Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C(OC(=O)[NH:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[S:24][C:23]3[C:18](=[N:19][CH:20]=[CH:21][C:22]=3[Cl:25])[CH:17]=2)=[O:15])[CH2:10]1)(C)(C)C.C(Cl)Cl.CO.CCOCC>CO>[NH2:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[S:24][C:23]3[C:18](=[N:19][CH:20]=[CH:21][C:22]=3[Cl:25])[CH:17]=2)=[O:15])[CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Solvent: ClCCl
Product: NC1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Reaction time: 0.17 h

Procedure:
HCl(g) was bubbled through a solution of [1-(7-chloro-thieno[3,2-b]pyridine-2-carbonyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (0.472 g, 1.23 mmol) in MeOH (10 mL). After 10 min, TLC (CH2Cl2/MeOH 9:1) showed the reaction to be complete. The reaction mixture was poured into Et2O (50 mL), and a white precipitate formed. The white solid was collected by filtration and washed with Et2O to afford the title compound. MS: 281.0/283.0 (MH+); HPLC Rf; 3.02 min; HPLC purity: 99%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]([C:11]#[N:12])=[CH:6][CH2:7][CH:8]([CH3:10])[CH3:9])[CH3:2].[N+]([CH3:17])([O-])=O.C1CCN2C(=NCCC2)CC1>C(#N)C>[CH2:1]([O:3][C:4]([C:5]1([C:11]#[N:12])[CH2:17][CH:6]1[CH2:7][CH:8]([CH3:10])[CH3:9])=[O:13])[CH3:2]
Reactant: CCOC(=O)C(C#N)=CCC(C)C
Reactant: C[N+](=O)[O-]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C1(C#N)CC1CC(C)C
Temperature: 60 °C
Yield: 70.3 %

Procedure:
To a solution of 2-cyano-5-methyl-hex-2-enoic acid ethyl ester (0.74 g, 4.08 mmol) in 16 mL acetonitrile was added nitromethane (1.11 mL, 20.4 mmol), followed by DBU (0.61 mL, 4.08 mmol) resulting in an orange solution. The reaction was heated to 60° C. for 16 hours, then cooled and partitioned between Et2O and 1N HCl (aq). The phases were separated, and the organic phase washed with brine, dried (MgSO4), and concentrated. Flash chromatography of the residue (5→10% EtOAc/hexanes) afforded 0.56 g (70%) of 1-cyano-2-isobutyl-cyclopropanecarboxylic acid ethyl ester as a pale yellow oil. 1H NMR (CDCl3) δ 4.22 (m, 2H), 1.75–1.90 (m, 3H), 1.63 (m, 1H), 1.36 (m, 2H), 1.30 (t, J=7.3 Hz, 3H), 0.95 (m, 6H). 13C NMR δ 168.25, 117.72, 62.94, 39.12, 30.25, 28.12, 25.66, 22.63, 22.40, 19.56, 14.30. LRMS: m/z 196.0 (M+1). Anal. Calcd for C11H17NO2: C, 67.66; H, 8.78; N, 7.17. Found: C, 67.32; H, 8.74; N, 7.32.
