Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[CH:2]1.C(Cl)Cl.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]Cl)=[CH:16][CH:15]=1>CCOCC>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20][C:5]2[NH:1][CH:2]=[C:3]([C:6]([O:8][CH3:9])=[O:7])[CH:4]=2)=[CH:16][CH:15]=1
Reactant: ClSc1ccc(Cl)cc1
Reactant: COC(=O)c1cc[nH]c1
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)c1c[nH]c(Sc2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.1 %

Procedure:
Methyl pyrrole-3-carboxylate (2.5 g., 20 mmole) was dissolved in 35 ml. of methylene chloride. p-Chlorobenzenesulfenyl chloride (4.0 g., 22 mmoles) was added dropwise over approximately 2 minutes, and the reaction mixture was stirred at room temperature for 1 hour. Two volumes of ether were added, the mixture extracted twice with 20 ml. portions of water and the organic layer evaporated in vacuo. The resulting oil was chromatographed on 100 g. of silica gel with approximately 25 ml. fractions of the ethyl acetate-1/hexane-7 eluant collected. Fractions 19 to 36 were combined and concentrated to yield methyl 5-(4-chlorophenylthio)pyrrole-3-carboxylate (1.4 g., m.p. 122°-124° C.).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[C@@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][NH:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CC=CC=1.Cl[C:28]([O:30][C:31]1[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=1)=[O:29]>C1COCC1>[Si:1]([O:8][CH2:9][C@@H:10]1[C@@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][N:12]([C:28]([O:30][C:31]2[CH:32]=[CH:33][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:39][CH:40]=2)=[O:29])[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CNC[C@@H]1c1ccccc1
Reactant: COC(=O)c1ccc(OC(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(OC(=O)N2C[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](c3ccccc3)C2)cc1
Temperature: 25 °C

Procedure:
A 16.28 g portion of (3R,4S)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-phenylpyrrolidine and 18 ml of pyridine were dissolved in 100 ml of THF, and 14.6 g of methyl 4-[(chlorocarbonyl)oxy]benzoate (mfd. by Fluka) was added under ice cooling in one portion thereto in an atmosphere of argon. After 1Hour of stirring at room temperature, 2.5 g of methyl 4-[(chlorocarbonyl)oxy]benzoate was further added at room temperature. After 2Hours of further stirring, the reaction solution was concentrated under a reduced pressure. The residue was diluted with water and diisopropyl ether, the thus precipitated insoluble matter was removed by filtration, and then the filtrated was concentrated under a reduced pressure and the resulting residue was extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order and dried with anhydrous sodium sulfate. This was concentrated under a reduced pressure, and the thus obtained residue was purified by a silica gel column chromatography (chloroform-ethyl acetate) to obtain 23.80 g of 4-(methoxycarbonyl)phenyl (3R,4S)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-phenylpyrrolidine-1-carboxylate as a colorless oily substance.
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[CH:8][NH:9][CH:10]=[C:6]2[C:5](=[O:11])[N:4]([CH3:12])[C:3]1=[O:13].[H-].[Na+].C([CH:20]1[CH2:24]OS(=O)(=O)[N:21]1[C:27]([O-:29])=[O:28])(C)(C)C>C1COCC1>[C:6]([O:29][C:27](=[O:28])[NH:21][CH2:20][CH2:24][N:9]1[CH:10]=[C:6]2[C:7]([N:2]([CH3:1])[C:3](=[O:13])[N:4]([CH3:12])[C:5]2=[O:11])=[CH:8]1)([CH3:7])([CH3:10])[CH3:5]
Reactant: Cn1c(=O)c2c[nH]cc2n(C)c1=O
Reactant: CC(C)(C)C1COS(=O)(=O)N1C(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(=O)c2cn(CCNC(=O)OC(C)(C)C)cc2n(C)c1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1,3-Dimethyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione) (step 1) (4.43 g, 24.72 mmol) and sodium hydride (commercial) (60% dispersion in mineral oil) (1.286 g, 32.1 mmol) were degassed with nitrogen for 15 min. The reagents were then suspended in anhydrous THF (44.5 mL) and stirred for 15 mins at room temperature, then cooled to 0° C. (external). After 10 mins, a solution of tert-butyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (step 2) (6.07 g, 27.2 mmol) in anhydrous THF (44.5 mL) was charged in two portions (2×24 mL). After addition was complete, the ice-bath was removed and the reaction stirred at room temperature for 50 mins. The reaction was then quenched by addition of saturated NH4Cl solution (30 mL). The reaction mixture was diluted with water (30 mL), EtOAc (60 mL) and the layers separated. The aqueous layer was extracted with EtOAc (2×50 mL), saturated with NaCl (s) and extracted with MeCN (4×50 mL). The aqueous layer was evaporated to (˜20 mL) and extracted further with MeCN (3×50 mL). The combined organic layers were dried (Na2SO4) and filtered under reduced pressure and the solvent was evaporated. The resulting solid was adsorbed onto silica and purified via ISCO SiO2 125 g column eluting with 60-95% EtOAc/hexane. The fractions containing product were combined and evaporated to afford a white crystalline solid. The solid was dried under vacuum at 50° C. for 3 h. The title compound was afforded as a white crystalline solid.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][CH:11]([O:14][CH3:15])[CH2:12][NH2:13]>O>[CH:1](=[N:13][CH2:12][CH:11]([O:14][CH3:15])[O:10][CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: COC(CN)OC
Solvent: O
Product: COC(CN=Cc1ccccc1)OC
Reaction time: 2.5 h
Yield: 52.9 %

