Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20](Cl)=[O:21])=[CH:15][CH:14]=1>>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([C:9]2[CH:10]=[CH:11][C:6]([Cl:5])=[CH:7][CH:8]=2)=[O:21])=[CH:15][CH:14]=1
Reactant: O=C(Cl)Cc1ccc(Br)cc1
Reactant: Clc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(Cc1ccc(Br)cc1)c1ccc(Cl)cc1
Yield: 86 %

Procedure:
To a 100 mL three-necked flask containing AlCl3 (4.797 g; 35.98 mmol) under N2, chlorobenzene (IVd) (36.6 mL; 359.76 mmol) was added in one portion at RT. To this suspension (4-bromo-phenyl)-acetyl chloride (IIIa) (7.0 g; 29.98 mmol) was added in one portion without cooling. Protocol and work-up was then similar with those described above. Title compound was obtained as a white powder (m=7.99 g) in a 86% yield.
Reaction SMILES: C([O:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12][C@@H:13]([O:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[C:28]([CH3:33])[CH:27]=1)[C:14]([N:16]1[C@@H:20]([CH:21]([CH3:23])[CH3:22])[CH2:19][O:18][C:17]1=[O:24])=[O:15])C1C=CC=CC=1>[Pd].CCO>[F:32][C:29]1[CH:30]=[CH:31][C:26]([O:25][C@H:13]([CH2:12][CH2:11][CH2:10][CH2:9][OH:8])[C:14]([N:16]2[C@@H:20]([CH:21]([CH3:23])[CH3:22])[CH2:19][O:18][C:17]2=[O:24])=[O:15])=[CH:27][C:28]=1[CH3:33]
Reactant: Cc1cc(O[C@H](C/C=C\COCc2ccccc2)C(=O)N2C(=O)OC[C@@H]2C(C)C)ccc1F
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(O[C@H](CCCCO)C(=O)N2C(=O)OC[C@@H]2C(C)C)ccc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(S)-3-((R,Z)-6-(benzyloxy)-2-(4-fluoro-3-methylphenoxy)hex-4-enoyl)-4-isopropyloxazolidin-2-one (250 mg, 0.54 mmol) was dissolved into 5 mL EtOH and to it added 10% Pd/C (250 mg). The solution was saturated with H2 (stream of H2 bubbled through solution) and then stirred for 3 h at room temperature under an atmosphere of hydrogen balloon. The mixture was filtered through a bed of Celite and rinsed with ethyl acetate. The solvent was removed under reduced pressure and the crude product used directly in the next step without further purification.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([CH:17]([CH3:19])[CH3:18])=[C:7]([CH:16]=1)[O:8][CH2:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.Br[CH2:21][CH2:22][CH2:23][N:24]1[C:32](=[O:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]1=[O:34].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([CH:17]([CH3:19])[CH3:18])=[C:7]([CH:16]=1)[O:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:21][CH2:22][CH2:23][N:24]2[C:32](=[O:33])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]2=[O:34])[CH2:12][CH2:11]1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: Cc1ccc(C(C)C)c(OCC2CCNCC2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(C)C)c(OCC2CCN(CCCN3C(=O)c4ccccc4C3=O)CC2)c1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
11.35 g (0.04 mol) of 4-[[5-methyl-2-(1methylethyl)phenoxy]methyl]piperidine hydrochloride, 10.72 g (0.04 mol) of 2-(3-bromopropyl)-1H-isoindole-1,3(2H)-dione and 13.8 g (0.1 mol) of potassium carbonate are reacted in 113 ml of N,N-dimethylformamide. The mixture is stirred for 3 h at 100° C. It is poured into ice-cold water. The solution is extracted with ethyl acetate and it is washed with water. The organic phase is dried over sodium sulphate, filtered and concentrated under reduced pressure. The product obtained is used as is in the following stage.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=1.[CH:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.S(=O)(=O)(O)O>>[CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CC1=CCCCC1
Reactant: c1ccccc1
Agent: O=S(=O)(O)O
Product: CC1(c2ccccc2)CCCCC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 36.5 %

