Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:11]3[C:12](=[O:15])[O:13][CH2:14][C:10]=3[C:9]=2[C:17]2[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][CH:18]=2)=[CH:4][CH:3]=1.C[OH:26]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:16][C:11]3[C:12](=[O:15])[O:13][CH2:14][C:10]=3[C:9]=2[C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:24])=[O:26])=[CH:19][CH:18]=2)=[CH:6][CH:7]=1
Reactant: CSc1ccc(-c2c(-c3ccc(F)cc3)sc3c2COC3=O)cc1
Reactant: CO
Solvent: ClCCl
Product: CS(=O)c1ccc(-c2c(-c3ccc(F)cc3)sc3c2COC3=O)cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
2-(4-Fluorophenyl)-3-(4-(methylthio)phenyl)-4H-thieno [2,3-c]furan-6-one (548 mg) (from Step 4) was dissolved in 10 mL of 10:1 CH2Cl2 /-MeOH and treated with 476 mg of MPPM at 0° C. After stirring for 15 min at 0° C. and 1.5 h at room temperature, the reaction mixture was quenched with 20 mL of sat. NaHCO3, and extracted with 50 ml of EtOAc. The extract was dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography eluted with EtOAc to give 490 mg of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:28]=[CH:27][C:6]([O:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C@H:17]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:16][CH2:15]3)=[C:5]([CH2:29][CH2:30][CH3:31])[CH:4]=1)#[N:2].[SH2:32].C(NCC)C>CN(C=O)C>[NH2:2][C:1]([C:3]1[CH:28]=[CH:27][C:6]([O:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C@H:17]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:16][CH2:15]3)=[C:5]([CH2:29][CH2:30][CH3:31])[CH:4]=1)=[S:32]
Reactant: CCCc1cc(C#N)ccc1OCCCOc1ccc2c(c1)CC[C@H]2CC(=O)OCC
Reactant: S
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CCCc1cc(C(N)=S)ccc1OCCCOc1ccc2c(c1)CC[C@H]2CC(=O)OCC
Temperature: 60 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
To a solution of ethyl {(1S)-5-[3-(4-cyano-2-propylphenoxy)propoxy]-2,3-dihydro-1H-inden-1-yl}acetate (Example 143, 1.2 g, 2.9 mmol) in DMF (anhydrous, 15 mL) under argon at rt was passed H2S gas at a moderate rate for 20 min. Then, a solution of diethylamine (0.3 g, 4.3 mmol) in DMF (3 mL) was added in one portion, and the reaction mixture was stirred at 60° C. for 3 h. Upon completion, the reaction was cooled to rt and argon was passed through the reaction mixture for 1 h to remove residual H2S. The reaction mixture was concentrated under reduced pressure and the residue purified by silica gel flash chromatography (EtOAc/Hexane (v/v)=1:1) to give 0.9 g (76%) of the title compound as a yellow solid. 1H NMR (300 MHz, CD3OD): δ 0.94 (t, 3H), 1.31 (t, 3H), 1.52-1.64 (m, 2H), 1.65-1.80 (m, 1H), 2.20-2.44 (m, 4H), 2.58-2.95 (m, 5H), 3.38-3.61 (m, 1H), 4.16-4.21 (m, 4H), 4.26 (t, 2H), 6.69 (d, 1H), 6.80 (s, 1H), 6.95 (d, 1H), 7.09 (d, 1H), 7.79 (d, 1H), 7.84 (s, 1H).
Reaction SMILES: [CH2:1]([N:8]1[C@@H:12]([C:13](OC)=[O:14])[C@@H:11]([C:17](O)=[O:18])[N:10]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:9]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].Cl>O1CCCC1>[CH2:20]([N:10]1[C@H:11]2[CH2:17][O:18][C:13](=[O:14])[C@H:12]2[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]1=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)[C@H]1[C@@H](C(=O)O)N(Cc2ccccc2)C(=O)N1Cc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1OC[C@H]2[C@@H]1N(Cc1ccccc1)C(=O)N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 14 %