Reaction SMILES: [C:1]1([C@H:7]([N:9]2[C@H:14]([C:15]([O:17][CH3:18])=[O:16])[C@@H:13]3[CH2:19][C@H:10]2[CH:11]=[CH:12]3)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I:20]N1C(C)(C)C(=O)N(I)C1=O.[C:31]([OH:34])(=[O:33])[CH3:32]>>[C:31]([O:34][C@H:11]1[C@H:10]2[C@@H:19]([I:20])[C@H:13]([C@@H:14]([C:15]([O:17][CH3:18])=[O:16])[N:9]2[C@@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:8])[CH2:12]1)(=[O:33])[CH3:32]
Reactant: CC(=O)O
Reactant: CC1(C)C(=O)N(I)C(=O)N1I
Reactant: COC(=O)[C@@H]1[C@H]2C=C[C@H](C2)N1[C@H](C)c1ccccc1
Product: COC(=O)[C@@H]1[C@@H]2C[C@@H](OC(C)=O)[C@@H]([C@H]2I)N1[C@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl (1S,3S,4R)-2-[(1R)-1-phenylethyl]-2-azabicyclo[2.2.1]hept-5-ene-3-carboxylate obtained in Example 42-2 (1.0 g) in acetic acid (9 mL), was added portionwise 1,3-diiodo-5,5-dimethylhydantoin (782 mg). The mixture was stirred at room temperature for 30 minutes. The solution was concentrated under reduced pressure. The resulting mixture was diluted with ethyl acetate, and washed successively with sodium hydrogencarbonate solution, sodium thiosulfate solution, sodium hydrogen carbonate solution and brine. The organic layer was dried over MgSO4 and evaporated in vacuo to give the target compound as a solid (1.74 g).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:3]=1[NH:4][C:5](=[O:9])[CH2:6][C:7]#[N:8].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>>[C:7]([C:6](=[CH:17][N:18]([CH3:20])[CH3:19])[C:5]([NH:4][C:3]1[CH:10]=[C:11]([Cl:14])[CH:12]=[CH:13][C:2]=1[Cl:1])=[O:9])#[N:8]
Reactant: COC(OC)N(C)C
Reactant: N#CCC(=O)Nc1cc(Cl)ccc1Cl
Product: CN(C)C=C(C#N)C(=O)Nc1cc(Cl)ccc1Cl

Procedure:
As for Example 1, 2',5'-dichloro-2-cyanoacetanilide, as a white crystalline product, m.p. 190.5°-191.5° C. (prepared by the procedure described in U.S. Pat. No. 3,116,312), is heated with N,N-dimethylformamide dimethylacetal to yield 2-cyano-2',5'-dichloro-3-dimethylaminoacrylanilide as colorless needles, m.p. 175°-176° C.
Reaction SMILES: [N:1]1([C:6]2[C:7]([OH:12])=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.CO[C:15]1(OC)[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:17][CH2:16]1.B(F)(F)F.CCOCC.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH:11]1[C:6]2[N:1]3[CH:2]=[CH:3][CH:4]=[C:5]3[C:15]3([CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[O:22])[CH2:17][CH2:16]3)[O:12][C:7]=2[N:8]=[CH:9][CH:10]=1
Reactant: Oc1ncccc1-n1cccc1
Reactant: COC1(OC)CCN(C(=O)OCc2ccccc2)CC1
Agent: FB(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC2(CC1)Oc1ncccc1-n1cccc12
Temperature: 40 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 3-pyrrol-1-ylpyridin-2-ol (481 mg, 3.00 mmol) and benzyl 4,4-dimethoxypiperidine-1-carboxylate (922 g, 3.3 mol) in CH2Cl2 (20 mL) at 40° C. was added BF3.OEt2 (407.3 μL, 3.300 mmol) drop-wise. The reaction mixture was stirred at 40° C. for 16 hours. The mixture was poured into sat. aq. Na2CO3 and was stirred for 5 min before it was extracted with EtOAc (3×). Organic layers were combined, washed with sat. aq. Na2CO3, water, brine, dried (Na2 SO4) and evaporated to dryness. The residue was purified by column chromatography (1-30% EtOAc/CH2Cl2) to give benzyl spiro[piperidine-4,6′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazine]-1-carboxylate as an oil. ESI-MS m/z calc. 375.2, found 376.5 (M+1)+; Retention time: 1.70 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 8.10 (dd, J=7.7, 1.1 Hz, 1H), 8.00 (dd, J=4.9, 1.5 Hz, 1H), 7.60-7.52 (m, 1H), 7.42-7.36 (m, 4H), 7.36-7.29 (m, 1H), 7.16 (dd, J=7.8, 4.9 Hz, 1H), 6.33 (t, J=3.2 Hz, 1H), 6.20 (d, J=3.4 Hz, 1H), 5.11 (s, 2H), 3.97 (d br, J=13.2 Hz, 2H), 3.28 (s br, 2H), 1.98-1.92 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4](Cl)[N:3]=1.[CH:10]1([NH2:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[OH-].[Na+].C1(C)C=CC=CC=1>O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:16][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[N:3]=1
Reactant: NC1CCCCC1
Reactant: Nc1nc(N)nc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1nc(N)nc(NC2CCCCC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
A mixed solution of 14.5 g (0.1 mol) of 2,4-diamino-6-chloro-1,3,5-triazine prepared in Reference Example 1, 140 mL of water, and 29.2 g (0.3 mol) of cyclohexylamine was warmed with stirring and allowed to react at a reflux temperature for 1 hour. Further, an aqueous solution of 12 g of sodium hydroxide in 40 mL of water was dropwise added thereto over 1 hour and the mixture was aged for 1 hour. To the reaction mixture thus obtained was added 200 mL of toluene, and the resulting mixture was cooled down to room temperature. The crystals obtained were collected by filtration, washed with 100 mL of toluene and then with 100 mL of water, followed by drying under reduced pressure to obtain 17.9 g (yield 86%) of the titled compound. Melting point: 151° C.
