Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.C(S[C:6](=[NH:47])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][N:14]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:8]=1)C.[CH3:48][O:49][C:50]1[CH:55]=[CH:54][C:53]([NH2:56])=[CH:52][CH:51]=1>C(Cl)(Cl)Cl>[CH2:15]([N:14]([CH2:13][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[C:6]([NH:56][C:53]1[CH:54]=[CH:55][C:50]([O:49][CH3:48])=[CH:51][CH:52]=1)=[NH:47])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCC)Cc1cccc(C(=N)SCC)c1
Reactant: COc1ccc(N)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCC)Cc1cccc(C(=N)Nc2ccc(OC)cc2)c1
Yield: 73 %

Procedure:
A mixture of ethyl-m-[N,N-di(n-hexadecyl)aminomethyl]-thiobenzimidate dihydrochloride (1.074 g., 1.5 mmoles), p-anisidine (369 mg., 3.0 mmoles) and chloroform (10 ml.) was held at room temperature for sixteen hours. It was then diluted to 400 ml. with chloroform, washed with 1N HCl (2 × 50 ml.), dried (Na2SO4) and evaporated in vacuo to a foam. The foam was crystallized from 1,2-dimethoxyethane [868 mg., 73% yield, Rf 0.64 (4:1, benzene:ethanol on silicic acid), m.p.-forms a gel at 84°-86° C⟧
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]1([CH3:19])[C:15]2[C:10](=[CH:11][C:12]([CH3:16])=[CH:13][CH:14]=2)[C:9]([CH3:18])([CH3:17])[CH2:8][CH2:7]1.[C:20](Cl)(=[O:22])[CH3:21]>ClCCCl>[C:20]([C:13]1[C:12]([CH3:16])=[CH:11][C:10]2[C:9]([CH3:18])([CH3:17])[CH2:8][CH2:7][C:6]([CH3:19])([CH3:5])[C:15]=2[CH:14]=1)(=[O:22])[CH3:21]
Reactant: Cc1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
To a suspension of aluminum chloride (0.96 g, 7.17 mmol) in 1 mL of 1,2-dichloroethane under argon at room temperature was added a solution of 1,2,3,4-tetrahydro-1,1,4,4,6-pentamethylnaphthalene 29 (1.2 g, 5.93 mmol) and acetyl chloride (0.51 g, 6.52 mmol) in 9 mL of 1,2-dichloroethane. The reaction mixture was stirred for 1 h and then was poured onto ice water and extracted with 40% ethyl acetate/hexane. The combined organic layers were washed with saturated aqueous NaHCO3 and brine. The solution was. dried over anhydrous MgSO4, filtered through a plug of silica gel, and concentrated to afford a white solid 39 (1.45 g, 99%): m.p. 54°-57° C.; Rf 0.62 (10% ethyl acetate/hexane). The structure of the product was also confirmed using IR, 1H NMR and mass spectroscopy.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])=O)=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:38])=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:28]=[CH:27][C:5]([C:6](=[S:38])[NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1ccc(S(=O)(=O)Nc2ccccc2NC(=O)c2ccc(F)cc2)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(S(=O)(=O)Nc2ccccc2NC(=S)c2ccc(F)cc2)cc1
Temperature: 100 °C
Yield: 147.6 %

Procedure:
A mixture of 549 mg (1.371 mmol) of the compound produced in Example 82, 333 mg (0.823 mmol) of Lawesson reagent and 10 ml of toluene was heated at 100° C. After the concentration, the residue was purified by silica gel column chromatography to obtain 506 mg of the title compound.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH2:35]([NH:37][C:38]([NH:40][CH:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)=[O:39])[CH3:36]>>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:44]4[CH2:45][CH2:46][CH:41]([NH:40][C:38]([NH:37][CH2:35][CH3:36])=[O:39])[CH2:42][CH2:43]4)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: CCNC(=O)NC1CCNCC1
Product: CCNC(=O)NC1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)CC1