Procedure:
A solution of (4S,5R)-1,3-dibenzyl-5-methoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid (mp., 149°-150° C., [α]36525 =-27.6° at c=1 in DMF, 368 mg) in tetrahydrofuran (6 ml) was added dropwise to a mixture of sodium borohydride (98 mg) and tetrahydrofuran (6 ml) at 5°-10° C. The obtained mixture was allowed to warm up to room temperature and to react at the same temperature for 20 hours. Then, 1N hydrochloric acid (10 ml) was added to the reaction mixture. The mixture was stirred at 55°-60° C. for 30 minutes and concentrated under reduced pressure. The residue was extracted with chloroform (30 ml) and water (30 ml). The chloroform layer was washed successively with 5% aqueous sodium hydrogen carbonate and water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel column to yield ( 3aS,6aR)-1,3-dibenzylhexahydro-1H-furo[3,4-d]imidazole-2,4-dione (45 mg). M.P., 116°-117° C. [α. ]D25 =+60.9° (c=1, CHCl3).
Reaction SMILES: [C:1]([C:9]1[CH:36]=[CH:35][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH:27]([O:32][CH2:33][CH3:34])[C:28]([O:30][CH3:31])=[O:29])=[CH:22][CH:21]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:37]([O:44][NH2:45])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH2:37]([O:44][N:45]=[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]1[CH:36]=[CH:35][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][CH:27]([O:32][CH2:33][CH3:34])[C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:25]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CCOC(Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1)C(=O)OC
Reactant: NOCc1ccccc1
Product: CCOC(Cc1ccc(OCCn2c(=O)sc3cc(C(=NOCc4ccccc4)c4ccccc4)ccc32)cc1)C(=O)OC

Procedure:
Starting from the compound obtained in Step C of Example 1, the procedure is as in Step B of Example 2, replacing the hydroxylamine by O-benzylhydroxylamine.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH2:5])=[S:4].Br.Br[CH:8]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:9]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=O.C(N(CC)CC)C>C(#N)C>[CH3:1][NH:2][C:3]1[S:4][C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:5]=1
Reactant: O=C(c1cccnc1)C(Br)c1ccccc1
Reactant: CNC(N)=S
Agent: Br
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CNc1nc(-c2cccnc2)c(-c2ccccc2)s1
Yield: 83.6 %

Procedure:
To a solution of N-methylthiourea (484 mg) in acetonitrile (40 mL), was added 2-bromo-2-phenyl-1-(3-pyridyl)ethanone hydrobromide (2.0 g), and then triethylamine (0.8 mL) was added dropwise to the mixture with stirring. After addition, the resulting mixture was stirred at reflux for 3 h and the solvent was evaporated. An aqueous saturated solution of sodium hydrogen carbonate was added to the residue and extracted with ethyl acetate. The extracts were washed with water, dried and the solvent was evaporated. The crystalline residue was recrystallized from ethyl acetate-isopropyl ether to give the title compound (1.2 g, yield 80%).
Reaction SMILES: [O:1]=[C:2]([CH2:25][OH:26])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C@@H:9]1[C@@H:13](/[CH:14]=[CH:15]/[CH2:16][C:17]([OH:23])([CH3:22])[CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][C:10]1=[O:24].[C:27](OC(=O)C)(=[O:29])[CH3:28]>N1C=CC=CC=1>[O:1]=[C:2]([CH2:25][O:26][C:27](=[O:29])[CH3:28])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C@@H:9]1[C@@H:13](/[CH:14]=[CH:15]/[CH2:16][C:17]([OH:23])([CH3:22])[CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][C:10]1=[O:24]
Reactant: CCCCC(C)(O)C/C=C/[C@H]1C=CC(=O)[C@@H]1CCCCCCC(=O)CO
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCCCC(C)(O)C/C=C/[C@H]1C=CC(=O)[C@@H]1CCCCCCC(=O)COC(C)=O
Reaction time: 18 h

Procedure:
To a solution of 0.1 g of 1,9-dioxo-16-hydroxy-1-hydroxymethyl-16-methyl-10,13-trans-prostadiene in 0.75 ml of pyridine is added 0.026 g of acetic anhydride. After 18 hours at room temperature, the solvent is removed at reduced pressure and the residue is chromatographed on silica gel to give the title compound.
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].CN1C(=O)N(C)CCC1.[H-].[Na+].[Cl:23][C:24]1[CH:25]=[C:26]([C@@H:30]2[C@@H:35]([C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=3)[N:34]([C@@H:43]([CH2:46][CH3:47])[CH:44]=O)[C:33](=[O:48])[C@:32]([CH2:50][CH:51]3[CH2:55][O:54][C:53]([CH3:57])([CH3:56])[O:52]3)([CH3:49])[CH2:31]2)[CH:27]=[CH:28][CH:29]=1>C1COCC1>[Cl:23][C:24]1[CH:25]=[C:26]([C@@H:30]2[C@@H:35]([C:36]3[CH:37]=[CH:38][C:39]([Cl:42])=[CH:40][CH:41]=3)[N:34]([C@@H:43]([CH2:46][CH3:47])[CH:44]=[CH:3][C:1]#[N:2])[C:33](=[O:48])[C@:32]([CH2:50][CH:51]3[CH2:55][O:54][C:53]([CH3:57])([CH3:56])[O:52]3)([CH3:49])[CH2:31]2)[CH:27]=[CH:28][CH:29]=1
Reactant: CC[C@@H](C=O)N1C(=O)[C@@](C)(CC2COC(C)(C)O2)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: CC[C@@H](C=CC#N)N1C(=O)[C@@](C)(CC2COC(C)(C)O2)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reaction time: 0.5 h