Procedure:
A mixed solution of 75.0 mL (632 mmol) of 1-methyl-1-cyclohexene and 56.4 mL (632 mmol) of benzene was added dropwise to 225.6 mL (2.53 mol) of a benzene solution of 231 g (2.36 mol) of sulfuric acid at 0° C. over 1.5 hours. The resulting mixture was stirred at 0° C. for 1.5 hours. The reaction mixture was quenched with 300 mL of water to separate the aqueous layer. The resulting organic layer thus obtained was washed with 100 mL of a saturated aqueous solution of sodium bicarbonate, 100 mL of water, and 100 mL of saturated saline and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated to obtain crude 1-methylcyclohexylbenzene. The resulting crude 1-methylcyclohexylbenzene was purified by distillation under reduced pressure (110 to 113° C./10 mmHg) to obtain 40.2 g of the intended product. Yield: 36.5%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[N:7]([C:18]1[CH:23]=[CH:22][C:21](Br)=[C:20]([F:25])[N:19]=1)[CH2:8][C:9]1[CH:10]=[N:11][C:12]([O:16][CH3:17])=[C:13]([F:15])[CH:14]=1)([CH3:4])([CH3:3])[CH3:2].C([Mg]Cl)(C)C.CN(C)[CH:34]=[O:35].[Cl-].[NH4+]>O1CCCC1>[C:1]([O:5][C:6](=[O:26])[N:7]([C:18]1[CH:23]=[CH:22][C:21]([CH:34]=[O:35])=[C:20]([F:25])[N:19]=1)[CH2:8][C:9]1[CH:10]=[N:11][C:12]([O:16][CH3:17])=[C:13]([F:15])[CH:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: COc1ncc(CN(C(=O)OC(C)(C)C)c2ccc(Br)c(F)n2)cc1F
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ncc(CN(C(=O)OC(C)(C)C)c2ccc(C=O)c(F)n2)cc1F
Temperature: -45 °C
Yield: 70.4 %

Procedure:
To (5-bromo-6-fluoro-pyridin-2-yl)-(5-fluoro-6-methoxy-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester (26, 2.90 g, 6.74 mmol) in 25.0 mL of tetrahydrofuran at −35° C. under an atmosphere of nitrogen, isopropylmagnesium chloride (3.54 mL, 2.00 M in tetrahydrofuran, 7.08 mmol) was added and the reaction was allowed to come to 0° C. over an hour. The reaction was cooled to −45° C. and N,N-dimethylformamide (1.0 mL, 13.0 mmol) was added. The reaction was allowed to warm to room temperature over 2 hours, then poured into aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with 20% ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound (27, 1.80 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[C:7]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:8]=2[S:9][CH:10]=1)[CH3:2].[Cl:18][S:19](O)(=[O:21])=[O:20]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[C:7]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([S:19]([Cl:18])(=[O:21])=[O:20])[C:8]=2[S:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)Cc1csc2cc(OC)ccc12
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: CCOC(=O)Cc1csc2c(S(=O)(=O)Cl)c(OC)ccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 3.6 %

Procedure:
To a solution of compound from step 2 (1.0 g, 4.0 mmol) in CH2Cl2 (10 mL) was added chlorosulfonic acid (0.56 mL, 8.0 mmol). The resulting mixture was stirred for 4 hours at room temperature. The solvent was evaporated in vacuo and the residue was dissolved in EtOAc. The solution was washed with Na2CO3, brine and dried over Na2SO4. Evaporation of solvent afforded 50 mg of desired compound. 1H NMR (400 MHz, CDCl3) δ 8.08 (d, 1H), 7.38 (s, 1H), 6.90 (d, 1H), 4.21 (q, 2H), 4.02 (s, 2H), 4.01 (s, 3H), 1.24 (t, 3H).
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C:10]4[C@:15]3([CH3:16])[CH:14]=[CH:13][C:12](=[O:20])[CH:11]=4)[C@@H:6]1[CH2:5][CH2:4][C:3]2=[O:21].[CH2:22]([Al](CC)CC)[CH3:23].O>O1CCOCC1.CCCCCC.[Cu]Br>[CH2:22]([C@@H:14]1[C@@:15]2([CH3:16])[C:10]([CH2:9][CH2:8][C@@H:7]3[C@@H:17]2[CH2:18][CH2:19][C@@:2]2([CH3:1])[C@H:6]3[CH2:5][CH2:4][C:3]2=[O:21])=[CH:11][C:12](=[O:20])[CH2:13]1)[CH3:23]
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: CC[Al](CC)CC
Agent: [Cu]Br
Solvent: C1COCCO1
Solvent: CCCCCC
Solvent: O
Product: CC[C@H]1CC(=O)C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21C
Temperature: 25 °C

