Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH3:18])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:19](Cl)(=[O:22])[CH2:20][CH3:21]>>[C:19]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH3:18])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)(=[O:22])[CH2:20][CH3:21]
Reactant: CCN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: CCC(=O)Cl
Product: CCC(=O)Nc1ccc2[nH]cc(C3CCN(CC)CC3)c2n1

Procedure:
Beginning with 0.015 gm (0.061 mMol) 5-amino-3-(1-ethylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.007 mL (0.080 mMol) propionyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15](N(OC)C)=[O:16])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:21]([Li])[CH2:22][CH2:23][CH3:24].C(=O)=O.CC(C)=O.C(OCC)(=O)C>C1COCC1>[CH:1]1([O:7][C:8]2[CH:9]=[CH:10][C:11]([CH2:14][C:15](=[O:16])[CH2:21][CH2:22][CH2:23][CH3:24])=[CH:12][CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: [Li]CCCC
Reactant: CON(C)C(=O)Cc1ccc(OC2CCCCC2)cc1
Agent: O=C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CCCCC(=O)Cc1ccc(OC2CCCCC2)cc1
Reaction time: 0.5 h

Procedure:
To a stirred solution of the 2-(4-cyclohexyloxy-phenyl)-N-methoxy-N-methyl-acetamide (149 mmol, 41.4 g) in anhydrous THF (150 mL) at −78° C. was added n-butyl lithium (1.6 M in hexanes, 298 mmol, 186 mL) dropwise over 45 minutes. The dry ice/acetone bath was replaced with an ice bath, and the reaction was stirred for an additional 30 min. TLC (30% ethyl acetate in hexanes) analysis indicated complete consumption of starting material. The reaction mixture was quenched by addition of saturated ammonium chloride (100 mL) at 0° C., further diluted with water (125 mL) and extracted with ethyl acetate (2×150 mL). The combined ethyl acetate layers were washed with brine (100 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was dissolved in 6% ethyl acetate in hexanes and filtered through a 110 g SiO2 column. The column was eluted with 6% ethyl acetate in hexanes to provide 1-(4-cyclohexyloxy-phenyl)-hexan-2-one upon evaporation of solvent.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=2)=[CH:5][N:6]2[C:11]=1[C:10]([CH2:12][OH:13])=[CH:9][CH:8]=[CH:7]2)[CH3:2].C(N(CC)CC)C.[Si:35](Cl)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36]>ClCCl>[CH2:21]([O:20][C:17]1[CH:18]=[CH:19][C:14]([C:4]2[C:3]([CH2:1][CH3:2])=[C:11]3[N:6]([CH:5]=2)[CH:7]=[CH:8][CH:9]=[C:10]3[CH2:12][O:13][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])=[CH:15][CH:16]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCc1c(-c2ccc(OCc3ccccc3)cc2)cn2cccc(CO)c12
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1c(-c2ccc(OCc3ccccc3)cc2)cn2cccc(CO[Si](C)(C)C(C)(C)C)c12
Reaction time: 48 h
Yield: 90.1 %

Procedure:
1-Ethyl-2-(4-benzyloxyphenyl)-8-hydroxymethylindolizine (21.3 g, 60 mmol), triethylamine (7.88 g, 78 mmol) and tert-butyldimethylsilylchloride (17.8 g, 118 mmol) was dissolved in 200 ml of dry dichloromethane, and the mixture was stirred for 2 days. The solvent was evaporated and the crude product was purified by column chromatography over silica gel 60, using diethyl ether as the eluent. Fractions containing the product were combined and the solvent was evaporated. The product was crystallised from diethyl ether and petroleum ether to afford 25.5 g (90%) of 2-(4-benzyloxyphenyl)-8-(tert-butyldimethylsilanyloxymethyl)-1-ethylindolizine as yellow crystals. M.p. 79-81° C. 1H--NMR (CDCl3, 200 MHz) δ: 0.01 (s, 6 H); 0.83 (s, 9 H); 1.02 (t, 3 H); 2.74 (q, 2 H); 4.92 (s, 2 H); 4.96 (s, 2 H); 6.25 (dd, 1 H); 6.61 (d, 1 H); 6.89 (d, 2 H); 7.11 (s, 1 H); 7.17-7.37 (m, 7 H); 7.59 (d, 1 H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.F[C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:14][O:13][C:11]([C:10]1[CH:15]=[CH:16][C:7]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:8][CH:9]=1)=[O:12]
Reactant: COC(=O)c1ccc(F)cc1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(-n2ccnc2)cc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 59 %

