Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH:9]1[C:14]1[N:15]([CH3:33])[C:16](=[O:32])[C:17]([OH:31])=[C:18]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[O:21])[N:19]=1)=O)(C)(C)C.ClCCl.C(O)(C(F)(F)F)=O>>[F:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][NH:22][C:20]([C:18]2[N:19]=[C:14]([CH:9]3[CH2:10][O:11][CH2:12][CH2:13][NH:8]3)[N:15]([CH3:33])[C:16](=[O:32])[C:17]=2[OH:31])=[O:21])=[CH:25][CH:26]=1
Reactant: Cn1c(C2COCCN2C(=O)OC(C)(C)C)nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(C2COCCN2)nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O

Procedure:
The compound from Step 9 was treated with a mixture of dichloromethane/TFA (2/1) for 1 hour at room temperature. Organics were removed in vacuo to give the title compound as a solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][C@@H:4]([CH2:7][O:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[NH:3]1.[H-].[Na+].[CH2:17](Br)[CH:18]=[CH2:19]>C1COCC1>[CH2:19]([N:3]1[C@H:4]([CH2:7][O:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH2:5][CH2:6][C:2]1=[O:1])[CH:18]=[CH2:17]
Reactant: O=C1CC[C@@H](COc2cccnc2)N1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCN1C(=O)CC[C@H]1COc1cccnc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 3-((2-oxo-5-(S)-pyrrolidinyl)methoxy)pyridine, from Example 22a (450 mg, 2.34 mmol), in 10 mL of anhydrous THF at 0° C. was added NaH (80% dispersion, 186 mg, 2.68 mmol) was added, and the reaction mixture was stirred for 20 minutes at this temperature. The reaction was then warmed to room temperature, and allyl bromide (425 mg, 3.51 mmol) was added via syringe. After starting material was consumed, water was added to quench the reaction. The desired compound was extracted from the aqueous phase with ethyl acetate and chloroform. The organic layer was dried over MgSO4, then taken to dryness. The residue was purified by silica gel flash chromatography (5% MeOH/CHCl3) to give 450 mg of the title compound. MS (DCI/NH3) m/e: 233 (M+H)+. 1H NMR (D2O, 300 MHz) δ: 8.37-8.26 (m, 2H), 7.38-7.29 (m, 2H), 5.83-5.69 (m, 1H), 5.26-5.13 (m, 2H), 4.35-4.24 (m, 1H), 4.16-3.96 (m, 3H), 3.77-3.67 (m, 1H), 2.68-2.54 (m, 1H), 2.50-2.38 (m, 1H), 2.36-2.20 (m, 1H), 2.09-1.96 (m, 1H),
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:6][C:5]([N:18]=C(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:4][N:3]=1.Cl>C1COCC1>[NH2:18][C:5]1[CH:6]=[C:7]([NH:8][S:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])[C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: O=S(=O)(Nc1cc(N=C(c2ccccc2)c2ccccc2)cnc1Cl)N1CCOCC1
Agent: Cl
Solvent: C1CCOC1
Product: Nc1cnc(Cl)c(NS(=O)(=O)N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of N-(2-chloro-5-(diphenylmethyleneamino)pyridin-3-yl)morpholine-4-sulfonamide (0.150 g, 0.328 mmol) in THF (3 mL) was added hydrochloric acid, 2n (JT Baker) (0.020 mL, 0.657 mmol). The reaction was stirred at rt in closed system for 20 min. The reaction mixture was partitioned between EtOAc and sat. NaHCO3. The aqueous layer was extracted with EtOAc (2×10 mL). The combined organic layer were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (24 g, 3% MeOH in DCM) to afford the desired product as a white foam-like solid (70.0 mg). MS (ESI pos. ion) m/z: 293.0. 1H NMR (300 MHz, CDCl3) δ ppm 3.16-3.32 (m, 4H) 3.61-3.74 (m, 4H) 3.84 (br. s., 2H) 6.67 (br. s., 1H) 7.31 (d, J=2.34 Hz, 1H) 7.64 (d, J=2.19 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]3[O:23][CH2:22][CH:21]([CH:24]4[CH2:29][CH2:28][CH:27]([CH2:30][CH2:31][CH3:32])[CH2:26][CH2:25]4)[CH2:20][CH:19]=3)=[C:12]([F:33])[C:11]=2[F:34])=[C:6]([F:35])[C:5]=1[F:36])[CH3:2]>C1(C)C=CC=CC=1.CC(O)C.[Pd]>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH:18]3[CH2:19][CH2:20][CH:21]([CH:24]4[CH2:29][CH2:28][CH:27]([CH2:30][CH2:31][CH3:32])[CH2:26][CH2:25]4)[CH2:22][O:23]3)=[C:12]([F:33])[C:11]=2[F:34])=[C:6]([F:35])[C:5]=1[F:36])[CH3:2]
Reactant: CCCC1CCC(C2CC=C(CCc3ccc(-c4ccc(OCC)c(F)c4F)c(F)c3F)OC2)CC1
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: CCCC1CCC(C2CCC(CCc3ccc(-c4ccc(OCC)c(F)c4F)c(F)c3F)OC2)CC1
Reaction time: 12 h
Yield: 27.9 %

