Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1.Cl[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][S:28]([NH2:31])(=[O:30])=[O:29]>C(N(C(C)C)C(C)C)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]2[CH2:10][CH2:11][N:12]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][S:28]([NH2:31])(=[O:30])=[O:29])[CH2:13][CH2:14]2)[CH:5]=[CH:6][CH:7]=1
Reactant: NS(=O)(=O)CCCCCCCl
Reactant: Clc1cccc(C(c2ccccc2)N2CCNCC2)c1
Solvent: CCN(C(C)C)C(C)C
Product: NS(=O)(=O)CCCCCCN1CCN(C(c2ccccc2)c2cccc(Cl)c2)CC1
Yield: 95.6 %

Procedure:
1-[(3-Chlorophenyl)phenylmethyl]piperazine (500 mg, 1.74 mmol) and 6-chlorohexanesulfonamide (383 mg, 1.92 mmol) synthesized referring to a process described in J. Org. Chem. 52, 2162 (1987) were refluxed in N-ethyldiisopropylamine (5 ml) for 6 hours. The reaction mixture was concentrated in vacuo, and water was added thereto. The mixture was extracted with chloroform. The chloroform layer was washed with water, and dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform-methanol (100:3), to give 6-[4-[(3-chlorophenyl)phenylmethyl]1-piperazinyl]hexanesulfonamide (749 mg) as a colorless oil (yield based on 1-[(3-chlorophenyl)phenylmethyl]piperazine: 95.4%).
Reaction SMILES: [Cl:1][C:2]1[C:11]([NH:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:10][C:9]([Cl:18])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:19](=O)([O-])[O-].[Cs+].[Cs+].CI>C(#N)C>[Cl:1][C:2]1[C:11]([N:12]([CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17]2)[CH3:19])=[CH:10][C:9]([Cl:18])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Cl)cc(NC2CCCC2)c1Cl
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CI
Product: COC(=O)c1cc(Cl)cc(N(C)C2CCCC2)c1Cl
Temperature: 80 °C
Yield: 93.3 %

Procedure:
To a stirred solution of methyl 2,5-dichloro-3-(cyclopentylamino)benzoate (0.275 g, 0.958 mmol) in acetonitrile (5 mL) was added cesium carbonate (0.622 g, 1.9 mmol) and methyl iodide (0.689 g, 4.78 mmol). The reaction mixture was heated at 80° C. for 18 h. On completion, the reaction was cooled to room temperature and filtered. The residue was washed with ethyl acetate and the filtrate was concentrated to afford methyl 2,5-dichloro-3-(cyclopentyl(methyl)amino)benzoate (0.27 g, 93%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]CCBr)=[CH:11][CH:10]=1)[C:2]1C=CC=CC=1.[NH:19]1[CH:23]=[N:22][CH:21]=[N:20]1>>[N:19]1([CH2:2][CH2:1][O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:23]=[N:22][CH:21]=[N:20]1
Reactant: c1nc[nH]n1
Reactant: BrCCOc1ccc(OCc2ccccc2)cc1
Product: Oc1ccc(OCCn2cncn2)cc1

Procedure:
In a manner analogous to that described in Example 1(b), from 1-benzyloxy-4-(2-bromoethoxy)benzene and 1H-1,2,4-triazole, 4-[2-(1H-1,2,4-triazol-1-yl)ethoxy]phenol was obtained.
Reaction SMILES: Br[CH2:2][C:3](=[CH2:7])[C:4]([OH:6])=[O:5].[CH2:8]([O:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([OH:21])=[O:20])=[CH:15][CH:14]=1)[CH2:9][CH2:10][CH3:11].[Na].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH2:8]([O:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH2:2][C:3](=[CH2:7])[C:4]([OH:6])=[O:5])(=[O:21])=[O:20])=[CH:15][CH:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCOc1ccc(S(=O)O)cc1
Reactant: C=C(CBr)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: C=C(CS(=O)(=O)c1ccc(OCCCC)cc1)C(=O)O

