Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)C.[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20](=[O:22])[CH3:21]>C1COCC1>[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]1([CH3:8])[CH2:21][O:22]1
Reactant: C[S+](C)C
Reactant: CC(=O)c1ccc(F)cc1F
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC1(c2ccc(F)cc2F)CO1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared by following general procedure 3. DMSO was added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv.) was added and stirred for 10 min. after which the solution of 1-(2,4-difluorophenyl)ethanone (1 equiv.) in THF was added dropwise. After complete addition, the reaction mixture was stirred at RT for 2 h. The product was detected by LCMS and the reaction mixture was poured into ice water, extracted in diethyl ether (4×50mL), dried over Na2SO4 and concentrated at 25° C. to obtain the product.
Reaction SMILES: Cl[C:2]1([O:12][C:13]2[CH:26]=[CH:25][C:16]([O:17][CH:18]([CH3:24])[C:19](OCC)=[O:20])=[CH:15][CH:14]=2)[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][NH:3]1.[F:27][C:28]([F:39])([F:38])[C:29]1[CH:30]=[C:31]([CH2:35][C:36]#[N:37])[CH:32]=[CH:33][CH:34]=1.[Na].[ClH:41]>C(O)C>[C:36]([CH:35]([C:31]1[CH:32]=[CH:33][CH:34]=[C:29]([C:28]([F:38])([F:39])[F:27])[CH:30]=1)[C:19](=[O:20])[CH:18]([O:17][C:16]1[CH:25]=[CH:26][C:13]([O:12][C:2]2[C:7]([Cl:41])=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=2)=[CH:14][CH:15]=1)[CH3:24])#[N:37]
Reactant: N#CCc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)C(C)Oc1ccc(OC2(Cl)C=CC(C(F)(F)F)=CN2)cc1
Reactant: Cl
Agent: [Na]
Solvent: CCO
Product: CC(Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1)C(=O)C(C#N)c1cccc(C(F)(F)F)c1
Yield: 56 %

Procedure:
3.0 Grams of ethyl 2-[4-(2-chloro-5-trifluoromethyl-2-pyridyloxy)-phenoxy]-propionate and 1.42 g of α-(3-trifluoromethylphenyl)-acetonitrile were added to a solution of 0.37 g of metal sodium in 50 ml of ethanol, and refluxed under heat for 3 hours. The reaction mixture was added to an aqueous solution of dilute hydrochloric acid, and the mixture was subjected to extraction with chloroform, the extract was concentrated. The residue was separated and purified by column chromatography to give 2.28 g of a compound No. 132 which was a light yellow solid (melting point 70°-71° C.). The yield was 56.0%. The compound No. 132 was analyzed, and the results are shown in Tables 1 to 23.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[C:10]([CH2:14][C:15](OC)=[O:16])(=O)[CH2:11][CH3:12].O>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:11]([C:10]1[NH:1][C:2]2[C:7]([C:15](=[O:16])[CH:14]=1)=[N:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)[CH3:12]
Reactant: COc1ccc(N)cn1
Reactant: CCC(=O)CC(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCc1cc(=O)c2nc(OC)ccc2[nH]1
Yield: 39.3 %

Procedure:
A solution of 5-amino-2-methoxypyridine (50 g), methyl propionylacetate (57.3 g) and p-toluenesulphonic acid (0.5 g) in benzene (200 ml) was heated under reflux with azeotropic removal of water for 20 hours. Volatile material was removed by evaporation and the residue added to a refluxing eutectic mixture of 26.5% v/v diphenyl and 73.5% v/v diphenyl oxide (140 ml). The solution was heated under reflux for 1 hour, cooled and diluted with hexane (500 ml). The precipitated solid was filtered off and triturated with hot methanol (500 ml) to give 2-ethyl-6-methoxy-1,5-naphthyridine-4 (1H)-one (B4) (32.3 g), as a pale brown solid, m.p. 279°-281° C.; NMR (d6 -DMSO): 1.2 (t, 3H), 2.65 (q, 2H), 3.95 (s, 3H), 6.3 (br s, 1H), 7.15 (d, 1H), 7.95 (d, 1H).
Reaction SMILES: [F:1][C:2]([C:12]1[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=1)([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6].[C:19]1(OB(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.O>[F:1][C:2]([C:12]1[CH:17]=[CH:16][C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:14][CH:13]=1)([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6]
Reactant: CC(C)S(=O)(=O)NCC(C)(F)c1ccc(I)cc1
Reactant: OB(O)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)S(=O)(=O)NCC(C)(F)c1ccc(-c2ccccc2)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 33.9 %