Procedure:
6-(2-(4′-Ethoxy-2,2′,3,3′-tetrafluorobiphenyl-4-yl)ethyl)-3-(4-propylcyclohexyl)-3,4-dihydro-2H-pyran (31) (2.5 g) prepared in the second step was dissolved in a mixture of toluene (5 ml) and IPA (5 ml), and 5%-Pd/C 125 mg) was added. The stirring was continued under a hydrogen atmosphere at room temperature for 12 hours. 5%-Pd/C was removed by filtration, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (silica gel: 20 g, eluent: toluene), and then by recrystallization (heptane/toluene=50/50 by volume) to give 2-(2-(4′-ethoxy-2,2′,3,3′-tetrafluorobiphenyl-4-yl)ethyl)-5-(4-propylcyclohexyl)tetrahydro-2H-pyran (32) (0.7 g) in 30.1% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:20][C:21]([CH3:32])=[C:22]([CH2:24][CH2:25][N:26]3[CH2:30][CH2:29][CH2:28][C@H:27]3[CH3:31])[N:23]=2)=[CH:15][CH:14]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[O:20][C:21]([CH3:32])=[C:22]([CH2:24][CH2:25][N:26]4[CH2:30][CH2:29][CH2:28][C@H:27]4[CH3:31])[N:23]=3)=[CH:15][CH:14]=2)=[CH:5][CH:4]=1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCC[C@H]1C
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2ccc(-c3nc(CCN4CCC[C@H]4C)c(C)o3)cc2)cc1

Procedure:
The title compound is prepared in a manner substantially analogous to example 133 starting from 4-methoxybenzene boronic acid (218 mg, 1.43 mmol) and 2-(4-Bromo-phenyl)-5-methyl-4-[2-((R)-2-methyl-pyrrolidin-1-yl)-ethyl]-oxazole (100 mg, 0.287 mmol) to give 61 mg (56%). MS (m/e) 377.2 (M+1)
Reaction SMILES: C(OC(O[CH2:8][CH3:9])CBr)C.C(O)C.C(=O)([O-])O.[Na+].[NH2:18][C:19]1[N:20]=[N:21][CH:22]=[C:23]([C:25]([F:28])([CH3:27])[CH3:26])[N:24]=1>Br.O>[F:28][C:25]([C:23]1[CH:22]=[N:21][N:20]2[CH:8]=[CH:9][N:18]=[C:19]2[N:24]=1)([CH3:27])[CH3:26]
Reactant: CC(C)(F)c1cnnc(N)n1
Reactant: CCOC(CBr)OCC
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(F)c1cnn2ccnc2n1
Temperature: 75 °C
Reaction time: 17 h
Yield: 17.3 %

