Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])=[CH:4][CH:3]=1.N1C=CN=C1.[C:25]([Si:29](Cl)([CH3:31])[CH3:30])([CH3:28])([CH3:27])[CH3:26]>ClCCl.O>[Si:29]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11])=[CH:6][CH:7]=1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:31])[CH3:30]
Reactant: O=C(CCc1ccc(O)cc1)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CCC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 92.3 %

Procedure:
A solution of benzyl 3-(4-hydroxyphenyl)propanoate (1.0 g, 11.70 mmol) in dichloromethane (60 ml) was cooled to 0° C., and imidazole (1.30 g, 18.73 mmol) and tert-butylchlorodimethylsilane (1.94 g, 12.87 mmol) were added thereto, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with water and was extracted with ethyl acetate. The organic layer was washed with saturated brine and was dried over anhydrous sodium sulfate, and the filtrate was removed by distillation under reduced pressure. The residue was chromatographed on silica gel column (hexane:ethyl acetate=95:5) to give the title compound as an oil (4.0 g, yield 95%).
Reaction SMILES: [CH3:1][CH2:2][CH:3](P(OCC)(OCC)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:17][C:18]1[CH2:23][CH2:22][CH2:21][C:20]([CH3:25])([CH3:24])[C:19]=1/[CH:26]=[CH:27]/[C:28](/[CH3:37])=[CH:29]/[CH:30]=[CH:31]/[C:32](/[CH3:36])=[CH:33]/[CH:34]=O>>[CH3:36][C:32]([CH:31]=[CH:30][CH:29]=[C:28]([CH3:37])[CH:27]=[CH:26][C:19]1[C:20]([CH3:25])([CH3:24])[CH2:21][CH2:22][CH2:23][C:18]=1[CH3:17])=[CH:33][CH:34]=[C:3]([CH2:2][CH3:1])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=O)C(C)(C)CCC1
Reactant: CCOC(=O)C(CC)P(=O)(OCC)OCC
Product: CCOC(=O)C(=CC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C)CC

Procedure:
In analogy to the procedure given in Example 1: Triethyl 2-phosphonobutyrate was reacted with retinal to give ethyl 5,9-dimethyl-2-ethyl-11-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8,10-undecapentaenoate, which was converted by the procedure of Example 2 to 5,9-dimethyl-2-ethyl-11(2,6,6-trimethyl -1-cyclohexen-1-yl)-2,4,6,8,10-undecapentaenoic acid, m.p.=164°-165° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH3:21].C(N(CC)CC)C.[CH:29]1([C:34](Cl)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]1>C(Cl)(Cl)Cl>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH3:21])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:34]([CH:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[O:35])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=C(Cl)C1CCCC1
Reactant: CCc1nc2c(N)nc3ccccc3c2n1CCCCN
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)C1CCCC1
Reaction time: 0.17 h
Yield: 76 %

Procedure:
A solution of 1-(4-aminobutyl)-2-ethyl-1H-imidazo[4,5-c]quinolin-4-amine (1.00 g, 3.5 mmol) and triethylamine (0.64 mL, 4.6 mmol) in chloroform (100 mL) was cooled with an acetone/ice bath. Cyclopentanecarbonyl chloride (0.47 mL, 3.9 mmol) was slowly added. The reaction was complete within 10 minutes. The reaction mixture was washed with water (1×100 mL) and brine (1×100 mL). The organic layer was dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was slurried with acetonitrile. The resulting solid was isolated by filtration and dried in an oven overnight to provide 1.01 g of N-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]cyclopentanecarboxamide as a light brown solid, m.p. 178.6-179.5° C. Analysis: Calculated for C22H29N5O.0.25 H2O: % C, 68.81; % H, 7.74; % N, 18.24. Found: % C, 68.77; % H, 7.87; % N, 18.19.
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][O:21][CH3:22])=[C:16]([O:23][C:24]1[CH:29]=[CH:28][C:27](Cl)=[CH:26][CH:25]=1)[CH:15]=[CH:14][CH:13]=3)=[O:6])([CH3:3])[CH3:2].C(N(CC)CC)C>C(O)(C)C.[Pd]>[CH:1]([O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][O:21][CH3:22])=[C:16]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:15]=[CH:14][CH:13]=3)=[O:6])([CH3:3])[CH3:2]
Reactant: COCc1c(C(=O)OC(C)C)ncc2[nH]c3cccc(Oc4ccc(Cl)cc4)c3c12
Agent: [Pd]
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: COCc1c(C(=O)OC(C)C)ncc2[nH]c3cccc(Oc4ccccc4)c3c12