Procedure:
Scheme VI, Step A′: Into a 10 mL single neck flask was placed [2-fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine (113 mg, 0.29 mmol, prepared in example 1), phenyl boric acid (54 mg, 0.44 mmol), potassium carbonate (61 mg, 0.44 mmol), and tetrakis(triphenyl phosphine)Pd(0) (17 mg, 0.02 mmol) in a mixture of dioxane/water (3:1, 7 mL). The mixture was then heated at 100° C. with stirring for 18 hours. The reaction was then cooled to room temperature and poured into H2O. The mixture was extracted with EtOAc and the organic layer was washed twice with H2O, dried over anhydrous Na2SO4, filtered, and concentrated under reduced vacuum. The resulting semi-solid was purified via radial chromatography (Chromatotron, Harrison Research Inc., 840 Moana Court, Palo Alto, Calif. 94306) using a 2000 micron rotor (silica gel) and eluting with a solvent of Hexane/EtOAc 4:1 to provide the title compound (33 mg, 34%) as a slowly crystallizing tan oil. Ion spray M.S. 335 (M*+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[O:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][N:22]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[O:8][C:9]1[S:13][C:12]([C:14]([NH:28][CH:25]2[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: CN1CCC(N)CC1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Oc2c(Cl)cncc2Cl)s1
Product: CN1CCC(NC(=O)c2cc([N+](=O)[O-])c(Oc3c(Cl)cncc3Cl)s2)CC1

Procedure:
Prepared according to the procedure described for example 70 from 5-((3,5-dichloropyridin-4-yl)oxy)-4-nitrothiophene-2-carboxylic acid (70 mg, 0.21 mmol) from above and 1-methylpiperidin-4-amine (28.5 mg, 0.25 mmol). The title compound was obtained as a solid (35.0 mg, 39% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.03 (1H, m), 8.62 (2H, m), 8.57 (1H, s), 3.88 (1H, m), 3.12 (2H, m), 2.60 (2H, m), 2.50 (3H, s), 1.93 (2H, m), 1.77 (2H, m). MS m/z: 431.05, 433.14 [M+H]+.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[C:8]2[N:13]([C:14](=[O:18])[C:15]=1[O:16][CH3:17])[CH2:12][CH2:11][O:10][C:9]2([CH3:20])[CH3:19])=[O:5].[CH3:22][Mg+].[Br-]>C1COCC1.CCOCC>[C:4]([C:6]1[N:7]=[C:8]2[N:13]([C:14](=[O:18])[C:15]=1[O:16][CH3:17])[CH2:12][CH2:11][O:10][C:9]2([CH3:19])[CH3:20])(=[O:5])[CH3:22]
Reactant: C[Mg+]
Reactant: COc1c(C(=O)N(C)OC)nc2n(c1=O)CCOC2(C)C
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1c(C(C)=O)nc2n(c1=O)CCOC2(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 16 %

Procedure:
To a solution of N,3-dimethoxy-N,9,9-trimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide (0.40 g, 1.35 mmol, 1.0 equiv) in THF (13 mL) at 0° C. (ice/water bath) under a nitrogen atmosphere, was added CH3MgBr (0.63 mL of a 3 M solution in ether, 1.88 mmol, 1.4 equiv). After stirring 3 h, the reaction was cautiously quenched by addition of 1N HCl (10 mL). After stirring 1 h, the reaction was poured into water and extracted with CH2Cl2 (×5). The combined CH2Cl2 extracts were dried (Na2SO4) and then concentrated in vacuo. The crude product was purified by silica gel chromatography (20-100% ethyl acetate/hexane) to provide the title compound (0.054 g, 16% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 3.98 (s, 3H), 3.96-4.05 (m, 4H), 2.52 (s, 3H), 1.61 (s, 6H); LCMS (ES+, (M+H)+) m/z 253.23.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-].[CH3:16][S+](C)(C)=O.[OH-].[K+]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]2([O:14][CH2:16]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C[S+](C)(C)=O
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Temperature: 25 °C
Reaction time: 48 h
Yield: 90.6 %