Procedure:
A stirred mixture of bromoacetaldehyde diethyl acetal (1.20 ml, 7.73 mmol) in concentrated hydrobromic acid (0.38 ml) and water (0.38 ml) was heated at reflux for 40 min, then poured into ethanol (3 ml). The solution was neutralised to pH 7 with solid sodium hydrogencarbonate, then filtered, washing the solid with more ethanol (3 ml). To the filtrate was added 3-amino-5-(1-fluoro-1-methylethyl)-1,2,4-triazine (1.0046 g, 6.43 mmol) and the mixture was stirred at 70-80° C. for 17 h. The mixture was evaporated in vacuo, and the residue was purified by flash chromatography (silica gel, 70% EtOAc/isohexane to 15% MeOH/EtOAc, then 20% EtOAc/CH2Cl2) to give 0.2000 g (17%) of the title compound as a pale yellow solid: 1H NMR (360 MHz, CDCl3) δ1.82 (6H, d, J 22.1 Hz), 7.97 (1H, d, J 1.3 Hz), 7.99 (1H, d, J 1.2 Hz), 8.69 (1H, d, J 1.0 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12]([CH3:14])=[O:13].[SH:15][CH2:16][CH2:17][CH2:18][Si:19]([O:24][CH3:25])([O:22][CH3:23])[O:20][CH3:21].Cl>C1CCN2C(=NCCC2)CC1>[CH3:21][O:20][Si:19]([O:22][CH3:23])([O:24][CH3:25])[CH2:18][CH2:17][CH2:16][S:15][CH:10]([C:3]1[C:4]([CH3:8])([CH3:9])[CH2:5][CH2:6][CH2:7][C:2]=1[CH3:1])[CH2:11][C:12](=[O:13])[CH3:14]
Reactant: CO[Si](CCCS)(OC)OC
Reactant: CC(=O)/C=C/C1=C(C)CCCC1(C)C
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Product: CO[Si](CCCSC(CC(C)=O)C1=C(C)CCCC1(C)C)(OC)OC
Reaction time: 72 h
Yield: 88.9 %

Procedure:
To a well-stirred mixture of β-ionone (10.00 g, 52.1 mmol) and DBU (79 mg, 0.52 mmol (1 mol-%)) was rapidly added 3-mercaptopropyltrimethoxysilane (10.21 g, 52.1 mmol) at 25-30° C. After 72 hours, the reaction mixture was poured onto a cold stirred 5% aqueous HCl solution and extracted twice with Et2O. The organic phases were washed (H2O, saturated aqueous NaHCO3 and brine), dried (Na2SO4), filtered and concentrated. The crude extract was dried for 1 hour at 65-70° C./0.01 Torr to give 18.00 g of the title thioether containing approximativaly 10% of β-ionone. Yield: 80%.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)[NH:4][N:3]=1.[CH3:12][S:13][C:14](SC)=[N:15][C:16]#[N:17]>>[NH2:17][C:16]1[N:3]2[N:4]=[C:5]([C:7]3[O:8][CH:9]=[CH:10][CH:11]=3)[N:6]=[C:2]2[N:1]=[C:14]([S:13][CH3:12])[N:15]=1
Reactant: Nc1n[nH]c(-c2ccco2)n1
Reactant: CSC(=NC#N)SC
Product: CSc1nc(N)n2nc(-c3ccco3)nc2n1
Temperature: 170 °C
Yield: 20.3 %

Procedure:
An intimate mixture of 3-amino-5-(2-furyl)-1,2,4-triazole (33.0 g) and dimethyl N-cyanodithioiminocarbonate (33.0 g) was heated at 170° C. for 1 hour, under a slow stream of argon. After cooling, the resulting solid was purified by column chromatography on silica (600 g) eluting with an increasing amount of ethyl acetate in dichloromethane (5-10% v/v) to give 7-amino-2-(2-furyl)-5-methylthio-[1,2,4]triazolo[1,5-a][1,3,5]triazine as a colourless solid (11.1 g), essentially pure by TLC, which was used without further purification. [A small amount of the above solid was recrystallised from ethanol and gave, crystals, m.p. 238°-240° C.; microanalysis, found: C, 44.0; H, 3.3; N, 33.7; C9H8N6SO/0.05C2H5OH requires C, 43.6; H, 3.3; N, 33.6; NMR 1.05 and 3.4 (t+q, ethanol of crystallisation), 2.5 (s, 3H, CH3S--), 6.7(dd, 1H, furyl-4H), 7.2(d, 1H, furyl-3H), 7.7(d, 1H, furyl-5H) 8.7-9.0(br d, 2H, NH2); m/e 248 (M+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.Cl.Cl.[CH3:20][N:21]([CH3:30])[C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([NH:27][CH2:26][C:25]2[CH:28]=[CH:29][C:22]([N:21]([CH3:30])[CH3:20])=[CH:23][CH:24]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CN(C)c1ccc(CN)cc1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Agent: Cl
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: CN(C)c1ccc(CNc2nc(N)nc(-c3ccco3)c2C#N)cc1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, 4-dimethylaminobenzylamine dihydrochloride and DBU in DME. ES-MS m/e (%): 335 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[Si](C)(C)C.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1.[F-].[Cs+]>O1CCCC1>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]([C:6]2[S:5][CH:4]=[N:3][C:2]=2[CH3:1])[OH:17])=[CH:14][CH:13]=1
Reactant: Cc1ncsc1[Si](C)(C)C
Reactant: O=Cc1ccc(Cl)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1ncsc1C(O)c1ccc(Cl)cc1

