Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH:16]([CH3:19])[CH2:17][OH:18])=[C:11]([CH:13]([CH3:15])[CH3:14])[N:12]=2)=[CH:4][CH:3]=1.[CH3:20][O:21][C:22](=[O:33])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][C:26]=1[CH3:32].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[CH3:20][O:21][C:22](=[O:33])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:18][CH2:17][CH:16]([C:10]2[O:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)=[N:12][C:11]=2[CH:13]([CH3:15])[CH3:14])[CH3:19])=[CH:27][C:26]=1[CH3:32]
Reactant: CC(C)c1nc(-c2ccc(Br)cc2)oc1C(C)CO
Reactant: COC(=O)CCc1ccc(O)cc1C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)CCc1ccc(OCC(C)c2oc(-c3ccc(Br)cc3)nc2C(C)C)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
A solution of 2-[2-(4-bromo-phenyl)-4-isopropyl-oxazol-5-yl]-propan-1-ol (225 mg, 0.694 mmol) and 3-(4-hydroxy-2-methyl-phenyl)-propionic acid methyl ester (190 mg, 0.972 mmol) in toluene (15 mL) is degassed and filled with nitrogen for 3 times. Tributylphosphine (224 mg, 1.11 mmol) is added to the reaction mixture under nitrogen at 0° C., followed by addition of of 1,1′-(azodicarbonyl)-dipiperidine (280 mg, 1.11 mmol). The reaction mixture is allowed to warm to room temperature and stirred overnight, the mixture is loaded directly on silica gel column chromatography with 10–15% EtOAc/Hexanes to afford the title compound (320 mg, 92%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]([C@@H:16]1[CH2:18][O:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C@@H:16]([OH:17])[CH2:18][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H]1CO1
Reactant: C1COCCN1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H](O)CN1CCOCC1

Procedure:
Using general procedure 1 with [(1R)-1-{(2R)-oxiran-2-yl}-2-phenyl-ethyl]carbamic acid tert-butylester (0.133 g, 0.50 mmol) and morpholine (0.220 mL, 2.50 mmol) gives the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([O:46]CC2C=CC=CC=2)[C@H:15]([N:31](CC2C=CC=CC=2)CC2C=CC=CC=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23]CC3C=CC=CC=3)[CH:18]=2)[CH2:12][O:11][C@@H:10]([O:54][CH2:55][C:56]([CH3:59])([CH3:58])[CH3:57])[C@@H:9]1[CH3:60])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)(C)(C)C.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([OH:46])[C@@H:15]([NH2:31])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=2)[CH2:12][O:11][C@@H:10]([O:54][CH2:55][C:56]([CH3:59])([CH3:58])[CH3:57])[C@@H:9]1[CH3:60])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: C[C@H]1[C@H](OCC(C)(C)C)OC[C@H]([C@@H](OCc2ccccc2)[C@@H](Cc2cccc(OCc3ccccc3)c2)N(Cc2ccccc2)Cc2ccccc2)N1C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: C[C@H]1[C@H](OCC(C)(C)C)OC[C@H]([C@@H](O)[C@@H](N)Cc2cccc(O)c2)N1C(=O)OC(C)(C)C
Yield: 104.2 %

Procedure:
Dissolve 5-(R)-[1-(S)-benzyloxy-3-(3-benzyloxyphenyl)-2-(R)-dibenzylaminopropyl]-2-(R)-(2,2-dimethylpropoxy)-3-(S)-methylmorpholine-4-carboxylic acid tert-butyl ester (1.38 g, 1.70 mmol) in tert-butanol (˜50 mL). Add 20% palladium hydroxide on carbon (4 g) and hydrogenate at 50 psi hydrogen gas at 40° C. for 18 hours. Filter and concentrate to give the desired compound (802 mg).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[C:13]([CH2:20][OH:21])=[CH:12][N:11]=2)=[CH:6][CH:5]=1.[S:24](Cl)([Cl:26])=[O:25]>ClCCl>[F:23][C:2]([F:1])([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[C:13]([CH2:20][O:21][S:24]([Cl:26])=[O:25])=[CH:12][N:11]=2)=[CH:6][CH:5]=1
Reactant: OCc1cnc(-c2ccc(OC(F)(F)F)cc2)nc1C(F)(F)F
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=S(Cl)OCc1cnc(-c2ccc(OC(F)(F)F)cc2)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.2 %

