Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[N:9]([C:12]1[CH:13]=[CH:14][C:15]([N+:24]([O-])=O)=[C:16]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:17]=1)=[N+:10]=[N-:11].[C:27]([C:29]1[O:33][C:32]([C:34](Cl)=[O:35])=[CH:31][CH:30]=1)#[N:28].CCN(C(C)C)C(C)C>O.C1COCC1.[Cl-].[Na+].O>[N:9]([C:12]1[CH:13]=[CH:14][C:15]([NH:24][C:34]([C:32]2[O:33][C:29]([C:27]#[N:28])=[CH:30][CH:31]=2)=[O:35])=[C:16]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:17]=1)=[N+:10]=[N-:11]
Reactant: N#Cc1ccc(C(=O)Cl)o1
Reactant: [N-]=[N+]=Nc1ccc([N+](=O)[O-])c(N2CCCCC2)c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(C(=O)Nc2ccc(N=[N+]=[N-])cc2N2CCCCC2)o1
Yield: 12 %

Procedure:
To a solution of sodium hydrosulfite (936 mg, 5.30 mmol) in 8 mL of water was added 1-(5-azido-2-nitro-phenyl)-piperidine (133 mg, 0.530 mmol, as prepared in the previous step) in 4 mL of THF dropwise. After 25 min the reaction was poured into 50 mL of brine, extracted with EtOAc (3×30 mL), dried (Na2SO4), and concentrated in vacuo. The crude product was then allowed to react in a manner similar to Example 4, step (c), with 5-cyano-furan-2-carbonyl chloride (31 mg, 0.20 mmol) in the presence of DIEA (203 μL, 1.16 mmol) to afford 8 mg (12%) of the title compound as an amber solid. 1H-NMR (CDCl3; 400 MHz): δ 9.58 (s, 1H), 8.44 (d, 1H, J=7.8 Hz), 7.22-7.30 (m, 2H), 6.81-6.89 (m, 2H), 2.81-2.86 (m, 4H), 1.79-1.82 (m, 4H), 1.62-1.65 (m, 2H); Mass spectrum (ESI, m/z): Calcd. for C17H16N6O2, 337.1 (M+H), found 337.0.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].[C:12](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH3:12][S:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:2]([F:1])([F:10])[F:11]
Reactant: O=C([O-])[O-]
Reactant: FC(F)(F)c1ccccc1S
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CSc1ccccc1C(F)(F)F
Reaction time: 12 h
Yield: 88.3 %

Procedure:
Dissolve 2-trifluoromethyl-benzenethiol (10 g; 56 mmol), potassium carbonate (25 g, 180 mmol), iodomethane (11 mL, 177 mmol) in DMF (100 mL). Stir for 12 hours. Filter the suspension through a pad of silica gel and elute with ethyl acetate (500 ne). Evaporate half of the solvent and wash the remaining solution with 10% aqueous LiCl (100 mL). Dry with MgSO4 and evaporate solvent. Chromatograph the residue on a SiO2 column eluting with hexane to give 9.5 g of 1-methylsulfanyl-2-trifluoromethyl-benzene (88%).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][CH:15]([CH3:20])[CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1CCCC1.[C:26]([O-])([O-])=[O:27].[K+].[K+].[C:32](Cl)(Cl)=[S:33].CO>C(Cl)(Cl)Cl>[CH3:26][O:27][C:32](=[S:33])[N:14]([C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:9][CH:10]=1)[CH:15]([CH3:20])[CH2:16][CH:17]([CH3:19])[CH3:18]
Reactant: S=C(Cl)Cl
Reactant: CC(C)CC(C)Nc1ccc(Nc2ccccc2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: C1CCNC1
Product: COC(=S)N(c1ccc(Nc2ccccc2)cc1)C(C)CC(C)C

Procedure:
N-phenyl-N'-(1,3-dimethylbutyl)-p-phenylenediamine (26.8g, 0.10 mol) in 100 mL chloroform and 30g (0.22 mol) of K2CO3 as a saturated aqueous solution are placed in a 250 mL, 3-neck round bottom flask. Thiophosgene (11.5g: 0.10 mol) in 20 mL chloroform is added at such a rate sufficient to reach and maintain reflux conditions. Stirring is continued until the mixture returns to room temperature. Methanol (6.4g, 0.2 mol) is then added and the mixture refluxed for 4 hours. The organic layer is separated, dried with MgSO4 and the solvent removed on a rotary evaporator to give the desired product.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]([CH3:21])([C:17]([F:20])([F:19])[F:18])[C:14](O)=[O:15].S(Cl)([Cl:24])=O.CN(C)C=O>C1C=CC=CC=1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]([CH3:21])([C:17]([F:20])([F:19])[F:18])[C:14]([Cl:24])=[O:15]
Reactant: O=S(Cl)Cl
Reactant: CC(OCc1ccc2ccccc2c1)(C(=O)O)C(F)(F)F
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CC(OCc1ccc2ccccc2c1)(C(=O)Cl)C(F)(F)F

