Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C@@H:15]2[C@@H:10]([N:11]([NH:18][C@@H:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:20])[C:12](=O)[CH2:13][O:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B#B.O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:16][C@@H:15]2[C@@H:10]([N:11]([NH:18][C@@H:19]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH3:20])[CH2:12][CH2:13][O:14]2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](NN1C(=O)CO[C@@H]2CN(C(=O)OC(C)(C)C)C[C@@H]21)c1ccccc1
Agent: B#B
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](NN1CCO[C@@H]2CN(C(=O)OC(C)(C)C)C[C@@H]21)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3.32 g of cis-8-tert-butoxycarbonyl -5-[(1R)-1-phenylethylamino]-4-oxo-2-oxa-5,8-diazabicyclo[4.3.0]nonane 13b in 6 ml of tetrahydrofuran was added 19.2 ml of 1M diborane tetrahydrofuran complex dropwise under ice-cooling. The mixture was stirred at room temperature overnight. To the mixture was added 5 ml of the diborane solution mentioned above and the mixture was stirred at room temperature for 2 hours. To an ice-cooled reaction mixture was added water and saturated potassium carbonate aqueous solution. The mixture was extracted by ethyl acetate. The organic layer was washed by saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. A residue was subjected to silica gel column chromatography. From an eluant of a mixture of hexane and ethyl acetate (3:1 by volume), the titled compound 14b weighing 2.17 g was obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.Cl[CH2:10][C:11]1[C:12]([O:17][CH3:18])=[N:13][CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:18][O:17][C:12]1[C:11]([CH2:10][N:1]2[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]2)=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: OCC1CCNCC1
Reactant: COc1ncccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ncccc1CN1CCC(CO)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.6 %

Procedure:
10 g of 4-piperidinemethanol, 13 g of 3-(chloromethyl)-2-methoxypyridine and 24 g of potassium carbonate were suspended in 80 ml of N,N-dimethylformamide, and the mixture was stirred at room temperature for 12 hours. Water was added to the reaction solution, the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and then the layer was dried over anhydrous magnesium sulfate. The solvent was evaporated, to give 16.1 g of the title compound as a pale brown oil.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]1[CH:25]=CN(C)C.N1C2C(=CC=CC=2)C(=[O:40])NC=1>O.O1CCCC1>[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]1[CH:25]=[O:40]
Reactant: O=c1[nH]cnc2ccccc12
Reactant: CN(C)C=Cc1nc2ccccc2c(=O)n1-c1ccccc1Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1nc2ccccc2c(=O)n1-c1ccccc1Cl

