Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([C:25]([F:28])([F:27])[F:26])([CH2:13]OS(C2C(C)=CC=CC=2)(=O)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:29]=[N+:30]=[N-:31].C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C.C(Cl)Cl>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([C:25]([F:28])([F:27])[F:26])([CH2:13][N:29]=[N+:30]=[N-:31])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccccc1S(=O)(=O)OCC1(C(F)(F)F)CCN(Cc2ccccc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: CC#N
Product: [N-]=[N+]=NCC1(C(F)(F)F)CCN(Cc2ccccc2)C1

Procedure:
The compound (2.43 g) from step 456c was dissolved in acetonitrile, then reacted with tetrabutylammonium azide at 80° C. for 16 hours. The mixture was diluted with methylene chloride, then washed with water and brine and dried. Removal of the solvent gave 0.751 g of the title compound.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[O:7][C:8]1[C:9]([CH2:15][CH3:16])=[N:10][NH:11][C:12]=1[CH2:13][CH3:14].[CH3:21][O:22][CH2:23][CH2:24]Br.[H][H]>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[C:6]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[O:7][C:8]1[C:12]([CH2:13][CH3:14])=[N:11][N:10]([CH2:24][CH2:23][O:22][CH3:21])[C:9]=1[CH2:15][CH3:16]
Reactant: [H][H]
Reactant: COCCBr
Reactant: CCc1n[nH]c(CC)c1Oc1cc(Cl)cc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nn(CCOC)c(CC)c1Oc1cc(Cl)cc(Cl)c1
Yield: 58.2 %

Procedure:
Sodium hydride (60% dispersion in oil, 34 mg, 0.850 mmol) was added to a stirred solution of 4-(3,5-dichlorophenoxy)-3,5-diethyl-1H-pyrazole of Example 3 (200 mg, 0.701 mmol) and methoxyethyl bromide (117 mg, 0.850 mmol) in dry N,N-dimethylformamide (2ml) at 0° C. under nitrogen. The mixture was stirred at 0° C. for 45 minutes during which time hydrogen was evolved and the yellow solution turned dark brown. The reaction mixture was quenched by the addition of water (5 ml) and the mixture concentrated under reduced pressure. The residue was dissolved in ethyl acetate (20 ml) and washed with water (10 ml) and brine (10 ml) and then dried over magnesium sulphate, filtered and concentrated under reduced pressure to leave a brown oil. The crude product was purified by flash column chromatography on silica gel eluting with pentane:diethyl ether (80:20, by volume) to provide the title compound (140 mg) as a colourless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:25]([O:32][C:33](=[O:37])[C@@H:34]([CH3:36])[NH2:35])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH2:25]([O:32][C:33](=[O:37])[C@@H:34]([CH3:36])[NH:35][C:11](=[O:13])[C@H:9]([CH3:10])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: C[C@@H](N)C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 23.0 g. (0.121 m) of N-t-butoxycarbonyl-L-alanine, 42.6 g. (0.121 m) of D-alanine benzyl ester p-toluenesulfonic acid salt and 17 ml. (0.121 m) of triethylamine in 400 ml. of cold (0° C.) methylene chloride was added dropwise 25.0 g. (0.121 m) of dicyclohexylcarbodiimide in 100 ml. of methylene chloride. After stirring overnight at room temperature the solids were filtered and the filtrate concentrated to an oil. The residue was dissolved in 400 ml. of ethyl acetate which was washed with a 1% hydrochloric acid solution, a 10% potassium carbonate solution, water and a brine solution. The organic phase was separated, dried over magnesium sulfate and concentrated to an oil. The residue was triturated with diethyl ether and the resulting solids filtered under nitrogen, 16.0 g. An additional 12.7 g. of the desired product crystallized from the filtrate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]([CH2:18]Cl)[C:9]2=[O:20])[CH:5]=[CH:6][CH:7]=1.N1C=[CH:24][N:23]=[N:22]1.[Na].[CH3:27][N:28](C)C=O>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]([CH2:18][N:23]3[CH:24]=[N:28][CH:27]=[N:22]3)[C:9]2=[O:20])[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: O=c1c(CCl)cc2ccccc2n1-c1cccc(Cl)c1
Reactant: c1c[nH]nn1
Agent: [Na]
Product: O=c1c(Cn2cncn2)cc2ccccc2n1-c1cccc(Cl)c1