Procedure:
A solution of (±)-2-(2-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionic acid (6.0 g.), thionyl chloride (7.5 ml.) and dimethylformamide (0.2 g.) in benzene (50 ml.) is heated under reflux for 10 minutes. The mixture is evaporated, benzene (20 ml.) is added and the evaporation repeated twice. Light petroleum (b.p. 40°-60° C., 150 ml.) and carton are added to the residue, and the solution is filtered and evaporated to give (±)-2-(2-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionyl chloride (5.35 g.) m.p. 39°-43° C.
Reaction SMILES: COC(C1CC(=O)[N:7](C2C=CC(O)=CC=2)[CH2:6]1)=O.FC1C(F)=CC=C(F)C=1CBr.C[O:30][C:31]([CH:33]1[CH2:37][C:36](=[O:38])[N:35]([C:39]2[CH:44]=[CH:43][C:42]([O:45][CH2:46][C:47]3[C:52]([F:53])=[CH:51][CH:50]=[C:49]([F:54])[C:48]=3[F:55])=[CH:41][CH:40]=2)[CH2:34]1)=O>>[CH3:6][NH2:7].[CH3:6][NH:7][C:31]([CH:33]1[CH2:37][C:36](=[O:38])[N:35]([C:39]2[CH:44]=[CH:43][C:42]([O:45][CH2:46][C:47]3[C:52]([F:53])=[CH:51][CH:50]=[C:49]([F:54])[C:48]=3[F:55])=[CH:41][CH:40]=2)[CH2:34]1)=[O:30]
Reactant: COC(=O)C1CC(=O)N(c2ccc(O)cc2)C1
Reactant: COC(=O)C1CC(=O)N(c2ccc(OCc3c(F)ccc(F)c3F)cc2)C1
Agent: Fc1ccc(F)c(CBr)c1F
Product: CN
Product: CNC(=O)C1CC(=O)N(c2ccc(OCc3c(F)ccc(F)c3F)cc2)C1

Procedure:
The title compound is prepared by alkylation of the (RS)-1-(4-hydroxyphenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester with 2,3,6-trifluorobenzyl bromide giving the (RS)-5-oxo-1-[4-(2,3,6-trifluoro-benzyloxy)-phenyl]-pyrrolidine-3-carboxylic acid methyl ester as a light yellow solid [73% of theory, MS: m/e=379 (M+H)+], which, thereupon, by treatment with methylamine yields the (RS)-5-oxo-1-[4-(2,3,6-trifluoro-benzyloxy)-phenyl]-pyrrolidine-3-carboxylic acid methylamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=O)[CH3:11])=[CH:5][CH:4]=1.[C:13]([NH:16][C:17]([NH2:19])=[S:18])(=[O:15])[CH3:14].II>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:18][C:17]([NH:16][C:13](=[O:15])[CH3:14])=[N:19][C:10]=2[CH3:11])=[CH:5][CH:4]=1
Reactant: CC(=O)NC(N)=S
Reactant: COc1ccc(CC(C)=O)cc1
Agent: II
Solvent: c1ccncc1
Product: COc1ccc(-c2sc(NC(C)=O)nc2C)cc1

