Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COS([O-])(=O)=O.C[S+](C)C1C=CC(O[C:16](=[O:36])[C@H:17]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[NH:18][C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])=CC=1.[NH:38]1[CH2:45][CH2:44][CH2:43][C@H:39]1[C:40]([OH:42])=[O:41].C(N(CC)CC)C.Cl>O>[CH2:22]([O:21][C:19]([NH:18][C@H:17]([C:16]([N:38]1[CH2:45][CH2:44][CH2:43][C@H:39]1[C:40]([OH:42])=[O:41])=[O:36])[CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:20])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: C[S+](C)c1ccc(OC(=O)[C@H](Cc2ccccc2)NC(=O)OCc2ccccc2)cc1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: COS(=O)(=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O)OCc1ccccc1

Procedure:
In 30 ml of water was dissolved 5.47 g of benzyloxycarbonylphenylalanine p-dimethylsulfoniophenyl ester methylsulfate obtained by a synthesizing method according to Synthetic Example 5, and 20 ml of an aqueous solution of 1.15 g of proline and 1.4 ml of triethylamine was added dropwise thereto while stirring. The reaction mixture was further stirred for 12 hours at room temperature, adjusted to pH 2 by adding 2% HCl, and extracted twice with 50 ml of ethyl acetate. The ethyl acetate layer was washed with water, dried, and concentrated under reduced pressure, and the resultant residue was recrystallized by adding ether. This crystalline product indicated only the peak of the desired product by HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][NH:14][C:13](=[O:17])[C@H:12]2[CH2:18][C:19](O)=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[S:22]1[CH2:27][CH2:26][CH2:25][S:24][CH:23]1[CH2:28][CH2:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38]C=1)[C@H:36](N)[CH2:35][CH2:34][CH2:33]2.C1C=CC2N(O)N=[N:47]C=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[S:24]1[CH2:25][CH2:26][CH2:27][S:22][CH:23]1[CH2:28][C:29]1[CH:38]=[C:37]2[C:32](=[CH:31][CH:30]=1)[C@H:33]([NH:47][C:19](=[O:20])[CH2:18][C@@H:12]1[C:13](=[O:17])[NH:14][CH2:15][CH2:16][N:11]1[S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:9])=[O:10])[CH2:34][CH2:35][CH2:36]2
Reactant: On1nnc2ccccc21
Reactant: O=C(O)C[C@@H]1C(=O)NCCN1S(=O)(=O)c1ccc(Cl)cc1
Reactant: N[C@@H]1CCCc2cc(CCC3SCCCS3)ccc21
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Product: O=C(C[C@@H]1C(=O)NCCN1S(=O)(=O)c1ccc(Cl)cc1)N[C@@H]1CCCc2cc(CC3SCCCS3)ccc21

