Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]([CH2:7][S:8][CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.C1(N=C=NC2CCCCC2)CCCCC1.[C:30]1([C@H:36]2[CH2:40][O:39][C:38](=[O:41])[NH:37]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8][CH2:9][C:10]([N:37]2[C@@H:36]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:40][O:39][C:38]2=[O:41])=[O:12])=[CH:13][CH:14]=1
Reactant: O=C1N[C@@H](c2ccccc2)CO1
Reactant: COc1ccc(CSCC(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc(CSCC(=O)N2C(=O)OC[C@@H]2c2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
[(4-Methoxybenzyl)thio]acetic acid (1.3 g, 6.1 mmol) was dissolved in dry CH2Cl2 (40 ml) and given 0° C. N,N′-Dicyclohexylcarbodiimide (DCC, 6.1 g, 6.1 mmol) and 4-(dimethylamino)pyridine (DMAP, 1.6 g, 12.9 mmol) were added and the mixture was stirred for 30 minutes. (S)-(+)-4-Phenyl-2-oxazolidinone (1.0 g, 6.1 mol) was added and the mixture was stirred at room temperature for 24 hours. The mixture was filtrated, concentrated under reduced pressure and purified by flash-chromatography (Hex:EtOAc 8:2 then 1:1). This afforded the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(C(F)(F)F)[C:4]([OH:6])=[O:5].[OH-].[Na+].O>CO>[F:1][C:2]([F:17])([F:18])[CH:3]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:4]([OH:6])=[O:5]
Reactant: O=C(O)C(c1ccccc1)(C(F)(F)F)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C(c1ccccc1)C(F)(F)F
Temperature: 90 °C
Yield: 62 %

Procedure:
2.9 g (10 millimole) of methyl ester of α,α-bis(trifluoromethyl)phenylacetic acid, 2.5 g (63 millimole) of sodium hydroxide, 3.0 g of water and 3.0 ml of methanol were charged into an eggplant-type flask having a capacity of 100 ml, provided with a marine-type condenser and refluxed at a bath temperature of 90° C. for 6 hours. Methanol was distilled off from the reaction mixture under reduced pressure, and the residue was dissolved in 30 ml of 3N hydrochloric acid and then extracted with ether. The ether layer was dried with anhydrous MgSO4 and then concentrated under reduced pressure. The thus obtained residue was subjected to silica gel column chromatography, using n-hexane/dichloromethane as a mobile phase, whereby 1.26 g of α-(trifluoromethyl)phenylacetic acid was obtained (yield: 62%).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:36][O:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:10]([NH:12][CH:13]2[C:34](=[O:35])[N:15]3[C:16]([C:21]([O:23]CC4C=CC([N+]([O-])=O)=CC=4)=[O:22])=[C:17]([Cl:20])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2].O.C(O)(=O)C.CO>[C].[Pd].O1CCCC1>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:36][O:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:10]([NH:12][CH:13]2[C:34](=[O:35])[N:15]3[C:16]([C:21]([OH:23])=[O:22])=[C:17]([Cl:20])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2]
Reactant: CCCCON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12)c1csc(NC=O)n1
Agent: [Pd]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12)c1csc(NC=O)n1
Yield: 66.2 %

