Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:5]1)[CH2:2][CH3:3].[F:15][C:16]([F:30])([F:29])[CH:17]([C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1)[CH3:18]>C(Cl)Cl.N1C=CC=CC=1>[CH2:1]([N:4]1[CH2:5][CH:6]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][S:25]([C:22]3[CH:21]=[CH:20][C:19]([CH:17]([CH3:18])[C:16]([F:15])([F:29])[F:30])=[CH:24][CH:23]=3)(=[O:27])=[O:26])=[CH:12][CH:13]=2)[CH2:7]1)[CH2:2][CH3:3]
Reactant: CC(c1ccc(S(=O)(=O)Cl)cc1)C(F)(F)F
Reactant: CCCN1CC(c2ccc(N)cc2)C1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCN1CC(c2ccc(NS(=O)(=O)c3ccc(C(C)C(F)(F)F)cc3)cc2)C1
Yield: 18 %

Procedure:
Following the same procedure as described in example 55, 4-(1-propyl-azetidin-3-yl)phenylamine (100 mg, 0.52 mmol) in CH2Cl2/pyridine 9:1 (15 ml) was treated with 4-(2,2,2-trifluoro-1-methyl-ethyl)-benzenesulfonyl chloride (145 mg, 0.52 mmol). Purification of the crude product by flash column chromatography (CH2Cl2:methanol, 95:5) provided the title compound (40 mg, 18%) as a pale yellow gum.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:27]=[CH:28][CH:29]=3)[CH2:19][S:20][CH2:21][CH2:22][C:23]([O:25]C)=[O:24])=[O:15])=[C:9]([C:30]3[CH:35]=[C:34]([NH:36][C:37](=[O:48])[C:38]4[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:47])([F:46])[F:45])[CH:39]=4)[CH:33]=[CH:32][N:31]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[OH-].[Li+]>O1CCCC1.O>[N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:27]=[CH:28][CH:29]=3)[CH2:19][S:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:15])=[C:9]([C:30]3[CH:35]=[C:34]([NH:36][C:37](=[O:48])[C:38]4[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:47])([F:45])[F:46])[CH:39]=4)[CH:33]=[CH:32][N:31]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(NC(=O)c3cccc(C(F)(F)F)c3)ccn2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(NC(=O)c3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.6 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of methyl 3-(3-((4-(piperidin-1-yl)-2-(4-(3-(trifluoromethyl)benzamido)pyridin-2-yl)phenyl)carbamoyl)benzylthio)propanoate (100 mg, 0.15 mmol, 1.00 equiv) and lithium hydroxide hydrate (62.0 mg, 1.48 mmol, 10.00 equiv) in tetrahydrofuran/water (1:1) (10/10 mL). The resulting solution was stirred for 2 h at room temperature. The resulting mixture was combined with the solution of the previous batch and then concentrated under vacuum. The residual solution was adjusted to pH 5˜6 with 1 N acetic acid. The resulting solution was extracted with 2×30 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate. The solvent was removed under vacuum. The crude product (140 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The fractions were collected and lyophilized to yield 100 mg (58%) of product as an off-white solid. 1H-NMR (300 MHz, DMSO-d6, ppm): δ 11.29 (br, 1H), 8.79 (d, J=6.0 Hz, 1H), 8.42 (s, 1H), 8.31-8.27 (m, 2H), 8.07-7.97 (m, 2H), 7.87-7.74 (m, 3H), 7.53-7.44 (m, 3H), 7.38-7.37 (m, 1H), 3.83 (s, 2H), 3.35 (s, 4H), 2.56 (t, J=6.3 Hz, 2H), 1.74-1.61 (m, 6H). MS (ES, m/z): 663 [M+H]+.
Reaction SMILES: CS[C:3]1[N:12]=[C:11]([NH2:13])[C:10]2[C:5](=[C:6]([O:17][CH3:18])[C:7]([O:15][CH3:16])=[C:8]([Cl:14])[CH:9]=2)[N:4]=1.[CH2:19]([CH:25]1[CH2:29][CH2:28][NH:27][CH2:26]1)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C(O)CC(C)C>[CH2:19]([CH:25]1[CH2:29][CH2:28][N:27]([C:3]2[N:12]=[C:11]([NH2:13])[C:10]3[C:5](=[C:6]([O:17][CH3:18])[C:7]([O:15][CH3:16])=[C:8]([Cl:14])[CH:9]=3)[N:4]=2)[CH2:26]1)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: COc1c(Cl)cc2c(N)nc(SC)nc2c1OC
Reactant: CCCCCCC1CCNC1
Solvent: CC(C)CCO
Product: CCCCCCC1CCN(c2nc(N)c3cc(Cl)c(OC)c(OC)c3n2)C1

