Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:18]3[C:13]([CH:14]=[C:15]([O:19][CH2:20][C:21]4[CH:30]=[CH:29][C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[N:22]=4)[CH:16]=[CH:17]3)=[C:12]([C:31](=[O:37])[CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34])[C:11]=2[CH2:38][C:39]([CH3:46])([CH3:45])[C:40]([O:42]CC)=[O:41])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[N:18]3[C:13]([CH:14]=[C:15]([O:19][CH2:20][C:21]4[CH:30]=[CH:29][C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[N:22]=4)[CH:16]=[CH:17]3)=[C:12]([C:31](=[O:37])[CH2:32][C:33]([CH3:35])([CH3:36])[CH3:34])[C:11]=2[CH2:38][C:39]([CH3:46])([CH3:45])[C:40]([OH:42])=[O:41])=[O:9])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(C)Cc1c(C(=O)CC(C)(C)C)c2cc(OCc3ccc4ccccc4n3)ccn2c1C(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)CC(=O)c1c(CC(C)(C)C(=O)O)c(C(=O)c2ccc(Cl)cc2)n2ccc(OCc3ccc4ccccc4n3)cc12
Temperature: 23 °C
Yield: 21.8 %

Procedure:
A solution of ethyl 3-{3-[(4-chlorophenyl)carbonyl]-1-(3,3-dimethylbutanoyl)-7-(quinolin-2-ylmethoxy)indolizin-2-yl}-2,2-dimethylpropanoate (39 mg, 0.06 mmol) in THF (1 mL), MeOH (1 mL), and 6M aqueous NaOH (1 mL) is heated at 70° C. for 2.5 h then cooled to 23° C. and acidified to pH=1 with 6 M aqueous HCl. The mixture is partitioned between CH2Cl2 and brine then the organics are collected and dried with MgSO4, filtered, and concentrated in vacuo. The crude is purified by flash chromatography (SiO2, CH2Cl2 to 10% MeOH in CH2Cl2) to give the title compound (8 mg, 22%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([O:15][CH:16]3[CH2:19][CH2:18][CH2:17]3)[CH:10]=2)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:26]([C:28]1[CH:29]=[C:30]([S:35]([N:38]([CH2:44][C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][C:46]=2[O:53][CH3:54])[C:39]2[S:43][N:42]=[CH:41][N:40]=2)(=[O:37])=[O:36])[CH:31]=[CH:32][C:33]=1F)#[N:27]>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:33]2[CH:32]=[CH:31][C:30]([S:35]([N:38]([CH2:44][C:45]3[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][C:46]=3[O:53][CH3:54])[C:39]3[S:43][N:42]=[CH:41][N:40]=3)(=[O:37])=[O:36])=[CH:29][C:28]=2[C:26]#[N:27])=[C:4]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([O:15][CH:16]3[CH2:19][CH2:18][CH2:17]3)[CH:10]=2)[CH:3]=1
Reactant: Oc1ccc(Cl)cc1-c1ccnc(OC2CCC2)c1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(F)c(C#N)c2)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(Oc3ccc(Cl)cc3-c3ccnc(OC4CCC4)c3)c(C#N)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-Chloro-2-[2-(cyclobutyloxy)pyridin-4-yl]phenol, (Preparation 862, 20.5 mg, 0.000074 mol) was dissolved in dimethylsulphoxide (1 mL). Potassium carbonate (24.6 mg, 0.00018 mol) was added and the reaction stirred for 10 minutes at room temperature. 3-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide, (Preparation 68, 32.2 mg, 0.000074 mol) was added and the reaction was stirred at room temperature for 15 hours under nitrogen. The reaction was partitioned between a saturated aqueous sodium chloride solution (10 mL) and ethyl acetate (10 mL), the organic layer was washed with water (30 mL). The organic extracts were dried over anhydrous magnesium sulphate, filtered and the solvent removed in vacuo to give a colourless foam (56 mg). The material was purified using an ISCO™ companion (4 g column, eluting with 100% heptane to 7:3 heptane/ethyl acetate). Fractions containing product were combined and concentrated in vacuo to obtain the title compound as a colourless oil (45 mg).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[CH2:15][OH:16])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.N1C=CC=CC=1.[C:30](Cl)(=[O:34])[C:31]([CH3:33])=[CH2:32]>C1COCC1>[C:30]([O:16][CH2:15][C:13]1[C:12]2[C:7]([CH:6]=[C:5]3[C:14]=1[CH:1]=[CH:2][CH:3]=[CH:4]3)=[CH:8][CH:9]=[CH:10][CH:11]=2)(=[O:34])[C:31]([CH3:33])=[CH2:32]
