Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:35]=[CH:34][C:25]([O:26][C:27]([CH3:33])([CH3:32])[C:28](OC)=[O:29])=[CH:24][CH:23]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[Si:1]([O:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:35]=[CH:34][C:25]([O:26][C:27]([CH3:33])([CH3:32])[CH2:28][OH:29])=[CH:24][CH:23]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)C(C)(C)Oc1ccc(CCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)(CO)Oc1ccc(CCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Yield: 92.7 %

Procedure:
A solution of methyl 2-[4-[3-(tert-butyldiphenylsilyloxy)propyl]phenoxy]-2-methylpropionate (5.88 g, 11.98 mmol) in diethyl ether (100 ml) was treated at 22° C. with 23 ml (23 mmol) of a 1M solution of lithium aluminum hydride in ether. The resulting mixture was then heated under reflux for 1 hour. The cooled mixture was quenched by addition of ethyl acetate, water (5 ml) and 1N sodium hydroxide (5 ml). The solid formed was filtered and the filtrate was evaporated and purified on silica gel. Elution with a mixture of toluene and ethyl acetate (9:1) gave 5.14 g (93%) of the title material as an oil.
Reaction SMILES: N1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3](N)=[O:4].[C:9]1([Se:15]N2C(=O)C3=CC=CC=C3C2=O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[C:7]1([CH2:6][CH:2]([Se:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:3]=[O:4])[CH:8]=[CH:7][CH:6]=[CH:2][CH:3]=1
Reactant: NC(=O)[C@@H]1CCCN1
Reactant: O=C1c2ccccc2C(=O)N1[Se]c1ccccc1
Solvent: ClCCl
Product: O=CC(Cc1ccccc1)[Se]c1ccccc1
Reaction time: 0.5 h

Procedure:
General Procedure B for α-Selenenylation of Aldehyde (Table 9, Entries 11 and 12): To a vial containing an aldehyde (0.25 mmol), and 0.5 mL of anhydrous CH2Cl2 was added catalyst L-prolinamide I (0.005 mmol) at room temperature. The mixture was vigorously stirred for 0.5 h in the presence of 4 Å molecule sieves (40 mg). Then N-(phenylseleno)phthalimide (0.3 mmol) was added. After 0.5 h, the molecule sieves were removed by filtrating paper and then the filtrate was treated with water (5 mL), the solution was extracted with ethyl acetate (3×5 mL). The combined extracts were dried over MgSO4, filtered, and concentrated iii vacuo. The resulting residue was then purified by silica gel chromatography, eluting with EtOAc/Hexane (1/40) to provide a clear oil.
Reaction SMILES: C(=O)(O)O.[Cl:5][C:6]1[CH:7]=[C:8]([NH:18][C:19]([NH2:21])=[NH:20])[CH:9]=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.CN(C)/[CH:24]=[CH:25]/[C:26]([C:28]1[N:32]([CH:33]([CH3:35])[CH3:34])[C:31]([CH3:36])=[N:30][CH:29]=1)=O>>[Cl:5][C:6]1[CH:7]=[C:8]([NH:18][C:19]2[N:21]=[C:26]([C:28]3[N:32]([CH:33]([CH3:35])[CH3:34])[C:31]([CH3:36])=[N:30][CH:29]=3)[CH:25]=[CH:24][N:20]=2)[CH:9]=[CH:10][C:11]=1[N:12]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1
Reactant: Cc1ncc(C(=O)/C=C/N(C)C)n1C(C)C
Reactant: N=C(N)Nc1ccc(N2CCOCC2)c(Cl)c1
Agent: O=C(O)O
Product: Cc1ncc(-c2ccnc(Nc3ccc(N4CCOCC4)c(Cl)c3)n2)n1C(C)C

