Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4]([CH:19]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[CH2:20][CH2:21][OH:22])=[C:5]([C:14]([O:16]CC)=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].[H-].[Na+].CCOC(C)=O>O1CCCC1.[Cl-].[Na+].O>[C:1]([C:3]1[C:4]([CH:19]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[CH2:20][CH2:21][OH:22])=[C:5]([C:14]([OH:16])=[O:15])[S:6][C:7]=1[N:8]1[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1)#[N:2]
Reactant: CCOC(=O)c1sc(N2CCOCC2)c(C#N)c1C(CCO)c1ccc(Cl)c(Cl)c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1c(N2CCOCC2)sc(C(=O)O)c1C(CCO)c1ccc(Cl)c(Cl)c1
Temperature: 60 °C
Yield: 18.2 %

Procedure:
To a solution of ethyl 4-cyano-3-[1-(3,4-dichlorophenyl)-3-hydroxypropyl]-5-(morpholin-4-yl)thiophene-2-carboxylate (38.0 mg, 0.0810 mmol) in tetrahydrofuran (1.00 mL) was added NaH 60% in mineral oil (60:40, Sodium hydride:mineral Oil, 3.56 mg, 0.0890 mmol). The mixture was heated to 60° C. for 3 hrs. The reaction was cooled to rt and distributed between brine and EtOAc. The aqueous layer was extracted with EtOAc (×2). The combined organic layer was washed with brine, dried, and concentrated to provide a yellow solid. Purification on HPLC (reverse phase, AA) provided 4-cyano-3-[1-(3,4-dichlorophenyl)-3-hydroxypropyl]-5-(morpholin-4-yl)thiophene-2-carboxylic acid as a white solid (6.5 mg, 18.2% yield). LCMS: (AA) ES+ 441, 443, 445; 1H NMR (400 MHz, MeOD) δ 7.50-7.45 (s, 1H), 7.45-7.37 (d, J=8.4 Hz, 1H), 7.30-7.22 (m, 1H), 5.79-5.63 (m, 1H), 3.83-3.71 (t, J=4.8 Hz, 4H), 3.60-3.50 (q, J=6.9, 6.0 Hz, 2H), 3.50-3.41 (d, J=3.2 Hz, 4H), 2.52-2.37 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12](C3CCCCC3)=[N:11][C:10]=2[C:21]2[CH:26]=[CH:25][C:24](S(C)(=O)=O)=[CH:23][CH:22]=2)=[CH:4][CH:3]=1.[Li+].CC([N-:35][CH:36](C)C)C.[I:39]I>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([I:39])=[N:11][C:10]=2[C:21]2[CH:26]=[CH:25][C:24]([C:36]#[N:35])=[CH:23][CH:22]=2)=[CH:4][CH:3]=1
Reactant: Cn1c(C2CCCCC2)nc(-c2ccc(S(C)(=O)=O)cc2)c1Sc1ccc(Cl)cc1
Reactant: II
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1c(I)nc(-c2ccc(C#N)cc2)c1Sc1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To 4-{5-[(4-chlorophenyl)thio]-1-methyl-1H-imidazol-4-yl}benzonitrile (Example 31, 50 mg, 0.153 mmol) in THF (0.75 mL) was added freshly made LDA (0.2 mL, 0.2 mmol) at −78° C. After stirring at −78° C. for 1 h, I2 (55 mg, 0.215 mmol) was added and the reaction was warmed up to rt and stirred overnight. The reaction was quenched with aq NH4Cl, and the product was extracted with EtOAc. The combined extracts were washed with aq Na2S2O3, water, and brine, dried over MgSO4, filtered, and concentrated. The residue was purified by silica column chromatography (5-20% EtOAc in hexanes) to give the title compound. 1H NMR (500 MHz, (CDCl3): 8.20 (d, 2H), 7.65 (d, 2H), 7.28 (d, 2H), 6.99 (d, 2H), 3.62 (s, 3H). LCMS: [M+1]=451.9.
Reaction SMILES: [N:1]1([CH:6]([C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)[CH2:7][CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[C:18]([CH:23]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:20][CH2:21][CH3:22])=[O:19].O>O1CCOCC1>[CH2:21]([O:20][C:18](=[O:19])/[CH:23]=[CH:14]/[C:13]1[CH:16]=[CH:17][C:10]([CH:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH2:7][CH2:8][CH3:9])=[CH:11][CH:12]=1)[CH3:22]
Reactant: CCCC(c1ccc(C=O)cc1)n1ccnc1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CCCC(c1ccc(/C=C/C(=O)OCC)cc1)n1ccnc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 50.3 %