Procedure:
4-methoxyphenylacetone (10 g, 60.9 mmol), N-acetylthiourea (7.2 g, 60.9 mmol), iodine (15.46 g, 60.9 mmol) in pyridine (50 ml) are stirred at 70° C. for 16 hours. The mixture is concentrated and the residue is purified by chromatography on silica with hexane-ethyl acetate (1:1) to give the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]([CH3:15])[C:12]([N+:16]([O-])=O)=[CH:11][CH:10]=1.[C:19](O)(=O)C>CN(C=O)C.CCOC(C)=O.C(O)C.[Fe]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]2[CH:15]=[CH:19][NH:16][C:12]2=[CH:11][CH:10]=1
Reactant: Cc1nc(-c2c(F)cccc2F)ccc1[N+](=O)[O-]
Reactant: CC(=O)O
Agent: [Fe]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Fc1cccc(F)c1-c1ccc2[nH]ccc2n1
Temperature: 125 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
A solution of 6-(2,6-difluorophenyl)-2-methyl-3-nitropyridine (1.929 g, 7.71 mmol) in DMF (25 mL) was treated with n,n-dimethylformamide dimethyl acetal (1.331 mL, 10.02 mmol). The reaction was heated to 125° C. under N2. After 3 h, the reaction was cooled to 23° C., diluted with EtOAc (200 ml) and washed with brine (150 ml), dried over MgSO4, concentrated in vacuo, affording a purple solid that was carried forward to the next step without further manipulation. A suspension of that solid in ethanol (40.0 mL) and acetic acid (40 mL) was treated with iron powder—325 mesh (4.31 g, 77 mmol, Aldrich). The reaction was heated to 90° C. under N2. After 2 h, the reaction was cooled to 23° C., filtered through Celite, concentrated in vacuo and purified by silica gel chromatography (eluent: 0.5-3% MeOH/DCM), affording 5-(2,6-difluorophenyl)-1H-pyrrolo[3,2-b]pyridine (1.271 g, 72%).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH3:20][C:21]1[CH:22]=[C:23]2[C:28](=O)[O:27][C:25](=[O:26])[C:24]2=[CH:30][CH:31]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[F:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[C:28](=[O:27])[C:23]5=[CH:22][C:21]([CH3:20])=[CH:31][CH:30]=[C:24]5[C:25]4=[O:26])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Cc1ccc2c(c1)C(=O)OC2=O
Reactant: NCCN1CCC(c2noc3cc(F)ccc23)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: Cc1ccc2c(c1)C(=O)N(CCN1CCC(c3noc4cc(F)ccc34)CC1)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.7 %

Procedure:
A mixture of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethylamine (2.44 gm, 9.24 mmoles), 4methylphthalic anhydride (1.76 gm, 10.8 mmoles) and dicyclohexylcarbodiimide (2 gm, 1,0 mmoles) in dichloromethane (DCM 100 ml) was stirred at room temperature for 2 hr. The insolubles were filtered off. The DCM solution was concentrated to a crude solid. This was purified on at flash chromatography column (35 gm, SiO3, Sorbsil-C-30; eluted with 1% CH3OH in 99% DCM). The material thus purified weighed 1.0 gm (26%) as a white solid. Recrystallization from hot ethanol gave 665 mg of crystals, m.p.=138°-140°]C.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[N:10]2[C:11]3[C:16]([NH:17][C:18](=[O:19])[C:9]2=[CH:8][N:7]=1)=[CH:15][C:14]([C:20](O)=[O:21])=[C:13]([O:23][CH3:24])[CH:12]=3)[CH2:4][CH3:5])[CH3:2].[C:25](N1C=CN=C1)([N:27]1C=CN=[CH:28]1)=O.Cl.CNC>O>[CH2:4]([CH:3]([C:6]1[N:10]2[C:11]3[C:16]([NH:17][C:18](=[O:19])[C:9]2=[CH:8][N:7]=1)=[CH:15][C:14]([C:20]([N:27]([CH3:28])[CH3:25])=[O:21])=[C:13]([O:23][CH3:24])[CH:12]=3)[CH2:1][CH3:2])[CH3:5]
Reactant: CCC(CC)c1ncc2c(=O)[nH]c3cc(C(=O)O)c(OC)cc3n12
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Agent: Cl
Solvent: O
Product: CCC(CC)c1ncc2c(=O)[nH]c3cc(C(=O)N(C)C)c(OC)cc3n12
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
1-(1-Ethylpropyl)-8-methoxy-4-oxo-4,5-dihydroimidazo[1,5-a]-quinoxaline-7-carboxyic acid as synthesized in above Example 32, 329 mg, N,N-diimethylformamide 5 mL and 1,1′-carbonyldiimidazole 275 mg were mixed and stirred for an hour at room temperature in nitrogen atmosphere. Dimethylamine hydrochloride 816 mg was added, followed by 5.5 hours' stirring. The reaction mixture was diluted with water, extracted with ethyl acetate and washed with saturated saline. The extract was dried over anhydrous sodium sulfate, and from which the solvent was distilled off. To the residue tert-butyl methyl ether was added, heated under stirring, and the precipitate was recovered by filtration, followed by washing with tert-butyl methyl ether. The product was dried in flowing air (40° C.) to provide 223 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][NH:7][C:8](=[O:19])[C:9]2[C:14]([OH:15])=[C:13]([O:16][CH3:17])[C:12]([CH3:18])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:22](O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(P(CCCC)CCCC)CCC.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(C)C=CC=CC=1>O1CCCC1>[CH2:22]([O:15][C:14]1[C:9]([C:8]([NH:7][CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:21][CH:20]=2)=[O:19])=[CH:10][N:11]=[C:12]([CH3:18])[C:13]=1[O:16][CH3:17])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1c(C)ncc(C(=O)NCc2ccc(F)cc2)c1O
Reactant: OCc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1c(C)ncc(C(=O)NCc2ccc(F)cc2)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.3 %