Procedure:
To a well stirred mixture of sodium periodate (1.38 g, 6.45 mmol) in water (6 mL) and tetrahydrofuran (6 mL) was added 3-(2-chloro-phenyl)-2-(2-dimethylamino-vinyl)-3,4-dihydro-quinazolin-4-one (0.70 g, 2.15 mmol) all at once. The mixture warmed slightly to the touch and was stirred for 1 hour at ambient temperature. The reaction was filtered through celite and the pad was rinsed with ether. The filtrate was rendered basic by addition of saturated aqueous sodium bicarbonate and phases were separated. The aqueous layer was extracted with ethyl acetate. The combined organic phase was washed with brine, dried over potassium carbonate, and concentrated. The residue was flash chromatographed on silica gel (1×3 inches) with elution proceeding as follows: 50% methylene chloride/hexane (400 mL), nil; (100 mL) and 50% ethyl acetate/hexane (150 mL), 0.51 g (82%) of 3-(2-chloro-phenyl)-3,4-dihydro-quinazolin-4-one-2-carboxaldehyde as about a 1:1 mixture of free aldehyde and hydrate which contained about 20% of 3-(2-chloro-phenyl)-3,4-dihydro-quinazolin-4-one-2-carboxaldehyde (from simple hydrolysis of the enamine; exists exclusively in its enolized form to take advantage of an internal hydrogen bond to N1 of the quinazolin-4-one). Identifying features of each of the components of this mixture can be observed in the NMR spectrum as defined in the table below:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:32])[C:13](=[O:31])[N:14]([C:15]4[C:16]([CH3:30])=[N:17][N:18]([CH2:20][C:21]([N:23]5[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]5)=[O:22])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[C:33]1(B(O)O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH3:32][N:12]1[C:6]2[CH:7]=[N:8][C:9]3[CH:10]=[CH:11][C:2]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:3][C:4]=3[C:5]=2[N:14]([C:15]2[C:16]([CH3:30])=[N:17][N:18]([CH2:20][C:21]([N:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)=[O:22])[CH:19]=2)[C:13]1=[O:31]
Reactant: OB(O)c1ccccc1
Reactant: Cc1nn(CC(=O)N2CCN(C)CC2)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(CC(=O)N2CCN(C)CC2)cc1-n1c(=O)n(C)c2cnc3ccc(-c4ccccc4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-3-methyl-1-{3-methyl-1-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-1H-pyrazol-4-yl}-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Stage 134.1.1) and phenylboronic acid (Aldrich, Buchs, Switzerland) to give the title compound as a white solid. (HPLC: tR 2.32 min (Method A); M+H=496 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.96 (s, 1H), 8.11-8.07 (m, 2H), 7.96-7.92 (m, 1H), 7.81-7.79 (m, 1H), 7.69-7.65 (m, 2H), 7.45-7.39 (m, 2H), 7.37-7.32 (m, 1H), 5.28-5.16 (m, 21-1), 3.59-3.43 (m, 7H), 2.40-2.29 (m, 4H), 2.20 (s, 3H), 1.92 (s, 3H))
Reaction SMILES: CC([O-])(C)C.[K+].Cl[CH2:8][C:9]([NH:11][C:12]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[F:26])([C:16]([F:19])([F:18])[F:17])[CH2:13][CH2:14][OH:15])=[O:10]>CC(O)(C)C.C1COCC1>[F:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:12]1([C:16]([F:19])([F:18])[F:17])[CH2:13][CH2:14][O:15][CH2:8][C:9](=[O:10])[NH:11]1
Reactant: O=C(CCl)NC(CCO)(c1ccccc1F)C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: O=C1COCCC(c2ccccc2F)(C(F)(F)F)N1
Yield: 76.1 %

Procedure:
To a refluxing solution of potassium tert-butylate (1.31 g, 11.29 mmol) in 43 ml t-BuOH was added dropwise a solution of 2-chloro-N-[1-(2-fluoro-phenyl)-3-hydroxy-1-trifluoromethyl-propyl]-acetamide (1.77 g, 5.64 mmol) in 35 ml THF over a period of 60 minutes. The reaction mixture was cooled down and quenched with 1N HCl. EtOAc was added and the organic layer was washed with brine, dried with MgSO4.H2O and evaporated. The crude product was purified on a silica gel column by eluting with hexane/EtOAc 3/1→2.5/1 to give 1.19 g of the title compound as white crystals.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)#[N:2].[Br:16]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>ClCCCl>[Br:16][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:1]#[N:2])=[CH:14][CH:13]=1
Reactant: Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCCl
Product: N#Cc1ccccc1-c1ccc(CBr)cc1
Temperature: 50 °C

