Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C@:16]12[CH2:25][O:24][C@@H](C=O)[CH2:22][C@H:21]1[CH2:20][S:19][C:18]([NH:28][C:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[N:17]2.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:5]([O:4][CH:1]=[C:2]1[O:24][CH2:25][C@:16]2([C:10]3[CH:11]=[CH:12][C:13]([F:15])=[CH:14][C:9]=3[F:8])[N:17]=[C:18]([NH:28][C:29](=[O:36])[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[S:19][CH2:20][C@@H:21]2[CH2:22]1)(=[O:7])[CH3:6]
Reactant: O=C[C@H]1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2ccc(F)cc2F)CO1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)OC=C1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2ccc(F)cc2F)CO1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Acetic anhydride (1.5 mL, 16 mmol) was added to a slurry of N-[(4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-formyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (P3) (661 mg, 1.59 mmol) and potassium carbonate (1.34 g, 9.70 mmol) in acetonitrile (16 mL). After the flask had been flushed with nitrogen, the reaction mixture was heated at reflux for 2.5 hours, then allowed to cool to room temperature and stir for 18 hours. The slurry was diluted with ethyl acetate and filtered; the solids were washed with ethyl acetate, and the combined filtrates were concentrated in vacuo. Purification using silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) afforded the product as a white solid, which was assigned as a roughly 4:1 mixture of geometric isomers from the 1H NMR. Yield: 437 mg, 0.953 mmol, 60%. LCMS m/z 459.1 [M+H+]. 1H NMR (400 MHz, CDCl3), major isomer only: δ 8.09-8.32 (br s, 2H), 7.50-7.56 (m, 1H), 7.39-7.45 (m, 3H), 6.85-6.99 (m, 2H), 6.75 (d, J=1.9 Hz, 1H), 4.31 (dd, J=11.7, 1.2 Hz, 1H), 4.02 (d, J=11.8 Hz, 1H), 3.13-3.26 (m, 1H), 2.97-3.07 (m, 1H), 2.70-2.87 (m, 2H), 2.19 (s, 3H), 2.17-2.25 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[C:21]([F:22])=[CH:20][CH:19]=[C:18](B2OC(C)(C)C(C)(C)O2)[C:17]=1[CH3:32])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-:33].[Na+].OO.Cl>C1COCC1>[C:11]([O:10][C:9]([N:8]([C:16]1[C:21]([F:22])=[CH:20][CH:19]=[C:18]([OH:33])[C:17]=1[CH3:32])[C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:15])([CH3:13])([CH3:14])[CH3:12]
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)ccc(F)c1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(O)ccc(F)c1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.6 %