Procedure:
To a three neck round bottom flask, equipped with a cold water condenser, 20 g of water and 21.2 g of benzaldehyde were added. The reactants were mixed using a magnetic stirrer at room temperature for 3 minutes. Aminoacetaldehyde dimethyl acetal (21 g) was added to the reaction flask in one portion, followed by vigorous stirring for 2.5 hours. The agitation was stopped and the reaction mixture was allowed to stand for at least 15 minutes. The lower aqueous layer was separated and discard. The upper layer was collected and washed with saturated sodium chloride solution. The organic layer was collected and dried over magnesium sulfate to give 20.4 g of product. 1H NMR (300 Hz, CDCl3, ppm): 8.26 (1H, s), 7.65 (2H, m), 7.40 (3H, m), 4.66 (1H, t, J=5.3 Hz), 3.77 (2H, d,d, J=5.3 Hz, J=1.5 Hz), 3.39 (6H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[C:18]([Cl:25])[C:3]=1[O:4][C:5]1[CH:6]=[N:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2.[CH3:26]C(O)=O>C1COCC1.CCOCC>[CH3:26][O:16][C:15]([C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]=[CH:6][C:5]([O:4][C:3]1[C:18]([Cl:25])=[CH:19][C:20]([N+:22]([O-:24])=[O:23])=[CH:21][C:2]=1[Cl:1])=[CH:14]2)=[O:17]
Reactant: O=C(O)c1ccc2ncc(Oc3c(Cl)cc([N+](=O)[O-])cc3Cl)cc2c1
Reactant: CC(=O)O
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)c1ccc2ncc(Oc3c(Cl)cc([N+](=O)[O-])cc3Cl)cc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(2,6-Dichloro-4-nitro-phenoxy)-quinoline-6-carboxylic acid (94) (443 mg, 0.93 mmol) in dry THF (20 mL) was added CH2N2 in Et2O solution [Prepared from nitrosomethylurea (1.65 g) and 50% KOH (5 mL)]. This mixture was stirred at room temperature for 1 h. AcOH (1 mL) was added to the reaction mixture, which was then concentrated. Sat NaHCO3 was added to the residue, which was extracted twice with AcOEt. Organic layer was washed by brine, dried over anhydrous MgSO4, and concentrated to afford compound 95 (415 mg). 1H NMR (300 MHz, DMSO-d6) δ 3.89 (3H, s), 5.75 (2H, br s), 6.76 (2H, s), 7.73 (1H, d, J=2.9 Hz), 8.09 (2H, s), 8.67 (1H, s), 8.94 (1H, d, J=2.9 Hz).
Reaction SMILES: [CH2:1]([N:5]([CH2:17][CH2:18][CH2:19][CH3:20])[C:6](=O)[N:7]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:9][CH2:10][CH3:11])[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)(Cl)=O.[CH2:26]([NH2:30])[CH2:27][CH2:28][CH3:29]>C(#N)C>[CH2:1]([N:5]([CH2:17][CH2:18][CH2:19][CH3:20])[C:6](=[N:30][CH2:26][CH2:27][CH2:28][CH3:29])[N:7]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:9][CH2:10][CH3:11])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN
Reactant: CCCCN(CCCC)C(=O)N(CCCC)CCCC
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CCCCN=C(N(CCCC)CCCC)N(CCCC)CCCC
Temperature: 75 °C