Procedure:
Following the procedure of example 22, react 1-(3-chlorophenyl)-3-chloromethyl-2(1H)-quinolone with sodium triazole in dimethylformamide. Chromatograph to obtain the major product, 1-(3-Chlorophenyl)-3-(1H-1,2,4-Triazol-1-ylmethyl)-2(1H)-Quinolone.
Reaction SMILES: C(SCCNC(=O)CCN1C=CC=C1)C=C.[Cl:17][C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=1)[C:21]([O:23]O)=[O:22]>ClCCl>[Cl:17][C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=1)[C:21]([OH:23])=[O:22]
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: C=CCSCCNC(=O)CCn1cccc1
Solvent: ClCCl
Product: O=C(O)c1cccc(Cl)c1
Yield: 60 %

Procedure:
N-(2-Allylsulfanyl-ethyl)-3-pyrrol-1-yl-propionamide (0.3704 g, 1.554 mmol, 1 equiv) was taken up in 100 ml of dichloromethane with stirring under nitrogen. The reaction mixture was cooled to between 0-4 C. Meta-chloroperoxybenzoic acid (0.4815 g, 2.790 mmol, 1.8 equiv) was added to the mixture and the reaction stirred at 0-4 C for 16 hours. The solvent was removed in vacuo and purification by flash chromatography on silica: eluting with ethyl acetate gave the by-product meta-chlorobenzoic acid. Further elution with the solvent mixture was gradually changed to a 1:1 ethyl acetate/ethanol gave the product which was isolated by removal of the solvent in vacuo as off-white crystals in 60% yield.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=2)[O:10][CH2:11][CH2:12][CH2:13][NH2:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.CS[C:20]([N:24]([CH3:33])[N:25]=CC1C=CC=CC=1)=[N:21][C:22]#[N:23].Cl>CC(C)=O>[CH3:33][N:24]1[C:20]([NH:14][CH2:13][CH2:12][CH2:11][O:10][C:9]2[CH:15]=[CH:16][CH:17]=[C:7]([CH2:6][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:8]=2)=[N:21][C:22]([NH2:23])=[N:25]1
Reactant: NCCCOc1cccc(CN2CCCC2)c1
Reactant: CSC(=NC#N)N(C)N=Cc1ccccc1
Agent: Cl
Solvent: CC(C)=O
Product: Cn1nc(N)nc1NCCCOc1cccc(CN2CCCC2)c1
Yield: 14.6 %