Procedure:
To a solution of diethyl cyanomethylphosphonate (126 μL, 0.799 mmol) and DMPU (481 μL, 3.99 mmol) in THF (1.33 mL) was added 60% sodium hydride in mineral oil (24.0 mg, 0.599 mmol) at 0° C. The mixture was stirred for 30 min, and then treated with a solution of (2S)-2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-methyl-2-oxopiperidin-1-yl)butanal prepared above in Step D (207 mg, 0.399 mmol) in THF (1.33 mL). After being stirred for 4 h, the reaction was quenched (water), extracted (2×EtOAc), and washed (sat. aq. NaCl solution). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Purification of the residue by chromatography on silica gel (24 g SiO2, 30 to 40% EtOAc/Hex, gradient elution) provided the title compound as a colorless liquid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][C:3]=1[C:13]([OH:15])=[O:14].[OH-].[Na+].[CH2:18](Br)[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20]>CN(C=O)C>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:18][C:19](=[O:20])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:4][C:3]=1[C:13]([OH:15])=[O:14]
Reactant: O=C(O)c1cc(O)c2ccccc2c1O
Reactant: O=C(CBr)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C(COc1cc(C(=O)O)c(O)c2ccccc12)c1ccccc1
Temperature: 40 °C
Reaction time: 3.5 h
Yield: 75 %

Procedure:
Into a solution of 0.05 mole of 1,4-dihydroxy-2-naphthoic acid in 70 ml. of DMF were dropped, with introduction of nitrogen gas, 10 ml. of a 40% aqueous sodium hydroxide solution and then a solution of 0.05 mole of phenacyl bromide in 10 ml. of DMF, and the resulting mixture was reacted with stirring at 40° C. for 3 to 4 hours. After completion of the reaction, the reaction liquid was poured into ice-hydrochloric acid to deposit crystals, which were then recovered by filtration and recrystallized from acetonitrile to obtain 1-hydroxy-4-benzoylmethoxy-2-naphthoic acid having having a melting point of 190° C. 0.01 Mole of the thus obtained compound and 0.01 mole of N-(δ-2,4-di-tert-amylphenoxy)butylamine were dissolved in 60 ml. of dehydrated dioxane and added with 0.01 mole of dicyclohexyl carbodiimide. The resulting mixture was reacted with stirring at room temperature for 2 hours. After completion of the reaction, the reaction liquid was subjected to filtration, and the filtrate was vaporized under reduced pressure. The residue was charged with n-hexane to deposit crystals, which werethen recoveredby filtration and recrystallized from benzene-n-hexane to obtain a compound having a melting point of 120° to 121° C. (yield 75%). From the measurement of its elementary analysis values and the like, the thus obtained compound was found to be the coupler (1).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[N+:10]([O-])([OH:12])=[O:11].O>C(O)(=O)C>[OH:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1ccccc1O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: O=Cc1cccc([N+](=O)[O-])c1O
Temperature: 25 °C
Yield: 26.3 %