Procedure:
0.228 g of 4-[1-(1-imidazolyl)-butyl]-benzaldehyde (example 6) is dissolved in 5 ml of dioxane and mixed with 0.35 g of carbethoxymethylene triphenyl phosphorane and stirred for 48 hours at room temperature. The reaction mixture is poured into 100 ml of water and extracted with ethyl acetate. The organic phases are combined and evaporated to dryness, the residue is distilled on a bulb tube. 0.15 g of the title compound with a boiling point of 200°-220° C./0.03 mbar is obtained.
Reaction SMILES: Br[C:2]1[C:3]([F:33])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH:19]([OH:31])[C:20]4[N:24]([CH:25]5[CH2:30][CH2:29][CH2:28][CH2:27][O:26]5)[N:23]=[CH:22][CH:21]=4)=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:32]=1.[C:34]([C:36]1([OH:41])[CH2:40][CH2:39][CH2:38][CH2:37]1)#[CH:35].C(NC(C)C)(C)C>CN(C=O)C>[N:15]1[C:14]([C:16]([NH2:18])=[O:17])=[CH:13][N:8]2[CH:9]3[CH2:12][CH:11]([CH2:10]3)[C:5]3[CH:4]=[CH:3][CH:2]=[CH:32][C:6]=3[C:7]=12.[F:33][C:3]1[C:2]([C:35]#[C:34][C:36]2([OH:41])[CH2:40][CH2:39][CH2:38][CH2:37]2)=[CH:32][C:6]2[C:7]3[N:8]([C:13]([CH:19]([OH:31])[C:20]4[N:24]([CH:25]5[CH2:30][CH2:29][CH2:28][CH2:27][O:26]5)[N:23]=[CH:22][CH:21]=4)=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=3)[CH:9]3[CH2:10][CH:11]([C:5]=2[CH:4]=1)[CH2:12]3
Reactant: NC(=O)c1nc2n(c1C(O)c1ccnn1C1CCCCO1)C1CC(C1)c1cc(F)c(Br)cc1-2
Reactant: C#CC1(O)CCCC1
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: NC(=O)c1cn2c(n1)-c1ccccc1C1CC2C1
Product: NC(=O)c1nc2n(c1C(O)c1ccnn1C1CCCCO1)C1CC(C1)c1cc(F)c(C#CC3(O)CCCC3)cc1-2

Procedure:
9-fluoro-3-(hydroxy(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)methyl)-104(1-hydroxycyclopentyl)ethynyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide was prepared similarly according to General Procedure E with slight modification. 10-bromo-9-fluoro-3-(hydroxy(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide was reacted with 1-ethynylcyclopentanol in a solution of DMF (1.3 mL/mmol) and diisopropylamine (2.6 mL/mmol) to afford the title compound which was carried forward to the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[N+:17]([O-])=O)[O:6][CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]2)[CH:14]=[CH:15][C:16]=1[NH2:17]
Reactant: COc1cc(OC2CCN(C)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: COc1cc(OC2CCN(C)CC2)ccc1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.2 %