Procedure:
A solution of (R)-2-(1-(4-chlorophenylsulfonyl)-3-oxopiperazin-2-yl)acetic acid (1.98 g, 6.0 mmol), crude (R)-6-(2-(1,3-dithian-2-yl)ethyl)-1,2,3,4-tetrahydronaphthalen-1-amine (1.8 g, 6.45 mmol), HOBt (892 mg, 6.6 mmol) and EDCI(1.265 g, 6.6 mmol)in 15 mL of DMF was stirred overnight at room temperature. After quenching with Sat. NaHCO3 solution, the reaction mixture was extracted with EtOAc/hexane (1:1, 200 mL×2). The combined organic phase was washed brine, dried over Na2SO4, and evaporated in vaco. Flash chromatography (SiO2, hexane/EtOAc=2:1 to 3:2 to 1:1) gave the title compound as a white solid. MS: 609.7 (M+1).
Reaction SMILES: BrN1C(=O)CCC1=O.[Cl:9][C:10]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][N:16]2[CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])=[C:12](/[CH:27]=[CH:28]/OCC)[N:11]=1.O1CCOCC1.[NH2:38][C:39]1[C:44]([CH3:45])=[CH:43][CH:42]=[CH:41][N:40]=1>C(OCC)(=O)C.O>[Cl:9][C:10]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][N:16]2[CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:24])([CH3:25])[CH3:26])=[C:12]([C:27]2[N:40]3[CH:41]=[CH:42][CH:43]=[C:44]([CH3:45])[C:39]3=[N:38][CH:28]=2)[N:11]=1
Reactant: CCO/C=C/c1nc(Cl)nc2c1ncn2COCC[Si](C)(C)C
Reactant: Cc1cccnc1N
Agent: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cccn2c(-c3nc(Cl)nc4c3ncn4COCC[Si](C)(C)C)cnc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
200 mg of N-bromosuccinimide was added to the mixture of 400 mg of 2-chloro-6-[(E)-2-ethoxyvinyl]-9-{[2-(trimethylsilyl)ethoxy]methyl}-9H-purine [56-2], 10 mL of 1,4-dioxane, and 2 mL of water under an ice-cold condition, and stirred at the same temperature for 30 minutes. Thereto, 122 mg of 2-amino-3-picoline was added, stirred at 50° C. for 1 hour, and the reaction mixture was cooled back to room temperature. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine in the subsequent order, and the thus obtained organic layer was dried over anhydrous magnesium sulfate. The insolubles were filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to obtain 360 mg of 2-chloro-6-(8-methylimidazo[1,2-a]pyridin-3-yl)-9-{[2-(trimethylsilyl)ethoxy]methyl}-9H-purine [56-3] as a light brown solid.
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])[CH3:3].[K+].[C:7]1([N:13]2[C:26]3[CH:25]=[CH:24][C:23]([CH:27]=O)=[CH:22][C:21]=3[S:20](=[O:30])(=[O:29])[C:19]3[C:14]2=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(OP([CH2:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[CH:51]=[CH:50][C:49]([CH2:52]P(OCC)(OCC)=O)=[CH:48][CH:47]=2)=[CH:42][CH:41]=1)(=O)OCC)C>CS(C)=O.C(Cl)Cl>[C:7]1([N:13]2[C:26]3[CH:25]=[CH:3][C:2]([CH:5]=[CH:52][C:49]4[CH:48]=[CH:47][C:46]([C:43]5[CH:42]=[CH:41][C:40]([CH:39]=[CH:27][C:23]6[CH:24]=[CH:25][C:26]7[N:13]([C:7]8[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=8)[C:14]8[C:19]([S:20](=[O:30])(=[O:29])[C:21]=7[CH:22]=6)=[CH:18][CH:17]=[CH:16][CH:15]=8)=[CH:45][CH:44]=5)=[CH:51][CH:50]=4)=[CH:1][C:21]=3[S:20](=[O:30])(=[O:29])[C:19]3[C:14]2=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)(C)[O-]
Reactant: O=Cc1ccc2c(c1)S(=O)(=O)c1ccccc1N2c1ccccc1
Reactant: CCOP(=O)(Cc1ccc(-c2ccc(CP(=O)(OCC)OCC)cc2)cc1)OCC
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=S1(=O)c2ccccc2N(c2ccccc2)c2ccc(C=Cc3ccc(-c4ccc(C=Cc5ccc6c(c5)S(=O)(=O)c5ccccc5N6c5ccccc5)cc4)cc3)cc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
2.28 g (19.9 mmol) of potassium tert-butoxide and then 5.90 g (17.6 mmol) of 10-phenyl-5,5-dioxophenothiazine-3-carbaldehyde (Example 21) were added under nitrogen at room temperature with stirring to a solution of 4.00 g (8.80 mmol) of diethyl[4′-(diethoxyphosphorylmethyl)biphenyl-4-ylmethyl]phosphonate in 45 ml of dimethyl sulfoxide dried over molecular sieve. After stirring at room temperature for 72 h, the reaction solution was diluted with 200 ml of methanol and stirred for a further 1 h. The precipitate was filtered off, washed with 500 ml of methanol and dried at 80° C. under reduced pressure. The crude product (5.44 g) was recrystallized in 250 ml of o-dichlorobenzene. The crystals were filtered off with suction, washed successively with o-dichlorobenzene and ethanol, filtered off with suction and dried at 80° C. under reduced pressure. After solvent residues had been removed in high vacuum (2×10−5 mbar) at 250° C., 4.35 g (60% of theory) of yellow microcrystals having a melting point of 392° C. were obtained, whose solution in methylene chloride fluoresced at λ=456 nm.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[C@@H:10]([NH:25]C(OC(C)(C)C)=O)[CH2:11][CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35]>ClCCl>[OH:40][C:34]([C:36]([F:39])([F:38])[F:37])=[O:35].[CH2:1]([O:8][C:9]([C@@H:10]1[CH2:11][CH2:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)=[N:25]1)=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)OCc2ccccc2)cc1OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C2=N[C@H](C(=O)OCc3ccccc3)CC2)cc1OC
Temperature: 25 °C
Yield: 91 %

