Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[C:30]([C:32]1([C:39]2[C:48]3[O:47][CH2:46][CH2:45][O:44][C:43]=3[C:42]([O:49][CH3:50])=[CH:41][CH:40]=2)[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1)#[N:31].O>C1COCC1>[CH3:50][O:49][C:42]1[C:43]2[O:44][CH2:45][CH2:46][O:47][C:48]=2[C:39]([C:32]2([C:30]#[N:31])[CH2:37][CH2:36][C:35](=[CH:2][O:3][CH3:4])[CH2:34][CH2:33]2)=[CH:40][CH:41]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(C2(C#N)CCC(=O)CC2)c2c1OCCO2
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC=C1CCC(C#N)(c2ccc(OC)c3c2OCCO3)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.4 %

Procedure:
To a suspension of (methoxymethyl)triphenylphosphonium chloride (34 g, 99 mmol) in THF (320 mL) was added potassium tert-butoxide (11 g, 99 mmol). The mixture was stirred at room temperature for 15 minutes, and a solution of Compound 1 (15 g, 52 mmol) obtained in Example 1 in THF (150 mL) was added dropwise, followed by stirring at room temperature for 45 minutes. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The solvent was evaporated in vacuo, and the residue was purified by silica gel column chromatography (eluted with hexane/ethyl acetate=3/1) to give Compound 6 (14 g, 82%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[O:15][C:14]4[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=4[C:7]=3[N:8]=[C:9]2O)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:22]>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[O:15][C:14]4[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=4[C:7]=3[N:8]=[C:9]2[Cl:22])=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nc2c3ccccc3oc2c2ccc(Cl)cc12
Product: Clc1ccc2c(c1)c(Cl)nc1c3ccccc3oc21
Reaction time: 0.17 h

Procedure:
A mixture of 19B (11.8 mmol) in POCl3 (20 mL) was refluxed for 2 hours. After reaction completed, POCl3 was evaporated under reduced pressure. The residue was added into crushed ice and stirred for 10 min. The solids were collected by filtration and dried to give 3.2 g of a crude product, which was dissolved in dichloromethane and purified by flash chromatography (petroleum ether 1:1) and concentrated to give a pure product M19 (3.1 g).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:18][C:19]1[N:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH:24]=[C:23]([C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([NH2:47])[CH:42]=2)[C:20]=1[C:21]#[N:22]>ClCCl.C(#N)C>[NH2:18][C:19]1[C:20]([C:21]#[N:22])=[C:23]([C:41]2[CH:42]=[C:43]([NH:47][C:9](=[O:11])[CH2:8][CH2:7][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH:44]=[CH:45][CH:46]=2)[CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:35])[CH3:36])[N:26]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccccc1-c1cc(-c2cccc(N)c2)c(C#N)c(N)n1
Reactant: O=C(O)CCN1CCCCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccccc1-c1cc(-c2cccc(NC(=O)CCN3CCCCC3)c2)c(C#N)c(N)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 43 %

Procedure:
To a cold (0° C.) solution of 3-(1-piperidinyl)-propanoic acid (0.676 g, 3.601 mmol) in dichloromethane was added oxalyl chloride (0.471 mL, 5.401 mmol) and stirred at room temperature for 12 hrs. The mixture was concentrated under reduced pressure. The residue was added to the solution of 2-amino-4-(3-aminophenyl)-6-(2-{[tert-butyl(dimethyl)silyl]oxy}-phenyl)nicotinonitrile (starting compound 2, 1.500 g, 3.601 mmol) in acetonitrile (3 mL), and the resulting mixture was stirred at 0° C. for 1 hr. The reaction mixture was extracted with ethyl acetate and water. The separated organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification was carried out by silica gel column chromatography (chloroform/methanol=10/1) to give N-{3-[2-amino-6-(2-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-3-cyano-4-pyridinyl]phenyl}-3-(1-piperidinyl)propanamide as a white solid (0.860 g, yield 45%).
Reaction SMILES: O[CH2:2][CH2:3][O:4][CH2:5][CH:6]=[CH2:7].C(N(C(C)C)CC)(C)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl>[CH3:17][S:18]([CH2:2][CH2:3][O:4][CH2:5][CH:6]=[CH2:7])(=[O:20])=[O:19]
Reactant: C=CCOCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCOCCS(C)(=O)=O
Reaction time: 1.5 h