Reaction SMILES: C(OC(=O)[NH:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[C:17](=[O:25])[NH:18][CH:19]([C:23]#[N:24])[CH:20]1[CH2:22][CH2:21]1)C1C=CC=CC=1.[CH3:27][C:28]([OH:30])=[O:29].C1CCCCC1>CCOC(C)=O.[Pd]>[C:28]([OH:30])(=[O:29])[CH3:27].[C:23]([CH:19]([NH:18][C:17]([CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]1[NH2:10])=[O:25])[CH:20]1[CH2:21][CH2:22]1)#[N:24]
Reactant: N#CC(NC(=O)C1CCCCC1NC(=O)OCc1ccccc1)C1CC1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: N#CC(NC(=O)C1CCCCC1N)C1CC1
Reaction time: 0.75 h

Procedure:
To a solution of 2-[(1-cyano-1-cyclopropyl-methyl)-carbamoyl]-cyclohexyl-carbamic acid benzyl ester (0.15 g, 0.42 mmol) in 50 ml EtOAc with 1% HOAc (v/v) is added Pd/C (10%) (0.05 g) carefully under nitrogen. The mixture is degassed completely before the reaction flask is filled with H2 through a balloon. The reaction mixture is stirred for 45 minutes. TLC showed that the starting material has disappeared. The reaction mixture is filtered through Celite. The filtrate is concentrated to give a yellow oil. Yield: 0.17 g, 100%. The isolated cis- and trans-forms of the product are obtained by starting from the corresponding cis- or trans-form of the cyclohexane derivative.
Reaction SMILES: [C:1](=[O:8])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[NH2:2].[Na+].[C:10]1([S:16]([O-:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=O.C(O)=O>CO.O>[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]([NH:2][C:1](=[O:8])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[S:16]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:18])=[O:17]
Reactant: CC(C)(C)OC(N)=O
Reactant: O=Cc1ccccc1Cl
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: CO
Solvent: O=CO
Solvent: O
Product: CC(C)(C)OC(=O)NC(c1ccccc1Cl)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Quantities of 2.78 g (23.7 mmol) of tert-butyl carbamate and 7.79 g (47.4 mmol) of benzenesulphinic acid sodium salt were introduced in 55 ml of methanol/water 1:2 at RT and admixed with 5 g (35.6 mmol) of 2-chlorobenzaldehyde and then with 1.78 ml (47.1 mmol) of formic acid. The mixture was stirred at RT for 2 days. The white solid precipitated was filtered off with suction and washed in succession twice each with water and diethyl ether. Drying in an HV gave 5.77 g (42% of theory) of the title compound.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:15][CH2:16][NH:17][C:18](=O)[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH3:28])=[C:22]([O:29][CH2:30][CH3:31])[CH:21]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])([CH3:3])[CH3:2].P(Cl)(Cl)([Cl:35])=O>C1C=CC=CC=1>[ClH:35].[CH2:30]([O:29][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[O:26][CH2:27][CH3:28])[CH2:19][C:18]1[C:8]2[C:7](=[CH:6][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[C:10]([O:11][CH:12]([CH3:14])[CH3:13])[CH:9]=2)[CH2:15][CH2:16][N:17]=1)[CH3:31]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOc1ccc(CC(=O)NCCc2ccc(OC(C)C)c(OC(C)C)c2)cc1OCC
Solvent: c1ccccc1
Product: CCOc1ccc(CC2=NCCc3cc(OC(C)C)c(OC(C)C)cc32)cc1OCC
Product: Cl
Reaction time: 2 h
Yield: 56.1 %

Procedure:
5.0 g (0.0113 mole) of N-[2-(3,4-diisopropoxyphenyl)-ethyl]-3,4-diethoxyphenylacetamide, 100 ml benzene, and 2.3 g (0.015 mole) of phosphorus oxychloride were introduced successively into a 250 ml 3-necked flask after being passed through an atmosphere of nitrogen. The mixture was heated under reflux with stirring over a period of 2 hours, 70 ml of solvent removed by distillation, 30 ml of ethanol, 1 ml of 12 N hydrochloric acid added and the bulk of solvent removed by distillation under reduced pressure. The residue obtained was washed several times with ether, taken up again in solution in 15 ml of ethanol, and 120 ml of ether added slowly. The slowly precipitated product was dried to give 2.93 g of 1-(3'4'-diethoxybenzyl)-6,7-diisopropoxy-3,4-dihydroisoquinoline hydrochloride. Yield=57%, m.p. 187° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][C:10](=[O:12])[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[Cl-].[Cl-].[Al+3].Cl>[N+](C1C=CC=CC=1)([O-])=O>[C:13]([C:4]1[CH:5]=[CH:6][C:1]([CH2:7][CH2:8][NH:9][C:10](=[O:12])[CH3:11])=[CH:2][CH:3]=1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(=O)NCCc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: CC(=O)NCCc1ccc(C(=O)c2ccccc2)cc1