Procedure:
A mixture of 2-bromomethylacrylic acid (1.0 g, 6.0 mmol), 4-butoxybenzenesulfinic acid, sodium salt (3.1 g, 13 mmol), sodium carbonate (1.9 g, 18 mmol) and dimethylformamide (20 mL) is refluxed overnight. The reaction mixture is then partitioned between ethyl acetate and aqueous 10% hydrochloric acid and the organic phase is concentrated in vacuo. The concentrate is chromatographed over silica gel 60 (230-400 mesh) with chloroform/methyl alcohol/acetic acid (94/5/1) and the eluate concentrated in vacuo to afford the title compound as a white solid.
Reaction SMILES: C(OP([CH2:9][CH:10]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[H-].[Na+].[C:19]1(=O)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.O>C(COC)OC>[C:19]1(=[CH:9][CH:10]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C1CCCCCC1
Reactant: CCOC(=O)C=CCP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C=CC=C1CCCCCC1
Temperature: 10 °C
Reaction time: 0.75 h

Procedure:
6.7 ml of ethyl 4-(diethoxyphosphoryl)-2-butenoate are dissolved in 7 ml of dimethoxyethane and the solution is then poured onto 1.3 g of 60% sodium hydride in 40 ml of dimethoxyethane. After stirring for 45 minutes, the mixture is cooled to 10° C., 3.2 ml of cycloheptanone are then added dropwise and the mixture is allowed to return to RT. After stirring for 4 hours, the mixture is poured onto cold water and then extracted with ether, and the extracts are dried and evaporated. The residue is chromatographed on silica, eluting with DCM. 1.9 g of the expected compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9](I)[O:10][C:3]=12.[C-:12]#[N:13].[K+]>CN(C=O)C.C(Cl)Cl.[Cu]I.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>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:12]#[N:13])[O:10][C:3]=12
Reactant: Clc1ccnc2cc(I)oc12
Reactant: [C-]#N
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#Cc1cc2nccc(Cl)c2o1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
In a sealed tube 7-chloro-2-iodofuro[3,2-b]pyridine (0.200 g, 0.72 mmol), KCN (0.093 g, 1.4 mmol), and copper (I) iodide (0.014 g, 0.072 mmol) were dissolved in 2 mL DMF. Pd(Ph3P)4 (0.041 g, 0.036 mmol) was added, the tube was flushed with nitrogen, and the reaction in the tube was stirred overnight at 100° C. The reaction was cooled to RT, diluted with DCM, and washed with water. The aqueous layer was extracted with DCM, and the combined organic layers were washed with brine, dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (gradient elution 0-50% EtOAc:Hex) to afford 7-chlorofuro[3,2-b]pyridine-2-carbonitrile as a white solid. MS: M+H+=179.4.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]=1)=O.[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:27]=1[NH:33]N.Cl>>[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:27]=1[N:33]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Reactant: Cc1ccc(C)c(NN)c1
Agent: Cl
Product: Cc1ccc(C)c(-n2nccc2-c2nn(-c3cccc(C(F)(F)F)c3)ccc2=O)c1
Yield: 88 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-trifluoromethyl-phenyl)-1H-pyridazin-4-one (A-3) and 2,5-dimethyl-phenylhydrazine×HCl according to the method described for Example 1 in 88% yield. MS: M=411.1 (M+H)+
Reaction SMILES: C([SiH](CC)CC)C.FC(F)(F)C(O)=O.[CH3:15][O:16][C:17](=[O:30])[CH2:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=2)[CH:21]=[C:20]1[CH3:29].[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[S:38]([C:41]1[C:46]([CH:47]=O)=[CH:45][CH:44]=[CH:43][N:42]=1)(=[O:40])=[O:39]>ClCCl.ClCCCl>[CH3:15][O:16][C:17](=[O:30])[CH2:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=2)[C:21]([CH2:47][C:46]2[C:41]([S:38]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[Cl:31])(=[O:40])=[O:39])=[N:42][CH:43]=[CH:44][CH:45]=2)=[C:20]1[CH3:29]
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Reactant: O=Cc1cccnc1S(=O)(=O)c1ccccc1Cl
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Cn1c(C)c(Cc2cccnc2S(=O)(=O)c2ccccc2Cl)c2cc(F)ccc21
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 71.5 %