Reactant: C=C(C)C(=O)Cl
Reactant: OCc1c2ccccc2cc2ccccc12
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C=C(C)C(=O)OCc1c2ccccc2cc2ccccc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
9-Anthracenemethanol (30 g) was dissolved in freshly distilled THF (150 mL). To the solution triethylamine (30 mL) and pyridine (20 mL) were added and the mixture was cooled down to 0° C. Then methacryloyl chloride (21 mL) was added dropwise. After the addition, ice-water bath was removed and the mixture was stirred for 1 hour. After water (75 mL) was added to the reaction flask, the solution was transferred into separatory funnel and extracted with diethyl ether (500 mL). The extract was washed with aqueous HCl (1 M, 150 mL), aqueous NaHCO3 (5%, 150 mL), and brine (150 mL), respectively. The solvent was evaporated in vacuum and recrystallized with methanol. (Product: 21 g) 1H NMR (500 MHz, CDCl3): δ 8.55 (s, 1H), 8.41 (d, J=8.9 Hz, 2H), 8.07 (d, J=8.4 Hz, 2H), 7.61 (t, J=7.7 Hz, 2H), 7.53 (t, J=7.9 Hz, 2H), 6.25 (s, 2H), 6.08 (s, 1H), 5.54 (s, 1H), 1.95 (s, 3H) ppm.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.[Li]CCCC.[S:17](Cl)([Cl:20])(=[O:19])=[O:18]>C1COCC1>[N:9]1[CH:10]=[CH:11][C:6]([C:2]2[S:1][C:5]([S:17]([Cl:20])(=[O:19])=[O:18])=[CH:4][CH:3]=2)=[CH:7][CH:8]=1
Reactant: c1csc(-c2ccncc2)c1
Reactant: O=S(=O)(Cl)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=S(=O)(Cl)c1ccc(-c2ccncc2)s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63.3 %

Procedure:
To a solution of 4-thiophen-2-yl-pyridine (3.33 g, 20.7 mmol) in THF (137 mL) at −78° C. is added n-BuLi (8.7 mL of a 2.5 M solution in hexanes, 21.7 mmol). After stirring for 15 minutes, SO2 gas is bubbled through the solution for 30 minutes. The solution is then allowed to warm to room temperature and stirred overnight. The solution is concentrated to dryness and the resulting solid is suspended in hexane (100 ml). To the ice-cooled solution is added sulfuryl chloride (1.7 mL. 21.7 mmol). The ice bath is removed and the suspension is stirred for 2 hours. The mixture is then concentrated to dryness and diluted with ethyl acetate and washed with saturated NaHCO3 (aq), water and brine. The organic layer is dried over MgSO4, filtered and concentrated to give a yellow solid as the title product (3.39 g, 13.1 mmol) which is used in the subsequent step without further purification.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[O:6][CH:7]=[CH:8][CH:9]=1)C.[Li]CCCC.[CH3:18][S:19]SC.Cl>C1COCC1>[CH3:18][S:19][C:7]1[O:6][C:5]([CH:4]=[O:3])=[CH:9][CH:8]=1
Reactant: CSSC
Reactant: CCOC(OCC)c1ccco1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1ccc(C=O)o1
Temperature: -78 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
To a solution of 2-(diethoxymethyl)furan (2.00 g, 11.75 mmol) in dry THF (8 mL) was added a solution of n-BuLi (1.6 M in Hexane) (8.80 mL, 14.1 mmol) at −78° C. The resulting mixture was stirred at −78° C. for 1 h and treated with methyldisulfide (1.06 mL, 11.75 mmol). The reaction mixture was stirred at −78° C. for 30 min followed by warming to 0° C. for 1 hour. HCl (1N) (20 mL) was added and the organic material was extracted with ether (2×50 mL). The combined organic fractions were dried (MgSO4) and concentrated in vacuo to afford 1.58 g (94%) of crude title compound. LCMS (+ESI, M+H+) m/z 143.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:4][C:3]=1[OH:14].C([O-])([O-])=O.[Cs+].[Cs+].[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[CH2:26]Br.CCOCC>CC(C)=O>[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[CH2:26][O:14][C:3]1[CH:4]=[C:5]([NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1ccc(Nc2nccs2)cc1O
