Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH2:2]([NH:4][C:5](=[O:32])[C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](=[O:31])[C@H:12]([CH2:24][CH2:25][CH2:26][NH:27][C:28](=[NH:30])[NH2:29])[NH:13]C(OCC1C=CC=CC=1)=O)[CH3:3].CO.[H][H]>[Pd].O>[ClH:1].[CH2:2]([NH:4][C:5](=[O:32])[C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](=[O:31])[C@H:12]([CH2:24][CH2:25][CH2:26][NH:27][C:28](=[NH:29])[NH2:30])[NH2:13])[CH3:3]
Reactant: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: CCNC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CCCNC(=N)N

Procedure:
A solution of 8.7 g. of Nα -benzyloxycarbonyl-L-arginyl-L-proline N-ethylamide hydrochloride in 100 ml. of methanol is stirred with 500 mg. of 20% palladium on carbon under one inch water pressure of hydrogen for three hours. The catalyst is removed by filtration and the filtrate evaporated under reduced pressure and at 35°-40° C. The residual foam is used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([NH2:9])[S:8][C:4]=2[CH:3]=1.[CH2:12]([N:14]=[C:15]=[O:16])[CH3:13].C(N(CC)CC)C>CN(C=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([NH:9][C:15]([NH:14][CH2:12][CH3:13])=[O:16])[S:8][C:4]=2[CH:3]=1
Reactant: CCN=C=O
Reactant: Nc1nc2ccc(Br)cc2s1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2ccc(Br)cc2s1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
About 0.75 g of 6-bromo-1,3-benzothiazol-2-amine (crude) is dissolved in about 15 mL DMF. About 0.5 mL of ethylisocyanate is added followed by about 0.9 mL triethylamine and the solution is heated to about 80° C. under good agitation. The solution is allowed to stir for about 4 hours then cooled to RT. The solvent is removed in vacuo and the solids are washed well with ether. The product is further purified by column chromatography.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[H-].[Na+].[F:12][C:13]([F:22])([F:21])[CH2:14][CH2:15][CH:16]([C:19]#[N:20])[C:17]#[N:18]>CN(C)C=O>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][C:16]([CH2:15][CH2:14][C:13]([F:12])([F:21])[F:22])([C:17]#[N:18])[C:19]#[N:20]
Reactant: Fc1ccccc1CBr
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1ccccc1F
Yield: 62.6 %

Procedure:
Using 0.19 g of 2-fluorobenzyl bromide, 3 ml of N,N-dimethylformamide, 0.05 g of sodium hydride (60% in oil), and 0.17 g of (3,3,3-trifluoropropyl)malononitrile, and according to the process described in the Production Example 26, there was obtained 0.17 g of 2-(2-fluorobenzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (75)).
Reaction SMILES: [CH:1]([CH:4]1[C:9](=[S:10])[N:8]([CH2:11][C:12]([O:14]C)=[O:13])[C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=2[S:5]1)([CH3:3])[CH3:2].Cl>[OH-].[Na+].O>[CH:1]([CH:4]1[C:9](=[S:10])[N:8]([CH2:11][C:12]([OH:14])=[O:13])[C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=2[S:5]1)([CH3:3])[CH3:2]
Reactant: COC(=O)CN1C(=S)C(C(C)C)Sc2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)C1Sc2ccccc2N(CC(=O)O)C1=S

Procedure:
Methyl 3,4-dihydro-2-isopropyl-3-thioxo-2H-1,4-benzothiazine-4-acetate (20.65 g) was dissolved in methanol-dioxane (1:2, v/v, 210 ml), to which 2N-NaOH (70 ml) was added dropwise with stirring. The mixture was stirred at room temperature for further 2 hours, diluted with water and acidified with hydrochloric acid. The crystalline precipitate was collected by filtration and recrystallized from 2-propanol-water to give 3,4-dihydro-2-isopropyl-3-thioxo-2H-1,4-benzothiazine-4-acetic acid as yellow prism. Yield was 18.0 g (91.5%). mp 175°-176° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[S:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[CH2:17][CH2:16]2.[OH:24]O>>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[S:7]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[CH2:17][CH2:16]2)=[O:24]
Reactant: OO
Reactant: O=C1CCc2cc(OCCCCSc3ncccn3)ccc2N1
Product: O=C1CCc2cc(OCCCCS(=O)c3ncccn3)ccc2N1