Procedure:
A mixture of 0.1 mole of 2-methylmercapto-4-amino-6-chloro-7,8-dimethoxyquinazoline and 0.12 mole of 3-n-hexylpyrrolidine in isoamyl alcohol is heated at reflux for 16 hours, cooled, washed with water and the organic phase is concentrated in vacuo. Hexane is slowly added to the residue and the solid title compound is collected and purified, if desired by silica gel column chromatography.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:7][N:6]=1)=[O:4].[OH-].[Li+].Cl>O1CCCC1.O>[Cl:18][C:13]1[CH:12]=[C:11]([C:9]2[C:8]([O:19][CH2:20][C:21]([F:23])([F:24])[F:22])=[CH:7][N:6]=[C:5]([C:3]([OH:4])=[O:2])[N:10]=2)[CH:16]=[CH:15][C:14]=1[Cl:17]
Reactant: COC(=O)c1ncc(OCC(F)(F)F)c(-c2ccc(Cl)c(Cl)c2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ncc(OCC(F)(F)F)c(-c2ccc(Cl)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
To a solution of 3.79 g 4-(3,4-dichloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyrimidine-2-carboxylic acid methyl ester in 28 mL tetrahydrofuran was added 13 mL of a 1M solution of lithium hydroxide in water and the mixture was stirred at room temperature for 1 h. The reaction mixture was acidified by addition of 1M hydrochloric acid. The precipitate was collected by filtration washed with water and dried to constant weight under high vacuum to yield 3.561 g (97.55%) of the title compound as white solid, MS 365.0 (M−H)−.
Reaction SMILES: C(NC(=O)C(N[C:13]([C:15]1[N:16]([CH3:44])[C:17]2[C:22]([C:23]=1[Cl:24])=[CH:21][C:20]([NH:25][C:26]([C:28]1[C:29]([C:34]3[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=3)=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:27])=[CH:19][CH:18]=2)=[O:14])C1C=CC=CC=1)C.CC(C[AlH]CC(C)C)C>C1COCC1.OS([O-])(=O)=O.[Na+].CCOC(C)=O>[Cl:24][C:23]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([NH:25][C:26]([C:28]3[C:29]([C:34]4[CH:39]=[CH:38][C:37]([C:40]([F:41])([F:43])[F:42])=[CH:36][CH:35]=4)=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:27])[CH:21]=2)[N:16]([CH3:44])[C:15]=1[CH:13]=[O:14]
Reactant: CCNC(=O)C(NC(=O)c1c(Cl)c2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2n1C)c1ccccc1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1c(C=O)c(Cl)c2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc21
Reaction time: 6 h
Yield: 51.2 %

Procedure:
To a solution of the product from step (a) (1.56 g, 3.02 mmol) in THF (25 ml) at −78° C. was added DIBAL in THF (1.0 M, 12 ml), and the reaction mixture was stirred at −78 co for 6 h. The reaction mixture was diluted with NaHSO4 (0.25 M, 86 ml) and EtOAc (115 ml), and the aqueous layer was extracted with EtOAc (2×100 ml). The combined organic layers were dried (MgSO4) and concentrated in vacuo to about 30 ml in volume. The product was purified by flash chromatography using 1:1 EtOAc/hexane to afford 0.706 g of the title compound.
Reaction SMILES: [N:1]1[CH2:6][CH2:5][CH2:4][N:3]2[C:7](=[O:10])[S:8][CH2:9][C:2]=12.[F:11][C:12]([F:33])([F:32])[C:13]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:14]=1[CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([CH:22]=O)[CH2:18][CH2:17]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:33][C:12]([F:11])([F:32])[C:13]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:14]=1[CH2:15][N:16]1[CH2:21][CH2:20][CH:19](/[CH:22]=[C:9]2\[S:8][C:7](=[O:10])[N:3]3[CH2:4][CH2:5][CH2:6][N:1]=[C:2]\23)[CH2:18][CH2:17]1
Reactant: O=C1SCC2=NCCCN12
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: O=c1s/c(=C\C2CCN(Cc3ccc(C(F)(F)F)cc3C(F)(F)F)CC2)c2n1CCCN=2
Temperature: 60 °C
Reaction time: 8 h
Yield: 75.3 %