Procedure:
A solution of (2S)2-tert-butoxycarbonylamino-5-(3,4-dimethoxy-phenyl)-5-oxo-pentanoic acid benzyl ester (10.46 g, 0.023 mol) in dichloromethane (150 ml) was cooled to 0° C. in an ice bath. TFA (40 ml) was slowly added to the stirring mixture and the reaction was allowed to warm to room temperature over two hours. The reaction mixture was concentrated in vacuo. The resulting residue was dissolved in ethyl acetate and the pH was adjusted to 7 with 1N NaOH. The organic extract was washed with brine (100 ml). The ethyl acetate extract was dried over anhydrous Na2SO4 and concentrated in vacuo to afford (2S)5-(3,4-dimethoxy-phenyl)-3,4-dihydro-2H-pyrrole-2-carboxylic acid benzyl ester TFA salt (7.24 g, 0.021 mol, 91% yield). MS (LC-MS): Calculated for C20H21NO4 339.15, found 340.16 (M+H)+.
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[NH:7]1[C:15]2[C:10](=[C:11]([C:16]3[N:17]=[C:18]([N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)[C:19]4[S:24][C:23]([C:25]5[CH:26]=[C:27]([S:31][CH2:32][C@H:33]([OH:35])[CH3:34])[CH:28]=[CH:29][CH:30]=5)=[CH:22][C:20]=4[N:21]=3)[CH:12]=[CH:13][CH:14]=2)[CH:9]=[N:8]1.[OH2:42]>CO>[NH:7]1[C:15]2[C:10](=[C:11]([C:16]3[N:17]=[C:18]([N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)[C:19]4[S:24][C:23]([C:25]5[CH:26]=[C:27]([S:31]([CH2:32][C@H:33]([OH:35])[CH3:34])(=[O:1])=[O:42])[CH:28]=[CH:29][CH:30]=5)=[CH:22][C:20]=4[N:21]=3)[CH:12]=[CH:13][CH:14]=2)[CH:9]=[N:8]1
Reactant: C[C@@H](O)CSc1cccc(-c2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)c1
Reactant: O=S([O-])OO
Reactant: O
Agent: [K+]
Solvent: CO
Product: C[C@@H](O)CS(=O)(=O)c1cccc(-c2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)c1
Reaction time: 2 h

Procedure:
A solution of 322 mg of oxone in 4 mL H2O was added to a mixture of 132 mg of (R)-1-(3-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenylthio)propan-2-ol in 8 mL of methanol. The reaction mixture was stirred for 2 h. The mixture was filtered and the filtrate was evaporated. The product was purified by reverse phase HPLC to yield 3.8 mg of 135. MS (Q1) 536 (M)+
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH:2]([CH:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3].[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[CH2:24][CH:23]([CH2:25][CH:26]3[CH2:31][CH2:30][N:29]([CH2:32][C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH2:28][CH2:27]3)[C:21](=[O:22])[C:16]2=[CH:17][C:18]=1[O:19][CH3:20]>C(O)C>[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[CH2:24][CH:23]([CH2:25][CH:26]3[CH2:27][CH2:28][N:29]([CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:30][CH2:31]3)[C:21](=[O:22])[C:16]2=[CH:17][C:18]=1[O:19][CH3:20].[C:6]([CH:4]([CH:2]([C:1]([O-:10])=[O:9])[OH:3])[OH:5])([O-:8])=[O:7]
Reactant: O=C(O)C(O)C(O)C(=O)O
Agent: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Solvent: CCO
Product: O=C([O-])C(O)C(O)C(=O)[O-]
Temperature: 25 °C