Procedure:
A mixture of 5.69 grams (20 mmol) of tetra-n-butylurea, 3.22 grams (21 mmol) of phosphorus oxychloride and 15 ml of acetonitrile was heated at 75° C. in a nitrogen atmosphere for one hour. The mixture was then cooled to 0° C. and 3.36 grams (46 mmol) of n-butylamine was added over 15 minutes with stirring. The mixture was warmed to 60° C. for one hour and again cooled to 0° C., quenched with 5 ml of 25% (by weight) aqueous sodium hydroxide solution and extracted with diethylether. The ether extracts were dried over sodium sulphate, filtered and stripped to give a pale yellow oil of penta-n-butylguanidine.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][CH2:5][CH2:6][S:7][CH2:8][CH2:9][N:10]1[C:14](=[O:15])[CH2:13][CH2:12][C@@H:11]1/[CH:16]=[CH:17]/[C@@H:18]([OH:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>CO.[OH-].[Na+]>[OH:24][C@@H:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])/[CH:17]=[CH:16]/[C@H:11]1[CH2:12][CH2:13][C:14](=[O:15])[N:10]1[CH2:9][CH2:8][S:7][CH2:6][CH2:5][CH2:4][C:3]([OH:25])=[O:2]
Reactant: CCCCC[C@H](O)/C=C/[C@H]1CCC(=O)N1CCSCCCC(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCC[C@H](O)/C=C/[C@H]1CCC(=O)N1CCSCCCC(=O)O
Reaction time: 4 h
Yield: 69.9 %

Procedure:
To a solution of 4-[(2-{(2R)-2-[(1E,3S)-3-hydroxyoct-1-enyl]-5-oxopyrrolidin-1-yl}ethyl)thio] butanoic acid methyl ester (0.011 g, 0.03 mmol) in 2 mL of methanol at room temperature under an argon atmosphere was added an aqueous solution of sodium hydroxide (1 M, 4-5 drops). The reaction was stirred for 4 hours, evaporated under reduced pressure and treated with aqueous hydrochloric acid (1 M) until acidic. The residue was diluted with water (10 mL) and extracted with ethyl acetate. The organic solution was dried (brine, Na2SO4) and evaporated to yield 7.5 mg of 4-[(2-{(2R)-2-[(1E,3S)-3-hydroxyoct-1-enyl]-5-oxopyrrolidin-1-yl}ethyl)thio]butanoic acid: 1H NMR (300 MHz, CDCl3) δ partial spectrum 5.74 (dd, 1H, J=5.7, 15.6 Hz), 5.53 (dd, 1 H, J=8.2, 15.6 Hz), 4.11-4.20 (m with apparent q, 2 H, J=6.0 Hz), 3.62-3.81 (m with dd, 2 H, J=2.4, 10.2 Hz), 3.08-3.20 (m, 1 H); MS m/z (M+), 357.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[CH:20]=[CH:19][C:18]([CH:21]([OH:23])[CH3:22])=[N:17][C:10]=3[N:11]([CH2:15][CH3:16])[C:12](=[O:14])[N:13]=2)[CH:5]=[CH:6][CH:7]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[C:21]([C:18]1[CH:19]=[CH:20][C:9]2[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)=[N:13][C:12](=[O:14])[N:11]([CH2:15][CH3:16])[C:10]=2[N:17]=1)(=[O:23])[CH3:22]
Reactant: CCn1c(=O)nc(-c2cccc(Cl)c2)c2ccc(C(C)O)nc21
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CCn1c(=O)nc(-c2cccc(Cl)c2)c2ccc(C(C)=O)nc21
Yield: 84 %

