Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([CH:8]=O)=[N:6][CH:7]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([NH:24][CH2:8][C:5]2[C:4]([CH3:10])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Cc1cc(Cl)cnc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(Cl)cnc1CNC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Using General Procedure B, reaction of 5-chloro-3-methylpyridine-2-carbaldehyde, 4-aminopiperidine-1-carboxylic acid tert-butyl ester and NaBH(OAc)3 in CH2Cl2 gave 4-[(5-chloro-3-methyl-pyridin-2-ylmethyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as a beige liquid. 1H NMR (CDCl3): δ 1.39 (m, 2H), 1.45 (s, 9H), 1.89 (d, 2H, J=12.0 Hz), 2.30 (s, 3H), 2.69 (m, 1H), 2.83 (t, 2H, J=12.0 Hz), 3.87 (s, 2H), 4.03 (br, 2H), 7.44 (s, 1H), 8.34 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[O:11]1[CH2:15][CH2:14][NH:13][C:12]1=[O:16]>>[C:8]([C:4]1[CH:3]=[C:2]([N:13]2[CH2:14][CH2:15][O:11][C:12]2=[O:16])[CH:7]=[CH:6][CH:5]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1cccc(Br)c1
Reactant: O=C1NCCO1
Product: CC(=O)c1cccc(N2CCOC2=O)c1

Procedure:
The title compound was prepared in quantitative yield according to the general procedure for the preparation of the amides, ureas and carbamates (Method A) starting from 1-(3-bromophenyl)ethanone and 1,3-oxazolidin-2-one.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(OC(C)C)(OC(C)C)O[CH:10]([CH3:12])[CH3:11].C(O)(C)C.O.S([O-])(O)(=O)=O.[Na+]>>[CH:10]([O:7][C:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1)([CH3:12])[CH3:11]
Reactant: O=C1CCCCC1
Reactant: CC(C)OC(OC(C)C)OC(C)C
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CC(C)OC1=CCCCC1
Temperature: 60 °C
Yield: 81.7 %

Procedure:
To a mixture at room temperature containing 196.32 grams (2 mol) of cyclohexanone, 390.4 grams (2.06 mol) of triisopropyl orthoformate and 12.00 grams of isopropanol (0.2 mol), was added 7.6 grams (0.055 mol) of sodium hydrogensulfate monohydrate. The reaction was exothermic and upon addition of the catalyst, the temperature of the reaction mixture rose to 35° C., and was heated and maintained at 60° C. for 1 hour. The progress of the reaction was monitored by GC until the cyclohexanone content dropped to less than 2%. The isopropanol and isopropyl formate were distilled off under reduced pressure until the reaction mixture's temperature reached a maximum of 100° C. The reaction mixture was cooled to room temperature and filtered to remove sodium hydrogensulfate monohydrate (recovered). The pH value of the filtrate was adjusted to about 7˜8 by adding 0.8 gram of potassium iso-propoxide. The mixture was then heated under reduced pressure to remove unreacted cyclohexanone. The product, 1-isopropoxy-1-cyclohexene was isolated by distillation as a clear liquid; the yield was 81.7% with a purity exceeding 98%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C@H:4]([OH:13])[C@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH2:6].[C:15]([N:19]=[C:20]=[O:21])([CH3:18])([CH3:17])[CH3:16].[N-]=C=O>C1COCC1>[CH3:1][O:2][C:3](=[O:14])[CH:4]([OH:13])[CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH:6][C:20]([NH:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:21]
Reactant: CC(C)(C)N=C=O
Reactant: COC(=O)[C@H](O)[C@@H](N)c1ccccc1
Agent: [N-]=C=O
Solvent: C1CCOC1
Product: COC(=O)C(O)C(NC(=O)NC(C)(C)C)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
(2R,3S)-β-phenyl-isoserine methyl ester (4.35 g, 22 mM) is dissolved in 100 mL dry THF and the flask cooled to 0° C. To the solution is added t-butyl isocyanate (2.8 mL, 25 mM). TLC after 15 minutes shows some starting material left so another 0.5 mL of the isocyanate is added. TLC after 1 hour shows no starting material so the solvent is concentrated in vacuo leaving N-(t-butylaminocarbonyl)-β-phenyl isoserine methyl ester (3K).
Reaction SMILES: C1(COC([N:11]2[CH2:16][CH:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:27][C@H:26]([CH2:28][NH:29][C:30](=[O:32])[CH3:31])[O:25][C:24]4=[O:33])=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=O)C=CC=CC=1>CO.[Pd]>[O:33]=[C:24]1[N:23]([C:20]2[CH:21]=[CH:22][C:17]([CH:14]3[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]3)=[CH:18][CH:19]=2)[CH2:27][C@H:26]([CH2:28][NH:29][C:30](=[O:32])[CH3:31])[O:25]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3=CCN(C(=O)OCc4ccccc4)CC3)cc2)C(=O)O1
Agent: [Pd]
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc(C3CCNCC3)cc2)C(=O)O1
Reaction time: 16 h