Temperature: 50 °C
Yield: 34.3 %

Procedure:
N-(2-Phenylethyl)acetamide (49.01 mmol, 8.00 g) was introduced into nitrobenzene (40 ml). Benzoyl chloride (54.07 mmol, 7.60 g) was added thereto and then, at room temperature, aluminum tri-chloride (73.52 mmol, 9.80 g) was introduced in portions. The mixture was then heated at 50° C. for 8 h. The reaction mixture was poured into a mixture of ice and concentrated hydrochloric acid, and nitrobenzene was removed by steam distillation. The aqueous residue was extracted with ethyl acetate. The residue after concentration of the organic phase was chromatographed on silica gel (mobile phase dichloromethane/methanol (3% by volume)), resulting in 4.5 g of the title compound as orange oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([N:17]2[CH2:22][CH2:21][C@@:20]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)([CH2:23][CH2:24][OH:25])[O:19][C:18]2=[O:33])[CH3:16])=[CH:11][CH:10]=1.[C:34](Cl)(=[O:45])OC1C=CC([N+]([O-])=O)=CC=1.[NH3:47]>C(Cl)Cl>[C:34](=[O:45])([O:25][CH2:24][CH2:23][C@@:20]1([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[O:19][C:18](=[O:33])[N:17]([C@H:15]([C:12]2[CH:13]=[CH:14][C:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[CH:10][CH:11]=2)[CH3:16])[CH2:22][CH2:21]1)[NH2:47]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCO)(c2ccc(F)cc2)OC1=O
Reactant: N
Solvent: ClCCl
Product: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCOC(N)=O)(c2ccc(F)cc2)OC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
(S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one (50 mg, 0.11 mmol) was dissolved in CH2Cl2 (3 mL), followed by the addition of TEA (1 mL) and 4-nitrophenyl carbonochloridate (88 mg, 0.44 mmol). The mixture was stirred at rt overnight. Aqueous ammonia (2 mL) was added and the mixture was stirred at rt for 3 h. After separation of the water layer, the organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo to give the crude product, which was purified by preparative TLC to afford 2-((S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl carbamate (20 mg, 35%). LC-MS Method 3 tR=1.36, min, m/z=499; 1H NMR (CDCl3): 1.48 (m, 3H), 2.14-2.33 (m, 5H), 2.91 (m, 1H), 3.42 (s, 1H), 3.95 (m, 1H), 4.07 (m, 1H), 4.62 (s, 2H), 5.61 (m, 1H), 6.79-7.01 (m, 6H), 7.23 (m, 5H).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:17]([NH2:23])[C:18]1[O:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C.C(O)C>O>[O:22]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:17][NH:23][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: NCc1ccco1
Reactant: Clc1ncnc2scc(-c3ccccc3)c12
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: c1ccc(-c2csc3ncnc(NCc4ccco4)c23)cc1
Temperature: 25 °C

Procedure:
A stirred mixture of 4-chloro-5-phenylthieno[2,3-d]pyrimidine (2.2 g, 0.009 mol), furfurylamine (1.26 g, 0.013 mol), triethylamine (1.3 g) and ethanol (20 ml) was heated under reflux for 2 hours then cooled to ambient temperature and poured into water (50 ml). The resulting solid was collected by filtration, washed with water (30 ml), dried in vacuo and crystallised from a mixture of hexane and toluene to give furan-2-ylmethyl-(5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-amine as a pale yellow solid, m.pt. 77-79° C.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[NH:10][C:9]1=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[C:24]#[CH:25].C(OCC)(=O)C.CCCCCC>CC(C)=O>[CH2:1]([N:8]1[C:12](=[O:13])[C:11]([CH3:14])([CH3:15])[N:10]([CH2:25][C:24]#[CH:23])[C:9]1=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)NC(=O)N(Cc2ccccc2)C1=O
