Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[N:26][CH:27]=[N:28][CH:29]=3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([S:38](Cl)(=[O:40])=[O:39])[CH:33]=1>>[C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([S:38]([C:34]2[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=2)(=[O:40])=[O:39])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:29]=[N:28][CH:27]=[N:26][CH:25]=3)=[CH:22][CH:23]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-c3cncnc3)cc2)c1
Agent: Cl
Product: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-c3cncnc3)cc2)S(=O)(=O)c2cccnc2)c1

Procedure:
The title compound of Step B was prepared from {3-[(4-pyrimidin-5-yl-benzylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester of Step A and pyridine-3-sulfonyl chloride hydrochloride, of Preparation 2, followed the method described in Example 3, Step B 1H NMR (400 MHz, CDCl3) δ 9.19 (s, 1H), 9.05 (s, 1H), 8.89 (s, 2H), 8.79 (dd, 1H), 8.06 (m, 1H), 7.65 (m, 1H), 7.44 (m, 2H), 7.24 (m, 2H), 7.12 (t, 1H), 6.74 (dd, 1H), 6.66 (m, 2H), 4.42 (s, 2H), 4.39 (s, 2H), 4.34 (s, 2H), 1.47 (s, 9H); MS 547 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[S:18][C:19]2[CH:25]=[C:24]([NH:26][C:27](=[O:39])[C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=3)[CH:23]=[CH:22][C:20]=2[N:21]=1.O1CCOCC1>CN(C)C=O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][N:3]=[C:2]2[NH:16][C:17]1[S:18][C:19]2[CH:25]=[C:24]([NH:26][C:27](=[O:39])[C:28]3[CH:29]=[CH:30][C:31]([O:34][C:35]([F:38])([F:36])[F:37])=[CH:32][CH:33]=3)[CH:23]=[CH:22][C:20]=2[N:21]=1
Reactant: Nc1nc2ccc(NC(=O)c3ccc(OC(F)(F)F)cc3)cc2s1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3nc4ccc(NC(=O)c5ccc(OC(F)(F)F)cc5)cc4s3)c2cc1OC

Procedure:
N-[2-(6,7-Dimethoxyquinazolin-4-ylamino)-benzothiazol-6-yl]-4-trifluoromethoxybenzamide was prepared from 4-chloro-6,7-dimethoxyquinazoline (44.9 mg, 0.2 mmol) and N-(2-aminobenzothiazol-6-yl)-4-trifluoromethoxybenzamide (Intermediate 2, 71 mg, 0.2 mmol) according to GP 1. Dimethylformamide was used as a solvent instead of dioxane. After removal of the solvent in vacuo, the residue was subjected to silica gel chromatography applying a dichloromethane-methanol gradient. The product was then further purified by recrystallisation from dichloromethane (3 mL) to obtain a yellow solid (10 mg, 19 μmol, 9%). LC/ESI-MS: m/z=542 [M+H]+; m/z=540 [M−H]−; Rt=3.87 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([CH2:15][CH2:16][CH2:17][CH:18]=[O:19])[C:13]([CH2:20][CH2:21][CH3:22])=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1.[CH3:23][Mg]I.Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([CH2:15][CH2:16][CH2:17][CH:18]([OH:19])[CH3:23])[C:13]([CH2:20][CH2:21][CH3:22])=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1
Reactant: CCCc1nc2cnc3cc(Br)ccc3c2n1CCCC=O
Reactant: C[Mg]I
Agent: Cl
Solvent: C1CCOC1
Product: CCCc1nc2cnc3cc(Br)ccc3c2n1CCCC(C)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
4-(7-Bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyraldehyde (2.77 g, 7.68 mmol) was dissolved in THF (75 mL), stirred at ambient temperature for 30 minutes, and cooled to 0° C. Methylmagnesium iodide (3.33 mL, 9.99 mmol, 3 M in diethyl ether) was added over 5 minutes. The reaction mixture was allowed to warm to ambient temperature. After 2 hours, 10% hydrochloric acid was added and the reaction mixture was concentrated under reduced pressure. The residue was neutralized with saturated aqueous sodium bicarbonate, extracted in 10% methanol in dichloromethane, dried over magnesium sulfate and concentrated under reduced pressure to provide 2.6 g of 5-(7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-ol as an orange-brown solid.
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]([O:6][CH:7]([CH3:16])[CH2:8][NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[CH:4][CH:3]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC>[CH3:19][O:20][C:21]1[CH:26]=[C:25]([C:2]2[CH:18]=[CH:17][C:5]([O:6][CH:7]([CH3:16])[CH2:8][NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[CH:4][CH:3]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: CC(CNS(=O)(=O)C(C)C)Oc1ccc(Br)cc1
Reactant: COc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cccc(-c2ccc(OC(C)CNS(=O)(=O)C(C)C)cc2)c1
Yield: 35.1 %