Procedure:
467.3 g of 2-cyano-4'-methylbiphenyl, prepared above, are dissolved in 4.7 l of 1,2-dichloroethane in the presence of 467.3 g of N-bromosuccinimide and 9.3 g of benzoyl peroxide. The mixture is heated very gradually so as to have good control over the exothermic effect. It is subsequently refluxed for 4 h, cooled to 50° C. and then washed 3 times with hot water and dried and the organic phase is concentrated to give cream-colored crystals.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].F[C:6]1[N:11]=[C:10]([F:12])[CH:9]=[C:8]([F:13])[N:7]=1>C(OCC)C>[F:13][C:8]1[CH:9]=[C:10]([F:12])[N:11]=[C:6]([NH:4][CH2:1][CH2:2][CH3:3])[N:7]=1
Reactant: CCCN
Reactant: Fc1cc(F)nc(F)n1
Solvent: CCOCC
Product: CCCNc1nc(F)cc(F)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
13.0 g (0.22 mol) of n-propylamine were added at -20° C. to a mixture of 13.4 g (0.1 mol) of 2,4,6-trifluoropyrimidine in 150 ml of diethyl ether within 20 minutes. After stirring at -20° C. for 1 hour and at 25° C. for 1 hour, the precipitate was filtered off, and the organic phase was washed with water, dried and concentrated under reduced pressure. 15.8 g (91.3% of theory) of the title compound were obtained as an oil (nD23 =1.4965).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]3[NH:17][C@H:16]([C:18]([F:21])([F:20])[F:19])[CH2:15][CH2:14][N:10]3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Na+].[F:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28]>O1CCCC1>[F:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([N:17]1[C:9]2=[N:8][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:12][C:11](=[O:13])[N:10]2[CH2:14][CH2:15][C@H:16]1[C:18]([F:20])([F:21])[F:19])=[O:28]
Reactant: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2
Reactant: O=C(Cl)c1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(c1ccccc1F)N1c2nc(N3CCOCC3)cc(=O)n2CC[C@H]1C(F)(F)F

Procedure:
The product is prepared according to the procedure described in Example 18, using 300 mg of (8S)-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (Example 1e), 47 mg of sodium hydride and 156 mg of 2-fluorobenzoyl chloride in 5 ml of tetrahydrofuran. After purification by silica chromatography (eluent: CH2Cl2/MeOH 98/02), 35 mg of (8S)-9-[(2-fluorophenyl)carbonyl]-2-(morpholin-4-yl)-8-(trifluoro-methyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are obtained in the form of a white foam, the characteristics of which are the following:
Reaction SMILES: CS(O[CH2:6][CH:7]1[O:12][C:11]2[CH:13]=[C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:15]=[CH:16][C:10]=2[O:9][CH2:8]1)(=O)=O.[I-:24].[Na+]>C(C(C)=O)C.C(OCC)(=O)C>[I:24][CH2:6][CH:7]1[O:12][C:11]2[CH:13]=[C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:15]=[CH:16][C:10]=2[O:9][CH2:8]1
Reactant: [I-]
Reactant: CS(=O)(=O)OCC1COc2ccc(Oc3ccccc3)cc2O1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Product: ICC1COc2ccc(Oc3ccccc3)cc2O1

Procedure:
2-Methanesulfonyloxymethyl-7-phenoxy-1,4-benzodioxane (1.85 g, 5.5 mmol) and sodium iodide (1.54 g, 11.0 mmol) are taken up in methyl ethyl ketone (60 mL) and heated at reflux for 3 hours. The mixture is cooled, diluted with ethyl acetate, washed with aqueous sodium bicarbonate, dried over magnesium sulfate and evaporated to give 2-iodomethyl-7-phenoxy-1,4-benzodioxane as a tan solid. This is used without further purification.
Reaction SMILES: C1C2C(COC(=O)[NH:17][C@H:18]([C:26](=[O:44])[NH:27][C@H:28]([C:33](=[O:43])[NH:34][C:35]3[CH:40]=[CH:39][C:38]([CH2:41][OH:42])=[CH:37][CH:36]=3)[CH2:29][CH2:30][CH2:31][CH3:32])[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)C3C(=CC=CC=3)C=2C=CC=1.C(NCC)C>C(Cl)Cl>[OH:42][CH2:41][C:38]1[CH:37]=[CH:36][C:35]([NH:34][C:33](=[O:43])[C@@H:28]([NH:27][C:26](=[O:44])[C@@H:18]([NH2:17])[CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:29][CH2:30][CH2:31][CH3:32])=[CH:40][CH:39]=1
Reactant: CCCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)Nc1ccc(CO)cc1
Solvent: ClCCl
Solvent: CCNCC
Product: CCCC[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)Nc1ccc(CO)cc1
Temperature: 25 °C
Yield: 70.5 %