Procedure:
A mixture of imidazole (132 g, 1.9 mol), methyl 4-fluorobenzoate (170 ml, 1.3 mol) and potassium carbonate (357 g, 2.6 mol) in DMSO (200 ml) is stirred at 120° C. for 3 h. After cooling to room temperature, the mixture is added to ice-water. Precipitated product is filtered off and washed with water. Yield: 59%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([NH2:10])[CH:9]=1)[C:5]#[N:6].Cl.Cl[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.CCN(C(C)C)C(C)C>CC(CC)CO>[NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([NH:10][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:9]=1)[C:5]#[N:6]
Reactant: N#Cc1cc(N)cc(N)c1
Reactant: ClCCN1CCCCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC(C)CO
Product: N#Cc1cc(N)cc(NCCN2CCCCC2)c1
Yield: 80 %

Procedure:
3,5-Diaminobenzonitrile prepared from step A of example 19 (511 mg, 3.84 mmol), 1-(2-chloroethyl)piperidine hydrochloride (707 mg, 1 eq) and DIEA (1.97 mL, 3 eq) were refluxed in 50 mL of 2-methylbutan-1-ol for 24 h. The reaction mixture was then evaporated to give 751 mg of expected compound which was used in the next step without further purification. m/z (ESI) 245.3 [M+H]+.
Reaction SMILES: COCN[C:5]([C:7]1[C:12]([N:13]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([C:27]([F:30])([F:29])[F:28])[CH:21]=2)(=[O:19])=[O:18])COC)=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:6].I[C:32]1[C:33]2[CH:40]=[CH:39][N:38](COCC[Si](C)(C)C)[C:34]=2[N:35]=[CH:36][N:37]=1.CO.Cl>C1COCC1.C([Mg]Cl)(C)C>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([S:17]([NH:13][C:12]2[C:7]([C:5]([C:32]3[C:33]4[CH:40]=[CH:39][NH:38][C:34]=4[N:35]=[CH:36][N:37]=3)=[O:6])=[N:8][CH:9]=[CH:10][CH:11]=2)(=[O:18])=[O:19])=[CH:21][C:22]=1[C:27]([F:29])([F:28])[F:30]
Reactant: COCNC(=O)c1ncccc1N(COC)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: C[Si](C)(C)CCOCn1ccc2c(I)ncnc21
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: O=C(c1ncccc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)c1ncnc2[nH]ccc12

Procedure:
Prepared from 248 mg (0.53 mmol) of 3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylic acid methoxymethyl-amide, 239 mg (0.58 mmol) of 90% 4-iodo-7-(2-trimethylsilanyl-ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine dissolved in 2 mL THF with 0.32 mL of 2 M isopropylmagnesium chloride solution in THF added. All of the resulting intermediate ketone was used in the second step with 4 mL methanol and 4 mL 6N hydrochloric acid mixture to give after purification 29 mg of the final product as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.[NH:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16](=[O:18])[CH3:17])[CH2:11][CH2:10]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:8][C:4]1[CH:3]=[C:2]([N:9]2[CH2:14][CH2:13][CH:12]([NH:15][C:16](=[O:18])[CH3:17])[CH2:11][CH2:10]2)[CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)NC1CCNCC1
Reactant: Brc1cccc(Br)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)NC1CCN(c2cccc(Br)c2)CC1
Temperature: 80 °C
Yield: 79.3 %