Procedure:
2.84 g (10 mmol) of androsta-1,4-diene-3,17-dione is dissolved under nitrogen atmosphere in 20 ml of anhydrous dioxane. 143 mg (1 mmol) of copper(I) bromide is added, and the solution is heated to 25° C. Then, 10 ml (10 mmol) of a 1 molar solution of triethylaluminum in hexane is added to the reaction, so that the temperature does not rise above 30° C. Then, it is stirred for 1.5 more hours at 30° C. For hydrolysis, 1 ml of water mixed with 5 ml of dioxane is added to the reaction, and the solution is stirred for 15 more minutes. The inorganic solid is suctioned off and rewashed with 30 ml of dioxane. After concentration by evaporation of the dioxane solution, 3 g of crude product is obtained, which is chromatographed on silica gel with a hexane/ethyl acetate mixture with an increasing portion of ethyl acetate as eluent. After concentration by evaporation of the fractions, 2.67 g of 1α-ethylandrost-4-ene-3,17-dione (85% of theory) of melting point 168° C. is obtained.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:15]1([O-:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Na+].O>CN(C)C=O>[O:21]([C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: [O-]c1ccccc1
Reactant: O=Cc1cc(-c2ccccc2)c(Br)s1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc(-c2ccccc2)c(Oc2ccccc2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.2 %

Procedure:
To a solution of 5-bromo-4-phenylthiophene-2-carbaldehyde (652 mg) in N,N-dimethylformamide (10 mL) was added sodium phenolate (425 mg) at room temperature. After stirring at room temperature overnight, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=99:1→9:1) to give the title compound as a pale-yellow solid (yield 152 mg, yield 22%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[C@@H:10]([NH:12][C:13](=[O:29])[O:14][CH2:15][CH:16]2[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:22]3[C:17]2=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH3:11])=[C:4](NC2C=CC(F)=CC=2)[CH:3]=1.C(Cl)Cl.C([O-])(O)=O.[Na+]>C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:8]=[C:9]([C@@H:10]([NH:12][C:13](=[O:29])[O:14][CH2:15][CH:16]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=4[C:23]4[C:28]3=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH3:11])[N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:6]=2[CH:7]=1
Reactant: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)Nc1ccc(F)cc1Nc1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)c1nc2ccc(F)cc2n1-c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 26 h

Procedure:
A Heterogeneous mixture of (S)-(9H-fluoren-9-yl)methyl 1-(4-fluoro-2-(4-fluorophenylamino)phenylamino)-1-oxopropan-2-ylcarbamate (3.500 g, 6.82 mmol) in acetic acid (45.4 mL) was heated at 100° C. with stirring. After 26 h, the mixture was cooled to rt and poured into DCM (100 mL) and satd. aq. NaHCO3 solution (100 mL). The aq. layer was removed and the organic layer was washed with satd. aq. NaHCO3 solution (100 mL×1), water (100 mL×1) and brine (100 mL×1), dried over MgSO4, filtered, and concentrated under reduced pressure to give (S)-(9H-fluoren-9-yl)methyl 1-(6-fluoro-1-(4-fluorophenyl)-1H-benzo[d]imidazol-2-yl)ethylcarbamate as a dark brown syrup: LC-MS (ESI) m/z 496.1 [M+H]+. Epimerization occurred during cyclization and the dark brown syrup was carried on crude without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[N:14]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[C:15]=[O:16]>CN(C)C=O>[CH2:17]([NH:14][C:15]([NH:13][C:10]1[CH:11]=[CH:12][C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:8][CH:9]=1)=[O:16])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ccc(-c2ccncc2)cc1
Reactant: O=C=NCc1ccccc1
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1)Nc1ccc(-c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.7 %