Procedure:
A cooled (0° C.) solution of 0.40 g (1.20 mmol) of [2-(4-trifluoromethoxy-phenyl)-4-trifluoromethyl-pyrimidin-5-yl]-methanol in 12 ml dichloromethane was treated with 0.10 ml (1.32 mmol) thionylchloride and stirred for 30 min at RT. The reaction was cooled (0° C.), treated with 0.08 ml (1.08 mmol) thionylchloride and stirred for 30 min at RT. The solution was evaporated, dissolved in ether and twice in heptane and evaporated to give 0.44 g of the title compound as an off-white powder.
Reaction SMILES: [C:1](=[S:3])=[O:2].[NH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH2:9]>O.C(O)C>[NH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:1](=[S:3])[OH:2]
Reactant: O=C=S
Reactant: NCCCCN
Solvent: O
Solvent: CCO
Product: NCCCCNC(O)=S

Procedure:
passing carbonyl sulfide gas into a solution of tetramethylene diamine dissolved in a mixture of water and ethanol in equal proportions by weight at a temperature of from about 30° C. to about 45° C. to form N-(4-aminobutyl)thiocarbamic acid or zwitterion thereof; and
Reaction SMILES: [C:1](OCC)(OCC)(OCC)[CH2:2][CH2:3][CH3:4].[CH3:14][S:15]([CH2:18][CH2:19][O:20][CH2:21][CH2:22][NH:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=[CH:26][C:25]=1[NH2:34])(=[O:17])=[O:16].Cl.N1C=CC=CC=1>C(#N)C>[CH3:14][S:15]([CH2:18][CH2:19][O:20][CH2:21][CH2:22][N:23]1[C:24]2[C:33]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[N:27]=[CH:26][C:25]=2[N:34]=[C:1]1[CH2:2][CH2:3][CH3:4])(=[O:17])=[O:16]
Reactant: CS(=O)(=O)CCOCCNc1c(N)cnc2ccccc12
Reactant: CCCC(OCC)(OCC)OCC
Agent: Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: CCCc1nc2cnc3ccccc3c2n1CCOCCS(C)(=O)=O
Reaction time: 0.67 h
Yield: 85.3 %

Procedure:
Triethyl orthobutyrate (2.2 mL, 14 mmol) was added to a stirred solution of N4-{2-[2-(methylsulfonyl)ethoxy]ethyl}quinoline-3,4-diamine (3.6 g, 12 mmol) in acetonitrile (60 mL). Pyridine hydrochloride (0.3 g) was added and the reaction mixture was heated to reflux with the volatiles being collected in a Dean Stark trap. After 40 minutes analysis by TLC indicated that the starting material was consumed. The reaction mixture was concentrated under reduced pressure to provide 3.7 g of 1-{2-[2-(methylsulfonyl)ethoxy]ethyl}-2-propyl-1H-imidazo[4,5-c]quinoline as a white solid.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[C:11](=[O:13])[N:10]([C@H:14]1[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]([O:25]C)=[O:24])[CH:21]=3)[CH2:16][CH2:15]1)[CH2:9]2>C(O)C.O>[Cl:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[C:11](=[O:13])[N:10]([C@H:14]1[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]([OH:25])=[O:24])[CH:21]=3)[CH2:16][CH2:15]1)[CH2:9]2
Reactant: COC(=O)c1ccc2c(c1)[C@H](N1Cc3cccc(Cl)c3C1=O)CC2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc2c(c1)[C@H](N1Cc3cccc(Cl)c3C1=O)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
KOH (1 mol/l aq) (2 eq) was added to a suspension of (R)-methyl 3-(7-chloro-1-oxoisoindolin-2-yl)-2,3-dihydro-1H-indene-5-carboxylate (D-01) (0.42 mmol, 1 eq) in a mixture of ethanol (4 ml) and water (1.6 ml). The reaction mixture was stirred overnight at RT. Ethanol was removed in vacuo, and the residue was taken up in diethyl ether and water. The phases were separated, and the aqueous phase was adjusted to pH 3 with 1N HCl. The aqueous phase was extracted with ethyl acetate (3×) and the combined organic phases were dried over sodium sulfate. After concentration, the desired product (R)-3-(7-chloro-1-oxoisoindolin-2-yl)-2,3-dihydro-1H-indene-5-carboxylic acid (G-01) was obtained. Yield: 82%
Reaction SMILES: [CH:1]([C:11]([O-])=O)([C:7]([O:9]C)=[O:8])[CH2:2][CH2:3][C:4]([O-:6])=O.Br[CH:15]([CH2:20][CH2:21][CH2:22]CC)[C:16](OC)=O>>[CH2:16]([CH:11]1[C:4](=[O:6])[CH2:3][CH2:2][CH:1]1[C:7]([OH:9])=[O:8])[CH2:15][CH2:20][CH2:21][CH3:22]
Reactant: COC(=O)C(CCC(=O)[O-])C(=O)[O-]
Reactant: CCCCCC(Br)C(=O)OC
Product: CCCCCC1C(=O)CCC1C(=O)O
Yield: 38.4 %