Procedure:
To a stirred solution of 4-(3-methoxy-4-nitro-phenoxy)-1-methyl-piperidine (Intermediate 44; 12.86 g, 48.34 mmol) in ethanol (250 mL) under nitrogen was added in one portion the Pd/C catalyst (10%, 1.29 g). The resulting mixture was evacuated and backfilled with nitrogen 4× before hydrogen gas was introduced via a balloon. The reaction mixture was stirred at room temperature for 18 hrs. The catalyst was removed by filtration through celite and the filtrate concentrated under reduced pressure to give a light red oil (11.1 g, 47.0 mmol, 97%).
Reaction SMILES: [F:1][C:2]1[C:22](F)=[CH:21][C:5]2=[N:6][C:7]3[N:8]([CH:18]4[CH2:20][CH2:19]4)[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1.[CH3:24][S:25]([OH:28])(=[O:27])=[O:26].CS(O)(=O)=O.[NH2:34][C:35]1([CH2:39][CH3:40])[CH2:38][NH:37][CH2:36]1.CS(O)(=O)=O>C(O)C>[CH3:24][S:25]([OH:28])(=[O:27])=[O:26].[NH2:34][C:35]1([CH2:39][CH3:40])[CH2:38][N:37]([C:22]2[C:2]([F:1])=[CH:3][C:4]3[C:5]([CH:21]=2)=[N:6][C:7]2[N:8]([CH:18]4[CH2:19][CH2:20]4)[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=2[CH:13]=3)[CH2:36]1
Reactant: CCC1(N)CNC1
Reactant: O=C(O)c1cn(C2CC2)c2nc3cc(F)c(F)cc3cc2c1=O
Agent: CS(=O)(=O)O
Solvent: CCO
Product: CCC1(N)CN(c2cc3nc4c(cc3cc2F)c(=O)c(C(=O)O)cn4C2CC2)C1
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 19.6 %

Procedure:
8-(3-Amino-3-ethyl-1-azetidinyl)-1-cyclopropyl-7-fluoro-4-oxo-1,4-dihydrobenzo[b][1,8]-naphthyridine-3-carboxylic acid methanesulphonate was prepared under the conditions of Example 15, but starting with 1.8 g of 7,8-difluoro-1-cyclopropyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid and 2.94 g of 3-amino-3-ethylazetidine dimethanesulphonate. After recrystallization in dimethylformamide, the product obtained, suspended in 20 cm3 of ethanol, is treated with 3.4 cm3 of a solution at a concentration of 9.6 g % of methanesulphonic acid in ethanol. The suspension is stirred for 5 minutes at approximately 80° C., cooled to a temperature in the region of 20° C., drained and washed with 3 times 10 cm3 of ethanol. 0.55 g of 8-(3-amino-3-ethyl-1-azetidinyl)-1-cyclopropyl-7-fluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid methanesulphonate is obtained in the form of a yellow solid, which decomposes at 248° C.
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].[Cl:16][C:17]1[CH:22]=[C:21]([CH:23]2[CH2:28][CH2:27][C:26]([CH3:30])([CH3:29])[CH2:25][CH2:24]2)[CH:20]=[CH:19][C:18]=1O>N1C=CC=CC=1.C1(C)C=CC=CC=1>[F:5][C:4]([F:7])([F:6])[S:1]([O:8][C:18]1[CH:19]=[CH:20][C:21]([CH:23]2[CH2:24][CH2:25][C:26]([CH3:29])([CH3:30])[CH2:27][CH2:28]2)=[CH:22][C:17]=1[Cl:16])(=[O:3])=[O:2]
Reactant: CC1(C)CCC(c2ccc(O)c(Cl)c2)CC1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC1(C)CCC(c2ccc(OS(=O)(=O)C(F)(F)F)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
8.2 ml of triflic anhydride are added at 5° C. to 9.7 g of 2-chloro-4-(4,4-dimethylcyclohexyl)phenol (compound IX.1) in 60 ml of pyridine, the reaction mixture is left to stand for 30 minutes at 0° C., and then the reaction mixture is stirred at room temperature for 12 hours. The reaction mixture is hydrolysed and then extracted with dichloromethane. The organic phase is dried over magnesium sulphate and the solvents are evaporated off under reduced pressure. The residue obtained is taken up in toluene, and then the solvents are evaporated off under reduced pressure. The residue obtained is purified by chromatography on a column of silica gel, eluting with a cyclohexane/ethyl acetate mixture which varies from 100/0 to 99/1 (v/v). 15 g of the compound are obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]#[N:9].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[CH:19])=[CH:14][CH:13]=1.C(N(CC)CC)C.O>CN(C)C=O>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[C:8]#[N:9])=[CH:14][CH:13]=1
Reactant: C#Cc1ccc(OC)cc1
Reactant: N#Cc1cnccc1Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C#Cc2ccncc2C#N)cc1
Yield: 84 %