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: C#CCN1C(=O)N(Cc2ccccc2)C(=O)C1(C)C
Temperature: 25 °C
Yield: 49.2 %

Procedure:
To a stirred solution of 3-benzyl-5,5-dimethylhydantoin (9.5 g, 43.6 mmole) in acetone (100 mL) at room temperature were added potassium carbonate (8.4 g, 60.9 mmole) and propargyl bromide (7.1 g of 80 % in toluene, 47.7 mmole). The reaction mixture was refluxed for 16 hr; cooled to room temperature and the solid was filtered off by suction-filtration. The filtrate was concentrated and the resultant residue was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulfate. After evaporation, a yellow crude oil was obtained. A pure product, 5.5 g (yield=50%) of 3-benzyl-1-propargyl-5,5-dimethylhydantoin as a yellow oil, was obtained by column chromatography on silica gel eluting with ethyl acetate:hexane (1:1 ).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:15]=[C:16]([C@H:20]2[CH2:25][C@H:24]([CH2:26][CH:27]=[CH2:28])[S:23][N:22]([CH:29]([CH3:31])[CH3:30])[C@@H:21]2[C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)[CH:17]=[CH:18][CH:19]=1.CI.[Li+].CC([N-]C(C)C)C>C1COCC1>[Cl:13][C:14]1[CH:15]=[C:16]([C@H:20]2[CH2:25][C@:24]([CH3:1])([CH2:26][CH:27]=[CH2:28])[S:23][N:22]([CH:29]([CH3:31])[CH3:30])[C@@H:21]2[C:32]2[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)NC(C)C
Reactant: C=CC[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(C(C)C)S1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(C(C)C)S1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a degassed solution of diisopropylamine (300 μL, 2.123 mmol) in THF (1.0 ml) was added dropwise at −78° C. n-butyllithium, 2.5 M in hexanes (800 μL, 2.000 mmol). After stirring the solution at −78° C. for 10 min, the reaction was warmed to room temperature. In a separate flask, a degassed solution of 111.9 mg (0.255 mmol) of (3S,4R,6R)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-2-(2-propanyl)-6-(2-propen-1-yl)-1,2-thiazinan (Example 117, Step E) and methyl iodide (0.6 ml, 9.62 mmol) in THF (1.0 ml) was heated to 50° C. After five minutes, the LDA solution was added dropwise to the other flask, and stirring continued for 14 hours at 50° C. Upon cooling to room temperature, the reaction was quenched with water (3 mL), then concentrated under reduced pressure. Purification by reverse-phase preparative HPLC using an Agilent Eclipse Plus C18 column (Agilent Technologies, Santa, Clara, Calif.), 0.1% TFA in CH3CN/H2O, gradient 60% to 80% over 25 minutes provided the title compound as a white solid.
Reaction SMILES: [P:1](=[O:5])([OH:4])([OH:3])[OH:2].[OH-].[Mg+2:7].[OH-].OC(CCCCCCCCC)=O.OCC(CO)O.OCC(CO)O>O>[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[Mg+2:7].[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[Mg+2:7].[Mg+2:7]
Reactant: O=P(O)(O)O
Agent: CCCCCCCCCC(=O)O
Agent: [Mg+2]
Agent: [OH-]
Solvent: O
Solvent: OCC(O)CO
Product: O=P([O-])([O-])[O-]

Procedure:
A solution obtained by diluting 2.7 kg of a 85% by weight solution of phosphoric acid with ion-exchanged water to a total quantity of 100 kg was gradually added with stirring to a solution obtained by adding 2 kg of magnesium hydroxide to 300 kg of ion-exchanged water, and then further adding and dissolving therein 2 kg of diglycerol monocaprate (trade name: “SUNSOFT Q-10 D”; HLB=9.5; monoester content: 85% by weight; specific gravity: 0.9; manufactured by Taiyo Kagaku Co., Ltd.). The pH of the resulting mixture was adjusted to 8 using a handy pH meter manufactured by HORIBA, Ltd. After forming of the salt of magnesium phosphate by neutralization reaction was terminated, the resulting reaction mixture was subjected to solid-liquid separation by centrifugation (3000×g, for 10 minutes), and 4 kg (dry weight basis) of magnesium