Procedure:
The title compound (110 mg, 35%, white foam) was prepared from [2-(4-bromophenoxy)propyl][(methylethyl)sulfonyl]amine (290 mg, 0.862 mmol, prepared in example 1), 3-methoxybenzeneboronic acid (160 mg, 1.053 mmol), dichlorobis(triphenylphosphine)palladium(II) (25 mg, 0.036 mmol), 2 M sodium carbonate (310 mg in 1.5 mL water), and 1,2-dimethoxyethane (5.75 mL) in a manner analogous to the procedure described in Example 8. The crude material was purified utilizing a Chromatotron® with a 2000 μm rotor in a 1:1 hexane:ethyl acetate solvent system, yielding 350 mg of a co-eluting mixture of unreacted starting material and title compound. This mixture was further purified by reverse phase chromatography on a Vydac C-18 column on a gradient of 5 to 70% of 0.1% trifluoroacetic acid/acetonitrile in water over 45 minutes at 200 mL/min elution rate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:9](O)[C:10]=1[OH:11])=[O:5])[CH3:2]>OS(O)(=O)=O.[Rh]>[CH2:1]([O:3][C:4]([CH:6]1[CH:10]([OH:11])[CH2:9][CH:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[NH:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c(C(=O)OCC)c(O)c1O
Agent: [Rh]
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1CC(O)C(C(=O)OCC)N1
Reaction time: 8 h

Procedure:
2,5-Bis-ethoxycarbonyl-3,4-dihydroxypyrrol (1.0 g, 4.1 mmol) was dissolved in ethanolic H2SO4 (3%) (50 ml). Rhodium on carbon (5 %) (1.0 g) was added and the reduction reaction was allowed to run under hydrogen (9.4 bar) at 80° C. overnight. The catalyst was filtered off and the solvent evaporated. The reaction mixture was dissolved in water, the pH was adjusted with Na2CO3, and extracted with dichloromethane. The crude mixture was chromatographed on silica and the title product was isolated. Yield: 0.2 g (21 %), FAB-MS: 232 (M+1).
Reaction SMILES: [Cl-:1].[Li+].[F:3][C:4]([F:24])([C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])[CH2:5]OS(C1C=CC(C)=CC=1)(=O)=O>CN1CCCC1=O>[Cl:1][CH2:5][C:4]([F:24])([F:3])[C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19]
Reactant: [Cl-]
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)C(F)(F)C(F)(F)F)cc1
Agent: [Li+]
Solvent: CN1CCCC1=O
Product: FC(F)(F)C(F)(F)C(F)(F)CCl

Procedure:
For example, to prepare 1,1-dichloro-2,2,3,3,4,4,4-heptafluorobutane, 2,2,3,3,4,4,4-heptafluorobutanol and p-toluenesulfonyl chloride are reacted to form 2,2,3,3,4,4,4-heptafluorobutyl-p-toluenesulfonate. Then, N-methylpyrrolidone, lithium chloride, and the 2,2,3,3,4,4,4-heptafluorobutyl-p-toluenesulfonate are reacted to form 1-chloro-2,2,3,3,4,4,4-heptafluorobutane. Finally, chlorine and the 1-chloro-2,2,3,3,4,4,4-heptafluorobutane are reacted to form the 1,1-dichloro-2,2,3,3,4,4,4-heptafluorobutane.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]1([C@H:19]([N:21]2[CH2:26][CH2:25][O:24][C@@H:23]([C:27]3[CH:35]=[CH:34][C:30]([C:31]([OH:33])=O)=[CH:29][CH:28]=3)[CH2:22]2)[CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>ClCCl>[N:36]1([C:31]([C:30]2[CH:34]=[CH:35][C:27]([C@@H:23]3[O:24][CH2:25][CH2:26][N:21]([C@@H:19]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH3:20])[CH2:22]3)=[CH:28][CH:29]=2)=[O:33])[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1
Reactant: C1COCCN1
Reactant: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(C(=O)O)cc2)C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(C(=O)N3CCOCC3)cc2)C1
Reaction time: 2 h
Yield: 61.1 %

