Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([C@H:10]1[NH:14][C:13](=[O:15])[C@H:12]([CH2:16][C:17]([OH:19])=O)[CH2:11]1)=[O:9])#[N:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH2:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36][NH:35]1>O1CCOCC1.C(Cl)Cl>[CH2:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36][N:35]1[C:17](=[O:19])[CH2:16][C@H:12]1[C:13](=[O:15])[NH:14][C@H:10]([C:8]([N:4]2[CH2:5][CH2:6][CH2:7][C@H:3]2[C:1]#[N:2])=[O:9])[CH2:11]1
Reactant: c1ccc2c(c1)CNC2
Reactant: N#C[C@@H]1CCCN1C(=O)[C@@H]1C[C@@H](CC(=O)O)C(=O)N1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: C1COCCO1
Product: N#C[C@@H]1CCCN1C(=O)[C@@H]1C[C@@H](CC(=O)N2Cc3ccccc3C2)C(=O)N1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
To a stirred solution of [(3S,5S)-5-{[(2S)-2-cyanopyrrolidin-1-yl]carbonyl}-2-oxopyrrolidin-3-yl]acetic acid (265 mg, 0.50 mmol) and HOBt (42 mg, 0.55 mmol) in 1,4-dioxane (3 mL) was added a solution of EDC (105 mg, 0.55 mmol) in CH2Cl2 (3 mL). The mixture was stirred for 10 min at room temperature. Isoindoline (65 mg, 0.55 mmol) in CH2Cl2 (2 mL) was added with stirring. After 16 h, the reaction mixture was washed with saturated aqueous NaHCO3 (10 mL), 1 N aqueous citric acid (10 mL), and brine (10 mL). The organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified over silica gel using CH2Cl2/MeOH (98:2) as an eluent to yield compound 1 (128 mg, 0.35 mmol, 70%). 1H NMR (300 MHz, CDCl3): (6/1 mixture of trans/cis amide rotomers) δ 7.30-7.26 (m, 4H), 6.56 (s, 0.86H), 6.06 (s, 0.14H), 4.82-4.77 (m, 4.86H, overlapped two singlet at 4.82, 4.77), 4.60 (d, J=6.6 Hz, 0.14H), 4.55 (d, J=9.0 Hz, 0.14H), 4.40 (dd, J=3.0, 9.0 Hz, 0.86H), 3.61-3.04 (m, 2H), 3.02-2.88 (m, 2H), 2.68-2.36 (m, 3H), 2.29-2.12 (m, 4H). MS (ES+) m/z calcd. for C20H22N4O3: 366.17. found: 367.1 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]([C:18](=[N:22][OH:23])[CH:19]([CH3:21])[CH3:20])=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)=[CH:5][CH:4]=1.C[Si]([N:28]=[C:29]=[O:30])(C)C.N1C=CC=CC=1>C1COCC1>[C:29]([O:23][N:22]=[C:18]([C:17]1[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:10][N:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=12)[CH:19]([CH3:20])[CH3:21])(=[O:30])[NH2:28]
Reactant: C[Si](C)(C)N=C=O
Reactant: COc1ccc(-c2nn3ccccc3c2C(=NO)C(C)C)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1ccc(-c2nn3ccccc3c2C(=NOC(N)=O)C(C)C)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 29.8 %