Procedure:
To a suspension of [4-(4-pyridinyl)phenyl]amine (100 mg) in N,N-dimethylformamide (4 ml) was added (isocyanatomethyl)benzene (86 mg) and the mixture was stirred at ambient temperature for 2 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried over sodium sulfate, and evaporated in vacuo. The residue was triturated with ethyl acetate to give 1-benzyl-3-[4-(4-pyridinyl)phenyl]urea (135 mg) as a yellow powder.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:16][CH2:17][C:18]([O-])=[O:19])[C:13]([O-])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Li+]>C1COCC1.[Cl-].[Na+].O.O>[OH:19][CH2:18][CH2:17][CH2:16][C@@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:13][OH:14]
Reactant: O=C([O-])CCC(NC(=O)OCc1ccccc1)C(=O)[O-]
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(N[C@@H](CO)CCCO)OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 81.2 %

Procedure:
A solution of dimethyl (2R)-2-{[((benzyloxy)carbonyl]amino}pentanedioate (22.4 g) in dry THF (74 ml) was added dropwise over 1 h to a stirred mixture of lithium borohydride (4.5 g) in THF (200 ml) at room temperature, under nitrogen. Stirring at room temperature was continued for 3 days. The reaction mixture was diluted with brine and water, and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (over magnesium sulphate) and concentrated under reduced pressure to give the title compound (16.5 g) as a white solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([N:9]2[C:13]3[CH:14]=[CH:15][C:16]([C:18]4[CH:23]=[CH:22][N:21]=[C:20](Cl)[N:19]=4)=[CH:17][C:12]=3[N:11]=[CH:10]2)[CH:6]=[CH:5][N:4]=1.Cl.[CH3:26][O:27][C:28]1[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[C:32]([O:38][CH3:39])[C:29]=1[CH2:30][NH2:31].C(N(C(C)C)CC)(C)C>CS(C)=O.CCOC(C)=O.CCOCC>[CH3:1][S:2][C:3]1[N:8]=[C:7]([N:9]2[C:13]3[CH:14]=[CH:15][C:16]([C:18]4[CH:23]=[CH:22][N:21]=[C:20]([NH:31][CH2:30][C:29]5[C:32]([O:38][CH3:39])=[CH:33][C:34]([O:36][CH3:37])=[CH:35][C:28]=5[O:27][CH3:26])[N:19]=4)=[CH:17][C:12]=3[N:11]=[CH:10]2)[CH:6]=[CH:5][N:4]=1
Reactant: CSc1nccc(-n2cnc3cc(-c4ccnc(Cl)n4)ccc32)n1
Reactant: COc1cc(OC)c(CN)c(OC)c1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(OC)c(CNc2nccc(-c3ccc4c(c3)ncn4-c3ccnc(SC)n3)n2)c(OC)c1
Temperature: 100 °C
Reaction time: 20 h
Yield: 79.3 %

Procedure:
A suspension of 2-methylthio-4-[5-(2-chloro-pyrimidin-4-yl)benzimidazol-1-yl]pyrimidine (EXAMPLE 34; 85 mg), 2,4,6-trimethoxybenzylamine hydrochloride (160 mg), and diisopropylethylamine (210 mL) in 3 mL of DMSO was heated to 100° C., at which point all solids were dissolved. The mixture was stirred at 100° C. for 20 h, then cooled and diluted with 15 mL of 1:1 EtOAc-Et2O, washed with 2×5 mL of water and 5 mL of brine, dried over Na2SO4 and concentrated. The residue was purified by preparative thin-layer chromatography) eluting with 95:5 CH2Cl2—MeOH to provide 98 mg of the title compound. Mass spectrum (ESI) 516.4 (M+1).
Reaction SMILES: [C:1]1([CH:7]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[O:8][C:9]([CH:11]([N:15]2[CH:18]([S:19][N:20]3[C:24](=[O:25])[C:23]4=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]4[C:21]3=[O:30])[CH:17]([NH:31][C:32](=[O:41])[CH2:33][O:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:16]2=[O:42])[C:12]([CH3:14])=[CH2:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:49]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>ClCCCl>[C:43]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:8][C:9]([CH:11]([N:15]2[CH:18]([S:19][N:20]3[C:21](=[O:30])[C:22]4=[CH:29][CH:28]=[CH:27][CH:26]=[C:23]4[C:24]3=[O:25])[CH:17]([NH:31][C:32](=[O:41])[CH2:33][O:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:16]2=[O:42])[C:12]([CH2:14][Br:49])=[CH2:13])=[O:10])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: C=C(C)C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SN1C(=O)c2ccccc2C1=O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCCl
Product: C=C(CBr)C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SN1C(=O)c2ccccc2C1=O
Temperature: 80 °C
Yield: 10 %