Procedure:
Tartaric acid (1.18 g, dissolved in 7 ml of water) is slowly added to a solution of Donepezil (3.79 g) in absolute ethanol (70 ml) with stirring at room temperature. The solid precipitated is filtered and dried at 55° C. under vacuum to give the title compound.
Reaction SMILES: [F:1][S:2]([OH:5])(=[O:4])=[O:3].[CH:6]1([P:12]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>C(OCC)C>[F:1][S:2]([O-:5])(=[O:4])=[O:3].[CH:19]1([PH+:12]([CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]2)[CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: O=S(=O)(O)F
Reactant: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: CCOCC
Product: C1CCC([PH+](C2CCCCC2)C2CCCCC2)CC1
Product: O=S(=O)([O-])F
Yield: 105.1 %

Procedure:
0.7 ml (12 mmol) fluorosulfonic acid is added to 25 ml of a solution of 12 mmol tricyclohexyl phosphine in diethylether prepared as in example 2. The product precipitates with a strong exotherm. 4.8 g of a colorless solid is obtained.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:23])[N:9]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][CH:3]=1.[CH2:24]([S:27](Cl)(=[O:29])=[O:28])[CH2:25][CH3:26]>>[Cl:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:23])[N:9]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]2)[CH:10]2[CH2:11][CH2:12][N:13]([S:27]([CH2:24][CH2:25][CH3:26])(=[O:29])=[O:28])[CH2:14][CH2:15]2)=[N:4][CH:3]=1
Reactant: CCCS(=O)(=O)Cl
Reactant: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(Cl)s2)C2CCNCC2)CC1
Product: CCCS(=O)(=O)N1CCC(N(C(=O)Nc2ncc(Cl)s2)[C@H]2CC[C@H](C)CC2)CC1

Procedure:
Prepared in a similar manner to Example 554 using 3-(5-chloro-thiazol-2-yl)-1-(trans-4-methyl-cyclohexyl)-1-piperidin-4-yl-urea and propanesulfonylchloride
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1F)[N:8]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH:7]=[C:6]([C:21]([OH:23])=[O:22])[C:5]2=[O:24].[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1[N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)[N:8]([C:14]1[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=1)[CH:7]=[C:6]([C:21]([OH:23])=[O:22])[C:5]2=[O:24]
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(F)c(F)cc2c1=O
Reactant: C1CCNC1
Solvent: c1ccncc1
Product: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(N3CCCC3)c(F)cc2c1=O

Procedure:
3.37 g of 6,7,8-trifluoro-1,4-dihydro-4-oxo-1-(4-fluorophenyl)-quinoline-3-carboxylic acid are refluxed with 2.3 g of pyrrolidine in 30 ml of absolute pyridine for 6 hours. The solvent is distilled off in vacuo, the residue is suspended in 50 ml of ice-water, the pH is brought to 1-2 with hydrochloric acid and the precipitate is filtered off with suction, washed with water and dried. 2.5 g of (I) ##STR41## of melting point 282°-284° C. are obtained. Recrystallization from glycol monomethyl ether/ethanol.
Reaction SMILES: N[C:2]1[C:7](Cl)=[CH:6][N:5]=[C:4]2[O:9][CH2:10][O:11][C:3]=12.[CH2:12]1[O:20]C2C(=NC=CC=2)[O:13]1.C(=O)=O>>[CH2:10]1[O:11][C:3]2[C:4](=[N:5][CH:6]=[CH:7][C:2]=2[C:12]([OH:20])=[O:13])[O:9]1
Reactant: Nc1c(Cl)cnc2c1OCO2
Reactant: c1cnc2c(c1)OCO2
Agent: O=C=O
Product: O=C(O)c1ccnc2c1OCO2
Yield: 80 %