Reactant: BrCc1ccco1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: Cc1ccc(Nc2nccs2)cc1OCc1ccco1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 36 %

Procedure:
Following the general procedure for O-alkylation, Method B, a mixture of 2-methyl-5-(thiazol-2-ylamino)phenol (100 mg, 0.48 mmol) and Cs2CO3 (158 mg, 0.48 mmol) in acetone (4.4 mL) was treated with a freshly prepared solution of 2-furylbromomethane in ether (0.85 mL, 0.44 mmol) at room temperature. After 2 h Cs2CO3 (150 mg, 0.46 mmol) was added and stirred for 5.5 h at rt. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 3/1) in 36% yield (50 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]([CH3:17])([CH3:16])[CH2:5]/[CH:6]=[N:7]/[CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[Cl:19][C:20]1[C:21]([F:38])=[C:22](/[CH:26]=[C:27](/[C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=2[F:37])\[C:28]#[N:29])[CH:23]=[CH:24][CH:25]=1.C(N(CC)CC)C.C1CCN2C(=NCCC2)CC1>ClCCl.C(O)(C)(C)C>[C:12]([O:11][C:9]([CH:8]1[CH:26]([C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([Cl:19])[C:21]=2[F:38])[C:27]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=2[F:37])([C:28]#[N:29])[CH:6]([CH2:5][C:4]([C:3]([O:2][CH3:1])=[O:18])([CH3:17])[CH3:16])[NH:7]1)=[O:10])([CH3:13])([CH3:15])[CH3:14]
Reactant: COC(=O)C(C)(C)C/C=N/CC(=O)OC(C)(C)C
Reactant: N#C/C(=C\c1cccc(Cl)c1F)c1ccc(Cl)cc1F
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)CC
Solvent: CC(C)(C)O
Product: COC(=O)C(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 19.7 %

Procedure:
In a manner similar to the method described in Example 100b, 4-[(E)-tert-butoxycarbonylmethylimino]-2,2-dimethyl-butyric acid methyl ester prepared in Example 104a (2.1 g, 8.3 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (2.05 g, 6.7 mmol) prepared in Example 52a, AgF (1.27 g, 10 mmol), and triethylamine (2.3 mL, 17 mmol) in dichloromethane (150 mL) at room temperature for 18 h, followed by the reaction with DBU (2 ml) in tert-butanol (10 mL) at 100° C. for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-methoxycarbonyl-2-methyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white solid (0.75 g, 20%).
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=[CH:5][CH:4]=1)[CH3:2].[C:16]([Li])(C)(C)C.CI>C(OCC)C.O>[CH2:1]([C:3]1[N:8]=[C:7]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]([CH3:16])=[CH:5][CH:4]=1)[CH3:2]
Reactant: [Li]C(C)(C)C
Reactant: CCc1cccc(NC(=O)C(C)(C)C)n1
Solvent: O
Solvent: CCOCC
Solvent: CI
Product: CCc1ccc(C)c(NC(=O)C(C)(C)C)n1
Temperature: -20 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
A solution of N-(6-ethyl-pyridin-2-yl)-2,2-dimethyl-propionamide (24.0 g, 0.116 mol) in diethyl ether (600 mL, 0.2 M) is cooled to −78° C. and treated with tert-butyllithium (144 mL 1.7 M in pentane). After the addition is complete the solution is warmed to −20° C. for 2 h, treated with a solution of methyliodide (23 mL, 0.372 mol) in diethylether (10 mL) and warmed to room temperature. After stirring overnight the reaction is diluted with water, extracted with diethyl ether and dried over MgSO4. The resulting solution is filtered through a short pad of silica gel, concentrated and recrystallized from heptane to give N-(6-ethyl-3-methyl-pyridin-2-yl)-2,2-dimethyl-propionamide (17.6 g, 69%) as an off-white crystalline solid. mp 72-75° C.; Rf 0.43 (50% ethyl acetate in hexanes); 1H NMR (DMSO-d6, 300 MHz) δ 9.48 (s, 1H), 7.53 (d, J=7.8 Hz, 1 H), 7.48 (d, J=7.5 Hz, 1 H), 2.65 (q, J=7.5 Hz, 2 H), 2.02 (s, 3 H), 1.20 (s, 9 H), 1.18 (t, J=7.5 Hz, 3 H); LRMS calcd for C13H20N2O: 220.3; found 220.0 (M)+. Anal. Calcd for C13H20N2O : C, 70.87; H, 9.15; N, 12.72. Found C, 70.70; H, 9.18; N, 12.74.