Procedure:
4-Chloro-3-cyanopyridine (1.50 g) and 4-methoxyphenylacetylene (1.60 g) were reacted in the presence of dichlorobistriphenylphosphinepalladium (0.14 g), cuprous iodide (75 mg) and triethylamine (10 ml) in N,N-dimethylformamide (25 ml) in nitrogen atmosphere at 100° C. overnight. The reaction mixture was poured into water (100 ml), and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system), to give 4-(4-methoxyphenylethynyl)-3-cyanopyridine (2.13 g, 95%) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1([CH:11]=[CH:10][CH:9]=[N:8][CH2:7]1)C(OC)=O.C(OC)(=[O:15])CC.CC(C)([O-])C.[Na+].[CH2:24]1[CH2:28][O:27][CH2:26][CH2:25]1>>[CH3:11][C:10]1[C:9]([OH:15])=[N:8][C:7]2[C:25]([C:26]=1[OH:27])=[CH:24][CH:28]=[N:1][CH:2]=2
Reactant: COC(=O)C1(N)C=CC=NC1
Reactant: CCC(=O)OC
Reactant: C1CCOC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: Cc1c(O)nc2cnccc2c1O
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a stirred solution of methyl 3-aminonicotinate (2.0 g, 13.14 mmol) and methyl propionate (30.9 mL, 329 mmol) in THF (30 mL) was added sodium tert-butoxide (3.16 g, 32.9 mmol) portionwise over 1 min. The reaction was stirred at rt for 40 min and at 100° C. for 4 h. After this time the reaction was cooled to rt and evaporated in vacuo. The resulting solid was dissolved in water (20 mL) and neutralized to pH 7 with 1.0M aqueous HCl. The resulting precipitate was filtered and dried under vacuum overnight to give 3-methyl-1,7-naphthyridine-2,4-diol. Mass Spectrum (ESI) m/e=177.2 (M+1).
Reaction SMILES: [C:1]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Br:14]Br>>[Br:14][CH2:13][C:10]1[CH:11]=[CH:12][C:7]([C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[CH:8][CH:9]=1
Reactant: Cc1ccc(C(=O)C(C)(C)C)cc1
Reactant: BrBr
Product: CC(C)(C)C(=O)c1ccc(CBr)cc1
Temperature: 150 °C
Reaction time: 0.17 h

Procedure:
To a flask equipped with stirrer, thermometer, condenser, addition funnel and heating mantle, there is added 44.0 grams (0.25 mole) of p-pivaloyl toluene at a temperature of 150°C. There is then added dropwise, while maintaining the temperature at 150°C., 40 grams (0.25 mole) of liquid bromine over a period of 10 to 15 minutes. The mixture is then stirred for an additional 10 minutes again while maintaining the temperature at about 140° to 150°C. The resulting brown liquid is cooled and degassed with nitrogen to obtain α-bromo-4-pivaloyl toluene in liquid form, b.p. 124° to 132°C. at 0.3 mm.
Reaction SMILES: [NH2:1][C:2]1[N:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5].[Cl-].[NH4+].C(O)C>[Fe].O>[NH2:1][C:2]1[N:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5]
Reactant: Nc1ncc([N+](=O)[O-])cc1C(=O)NCc1ccc(Oc2ccccc2)s1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1cnc(N)c(C(=O)NCc2ccc(Oc3ccccc3)s2)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 79.9 %

Procedure:
2-Amino-5-nitro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide (74 mg, 0.20 mmol) described in Preparation Example A+-9, an iron powder (56 mg, 1.0 mmol) and ammonium chloride (21 mg, 0.40 mmol) were suspended in a solvent mixture of ethanol (2 mL) and water (0.5 mL), the solution was stirred at 60° C. for 3 hours, then, it was stirred at 90° C. for 6 hours. The reaction solution was cooled to room temperature, then, it was filtered through Celite pad. The filtrate was evaporated in vacuo, the residue was purified by reverse phase high performance liquid chromatography (acetonitrile-water:mobile phase (containing 0.1% trifluoroacetic acid) was used), and the title compound (54.4 mg) was obtained as a trifluoroacetic acid salt.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH2:22][C:23]2([CH3:27])[CH2:26][O:25][CH2:24]2)C(=O)OC(C)(C)C)=[C:4]([O:28][CH3:29])[CH:3]=1>FC(F)(F)CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][CH2:22][C:23]2([CH3:27])[CH2:26][O:25][CH2:24]2)=[C:4]([O:28][CH3:29])[CH:3]=1
Reactant: COc1cc(F)ccc1-c1ccncc1N(CC1(C)COC1)C(=O)OC(C)(C)C
Solvent: OCC(F)(F)F
Product: COc1cc(F)ccc1-c1ccncc1NCC1(C)COC1
Yield: 49.3 %

