Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[CH:2][CH:3]1[CH:8]2[CH2:9][CH:10]([C@H:11]([OH:23])[C:12]3[CH:21]=[CH:20][N:19]=[C:18]4[C:13]=3[CH:14]=[C:15]([OH:22])[CH:16]=[CH:17]4)[N:5]([CH2:6][CH2:7]2)[CH2:4]1.Br[CH2:25][CH2:26][CH2:27][N:28]1[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]2[C:29]1=[O:38].C(=O)([O-])[O-].[K+].[K+].CO>CC(C)=O.C1OCCOCCOCCOCCOCCOC1>[OH:23][C@@H:11]([C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[C:15]([O:22][CH2:25][CH2:26][CH2:27][N:28]3[C:32](=[O:33])[C:31]4[C:30](=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:29]3=[O:38])[CH:14]=2)[N:19]=[CH:20][CH:21]=1)[C@@H:10]1[N:5]2[CH2:6][CH2:7][C@H:8]([C@@H:3]([CH:2]=[CH2:1])[CH2:4]2)[CH2:9]1
Reactant: C=CC1CN2CCC1CC2[C@H](O)c1ccnc2ccc(O)cc12
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CO
Product: C=C[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](O)c1ccnc2ccc(OCCCN3C(=O)c4ccccc4C3=O)cc12
Temperature: 25 °C
Yield: 26.9 %

Procedure:
A mixture of 6-hydroxycinchonine (1) (2.5 g, 8.06 mmol), N-(3-bromopropyl)phthalimide (2.16 g, 8.06 mmol), anhydrous potassium carbonate (1.3 g, 9.4 mmol) and 18-crown-6 (5 mg) in 75 ml of dry acetone was allowed to reflux for 16 h under argon atmosphere. The reaction was cooled to room temperature and 30 ml of methanol was added to make a homogeneous solution. The resulting solution was concentrated and the residue was partially purified on silica gel column chromatography using 5% methanol in chloroform as the eluent. This product was repurified on silica gel column chromatography using 10% methanol in chloroform and yielded 1.08 g (2.17 mmol, 27%) of (11) as off-white solids. MS, IR and NMR data confirmed compound identity.
Reaction SMILES: C([O:4][C@H:5]1[O:10][C@H:9]([CH2:11][O:12][C:13](=[O:15])[CH3:14])[CH:8]=[C:7]([Br:16])[C:6]1=[O:17])(=O)C.BrC1C(=O)[C@@H]2OC[C@H](C=1)O2.O.[OH-].[Li+].C(OCC)(=O)C>O1CCCC1.O>[C:13]([O:12][CH2:11][C@H:9]1[O:10][CH:5]([OH:4])[C:6](=[O:17])[C:7]([Br:16])=[CH:8]1)(=[O:15])[CH3:14]
Reactant: CC(=O)OC[C@@H]1C=C(Br)C(=O)[C@@H](OC(C)=O)O1
Agent: O=C1C(Br)=C[C@H]2CO[C@@H]1O2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@@H]1C=C(Br)C(=O)C(O)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.2 %