Procedure:
A mixture of 4-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-butoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylate (syn isomer, 2.7 g.), 10% palladium carbon (1.3 g.), water (4 ml.), acetic acid (0.4 ml.), methanol (27 ml.) and tetrahydrofuran (54 ml.) was treated in a similar manner to that of Example 21-(2) to give 7-[2-(2-formamidothiazol-4-yl)-2-butoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer, 1.4 g.), pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[CH:5]=[O:6].[BH4-].[Na+].Cl.[H][H]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[CH2:5][OH:6]
Reactant: COc1cc(Cl)cc(C=O)c1
Reactant: [H][H]
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc(Cl)cc(CO)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
To an ice-cold solution of 3-chloro-5-methoxybenzaldehyde (27 mmol, 4.60 g) in ethanol (90 ml) was added NaBH4 (30 mmol, 1.14 g) in one portion under stirring. After 0.5 h the mixture was allowed to reach room temperature and stirred for another 0.5 h. HCl (2 M, ˜25 ml)) was added slowly until no more hydrogen gas evolved, the resulting mixture was concentrated under reduced pressure and the residue separated between water and ether, the organic phase was washed with braine and dried (MgSO4). Filtration and evaporation of solvents afforded the title compound (4.53 g, 97%) as a white solid. The product was used without further purification in the next step. An analytically pure sample was obtained be means of flash chromatography (silica, hexane/ether grad.). 1H NMR (CDCl3, 500 MHz) δ 2.77 (br, 1H), 3.76 (s, 3H), 4.55 (s, 2H), 6.74 (s, 1H), 6.77 (s, 1H) and 6.88 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[Br-].[C:10]1([Zn+])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl-].[NH4+]>C1COCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1
Reactant: [Zn+]c1ccccc1
Reactant: Clc1ccnc(Cl)n1
Agent: [Pd]
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: Clc1nccc(-c2ccccc2)n1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 2,4-dichloropyrimidine (149 mg, 1 mmol) in THF (5 mL), tetrakis(triphenylphosphine) palladium (23 mg, 2 mol %) and 0.5M solution of phenylzinc bromide (2.1 mL, 1.05 mmol) in THF were added. The reaction mixture was stirred at 50° C. for overnight. Then it was added saturated ammonium chloride solution and extracted with EtOAc twice. The organic layers were combined, washed with water and dried (MgSO4). Evaporation of solvent gave a yellow residue which was purified by Prep. HPLC to afford a yellowish oil as 2-chloro-4-phenyl-pyrimidine to carry on.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]=[CH:15][C:14](=[O:17])[CH2:13][CH:12]2[C:18]([O:20][CH2:21][CH3:22])=[O:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:23][N:24]([CH:26](OC)OC)[CH3:25]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]=[CH:15][C:14](=[O:17])[C:13](=[CH:23][N:24]([CH3:26])[CH3:25])[CH:12]2[C:18]([O:20][CH2:21][CH3:22])=[O:19])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)C1CC(=O)C=CN1S(=O)(=O)c1ccc(Cl)cc1
Product: CCOC(=O)C1C(=CN(C)C)C(=O)C=CN1S(=O)(=O)c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
Compound 103 (5.0 g, 15 mmol) was dissolved in DMF-DMA (20 mL) and heated at 100° C. for 30 minutes. The reaction mixture was concentrated in vacuo to yield compound 104 as a yellow oil that was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:16]1[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=1.B(Br)(Br)Br.C1CCCCC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:16]1[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=1
Reactant: CCCCCn1nc(-c2ccc(OC)cc2)c2cccc(Cl)c21
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Product: CCCCCn1nc(-c2ccc(O)cc2)c2cccc(Cl)c21
Yield: 64.9 %

Procedure:
Prepared according to Method D step C from 7-chloro-3-(4-methoxyphenyl)-1-pentyl-1H-indazole (0.070 g, 0.23 mmol), boron tribromide (0.094 mL, 1.0 mmol) and 0.3 mL of cyclohexene to give the product (0.047 g) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:41]=[CH:40][C:5]2[NH:6][C:7]([C@@H:9]([NH:14][C:15](=[O:39])[C:16]3[CH:21]=[CH:20][C:19]([C:22]([N:24]4[CH2:28][CH2:27][CH2:26][C@H:25]4[CH2:29][NH:30]C(OC(C)(C)C)=O)=[O:23])=[C:18]([Cl:38])[CH:17]=3)[CH2:10][CH2:11][S:12][CH3:13])=[N:8][C:4]=2[CH:3]=1.FC(F)(F)C(O)=O.ClCCl.CO.N.ClCl>>[Cl:1][C:2]1[CH:41]=[CH:40][C:5]2[NH:6][C:7]([C@@H:9]([NH:14][C:15](=[O:39])[C:16]3[CH:21]=[CH:20][C:19]([C:22]([N:24]4[CH2:28][CH2:27][CH2:26][C@H:25]4[CH2:29][NH2:30])=[O:23])=[C:18]([Cl:38])[CH:17]=3)[CH2:10][CH2:11][S:12][CH3:13])=[N:8][C:4]=2[CH:3]=1
Reactant: CSCC[C@H](NC(=O)c1ccc(C(=O)N2CCC[C@H]2CNC(=O)OC(C)(C)C)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: CSCC[C@H](NC(=O)c1ccc(C(=O)N2CCC[C@H]2CN)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 81 %