Procedure:
A mixture of 1,3-dibromobenzene (7.98 mL, 49.2 mmol), N-(4-piperidyl)acetamide (7.00 g, 49.2 mmol), Pd2(dba)3 (2.25 g, 2.46 mmol), (rac)-BINAP (2.30 g, 3.69 mmol) and sodium tert-butoxide (5.68 g, 59.1 mmol) in toluene (492 mL) was heated at 80° C. for 17 hours under nitrogen. After cooling to room temperature, the mixture was diluted with EtOAc and filtered through a Celite pad. The combined filtrate and washings were concentrated. The residue was purified by silica gel column chromatography (hexane/AcOEt=50:50 to 0:100) to afford the desired product (11.6 g, 80%) as pale orange solid.
Reaction SMILES: C([O:5][C:6](=[O:29])[CH2:7][C:8]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:17][CH:16]=1)([OH:12])[CH:9]([CH3:11])[CH3:10])(C)(C)C.[OH-].[Li+]>CO.O>[CH2:22]([O:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][CH2:13][C:8]([OH:12])([CH:9]([CH3:10])[CH3:11])[CH2:7][C:6]([OH:29])=[O:5])=[CH:16][CH:17]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)C(O)(CCc1ccc(OCc2ccccc2)cc1)CC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)C(O)(CCc1ccc(OCc2ccccc2)cc1)CC(=O)O

Procedure:
The title compound was prepared by dissolving 3-[2-(4-benzyloxy-phenyl)ethyl]-3-hydroxy-4-methyl-pentanoic acid tert-butyl ester (28 g, 70.3 mmol) from Example QQQQ in MeOH (150 mL). Lithium hydroxide (5.9 g, 140.6 mmol) in water (50 mL) was added and the reaction heated to reflux for 5 hours, cooled and pumped to dryness under vacuum. The product was partitioned between water and Et2O. The aqueous layer was decanted, acidified with 1N HCL, and the precipitate was filtered and dried under vacuum to give the title compound (mp 97°-98° C.).
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:7]=[CH:8][C:9]2[N:15]([CH3:16])[C:14](=[O:17])[CH:13]3[CH2:18][CH2:19][CH2:20][N:12]3[CH2:11][C:10]=2[CH:21]=1.Cl.[C:23](=O)([O-])[O-:24].[Na+].[Na+]>O.CO>[CH3:23][O:24][C:6]1[CH:7]=[CH:8][C:9]2[N:15]([CH3:16])[C:14](=[O:17])[CH:13]3[CH2:18][CH2:19][CH2:20][N:12]3[CH2:11][C:10]=2[CH:21]=1
Reactant: CN1C(=O)C2CCCN2Cc2cc(N)ccc21
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc2c(c1)CN1CCCC1C(=O)N2C
Reaction time: 1 h

Procedure:
A solution of 3.5 g. of sodium nitrite in 30 ml. of water is added over 1 hour at 48°-50°C. to a solution of 11.5 g. of 7-amino-1,2,3,5,10,11a-hexahydro-10-methyl-11H- pyrrolo[2,1-c] [1,4]benzodiazepin-11-one in 20 ml. of concentrated hydrochloric acid and 500 ml. of methanol. The reaction mixture is held at this temperature for 1 hour longer, diluted with an equal volume of water, neutralized with sodium carbonate and concentrated under reduced pressure to remove the methanol. The aqueous residue is extracted with benzene and the benzene layer is concentrated to remove the crude 1,2,3,5,10,11a-hexahydro-7-methoxy-10-methyl-11H- pyrrolo[2,1-c] [1,4]benzodiazepin-11-one. Further purification is by partition chromatography on a diatomaceous earth column using a heptane/methyl cellosolve solvent system.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[OH:15])(=[O:3])[CH3:2].Cl[CH2:17][C:18]([NH2:20])=[O:19].C(=O)([O-])[O-].[Ca+2].[I-].[K+]>CC(C)=O.O>[C:1]([NH:4][CH2:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[O:15][CH2:17][C:18]([NH2:20])=[O:19])(=[O:3])[CH3:2]
Reactant: CC(=O)NCc1cc([N+](=O)[O-])ccc1O
Reactant: NC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Agent: [I-]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)NCc1cc([N+](=O)[O-])ccc1OCC(N)=O
Temperature: 25 °C
Yield: 71.8 %

