Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C@@:2]([CH3:54])([C:5](=[O:53])[C@@H:6]([NH:11][C:12](=[O:52])[C@@H:13]([NH:21][C:22](=[O:51])[C@@H:23]([N:28](C)[C:29](=[O:49])[C@@H:30]([NH:39][C:40](=[O:48])[CH2:41][N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1)[CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:7][CH:8]([CH3:10])[CH3:9])[CH2:3][I:4].[CH3:55][O:56][C:57]1[CH:71]=[CH:70][C:60]([CH2:61][O:62][C:63](=[O:69])[CH2:64][CH2:65][C:66]([OH:68])=[O:67])=[CH:59][CH:58]=1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:66]([O:68][C@:2]([CH3:54])([CH2:3][I:4])[C:5](=[O:53])[C@H:6]([CH2:7][CH:8]([CH3:9])[CH3:10])[NH:11][C:12](=[O:52])[C@H:13]([CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[NH:21][C:22](=[O:51])[C@H:23]([CH2:24][CH:25]([CH3:27])[CH3:26])[NH:28][C:29](=[O:49])[C@H:30]([CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[NH:39][C:40](=[O:48])[CH2:41][N:42]1[CH2:43][CH2:44][O:45][CH2:46][CH2:47]1)(=[O:67])[CH2:65][CH2:64][C:63]([O:62][CH2:61][C:60]1[CH:59]=[CH:58][C:57]([O:56][CH3:55])=[CH:71][CH:70]=1)=[O:69]
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CCc1ccccc1)NC(=O)CN1CCOCC1)C(=O)[C@](C)(O)CI
Reactant: COc1ccc(COC(=O)CCC(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc(COC(=O)CCC(=O)O[C@](C)(CI)C(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCc2ccccc2)NC(=O)CN2CCOCC2)cc1
Temperature: 30 °C
Reaction time: 3 h
Yield: 89.9 %

Procedure:
Referring to FIG. 43, to a solution of compound (S)—N—((S)-1-(((2S,4S)-2-hydroxy-1-iodo-2,6-dimethyl-3-oxoheptan-4-yl)amino)-1-oxo-3-phenylpropan-2-yl)-4-methyl-2-((S)—N-methyl-2-(2-morpholinoacetamido)-4-phenylbutanamido)pentanamide (20, 1.5 g, 1.77 mmol) in DCM (10 mL) were added 4-((4-methoxybenzyl)oxy)-4-oxobutanoic acid (2.1 g, 8.81 mmol), DCC (1.82 g, 8.82 mmol) and DMAP (1.08 g, 8.84 mmol). The reaction mixture was stirred for 3 h at 30° C. (TLC analysis showed very little of 19 was left). The mixture was diluted with DCM (100 mL) and then filtered. The filtrate was washed with saturated citric acid solution (50 mL×2) and saturated NaHCO3 solution (50 mL×3), dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column chromatography (EtOAc/DCM=1:15 to 2:1) to give product (1.7 g, 90% yield) as a yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:12](=[C:14]([C:18]([O-:20])=O)[CH:15]=[CH:16][CH:17]=3)[N:13]=2)=[CH:5][CH:4]=1.O.[NH4+:22]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:12](=[C:14]([C:18]([NH2:22])=[O:20])[CH:15]=[CH:16][CH:17]=3)[N:13]=2)=[CH:5][CH:4]=1
Reactant: [NH4+]
Reactant: COc1ccc(-c2nc3c(C(=O)[O-])cccc3o2)cc1
Solvent: O
Product: COc1ccc(-c2nc3c(C(N)=O)cccc3o2)cc1
Yield: 45 %

Procedure:
Methyl 2-(4-methoxyphenylbenzo[d]oxazole-4-carboxylate (68 mg, 0.24 mmol) in ammonium water (10 mL) was stirred at 30° C. overnight, then filtered, and the cake was washed with water, dried in vacuum to obtain 2-(4-methoxyphenylbenzo[d]oxazole-4-carboxamide (29 mg, yield 45%). 1H-NMR (400 MHz, DMSO-d6) δ 3.88 (s, 3H), 7.17-7.19 (d, J=8 Hz, 1H), 7.49 (dd, 1H), 7.94-7.97 (m, 3H), 8.25-8.26 (d, J=8 Hz, 2H), 8.49 (brs, 1H); LC-MS (ESI) m/z 269 [M+1]−.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=[O:5].[C:17]([O-])([O-])([O:19][CH3:20])[CH3:18].C(O)(=O)C>C1C=CC=CC=1>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:4](=[O:5])[C:3]1[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=1[N:1]=[C:17]([O:19][CH3:20])[CH3:18]
Reactant: Nc1ccccc1C(=O)c1ccccc1Cl
Reactant: COC(C)([O-])[O-]
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: COC(C)=Nc1ccccc1C(=O)c1ccccc1Cl