Procedure:
A mixture of 5.6 g (8 mmoles) of 1-(1-diphenylmethoxycarbonyl-2-methylprop-2-enyl)-3-phenoxyacetamido-4-phthalimidothio-azetidin-2-one, 2.8 g (16 mmoles) of N-bromosuccinimide, 150 mg of benzoyl peroxide and 350 ml of 1,2 -dichloroethane was heated in the dark under nitrogen at 80° C for 2.5 hours. After washing with water, drying and concentrating of the reaction mixture, n-hexane was added to the residue to obtain 3 g of crude material which was chromatographed with silica gel [toluene-ethyl acetate 7:1 (v/v)] to obtain 630 mg (0.8 mmole) of 1-(1-diphenylmethoxycarbonyl-2-bromomethylprop-2-enyl)-3-phenoxyacetamido-4-phthalimidothio-azetidin-2-one.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]1[CH:15]=[CH:14][C:13](/[CH:16]=[C:17]2\[CH2:18][N:19]([C:24]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:20][CH2:21][C:22]\2=[O:23])=[N:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClCCl.CO.[BH4-].[Na+]>O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]1[CH:15]=[CH:14][C:13](/[CH:16]=[C:17]2\[CH2:18][N:19]([C:24]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:20][CH2:21][CH:22]\2[OH:23])=[N:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCn1ccc(/C=C2\CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2=O)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NCCn1ccc(/C=C2\CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2O)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
To a solution of (E)-3-({1-[2-(t-butoxycarbonylamino)ethyl]-1H-pyrazol-3-yl}methylidene)-1-(triphenylmethyl)piperidin-4-one (6.41 g) in a mixed solvent of dichloromethane (40 ml) and methanol (40 ml) was added sodium borohydride (436 mg) at 0° C. After the resulting mixture was stirred at 0° C. for 30 minutes, water was added to the mixture to stop the reaction and the product was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride successively, and dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by chromatography on silica gel using a mixture of ethyl acetate and hexane (3:7 to 7:3) as eluents to afford the title compound as a colourless solid (5.35 g, yield: 84%)
Reaction SMILES: O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].[C:28]([O:32][C:33]([NH:35][C@:36]([CH:71]1[CH2:76][CH2:75][CH2:74][CH2:73][CH2:72]1)([C:38]([N:40]1[CH2:70][CH2:69][CH2:68][C@H:41]1[C:42]([NH:44][CH2:45][C:46]1[CH:51]=[C:50]([Cl:52])[CH:49]=[CH:48][C:47]=1[CH2:53][CH:54]([NH:59]C1C=CC(OC)=CC=1)[C:55]([F:58])([F:57])[F:56])=[O:43])=[O:39])N)=[O:34])([CH3:31])([CH3:30])[CH3:29]>O.CC#N>[NH2:59][CH:54]([C:55]([F:58])([F:57])[F:56])[CH2:53][C:47]1[CH:48]=[CH:49][C:50]([Cl:52])=[CH:51][C:46]=1[CH2:45][NH:44][C:42](=[O:43])[C@@H:41]1[CH2:68][CH2:69][CH2:70][N:40]1[C:38](=[O:39])[C@H:36]([NH:35][C:33]([O:32][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:34])[CH:71]1[CH2:72][CH2:73][CH2:74][CH2:75][CH2:76]1
Reactant: COc1ccc(NC(Cc2ccc(Cl)cc2CNC(=O)[C@@H]2CCCN2C(=O)[C@](N)(NC(=O)OC(C)(C)C)C2CCCCC2)C(F)(F)F)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1CC(N)C(F)(F)F)C1CCCCC1
Temperature: 25 °C
Yield: 41.6 %