Procedure:
A mixture of triethylsilane (0.76 mL), trifluoroacetic acid (0.61 mL) and 1,2-dichloroethane (3.0 mL) at −10° C. was treated dropwise with a mixture of (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester (0.070 g), 2-(2-chlorobenzenesulfonyl)-pyridine-3-carbaldehyde (0.089 g) and 1,2-dichloroethane (6.0 mL), and the resulting mixture was stirred at −10° C. for 15 minutes and then at room temperature for 4 hours. The mixture was diluted with dichloromethane, washed with saturated aqueous sodium hydrogen carbonate solution and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and pentane (1:4 to 4:1 by volume). Further purification by crystallisation from ethyl acetate and pentane gave the title compound as a white solid (0.11 g).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Cl:7][C:8]1[CH:9]=[C:10]([C:14](=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18]Cl)[CH:11]=[CH:12][CH:13]=1.[CH3:21][CH:22]([CH3:38])[C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:27]=1)=[O:24]>>[Cl:7][C:8]1[CH:9]=[C:10]([C:14](=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18][N:35]2[CH2:36][CH2:37][CH:32]([C:28]3[CH:27]=[C:26]([NH:25][C:23](=[O:24])[CH:22]([CH3:21])[CH3:38])[CH:31]=[CH:30][CH:29]=3)[CH2:33][CH2:34]2)[CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=C(CCCCCl)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(Cl)c3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 (K2CO3) using 1-(3-chlorophenyl)-5-chloro-1-pentanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 441.1 (M+H)+.
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]([CH3:28])[C:14](=[O:27])[C:15]3[CH:20]=[CH:19][C:18]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[CH:9][CH:8]=2)[C:3]1=[O:29].[CH:30]1([NH2:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH:21]1([C:18]2[CH:19]=[CH:20][C:15]([C:14]([N:13]([C:10]3[CH:11]=[CH:12][C:7]([N:4]4[CH2:5][CH2:6][CH:2]([NH:36][CH:30]5[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]5)[C:3]4=[O:29])=[CH:8][CH:9]=3)[CH3:28])=[O:27])=[CH:16][CH:17]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CN(C(=O)c1ccc(C2CCCCC2)cc1)c1ccc(N2CCC(Br)C2=O)cc1
Reactant: NC1CCCCC1
Product: CN(C(=O)c1ccc(C2CCCCC2)cc1)c1ccc(N2CCC(NC3CCCCC3)C2=O)cc1

Procedure:
N-[4-(3-Bromo-2-oxo-pyrrolidin-1-yl )phenyl]-4-cyclohexyl-N-methylbenzamide was reacted with cyclohexylamine by method L. This resulted in the product with the molecular weight of 473.66 (C30H39N3O2); MS (ESI): 474 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[F:9].[CH3:10][O:11][C:12](=[O:37])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][N:20]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:21](=[O:30])[C:22]#[C:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:14]=1>>[CH3:10][O:11][C:12](=[O:37])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][N:20]2[C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)/[C:22](=[C:23](\[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[C:3]([F:9])[CH:4]=3)/[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)/[C:21]2=[O:30])[CH:14]=1
Reactant: Fc1ccc(I)cc1F
Reactant: COC(=O)c1cccc(CN(C(=O)C#Cc2ccccc2)c2ccccc2)c1
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(\c3ccccc3)c3ccc(F)c(F)c3)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 5 starting from 1,2-difluoro-4-iodo-benzene (commercially available) and 3-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (300 Hz, CDCl3): δppm 3.90 (s, 3H), 4.96 (s, 2H), 6.58 (d, 1H), 6.70 (m, 2H), 7.07-7.32 (m, 4H), 7.34-7.43 (m, 6H), 7.50 (d, 1H), 7.94 (d, 1H), 8.02 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:18])([O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:17])[NH:15][NH2:16])=[CH:9][CH:8]=1)[CH:3]([F:5])[F:4].Cl.[C:20](N)(=N)[CH3:21].C(O)(=O)C>CN(C)C=O>[CH3:20][C:21]1[N:13]([C:10]2[CH:9]=[CH:8][C:7]([O:6][C:2]([F:18])([F:1])[CH:3]([F:4])[F:5])=[CH:12][CH:11]=2)[C:14](=[O:17])[NH:15][N:16]=1
Reactant: NNC(=O)Nc1ccc(OC(F)(F)C(F)F)cc1
Reactant: CC(=N)N
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Cc1n[nH]c(=O)n1-c1ccc(OC(F)(F)C(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.1 %