Procedure:
Prepared analogous to Example 2 from 6-[4-(2-pyrimidyl-mercapto)-butoxy]-3,4-dihydro-carbostyril and hydrogen peroxide.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][N:11]=2)[CH2:6][CH2:5]1.F[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]([F:29])([F:28])[F:27].O>CN(C)C=O>[F:27][C:26]([F:29])([F:28])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH:7]2[CH2:6][CH2:5][N:4]([CH3:3])[CH2:9][CH2:8]2)=[N:11]1
Reactant: CN1CCC(c2n[nH]c3ccccc23)CC1
Reactant: Fc1ccccc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCC(c2nn(-c3ccccc3C(F)(F)F)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
To a stirred suspension of 1.0 g of a 50% oil dispersion of sodium hydride in 20 ml of dimethylformamide was added, dropwise, 3.2 g of 3-(1-methyl-4-piperidinyl)-1H-indazole dissolved in 25 ml of hot dimethylformamide. After stirring for one hr at ambient temperature, 3.75 ml of 2-fluorobenzotrifluoride was added. The reaction mixture was heated to 90° C. and stirred for 17 hrs. The mixture was then poured into water, extracted with ether, dried over anhydrous magnesium sulfate and concentrated. The residue was purified using flash chromatography (silica gel, diethylamine-ethyl acetate, 1:9). The appropriate fractions were g evaporated The residue was recrystallized once from hexane, then combined with a previously prepared sample (1.1 g), and recrystallized from hexane to yield 2.17 g (24%) of product, mp 110°-111° C.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1.[OH-].[Li+]>CO.C1COCC1.O.O>[Cl:20][C:16]1[CH:15]=[C:14](/[CH:13]=[CH:12]/[C:5]2[CH:6]=[CH:7][C:8]([O:10][CH3:11])=[CH:9][C:4]=2[C:3]([OH:21])=[O:2])[CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1cc(OC)ccc1/C=C/c1cccc(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(/C=C/c2cccc(Cl)c2)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 74 %

Procedure:
Crude 2-[(E)-2-(3-chlorophenyl)vinyl]-5-methoxybenzoic acid methyl ester was suspended in methanol:THF:water (3:1:1 [v/v], 400 mL) and lithium hydroxide (12.10 g, 289 mmol) added. The mixture was stirred for 22 h at ambient temperature and concentrated in vacuo to give a pale brown solid. The crude product was re-dissolved in water (400 mL), the solution washed with diethyl ether (3×250 mL) and acidified to pH 2 with 1 N HCl (aq.). The aqueous was extracted with ethyl acetate (3×200 mL), the organic phase dried (MgSO4) and concentrated in vacuo to give a tan solid which was triturated with methanol and filtered to give (E)-2-[2-(3-chlorophenyl)vinyl]-5-methoxybenzoic acid (15.43 g, 53.44 mmol, 74% for 2 steps from 2-bromo-5-methoxybenzoic acid methyl ester) as an off-white powder.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][CH:5]([C:18]1[CH:23]=[CH:22][N:21]=[C:20]([S:24][CH3:25])[N:19]=1)[C:6](=[O:17])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1.O1CCOCC1.Cl.CCCCCC>CCOCC>[CH3:25][S:24][C:20]1[N:19]=[C:18]([CH:5]([C:6](=[O:17])[C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:15])([F:14])[F:16])[CH:8]=2)[CH2:4][C:3]([OH:26])=[O:2])[CH:23]=[CH:22][N:21]=1
Reactant: COC(=O)CC(C(=O)c1cccc(C(F)(F)F)c1)c1ccnc(SC)n1
Agent: Cl
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1COCCO1
Product: CSc1nccc(C(CC(=O)O)C(=O)c2cccc(C(F)(F)F)c2)n1

Procedure:
A solution of Compound 4 (27.1 g, 64 mmol) and dioxane (500 mL) were stirred under argon. Hydrochloric acid (6N, 250 mL) was added dropwise using an addition funnel. After 3d dioxane was removed in vacuo. The remaining aqueous mixture was extracted exhaustively with methylene chloride. The combined organic extracts were dried over anhydrous sodium sulfate then the solvent was removed in vacuo to give a yellow oil. Hexane followed by ether was added to afford a solid (5) which was isolated by vacuum filtration: 18.6 g (50.4 mmol, 79%)
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH:5]1[C:13]2[C:8](=[C:9]([NH2:14])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[N:6]1.[F:15][B-:16]([F:19])([F:18])[F:17].[Na+]>O.Cl>[F:15][B-:16]([F:19])([F:18])[F:17].[NH:5]1[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:14]#[N:1])[C:8]=2[CH:7]=[N:6]1
Reactant: O=N[O-]
Reactant: Nc1cccc2[nH]ncc12
Agent: Cl
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: O
Product: N#[N+]c1cccc2[nH]ncc12
Reaction time: 0.5 h