Procedure:
To a solution of 2-hydroxybenzaldehyde (5.0 g, 41 mmol) in acetic acid (50 mL) at 0° C. was added nitric acid (65%, 4 g) dropwise. The reaction mixture was slowly warmed to room temperature for 2 hours and then heated at 40° C. for another 5 hours. The resulting mixture was poured into ice (75 g) and water (500 g). The precipitates were filtrated and purified by silica gel chromatography to afford the product 2-hydroxy-3-nitrobenzaldehyde (1.8 g, yield 26%). 1H NMR (400 MHz, CDCl3) δ ppm 11.44 (s, 1H), 10.42 (s, 1H), 8.34-8.37 (dd, 1H, J=2.0 Hz, 8.4 Hz), 8.10-8.13 (dd, 1H, J=2.0 Hz, 7.6 Hz), 7.12-7.16 (t, 1H, J=8.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]1.[OH:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:48].Cl>>[ClH:1].[ClH:48].[CH3:24][N:23]([CH2:22][C@H:19]1[CH2:20][CH2:21][C@H:16]([NH:15][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([C:30]4[CH:31]=[CH:32][C:27]([OH:26])=[CH:28][CH:29]=4)[N:3]=3)[N:8]=[CH:7][C:6]=2[C:12](=[O:14])[CH3:13])[CH2:17][CH2:18]1)[CH3:25]
Reactant: OB(O)c1ccc(O)cc1
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](CN(C)C)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CC(=O)c1cnc2ccc(-c3ccc(O)cc3)nc2c1N[C@H]1CC[C@H](CN(C)C)CC1

Procedure:
Following general procedure II, 1-(6-chloro-4-{trans-4-[(dimethylamino)methyl]-cyclohexylamino}-1,5-naphthyridin-3-yl)ethanone (76 g, 0.21 mmol) was reacted with (4-hydroxyphenyl)boronic acid (43 g, 0.32 mmol) followed by formation of the dihydrochloride salt to afford the desired product (35 g, 34%) as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 9.11 (s, 1H), 8.41 (d, J=8.9 Hz, 1H), 8.28 (d, J=8.9 Hz, 1H), 8.03-7.97 (m, 2H), 7.04-6.98 (m, 2H), 5.73-5.62 (m, 1H), 3.11 (d, J=6.8 Hz, 2H), 2.94 (s, 6H), 2.75 (s, 3H), 2.50-2.42 (m, 2H), 2.06-1.99 (m, 3H), 1.73-1.61 (m, 2H), 1.40-1.27 (m, 2H); ESI MS m/z 419 [M+H]+; HPLC>99% (AUC), tR=9.24 min.
Reaction SMILES: [Br-].[CH3:2][C:3]1([CH3:36])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([CH:15]([P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH3:16])[CH:6]=[CH:5][C:4]1=2.[N:37]1[CH:42]=[CH:41][C:40]([CH:43]=O)=[CH:39][CH:38]=1>C1OCCC1>[CH3:2][C:3]1([CH3:36])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7](/[C:15](/[CH3:16])=[CH:43]/[C:40]3[CH:41]=[CH:42][N:37]=[CH:38][CH:39]=3)[CH:6]=[CH:5][C:4]1=2
Reactant: O=Cc1ccncc1
Reactant: CC(c1ccc2c(c1)C(C)(C)CCC2(C)C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C/C(=C\c1ccncc1)c1ccc2c(c1)C(C)(C)CCC2(C)C

Procedure:
378 g of [1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethyl]triphenylphosphonium bromide were suspended in 4 l of butylene oxide. After the addition of 51 ml of 4-pyridinecarbaldehyde the mixture was boiled at reflux for 1.5 hours. After cooling the majority of the solvent was evaporated in a water-jet vacuum, the residue was poured into 1.5 l of a methanol/water mixture (ratio 6:4) and extracted repeatedly with hexane. The organic phase was washed three times with water and, after drying over sodium sulphate, evaporated. After flash chromatography (eluting agent hexane/ether=2:1) and recrystallization from hexane there were obtained 216 g of 4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]pyridine in colorless crystals, melting point 84°-85°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([C:10]#[C:11][C:12]2[CH:13]=[N:14][C:15]([Cl:19])=[CH:16][C:17]=2[NH2:18])[CH:7]=[N:6][CH:5]=1.[CH3:21]C([O-])(C)C.[K+].CI>CN1C(=O)CCC1>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([C:10]2[N:18]([CH3:21])[C:17]3[CH:16]=[C:15]([Cl:19])[N:14]=[CH:13][C:12]=3[CH:11]=2)[CH:7]=[N:6][CH:5]=1
Reactant: COC(=O)c1cncc(C#Cc2cnc(Cl)cc2N)c1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CI
Product: COC(=O)c1cncc(-c2cc3cnc(Cl)cc3n2C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5-(4-amino-6-chloro-pyridin-3-ylethynyl)-nicotinic acid methyl ester (0.950 mg, 3.30 μmol) in NMP (15 mL) was added KOtBu (1.112 mg, 9.91 μmol) and the reaction was left to stir overnight at room temperature. The reaction was cooled to 0° C. and methyl iodide (0.619 μl, 9.91 μmol) was added. The reaction mixture was stirred for 30 min. The reaction was quenched with water and extracted with ethyl acetate twice. The combined organic layer was washed with water thrice, dried over sodium sulfate and concentrated in vacuo to afford desired product 5-(6-chloro-1-methyl-1H-pyrrolo[3,2-c]pyridin-2-yl)-nicotinic acid methyl ester as a brown color oil which was taken onto next step without further purification. ESI-MS: m/z 302.0 (M+H)+
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].[OH:7][CH2:8][CH2:9][N:10]([CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:11](=[O:33])[NH:12][C@@H:13]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)[C:14](OC1C=CC=CC=1)=[O:15]>O1CCCC1>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH:5][C:14](=[O:15])[C@@H:13]([NH:12][C:11]([N:10]([CH2:9][CH2:8][OH:7])[CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=1
Reactant: CN(C)CCN
Reactant: O=C(Oc1ccccc1)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)N(CCO)CCc1ccccc1
Solvent: C1CCOC1
Product: CN(C)CCNC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)N(CCO)CCc1ccccc1
Yield: 81 %