Procedure:
By repeating the procedure described in Example 1 (a) but starting from 195 g of methyl propane-1,1,3-tricarboxylate (F. L. M. Pattison, R. L. Buchanan and F. H. Dean, Can. J. Chem. 43(6), 1700 (1965)) and 176 g of methyl α-bromoheptanoate (H. Reinheckel, Ber. 93, 2222 (1960)), there is obtained 60 g (41%) of 2-n-pentyl-3-oxo-cyclopentanecarboxylic acid, melting at 52°C.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][N:10]2[CH:13]2[CH2:18][CH2:17][N:16](C(OCC3C=CC=CC=3)=O)[CH2:15][CH2:14]2)=[CH:6][CH:5]=1)(=[O:3])[NH2:2].CO.[H][H]>[C].[Pd].O1CCCC1>[NH:16]1[CH2:15][CH2:14][CH:13]([N:10]2[C:11]3[C:7](=[CH:6][CH:5]=[C:4]([C:1]([NH2:2])=[O:3])[CH:12]=3)[CH:8]=[CH:9]2)[CH2:18][CH2:17]1
Reactant: NC(=O)c1ccc2ccn(C3CCN(C(=O)OCc4ccccc4)CC3)c2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)c1ccc2ccn(C3CCNCC3)c2c1
Temperature: 25 °C

Procedure:
43 g of benzyl 4-(6-carbamoyl-1H-indol-1-yl)piperidin-1-carboxylate was suspended in a mixed solution consisting of 400 ml of methanol and 600 ml of tetrahydrofuran. Thereafter, 3.3 g of 10% palladium carbon was added thereto. This suspension was substituted by hydrogen, and it was then stirred at room temperature. After completion of the reaction, 10% palladium carbon was filtered off from the reaction solution, and the reaction solution was then concentrated under a reduced pressure. Tetrahydrofuran was added to the residue, and the obtained mixture was concentrated again under a reduced pressure. Tetrahydrofuran was added to the generated residue, followed by stirring, so as to solidify the subject compound. Thereafter, tetrahydrofuran and ether were added thereto, followed by cooling on ice. The solidified subject compound was collected by filtration. The generated filtrate was concentrated, and thus, the subject compound was obtained in the same above manner. The total amount of the subject compounds was 25.2 g.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][CH2:7][CH:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1.CC(C)([O-])C.[Na+].Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][C:25]=1[Cl:34]>CS(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:26][C:25]=3[Cl:34])[CH2:7][CH:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1
Reactant: Clc1ncc2c(n1)N1CCOCC1CN2
Reactant: CS(=O)(=O)c1ccc(CBr)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(CN2CC3COCCN3c3nc(Cl)ncc32)c(Cl)c1
Reaction time: 0.08 h
Yield: 37.8 %

Procedure:
2-Chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x2, 200 mg, 0.882 mmol) was dissolved in DMSO (4.4 mL). Sodium tert-butoxide (102 mg, 1.059 mmol) was then added to give a brown solution. After 5 minutes, 1-(bromomethyl)-2-chloro-4-(methylsulfonyl)benzene (250 mg, 0.882 mmol) was added dropwise. The reaction mixture was stirred for 18 hours. Additional sodium tert-butoxide (0.5 eq) was added and the reaction mixture was stirred for an additional 18 hours. The reaction mixture was subsequently diluted with ethyl acetate and was washed with aqueous saturated NH4Cl (3×25 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was loaded onto an ISCO® silica gel cartridge (12 g) and eluted with an ethyl acetatehexane gradient. The product was collected and concentrated in vacuo to afford the title compound as a yellow oil (143 mg, 37%). ESI-MS m/z [M+H]+ calc'd for C17H18Cl2N4O3S, 430.3; found 431.3.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:20])[C:4]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:13][CH2:12][C:7]2(OCC[O:8]2)[CH2:6][CH2:5]1>O>[CH3:2][N:3]([CH3:20])[C:4]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:13][CH2:12][C:7](=[O:8])[CH2:6][CH2:5]1
Reactant: CN(C)C1(c2ccccc2)CCC2(CC1)OCCO2
Agent: Cl
Solvent: O
Product: CN(C)C1(c2ccccc2)CCC(=O)CC1
Reaction time: 24 h
Yield: 72.4 %