Procedure:
2 g of 5-(4-chlorophenoxy)-4-methoxymethyl-beta-carboline-3-carboxylic acid isopropyl ester in 40 ml of isopropanol is hydrogenated with 200 mg of palladium on carbon (10%) and 0.9 ml of triethylamine at room temperature under normal hydrogen pressure. After filtering off of the catalyst, concentration of the filtrate and digesting of the residue with diisopropyl ether, 1.4 g of 5-phenoxy-4-methoxymethyl-beta-carboline-3-carboxylic acid isopropyl ester with a melting point of 201°-203° C. is obtained.
Reaction SMILES: [NH2:1][C:2]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[CH2:5][N:4]1[C:11](=[O:29])[C:12]([OH:28])=[C:13]([C:15]3[NH:16][CH:17]=[C:18]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[N:19]=3)[N:14]=[C:3]21.[CH3:30][N:31]([CH3:37])[C:32](=[O:36])[C:33](O)=[O:34].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CN(C1C=CN=CC=1)C>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][C:18]2[N:19]=[C:15]([C:13]3[N:14]=[C:3]4[C:2]5([NH:1][C:33](=[O:34])[C:32]([N:31]([CH3:37])[CH3:30])=[O:36])[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10]5)[CH2:5][N:4]4[C:11](=[O:29])[C:12]=3[OH:28])[NH:16][CH:17]=2)=[CH:22][CH:23]=1
Reactant: CN(C)C(=O)C(=O)O
Reactant: NC12CCC(CC1)Cn1c2nc(-c2nc(Cc3ccc(F)cc3)c[nH]2)c(O)c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)C(=O)NC12CCC(CC1)Cn1c2nc(-c2nc(Cc3ccc(F)cc3)c[nH]2)c(O)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 8 %

Procedure:
To a stirred solution of 10-amino-2-(4-(4-fluorobenzyl)-1H-imidazol-2-yl)-3-hydroxy-7,8,9,10-tetrahydro-7,10-ethanopyrimido[1,2-a]azepin-4(6H)-one, Example 1 (27 mg, 0.068 mmol) and 2-(dimethylamino)-2-oxoacetic acid (11.99 mg, 0.102 mmol) in DMF (3 mL) was added N,N-diisopropylethylamine (0.061 mL, 0.35 mmol), DMAP (1.668 mg, 0.014 mmol) and HATU (38.9 mg, 0.102 mmol) and the resulting mixture stirred at room temp for 3 h. The mixture was then concentrated and purified by preparative HPLC to afford the title compound (6 mg, 8% yield) as an off-white solid. 1H NMR (500 MHz, CDCl3) δ ppm 1.63-1.77 (m, 2H), 1.93-1.98 (m, 2H), 2.29-2.38 (m, 4H), 2.50 (br. s., 1H), 3.00 (s, 3H), 3.17 (s, 3H), 4.03 (s, 2H), 4.14 (s, 2H), 6.82 (br. s., 1H), 7.00 (t, J=8.39 Hz, 1H), 7.21-7.27 (m, 3H), 7.70 (s, 1H). LCMS (M+H)=495.20.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)[C:4]=1[CH3:16].[NH:19]1[CH2:24][CH2:23][CH2:22][CH:21]([CH2:25][OH:26])[CH2:20]1.C1COCC1.N1CCCCC1>C(N(CC)CC)C>[OH:26][CH2:25][CH:21]1[CH2:22][CH2:23][CH2:24][N:19]([C:13]([C:11]2[S:12][C:8]([C:5]3[C:4]([CH3:16])=[C:3]([C:2]([F:1])([F:18])[F:17])[O:7][N:6]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:20]1
Reactant: OCC1CCCNC1
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Solvent: C1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccc(C(=O)N3CCCC(CO)C3)s2)noc1C(F)(F)F