Procedure:
200 mg of 1,6-di-O-acetyl-3-bromo-3,4-dideoxy-α-D-glycero-hex-3-enopyranos-2-ulose prepared in the same manner as in the above Intermediate Preparation Example 4 from 1,6-anhydro-3-bromo-3,4-dideoxy-β-D-glycero-hex-3-enopyranos-2-ulose (Intermediate No. 4) prepared by the method disclosed in Carbohydrate Research (1981), Vol. 93, 284-287, was dissolved in 6 ml of tetrahydrofuran-water (5:1), and 70 mg of lithium hydroxide monohydrate was added thereto. The mixture was stirred at room temperature for 30 minutes. To the reaction solution, 100 ml of ethyl acetate was added. The mixture was washed three times with 100 ml of a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained syrup crude product was purified by thin layer chromatography for separation (NO-5744, manufactured by Merck, ethyl acetate: hexane=1:1) to obtain 40 mg of the desired product (Intermediate No. 18) as a slightly yellow liquid. The NMR analytical data of this product are as follows.
Reaction SMILES: [CH2:1]([OH:7])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH3:6].[H-].[Na+].Cl[C:11]1[C:15]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:14][S:13][N:12]=1.O>O1CCCC1>[CH2:1]([O:7][C:11]1[C:15]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:14][S:13][N:12]=1)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH3:6]
Reactant: CCC/C=C/CO
Reactant: Clc1nsnc1-c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCC/C=C/COc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of trans-2-hexen-1-ol (900 mg, 9 mmol) and sodium hydride (310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl) pyridine (590 mg, 3 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 1 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[CH:10]([NH:13][CH:14]([CH3:16])[CH3:15])([CH3:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:13]([CH:14]([CH3:16])[CH3:15])[CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(C)NC(C)C
Reactant: BrCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)N(Cc1ccc(Br)cc1)C(C)C
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of 4-bromobenzylbromide (5.0 g), N,N-diisopropylamine (7.85 ml) and potassium carbonate (2.76 g) in dimethylformamide (50 ml) was stirred at 80° C. for 2 hours. To the mixture was added water, and the mixture was extracted with ether. The extract was washed with water, dried (MgSO4) and concentrated to give the title compound (5.0 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.[C:23]([CH:27]1[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]1)([CH3:26])([CH3:25])[CH3:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>CN(C)C=O.C(OCC)(=O)C>[C:23]([CH:27]1[CH2:32][CH2:31][CH:30]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:17][CH:18]=2)[CH2:29][CH2:28]1)([CH3:26])([CH3:25])[CH3:24]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: CC(C)(C)C1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc2nccc(Oc3ccc(NC4CCC(C(C)(C)C)CC4)cc3)c2cc1OC
Temperature: 60 °C
Reaction time: 1 h
Yield: 11.4 %

Procedure:
4-(6,7-Dimethoxy-4-quinolyloxy)aniline (300 mg) was dissolved in N,N-dimethylformamide (10 ml) to prepare a solution. 4-Tert-butylcyclohexanone (200 mg) was then added to the solution, and the mixture was stirred at 60° C. for one hr. The reaction solution was cooled to room temperature before sodium triacetoxy borohydride (400 mg) was added thereto. The mixture was then stirred at room temperature for 3 hr. Water and ethyl acetate were added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and was dried over sodium sulfate. The solvent was removed by evaporation under the reduced pressure, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (50 mg, yield 11%).
Reaction SMILES: [C:1]12([CH2:11][NH:12][CH2:13][C@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[OH:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.CCN(CC)CC.Cl[C:30](Cl)([O:32]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[C:1]12([CH2:11][N:12]3[CH2:13][C@H:14]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[O:15][C:30]3=[O:32])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: O[C@H](CNCC12CC3CC(CC(C3)C1)C2)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1O[C@@H](c2ccccc2)CN1CC12CC3CC(CC(C3)C1)C2
Reaction time: 0.5 h
Yield: 64.2 %

Procedure:
To a solution of (S)-2-((1-adamantylmethyl)amino)-1-phenylethanol (35 mg, 0.12 mmol), Et3N (24.8 mg, 0.25 mmol) in CH2Cl2 (2 mL) at 0° C. was added triphosgene (14.6 mg, 0.05 mmol) and the mixture was stirred for 30 min. The mixture was concentrated under vacuum to give the crude product, which was purified by preparative TLC to give (S)-3-((1-adamantyl)methyl)-5-phenyloxazolidin-2-one (10 mg, 26%). 1H NMR (MeOD, 400 MHZ): δ=1.51-1.95 (m, 15H), 2.89 (q, 2H), 3.55 (q, 1H), 4.10 (t, 1H), 5.57 (q, 1H), 7.34˜7.45 (m, 5H); MS m/z=312.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:18][C:19]1[CH:27]=[C:26]2[C:22]([CH2:23][CH2:24][NH:25]2)=[CH:21][CH:20]=1.N1C=CC=CC=1.CO>ClCCCl.Cl.CCOCC>[Cl:18][C:19]1[CH:27]=[C:26]2[C:22]([CH2:23][CH2:24][N:25]2[C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N:12]4[CH2:17][CH2:16][O:15][CH2:14][CH2:13]4)[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:21][CH:20]=1
Reactant: Clc1ccc2c(c1)NCC2
Reactant: Clc1ncnc2ccc(N3CCOCC3)cc12
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Solvent: CCOCC
Product: Clc1ccc2c(c1)N(c1ncnc3ccc(N4CCOCC4)cc13)CC2