Procedure:
165 ml of hydrochloric acid (32 wt. %) were diluted with 100 ml of water; 60.0 g of dimethyl-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-yl)-amine were added to this approximately six molar hydrochloric acid, and stirring was carried out for 24 hours. The reaction mixture was washed three times using 50 ml of diethyl ether each time, rendered alkaline (pH>10) with 100 ml of sodium hydroxide solution (32 wt. %) and extracted three times using 100 ml of dichloromethane each time. The extracts were combined, dried over sodium sulfate, filtered and concentrated. 36.1 g of 4-dimethylamino-4-phenylcyclohexanone were obtained.
Reaction SMILES: [CH3:1][O:2]/[CH:3]=[C:4]1\[CH2:5][C@@H:6]([C:16]([O:18][CH3:19])=[O:17])[N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8]\1.[O-2].[Mg+2].[H][H]>[Pd].CO>[CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:6]([C:16]([O:18][CH3:19])=[O:17])[CH2:5]1
Reactant: CO/C=C1\C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1
Reactant: [H][H]
Agent: [Pd]
Agent: [Mg+2]
Agent: [O-2]
Solvent: CO
Product: COC[C@H]1C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1
Yield: 99.2 %

Procedure:
A solution of (5,E)-1-tert-butyl 2-methyl 4-(methoxymethylene)pyrrolidine-1,2-dicarboxylate (9 g, 33.21 mmol), magnesium oxide (12 g, 33.21 mmol) and palladium on carbon (3 g) in methanol (100 mL) was held under a steady flow of hydrogen at RT for 2 h, and filtered. The organic phase was concentrated to provide the title intermediate (9 g, 100% yield) as a colorless oil. 1H NMR (400 MHz, (CD3)2S═O): δ(ppm) 1.367 (s, 9H), 1.620-1.670 (m, 1H), 1.904-1.953 (m, 1H), 3.110-3.140 (s, 3H, J=12 Hz), 3.255-3.360 (m, 2H), 3.523-3.561 (m, 1H), 3.653 (s, 3H), 4.241-4.283 (m, 1H).
Reaction SMILES: C([O:3][C:4](=[O:43])[CH2:5][CH:6]([C:33]1[CH:34]=[N:35][C:36]2[C:41]([CH:42]=1)=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[N:18]=[C:17]([NH:19]C(=O)C(C)(C)C)[N:16]=[C:15]([NH:26]C(=O)C(C)(C)C)[CH:14]=1)C.O.[Li+].[OH-]>C1COCC1>[NH2:19][C:17]1[N:16]=[C:15]([NH2:26])[CH:14]=[C:13]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH:6]([C:33]2[CH:34]=[N:35][C:36]3[C:41]([CH:42]=2)=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:5][C:4]([OH:43])=[O:3])[N:18]=1
Reactant: CCOC(=O)CC(CCCCCCc1cc(NC(=O)C(C)(C)C)nc(NC(=O)C(C)(C)C)n1)c1cnc2ccccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Nc1cc(CCCCCCC(CC(=O)O)c2cnc3ccccc3c2)nc(N)n1

Procedure:
The ester 7-8 (1 g, 1.7 mmol) was dissolved in THF (20 mL) and water (20 mL) and treated with 1N LiOH (7 mL) at room temperature for 16 hours. After neutralization with 3N HCl, the solution was concentrated in vacuo, filtered through a bed of silica gel (EtOH:H2O:NH4OH 10:1:1) and the residue purified by reverse phase HPLC (preppak C-18 column; water/acetonitrile/0.1% TFA gradient). After lyophilization, the title compound 7-9 (TFA salt) was obtained as a white powder.
Reaction SMILES: [CH2:1]([C:4]1[C:5]([OH:16])=[C:6]2[C:11](=[C:12]([CH3:14])[CH:13]=1)[NH:10][C:9](=[O:15])[CH:8]=[CH:7]2)[CH:2]=[CH2:3].[C:17](O)(=[O:19])[CH3:18]>N1C=CC=CC=1.C(Cl)(Cl)Cl>[C:17]([O:16][C:5]1[C:4]([CH2:1][CH:2]=[CH2:3])=[CH:13][C:12]([CH3:14])=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:15])[NH:10]2)(=[O:19])[CH3:18]
Reactant: C=CCc1cc(C)c2[nH]c(=O)ccc2c1O
Reactant: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: C=CCc1cc(C)c2[nH]c(=O)ccc2c1OC(C)=O
Temperature: 25 °C
Yield: 91.3 %