Procedure:
1,1′-Carbonyldiimidazole (357 mg, 2.20 mmol) was added to a solution of 4-[(2S)-4-((1R)-1-phenylethyl)-morpholin-2-yl]-benzoic acid (623 mg, 2.00 mmol) in dichloromethane at 0° C. After stirring for 2 hours, morpholine (0.35 ml, 4.0 mmol) was added to the reaction mixture. After stirring over night, the resulting suspension was concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to afford morpholin-4-yl-{4-[(2S)-4-((1R)-1-phenylethyl)-morpholin-2-yl]-phenyl}-methanone (465 mg, 60%.) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@@:8]([NH:13][S@@:14]([C:16]([CH3:19])([CH3:18])[CH3:17])=[O:15])([CH2:10][CH2:11][OH:12])[CH3:9])[CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@@:8]([NH:13][S@@:14]([C:16]([CH3:19])([CH3:18])[CH3:17])=[O:15])([CH2:10][CH:11]=[O:12])[CH3:9])[CH:7]=1
Reactant: CC(C)(C)[S@@](=O)N[C@@](C)(CCO)c1cc(Br)ccc1F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Product: CC(C)(C)[S@@](=O)N[C@@](C)(CC=O)c1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.5 %

Procedure:
A 100 mL flask containing (R)-N-((S)-2-(5-Bromo-2-fluorophenyl)-4-hydroxybutan-2-yl)-2-methylpropane-2-sulfinamide (4c, 2.472 g, 6.75 mmol) under nitrogen was placed in a water bath and treated with Dess-Martin periodinane (Aldrich; 0.3 M in CH2Cl2; 25 mL, 7.50 mmol). The mixture was stirred at ambient temperature for 3 h, after which the reaction was quenched with saturated aqueous sodium thiosulfate solution (7.5 mL) and stirred for 15 min. The product was extracted into CH2Cl2 from saturated aqueous NaHCO3, dried over Na2SO4, concentrated, and purified by chromatography on silica gel [Gradient: 20%→100% EtOAc/hexane] to give (R)-N-((S)-2-(5-bromo-2-fluorophenyl)-4-oxobutan-2-yl)-2-methylpropane-2-sulfinamide (2.03 g, 5.57 mmol) as a colorless gum. MS m/z=365.9 [M+H]+. Calculated for C14H19BrFNO2S: 364.3
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=2)[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[NH:9]1)=[O:7])(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[Cl:20][C:15]1[CH:14]=[C:13]([CH:12]2[C:11]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH3:34])([CH3:35])[CH3:33])[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][C:16]=1[F:19]
Reactant: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2ccc(F)c(Cl)c2)C1(C#N)c1ccc(Cl)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)O)C(c2ccc(F)c(Cl)c2)C1(C#N)c1ccc(Cl)cc1F
Yield: 90 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 69b (1 g, 1.9 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1 g, 90%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C:10](=[CH:11][C:12]3[C:17]2=[N:16][C:15]([CH3:22])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:23]N1C(=O)CCC1=O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH3:22])=[C:14]([Cl:23])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1ccc2cc3n(c2n1)[C@H](C)CN(C(=O)OC(C)(C)C)C3
Solvent: C1CCOC1
Product: Cc1nc2c(cc1Cl)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21
Reaction time: 18 h