Procedure:
Using an analogous procedure to that described in the second paragraph of the portion of Example 1 that is concerned with the preparation of the starting material 4-amino-5-chloro-2,3-methylenedioxypyridine, 2,3-methylenedioxypyridine was reacted with carbon dioxide gas to give 2,3-methylenedioxypyridine-4-carboxylic acid in 80% yield; NMR Spectrum: (DMSOd6) 6.24 (s, 2H), 7.13 (d, 1H); 7.63 (d, 1H).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[N:14][C:15]([N:18]3[C:26]4[C:21](=[CH:22][C:23]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:24][CH:25]=4)[CH:20]=[CH:19]3)=[CH:16][CH:17]=2)[CH2:7][CH2:6]1)=[O:4].[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH3:30][S:27]([C:23]1[CH:22]=[C:21]2[C:26](=[CH:25][CH:24]=1)[N:18]([C:15]1[N:14]=[CH:13][C:12]([O:11][CH:8]3[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)[CH2:6][CH2:7]3)=[CH:17][CH:16]=1)[CH:19]=[CH:20]2)(=[O:28])=[O:29]
Reactant: CS(=O)(=O)c1ccc2c(ccn2-c2ccc(OC3CCN(C(=O)CCl)CC3)cn2)c1
Reactant: C1CCNCC1
Product: CS(=O)(=O)c1ccc2c(ccn2-c2ccc(OC3CCN(C(=O)CN4CCCCC4)CC3)cn2)c1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-196 using 2-chloro-1-(4-((6-(5-(methylsulfonyl)-1H-indol-1-yl)pyridin-3-yl)oxy)piperidin-1-yl)ethanone and piperidine (0.045 g, 50.56%).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.C([O:12]OC(C)(C)C)(C)(C)C.[C:18]([OH:23])(=[O:22])[C:19]([CH3:21])=[CH2:20].O>C(C(C)=O)C(C)C>[C:18]([O-:23])(=[O:22])[C:19]([CH3:21])=[CH2:20].[C:1]([O-:6])(=[O:7])/[CH:2]=[CH:3]\[C:4]([O-:12])=[O:5]
Reactant: O=C1C=CC(=O)O1
Reactant: C=C(C)C(=O)O
Reactant: CC(C)(C)OOC(C)(C)C
Solvent: CC(=O)CC(C)C
Solvent: O
Product: C=C(C)C(=O)[O-]
Product: O=C([O-])/C=C\C(=O)[O-]
Temperature: 115 °C

Procedure:
In a 3-neck, 300 ml round bottom flask equipped with reflux condenser, nitrogen inlet, mechanical stirrer and pressure-equalizing dropping funnel were combined 58.8 g (0.60 mole) maleic anhydride, 14.6 g di-t-butyl peroxide, 115 g methyl isobutyl ketone and 3.4 g (0.040 mole) glacial methacrylic acid. The system was purged with nitrogen and then heated to reflux under a static positive nitrogen pressure. A small amount of solids momentarily precipitated and then redissolved at about 100° C. When the reaction mixture reached reflux (about 115° C.), the remaining 31.0 g (0.36 mole) methacrylic acid in 60 g of methyl isobutyl ketone was added continuously over a 3-hour period. The reaction solution was refluxed for 15 minutes following the addition, 150 g of water was then added, and the ketone-water mixture refluxed for an additional hour. The isolation procedure of Example 4 was followed to produce a 57 weight percent aqueous solution of homogeneous hydrolyzed methacrylate/maleate copolymer of number average molecular weight of 610 in 98 weight percent yield.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][NH:11]2)=[CH:7][C:6]=1[OH:14])([CH3:3])[CH3:2].Cl[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23](=[O:25])[CH3:24])[CH:17]=1.CC(C)([O-])C.[K+].O>CS(C)=O.C(OCC)(=O)C>[CH:1]([O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][NH:11]2)=[CH:7][C:6]=1[O:14][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23](=[O:25])[CH3:24])[CH:17]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cc2[nH]ccc2cc1O
Reactant: CC(=O)Nc1cc(Cl)ccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)Nc1cc(Oc2cc3cc[nH]c3cc2OC(C)C)ccn1
Temperature: 160 °C
Reaction time: 3 h
Yield: 41 %