Procedure:
131.4 g of 2-acetylaminomethyl-4-nitrophenol, 64.4 g of chloroacetamide, 86.4 g of calcium carbonate and 57.1 g of potassium iodide in 800 ml of acetone are heated under reflux for four hours. Subsequently the reaction mixture is cooled to room temperature and poured into 1300 ml of water. The resulting precipitate is filtered, washed with water and subsequently dried. 120 g of a yellow product are obtained having a melting point of from 236 to 240° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:21]=[CH:22][CH:23]=1)[CH:7]=[C:8]1[S:12][C:11](=[S:13])[N:10](C2C=CC=CC=2)[C:9]1=[O:20])([O-:3])=[O:2].C(N1C(=O)C(=CC2C=CC=C([N+]([O-])=O)C=2)SC1=S)C.C(N1C(=O)C(=CC2C=CC([N+]([O-])=O)=CC=2[N+]([O-])=O)SC1=S)C.[N+](C1C=CC=CC=1C=C1SC(=S)N(C2C=CC=CC=2)C1=O)([O-])=O.ClC1C=C([N+]([O-])=O)C2N=NNC=2C=1.CN(C)C1C=CC(N=CC2SC3C=CC=CC=3N=2)=CC=1.[Cl-].NC1C2C(=[N+](C)C3C(N=2)=CC=CC=3)C=C(N)C=1.[I-].S1C2C=CC=CC=2N=C1N1C(C2C=CC=CC=2)=CC(C2C=CC=CC=2)=CC1C=CC1C=CC(N(C)C)=CC=1.[Cl-].C1(N2N(C3C=CC=CC=3)N=C(C3C=CC=CC=3)[NH2+]2)C=CC=CC=1.[Cl-].IC1C=CC(N2N(C3C=CC([N+]([O-])=O)=CC=3)N=C(C3C=CC=CC=3)[NH2+]2)=CC=1.COS([O-])(=O)=O.C[N+]1C2C(=CC=CC=2[N+]([O-])=O)C=CC=1.C(N1C2C=CC=CC=2SC1=CC=CC=C1C(=O)C(=O)C(=CC=CC=C2N(CC)C3C=CC=CC=3S2)C(=O)C1=O)C>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:21]=[CH:22][CH:23]=1)[CH:7]=[C:8]1[S:12][C:11](=[S:13])[NH:10][C:9]1=[O:20])([O-:3])=[O:2]
Reactant: O=C1C(=Cc2cccc([N+](=O)[O-])c2)SC(=S)N1c1ccccc1
Agent: CCN1C(=CC=CC=c2c(=O)c(=O)c(=CC=CC=C3Sc4ccccc4N3CC)c(=O)c2=O)Sc2ccccc21
Agent: CCN1C(=O)C(=Cc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])SC1=S
Agent: CCN1C(=O)C(=Cc2cccc([N+](=O)[O-])c2)SC1=S
Product: O=C1NC(=S)SC1=Cc1cccc([N+](=O)[O-])c1