Procedure:
4-Chloro-6-morpholino-quinazoline (382 mg, 1.53 mmol) and 6-chloroindoline (258 mg, 1.63 mmol) were heated at reflux in 8 mL of 1,2-dichloroethane and pyridine (264 mg, 3.36 mmol) for 16 hours. The reaction mixture was vacuum evaporated and partitioned between 100 mL of ethyl acetate and 50 mL of 5% sodium bicarbonate. The organic layer was washed with an additional 50 mL of bicarbonate and 50 mL of brine, dried with magnesium sulfate, filtered and evaporated in vacuo to a residue. This was purified by flash chromatography on silica gel eluted with 20% acetone/methylene chloride. The pure solid isolated from the column was converted to its hydrochloride salt by dissolution in methanol containing 1.1 equivalents of anhydrous hydrogen chloride and precipitation with ether; 396 mg (65%); M.P. 277°-279° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=O)[C:3]=1[C:11]([OH:13])=O.[NH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][NH:17][C:16]1=[O:21]>CN(C=O)C>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]2[C:3]=1[C:11](=[O:13])[N:14]([CH:15]1[CH2:20][CH2:19][CH2:18][NH:17][C:16]1=[O:21])[C:5]2=[O:7]
Reactant: Nc1cccc(C(=O)O)c1C(=O)O
Reactant: NC1CCCNC1=O
Solvent: CN(C)C=O
Product: Nc1cccc2c1C(=O)N(C1CCCNC1=O)C2=O
Temperature: 90 °C
Reaction time: 18 h
Yield: 34.9 %

Procedure:
To a solution of 3-aminophthalic acid (0.100 g, 0.552 mmol) in DMF (1.1 mL) was added 3-aminopiperidine-2-one (0.063 g, 0.552 mmol) and the reaction was stirred at 90° C. over 18 h. Volatiles were removed in vacuo and the dark-brown crude residue was purified by preparative reverse phase HPLC to give the desired product 28 (0.050 g, 35%) as an off-white powder. 1H NMR (400 MHz, DMSO) δ 7.83 (s, 1H), 7.43 (dd, J=8.3, 7.1 Hz, 1H), 7.07-6.87 (m, 2H), 6.47 (br s, 2H), 4.49 (dd, J=11.9, 6.3 Hz, 1H), 3.27-3.10 (m, 2H), 2.19 (dt, J=12.0, 7.7 Hz, 1H), 2.05-1.72 (m, 3H). MS (ESI) m/z calcd for C13H14N3O3 [M+H]+ 260.3, found: 260.9.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16])[CH2:5][C:6](OC)=O.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[C:20](CBr)[CH:19]=1>O1CCCC1>[Br:17][C:18]1[CH:19]=[CH:20][C:21]([F:24])=[C:22]([CH2:6][CH2:5][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[O:3])[CH:23]=1
Reactant: COC(=O)CC(=O)c1ccccc1C
Reactant: Fc1ccc(Br)cc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)CCc1cc(Br)ccc1F
Yield: 67.1 %

Procedure:
Sodium hydride (60% in oil, 2.1 g, 52 mmol) and methyl 3-oxo-3-o-tolylpropanoate (10 g, 52 mmol) were suspended in tetrahydrofuran and 4-bromo-2-(bromomethyl)-1-fluoro-benzene (15.3 g, 57 mmol) was added. After complete conversion, the mixture was quenched with ice and a saturated solution of ammonium chloride and extracted with n-heptane. The combined organic layers were washed once with a saturated solution of ammonium chloride, water and brine. The organic layer was dried over magnesium sulfate and evaporated to dryness. The obtained yellow oil was dissolved in 25 ml of acetic acid, 25 ml of concentrated hydrochloric acid and 20 ml of 1,4-dioxane and heated under reflux for 4 h until LC/MS showed consumption of the starting material. 50 ml of water and 100 ml of tert-butyl methyl ether were added and the product was extracted. The combined organic layers were washed once with saturated solution of ammonium chloride, water and brine. The organic layer was dried over magnesium sulfate and evaporated to dryness. The residue was purified by column chromatography (silica gel, heptane/ethyl acetate gradient) to give 11.2 g of 3-(5-bromo-2-fluoro-phenyl)-1-o-tolyl-propan-1-one as a colorless oil.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:20][C:21]([O:23][CH3:24])=[O:22].O>CN(C=O)C>[CH2:3]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:11]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)CBr
Reactant: c1ccc(Cc2c[nH]c3ccccc23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cn1cc(Cc2ccccc2)c2ccccc21
Reaction time: 1 h