Procedure:
The title compound was prepared using the procedure described in Example 112, employing N-(3-chloro-4-morpholin-4-yl-phenyl)-guanidine carbonate (Method 17; 500 mg, 1.97 mmol), and (2E)-3-(dimethylamino)-1-(1-isopropyl-2-methyl-1H-imidazol-5-yl)prop-2-en-1-one (Method 24 of WO 03/076436; 363 mg, 1.64 mmol). Yield: 412 mg, 61% as a white solid. NMR: 1.42 (d, 6H), 2.47 (s, 3H), 2.90 (t, 4H), 3.72 (t, 4H), 5.60 (m, 1H), 7.02 (d, 1H), 7.10 (d, 1H), 7.40 (s, 1H), 7.54 (dd, 1H), 7.78 (d, 1H), 8.37 (d, 1H), 9.43 (s, 1H); m/z 413.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=[O:10].[BH4-].[Na+].[H-].Cl>C(O)C>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH2:9][OH:10]
Reactant: O=Cc1cccc(OCCCCl)c1
Agent: Cl
Agent: [BH4-]
Agent: [H-]
Solvent: CCO
Product: OCc1cccc(OCCCCl)c1
Yield: 99 %

Procedure:
m-(3-Chloropropyloxy)benzaldehyde (15 g) was dissolved in 200 ml of ethanol. With ice cooling, 1.5 g of sodium borohydride was added little by little. Two hours later, the excess of the hydride was decomposed with 5% hydrochloric acid, followed by concentration. The residue was extracted with ethyl acetate, and dried. The solvent was evaporated to give 15 g of m-(3-chloropropyloxy)benzyl alcohol quantitatively.
Reaction SMILES: C([C:3]([C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:5]([CH3:10])=[CH:6][N:7](C)[CH3:8])#N.[ClH:15]>ClCCCl>[CH3:14][O:13][C:11](=[O:12])[C:3]1[CH:4]=[C:5]([CH3:10])[CH:6]=[N:7][C:8]=1[Cl:15]
Reactant: Cl
Reactant: COC(=O)C(C#N)=CC(C)=CN(C)C
Solvent: ClCCCl
Product: COC(=O)c1cc(C)cnc1Cl
Temperature: 50 °C

Procedure:
1-Cyano-4-(N,N-dimethylamino)-1-methoxycarbonyl-3-methyl-1,3-butadiene (33.6 g, 0.173 mol) prepared in a manner analogous to that described in Example 1(i) above was suspended in 1,2-dichloroethane (330 ml) and heated to 50° C. with stirring whereupon a steady stream of hydrogen chloride was passed through the mixture. After 21/4 hours, the clear solution was concentrated. The residue was dissolved in water and this solution was extracted with dichloromethane (3×100 ml). The pooled organic layers were dried with sodium sulphate and evaporated. Crystallisation of the residue from petrol yielded colourless crystals of 2-chloro-5-methylnicotinic acid methyl ester (30.0g, 93.4% of theoretical yield) with m.pt. 31° C.-33° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.II.[CH2:11]([N:18]1[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[NH4+].[Cl-]>CCOCC.CCOC(C)=O>[CH2:11]([N:18]1[CH2:23][CH2:22][C:21]([C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)([OH:24])[CH2:20][CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Cc1ccc(Br)cc1
Agent: II
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: Cc1ccc(C2(O)CCN(Cc3ccccc3)CC2)cc1

Procedure:
A solution of 4-bromotoluene (1.017 g, 5.94 mmol) in anhydrous Et2O (6 mL), is added dropwise to a mixture of Mg (0.159 g, 6.54 mmol) and a catalytic amount of I2 (0.015 g, 0.26 mmol) in anhydrous Et2O (10 mL). The mixture is stirred at reflux for 5 h under nitrogen. To this cloudy solution is added dropwise at 0° C., a solution of N-benzyl-4-piperidone (1.063 mL, 5.94 mmol) in anhydrous Et2O (6 mL) and the mixture is stirred at reflux for 1.5 h. After cooling, the mixture is poured into sat. NH4Cl (20 mL) and extracted with EtOAc (3×30 mL). The combined organic extracts are washed with brine, dried (MgSO4), filtered and concentrated to provide a crude oil. Flash chromatography (EtOAc/Hex: 3/7) affords the title compound.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[CH:10]=2)O1.Cl[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:24]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:18]=1[C:9]1[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[CH:10]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: CC1(C)OB(C2=CC(=O)CCC2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C1C=C(c2ccncc2[N+](=O)[O-])CCC1
Temperature: 120 °C
Yield: 60.2 %