Reaction SMILES: [CH2:1]([OH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].CN(C1C=CC=CN=1)C.Br[CH2:28][C:29](=[CH2:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31]>C(Cl)Cl>[CH2:1]([O:17][CH2:35][C:29](=[CH2:28])[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C=C(CBr)C(=O)OCC
Reactant: CCCCCCCCCCCCCCCCO
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: C=C(COCCCCCCCCCCCCCCCC)C(=O)OCC
Reaction time: 18 h
Yield: 261.3 %

Procedure:
To a stirred solution of 1.9 g of hexadecanol in 40 ml of methylene chloride containing 700 mg of dimethylaminopyridine is added 500 mg of ethyl 2-bromomethyl-2-propenoate followed by continued stirring for 18 hours. The solvent is evaporated to give 2.4 g of the desired product.
Reaction SMILES: C1COCC1.[C:6]1([CH2:12][C:13](Cl)=[O:14])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH2:16][C:17]1[CH:38]=[CH:37][C:20]([CH2:21][O:22][C:23]2[CH:24]=[C:25]3[C:30](=[CH:31][CH:32]=2)[CH2:29][CH:28]([CH2:33][N:34]([CH3:36])[CH3:35])[CH2:27][CH2:26]3)=[CH:19][CH:18]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.N1C=CC=CC=1>[CH2:12]([C:13]([NH:16][C:17]1[CH:38]=[CH:37][C:20]([CH2:21][O:22][C:23]2[CH:24]=[C:25]3[C:30](=[CH:31][CH:32]=2)[CH2:29][CH:28]([CH2:33][N:34]([CH3:35])[CH3:36])[CH2:27][CH2:26]3)=[CH:19][CH:18]=1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CN(C)CC1CCc2cc(OCc3ccc(N)cc3)ccc2C1
Reactant: O=C(Cl)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CN(C)CC1CCc2cc(OCc3ccc(NC(=O)Cc4ccccc4)cc3)ccc2C1
Reaction time: 0.25 h
Yield: 42.3 %

Procedure:
THF solution (1 ml) of phenylacetyl chloride (200 mg) was added dropwise to pyridine solution (6 ml) of 6-[(4-aminobenzyl)oxy]-2-[(N,N-dimethylamino)methyl]tetralin (300 mg) under ice-cooling, which was stirred for 15 minutes. After stirring at room temperature for further 15 minutes, saturated sodium bicarbonate solution was added to the reaction mixture, and extraction was conducted using ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried, and then concentrated. The residue was purified using alumina column chromatography (development solvent; hexane˜hexane:ethyl acetate=2:1), and recrystallized to give the titled compound (175 mg).