Procedure:
A solution of 20 parts of 2-amino-2'-chlorobenzophenone, 15 parts of methyl orthoacetate, 12 volume parts of acetic acid in 250 parts of benzene is refluxed for 5 hours. The mixture is washed with saturated aqueous sodium bicarbonate solution and water, and then dried over sodium sulfate. Evaporation of the solvent gives 2'-chloro-2-(1-methoxyethylideneamino) benzophenone as an oily substance in almost quantitative yield.
Reaction SMILES: C(N(CC)CC)C.Cl.Cl.[N:10]1[CH:15]=[CH:14][CH:13]=[N:12][C:11]=1[C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[CH:21]([N:25]1[CH2:28][C:27]3([CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[CH2:26]1)[CH2:20][CH2:19]2.[CH:34]1([C:37]2[CH:42]=[CH:41][C:40]([CH2:43][C:44](O)=[O:45])=[CH:39][CH:38]=2)[CH2:36][CH2:35]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH:34]1([C:37]2[CH:38]=[CH:39][C:40]([CH2:43][C:44]([N:31]3[CH2:30][CH2:29][C:27]4([CH2:26][N:25]([CH:21]5[C:22]6[C:18](=[CH:17][C:16]([C:11]7[N:12]=[CH:13][CH:14]=[CH:15][N:10]=7)=[CH:24][CH:23]=6)[CH2:19][CH2:20]5)[CH2:28]4)[CH2:33][CH2:32]3)=[O:45])=[CH:41][CH:42]=2)[CH2:36][CH2:35]1
Reactant: c1cnc(-c2ccc3c(c2)CCC3N2CC3(CCNCC3)C2)nc1
Reactant: O=C(O)Cc1ccc(C2CC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1ccc(C2CC2)cc1)N1CCC2(CC1)CN(C1CCc3cc(-c4ncccn4)ccc31)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (0.1 mL) was added to a solution of 2-(5-pyrimidin-2-yl-2,3-dihydro-1H-inden-1-yl)-2,7-diazaspiro[3.5]nonane dihydrochloride (5-1b, 80 mg, 0.2 mmol), 4-cyclopropylphenylacetic acid (SM-1ag, 31 mg, 0.2 mmol), and HATU (93 mg, 0.24 mmol) in dichloromethane (5 mL) in a vial. The reaction was stirred at room temperature overnight and was quenched with aqueous sodium bicarbonate. The organic layer was dried over MgSO4, filtered and concentrated. The residue was chromatographed on a Combiflash ISCO purification system (Teledyne Corp., Lincoln, Nebr.) using a 12 g silica column with dichloromethane-methanol as eluant. The final product was obtained as off-white solid (89 mg, 92%). MS (APCI) 478.6 (M+H)+. 1H NMR (CDCl3) δ 0.65-0.69 (m, 3H), 0.92-0.97 (m, 2H), 1.67-1.71 (m, 2H), 1.83-1.90 (m, 2H), 2.19-2.22 (m, 1H), 2.89 (s, 1H), 3.18-3.26 (m, 5H), 3.31-3.35 (m, 2H), 3.51-3.55 (m, 2H), 3.66-3.70 (m, 3H), 4.01-4.06 (m, 1H), 7.00-7.04 (m, 2H), 7.10-7.13 (m, 2H), 7.17-7.21 (m, 1H), 7.41 (s, 1H), 8.31 (s, 2H), 8.79-8.82 (m, 2H).
Reaction SMILES: [P:1]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[O:2]CCCCCCCCCCCC.[C:41]([C:45]1[C:50]([OH:51])=[C:49]([CH3:52])[C:48]([CH2:53]Cl)=[C:47]([CH3:55])[CH:46]=1)([CH3:44])([CH3:43])[CH3:42]>>[C:41]([C:45]1[CH:46]=[C:47]([CH3:55])[C:48]([CH2:53][P:1](=[O:2])([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[C:49]([CH3:52])[C:50]=1[OH:51])([CH3:44])([CH3:43])[CH3:42]
Reactant: CCCCCCCCCCCCOP(OCCCCCCCCCCCC)OCCCCCCCCCCCC
Reactant: Cc1cc(C(C)(C)C)c(O)c(C)c1CCl
Product: CCCCCCCCCCCCOP(=O)(Cc1c(C)cc(C(C)(C)C)c(O)c1C)OCCCCCCCCCCCC
Reaction time: 4 h