Procedure:
To a solution of 6-allyl-5-hydroxy-8-methylcarbostyril (3.2 g, 14.9 mmol) in pyridine (50 ml), acetic acid (3.5 34.3 mmol) was added and stirred at room temperature for hour. The mixture was condensed and dissolved in chloroform. The resultant solution was washed with saturated aqueous sodium bicarbonate solution, aqueous 2N-HCl solution, and water, and dried and condensed. As a result, 3.5 g of 5-acetoxy-6-allyl-8-methylcarbostyril was obtained as colorless crystals (91.4%).
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[CH2:23]([N:30]1[C@@H:35]2[C@H:36]([C:38]([NH2:40])=O)[CH2:37][C@@:31]1([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C@H:32]([O:41][CH2:42][C:43]1[CH:48]=[C:47]([C:49]([F:52])([F:51])[F:50])[CH:46]=[C:45]([C:53]([F:56])([F:55])[F:54])[CH:44]=1)[CH2:33][CH2:34]2)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[CH2:23]([N:30]1[C@@H:35]2[C@H:36]([C:38](=[S:10])[NH2:40])[CH2:37][C@@:31]1([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C@H:32]([O:41][CH2:42][C:43]1[CH:48]=[C:47]([C:49]([F:52])([F:51])[F:50])[CH:46]=[C:45]([C:53]([F:56])([F:55])[F:54])[CH:44]=1)[CH2:33][CH2:34]2)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NC(=O)[C@@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: NC(=S)[C@@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 49.1 %

Procedure:
Lawesson's reagent (0.23 g, 0.57 mmol) was added to a solution of (1R*,2R*,5S*,6R*)-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxyl}-1-phenyl-8-azabicyclo[3.2.1]octan-6-carboxamide (Example 75; 0.64 g, 1.14 mmol) in toluene (20 ml). The mixture was stirred at 100° C. for 1 hour then concentrated in vacuo. The residue was chromatographed on silica gel eluting with 2 and 3% methanol/dichloromethane to yield the title compound (0.162 g, 25%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:21])[C:5]([O:8][C:9]2[CH:20]=[CH:19][C:12]([O:13][CH:14]([CH3:18])[C:15](Cl)=[O:16])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.C(N(CC)CC)C.[CH2:29]([NH:33][C:34]#[N:35])[CH2:30][CH2:31][CH3:32]>C1(C)C=CC=CC=1>[CH2:29]([N:33]([C:34]#[N:35])[C:15](=[O:16])[CH:14]([O:13][C:12]1[CH:19]=[CH:20][C:9]([O:8][C:5]2[C:4]([F:21])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[CH:10][CH:11]=1)[CH3:18])[CH2:30][CH2:31][CH3:32]
Reactant: CC(Oc1ccc(Oc2ncc(Cl)cc2F)cc1)C(=O)Cl
Reactant: CCCCNC#N
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCN(C#N)C(=O)C(C)Oc1ccc(Oc2ncc(Cl)cc2F)cc1
Reaction time: 5 h

Procedure:
While cooling with ice, a solution of 9.9 g (0.030 mole) of 2-[4-(5-chloro-3-fluoropyridin-2-yloxy)phenoxy]propionyl chloride in 30 ml of toluene is added dropwise to a solution of 3.5 g (0.035 mole) of triethylamine and 3.2 g (0.033 mole) of n-butylcyanamine in 40 m of toluene. After 5 hours, the precipitate is removed by filtration and the filtrate is purified by chromatography through silica gel. The eluate is concentrated by evaporation, affording 2-[4-(5-chloro-3-fluoropyridin-2-yloxy)phenoxy]propionic acid N-n-butyl-N-cyanamide as a yellowish oil. nD25 : 1.5482.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[N:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[C:2]=1[O:21][C:18]1[CH:19]=[CH:20][C:15]([NH2:14])=[CH:16][CH:17]=1
Reactant: Nc1ccc(O)cc1
Reactant: Clc1ncccc1-c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ccc(Oc2ncccc2-c2ccncc2)cc1
Temperature: 25 °C

