Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6]([CH3:9])=[N:7][O:8][C:4]=2[CH:3]=1.[Br:12]N1C(=O)CCC1=O.N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6]([CH2:9][Br:12])=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Cc1noc2cc(Br)ccc12
Reactant: O=C1CCC(=O)N1Br
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1noc2cc(Br)ccc12
Yield: 37.8 %

Procedure:
A mixture of 6-bromo-3-methyl-1,2-benzisoxazole (675 mg), N-bromosuccinimide (642 mg) and 1,1′-azobis(cyclohexanecarbonitrile) (90 mg) in carbon tetrachloride (7 ml) was irradiated using a 300W lamp at reflux under nitrogen for 40 h. On cooling the precipitate was removed by filtration, the solvent was evaporated and the residue was purified by flash chromatography on a silica column (4 cm diam) eluting with a cyclohexane-ethyl acetate gradient (49:1 to 24:1) to give the title compound as a pale yellow solid (350 mg).
Reaction SMILES: C[Al](C)C.[CH2:5]([CH2:7][NH2:8])[OH:6].C([O:11][C:12]([C:14]1[N:15]=[N:16][C:17]([O:20][CH2:21][C:22]2[C:23]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=3)=[N:24][O:25][C:26]=2[CH3:27])=[CH:18][CH:19]=1)=O)C.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>O1CCOCC1>[OH:6][CH2:5][CH2:7][NH:8][C:12]([C:14]1[N:15]=[N:16][C:17]([O:20][CH2:21][C:22]2[C:23]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=3)=[N:24][O:25][C:26]=2[CH3:27])=[CH:18][CH:19]=1)=[O:11]
Reactant: NCCO
Reactant: CCOC(=O)c1ccc(OCc2c(-c3cccc(F)c3)noc2C)nn1
Agent: C[Al](C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1onc(-c2cccc(F)c2)c1COc1ccc(C(=O)NCCO)nn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.2 %

Procedure:
A solution of trimethylaluminium (2 M in toluene, 800 μL, 1.6 mmol) was added dropwise (exothermic) to a solution of ethanolamine (96 μL, 1.6 mmol) in dioxane (10 mL) and the resulting mixture was stirred at room temperature for 1 h. Then a solution of 6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridazine-3-carboxylic acid ethyl ester (143 mg, 0.4 mmol) in dioxane (5 mL) was added. The resulting mixture was then heated at 85-95° C. for 2 h, cooled to room temperature, poured into a sodium potassium tartrate solution and extracted with ethyl acetate which was then washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 0:100) afforded the title compound (36 mg, 24%) which was obtained as a white solid. MS: m/e=373.1 [M+H]+.
Reaction SMILES: C([S:4][CH2:5][C:6]([N:8]1[CH2:15][C:14]([CH2:17][C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)([OH:16])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])(=O)C.N>>[O:19]1[CH:20]=[CH:21][CH:22]=[C:18]1[CH2:17][C:14]1([OH:16])[CH2:15][N:8]([C:6](=[O:7])[CH2:5][SH:4])[C@H:9]([C:10]([OH:12])=[O:11])[CH2:13]1
Reactant: CC(=O)SCC(=O)N1CC(O)(Cc2ccco2)C[C@H]1C(=O)O
Agent: N
Product: O=C(O)[C@@H]1CC(O)(Cc2ccco2)CN1C(=O)CS

Procedure:
The product from part (b) is treated with concentrated ammonia according to the procedure of Example 2 to yield 4-[(2-furyl)methyl]-4-hydroxy-1-(2-mercapto-1-oxoethyl)-L-proline.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:15]([NH2:18])(=[S:17])[CH3:16]>>[CH3:1][O:2][C:3]([C:4]1[N:18]=[C:15]([CH3:16])[S:17][C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:14]
Reactant: CC(N)=S
Reactant: COC(=O)C(=O)C(Cl)c1ccccc1
Product: COC(=O)c1nc(C)sc1-c1ccccc1