Procedure:
Prepared analogously to Example 17 from N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulfanylpropyl]-3-chloro-4-[(2S)-2-(N-tert-butoxycarbonylaminomethyl)pyrrolidin-1-ylcarbonyl]benzamide and trifluoroacetic acid. Yield: 81%; Rf value: 0.18 (silica gel; dichloromethane/methanol/ammonia=9:1:0.1); C24H27Cl2N5O2S (520.48); mass spectrum: (M+H)-=520/522/524 (chlorine isotope).
Reaction SMILES: [H-].[Na+].[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:13][C:14]#[N:15].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>COCCOC>[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH:13]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14]#[N:15]
Reactant: BrCc1ccccc1
Reactant: N#CCc1ccc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: N#CC(Cc1ccccc1)c1ccc2ccccc2c1
Temperature: 25 °C
Yield: 39.9 %

Procedure:
To a refluxing solution of NaH (3.00 g, 75 mmol, 60% dispersion) in DME (150 mL) was added a solution of 2-naphthaleneacetonitrile (12.5 g, 75 mmol) and benzyl bromide (12.8 g, 75 mmol) in DME (75 mL) dropwise over 50 minutes. The resulting solution was kept at reflux for 3 hours and then cooled to room temperature. The volatiles were removed in vacuo and the residue was partitioned between Et2O (100 mL) and H2O (100 mL). The aqueous phase was washed with Et2O (1×150 mL), the organics were dried (MgSO4) and concentrated in vacuo. This residue was purified by preparative HPLC (SiO2 : gradient hexane/EtOAc) to give the title compound as a white solid (7.71 g, 40%).
Reaction SMILES: [N:1]1[C:2]([CH2:14][OH:15])=[N:3][N:4]2[C:13]=1[C:12]1[N:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:6]=[CH:5]2>CCO.[O-2].[O-2].[Mn+4]>[N:1]1[C:2]([CH:14]=[O:15])=[N:3][N:4]2[C:13]=1[C:12]1[N:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:6]=[CH:5]2
Reactant: OCc1nc2c3ncccc3ccn2n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCO
Product: O=Cc1nc2c3ncccc3ccn2n1
Yield: 100.9 %

Procedure:
To a solution of [1,2,4]triazolo[1,5-h][1,7]naphthyridin-2-ylmethanol (280 mg, 1.4 mmol) in EtOH (20 mL) was added activated manganese (IV) dioxide (1.21 g, 14.0 mmol). The mixture was stirred at reflux for 2 h. Then the mixture was filtered and the filtrate was concentrated under reduce pressure to give [1,2,4]triazolo[1,5-h][1,7]naphthyridine-2-carbaldehyde as a yellow solid (280 mg, yield 88%). ESI MS: m/z 199.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 10.34 (s, 1H), 9.16 (dd, J=1.6, 4.4 Hz, 1H), 8.55 (d, J=7.2 Hz, 1H), 8.28 (dd, J=1.6, 8.0 Hz, 1H), 7.76 (dd, J=4.4, 8.0 Hz, 1H), 7.47 (d, J=8.8 Hz, 1H).
Reaction SMILES: C(OC([C:6]1[CH2:7][C:8](=[O:22])[NH:9][C:10]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:11]=2[C:12]=1[OH:13])=O)C.O>CS(C)=O>[CH3:21][O:20][C:15]1[C:16]([O:18][CH3:19])=[CH:17][C:10]2[NH:9][C:8](=[O:22])[CH2:7][CH2:6][C:12](=[O:13])[C:11]=2[CH:14]=1
Reactant: CCOC(=O)C1=C(O)c2cc(OC)c(OC)cc2NC(=O)C1
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2c(cc1OC)C(=O)CCC(=O)N2
Temperature: 150 °C
Reaction time: 6 h
Yield: 72.7 %