Procedure:
Combine allyl hydroxyethyl ether (1.02 g, 10 mmol), and diisopropylethylamine (4.0 mL, 23 mmol), and dichloromethane (20 mL). Cool in an ice-bath. Add dropwise, methanesulfonyl chloride (1.0 mL, 13 mmol). After 1.5 hours, extract the reaction mixture with 1M aqueous hydrochloric acid solution, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to obtain allyl methanesulfonylethyl ether: Rf=0.80 (silica gel, 20% ethyl acetate/dichloromethane).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[NH2:12][C:13]1[C:18]([O:19][CH3:20])=[N:17][C:16]([CH3:21])=[CH:15][N:14]=1>N1C=CC=CC=1>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:12][C:13]1[C:18]([O:19][CH3:20])=[N:17][C:16]([CH3:21])=[CH:15][N:14]=1)(=[O:10])=[O:9]
Reactant: COc1nc(C)cnc1N
Reactant: O=S(=O)(Cl)c1ccccc1I
Solvent: c1ccncc1
Product: COc1nc(C)cnc1NS(=O)(=O)c1ccccc1I
Temperature: 70 °C
Yield: 44.4 %

Procedure:
2-IodobenzenesulphonyI chloride (obtained as described in J Org Chem, (1977), 42, 3265) (12.1 g) was added to a solution of 2-amino-3-methoxy-5-methylpyrazine (5.6 g) in pyridine (100 ml) and the solution was heated at 70° C. for 8 hours. Volatile material was removed by evaporation and water (200 ml) was added to the residue. The mixture was extracted with ethyl acetate (2×200 ml) and the extracts were washed with 2M hydrochloric acid (200 ml) and water (200 ml). The extracts were dried (MgSO4) and the solvent was removed by evaporation. The residue was triturated with ether to give 2-iodo- N-(3-methoxy-5-methylpyrazin-2-yl)benzenesulphonamide (7.2 g), m.p. 136°-138° C.; 1H NMR (d6 -DMSO): 2.3 (s, 3H), 3.9 (s, 3H), 7.3(dt, 1H), 7.5-7.65 (m, 2H), 8.05-8.15 (m, 2H), 10.7-10.8 (br s, 1H).
Reaction SMILES: CN(C)C=O.[C:6]([N:10]1[C:15](=[O:16])[C:14]([Br:17])=[C:13]([SH:18])[CH:12]=[N:11]1)([CH3:9])([CH3:8])[CH3:7].[C:19]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[Na+].[Na+]>O>[C:6]([N:10]1[C:15](=[O:16])[C:14]([Br:17])=[C:13]([S:18][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:24][CH:25]=2)[CH:12]=[N:11]1)([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)n1ncc(S)c(Br)c1=O
Reactant: CC(C)(C)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CSc2cnn(C(C)(C)C)c(=O)c2Br)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 64 %

Procedure:
To a dimethylformamide solution of 4.4 g of 2-tert.-butyl-4-bromo-5-mercapto-3(2H)-pyridazinone and 4.7 g of 4-tert.-butylbenzyl bromide was added 3.5 g of sodium carbonate. The resulting reaction liquid was stirred at 80° C. for 4 hours, allowed to cool to room temperature, incorporated with water and extracted with benzene. The benzene layer was washed with 3% aqueous solution of sodium hydroxide and then with water, dried and then freed of benzene by distillation to give yellowish brown solid. The solid was recrystallized from a mixed solvent of benzene and n-hexane to obtain white crystals (yield: 64%).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[NH2:2].[CH3:14][O:15][C:16]1[CH:25]=[CH:24][C:19]([C:20](=O)[CH2:21]Br)=[CH:18][CH:17]=1>>[CH3:14][O:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]2[N:2]=[C:1]([C:4]3[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=3)[O:3][CH:21]=2)=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(C(N)=O)cc1
Reactant: COc1ccc(C(=O)CBr)cc1
Product: COC(=O)c1ccc(-c2nc(-c3ccc(OC)cc3)co2)cc1
Yield: 18 %