Procedure:
4-Methyl-5-trimethylsilylthiazole (3 g), 4-chloro-benzaldehyde (4.9 g) and caesium fluoride (2.7 g) in dry tetrahydrofuran (150 ml) were heated under reflux for 30 hours. The mixture was cooled, evaporated to dryness and the residue thus obtained was purified by flash chromatography to afford the title compound. M.p. 133.5°-134.5° C.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[I:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23]>>[I:19][C:20]1[CH:21]=[C:22]([NH:23][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Nc1cccc(I)c1
Agent: [Na+]
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cccc(I)c1
Yield: 76.4 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 268 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 324 mg of 3-iodoaniline in place of the 2,4-difluoroaniline. 345 mg of N-(3-iodophenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1.[H-].C([Al+]CC(C)C)C(C)C.CC(O)=O>C1(C)C=CC=CC=1>[C:24]([O:23][C:21](=[O:22])[NH:20][C@H:4]([CH:3]=[O:2])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[CH:8][CH:7]=1)([CH3:25])([CH3:27])[CH3:26]
Reactant: COC(=O)[C@H](Cc1ccc(Oc2ccc(Cl)cc2)cc1)NC(=O)OC(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@H](C=O)Cc1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: -78 °C
Yield: 70 %

Procedure:
To a solution of (S)-2-tert-Butoxycarbonylamino-3-[4-(4-chloro-phenoxy)-phenyl]-propionic acid methyl ester (107 mg, 0.26 mmol, 1 eq.) in toluene (5 ml) was added dropwise diisobutylaluminium hydride (1 M in hexane, 0.6 ml, 2.3 eq.) by a syringe with stirring under Ar at −78° C. After the addition was complete, the mixture was stirred at the same temperature for 2 hr and then AcOH (0.2 ml) was added. The mixture was allowed to warm to room temperature overnight. The mixture was partitioned between water and ethyl acetate. EA layer was separated and aqueous layer was extracted with EA. The combined EA layers were dried over anhydrous MgSO4. After the volatile material was removed, the desired product was obtained (68 mg, 70% yield). The product thus obtained was forward to the next step without any further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:3]=1[C:4]([NH:6][C:7]1[CH:34]=[CH:33][C:10]([C:11]([N:13]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[C:17]3=[N:24][N:25]([CH2:27][C:28]([O:30]CC)=[O:29])[CH:26]=[C:16]3[CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=1)=[O:5].O1CCCC1.[OH-].[Na+].Cl>C(O)C>[Cl:1][C:2]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:3]=1[C:4]([NH:6][C:7]1[CH:34]=[CH:33][C:10]([C:11]([N:13]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[C:17]3=[N:24][N:25]([CH2:27][C:28]([OH:30])=[O:29])[CH:26]=[C:16]3[CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=1)=[O:5]
Reactant: CCOC(=O)Cn1cc2c(n1)-c1ccccc1N(C(=O)c1ccc(NC(=O)c3ccc(Cl)cc3Cl)cc1)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)Cn1cc2c(n1)-c1ccccc1N(C(=O)c1ccc(NC(=O)c3ccc(Cl)cc3Cl)cc1)CC2
Temperature: 25 °C
Reaction time: 6 h
Yield: 0.1 %