Procedure:
To a solution of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-2-en-1-one (6.0 g, 27 mmol) and 4-chloro-3-nitropyridine (2.4 g, 15 mmol) in 1,4-dioxane (60 mL), 2.0 N aq. Na2CO3 (12 mL, 24 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.8 g, 1.5 mmol) were added. The reaction mixture was heated at 120° C. for 1 h. The reaction mixture was filtered through diatomaceous earth, which was washed with EtOAc. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluting with 10-100% EtOAc in hexanes) to give the sub-title compound as a brown solid (1.97 g, 87%). LCMS calc. for C11H11N2O3 (M+H)+: m/z=219.1. Found: 219.0.
Reaction SMILES: O[N:2]1[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[C:5]([CH3:13])[N:4]=[C:3]1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[O:22][CH3:23].P(Cl)(Cl)Cl.O.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:23][O:22][C:15]1[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:14]=1[C:3]1[NH:4][C:5]([CH3:13])=[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:2]=1
Reactant: COc1ccc(-c2nc(C)c(-c3cccnc3)n2O)c(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClP(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(-c3cccnc3)c(C)[nH]2)c(OC)c1
Reaction time: 2 h
Yield: 45 %

Procedure:
To a solution of 1-hydroxy-2-(2,4-dimethoxyphenyl)-4-methyl-5-(3-pyridyl)imidazole (6.6 g) in N,N-dimethylformamide (130 ml) was added phosphorus trichloride (3.7 ml) under ice-cooling. The mixture was stirred for 2 hours at 5° to 10° C. The reaction mixture was poured into water, neutralized with aqueous sodium bicarbonate, and extracted with ethyl acetate. The extract was washed with water, dried, and evaporated. The residue was subjected to column chromatography on silica gel eluting with a mixture of chloroform and methanol (methanol 0% to 15%). The fractions were collected and evaporated to give 2-(2,4-dimethoxypheyl)-5-methyl-4-(3-pyridyl)imidazole (2.82 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)[CH2:3]1.[C:13]1([NH:19]N)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl.O>C(O)(=O)C>[CH3:1][C:2]1([CH3:12])[C:3]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[NH:19][C:4]=2[C:5]2[C:10]1=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: CC1(C)CC(=O)c2ccccc21
Reactant: NNc1ccccc1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)c2ccccc2-c2[nH]c3ccccc3c21
Reaction time: 2 h

Procedure:
A solution of 3,3-dimethyl-1-indanone (20,0 q, 0,125 mol) prepared by the method described by R. Knorr et al., Leibig's Annalen, 1207 (1980) and phenylhydrazine (12.3 cm3, 0.125 mol) in glacial acetic acid (200 cm3), was heated to reflux. Concentrated hydrochloric acid (10 cm3) was added via the condenser, and boiling continued for a further 2 hours. The solution was allowed to cool, and then poured into water (500 cm3). The water was extracted with diethylether three times, the combined extracts were washed with brine and water, and dried (MgSO4). The solvent was removed, and petrol (60°-80° C.) added to the residue. The suspension was heated until boiling, The solid product was filtered off and the mother liquor concentrated. On cooling, more solid was obtained, and additional product separated out as the mother liquor was concentrated further. The solids were combined and crystallised from petrol to give the title compound. Yield: 10,2 g (35%). M.p. 160 ° C. 1H NMR: (CDCl3) δ: 1.60 (6H, s,), 7.1-7.7 (8H, m,), 8.16 (1H, s,).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[CH:5]=[CH:4][N:3]=1.C[O:11][C:12]([CH:14]1[C:18](=O)[CH2:17][CH2:16][CH2:15]1)=O>COCCO>[CH3:8][C:7]1[C:2]2=[N:1][C:15]3[CH2:16][CH2:17][CH2:18][C:14]=3[C:12](=[O:11])[N:3]2[CH:4]=[CH:5][C:6]=1[CH3:9]
Reactant: COC(=O)C1CCCC1=O
Reactant: Cc1ccnc(N)c1C
Solvent: COCCO
Product: Cc1ccn2c(=O)c3c(nc2c1C)CCC3