Procedure:
To a solution of tert-butyl N-tert-butoxycarbonyl-N-[6-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (800 mg, 41.7 mmol, 1.0 eq) in a mixture of THF (10 mL) and NaOH (1M aqueous solution, 5.3 mL, 5.3 mmol, 3.0 eq) at 0° C. was added H2O2 (30% aqueous solution, 603 mg, 5.32 mmol, 3.0 eq). The reaction mixture was stirred at room temperature for 3 h. The resulting mixture was acidified to pH 5-7 by addition of diluted HCl, and extracted with EtOAc. The organic extract was washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography, (EtOAc:petroleum ether, 0:1 to 1:10) to give the title product as an oil (500 mg, 83%).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].C[O-].[Na+:7].CN(C)/[CH:10]=[CH:11]/[C:12](=O)[CH:13]([O:16][CH3:17])[O:14][CH3:15]>CO>[CH3:15][O:14][CH:13]([O:16][CH3:17])[C:12]1[CH:11]=[CH:10][N:4]=[C:2]([S-:3])[N:1]=1.[Na+:7]
Reactant: NC(N)=S
Reactant: COC(OC)C(=O)/C=C/N(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(OC)c1ccnc([S-])n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of thiourea (64.7 g, 850 mmol, 1.13 equiv.), sodium methanolate (95%, 40.5 g, 751 mmol, 1.0 equiv.) in methanol (500 mL, 1.5 M) was stirred at room temperature for 30 minutes. A solution of (E)-4-(dimethylamino)-1,1-dimethoxybut-3-en-2-one (1) (130 g, 751 mmol) in methanol (200 mL) was added and the reaction stirred at room temperature for 2 h. The crude sodium 4-(dimethoxymethyl)pyrimidine-2-thiolate (2) was used directly in the next step without further purification. LC-MS m/z 209 (M+1). Reference: WO 2006/0097341A1, pg 67.
Reaction SMILES: C([S-])C.[Na+].[CH2:5]([O:12][C@@H:13]1[C@@H:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:17]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C@@H:16]([CH2:35][O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[O:15][C@:14]1([C:48]1[CH:53]=[C:52]([CH2:54][C:55]2[CH:60]=[CH:59][C:58]([CH2:61][CH3:62])=[CH:57][CH:56]=2)[C:51]([Cl:63])=[CH:50][C:49]=1[O:64]C)[CH2:44][C:45]([CH3:47])=[CH2:46])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN(C=O)C>[Cl:63][C:51]1[C:52]([CH2:54][C:55]2[CH:60]=[CH:59][C:58]([CH2:61][CH3:62])=[CH:57][CH:56]=2)=[CH:53][C:48]([C@@:14]2([CH2:44][C:45]([CH3:47])=[CH2:46])[C@H:13]([O:12][CH2:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=3)[C@@H:18]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:17]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C@@H:16]([CH2:35][O:36][CH2:37][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[O:15]2)=[C:49]([OH:64])[CH:50]=1
Reactant: C=C(C)C[C@@]1(c2cc(Cc3ccc(CC)cc3)c(Cl)cc2OC)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: CC[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(C)C[C@@]1(c2cc(Cc3ccc(CC)cc3)c(Cl)cc2O)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 91.6 %

Procedure:
A mixture of sodium ethanethiolate (151 mg, 1.79 mmol) and 24 (150 mg, 0.179 mmol) in DMF (3 mL) was flushed with argon and heated at 90° C. for 3 h. The reaction mixture was cooled to 0° C. A mixture of acetic acid and water (1:1, 2 mL) was added. The resulting mixture was stirred for 10 min and then concentrated to dryness. The residue was partitioned between water and dichloromethane. The organic layer was separated, dried (Na2SO4), and evaporated. The residue was purified by preparatory TLC eluting with 10% EtOAc in petroleum ether to give 25 (135 mg, 92%). LC/MS m/z 846 (M+Na).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.C([O:15][C:16]1[CH2:21][CH2:20][CH2:19][C:18](=O)[CH:17]=1)C.Cl>CCOCC>[N:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:18]2[CH2:19][CH2:20][CH2:21][C:16](=[O:15])[CH:17]=2)[CH:8]=1
Reactant: CCOC1=CC(=O)CCC1
Reactant: Brc1cccnc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=C1C=C(c2cccnc2)CCC1
Reaction time: 0.33 h
Yield: 66.4 %

Procedure:
To a solution of n-BuLi (1.54 M in Hexane, 145 mL. 224 mmol) in Et2O (600 ml) was added dropwise 3-Bromopyridine (22.0 mL, 224 mmol) at −75˜−68° C., and stirred for 20 min. To a reaction mixture was added dropwise 3-ethoxy-2-cyclohexenone (25.0 mL, 187 mmol) at −75˜−69° C., and stirred at room temperature for 1 h. The reaction mixture was acidified with 2M HCl (300 mL), and aqueous layer was washed with AcOEt. The aqueous layer was basified with 1M NaOH aq., and then extracted with CH2Cl2. The organic layer was washed with brine, and dried over anhyd Na2SO4 followed by the removal of solvent. The crude product was purified by column chromatography (Hexane/EtOAc=1/2) to yield 3-(3-pyridyl)-2-cyclohexen-1-one (21.5 g, 66%) as yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([C:10]2[C:14]3[CH:15]=[C:16]([N:19]4[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[NH:21][C:20]4=[O:30])[CH:17]=[CH:18][C:13]=3[O:12][N:11]=2)=[CH:5][CH:4]=1.[C:31](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([C:10]2[C:14]3[CH:15]=[C:16]([N:19]4[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:28])([F:29])[F:27])[N:21]([CH3:31])[C:20]4=[O:30])[CH:17]=[CH:18][C:13]=3[O:12][N:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2noc3ccc(-n4c(=O)cc(C(F)(F)F)[nH]c4=O)cc23)cc1C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(-c2noc3ccc(-n4c(=O)cc(C(F)(F)F)n(C)c4=O)cc23)cc1C
Reaction time: 0.25 h