Procedure:
41 Grams of trilauryl phosphite and 16.1 grams of 6-tert.-butyl-3-chloromethyl-2,4-dimethylphenol were stirred together as a melt at 105° to 110° for 1 hour, followed by 110° to 120° for 2 hours, 120° to 125° for 10 hours and finally at 140° to 145° for 4 hours. The crude was topped in the "ASCO 50" Rotafilm Molecular Still at a wall temperature of 80° to 90° at 1 to 5 microns Hg. pressure to remove most of the by-product dodecyl chloride as well as small amounts of other volatiles. This topping procedure was repeated at a wall temperature of 200° to 210° at the same pressure to remove additional volatiles. The desired product distilled at a wall temperature of 250° to 260° at 1 micron Hg. pressure yielding the desired product as a colorless liquid which solidified to a white solid (m.p. 36° to 42°). (compound 3)
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C.Cl[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=1[Cl:23].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([SH:31])=[CH:27][CH:26]=1>O>[Cl:23][C:15]1[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:14]=1[S:31][C:28]1[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Reactant: Sc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=[N+]([O-])c1ccc(Sc2ccc(Cl)cc2)c(Cl)c1
Temperature: 37.5 °C
Reaction time: 2.5 h
Yield: 92.6 %

Procedure:
Potassium carbonate (10.4 g) was added to a mixture composed of 50 mL of N,N-dimethylacetamide, 19.2 g of 1,2-dichloro-4-nitrobenzene, and 14.5 g of 4-chlorobenzenethiol. This mixed solution was stirred at 35 to 40° C. for 2.5 hr. This reaction solution was poured into 500 mL of iced water, and the precipitated crystals were collected by filtration to give 27.8 g of 2-chloro-1-(4-chlorophenylthio)-4-nitrobenzene (yield 92.5%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.N1C=CC=CC=1>O1CCCC1>[N:12]1([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: C1CNCCN1
Reactant: Clc1ccc2ccccc2n1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: c1ccc2nc(N3CCNCC3)ccc2c1
Yield: 91.4 %

Procedure:
A mixture of 2-chloroquinoline (10.0 g, 60.5 mmol), piperazine (26.1 g, 303 mmol) and pyridine (15 ml) was heated reflux temperature for 4 h. The hot reaction mixture was poured into a conical flask and diluted with tetrahydrofuran (150 ml). The precipitated solid was filtered off and washed with diethyl ether (3×50 ml) and the combined organic phases were evaporated in vacuo. The residue was suspended in a mixture of diethyl ether (200 ml) and 96% ethanol (80 ml) and undissolved solid was filtered off and washed with diethyl ether. The organic phase was evaporated in vacuo affording a solid which was crushed under water (200 ml) filtered off and washed with water (3×50 ml), diethyl ether (3×40 ml), dried in vacuo at 50° C. affording 11.8 g (92%) of 2-(1-piperazinyl)quinoline as a solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.[CH2:18]([O:20][C:21](=[O:25])[CH:22]=[N+]=[N-])[CH3:19].B(F)(F)F.CCOCC>CCOCC>[O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:9])[CH2:4][CH2:3][CH:22]1[C:21]([O:20][CH2:18][CH3:19])=[O:25]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: FB(F)F
Solvent: CCOCC
Product: CCOC(=O)C1CCN(C(=O)OCc2ccccc2)CCC1=O
Temperature: -45 °C
Reaction time: 0.5 h
Yield: 87.9 %