Procedure:
In a round-bottomed flask, the above prepared {(S)-1-[(S)-1-(4-hydroxymethyl-phenylcarbamoyl)-pentylcarbamoyl]-2-phenyl-ethyl}-carbamic acid 9H-fluoren-9-ylmethyl ester (4.738 g, 7.822 mmol, Eq: 1.0) was dissolved in CH2Cl2 (28 ml). At 0°, diethylamine (28 ml, 19.80 g, 271 mmol, Eq: 35) was added and the reaction mixture stirred at ambient temperature over night. All volatiles were evaporated i. V.; ensuing flash chromatography SiO2/CH2Cl2/10% MeOH, followed by crystallization from AcOEt, yielded 2.116 g of the title compound as light brown crystals. MS (ISP): (M+H) 384.2.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>CCOCC>[CH3:12][N:9]1[CH2:10][CH2:11][CH:6]([CH2:4][OH:3])[CH2:7][CH2:8]1
Reactant: CCOC(=O)C1CCN(C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CN1CCC(CO)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
A solution of ester 21 (10.1 g, 59.0 mmol) in Et2O (40 mL) was added dropwise to a suspension of LiAlH4 (2.46 g, 64.9 mmol) in Et2O (200 mL) at 0° C. Then, the reaction mixture was allowed to warm to room temperature and was then stirred for 4 h at this temperature. Water (10 mL) was added slowly and stirring was continued for a further 30 min. The formed white precipitate was separated by filtration and washed thoroughly with Et2O (250 mL). After removal of the solvent under reduced pressure the resulting oil was purified by distillation (bp. 108° C., 14 mbar) to give alcohol 22 (6.40 g, 84%) as a colorless oil. −Rf=0.53 (CH2Cl2/MeOH, 5:1, 5% NEt3, PMA: dark blue). 1H NMR (300 MHz, CDCl3): δ=1.28 (dq, J=12.2, 3.7 Hz, 2 H, 3-Hax, 5-Hax), 1.38-1.55 (m, 1 H, 4-H), 1.68-1.79 (m, 2 H, 3-Heq, 5-Heq), 1.93 (dt, J=11.8, 2.3 Hz, 2 H, 2-Hax, 6-Hax), 2.26 (s, 3 H, NMe), 2.82-2.92 (m, 2 H, 2-Heq, 6-Heq), 3.12 (sbr, 1 H, OH), 3.46 (d, J=6.4 Hz, 2 H, CH2OH) ppm. —13C NMR (75.5 MHz, CDCl3): δ=28.8 (C-3, C-5), 37.9 (C-4), 46.3 (NMe), 55.5 (C-2, C-6), 67.4 (CH2OH) ppm. −MS (70 eV, EI): m/z (%)=129 (55) [M]+, 128 (100) [M−H]+, 112 (10) [M-OH]+, 98 (21) [M-CH2OH]+. —C7H15NO (129.20).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:13][CH:14]([CH3:19])[CH2:15][C:16](O)=[O:17].C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:16](=[O:17])[CH2:15][CH:14]([CH3:19])[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: CC(C)CC(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CC(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Yield: 66.7 %

Procedure:
A mixture of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.869 mmol, Example 1, Step H), 3-methylbutanoic acid (isovaleric acid) (222 mg, 2.17 mmol) and triethylamine (606 μL, 4.35 mmol) in CH2Cl2 (10 mL) was processed as described in Example 56, Step A, to provide N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methylbutanamide (182 mg, 67% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 12.04 (s, 1H), 9.46 (s, 1H), 8.34 (d, 1H), 7.56 (s, 1H), 2.20 (d, 2H), 2.11-2.05 (m, 1H), 0.96 (d, 6H); LCMS (APCI+) m/z 314, 316 (M+H)+, Retention time=3.02 minutes (Method 2).
Reaction SMILES: [H-].[Na+].[SH:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH:10]([C:17]1[N:18]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:19]2[C:24]([C:25](=[O:27])[CH:26]=1)=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=[C:21](Cl)[N:20]=2)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CN(C=O)C>[NH:10]([C:17]1[N:18]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:19]2[N:20]=[C:21]([S:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:22]=[C:23]([C:28]([F:31])([F:30])[F:29])[C:24]=2[C:25](=[O:27])[CH:26]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)CS
Reactant: O=c1cc(Nc2ccccc2)n(-c2ccccc2)c2nc(Cl)cc(C(F)(F)F)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CSc1cc(C(F)(F)F)c2c(=O)cc(Nc3ccccc3)n(-c3ccccc3)c2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 27.7 %