Procedure:
prepared by reaction of 3-chloro-2-oxo-3-phenyl-propionic acid methyl ester with thioacetamide. LC-MS: tR=0.87 min; [M+H]+=234.3.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][O:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[C:5]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[CH:39][C:40]([C:43]([O:45][CH3:46])=[O:44])=[N:41][CH:42]=2)O1>>[N:23]1([C:5]2[C:6]3[N:7]([CH:8]=[C:9]([CH2:11][O:12][C:13]4[CH:22]=[CH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]=4)[N:10]=3)[C:2]([C:37]3[CH:38]=[CH:39][C:40]([C:43]([O:45][CH3:46])=[O:44])=[N:41][CH:42]=3)=[CH:3][N:4]=2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: Brc1cnc(N2CCOCC2)c2nc(COc3ccc4ccccc4n3)cn12
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Product: COC(=O)c1ccc(-c2cnc(N3CCOCC3)c3nc(COc4ccc5ccccc5n4)cn23)cn1
Yield: 35 %

Procedure:
Compound 15a (1.50 g, 3.24 mmol) was subjected to Suzuki coupling conditions with methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinate using the reaction conditions described in Example 1, Step G to obtain compound 15b as a yellow solid (600 mg, 35% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C27H24N6O4: 497.2 (M+H). Found 497.2.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][N:6]([CH3:8])[CH3:7])C.Cl.[OH-].[K+].[F:15][C:16]1[CH:17]=[C:18]([CH:52]=[CH:53][CH:54]=1)[CH2:19][N:20]1[C:28]2[C:23](=[CH:24][C:25]([NH:29][C:30]3[C:31]4[CH:39]=[C:38]([NH:40][C:41](=[O:51])[CH2:42]P(=O)(OCC)OCC)[N:37]=[CH:36][C:32]=4[N:33]=[CH:34][N:35]=3)=[CH:26][CH:27]=2)[CH:22]=[N:21]1.[Li+].[Cl-]>O.C(Cl)Cl.CO.CC(N(C)C)=O.C1COCC1>[CH3:8][N:6]([CH3:7])[CH2:5]/[CH:4]=[CH:42]/[C:41]([NH:40][C:38]1[N:37]=[CH:36][C:32]2[N:33]=[CH:34][N:35]=[C:30]([NH:29][C:25]3[CH:24]=[C:23]4[C:28](=[CH:27][CH:26]=3)[N:20]([CH2:19][C:18]3[CH:52]=[CH:53][CH:54]=[C:16]([F:15])[CH:17]=3)[N:21]=[CH:22]4)[C:31]=2[CH:39]=1)=[O:51]
Reactant: CCOC(CN(C)C)OCC
Reactant: CCOP(=O)(CC(=O)Nc1cc2c(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)ncnc2cn1)OCC
Agent: Cl
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN(C)C/C=C/C(=O)Nc1cc2c(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)ncnc2cn1
Temperature: 45 °C
Reaction time: 25 h
Yield: 95.2 %