Procedure:
To a solution of 2,3,4,8-tetrahydro[1,3]thiazolo[3,4-a]pyrimidin-6-one (0.469 g) and 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (1.12 g) in 2-propanol (10 mL) was added piperidinium acetate (0.479 g) at room temperature. The reaction mixture was stirred at 60° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) and recrystallized from heptane to give the title compound (1.08 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>>[CH3:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([S:34]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:16]=[C:15]4[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]4=[O:17])=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)(=[O:36])=[O:35])=[CH:32][CH:33]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NS(=O)(=O)c4ccc(OC)cc4)cc3)cc2C1=O

Procedure:
The compound of example 89 was prepared analogous to compound of example 77 by reaction of compound of example 6 with 4-methoxybenzene sulfonyl chloride. The compound of example 89 was used directly without isolation for the preparation of compound of example 90.
Reaction SMILES: Cl.Cl.[C:3]([C:5]1([NH:12][C:13]([CH:15]([NH2:21])[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:14])[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]1)#[N:4].CN1CCOCC1.[N:29]1([C:35](Cl)=[O:36])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>CN(C=O)C>[C:3]([C:5]1([NH:12][C:13]([CH:15]([NH:21][C:35]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:36])[CH2:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:14])[CH2:6][CH2:7][N:8]([CH3:11])[CH2:9][CH2:10]1)#[N:4]
Reactant: CN1CCC(C#N)(NC(=O)C(N)CC(C)(C)C)CC1
Reactant: O=C(Cl)N1CCOCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CN1CCC(C#N)(NC(=O)C(CC(C)(C)C)NC(=O)N2CCOCC2)CC1
Reaction time: 16 h
Yield: 21.7 %

Procedure:
[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amine dihydrochloride (350 mg, 1.03 mmol) was mixed in 10 mL of DMF to which was added 1 mL of N-methyl morpholine followed by addition of 4-morpholine carbonyl chloride (180 mg, 1.20 mmol) as a solution in 5 mL of DMF. The reaction was stirred for 16 hours at which time the volatiles were removed in vacuo. The residue was redissolved in 150 mL of EtOAc and washed sequentially with 50 mL of saturated aqueous bicarbonate and 50 mL of brine. The organic layer was dried over sodium sulfate, decanted and concentrated. The product was purified by flash chromatography on silica gel using 100% methylene chloride to 12% methanol in methylene chloride as eluent to give the title compound as a thick oil (85 mg); MS, m/z 380=M+1.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.[NH2:15][C:16]1[CH:17]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:20][CH:21]=1>>[F:23][C:22]([F:24])([F:25])[C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[NH:15][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1
Reactant: Cc1cc(Cl)nc(-c2ccccn2)n1
Reactant: Nc1cccc(C(F)(F)F)c1
Product: Cc1cc(Nc2cccc(C(F)(F)F)c2)nc(-c2ccccn2)n1

Procedure:
The title compound was prepared from 4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (50 mg, 0.243 mmol) and 3-aminobenzotrifluoride (30 μl, 0.243 mmol) similar to Example 11 and isolated as a pale white solid (74 mg, 93%). 1H NMR (CDCl3): 8.84–8.82 (m, 1H), 8.49–8.45 (m, 1H), 7.95 (s, 1H), 7.90–7.85 (m, 1H), 7.62 (d, J=7.8 Hz, 1H), 7.52 (t, J=7.8 Hz, 1H), 7.45–7.40 (m, 2H), 6.78 (s, 1H), 2.55 (s, 3H).
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:9]([OH:11])=[O:10])[CH2:5][N:6]([CH3:8])[CH3:7].[C:12](O[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])(OC(C)(C)C)=O.C([O-])([O-])=O.[Na+].[Na+]>CC#N>[CH3:7][N:6]([CH3:8])[CH2:5][CH:4]([NH:3][CH3:12])[CH2:9][OH:11].[C:23]([O:22][C:20]([NH:3][CH:4]([CH2:5][N:6]([CH3:8])[CH3:7])[C:9]([OH:11])=[O:10])=[O:21])([CH3:24])([CH3:25])[CH3:26]
Reactant: CN(C)CC(N)C(=O)O
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CN(C)CC(NC(=O)OC(C)(C)C)C(=O)O
Product: CNC(CO)CN(C)C
Reaction time: 16 h
Yield: 31 %