Procedure:
To a solution of 775 mg (2.5 mmol) of 1-(2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one oxime in 5 ml of anhydrous THF was added 2 ml of trimethylsilyl isocyanate (85%) dropwise at 0° C. over 30 minutes. The mixture was stirred at room temperature over 48 hours, followed by addition of 500 μl pyridine. After stirring for another 4 hours the solvent was removed, and the residue was extracted with ethyl acetate three times. The combined organic layers were washed with 10% citric acid twice and dried over MgSO4. After evaporation of the solvent, 900 mg of crude product was obtained, which was purified on an aluminum oxide column with hexane-dichloromethane-ethyl acetate as eluant to yield 263 mg (29.8%) of 1-(2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one O-carbamoyl oxime. Compound 1023.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH3:22])=[CH:17][CH:16]=2)[C:3]=1[CH2:23][C:24]([O:26][CH3:27])=[O:25].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:38]1[CH2:42]OC[CH2:39]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH3:22])=[CH:19][CH:20]=2)[C:3]=1[CH:23]([CH2:39][CH2:38][CH3:42])[C:24]([O:26][CH3:27])=[O:25]
Reactant: CCc1ccc(-c2c(CC(=O)OC)c(C)nc3sc4c(c23)CCCC4)cc1
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCI
Solvent: CN(C)C=O
Product: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccc(CC)cc1)CCCC3
Yield: 76.6 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-(4-ethylphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.231 g; 0.61 mmol), LHMDS 1N in THF (0.67 mL; 0.67 mmol), 1-iodopropane (0.089 mL; 0.913 mmol) in DMF (2.4 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (3-30%) in heptane furnished 0.197 g (77%) of the title compound as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:19])([CH3:18])[CH2:3][N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([NH2:17])[C:13]([O:15][CH3:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:38]=[CH:37][CH:36]=[CH:35][C:29]=2[C:30]([NH:32][CH2:33][CH3:34])=[O:31])[C:24]([Cl:39])=[CH:23][N:22]=1>>[Cl:39][C:24]1[C:25]([NH:27][C:28]2[CH:38]=[CH:37][CH:36]=[CH:35][C:29]=2[C:30]([NH:32][CH2:33][CH3:34])=[O:31])=[N:26][C:21]([NH:17][C:12]2[C:13]([O:15][CH3:16])=[CH:14][C:7]3[CH2:6][CH2:5][N:4]([CH2:3][C:2]([F:1])([F:19])[CH3:18])[CH2:10][CH2:9][C:8]=3[CH:11]=2)=[N:22][CH:23]=1
Reactant: CCNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc2c(cc1N)CCN(CC(C)(F)F)CC2
Product: CCNC(=O)c1ccccc1Nc1nc(Nc2cc3c(cc2OC)CCN(CC(C)(F)F)CC3)ncc1Cl

Procedure:
The title compound was prepared from 3-(2,2-Difluoro-propyl)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-ethyl-benzamide in an analogous manner to Example 61e. Product isolated as a white solid (0.011 g, 11%). MP: 165-167° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 10.94 (s, 1H), 8.65 (d, 1H, J=8.6 Hz), 8.10 (d, 1H, J=1.5 Hz), 8.09-8.07 (m, 1H), 7.53-7.39 (m, 3H), 7.12-7.06 (m, 1H), 6.64 (s, 1H), 6.13 (br s, 1H), 3.86 (s, 3H), 3.57-3.48 (m, 2H), 2.90-2.73 (m, 10H), 1.69 (t, 3H, J=18.6 Hz), 1.30-1.24 (m, 3H). MS: 545.21 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:13]3[CH:14]=[CH:15][CH:16]=[C:17]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4C(OC)=O)=[O:19])[C:12]=3[O:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[OH-:31].[Na+].Cl.[O:34]1[CH2:38]CCC1>CO>[C:38]([C:24]1[CH:23]=[CH:22][C:21]([NH:20][C:18]([C:17]2[C:12]3[O:11][CH2:10][CH2:9][N:8]([C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=4)[C:13]=3[CH:14]=[CH:15][CH:16]=2)=[O:19])=[CH:26][CH:25]=1)([OH:34])=[O:31]
Reactant: COC(=O)c1ccccc1NC(=O)c1cccc2c1OCCN2c1ncccc1Cl
Reactant: [OH-]
Reactant: C1CCOC1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C(O)c1ccc(NC(=O)c2cccc3c2OCCN3c2ncccc2Cl)cc1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
4-(3-Chloropyridin-2-yl)-N-(methoxycarbonylphenyl)-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxamide (500 mg) produced in Example 1-034 was dissolved in tetrahydrofuran (5 ml) and methanol (5 ml), 4 M sodium hydroxide solution (1 ml) was added, and the mixture was stirred at 60° C. for 5 hours. The reaction mixture was neutralized by adding 1 M hydrochloric acid and then concentrated. The concentrate was diluted with water and stirred, and white solid substance was collected by filtration and dried to obtain the title compound (433 mg)
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:11].C[O:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.[CH:20]([O:22][CH:23](Cl)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[CH2:23]([O:22][C:20]([N:17]1[CH:18]=[CH:19][C:14](=[O:13])[CH2:15][CH:16]1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:11])=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COc1ccncc1
Reactant: O=COC(Cl)c1ccccc1
Reactant: Cc1ccccc1Br
Agent: II
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1ccccc1C1CC(=O)C=CN1C(=O)OCc1ccccc1
Temperature: -40 °C
Reaction time: 3 h
Yield: 69.3 %