Procedure:
A mixture of 3-[3-[1-pyrrolidinylmethyl]phenoxy]propanamine (0.97 g) and N-cyano-1-methyl-2-(phenylmethylene)hydrazine carboximidothioic acid methyl ester (0.97 g) was heated at 70° for 8 hr under a reduced pressure of 20 mm of mercury. Acetone was added and the solution was treated with hydrochloric acid at room temperature for one hour, washed with ether, basified with sodium carbonate and extracted with ethyl acetate. Evaporation of the ethyl acetate extracts gave a thick oil which crystallised from ethyl acetate/light petroleum (b.p. 60°-80° ) to give the title compound as a white solid (0.2 g). TLC; silica/methanol/0.88 ammonia 80:1) Rf 0.5, m.p. 95°-95.5°.
Reaction SMILES: [P:1]([O:5]P(O)(O)=O)([OH:4])([OH:3])=[O:2].[C@@H:10]1([N:19]2[C:28]3[N:27]=[CH:26][N:25]=[C:23]([OH:24])[C:22]=3[N:21]=[CH:20]2)[O:18][C@H:15]([CH2:16]O)[C@@H:13]([OH:14])[C@H:11]1[OH:12].[C@@H:29]1([N:38]2[C:48]3[N:47]=[C:45]([NH2:46])[NH:44][C:42](=[O:43])[C:41]=3[N:40]=[CH:39]2)[O:37][C@H:34]([CH2:35][OH:36])[C@@H:32]([OH:33])[C@H:30]1[OH:31]>C([O-])(=O)C>[C@@H:10]1([N:19]2[C:28]3[N:27]=[CH:26][N:25]=[C:23]([OH:24])[C:22]=3[N:21]=[CH:20]2)[O:18][C@H:15]([CH2:16][O:5][P:1]([OH:3])([OH:4])=[O:2])[C@@H:13]([OH:14])[C@H:11]1[OH:12].[C@@H:29]1([N:38]2[C:48]3[N:47]=[C:45]([NH2:46])[NH:44][C:42](=[O:43])[C:41]=3[N:40]=[CH:39]2)[O:37][C@H:34]([CH2:35][O:36][P:1]([OH:4])([OH:3])=[O:2])[C@@H:32]([OH:33])[C@H:30]1[OH:31]
Reactant: OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)[C@H](O)[C@@H]1O
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: O=P(O)(O)OP(=O)(O)O
Agent: CC(=O)[O-]
Product: Nc1nc2c(ncn2[C@@H]2O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]2O)c(=O)[nH]1
Product: O=P(O)(O)OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)[C@H](O)[C@@H]1O
Reaction time: 9 h

Procedure:
Pyrophosphoric acid (15 g/dl) and 8 g/dl of inosine or guanosine were dissolved in an acetate buffer (pH 4.0). To this was added E. coli JM109 strain having introduced therein each mutant acid phosphatase gene such that the concentration reached 100 mg/dl in terms of the dry cell weight. The reaction was conducted at 50° C. for 9 hours while maintaining the pH at 4.0, and the amount of 5′-inosinic acid or 5′-guanylic acid formed was measured. The results are shown in Table 17. The nucleoside phosphate ester formed was only a nucleoside-5′-phosphate ester, and the production of a nucleoside-2′-phosphate ester and a nucleoside-3′-phosphate ester as by-products was not observed at all. The reaction was also conducted at 30° C. for 12 hours using E. coli JM109/pEPI380 strain as a control. The results are also shown in Table 17.
Reaction SMILES: CCC[C@@](O)([C@@H]1[C@:11]2(OC)[C@@H:12]3OC4=C(O)C=CC5=C4[C@:13]43[CH2:14][CH2:15][N:16](C)[C@H](C5)C4(C=C2)C1)C.C[C@H](CN(C)C)CN1C2C=C([O:48]C)C=CC=2SC2C1=CC=CC=2.ON1C2C=CC=CC=2N=N1.CN([CH:67]=[O:68])C>>[NH2:16][C@H:15]([C:67]([OH:68])=[O:48])[CH2:14][CH2:13][CH2:12][CH3:11]
Reactant: CN(C)C=O
Reactant: COc1ccc2c(c1)N(C[C@H](C)CN(C)C)c1ccccc1S2
Reactant: CCC[C@@](C)(O)[C@H]1CC23C=C[C@@]1(OC)[C@@H]1Oc4c(O)ccc5c4[C@@]12CCN(C)[C@@H]3C5
Agent: On1nnc2ccccc21
Product: CCCC[C@H](N)C(=O)O
Reaction time: 0.5 h