Procedure:
A solution of tert-butyl 4-(4-fluoro-2-methoxyphenyl)pyridin-3-yl((3-methyloxetan-3-yl)methyl)carbamate (0.3 g, 745 μmol) in 2,2,2-trifluorethanol (3.0 mL) was stirred in a microwave oven at 150° C. for 2 hours. The compound was purified by silica gel chromatography on a 10 g column using an MPLC (ISCO) system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100) to give the desired compound as a light brown oil (0.111 g; 49%). MS (ESI): m/z=303.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11]/[C:12](=[CH:17]\[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)/[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C=C.[SH:33][CH2:34][CH2:35][NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40]>>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:13]([O:15][CH3:16])=[O:14])[CH:17]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)[S:33][CH2:34][CH2:35][NH:36][C:37]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:43])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCS
Reactant: COC(=O)/C(=C/c1cccc2ccccc12)NC(=O)OCc1ccccc1
Agent: C=CC(=O)[O-]
Product: COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(SCCNC(=O)OC(C)(C)C)c1cccc2ccccc12

Procedure:
Using a procedure similar to that described in Example 10 part b, substituting methyl (2Z)-2-{[(benzyloxy)carbonyl]amino}-3-(1-naphthyl)acrylate (5a) (2.8 g, 7.75 mmol) as the acrylate component and tert-butyl (2-mercaptoethyl)carbamate (5.3 g, 29.9 mmol) as the thio component (stirred 5 days), the title compound (25b) was obtained (3.3 g, 79%) as a semi-solid.
Reaction SMILES: [CH2:1]([S:3][CH2:4][C:5]([NH:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1)=[O:6])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)=[CH:32][CH:31]=1>CN(C)C=O>[ClH:29].[CH2:1]([S:3][CH2:4][C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([N:41]2[CH2:40][CH2:39][N:38]([CH2:37][CH2:36][C:33]3[CH:34]=[CH:35][C:30]([Cl:29])=[CH:31][CH:32]=3)[CH2:43][CH2:42]2)=[O:14])=[CH:15][CH:16]=1)=[O:6])[CH3:2]
Reactant: CCSCC(=O)Nc1ccc(C(=O)O)cc1
Reactant: Clc1ccc(CCN2CCNCC2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CCSCC(=O)Nc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2.5 g of 4-ethylmercaptoacetylaminobenzoic acid are introduced into 30 ml of dimethylformamide, and 1.75 g of N,N-carbonyldiimidazole are added. The mixture is stirred for 10 minutes at room temperature. At 80°, 1.75 g of 1-[2-(4-chlorophenyl)ethyl]piperazine are added thereto. The mixture is stirred for a further 45 minutes at 80°. The reaction solution is concentrated by evaporation and the oil is chromatographed. The hydrochloride is recrystallised from ethanol/ether, yielding 1-[4-(ethylmercaptoacetylamino)benzoyl]-4-[2-(4-chlorophenyl)ethyl]piperazine hydrochloride having a melting point of 229°-231°.
Reaction SMILES: [N:1]([C@@H:4]1[C@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:15]([CH3:26])[O:14][C@H:6]([S:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@H:5]1[O:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[N+:2]=[N-:3].C1C=C(Cl)C=C(C(OO)=[O:42])C=1>C(Cl)Cl>[N:1]([C@@H:4]1[C@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C@H:15]([CH3:26])[O:14][C@H:6]([S:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:42])[C@H:5]1[O:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[N+:2]=[N-:3]
Reactant: C[C@@H]1O[C@H](Sc2ccccc2)[C@@H](OC(=O)C(C)(C)C)[C@H](N=[N+]=[N-])[C@@H]1OC(=O)c1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: C[C@@H]1O[C@H](S(=O)c2ccccc2)[C@@H](OC(=O)C(C)(C)C)[C@H](N=[N+]=[N-])[C@@H]1OC(=O)c1ccccc1
Temperature: -20 °C
Yield: 82.7 %