Procedure:
A mixture of 3-[3-(6-methoxy-m-tolyl)-1,2-benzisoxazol-5-yl]-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (10.5 g, 0.0255 mol) and potassium carbonate (7.04 g, 0.051 mol) in N,N-dimethylformamide is stirred for 15 minutes, treated with methyl iodide (7.24 g, 0.051 mol), stirred overnight, and poured onto ice. The resultant aqueous mixture is extracted with methylene chloride. The organic extracts are combined, washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a brown glass. Dry column chromatography of the glass using silica gel and a hexanes/ethyl acetate solution (3:1) gives the title product as an off-white solid which is identified by NMR spectral analyses.
Reaction SMILES: [C:1]1([CH2:7][C:8]2([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:12]3[CH2:13][NH:14][CH2:15][CH2:16][N:11]3[C:10](=[O:17])[O:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:32](Cl)(=[O:40])[O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.O>O1CCCC1>[C:19]1([CH2:18][C:8]2([CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:12]3[CH2:13][N:14]([C:32]([O:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[O:40])[CH2:15][CH2:16][N:11]3[C:10](=[O:17])[O:9]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: O=C1OC(Cc2ccccc2)(Cc2ccccc2)C2CNCCN12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: O=C(Oc1ccccc1)N1CCN2C(=O)OC(Cc3ccccc3)(Cc3ccccc3)C2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.9 %

Procedure:
To a solution of 1,1-bis(phenylmethyl)-hexahydro-3H-oxazolo[3,4-a]pyrazin-3-one (0.16 g, 0.50 mmol) in tetrahydrofuran (10 mL) were sequentially added triethylamine (0.14 mL) and phenyl chlorocarbonate (0.12 g, 0.75 mmol), and the mixture was stirred at room temperature for 3 hours. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The extract was washed with a 0.5 M aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=10:1 to ethyl acetate). The fractions were concentrated, and to the obtained crystals was added diisopropyl ether, collected by filtration and washed with diisopropyl ether to obtain the title compound (0.19 g, yield 85%).
Reaction SMILES: N1CCCCC1.[C:7]([CH2:9][C:10]([NH2:12])=[O:11])#[N:8].[N+:13]([C:16]1[C:21]([CH:22]=O)=[CH:20][C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=1)([O-:15])=[O:14]>CO>[C:7]([C:9](=[CH:22][C:21]1[CH:20]=[C:19]([O:24][CH3:25])[C:18]([O:26][CH3:27])=[CH:17][C:16]=1[N+:13]([O-:15])=[O:14])[C:10]([NH2:12])=[O:11])#[N:8]
Reactant: COc1cc(C=O)c([N+](=O)[O-])cc1OC
Reactant: N#CCC(N)=O
Solvent: C1CCNCC1
Solvent: CO
Product: COc1cc(C=C(C#N)C(N)=O)c([N+](=O)[O-])cc1OC

Procedure:
Piperidine (2.1 g., 0.0237 mole) and 2-cyanoacetamide (22.0 g. 0.263 mole) are added to a slurry of 6-nitroveratraldehyde (50.0 g., 0.237 mole in methanol (500 ml.). The mixture is heated to reflux for 2 hours, and then cooled in an ice bath and filtered. The bright yellow filter cake is washed with cold isopropanol (300 ml.) and then air dried. Yield = 60.1 g. (93%); m.p. 265°-266° C.
Reaction SMILES: [CH2:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11]Cl)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[C-:13]#[N:14].[Na+].O>CS(C)=O>[CH2:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][C:13]#[N:14])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: [C-]#N
Reactant: CCCC[C@H]1CC[C@H](CCl)CC1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCC[C@H]1CC[C@H](CC#N)CC1
Temperature: 140 °C

