Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:9]=1[C:10]#[N:11].I[CH:19]([CH3:21])[CH3:20].O>CC(C)=O>[CH:19]([O:7][C:8]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:9]=1[C:10]#[N:11])([CH3:21])[CH3:20]
Reactant: COc1ccc(C#N)c(O)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(C#N)c(OC(C)C)c1
Yield: 87.4 %

Procedure:
Cesium carbonate (51.5 g, 158 mmol) was added to a solution of 2-hydroxy-4-methoxybenzonitrile (11.8 g, 79 mmol) in acetone (100 mL). 2-Iodopropane (12.5 mL, 125 mmol) was added. The mixture was heated at reflux for 3 h. Water was added and the mixture was extracted with diethyl ether (4×100 mL). The combined organic extracts were washed with diluted ammonium hydroxide, brine and dried (MgSO4). Evaporation of the solvents and chromatography of the residue over silica gel using 5% diethyl ether in hexanes gave 2-isopropoxy-4-methoxybenzonitrile (13.2 g, 87%).
Reaction SMILES: [CH2:1]([N:7]([C:9]([NH:11][C:12]1[S:13][C:14]([S:17]([CH3:19])=[O:18])=[N:15][N:16]=1)=[O:10])[NH2:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:20]=O.[OH-].[K+]>CO>[CH2:1]([N:7]1[C:9](=[O:10])[N:11]([C:12]2[S:13][C:14]([S:17]([CH3:19])=[O:18])=[N:15][N:16]=2)[CH2:20][NH:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN(N)C(=O)Nc1nnc(S(C)=O)s1
Reactant: C=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCN1NCN(c2nnc(S(C)=O)s2)C1=O
Reaction time: 0.33 h

Procedure:
2-n-Hexyl-4-(5-methylsulfinyl-1,3,4-thiadiazol-2-yl)-semicarbazide (0.1 mole) dissolved in methanol (100 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. Aqueous formaldehyde (0.2 mole; 37% concentration) is then added to the reaction vessel with stirring. Dilute aqueous potassium hydroxide is added to the reaction mixture to adjust the pH to between 7 and 8 and stirring is continued for a period of about 20 minutes resulting in the formation of a solid precipitate. The precipitate is recovered by filtration, is recrystallized and is dried under vacuum to yield the desired product 2-n-hexyl-4-(5-methylsulfinyl-1,3,4-thiadiazol-2-yl)-1,2,4-triazolidin-3-one.
Reaction SMILES: [CH2:1]([N:3](S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)[CH:4]([CH3:9])[C:5]([O:7][CH3:8])=[O:6])[CH3:2].C1(S)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH2:1]([NH:3][CH:4]([CH3:9])[C:5]([O:7][CH3:8])=[O:6])[CH3:2]
Reactant: CCN(C(C)C(=O)OC)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CC#N
Product: CCNC(C)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.1 %

Procedure:
Methyl 2-[ethyl(2-nitrobenzenesulfonyl)amino]propionate (8.07 g; 25.5 mmol) is dissolved in 250 ml of acetonitrile, and thiophenol (1.12 eq.; 28.7 mmol; 2.93 ml) and K2CO3 (3.25 eq.; 82.9 mmol; 11.45 g) are then added. The reaction medium is stirred overnight at room temperature. The crude product is evaporated to dryness and then taken up in ether. The organic phase is acidified with 1N hydrochloric acid and then washed with water. The aqueous phases are combined and then washed with ether and basified with potassium carbonate. The basic aqueous phase is extracted with ether three times. The three ether phases are washed with water and then with saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated to dryness to give 1.04 g of the expected product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9](B(O)O)[S:8][C:7]=2[CH:14]=1.Br[C:16]1[CH:29]=[CH:28][C:19]([O:20][CH2:21][CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:18][CH:17]=1.[Al].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1.[Cl-].[Na+].O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([C:16]3[CH:17]=[CH:18][C:19]([O:20][CH2:21][CH2:22][N:23]4[CH2:24][CH2:25][CH2:26][CH2:27]4)=[CH:28][CH:29]=3)[S:8][C:7]=2[CH:14]=1
Reactant: COc1ccc2cc(B(O)O)sc2c1
Reactant: Brc1ccc(OCCN2CCCC2)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Al]
Solvent: c1ccccc1
Solvent: O
Product: COc1ccc2cc(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Temperature: 85 °C
Yield: 54.4 %