Procedure:
NaH (60% dispersion in oil, 18.0 mg, 0.434 mmol) was added to a cooled (0° C.) and stirred solution of ethyl mercaptoacetate (0.05 mL, 0.434 mmol) in DMF. After 0.5 h, 2-anilino-7-chloro-1-phenyl-5-trifluoromethyl-1,8-naphthyridin-4(1H)-one (150.0 mg, 0.361 mmol) was added as a solid in a single portion. The mixture was allowed to warm to room temperature and was stirred for 24 h. The reaction was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. Purification by preparative HPLC (10% CH3CN in water with 0.1% TFA to 95% CH3CN in water, 10 mL/min, 10 min) provided ethyl {[7-anilino-5-oxo-8-phenyl-4-(trifluoromethyl)-5,8-dihydro-1,8-naphthyridin-2-yl]sulfanyl}acetate (50 mg, 53%): LCMS RT: 3.91 min, MH+: 500.2, Rf=0.24 (1:1 EtOAc:Hex).
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[C:13]2[C:8]([C:9]([C:16]([OH:18])=[O:17])=[CH:10][NH:11][C:12]2=[O:15])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:19][NH:20][CH3:21].Cl>>[CH3:19][N:20]([CH3:21])[S:2]([C:5]1[CH:14]=[C:13]2[C:8]([C:9]([C:16]([OH:18])=[O:17])=[CH:10][NH:11][C:12]2=[O:15])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CNC
Reactant: O=C(O)c1c[nH]c(=O)c2cc(S(=O)(=O)Cl)ccc12
Agent: Cl
Product: CN(C)S(=O)(=O)c1ccc2c(C(=O)O)c[nH]c(=O)c2c1
Reaction time: 18 h

Procedure:
7-(Chlorosulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid (0.8 g) was added to dimethylamine (15 ml) and the mixture was stirred for 18 h. The mixture was acidified with concentrated hydrochloric acid and then filtered to yield 7-[(dimethylamino)sulfonyl]-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid as a white solid.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=2)[CH:5]=1.[C:17]([C:19]1[CH:20]=[C:21]([S:26]([N:29]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][C:37]=2[O:44][CH3:45])[C:30]2[S:31][CH:32]=[CH:33][N:34]=2)(=[O:28])=[O:27])[CH:22]=[CH:23][C:24]=1F)#[N:18]>CN(C=O)C.C(OCC)(=O)C>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:24]2[CH:23]=[CH:22][C:21]([S:26]([N:29]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][C:37]=3[O:44][CH3:45])[C:30]3[S:31][CH:32]=[CH:33][N:34]=3)(=[O:28])=[O:27])=[CH:20][C:19]=2[C:17]#[N:18])=[C:6]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=2)[CH:5]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc(F)c(C#N)c2)c(OC)c1
Reactant: Cn1nccc1-c1cc(Br)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc(Oc3ccc(Br)cc3-c3ccnn3C)c(C#N)c2)c(OC)c1
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
To a slurry of sodium hydride (54 mg, 1.4 mmol, 60% in mineral oil) in DMF (1 mL) was added 4-bromo-2-(1-methyl-1H-pyrazol-5-yl)phenol (Preparation 89, 210 mg, 0.83 mmol) as a solution in DMF (3 mL). After stirring for 30 minutes, 3-cyano-N-(2,4-dimethoxy-benzyl)-4-fluoro-N-thiazol-2-yl-benzenesulfonamide (Preparation 90, 415 mg, 0.957 mmol) was added. After 3 hours the reaction mixture was diluted with ethyl acetate (10 mL) and washed with water (5 mL) and brine (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. Purification by automated flash column chromatography using a 0-100% ethyl acetate/dichloromethane gradient provided the title compound (482 mg, 87%) as a yellow foam.
Reaction SMILES: [NH+]1C=CC=CC=1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.[Br:18][C:19]1[CH:20]=[C:21]([CH2:27][OH:28])[CH:22]=[C:23]([Br:26])[C:24]=1[Cl:25]>C(Cl)(Cl)Cl>[Br:18][C:19]1[CH:20]=[C:21]([CH:22]=[C:23]([Br:26])[C:24]=1[Cl:25])[CH:27]=[O:28]
Reactant: OCc1cc(Br)c(Cl)c(Br)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Product: O=Cc1cc(Br)c(Cl)c(Br)c1
Reaction time: 8 h