Procedure:
Immobilon affinity membrane 4 (n=2, scheme I), 3.20 g (0.349 mmol of amino groups), was reacted with N--Fmoc--Nle--O--Pfp (6.0 mmol) in the presence of 1-hydroxybenzotriazole (6.0 mmole) in 20 mL of dry DMF for 2.0 hours at room temperature. The support was washed with methanol, dried, and then treated for an additional 2.0 hours at room temperature, with 40 mL pyridine/acetic acid anhydride, 3/1 (v/v). The acylation reaction was terminated by washing the membrane with methanol. The amount of incorporated norleucine was 0.093 mmol/g membrane as determined by quantitation of the fluorenylmethyloxycarbonyl moiety. The assay is performed by carefully weighing in 5.0 mg of the membrane 8 (scheme III) and treatment with 0.4 mL of a mixture of piperidine and 0.4 mL dichloromethane for 30 minutes at room temperature. The solution was diluted to 10.0 mL with dichloromethane and the absorbance at 301 nm determined (ε301 =7,800 for N-fluorenylmethyl piperidine in dichloromethane).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]([O:12][C:13]([NH:15][CH2:16][CH2:17][NH2:18])=[O:14])([CH3:11])[CH3:10].[CH2:19]([O:26][C:27]1[CH:36]=[C:35]2[C:30]([C:31](Cl)=[C:32]([N+:37]([O-:39])=[O:38])[CH:33]=[N:34]2)=[CH:29][CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CN(C=O)C>[CH2:19]([O:26][C:27]1[CH:36]=[C:35]2[C:30]([C:31]([NH:18][CH2:17][CH2:16][NH:15][C:13](=[O:14])[O:12][C:9]([CH3:8])([CH3:10])[CH3:11])=[C:32]([N+:37]([O-:39])=[O:38])[CH:33]=[N:34]2)=[CH:29][CH:28]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)NCCNc1c([N+](=O)[O-])cnc2cc(OCc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.1 %

Procedure:
Triethylamine (58.9 mL, 422.4 mmol, 1.5 eq) and tert-butyl N-(2-aminoethyl) carbamate (54.1 g, 337.9 mmol, 1.2 eq) were added sequentially to a solution of 7-benzyloxy-4-chloro-3-nitroquinoline (88.63 g, 281.6 mmol) in DMF (800 mL) and stirred for 4 hours at ambient temperature. The crude reaction mixture was poured into hot water with continuous stirring to afford bright a yellow precipitate. The yellow solid was filtered and dried under reduced pressure at 65° C. to afford 123.65 g of tert-butyl 2-[(7-benzyloxy-3-nitroquinolin-4-yl)amino]ethylcarbamate.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1.Cl[C:16]1[C:17]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][C:29]3[C:30]([CH3:35])=[N:31][N:32]([CH3:34])[CH:33]=3)[CH2:24][CH2:23]2)=[N:18][CH:19]=[CH:20][N:21]=1.CN(C)C(=O)C.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:34][N:32]1[CH:33]=[C:29]([CH2:28][N:25]2[CH2:24][CH2:23][N:22]([C:17]3[C:16]([C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:14])([F:13])[F:1])[CH:5]=4)=[N:21][CH:20]=[CH:19][N:18]=3)[CH2:27][CH2:26]2)[C:30]([CH3:35])=[N:31]1
Reactant: Cc1nn(C)cc1CN1CCN(c2nccnc2Cl)CC1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1nn(C)cc1CN1CCN(c2nccnc2-c2cccc(OC(F)(F)F)c2)CC1
Temperature: 110 °C
Yield: 35.9 %