Procedure:
5-m-nitrobenzylidene-3-phenylrhodanine; 3-ethyl-5-m-nitrobenzylidenerhodanine; 3-ethyl-5-(2,4-dinitrobenzylidene)rhodanine; 5-o-nitrobenzylidene-3-phenylrhodanine; 6-chloro-4-nitrobenzotriazole; 2-(p-dimethylaminophenyliminomethyl)-benzothiazole ethoethylsulfate; 1,3-diamino-5-methylphenazinium chloride; 4-nitro-6-chlorobenzotriazole; anhydro-2-p-dimethylaminophenyliminomethyl-6-nitro-3-(4-sulfobutyl)benzothiazoline hydroxide; 1-(2-benzothiazolyl)-2-(p-dimethylaminostyryl)-4,6-diphenylpyridine iodide; 1,3-diethyl-5-[1,3-neopentylene-6-(1,3,3-trimethyl-2-indolinylidene)-2,4-hexadienylidene]-2-thiobarbituric acid; 2,3,5-triphenyl-2H-tetrazolium chloride; 2-(4-iodophenyl)-3-(4-nitrophenyl)-5-phenyl-tetrazolium chloride; 1-methyl-8-nitroquinolinium methylsulfate; 3,6-bis[4-(3-ethyl-2-benzothiazolinylidene)-2-butenylidene]-1,2,4,5-cyclohexanetetrone; and the like. The proportion of these electron acceptors added can range from about 100 mg to 2 g per 1 mole of silver halide.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH3:8])[C:6]=1[NH2:7].C([O-])([O-])=O.[K+].[K+].O.[C:16]([O:19][CH2:20][C:21](Cl)=[O:22])(=[O:18])[CH3:17]>C(Cl)Cl>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH3:8])[C:6]=1[NH:7][C:21](=[O:22])[CH2:20][O:19][C:16](=[O:18])[CH3:17]
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1csc(C)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CC(=O)OCC(=O)Nc1c(C)csc1C

Procedure:
To 12.7 g (0.1 mol) of 2,4-dimethyl-3-aminothiophene, 13.8 g (0.1 mol) of K2CO3, 20 ml of water and 150 ml of methylene chloride are added dropwise at ambient temperature 15 g (0.11 mol) of acetoxyacetyl chloride.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=2)[C:31]([OH:33])=O)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:37]1([NH2:40])[CH2:39][CH2:38]1>>[CH:37]1([NH:40][C:31](=[O:33])[C:30]2[CH:34]=[CH:35][CH:36]=[C:28]([S:27][CH2:26][C:16]3[C:17]4[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=4[CH:23]=[CH:24][C:15]=3[O:14][C@@H:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:6][N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)[CH:29]=2)[CH2:39][CH2:38]1
Reactant: O=C(O)c1cccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Reactant: NC1CC1
Product: O=C(NC1CC1)c1cccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Yield: 96.7 %

Procedure:
Using the method in Example 172, 3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and cyclopropylamine (17 mg, 0.30 mmol, 0.6M in DMF) were combined to give 52 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 538 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[F:17][C:18]1([F:28])[O:22][C:21]2[CH:23]=[CH:24][CH:25]=[C:26]([NH2:27])[C:20]=2[O:19]1>>[F:28][C:18]1([F:17])[O:22][C:21]2[CH:23]=[CH:24][CH:25]=[C:26]([NH:27][C:2]3[CH:11]=[CH:10][N:9]=[C:8]4[C:3]=3[C:4]3[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=3[C:6](=[O:12])[NH:7]4)[C:20]=2[O:19]1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Reactant: Nc1cccc2c1OC(F)(F)O2
Product: O=c1[nH]c2nccc(Nc3cccc4c3OC(F)(F)O4)c2c2ccccc12
Yield: 77.2 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 188 using Compound 83 (100 mg, 0.43 mmol) and 2,2-difluoro-benzo[1,3]dioxol-4-ylamine (150 mg, 0.87 mmol) to provide 196 (122 mg, 77% yield) as a white solid. LC-MS (M+H=368, obsd.=368).
Reaction SMILES: [N:1]#[N:2].[CH2:3]([O:5][C:6]([CH:8]([NH:18][C@H:19]([C:31]([OH:33])=[O:32])[CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:9][C:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])[CH3:4].N#N.C(C(N[C@H](C(O)=O)CCCCN)CCC1C=CC=CC=1)(O)=O>[Ni].[Pd]>[N:1]#[N:2].[CH2:3]([O:5][C:6]([CH:8]([NH:18][C@H:19]([C:31]([OH:33])=[O:32])[CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:30])[C:26]([F:27])([F:28])[F:29])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])[CH3:4]
Reactant: CCOC(=O)C(CC(=O)c1ccccc1)N[C@@H](CCCCNC(=O)C(F)(F)F)C(=O)O
Agent: [Ni]
Agent: [Pd]
Agent: N#N
Product: CCOC(=O)C(CCc1ccccc1)N[C@@H](CCCCNC(=O)C(F)(F)F)C(=O)O