Procedure:
To 20 ml of tetrahydrofuran were added 1.34 g of magnesium and trace of iodine, and added dropwise thereto was a solution of 9.50 g of 2-bromotoluene in 45 ml of tetrahydrofuran, to prepare Grignard reagent. To the Grignard reagent was added dropwise a solution of 5.46 g of 4-methoxypyridine in 20 ml of tetrahydrofuran under nitrogen atmosphere at −60° C. or below. Subsequently, a solution of 10.24 g of chlorobenzyl formate in 50 ml of tetrahydrofuran was added dropwise thereto at −40° C. and the mixture was stirred for 3 hours. The temperature of the mixture was raised to room temperature and added thereto was 120 ml of a 5% aqueous citric acid solution. The mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried and concentrated under reduced pressure. The residue was crystallized with diisopropyl ether, and the crystals were collected by filtration, to give 11.15 g of 1-benzyloxycarbonyl-2-(2-methylphenyl)-4-oxo-3,4-dihydro-2H-pyridine.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([CH3:27])=[C:5]2[C:9](=[C:10]([O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:11]=1[CH2:12][CH:13]=[C:14]([CH2:17]O)[CH2:15][CH3:16])[C:8](=[O:26])[O:7][CH2:6]2)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:48]>C(Cl)Cl>[Br:48][CH2:17][C:14]([CH2:15][CH3:16])=[CH:13][CH2:12][C:11]1[C:10]([O:19][CH2:20][CH2:21][Si:22]([CH3:23])([CH3:25])[CH3:24])=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[O:26])=[C:4]([CH3:27])[C:3]=1[CH2:1][CH3:2]
Reactant: CCC(=CCc1c(CC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)CO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCC(=CCc1c(CC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)CBr
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.4 %

Procedure:
5-Ethyl-6-(3-hydroxymethyl-pent-2-enyl)-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one (35.4 mg, 0.090 mmol) was dissolved in DCM (3.0 mL). Polymer-bound triphenylphosphine (3 mmol/g, 90.7 mg) was added and the mixture was mechanically stirred at room temperature. Carbon tetrabromide (90.2 mg, 0.272 mmol) was added and the solution was stirred at room temperature. After 2 hrs, the reaction was filtered and the solvent was removed in vacuo. The crude material was purified by silica gel chromatography to provide 32.0 mg (78%) of the desired product. The material was used in the next step without further characterization.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:15]1[N:16]([C:40]2[CH:45]=[CH:44][C:43]([O:46][CH2:47][CH3:48])=[CH:42][CH:41]=2)[C:17](=[O:39])[C:18]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:27][CH:26]=2)=[C:19]([CH2:21][CH2:22][CH3:23])[N:20]=1)[CH3:14]>C(OCC)(=O)C>[CH2:13]([C:15]1[N:16]([C:40]2[CH:45]=[CH:44][C:43]([O:46][CH2:47][CH3:48])=[CH:42][CH:41]=2)[C:17](=[O:39])[C:18]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]3[NH:3][C:4](=[O:7])[O:5][N:38]=3)=[CH:27][CH:26]=2)=[C:19]([CH2:21][CH2:22][CH3:23])[N:20]=1)[CH3:14]
Reactant: CCCc1nc(CC)n(-c2ccc(OCC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)n(-c2ccc(OCC)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 46.7 %

Procedure:
A mixture of hydroxylammonium chloride (5.8 g), sodium hydrogen carbonate (8.5 g) and dimethyl sulfoxide (30 mL) was stirred at 50° C. for 30 min, 4′-{[2-ethyl-1-(4-ethoxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (4.0 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (30 mL), N,N′-carbonyldiimidazole (2.0 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (1.9 mL) were added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (2.1 g, 46%) as a colorless solid.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH:10]=O)[C:5]#[N:6].CS(C)=O.C(N(CC)CC)C.[SH:23][CH2:24][C:25]([O:27][CH3:28])=[O:26]>O>[C:5]([C:4]1[CH:7]=[CH:8][C:9]2[CH:10]=[C:24]([C:25]([O:27][CH3:28])=[O:26])[S:23][C:2]=2[CH:3]=1)#[N:6]
Reactant: N#Cc1ccc(C=O)c(F)c1
Reactant: COC(=O)CS
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1cc2ccc(C#N)cc2s1
Temperature: 80 °C