Procedure:
To a stirred slurry of 0.477 g of 6-[4-[(2,4-dichlorobenzoyl)amino]benzoyl]-5,6-dihydropyrazolo-[4,3-d][1]benzazepine-2 (4H)-acetic acid, ethyl ester in 15 ml of ethyl alcohol is added 5 ml of tetrahydrofuran followed by 1.30 ml of 1M NaOH. The reaction mixture is stirred at room temperature for 6 hours followed by the addition of 0.750 ml of 2N HCl. The acidic reaction mixture is evaporated in vacuo, triturated with CHCl3, combined, treated with activated carbon, filtered through MgSO4 and evaporated in vacuo to give 0.380 mg of the desired product as a clear foam.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]([OH:24])(=[O:23])[C:14]1[CH:22]=[CH:21][CH:20]=[C:16]([C:17]([OH:19])=O)[CH:15]=1.[F:25][C:26]([F:35])([F:34])[C:27]1[CH:28]=[C:29]([NH2:33])[CH:30]=[CH:31][CH:32]=1>C(Cl)Cl.CN(C=O)C>[F:25][C:26]([F:34])([F:35])[C:27]1[CH:28]=[C:29]([NH:33][C:17]([C:16]2[CH:15]=[C:14]([CH:22]=[CH:21][CH:20]=2)[C:13]([OH:24])=[O:23])=[O:19])[CH:30]=[CH:31][CH:32]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=C(O)c1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(O)c1cccc(C(=O)Nc2cccc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.34 g, 7 mmol) was added to a stirring solution of isophthalic acid (1.66 g, 10 mmol) and 3-(trifluoromethyl)benzenamine (0.8 g, 5 mmol) in anhydrous CH2Cl2 (10 mL) and DMF (10 mL). The mixture was stirred at room temperature under argon for 2 h. The solvent was removed under reduced pressure and recrystalized from water to afford the title compound as a white solid after washed by CHCl3 (1.5 g, 49%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:12]1[O:29][C@H:28]([CH2:30][O:31]C(=O)C)[C@@H:23]([O:24]C(=O)C)[C@H:18]([O:19]C(=O)C)[C@H:13]1[O:14]C(=O)C.[CH2:35]([O:37][C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=O)=[CH:40][CH:39]=1)[CH3:36]>>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:42][C:41]1[CH:45]=[CH:46][C:38]([O:37][CH2:35][CH3:36])=[CH:39][CH:40]=1)=[CH:5][N:6]2[C@@H:12]1[O:29][C@H:28]([CH2:30][OH:31])[C@@H:23]([OH:24])[C@H:18]([OH:19])[C@H:13]1[OH:14]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(Cl)c(F)ccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCOc1ccc(C(=O)Cl)cc1
Product: CCOc1ccc(Cc2cn([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c3ccc(F)c(Cl)c23)cc1

Procedure:
4-Chloro-5-fluoro-1-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyl)indole obtained in Example 34-(3) and 4-ethoxybenzoyl chloride were treated in a manner similar to Example 27 to give the titled compound as a colorless powder. APCI-Mass m/Z 483/485 (M+NH4). 1H-NMR (DMSO-d6) δ 1.30 (t, J=6.9 Hz, 3H), 3.15-3.50 (m, 4H), 3.64 (m, 2H), 3.96 (q, J=6.9 Hz, 2H), 4.18 (s, 2H), 4.54 (t, J=5.4 Hz, 1H), 5.11 (t, J=5.3 Hz, 1H), 5.17 (d, J=5.0 Hz, 1H), 5.23 (d, J=5.8 Hz, 1H), 5.39 (d, J=9.1 Hz, 1H), 6.82 (d, J=8.5 Hz, 2H), 7.12 (d, J=8.5 Hz, 2H), 7.16 (t, J=9.4 Hz, 1H), 7.30 (s, 1H), 7.56 (dd, J=8.9, 3.9 Hz, 1H).
Reaction SMILES: [OH:1]O.[Cl:3][C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:7][NH:8][C:9]1[C:18]2[C:13](=[C:14]([S:19][CH3:20])[CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH3:21])[CH:10]=1>C(O)(=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:7][NH:8][C:9]1[C:18]2[C:13](=[C:14]([S:19]([CH3:20])=[O:1])[CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH3:21])[CH:10]=1
Reactant: CSc1cccc2c(NCc3ccc(Cl)c(Cl)c3)cc(C)nc12
Reactant: OO
Solvent: CC(=O)O
Product: Cc1cc(NCc2ccc(Cl)c(Cl)c2)c2cccc(S(C)=O)c2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.5 %

Procedure:
H2O2 (30%, 20.0 mg, 0.55 mmole) was added dropwise to a solution of (3,4-dichlorobenzyl)-(2-methyl-8-methylsulfanylquinolin-4-yl)-amine (100 mg, 0.275 mmole) in acetic acid (3.5 mL) at 0° C. The mixture was stirred at RT for 16 hrs, concentrated by half, 2N NaOH was added and the resulting mixture was extracted with ethyl acetate. The organic phases were dried and concentrated. Precipitation in isopropyl ether gave the product as a white solid (37 mg, 35%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)=[CH:13][CH:14]=2)[C:9]([CH:26]=O)=[N:8]1.[C:28]1([NH2:35])[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[NH2:34].S(=O)(O)[O-].[Na+]>C1COCC1.Cl.C(OCC)(=O)C>[NH:34]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:35]=[C:26]1[C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)[CH:11]=2)[N:7]([CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[N:8]=1
Reactant: O=Cc1nn(C2CCCCO2)c2ccc(-c3cccc(C(F)(F)F)c3)cc12
Reactant: Nc1ccccc1N
Agent: Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: FC(F)(F)c1cccc(-c2ccc3c(c2)c(-c2nc4ccccc4[nH]2)nn3C2CCCCO2)c1
Temperature: 25 °C
Yield: 50 %

