atmosphere for 2.5 hours.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][N:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].Br[CH2:16][CH2:17]Br.Cl>C(OCC)C.CS(C)=O.O>[CH:7](=[N:6][C:5]1([C:4]([O:3][CH2:1][CH3:2])=[O:14])[CH2:17][CH2:16]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCCBr
Reactant: CCOC(=O)CN=Cc1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C1(N=Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.9 %

Procedure:
260 g (2.3 moles) of potassium tert.-butylate are added a little at a time to 200 g (1.05 moles) of N-benzylideneglycine ethyl ester and 90.5 ml (1.05 moles) of 1,2-dibromoethane in 900 ml of dry diethyl ether and 300 l of dry dimethylsulfoxide, so that the well-stirred mixture remains at from 25° to 35° C. The mixture is stirred at room temperature overnight and excess base is then neutralized by addition of 4N hydrochloric acid. The mixture is diluted with 1.5 l of water and the ethereal phase is separated off, washed with twice 300 ml of water, dried with sodium sulfate and evaporated to give 155 g (68%) of ethyl N-benzylidene-1-aminocyclopropanecarboxylate as an oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]>O>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[NH2:10])=[CH:5][CH:4]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)N(N)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 64 h

Procedure:
A quantity (25.0 g.; 0.14 mole) of (4-chlorophenyl)-hydrazine hydrochloride was suspended in 150 ml. of pyridine. The suspension was cooled to 0° C. and 16.9 g. (0.14 mole) of pivaloyl chloride was added with stirring. The reaction mixture was set aside at about 25° C. for 64 hrs. when 300 ml. of water was added. The precipitate that formed was collected on a filter and washed repeatedly with water, 1 N hydrochloric acid, and finally with water. The filter cake was dried under reduced pressure and 60° C. to remove water. After two recrystallizations from benzene and technical hexane there was thus obtained 24.1 g. of pivalic acid (4-chlorophenyl)hydrazide having a melting point of 137° to 138° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[NH2:5])[CH3:2].Cl[CH2:13][CH:14]1[O:19][CH2:18][CH2:17][CH2:16][O:15]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:15]1[CH2:16][CH2:17][CH2:18][O:19][CH:14]1[CH2:13][NH:5][C:4]1[C:6]([CH2:10][CH3:11])=[CH:7][CH:8]=[CH:9][C:3]=1[CH2:1][CH3:2]
Reactant: ClCC1OCCCO1
Reactant: CCc1cccc(CC)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cccc(CC)c1NCC1OCCCO1

Procedure:
2,6-Diethylaniline (75 grams), 2-chloromethyl-1,3-dioxane (14 grams), potassium carbonate (34 grams) and dimethylformamide (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 18 hours. After this time the mixture is filtered and distilled to yield the desired product N-(1,3-dioxan-2-ylmethyl)-2,6-diethylaniline.
Reaction SMILES: Br.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH2:6][CH2:5][CH2:4][CH2:3]1.C(N1CCOCC1)C.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[O:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH:42]1[O:47][NH:48][C:49]([C@H:51]([C@@H:61]([CH2:70][CH:71]([CH3:73])[CH3:72])[C:62]([NH:64][NH:65][CH2:66][CH:67]([CH3:69])[CH3:68])=[O:63])[CH2:52]/[CH:53]=[CH:54]/[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:50]>CN(C)C=O>[O:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH:42]1[O:47][NH:48][C:49]([C@H:51]([C@@:61]([C:8](=[O:10])[CH2:7][N:2]1[CH2:3][CH2:4][CH2:5][CH2:6]1)([CH2:70][CH:71]([CH3:73])[CH3:72])[C:62]([NH:64][NH:65][CH2:66][CH:67]([CH3:68])[CH3:69])=[O:63])[CH2:52]/[CH:53]=[CH:54]/[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:50]
Reactant: CC(C)CNNC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Reactant: O=C(O)CN1CCCC1
Agent: Br
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Product: CC(C)CNNC(=O)[C@@](CC(C)C)(C(=O)CN1CCCC1)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Reaction time: 1 h
Yield: 65 %