Procedure:
To a suspension of NaH (50% dispersion in oil, 170 mg, 3.5 mmol) in DMF (15 mL), at r.t. and under an atmosphere of nitrogen, there was added in portions 3-benzylindole (ref: Tetrahedron 23, 3771-83 (1967)) (621 mg, 3 mmol) and the mixture was stirred for 1 hour. There added methyl bromoacetate (765 mg, 5 mmol) and stirring was continued for 1.5 hours. H2O (100 mL) was added and the mixture was extracted twice with Et2O. These extracts were H2O with water, dried over MgSO4 and evaporated to a residue which was chromatographed on silica gel eluting with a 1:5 mixture of EtOAc acetate and hexane to afford the title product as an oil.
Reaction SMILES: [S:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[N:21]=[CH:20][C:19]3[C:14](=[CH:15][C:16]([C:22]([O-:24])=[O:23])=[CH:17][CH:18]=3)[N:13]=2)=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2].[OH-].[Na+].[CH3:27]O>>[CH3:27][C:20]1[C:19]2[C:14](=[CH:15][C:16]([C:22]([OH:24])=[O:23])=[CH:17][CH:18]=2)[N:13]=[C:12]([NH:11][C:8]2[CH:7]=[CH:6][C:5]([S:1](=[O:3])(=[O:4])[NH2:2])=[CH:10][CH:9]=2)[N:21]=1
Reactant: CO
Reactant: NS(=O)(=O)c1ccc(Nc2ncc3ccc(C(=O)[O-])cc3n2)cc1
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc(Nc2ccc(S(N)(=O)=O)cc2)nc2cc(C(=O)O)ccc12
Temperature: 80 °C

Procedure:
To 2-(4-sulfamoylphenyl amino)quinazolin-7-carboxylate was added 2N sodium hydroxide (4 eq) and methanol and the mixture was heated to 80° C. for 10 min. The saponification went to completion. The reaction mixture was concentrated and 1N HCl was added to precipitate methyl 2-(4-sulfamoylphenylamino)quinazolin-7-carboxylic acid as the HCl salt in quantitative yield. ES/MS m/z 344 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][S:16][C:17]3[NH:18][CH:19]=[C:20]([C:24](OCC)=[O:25])[C:21](=[O:23])[N:22]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30].B.CSC>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][S:16][C:17]3[NH:18][CH:19]=[C:20]([CH2:24][OH:25])[C:21](=[O:23])[N:22]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[C:29]([F:30])([F:32])[F:31]
Reactant: CCOC(=O)c1c[nH]c(SCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)nc1=O
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: O=c1nc(SCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)[nH]cc1CO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42.7 %

Procedure:
To a solution of ethyl 2-{[(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)methyl]thio}-4-oxo-1,4-dihydro-5-pyrimidinecarboxylate (2.36 g, 4.87 mmol) in dry THF (20 mL) was added borane-methyl sulfide complex (2.0M in toluene) (7.30 mL, 14.60 mmol) dropwise under argon at 0° C. The mixture was stirred at 0° C. for 0.5 h, and warmed to room temperature for 1 h, then quenched with acetone. Purification via reverse phase flash chromatography then afforded the title compound (921 mg, 2.080 mmol, 42.7% yield). LCMS: rt=3.28 min, [M+H+]=443
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[NH:11][C:10](=[S:12])[NH:9][C:5]2=[N:6][C:7]=1[I:8].[OH-].[K+].I[CH3:16]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[NH:11][C:10]([S:12][CH3:16])=[N:9][C:5]2=[N:6][C:7]=1[I:8]
Reactant: S=c1[nH]c2cc(Cl)c(I)nc2[nH]1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CSc1nc2nc(I)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 6-chloro-5-iodo-1,3-dihydro-2H-imidazo[4,5-b]pyridine-2-thione (11.0 g, 35.3 mmol) and KOH (2.38 g, 42.4 mmol) in ethanol (200 mL) was stirred at rt for 0.5 h. Iodomethane (2.2 mL, 35.3 mmol) was then added and the reaction was allowed to stir for 1 h at rt. The ethanol was removed in vacuo and the resulting residue was partitioned between ethyl acetate (250 mL) and 2N HCl (50 mL). The ethyl acetate layer was washed with brine, dried over magnesium sulfate, filtered through a 100 g pad of silica gel and concentrated to give the desired product as a white solid. LC-MS: calculated for C2H5ClIN3S 325.56, observed m/e: 325.88 (M+H)+ (Rt 2.05/5 min).
Reaction SMILES: C(O[C:6]([N:8](C(OC(C)(C)C)=O)[C:9](=[O:40])[C:10]1[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][S:17]2(=[O:22])=[O:21])[CH:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[C:36]([CH3:37])=[CH:35][C:34]([CH3:38])=[C:33]([CH3:39])[N:32]=2)[CH2:27][CH2:26]1)=[O:24])=O)(C)(C)C.N1C[CH2:51][CH2:50][CH2:49]1>>[O:21]=[S:17]1(=[O:22])[CH2:18][CH2:19][CH2:20][N:16]1[C:14]1[CH:13]=[CH:12][C:11]([C:23]([N:25]2[CH2:30][CH2:29][N:28]([C:31]3[C:36]([CH3:37])=[CH:35][C:34]([CH3:38])=[C:33]([CH3:39])[N:32]=3)[CH2:27][CH2:26]2)=[O:24])=[C:10]([C:9]([N:8]2[CH2:6][CH2:51][CH2:50][CH2:49]2)=[O:40])[CH:15]=1
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3C(=O)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC2)nc1C
Reactant: C1CCNC1
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3C(=O)N3CCCC3)CC2)nc1C