Procedure:
A mixture of (S)-(-)-4-[4-[5-[(acetylamino)methyl]-2-oxo-3-oxazolidinyl]phenyl]-3,6-dihydro-1(2H)-pyridinecarboxylic acid phenylmethyl ester (EXAMPLE 17, Step 5, 625 mg) and 10% palladium-on-carbon (300 mg) in methanol (100 mL) is shaken on a Parr apparatus under a hydrogen atmosphere at 40 psi for one hour and at 20 psi for 16 hours, the catalyst is removed by filtration through Celite and the filtrate is 6011.N DV1 concentrated under reduced pressure to give the title compound, mp 169-171° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][N:12]=1)[C:6]([O:8][CH3:9])=[O:7].[C:13](Cl)(=[O:17])[CH:14]([CH3:16])[CH3:15]>>[C:13]([NH:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][N:12]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:17])[CH:14]([CH3:16])[CH3:15]
Reactant: COC(=O)c1ccnc(N)c1
Reactant: CC(C)C(=O)Cl
Agent: Cl
Product: COC(=O)c1ccnc(NC(=O)C(C)C)c1
Yield: 93 %

Procedure:
The title compound is prepared in 93% yield (2.20 g, a yellow solid) from methyl 2-aminoisonicotinate hydrochloride (2.00 g, 10.6 mmol) and isobutyryl chloride by the similar manner in Step-1 of Carboxylic acid-1.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][S:17][CH2:16][CH2:15]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH3:13])[C:6]=2[N:7]=1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH3:13][S:12][C:8]1[C:6]2[N:7]=[C:2]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:3]=[C:4]([N:14]3[CH2:19][CH2:18][S:17][CH2:16][CH2:15]3)[C:5]=2[N:11]=[CH:10][N:9]=1
Reactant: C1CNCCN1
Reactant: CSc1ncnc2c(N3CCSCC3)nc(Cl)nc12
Product: CSc1ncnc2c(N3CCSCC3)nc(N3CCNCC3)nc12

Procedure:
This compound was prepared analogous to Example 2 from 2-chloro-8-methylthio-4-thiomorpholino-pyrimido-[5,4-d]-pyrimidine (m.p.: 165°-167° C.) and piperazine at room temperature.
Reaction SMILES: [OH:1][CH:2]([C:9]([OH:11])=[O:10])[C:3]([CH3:8])([CH3:7])[C:4]([OH:6])=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[OH:1][CH:2]1[C:9](=[O:10])[O:11][C:4](=[O:6])[C:3]1([CH3:7])[CH3:8]
Reactant: CC(C)(C(=O)O)C(O)C(=O)O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)C(=O)OC(=O)C1O
Temperature: 2.5 °C
Reaction time: 2 h

Procedure:
(3RS)-3-Hydroxy-2,2-dimethyl-succinic acid [Tetrahedron Letters (2002), 43(52), 9513-9515] (120 mg, 0.74 mmol) was suspended in CH2Cl2 (2 ml) and cooled to 0-5° C. Trifluoroacetic anhydride (260 μl, 1.85 mmol) was added and the reaction mixture stirred for 2 hours at room temperature. The reaction mixture was evaporated to dryness and used without any further purification in the next step.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17](/[CH:22]=[CH:23]/[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:30]([O:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][C:45](Cl)=[O:46])=[CH:40][CH:39]=1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Si:30]([O:37][C:38]1[CH:39]=[CH:40][C:41]([CH2:44][C:45]([NH:21][C:18]2[C:17]([CH:22]=[CH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:16][C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3])=[CH:14][CH:13]=3)=[CH:20][N:19]=2)=[O:46])=[CH:42][CH:43]=1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cnc(N)c(/C=C/c3ccccc3)n2)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Nc2ncc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)nc2C=Cc2ccccc2)cc1
Temperature: 50 °C
Reaction time: 15 h
Yield: 69.7 %