Procedure:
To a solution of phenyl 3-azido-4-O-benzoyl-3,6-di-deoxy-2-O-pivaloyl-1-thio-β-L-galactopyranoside (β-19) (270 mg, 0.575 mmol) in 10 mL of CH2Cl2 at -78° C. is added a solution of mCPBA (159 mg of 64% material, 0.920 mmol) in 2 mL of CH2Cl2. The reaction mixture is allowed to warm to -20° C. and then quenched with TEA (500 μL, 3.59 mmol). The reaction mixture is diluted with 10 mL of CH2Cl2. washed with saturated NaHSO3 (10 mL), saturated NaHCO3 (10 mL), dried over Na2SO4, filtered and concentrated. The crude product is purified by flash chromatography (60% EtOAc/petroleum ether) to give 231 mg (83%) of 3-azido-4-O-benzoyl1,3,6-tri-deoxy-2-O-pivaloyl-1-(phenylsulfinyl)-β-L-galactopyranose (β-20) as a mixture of diastereomers: Rf 0.26 (50% EtOAc/petroleum ether).
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][C@@H:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:14][N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:26].N1C=CC=CC=1.[C:33]1([S:39](Cl)(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)Cl>[N:15]1([CH2:14][C@H:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:12][C:11]2[CH:10]=[CH:9][C:8]3[C:7](=[O:26])[CH2:6][CH2:5][CH2:4][C:3]=3[C:2]=2[NH:1][S:39]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)(=[O:41])=[O:40])[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C1CCCc2c1ccc(O[C@H](Cn1ccnc1)c1ccccc1)c2NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
To a solution of 5-amino-6-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (100 mg, 0.288 mmol) in CH2Cl2 (2 mL) was added pyridine (47 mL, 0.576 mmol, 2 equiv) followed by benzenesulfonyl chloride (44 μL, 0.345 mmol, 1.2 equiv). The reaction was allowed to stir overnight at RT. The reaction was diluted with CH2Cl2, washed with saturated aqueous NH4Cl and brine, dried over MgSO4 to give an oil. Purification by chromatography (4% MeOH/CH2Cl2) gave the title compound as a white foam (114 mg, 0.234 mmol, 81%). The structure was confirmed by NMR and mass spectrometry. MS m/z 488 (M++H).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:21]1([CH3:30])[CH:26]=[CH:25][C:24]([C:27](Cl)=[O:28])=[CH:23][CH:22]=1>>[C:21]1([CH3:30])[CH:26]=[CH:25][C:24]([C:27]([N:20]=[C:16]([N:7]2[CH2:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8]2)[O:17][CH2:18][CH3:19])=[O:28])=[CH:23][CH:22]=1
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Reactant: Cc1ccc(C(=O)Cl)cc1
Product: CCOC(=NC(=O)c1ccc(C)cc1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and p-toluoyl chloride, there is obtained ethyl N-(p-toluoyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a resin, mass spectrum m/e: M+ 384 (9), 355 (15), 194 (100);
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[NH:8][CH2:9][CH2:10][C:4]2=[N:3][N:2]=1.[CH3:15][C:16]1[CH:33]=[CH:32][CH:31]=[CH:30][C:17]=1[C:18]([NH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)=[O:19].C(N(CC)CC)C>ClCCl>[CH:1]1[N:5]2[C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[N:8]([C:25]([C:24]3[CH:23]=[CH:22][C:21]([NH:20][C:18](=[O:19])[C:17]4[CH:30]=[CH:31][CH:32]=[CH:33][C:16]=4[CH3:15])=[CH:29][CH:28]=3)=[O:26])[CH2:9][CH2:10][C:4]2=[N:3][N:2]=1
Reactant: c1ccc2c(c1)NCCc1nncn1-2
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCc3nncn3-c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5 mmol of 5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepine in 20 ml of dichloromethane is added 5.5 mmol of 4-[(2-methylbenzoyl)amino]benzoyl chloride and then 7.5 mmol of triethylamine. The mixture is stirred at room temperature for 8 hours and then washed with water, aqueous NaHCO3 and brine. The solution is dried (Na2SO4) and the solvent removed in vacuo to give a solid. The solid is purified by chromatography on silica gel with ethyl acetate-hexane as solvent to give the desired product as a glass.