Procedure:
Using N,N-di-tert-butyloxycarbonyl-5-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-[4-(3,5,6-trimethylpyridin-2-yl)piperazine-1-carbonyl]benzamide (202 mg) described in Example 768 and pyrrolidine (30 μL) and by the reaction and treatment in the same manner as in Example 770, the title compound (127 mg) was obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:38]=[CH:37][C:8]2[N:9]([CH2:27][CH2:28][NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:10]([NH:12][C:13]3[S:14][C:15]4[CH:21]=[C:20]([O:22][C:23]([F:26])([F:25])[F:24])[CH:19]=[CH:18][C:16]=4[N:17]=3)=[N:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+].CO>C1COCC1>[C:33]([O:32][C:30]([NH:29][CH2:28][CH2:27][N:9]1[C:8]2[CH:37]=[CH:38][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[N:11]=[C:10]1[NH:12][C:13]1[S:14][C:15]2[CH:21]=[C:20]([O:22][C:23]([F:24])([F:25])[F:26])[CH:19]=[CH:18][C:16]=2[N:17]=1)=[O:31])([CH3:36])([CH3:34])[CH3:35]
Reactant: COC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2CCNC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)NCCn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Yield: 89.7 %

Procedure:
1-(2-tert-Butoxycarbonylamino-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (327.0 mg) was prepared by following General Procedure E starting from 1-(2-tert-butoxycarbonylamino-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid methyl ester (374.0 mg) and sodium hydroxide (2.0 N solution, 1.0 mL) MeOH (0.5 mL) and THF (2.0 mL).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]1.[CH2:12]([O:14][C:15](=[O:27])[C:16]([C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)=[O:17])[CH3:13].C([O-])([O-])=O.[K+].[K+]>>[CH2:12]([O:14][C:15](=[O:27])[C:16]([C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]([CH2:2][CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]2)[CH:19]=1)=[O:17])[CH3:13]
Reactant: CCOC(=O)C(=O)c1c[nH]c2ccccc12
Reactant: CN1CCN(CCCCl)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)C(=O)c1cn(CCCN2CCN(C)CC2)c2ccccc12
Yield: 53 %

Procedure:
The general procedure 1 was then followed using 1-(3-chloropropyl)-4-methylpiperazine (12.5 mmol, 2.2 g), ethyl-2-(1H-indol-3-yl)-2-oxoacetate (10 mmol, 2.17 g) and K2CO3 (10.8 mmol, 1.5 g). The purification was achieved by column chromatography (petrolether:ethylacetate:diethylamine 5:5:1) to yield ethyl-2-{1-[3-(4-methylpiperazin-1-yl)propyl]-1H-indol-3-yl}-2-oxoacetate (5.3 mmol, 42%). IR {tilde over (ν)} [cm−1]=2936; 2790; 1727; 1638. FD-MS m/z (rel. int.)=359.9 (2.05%; M+•). 1H NMR (300 MHz, CDCl3) 8.40 (m; 2H; indole-H); 7.36 (m; 3H; indole-H); 4.38 (q; 3J=7.1 Hz; 2H; OCH2CH3); 4.25 (t; 3J=6.5 Hz; 2H; indole-CH2CH2CH2N); 2.44 (m; 8H; 4′piperazin-CH2); 2.30 (s; 3H; CH3); 2.26 (t; 3J=6.5 Hz; 2H; indole-CH2CH2CH2N); 2.00 (m; 2H;
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl[CH2:10]Cl>>[CH3:10][CH:5]1[CH2:6][CH2:7][CH2:8][CH:3]([CH:2]=[O:1])[CH2:4]1
Reactant: ClCCl
Reactant: OCC1CCCCC1
Product: CC1CCCC(C=O)C1
Reaction time: 1 h