Procedure:
Under an argon atmosphere, to a mixture of (E)-5-[4-(tert-butyldimethylsilyloxy)phenyl]-3-styrylpyrazin-2-amine (7b) (500 mg, 1.24 mmol) and 4-(dimethylamino)pyridine (15.3 mg, 125 μmol) dissolved in anhydrous pyridine (20 mL) was added 2-[4-(tert-butyldimethylsilyloxy)phenyl]acetyl chloride (10) prepared above at 0° C. and the mixture was heated with stirring at 50° C. for 15 hours. After cooling to room temperature, to this was added water and the product was extracted with ethyl acetate (100 mL×3). The combined organic extract was washed successively with water (200 mL) and brine (200 mL), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by column chromatography (silica gel 50 g, n-hexane/ethyl acetate=3/1) to give Compound 11b (563 mg, 864 mol, 69.7%) as a yellow solid. Rf=0.29 (n-hexane/ethyl acetate=3/1); 1H NMR (400 MHz, DMSO-d6) δ 0.17 (s, 6H), 0.24 (s, 6H), 0.96 (s, 9H), 0.97 (s, 9H), 3.66 (s, 2H), 6.81-6.91 (m, 3H, includes AA′BB′), 6.99-7.04 (AA′BB′, 2H), 7.28-7.40 (m, 7H, includes AA′BB′), 7.82 (d, 1H, J=16 Hz), 8.11-8.19 (AA′BB′, 2H), 8.91 (s, 1H), 10.66 (s, 1H); 13C NMR (75.5 MHz, DMSO-d6) δ −4.5 (2C), −4.6 (2C), 17.8, 17.9, 25.5 (6C), 42.0, 119.7 (2C), 120.3 (2C), 122.5, 127.1 (2C), 128.2 (2C), 128.5, 128.7 (2C), 128.9, 129.0, 130.3 (2C), 133.8, 136.0, 137.8, 142.8, 143.9, 148.0, 154.0, 156.7, 170.6; IR (KBr, cm−1) 471, 521, 638, 691, 746, 781, 806, 839, 914, 968, 1007, 1080, 1103, 1169, 1263, 1325, 1371, 1391, 1414, 1439, 1472, 1510, 1566, 1605, 1659, 2857, 2886, 2930, 2055, 3028, 3057, 3217; HRMS (ESI+) m/z 674.3203 ([M+Na]+, C38H49N3NaO3Si2+ requires 674.3205).
Reaction SMILES: Cl.[C:2]1([C@H:8]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:24][CH2:25][CH2:26][O:27]C4CCCCO4)=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH3:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+]>CO>[C:2]1([C@H:8]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:24][CH2:25][CH2:26][OH:27])=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH3:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](Nc1ncnc2cc(OCCOC3CCCCO3)c([N+](=O)[O-])cc12)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: C[C@@H](Nc1ncnc2cc(OCCO)c([N+](=O)[O-])cc12)c1ccccc1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
120 ml of methanol and 2 ml of concentrated hydrochloric acid were given to 8.05 g of 4-[(R)-(1-Phenylethyl) amino]-7-[2-(tetrahydropyran-2-yloxy)ethoxy]-6-nitroquinazoline. After stirring for 1.5 hours at 50° C. the reaction mixture was neutralized with concentrated aqueous sodium carbonate solution and evaporated. The solid residue was dissolved in ethyl acetate and the obtained solution was washed with water, with concentrated aqueous sodium chloride solution, dried over magnesium sulfate solution and evaporated. The obtained yellow residue was stirred with 20 ml of tert-butyl methyl ether, suction filtered and dried in an exsiccator. Yield: 4.53 g (91% of theory); melting point: 192° C.–194° C.; mass spectrum (ESI−): m/z=353 [M−H]−.
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH2:14][CH2:13][CH2:12][C:11]1=[O:15])([O:3]CC)=[O:2].Cl.C(O)(=O)C>O>[C:1]([CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH2:14][CH2:13][CH2:12][C:11]1=[O:15])([OH:3])=[O:2]
Reactant: CCOC(=O)CCCCC1CCCC1=O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)CCCCC1CCCC1=O