Procedure:
To a solution of 44.9 g (0.225 mol) of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (31) in 500 ml acetonitrile was added successively 59.5 g (0.27 mol) trimethyl sulphoxonium iodide and 18.9 g (0.338 mol) fine crushed potassium hydroxide. The reaction mixture was vigorously stirred for two days under a nitrogen atmosphere at room temperature. After complete conversion the solvent was evaporated in vacuo and the residue was taken up in dichloromethane. The organic layer was washed with aqueous citric acid solution (6×), dried over sodium sulphate and concentrated in vacuo. This crude product was used without further purification for the next step (43.5 g, 0.204 mol, 90.6% yield).
Reaction SMILES: BrCCCCl.[Cl:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[C:19]([CH3:25])[C:20](=[O:24])[N:21]([CH3:23])[N:22]=2)=[CH:13][CH:12]=1.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[Cl:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:18]=[C:19]([CH3:25])[C:20](=[O:24])[N:21]([CH3:23])[N:22]=2)=[CH:15][CH:16]=1.[CH3:23][N:21]1[C:20](=[O:24])[C:19]([CH3:25])=[CH:18][C:17]([C:14]2[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][CH2:7][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:12][CH:13]=2)=[N:22]1
Reactant: C1CCNCC1
Agent: Cc1cc(-c2ccc(OCCCCl)cc2)nn(C)c1=O
Agent: ClCCCBr
Product: Cc1cc(-c2ccc(OCCCN3CCCCC3)cc2)nn(C)c1=O

Procedure:
6-(4-(3-Chloropropoxy)-phenyl)-2,4-dimethyl-2H-pyridazin-3-one was prepared from the product of step 3 and 3-bromo-1-chloropropane using the procedure described for Example 22 step 4. Example 39 (2,4-dimethyl-6-[4-(3-piperidin-1-yl-propoxy)-phenyl]-2H-pyridazin-3-one) was prepared using 6-(4-(3-chloropropoxy)-phenyl)-2,4-dimethyl-2H-pyridazin-3-one and piperidine by the methods described for example 22 step 5. The hydrochloride salt was prepared; Mp 222-3° C.; MS m/z 342 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]1=[S:12].[C:13]1([CH3:24])[CH:18]=[CH:17][C:16]([S:19]([O:22]C)(=[O:21])=[O:20])=[CH:15][CH:14]=1>>[C:13]1([CH3:24])[CH:14]=[CH:15][C:16]([S:19]([O-:22])(=[O:20])=[O:21])=[CH:17][CH:18]=1.[CH3:1][N+:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[S:12][CH3:13]
Reactant: Cn1c(=S)ccc2ccccc21
Reactant: COS(=O)(=O)c1ccc(C)cc1
Product: CSc1ccc2ccccc2[n+]1C
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 130 °C
Yield: 193.6 %

Procedure:
A mixture of 1-methylquinolin-2-thione (175 mg, 1.0 mmol) and methyl p-toluenesulfonate (186 mg, 1.0 mmol) was heated at 130° C. After 30 min the resulting solid was cooled, crushed, triturated with Et2O (4×1 mL) and dried under high vacuum to give the title compound (0.35 g, 97%) as a white solid. 1H-NMR (DMSO-d6): δ 8.96 (1H, d), 8.46 (1H, d), 8.35 (1H, dd), 8.16 (1H, m), 8.08 (1H, d), 7.91 (1H, m), 7.47 (2H, d), 7.10 (2H, d), 4.40 (3H, s), 3.02 (3H, s), 2.28 (3H, s)
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=[CH:4][NH:3]1.[OH-].[K+].I[CH3:14]>CO.O>[CH3:14][N:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([OH:10])=[O:9])[C:2]1=[O:1]
Reactant: CI
Reactant: O=C(O)c1ccc[nH]c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1cccc(C(=O)O)c1=O

Procedure:
To 2-oxo-1H-pyridine-3-carboxylic acid (2.00 g, 14.4 mmol) in methanol (20 mL) was added a solution of KOH (1.60 g, 28.5 mmol) in water (3 mL) and the mixture was vigorously stirred until a thick suspension formed. Iodomethane (10 μL, 0.16 mmol) was added and the mixture was heated at reflux for 1.5 h. The mixture was concentrated to ⅓ volume and was acidified to pH 1 with 6N HCl. The solids were filtered off and were washed with water (3×2 mL) and acetonitrile (2×2 mL), and then dried in vacuo to give 1-methyl-2-oxo-pyridine-3-carboxylic acid as a white solid. ESI-MS m/z calc 153.0. found 154.1 (M−1)−. Retention time: 0.65 minutes (3 min run).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH2:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:10][C:11]1[O:15][C:14]([CH:16]=O)=[CH:13][CH:12]=1.C([O:20][C:21](=O)[C:22](=[O:29])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])C>C(O)C>[OH:29][C:22]1[C:21](=[O:20])[N:9]([CH2:8][CH2:7][CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH:16]([C:14]2[O:15][C:11]([CH3:10])=[CH:12][CH:13]=2)[C:23]=1[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: NCCCn1ccnc1
Reactant: Cc1ccc(C=O)o1
Reactant: CCCCCCC(=O)C(=O)OCC
Solvent: CCO
Product: CCCCCC1=C(O)C(=O)N(CCCn2ccnc2)C1c1ccc(C)o1