Procedure:
A solution of 2-(dimethylamino)ethylamine (362 mg) in tetrahydrofuran (3 ml) is added to a solution of phenyl (2S)-2-[3-(2-hydroxyethyl)-3-phenethylureido]-3-(4-nitrophenyl)propionate (Compound No. 1-35, 392 mg) in tetrahydrofuran (5 ml) under ice cooling, and the mixture is stirred at room temperature for 1.5 hours. The reaction mixture is concentrated under reduced pressure, water is added to the concentrate, and the whole is extracted with ethyl acetate. The organic layer is washed with water and saturated brine successively, dried over andhydrous sodium sulfate and concentrated under reduced pressure. The resulting oily matter is purified by silica gel column chromatography to give 314 mg (81%) of the titled compound (Compound No. 19-1).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:12][CH2:13][O:14][C:15]3[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:23]([O:30][CH3:31])(=[O:29])[CH2:24][C:25]([O:27][CH3:28])=[O:26].C([O-])(=O)C.[NH2+]1CCCCC1>C1(C)C=CC=CC=1>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:12][CH2:13][O:14][C:15]3[CH:22]=[CH:21][C:18]([CH:19]=[C:24]([C:23]([O:30][CH3:31])=[O:29])[C:25]([O:27][CH3:28])=[O:26])=[CH:17][CH:16]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(OCCOc2ccc3ncccc3c2)cc1
Reactant: COC(=O)CC(=O)OC
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: COC(=O)C(=Cc1ccc(OCCOc2ccc3ncccc3c2)cc1)C(=O)OC
Temperature: 25 °C
Yield: 87 %

Procedure:
To a solution of 4-[2-(6-quinolinoxy)ethoxy]benzaldehyde (1.25 g, 4.26 mmol) and dimethyl malonate (1.69 g, 12.78 mmol) in toluene (30 ml) is added a catalytic quantity of piperidinium acetate. Then the mixture is refluxed in a Dean-Stark trap for 8 hours. After cooled to room temperature, the solution was concentrated under a vacuum to give title compound (1.51 g, 87%).
Reaction SMILES: C([O:4][C:5]1[C:18](=[O:19])[C:17]2[C:8](=[CH:9][CH:10]=[C:11]3[C:16]=2[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:7](=[O:20])[CH:6]=1)C=C.[C:21]1(C)[CH:26]=CC=C[CH:22]=1>>[CH2:26]([C:6]1[C:7](=[O:20])[C:8]2[C:17]([C:18](=[O:19])[C:5]=1[OH:4])=[C:16]1[C:11]([CH2:12][CH2:13][CH2:14][CH2:15]1)=[CH:10][CH:9]=2)[CH:21]=[CH2:22]
Reactant: C=CCOC1=CC(=O)c2ccc3c(c2C1=O)CCCC3
Reactant: Cc1ccccc1
Product: C=CCC1=C(O)C(=O)c2c(ccc3c2CCCC3)C1=O