Procedure:
1-(1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidin-4-yl)-3-ethyl-urea was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 1-Ethyl-3-piperidin-4-yl-urea following General Procedure B.
Reaction SMILES: C([NH:8][CH:9]([CH2:23][CH3:24])[CH:10]([C:12]1[O:13][C:14]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[N:15][N:16]=1)[OH:11])(OC(C)(C)C)=O.[C:25]([OH:31])([C:27]([F:30])([F:29])[F:28])=[O:26]>C(Cl)Cl>[OH:31][C:25]([C:27]([F:30])([F:29])[F:28])=[O:26].[NH2:8][CH:9]([CH2:23][CH3:24])[C:10]([C:12]1[O:13][C:14]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[N:15][N:16]=1)=[O:11]
Reactant: CCC(NC(=O)OC(C)(C)C)C(O)c1nnc(-c2ccncc2)o1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(N)C(=O)c1nnc(-c2ccncc2)o1
Reaction time: 1 h

Procedure:
2-Bocamino-1-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)-butan-1-ol (334 mg, 1 mmol) and MeCl2 (5 ml) were mixed and TFA (0.5 ml) was added at room temperature. After stirring for 1 hour, the solvent and excess TFA were removed under vacuum to produce 350 mg of 2-amino-1-(5-pyridin-4-yl-[1,3,4]oxadiazol-2-yl)-butan-1-one TFA salt.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:13]([C:14]2[CH2:18][CH:17]([CH3:19])[O:16][N:15]=2)=[C:12]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:11]=[CH:10][C:5]=1[C:6]([O:8]C)=[O:7]>CO>[Cl:3][C:4]1[C:13]([C:14]2[CH2:18][CH:17]([CH3:19])[O:16][N:15]=2)=[C:12]([S:20]([CH3:23])(=[O:21])=[O:22])[CH:11]=[CH:10][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C2=NOC(C)C2)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1CC(c2c(S(C)(=O)=O)ccc(C(=O)O)c2Cl)=NO1
Temperature: 25 °C
Reaction time: 48 h
Yield: 92.3 %

Procedure:
A solution of 3.52 g (88 mmol) of sodium hydroxide in 100 ml of methanol was slowly added dropwise to a mixture of 15.00 g (45 mmol) of methyl 2-chloro-3-(5-methyl-4,5-dihydroisoxazol-3-yl)-4-methylsulfonylbenzoate and 200 ml of methanol. The suspension was stirred at room temperature for 48 hours. The solvent was distilled off, the residue was taken up in water and the aqueous phase was washed three times with ethyl acetate. The aqueous phase was acidified with hydrochloric acid and extracted three times with ethyl acetate. The combined organic phases were subsequently washed neutral with water, dried and concentrated. 13.20 g (92% of theory) of 2-chloro-3-(5-methyl-4,5-dihydroisoxazol-3-yl)-4-methylsulfonylbenzoic acid were obtained.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:14]2[C:9](=[CH:10][C:11]([Cl:15])=[CH:12][CH:13]=2)[NH:8][N:7]=1)=[O:4].[CH3:16][N:17]([CH3:22])[CH2:18][CH2:19][CH2:20][NH2:21]>C(#N)C>[Cl:15][C:11]1[CH:10]=[C:9]2[C:14]([C:6]([NH:5][C:3](=[O:4])[CH2:2][NH:21][CH2:20][CH2:19][CH2:18][N:17]([CH3:22])[CH3:16])=[N:7][NH:8]2)=[CH:13][CH:12]=1
Reactant: CN(C)CCCN
Reactant: O=C(CCl)Nc1n[nH]c2cc(Cl)ccc12
Solvent: CC#N
Product: CN(C)CCCNCC(=O)Nc1n[nH]c2cc(Cl)ccc12