Procedure:
To a slurry of 6-methoxybenzo[b]thiophene-2-boronic acid (Example 1, Part A) (6.43 g, 30.9 mmol) in 310 mL of benzene was added 1-(2-(4-bromophenoxy)ethyl)pyrrolidine (5.80 mL, 28.1 mmol). Upon addition the reaction mixture turned to a yellow homogeneous solution. The reaction flask was then covered with aluminum foil to keep out light. To this was added 1.07 g (0.92 mmol) of tetrakis(triphenylphosphine)-palladium(0), followed by 30 mL of 2.0 N sodium carbonate solution. The biphasic mixture was heated at 85° C. for 3 h with vigorous stirring. The mixture was cooled to 0° C. and 175 mL of brine solution was added. The layers were separated and the aqueous layer was extracted with 1.0 L of EtOAc. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The residue was purified by PrepLC (53:35:2 THF-hexanes-TEA) to afford 5.42 g (15.3 mmol, 55%) of an off-white solid.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[CH:10]=[C:11]3[N:17]([N:18]=2)[C:16]2[CH:19]=[C:20]([C:23](O)=[O:24])[CH:21]=[CH:22][C:15]=2[O:14][CH2:13][CH2:12]3)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[NH2:69][CH2:70][C:71]([CH3:74])([OH:73])[CH3:72]>CN(C=O)C>[OH:73][C:71]([CH3:74])([CH3:72])[CH2:70][NH:69][C:23]([C:20]1[CH:21]=[CH:22][C:15]2[O:14][CH2:13][CH2:12][C:11]3[N:17]([N:18]=[C:9]([C:8]4[N:4]([CH:1]([CH3:2])[CH3:3])[N:5]=[CH:6][N:7]=4)[CH:10]=3)[C:16]=2[CH:19]=1)=[O:24]
Reactant: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(C(=O)O)ccc1OCC2
Reactant: CC(C)(O)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(C(=O)NCC(C)(C)O)ccc1OCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.3 %

Procedure:
2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-9-carboxylic acid (0.2 g, 0.59 mmol) was suspended in DMF (5 mL) and DIPEA (0.21 mL, 1.2 mmol) added. The resultant solution was treated with HATU (0.23 g, 0.6 mmol) and HOBT (81 mg, 0.6 mmol) before the addition of 1-amino-2-methyl-propan-2-ol (52.5 mg, 0.59 mmol) then stirred for 18 h at RT. The reaction mixture was concentrated in vacuo and the resultant residue partitioned between DCM and water. The aqueous layer was extracted three times with DCM and the combined organic extracts washed with water, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 10% MeOH in ethyl acetate) and recrystallistion from ethyl acetate to give 116 (163 mg, 67%). 1H NMR (CDCl3, 400 MHz): δ 8.46 (d, J=2.2 Hz, 1H); 7.94 (s, 1H); 7.72 (dd, J=8.4, 2.2 Hz, 1H); 7.22 (d, J=8.4 Hz, 1H); 6.86 (s, 1H); 6.66 (s, 1H); 5.74-5.61 (m, 1H); 4.57 (t, J=5.7 Hz, 2H); 3.50 (d, J=5.9 Hz, 2H); 3.22 (t, J=5.7 Hz, 2H); 2.18 (s, 1H); 1.59 (d, J=6.6 Hz, 6H); 1.31 (s, 6H). LCMS: RT=9.53 min, M+H+=411
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH:16][CH:17]1[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]1)([CH3:3])[CH3:2].[IH:30].C(O)C>C(OCC)C>[IH:30].[CH:1]([O:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([CH3:3])[CH3:2]
Reactant: CC(C)OCCn1c(NC2CCN(C(=O)OC(C)(C)C)CC2)nc2ccccc21
Agent: I
Solvent: CCOCC
Solvent: CCO
Product: CC(C)OCCn1c(NC2CCNCC2)nc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Combine (1-(2-(isopropoxy)ethyl)-1H-benzimidazol-2-yl)(1-(t-butoxycarbonyl)piperidin-4-yl)amine (2.97 g, 7.38 mmol), aqueous hydriodic acid (5 mL, 57%), and ethanol (10 mL). Heat to reflux. After 1 hour, cool to ambient temperature and pour the reaction mixture into diethyl ether (350 mL) and stir to give a solid. After 1 hour, collect the solid by filtration, rinse with diethyl ether, and dry in vacuo to give the title compound.
Reaction SMILES: [CH:1]1([NH:8][C:9]2[N:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([O:13][CH2:14]C)=[O:12])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(C(CC)CNC1N=CC=CC=1C(OCC)=[O:28])C>>[CH:1]1([N:8]2[C:9]3[N:19]=[CH:18][CH:17]=[CH:16][C:10]=3[C:11](=[O:12])[O:13][C:14]2=[O:28])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cccnc1NC1CCCCCC1
Reactant: CCOC(=O)c1cccnc1NCC(CC)CC
Product: O=c1oc(=O)n(C2CCCCCC2)c2ncccc12