Procedure:
A round bottom flask was charged with 3-fluoro-4-formylbenzonitrile (9.00 g, 60.4 mmol), dimethyl sulfoxide (90 mL), triethylamine (18.0 mL, 129 mmol), and subsequently methyl 2-mercaptoacetate (5.40 mL, 60.4 mmol). The reaction mixture was heated at 80° C. for 2 hours. After cooling, the reaction mixture was poured into water and the precipitated product was collected by filtration, dried and used in the next step without further purification.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([C:9]([NH:11][NH2:12])=[O:10])[CH2:2]2.[C:13](OCC)(OCC)(OCC)[CH3:14]>>[CH3:13][C:14]1[O:10][C:9]([CH:3]2[CH:4]3[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]3)[CH2:2]2)=[N:11][N:12]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: NNC(=O)C1CN2CCC1CC2
Product: Cc1nnc(C2CN3CCC2CC3)o1
Temperature: 140 °C
Yield: 72 %

Procedure:
(±) 1-Azabicyclo[2.2.2]octane-3-carboxylic acid hydrazide (D8) (0.36 g; 2.1 mmoles) and triethyl orthoacetate (3 ml) were heated at 120° C. for 2 h. Excess triethyl orthoacetate was evaporated in vacuo and the residue was heated for a further 2 h at 140° C. The reaction was diluted with water (10 ml), saturated with potassium carbonate and extracted into ether (3×15 ml). Combined organic extracts were dried (Na2SO4) and concentrated to give the title compound as an oil (0.29 g; 72%), which was purified as the oxalate salt. m.p. 147°-8° (Acetone-methanol).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:41][C:42]1[CH:49]=[CH:48][C:45]([CH2:46][NH2:47])=[CH:44][CH:43]=1>C(Cl)Cl>[CH3:41][C:42]1[CH:49]=[CH:48][C:45]([CH2:46][NH:47][C:14]([C@H:10]2[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]2)=[O:16])=[CH:44][CH:43]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](C(=O)O)C1
Reactant: Cc1ccc(CN)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(CNC(=O)[C@H]2CCCN(C(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 70 %

Procedure:
To a solution of (S)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (Beta Pharma Inc., 500 mg, 2.181 mmol) and TEA (0.912 mL, 6.54 mmol) in DCM (11 mL) was added HATU (912 mg, 2.399 mmol) followed by 4-methylbenzylamine (0.305 mL, 2.399 mmol). The resulting solution was stirred at room temperature for 48 hours. The reaction was concentrated, and the residue was adsorbed onto a plug of silica gel and purified by chromatography through a 50 g silica gel column, eluting with 0.5% to 5% MeOH in DCM, to provide M5.1 in 70% yield as a white foam. 1H NMR (300 MHz, CDCl3) δ ppm 7.08-7.20 (m, 4H), 6.13 (br. s., 1H), 4.38 (d, J=5.26 Hz, 2H), 3.92 (d, J=13.30 Hz, 1H), 3.62-3.83 (m, 1H), 3.21 (dd, J=13.01, 9.65 Hz, 1H), 3.00 (dd, J=10.40 Hz, 1H), 2.33 (s, 3H), 2.20-2.30 (m, 1H), 1.80-1.95 (m, 2H), 1.58-1.71 (m, 1H), 1.43-1.52 (m, 1H), 1.42 (s, 9H); ESI-MS M+Na 355.2.
Reaction SMILES: OS(O)(=O)=O.O=S(=O)=O.[C:10]([OH:21])(=[O:20])[C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1.O1COCO[CH2:23]1.C(O)(=O)C>O>[C:15]([C:14]1[CH:18]=[C:19]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:21])[O:20][CH2:23]2)([OH:17])=[O:16]
Reactant: C1OCOCO1
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1ccc2c(c1)COC2=O
Temperature: 131.5 °C