Procedure:
To a solution of 0.20 g (0.66 mmol) (R)-4,6-dimethyl-3,4-dihydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester in 2 mL tetrahydrofuran was added 92.1 μg (0.69 mmol) N-chlorosuccinimide. The reaction was stirred at 50 deg C. for 18 h, then the solvent was evaporated and the residue was purified by column chromatography on silica gel (0.032–0.063 mm) with ethyl acetate:dichloromethane (1:19) as eluant.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=[N:3]1.S(Cl)(Cl)=O.[NH2:14][C:15]1[CH:16]=[C:17]([CH:30]=[CH:31][CH:32]=1)[C:18]([C:20]1[CH:28]=[C:27]2[C:23]([CH2:24][C:25](=[O:29])[NH:26]2)=[CH:22][CH:21]=1)=[O:19]>C1COCC1>[O:29]=[C:25]1[CH2:24][C:23]2[C:27](=[CH:28][C:20]([C:18]([C:17]3[CH:16]=[C:15]([NH:14][C:7]([C:6]4[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=4)=[O:9])[CH:32]=[CH:31][CH:30]=3)=[O:19])=[CH:21][CH:22]=2)[NH:26]1
Reactant: Cn1nccc1C(=O)O
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: Cn1nccc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Temperature: 79 °C
Reaction time: 2 h
Yield: 55.9 %

Procedure:
A dry 25 mL flask was charged with 2-Methyl-2H-pyrazole-3-carboxylic acid (0.110 g, 0.873 mmol) and thionyl chloride (5 mL) and allowed to stir at 79° C. for 2 h. The thionyl chloride was then removed by concentration in vacuo. The crude acid chloride was cooled to room temperature, and then dissolved in THF (5 mL). 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 0.200 g, 0.794 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux for 2 h. The reaction mixture was then allowed to cool to room temperature. The room temperature reaction mixture was concentrated in vacuo, and the crude residue was dissolved in EtOH (5 mL). The ethanolic solution was treated with 1M NaOH(aq) (2 mL) and stirred for 30 min. The basic solution was acidified to a pH of 1 with 1M HCl(aq) yielding a tan precipitate. The tan solids were filtered to afford the pure 2-Methyl-2H-pyrazole-3-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.160 g, 0.444 mmol, 56%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([CH3:11])=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1.CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>CN(C)C=O>[CH3:17][N:18]([CH3:20])/[CH:19]=[CH:11]/[C:6]1[CH:7]=[C:8]([O:9][CH3:10])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[N+:12]([O-:14])=[O:13]
Reactant: COc1cc(C)c([N+](=O)[O-])cc1OC
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: COc1cc(/C=C/N(C)C)c([N+](=O)[O-])cc1OC

Procedure:
A 1-l. three-necked flask fitted with a thermometer and a 15-cm. Vigreux column connected to a descending condenser with a receiver and nitrogen inlet was charged with 98.6 g. of 4,5-dimethoxy-2-nitrotoluene, 500 ml. of N,N-dimethylformamide, and 120 g. of N,N-dimethylformamide dimethyl acetal. The reaction temperature was maintained at 140° for 42 hours. The volatile compounds were removed by vacuum distillation at 25°/0.1 mm. to give a solid residue of crude trans-β-dimethylamino-4,5-dimethoxy-2-nitrostyrene.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[S:9])[O:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH2:19]([CH:26]1[CH2:31][CH2:30][N:29]([C:32](=[O:36])[C:33](Cl)=[O:34])[CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)(Cl)Cl>[CH2:19]([CH:26]1[CH2:27][CH2:28][N:29]([C:32](=[O:36])[C:33]([NH:1][C:2]2[CH:11]=[CH:10][C:5]3[NH:6][C:7](=[S:9])[O:8][C:4]=3[CH:3]=2)=[O:34])[CH2:30][CH2:31]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Nc1ccc2[nH]c(=S)oc2c1
Reactant: O=C(Cl)C(=O)N1CCC(Cc2ccccc2)CC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2[nH]c(=S)oc2c1)C(=O)N1CCC(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
To a stirred solution of 0.3 g (1.8 mmol) of 6-amino-3H-benzoxazole-2-thione [J. Org. Chem., 19; 758. (1954)] and 0.6 ml (4.3 mmol) of triethylamine in 20 ml of chloroform 0.5 g (1.8 mmol) of (4-benzyl-piperidine-1-yl)-oxo-acetyl chloride (Example 38c) in 10 ml of chloroform is added dropwise at 0° C. The reaction mixture is stirred at room temperature for 1 hour, then washed with water and the organic layer is concentrated. The residue is purified by column chromatography using Kieselgel 60 (Merck) as adsorbent and toluene:methanol=4:1 as eluent to yield 0.46 g (61.9%) of the title compound. Melting Point: 203° C. (isopropanol)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[C:6]([CH:24]=[O:25])=[C:5]2[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[CH3:32][Mg]Br.O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:18][CH:19]=1)[C:6]([CH:24]([OH:25])[CH3:32])=[C:5]2[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CS(=O)(=O)c1ccc(Cn2c(C=O)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Reactant: C[Mg]Br
Solvent: O
Solvent: C1CCOC1
Product: CC(O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1
Reaction time: 0.17 h