Procedure:
An aqueous solution of sodium nitrite (337 mg, 4.89 mmol) in water (2 mL) was added dropwise to a suspension of 1H-indazol-4-ylamine D (631 mg, 4.74 mmol) in 6M hydrochloric acid (7.2 mL) at below 0° C. After stirring for 30 minutes, sodium tetrafluoroborate (724 mg) was added to the reaction mixture. A viscous solution resulted, which was filtered and washed briefly with water to yield 1H-indazole-4-diazonium tetrafluoroborate salt E (218 mg, 20%) as a deep red solid.
Reaction SMILES: [S:1]1[C:5]([CH:6]=O)=[CH:4][CH:3]=[N:2]1.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:15][CH2:16][C:17]([O-:19])=[O:18])C=CC=CC=1.[Li+]>>[S:1]1[C:5]([CH:6]=[CH:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:4][CH:3]=[N:2]1
Reactant: O=C([O-])CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccns1
Agent: [Li+]
Product: O=C(O)CC=Cc1ccns1

Procedure:
Reaction of isothiazole-5-carboxaldehyde with lithium 3-(triphenylphosphoranylidene)propanoate under standard Wittig conditions provides 4-(5-isothiazolyl)-3-butenoic acid which is reduced and cyclized with aluminum chloride to provide 4-oxo-4,5,6,7-tetrahydrobenzisothiazole. The 4-oxo compound is reacted with methylenetriphenyl phosphorane under standard Wittig conditions and a methylene is inserted into the resulting 4-methylene compound via a Simmons Smith reaction to provide 6,7-dihydrospiro [benzisothiazol-4 (SH), 1'-cyclopropane]which is oxidized with hydrogen peroxide in acetic acid to give 6,7-dihydrospiro[-3-oxo-benzisothiazol-4(5H),1'-cyclopropane 1,1-dioxide (4-spirocyclopropyl tetrahydrosaccharin). This is chloromethylated according to the procedure of Preparation 1A to give 2-chloromethyl-4-spirocyclopropyl-4,5,6,7-tetrahydrosaccharin.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[NH:11][C:12]([S:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26](Br)[CH:27]=[CH2:28].[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[CH2:28]([N:11]1[C:12]([S:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=[C:10]1[CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:27]=[CH2:26]
Reactant: C=CCBr
Reactant: CC(C)c1nc(COCc2ccccc2)[nH]c1Sc1cccc(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCn1c(COCc2ccccc2)nc(C(C)C)c1Sc1cccc(Cl)c1
Yield: 58.1 %

Procedure:
(1)In 10 ml of dry tetrahydrofuran was dissolved 744 mg (2.00 mmol)of 2-(benzyloxymethyl)-5-(3-chlorophenylthio)-4-isopropyl-1H-imidazole (16e), followed by addition of 410 mg (2.40 mmol)of allyl bromide, 96 mg (2.40 mmol)of sodium hydroxide and 5 mg (0.015 mg)of tetrabutylammoniumbromide at room temperature with stirring, and the mixture was stirred at room temperature for 3 hours. This reaction mixture was concentrated under reduced pressure, the residue was extracted with methylene chloride, the organic layer was washed with water and dried over sodium sulfate. The solvent was concentrated under reduced pressure and the residual oil was fractionated by silica gel chromatography (ethyl acetate:methylene chloride=1:9). From the first fraction, 50 mg (yield 6.7%)of the objective position isomer (17g')was obtained, and then, 480 mg (yield 58%)of 1-allyl-2-benzyloxymethyl-5-(3-chlorophenylthio)-4-isopropyl-1H-imidazole (17g)was obtained.
Reaction SMILES: Br.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([NH2:15])[S:13][CH:14]=2)=[CH:6][CH:5]=1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.Cl>N1C=CC=CC=1>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[C:12]([NH:15][S:22]([C:19]3[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=3)(=[O:24])=[O:23])[S:13][CH:14]=2)=[CH:8][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc(-c2csc(N)n2)cc1
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(-c2csc(NS(=O)(=O)c3ccc(C)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.2 %