Procedure:
A solution of 2,3-dihydro-7,8-dimethoxy-5-hydroxy-2-oxo-1H-[1]-benzazepine-4-carboxylic acid ethyl ester (0.614 g, 1.9 mmol) and water (1 ml) in dimethylsulfoxide (20 ml) was stirred at 150° C. under argon. Portions of water (1 ml) were added after 1 hour and 3 hours heating. After stirring for a total of 6 hours at 150° C., the mixture was cooled to 20° C., poured into ice cold water (20 ml) and allowed to stand overnight at 4° C. The crystals were filtered off and washed with water and hexanes to give the title compound as yellowish crystals (0.325 g, yield 67.7%), mp 230° C.; 1H-NMR (DMSO-d6, 300 MHz): δ (ppm)=8.42 (s; 1H), 7.5 (s; 1H), 6.43 (s; 1H), 3.96 and 3.92 (s; 6H), 2.90 (m, 2H), 2.8 (m; 2H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2.[SH:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1>>[N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[CH:28][C:19]=1[S:18][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2
Reactant: Sc1ccc2ccccc2n1
Reactant: O=C1CCc2cc(OCCCCBr)ccc2N1
Product: O=C1CCc2cc(OCCCCSc3ccc4ccccc4n3)ccc2N1

Procedure:
Prepared analogous to Example 1 from 6-(4-bromobutoxy)-3,4-dihydro-carbostyril (m.p. 142°-147° C.) and 2-mercapto-quinoline.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([NH:12][NH:13]C(OC(C)(C)C)=O)=[O:11])[CH:3]=[CH:2]1.Cl>O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([NH:12][NH2:13])=[O:11])[CH:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)NNC(=O)c1cccc2cc[nH]c12
Agent: Cl
Solvent: C1COCCO1
Product: NNC(=O)c1cccc2cc[nH]c12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1,1-dimethylethyl 2-(1H-indol-7-ylcarbonyl)hydrazinecarboxylate (I43) (0.202 g, 0.734 mmol) in 1,4-Dioxane (8 mL) was added 4M HCl in Dioxane (1.834 mL, 7.34 mmol) dropwise over 1 minutes. The solution was then allowed to stir at room temperature and under argon for 18 hours. Analysis by LCMS and TLC showed starting material to still be present, 4M HCl in Dioxane (5.50 mL, 22.01 mmol) was thus added and the solution was further stirred for 2 hours. TLC confirmed reaction completion and the solvent was evaporated in vacuo. The remaining solid was then azeotroped with ether (2×10 mL). The remaining solid was then loaded onto an SCX cartridge (5 g) and washed with methanol (2×20 mL) before being eluted with 2M NH3/MeOH. The solvent was then evaporated in vacuo and the remaining solid was dried in a vac-oven to yield the product in 0.113 g.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N+:5]([O-:8])=[CH:4][CH:3]=1.[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.Cl[Pd]Cl>[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[CH:15][C:14]([C:2]2[CH:7]=[CH:6][N+:5]([O-:8])=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: [O-][n+]1ccc(Cl)cc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: [O-][n+]1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 80 °C
Yield: 34.5 %

Procedure:
4-Chloropyridine-N-oxide (3.0 g, 23 mmol), 4-trifluoromethylphenylboronic acid (6.57 g, 34.6 mmol), K2CO3 (4.8 g, 35 mmol) and PdCl2 (dppf) (470 mg, 0.57 mmol) were stirred in DMSO (40 mL) under vacuum for 30 min. The flask was flushed with nitrogen, and the mixture was heated to 80° C. for 10 min. Upon cooling, the mixture was diluted with methylene chloride and washed with 5% lithium chloride solution (5×), dried, concentrated, and the residue was purified by flash column chromatography (40 g ISCO column eluting with methylene chloride and a methanol/ammonia mixture (10:1); gradient 100% methylene chloride to 80% methylene chloride over 30 min at 40 mL/min) to provide the title compound (1.90 g, 34%) as a tan solid: ESI MS m/z 240 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:23][N:24]([CH2:32][C:33]#[CH:34])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28]>C(N(CC)CC)C>[CH3:23][N:24]([CH2:32][C:33]#[C:34][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:9])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)=[CH:12][CH:11]=2)=[CH:6][N:7]=1)[C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:30])[CH3:28]
Reactant: O=C(c1ccc(OC2CCCCO2)cc1)c1ccc(Cl)nc1
Reactant: C#CCN(C)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Product: CN(CC#Cc1ccc(C(=O)c2ccc(OC3CCCCO3)cc2)cn1)C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
A 25 mL Schlenk flask was charged with (6-chloropyridin-3-yl)(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)methanone (318 mg, 1.0 mmol), tetrakis(triphenylphos-phine)Palladium(0) (116 mg, 0.1 mmol, 10 mol %), cuprous iodide (38 g, 0.2 mmol, 20 mol %), triethylamine (5 mL), and tert-butyl methyl(prop-2-ynyl)carbamate (169 mg, 1 mmol). The flask was flushed with nitrogen three times and the mixture was stirred at 80° C. for 2 h. The solvent was evaporated under vacuum and the residue was purified by column chromatography to afford the desired product as yellow solid (180 mg, 40% yield).
Reaction SMILES: Cl.S(Cl)(Cl)(=O)=O.[Cl:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][N:12]=[C:11]2[NH:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([OH:28])(=[O:27])=O)=[CH:21][CH:20]=1.[CH2:29]([N:31]([CH2:35][CH3:36])[CH2:32][CH2:33][NH2:34])[CH3:30]>>[Cl:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][N:12]=[C:11]2[NH:18][C:19]1[CH:20]=[CH:21][C:22]([S:25]([NH:34][CH2:33][CH2:32][N:31]([CH2:35][CH3:36])[CH2:29][CH3:30])(=[O:27])=[O:28])=[CH:23][CH:24]=1
Reactant: O=S(=O)(O)c1ccc(Nc2ncnc3ccc(Cl)cc23)cc1
Reactant: CCN(CC)CCN
Agent: Cl
Solvent: O=S(=O)(Cl)Cl
Product: CCN(CC)CCNS(=O)(=O)c1ccc(Nc2ncnc3ccc(Cl)cc23)cc1