Procedure:
To a solution of 6-bromo-2-(4-methanesulfonylbenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carbaldehyde (500 mg) in THF (10 ml) was added dropwise a solution of methyl magnesium bromide in THF (3M, 0.4 ml) at room temperature, and the mixture was stirred for 10 min. The reaction mixture was added to water and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was crystallized from diisopropyl ether to give the title compound (490 mg).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>C(Cl)Cl>[OH:9][CH2:8][CH2:7][N:1]1[CH2:6][CH2:5][N:4]([C:10](=[O:12])[CH3:11])[CH2:3][CH2:2]1
Reactant: CC(=O)OC(C)=O
Reactant: OCCN1CCNCC1
Solvent: ClCCl
Product: CC(=O)N1CCN(CCO)CC1
Yield: 65 %

Procedure:
A solution of 2-(1-piperazinyl)-1-ethanol (6.5 g 0.05 mol) in DCM (5 mL) was treated with acetic acid anhydride (5.1 g, 0.05 mol), added dropwise. During addition, the reaction temperature rose from 22 to 60° C. The reaction mixture was evaporated several times with toluene to yield 5.6 g (65%) of the sub-title compound.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].C(Cl)Cl.C(OC([N:18]1[CH2:23][CH2:22][CH:21]([NH:24][C:25]([C@H:27]2[C@H:31]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=3[F:39])[C@:30]([C:42]3[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][C:43]=3[F:49])([C:40]#[N:41])[C@H:29]([CH2:50][C:51]([CH3:54])([CH3:53])[CH3:52])[NH:28]2)=[O:26])[CH2:20][CH2:19]1)=O)(C)(C)C>>[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[NH:18]1[CH2:19][CH2:20][CH:21]([NH:24][C:25]([CH:27]2[CH:31]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=3[F:39])[C:30]([C:42]3[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][C:43]=3[F:49])([C:40]#[N:41])[CH:29]([CH2:50][C:51]([CH3:54])([CH3:53])[CH3:52])[NH:28]2)=[O:26])[CH2:22][CH2:23]1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)NC2CCNCC2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of a mixture of TFA/CH2Cl2 (5 mL/10 mL), rac-4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester (example 92, 510 mg, 0.79 mmol) was added and the mixture was stirred at rt for 15 min. The solvent was removed and the residue dried to give a white solid after precipation from methylene chloride and ethyl acetate. 492 mg.
Reaction SMILES: C[O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][CH:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:28])[C:15]([NH:17][C:18]3[CH:27]=[CH:26][C:21]4[NH:22][C:23](=[O:25])[O:24][C:20]=4[CH:19]=3)=[O:16])[CH2:10][CH2:9]2)=[CH:5][CH:4]=1>C(OCC)C>[OH:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][CH:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:28])[C:15]([NH:17][C:18]3[CH:27]=[CH:26][C:21]4[NH:22][C:23](=[O:25])[O:24][C:20]=4[CH:19]=3)=[O:16])[CH2:10][CH2:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CC2CCN(C(=O)C(=O)Nc3ccc4[nH]c(=O)oc4c3)CC2)cc1
Solvent: CCOCC
Product: O=C(Nc1ccc2[nH]c(=O)oc2c1)C(=O)N1CCC(Cc2ccc(O)cc2)CC1