Reaction SMILES: [C:1]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])(=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13].[SiH:21]([Cl:24])([Cl:23])[Cl:22]>>[Cl:22][Si:21]([Cl:24])([Cl:23])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:15][CH2:16][C:17]([F:18])([F:19])[F:20])=[O:14]
Reactant: Cl[SiH](Cl)Cl
Reactant: C=CCCCCCCCCCCC(=O)OCC(F)(F)F
Product: O=C(CCCCCCCCCCCC[Si](Cl)(Cl)Cl)OCC(F)(F)F
Temperature: 80 °C
Reaction time: 22 h

Procedure:
In a heavy-walled tube equipped with a magnetic stir bar, ester (5) (1.18 g, 4.00 mmol, 1.0 equiv.) and H2PtCl6.6H2O (21 mg, 0.14 mmol, 1.0 mol. %) were loaded. The tube was transferred into a glovebox and HSiCl3 (0.82 mL, 8.04 mmol, 2.0 equiv.) was added to the solution. The tube was tightly fastened then removed from the glovebox. The resulting solution was stirred at 80° C. for 22 h behind a protecting shield. Purification was achieved by Kugelrohr distillation under high vacuum and provided 1.16 g (67%) of TTTA (6) as a colorless oil; bp=170-180° C. (0.15 Torr); 1H NMR (400 MHz, CDCl3) δ 4.45 (q, J=8.5 Hz, 2H), 2.41 (t, J=7.4 Hz, 2H), 1.72-1.55 (m, 4H), 1.45-1.22 (m, 18H); 13C NMR (100 MHz, CDCl3) δ 172.4, 123.3 (q, J=275.8 Hz), 60.3 (q, J=36.4 Hz), 33.9, 32.0, 29.8, 29.7, 29.6, 29.5, 29.4, 29.2, 29.1, 24.9, 24.5, 22.5.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(O)(=O)C.[F:27][C:28]([F:48])([F:47])[O:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:40][CH2:39][C:38]3([CH2:45][CH2:44][NH:43][CH2:42][CH2:41]3)[C:37]2=[O:46])=[CH:32][CH:31]=1.[OH:49][C:50]1([C:53](O)=[O:54])[CH2:52][CH2:51]1>>[OH:49][C:50]1([C:53]([N:43]2[CH2:42][CH2:41][C:38]3([C:37](=[O:46])[N:36]([C:33]4[CH:34]=[CH:35][C:30]([O:29][C:28]([F:27])([F:47])[F:48])=[CH:31][CH:32]=4)[CH2:40][CH2:39]3)[CH2:45][CH2:44]2)=[O:54])[CH2:52][CH2:51]1
Reactant: O=C(O)C1(O)CC1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC(=O)O
Product: O=C(N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O)C1(O)CC1

Procedure:
The title compound was prepared in analogy to example 13 step A (using TBTU instead of BOP as the coupling reagent) from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one acetic acid salt (described in example 180 step C) and 1-hydroxy-cyclopropanecarboxylic acid. White solid. MS (ESI): 399.1 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([F:12])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH:13]([C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)=O.S(OS([O-])=O)([O-])=O.[Na+].[Na+]>CN1CCCC1=O>[CH3:22][O:21][C:19](=[O:20])[C:18]1[CH:23]=[CH:24][C:15]([C:13]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[C:10]([F:11])[CH:9]=[C:8]([F:12])[CH:7]=3)[N:1]=2)=[CH:16][CH:17]=1
Reactant: NC(=O)c1cc(F)cc(F)c1N
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: O=S([O-])OS(=O)[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc(-c2nc3c(F)cc(F)cc3c(=O)[nH]2)cc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A solution of 2-amino-3,5-difluoro-benzamide (86.2 mg, 0.50 mmol), methyl 4-formylbenzoate (82.1 mg, 0.50 mmol) and sodium disulfite (97 mg, 0.51 mmol) in N-methyl-pyrrolidone (1 ml) is heated to 150° C. and stirred at this temperature for 16 hours. The reaction mixture is allowed to reach room temperature and poured into ice water. The resulting precipitate is collected by filtration, washed with water and dried under vacuum to afford 4-(6,8-difluoro-4-oxo-3,4-dihydro-quinazolin-2-yl)-benzoic acid methyl ester as brown solid; HPLC/MS 1.88 min (A), [M+H] 316.