Procedure:
The sulphonyl chloride hydrochloride derivative of the sulphonic acid of part (a) was used to sulphonylate N,N-diethylethylenediamine using a similar procedure to Example 8. The crude product obtained after evaporation of solvent from the chloroform layer was a brown solid which was purified by column chromatography (basic alumina: 1% ethanol/chloroform) to give a creamy white solid. Recrystallisation from ethanol/water gave the title compound hemihydrate, m.p. 110°-113° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[CH3:19])[N:10]=[C:9]2[CH:20]([NH:22][C:23]2[N:31]=[CH:30][N:29]=[C:28]3[C:24]=2[N:25]=[CH:26][N:27]3COCC[Si](C)(C)C)[CH3:21])[CH:5]=[CH:6][CH:7]=1.Cl>CO>[OH:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[CH3:19])[N:10]=[C:9]2[CH:20]([NH:22][C:23]2[N:31]=[CH:30][N:29]=[C:28]3[C:24]=2[N:25]=[CH:26][NH:27]3)[CH3:21])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc2nc(C(C)Nc3ncnc4c3ncn4COCC[Si](C)(C)C)n(-c3cccc(O)c3)c(=O)c12
Agent: Cl
Solvent: CO
Product: Cc1cccc2nc(C(C)Nc3ncnc4[nH]cnc34)n(-c3cccc(O)c3)c(=O)c12
Temperature: 40 °C

Procedure:
A 100-mL, one-neck, round bottomed flask equipped with a magnetic stirrer was charged with compound 126 (294 mg, 0.5 mmol), MeOH (15 mL) and 4N hydrochloric acid (15 mL), and the reaction mixture was heated for 5 h at 40° C. Evaporation of the methanol under reduced pressure followed by basification to pH 10 with 10% aqueous potassium carbonate gave a white precipitate. The precipitate was filtered, washed with water and dried under vacuum overnight at ambient temperature to afford compound 121 as a white solid. m/z=414 (M+H). The preparation of compound 121 is generally shown above as step D of Procedure C.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH:16]1[C:28]2[CH:27]([CH2:29][O:30][C:31]([NH:33][C@H:34]([C:39]([NH:41][C:42]3[CH:50]=[CH:49][CH:48]=[C:47]([CH3:51])[C:43]=3[C:44]([OH:46])=[O:45])=O)[CH2:35][CH:36]([CH3:38])[CH3:37])=[O:32])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1>C(OCC)(=O)C>[CH:25]1[C:26]2[CH:27]([CH2:29][O:30][C:31]([NH:33][C@H:34]([C:39]3[O:46][C:44](=[O:45])[C:43]4[C:47]([CH3:51])=[CH:48][CH:49]=[CH:50][C:42]=4[N:41]=3)[CH2:35][CH:36]([CH3:38])[CH3:37])=[O:32])[C:28]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]=2[CH:22]=[CH:23][CH:24]=1
Reactant: Cc1cccc(NC(=O)[C@H](CC(C)C)NC(=O)OCC2c3ccccc3-c3ccccc32)c1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: Cc1cccc2nc([C@H](CC(C)C)NC(=O)OCC3c4ccccc4-c4ccccc43)oc(=O)c12
Reaction time: 8 h
Yield: 70.1 %