Procedure:
A stirred mixture of 274 g. of 2-carbalkoxy(mixed methyl and ethyl esters)-2-(4-carbethoxybutyl)cyclopentan-1-one (Example 1), 600 ml. of 20% hydrochloric acid and 325 ml. of acetic acid is heated at reflux for 20 hours. Solution occurs in approximately one-half hour. The solution is cooled and diluted with water and extracted with ether. The combined extracts are washed with saline and dried over magnesium sulfate and evaporated. The residue is evaporated twice with toluene to give 144 g. of an oil.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[CH:34]1([N:40]=[C:41]=[O:42])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:41]([NH:40][CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[O:42])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C=NC1CCCCC1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)NC4CCCCC4)c3C2=O)C(=O)N1
Reaction time: 0.33 h
Yield: 48.5 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.29 g, 1.90 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.6 g, 1.85 mmol) in CH3CN (50 mL). After stirring for 20 min, cyclohexyl isocyanate (0.35 g, 2.77 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 mL). The CH2Cl2 solution was washed with 1N HCl (30 mL), H2O (30 mL), brine (30 mL) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by chromatography (SiO2, CH2Cl2:EtOAc 1:1) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}(cyclohexylamino)carboxamide (0.37 g, 49%) as a white solid: mp 208-210° C.; 1H NMR (DMSO-d6) δ 11.13 (s, 1H), 7.86-7.68 (m, 3H), 6.34 (t, J=5.8 Hz, 1H), 6.04 (d, J=7.9 Hz, 1H), 5.18-5.11 (dd, J=5.3 and 12.4 Hz, 1H), 4.62 (d, J=5.8 Hz, 2H), 3.37 (m, 1H), 2.96-2.83 (m, 1H), 2.63-2.50 (m, 2H), 2.08-2.04 (m, 1H), 1.76-1.02 (m, 10H); 13C NMR (DMSO-d6) δ 172.78, 169.84, 167.59, 167.04, 157.28, 141.13, 134.64, 133.42, 131.51, 126.98, 121.64, 48.82, 47.91, 38.66, 33.23, 30.94, 25.27, 24.47, 21.99; Anal. Calcd. For C21H24N4O5: C, 61.16; H, 5.87; N, 13.58. Found: C, 61.21; H, 5.79; N, 13.63.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]2[C@H:15]3[C@H:25]([CH2:26][CH2:27][C@:10]12[CH3:11])[C@:23]1([CH3:24])[C:18]([NH:19][C:20](=[O:28])[CH2:21][CH2:22]1)=[CH:17][CH2:16]3)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>N1C=CC=CC=1.C(Cl)Cl>[C:29]([N:19]1[C:20](=[O:28])[CH2:21][CH2:22][C@@:23]2([CH3:24])[C:18]1=[CH:17][CH2:16][C@@H:15]1[C@@H:25]2[CH2:26][CH2:27][C@@:10]2([CH3:11])[C@H:12]1[CH2:13][CH2:14][C@@H:9]2[O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H]2[C@@H]3CC=C4NC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H]2[C@@H]3CC=C4N(C(=O)c5ccccc5)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To 17β-t-butyldimethylsilyloxy-4-azaandrost-5-en-3-one (2 g) in pyridine (5 ml) at 5°-10° C. was added benzoyl chloride (2 ml) in CH2Cl2 (10 ml) dropwise. After the addition, the mixture was stirred at 60° C. for 3 hours and poured onto ice-water. The mixture was extracted with methylene chloride, and dried (Na2 SO4). Removal of solvent gave the crude product which was recrystallized from CH2Cl2 -hexane to afford the title product.
Reaction SMILES: [CH2:1]1[CH:11]2[CH:12]3[CH:7]([CH2:8][CH2:9][CH2:10]2)[CH2:6][CH2:5][C:4](=[O:13])[N:3]3[C:2]1=[O:14].[OH-:15].[Na+]>O>[O:14]=[C:2]1[CH2:1][CH:11]2[CH:12]([CH:7]([CH2:6][CH2:5][C:4]([OH:15])=[O:13])[CH2:8][CH2:9][CH2:10]2)[NH:3]1
Reactant: [OH-]
Reactant: O=C1CCC2CCCC3CC(=O)N1C23
Agent: [Na+]
Solvent: O
Product: O=C(O)CCC1CCCC2CC(=O)NC12
Reaction time: 1 h