Procedure:
Charge a carousel tube with 3-(trifluoromethoxy)benzeneboronic acid (140 mg, 0.68 mmol), 3′-chloro-4-(1,3-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (173 mg, 0.56 mmol) and N,N-dimethylacetamide (1 mL). Add N,N-dimethylacetamide (3 mL) and potassium carbonate (190 mg, 1.35 mmol) and purge with nitrogen for about 45 min. Add water (2 mL, purged with nitrogen for 1 hr.), then tetrakis(triphenylphosphine)palladium(0) (0.004 g, 0.0034 mmol), purge the reaction for about 30 min., and then heat overnight at 110° C. Cool to room temperature, add water and extract with DCM (3×30 mL). Concentrate the combined DCM extracts and purify using silica gel chromatography followed by reverse phase HPLC to give the title compound (0.087 g, 30%). MS (ES): m/z=433.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH:5]=[C:6]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=1)[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:2].[Cl:25][C:26]1[C:27](=[O:33])[CH:28]=[CH:29][C:30](=O)[CH:31]=1>>[CH2:1]([O:3][C:4]([C:5]1[C:29]2[C:30](=[CH:31][C:26]([Cl:25])=[C:27]([OH:33])[CH:28]=2)[N:13]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:22])([CH3:21])[CH3:23])=[CH:16][CH:15]=2)[C:6]=1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:24])[CH3:2]
Reactant: O=C1C=CC(=O)C(Cl)=C1
Reactant: CCOC(=O)C=C(CC(=O)OCC)Nc1ccc(C(C)(C)C)cc1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)c(Cl)cc2n1-c1ccc(C(C)(C)C)cc1

Procedure:
The sub-title compound was prepared in accordance with step (b) Example 1 from 3-(4-tert-butylphenylamino)pent-2-enedioic acid diethyl ester (6.2 g, 18.6 mmol, see step (a) above) and 2-chloro-1,4-benzoquinone (3.1 g, 22 mmol). Yield 266 mg (3%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:25](=[O:32])[CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29]>C(Cl)Cl>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:25](=[O:32])[CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH2:13][CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Reactant: COC(=O)CCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCC(=O)N1CCN(c2ccccc2C(C)(C)C)CC1
Temperature: 25 °C
Yield: 73.7 %

Procedure:
To a stirred solution at 0° C. of 1-(2-tert-butylphenyl)piperazine (0.218 g, 1.00 mmol) and triethylamine (0.303 g, 3.00 mmol) in methylene chloride (5.0 mL) was added methyl 4-chloro-4-oxobutanoate (0.171 g, 1.10 mmol) and the resulting reaction mixture was warmed to room temperature. After 2 h the reaction mixture was diluted with methylene chloride (10.0 mL), washed with water (20.0 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 50% ethyl acetate/heptanes) to provide methyl 4-(4-(2-tert-butylphenyl)-piperazin-1-yl)-4-oxobutanoate (0.245 g, 74%) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]([CH3:28])[C:12]([C:14]1[S:27][C:17]2[C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1)=[O:13])[C:5](O)=[O:6].[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:6])[CH:8]=[CH:9][C:10]=1[N:11]([CH3:28])[C:12]([C:14]1[S:27][C:17]2[C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1)=[O:13]
Reactant: C1COCCN1
Reactant: CN(C(=O)c1cc2c(s1)-c1ccccc1OCC2)c1ccc(C(=O)O)cc1Cl
Product: CN(C(=O)c1cc2c(s1)-c1ccccc1OCC2)c1ccc(C(=O)N2CCOCC2)cc1Cl

Procedure:
3-Chloro-4-(N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)benzoic acid and morpholine were reacted by a procedure similar to Example 47 to give 251. MS: (ESI+) 483.1
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:21]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][S:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:21])[N:3]=1
Reactant: Cc1cccc(CSc2ccccc2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: Cc1cccc(CS(=O)c2ccccc2)n1

Procedure:
A solution of 2-methyl-6-((phenylthio)methyl)pyridine is reacted with m-chloroperoxybenzoic acid according to the method of Example 1B to give the title compound.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1.[CH3:24][O:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29]>>[O:22]=[C:20]1[NH:19][C:18](=[O:23])[CH:17]([CH2:16][C:13]2[CH:12]=[CH:11][C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][N:2]([CH3:1])[C:28](=[O:29])[C:27]4[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=4[O:25][CH3:24])[CH:5]=3)=[CH:15][CH:14]=2)[S:21]1
Reactant: COc1ccccc1C(=O)Cl
Reactant: CNCc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1
Product: COc1ccccc1C(=O)N(C)Cc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1