Procedure:
A dry 500 ml 3-neck flask was charged with benzyl 4-oxo-1-piperidinecarboxylate (35.08 g, 150 mmol). It was dissolved in 130 ml Et2O and cooled to −45° C. Ethyldiazoacetate (20.5 ml, 195 mmol) and boron trifluoride ethyl ether (19.4 ml, 158 mol) were added simultaneously by syringe pump over 45 minutes. The temperature was kept below −25° C. The reaction was stirred for 30 minutes longer, and then quenched with sat. NaHCO3. The ice bath was removed. The reaction was diluted with EtOAc (250 ml) and H2O (150 ml). The layers were separated, and the organic phase was dried over MgSO4. It was concentrated under reduced pressure to an orange oil. The product was purified by flash chromatography (silica gel, 40% EtOAc/hexane), yielding product as pale yellow oil (42.1 g, 88%). 1H NMR (CDCl3)δ 67.39-7.31, 5.15-5.12, 4.42-4.17, 3.96-3.83, 3.75-3.70, 3.65, 3.54-3.37, 2.08-2.03, 1.29-1.24; IR (liq.) 1743, 1702, 1476, 1455, 1443, 1425, 1371, 1318, 1295, 1238, 1213, 1178, 1098, 1068, 1028 cm−1.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Cl:12])=[N:4][C:3]=1[CH3:13].CN([CH:17]=[O:18])C>CCCCCC.C1COCC1>[Cl:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([CH:17]=[O:18])=[C:3]([CH3:13])[N:4]=1
Reactant: CN(C)C=O
Reactant: Cc1nc(Cl)c2ccccc2c1Br
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1nc(Cl)c2ccccc2c1C=O
Reaction time: 0.67 h
Yield: 81 %

Procedure:
n-BiLi (12.3 ml of 1.6 M in hexane, 20 mmol) is added dropwise to a solution of 4-bromo-1-chloro-3-methyl-isoquinoline (4.6 g, 18 mmol) in THF (80 ml) at −78° C. and the mixture is stirred for 40 min. DMF (4.2 ml, 54 mmol) is then added slowly. The cold bath is removed, and stirring is continued for 15 min. The mixture is acidified with 1N—HCl to pH 2 and extracted with ether. The combined extracts are dried over Na2SO4 and concentrated in vacuo. The residue is chromatographed on silica gel to give 3.0 g of 1-chloro-3-methyl-isoquinoline-4-carbaldehyde. 1H NMR (CDCl3) 10.9 (s, 1H), 9.06 (d, 1H), 8.40 (d, 1H), 7.88 (t, 1H), 7.70 (t, 1H), 2.99 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].Br[CH2:10][CH2:11]Br.C([O-])([O-])=O.[K+].[K+].O>C1COCC1>[S:8]1[CH2:11][CH2:10][NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2
Reactant: BrCCBr
Reactant: Nc1ccccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc2c(c1)NCCS2
Temperature: 100 °C
Yield: 72.7 %

Procedure:
A mixture of 2-aminothiophenol (5 g, 40 mmol), 1,2-dibromoethane (3.75 g, 20 mmol), K2CO3 (13.8 g, 100 mmol) in THF (30 mL) was heated at 100° C. for 16 h. After completion of reaction, water was added and extracted with EtOAc. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The reaction mixture was purified by column chromatography (using 100-200 mesh silica) and the desired product was eluted at 15% EtOAc in hexane) to obtained 2.2 g of desired product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:23](O)=[O:24])=[N:11][CH:12]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)CCCN=C=NCC.Cl.[C:38]([O:42][C:43](=[O:46])[CH2:44][NH2:45])([CH3:41])([CH3:40])[CH3:39].C(N(C(C)C)CC)(C)C>CN(C=O)C.ON1C2C=CC=CC=2N=N1>[C:38]([O:42][C:43](=[O:46])[CH2:44][NH:45][C:23]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:14][C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][N:11]=1)=[O:24])([CH3:41])([CH3:40])[CH3:39]
Reactant: O=C(O)c1ncc(OCc2ccccc2)cc1OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CNC(=O)c1ncc(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 99 %