Procedure:
The N2 -(1-carboxy-3-oxo-3-phenylpropyl)-L-lysine derivative can be subjected to catalytic hydrogenolysis proceeding gently in water, an alcohol or a polar protic solvent such as acetic acid in the presence of a suitable amount of an acid such as sulfuric acid, hydrochloric acid or formic acid to give the N2 -(1-carboxy-3-phenylpropyl)-L-lysine derivative in a high yield. In catalytic hydrogenolysis, palladium, Raney nickel, and the like are examples of suitable catalysts. For instance, when N2 -[1-ethoxycarbonyl-3-oxo-3-phenylpropyl]-N6 -trifluoroacetyl-L-lysine is subjected to catalytic hydrogenolysis, the lysine derivative is hydrogenated in an alcohol (such as ethanol) as the solvent in the presence of the acid at a temperature of 0° C. to 60° C., preferably from 5° C. to 40° C. for several to 24 hours by using palladium/carbon as the catalyst to give almost quantitatively N2 -(1-ethoxycarbonyl-3-phenylpropyl)-N6 -trifluoroacetyl-L-lysine. After completing the hydrogenation, the catalyst is removed from the reaction mixture, the acid of the resulting solution is neutralized with an alkali, from which the solvent is distilled away, and then the desired compound having the (S,S)-configuration can be isolated in a usual manner such as extraction. If necessary, recrystallization can be conducted from the obtained reaction mixture.
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[Br:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:22][N:21]=[C:20]([CH3:23])[C:19]=2[CH2:24][CH2:25]OS(C)(=O)=O)=[CH:14][CH:13]=1>CCO.CCOC(C)=O.O>[CH2:1]([S:8][CH2:25][CH2:24][C:19]1[C:20]([CH3:23])=[N:21][O:22][C:18]=1[C:15]1[CH:16]=[CH:17][C:12]([Br:11])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CCOS(C)(=O)=O
Reactant: SCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: Cc1noc(-c2ccc(Br)cc2)c1CCSCc1ccccc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Benzyl mercaptan (0.06 mL, 0.45 mmol) and sodium hydroxide (0.030 g, 0.76 mmol) were combined in EtOH. Methanesulfonic acid 2-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]ethyl ester (0.161 g, 0.45 mmol) was added and the reaction was stirred at 70° C. for 2 hours. The mixture was diluted with EtOAc and H2O and separated. The organic layer was washed with H2O and brine, dried over Na2SO4, filtered, and concentrated to give the title compound.
Reaction SMILES: C(N(CC)CC)C.[SH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([NH2:18])(=[O:17])=[O:16].Br[CH2:20][CH2:21][F:22]>O1CCCC1>[F:22][CH2:21][CH2:20][S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([NH2:18])(=[O:17])=[O:16]
Reactant: FCCBr
Reactant: NS(=O)(=O)c1ccccc1S
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NS(=O)(=O)c1ccccc1SCCF
Temperature: 0 °C
Reaction time: 6 h
Yield: 571.9 %