Procedure:
6-Isopropoxy-1H-indol-5-ol described in Production Example 17-4 (165 mg, 0.863 mmol) and N-(4-chloropyridin-2-yl)acetamide described in Production Example 1-5 (442 mg, 2.59 mmol) were dissolved in dimethylsulfoxide (2.0 mL) under nitrogen atmosphere, then potassium tert-butoxide (194 mg, 1.73 mmol) was added at room temperature, and the mixture was heated and stirred at 160° C. for 3 hours. The reaction liquid was cooled to room temperature and water and ethyl acetate were added for partition. The aqueous layer was extracted with ethyl acetate and the combined organic layer was washed with water and a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate and then filtered, then the filtrate was concentrated under vacuum. The residue was dissolved in dichloromethane, the resultant was purified with NH silica gel column chromatography (n-heptane:ethyl acetate=3:2-1:3), and then the target fraction was concentrated under vacuum to obtain the title compound (116 mg, 41%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:22])[C:5]2[O:14][C:13]3[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=3[C:6]=2[CH:7]=1.[C:23]1([SH:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[Cl:22][C:4]1[C:5]2[O:14][C:13]3[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=3[C:6]=2[CH:7]=[C:2]([S:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:3]=1
Reactant: Sc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3c(Cl)cc(Br)cc3c2C1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCc2oc3c(Cl)cc(Sc4ccccc4)cc3c2C1
Temperature: 110 °C
Yield: 102.5 %

Procedure:
A mixture of tert-butyl 8-bromo-6-chloro-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (1.00 g, 2.58 mmol), benzenethiol (0.40 mL, 3.87 mmol), di-palladium-tris(dibenzylideneacetone) (118 mg, 0.13 mmol), N,N-diisopropylethylamine (0.9 mL, 5.16 mmol) and xantphos (149 mg, 0.26 mmol) were suspended in anhydrous dioxane (10 mL). The reaction flask was purged with argon and the mixture heated to 110° C. for 14 h. After cooling, the reaction mixture was diluted with dichloromethane and filtered through a celite bed. The filtrate was concentrated in vacuo and the residue purified by flash column chromatography (SiO2, 9:1 hexanes/ethyl acetate) to give tert-butyl 6-chloro-8-(phenylthio)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (1.10 g, 91%) as an off-white solid: 1H NMR (CDCl3, 400 MHz) δ 7.47-7.38 (m, 1H), 7.34 (d, J=1.2 Hz, 1H), 7.31-7.27 (m, 1H), 7.26-7.25 (m, 2H), 7.24-7.19 (m, 2H), 4.50 (s, 2H), 3.86-3.79 (m, 2H), 2.92-2.87 (m, 2H), 1.50 (s, 9H).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:25][C:9]2=[CH:10][N:11]=[C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)[CH2:16][CH2:15]3)[CH:13]=[C:8]2[CH:7]=1)=[O:5])C>C1COCC1.CO.O>[CH:20]1([N:17]2[CH2:16][CH2:15][N:14]([C:12]3[CH:13]=[C:8]4[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[NH:25][C:9]4=[CH:10][N:11]=3)[CH2:19][CH2:18]2)[CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: CCOC(=O)c1cc2cc(N3CCN(C4CCCC4)CC3)ncc2[nH]1
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc2cc(N3CCN(C4CCCC4)CC3)ncc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77 %