Procedure:
3-Imidazol-1-yl-propylamine (1 mmol) and 5-Methyl-furan-2-carbaldehyde (1 mmol) were added to ethanol (5 ml). After 30 min 2-Oxo-octanoic acid ethyl ester (1 mmol) was added.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([O:13]CC)=O.[CH2:16]([O:18][C:19](=[O:26])[CH:20]=[C:21](OCC)[CH3:22])[CH3:17].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O-]CC.[Na+]>C1(C)C(C)=CC=CC=1.C(O)C.O>[CH2:16]([O:18][C:19]([C:20]1[C:11]([OH:13])=[C:3]2[C:4]3[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=3[S:6][C:2]2=[N:1][C:21]=1[CH3:22])=[O:26])[CH3:17]
Reactant: CCOC(=O)c1c(N)sc2c1CCCC2
Reactant: CCOC(=O)C=C(C)OCC
Agent: CC[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1c(C)nc2sc3c(c2c1O)CCCC3
Temperature: 165 °C
Reaction time: 18 h
Yield: 58.3 %

Procedure:
To a solution of ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (33.8 g; 150 mmol) and ethyl-3-ethoxybut-2-enoate (25 g; 157.5 mmol) in xylene (600 mL) was added a catalytic amount of p-toluenesulfonic acid mono hydrate. The resulting reaction mixture was heated to reflux (temp. of bath 165° C.) equipped with a Dean-Stark trap and condenser to collect ethanol. After 18 h, the solution was cooled to room temperature, transferred to a dropping funnel and then added dropwise to a stirred solution of sodium ethoxide (21% in ethanol, 59 mL; 157.5 mmol) in ethanol (350 mL). The resulting solution is heated to reflux for 18 h and, after cooling, the volatiles were removed under reduced pressure to yield a black oil. This material was suspended in water (150 mL) and washed with diethylether (2×150 mL). The aqueous phase was separated, cooled at 0° C. and slowly acidified to pH 4 with a 1N HCl with rapid stirring. The resulting precipitate was filtered, washed with diluted hydrochloric acid solution and dried to furnish 25.5 g (58%) of the title compound as a black solid.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:30][CH2:31][NH:32][C:33]2[C:34]([CH3:50])=[N:35][C:36]([N:39]3[CH2:43][CH2:42][C@@H:41]([N:44]4[CH2:48][CH2:47][CH2:46][C@@H:45]4[CH3:49])[CH2:40]3)=[CH:37][CH:38]=2)[CH2:11][CH2:10][CH:9]([O:12][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][CH2:7]1)=O)C>CO.C(Cl)Cl>[C:26]([Si:13]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[O:12][CH:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:3])[N:32]([C:33]3[C:34]([CH3:50])=[N:35][C:36]([N:39]4[CH2:43][CH2:42][C@@H:41]([N:44]5[CH2:48][CH2:47][CH2:46][C@@H:45]5[CH3:49])[CH2:40]4)=[CH:37][CH:38]=3)[CH2:31][CH2:30]2)[CH2:11][CH2:10]1)([CH3:29])([CH3:28])[CH3:27].[NH3:32]
Reactant: CCOC(=O)C1(CCNc2ccc(N3CC[C@@H](N4CCC[C@@H]4C)C3)nc2C)CCC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Solvent: CO
Solvent: ClCCl
Product: Cc1nc(N2CC[C@@H](N3CCC[C@@H]3C)C2)ccc1N1CCC2(CCC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CC2)C1=O
Product: N
Yield: 5 %