Procedure:
In 40 cm3 of DMSO, 38 g (0.20 mol) of trans-4-butyl cyclohexylchloromethane and 12 g (0.24 mol) of NaCN were stirred and heated with a mantle heater to 140° C. The reaction product was cooled to room temperature, combined with 100 cm3 of water, extracted with chloroform, and washed with water. The chloroform was distilled off. The oily residue was subjected to vacuum distillation (b.p. 90° C./3 mmHg) to yield 34 g (0.19 mol) of trans-4-butylcyclohexyl acetonitrile.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:10]([O:12][C:13](=[O:22])[C:14]1[C:19](Cl)=[CH:18][C:17]([Cl:21])=[N:16][CH:15]=1)[CH3:11]>CN(C)C=O>[CH2:10]([O:12][C:13](=[O:22])[C:14]1[C:19]([O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:18][C:17]([Cl:21])=[N:16][CH:15]=1)[CH3:11]
Reactant: Oc1ccccc1
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(Cl)cc1Oc1ccccc1
Yield: 70.4 %

Procedure:
To a solution of 196 mg (ca. 4 mmol) sodium hydride dispersion in mineral oil (ca. 50%) in 15 ml N,N-dimethylformamide a solution of 385 mg (4.09 mmol) phenol in 10 ml N,N-dimethylformamide was added dropwise at room temperature under argon. After 15 min. this solution was slowly added via cannula to a solution of 4,6-dichloro-nicotinic acid ethyl ester in 20 ml N,N-dimethylformamide at room temperature. After 2 h the reaction was quenched with 20 ml water. The mixture was extracted with 3 50-ml portions of ethyl acetate. The combined organic extracts were dried with sodium sulfate and concentrated. After drying in high vacuo at 50° C. and flash column chromatography 800 mg (70.4%) of the title compound was obtained as a white solid. As a side product 130 mg (11.4%) 4-chloro-6-phenoxy-nicotinic acid ethyl ester were also isolated.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([OH:10])[CH:7]=[CH:6][N:5]=2)[CH2:3][CH2:2]1.[OH-].[K+].[Br:13]Br>O>[CH:1]1([C:4]2[N:9]=[C:8]([OH:10])[C:7]([Br:13])=[CH:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: Oc1ccnc(C2CC2)n1
Reactant: BrBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Oc1nc(C2CC2)ncc1Br
Temperature: 25 °C
Yield: 69.8 %

Procedure:
13.6 g (0.1 mol) of 2-cyclopropyl-4-hydroxy-pyrimidine were added to a solution of 5.6 g (0.1 mol) of potassium hydroxide in 100 ml of water. 16 g (0.1 mol) of bromine were then added dropwise at 15°-20° C., with slight cooling, and the mixture was stirred for a further hour at room temperature. The product which had precipitated was filtered off and rinsed with water. 15 g (70% of theory) of 2-cyclopropyl-4-hydroxy-5-bromo-pyrimidine were thus obtained in the form of colorless crystals of melting point 200° C.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][N:18]([C:21]([CH2:30][NH:31][S:32]([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH2:42][C:43]#[C:44][CH3:45])=[CH:37][CH:36]=2)(=[O:34])=[O:33])([C:26]([O:28][CH3:29])=[O:27])[C:22]([O:24][CH3:25])=[O:23])[CH2:17][CH2:16]1)=O)(C)(C)C.C(=O)([O-])O.[Na+]>ClCCl>[CH2:42]([O:41][C:38]1[CH:39]=[CH:40][C:35]([S:32]([NH:31][CH2:30][C:21]([N:18]2[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]2)([C:22]([O:24][CH3:25])=[O:23])[C:26]([O:28][CH3:29])=[O:27])(=[O:34])=[O:33])=[CH:36][CH:37]=1)[C:43]#[C:44][CH3:45]
Reactant: CC#CCOc1ccc(S(=O)(=O)NCC(C(=O)OC)(C(=O)OC)N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC#CCOc1ccc(S(=O)(=O)NCC(C(=O)OC)(C(=O)OC)N2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.7 %