Procedure:
3-Dimethylamino-2-methylamino-propan-1-ol is prepared from 4-aza-DL-leucine 2 HCl. Di-tert-butyl dicarbonate (0.65 g, 2.97 mmol) is added to a biphasic mixture of 4-aza-DL-leucine 2 HCl (0.51 g, 2.47 mmol) in 10 ml 1:1 10% Na2CO3:MeCN. After stirring 16 hours, the MeCN is removed under reduced pressure and the aqueous layer is extracted with ethyl acetate. The aqueous layer is concentrated and purified by reverse phase column chromatography on a sep-pak C18 column (water) yielding 0.19 g (31%) 2-tert-butoxycarbonylamino-3-dimethylamino-propionic acid, sodium salt. The sodium salt is suspended in THF (5 ml) and cooled to 0° C. under N2. LAH (3.8 ml of a 1.0 M solution in THF) is added and the reaction mixture warmed to rt and than to reflux. After stirring at reflux for 16 h, the reaction mixture is cooled to 0° C. and carefully quenched by the slow addition of Na2SO4.10 H2O. The reaction mixture is diluted with diethyl ether, warmed to room temperature and stirred for 30 min. The gray suspension is filtered through Celite and the filtrate concentrated to give 83 mg (82%) of 3-dimethylamino-2-methylamino-propan-1ol as an oil.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[N+:7]([C:10]1[CH:24]=[CH:23][C:13]([CH2:14][P:15](=O)([O:19]CC)[O:16][CH2:17][CH3:18])=[CH:12][CH:11]=1)([O-:9])=[O:8]>C(Cl)Cl.C(Cl)(Cl)Cl>[N+:7]([C:10]1[CH:24]=[CH:23][C:13]([CH2:14][P:15]([Cl:4])(=[O:19])[O:16][CH2:17][CH3:18])=[CH:12][CH:11]=1)([O-:9])=[O:8]
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])cc1)OCC
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCOP(=O)(Cl)Cc1ccc([N+](=O)[O-])cc1
Reaction time: 48 h
Yield: 98.6 %

Procedure:
Oxalyl chloride (4.8 mL, 9.6 mmol, 2 M solution in methylene chloride) was added to a solution of diethyl 4-nitrobenzylphosphonate 298 (546 mg, 2.0 mmol) in methylene chloride (10 mL) at room temperature under nitrogen, and the mixture was stirred for 48 h. The mixture was diluted with chloroform (10 mL), and the solvent was concentrated to provide 520 mg (99% yield) of ethyl 4-nitrobenzylphosphonochloridate 299 as a thick yellow oil that was used in the next step without purification.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][N:8]=[C:9]([C:41]1[N:42]=[C:43]([NH:46][C:47]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[S:44][CH:45]=1)[C:10]([NH:12][CH:13]1[C:39](=[O:40])[N:15]2[C:16]([C:23]([O:25][CH:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])=[C:17]([CH2:21]Cl)[CH2:18][S:19](=[O:20])[C@H:14]12)=[O:11].[I-:66].[Na+].C(O[CH2:72][CH3:73])(=O)C.O>CC(C)=O>[I-:66].[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][N:8]=[C:9]([C:41]1[N:42]=[C:43]([NH:46][C:47]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[S:44][CH:45]=1)[C:10]([NH:12][CH:13]1[C:39](=[O:40])[N:15]2[C:16]([C:23]([O:25][CH:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])=[C:17]([CH2:21][N+:12]3([CH3:13])[CH2:73][CH2:72][CH2:9][CH2:10]3)[CH2:18][S:19](=[O:20])[C@H:14]12)=[O:11]
Reactant: CCOC(C)=O
Reactant: O=C(NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS(=O)[C@H]12)C(=NOC1CCCCO1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: C[N+]1(CC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)C(=NOC4CCCCO4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)[C@H]3S(=O)C2)CCCC1
Reaction time: 4.5 h