Procedure:
The title compound was synthesized in essentially the same manner using the procedures as set forth in Step 2 of Example 1, by cyclizing 4-(tert-butyl-diphenyl-silanyloxy)-1-{2-[2-methyl-6-((2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-ylamino]-ethyl}-cyclohexanecarboxylic acid ethyl ester (132 mg, 0.19 mmol) to obtain 89 mg (72% over two steps) of the title compound after flash column chromatography (5% 7N NH3 in MeOH/CH2Cl2).
Reaction SMILES: O=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.Cl.[CH2:13]([O:15][C:16](=[O:21])[C@H:17]([CH2:19][SH:20])[NH2:18])[CH3:14].C(N(C(C)C)C(C)C)C.O>C(O)C>[OH:9][C:8]1[CH:10]=[CH:11][C:3]([CH:2]2[NH:18][CH:17]([C:16]([O:15][CH2:13][CH3:14])=[O:21])[CH2:19][S:20]2)=[CH:4][C:5]=1[O:6][CH3:7]
Reactant: CCOC(=O)[C@@H](N)CS
Reactant: COc1cc(C=O)ccc1O
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CSC(c2ccc(O)c(OC)c2)N1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 1.52 g (10 mM) of vanillin (4-hydroxy-3-methoxybenzaldehyde) in 20 mL of absolute ethanol was added a solution of 1.85 g (10 mM) L-cysteine ethyl ester hydrochloride in 15 mL absolute ethanol, containing 1.7 mL (10 mM) of N-ethyldiisopropylamine. The reaction mixture was stirred at room temperature for about six hrs, until no starting material was present when monitored by thin layer chromatography (TLC). After adding 200 mL of water with stirring, the white precipitate was filtered, washed with 2×50 mL water, and vacuum dried. Yield 1.9 g (67%) of 1.1H NMR (DMSO-d6; ˜1:1 diastereoisomeric mixture at C2) δ; (1.22 m, 3H); (3.01m and 3.15 m, 1H); (3.33 m, 2H); (3.75 s and 3.77s, 3H); (4.15 m, and 4.38 bs, 2H); (5.40 d and 5.49d, 1H); 6.79-6.73 m, 2H); 6.83-6.89 m 1H); (7.02 d and 7.12d, 1H); (8.99 s and 9.05 s, 1H). Mass analysis: Calculated for C13H17NO4S: 284 [M+H]+. Found: 284.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)(=O)=O.[NH2:19][C:20]1[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=1.CN(C)P(N(C)C)(N(C)C)=O>O>[CH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][C:9]=1[O:8][CH2:7][CH2:6][NH:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:29][CH:30]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CS(=O)(=O)OCCOc1ccc2ccccc2c1
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1ccc(NCCOc2ccc3ccccc3c2)cc1

Procedure:
A mixture of 18.7 g. of 2-(2-naphthyloxy)ethanol O-methanesulfonate and 23.6 g. of ethyl p-aminobenzoate is heated in 300 ml. of hexamethylphosphoramide at 110° C. for 16 hours. The mixture is cooled, diluted with water and worked up as described in Example 3 to give the crystalline product. Recrystallization from ethanol gives crystals, m.p. 158°-162° C.
Reaction SMILES: C1COCC1.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C@H:14]([NH:16][CH2:17][C@@H:18]2[C@@H:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:21][N:20]([C:29]([O:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]([O:40]C)=[O:39])=[CH:34][CH:33]=3)=[O:30])[CH2:19]2)[CH3:15])[CH:11]=[CH:12][CH:13]=1.[OH-].[Li+].Cl>CO.O>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C@H:14]([NH:16][CH2:17][C@@H:18]2[C@@H:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:21][N:20]([C:29]([O:31][C:32]3[CH:33]=[CH:34][C:35]([C:38]([OH:40])=[O:39])=[CH:36][CH:37]=3)=[O:30])[CH2:19]2)[CH3:15])[CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)c1ccc(OC(=O)N2C[C@H](CN[C@H](C)c3cccc(OC)c3)[C@@H](c3ccccc3)C2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc([C@@H](C)NC[C@H]2CN(C(=O)Oc3ccc(C(=O)O)cc3)C[C@@H]2c2ccccc2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A 2.0 ml THF, 1.0 ml water and 0.5 ml methanol mixed solution of 261 mg of 4-(methoxycarbonyl)phenyl(3S,4S)-3-({[(1R)-1-(3-methoxyphenyl)ethyl]amino}methyl)-4-phenylpyrrolidine-1-carboxylate was mixed with 45 mg of lithium hydroxide and stirred at room temperature for 20 hours. The reaction solution was acidified by adding 1 M hydrochloric acid and post-treated and purified in the standard method to obtain 136 ml of 4-({[(3S,4S)-3-({[(1R)-1-(3-methoxyphenyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]carbonyl}oxy)benzoic acid as a colorless amorphous substance.
Reaction SMILES: [NH2:1][C:2]1[C:13]([Br:14])=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([NH:6][CH:7]([CH3:9])[CH3:8])=[O:5].[C:15](OC(Cl)(Cl)Cl)(OC(Cl)(Cl)Cl)=[O:16].O>C(Cl)Cl>[Br:14][C:13]1[CH:12]=[CH:11][CH:10]=[C:3]2[C:2]=1[NH:1][C:15](=[O:16])[N:6]([CH:7]([CH3:9])[CH3:8])[C:4]2=[O:5]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)NC(=O)c1cccc(Br)c1N
Solvent: O
Solvent: ClCCl
Product: CC(C)n1c(=O)[nH]c2c(Br)cccc2c1=O
Yield: 250 %