Procedure:
To a stirred mixture of 2,2-diethoxy-N,N-dimethylethanamine (1.32 g, 8.20 mmol) and water (1.4 mL) at room temperature and under a nitrogen atmosphere was added an aq. 37% HCl (1.38 mL, 16.4 mmol). After addition the mixture was stirred at 45° C. (bath) for 25 h. It was cooled to 0° C. (bath). This is called solution A. KOH (2.36 g, 42.0 mmol) was dissolved in water (7 mL) at room temperature under a nitrogen atmosphere. It was cooled to 0° C. (bath). This is called solution B. To a stirred heterogeneous mixture of compound 229 (1.85 g, 3.28 mmol) and THF (7 mL) at room temperature and under a nitrogen atmosphere was added minimum amount of DMA (4 mL) to give a homogeneous solution. LiCl (139 mg, 3.28 mmol) was added and stirred at 0° C. (bath) for 15 min. The cold solution B was added and stirred at 0° C. for 2 min. Then the cold solution A was added and the final reaction mixture was continued to stir at 0° C. under a nitrogen atmosphere. The reaction was monitored by TLC (DCM-MeOH-10:1). After stirred further for 30 min. it was poured into water (200 mL). Petroleum ether (200 mL) was added and stirred at room temperature for 15 min. Petroleum ether layer was decanted. More petroleum ether (200 mL) was added and stirred for 15 min. The solid was collected by suction filtration; washed with water (4×30 mL); dried under reduced pressure over silica gel/KOH to give (2E)-4-(dimethylamino)-N-(4-{[1-(3-fluorobenzyl)-1H-indazol-5-yl]amino}pyrido[3,4-d]pyrimidin-6-yl)-2-butenamide (2) (1.55 g, 95%) as a pale yellow solid, mp 240-243; HPLC: 96.7% pure; 1H NMR δ [(CD3)2SO] 10.87 (s, 1H), 10.29 (s, 1H), 9.01 (s, 1H), 8.98 (s, 1H), 8.53 (s, 1 H), 8.18 (d, J=0.7 Hz, 1H), 8.16 (d, J=0.4 Hz, 1H), 7.73 (br d, J=9.0 Hz, 1H), 7.70 (dd, J=9.0, 1.7 Hz, 1H), 7.41-7.33 (m, 1H), 7.14-7.02 (m, 3H), 6.87 (dt, J=15.4, 6.0 Hz, 1H), 6.52 (br d, J=15.4 Hz, 1H), 5.70 (s, 2 H), 3.09 (dd, J=6.0, 1.1 Hz, 2H), 2.19 (s, 6H). Anal. Calcd for C27H25FN8O.1.2H2O: C, 62.59; H, 5.33; N, 21.63%. Found C, 62.59; H, 5.25; N, 21.59%.
Reaction SMILES: [N:1]1([CH2:10][CH2:11][C:12](=O)[CH3:13])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH3:15]>[Ni].C(OCC)(=O)C>[NH2:15][CH:12]([CH3:13])[CH2:11][CH2:10][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: N
Reactant: CC(=O)CCn1cnc2ccccc21
Agent: [Ni]
Solvent: CCOC(C)=O
Product: CC(N)CCn1cnc2ccccc21

Procedure:
Benzimidazole (VIII) (1 mole), condensed with methylvinylketone in slight excess (1-1.1 mole), in the presence of a catalytic amount of Triton B (benzyltrimethylammonium hydroxide), gives 1-[1-benzimidazolyl]-3-oxo butane (IX). This reaction is conducted in a non-polar neutral solvent, such as an aromatic hydrocarbon (for example toluene) or, preferably, ethyl acetate. The ketone (IX) is converted, by known process, into its oxime ((X). The latter, by catalytic hydrogenation, in an alcoholic medium, in the presence of ammonia and Raney nickel, under pressure (20-80 bars) and heat (50° to 100° C.), results in the amine (III). ##STR6##
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:16]=[C:17]([NH:21][C:22](=[O:34])[C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]5([C:32]#[N:33])[CH2:31][CH2:30]5)[CH:24]=4)[CH:18]=[CH:19][CH:20]=3)=[N:10][N:9]2[CH:35]=1)=[O:4].[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.C(=O)([O-])O.[Na+]>C(#N)C>[C:32]([C:29]1([C:25]2[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=2)[C:22]([NH:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([O:14][C:11]3[CH:12]=[CH:13][C:8]4[N:9]([CH:35]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:40]5[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]5)[N:7]=4)[N:10]=3)[CH:16]=2)=[O:34])[CH2:31][CH2:30]1)#[N:33]
Reactant: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(NC(=O)CCl)cn5n4)c3)c2)CC1
Reactant: CN1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CN1CCN(CC(=O)Nc2cn3nc(Oc4cccc(NC(=O)c5cccc(C6(C#N)CC6)c5)c4)ccc3n2)CC1
Temperature: 80 °C
Yield: 41 %