Procedure:
The thus-obtained 3-Allyloxy-5,6,7,8-tetrahydro-1,4-phenanthrenequinone was dissolved in 50 ml of toluene and refluxed for 5 hours and then was concentrated by distillation under reduced pressure and was then purified by chromatography on silica gel to give 7.3 g (27.2 mM) of 2-Allyl-3-hydroxy-5,6,7,8-tetrahydro-1,4-phenanthrenequinone.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[CH:5]=[C:6]([F:9])[C:7]=1F.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C:21]1([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CS(C)=O>[F:9][C:6]1[CH:5]=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=[C:2]([F:1])[C:7]=1[N:30]1[CH2:31][CH2:32][CH:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:28][CH2:29]1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cc(F)c(N2CCC(c3ccccc3)CC2)c(F)c1
Reaction time: 1 h
Yield: 94.9 %

Procedure:
In a 100 mL round-bottom flask was mixed 3,4,5-trifluoronitrobenzene (1.751 mL, 15 mmol) and potassium phosphate, dibasic (5.23 g, 30.0 mmol) in DMSO (15.00 mL) to give a yellow suspension. 4-Phenylpiperidine (2.419 g, 15.00 mmol) was added portion-wise as a solid over 10 minutes to produce a deeper yellow suspension and a mild exotherm. The mixture was stirred for 1 hour and partitioned between EtOAc and water. The EtOAc layer was washed 2× by 50 mL each with water and brine, dried (Na2SO4), filtered and concentrated to give the title compound as a yellow solid (4.53 g, 95% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[CH3:24])[CH2:13][CH2:12]2)=[O:10])=[C:4]([F:25])[CH:3]=1.[OH:26][CH2:27][CH:28]1[NH:32][C:31](=[O:33])[CH2:30][CH2:29]1>>[CH3:24][C:18]1[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=1[N:14]1[CH2:15][CH2:16][N:11]([C:9]([C:5]2[C:6]([F:8])=[CH:7][C:2]([N:32]3[C@H:28]([CH2:27][OH:26])[CH2:29][CH2:30][C:31]3=[O:33])=[CH:3][C:4]=2[F:25])=[O:10])[CH2:12][CH2:13]1
Reactant: O=C1CCC(CO)N1
Reactant: Cc1ccc(N2CCN(C(=O)c3c(F)cc(Br)cc3F)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3c(F)cc(N4C(=O)CC[C@H]4CO)cc3F)CC2)c(C)c1
Yield: 15 %

Procedure:
Using (4-bromo-2,6-difluorophenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (819 mg) described in Preparation Example 109 and 5-hydroxymethylpyrrolidin-2-one (230 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (133 mg) was obtained.
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[C:9]1([CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C@H:23](/[CH:29]=[CH:30]\[CH3:31])[CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:19][CH:18]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.IC>C1COCC1>[CH3:1][C@@H:24]([C@H:23]([C:20]1[CH:19]=[CH:18][C:17]([O:16][CH2:15][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:22][CH:21]=1)/[CH:29]=[CH:30]\[CH3:31])[C:25]([O:27][CH3:28])=[O:26]
Reactant: C/C=C\[C@H](CC(=O)OC)c1ccc(OCc2ccccc2)cc1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: C/C=C\[C@@H](c1ccc(OCc2ccccc2)cc1)[C@H](C)C(=O)OC
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of lithium diisopropylamide (0.2 mL, 2 mmol in heptane/THF/ethylbenzene) in THF (1.0 mL) was slowly added (S,Z)-methyl 3-(4-(benzyloxy)phenyl)hex-4-enoate 41.1 (0.50 g, 2 mmol) in THF (5.0 mL) at −78° C. The resulting mixture was stirred at −78° C. for 1 hour and then iodomethane (0.1 mL, 2 mmol) was added. The reaction mixture was stirred at the same temperature for 20 minutes, and then stirred at room temperature for 16 hours. The solvent was removed in vacuo. The residue was purified by silica gel, eluent with hexane/EtOAc 95/5 to 10/90 to give the title compound as a major product 41.2 in a ratio of 95:5. 1H NMR (400 MHz, CDCl3) δ ppm 1.08 (d, J=7.04 Hz, 3H) 1.46-1.61 (m, 1H) 2.64 (m, 1H) 3.34 (s, 3H) 4.90 (s, 2H) 5.35-5.53 (m, 2H) 6.76-6.84 (m, 2H) 6.97-7.07 (m, 2H) 7.15-7.34 (m, 5H). MS ESI (pos.) m/e: 325.1 (M+H)+. It is possible that the stereochemistry at the carbon atom adjacent to the carbonyl is opposite that shown which would carry through to the final product of this Example. However, it is believed that the structure of 41.2 is as shown above.