Procedure:
A solution of 0.309 g of 2-(1-pyrrolidinyl)acetic acid hydrogen bromide in 20 ml of dimethylformamide was treated in sequence with 0.324 ml of N-ethylmorpholine, 0.212 g of 1-hydroxybenzotriazole and 0.301 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride. Stirring was continued at room temperature and for 1 hour then 0.450 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide was added. Stirring was continued overnight at room temperature and then the solvent was evaporated and replaced by ethyl acetate. The ethyl acetate phase was washed with 5% aqueous sodium hydrogen carbonate and brine and then dried over anhydrous magnesium sulphate. Evaporation and trituration of the residue with diethyl ether gave 0.363 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methyl-2-[2-(1-pyrrolidinyl)acetyl]valerohydrazide in the form of a white solid.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([N:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)[CH:17]=2)=[O:14])=[CH:4][CH:3]=1.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33](B(O)O)[CH:32]=1>>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:13](=[O:14])[CH2:12][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([C:33]3[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=3)=[CH:3][CH:4]=2)=[CH:17][C:18]=1[N:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1
Reactant: OB(O)c1cccnc1
Reactant: COc1ccc(NC(=O)Cc2ccc(Br)c3ccccc23)cc1N1CCN(C)CC1
Product: COc1ccc(NC(=O)Cc2ccc(-c3cccnc3)c3ccccc23)cc1N1CCN(C)CC1

Procedure:
The title compound was prepared from 4-bromo-N-[4-methoxy-3-(4-methyipiperazin-1-yl)phenyl]-1-naphthylacetamide (E9) and 3-pyridylboronic acid using a similar procedure to Example 4 as a white solid (32%).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[N:6]([CH:8]=[N:9][N:10]=2)[CH:7]=1.[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C1COCC1>O>[Br:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:14][CH2:13][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]2)[C:5]2[N:6]([CH:8]=[N:9][N:10]=2)[CH:7]=1
Reactant: Clc1nc(Br)cn2cnnc12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2nc(Br)cn3cnnc23)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.4 %

Procedure:
A 100 mL round bottom flask was charged with 6-bromo-8-chloro-[1,2,4]triazolo[4,3-a]pyrazine (1.11 g, 4.73 mmol), tert-butyl piperazine-1-carboxylate (2.64 g, 14.2 mmol) and THF (50 mL). The resulting mixture was stirred at room temperature for 0.5 h. Reaction progress was monitored by TLC (EtOAc/petroleum ether=1:2). Work-up: the reaction mixture was diluted with water and extracted with EtOAc (50 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was further purified by flash column chromatography on silica gel with 20% EtOAc in petroleum ether, to afford 1.62 g (89%) of the product as a yellow solid.
Reaction SMILES: [CH:1]1([C:6](Cl)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:10][C:11]1[N:16]=[C:15]([C:17]2[CH:26]=[C:25]3[C:20]([CH2:21][CH2:22][N:23]([C:27]([O:29][CH:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)=[O:28])[CH2:24]3)=[CH:19][CH:18]=2)[CH:14]=[C:13]([N:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)[N:12]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[NH2:10][C:11]1[N:16]=[C:15]([C:17]2[CH:26]=[C:25]3[C:20]([CH2:21][CH2:22][N:23]([C:27]([O:29][CH:30]4[CH2:35][CH2:34][N:33]([C:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)=[O:7])[CH2:32][CH2:31]4)=[O:28])[CH2:24]3)=[CH:19][CH:18]=2)[CH:14]=[C:13]([N:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)[N:12]=1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)OC3CCNCC3)CC4)nc(N)n2)CC1
Reactant: O=C(Cl)C1CCCC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)OC3CCN(C(=O)C5CCCC5)CC3)CC4)nc(N)n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Cyclopentanecarbonyl chloride (2.0 uL, 0.016 mmol) was added to a mixture of piperidin-4-yl 7-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3,4-dihydroisoquinoline-2(1H)-carboxylate HCl salt (6.0 mg, 0.011 mmol) and N,N-diisopropylethylamine (9.3 uL, 0.054 mmol) in acetonitrile (0.4 mL). The reaction mixture was stirred at r.t. for 30 min., purified by RP-LCMS (pH=10) to afford the desired product. Analytic LCMS (M+H)+: m/z=548.3.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][C:13]2[CH:18]=[N:17][C:16]([O:19][CH3:20])=[CH:15][N:14]=2)=[CH:7][C:6]=1[CH3:21])=O.[NH2:22][C:23]([NH2:25])=[S:24]>CCO>[CH3:20][O:19][C:16]1[N:17]=[CH:18][C:13]([O:12][C:8]2[CH:9]=[C:10]([CH3:11])[C:5]([C:3]3[N:22]=[C:23]([NH2:25])[S:24][CH:2]=3)=[C:6]([CH3:21])[CH:7]=2)=[N:14][CH:15]=1
Reactant: NC(N)=S
Reactant: COc1cnc(Oc2cc(C)c(C(=O)CBr)c(C)c2)cn1
Solvent: CCO
Product: COc1cnc(Oc2cc(C)c(-c3csc(N)n3)c(C)c2)cn1
Yield: 15.8 %