Procedure:
In a manner similar to that of Example 37(e), by reacting 500 mg (1.5 mmol) of 5-(3′-methylaminomethylbiphenyl-4-ylmethyl)thiazolidine-2,4-dione with 230 μl (1.5 mmol) of 2-methoxybenzoyl chloride, and after purification, 500 mg (70%) of N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-2-methoxy-N-methylbenzamide are obtained in the form of a white solid with a melting point of 96° C.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[S:2].[C:13]([O:17][C:18](=[O:33])[N:19]([CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1)[CH:20]([CH3:22])[CH3:21])([CH3:16])([CH3:15])[CH3:14]>CN(C)C=O>[C:13]([O:17][C:18](=[O:33])[N:19]([CH:20]([CH3:21])[CH3:22])[CH2:23][CH2:24][O:25][C:26]1[CH:27]=[CH:28][C:29]([N:32]=[C:1]=[S:2])=[CH:30][CH:31]=1)([CH3:15])([CH3:16])[CH3:14]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CC(C)N(CCOc1ccc(N)cc1)C(=O)OC(C)(C)C
Solvent: CN(C)C=O
Product: CC(C)N(CCOc1ccc(N=C=S)cc1)C(=O)OC(C)(C)C
Temperature: -15 °C
Reaction time: 1.5 h
Yield: 95 %

Procedure:
Thiocarbonyldiimidazole (3.64 g, 20.44 mmol) (Aldrich) was dissolved in N,N-dimethylformamide (3 mL) and the solution was cooled to −15° C. A solution [2-(4-amino-phenoxy)-ethyl]-isopropyl-carbamic acid tert-butyl ester (from step C above) in N,N-dimethylformamide (7 mL) was added dropwise and stirred at room temperature for 90 minutes. The mixture was poured into ice/water (1500 mL) and extracted with ether (4×250 mL). The ether was dried (Na2SO4) and concentrated in vacuo to give 6.5 g, (95%) isopropyl-[2-(4-isothiocyanato-phenoxy)-ethyl]-carbamic acid tert-butyl ester. Mass spectrum (ES) MH+=367.
Reaction SMILES: C(O[C:9]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:24]([OH:26])=O)[NH:16]C(OC(C)(C)C)=O)=O)C1C=CC=CC=1.[CH:27]1([S:33]([Cl:36])(=[O:35])=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.Cl.[C:38]([C@@H:40]1[CH2:44][CH2:43][CH2:42][NH:41]1)#[N:39]>>[ClH:36].[NH2:16][C@H:15]([C:24](=[O:26])[N:41]1[CH2:42][CH2:43][CH2:44][C@H:40]1[C:38]#[N:39])[CH2:14][CH2:13][CH2:12][N:11]([CH3:9])[S:33]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)(=[O:35])=[O:34]
Reactant: N#C[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: O=S(=O)(Cl)C1CCCCC1
Agent: Cl
Product: CN(CCC[C@H](N)C(=O)N1CCC[C@H]1C#N)S(=O)(=O)C1CCCCC1

Procedure:
Starting from (S)-N5-(benzyloxycarbonyl)-N2-(tert-butyloxycarbonyl)-ornithine, cyclohexanesulphonyl chloride and (S)-2-cyano-pyrrolidine hydrochloride, the expected product is obtained according to the procedure described in Example 68.
Reaction SMILES: C[S:2]([CH3:4])=O.O([C:7]([CH3:10])([CH3:9])[CH3:8])[Na].Cl[C:12]1[CH:17]=[CH:16]C=[CH:14][CH:13]=1>CC([O-])=O.CC([O-])=O.[Pd+2]>[C:4]1([S:2][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:16]=[CH:17][CH:12]=[CH:13][CH:14]=1
Reactant: Clc1ccccc1
Reactant: CC(C)(C)O[Na]
Reactant: CS(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: CC(C)(C)Sc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 33 %