Procedure:
Manganese dioxide (1.00 g) was added to a solution of 366 mg (1.1 mmol) of 4-(3-chlorophenyl)-1-ethyl-7-(1-hydroxyethyl)pyrido[2,3-d]pyrimidin-2(1H)-one dissolved in 20 ml of chloroform, and the mixture was heated under reflux for 1 hour. The reaction solution was mixed with 1.00 g of manganese dioxide and heated under reflux for 1 hour and then again mixed with 500 mg of manganese dioxide and heated under reflux for 1 hour. After removing insoluble matter by filtration, the filtrate was concentrated under a reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate-chloroform) to give 303 mg of 7-acetyl-4-(3-chlorophenyl)-1-ethylpyrido[2,3-d]pyrimidin-2(1H)-one. The yield was 84%.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22](B(O)O)[CH:23]=2)[CH:18]=[CH:17]1>>[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:2]3[N:6]([CH3:7])[CH:5]=[N:4][C:3]=3[C:8]3[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=3)[CH:23]=2)[CH:18]=[CH:17]1
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Reactant: OB(O)c1ccc2cc[nH]c2c1
Product: Cn1cnc(-c2cc(C#N)ccn2)c1-c1ccc2cc[nH]c2c1

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile and 6-indolylboronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C18H13N5, 300. Found, 300.
Reaction SMILES: [CH:1]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH:7]([C:15]([OH:17])=[O:16])[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:18][N:19]([CH3:23])[CH2:20][CH2:21]O>S(Cl)(Cl)=O.C1C=CC=CC=1>[CH:1]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH:7]([C:15]([O:17][CH2:21][CH2:20][N:19]([CH3:23])[CH3:18])=[O:16])[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CN(C)CCO
Reactant: O=C(O)C1Sc2ccccc2-c2ccccc21
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CN(C)CCOC(=O)C1Sc2ccccc2-c2ccccc21
Yield: 70 %

Procedure:
6H-dibenzo[b,d]thiopyran-6-carboxylic acid (3.4 g; 0.014 mol) was suspended in thionyl chloride (30 ml) and after 20 hours at room temperature the solution was evaporated in vacuo. The crude residue was dissolved in 80 ml of benzene and the obtained solution was added dropwise, at room temperature, to a solution of 2-dimethylaminoethanol (42 ml; 0.042 mol) in 80 ml of benzene. After half an hour the solution was washed with water and dried over sodium sulfate and concentrated to dryness. 6H-dibenzo[b,d]thiopyran-6-carboxylic acid, 2-dimethylamino-ethyl ester was obtained as oil; (3.0 g; yield 70%); NMR (CDCl3) δ ppm: 2.12 (s) (6H,CH3), 2.37 (t) (2H, --CH2NMe2), 4.07 (t) (2H, COOCH2), 4.59 (s) (1H,C-6 proton), 7.1-7.5 (m) (6H; C-2, C-3, C-4, C-7, C-8 and C-9 phenyl protons), 7.78 (m) (2H; C-1 and C-10 phenyl protons). By proceeding analogously the following compounds were obtained:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([S:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)(=[O:8])=[O:7])[N:3]=[N:2]1.[C:22]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH3:22][N:1]1[CH:5]=[C:4]([S:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]2)(=[O:8])=[O:7])[N:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2c[nH]nn2)CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1cc(S(=O)(=O)N2CCN(C(=O)OC(C)(C)C)CC2)nn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution tert-butyl 4-(1H-1,2,3-triazol-4-ylsulfonyl)piperazine-1-carboxylate (0.54 g, 1.15 mmol) in DMF (10 mL) at 0° C. was added K2CO3 (0.32 g, 2.30 mmol) followed by MeI (0.09 mL, 1.49 mmol) drop wise. Then the reaction mixture was stirred at room temperature for 16 hours. Then the reaction mixture was concentrated under reduced pressure and dissolved in CH2Cl2 (20 mL), washed with H2O (20 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (Isco CombiFlash Companion unit, 12 g Redisep column, 9:1 mixture of CH2Cl2/CH3OH) to give tert-butyl 4-(1-methyl-1H-1,2,3-triazol-4-ylsulfonyl)piperazine-1-carboxylate as a white foam (32, 0.30 g, 57%): MS (ESI+) m/z 332.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([OH:12])[C:8]=1[C:9]([OH:11])=[O:10].[CH3:13]O>S(=O)(=O)(O)O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([OH:12])[C:8]=1[C:9]([O:11][CH3:13])=[O:10]
Reactant: COc1cccc(O)c1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1c(O)cccc1OC