Procedure:
A solution of 0.15 g (0.0007 mol)octahydro-4Hpyrrolo [3,2,1-ij]quinoline-2,4(1H)-dione (6aα, 9aα, 9bα) in 1 ml of water is treated with 0.7 ml of 1N sodium hydroxide solution. The solution is stirred one hour and is passed over a 2 g Dowex-H+ column. The eluate is concentrated at reduced pressure and the solid is recrystallized from ethanol to yield crystalline octahydro-2-oxo-1H-indole-7-propanoic acid (3aα, 7β, 7aα) with a melting point of 180°-181° C.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24]Br)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[CH3:28][C@H:29]1[NH:34][C@@H:33]([CH3:35])[CH2:32][N:31]([C:36]2[CH:45]=[CH:44][C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:37]=2)[CH2:30]1>>[F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24][N:34]2[C@H:33]([CH3:35])[CH2:32][N:31]([C:36]3[CH:45]=[CH:44][C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[N:37]=3)[CH2:30][C@@H:29]2[CH3:28])[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2Oc2ccccc21
Reactant: C[C@@H]1CN(c2ccc3ccccc3n2)C[C@H](C)N1
Product: C[C@@H]1CN(c2ccc3ccccc3n2)C[C@H](C)N1CCCCC1(C(=O)NCC(F)(F)F)c2ccccc2Oc2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-xanthene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 2-(cis-3,5-dimethyl-piperazin-1-yl)-quinoline
Reaction SMILES: CS(O)(=O)=O.[NH2:6][C:7](=[S:28])[NH:8][NH:9][C:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:17][C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[C:20]([CH3:25])[C:19]=1[Cl:26]>C1(C)C=CC=CC=1>[Cl:26][C:19]1[C:20]([CH3:25])=[CH:21][CH:22]=[C:23]([Cl:24])[C:18]=1[NH:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:10]1[S:28][C:7]([NH2:6])=[N:8][N:9]=1
Reactant: Cc1ccc(Cl)c(Nc2ccccc2C(=O)NNC(N)=S)c1Cl
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: Cc1ccc(Cl)c(Nc2ccccc2-c2nnc(N)s2)c1Cl
Temperature: 25 °C
Yield: 58.5 %

Procedure:
Methanesulfonic acid (280 μl, 4.31 mol) is added dropwise to a suspension of 2-[(2,6-dichloro-3-methylphenyl) amino]-benzoic acid, 2-(aminothioxomethyl)hydrazide (1.008 g, 2.73 mmol) in 30 ml of toluene. The mixture is heated at reflux for three hours under a nitrogen atmosphere and allowed to cool to room temperature overnight. The tan solid is filtered off and suspended in 100 ml of ethyl acetate. The suspension is then stirred vigorously with 40 ml of 10% aqueous ammonium hydroxide, and the layers are separated. The ethyl acetate layer is washed with water, and dried over magnesium sulfate. Filtration and concentration in vacuo gives a white solid. Drying at 60° C. in vacuo overnight provides 560.8 mg (59%) of product, mp 219°-226° C.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[S:23]([CH3:25])=[O:24])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[CH3:25][S:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1)=[O:24]
Reactant: CS(=O)c1ccccc1C1CCN(C(=O)OCc2ccccc2)CC1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)c1ccccc1C1CCNCC1
Yield: 96 %