Procedure:
The process is performed as in Example 75, starting with 500 mg of 2-chloro-N-(6-chloro-1H-indazol-3-yl)acetamide, 15 cm3 of acetonitrile and 0.77 cm3 of 3-(dimethylamino)propylamine. The reaction medium is refluxed for 3 hours and then concentrated to dryness under reduced pressure (2 kPa; 50° C.); the crude product is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with a methylene chloride/methanol/aqueous ammonia mixture (90/10/1 by volume). The fractions containing the expected product are combined, concentrated under reduced pressure and then dried (90 Pa; 45° C.) to give 300 mg of N-(6-chloro-1H-indazol-3-yl)-2-[[3-(dimethylamino)propyl]amino]acetamide in the form of light-brown foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[C:13]1[N:18]=[CH:17][N:16]=[C:15]([NH:19][CH:20]([CH:22]2[CH2:24][CH2:23]2)[CH3:21])[C:14]=1[NH2:25].[C:26](OCC)(=[O:30])[C:27]([CH3:29])=O>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:11])([F:12])[F:10])[CH:5]=[CH:4][C:3]=1[C:13]1[C:14]2[N:25]=[C:27]([CH3:29])[C:26](=[O:30])[N:19]([CH:20]([CH:22]3[CH2:24][CH2:23]3)[CH3:21])[C:15]=2[N:16]=[CH:17][N:18]=1
Reactant: CC(Nc1ncnc(-c2ccc(OC(F)(F)F)cc2Cl)c1N)C1CC1
Reactant: CCOC(=O)C(C)=O
Solvent: CCO
Product: Cc1nc2c(-c3ccc(OC(F)(F)F)cc3Cl)ncnc2n(C(C)C2CC2)c1=O
Reaction time: 18 h

Procedure:
6-(2-Chloro-4-trifluoromethoxy-phenyl)-N4-(1-cyclopropyl-ethyl)-pyrimidine-4,5-diamine (0.20 g, 0.52 mmol) was diluted in ethanol (6 ml) and ethyl pyruvate was added (0.58 ml, 5.2 mmol). The mixture was stirred for 18 hours at which time the solution was concentrated. After concentrating the solution the product was purified by reverse phase HPLC to yield 4.5 mg of 4-(2-chloro-4-trifluoromethoxy-phenyl)-8-(1-cyclopropyl-ethyl)-6-methyl-8H-pteridin-7-one (Example 1062). 1H NMR (300 MHz, CDCl3) δ ppm 8.99 (s, 1 H), 7.50 (d, J=8.79 Hz, 1 H), 7.39 (d, J=1.10 Hz, 1 H), 7.26 (dd, J=8.79, 1.10 Hz, 1 H), 4.91 (m, 1 H), 2.49 (s, 3 H), 1.71 (d, J=7.32, 3 H), 0.69 (m, 2 H), 0.41 (m, 2 H), 0.22 (m, 1 H). MS (EI) 425.2 [(M+H)+, 100].
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[CH:25]([CH:27]1[CH2:30][CH2:29][CH2:28]1)[OH:26])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[H-].[Na+].[CH2:42](I)[CH3:43]>C1COCC1>[F:39][C:2]([F:1])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:33]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[CH:25]([CH:27]1[CH2:28][CH2:29][CH2:30]1)[O:26][CH2:42][CH3:43])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C(O)C2CCC2)n1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)C1CCC1
Reaction time: 2 h
Yield: 86 %

Procedure:
To a solution of (2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-cyclobutyl-methanol (23 mg; 0.041 mmol) in THF (1.5 mL) at 0° C. was added sodium hydride (15 mg; 0.375 mmol; 60% dispersion in mineral oil). After stirring at room temperature for 30 minutes ethyl iodide (0.05 mL; 0.625 mmol) was added. Reaction was stirred for 2 hours. More sodium hydride (15 mg; 0.375 mmol; 60% dispersion in mineral oil) and iodoethane (0.05 mL; 0.625 mmol) were added. Reaction stirred for 72 hours. Reaction was quenched with 2 drops of water. The reaction was filtered over a 1 g Bakerbond silica cartridge (Mallinkrodt Baker Inc. Phillipsburg, N.J.) (eluted with ethyl acetate). The crude was purified by RediSep column (Teledyne Isco Inc., Lincoln Nebr.) (eluted with 5-30% ethyl acetate in heptane) to give 21 mg (87% yield) of a gum. MS (ES+): Calc: 595.5, Found: 596.4 (M+H). 1H NMR (400 MHz, CDCl3) δ ppm 7.78 (s, 1H), 7.65 (s, 2H), 7.53 (s, 2H), 7.33 (s, 1H), 4.83 (q, J=16.18 Hz, 2H), 4.73 (q, J=16.18, 14.11 Hz, 2H), 4.42 (d, J=6.64 Hz, 1H), 4.22 (s, 3H), 3.20 (m, J=7.05, 6.64 Hz, 2H), 2.49 (m, J=7.88, 7.05 Hz, 1H), 2.07-1.57 (m, 6H), 1.11 (t, J=7.05 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:12][C:13]([OH:15])=[O:14].[CH3:16][C:17](N=C([O-])N(C(C)C)C(C)C)([CH3:19])[CH3:18]>C(Cl)Cl>[CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:12][C:13]([O:15][C:17]([CH3:19])([CH3:18])[CH3:16])=[O:14]
Reactant: Cc1c(CC(=O)O)ccc2c1COC2=O
Reactant: CC(C)N(C([O-])=NC(C)(C)C)C(C)C
Solvent: ClCCl
Product: Cc1c(CC(=O)OC(C)(C)C)ccc2c1COC2=O
Temperature: 25 °C