Procedure:
A mixture of 0.5 g of 4-(4-methoxy-phenyl)-thiazol-2-ylamine hydrobromide with 0.37 g of p-toluenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting, red colored suspension was poured into 30 ml of 1N hydrochloric acid and the mixture was extracted twice with 40 ml of ethyl acetate each time. The organic phases were combined, dried with magnesium sulphate and the solvent was removed on a rotary evaporator. The residue was dissolved in a mixture of 20 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.4 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. The product separated upon neutralization with concentrated hydrochloric acid. Recrystallization from 30 ml of 50% ethanol yielded 0.24 g of N-[4-(4-methoxy-phenyl)-thiazol-2-yl]-4-methyl-benzenesulfonamide as beige crystals.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]=2)=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH:27]([F:29])[F:28])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[Li+].[OH-].O>C1COCC1.O.CO>[C:30]1([C:7]2[S:6][C:5]([C:3]([OH:4])=[O:2])=[C:9]([N:10]([CH:20]3[CH2:21][CH2:22][N:23]([CH2:26][CH:27]([F:28])[F:29])[CH2:24][CH2:25]3)[C:11]([C@H:13]3[CH2:14][CH2:15][C@H:16]([CH3:19])[CH2:17][CH2:18]3)=[O:12])[CH:8]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]=1
Reactant: COC(=O)c1sc(C2=CCCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCN(CC(F)F)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C[C@H]1CC[C@H](C(=O)N(c2cc(C3=CCCCC3)sc2C(=O)O)C2CCN(CC(F)F)CC2)CC1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
To a stirred solution of 5-cyclohex-1-enyl-3-[[1-(2,2-difluoro-ethyl)-piperidin-4-yl]-(trans-4-methylcyclohexanecarbonyl)amino]-thiophene-2-carboxylic acid methyl ester (40 mg, 0.08 mmol) in THF: H2O: MeOH (3:1:2) (1 mL), was added LiOH in water (1N) (0.16 mL, 0.16 mmol). The reaction mixture was stirred at 70° C. for 5 h. The mixture was concentrated under reduced pressure on a rotary evaporator and the residue was treated with a solution of 0.1 N HCl and extracted in EtOAc. The EtOAc layer was dried over Na2SO4. Filtration and removal of the solvent under reduced pressure on a rotary evaporator followed by HPLC purification afforded 5-cyclohex-1-enyl-3-[[1-(2,2-difluoro-ethyl)-piperidin-4-yl]-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid (9.0 mg, 39%) as a foam.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]([CH3:20])([CH3:19])[CH2:7][CH:8]([NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.Cl[C:24]1[N:29]=[C:28]([NH:30][C:31]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:32]=2[C:33]([NH:35][CH3:36])=[O:34])[C:27]([Cl:42])=[CH:26][N:25]=1>>[Cl:42][C:27]1[C:28]([NH:30][C:31]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:32]=2[C:33]([NH:35][CH3:36])=[O:34])=[N:29][C:24]([NH:1][C:2]2[CH:22]=[CH:21][C:5]3[C:6]([CH3:19])([CH3:20])[CH2:7][CH:8]([NH:12][C:13](=[O:18])[C:14]([F:17])([F:15])[F:16])[C:9](=[O:11])[NH:10][C:4]=3[CH:3]=2)=[N:25][CH:26]=1
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CC1(C)CC(NC(=O)C(F)(F)F)C(=O)Nc2cc(N)ccc21
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)NC(=O)C(NC(=O)C(F)(F)F)CC3(C)C)ncc1Cl