Procedure:
2.8 ml of trifluoroacetic acid are added to a solution of 2.1 g (4 mmol) of dimethyl 2-(4-tert-butoxycarbonylpiperazin-1-yl)-2-[(4-but-2-ynyloxybenzenesulfonylamino)methyl]malonate diluted in 30 ml of dichloromethane. After stirring at ambient temperature for 24 h, a saturated aqueous solution of sodium hydrogen carbonate is added to pH=8 and the reaction medium is extracted with dichloromethane. The organic phases are combined, washed with water, dried over magnesium sulfate, and then filtered and evaporated. 1.7 g (98%) of dimethyl 2-[(4-but-2-ynyloxybenzenesulfonylamino)methyl]-2-piperazin-1-ylmalonate are obtained in the form of a white solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-])=O)=[C:6]([CH:9]=1)[C:7]#[N:8].[O:13]1[CH2:18][CH2:17][N:16]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH2:15][CH2:14]1>>[NH2:10][C:5]1[CH:4]=[CH:3][C:2]([N:22]2[CH2:23][CH2:24][CH:19]([N:16]3[CH2:17][CH2:18][O:13][CH2:14][CH2:15]3)[CH2:20][CH2:21]2)=[CH:9][C:6]=1[C:7]#[N:8]
Reactant: N#Cc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: C1CC(N2CCOCC2)CCN1
Product: N#Cc1cc(N2CCC(N3CCOCC3)CC2)ccc1N

Procedure:
By the reaction and treatment in the same manner as in Starting Material Synthesis Example 40 using 5-chloro-2-nitrobenzonitrile and 4-morpholinopiperidine, the title compound was obtained, melting point: 178–180° C.
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[CH:7][N:8]=[C:9]([N:10]3[CH2:14][CH2:13][C@H:12]([NH:15]C(=O)OC(C)(C)C)[CH2:11]3)[C:4]2=[CH:3][CH:2]=1.Cl>O1CCOCC1>[N:1]1[N:5]2[CH:6]=[CH:7][N:8]=[C:9]([N:10]3[CH2:14][CH2:13][C@H:12]([NH2:15])[CH2:11]3)[C:4]2=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(c2nccn3nccc23)C1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H]1CCN(c2nccn3nccc23)C1
Temperature: 60 °C
Yield: 100 %

Procedure:
To a solution of (S)-tert-butyl (1-(pyrazolo[1,5-a]pyrazin-4-yl)pyrrolidin-3-yl)carbamate (0.74 g, 2.4 mmol, 1 eq) in 3 mL of dioxane was added a solution of 4.0 M HCl in dioxane (3 mL, 20 mmol, 4 eq). After heating for 3 h at 60° C., the mixture was concentrated to afford (S)-1-(pyrazolo[1,5-a]pyrazin-4-yl)pyrrolidin-3-amine (0.670 g, 2.4 mmol, 100%).
Reaction SMILES: [CH2:1]1[CH2:26][O:25][C:3]2([CH2:20][CH2:19][C@@:18]3([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]4[C@:17]3([OH:22])[CH2:16][CH2:15][C@@:13]3([CH3:14])[C@H:9]4[CH2:10][C@H:11]([CH3:24])[C:12]3=O)[CH2:4]2)[O:2]1.[Cl:27][C:28](Cl)(Cl)[C:29]([O:31][CH2:32][CH3:33])=[O:30].[Cl-].C([Al+]CC)C>[Zn].C1(C)C=CC=CC=1.CC(C)=O>[Cl:27]/[C:28](=[C:12]1\[C@@H:11]([CH3:24])[CH2:10][C@@H:9]2[C@:13]\1([CH3:14])[CH2:15][CH2:16][C@@:17]1([OH:22])[C@H:8]2[CH2:7][CH:6]=[C:5]2[C@:18]1([CH3:21])[CH2:19][CH2:20][C:3]1([O:25][CH2:26][CH2:1][O:2]1)[CH2:4]2)/[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: C[C@H]1C[C@H]2[C@@H]3CC=C4CC5(CC[C@]4(C)[C@@]3(O)CC[C@]2(C)C1=O)OCCO5
Reactant: CCOC(=O)C(Cl)(Cl)Cl
Agent: CC[Al+]CC
Agent: [Cl-]
Agent: [Zn]
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: CCOC(=O)/C(Cl)=C1/[C@@H](C)C[C@H]2[C@@H]3CC=C4CC5(CC[C@]4(C)[C@@]3(O)CC[C@]12C)OCCO5