Procedure:
Pyridinium chlorochormate (PCC, 3.44 g, 15.9 mmol) was added in one portion to a stirred solution of (3,5-dibromo-4-chlorophenyl)methanol (3.2 g, 11.0 mmol) in CHCl3 (40 mL) at ambient temperature and the reaction mixture was stirred overnight. The reaction mixture was filtered through Celite®, the Celite® pad was washed with CHCl3 and the filtrate was concentrated to afford the title compound as an off white solid (2.0 g, 62%): mp 110-113° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.93 (s, 1H), 8.27 (s, 2H); ESIMS m/z 297.0 ([M]+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([F:9])[CH:3]=1.C([Li])CCC.[C:15]([N:22]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)C>[F:9][C:4]1[CH:3]=[C:2]([C:24]2([OH:27])[CH2:25][CH2:26][N:22]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:23]2)[CH:7]=[CH:6][C:5]=1[F:8]
Reactant: Fc1ccc(Br)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: O=C([O-])[O-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(F)c(F)c2)C1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 47.9 %

Procedure:
To a solution of 1-bromo-3,4-difluorobenzene (3.5 g, 18.13 mmol) in dry diethyl ether (25 mL) under nitrogen at −78° C., was added dropwise n-butyllithium (2.5 M in hexane, 7.25 mL, 18.13 mmol). The mixture was stirred for 30 min at −78° C. after which a solution of 1-N-boc-3-pyrrolidinone (3.35 g, 18.13 mmol) in dry diethyl ether (25 mL) was added drop wise. The mixture was stirred at −78° C. for 10 min and then brought to ambient temperature over a period of 2 h. Aqueous sodium carbonate (10%) was added and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic phase was dried (Na2SO4), filtered and evaporated. Purification by flash column chromatography on silica gel (isooctane/ethyl acetate, 4:1 to 1:1) gave the title compound (2.6 g). MS m/z (rel. intensity, 70 eV) 243 (18), 198 (23), 141 (18), 127 (21), 57 (bp).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH:7]([NH2:13])[CH2:8]2.[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH:7]([NH:13][C:14](=[O:16])[CH3:15])[CH2:8]2
Reactant: COc1cccc2c1CCC(N)C2
Reactant: CC(=O)OC(C)=O
Product: COc1cccc2c1CCC(NC(C)=O)C2
Yield: 20 %

Procedure:
Using a procedure similar to that described in Example 1, 0.30 g of 5-methoxy-2-amino-tetralin yielded 0.06 g (20%) of 5-methoxy-2-acetamido tetralin following treatment with acetic anhydride.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].Br[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1>>[F:23][C:18]1[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: Brc1ccccn1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3cccnc3F)c2)cn1
Product: O=C(c1ccccn1)c1cn(-c2cccc(-c3cccnc3F)c2)cn1

Procedure:
This compound is prepared by method C using compound 12i and 2-bromopyridine