Procedure:
Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and 3-piperidinemethanol by the method described in Example 2 Method B reversing the order of addition such that solid acid chloride was added to a THF solution of triethylamine and piperidine derivative. The reaction mixture was evaporated to an oil then partitioned between EtOAc (5 mL) and water (5 mL). The organic fraction was further washed with brine (2×5 mL), dried over MgSO4, filtered, and evaporated to an oil. The crude product was then chromatographed on silica gel with EtOAc/hexanes (75%) as eluant to (190 mg, 75%). 1H NMR (CDCl3) 1.28-1.35 (m, 1 H), 1.44-1.56 (m, 1 H), 1.67-1.82 (m, 3 H), 2.28 (d, J=0.9, 3 H), 2.99 (dd, J=13.2, 9.7, 1 H), 3.32 (br s, 1 H), 3.41-3.52 (m, 2 H), 4.10 (br s, 1 H), 4.21 (d, J=11.4, 1 H), 7.29 (d, J=4.0, 1 H), 7.37 (d, J=4.0, 1 H). 13C NMR 7.8, 24.9, 27.2, 39.1, ˜49 (br), 64.5, 114.8, 118.7 (q, J=271), 128.1, 129.3, 131.2, 140.3, 155.0 (q, J=40), 157.9, 162.9. 19F NMR −63.2. LC/MS 5.91 min, [M+1]+ 375.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH2:14][O:13][CH:12]([CH2:17][NH2:18])[C:11]=2[S:10][C:9]=1[NH2:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:27](Cl)(=[O:29])[CH3:28]>ClCCl>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH2:14][O:13][CH:12]([CH2:17][NH:18][C:27](=[O:29])[CH3:28])[C:11]=2[S:10][C:9]=1[NH2:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CCOC2CN
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCC1OCCc2c1sc(N)c2C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 17.4 %

Procedure:
To a ice water cooled solution of the above 2-amino-7-aminomethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (1.5 g 5.27 mmol) and triethylamine (1.5 ml) in dichloromethane (50 ml) was added dropwise acetylchloride (0.46 g, 5.80 mmol). The reaction mixture was allowed to reach room temperature and stirred for an additional 0.5 h. The reaction mixture was washed with water (2×25 ml), dried (Na2SO4), filtered and the solvent evaporated in vacuo. The residue was purified by column chromatography on silicagel (1 L) using first ethyl acetate and later on a mixture of ethyl acetate and ethanol (20:1) as eluents. Pure fractions were collected and the solvent evaporated in vacuo affording 0.3 g (17%) of 7-(acetylaminomethyl)-2-amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as a solid.
Reaction SMILES: [C:1]1([C:7]2([CH2:16][CH2:17][CH2:18][N:19](C)[CH3:20])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:29]([O:31][CH2:32][C:33]([Cl:36])([Cl:35])[Cl:34])=[O:30].O>C(Cl)Cl>[C:1]1([C:7]2([CH2:16][CH2:17][CH2:18][N:19]([C:29]([O:31][CH2:32][C:33]([Cl:36])([Cl:35])[Cl:34])=[O:30])[CH3:20])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN(C)CCCC1(c2ccccc2)COc2ccccc21
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CN(CCCC1(c2ccccc2)COc2ccccc21)C(=O)OCC(Cl)(Cl)Cl
Yield: 30.4 %