Procedure:
The title compound was prepared according to the procedure of Example 3B substituting the product of Example 71A for the product of Example 3A (0.205 g, 55%). MS (ESI+) m/z 249.1 (M+H)+; 1H NMR (300 MHz, CDCl3) δ 1.63 (m, 6H), 1.84 (m, 4H), 2.43 (m, 2H), 5.39 (s, 1H), 7.24 (dd, J=7.72, 4.78 Hz, 1H), 8.40 (m, 1H), 8.71 (dd, J=4.78, 1.84 Hz, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[N:20]=[C:19]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:23][CH2:22]3)[N:18]=[C:17]([O:33][CH2:34][CH2:35][C:36]([OH:38])=O)[C:16]=2[O:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[O:46][CH3:47])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:48]([C:51]1[CH:57]=[CH:56][CH:55]=[CH:54][C:52]=1[NH2:53])([CH3:50])[CH3:49]>>[CH:48]([C:51]1[CH:57]=[CH:56][CH:55]=[CH:54][C:52]=1[NH:53][C:36](=[O:38])[CH2:35][CH2:34][O:33][C:17]1[C:16]([O:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[O:46][CH3:47])=[C:15]([NH:14][S:11]([C:8]2[CH:7]=[CH:6][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:10][CH:9]=2)(=[O:13])=[O:12])[N:20]=[C:19]([N:21]2[CH2:26][CH2:25][N:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:23][CH2:22]2)[N:18]=1)([CH3:50])[CH3:49]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCN(c3ccccc3)CC2)nc1OCCC(=O)O
Reactant: CC(C)c1ccccc1N
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCN(c3ccccc3)CC2)nc1OCCC(=O)Nc1ccccc1C(C)C

Procedure:
The procedure described in Example 2 was repeated by use of 3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(4-phenylpiperazinyl)-4-pyrimidinyloxy]propionic acid and 2-isopropylaniline, to thereby obtain the title compound as a pale yellow oil.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12](Cl)=[O:13].[NH2:15][C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=1>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:25][CH:26]=1)=[O:13]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=C(Cl)CCCCCCCCCCBr
Solvent: ClCCl
Product: CCOC(=O)c1ccc(NC(=O)CCCCCCCCCCBr)cc1

Procedure:
A solution of 28 g. of 11-bromoundecanoyl chloride in 100 ml. of methylene chloride is slowly added with stirring to a solution of 20 g. of ethyl 4-aminobenzoate in 100 ml. of methylene chloride. The mixture is filtered and the filtrate is washed with dilute hydrochloric acid and water, dried, and evaporated. Crystallization from acetonitrile affords ethyl 4-(11-bromoundecanamido)benzoate as a white solid.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].C(S)C.[N:8]1([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[C:28]([C:29]4[CH:34]=[CH:33][C:32]([O:35]C)=[CH:31][CH:30]=4)=[CH:27][CH:26]=[C:25]([C:37]4[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=4)[N:24]=3)=[CH:19][CH:18]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>ClCCCl>[N:8]1([CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[C:28]([C:29]4[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=4)=[CH:27][CH:26]=[C:25]([C:37]4[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=4)[N:24]=3)=[CH:21][CH:22]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: COc1ccc(-c2ccc(-c3ccc(F)cc3)nc2-c2ccc(OCCN3CCCCC3)cc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CCS
Product: Oc1ccc(-c2ccc(-c3ccc(F)cc3)nc2-c2ccc(OCCN3CCCCC3)cc2)cc1
Reaction time: 0.25 h
Yield: 91.8 %