Procedure:
To a solution of 1-hydroxymethylcyclohexane (6.8 g, 0.053 mole) in 150 ml dichloromethane was added pcc (22.9 g, 0.106 mole) under nitrogen. Stirring continued for 1 hour at room temperature. The solids were removed by filtration through Florisil and the filtrate was concentrated to give 8 g of the title compound. The NMR spectrum showed 0.90, 0.95 (d, 3H, J=8 Hz), 0.86-2.32 (m, 10H), and 9.68, 9.70 (d, 1H, J=2 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[C:16]([F:24])[CH:15]=3)[CH:11]=[C:10]([C:25]([F:28])([F:27])[F:26])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:29]([NH:33][S:34]([C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=1)(=[O:36])=[O:35])([CH3:32])([CH3:31])[CH3:30]>>[C:29]([NH:33][S:34]([C:37]1[CH:42]=[C:41]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:22])[F:23])=[C:16]([F:24])[CH:15]=4)[CH:11]=[C:10]([C:25]([F:28])([F:26])[F:27])[N:9]=3)[CH:3]=2)[CH:40]=[CH:39][CH:38]=1)(=[O:36])=[O:35])([CH3:32])([CH3:30])[CH3:31]
Reactant: Fc1cc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)ccc1C(F)(F)F
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)c(F)c4)cc(C(F)(F)F)n3)c2)c1

Procedure:
3′-[4-(3-Fluoro-4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide was prepared from 2-(3-bromo-phenyl)-4-(3-fluoro-4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine (example E.109) (0.465 g, 1.0 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.31 g, 1.2 mmol) according to the general procedure VI. Obtained as light yellow solid (0.47 g), which was subsequently deprotected.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]([OH:15])[CH:10]([N+:12]([O-:14])=[O:13])[CH3:11])=[CH:5][CH:4]=1.[H][H]>CO.[Pd]>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]([OH:15])[CH:10]([N+:12]([O-:14])=[O:13])[CH3:11])=[CH:5][CH:4]=1.[NH2:12][C@@H:10]([CH3:11])[C@@H:9]([C:6]1[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[OH:15]
Reactant: [H][H]
Agent: [Pd]
Agent: COc1ccc(C(O)C(C)[N+](=O)[O-])cn1
Solvent: CO
Product: COc1ccc([C@@H](O)[C@H](C)N)cn1

Procedure:
1-(6-methoxypyridin-3-yl)-2-nitro-propan-1-ol (17c) (2.20 g, 10.37 mmol) was dissolved in methanol (410 mL) and hydrogenated using a H-Cube™ hydrogenation reactor (THALES nanotechnology) equipped with a cartridge of 10% Pd/C. The flow rate was set to 0.8 mL/min, temperature 80° C. and full the hydrogen production at full mode. After evaporation of the solution diastereomers were separated on preparative HPLC (XTerrra C18, 19×50 mm) using a gradient of 5-30% acetonitrile in water (+1% NH3) gave the subtitle compound 17b (448 mg, 24%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:23]([F:26])([F:25])[F:24])[O:13][N:12]=[C:11]([C:14]3[CH:21]=[CH:20][C:17]([CH:18]=O)=[C:16]([CH3:22])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.O.[NH2:28][NH2:29]>Cl.CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:23]([F:26])([F:25])[F:24])[O:13][N:12]=[C:11]([C:14]3[CH:21]=[CH:20][C:17]([CH:18]=[N:28][NH2:29])=[C:16]([CH3:22])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C=O
Reactant: NN
Agent: Cl
Solvent: CO
Solvent: O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C=NN
Yield: 61 %

Procedure:
A solution of 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzaldehyde (i.e. the product of Step 1, Example 1, 500 mg), concentrated hydrochloric acid (5 drops) and hydrazine hydrate (86 mg) in methanol (20 mL) were heated at reflux for 5 h. The mixture was concentrated and the residue was triturated with water. Filtration yielded the title compound (317 mg, 61%).