Procedure:
To a solution of benzhydryl 7-[2-(2-tetrahydropyranyl)oxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-chloromethyl-3-cephem-4-carboxylate-1-oxide (syn isomer) in acetone (100 ml) was added sodium iodide (2.5 g) under ice-cooling. The mixture was stirred for 4.5 hours at the same temperature and then poured into a mixure of ethyl acetate (150 ml) and water (150 ml). The organic layer was separated, washed with brine and dried over magnesium sulfate. The solvent was distilled off. To the residue was added tetrahydrofuran (25 ml) and then 1-methylpyrrolidine (0.52 ml) was added thereto under cooling. The mixture was stirred for 1 hour at the same temperature and then the mixture was poured into ice-water. The resulting precipitates were collected by filtration, dried over phosphorus pentoxide and then subjected to column chromatography on silica gel using methylene chloride and methanol (5:2) as an eluent. The fractions containing the object compound were collected and evaporated to give benzhydryl 7-[2-(2-tetrahydropyranyl)oxyimino-2-(2 -tritylaminothiazol-4-yl)acetamido]-3-(1-methyl-1-pyrrolidinio)methyl-3-cephem-4-carboxylate-1-oxide iodide (syn isomer) (1.0 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([CH:11]=[O:12])[CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].C(Cl)(=O)C([Cl:18])=O.CN(C)C=O>O1CCCC1>[Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([CH:11]=[O:12])[CH:5]=[C:6]([CH:10]=1)[C:7]([Cl:18])=[O:8]
Reactant: COc1c(Br)cc(C(=O)O)cc1C=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1c(Br)cc(C(=O)Cl)cc1C=O
Yield: 98.1 %

Procedure:
5-Bromo-3-formyl-4-methoxybenzoic acid (480 mg, 1.84 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL) and the solution was flushed with dry nitrogen for 5 minutes. Oxalyl chloride (1.2 mL, 2.4 mmol, 1.3 eq) was added slowly to the solution while vigorous stirring and then a catalytic amount of dry dimethylformamide was added. The mixture was stirred for 1 hour and then concentrated by rotary evaporation and dried on high vacuum to give 5-bromo-3-formyl-4-methoxybenzoyl chloride (501 mg) as yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.[C:13]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])#N.[NH:21]1CCCCC1.C(O)(=O)C>C1C=CC=CC=1>[C:16]([O:18][CH:19]([C:20]#[N:21])[CH2:6][C:5]1[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:17])[CH:15]=[CH2:13]
Reactant: CCOC(=O)CC#N
Reactant: COc1ccc(C=O)cc1OC
Reactant: C1CCNCC1
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: C=CC(=O)OC(C#N)Cc1ccc(OC)c(OC)c1
Temperature: 125 °C

Procedure:
Add 3,4-dimethoxy benzaldehyde 26 g (0.16 mol), ethyl cyanoacetate 18 g (0.16 mol), piperidine 0.8 ml, acetic acid 2.4 g, and benzene 60 ml into 250 ml eggplant-shaped flask, increase temperature to 120-130° C. for intensive reflux, separate water with water separator, react for 12 h. Vacuum evaporate to remove benzene, pour ice water into the reaction solution to precipitate yellow solid, filter and dry to obtain pale yellow crystal VIII-b-2 41 g, with yield almost reaching theoretical value and m.p. 154-156° C. (reference value 156° C.).
Reaction SMILES: I[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:11][C:12]1[CH:13]=[CH:14][C:15]2[S:20][C:19]3[N:21]=[CH:22][CH:23]=[N:24][C:18]=3[N:17](COC)[C:16]=2[CH:28]=1.IC1N=CN=C2C=1N=CN2CC1C=CC2SC3N=CC=NC=3NC=2C=1.[O:54]([CH2:62][C:63]([CH2:67][O:68][Si](C(C)(C)C)(C)C)([OH:66])[C:64]#[CH:65])[Si](C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[N:24]1[C:18]2[NH:17][C:16]3[CH:28]=[C:12]([CH2:11][N:6]4[CH:5]=[N:4][C:3]5[C:7]4=[N:8][CH:9]=[N:10][C:2]=5[CH:62]([OH:54])[C:63]([CH2:67][OH:68])([OH:66])[C:64]#[CH:65])[CH:13]=[CH:14][C:15]=3[S:20][C:19]=2[N:21]=[CH:22][CH:23]=1
Reactant: COCN1c2cc(Cn3cnc4c(I)ncnc43)ccc2Sc2nccnc21
Reactant: C#CC(O)(CO[Si](C)(C)C(C)(C)C)CO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Ic1ncnc2c1ncn2Cc1ccc2c(c1)Nc1nccnc1S2
Agent: [F-]
Product: C#CC(O)(CO)C(O)c1ncnc2c1ncn2Cc1ccc2c(c1)Nc1nccnc1S2