Procedure:
A mixture of N-[3-({2-[(chloroacetyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-3-(1-cyanocyclopropyl)benzamide (140 mg, 0.287 mmol), 1-methylpiperazine (1 mL) and acetonitrile (2 mL) was stirred with heating at 80° C. for 4 hr. After the reaction mixture was allowed to cool to room temperature, saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate/hexane=0/100→100/0) to give the title compound (65 mg, 41%) as a white powder.
Reaction SMILES: S(=O)(=O)=O.[C:5]([NH:13][NH:14][C:15](=[O:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([OH:24])=O)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN(C)C=O>[C:15]1(=[O:25])[N:14]([NH:13][C:5](=[O:12])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:22](=[O:24])[C:17]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:16]12
Reactant: O=C(NNC(=O)c1ccccc1C(=O)O)c1ccccc1
Agent: O=S(=O)=O
Solvent: CN(C)C=O
Product: O=C(NN1C(=O)c2ccccc2C1=O)c1ccccc1

Procedure:
Dry dimethylformamide (D.M.F.) (300 ml) was cooled in an ice-bath and with stirring treated dropwise with sulphur trioxide (SO3) (100 ml) such that the temperature did not exceed 5°. With continued ice-bath cooling the D.M.F./SO3 complex was treated dropwise with a solution of 1-benzoyl-2-(2-carboxybenzoyl)-hydrazine (148.5 g, 0.52 mole) dissolved in dry D.M.F. (200 ml). After the addition, the reaction was stirred for a further 1/2 hour at 0° and then for several hours with the ice-bath removed. The reaction mixture was poured into water (2 l) and allowed to stand until the paste which separated became hard. The crude product was collected on a filter, washed well with water, then air dried, wt. 143 g. This crude product was stirred into a solution of sodium bicarbonate (150 g) in water (1.4 l) till all effervescence had ceased. Undissolved material was collected on a filter, washed with water and air dried, 26 g (18%). Recrystallization from methanol gave white crystals of N-phthalimidobenzamide, (IV) (R1 =H), M.P. 215°-218°.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1)=O.[N:11]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[C:20]([O:19][C:17]([N:11]1[CH2:16][CH2:15][N:14]([CH2:1][C:3]2[S:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=2)[CH2:13][CH2:12]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: O=Cc1ccc(C(=O)O)s1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(C(=O)O)s2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 194.1 %

Procedure:
To a solution of 5-formylthiophene-2-carboxylic acid (0.505 g, 3.23 mmol) in MeOH (35 mL) and acetic acid (0.30 mL) was added tert-butyl piperazine-1-carboxylate (1.20 g, 6.47 mmol) and sodium cyanoborohydride (0.406 g, 6.47 mmol). The reaction mixture was allowed to stir at rt for 15 h and was then concentrated to give 5-{[4-(tert-butoxycarbonyl)piperazin-1-yl]methyl}thiophene-2-carboxylic acid (2.05 g, 6.27 mmol) as a white solid. LCMS: (FA) ES+ 327.3, ES-325.4.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]2[N:18]([CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[F:43])[C:19]3[C:24]([CH:25]=2)=[CH:23][C:22]([NH:26][C:27](=[O:35])[CH2:28][CH:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[CH:21][CH:20]=3)=[O:16])=[CH:10][CH:9]=1)(C)(C)C.[ClH:45]>O1CCOCC1>[ClH:45].[NH2:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]([C:17]2[N:18]([CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[F:43])[C:19]3[C:24]([CH:25]=2)=[CH:23][C:22]([NH:26][C:27](=[O:35])[CH2:28][CH:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[CH:21][CH:20]=3)=[O:16])=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(NC(=O)c2cc3cc(NC(=O)CC4CCOCC4)ccc3n2Cc2ccccc2F)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1ccc(NC(=O)c2cc3cc(NC(=O)CC4CCOCC4)ccc3n2Cc2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
121 mg (0.20 mmol) of tert-butyl-4-[({1-(2-fluorobenzyl)-5-[(tetrahydro-2H-pyran-4-ylacetyl)amino]-1H-indol-2-yl}carbonyl)amino]phenylcarbamate from Example XXXIII, 1.40 ml of dioxane and 1.40 ml of conc. hydrochloric acid are combined and stirred at RT for one hour. The mixture is evaporated to dryness using a rotary evaporator.
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][C@@:7]([NH2:16])([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=2)[C@H:6]([CH2:17]O)[CH2:5]1)[CH:2]=[CH2:3].[C:19]([N:27]=[C:28]=[S:29])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>O1CCCC1>[CH2:1]([N:4]1[CH2:5][C@@H:6]2[C@@:7]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=3)([N:16]=[C:28]([NH:27][C:19](=[O:26])[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[S:29][CH2:17]2)[CH2:8]1)[CH:2]=[CH2:3]
Reactant: C=CCN1C[C@@H](CO)[C@](N)(c2cccc(Br)c2)C1
Reactant: O=C(N=C=S)c1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: C=CCN1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2cccc(Br)c2)C1
Temperature: 22 °C
Reaction time: 1 h
Yield: 68.2 %