Procedure:
A mixture of 29 g of the 2-mercaptophenylsulfonamide triethylamine salt obtained in accordance with Example H6 and 2 g of 2-bromo-1-fluoroethane in 130 ml of tetrahydrofuran is stirred for 6 hours at a temperature of +40° C. to +45° C. The reaction mixture is then cooled to 0° C. and filtered. The filtrate is evaporated and the resulting residue is crystallized from methylene dichloride to give 21.2 g (90.2% of theory) of 2-(2-fluoroethylthio)-phenylsulfonamide having a melting point of +84° to +85° C.
Reaction SMILES: [CH2:1](Br)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:10]1([CH:16]2[CH2:21][NH:20][CH2:19][C:18]3[S:22][CH:23]=[CH:24][C:17]2=3)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:1]([N:20]1[CH2:21][CH:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:17]2[CH:24]=[CH:23][S:22][C:18]=2[CH2:19]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: c1ccc(C2CNCc3sccc32)cc1
Reactant: BrCCc1ccccc1
Product: c1ccc(CCN2Cc3sccc3C(c3ccccc3)C2)cc1
Yield: 59 %

Procedure:
Phenethyl bromide is condensed with 4-phenyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine (Example 3), according to the procedure of Example 8. Base: M.p. = 110° C; yield: 59%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:3]=1.Cl.[NH:21]1[CH2:26][CH2:25][CH2:24][CH:23]([CH2:27][NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:22]1.C(N(CC)CC)C>C(Cl)Cl>[OH:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:4]1[N:3]=[C:2]([N:21]2[CH2:26][CH2:25][CH2:24][CH:23]([CH2:27][NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:22]2)[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=1
Reactant: O=C(NCC1CCCNC1)OCc1ccccc1
Reactant: Cc1ccc2c(Cl)nc(-c3ccccc3O)nc2c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(N3CCCC(CNC(=O)OCc4ccccc4)C3)nc(-c3ccccc3O)nc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.5 %

Procedure:
2-(4-Chloro-7-methylquinazolin-2-yl)phenol (1.5 g, 5.54 mmol) was suspended in anhydrous CH2Cl2 (15 μL) and cooled to 0° C. under an N2 atmosphere. A mixture of benzyl (piperidin-3-yl)methylcarbamate hydrochloride (1.73 g, 6.09 mmol) in CH2Cl2 (20 mL), and triethylamine (23 mL, 16.67 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature, and the reaction was complete after one hour. It was then partitioned between CH2Cl2/H2O, and separated, and the organic phase was dried over Na2SO4, filtered, and concentrated to an orange solid. Purification by silica gel chromatography using 98% CH2Cl2/2% EtOAc gave benzyl (1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate as a bright yellow solid (1.75 g, 66%). LC/MS: m/z 483.5 (M+H)+ at 2.81 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15])[CH:7]=[CH:6]2)=[CH2:2].C(Cl)(Cl)Cl.[Br].BrBr.N.[NH2-].[Na+]>C(Cl)(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15])[CH:7]=[CH:6]2)#[CH:2]
Reactant: C=Cc1ccc2cc(C(C)C(=O)OC)ccc2c1
Agent: BrBr
Agent: N
Agent: [Br]
Solvent: ClC(Cl)Cl
Product: C#Cc1ccc2cc(C(C)C(=O)OC)ccc2c1

Procedure:
To a mixture of 25.2 g. of methyl 6-vinyl-2-naphthyl-α-methylacetate and 300 ml. of chloroform, a 5% bromine chloroform solution is added at -10° C until the bromine color persists. The mixture is then added to 200 ml. of ammonia containing 15 g. of sodium amide. The mxiture is allowed to evaporate; the residue is extracted with diethyl ether. The extracts are combined, washed to neutrality with water, dried, and evaporated to yield methyl 6-ethynyl-2-naphthyl-α-methylacetate.