Reaction SMILES: [O:1]1[CH:3]2[CH2:4][CH2:5][CH:6]=[CH:7][CH2:8][CH2:9][CH:10]=[CH:11][CH2:12][CH2:13][CH:2]12.[H][H]>[Pd]>[O:1]1[CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:2]12
Reactant: [H][H]
Reactant: C1=CCCC2OC2CCC=CCC1
Agent: [Pd]
Product: C1CCCCCC2OC2CCCC1

Procedure:
As a process for producing cyclododecanone and cyclododecanol by a catalytic reaction of epoxycyclododecane compounds with hydrogen, J. Mol. Catal., Vol 169, pp 95-103 (1991) discloses a catalytic hydrogenating reaction of 2-epoxy-5,9-cyclododecadiene with hydrogen. In this reaction of the reference, 1,2-epoxy-5,9-cyclododecadiene is brought into contact with hydrogen in the presence of a palladium-carrying catalyst at a reaction temperature of 90° C. under a hydrogen gas pressure of 1,275 kPa (13 kg/cm2) on gauge, and epoxycyclododecane is produced as a principal reaction product. Cyclododecanol is produced as a by-product in a yield of 4% and no cyclododecanone is produced. Also, the Draft of 24-th Symposium “Development of Reaction and Synthesis, Nov. 5-6, 1998, pp 68, discloses a process of catalytic reaction of 1,2-epoxy-5,9-cyclododecadiene with hydrogen in the presence of a palladium catalyst at room temperature under the ambient atmospheric pressure. In this process, epoxycyclododecane is produced as a principal product, cyclododecanol is produced, as a by-product, in a yield of 5%, and no cyclododecanone is produced.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:43]1[N:44]=[C:45]([NH:48][CH:49]=[O:50])[S:46][CH:47]=1)[C:5]([NH:7][CH:8]1[C:41](=[O:42])[N:10]2[C:11]([C:25]([O:27]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:26])=[C:12]([CH2:15][S:16][C:17]3[N:21]([CH2:22][C:23]#[CH:24])[N:20]=[N:19][N:18]=3)[CH2:13][S:14][C@H:9]12)=[O:6].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][N:3]=[C:4]([C:43]1[N:44]=[C:45]([NH:48][CH:49]=[O:50])[S:46][CH:47]=1)[C:5]([NH:7][CH:8]1[C:41](=[O:42])[N:10]2[C:11]([C:25]([OH:27])=[O:26])=[C:12]([CH2:15][S:16][C:17]3[N:21]([CH2:22][C:23]#[CH:24])[N:20]=[N:19][N:18]=3)[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: C#CCn1nnnc1SCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC)c3csc(NC=O)n3)[C@H]2SC1
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C#CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC)c3csc(NC=O)n3)[C@H]2SC1
Yield: 68.4 %

Procedure:
To a mixture of benzhydryl 7-[2-methoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-[1-(2-propynyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylate (syn isomer) (2.8 g) in methylene chloride (24 ml) were added anisole (2.8 g) and trifluoroacetic acid (7.5 g) with stirring under ice-cooling and then the resulting mixture was stirred for one hour and 15 minutes at room temperature. After the evaporation of the reaction mixture, to the residue were added water and ethyl acetate. The mixture was adjusted to pH 7.0 with a saturated aqueous solution of sodium carbonate. The aqueous layer was separated and washed with ethyl acetate (×2) and thereto were added ethyl acetate and tetrahydrofuran. The mixture was adjusted to pH 2.0 with 10% hydrochloric acid. The organic layer was separated, washed with water, dried over magnesium sulfate, treated with activated charcoal and evaporated. The residue was pulverized in isopropyl ether, collected by filtration, washed with isopropyl ether and dried to give 7-[2-methoxyimino-2-(2-formamidothiazol- 4-yl)acetamido]-3-[1-(2-propynyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.48 g).