Procedure:
A mixture of 3-(3-phenyl-2,3-dihydrobenzofuran-3-yl)-N,N-dimethylpropylamine (7.40 g, 26 mmol), anhydrous K2CO3 (14.3 g, 104 mmol), and CH2Cl2 (125 ml) was stirred at 5°. A solution of 2,2,2-trichloroethyl chloroformate (4.3 ml, 32 mmol) in CH2Cl2 (5 ml) was added dropwise over 15 minutes. The reaction mixture was stirred at room temperature for 4 hours. Water was then added to dissolve the inorganic salts and the phases were separated. The organic phase was washed with saturated NaHCO3 and saturated NaCl, dried over Na2SO4, filtered, and evaporated in vacuo to give 7.6 g of a crude oil. This residue was chromatographed by HPLC using CH2Cl2 /hexane (2:1, by volume) as an eluent to yield 3.5 g (30%) of an oil.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:9]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([I:17])=[CH:13][C:12]=2[F:18])=[CH:8][S:7][CH2:6]1)=[O:4].C1(Cl)C(=O)C(Cl)=C(Cl)C(=O)C=1Cl>C1(C)C=CC=CC=1>[F:18][C:12]1[CH:13]=[C:14]([I:17])[CH:15]=[CH:16][C:11]=1[NH:10][C:9]1[C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][S:7][CH:8]=1
Reactant: COC(=O)C1CSC=C1Nc1ccc(I)cc1F
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1cscc1Nc1ccc(I)cc1F
Temperature: 25 °C
Yield: 49.5 %

Procedure:
A mixture of methyl-4-(2-fluoro-4-iodo-phenylamino)-2,3-dihydro-thiophene-3-carboxylate (5.7 g, 15.0 mmol) and chloranil (5.7 g, 15.0 mmol) in toluene (50 mL) was heated to reflux for 2 hours. The solution was cooled to room temperature and the solvent was evaporated. The resulting dark brown solid was recrystallized from methanol to provide methyl 4-(2-fluoro-4-iodo-phenylamino)-thiophene-3-carboxylate (2.8 g, 49.5% yield). MS (EI) for C12H9FINO2S: 378 (MH+).
Reaction SMILES: C1(N2CC[O:9]CC2)CCCC=1.[CH3:12][S:13]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)(=[O:15])=[O:14].Cl.[CH:25]1[CH:30]=[CH:29][CH:28]=[CH:27]C=1>>[CH3:12][S:13]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[C:27]2[CH2:28][CH2:29][CH2:30][C:25]2=[O:9])=[CH:18][CH:17]=1)(=[O:15])=[O:14]
Reactant: c1ccccc1
Reactant: CS(=O)(=O)c1ccc(C=O)cc1
Reactant: C1=C(N2CCOCC2)CCC1
Agent: Cl
Product: CS(=O)(=O)c1ccc(C=C2CCCC2=O)cc1
Temperature: 30 °C
Reaction time: 2 h
Yield: 69.9 %