Procedure:
The product of Step 4 (0.5 g) was treated with trifluoroacetic acid (10 mL) and heated at reflux temperature for 45 minutes. The reaction mixture was cooled, diluted with toluene (40 mL) and evaporated. This procedure was repeated two more times. The residue was treated with CH2Cl2 (70 mL) and adjusted to alkaline pH via addition of NH4OH solution. The organic layer was separated, dried over MgSO4, filtered and evaporated to give 4-(2-methylsulfinylphenyl)piperidine (0.3 g).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][C@@H:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C@H:9]([CH3:13])[C:10]([NH2:12])=O>O1CCCC1>[CH3:13][C@H:9]([CH2:10][NH2:12])[C@H:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH2:7]
Reactant: C[C@H](C(N)=O)[C@@H](N)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H](CN)[C@@H](N)c1ccccc1
Reaction time: 0.75 h

Procedure:
Lithium aluminium hydride (2.3 g, 60.60 mmol) was added in portions to a stirring solution of (2S,3R)-3-amino-2-methyl-3-phenylpropionamide (2.6 g, 14.59 mmol) in tetrahydrofuran (54 ml) at ice-bath temperature. After 45 min, the mixture was heated at reflux for; 16 h. With ice-bath cooling, the reaction was quenched by the portionwise addition of sodium sulfate decahydrate and, some methanol until hydrogen evolution ceased. The solids were removed by filtration and washed with dichloromethane. The combined filtrates were evaporated to provide the title compound. MS (m/z): 165.2 (M+H)+; C10H16N2 requir. 164.3.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](I)[CH3:8].[CH3:10][C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[C:13]([CH3:18])[C:12]=1[OH:19]>C(#N)C.C(OCC)(=O)C>[CH2:7]([O:19][C:12]1[C:11]([CH3:10])=[C:16]([CH3:17])[CH:15]=[CH:14][C:13]=1[CH3:18])[CH3:8]
Reactant: Cc1ccc(C)c(O)c1C
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOc1c(C)ccc(C)c1C

Procedure:
734 mmol (101.5 g) of potassium carbonate and 917 mmol (143.1 g) of ethyl iodide are added in succession to a solution of 367 mmol (50 g) of 2,3,6-trimethylphenol in 1500 ml of acetonitrile. The whole is heated at reflux for 48 hours. The reaction mixture is subsequently cooled and then filtered and the filtrate is concentrated. The residue obtained is dissolved in ethyl acetate and washed with water and then with 10% aqueous sodium chloride solution. After drying the organic phase and then concentrating, an oily residue is obtained which is purified by chromatography on silica gel, using a petroleum ether: ethyl acetate mixture 95:5 as eluant, to yield the expected product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([CH:17]2[N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:20](=[O:28])[NH:19][CH2:18]2)=[O:16])[CH2:11][CH2:10]1.[H-].[Na+].[Cl:31][C:32]1[CH:33]=[C:34]([S:38](Cl)(=[O:40])=[O:39])[CH:35]=[CH:36][CH:37]=1.O>CC(N(C)C)=O>[Cl:31][C:32]1[CH:33]=[C:34]([S:38]([N:19]2[CH2:18][CH:17]([C:15]([N:12]3[CH2:13][CH2:14][N:9]([C:3]4[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=4[CH3:1])[CH2:10][CH2:11]3)=[O:16])[N:21]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:20]2=[O:28])(=[O:40])=[O:39])[CH:35]=[CH:36][CH:37]=1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CNC(=O)N3c3ccccc3)CC2)c1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1ccc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)c4cccc(Cl)c4)C(=O)N3c3ccccc3)CC2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (RS)-5-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-1-phenyl-imidazolidin-2-one (0.050 g) in dimethylacetamide (1 ml) under an argon atmosphere was added sodium hydride (55% in mineral oil, 6.3 mg) at 0° C. The mixture was stirred at 0° C. for 30 min. 3-Chlorobenzenesulfonyl chloride was added. The mixture was stirred at 0° C. for 30 min and at room temperature for 2 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with water and concentrated. The product was purified by chromatography ((SiO2, cyclohexane=>cyclohexane/ethyl acetate 1:2) to give (RS)-1-(3-chloro-benzenesulfonyl)-4-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-3-phenyl-imidazolidin-2-one (0.049 g) as a colorless solid. MS: 552.7 ([M+H]+)