Procedure:
A mixture of 2-bromo-1-{4-((5-methoxypyrazin-2-yl)oxy)-2,6-dimethylphenyl}ethanone (15-2, 2.70 g, 7.69 mmol) and thiourea (0.59 g, 7.69 mmol) in 95% EtOH (11.0 mL) was heated at reflux for 60 min. The solution was concentrated and added with water and saturated aqueous Na2CO3 (1.0 mL). The resultant precipitate was purified by column chromatography on silica gel (EtOAc:hexanes=2:1 as eluant) to give 4-{4-((5-methoxypyrazin-2-yl)oxy)-2,6-dimethylphenyl}thiazol-2-amine (15-3, 0.40 g) as yellow oils in 16% yield: 1H NMR (500 MHz, CDCl3) δ 7.91 (s, 1 H), 7.87 (s, 1 H), 6.77 (s, 2 H), 6.28 (s, 1 H), 5.19 (bs, 2 H), 3.96 (s, 3 H), 2.15 (s, 6 H).
Reaction SMILES: [CH:1]1([O:5][CH2:6][C:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[N:12]=[CH:11][C:10]=3[N:9](COCC[Si](C)(C)C)[C:8]=2[C:33]2[CH:38]=[CH:37][C:36]([O:39][CH:40]([F:42])[F:41])=[C:35]([O:43][CH:44]3[CH2:46][CH2:45]3)[CH:34]=2)[CH2:4][CH2:3][CH2:2]1.C1(OC2C=C(C3N(COCC[Si](C)(C)C)C4C=NN(COCC[Si](C)(C)C)C(=O)C=4C=3C)C=CC=2OC(F)F)CC1>>[CH:1]1([O:5][CH2:6][C:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:22])[CH3:23])[N:12]=[CH:11][C:10]=3[NH:9][C:8]=2[C:33]2[CH:38]=[CH:37][C:36]([O:39][CH:40]([F:41])[F:42])=[C:35]([O:43][CH:44]3[CH2:46][CH2:45]3)[CH:34]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(COC3CCC3)c(-c3ccc(OC(F)F)c(OC4CC4)c3)n2COCC[Si](C)(C)C)c1=O
Agent: Cc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)n(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Product: C[Si](C)(C)CCOCn1ncc2[nH]c(-c3ccc(OC(F)F)c(OC4CC4)c3)c(COC3CCC3)c2c1=O
Yield: 96.8 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Example 4-(b) except for using 479 mg (0.696 mmol) of 3-cyclobutoxymethyl-2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Example 13-(a) in place of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-methyl-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one, whereby 369 mg of the title compound was obtained as a white foam. (Yield: 97%)
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(N(CC)CC)C.Cl[C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22].O>C1COCC1>[NH2:6][C:4]([C:3]1[CH:7]=[C:8]([I:11])[CH:9]=[CH:10][C:2]=1[NH:1][C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:5]
Reactant: CCOC(=O)C(=O)Cl
Reactant: NC(=O)c1cc(I)ccc1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(=O)Nc1ccc(I)cc1C(N)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
To a solution of 2-amino-5-iodobenzamide (15.8 g, 60.3 mmol) and triethylamine (7.32 g, 72.4 mmol) in THF (300 mL) was added dropwise ethyl chloroglyoxylate (9.05 g, 66.3 mmol) under ice-cooling, and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the precipitated insoluble material was collected by filtration. The solid was washed with water to give ethyl ((2-(aminocarbonyl)-4-iodophenyl)amino)(oxo)acetate as a white powder (20.9 g, 96%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH:43]1[CH2:48][CH2:47][CH:46]([C:49]([O:51][CH2:52][CH3:53])=[O:50])[CH2:45][CH2:44]1>C1COCC1.O.C(OCC)(=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([N:43]1[CH2:48][CH2:47][CH:46]([C:49]([O:51][CH2:52][CH3:53])=[O:50])[CH2:45][CH2:44]1)=[O:12]
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCN(C(=O)c2cc3ccccc3[nH]2)CC1