Procedure:
A solution of 24.4 g. of 2-amino-3,4-dimethylpyridine, 62.4 g. of methyl cyclopentanone-2-carboxylate and 250 ml of ethylene glycol monomethyl ether is stirred and heated under reflux for 40 hours. Workup as in Example 3 gives 28.3 g. of the named product as colorless plates after recrystallization from cyclohexane.
Reaction SMILES: C1(N[C:8](=[O:35])[C@H:9]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31]C=3)=O)=[CH:21][CH:20]=2)[NH:10]C(OC(C)(C)C)=O)CCCCC1.Cl.[O:37]1CCOCC1>CCCCCC>[CH2:26]([O:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][C@@H:9]([C:8]([OH:35])=[O:37])[NH2:10])=[CH:24][CH:23]=1)[C:27]1[CH:29]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCC(=O)c2ccccc2)cc1)C(=O)NC1CCCCC1
Reactant: C1COCCO1
Agent: Cl
Solvent: CCCCCC
Product: N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To the above compound (II) (1.0 g) was added under ice-cooling 4N-hydrogen chloride/dioxane solution (4.5 ml) and the mixture was stirred at room temperature for 30 minutes. Hexane (30 ml) was added to this solution and the precipitated crystalline substance was collected by filtration, washed with ether and then dried under reduced pressure to give quantitatively 4-benzyloxy-L-phenylalanine 4-cis/trans-methylcyclohexylamide hydrochloride (III). On the other hand, triethylamine (0.6 ml) was added to a solution of trans-4-(t-butyloxycarbonyl)aminomethylcyclohexylcarboxylic acid (0.62 g) dissolved in dry tetrahydrofuran (30 ml) and ethyl chlorocarbonate (0.25 g) was added under ice-cooling, followed by stirring for 30 minutes. To this solution were added the above compound (III) (0.73 g) and triethylamine (1 ml), and the mixture was stirred at room temperature for 3 hours. After evaporation of the solvent, the residue was extracted with ethyl acetate, washed with water and dried to give 0.2 g of N-[trans-4-(t-butyloxycarbonyl)aminomethylcyclohexylcarbonyl]-4-benzyloxyl-L-phenylalanine 4-cis/trans-methylcyclohexylamide (IV). To the above compound (IV) (0.2 g) was added under ice-cooling 4N-hydrogen chloride/dioxane solution (0.5 ml) and the mixture was stirred at room temperature for 30 minutes. Hexane (20 ml) was added to this solution and the precipitated crystalline substance was collected by filtration, washed with ether and then dried under a reduced pressure to give 0.1 g of N-(trans-4-aminomethylcyclohexylcarbonyl)-4-benzyloxy-L-phenylalanine 4-cis/trans-methylcyclohexylamide hydrochloride.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:17]=3[N:18]=[CH:19][C:20](=[O:26])[NH:21]4)[CH:10]=2)=[CH:5][CH:4]=1.[C:29]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[CH3:29][N:21]1[C:22]2[C:17](=[C:16]([O:15][C:11]3[CH:10]=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:27])([F:1])[F:28])=[CH:4][CH:5]=4)[N:14]=[CH:13][N:12]=3)[CH:25]=[CH:24][CH:23]=2)[N:18]=[CH:19][C:20]1=[O:26]
Reactant: O=C([O-])[O-]
Reactant: O=c1cnc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cccc2[nH]1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1c(=O)cnc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cccc21

Procedure:
The title compound was prepared analogous to the methods used in Example 42 using 5-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-1H-quinoxalin-2-one, (Example 34(b)), (0.10 g, 0.26 mmol), K2CO3 (0.043 g, 0.31 mmol, Aldrich) and iodomethane (0.019 mL, 0.31 mmol, Aldrich) in DMF (1 mL). Purification by flash chromatography (0→5% 2M NH3 in MeOH/CH2Cl2) afforded the title compound as a white amorphous solid. Mp: 258° C. MS (ESI, pos. ion) m/z: 399 (M+1)
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([O:11][C:12]2[CH:29]=[CH:28][C:15]3[CH2:16][CH2:17][N:18](C(OC(C)(C)C)=O)[CH2:19][CH2:20][C:14]=3[CH:13]=2)=[N:9][CH:10]=1)=[O:4].Cl>O1CCOCC1>[CH3:1][NH:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([O:11][C:12]2[CH:29]=[CH:28][C:15]3[CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:14]=3[CH:13]=2)=[CH:7][CH:6]=1)=[O:4]
Reactant: CNC(=O)c1ccc(Oc2ccc3c(c2)CCN(C(=O)OC(C)(C)C)CC3)nc1
Agent: Cl
Solvent: C1COCCO1
Product: CNC(=O)c1ccc(Oc2ccc3c(c2)CCNCC3)nc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
1,1-Dimethylethyl 7-({5-[(methylamino)carbonyl]-2-pyridinyl}oxy)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (D39) (3.98 g, 10 mmol) was dissolved in dioxane (40 ml) and treated with a solution of 4M hydrogen chloride in dioxane (35 ml). The reaction mixture was allowed to stir at room temperature for 6 hours and then concentrated in vacuo to afford the title compound (D40); MS (ES+) m/e 298 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH:24]([CH3:26])[CH3:25])[C:5]1([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:15].C([O-])([O-])=O.[K+].[K+].[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl>[Cl:14][C:10]1[CH:9]=[C:8]2[C:13]([C:5]([N:4]([CH:24]([CH3:26])[CH3:25])[CH2:3][CH2:2][NH:1][S:34]([CH3:33])(=[O:36])=[O:35])([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[C:6](=[O:15])[NH:7]2)=[CH:12][CH:11]=1
Reactant: CC(C)N(CCN)C1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)N(CCNS(C)(=O)=O)C1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.3 %