Procedure:
A solution of [(3R,4S)-1-allyl-4-amino-4-(3-bromophenyl)pyrrolidin-3-yl]methanol (27 g; 86.7 mmol) in tetrahydrofuran (270 mL) is cooled to −5° C. under a nitrogen atmosphere. Benzoyl isothiocyanate (12.3 mL, 91 mmol) is added drop wise keeping the temperature below 0° C. The reaction is allowed to warm to 22° C. over 1 hour. 1,1′-Carbonyldiimidazole (28.1 g, 173.5 mmol) is added in a single portion and the reaction is stirred for 1 hour at 22° C. and then heated to reflux for 16 hours. The solvent is removed in vacuo and the residue dried under vacuum. The crude material is partitioned in methyl tert-butyl ether (500 mL) and water (250 mL). The organic layer is separated, dried over magnesium sulfate, filtered and evaporated to dryness. The crude material is purified over a silica gel gradient of 90/10 to 60/40 methylene chloride/ethyl acetate to give the title compound (27 g, 68%). ES/MS (m/e): 456 (M+1).
Reaction SMILES: Br[C:2]([F:9])([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:10]([O:14][C:15]([NH:17][C@H:18]([CH:23]=[O:24])[CH2:19][CH:20]([CH3:22])[CH3:21])=[O:16])([CH3:13])([CH3:12])[CH3:11].[Cl-].[Na+].S(=O)(=O)(O)[O-].[K+]>Cl.[Zn].O1CCCC1>[C:10]([O:14][C:15]([NH:17][CH:18]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH:23]([OH:24])[C:2]([F:9])([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)C[C@@H](C=O)NC(=O)OC(C)(C)C
Reactant: CCOC(=O)C(F)(F)Br
Agent: Cl
Agent: O=S(=O)([O-])O
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCOC(=O)C(F)(F)C(O)C(CC(C)C)NC(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 145.3 %