Procedure:
1H-indole-2-carboxylic acid (2.49 g, 15.45 mmol), EDCI (4.44 g, 23.18 mmol), and HOBT (3.55 g, 23.18 mmol) were dissolved in THF (Volume: 30.0 ml). The reaction was allowed to stir for 15 minutes before DIEA (4.05 ml, 23.18 mmol) and ethyl piperidine-4-carboxylate (3.57 ml, 23.18 mmol) were added to the reaction. The reaction was diluted with water and ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, 1H HCl, and saturated sodium chloride. The organic layer was then dried over magnesium sulfate, filtered and concentrated. the resulting solid is then triturated with ethyl acetate. (Yield: 3.27 g, white solid) 1H-NMR (400 MHz, DMSO-d6) 11.55, 7.60, 7.41, 7.18, 7.04, 6.77, 4.40-4.27, 4.09, 3.18, 2.76-2.63, 1.97-1.88, 1.65-1.51, 1.20
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])=[CH:5]2.[Cl:20]C1C=C2C(=CC=1)C=NC(O)=C2>>[Cl:20][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])=[CH:5]2
Reactant: O=S(=O)(Oc1cc2cc(F)ccc2cn1)C(F)(F)F
Reactant: Oc1cc2cc(Cl)ccc2cn1
Product: O=S(=O)(Oc1cc2cc(Cl)ccc2cn1)C(F)(F)F

Procedure:
Following the procedure for trifluoromethanesulfonic acid 6-fluoroisoquinolin-3-yl ester, using 6-chloroisoquinolin-3-ol in place of 6-fluoroisoquinolin-3-ol, the title compound was obtained as a yellow solid. MS (ES+): m/z=311.69/313.63 [MH+]. HPLC: tR=3.88 min (ZQ2, polar—5 min).
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[F:14][C:15]1[CH:16]=[C:17](O)[CH:18]=[CH:19][CH:20]=1>>[F:14][C:15]1[CH:20]=[C:19]([CH:18]=[CH:17][CH:16]=1)[O:13][CH:10]1[CH2:11][CH2:12][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Reactant: Oc1cccc(F)c1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc(F)c2)C1
Yield: 83.9 %

Procedure:
The title compound (D37) (1.26 g) was prepared according to the experimental procedure described in Description 34 starting from 1-Boc-3-pyrrolidinol (1 g, 5.34 mmol) and 3-Fluorophenol (0.478 ml, 5.34 mmol).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35](Cl)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:38][CH2:39][CH:40]1[CH2:45][CH2:44][CH2:43][N:42]([CH:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)[CH2:41]1>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35]([N:49]3[CH2:48][CH2:47][CH:46]([N:42]4[CH2:43][CH2:44][CH2:45][CH:40]([CH2:39][OH:38])[CH2:41]4)[CH2:51][CH2:50]3)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: OCC1CCCN(C2CCNCC2)C1
Product: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(N2CCCC(CO)C2)CC1