Procedure:
To a solution of the compound 22 (100 g, 344 mmol), benzyl alcohol (46 ml, 447 mmol), and tributylphosphine (128 ml, 516 mmol) in tetrahydrofuran (1000 ml) was added a 40% diisopropyl azodicarboxylate-toluene solution (280 ml, 516 mmol) under ice-cooling over 30 minutes. After stirred for 30 minutes under ice-cooling, a temperature was raised to room temperature, followed by stirring for 2 hours. The solvent was distilled off under reduced pressure, to the residue were added toluene (100 ml) and hexane (2000 ml), and precipitated crystals were filtered. The solvent was distilled off under reduced pressure, to the residue were added diethyl ether (200 ml) and hexane (2000 ml), and precipitated crystals were filtered. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate). 4-Benzyloxy-N-(4-fluorobenzyl)-5-methoxy-6-methylnicotinamide 23 (68.5 g, 52%) was obtained as a colorless crystal.
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].[Br:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1Cl>C1COCC1>[Br:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[O:5][CH2:4][CH:1]1[CH2:3][CH2:2]1
Reactant: OCC1CC1
Reactant: Clc1ccncc1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Brc1cnccc1OCC1CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To an ice-cold solution of cyclopropylmethanol (0.562 g, 7.79 mmol) in THF (Volume: 15.06 ml) was added NaH (0.270 g, 6.76 mmol). The reaction was stirred at room temperature for 30 min, and then cooled to 0° C. To this mixture was added 3-bromo-4-chloropyridine (1 g, 5.20 mmol). The resulting mixture was refluxed for 16 hours, cooled to room temperature, and quenched with water. The mixture was evaporated to remove the THF and then extracted with DCM (2×). The combined organic layers were washed with water and brine, dried, and concentrated to give an oil. The oil was purified by silica gel chromatography (hexane: ethyl acetate 50:50) to afforded the title compound as a colorless oil. MS (ES): m/z=229 [M+H]+. Intermediate 66 was used in the synthesis of Example 255.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[NH:7][N:6]=[N:5][N:4]=1.[C:10](Cl)(=[O:26])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].N1C=CC=CC=1>C(#N)C>[C:10]([N:4]1[C:3]([C:2]([F:9])([F:8])[F:1])=[N:7][N:6]=[N:5]1)(=[O:26])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: FC(F)(F)c1nnn[nH]1
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: CCCCCCCCCCCCCCCC(=O)n1nnnc1C(F)(F)F
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 43.7 %

Procedure:
6.9 g of 5-trifluoromethyl-1,2,3,4-tetrazole and 13.7 g of palmitoyl chloride were dissolved in 100 ml of acetonitrile while cooling with ice and to the solution was added dropwise 4.5 ml of pyridine over a period of about 10 minutes. After the completion of the dropwise addition, the mixture was stirred at about 5° C. for 30 minutes and then at room temperature for 1 hour, and to the mixture was added dropwise about 100 ml of ice water. The crystals thus-deposited were collected by filtration to obtain 8.2 g of 1-hexadecanoyl-5-trifluoromethyl-1,2,3,4 -tetrazole. A melting point was 66° to 69° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([O:27][C:28]([NH:30][C:31]([C:33]1[CH:42]=[CH:41][C:36]([CH2:37][N:38]=[N+]=[N-])=[CH:35][CH:34]=1)=[NH:32])=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(C(Br)C1C=CC=CC=1)#N>C1COCC1>[NH2:38][CH2:37][C:36]1[CH:41]=[CH:42][C:33]([C:31](=[NH:32])[NH:30][C:28]([O:27][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:29])=[CH:34][CH:35]=1
Reactant: [N-]=[N+]=NCc1ccc(C(=N)NC(=O)OCc2ccccc2)cc1
Agent: N#CC(Br)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N=C(NC(=O)OCc1ccccc1)c1ccc(CN)cc1