Procedure:
A mixture of 6-methoxysalicylic acid (10.0 g, 59.5 mmol) in methanol (40 mL) and sulfuric acid (2 mL) is heated at reflux 48 h. Although some acid remains the reaction is concentrated to remove the methanol and partitioned between ethyl acetate and saturated sodium carbonate solution. The organic phase is separated and washed with sodium carbonate until no acid remains by TLC analysis. The organic phase is dried and concentrated to provide the title compound as a low melting solid.
Reaction SMILES: [ClH:1].Cl.[C:3]([C:6]1[CH:31]=[CH:30][C:9]2[S:10][C:11]([CH2:13][CH:14]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C@H:25]4[CH2:29][CH2:28][NH:27][CH2:26]4)=[CH:20][CH:19]=3)[C:15]([OH:17])=[O:16])=[CH:12][C:8]=2[CH:7]=1)(=[NH:5])[NH2:4].Cl.[CH3:33][N:34]=[C:35](OCC)[CH3:36].[OH-].[Na+]>O.C(#N)C>[ClH:1].[ClH:1].[C:3]([C:6]1[CH:31]=[CH:30][C:9]2[S:10][C:11]([CH2:13][CH:14]([C:18]3[CH:19]=[CH:20][C:21]([O:24][C@H:25]4[CH2:29][CH2:28][N:27]([C:35](=[N:34][CH3:33])[CH3:36])[CH2:26]4)=[CH:22][CH:23]=3)[C:15]([OH:17])=[O:16])=[CH:12][C:8]=2[CH:7]=1)(=[NH:4])[NH2:5]
Reactant: N=C(N)c1ccc2sc(CC(C(=O)O)c3ccc(O[C@H]4CCNC4)cc3)cc2c1
Reactant: CCOC(C)=NC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CN=C(C)N1CC[C@H](Oc2ccc(C(Cc3cc4cc(C(=N)N)ccc4s3)C(=O)O)cc2)C1
Yield: 33.2 %

Procedure:
2.0 g of 3-(5-amidinobenzo[b]thien-2-yl)-2-[4-[((3S)-3-pyrrolidinyl)oxy]phenyl]propionic acid dihydrochloride was dissolved in a solvent mixture of 10 ml of water and 10 ml of acetonitrile. With stirring, to the thus prepared solution was gradually added 20 g of ethyl (N-methyl)acetimidate hydrochloride which has been prepared in accordance with the procedure disclosed in The Journal of Organic Chemistry (vol.33, pp.1679-1681, 1968), while maintaining the pH level of the solution at 8.5 with 2N sodium hydroxide aqueous solution. After distilling off the solvent, the resulting residue was washed with dichloromethane and then subjected to column chromatography using a column packed with a highly porous polymer type synthetic adsorbent (styrene-divinylbenzene polymer: Diaion HP-20) and using a water/acetonitrile mixture as an elution solvent, thereby effecting desalting. Fractions of interest thus pooled were subjected to reversed phase high performance liquid chromatography using a column packed with octadecyl-bonded silica gel. Thereafter, the thus eluted fractions of interest were pooled and then concentrated to dryness by passing through a C1 type of strongly basic ion exchange resin (Diaion SA-10, Nippon Rensui Co., Ltd.). In this way, 370 mg of the title compound was obtained in a solid form.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[CH2:5][NH:4][C:3]1=[O:13].C(=O)([O-])[O-].[K+].[K+].Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>O1CCCC1.CCOCC>[CH2:24]([O:23][C:21]([NH:1][C@@H:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[CH2:5][NH:4][C:3]1=[O:13])=[O:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N[C@@H]1Cc2ccccc2CNC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(N[C@@H]1Cc2ccccc2CNC1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 95.8 %