Procedure:
In the same manner as in Example 1, methyl 4-carbamoylbenzoate was reacted with 4-methoxyphenacyl bromide to obtain methyl 4-[4-(4-methoxyphenyl)-2-oxazolyl]benzoate. The product was recrystallized from ethanol. Yield: 18%. Pale yellow prisms. Melting Point: 200 to 202° C.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[CH3:20][S:21]([O:1][CH2:2][C@@H:3]([NH:5][C:6]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:12])[CH3:4])(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 36 h
Yield: 59.2 %

Procedure:
(S)-tert-Butyl 1-hydroxypropan-2-ylcarbamate (10.25 g, 58.5 mmol) was dissolved DCM (20 ml). Triethylamine (12.23 ml, 87.7 mmol) was added and the solution was cooled to 0° C. under nitrogen. Methanesulfonylchloride (5.0 ml, 64.3 mmol) was diluted with DCM (5 ml) and added drop wise to the reaction mixture keeping the temperature under 10° C. After addition, the reaction mixture was allowed to warm up to RT and stirring was continued for 36 h. Next, the reaction mixture was diluted with DCM (150 ml) and washed several times with NaHCO3-solution and water, the organic layer dried with Na2SO4, filtered and evaporated affording 8.78 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.06 (d, 3H), 1.38 (s, 9H), 3.16 (s, 3H), 3.75 (m, 1H), 4.04 (m, 2H), 6.93 (m, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[NH:11][S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13].Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[N:11]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[CH:24]=1)[S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:13])=[O:14]
Reactant: Cn1c(NS(=O)(=O)c2ccccc2)nc2ccccc21
Reactant: FC(F)(F)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1c(N(Cc2cccc(C(F)(F)F)c2)S(=O)(=O)c2ccccc2)nc2ccccc21
Temperature: 120 °C

Procedure:
To a solution of N-(1-methyl-1H-benzimidazol-2-yl)-benzenesulfonamide (100 mg, 0.35 mmol) in DMF (2 mL) was added 1-bromomethyl-3-trifluoromethyl-benzene (166.4 mg, 0.70 mmol) and potassium carbonate (48 mg). The resulting mixture was heated to 120° C. in a microwave reactor for 1 h. The resulting mixture was then diluted with EtOAc, washed with H2O and the organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resultant residue was purified by flash column chromatography (SiO2), eluting with a hexanes-EtOAc gradient to yield N-(1-methyl-1H-benzimidazol-2-yl)-N-(3-trifluoromethyl-benzyl)-benzenesulfonamide (1st compound to elute off the column) MS 446 (M+1)+
Reaction SMILES: [Br-:1].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:55]([CH:63]1[C:70]2[CH:69]=[C:68]([C:71]([O:73]C)=[O:72])[NH:67][C:66]=2[CH2:65][CH2:64]1)[CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1>C(#N)C.O>[Br:1][C:69]1[C:70]2[CH:63]([CH2:55][CH2:56][C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)[CH2:64][CH2:65][C:66]=2[NH:67][C:68]=1[C:71]([OH:73])=[O:72]
Reactant: [Br-]
Reactant: COC(=O)c1cc2c([nH]1)CCC2CCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Solvent: O
Product: O=C(O)c1[nH]c2c(c1Br)C(CCc1ccccc1)CC2
Reaction time: 8 h

Procedure:
Tetrabutylammonium tribromide (114 mg, 0.24 mmol) was added to a solution of methyl 4-phenethyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (53 mg, 0.2 mmol) in 5 mL of acetonitrile at room temperature. After reacting overnight, the reaction was diluted with water and extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated with silica gel. Purification by column chromatography (Isco CombiFlash) eluting with a gradient of 0-30% EtOAc/heptane gave the title compound. 54.2 mg. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.69-1.80 (m, 1H), 2.10-2.22 (m, 2H), 2.56-2.71 (m, 4H), 2.72-2.83 (m, 1H), 3.00-3.09 (m, 1H), 3.80 (s, 3H), 7.11-7.16 (m, 1H), 7.17-7.21 (m, 2H), 7.22-7.27 (m, 2H); LCMS-MS (ESI+) 372.0 (M+Na).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=O)[CH3:16])[C:10]=2[OH:18])=[CH:5][CH:4]=1)[CH3:2].[NH:19]([C:21]([NH:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=1)=[S:22])[NH2:20].CN(C)C=O>Cl.O>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=[N:20][NH:19][C:21]([NH:23][C:24]3[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)=[S:22])[CH3:16])[C:10]=2[OH:18])=[CH:5][CH:4]=1)[CH3:2]
Reactant: NNC(=S)Nc1ccc(C(=O)O)cc1
Reactant: CCc1ccc(-c2c(O)c(C(C)=O)nn2C)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCc1ccc(-c2c(O)c(C(C)=NNC(=S)Nc3ccc(C(=O)O)cc3)nn2C)cc1
Yield: 72.7 %

Procedure:
1-[5-(4-Ethylphenyl)-1-methyl-4-hydroxy-1H-pyrazol-3-yl]ethanone (0.159 mmol, 38.8 mg) and 4-hydrazinocarbonothioylaminobenzoic acid (0.159 mmol, 33.6 mg) were stirred with dimethylformamide (2.3 mL) and three drops of concentrated hydrochloric acid at room temperature for 23.5 hours. After addition of water, the precipitated yellow solid was recovered by filtration, washed with water and dried by means of a vacuum pump. The resulting solid was stirred with chloroform/n-hexane for a while, then recovered by filtration and dried by means of a vacuum pump to give the desired product as a pale yellow solid (50.6 mg, yield 730).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[O:9]([CH:16]([CH3:20])[C:17]([OH:19])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:21]([O:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=[O:34])=[CH:31][C:30]=1[O:37][CH3:38])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1CCCCC1.C1COCC1>[CH2:21]([O:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]([OH:34])[C:16]([CH3:20])([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:17]([OH:19])=[O:18])=[CH:31][C:30]=1[O:37][CH3:38])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(Oc1ccccc1)C(=O)O
Reactant: COc1cc(C=O)ccc1OCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: COc1cc(C(O)C(C)(Oc2ccccc2)C(=O)O)ccc1OCc1ccccc1
Reaction time: 0.25 h

Procedure:
A stirred solution of LDA in cyclohexane (1.5 M) was cooled to −20° C., to which a solution of 2-phenoxypropionic acid (10 g, 60.2 mmol) in THF (80.3 mL) was slowly added, keeping the temperature below −10° C. The resulting dianion solution was stirred for 15 min, then a solution of 4-benzyloxy-3-methoxybenzaldehyde (14.58 g, 60.2 mmol) in THF (80.3 mL) was added over 1 h, maintaining temperature below −10° C. Fifteen minutes after completion of aldehyde addition, the reaction mixture was poured onto ice water (200 mL), and extracted using 1:2 Et2O:hexane (500 mL). The aqueous layer was isolated, extracted again with 1:2 Et2O:hexane (240 mL), then acidified with concentrated HCl until pH=3. The product acid was extracted into EtOAc (2×165 mL), which was dried over Na2SO4 and concentrated to an orange paste (16.5 g crude, 67%): MS (EI) 426.2 (M+NH4)+, 407.2 (M−H)−.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][C:11]1[C:15]([CH2:18][S:19][C:20]2[NH:24][C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[N:21]=2)([CH2:16][OH:17])[O:14][C:13](=[O:29])[C:12]=1[OH:30].Cl.[CH3:32][N:33]([CH2:35][C:36](Cl)=[O:37])[CH3:34].C(N(CC)CC)C>CN(C=O)C.Cl>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][C:11]1[C:15]([CH2:16][O:17][C:36](=[O:37])[CH2:35][N:33]([CH3:34])[CH3:32])([CH2:18][S:19][C:20]2[NH:21][C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=3[N:24]=2)[O:14][C:13](=[O:29])[C:12]=1[OH:30]
Reactant: CN(C)CC(=O)Cl
Reactant: O=C1OC(CO)(CSc2nc3ccccc3[nH]2)C(Sc2nc3ccccc3[nH]2)=C1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)CC(=O)OCC1(CSc2nc3ccccc3[nH]2)OC(=O)C(O)=C1Sc1nc2ccccc2[nH]1

Procedure:
A solution of 4-(1H-benzoimidazol-2-ylsulfanyl)-5-(1H-benzoimidazol-2-ylsulfanylmethyl)-3-hydroxy-5-hydroxymethyl-5H-furan-2-one (220 mg, 0.50 mmol), dimethylaminoacetyl chloride hydrochloride (174 mg, 1.10 mmol) and triethylamine (0.280 mL, 2.00 mmol) in DMF (15 mL) was stirred for 22 h. The reaction mixture was then passed through a plug of SiO2, which was then washed with hexane to remove excess DMF, and subsequently with a 1:1 mixture of EtOAc and MeOH to collect dimethylamino-acetic acid 3-(1H-benzoimidazol-2-ylsulfanyl)-2-(1H-benzoimidazol-2-ylsulfanylmethyl)-4-hydroxy-5-oxo-2,5-dihydro-furan-2-ylmethyl ester. Upon evaporation of solvent, the residue was subjected to column chromatography (SiO2: CH2Cl2:MeOH:Acetic Acid, 87:10:3 v/v/v) which yielded an off-white solid which was dissolved in 0.5 M HCl and lyophilized (73 mg, 26%, GLI-1007817b). 1H NMR (D2O, 300.16 MHz) δ: 7.20-7.38 (m, 8H), 4.67 (q, J=12.0 Hz, 2H), 3.9104.18 (m, 4H), 2.86-2.96 (m, 6H).). 13C NMR (D2O, 75.04 MHz) δ: 167.4, 165.4, 155.7, 147.2, 145.3, 131.5, 130.9, 126.2, 126.1, 113.1, 112.7, 102.0, 85.2, 65.8, 56.6, 43.7, 36.4. MS (ESI-Pos) m/z: 526.2 (M+H+).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[C:5]([C:10]([NH2:12])=[O:11])=[N:6][C:7]=1[CH2:8][CH3:9].[CH3:24][N:25]1[CH2:30][CH2:29][CH2:28][CH:27]([NH2:31])[CH2:26]1>CN1C(=O)CCC1>[CH2:8]([C:7]1[N:6]=[C:5]([C:10]([NH2:12])=[O:11])[C:4]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)=[N:3][C:2]=1[NH:31][CH:27]1[CH2:28][CH2:29][CH2:30][N:25]([CH3:24])[CH2:26]1)[CH3:9]
Reactant: CCc1nc(C(N)=O)c(Nc2cccc(S(C)(=O)=O)c2)nc1Cl
Reactant: CN1CCCC(N)C1
Solvent: CN1CCCC1=O
Product: CCc1nc(C(N)=O)c(Nc2cccc(S(C)(=O)=O)c2)nc1NC1CCCN(C)C1
Temperature: 190 °C
Yield: 22.4 %

Procedure:
A mixture of 5-chloro-6-ethyl-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide (Preparation Example 353) (8.8 mg), 1-methyl-piperidin-3-ylamine (8.0 mg) and NMP (0.5 mL) was heated at 190° C. for 30 minutes using a microwave reaction system. After the reaction liquid was cooled, the organic layer was distilled off under reduced pressure, and the residue was separated and purified by HPLC (column: SunFire® C18, 5 μm, 19 mm×100 mm, solvent: MeOH/0.1% HCOOH—H2O=10/90 (0 min)-10/90 (1 min)-95/5 (9 min)-95/5 (12 min), flow rate: 25 mL/min) to give (6-ethyl-5-[(1-methylpiperidin-3-yl)amino]-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide (2.4 mg).
Reaction SMILES: [NH2:1][C@@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[C:7](Cl)(=[O:13])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>>[C:7]([NH:1][C@H:2]([CH3:3])[C:4]([OH:6])=[O:5])(=[O:13])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: C[C@@H](N)C(=O)O
Reactant: CCCCCC(=O)Cl
Product: CCCCCC(=O)N[C@H](C)C(=O)O

Procedure:
D-alanine (20 mmol) and hexanoyl chloride (22 mmol) were reacted using the method as described in Example 1 Part B to give the title compound as a white crystalline material (2.45 g, 65.5%) after recrystallization from isopropyl ether (20 ml), m.p. 82°-95° C.
Reaction SMILES: [CH3:1][C:2]([CH3:26])([CH3:25])[C@H:3]([N:8]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=3[N:15]=2)[C:9]1=[O:24])[C:4]([O:6]C)=[O:5].[Li+].[OH-]>O1CCCC1.O>[CH3:1][C:2]([CH3:26])([CH3:25])[C@H:3]([N:8]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=3[N:15]=2)[C:9]1=[O:24])[C:4]([OH:6])=[O:5]
Reactant: COC(=O)[C@@H](N1CCN(Cc2nc3ccccc3n2C)C1=O)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(CN2CCN([C@H](C(=O)O)C(C)(C)C)C2=O)nc2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of the product of Example 148E (37 mg) in tetrahydrofuran (0.26 mL) and water (0.13 mL) was treated with LiOH (6.1 mg, 1.4 equivalents), stirred at 25° C. for 16 hours, quenched with 1N HCl (0.15 mL) at 0° C., and the solvents were evaporated to give the crude product to be used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]4=3)[C:14]3[C:9]2=[CH:10][C:11]([O:25][CH3:26])=[CH:12][CH:13]=3)=[CH:4][CH:3]=1.C(C(C)=O)C.C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:39][N:40]([CH3:44])[CH2:41][CH2:42]Cl>C(OCC)(=O)C>[CH3:26][O:25][C:11]1[CH:10]=[C:9]2[C:14]([C:15]3[C:20]([CH:8]2[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:42][CH2:41][N:40]([CH3:44])[CH3:39])=[CH:7][CH:6]=2)=[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]2=[CH:17][CH:16]=3)=[CH:13][CH:12]=1
Reactant: COc1ccc2c(c1)C(c1ccc(O)cc1)c1c-2ccc2ccccc12
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Product: COc1ccc2c(c1)C(c1ccc(OCCN(C)C)cc1)c1c-2ccc2ccccc12
Temperature: 25 °C

Procedure:
A 3.4 g portion of the compound of Example 1 was combined with 75 ml of methyl ethyl ketone, 6.1 g of potassium carbonate, and 2.45 g of dimethyl-(2-chloroethyl)amine hydrochloride. The mixture was stirred under reflux for 24 hours. After cooling to 25° C., 50 g of ice and 100 ml of ethyl acetate were added. The organic layer was separated, washed with brine, and concentrated to provide the crude product which was then purified on a silica gel column (120 mm high and 70 mm in diameter). The elution started with 500 ml of toluene, and proceeded through 300 ml increments of toluene containing from 1 to 10% triethylamine, in 1% increments. The product-containing fractions were combined and concentrated to dryness under vacuum to obtain 3.1 g of partially purified product, which was chromatographed again on a similar column, beginning with 100 ml of toluene. The gradient solvent was then changed in 100 ml increments from toluene containing 10% of 5:3 ethyl acetate:acetonitrile, to 10% of toluene in the ethyl acetate:acetonitrile mixture. Then a second gradient solvent was used, again in 100 ml increments, starting with the 5:3 ethyl acetate:acetonitrile mixture, going to the same solvent containing 10% of triethylamine. The product-containing fractions were then evaporated under vacuum to obtain 2.9 g of purified desired product, m.p. 159°-160° C.
Reaction SMILES: Br[C:2]1[CH:26]=[CH:25][C:5]([CH2:6][O:7][CH2:8][C@@H:9]2[CH2:11][C@@H:10]2[CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:27].C([Li])CCC.CCCCCC.[CH3:39][S:40]SC>C(OCC)C>[F:27][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:2]=1[S:40][CH3:39])[CH2:6][O:7][CH2:8][C@@H:9]1[CH2:11][C@@H:10]1[CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC([C@H]2C[C@H]2COCc2ccc(Br)c(F)c2)CC1
Reactant: CSSC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CSc1ccc(COC[C@@H]2C[C@@H]2C2CCN(C(=O)OC(C)(C)C)CC2)cc1F
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 100.1 %

Procedure:
tert-butyl 4-((1R,2R)-2-(((4-bromo-3-fluorobenzyl)oxy)methyl)cyclopropyl)piperidine-1-carboxylate (Step A product, 7.7 g, 17.4 mmol) was dissolved in Diethyl ether (70 ml) and cooled to −78° C. The mixture was stirred for 5 min, then n-Butyllithium in hexane (2.5 M, 7.66 ml, 19.15 mmol) was added dropwise. The mixture was stirred at −78° C. for 10 min and dimethyl disulfide (1.85 ml, 20.9 mmol) was added dropwise. The mixture was stirred at −78° C. for 30 min and TLC showed the SM was almost consumed. The mixture was quenched with sat. NH4Cl at −78° C., extracted with EtOAc (2×). The EtOAc phase was washed with brine, dried over MgSO4, and concentrated to afford 7.13 g (100%) of the designed product. This crude product was used for the next step without further purification.