Procedure:
In a 3000-1 glass lined reactor, 550 Kg of oleum containing 25% of SO3 are charged under vacuum and good aspiration, then, consecutively, under stirring, 56 Kg of terephthalic acid at 20-23° C. and 26 Kg of 1,3,5-trioxane at 15-20° C. are added thereinto. The reactor is heated at 130-133° C. for 4 hours, then the mixture is cooled to 20-23° C. and 118 Kg of glacial acetic acid are couled portionwise thereinto at a temperature not higher than 25° C. At the end of this operation, 1000 Kg of water are added portionwise, whereby the temperature is maintained not higher than 43-45° C. by circulation of water in the jacket. The mixture is stirred for about 1 hour at 20-23° C., then the product is centrifugated, squeezed and abundantly washed with water in order to remove the larger amount of sulfuric acid from the mother liquors and to obtain 100-105 Kg of 5-carboxyphthalide as a well squeezed, wet raw-product. In a 3000-1 stainless steel reactor the product thus obtained is suspended in 680 Kg of deionized water and a solution of 60 Kg of sodium bicarbonate in 540 Kg of deionized water is then slowly added to said suspension to a pH of 7.0-7.2. To the solution thus obtained, lightly cloudy, 10 Kg of Celite® are added, the solid is filtered off and the solution, at a temperature of 22-25° C., is brought to pH=3 with 32% hydrochl 20-22° C. and centrifugated. The product is well squeezed, abundantly washed with deionized water and dried under vacuum to give 41-43.7 Kg of 5-carboxyphthalide.
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH3:4].[O-:6][C:7]#[N:8].[K+].[CH:10]1([NH2:13])[CH2:12][CH2:11]1>CN(C=O)C>[CH:3]1([N:8]2[C:11]([CH3:12])=[CH:10][NH:13][C:7]2=[O:6])[CH2:4][CH2:2]1
Reactant: N#C[O-]
Reactant: NC1CC1
Reactant: CC(=O)CCl
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c[nH]c(=O)n1C1CC1
Temperature: 50 °C
Yield: 35.2 %

Procedure:
Chloroacetone (2.0 g), potassium cyanate (1.84 g) and cyclopropylamine (6.17 g) were dissolved or suspended in DMF (25 mL) and heated to 50° C. over night. The appearance of the suspension changed and on the second day a fine precipitate was observed. The suspension was concentrated in vacuo and the residue was treated with 25% HCl (25 mL) and DCM (50 mL) for one hour with vigorous stirring. The layers were separated and the organic phase was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography using a gradient of methanol in ethyl acetate (0 to 5%) as an eluent to give 1-cyclopropyl-5-methyl-1,3-dihydro-imidazol-2-one as colorless solid (1.05 g). 1H-NMR (δ, CDCl3): 9.80 (br s, 1H), 5.79 (d, J=1.2 Hz, 1H), 2.91 (m, 1H), 2.012 (d, J=1.2 Hz, 3H), 0.92-0.84 (m, 2H), 0.82-0.77 (m, 2H).
Reaction SMILES: [CH3:1][O:2][CH:3]1[N:8](Cl)[CH:7]=[CH:6][C:5]([Cl:10])=[N:4]1.Cl.[C:12](=[O:15])(O)[O-:13].[Na+].[CH3:17][CH2:18]O>>[Cl:10][C:5]1[N:4]=[C:3]([O:2][CH3:1])[N:8]=[C:7]([N:4]2[CH2:18][CH2:17][CH:7]([C:12]([OH:13])=[O:15])[CH2:6][CH2:5]2)[CH:6]=1
Reactant: O=C([O-])O
Reactant: COC1N=C(Cl)C=CN1Cl
Reactant: CCO
Agent: Cl
Agent: [Na+]
Product: COc1nc(Cl)cc(N2CCC(C(=O)O)CC2)n1
Temperature: 90 °C
Yield: 70 %

Procedure:
A mixture of 2-methoxy-3,6-dichloropyrimidine (635 mg, 3.55 mmol), isonipecotic hydrochloride (706 mg, 4.26 mmol) and sodium bicarbonate (895 mg, 10.65 mmol) in EtOH (12 mL) is heated at 90° C. for 15 hours. The mixture is concentrated, and the residue is taken up in water (30 mL) and extracted three times with EtOAc (25 mL). The aqueous solution is acidified to pH 3 with 10% citric acid and extracted three times with EtOAc (25 mL). The organic extracts from the acidic layer are combined and dried over magnesium sulfate, filtered and concentrated to afford 1-(6-chloro-2-methoxy-pyrimidin-4-yl)-piperidine-4-carboxylic acid [680 mg, 70%] as a solid.
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH3:13])[C:7](=[NH:14])[S:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:15][O:16][C:17]([C:19]12[CH2:26][CH2:25][C:22]([C:27](O)=[O:28])([CH2:23][CH2:24]1)[CH2:21][CH2:20]2)=[O:18]>>[CH2:10]([C:8]1=[CH:9][N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[S:6]/[C:7]/1=[N:14]\[C:27]([C:22]12[CH2:25][CH2:26][C:19]([C:17]([O:16][CH3:15])=[O:18])([CH2:20][CH2:21]1)[CH2:24][CH2:23]2)=[O:28])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCc1cn(C(C)(C)C)sc1=N
Reactant: COC(=O)C12CCC(C(=O)O)(CC1)CC2
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)C12CCC(C(=O)OC)(CC1)CC2