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 3-hydroxymethyl-[1,4′]bipiperidine (ChemBridge) to give the title compound as a racemic mixture. HR-MS (ES, m/z) calculated for C39H51N6O3Cl2 [(M+H)+] 721.3394, observed 721.3392.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[C:10]2[CH:11]=[CH:12][C:13]([S:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])=[CH:14][C:9]=2[S:8][CH:7]=1)[CH3:2].O.[O-:27]S([O-])(=S)=O.[Na+].[Na+]>CC#N>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[C:10]2[CH:11]=[CH:12][C:13]([S:15]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])=[O:27])=[CH:14][C:9]=2[S:8][CH:7]=1)[CH3:2]
Reactant: O=S([O-])([O-])=S
Reactant: CCOC(=O)Cc1csc2cc(SCc3ccc(Cl)cc3Cl)ccc12
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)Cc1csc2cc(S(=O)Cc3ccc(Cl)cc3Cl)ccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of ethyl(6-((2,4-dichlorobenzyl)sulfanyl)-1-benzothiophen-3-yl)acetate (315 mg), water (3.00 mL) and CH3CN (3.00 mL) was added NaIO4 (164 mg) at room temperature. The mixture was stirred at room temperature for 1 day. To the mixture was added NaIO4 (164 mg), and the mixture was stirred for further 1 day. To the mixture was added saturated aqueous Na2S2O3 at room temperature, and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (204 mg). The residue was recrystallized from EtOAc-hexane to give the title compound.
Reaction SMILES: Br[C:2]1[N:13]2[C:5]([C:6]([CH3:14])=[N:7][C:8]3[S:9][CH:10]=[N:11][C:12]=32)=[C:4]([CH3:15])[N:3]=1.[C:16]([C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1)(=[O:18])[NH2:17].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:14][C:6]1[C:5]2[N:13]([C:2]([C:23]3[CH:24]=[C:19]([CH:20]=[CH:21][CH:22]=3)[C:16]([NH2:17])=[O:18])=[N:3][C:4]=2[CH3:15])[C:12]2[N:11]=[CH:10][S:9][C:8]=2[N:7]=1
Reactant: NC(=O)c1cccc(B(O)O)c1
Reactant: Cc1nc(Br)n2c1c(C)nc1scnc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Cc1nc(-c2cccc(C(N)=O)c2)n2c1c(C)nc1scnc12
Temperature: 100 °C
Yield: 53 %

Procedure:
Under argon atmosphere, a 5 mL microwave reaction vial was charged with 8-bromo-5,6-dimethyl-3-thia-1,4,7,8a-tetraaza-as-indacene from example 7 (10 mg, 0.035 mmol), 3-carbamoylphenylboronic acid (9 mg, 0.053 mmol) and Cs2CO3 (23 mg, 0.071 mmol) in DMF (3 mL) followed by the addition of Pd(dppf)Cl2 (3 mg, 3.5 μmol). The resulting suspension was heated on microwave at 100° C. for 1 hr. The reaction mixture was filtered and the filtrate was purified by Prep-HPLC to give the title compound (6 mg, yield: 52%) as a white solid.
Reaction SMILES: [CH2:1]([C:4]1[S:5][C:6]([CH:9]=O)=[CH:7][N:8]=1)[CH2:2][CH3:3].C(OP(/[C:19](=[CH:25]\[CH3:26])/[C:20]([O:22][CH2:23][CH3:24])=[O:21])(OCC)=O)C>>[CH2:1]([C:4]1[S:5][C:6]([CH:9]=[CH:26][CH:25]=[CH:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:7][N:8]=1)[CH2:2][CH3:3]
Reactant: C/C=C(/C(=O)OCC)P(=O)(OCC)OCC
Reactant: CCCc1ncc(C=O)s1
Product: CCCc1ncc(C=CC=CC(=O)OCC)s1

Procedure:
Using the procedure of Example 4, 2-propyl-5-thiazole-carboxaldehyde [prepared by reaction of manganese dioxide and 2-propyl-5-hydroxymethyl-thiazole in benzene] and ethyl diethylphosphonocrotonate were reacted to obtain ethyl 5-(2-propyl-5-thiazolyl)-2,4-pentadienoate melting at 52°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:13]2[CH2:18][CH2:17][N:16]([C:19]([SH:21])=[S:20])[CH2:15][CH2:14]2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[OH-].[Na+].[CH3:24]I>CO.[Cl-].[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:13]2[CH2:14][CH2:15][N:16]([C:19]([S:21][CH3:24])=[S:20])[CH2:17][CH2:18]2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(N2CCN(C(=S)S)CC2)cc(OC)c1OC
Reactant: CI
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(N2CCN(C(=S)SC)CC2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.8 %

Procedure:
In a nitrogen atmosphere, 1.5 g (4.6 mmol.) of 4-(3,4,5-trimethoxyphenyl)-1-piperazinecarbodithioic acid was suspended in methanol. After addition of 0.2 g of granular sodium hydroxide, the suspension was stirred at room temperature for one hour. The reaction mixture was chilled in a mixture of ice and sodium chloride. To the reaction mixture was dropwise added a solution of 0.29 ml of methyl iodide in 3.7 ml of methanol. After the addition was complete, the mixture was stirred at room temperature for 1 hour. Precipitated crystals were collected by filtration to give 0.8 g of the desired compound as a gray-brown powder, m.p. 135°-137° C. (decomp.), yield 50.8%.