Procedure:
69 mg of N,N'-dicyclohexylcarbodiimide was added under ice-cooling to a solution of 163 mg of 2-{[N-(9-fluorenylmethoxycarbonyl)-L-leucyl]amino}-6-methylbenzoic acid in 4 ml of ethyl acetate. After stirring overnight, dicyclohexylurea precipitated was filtered off and the filtrate was concentrated. The residue was purified by a silica gel column chromatography (eluting solution: hexane-ethyl acetate) to give 110 mg of 2-{1(S)-[(9-fluorenylmethoxycarbonyl)amino]-3-methylbutyl}-5-methyl-4H-3,1-benzoxazine-4-one. The physicochemical data are shown in Table 1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)[CH:2]=1.[Cl-].[CH2:17]([O:19][C:20](=[O:27])[CH2:21][CH2:22][CH2:23][C:24](O)=[O:25])[CH3:18].[OH-].[NH4+]>C(Cl)Cl>[O:25]=[C:24]([C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:8]=1)[CH2:23][CH2:22][CH2:21][C:20]([O:19][CH2:17][CH3:18])=[O:27]
Reactant: c1cncc(-n2ccc3ccccc32)c1
Reactant: CCOC(=O)CCCC(=O)O
Agent: [Cl-]
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: CCOC(=O)CCCC(=O)c1cn(-c2cccnc2)c2ccccc12
Reaction time: 8 h

Procedure:
To a mixture of 10.0 g of N-(3-pyridyl)-indole (J. Chem. Soc. (C), 85, 1970) and 13.8 g of glutaric acid monoethyl ester chloride in 90 ml of methylene chloride is added dropwise over a period of 3 hours a solution of 20.1 g of stannic chloride in 60 ml of methylene chloride. The reaction mixture is stirred at room temperative overnight. The reaction mixture is cooled to 10°-15° and 150 ml of 14% aqueous ammonium hydroxide is added. The organic layer is separated, washed with water and dried over sodium sulfate to yield 3-(1-oxo-4-ethoxycarbonylbutyl)-N-(3-pyridyl)indole, melting at 95°-97°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[F:12][C:13]([F:25])([F:24])[O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1>N1C=CC=CC=1>[NH2:11][S:8]([C:4]1[CH:3]=[C:2]([NH:1][C:19](=[O:20])[C:18]2[CH:22]=[CH:23][C:15]([O:14][C:13]([F:12])([F:24])[F:25])=[CH:16][CH:17]=2)[CH:7]=[CH:6][CH:5]=1)(=[O:9])=[O:10]
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: Nc1cccc(S(N)(=O)=O)c1
Solvent: c1ccncc1
Product: NS(=O)(=O)c1cccc(NC(=O)c2ccc(OC(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 3-amino-benzenesulfonamide (17 mg, 0.10 mmol) in pyridine (1 mL) was added 4-trifluoromethoxy benzoyl chloride (16 μL, 0.10 mmol). The reaction was stirred at room temperature for 15 h and purified by preparative reverse phase HPLC using 10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA) to give N-(3-(aminosulfonyl)phenyl)-4-(trifluoromethoxy)benzamide. LC/MS: m/z 360.9 (M+H)+ at 3.02 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[N:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[NH4+]>[Ni].C(O)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CCCCCCc1ccccc1
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: NCCCCCCc1ccccc1
Reaction time: 24 h
Yield: 75.5 %

Procedure:
A mixture of 42.4 g (0.245 mole) of 6-phenylcapronitrile, 3 g of Raney nickel, 200 ml of ethanol, and 30 ml of concentrated ammonium hydroxide was hydrogenated at 43 psi, and room temperature for 24 hours. The catalyst was removed by filtration and the filtrate concentrated leaving an oil. Distillation under reduced pressure afforded 32.8 g (75.6%) of 6-phenylhexylamine as a colorless oil, bp 118°-123° C./1.5 mm of Hg. NMR (CDCl3): 7.20 (s, 5H); 2.80-2.55 (m, 4H); 1.80-1.10 (m, 8H); 1.00 (s, 2H - exchangeable with D2O).