Procedure:
To a mixture of rac-3-[(2-Amino-ethyl)-isopropyl-amino]-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (50 mg, 0.13 mmol) and K2CO3 (35 mg, 0.25 mmol) in DCM (2 mL) was added methylsulfonyl chloride (16 mg, 0.14 mmol). The resulting solution was stirred at room temperature for 2 hr, then purified by flash column chromatography to give 65 mg rac-N-(2-{[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-isopropyl-amino}-ethyl)-methanesulfonamide. MS: [M+H]+=470
Reaction SMILES: [Br-].[Br:2][C:3]1[CH:4]=[C:5]([CH:9]([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH3:10])[CH:6]=[CH:7][CH:8]=1.CC(C)([O-])C.[K+].[C:36]1(=[O:46])[C:44]2[CH2:43][CH2:42][CH2:41][CH2:40][C:39]=2[C:38](=O)[O:37]1>O1CCCC1>[Br:2][C:3]1[CH:4]=[C:5]([C:9](=[C:38]2[C:39]3[CH2:40][CH2:41][CH2:42][CH2:43][C:44]=3[C:36](=[O:46])[O:37]2)[CH3:10])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(c1cccc(Br)c1)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1OC(=O)C2=C1CCCC2
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=C1OC(=O)C2=C1CCCC2)c1cccc(Br)c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A suspension of EXAMPLE 285B (1.88 g, 3.4 mmol) in tetrahydrofuran (100 ml) was treated with potassium t-butoxide (1N solution in tetrahydrofuran, 3.4 ml, 3.4 mmol) at −78° C. for 1 hour, and was allowed to warm up to 0° C. over 30 minutes. A solution of 4,5,6,7-tetrahydroisobenzofuran-1,3-dione (0.54 g, 3.4 mmol) in tetrahydrofuran (10 ml) was then added. The reaction mixture was warmed up to room temperature, and stirred at room temperature for additional 4 hours. After quenching with water, the reaction mixture was partitioned between ethyl acetate and brine. The organic phase was washed with brine, and concentrated. The residue was separated by flash chromatography (20% ethyl acetate in hexane) to provide the title compound. MS (DCI/NH3) m/z 320 (M+H)+.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:41])[CH:7]=[CH:8][CH:9]([N:23]([C:25](=[O:40])[C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=1)[CH3:24])[CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)C>O1CCCC1.CO>[F:33][C:32]([F:34])([F:35])[C:30]1[CH:31]=[C:26]([CH:27]=[C:28]([C:36]([F:38])([F:37])[F:39])[CH:29]=1)[C:25]([N:23]([CH:9]([CH:10]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH:8]=[CH:7][C:6]([OH:41])=[O:5])[CH3:24])=[O:40]
Reactant: CCOC(=O)C=CC(C(c1ccccc1)c1ccccc1)N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(C=CC(=O)O)C(c1ccccc1)c1ccccc1
Reaction time: 5 h