Procedure:
A solution of CAN (1.259 g, 2.30 mmol) in water (12 mL) was added to a stirred solution of 1-{(2R)-2-[(tert-butoxycarbonyl)amino]-2-cyclohexylglycyl}-N-(5-chloro-2-{3,3,3-trifluoro-2-[(4-methoxyphenyl)amino]propyl}benzyl)-L-prolinamide (0.798 g, 1.15 mmol) in CH3CN (20 mL) at 0° C. and the resulting solution was warmed to ambient temperature. The solution was partitioned between EtOAc and 10% aqueous NH4OH and the resulting two phase suspension was filtered and the organic layer was washed with 10% sodium sulfite and brine, dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash column chromatography on silica (eluting with 1-10% of 10% ammonium hydroxide in methanol/chloroform gradient) to give N-[2-(2-amino-3,3,3-trifluoropropyl)-5-chlorobenzyl]-1-{(2R)-2-[(tert-butoxycarbonyl)amino]-2-cyclohexylethanoyl}-L-prolinamide (0.282 g) as a foam; MS m/z=589.6.
Reaction SMILES: [C:1]([OH:6])(=O)[C:2]#[C:3][CH3:4].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:22][C:23]1[CH:24]=[C:25]2[C:30](=[C:31]([CH2:33][N:34]([CH3:36])[CH3:35])[CH:32]=1)[N:29]=[CH:28][C:27]([C:37]#[N:38])=[C:26]2[NH:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([Br:46])[CH:41]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O.C(Cl)Cl.C(OCC)(=O)C.CO.C(N(CC)CC)C>[Br:46][C:42]1[CH:41]=[C:40]([NH:39][C:26]2[C:25]3[C:30](=[C:31]([CH2:33][N:34]([CH3:36])[CH3:35])[CH:32]=[C:23]([NH:22][C:1](=[O:6])[C:2]#[C:3][CH3:4])[CH:24]=3)[N:29]=[CH:28][C:27]=2[C:37]#[N:38])[CH:45]=[CH:44][CH:43]=1
Reactant: CC#CC(=O)O
Reactant: CN(C)Cc1cc(N)cc2c(Nc3cccc(Br)c3)c(C#N)cnc12
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CC#CC(=O)Nc1cc(CN(C)C)c2ncc(C#N)c(Nc3cccc(Br)c3)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of 2-butynoic acid (0.42 g, 5.0 mmol) and N-methylmorpholine (0.66 ml, 6.0 mmol) in 4.0 ml of THF at 0° C. was added i-butyl chloroformate (0.52 ml, 4.0 mmol)during 10 m. After 10 m a solution of 6-amino-4-[(3-bromophenyl)amino]-8-dimethylaminomethyl -3-quinolinecarbonitrile (0.79 g, 2.0 mmol) in 4.0 ml of THF was added during 60 s. The mixture was warmed to 25° C., stirred for 2 h, and diluted with water. The pH was adjusted to 9-10 with potassium carbonate, and the resulting solid was filtered off, washed with water, stirred with methylene chloride, and filtered. The latter filtrate was concentrated to give a solid which was subjected to chromatography on silica gel with methylene chloride-ethyl acetate-methanol-triethylamine to give an amber solid; mass spectrum (electrospray, m/e) M+H 462, 464.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH3:33])[N:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:31])[CH:18]=2)[C:13]1=[O:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:53](O)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH2:53]([O:23][C:22]([C:21]1[N:12]([N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH3:33])[C:13](=[O:32])[C:14]2[C:19]([C:20]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:18][C:17]([Cl:31])=[CH:16][CH:15]=2)=[O:24])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: CN(C(=O)OCc1ccccc1)n1c(C(=O)O)c(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: OCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C(=O)OCc1ccccc1)n1c(C(=O)OCc2ccccc2)c(-c2ccccc2)c2cc(Cl)ccc2c1=O

Procedure:
To a mixture of 2-[(benzyloxycarbonyl)(methyl)amino]-6-chloro-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (190 mg), triphenylphosphine (130 mg), benzyl alcohol (52 μl) and THF (6.0 ml) was added diethyl azodicarboxylate (86 μl) at 0° C. with stirring, and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was concentrated under reduced pressure, the residue was purified by medium pressure preparative LC (hexane/ethyl acetate=9/1-3/2) to give 2-[(benzyloxycarbonyl)(methyl)amino]-6-chloro-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid benzyl ester as a colorless powder.