Procedure:
2-{5-Chloro-2-[5,5-dimethyl-2-oxo-3-(2,2,2-trifluoro-acetylamino)-2,3,4,5-tetrahydro-1H-1-benzazepin-8-ylamino]-pyrimidin-4-ylamino}-3-fluoro-N-methyl-benzamide was prepared from N-(8-Amino-5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl)-2,2,2-trifluoro-acetamide and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide in an analogous manner to Example 12211d. The title compound was isolated as a white solid (73 mg, 25%). HPLC purity 99%, LCMS 594.24 (M+H), HNMR (DMSO) 9.73 (s, 1H), 9.60 (d, J=7.8 Hz, 1H), 9.43 (s, 1H), 9.37 (s, 1H), 8.50 (d, J=4.5 Hz, 1H), 8.19 (s, 1H), 7.48-7.44 (m, 2H), 7.35-7.30 (m, 2H), 7.18 (s, 1H), 7.10 (d, J=8.9 Hz, 1H), 4.27-4.20 (m, 1H), 2.73 (d, J=4.2 Hz, 3H), 2.18-2.12 (m, 2H), 1.35 (s, 3H), 1.26 (s, 3H).
Reaction SMILES: [C:1]([CH:5]1[CH2:9][O:8][CH:7]([C:10]2[O:14][N:13]=[C:12]([C:15]([O:17]CC)=[O:16])[C:11]=2[CH3:20])[O:6]1)([CH3:4])([CH3:3])[CH3:2].C[Si](C)(C)[O-].[K+:26]>C1COCC1>[C:1]([CH:5]1[CH2:9][O:8][CH:7]([C:10]2[O:14][N:13]=[C:12]([C:15]([O-:17])=[O:16])[C:11]=2[CH3:20])[O:6]1)([CH3:4])([CH3:3])[CH3:2].[K+:26]
Reactant: CCOC(=O)c1noc(C2OCC(C(C)(C)C)O2)c1C
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1c(C(=O)[O-])noc1C1OCC(C(C)(C)C)O1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of ethyl 5-(4-(tert-butyl)-1,3-dioxolan-2-yl)-4-methylisoxazole-3-carboxylate (42 mg, 0.148 mmol) in THF (4 mL) was added potassium trimethylsilanolate (19.02 mg, 0.148 mmol) and the mixture was stirred at room temperature for 1.5 hours. The resulting mixture was concentrated under reduced pressure to afford the title compound.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH:21]([C:32]2[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=2[F:39])[C:22]2[C:23]([CH3:31])=[CH:24][C:25]([C:28]([NH2:30])=[O:29])=[N:26][CH:27]=2)=[O:20])=[CH:15][CH:14]=1>C(Cl)Cl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH:21]([C:32]2[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=2[F:39])[C:22]2[C:23]([CH3:31])=[CH:24][C:25]([C:28]([NH2:30])=[O:29])=[N:26][CH:27]=2)(=[O:9])=[O:20])=[CH:15][CH:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(C(N)=O)ncc1C(c1cc(F)ccc1F)S(=O)c1ccc(Cl)cc1
Solvent: ClCCl
Product: Cc1cc(C(N)=O)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 52 %