Procedure:
4-[4-(1,1,2,2-Tetrafluoroethoxy)phenyl]semicarbazide (6.0 g) and 10.6 g of acetamidine hydrochloride were dissolved in 100 ml of dimethylformamide. The solution was stirred for one hour at room temperature. After adding 6.6 g of acetic acid, the reaction solution was heated at 80° C. for seven hours and concentrated under reduced pressure. The residue was dissolved in a mixture of 200 ml of ethyl acetate and 40 ml of water. The separated organic layer was washed with water and saturated sodium chloride solution, dried and distilled off to remove the solvent. The residue was recrystallized from ethyl acetate to give 3.6 g of 5-methyl-4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-3(2H,4H)-1,2,4-triazolone as colorless needles.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[SH:15][CH2:16][CH2:17][C:18](O)=[O:19].C1(C)C(C)=CC=CC=1>CCCCCC>[NH:7]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:18](=[O:19])[CH2:17][CH2:16][SH:15])=[CH:10][CH:9]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CCS
Reactant: Nc1ccc(Nc2ccccc2)cc1
Solvent: CCCCCC
Solvent: Cc1ccccc1C
Product: O=C(CCS)Nc1ccc(Nc2ccccc2)cc1
Temperature: 140 °C

Procedure:
A mixture of 18.4 grams of N-phenyl-p-phenylene diamine, 10.6 grams of β-mercaptopropionic acid and 120 milliliters of xylene (technical grade) was heated to reflux (about 140° C.) under nitrogen atmosphere, with stirring. A 1.6 milliliter quantity of water (90% of theory) was removed from this mixture by azetropic distillation through a Vigreux column with the aid of Dean-Start trap, during a 13-hour period. A solid product was isolated in 18.7 grams quantity from the reaction mixture by cooling the latter, pouring into hexane, collecting the resultant crystalline product by filtration, washing the crushed crystalline product with more hexane and evaporating to dryness. The product was recrystallized from hot toluene to 17.6 grams (64.5%) of white platelets melting at 98.3°-99.5° C. The resultant new compound, N-(4-anilino-phenyl)beta-mercaptopropionamide, sometimes referred to hereafter as MPDA, had mercaptan assay of 93.8% of theoretical, on the basis of a potentiometric titration with an isopropyl alcohol solution of silver nitrate, following a method described R. M. Pierson, A. J. Costanza and A. H. Weinstein, J. Polymer Sci., 17, 234 (1955).
Reaction SMILES: [SH:1][C:2]1[C:3]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.Br[C:17]([CH3:24])([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:12]([C:11]1[CH:14]=[CH:15][C:8]([C:3]2[C:2]([S:1][C:17]([CH3:24])([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:7][CH:6]=[CH:5][N:4]=2)=[CH:9][CH:10]=1)#[N:13]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: N#Cc1ccc(-c2ncccc2S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Sc1cccnc1-c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.4 %

Procedure:
A mixture of 4-(3-mercaptopyridin-2-yl)benzonitrile (0.18 g, 0.85 mmol), ethyl 2-bromo-2-methylpropanoate (0.195 g, 1 mmol), and K2CO3 (0.138 g, 1.0 mmol) in DMF (2 mL) was stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was washed with water and extracted with ethyl acetate. The organic layer was dried over MgSO4, concentrated and purified by chromatography to yield ethyl 2-(2-(4-cyanophenyl)pyridin-3-ylthio)-2-methylpropanoate (0.137 g, 49%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:12]=[C:11]([Cl:20])[C:10]=1[F:21])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][C:9]1[CH:14]=[C:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:12]=[C:11]([Cl:20])[C:10]=1[F:21]
Reactant: CCN(CC)c1cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)c1cc(Cl)c(F)c(CN)c1