Procedure:
To a solution of 3,5-bis-benzyloxy-pyridine-2-carboxylic acid, 2, (2.36 g, 6.36 mmol) in DMF (20 mL) at room temperature under N2 is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (1.83 g, 9.54 mmol) and 1-hydroxybenzotriazole (HOBt) (0.086 g, 0.64 mmol). The mixture is stirred for 15 minutes after which time glycine tert-butyl ester hydrochloride (1.60 g, 9.54 mmol) and diisopropylethylamine (DIPEA) (3.32 ml, 19.08 mmol) are added. The resulting solution is stirred at room temperature for 48 hours then concentrated under reduced pressure. The resulting brown oil is purified over silica (EtOAc) to afford 3.04 g (99% yield) of the desired compound as a yellow solid. 1H NMR (250 MHz, CDCl3) δ ppm 8.19 (1H, t, J=5.2 Hz), 8.01-8.08 (2H, m), 7.27-7.54 (9H, m), 6.97 (1H, d, J=2.4 Hz), 5.24 (2H, s), 5.13 (2H, s), 4.17 (2H, d, J=5.2 Hz), 1.51 (9H, s). HPLC-MS: m/z 449 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH2:10][CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.C1C=C(Cl)C=C(C(OO)=[O:19])C=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][N+:5]([O-:19])=[C:4]2[CH2:8][CH2:9][CH2:10][C:3]=12
Reactant: Clc1ncnc2c1CCC2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: [O-][n+]1cnc(Cl)c2c1CCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.7 %

Procedure:
To a solution of 4-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (5.69 g, 36.8 mmol) in chloroform (200 mL) was added MCPBA (19 g, 84.8 mmol) in chloroform (50 mL) dropwise. The mixture was stirred at room temperature for 16 hour. After cooling with ice-water, the mixture was quenched with Na2S2O3 (27.5 g) in water (110 mL) dropwise and followed by Na2CO3 (14 g) in water (52 mL) dropwise. The organic phase was separated and the aqueous phase was extracted with chloroform (3×200 mL). The organic phase was dried and concentrated at low temperature (<25° C.). The residue was subject to chromatography on silica gel, eluting by ethyl acetate to afford 4-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine 1-oxide (2.93 g, 47%). MS (APCI+) [M+H]+171.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Cl:9][C:10]1[CH:11]=[C:12]([CH2:17][C:18]([OH:20])=[O:19])[CH:13]=[CH:14][C:15]=1[Cl:16].Br[CH2:22][CH:23]1[CH2:27][CH2:26][CH2:25][O:24]1>O1CCCC1.CN1CCCN(C)C1=O.CN1CCCN(C)C1=O>[Cl:9][C:10]1[CH:11]=[C:12]([CH:17]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][O:24]2)[C:18]([OH:20])=[O:19])[CH:13]=[CH:14][C:15]=1[Cl:16]
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: BrCC1CCCO1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: O=C(O)C(CC1CCCO1)c1ccc(Cl)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 70.6 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (23 mL of a 0.31M stock solution, 7.13 mmol) cooled to −78° C. was treated with (3,4-dichloro-phenyl)-acetic acid (696 mg, 3.39 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (8.5 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. At this time, the reaction was treated with a solution of 2-bromomethyl-tetrahydro-furan (672 mg, 4.07 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2 mL). The reaction mixture was stirred at −78° C. for 2 h. The reaction was then warmed to 25° C. and was stirred at 25° C. for 18 h. The reaction mixture was then quenched by the dropwise addition of a saturated aqueous ammonium chloride solution. The excess solvent was removed in vacuo. The residue was diluted with water (50 mL) and was treated with a 1N aqueous hydrochloric acid solution until the solution was acidic. The resulting solution was extracted into ethyl acetate (3×50 mL). The organics were washed with a saturated aqueous lithium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate with glacial acetic acid) afforded 2-(3,4-dichloro-phenyl)-3-(tetrahydro-furan-2-yl)-propionic acid (692.3 mg, 70.8%) as a white solid: mp 100-102° C.; FAB-HRMS m/e calcd for C13H14Cl2O3 (M+H)+ 289.0399. found 289.0404.
Reaction SMILES: [C:1]([C:3]1[C:8]2[CH2:9][C:10](=O)[C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[S:13][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2].O.[NH2:20][NH2:21]>C(O)C>[C:1]([C:3]1[C:8]2[CH2:9][C:10](=[N:20][NH2:21])[C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[S:13][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1cccc2c1CC(=O)c1ccccc1S2
Reactant: NN
Solvent: O
Solvent: CCO
Product: N#Cc1cccc2c1CC(=NN)c1ccccc1S2
Yield: 63.1 %