Procedure:
3-Chloroperbenzoic acid (66 mg, 0.25 mmol) was added to a solution of 5-[[(4-chlorophenyl)sulfinyl](2,5-difluorophenyl)methyl]-4-methylpyridine-2-carboxamide (105 mg, 0.25 mmol) in methylene chloride (5 ml) at 0° C. After stirring for 5 days at room temperature, the reaction mixture was washed with 1 N aqueous sodium hydroxide. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to preparative thin-layer chromatography (developed with methylene chloride:methanol=40:1, and eluted with methylene chloride:methanol=4:1). The obtained fraction was concentrated under reduced pressure, and the resulting residue was washed with a mixed solvent of ethanol and diethyl ether and collected by filtration, thus to obtain the title compound (56 mg, 0.13 mmol, 51%) as a white solid.
Reaction SMILES: [OH:1]N1C(=O)CCC1=O.[CH3:9][CH:10]([CH3:17])[N:11]=[C:12]=[N:13][CH:14]([CH3:16])[CH3:15].N(C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)CC(O)=O>ClCCl>[CH:10]([NH:11][C:12]([NH:13][CH:14]([CH3:16])[CH3:15])=[O:1])([CH3:17])[CH3:9]
Reactant: O=C1CCC(=O)N1O
Reactant: CC(C)N=C=NC(C)C
Agent: O=C(O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: ClCCl
Product: CC(C)NC(=O)NC(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
N-Hydroxysuccinimide (1.70 g, 14.77 mmol) and DIC (1.87 g, 14.77 mmol) were added sequentially to a stirred solution of Fmoc-Gly-OH (4.0 g, 13.45 mmol) in dichloromethane (15 mL); the resulting mixture was stirred at room temperature for 4 h. The N,N′-diisopropylurea formed was removed by filtration and the solid was washed with ether (20 mL). The volatiles were removed and the solid Fmoc-Gly-succinimidyl ester formed was washed with ether (3×20 mL). Fmoc-Gly-succinimidyl ester was then redissolved in dry DMF (15 mL) and 3-aminodeoxycholic acid (5.21 g, 12.78 mmol) was added to the clear solution. The reaction mixture was stirred at room temperature for 4 h, water (200 mL) was added and the precipitated solid was filtered, washed with water, dried and purified by silica gel chromatography (TLC (silica): (Rf: 0.50, silica gel, CH2Cl2/CH3OH, 9:1) (eluant: CH2Cl2/CH3OH (9:1)) to give (3β,5β,7α,12α)-3-[[(9H-Fluoren-9-ylmethoxy)amino]acetyl]amino-7,12-dihydroxycholan-24-oic acid as a colorless solid. Yield: 7.46 g (85%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH2:15]([N:17]([CH2:21][CH3:22])[C:18](Cl)=[O:19])[CH3:16]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:18](=[O:19])[N:17]([CH2:21][CH3:22])[CH2:15][CH3:16])[CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: CCN(CC)C(=O)Cl
Solvent: ClC(Cl)Cl
Product: CCN(CC)C(=O)N1CCN(c2ccc(OC)cc2)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
In 75 ml of chloroform was dissolved 10.4 g (0.054 mole) of 1-(4-methoxyphenyl)piperazine at room temperature, and a solution of 7.4 g (0.054 mole) of diethylcarbamoyl chloride in 50 ml of chloroform was dropped to the above solution over a period of 30 minutes. The mixture was stirred at 50° C. for 2 hours, and the insoluble substance was removed, and the filtrate was concentrated under reduced pressure and 100 ml of a 35% aqueous solution of sodium hydroxide and 300 ml of ether were added to the concentrate. The mixture was stirred for a certain time, and the ether layer was dried with anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel chromatography and distillation under reduced pressure to obtain 7.4 of purified 1-(4-methoxyphenyl)-4-diethylcarbamoylpiperazine having a boiling point 195° C. at 0.5 mm Hg. The yield was 47.0%. Elementary analysis values are as follows.
Reaction SMILES: Cl[C:2](Cl)=[N:3][C:4](=[O:7])[O:5][CH3:6].[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:32])([F:31])[CH:28]([F:30])[F:29])[CH:21]=2)(=[O:19])=[O:18])=[CH:12][C:11]=1[NH2:33].C(N(CC)CC)C>C(Cl)Cl>[F:32][C:27]([F:31])([O:26][C:22]1[CH:21]=[C:20]([S:17]([O:16][C:13]2[CH:14]=[CH:15][C:10]3[N:9]=[C:2]([NH:3][C:4]([O:5][CH3:6])=[O:7])[NH:33][C:11]=3[CH:12]=2)(=[O:18])=[O:19])[CH:25]=[CH:24][CH:23]=1)[CH:28]([F:30])[F:29]
Reactant: COC(=O)N=C(Cl)Cl
Reactant: Nc1ccc(OS(=O)(=O)c2cccc(OC(F)(F)C(F)F)c2)cc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Nc1nc2ccc(OS(=O)(=O)c3cccc(OC(F)(F)C(F)F)c3)cc2[nH]1
Reaction time: 1 h

Procedure:
A solution of 15.6 g of methyl N-dichloromethylenecarbamate in 50 ml of methylene chloride is added slowly, with stirring, to a mixture of 38 g of 1,2-diamino-4-[3-(1,1,2,2-tetrafluoroethoxy)phenylsulfonyloxy]benzene (see Example 2), 20.2 g of triethylamine and 300 ml of methylene chloride at a temperature of about 20° C. The mixture is stirred for one hour and the precipitate is filtered off with suction and washed with diisopropyl ether. For purification, it is recrystallized from methanol, melting point 186° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@@H:11]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:12]([OH:14])=O.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[N:28]([CH2:32][CH2:33][NH2:34])[CH2:27][CH2:26]2>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@@H:11]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:12]([NH:34][CH2:33][CH2:32][N:28]1[C:29]2[C:25](=[CH:24][C:23]([F:22])=[CH:31][CH:30]=2)[CH2:26][CH2:27]1)=[O:14]
Reactant: O=C(O)[C@H](CC1CCCCC1)Nc1nc2ccccc2o1
Reactant: NCCN1CCc2cc(F)ccc21
Product: O=C(NCCN1CCc2cc(F)ccc21)[C@H](CC1CCCCC1)Nc1nc2ccccc2o1

Procedure:
The title compound was prepared from 2-(S)-(benzooxazol-2-ylamino)-3-cyclohexyl propionic acid and 2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylamine using the procedure analogous to that described in example 2. HPLC-MS calcd. for C26H31FN4O2 (M+H+) 451.24. found 451.5.