Procedure:
The AlCl3 (1.9 g, 14 mmol) was stirred in 50 mL of DCE at 0° C., ethanethiol (1.5 mL, 20 mmol) was added, and the mixture stirred for 15 min. The 2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-3-(4-methoxyphenyl)-6-(4-fluorophenyl)pyridine (1 g, 2 mmol) in 25 mL DCE was added dropwise to the reaction mixture and stirred for 2 h as it was allowed to come to rt, then quenched with 25 mL THF at 0° C., followed by 25 mL 1N HCl and worked up. The crude product was triturated with Et2O, filtered, and dried in vacuo to give 0.86 g (91% yield) of white solid: mp 194°-195° C.; 1H NMR (CDCl3) d 1.63-167 (comp, 6H, piperidine), 2.59 (bs, 4H, piperidine), 2.81-2.84 (t, 2H, J=5 Hz, CH2N), 4.12-4.15 (t, 2H, J=5 Hz, OCH2), 6.64-6.70 (m, 4H, ArH), 7.00-7.03 (d, 2H, J=8 Hz, ArH), 7.12-7.18 (m, 2H, ArH), 7.37-7.40 (d, 2H, J=8 Hz, ArH), 7.61-7.67 (m, 2H, ArH), 8.08-8.12 (m, 2H, ArH); MS (FD) 468 (M+). Anal. Calcd for C30H29N2O2F: C, 76.90; H, 6.24; N, 5.98. Found: C, 77.13; H, 6.36; N, 5.86.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[C:4]([CH3:9])[CH:3]=1.C(N(CC)CC)C.Cl.Cl[CH2:19][C:20]1[N:24]([CH2:25][CH2:26][CH3:27])[CH:23]=[N:22][CH:21]=1.O>O1CCCC1.CO>[CH3:9][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[S:8][CH2:19][C:20]1[N:24]([CH2:25][CH2:26][CH3:27])[CH:23]=[N:22][CH:21]=1)[NH2:1]
Reactant: Cc1cc(N)ccc1S
Reactant: CCCn1cncc1CCl
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCCn1cncc1CSc1ccc(N)cc1C
Reaction time: 3 h
Yield: 64 %

Procedure:
To a solution of 4-amino-2-methylthiophenol (500 mg) and triethylamine (3.0 ml) in tetrahydrofuran (15 ml) was added dropwise a solution of 5-chloromethyl-1-propylimidazole hydrochloride (847 mg) in methanol (5 ml) at 0° C. under argon atmosphere, after which the mixture was returned to room temperature and stirred for 3 hours. Water was added and the mixture was extracted with ethyl acetate, and organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by basic silica gel column chromatography (hexane:ethyl acetate 1:1→ethyl acetate) and was recrystallized from hexane-ethyl acetate to give 3-methyl-4-[((1-propylimidazol-5-yl)methyl)sulfanyl]aniline (601 mg) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[CH:4][C:3]=1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)=[S:8].N12CCCN=C1CCCCC2.Cl>C(O)C>[C:4]([C:3]([C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:12][CH:11]=1)=[S:8])=[C:2]([OH:6])[CH3:1])#[N:5]
Reactant: Cc1oncc1C(=S)Nc1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Product: CC(O)=C(C#N)C(=S)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 71.4 %