Procedure:
With reflux device installed, 36.8 g (0.24 mol) of N-cyclopentenyl morpholine, 0.20 mol of 4-methanesulfonylbenzaldehyde and 200 mL of benzene were added to a round bottom flask and heated under reflux for 20 h. The resulting solution was cooled to 30° C., and slowly stirred while 62 mL of hydrochloric acid (6 mol/L) was added. After stirring for 2 h at room temperature, the benzene layer was separated and washed with water to neutral, and dried over anhydrous sodium sulfate overnight. Then the mixture was filtered to remove anhydrous sodium sulfate and benzene was recovered by evaporation under reduced pressure. The residue was cooled and solidified, then recrystallized in cyclohexane/ethanol to yield a light yellow flaky crystal product with a yield of 69.9%.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:34]([O:41][N:42]1[C:48](=[O:49])[N:47]2[CH2:50][C@H:43]1[CH2:44][CH2:45][C@H:46]2[C:51]([OH:53])=O)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[NH:54]([C:56](=[O:69])[CH2:57][CH:58]1[CH2:61][N:60]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[CH2:59]1)[NH2:55]>C(Cl)Cl>[CH2:34]([O:41][N:42]1[C:48](=[O:49])[N:47]2[CH2:50][C@H:43]1[CH2:44][CH2:45][C@H:46]2[C:51]([NH:55][NH:54][C:56](=[O:69])[CH2:57][CH:58]1[CH2:61][N:60]([C:62]([O:64][C:65]([CH3:67])([CH3:66])[CH3:68])=[O:63])[CH2:59]1)=[O:53])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC(C)(C)OC(=O)N1CC(CC(=O)NN)C1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(CC(=O)NNC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 91 %

Procedure:
HATU (19.6 g, 52.2 mmol) and DIPEA (16.6 g, 130.5 mmol) were added to a 0° C. solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carboxylic acid (12.0 g, 43.5 mmol), tert-butyl 3-(2-hydrazinyl-2-oxoethyl)azetidine-1-carboxylate (11.3 g, 49.8 mmol) in CH2Cl2 (360 mL). The mixture was allowed to warm to rt then the mixture was stirred at rt for 12 hrs. The mixture was then diluted with CH2Cl2 (300 mL), washed with water (2×) and saturated sodium chloride (2×), dried and concentrated. The residue was purified by silica gel column chromatography (0-20% gradient elution EtOAc/petroleum ether) to afford tert-butyl 3-(2-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza bicyclo[3.2.1]octane-2-carbonyl)hydrazinyl)-2-oxoethyl)azetidine-1-carboxylate (19.3 g, 93%) as a white solid. ESI-MS (EI+, m/z): 488 [M+H]+.
Reaction SMILES: [OH:1][C@@H:2]([C@@H:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3](N)=[O:4].[C:14]([Cl:17])(=[O:16])C>CO>[ClH:17].[OH:1][C@@H:2]([C@@H:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([O:16][CH3:14])=[O:4]
Reactant: CC(=O)Cl
Reactant: NC(=O)[C@@H](O)[C@@H](N)c1ccccc1
Solvent: CO
Product: COC(=O)[C@@H](O)[C@@H](N)c1ccccc1
Product: Cl
Temperature: 25 °C

Procedure:
To a solution of 10.0 g of (2S, 3S) 2-hydroxy-3-amino-3-phenylpropionamide in 100 ml of methanol was slowly added 16 ml of acetyl chloride at 0° C. The reaction mixture was refluxed for 20 h then cooled to room temperature and filtered to remove the ammonium chloride salt. The filtrate was concentrated to one third of its original volume and diluted with 150 ml of ether. The precipitated salt was filtered off and washed with 100 ml of ether to give 10.6 g of methyl (2S, 3S) 2-hydroxy-3-amino-3-phenylpropionate hydrochloride as a colorless solid.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[OH:5][CH:6]1[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]1.C(N(CC)CC)C.C(Cl)[Cl:21]>C1(C)C=CC=CC=1>[Cl:21][CH2:10][CH2:11][CH:6]1[O:5][C:1](=[O:2])[N:9]([CH3:12])[CH2:8][CH2:7]1
Reactant: O=C(Cl)Cl
Reactant: ClCCl
Reactant: CN1CCC(O)CC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CN1CCC(CCCl)OC1=O
Reaction time: 1 h
Yield: 22 %