Reaction SMILES: [OH:1][CH2:2][CH:3]([O:6][N:7]1C(=O)C2[C:9](=CC=CC=2)[C:8]1=O)[CH2:4][OH:5].O.NN.[N:21]1[C:30]2[C:25](=[CH:26][C:27]([CH2:31][C:32]3[N:36]4[N:37]=[C:38](C(=O)C)[CH:39]=[CH:40][C:35]4=[N:34][N:33]=3)=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1>>[OH:1][CH2:2][CH:3]([O:6]/[N:7]=[C:8](/[C:35]1[CH:40]=[CH:39][C:38]2[N:33]([C:32]([CH2:31][C:27]3[CH:26]=[C:25]4[C:30](=[CH:29][CH:28]=3)[N:21]=[CH:22][CH:23]=[CH:24]4)=[N:36][N:37]=2)[N:34]=1)\[CH3:9])[CH2:4][OH:5]
Reactant: O=C1c2ccccc2C(=O)N1OC(CO)CO
Reactant: CC(=O)c1ccc2nnc(Cc3ccc4ncccc4c3)n2n1
Agent: NN
Solvent: O
Product: C/C(=N\OC(CO)CO)c1ccc2nnc(Cc3ccc4ncccc4c3)n2n1
Yield: 27.8 %

Procedure:
The title compound (12 mg, 28.6%) was synthesized from 2-(1,3-dihydroxypropan-2-yloxy)isoindoline-1,3-dione (intermediate B) (152 mg, 0.643 mmol, isomer mixture), hydrazine monohydrate (14 mg, 0.27 mmol) and 1-(3-(quinolin-6-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (41.2) (30 mg, 0.11 mmol) using the same procedure as described in the synthesis of example 44. After purification by HPLC (acidic with 0.05% TFA, then neutralized to basic), the title compound was obtained as a white solid. 1H-NMR (400 MHz, CDCl3) δ ppm 8.89 (d, 1H), 8.12 (d, 1H), 8.08 (d, 1H), 7.97 (d, 1H), 7.86 (s, 1H), 7.82 (d, 1H), 7.73 (d, 1H), 7.42 (m, 1H), 4.77 (s, 2H), 4.49 (m, 1H), 4.00 (dd, 4H), 2.33 (s, 3H). LC-MS (method B): [MH]+=393.2, tR=1.708 min.
Reaction SMILES: [CH2:1](I)[CH3:2].[O:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9](=[CH2:13])[C:10]([OH:12])=[O:11].C(N(C(C)C)CC)(C)C>C(#N)C>[O:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9](=[CH2:13])[C:10]([O:12][CH2:1][CH3:2])=[O:11]
Reactant: CCI
Reactant: C=C(C(=O)O)c1ccco1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C=C(C(=O)OCC)c1ccco1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
Ethyl iodide (64 mL, 0.796 mol) was added to furylacrylic acid (100 g, 0.724 mol), diisopropylethyl amine (140 mL, 0.796 mmol), in acetonitrile (1100 mL), and the mixture was heated to 60° C. After 18 h, the dark solution was cooled to room temperature and concentrated in vacuo. The resulting brown sludge was diluted with Et2O (500 mL), washed with 1 N aqueous HCl (2×250 mL), washed with 0.2 N aqueous NaOH (2×250 mL), washed with saturated aqueous NaHCO3 (1×250 mL), dried (MgSO4), filtered, and concentrated to a black oil (114 g, 95%). 1H NMR (DMSO-d6, 300 MHz) δ 7.84 (d, J=1.7 Hz, 1H), 7.46 (d, J=15.6 Hz, 1H), 6.97 (d, J=3.4 Hz, 1H), 6.33 (dd, J=3.4 Hz, J=1.7 Hz, 1H), 6.22 (d, J=15.9 Hz, 1H), 4.17 (q, J=7.1 Hz, 2H), 1.24 (t, J=7.1 Hz, 3H); MS (APCI) m/z 167 (M+H)+.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[NH:16][C:15](=[O:17])[O:14][C:13]([CH3:19])([CH3:18])[C:12]=2[CH:20]=1.[OH:21]O>>[CH3:1][S:2]([CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[NH:16][C:15](=[O:17])[O:14][C:13]([CH3:18])([CH3:19])[C:12]=2[CH:20]=1)=[O:21]
Reactant: OO
Reactant: CSCCCCOc1ccc2c(c1)C(C)(C)OC(=O)N2
Product: CS(=O)CCCCOc1ccc2c(c1)C(C)(C)OC(=O)N2

Procedure:
Prepared analogously to Example 2 from 6-(4-methylmercapto-butoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.