Procedure:
To a 50 mL round-bottomed flask was added 2-chloro-3-(pyridin-4-yl)pyridine (0.75031 g, 3.9 mmol), 4-aminophenol (0.4302 g, 3.9 mmol), cesium carbonate (0.38 ml, 4.7 mmol) in DMSO at 80° C. Upon completion, the reaction was allowed to cool to room temperature. The reaction mixture was diluted with water (10 ml) and extracted with DCM (3 15 mL). The organic extract was washed with water (1 10 mL), brine (1 10 mL), dried with magnesium sulfate, filtered and concentrated. The residue was taken up in DCM and was loaded onto a SCX cartridge. The impurities were filtered off with DCM and MeOH. 4-(3,4′-Bipyridin-2-yloxy)aniline was filtered from cartridge using 2.0M ammonia in MeOH (MS 264.0).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.[Na].[CH2:22]([CH:24]1[O:29][CH2:28][CH2:27][N:26]([C:30]2[N:31]=[C:32]([CH2:37][C:38](O)=[O:39])[NH:33][C:34](=[O:36])[CH:35]=2)[CH2:25]1)[CH3:23]>CN(C)C=O.N1C=CC=CC=1>[CH2:22]([CH:24]1[O:29][CH2:28][CH2:27][N:26]([C:30]2[N:31]=[C:32]([CH2:37][C:38]([NH:6][C:5]3[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=3)=[O:39])[NH:33][C:34](=[O:36])[CH:35]=2)[CH2:25]1)[CH3:23]
Reactant: Nc1ccc(F)cc1
Reactant: CCC1CN(c2cc(=O)[nH]c(CC(=O)O)n2)CCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCC1CN(c2cc(=O)[nH]c(CC(=O)Nc3ccc(F)cc3)n2)CCO1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4 ml of pyridine, 472 mg of 4-fluoroaniline and 815 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride are successively added to a solution of 410 mg of the sodium salt of [4-(2-ethylmorpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetic acid in 4 ml of N,N-dimethylformamide. The reaction mixture is stirred at ambient temperature for 16 hours, and then concentrated under reduced pressure. The residue is taken up in 25 ml of water and then the pH is brought back to about 7 with a 2M hydrochloric acid solution. 30 ml of ethyl acetate are added and then the resulting mixture is allowed to stir at ambient temperature for 1 hour. The precipitate formed is filtered off, and then rinsed successively with water and diethyl ether. 300 mg of (±)-2-[4-(2-ethylmorpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]-N-(4-fluorophenyl)-acetamide are thus obtained in the form of an off-white powder, the characteristics of which are the following:
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]1([CH3:15])[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1.[Cl-].[Na+]>O.C(O)C>[C:5]1([CH3:15])[CH:10]=[CH:9][C:8]([S:11]([N:1]=[N+:2]=[N-:3])(=[O:13])=[O:12])=[CH:7][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Temperature: 45 °C

Procedure:
A solution of 35 g. (0.5 moles) of sodium azide in 200 ml of water was placed in a 2 litre Erlenmeyer flask and diluted with 400 ml of 90% aqueous ethanol. To this solution was added with stirring a warm (45° C.) solution of 96 g. (0.50 mole) of p-toluenesulfonyl chloride in 1 litre of 99% ethanol. During the addition, sodium chloride separated. The reaction mixture was stirred at room temperature for 2.5 hours. Most of the solvent is removed at 35° C. (15 mm) with a rotary evaporator. The residue was mixed with 1.2 liters of water in a separatory funnel, and the oily p-toluenesulfonyl azide separated. This oil was washed with two 100 ml portions of water and dried over anhydrous sodium sulfate. Filtration with suction gave 50 g (60%, based on p-toluenesulfonyl chloride) of pure, colorless p-toluenesulfonyl azide which completely crystallised on standing at 5°.
Reaction SMILES: [F:1][C@H:2]([C@H:5]1[CH2:9][O:8]C(C)(C)[N:6]1C([O-])=O)[CH2:3][CH3:4].[ClH:15].CO>>[ClH:15].[NH2:6][C@@H:5]([C@@H:2]([F:1])[CH2:3][CH3:4])[CH2:9][OH:8]
Reactant: CC[C@H](F)[C@H]1COC(C)(C)N1C(=O)[O-]
Agent: Cl
Solvent: CO
Product: CC[C@H](F)[C@H](N)CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 5-10% HCl/methanol solution (70 mL) was added to tert-butyl((4R)-4-[(1S)-1-fluoropropyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (4.9 g), and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure to afford the title compound (2.96 g).