Procedure:
A solution of 210 mg (1.19 mmol) of 4(R)-amino-2,3,4,5-tetrahydro-1H-2-benzazepin-3-one in 5 mL of tetrahydrofuran was treated with 5 mL of 10% aqueous potassium carbonate followed by 0.20 mL (0.24 g, 1.3 mmol, 1.1 eq) of 95% benzyl chloroformate. The mixture was stirred vigorously at room temperature for 6 hours then diluted with 20 mL of ether and the mixture transferred to a separatory funnel. The lower aqueous layer was removed and washed with several portions of ether. The combined ether washes and ether layer were washed, with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and solvents removed under vacuum to give 365 mg (1.14 mmol, 96%) of the product. 1H NMR (400 MHz, CDCl3): δ3.08 (dd; 12, 16 Hz; 1H), 3.27 (dd; 7, 16 Hz; 1H), 4.06 (d, 16 Hz, 1H), 4.75 (d, 16 Hz, 1H), 5.00 (dd; 7, 12 Hz; 1H), 5.12 (s, 2H), 7.1-7.4 (m, 9H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[CH:3]=1.[C:17]([C:20]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)([CH3:22])[CH3:21])([OH:19])=[O:18].C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.O.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>[CH3:9][O:8][C:6]1[N:7]=[C:2]([C:25]2[CH:24]=[C:23]([C:20]([CH3:22])([CH3:21])[C:17]([OH:19])=[O:18])[CH:28]=[CH:27][CH:26]=2)[CH:3]=[C:4]([NH:10][CH2:11][C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[N:5]=1
Reactant: CC(C)(C(=O)O)c1cccc(B(O)O)c1
Reactant: COc1nc(Cl)cc(NCc2ccsc2)n1
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: [Cs+]
Solvent: O
Solvent: COCCOC
Product: COc1nc(NCc2ccsc2)cc(-c2cccc(C(C)(C)C(=O)O)c2)n1
Temperature: 90 °C
Reaction time: 6 h
Yield: 4.7 %

Procedure:
Argon is bubbled through a mixture of (6-chloro-2-methoxy-pyrimidin-4-yl)-thiophen-3-ylmethyl-amine (216 mg, 0.84 mmol), 3-(1-carboxy-1-methyl-ethyl)-phenyl boronic acid [312 mg, 1.5 mmol, see Example 49(b) step 2], Cs2CO3 (821 mg, 2.52 mmol), and tetrakis(triphenylphosphine)palladium (0) (92 mg, 0.08 mmol) in ethylene glycol dimethyl ether (2.5 mL) and water (0.5 mL), for a period of 10 minutes. The reaction vessel is sealed and heated to 90° C. After stirring for 6 hours the heating is turned off and the mixture is allowed to cool to ambient temperature upon standing for 24 hours. The mixture is diluted with water (40 mL) and extracted twice with EtOAc (25 mL). The organic extracts are combined and dried over magnesium sulfate, filtered and concentrated to afford 2-(3-{2-methoxy-6-[(thiophen-3-ylmethyl)-amino]-pyrimidin-4-yl}-phenyl)-2-methyl-propionic acid [15 mg, 4.6%, Example 71] as a solid. LCMS RT=1.94 minutes, MS: 384 (M+H). IC50=393 nM
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:29])([F:30])[F:31])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)=[O:23])=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1)N1CCOCC1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with morpholine as in General Procedure 10 to give the title compound. LCMS: m/z=516.96 (M+H+); retention time=0.74 minutes.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=[C:4]([Cl:10])[N:3]=1.[CH3:11][NH:12][CH:13](SC)[CH2:14][N+:15]([O-:17])=[O:16]>CCO>[Cl:1][C:2]1[C:7]([CH2:8][NH:9][C:13]([NH:12][CH3:11])=[CH:14][N+:15]([O-:17])=[O:16])=[CH:6][CH:5]=[C:4]([Cl:10])[N:3]=1
Reactant: NCc1ccc(Cl)nc1Cl
Reactant: CNC(C[N+](=O)[O-])SC
Solvent: CCO
Product: CNC(=C[N+](=O)[O-])NCc1ccc(Cl)nc1Cl
Yield: 27.3 %

Procedure:
A mixture of 1.2 g (0.007 mole) of (2,6dichloro-3-pyridylmethyl)amine and 1 g (0.007 mole) of 1-methylamino-1-methylthio-2-nitroethane was refluxed in 50 ml of EtOH for 6 hours. After cooling, the reaction mixture was concentrated and the resulting crystals were collected by filtration, washed with CH2Cl2 and a small amount of EtOH in that order and dried. The procedure gave 0.53 g of the title compound as a white powder.