Procedure:
was prepared according to Scheme C1 (step B) from (3-chloro-5-diethylamino-2-fluoro-benzyl)-carbamic acid tert-butyl ester and TFA in CH2Cl2. MS (LC-MS): 231.0 [M]+; tR (HPLC conditions c): 2.29 min.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1.Cl.[CH3:19][NH:20][O:21][CH3:22].C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:20]([O:21][CH3:22])[CH3:19])=[O:7])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1
Reactant: O=C(O)c1ccc(F)cc1Nc1ccccc1
Reactant: CNOC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccc(F)cc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.9 %

Procedure:
To a solution of 4-fluoro-2-phenylamino-benzoic acid (10 g, 43.2 mmol) in DMF (100 mL) was added O-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluorophosphate (HBTU) (32.8 g, 86.5 mmol), N,O-dimethylhydroxylamine hydrochloride (5.3 g, 86.5 mmol), and triethylamine (26.0 g, 36.2 mL, 259 mmol) at room temp. The resulting mixture was stirred for 24 hr at room temperature. The reaction mixture was diluted with ethyl acetate and the organic layer was washed with water and brine. The organic layer was dried over anhydrous Na2SO4 and volatiles were removed under reduced pressure. The crude material was purified using silica gel column chromatography (100% hexanes ramped to 30% ethyl acetate in hexanes). Further purification was accomplished by recrystallization from 10% ethyl acetate in petroleum ether. The product 4-fluoro-N-methoxy-N-methyl-2-phenylamino-benzamide (9.35 g, 79%) was obtained as an off-white solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[F:28][C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][C:35]=1[O:36][C:37]1[CH:42]=[CH:41][N:40]=[C:39]2[CH:43]=[CH:44][S:45][C:38]=12)[NH2:32]>C1COCC1>[F:28][C:29]1[CH:30]=[C:31]([NH:32][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:33]=[CH:34][C:35]=1[O:36][C:37]1[CH:42]=[CH:41][N:40]=[C:39]2[CH:43]=[CH:44][S:45][C:38]=12
Reactant: Nc1ccc(Oc2ccnc3ccsc23)c(F)c1
Reactant: O=C(O)CCCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: O=C(CCCc1ccccc1)Nc1ccc(Oc2ccnc3ccsc23)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 4-phenylbutanoic acid (49 mg, 0.3 mmol) in 1 mL THF at −78° C. under nitrogen was added N-methyl morpholine (66 μL, 0.6 mmol) followed by isobutyl chloroformate (34 μL, 0.26 mmol). After 15 minutes, a solution of 3-fluoro-4-(thieno[3,2-b]pyridin-7-yloxy)aniline (Example 1, Step B) in 1 mL THF was added and the reaction mixture was warmed to reflux. After refluxing overnight, the reaction was cooled to room temperature and partitioned between CH2Cl2 (30 mL) and 10% citric acid (30 mL). The organics were isolated and washed 1×30 mL with 10% citric acid and 2×30 mL with saturated NaHCO3. The organics were dried (MgSO4), filtered, concentrated and loaded onto a Biotage 12S column with 2/3 EtOAc/hexanes and eluted. The fractions containing the product were pooled and concentrated to a white foam (63 mg, 77%). 1H NMR (400 MHz, CDCl3) δ 8.48 (d, 1H), 7.75 (d, 1H), 7.73 (m, 1H), 7.69 (br s, 1H), 7.55 (d, 1H), 7.29 (m, 2H), 7.20 (m, 5H), 6.50 (d, 1H), 2.72 (m, 2H), 2.38 (m, 2H), 2.09 (m, 2H). LRMS (ESI pos) m/e 407.0 (M+1).
Reaction SMILES: C(B([C:10]#[C:11][CH2:12][CH2:13][CH2:14][Cl:15])OC(C)C)(CC)C.[CH3:16][OH:17]>>[Cl:15][CH2:14][CH2:13][CH2:12][C:11]#[C:10][C:16](=[O:17])[C@H:11]([CH3:10])[CH2:12][CH3:13]
Reactant: CO
Reactant: CCC(C)B(C#CCCCCl)OC(C)C
Product: CC[C@@H](C)C(=O)C#CCCCCl