Procedure:
26.3 g (100 mmol) triphenylphosphine was added at room temperature to the 4-(benzyloxycarbonylamidino) benzyl azide from (iii) above dissolved in 160 ml THF. After 16 h an additional 6.6 g (25 mmol) triphenylphosphine was added and the solution was allowed to stand for 4 h before removal of the solvent in vacuo. The residue was dissolved in methylene chloride and extracted with 2M HCl. The aqueous phase was washed with methylene chloride and ether and was subsequently made alkaline with 3.75M sodium hydroxide solution. Extraction with methylene chloride followed by drying (K2CO3) and removal of the solvent in vacuo gave 20 g (The total yield starting from cyanobenzyl bromide is 28%) of a yellow oil which solidified on standing.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH:16]=[N:15][C:14]([C:22]3[CH2:26][CH:25]([O:27][CH2:28][CH3:29])[O:24][N:23]=3)=[C:13]([CH2:30][O:31][CH3:32])[C:12]2=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:33]([O:35]C=C)C>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH:16]=[N:15][C:14]([C:22]3[C:26]([C:25]([O:27][CH2:28][CH3:29])=[O:24])=[CH:33][O:35][N:23]=3)=[C:13]([CH2:30][O:31][CH3:32])[C:12]2=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC1CC(c2ncc3[nH]c4ccc(OCc5ccccc5)cc4c3c2COC)=NO1
Reactant: C=COCC
Product: CCOC(=O)c1conc1-c1ncc2[nH]c3ccc(OCc4ccccc4)cc3c2c1COC

Procedure:
6-benzyloxy-3-(5-ethoxy-4,5-dihydro-3-isoxazolyl)-4-methoxymethyl-β-carboline with vinyl ethyl ether; melting point: 149°-150° C.,
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[CH3:21][CH:22]([NH2:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][C:15](=[O:17])[NH:28][CH:22]([CH3:21])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Reactant: CCCCCC(C)N
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CCCCCC(C)NC(=O)COc1ccc(C[C@H](OC)C(=O)O)cc1

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and 1-methyl-hexylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C19H29NO5 [M−H]−: 350.
Reaction SMILES: [C:1]1([C:7](=[N:14][CH:15]([CH2:23][CH2:24][CH:25]=[CH2:26])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].I[CH2:43][CH2:44][CH2:45][CH2:46][B:47]1[O:51][C:50]([CH3:53])([CH3:52])[C:49]([CH3:55])([CH3:54])[O:48]1>C(OCC)C>[C:1]1([C:7](=[N:14][C:15]([CH2:43][CH2:44][CH2:45][CH2:46][B:47]2[O:51][C:50]([CH3:53])([CH3:52])[C:49]([CH3:54])([CH3:55])[O:48]2)([CH2:23][CH2:24][CH:25]=[CH2:26])[C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC1(C)OB(CCCCI)OC1(C)C
Reactant: C=CCCC(N=C(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCCC(CCCCB1OC(C)(C)C(C)(C)O1)(N=C(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 16 h
Yield: 79.7 %

Procedure:
While under an atmosphere of argon, a solution of tert-butyl 2-(diphenylmethyleneamino)hex-5-enoate (7.00 g, 20.06 mmol) in freshly distilled (THF 50 mL) was cooled to −78° C. and treated with sodium bis(trimethylsilyl)amide (60 mL, 1.0 M in THF). After stirring for 10 min 2-(4-iodobutyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (12.4 g, 40.0 mmol) was added and the reaction was warmed to room temperature and stirred for 16 h. Next, the reaction mixture was cooled to 0° C., diluted with ethyl ether and washed successively with saturated aqueous NaHCO3 and saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. Purification by MPLC (1-20% ethyl acetate in heptane with 0.5% triethylamine over 6 CV) gave tert-butyl 2-(diphenylmethyleneamino)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butyl)hex-5-enoate as a colorless oil (8.50 g, 80%). Rf 0.55 (30% ethyl acetate in heptane). ESI MS found for C33H46BNO4 m/z [532.5 (M+1)].
Reaction SMILES: [CH2:1]([N:3]1[CH:10]=[C:9]([CH3:11])[C:7]([NH2:8])=[N:6][C:4]1=[O:5])[CH3:2].[C:12]([NH:15][C:16]1[CH:25]=[CH:24][C:19]([S:20](Cl)(=[O:22])=[O:21])=[CH:18][CH:17]=1)(=[O:14])[CH3:13].C(NC1C=CC(S(NC2C(C)=CN(CC)CN=2)(=O)=O)=CC=1)(=O)C>N1C=CC=CC=1>[C:12]([NH:15][C:16]1[CH:25]=[CH:24][C:19]([S:20]([NH:8][C:7]2[C:9]([CH3:11])=[CH:10][N:3]([CH2:1][CH3:2])[C:4](=[O:5])[N:6]=2)(=[O:22])=[O:21])=[CH:18][CH:17]=1)(=[O:14])[CH3:13]
Reactant: CCn1cc(C)c(N)nc1=O
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Agent: CCN1C=C(C)C(NS(=O)(=O)c2ccc(NC(C)=O)cc2)=NC1
Solvent: c1ccncc1
Product: CCn1cc(C)c(NS(=O)(=O)c2ccc(NC(C)=O)cc2)nc1=O