Procedure:
15 ml of 1N sodium hydroxide solution are added to a solution of 5.0 g (9.1 mmol) of 4-[N-(3,5-bistrifluoromethyl-benzoyl)-N-methyl-amino]-5,5-diphenyl-pent-2-enoic acid ethyl ester in 60 ml of 2:1 tetrahydrofuran/methanol at room temperature. After stirring for 5 h, the reaction mixture is concentrated, diluted with water, and then acidified with ice-cold 2N hydrochloric acid solution. The resulting precipitate is filtered, washed with water and a small amount of hexanes, and then dried overnight under vacuum at 50° C. to give the title compound as a white solid. TLC: methylene chloride/methanol (95:5) Rf =0.08.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH2:14][C:15]([F:18])([F:17])[F:16]>C(Cl)Cl>[F:16][C:15]([F:17])([F:18])[CH2:14][O:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[OH:6]
Reactant: COc1ccccc1OCC(F)(F)F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccccc1OCC(F)(F)F
Yield: 69.4 %

Procedure:
Boron tribromide (2.8 ml, 0.03 mole) was added to a solution of 1-methoxy-2-(2,2,2-trifluoroethoxy)benzene (X) (6.0 g, 0.03 mole) in methylene chloride (90 ml) with stirring below −10° C. Reaction was stirred at −10 to −20° C. for 30 minutes. The reaction mixture was quenched using aqueous sodium bicarbonate solution. Organic layer was separated, washed with water and dried over sodium sulphate. The solvent was evaporated under reduced pressure to give 4.0 g of (XI) as oil. Purity (by GC)=95%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]([S:16]([CH3:19])(=[O:18])=[O:17])=[C:9]2O)=[O:5])[CH3:2].P(Cl)(Cl)([Cl:23])=O>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]([S:16]([CH3:19])(=[O:18])=[O:17])=[C:9]2[Cl:23])=[O:5])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1ccc2ncc(S(C)(=O)=O)c(O)c2c1
Product: CCOC(=O)c1ccc2ncc(S(C)(=O)=O)c(Cl)c2c1

Procedure:
4-Hydroxy-3-methanesulfonyl-quinoline-6-carboxylic acid ethyl ester (example 61e, 15 g, 51 mmol) was dissolved in phosphorous oxychloride (450 mL). Then the reaction mixture was heated at the refluxing temperature for 6 hours. After cooling the reaction to about room temperature, the solvent was evaporated under reduced pressure. Dichloromethane was added to the residue, followed by extraction with water. The organic layers were collected, dried over sodium sulfate, filtered, and then concentrated in vacuo. Column chromatography gave 4-chloro-3-methanesulfonyl-quinoline-6-carboxylic acid ethyl ester (22 g, purity 70%). LC-MS m/e 250 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11](=[O:13])[CH3:12])[CH2:6][CH2:5]2.[Cl:14][S:15](O)(=[O:17])=[O:16]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[S:15]([Cl:14])(=[O:17])=[O:16])[N:7]([C:11](=[O:13])[CH3:12])[CH2:6][CH2:5]2
Reactant: O=S(=O)(O)Cl
Reactant: CC(=O)N1CCc2cc(Br)ccc21
Product: CC(=O)N1CCc2cc(Br)c(S(=O)(=O)Cl)cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 5-bromo-N-acetylindoline 122.86 g (0.51 mol) cooled in an ice bath was added chlorosulfonic acid, 116.52 g (2.6 moles) very cautiously. The mixture was stirred for about 30 minutes at 0° C. and then allowed to warm to room temperature. The mixture was then heated slowly to about 70°-90° C. overnight. After cooling, the cold solution was slowly added to ice and the solids collected by suction filtration, washed several times with water and allowed to dry overnight. The product was recrystallized from chloroform to give 72.5 g (42% by weight yield) of 5-bromo-6-chlorosulfonyl-N-acetylindoline.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Br:16]Br>C(Cl)(Cl)Cl>[Br:16][CH:9]([CH3:10])[C:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:11]
Reactant: BrBr
Reactant: CCC(=O)c1ccc(C)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C(=O)C(C)Br)cc1

Procedure:
14.8 g (0.1 mol) of 4'-methylpropiophenone are introduced into 100 ml of chloroform, in the presence of a small amount of finely ground aluminium chloride, and a solution of 15.9 g (0.1 mol; 5 ml) of bromine, in 20 ml of chloroform is added dropwise whilst cooling with an ice bath. The mixture is left to react overnight at ambient temperature. It is then filtered, the solvent is evaporated off from the filtrate and the crystalline residue is washed with diethyl ether. 21.5 g of crystals are collected.