Procedure:
Using the procedure of Example 18, 3,3-ethylenedioxy-9α-hydroxy-16β-methylandrost-5-en-17-one (3.60 g) was reacted with ethyl trichloroacetate (2.78 ml) in the presence of zinc dust (2.83 g) and diethylaluminium chloride (20 ml, 1M in hexane). Chromatography (silica gel, toluene/acetone 3/1) of the crude product (3.0 g) afforded the title compound as a single isomer.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([OH:19])[CH2:14][S:15][CH:16]([CH3:18])[CH3:17])[CH2:9]1)=O)(C)(C)C.[H-].[Na+].[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25](F)[C:24]=1[C:30]([F:33])([F:32])[F:31].CCO>CN(C=O)C.Cl>[Cl:22][C:23]1[C:24]([C:30]([F:31])([F:32])[F:33])=[C:25]([CH:26]=[CH:27][CH:28]=1)[O:19][C@H:13]([C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[CH2:14][S:15][CH:16]([CH3:17])[CH3:18]
Reactant: Fc1cccc(Cl)c1C(F)(F)F
Reactant: CC(C)SC[C@H](O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(C)SC[C@H](Oc1cccc(Cl)c1C(F)(F)F)[C@H]1CCNC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(S)-3-((R)-1-Hydroxy-2-isopropylsulfanylethyl)pyrrolidine-1-carboxylic acid t-butyl ester (10 mg, 0.030 μmol) was dissolved in DMF (166 μL). NaH (1.7 mg, 69.1 μmol) was added and the mixture was stirred at room temperature for 15 minutes. 2-Chloro-6-fluorobenzotrifluoride (20.6 mg, 104 μmol) was added and the mixture was stirred at 100° C. for 1 hour. The mixture was cooled to room temperature, concentrated then dissolved in 1.2M HCl in EtOH (1.0 mL, 1.2 mmol) and stirred overnight at room temperature. The product was concentrated and the crude product was dissolved in 1:1 AcOH/H2O (1.5 mL) then purified by preparative HPLC to yield the title compound as a mono-TFA salt (9.2 mg, purity 94%). MS m/z: [M+H]+ calcd for C16H21ClF3NOS, 368.10. found 368.0.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][CH2:9][C:10]([OH:12])=O.N1C=CC=CC=1CCC(O)=O.[P:24]([OH:27])([OH:26])[OH:25].P(Cl)(Cl)Cl.C.[Na]>Cl.[Pt]=O.O>[OH:12][C:10]([P:24]([OH:27])(=[O:25])[OH:26])([P:24]([OH:27])(=[O:26])[OH:25])[CH2:9][CH2:8][CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][NH:2]1
Reactant: OP(O)O
Reactant: O=C(O)CCC1CCCCN1
Agent: O=[Pt]
Agent: Cl
Agent: O=C(O)CCc1ccccn1
Solvent: ClP(Cl)Cl
Solvent: O
Product: O=P(O)(O)C(O)(CCC1CCCCN1)P(=O)(O)O