Procedure:
8-(6-Iodopurin-9-ylmethyl)-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine was treated by the same method as the one of Example 9 to thereby give 8-(6-iodopurin-9-ylmethyl)-10H-pyrazino[2,3-b][1,4]benzothiazine. Next, this product was treated with bis(tert-butyldimethylsiloxymethyl)-2-propyn-1-ol by the same method as the one of Example 1417. The compound thus obtained was further treated with tetrabutylammonium fluoride in accordance with the method of Example 1386-3 to thereby give the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11](Cl)(=[O:13])=[O:12])([O:3][CH3:4])=[O:2].[CH3:15][O:16][C:17]1[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH2:24])[N:18]=1.[O-:25][C:26]#[N:27].[Na+]>CN1CCCC1=O.C(=O)(O)[O-].[Na+]>[CH3:15][O:16][C:17]1[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH:24][C:26]([NH:27][S:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:1]([O:3][CH3:4])=[O:2])(=[O:13])=[O:12])=[O:25])[N:18]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)Cl
Reactant: N#C[O-]
Reactant: COc1nc(C)nc(N)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)nc(OC)n1
Temperature: 25 °C
Yield: 55 %

Procedure:
A slurry of 10.0 grams (0.042 moles) of 2-carbomethoxybenzenesulfonyl chloride, 5.0 grams (0.0357 moles) 4-methoxy-6-methyl-1,3,5-triazin-2-amine and 6.0 grams (0.092 moles) sodium cyanate in 60 ml N-methylpyrrolidinone was stirred 2 hours at 80° C. The reaction was cooled to 25° C., diluted with 200 ml saturated sodium bicarbonate solution, and filtered. The filtrate was acidified with dilute hydrochloric acid and the product was collected by filtration and dried to give the title compound in 55% yield. The IR spectrum of the title compound was identical to that of an authentic sample prepared as taught in U.S. Pat. No. 4,383,113.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1C(C)=CC=CN=1.C(O)(=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C=CCCCC.C1(C)C=CC=CC=1>>[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:8])[CH2:22][CH2:23][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=C(O)c1ccccc1
Reactant: O=Cc1ccccc1
Agent: Cc1cccnc1N
Solvent: Cc1ccccc1
Solvent: C=CCCCC
Product: CCCCCCC(=O)c1ccccc1
Temperature: 130 °C
Reaction time: 0.04 h

Procedure:
Under the same reaction procedure and conditions as in Example 1 (benzaldehyde 0.5 mmol, 2-amino-3-picoline 0.1 mmol, bezoic acid 0.03 mmol, 1-hexene 2.5 mmol, toluene 0.87 mmol), various kinds of amines 0.3 mmol as shown in the following table 5, were added to each 500 ml pressure reactor. The mixture was stirred at normal temperature for 2-3 minutes and then combined with Rh(PPh3)3Cl 0.01 mmol. While the reactor was stopped with a stopper, the reactants were heated at 130° C. for 1 hour with stirring. After completion of the reaction, column chromatography was conducted to determine the yields of heptanophenone, products according to various amines. The results are given in Table 5, below.
Reaction SMILES: [C:1]1([C:7]([CH:9](Br)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22](/[CH:25]=[N:26]/[NH:27][C:28](=[NH:30])[NH2:29])=[CH:21][CH:20]=1>C(O)C>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22](/[CH:25]=[N:26]/[N:27]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:29]=[C:28]2[NH2:30])=[CH:21][CH:20]=1
Reactant: COc1ccc(/C=N/NC(=N)N)cc1
Reactant: O=C(c1ccccc1)C(Br)c1ccccc1
Solvent: CCO
Product: COc1ccc(/C=N/n2c(N)nc(-c3ccccc3)c2-c2ccccc2)cc1
Temperature: 25 °C
Yield: 68.1 %

Procedure:
A solution of desyl bromide (1.72 g, 6.26 mmol), and 2-[(E)-1-(4-methoxyphenyl) methylidene]-1-hydrazinecarboximidamide (2.4 g, 12.5 mmol) was heated at reflux in ethanol (10 mL) for 2 h. The mixture was cooled at room temperature for additional 10 h, and a yellow precipitate formed. The yellow precipitate was filtered, washed with hot water and recrystallized from ethanol to give N1-[(E)-1-(4-methoxyphenyl)methylidene]-4,5-diphenyl-1H-1,2-imidazolediamine 3 (1.57 g, 68%) as a yellow solid.