Procedure:
A solution of 7.0 grams of 5-methyl-4-(4-trifluoromethylphenyl)aminothiocarbonylisoxazole and 5 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene in 50 ml of ethanol was heated at 80° C. for 8 hours. The reaction mixture was cooled to room temperature and acidified with 6N hydrochloric acid solution until pH 2. The mixture was then cooled in an ice-water bath for 30 minutes and the solid was filtered, washed with a chilled solution of ethanol and water (2:1) and dried by suction to provide 5.0 grams of 1-cyano-2-hydroxy-1-(4-trifluoromethylphenyl)aminothiocarbonylpropene.
Reaction SMILES: [CH:1]([C:3]1[C:9](=[O:10])[C:8]([O:11]C)=[CH:7][C:6]([CH:13]([CH3:15])[CH3:14])=[CH:5][CH:4]=1)=[O:2].Cl>[OH-].[Na+]>[CH:1]([C:3]1[C:9](=[O:10])[C:8]([OH:11])=[CH:7][C:6]([CH:13]([CH3:15])[CH3:14])=[CH:5][CH:4]=1)=[O:2]
Reactant: COc1cc(C(C)C)ccc(C=O)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)c1ccc(C=O)c(=O)c(O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7-hydroxymethyl-4-isopropyl-2-methoxy-2,4,6-cycloheptatrien-1-one (20 g, 96 mmol) was dissolved in chloroform (300 ml), to which was added active manganese dioxide (80 g, 920 mmol) in several portions, and the resultant was stirred at room temperature for 4 hours. The insoluble matter was removed by filtration under reduced pressure, the filtrate was concentrated under reduced pressure and the resulting crude product was recrystallized from toluene to give 12.31 g of 7-formyl-4-isopropyl-2-methoxy-2,4,6-cycloheptatrien-1-one as yellow needle-like crystal (yield: 62%). Melting point of the product was 73°-75° C. 10% aqueous sodium hydroxide (50 ml) was added to the aldehyde (5 g, 24 mmol) and stirred overnight at room temperature. The reaction solution was acidified with 10% dilute hydrochloric acid, then extracted with methylene chloride, washed with water, dried, and solvent was distilled off to give a crude crystal (4.78 g). The crude crystal was recrystallized from ethyl acetate/hexane to give 7-formyl-4-isopropyl-2-hydroxy-2,4,6-cycloheptatrien-1-one as a colorless needle-like crystal (yield: quantitative). This compound showed melting point of 76° C., which is identical to that described in the literature (Sci. Repts. Tohoku Univ., I, 37, 367 (1953)]. The compound (1.94 g, 10 mmol) was dissolved in tetrahydrofuran (20 ml), to which was added dropwise 2M phenyl lithium solution (5.2 ml, ca 10 mmol) in a nitrogen atmosphere while cooling to -78° C. The resultant was stirred for 10 minutes. An aqueous saturated sodium chloride was added to the reaction solution, and the resultant was extracted with methylene chloride, dried and the solvent was distilled off. The residue was purified by silica gel column chromatography to give 1.95 g of 7-(α-hydroxybenzyl)-4-isopropyl-2-methoxy-2,4,6-cycloheptatrien-1-one as brown oil (yield: 71%). The compound (1 g, 3.7 mmol) and 1-(4-chlorobenzhydryl)piperazine (1.27 g, 4.4 mmol) were heated and refluxed in xylene (20 ml) for 2 hours, solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography [(ethyl acetate/hexane (1:2)] to give 1.71 g of 7-{1-[4-(4-chlorobenzhydryl)piperazinomethyl]-α-phenyl}-4-isopropyl-2-hydroxy-2,4,6-cycloheptatrien-1-one (yield: 86%).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([CH2:7][CH:8]([O:11][CH3:12])[O:9][CH3:10])[CH3:6])=[O:4].[NH2:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>C(OCCCC)(=O)C>[OH:20][C@H:17]1[CH2:18][CH2:19][C@H:14]([NH:13][CH2:2][C:3]([N:5]([CH2:7][CH:8]([O:11][CH3:12])[O:9][CH3:10])[CH3:6])=[O:4])[CH2:15][CH2:16]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: COC(CN(C)C(=O)CCl)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCOC(C)=O
Product: COC(CN(C)C(=O)CN[C@H]1CC[C@H](O)CC1)OC
Temperature: 65 °C

Procedure:
50 g 2-chloro-N-(2,2-dimethoxy-ethyl)-N-methyl-acetamide in 100 ml n-butyl acetate are added dropwise to a suspension of 35.3 g trans-4-aminocyclohexanol and 53 g potassium carbonate in 150 ml n-butyl acetate at 90-100° C. within 2.5 h. After 45 min the suspension is filtered at 65° C. and washed with 70 ml of n-butyl acetate warmed to 65° C. 100 ml solvent are distilled off from the filtrate and the solution evaporated down is inoculated with product at 40° C. After 16 h at ambient temperature the precipitate is filtered off and washed with 70 ml tert-butylmethylether. After drying, 50 g product is obtained.
Reaction SMILES: [CH2:1](OC(OCC)CBr)[CH3:2].Cl.C([O-])(=O)C.[Na+].[NH2:16][C:17]1[N:22]=[C:21]([NH2:23])[CH:20]=[C:19]([OH:24])[N:18]=1>O>[NH2:16][C:17]1[N:18]=[C:19]([OH:24])[C:20]2[CH:2]=[CH:1][NH:23][C:21]=2[N:22]=1
Reactant: CCOC(CBr)OCC
Reactant: Nc1cc(O)nc(N)n1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Nc1nc(O)c2cc[nH]c2n1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 69.4 %