Procedure:
A slurry of 2-amino-3-bromo-N-isopropylbenzamide (406a, 1.00 g, 3.89 mmol) and tri-phosgene (Aldrich; 0.462 g, 1.556 mmol) in 50 mL DCM was fitted with a water cooled reflux condenser and drying tube and heated to reflux overnight. In the morning, complete conversion to desired product. The reaction was cooled and concentrated in vacuo to give 8-bromo-3-isopropylquinazoline-2,4(1H,3H)-dione (1.1 g, 3.89 mmol, 100% yield) as a white solid: 1H NMR (400 MHz, CDCl3) δ ppm 8.02-8.25 (1H, m), 7.98 (1H, br. s.), 7.78 (1H, dd, J=7.8, 1.4 Hz), 7.11 (1H, t, J=7.9 Hz), 5.27 (1H, dt, J=13.9, 6.9 Hz), 1.56 (6H, s). m/z (ESI, +ve) 282.9/284.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5](=O)[CH2:6]Br.[N:12]1([CH2:18][CH2:19][CH2:20][NH:21][C:22]([NH2:24])=[S:23])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(N(CC)C(C)C)(C)C.[S:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[C:39](Cl)=[O:40]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[N:24]=[C:22]([N:21]([CH2:20][CH2:19][CH2:18][N:12]3[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)[C:39]([C:35]3[S:34][CH:38]=[CH:37][CH:36]=3)=[O:40])[S:23][CH:6]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: NC(=S)NCCCN1CCOCC1
Reactant: O=C(CBr)c1cccc(Cl)c1
Reactant: O=C(Cl)c1cccs1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cccs1)N(CCCN1CCOCC1)c1nc(-c2cccc(Cl)c2)cs1
Temperature: 25 °C
Yield: 54.6 %

Procedure:
A mixture of 3-chlorophenacyl bromide (467 mg, 2 mmol) and (3-morpholin-4-yl-propyl)-thiourea (407 mg, 2 mmol) in dry ethanol (4 ml) was heated at reflux for 2 min, cooled to room temperature, and concentrated in vacuo. The resulting residue was suspended in dichloromethane (5 mL) followed by the addition of N,N-diisopropylethylamine (554 μL, 3 mmol) and thiophene-2-carbonyl chloride (160 μL, 1.5 mmol). The reaction mixture was maintained at room temperature overnight, then concentrated in vacuo. The resulting residue was dissolved in DMSO (3 mL) and subjected to HPLC purification (Method Y). The resulting free amine was dissolved in MeOH (2 mL) and 1M HCl/ether (75 mL) was added. The precipitate was filtered and dried in vacuo to provide the title compound (367 mg) as an off-white solid as the hydrochloride salt. LC/MS (ESI) m/z 447.9 [M+H]. HPLC retention time (Method A)=2.95 min.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6]2[NH:8][CH:9]=[C:10]([CH2:11][CH2:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=3)[C:5]=2[C:4](=[O:22])[N:3]=1.[NH2:23][C@H:24]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>>[CH2:35]([O:34][C:32](=[O:33])[C@H:24]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[NH:23][C:17](=[O:19])[C:16]1[CH:20]=[CH:21][C:13]([CH2:12][CH2:11][C:10]2[C:5]3[C:4](=[O:22])[N:3]=[C:2]([NH2:1])[NH:7][C:6]=3[NH:8][CH:9]=2)=[CH:14][CH:15]=1)[CH3:36]
Reactant: Nc1nc(=O)c2c(CCc3ccc(C(=O)O)cc3)c[nH]c2[nH]1
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(CCc2c[nH]c3[nH]c(N)nc(=O)c23)cc1)C(=O)OCC

Procedure:
condensing 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic acid with diethyl L-glutamate hydrochlorate to give N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl-L-glutamic acid diethyl ester, and then forming a p-toluenesulfonate salt thereof; and