Procedure:
To a cold (ice bath) solution of 85.8 g (0.868 mole) of phosgene in 500 ml of methylene chloride was added dropwise a solution of 100 g (0.868 mole) of 4-hydroxy-1-methylpiperidine in 250 ml of methylene chloride at such a rate that the internal temperature did not exceed 12° C. A crystalline solid precipitated during addition. The mixture was stirred in the cold for 1 hr after addition was complete and then 120.8 ml (87.7 g, 0.868 mole) of triethylamine was added dropwise at such a rate that the internal temperature did not exceed 25° C. The mixture was stirred at ambient temperature overnight and then diluted with 500 ml of toluene. The methylene chloride was removed by distillation and the resultant mixture was heated at reflux for 2 hr. The mixture was cooled and treated with 500 ml of 1N hydrochloric acid. The layers were separated and the organic layer was washed successively with 500 ml of 1N hydrochloric acid, 500 ml of a 4% sodium hydroxide solution and once with brine, dried over anhydrous sodium sulfate and concentrated to give an oil as residue. The oil was subjected to vacuum distillation to give 34.4 g (22%) of clear oil (b.p. 147°-150° C. at 0.4 mm).
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]2)[O:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C([C:24]([O:26][CH2:27][CH3:28])=[O:25])#N.CCOC(C)=O>C1COCC1.O>[CH2:27]([O:26][C:24]([CH:8]1[C:7](=[O:10])[CH2:6][CH2:5][C:4]2([O:3][CH2:2][CH2:1][O:11]2)[CH2:9]1)=[O:25])[CH3:28]
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: CCOC(=O)C#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C1CC2(CCC1=O)OCCO2
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
1,4-Cyclohexanedione mono-ethylene ketal (25 g) was dissolved in THF and cooled to −78° C. 1.0 M Lithium bis(trimethylsily)amide (160 mL) in THF was added dropwise. After 30 min, ethyl cyanoformate (15.9 mL) was added dropwise. After 60 min, the solution was poured into EtOAc and water containing ice. The organic layer was washed with water and brine before it was dried and concentrated. This crude was filtered through a plug of silica to give the 8-oxo-1,4-dioxa-spiro[4.5]decane-7-carboxylic acid ethyl ester (32.4 g). MS found: (M+H)+=228.9.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:27])[CH2:11][CH2:12][C:13]1[N:14]=[C:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([OH:26])[CH:19]=2)[O:16][CH:17]=1)[CH3:2].N12CCCN=C1CCC[CH2:30][CH2:29]2.C(I)C>C(O)C>[CH2:29]([O:26][C:20]1[CH:19]=[C:18]([C:15]2[O:16][CH:17]=[C:13]([CH2:12][CH2:11][C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[O:3][CH2:1][CH3:2])=[O:27])[N:14]=2)[CH:23]=[CH:22][C:21]=1[O:24][CH3:25])[CH3:30]
Reactant: CCOc1ccccc1C(=O)CCc1coc(-c2ccc(OC)c(O)c2)n1
Reactant: C1CCC2=NCCCN2CC1
Solvent: CCI
Solvent: CCO
Product: CCOc1cc(-c2nc(CCC(=O)c3ccccc3OCC)co2)ccc1OC
Reaction time: 4 h

Procedure:
A 0.3 g quantity of 1-(2-ethoxyphenyl)-3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]propan-1-one obtained in Example 101 was suspended in 10 ml of ethanol, 0.37 g of 1,8-diazabicyclo[5,4,0]undec-7-ene and 0.26 g of ethyl iodide were added thereto, and the suspension was stirred for 4 hours while heating and refluxing. After distilling off ethanol under reduced pressure, water was added, ethyl acetate extraction was performed, followed by drying over anhydrous magnesium sulfate and distilling the solvent off. The residue was subjected to silica gel column purification (n-hexane:ethyl acetate=3:1), thereby yielding 0.15 g of white powdery 3-[2-(3-ethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-one.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([NH:10][C:11](=[O:15])OCC)=[N:2]1.[CH2:16]1[CH2:26][CH2:25][N:24]2[C:19](=NC[CH2:22][CH2:23]2)[CH2:18][CH2:17]1.[OH2:27]>CN(C)C=O.CO.Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([NH:10][C:11]([N:24]2[CH2:25][CH2:26][C:16]([C:17]3[CH:18]=[CH:19][CH:3]=[C:4]([CH3:9])[C:5]=3[CH3:6])([OH:27])[CH2:22][CH2:23]2)=[O:15])=[N:2]1
Reactant: CCOC(=O)Nc1n[nH]c2ccccc12
Reactant: C1CCC2=NCCCN2CC1
Reactant: O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cccc(C2(O)CCN(C(=O)Nc3n[nH]c4ccccc34)CC2)c1C
Temperature: 120 °C
Yield: 47 %