Procedure:
A mixture of 136.7 g of bromoacetaldehyde diethylacetal, 347 mL of water, and 17.3 mL of concentrated HCl was heated to about 90° C. with vigorous stirring for about 30 minutes, at which time a clear solution was obtained. The solution was cooled to ambient temperature and 68.3 g of sodium acetate was added. The resulting solution was added, with stirring, to a suspension of 100 g of 2,4-diamino-6-hydroxypyrimidine and 34.2 g of sodium acetate in 739 mL of water, which had been heated to 70°-85° C. The reaction was allowed to proceed for 2 hours at 70°-85° C., at which time the reaction was complete. The mixture was cooled to 0° C. and stirred for about 1.5 hours. The mixture was then filtered and the collected product was washed with 500 mL of water and 500 mL of acetone, and dried, affording 72.3 g (79%) of 2-amino-4 -hydroxy-7H-pyrrolo[2,3-d]pyrimidine, mp>300° C. NMR δ6.03 (s, 2H), 6.13 (m, 1H), 6.56 (dd, J=3.3, 2.3 Hz, 1H), 10.23 (br s, 1H), 10.93 (br s, 1H).
Reaction SMILES: Cl.[N:2]1([CH2:7][C@H:8]2[CH2:12][CH2:11][NH:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.C(OC(N1CC[C@@H](CO)C1)=O)(C)(C)C.[CH3:27][O:28][C:29]1[CH:57]=[CH:56][C:32]([CH2:33][S:34][C@@H:35]2[CH2:39][N:38]([C:40]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][C:47]([N+:50]([O-:52])=[O:51])=[CH:46][CH:45]=3)=[O:41])[C@H:37]([C:53](O)=[O:54])[CH2:36]2)=[CH:31][CH:30]=1.C(N(C(C)C)CC)(C)C.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH3:27][O:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:33][S:34][C@@H:35]2[CH2:39][N:38]([C:40]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][C:47]([N+:50]([O-:52])=[O:51])=[CH:46][CH:45]=3)=[O:41])[C@H:37]([C:53]([N:10]3[CH2:11][CH2:12][C@H:8]([CH2:7][N:2]4[CH2:6][CH2:5][CH2:4][CH2:3]4)[CH2:9]3)=[O:54])[CH2:36]2)=[CH:56][CH:57]=1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: C1CCN(C[C@H]2CCNC2)C1
Agent: CC(C)(C)OC(=O)N1CC[C@@H](CO)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CC[C@H](CN4CCCC4)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 34.5 %

Procedure:
To a solution of (3S)-3-(pyrrolidin-1-ylmethyl)pyrrolidine hydrochloride (367 mg), which had been prepared from (3R)-1-tert-butoxycarbonyl-3-hydroxymethylpyrrolidine, in anhydrous dimethylformamide (10 ml), (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-pyrrolidinecarboxylic acid (804 mg), diisopropylethylamine (1.16 ml), 1-hydroxybenzotriazole (243 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (483 mg) were added. The resulting mixture was stirred at room temperature for 10 hours. The solvent was then distilled off under reduced pressure. The residue was dissolved in ethyl acetate. The resulting solution was washed with a saturated aqueous solution of sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate and then concentrated by evaporation under reduced pressure. The residue was purified by chromatography through a silica gel column (ethyl acetate/methanol=5/1-1/1), whereby (2S,4S)-4-(4-methoxybenzylthio)-2-[(3R)-3-(pyrrolidin-1-ylmethyl)pyrrolidin-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (362 mg) was obtained.
Reaction SMILES: C([O:5][C:6](=[O:38])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:25]=[N:26][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[F:36])=[CH:28][CH:29]=3)[S:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH3:37])(C)(C)C.[C:39](O)(C(F)(F)F)=O>C(Cl)Cl.O>[F:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:27]1[N:26]=[CH:25][C:24]([C:20]2[S:21][C:22]([CH3:23])=[C:18]([CH:17]([CH3:39])[CH2:16][O:15][C:12]3[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][C:6]([OH:5])=[O:38])=[C:10]([CH3:37])[CH:11]=3)[N:19]=2)=[CH:29][CH:28]=1
Reactant: Cc1cc(OCCc2nc(-c3ccc(-c4ccccc4F)nc3)sc2C)ccc1CCC(=O)OC(C)(C)C
Reactant: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: Cc1cc(OCC(C)c2nc(-c3ccc(-c4ccccc4F)nc3)sc2C)ccc1CCC(=O)O
Reaction time: 2 h

Procedure:
To a solution of 3-[4-(2-{2-[6-(2-Fluoro-phenyl)-pyridin-3-yl]-5-methyl-thiazol-4-yl}-ethoxy)-2-methyl-phenyl]-propionic acid tert-butyl ester (120 mg) in methylene chloride (1 mL) is added TFA (0.8 mL) and two drops of water. The mixture is stirred for 2 h, and concentrated and purified by reversed phase HPLC (water-acetonitrile with 0.1% TFA). MS (ES): 491.4 (M++1).