Procedure:
The product from Example 92B and 4-(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid (Oakwood) were processed using the method described in Example 92C to afford the title compound. 1H NMR (DMSO-d6) δ ppm 0.91 (t, J=7.3 Hz, 3H), 1.23-1.36 (m, 2H), 1.58 (s, 9H), 1.58-1.66 (m, 2H), 1.70-1.83 (m, 12H), 2.61-2.66 (m, 2H), 3.58 (s, 3H), 8.49 (s, 1H). (ESI+) m/z 407 (M+H)+. Anal. calcd. for C22H34N2O3S: C, 64.99; H, 8.43; N, 6.89. Found: C, 64.65; H, 8.24; N, 6.72.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:5]=1[O:6][C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1)([O-:3])=[O:2].[CH3:22][S:23]Cl.[CH3:25][S:26]SC.ClCl>C(Cl)Cl>[N+:1]([C:4]1[CH:17]=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:15]=[CH:14][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:9])=[C:22]([SH:23])[CH:8]=1)([O-:3])=[O:2].[N+:1]([C:4]1[CH:17]=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:15]=[CH:14][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][C:10]([S:26][CH3:25])=[C:9]([OH:13])[CH:8]=1)([O-:3])=[O:2]
Reactant: CSCl
Reactant: CSSC
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Oc1cccc(O)c1
Agent: ClCl
Solvent: ClCCl
Product: CSc1ccc(Oc2ccc(C(F)(F)F)cc2[N+](=O)[O-])cc1O
Product: Cc1ccc(Oc2ccc(C(F)(F)F)cc2[N+](=O)[O-])cc1S
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
3-(2-Nitro-4-trifluoromethylphenoxy)phenol (0.1 mole) and methylene chloride (200 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and addition funnel. The mixture is stirred until dissolved and cooled to about -20° C. A solution of methyl sulfenyl chloride freshly prepared by reacting dimethyl disulfide (0.15 mole) with chlorine (0.18 mole) in methylene chloride (100 ml) is then added dropwise to the reaction vessel over a period of about 40 minutes. After the addition is completed stirring is continued for 30 minutes with cooling and 30 minutes at room temperature. After this time the reaction mixture is washed with water (200 ml), with 5% aqueous sodium bicarbonate (200 ml) and again with water (200 ml). The washed solution is then dried by passing it through a phase separator. The dried solution is stripped of solvent under reduced pressure and the residue chromatographed using a clay column and hexane/ethyl acetate as the eluant. The fractions containing the product are combined and stripped of solvent to yield the desired product 5-(2-nitro-4-trifluoromethylphenoxy) 2-(methylthio)phenol as the residue.
Reaction SMILES: [CH3:1][CH:2]([C@H:4]([CH:6]=[CH:7][C@H:8]([C@@H:10]1[C@:27]2([CH3:28])[C@H:13]([C:14]3[CH2:15][CH2:16][C:17]4[C@:22]([C:24]=3[CH2:25][CH2:26]2)([CH3:23])[CH2:21][CH2:20][C:19](=[O:29])[CH:18]=4)[CH2:12][CH2:11]1)[CH3:9])[CH3:5])[CH3:3].[C-:30]#[N:31].C([Al+]CC)C>>[C:30]([C@:17]12[CH2:18][C:19](=[O:29])[CH2:20][CH2:21][C@:22]1([CH3:23])[C:24]1[CH2:25][CH2:26][C@@:27]3([CH3:28])[C@@H:13]([CH2:12][CH2:11][C@@H:10]3[C@H:8]([CH3:9])[CH:7]=[CH:6][C@H:4]([CH3:5])[CH:2]([CH3:1])[CH3:3])[C:14]=1[CH2:15][CH2:16]2)#[N:31]
Reactant: [C-]#N
Reactant: CC(C)[C@@H](C)C=C[C@@H](C)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CCC(=O)C=C1CC3
Agent: CC[Al+]CC
Product: CC(C)[C@@H](C)C=C[C@@H](C)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CCC(=O)C[C@]1(C#N)CC3

Procedure:
1.54 g ergosta-4,8,22-trien-3-one were treated with 11.73 ml diethylaluminum cyanide solution (1 N, toluene) as described in example 58. After aqueous work up and chromatography 0.90 g 5-cyano-5α-ergosta-8,22-dien-3-one were isolated as a white solid (beside the corresponding 5β-cyano-compound).