Procedure:
0.9 g of 9-cyano-10,11-dihydro-11-oxo-dibenzo[b,f]thiepin and 1 g of 100% hydrazine hydrate were dissolved in 10 ml of ethanol and the resulting mixture was heated under reflux for 3.5 hours. The reaction mixture was concentrated to 5 ml to separate crystals on cooling, which were collected by filtration. Recrystallization from ethanol afforded 0.6 g of 9-cyano-10,11-dihydro-11-oxo-dibenzo[b,f]thiepin hydrazone as palo brown prismatic crystals having a melting point of 175°-177° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[C:14]#[N:15].S(=O)(=O)(O)[OH:17]>>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[C:14]([NH2:15])=[O:17]
Reactant: O=S(=O)(O)O
Reactant: Cc1nn(-c2ccccc2)c(N)c1C#N
Product: Cc1nn(-c2ccccc2)c(N)c1C(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 100-mL 3-necked round-bottom flask, was placed sulfuric acid (90 mL). To the resulting mixture was then added 5-amino-3-methyl-1-phenyl-1H-pyrazole-4-carbonitrile (30 g, 151.52 mmol, 1.00 equiv), in portions at 10° C. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of water/ice (100 mL). The pH value of the solution was adjusted to about 8-9 with potassium carbonate (conc.). The solids were collected by filtration, to yield 5-amino-3-methyl-1-phenyl-1H-pyrazole-4-carboxamide as a white solid.
Reaction SMILES: [OH:1][C@@H:2]([CH3:21])[CH2:3][C@@H:4]([CH3:20])[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(OCC)C>[C:22]([O:1][C@@H:2]([CH3:21])[CH2:3][C@H:4]([CH3:20])[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H](O)C[C@@H](C)Oc1ccc(-c2ccc(C#N)cc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: CC(=O)O[C@@H](C)C[C@H](C)Oc1ccc(-c2ccc(C#N)cc2)cc1
Yield: 47.4 %

Procedure:
0.50 g of the (R,S)-4-[4'-(3"-hydroxy-1"-methylbutoxy)phenyl]benzonitrile obtained in the above Example 1 was mixed with 0.12 g of acetic anhydride, 0.51 g of triphenylphosphine and 5 ml of ethyl ether. To the obtained mixture, was added dropwise 0.34 g of diethyl azodicarboxylate under stirring. The obtained mixture was stirred at room temperature for three hours. The triphenylphosphine oxide thus precipitated was filtered and desolvated to thereby give a crude product which was purified by silica gel column chromatography with the use of a mixture of ethyl acetate and n-hexane (1:3) as a developing solvent. Thus 0.18 g of the title compound as obtained.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:17]=[C:16]2[C:8]([C:9]3[C:10](=[O:18])[CH2:11][CH2:12][CH2:13][C:14]=3[NH:15]2)=[CH:7][CH:6]=1.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH2:19]([N:15]1[C:14]2[CH2:13][CH2:12][CH2:11][C:10](=[O:18])[C:9]=2[C:8]2[C:16]1=[CH:17][C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc2c3c([nH]c2c1)CCCC3=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c3c(n(Cc4ccccc4)c2c1)CCCC3=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.6 %

Procedure:
To a slurry of sodium hydride (0.26 g, 11 mmol) in dry DMF (50 mL) is added 7-methoxy-1,2,3,9-tetrahydro-4H-carbazol-4-one (2.2 g, 10.2 mmol). The mixture is stirred at room temperature for 30 min. To this is added benzyl bromide (1.3 mL, 11 mmol). The mixture is stirred at room temperature overnight. The mixture is partitioned between water and Et2O. The layers are separated and the organic layer washed twice with water (200 mL). The organic layer is dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (200 mL) silica gel using CH3OH/CH2Cl2 (2/98) gave 1.7 g (55%) of the title compound; IR (drift) 1638, 1628, 1578, 1535, 1497, 1461, 1449, 1357, 1266, 1200, 1149, 1105, 834, 807, 700 cm−1. 1H NMR (CDCl3) δ2.2, 2.6, 2.8, 3.8, 6.7, 6.9, 7.0, 7.3, 8.1; Anal. Calcd for C20H19NO2: C, 78.66; H, 6.27; N, 4.59. Found: C, 78.29; H, 6.39; N, 4.53.