Procedure:
A mixture of 1.53 g. of 1-ethyl-5-methylcytosine, 2.34 g. of N-acetylsulfanilyl chloride and 10 ml. of pyridine was stirred overnight, diluted with 100 ml. of cold water, filtered with a little Hyflo to remove turbidity and acidified by addition of 19 ml. of 6N hydrochloric acid. The product was allowed to crystallize for several hours at room temperature before filtering, washing with water, and drying in a vacuum desiccator over potassium hydroxide to obtain 1.78 g. of N4 -acetyl-N1 -(1-ethyl-1,2-dihydro-5-methyl-4-pyrimidinyl)-sulfanilamide, melting at 235°-239°.
Reaction SMILES: Br[C:2]1[C:3]([CH3:28])=[C:4]([N:8]([CH2:13][C:14]2[CH:26]=[CH:25][C:17]([O:18][CH2:19][C:20]([O:22]CC)=[O:21])=[C:16]([CH3:27])[CH:15]=2)[CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:6][CH:7]=1.[Cl:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[CH2:9]([N:8]([CH2:13][C:14]1[CH:26]=[CH:25][C:17]([O:18][CH2:19][C:20]([OH:22])=[O:21])=[C:16]([CH3:27])[CH:15]=1)[C:4]1[C:3]([CH3:28])=[C:2]([C:33]2[CH:34]=[CH:35][C:30]([Cl:29])=[CH:31][CH:32]=2)[CH:7]=[CH:6][CH:5]=1)[CH2:10][CH2:11][CH3:12]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(Br)c1C
Product: CCCCN(Cc1ccc(OCC(=O)O)c(C)c1)c1cccc(-c2ccc(Cl)cc2)c1C

Procedure:
Prepared from ethyl (4-{[(3-bromo-2-methylphenyl)(butyl)amino]methyl}-2-methylphenoxy)acetate and 4-chlorophenylboronic acid using the procedure described for Example 25 (Method A).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[CH:7][C:8]([F:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].[CH:15]([NH2:19])([CH2:17][CH3:18])[CH3:16].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:15]([NH:19][S:2]([C:5]1[CH:6]=[CH:7][C:8]([F:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3])([CH2:17][CH3:18])[CH3:16]
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1F
Reactant: CCC(C)N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C)NS(=O)(=O)c1ccc(F)c(C(=O)O)c1
Yield: 96 %

Procedure:
5-Chlorosulfonyl-2-fluoro-benzoic acid (A, 0.506 g, 0.0021 mol), sec-butylamine (E, 0.155 g, 0.00212 mol) and DIEA (1.1 mL, 0.00636 mol) in CH2Cl2 were stirred at room temperature overnight. The solvent was evaporated and the crude product was purified by silica gel chromatography (MeOH containing 10% AcOH)/CH2Cl2) to give 5-sec-Butylsulfamoyl-2-fluoro-benzoic acid (F, 0.56 g, 96%). After drying overnight under vacuum, F (0.56 g, 0.0020 mol) in SOCl2 (5 mL) was heated at 80° C. for 3 hours, after which the SOCl2 was evaporated and the residue was dried overnight. The residue was then dissolved in tetrahydrofuran (5 mL), 3,4-difluoro-phenylamine (D, 0.26 g, 0.0020 mol) was added followed by DIEA (0.8 mL). The mixture was heated to 70° C. overnight. The solvent was evaporated, followed by ethyl acetate extraction. After purification by silica gel chromatography (ethyl acetate/hexane), 0.45 g (57%) of 5-sec-butylsulfamoyl-N-(3,4-difluoro-phenyl)-2-fluoro-benzamide (DVR-23) was obtained.