Procedure:
In the drybox, 133.7 mg (0.75 mm) of (Me3C)2PH(S), 170.0 mg (0.75 mm) of Pd(OAc)2 and 10.0 mL of DMSO were loaded into a reactor (50 mL) equipped with a magnetic stir bar. The resulting mixture was stirred at room temperature for 12 h. Next, 2.0 g (17.7 mm) of chlorobenzene, 1.35 g (15.0 mm) of t-butylthiol, and 2.16 g (22.5 mm) of NaO—tBu were added into the reactor. The resulting mixture was refluxed for 12 h. The reaction mixture was then cooled to room temperature, chromatographed on silicon gel using t-butylmethylether/hexane (1% volume ratio) as eluant. The eluate was concentrated by rotary evaporation followed by high vacuum to yield 812 mg (33% yield) of t-butyl phenyl sulfide. It was >95% pure by 1H NMR and GC/MS. 1H NMR (500 MHz, CDCl3): δ7.4-7.2 (m, 5H), 1.17 (s, 9H) ppm. 13C NMR (125 MHz, CDCl3): δ137.4, 132.7, 128.5, 128.3, 45.6, 30.9 ppm. HRMS: Calcd for C10H15S(M++H): 167.0894. Found: 167.0888.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][CH2:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:12][C:11](N)=[CH:10][CH:9]=2)=[O:5])[CH3:2].[CH2:27]([O:34][C:35](Cl)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([N:40](CC)CC)C>C1COCC1.O.C(OCC)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([NH2:40])[C:8]2[C:13]([C:14]=1[CH2:15][CH2:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:12][C:11]([C:35]([O:34][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:36])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)c1[nH]c2ccc(N)cc2c1CCCNC(=O)OC(C)(C)C
Reactant: O=C(Cl)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)c1c(CCCNC(=O)OC(C)(C)C)c2cc(C(=O)OCc3ccccc3)ccc2n1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5-Amino-3-[3-(t-butoxycarbonylamino)-propyl]-1H-indole-2-carboxylic acid ethyl ester (125 mg) was dissolved in 10 mL of THF. To the solution was added 0.5 mL of benzylchloroformate and 0.5 mL of triethylamine. The resulting solution was stirred at ambient temperature overnight (16 h). In the morning the reaction mixture was diluted with 20 mL of water and 20 mL of diethyl ether. The layers were separated and the aqueous layer was washed with 20 mL of diethyl ether. The organic layers were combined and dried over sodium sulfate. After decantation, the solvent was removed on the rotary evaporator. The residue was purified by flash chromatography on silica using 5% EtOAc in hexanes graded to 50% EtOAc in hexanes as the mobile phase to yield 5-(benzyloxycarbonyl)-amino-3-[3-(t-butoxycarbonylamino)-propyl]-1H-indole-2-carboxylic acid ethyl ester (101 mg). This material was clean by 1H NMR and used in the next step without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:22][CH2:21][C:12]2=[C:13](Cl)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=O)(C)(C)C.[C:23]1([CH:29]2[CH2:32][CH2:31][NH:30]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:23]1([CH:29]2[CH2:32][CH2:31][N:30]2[C:13]2[N:14]3[C:18]([N:19]=[C:11]4[CH2:10][CH2:9][NH:8][CH2:22][CH2:21][C:12]=24)=[CH:17][CH:16]=[N:15]3)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nc3ccnn3c(Cl)c2CC1
Reactant: c1ccc(C2CCN2)cc1
Product: c1ccc(C2CCN2c2c3c(nc4ccnn24)CCNCC3)cc1

Procedure:
The product was prepared using 10-chloro-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester in route 1 (step e and f), in step e (route 1) 2-phenyl-azetidine was used as the amine.