Procedure:
Ethyl 1H-indazol-3-ylcarbamate (1.2 g) and the compound (1.46 g) of Starting Material Synthetic Example 106 were dissolved in dimethylformamide (10 ml), DBU (2.3 ml) was added thereto, and the mixture was stirred with heating at 120° C. for 2 hr. After completion of the reaction, the reaction mixture was diluted with methanol (3 ml) and 1N hydrochloric acid and water were added to the mixture. The precipitated solid was collected by filtration and vacuum dried to give 4-(2,3-dimethylphenyl)-4-hydroxy-1-piperidinecarboxylic acid (1H-indazol-3-yl)amide (1.02 g, yield 47%).
Reaction SMILES: [N:1]1([CH2:10][CH2:11][OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Cl:13][C:14]1[CH:19]=[N:18][CH:17]=[C:16](Cl)[N:15]=1>O1CCOCC1.ClCCl>[Cl:13][C:14]1[CH:19]=[N:18][CH:17]=[C:16]([O:12][CH2:11][CH2:10][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[N:15]=1
Reactant: OCCn1ccc2ccccc21
Reactant: Clc1cncc(Cl)n1
Solvent: C1COCCO1
Solvent: ClCCl
Product: Clc1cncc(OCCn2ccc3ccccc32)n1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
K-t-BuO (0.67 g, 5.93 mmol) was added to a stirred solution of the product obtained in step 1 above (0.67 g, 5.93 mmol) in dioxane (20 mL) at 0° C. (ice-bath). After being stirred for 7 min at 0° C. and 5 min at room temperature, the mixture was chilled to 0° C. (ice-bath) and 2,6-dichloropyrazine (2.62 g, 17.6 mmol) was added. The yellowish reaction mixture was stirred at 0° C. for 20 min and at room temperature for 10 min and then diluted with dichloromethane. Drying (K2CO3), filtration, and concentration in vacuo furnished a beige oil. This material was purified by chromatography on silica gel (13×4 cm) using n-hexane/ethyl acetate (80:20). This furnished 1.39 g (94%) of the title compound as an oil that solidified upon standing. HRMS m/z calcd for C14H12ClN3O (M)+ 273.0669, found 273.0671. Anal. (C14H12ClN3O) C, H, N.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.IC.[C:14](=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:14][O:8][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
3 g of 5-fluoro-2-nitrophenol are dissolved in DMF and, after addition of 1.1 equivalent each of iodomethane and cesium carbonate, stirred at room temperature. After the reaction is complete, the reaction mixture is poured into water, extracted with diethyl ether, washed and concentrated. 3.2 g of 2-methoxy-4-fluoronitro-benzene are produced. Starting from this, 4.2 g of 2-methoxy-4-pyrrolidinylnitrobenzene are prepared by reaction with pyrrolidine by general reaction method A. The crude product is hydrogenated by general method B. 3.6 g of 2-methoxy-4-pyrrolidinylaminobenzene are obtained. Starting from 150 mg of the crude product and by reaction with 2-thiophenesulfonyl chloride, 154 mg of thiophene-2-sulfonic acid 2-methoxy-4-pyrrolidin-1-ylphenylamide are prepared by general method C.