Procedure:
1.5 g. 3-(Piperidin-2-yl)-propionic acid hydrochloride (m.p.: 193°-195° C., prepared by hydrogenation of 3-(2-pyridyl)-propionic acid in hydrochloric acid medium in the presence of platinum oxide) and 1.3 g. phosphorous acid are melted together at 80° C. After allowing to cool, 1.4 ml. phosphorus trichloride is added dropwise and further heated for 20 hours to 90° C. After cooling, 20 ml. water are carefully added thereto and heated under reflux for 7 hours. The cooled solution is treated with charcoal, filtered and the filtrate evaporated. After drying, the residue is stirred up several times with acetone, then taken up in water, the solution brought with 2N aqueous sodium hydroxide solution to a pH ≈5 and mixed with methanol. After stirring for some time with ice cooling, the precipitate is filtered off with suction and dried. There is obtained 1.05 g. (37% of theory) of the monosodium salt x 2 mole water; m.p. 270°-274° C.; Mrel : 0.41.
Reaction SMILES: O.CC1C=CC(S(O)(=O)=O)=CC=1.[F:13][C:14]1[C:15]([OH:37])=[C:16]([NH:20][C:21](=O)[CH2:22][C:23]2[NH:24][C:25](=[O:35])[CH:26]=[C:27]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[N:28]=2)[CH:17]=[CH:18][CH:19]=1.C(OCC)C>C1(C)C(C)=CC=CC=1>[F:13][C:14]1[C:15]2[O:37][C:21]([CH2:22][C:23]3[NH:24][C:25](=[O:35])[CH:26]=[C:27]([N:29]4[CH2:30][CH2:31][O:32][CH2:33][CH2:34]4)[N:28]=3)=[N:20][C:16]=2[CH:17]=[CH:18][CH:19]=1
Reactant: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cccc(F)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Solvent: CCOCC
Product: O=c1cc(N2CCOCC2)nc(Cc2nc3cccc(F)c3o2)[nH]1
Yield: 38.7 %

Procedure:
42 mg of 4-methylbenzenesulphonic acid hydrate are added to a solution of 300 mg of N-(3-fluoro-2-hydroxyphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide in 20 ml of xylene. After refluxing for six hours (assembly with Dean-Stark apparatus), the medium is concentrated to dryness under reduced pressure. After purification by silica column chromatography of the solid residue, eluent: gradient of pure CH2Cl2 to CH2Cl2/MeOH: 95/05, the product obtained is taken up with twice 20 ml of diethyl ether and then spin-filter-dried and dried under vacuum. 110 mg of 2-[(7-fluoro-1,3-benzoxazol-2-yl)methyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a white powder, the characteristics of which are the following:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[C:9]([CH3:16])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[N+:17]([O-])([OH:19])=[O:18].S(=O)(=O)(O)O>ClCCl>[CH3:16][C:9]1[C:8]([N+:17]([O-:19])=[O:18])=[C:3]([C:4]([O:6][CH3:7])=[O:5])[C:2]([CH3:1])=[CH:11][C:10]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1cc(C)c(C(=O)OC)cc1C
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: COC(=O)c1cc(C)c(C(=O)OC)c([N+](=O)[O-])c1C
Reaction time: 1.75 h
Yield: 74 %

Procedure:
Dimethyl 2,5-dimethylterephthalate (3.14 g, 14.1 mmol) was dissolved in dichloromethane (30 mL) and was cooled in an ice bath. Fuming nitric acid (7.6 mL) and concentrated sulfuric acid (0.92 mL) were added carefully, and the mixture was stirred for 1.75 h. The mixture was then quenched with water and diluted with dichloromethane. The aqueous portion was extracted with dichloromethane. The combined organic portion was dried over sodium sulfate, then filtered and concentrated to afford a yellow oil which was purified by column chromatography (silica gel, 10-20% ethyl acetate in hexanes) to afford dimethyl 2,5-dimethyl-3-nitroterephthalate (2.78 g, 10.4 mmol, 74% yield). 1H NMR (400 MHz, CDCl3): δ 7.85 (s, 1H), 3.94 (s, 3H), 3.89 (s, 3H), 2.49 (s, 3H), 2.46 (s, 3H); GCMS for C12H13NO6: 267 (M+).