phosphate of the solid phase portion was collected (average particle size of fine metal particles: about 0.31 μm). The magnesium phosphate was resuspended in ion-exchanged water, to give a magnesium phosphate dispersion composition having a solid content of 10% by weight (20 parts by weight of an emulsifier were contained based on 100 parts by weight of the metal salt). The resulting composition was filled in a clear container, and stored with leaving it at rest for 1 month at normal temperatures. As a result, the composition was excellent in dispersion stability, with no occurrence of separation and precipitation of the constituents.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[F:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[CH3:18])[NH2:14].[OH-].[Na+]>CC(C)=O>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([NH:14][C:13]2[CH:15]=[CH:16][C:17]([CH3:18])=[C:11]([F:10])[CH:12]=2)[N:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Cc1ccc(N)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Cc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1F
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
To cyanuric chloride (1.4821 g, 8 mmol) dissolved in acetone (115 mL) stiffing at 0-5° C., was added a solution of 3-fluoro-4-methylaniline (1.0017 g, 8 mmol) in acetone (15 mL) followed by the addition of 2.5 N NaOH (3.2 mL, 8 mmol). The reaction mixture was allowed to stir at 0-5° C. for 1 hour under nitrogen. The reaction mixture was poured over crushed ice and neutralized with 10% NaOH. The solid that formed was collected by vacuum filtration and the resulting solid was dried overnight under vacuum. The product was used with no further purification, (156a, 1.88 g, 86%), mp 130° C.; HPLC: Inertsil ODS-3V C 18, 40:30:30 [KH2PO4 (0.01M, pH 3.2): CH3OH: CH3CN], 264 nm, Rt 36.8 min, 99.1% purity;
Reaction SMILES: [CH3:1][C:2]1([C:9]([OH:11])=O)[CH2:5][C:4]2([CH2:8][CH2:7][CH2:6]2)[CH2:3]1.[CH3:12][Li]>CCOCC>[CH3:1][C:2]1([C:9](=[O:11])[CH3:12])[CH2:3][C:4]2([CH2:6][CH2:7][CH2:8]2)[CH2:5]1
Reactant: [Li]C
Reactant: CC1(C(=O)O)CC2(CCC2)C1
Solvent: CCOCC
Product: CC(=O)C1(C)CC2(CCC2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 5.0 g (33.0 mmol) 2-methylspiro[3.3]heptane-2-carboxylic acid in 33.0 ml of dry ether was stirred under argon at 0° C and 47.6 ml (74.3 mmol) of 1.56 M methyl lithium in ether added dropwise. The reaction mixture was allowed to warm to 25° C and was stirred for 3.0 hr. The reaction mixture was cooled to -20° C and quenched by addition of 10% aqueous HCl. The layers were separated and the aqueous layer extracted with ether. The combined organic layers were washed with saturated aqueous sodium bicarbonate and brine, then dried (MgSO4), filtered, and evaporated in vacuo to afford 2-methyl-2-acetylspiro[3.3]heptane as a light yellow oil (4.91 g 98%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([Br:9])[CH:3]=1.[Cu](C#N)[C:11]#[N:12].N1C=CC=CC=1.N>O.CN(C=O)C>[Br:9][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([CH3:8])[CH:5]=1)[C:11]#[N:12]
Reactant: Cc1cc(Br)cc(Br)c1
Reactant: N#C[Cu]C#N
Agent: N
Solvent: O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1cc(Br)cc(C#N)c1
Temperature: 190 °C
Yield: 147.9 %

Procedure:
A mixture of 1,3-dibromo-5-methylbenzene (1.0 g, 4.0 mmol), copper cyanide (0.179 g, 2.00 mmol), pyridine (0.323 mL, 4.00 mmol), and DMF (15 mL) were heated at 190° C. for 10 h in microwave reactor. The reaction mixture was allowed to cool to r.t., and then poured into a solution of H2O (20 mL) and aq. NH3 solution (25-35% NH3, 10 mL) and the water phase was extracted with EtOAc. The combined organic extracts were dried (Mg2SO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (hexane/EtOAc gradient elution) to afford the title compound (0.58 g, 74% yield): 1H NMR (500 MHz, CDCl3) δ ppm 2.39 (s, 3H) 7.41 (s, 1H) 7.58 (s, 1H) 7.60 (s, 1H); MS (EI) m/z 195 M+.