Procedure:
A 3 neck flask was equipped with a magnetic stirrer, 2 dropping funnels, a condenser and a nitrogen atmosphere. In the flask was placed 7.56g (116 mmol) of activated zinc (made by stirring zinc dust in 2% hydrochloric acid for 1/2 hour, filtering, washing with alcohol, acetone then ether and drying in vacuum) and 220 mL of anhydrous tetrahydrofuran (dried over sodium/benzophenone and distilled). In one dropping funnel was placed ethyl bromodifluoroacetate (23.62 g, 0.116 mol) and in the other was placed 13.90g (42mmole based on 65% purity) of N-(tert-butyloxycarbonyl) leucinal and anhydrous tetrahydrofuran (30 mL). The contents of the flask was heated to reflux and the ethyl bromodifluoroacetate was added at a rapid controlled rate. This was followed immediately by the addition of the aldehyde solution. The resulting mixture was refluxed an additional 15 minutes and then cooled for 10 minutes. Then a mixture of 75 mL saturated aqueous sodium chloride and 75 ml of IM potassium bisulfate was added. The resulting mixture was stirred for 15 minutes and was filtered through celite. The filter cake was washed with ethyl acetate. The combined filtrate was separated by phase. The aqueous layer was extracted with ethyl acetate (2×50 ml) and the combined organic phases were dried over MgSO4. Solvent was removed under vacuum to give 20.71 g of oil. This product was put on silica column and was eluted with 20% ethyl acetate in hexane for a crude separation. Product containing fractions were chromatographed on a Waters Prep 500 HPLC. The chromatography was done on silica and the eluent was 20% ethyl acetate in hexane. Two isomers were collected: 4.21 g of the 3(R), 4(S) isomer (mp 72°-76° C.) and 0.58 g of the 3(S), 4(S) isomer, and oil. In addition 0.43 g of a mixture of isomers from middle cuts was collected.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])=[C:6]([N:8]2[CH2:12][C:11](=[O:13])[N:10]([CH3:14])[C:9]2=[O:15])[CH:7]=1.[S:32]1(=[O:38])(=[O:37])[CH2:36][CH2:35][CH2:34][NH:33]1>>[CH3:30][C:29]1[C:24]([N:21]2[CH2:22][CH2:23][N:18]([C:16]([C:5]3[CH:4]=[CH:3][C:2]([N:33]4[CH2:34][CH2:35][CH2:36][S:32]4(=[O:38])=[O:37])=[CH:7][C:6]=3[N:8]3[CH2:12][C:11](=[O:13])[N:10]([CH3:14])[C:9]3=[O:15])=[O:17])[CH2:19][CH2:20]2)=[N:25][CH:26]=[C:27]([CH3:31])[CH:28]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)cc3N3CC(=O)N(C)C3=O)CC2)c(C)c1
Reactant: O=S1(=O)CCCN1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3N3CC(=O)N(C)C3=O)CC2)c(C)c1
Yield: 37.2 %

Procedure:
Using 1-{5-chloro-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-3-methylimidazolidine-2,4-dione (149 mg) described in Preparation Example 256 and isothiazolidine 1,1-dioxide (61 mg) and by the reaction and treatment in the same manner as in Example 666, the title compound (66 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.CN(C=O)C.Cl.[CH3:27][NH:28][O:29][CH3:30]>C(Cl)Cl.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([N:28]([O:29][CH3:30])[CH3:27])=[O:6]
Reactant: CNOC
Reactant: O=C(O)c1cc(Br)cc(C(F)(F)F)c1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1cc(Br)cc(C(F)(F)F)c1
Reaction time: 0.5 h
Yield: 81 %

Procedure:
To a solution of 3-bromo-5-(trifluoromethyl)benzoic acid (50 g, 186 mmol) in DCM (500 mL) at 0° C., was added Oxalyl chloride (30.7 g, 242 mmol) with catalytical amount of DMF (0.5 mL). After stirring for 30 min the reaction mixture was concentrated. To a suspension of N,O-dimethylhydroxylamine hydrochloride (23.5 g, 242 mmol) in DCM (300 mL) at 0° C. was added TEA (51 g, 500 mol). Then a solution of acid chloride in DCM (300 mL) was added slowly. After stirring for 1 h, the reaction mixture was poured into water (200 mL) with vigorous stirring, extracted with DCM (2×200 mL). The organic layers were washed with brine (50 mL), dried over anhydrous MgSO4 and then concentrated. The residue was purified by silica gel chromatography (PE/EtOAc=20/1 to 5/1) to give the title compound (47 g, yield: 81%); m/z (ES+): 312 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C@H:8]([CH:12]([CH3:14])[CH3:13])[C@:7]([CH2:16][CH2:17][O:18]S(C1C=CC(C)=CC=1)(=O)=O)([OH:15])[CH2:6][CH2:5]2.FC1C=C2C(=CC=1)[C@H](C(C)C)C(=O)CC2.BrCC([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=O.[Mg]>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C@H:8]([CH:12]([CH3:14])[CH3:13])[C@:7]([CH2:16][C:17]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:18])([OH:15])[CH2:6][CH2:5]2
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1ccc(S(=O)(=O)OCC[C@@]2(O)CCc3cc(F)ccc3[C@@H]2C(C)C)cc1
Agent: CC(C)[C@@H]1C(=O)CCc2cc(F)ccc21
Agent: [Mg]
Product: CC(C)[C@H]1c2ccc(F)cc2CC[C@]1(O)CC(=O)OC(C)(C)C