Procedure:
A mixture of 0.65 g (1.9 mmol) 5-(4-cyclopentyl-piperazin-1-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester and LiOHxH2O in THF/methanol/water was stirred at room temperature for 16 h. After evaporation of all volatiles the residue was taken up in water and HCl conc. was added. After evaporation the residue was treated with diethyl ether filtered, washed again with diethyl ether and dried to yield 0.46 g (69%) of the title compound as orange solid.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C(OC([N:12]1[CH2:17][C@H:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]3[O:28][CH2:27][CH2:26][N:25]([CH2:29][CH2:30][CH2:31][O:32][CH3:33])[C:24]=3[CH:34]=2)[C@@H:15]([C:35]2[CH:40]=[CH:39][C:38]([CH2:41][O:42][CH2:43][C@H:44]([O:46][CH2:47][CH3:48])[CH3:45])=[CH:37][CH:36]=2)[C@H:14]([CH2:49][OH:50])[CH2:13]1)=O)(C)(C)C.CCN(CC)CC>C(Cl)Cl>[CH2:47]([O:46][C@H:44]([CH3:45])[CH2:43][O:42][CH2:41][C:38]1[CH:39]=[CH:40][C:35]([C@@H:15]2[C@@H:16]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]4[O:28][CH2:27][CH2:26][N:25]([CH2:29][CH2:30][CH2:31][O:32][CH3:33])[C:24]=4[CH:34]=3)[CH2:17][NH:12][CH2:13][C@H:14]2[CH2:49][O:50][C:1](=[O:3])[CH3:2])=[CH:36][CH:37]=1)[CH3:48]
Reactant: CCO[C@H](C)COCc1ccc([C@H]2[C@H](CO)CN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCO[C@H](C)COCc1ccc([C@H]2[C@H](COC(C)=O)CNC[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Reaction time: 1 h

Procedure:
0.89 mmol of acetyl chloride are added to a solution of 0.81 mmol of (3S,4R,5R)-4-[4-((R)-2-ethoxy-propoxymethyl)-phenyl]-3-hydroxymethyl-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylic acid tert-butyl ester (example 1a) and 0.97 mmol of Et3N in 7 ml of CH2Cl2 under argon at 0° C. After 1 h, the reaction mixture is diluted with CH2Cl2 and washed with successively with saturated aqueous NaHCO3 solution and brine. The combined aqueous phases are extracted with CH2Cl2—the combined organic layers are dried over Na2SO4 and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) and is identified based on the Rf value.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2([C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=3)[O:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[O:13]2)[CH2:8][CH2:7]1)[CH3:5].[CH3:29][C:30]1[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[C:31]=1[C:32](O)=[O:33]>>[C:25]([C:24]1[CH:23]=[CH:22][C:21]([C:12]2([CH:9]3[CH2:10][CH2:11][N:6]([CH:4]([CH3:5])[CH2:3][CH2:2][NH:1][C:32](=[O:33])[C:31]4[C:35]([CH3:39])=[CH:36][CH:37]=[CH:38][C:30]=4[CH3:29])[CH2:7][CH2:8]3)[O:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[O:13]2)=[CH:28][CH:27]=1)#[N:26]
Reactant: Cc1cccc(C)c1C(=O)O
Reactant: CC(CCN)N1CCC(C2(c3ccc(C#N)cc3)Oc3ccccc3O2)CC1
Product: Cc1cccc(C)c1C(=O)NCCC(C)N1CCC(C2(c3ccc(C#N)cc3)Oc3ccccc3O2)CC1
Yield: 75 %

Procedure:
Using general procedure E, 4-{2-[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-benzo[1,3]dioxol-2-yl}-benzonitrile (see EXAMPLE 277) (64 mg, 0.17 mmol) and 2,6-dimethylbenzoic acid (28 mg, 0.19 mmol) afforded COMPOUND 279 as a white foam (65 mg, 75%). 1H NMR (CDCl3) δ0.93 (d, 3H, J=6.6 Hz), 0.94-1.23 (m, 2H), 1.42-1.58 (m, 3H), 1.65-1.78 (m, 1H), 1.86-1.98 (m, 2H), 2.28-2.36 (m, 1H), 2.31 (s, 6H), 2.68-2.79 (m, 3H), 3.26-3.36 (m, 1H), 3.71-3.82 (m, 1H), 6.76-6.80 (m, 4H), 7.03 (d, 2H, J=7.8 Hz), 7.15-7.20 (m, 1H), 7.43 (br s, 1H), 7.51-7.53 (m, 2H), 7.61-7.64 (m, 2H). ES-MS m/z 510 (M+H).