Procedure:
To a solution of (4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetic acid (100 mg, 0.48 mmol) in anhydrous DCM (10 mL) was added 1,1-dimethylethyl-N,N-bis(1-methylethyl)imidocarbamate (485 mg, 2.50 mmol) dropwise at 0° C. under N2. Then the mixture was stirred at r.t. over night. The mixture was filtered and the filtrate was washed with 2N HCl and brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative TLC to give 1,1-dimethylethyl (4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetate. 1H-NMR (400 MHz, CDCl3) δ ppm 7.70 (d, J=7.8 Hz, 1H), 7.38 (d, J=7.0 Hz, 1H), 5.25 (s, 2H), 3.67 (s, 3H), 2.27 (s, 3H), 1.44 (s, 9H).
Reaction SMILES: [O:1]=[S:2]1(=[O:16])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1.Cl.[CH:18]1([C:21]2[C:22]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=2)[CH2:20][CH2:19]1>>[CH:18]1([C:21]2[C:22]([N:28]3[CH2:33][CH2:32][N:31]([C:11]([C:10]4[CH:9]=[CH:8][C:7]([N:3]5[CH2:4][CH2:5][CH2:6][S:2]5(=[O:1])=[O:16])=[CH:15][CH:14]=4)=[O:13])[CH2:30][CH2:29]3)=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=2)[CH2:19][CH2:20]1
Reactant: O=C(O)c1ccc(N2CCCS2(=O)=O)cc1
Reactant: Cc1cnc(N2CCNCC2)c(C2CC2)c1
Agent: Cl
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3)CC2)c(C2CC2)c1
Yield: 9.5 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoic acid (241 mg) described in Preparation Example 16 and 1-(3-cyclopropyl-5-methylpyridin-2-yl)piperazine hydrochloride (254 mg) described in Preparation Example 85 and by the reaction and treatment in the same manner as in Example 86, the title compound (42 mg) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([NH:23][C@@H:24]1[C:30](=[O:31])[N:29]([CH2:32][C:33]([O:35]C(C)(C)C)=[O:34])[C:28]2[CH:40]=[CH:41][CH:42]=[CH:43][C:27]=2[S:26][CH2:25]1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22])=[O:5])[CH3:2].C(OCC)(=O)C.[ClH:50]>>[ClH:50].[CH2:1]([O:3][C:4]([C@@H:6]([NH:23][C@@H:24]1[C:30](=[O:31])[N:29]([CH2:32][C:33]([OH:35])=[O:34])[C:28]2[CH:40]=[CH:41][CH:42]=[CH:43][C:27]=2[S:26][CH2:25]1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:13](=[O:22])[C:14]2=[CH:21][CH:20]=[CH:19][CH:18]=[C:15]2[C:16]1=[O:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H](CCCCCN1C(=O)c2ccccc2C1=O)N[C@H]1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](CCCCCN1C(=O)c2ccccc2C1=O)N[C@H]1CSc2ccccc2N(CC(=O)O)C1=O
Reaction time: 1 h