Procedure:
[R]-(-)-9-chloro-3-methyl-5-nonyn-4-one was prepared by the method of Example 35 from sec-butyl(5-chloro-1-pentynyl)isopropoxyborane. [α]75D -12.84 (c 1.89, MeOH); IR (neat) 2213, 1671 cm-1. 13C NMR (CDCl3) δ191.9, 92.2, 80.5, 50.0, 43.2, 30.5, 25.8, 16.4, 15.5, 11.4. MS m/e % (chemical ionization) 187 (100).
Reaction SMILES: [C:1]1([CH:7](O)[C:8]#[CH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C(C)=CC=CC=1C.FC(F)(F)S([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])(=O)=O>ClCCl>[Si:25]([O:24][CH2:9][C:8]#[C:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: C#CC(O)c1ccccc1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC#Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Phenyl-2-propyn-1-ol (7 g) was dissolved in dichloromethane at 0° C. under nitrogen. 2,6-Lutidine (6.17 ml) was added to the solution followed by dropwise addition of tert-butyldimethylsilyl trifluoromethane sulfonate (12.16 ml); the resulting solution was stirred overnight at room temperature. The dichloromethane was washed with water (2×), brine and dried (MgSO4) and solvent removed in vacuo. The residue was purified on flash silica using 100% petrol moving to 5% ethyl acetate/petrol, to afford the title compound as a yellow oil (10.31 g).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:18])[N:8]([CH2:11][CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:19]=O.[NH:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:28]=2[CH2:29][C:30](=[O:36])[NH:31]3)[CH2:23][CH2:22]1>>[CH3:1][C:2]1[C:6]2[C:7](=[O:18])[N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:19]=[C:29]1[C:28]2[C:32](=[CH:33][CH:34]=[CH:35][C:27]=2[CH:24]2[CH2:23][CH2:22][NH:21][CH2:26][CH2:25]2)[NH:31][C:30]1=[O:36]
Reactant: O=C1Cc2c(cccc2C2CCNCC2)N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Product: Cc1c(C=C2C(=O)Nc3cccc(C4CCNCC4)c32)[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Yield: 30.2 %

Procedure:
The title compound was prepared under the same conditions as described in Example 13 with 3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-piperidin-4-yl-1,3-dihydro-indol-2-one as starting materials to give 3-methyl-2-(2-oxo-4-piperidin-4-yl-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-pyrrolidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (18 mg, 30.2%) as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([NH2:10])[C:7](Cl)=[CH:6][C:5]=1[NH2:12])([O-:3])=[O:2].[Na].[SH:14][CH2:15][CH2:16][S:17]([OH:20])(=[O:19])=[O:18]>>[OH2:2].[N+:1]([C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([S:14][CH2:15][CH2:16][S:17]([OH:20])(=[O:19])=[O:18])=[CH:6][C:5]=1[NH2:12])([O-:3])=[O:2]
Reactant: Nc1cc([N+](=O)[O-])c(N)cc1Cl
Reactant: O=S(=O)(O)CCS
Agent: [Na]
Product: Nc1cc([N+](=O)[O-])c(N)cc1SCCS(=O)(=O)O
Product: O

Procedure:
18.7 g (0.1 mol) of 2-nitro-5-chloropara-phenylenediamine and 24.6 g (0.15 mol) of the sodium salt of 2-mercaptoethanesulphonic acid were used as the starting materials to give yellow-orange crystals (27.6 g) melting above 260° C., whose elemental analysis calculated for C8H11N3O5S2.H2O was: