Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(OO)=[O:3].[Cl:6][C:7]1[CH:24]=[CH:23][C:10]([CH2:11][C:12]2[CH2:16][CH2:15][C:14]([CH3:18])([CH3:17])[C:13]=2[C:19]([O:21][CH3:22])=[O:20])=[CH:9][CH:8]=1>C(O)(=O)C.ClC(Cl)Cl>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][C:12]23[O:3][C:13]2([C:19]([O:21][CH3:22])=[O:20])[C:14]([CH3:18])([CH3:17])[CH2:15][CH2:16]3)=[CH:23][CH:24]=1
Reactant: CC(=O)OO
Reactant: COC(=O)C1=C(Cc2ccc(Cl)cc2)CCC1(C)C
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)C12OC1(Cc1ccc(Cl)cc1)CCC2(C)C

Procedure:
23.5 g (3 equivalents) "PROXITANE 4002" (Trade Mark: 36-40% (w/w) peracetic acid in acetic acid) were added to 9.8 g (35.1 mmols) 1-(4-chlorobenzyl)-3,3-dimethyl-2-methoxycarbonylcyclopent-1-ene prepared as described in Example 1 (f) in 90 ml trichloromethane. The resulting mixture was refluxed for 3 hours and then extracted twice with 50 ml aliquots of trichloromethane, backwashed once with 50 ml dilute aqueous sodium bicarbonate solution and twice with 50 ml aliquots of saturated aqueous sodium metabisulphite solution, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulphate and flashed to give 12 g of a pale yellow oil which crystallised on cooling. Trituration in 30/40 petroleum gave 5.8 g 1-(4-chlorobenzyl)-1,2-epoxy-3,3-dimethyl-2-methoxy-carbonylcyclopentane as a white crystalline solid, m.pt. 86°-87° C. Yield 56%.
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[N:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1.C([O-])(=O)C.[K+]>CN(C)C(=O)C.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>[CH3:15][O:14][C:10]1[CH:11]=[CH:12][C:13]2[N:5]3[CH2:4][C:3]4[C:16]([C:6]3=[CH:7][C:8]=2[N:9]=1)=[CH:17][CH:18]=[CH:19][CH:2]=4
Reactant: COc1ccc2c(ccn2Cc2ccccc2Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1ccc2c(cc3n2Cc2ccccc2-3)n1

Procedure:
Under an inert atmosphere, 500 mg (1.57 mmol) of the compound obtained in Step C, 88 mg (78.9 μmol) of tetrakis(triphenylphosphine)palladium(0) and 155 mg (1.57 mmol) of potassium acetate in 15 ml of N,N-dimethylacetamide are heated at 160° C. for 2 hours. After returning to room temperature, the reaction mixture is filtered using a Büchner funnel and then evaporated to dryness. The residue is then hydrolysed and subsequently extracted with ethyl acetate. The organic phase is dried over magnesium sulphate, concentrated and purified by flash chromatography over silica gel (eluant:petroleum ether/ethyl acetate, 8:2) to yield the title compound in the form of a brown solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([CH3:21])([CH3:20])[C:17]([NH2:19])=[O:18])[C:5]([Cl:22])=[CH:4][N:3]=1.[CH3:23][N:24]1[CH:28]=[C:27]([NH2:29])[CH:26]=[N:25]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[Cl:22][C:5]1[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([CH3:21])([CH3:20])[C:17]([NH2:19])=[O:18])=[N:7][C:2]([NH:29][C:27]2[CH:26]=[N:25][N:24]([CH3:23])[CH:28]=2)=[N:3][CH:4]=1
Reactant: CC(C)(C(N)=O)c1ccccc1CCc1nc(Cl)ncc1Cl
Reactant: Cn1cc(N)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(Nc2ncc(Cl)c(CCc3ccccc3C(C)(C)C(N)=O)n2)cn1
Temperature: 120 °C
Yield: 18 %

Procedure:
A mixture of 2-(2-(2-(2,5-dichloropyrimidin-4-yl)ethyl)phenyl)-2-methylpropanamide A38 (0.042 g, 0.12 mmol), 1-methyl-1H-pyrazol-4-amine (0.022 g, 0.23 mmol), and p-toluenesulfonic acid monohydrate (0.002 g, 0.012 mmol) in 1,4-dioxane (4.0 mL) was heated in the microwave at 120° C. for 3 hours. After cooling, the volatiles were removed in vacuo and the residue was adsorbed onto silica. Purification by column chromatography (Biotage Isolera, 12 g SiO2, 0-5% MeOH in DCM) gave the title compound 45 as an off-white solid (0.009 g, 18%). LCMS-D: rt 3.29 min; m/z 399 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1CC([O-])=O.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:18]>CO.O>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[OH:18]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: O=C([O-])Cc1ccc(I)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Oc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 2-fluoro-4-iodophenylacetate (500 mg) in methanol (3 ml) was added 1.07 ml of 2N aqueous sodium hydroxide. The reaction solution was stirred at room temperature for 40 minutes, followed by vacuum concentration of the reaction solution. The residue obtained was diluted with water, acidified with 10% aqueous citric acid to pH 4, then extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to afford the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:6]=[C:5](Cl)[S:4][N:3]=1.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O.C([O-])([O-])=O.[K+].[K+].CC#N>O.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[N:6]=[C:5]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][CH3:8])[S:4][N:3]=1
Reactant: Clc1nsc(Cl)n1
Reactant: COc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1ccccc1-c1nc(Cl)ns1
Temperature: 100 °C

Procedure:
A mixture of 3,5-dichloro-1,2,4-thiadiazole (0.14 g, 0.93 mmol), 2-methoxyphenylboronic acid (0.16 g, 1.0 mmol), Pd(PPh3)4 (11 mg, 9.3 μmol), K2CO3 (0.26 g, 1.9 mmol), and CH3CN (3 mL containing 10% H2O) was sealed in a microwave vessel and heated by microwave irradiation at 100° C. for three minutes. The reaction was cooled to room temperature, diluted with water, and extracted with CH2Cl2. The combined extracts were washed with water, dried over Na2SO4, and concentrated under reduced pressure to yield 3-chloro-5-(2-methoxyphenyl)-1,2,4-thiadiazole. LC/MS: m/z 227 (M+H)+ at 3.45 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH:1]1([N:7]([CH2:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([CH2:27][N:28]([CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]3)[C:29]([NH:31][C:32]3[CH:37]=[CH:36][C:35]([N+:38]([O-])=O)=[CH:34][CH:33]=3)=[O:30])[CH2:23][CH2:22]2)[C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>[C].[Pd].[Pd].CN(C=O)C>[CH:1]1([N:7]([CH2:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([CH2:27][N:28]([CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]3)[C:29]([NH:31][C:32]3[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=3)=[O:30])[CH2:23][CH2:22]2)[C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(Nc1ccc([N+](=O)[O-])cc1)N(C[C@H]1CC[C@H](CN(C(=O)Nc2ccc([N+](=O)[O-])cc2)C2CCCCC2)CC1)C1CCCCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Product: Nc1ccc(NC(=O)N(C[C@H]2CC[C@H](CN(C(=O)Nc3ccc(N)cc3)C3CCCCC3)CC2)C2CCCCC2)cc1

Procedure:
A 0.6 g quantity of 10% palladium carbon was added to 100 ml of a DMF solution containing 5.7 g of trans-1,4-bis[[1-cyclohexyl-3-(4-nitrophenyl)ureido]-metyl]cyclohexane synthesized in accordance with Example 2. Hydrogen was added at ordinal pressure and normal temperature for 15 hours. After completion of the reaction, palladium was separated by filtration and the reaction mixture was concentrated under reduced pressure. The reaction mixture was dissolved in chloroform and a 4N hydrochloric acid-dioxyane solution was added to provide 5.5 g (95%) of white crystals precipitated.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[O:4]([C:11]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:12]=1[C:13](Cl)=[O:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>N1C=CC=CC=1>[CH3:1][N:2]([CH3:3])[C:13](=[O:14])[C:12]1[C:11]([O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[CH:19][CH:18]=[CH:17][C:16]=1[O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1c(Oc2ccccc2)cccc1Oc1ccccc1
Reactant: CNC
Solvent: c1ccncc1
Product: CN(C)C(=O)c1c(Oc2ccccc2)cccc1Oc1ccccc1
Reaction time: 0.5 h

Procedure:
To 18 parts of pyridine which has been saturated with dry gaseous dimethylamine is added dropwise 1 part of 2,6-diphenoxybenzoyl chloride in 2 parts of pyridine. The resulting mixture is stirred for 30 minutes, concentrated under reduced pressure, and poured into 54 parts of water. The mixture is made acidic with concentrated hydrochloric acid, and the solid precipitate is collected, washed with water, dried, and recrystallized first from acetonitrile and then from 1-chlorobutane to give N,N dimethyl-2,6-diphenoxybenzamide, M.P. 109°-111°.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1>>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)=[CH:13][CH:12]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: Clc1ccc(I)cc1
Product: Clc1ccc(-n2ccc3ccccc32)cc1

Procedure:
Prepared by Procedure C and Scheme O using 1H-indole and 1-chloro-4-iodobenzene: ESMS m/e: 227.9 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:6]=[C:5]([C:19]2[CH:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([NH2:31])[CH:26]=3)[CH:22]=[CH:23][CH:24]=2)[N:4]=1.C(N(CC)CC)C.[CH3:41][N:42]([CH3:47])[S:43](Cl)(=[O:45])=[O:44]>C1(C)C=CC=CC=1>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:6]=[C:5]([C:19]2[CH:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][S:43]([N:42]([CH3:47])[CH3:41])(=[O:45])=[O:44])[CH:26]=3)[CH:22]=[CH:23][CH:24]=2)[N:4]=1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Nc1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN(C)S(=O)(=O)Nc1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)c1
Temperature: 70 °C
Reaction time: 22 h
Yield: 36.7 %

Procedure:
To a stirred solution of 3′-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-biphenyl-3-ylamine (example 220) (0.23 g, 0.5 mmol) in toluene (5 mL) was added triethylamine (0.21 mL) and dimethylsulfamoyl chloride (0.14 g, 1.0 mmol), the reaction mixture was allowed to stir at 70° C. for 22 h, poured into ice-water (20 mL) and extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with brine (30 mL), dried (MgSO4) and evaporated. Further purification by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (EtOH/hexane) yielded the title compound (0.104 g, 37%) as an off-white solid. MS (ISP) 567.3 [(M+H)+]; mp 113° C.
Reaction SMILES: [CH:1]1([CH3:11])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([OH:10])[CH2:2]1.CCN(CC)CC.[Br:19][CH2:20][C:21](Br)=[O:22].Cl>C1COCC1>[CH:7]([CH:4]1[CH2:5][CH2:6][CH:1]([CH3:11])[CH2:2][CH:3]1[O:10][C:21](=[O:22])[CH2:20][Br:19])([CH3:8])[CH3:9]
Reactant: CC1CCC(C(C)C)C(O)C1
Reactant: O=C(Br)CBr
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1CCC(C(C)C)C(OC(=O)CBr)C1
Temperature: 25 °C
Yield: 51 %

Procedure:
To a solution of (−) Menthol (2.75 mmoles) in anhydrous THF (5 ml), Et3N (2.75 mmoles) is added under stirring. The solution temperature is lowered to 0° C. and bromo-acetylbromide (2.5 mmoles) added. The solution temperature is then allowed to raise to room temperature and the reaction mixture is stirred for 2 hours. An HCl 1N (2 ml) aqueous solution is added and the organic phase is extracted with ethyl acetate (3×5 ml). The pooled organic phases are washed with a saturated aqueous NaCl solution (1×15 ml), dehydrated on Na2SO4 and filtered. The solvent is evaporated under a reduced pressure and the crude product is purified by flash chromatography in n-hexane/ethyl acetate 97/3 volume/volume. 388 mg of 2-isopropyl-5-methyl-cyclohexyl ester of the bromo acetic acid (51% yield) are recovered.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[CH2:17][C:16]2([CH3:31])[CH3:30])=[CH:10][N:9]=1)(C)(C)C.Cl>O1CCOCC1.CO>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:18]2[CH2:19][CH2:20][N:15]([CH2:14][C:11]3[CH:12]=[CH:13][C:8]([NH2:7])=[N:9][CH:10]=3)[C:16]([CH3:31])([CH3:30])[CH2:17]2)=[CH:27][CH:26]=1
Reactant: COc1ccc(CN2CCN(Cc3ccc(NC(=O)OC(C)(C)C)nc3)C(C)(C)C2)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc(CN2CCN(Cc3ccc(N)nc3)C(C)(C)C2)cc1
Yield: 102.5 %

Procedure:
A mixture of {5-[4-(4-methoxy-benzyl)-2,2-dimethyl-piperazin-1-ylmethyl]-pyridin-2-yl}-carbamic acid tert-butyl ester (Step 109.2) (1.88 g, 4.3 mmol), a 4 N solution of HCl in dioxane (25 mL) and MeOH (25 mL) was stirred for 22 h at rt. The reaction mixture was allowed to cool, quenched by addition of a saturated aqueous solution of NaHCO3 and extracted with DCM. The organic layer was washed with a saturated aqueous solution of NaHCO3, dried (Na2SO4), filtered and concentrated to provide 1.5 g of the title compound as a brown solid: ESI-MS: 341.3 [M+H]+;]+; tR=1.72 min (System 1).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7]([O:16][CH3:17])[C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4](Cl)[N:3]=1.[CH3:19][O:20][C:21]1[C:30]([O:31][CH3:32])=[C:29]2[C:24]([CH2:25][CH2:26][NH:27][CH2:28]2)=[CH:23][CH:22]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([O:16][CH3:17])[C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:27]2[CH2:26][CH2:25][C:24]3[C:29](=[C:30]([O:31][CH3:32])[C:21]([O:20][CH3:19])=[CH:22][CH:23]=3)[CH2:28]2)[N:3]=1
Reactant: COc1cc2c(N)nc(Cl)nc2c(OC)c1OC
Reactant: COc1ccc2c(c1OC)CNCC2
Product: COc1ccc2c(c1OC)CN(c1nc(N)c3cc(OC)c(OC)c(OC)c3n1)CC2

Procedure:
The procedure described in Example 1 was followed to prepare the above compound, starting from 4-amino-2-chloro-6,7,8-trimethoxyquinazoline and using 7,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline as the reagent of choice on the same molar basis as before. In this particular instance, the final product was isolated as the free base compound, m.p. 190°C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=4)[CH:15]=3)=[CH:9][N:8]([S:25]([C:28]3[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:5]2=[N:6][CH:7]=1.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40](B2OC(C)(C)C(C)(C)O2)=[CH:39][C:38]=1CS(N)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:24][C:19]1[CH:18]=[C:17]([CH:22]=[C:21]([F:23])[CH:20]=1)[CH2:16][N:14]1[CH:15]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:40]4[CH:41]=[CH:42][C:37]([O:36][CH3:35])=[C:38]([NH:8][S:25]([CH3:28])(=[O:27])=[O:26])[CH:39]=4)[CH:3]=3)[N:8]([S:25]([C:28]3[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=3)(=[O:26])=[O:27])[CH:9]=2)[CH:12]=[N:13]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cc(F)cc(F)c4)c3)c3cc(Br)cnc32)cc1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1CS(N)(=O)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(-c2cnc3c(c2)c(-c2cnn(Cc4cc(F)cc(F)c4)c2)cn3S(=O)(=O)c2ccc(C)cc2)cc1NS(C)(=O)=O
Yield: 43.8 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3,5-difluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (200 mg, 0.3683 mmol) was coupled with N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl methane sulfonamide (Intermediate 17), (120 mg, 0.368 mmol) using sodium carbonate (117 mg, 1.1049 mmol) and Pd(PPh3)2Cl2 (14 mg, 0.0184 mmol) in DME/water (15/2 ml). This afforded 107 mg (43.8% yield) after purification by column (Silica gel 230/400) using 65% ethyl acetate in hexane as eluent. MS: m/z=664.1 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([OH:17])(O)[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Br:15])[CH:2]=1.C[O:19][CH:20](OC)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClC1C=CC=CC=1.C1(C)C=CC=CC=1>[C:21]1([CH:20]2[O:17][CH:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[Br:15])[O:19]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(OC)c1ccccc1
Reactant: OC(O)(Cc1ccccc1Br)c1cccnc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Clc1ccccc1
Solvent: Cc1ccccc1
Product: Brc1ccccc1C1OC(c2ccccc2)OC1c1cccnc1

Procedure:
37 g (0.1258 mol) of 1-(pyrid-3-yl)-2-(2-bromophenyl)-ethanediol and 38.5 g (0.2516 mol) of benzaldehyde dimethyl acetal were refluxed together in 440 ml of 10:1 chlorobenzene/toluene with 1 g of p-toluenesulfonic acid. The resulting methanol was distilled off as an azeotrope with toluene. After the end of the reaction, the chlorobenzene was distilled off under reduced pressure and the product wa purified by chromatography over silica gel.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[C:4]1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.[Br:14][C:15]1[N:16]=[C:17](Br)[C:18]2[N:19]([CH:21]=[CH:22][N:23]=2)[CH:20]=1.O>CN(C=O)C>[Br:14][C:15]1[N:16]=[C:17]([N:3]2[CH:7]=[CH:6][N:5]=[C:4]2[C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[C:18]2[N:19]([CH:21]=[CH:22][N:23]=2)[CH:20]=1
Reactant: Brc1cn2ccnc2c(Br)n1
Reactant: c1cc(-c2ncc[nH]2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cn2ccnc2c(-n2ccnc2-c2ccncc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.4 %

Procedure:
Sodium hydride (NaH) (730 milligrams (mg) of a 95% dispersion in mineral oil) is added to a solution of 4-(1H-Imidazol-2-yl)-pyridine (4.0 g) in N,N,-dimethylformamide (DMF) (150 ml) and the mixture is stirred at room temperature (rt) for 0.5 hr. A solution of 6,8-dibromoimidazo[1,2-a]pyrazine (3) (7.63 g) in DMF (10 ml) is added. The mixture is stirred at room temperature (rt) for 16 hr. Water (50 ml) is added and the mixture is extracted with ethyl acetate (3×70 ml); extracts are washed with water (2×50 ml) and brine (1×50 ml), dried over sodium sulfate (Na2SO4), and evaporated in vacuo. Purification on SiO2 (5% MeOH, DCM) yielded 6-Bromo-8-(2-pyridin-4-yl-imidazol-1-yl)-imidazo[1,2-a]pyrazine (4) (4.08 g) as an off-white solid.
Reaction SMILES: C([O:3][C:4](=O)[CH:5](O)[CH:6]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:15][CH:14]=1)[C:7](=O)[CH2:8][CH2:9][CH2:10][CH3:11])C.O.[NH2:29][NH2:30]>C(O)(=O)C>[CH2:8]([C:7]1[C:6]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:15][CH:14]=2)=[CH:5][C:4](=[O:3])[NH:29][N:30]=1)[CH2:9][CH2:10][CH3:11]
Reactant: NN
Reactant: CCCCC(=O)C(c1ccc(OC2CCCCC2)cc1)C(O)C(=O)OCC
Solvent: CC(=O)O
Solvent: O
Product: CCCCc1n[nH]c(=O)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 100 °C

Procedure:
To a stirred solution of the octanoic acid ethyl ester (105 mmol, 39.5 g) in glacial acetic acid (25.5 mL) was added hydrazine hydrate (525 mmol, 25.5 mL), and the reaction was heated at 100° C. for 12 h. After cooling, the volatiles were removed in vacuo, the residue was dissolved in ethyl acetate (300 mL). The organic layer was washed with water (100 mL), saturated NaHCO3 (3×100 mL), brine (100 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was recrystallized from a mixture of ethyl acetate (200 mL) and hexanes (300 mL) to afford 6-butyl-5-(4-cyclohexyloxy-phenyl)-2H-pyridazin-3-one.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=O)[CH3:8])=[CH:3][CH:2]=1.[CH:10]([NH2:12])=[O:11].[OH-].[Na+]>C(O)=O.O>[N:1]1[CH:6]=[CH:5][C:4]([CH:7]([NH:12][CH:10]=[O:11])[CH3:8])=[CH:3][CH:2]=1
Reactant: NC=O
Reactant: CC(=O)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=CO
Product: CC(NC=O)c1ccncc1
Reaction time: 1.5 h

Procedure:
1-Pyridin-4-yl-ethanone (24.2 g, 199.77 mmol) and 10 ml of formic acid were heated to 180° C. and formamide (126 g, 2.797 mol) in 10 ml of formic acid was added within 30 min. The mixture was stirred for 90 min., cooled and poured in 100 ml of water. After addition of conc. sodium hydroxide solution until pH13 the product was extracted with diethyl-ether. The organic layer was dried with MgSO4 and evaporated. Purification by distillation (165° C./4 mbar) yields pure product.
Reaction SMILES: C[C:2](C)([CH2:6][S:7][S:8][CH2:9][CH2:10][C:11]([NH2:13])=[O:12])[C:3]([NH2:5])=[O:4].[CH2:15](N)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>CO>[CH2:15]([NH:13][C:11](=[O:12])[CH2:10][CH2:9][S:8][S:7][CH2:6][CH2:2][C:3]([NH:5][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:4])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCN
Reactant: CC(C)(CSSCCC(N)=O)C(N)=O
Solvent: CO
Product: CCCCCCCCNC(=O)CCSSCCC(=O)NCCCCCCCC
Temperature: 5 °C
Reaction time: 120 h
Yield: 76 %

Procedure:
238 g (1 mol) of dimethyl 3,3′-dithiodipropionamide and 280 g (2.17 mol) of n-octylamine were added into 300 ml of methanol in a 1,000 ml reaction flask, and the reactants stirred at 5° C. for 5 days (under nitrogen atmosphere, if desired). The reaction mixture was then cooled to −10° C., and separated by centrifuging to give 329 g of a solid of N,N′-di-n-octyl-3,3′-dithiodipropionamide (purity >95%, yield 76%). The mother liquor was recycled after methanol was recovered by evaporation.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:28](N)([NH2:31])(=[O:30])=[O:29]>O1CCOCC1>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:12][N:13]1[S:28]([NH2:31])(=[O:30])=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NS(N)(=O)=O
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Solvent: C1COCCO1
Product: COc1ccc(N2CCN(S(N)(=O)=O)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Temperature: 25 °C
Yield: 72.2 %

Procedure:
Into a 25 mL round bottomed flask were added (S)-3-benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine (188 mg, 0.513 mmol), sulfamide (103 mg, 1.07 mmol) and 1,4-dioxane (3 mL). The reaction mixture was refluxed under nitrogen for 3.5 h then cooled to room temperature and adsorbed onto silica gel. Purification by silica gel flash chromatography with a 0-100% EtOAc/Hexanes gradient to afford product as tan solid (165 mg, 72%). LC/MS (Method B) 3.90 min, [M+1]+ 446.
Reaction SMILES: C([O:3][C:4](=[O:37])[CH:5]([NH:18][C:19]([C:21]1([NH:26][C:27](=[O:36])[CH:28]([S:32]C(=O)C)[CH:29]([CH3:31])[CH3:30])[CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:20])[CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][CH:11]=1)C.[OH-].[Na+]>CO.O>[SH:32][CH:28]([CH:29]([CH3:31])[CH3:30])[C:27]([NH:26][C:21]1([C:19]([NH:18][CH:5]([CH2:6][C:7]2[S:8][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][CH:11]=2)[C:4]([OH:37])=[O:3])=[O:20])[CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:36]
Reactant: CCOC(=O)C(Cc1ccc(-c2ccccc2)s1)NC(=O)C1(NC(=O)C(SC(C)=O)C(C)C)CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)C(S)C(=O)NC1(C(=O)NC(Cc2ccc(-c3ccccc3)s2)C(=O)O)CCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
55 mg (0.101 mmol) of 2-{[1-(2-Acetylthio-3-methyl-butanoylamino)-cyclopentanecarbonyl]-amino}3-(5-phenyl-thien-2-yl)-propionic acid ethyl ester is dissolved in 2 mL of MeOH. 0.41 mL of 1N NaOH is added, and the solution is stirred at room temperature for 3 h. The reaction mixture is diluted with water, and MeOH is removed in vacuo. The residue is partitioned between water and Et2O. The aqueous phase is extracted twice with Et2O, acidified with 0.41 mL of 1N HCl, and then extracted with EtOAc. The EtOAc phase is concentrated to furnish the product; mp 154-155° C.