Procedure:
In 5 ml of 5 N hydrogen chloride-ethyl acetate solution is dissolved 0.12 g of tert-butyl 3(R)-[1(S)-ethoxycarbonyl-6-phthalimidohexyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine -5-acetate, and the solution is left standing at room temperature for 1 hour. Petroleum ether (50 ml) is added to the solution and the deposited precipitate is dried under reduced pressure to give 0.1 g of 3(R)-[1(S)-ethoxycarbonyl-6-phthalimidohexyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid hydrochloride as a colorless powder.
Reaction SMILES: [F:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH3:16])([CH3:15])[C:5](=[O:14])[NH:6]2.[CH:17]1(O)[CH2:20][CH2:19][CH2:18]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.O>[CH:17]1([N:6]2[C:7]3[C:3](=[C:2]([F:1])[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=3)[C:4]([CH3:16])([CH3:15])[C:5]2=[O:14])[CH2:20][CH2:19][CH2:18]1
Reactant: CC1(C)C(=O)Nc2ccc([N+](=O)[O-])c(F)c21
Reactant: OC1CCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)C(=O)N(C2CCC2)c2ccc([N+](=O)[O-])c(F)c21
Reaction time: 5 h

Procedure:
To a solution of 4-fluoro-3,3-dimethyl-5-nitro-1,3-dihydro-2H-indol-2-one (300 mg), cyclobutanol (0.136 mL) and triphenylphosphine (702 mg) in THF (15 mL) was added dropwise diethyl azocarboxylate (40% toluene solution, 1.48 mL) at 0° C., and the mixture was stirred for 5 hr under a nitrogen atmosphere. To the reaction mixture was added water at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (200 mg).
Reaction SMILES: [CH3:1][C:2]([CH3:12])([O:4][C:5]([NH:7][CH2:8][C:9]([OH:11])=[O:10])=[O:6])[CH3:3].[CH2:13]([O:20][CH2:21]/[CH:22]=[CH:23]\[CH2:24]O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:14]1([CH2:13][O:20][CH2:21][CH:22]=[CH:23][CH2:24][O:10][C:9](=[O:11])[CH2:8][NH:7][C:5]([O:4][C:2]([CH3:12])([CH3:1])[CH3:3])=[O:6])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OC/C=C\COCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)OCC=CCOCc1ccccc1
Temperature: 0 °C

Procedure:
N-[(1,1-Dimethylethoxy)carbonyl]glycine (21.9 grams, 0.125 mol), cis-4-benzyloxy-2-buten-1-ol (25 mL, 0.15 mol), and 4-dimethylaminopyridine (1.5 grams, 0.013 mol) are dissolved in methylene chloride and stirred at 0° C. Then N,N-dicyclohexylcarbodiimide (31 grams, 0.15 mol) in 30 mL methylene chloride is added and the reaction is stirred at 0° C. for five minutes. The reaction is then stirred for an additional twelve hours at 25° C. Additional methylene chloride is added and the reaction is washed consecutively with 1 N HCl, sodium bicarbonate and then with brine. The organic extract is dried over magnesium sulfate and the solvent evaporated in vacuo to give an orange oil which is absorbed onto silica gel and applied to a dry silica column. The column is eluted with hexane/EtOAc (9:1) then with hexane/EtOAc (8:2) Product fractions are combined and dried in vacuo to give the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][S:8][C:9]2[CH:10]=[N:11][CH:12]=[C:13]([CH:17]=2)[C:14]([OH:16])=[O:15])=[CH:5][CH:4]=1.Cl.[CH3:21]O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8][C:9]2[CH:10]=[N:11][CH:12]=[C:13]([CH:17]=2)[C:14]([O:16][CH3:21])=[O:15])=[CH:18][CH:19]=1
Reactant: COc1ccc(CSc2cncc(C(=O)O)c2)cc1
Reactant: CO
Agent: Cl
Product: COC(=O)c1cncc(SCc2ccc(OC)cc2)c1