Procedure:
1-(Tetrahydro-2H-pyran-2-yl)-5-(3-(trifluoromethyl)phenyl)-1H-indazole-3-carbaldehyde (15 mg, 0.040 mmol) and o-phenylene diamine (5 mg, 0.046 mmol) were dissolved in dry THF (5 mL) and 2N HCl (1 drop) was added. The solution was heated at a gentle reflux for 30 min and then 1N sodium bisulfite (1 mL) was added. After overnight at reflux, the solution was cooled to room temperature, and diluted with ethyl acetate (25 mL). The mixture was washed with water and brine, dried over Na2SO4, and concentrated. Purification by flash chromatography (20% ethyl acetate/hexane) afforded the title compound as a pale yellow solid in a 50% yield. 1H NMR (400 MHz, CD3OD): δ 9.91 (s, 1H), 8.81 (s, 1H), 7.89-7.82 (m, 2H), 7.66 (m, 2H), 7.55-7.44 (m, 3H), 7.24 (m, 2H), 5.77 (dd, 1H, J=2.4 and 9.2 Hz), 4.02 (m, 1H), 3.75 (m, 1H), 2.59 (m, 1H), 2.12 (m, 2H), 1.75 (m, 3H); ESI-MS [M+H]+: 463.3.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][C:13](=[O:17])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:26][C:25]2[CH:28]=[CH:29][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)[C:13](=[O:17])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(CN2CCN(C(=O)OCc3ccccc3)CC2=O)cc1
Yield: 52.5 %

Procedure:
Add to a solution of 4-benzyloxycarbonyl-piperazin-2-one (2 g, 8.6 mmol) in dry THF (10 mL/mmol) under nitrogen, sodium hydride (236 mg, 9.4 mmol, 60% dispersion in mineral oil) in one portion and stir at room temperature for 30 min. Add p-methoxybenzyl chloride (1.86 mL, 13 mmol) and stir at room temperature overnight. Concentrate, add ethyl acetate, wash with water, saturated aqueous sodium chloride, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 1:1 hexanes:ethyl acetate) to give the title compound as an oil (1.6 g, 54%).
Reaction SMILES: [C:1]1([S:11]([NH:14][C@@H:15]([CH2:19][NH:20][C:21](=[O:39])[C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30](=[O:38])[NH:31][C:32]3[NH:33][CH2:34][CH2:35][CH2:36][N:37]=3)=[CH:24][CH:23]=2)[C:16]([OH:18])=[O:17])(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH:45](O)([CH3:47])[CH3:46]>>[CH:45]([O:17][C:16](=[O:18])[C@@H:15]([NH:14][S:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)(=[O:13])=[O:12])[CH2:19][NH:20][C:21](=[O:39])[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30](=[O:38])[NH:31][C:32]2[NH:37][CH2:36][CH2:35][CH2:34][N:33]=2)=[CH:24][CH:23]=1)([CH3:47])[CH3:46]
Reactant: CC(C)O
Reactant: O=C(CCc1ccc(C(=O)NC[C@H](NS(=O)(=O)c2cccc3ccccc23)C(=O)O)cc1)NC1=NCCCN1
Agent: O=S(=O)(O)O
Product: CC(C)OC(=O)[C@H](CNC(=O)c1ccc(CCC(=O)NC2=NCCCN2)cc1)NS(=O)(=O)c1cccc2ccccc12
Reaction time: 72 h

Procedure:
1.5 g of (2S)-2-(naphthalene-1-sulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-ethyl)-benzoylamino)-propionic acid was dissolved in 250 ml of isopropanol and 1 ml of concentrated sulfuric acid was added. The reaction solution was boiled for 3 days. The solvent was removed in vacuo, the residue was dissolved in dichloromethane and washed three times with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted once with dichloromethane and the combined organic phase was washed twice with saturated aqueous sodium chloride solution. The organic phase was dried with sodium sulfate, filtered and the solvent was removed in vacuo. The residue was dissolved in 2N aqueous hydrochloric acid. The hydrochloric acid was removed in vacuo, the residue was dissolved in acetonitrile and added to water. This mixture was lyophilized. Yield 950 mg. MS (ES+): m/e=594.4 (M+H)+.