Procedure:
The title compound is prepared from 2-[4-(4-methoxy-benzyl)-piperidin-1-yl]-2-oxo-N-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-acetamide (Example 122) according to the method described in Example 192. Melting Point:235-239° C. (diethylether)
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:13]=[C:6]2[N:7]=[C:8]([CH3:12])[CH:9]=[C:10]([SH:11])[N:5]2[N:4]=1.CC(O[CH2:18][C:19]1[CH2:28][S:27][C@@H:22]2[C@H:23]([NH2:26])[C:24](=[O:25])[N:21]2[C:20]=1[C:29]([OH:31])=[O:30])=O.O.N>C(#N)C>[NH2:26][CH:23]1[C:24](=[O:25])[N:21]2[C:20]([C:29]([OH:31])=[O:30])=[C:19]([CH2:18][S:11][C:10]3[N:5]4[N:4]=[C:3]([CH2:2][OH:1])[N:13]=[C:6]4[N:7]=[C:8]([CH3:12])[CH:9]=3)[CH2:28][S:27][C@H:22]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: Cc1cc(S)n2nc(CO)nc2n1
Agent: N
Solvent: CC#N
Solvent: O
Product: Cc1cc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)n2nc(CO)nc2n1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
In 130 ml of acetonitrile were suspended 11.08 g of 2- hydroxymethyl-7-mercapto-5-methyl-s-triazolo[1,5-a]pyrimidine and 15.38 g of 7-aminocephalosporanic acid, and 24.6 ml of boron trifluoride-ethy: ether complex was added thereto and the mixture was stirred at 50° C. for 2 hours. After the reaction mixture was ice-cooled, 300 ml of water was added thereto and pH thereof was adjusted to 2 with conc. aqueous ammonia. The precipitated crystals were collected by filtration, washed with water and with acetone, and then dried to obtain 18.5 of the title compound.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]1=[C:13](Br)[C:14](=[C:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:26])O)[CH3:2].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]1=[C:13]=[C:14]=[C:16]1[C:17](=[O:26])[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:24]1=[O:25])[CH3:2]
Reactant: CCN1C(=C(Br)C(O)=C2C(=O)c3ccccc3C2=O)C=Cc2ccccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCN1C(=C=C=C2C(=O)c3ccccc3C2=O)C=Cc2ccccc21
Reaction time: 0.08 h

Procedure:
The product of Example 14 (1.33 g, 0.002 mol) and triethylamine (1.0 g, 0.01 mol) in dry acetonitrile (25 ml) is stirred as triphenylphosphine (1.15 g, 0.0044 mol) is added in one lot. After stirring for a further 5 minutes, the dye separates, is collected and washed with acetonitrile, to yield 0.34 g (53 %) of crude dye, which is purified by recrystallization from acetonitrile, mp. indistinct.
Reaction SMILES: C([BH3-])#N.[Na+].[C:5]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([CH3:20])[CH2:17][NH:18][CH3:19])=[CH:11][CH:10]=1)([CH3:8])([CH3:7])[CH3:6].[CH:21]([C:23]1[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=1)=O.C(O)(=O)C>CO>[C:5]([C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH:16]([CH3:20])[CH2:17][N:18]([CH2:21][C:23]2[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=2)[CH3:19])=[CH:13][CH:14]=1)([CH3:8])([CH3:6])[CH3:7]
Reactant: Cn1cc(C=O)cn1
Reactant: CNCC(C)Cc1ccc(C(C)(C)C)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(Cc1ccc(C(C)(C)C)cc1)CN(C)Cc1cnn(C)c1
Reaction time: 8 h

Procedure:
Route B-2: After suspending 200 mg (3.2 mmol) of sodium cyanoborohydride in 2 ml of absolute methanol, 380 mg (1.7 mmol) of 3-(4-t-butylphenyl)-N,2-dimethylpropylamine (IV-1) was added thereto. Subsequently, to this was added a solution of 170 mg (1.6 mmol) 4-formyl-1-methylpyrazole/2 ml absolute methanol by portions, the pH was adjusted to 7 with acetic acid, and then stirring was conducted at room temperature for 8 h.