Procedure:
The (1S,2S)-6-fluoro-1-isopropyl-2-[2-(4-toluenesulfonyloxy)ethyl]-1,2,3,4-tetrahydronaphthalene-2-ol, as described in U.S. Pat. No. 4,680,310 (also to Hoffmnann-La Roche), is prepared by reacting (S)-6-fluoro-1-isopropyl-3,4-dihydro-1H-naphthalen-2-one with tert-butyl bromoacetate in the presence of activated magnesium to form tert-butyl (1S,2S)-(6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydro-naphthalen-2-yl)acetate, which is reduced with lithium aluminum hydride to form (1S,2S)-6-fluoro-2-(2-hydroxyethyl)-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-ol, and then reacted with 4-toluenesulfonyl chloride in pyridine to form the (1S,2S)-6-fluoro-1-isopropyl-2-[2-(4-toluenesulfonyloxy)ethyl]-1,2,3,4-tetrahydronaphthalene-2-ol.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH2:8][C:7]([CH3:15])([CH3:14])[C:6]=2[C:5]([CH3:16])=[C:4]([CH3:17])[CH:3]=1.[C:18](O)(=[O:20])C.C1N2CN3CN(C2)CN1C3.O>C1(C)C=CC=CC=1>[CH:18]([C:3]1[C:4]([CH3:17])=[C:5]([CH3:16])[C:6]2[C:7]([CH3:15])([CH3:14])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:13])[C:11]=2[C:2]=1[OH:1])=[O:20]
Reactant: CC(=O)O
Reactant: Cc1cc(O)c2c(c1C)C(C)(C)CCC2(C)C
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1c(C)c2c(c(O)c1C=O)C(C)(C)CCC2(C)C
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
Formylation. 1-Hydroxy-3,4,5,5,8,8-hexamethyl-5,6,7,8-tetrahydronaphthalene (15 g, 0.0646 mol) was stirred with glacial acetic acid (100 mL), and hexamethylenetetramine (15 g, 0.107 mol) was added in one portion. The mixture was heated at 100° C. for 2 h. Hot water (100 mL) was added and the heating continued for an additional 0.5 h at 100° C. The mixture was cooled to 20° C., toluene (25 mL) was added, and the mixture was stirred vigorously. The organic layer was separated, washed with water (2×10 mL), then neutralized with 5% NaHCO3 solution and finally washed with brine (10 mL). The solvent was removed by distillation, and the residue crystallized from hexane, to give 2-formyl-1-hydroxy-3,4,5,5,8,8-hexamethyl-5,6,7,8-tetrahydronaphthalene (8.8 g), GLC purity 94%. 1H-NMR (CDCl3) δ12.94 (1H, s), 10.36 (1H, s), 2.43 (3H, s), 2.36 (3H, s), 1.65 (4H, s), 1.48 (6H, s), 1.46 (6H, s). 13C-NMR (CDCl3) δ195.4 (1C, d), 161.4 (1C, s), 156.0 (1C, s), 138.0 (1C, s), 131.9 (1C, s), 126.6 (1C, s), 116.7 (1C, s), 40.2 (1C, t), 37.9 (1C, t), 36.5 (1C, s), 35.1 (1C, s), 29.5 (2C, q), 28.1 (2C, q), 19.3 (1C, q), 14.1 (1C, q). IR (KBr) 1628 cm-1, MS (m/e) 260.3 (M+, 38.6), 245.2 (100.0), 175.1 (28.7), 189.1 (20.1).