Procedure:
A solution of 2.02 g of 5-(p-methoxybenzylthio)nicotinic acid in hydrochloric acid-methanol is refluxed. The reaction mixture is concentrated. To the residue is added a mixture of chloroform and water. The mixture is extracted with chloroform. The chloroform layer is dried and evaporated to dryness. The resulting residue is recrystallized from isopropyl ether, giving methyl 5-(p-methoxybenzylthio)nicotinate melting at 72°-74° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH:11][NH:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:9]=O)=[CH:4][CH:3]=1.C(O)C[OH:21]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:13]([C:14]([O:16][CH2:17][CH2:18][OH:21])=[O:15])[NH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: OCCO
Reactant: CCOC(=O)CNC=C(C=O)c1ccc(Cl)cc1
Solvent: O
Product: O=C(OCCO)c1cc(-c2ccc(Cl)cc2)c[nH]1

Procedure:
2-(4-Chlorophenyl)-3-carbethoxymethylaminoacrylaldehyde (73.6 g.) was refluxed in 300 ml. of ethylene glycol for 10 minutes. The reaction mixture was cooled, diluted with 1 liter of water, product extracted into chloroform, treated with activated carbon and evaporated to solids. Trituration with ether gave crude product (8 g.). An additional quantity of crude product (7.5 g.) crystallized from the aqueous phase which had been standing. Recrystallization of the combined crude solids from chloroform gave 2-hydroxyethyl 4-(4-chlorophenyl)pyrrole-2-carboxylate (5 g., m.p. 128°-130° C.). The ether and chloroform mother liquors were combined and evaporated to yield an additional 40 g. of crude product.
Reaction SMILES: N([O-])=O.[Na+].N[C@H:6]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[C:13]([CH2:19][CH3:20])[CH:12]=1)[C:7]([OH:9])=[O:8].C([O:23]CC)C>O.OS(O)(=O)=O>[CH2:19]([C:13]1[CH:12]=[C:11]([CH2:10][C@@H:6]([OH:23])[C:7]([OH:9])=[O:8])[CH:16]=[CH:15][C:14]=1[CH2:17][CH3:18])[CH3:20]
Reactant: CCc1ccc(C[C@@H](N)C(=O)O)cc1CC
Reactant: CCOCC
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCc1ccc(C[C@@H](O)C(=O)O)cc1CC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 3.2 g (47 mmol) sodium nitrite in 20 mL water was slowly added dropwise with stirring to an ice-cooled mixture of 2.0 g (7.8 mmol) (R)-2-amino-3-(3,4-diethyl-phenyl)-propionic acid in 60 mL 0.5 M H2SO4. The reaction mixture was stirred for 3 h while cooling with ice and for 3 days at RT, combined with 80 mL diethyl ether, vigorously stirred and the organic phase is separated off. The aqueous phase was again extracted with 80 mL diethyl ether, the combined organic phases were dried and evaporated down under reduced pressure. The residue was purified by chromatography on silica gel and the product fractions were evaporated down under reduced pressure.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](OS(C(F)(F)F)(=O)=O)=[C:5]([O:17][CH3:18])[CH:4]=1)=[O:2].[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>CN(C)C=O>[CH3:18][O:17][C:5]1[CH:4]=[C:3]([CH:1]=[O:2])[CH:8]=[CH:7][C:6]=1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:20]([F:31])([F:30])[F:19]
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: COc1cc(C=O)ccc1OS(=O)(=O)C(F)(F)F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1-c1ccccc1C(F)(F)F
Temperature: 120 °C
Yield: 73.3 %

Procedure:
A stirred solution of trifluoromethanesulfonic acid 4-formyl-2-methoxy-phenyl ester of Step A (6.9 g, 22.1 mmol), 2-trifluoromethyl phenyl boronic acid (5.4 g, 28.6 mmol) and potassium phosphate (13.2 g, 62.2 mmol) in N,N-dimethylformamide (120 mL) was degassed with nitrogen, whereupon a catalytic amount (0.285 g) of [1,4-bis-(diphenylphosphine)butane]palladium (II) dichloride was added. The solution was heated to 120° C. for 5 hours, poured into water and extracted with ethyl acetate. The combined extracts were washed with water, dried over anhydrous magnesium sulfate and filtered through a plug of silica gel. Removal of the solvent provided the crude title compound (4.54 g) as an oil, which was used as such in the next step.