Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9]Cl)[C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:11][S:12]([O-:14])=[O:13].[Na+]>O1CCOCC1.O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][S:12]([CH3:11])(=[O:14])=[O:13])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: ClCc1cc(Br)cnc1Cl
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CS(=O)(=O)Cc1cc(Br)cnc1Cl
Temperature: 110 °C
Yield: 94.2 %

Procedure:
A mixture of 5-bromo-2-chloro-3-(chloromethyl)pyridine (124 mg, 0.52 mmol) and sodium methanesulfinate (52 mg, 0.52 mmol) in dioxane (1.4 mL) and water (1.4 mL) was heated to 110° C. in a microwave reactor for 15 min. After cooling to rt, water was added to the reaction mixture which was subsequently extracted twice with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo to provide 5-bromo-2-chloro-3-(methylsulfonylmethyl)pyridine (140 mg, 0.49 mmol, 94% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.63 (d, 1H), 8.21 (d, 1H), 4.70 (s, 2H), 3.10 (s, 3H); MS (EI) for C7H7BrClNO2S: 284, 286, 288 (Br+Cl isotopes, MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:22][CH2:23][CH:24]([OH:27])[CH2:25][OH:26].O.Cl.CCOCC>CO>[ClH:1].[CH2:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:20][CH2:21][N:12]1[C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([NH:22][CH2:23][CH:24]([OH:27])[CH2:25][OH:26])[CH:11]=1
Reactant: NCC(O)CO
Reactant: Clc1cc(N2CCc3ccccc3C2)c2ccccc2n1
Agent: Cl
Solvent: CO
Solvent: O
Solvent: CCOCC
Product: OCC(O)CNc1cc(N2CCc3ccccc3C2)c2ccccc2n1
Temperature: 155 °C
Yield: 69.1 %

Procedure:
2-Chloro-4-(3,4-dihydro-1H-isoquinolin-2-yl)-quinoline (0.44 g, 1.5 mmol) and (RS)-3-amino-1,2-propanediol (0.82 g, 9.0 mmol) were mixed and heated at 150-160° C. for 5 hours. The reaction mixture was cooled to room temperature and water (15 ml) was added. The resulting solid was filtered, dried and chromatographed over silica gel (CH2Cl2—MeOH, 19:1 then 9:1) to provide a white foam which was dissolved in MeOH. HCl—Et2O was added to provide (RS)-3-[4-(3,4-dihydro-1H-isoquinolin-2-yl)-quinolin-2-ylamino]-propane-1,2-diol hydrochloride (0.4 g, 69%) as an offwhite foam, MS: m/=349 (M+).
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([C@@H:28]2[CH2:32][CH2:31][CH2:30][N:29]2C(OC(C)(C)C)=O)[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH3:24])=[CH:22][N:21]=[C:20]4[NH:25][N:26]=[CH:27][C:19]=34)[CH2:14][CH2:13]2)=[O:11])=[CH:5][CH:4]=1>O1CCOCC1>[ClH:2].[ClH:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([C@@H:28]2[CH2:32][CH2:31][CH2:30][NH:29]2)[C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]3[C:23]([CH3:24])=[CH:22][N:21]=[C:20]4[NH:25][N:26]=[CH:27][C:19]=34)[CH2:16][CH2:17]2)=[O:11])=[CH:5][CH:4]=1
Reactant: Cc1cnc2[nH]ncc2c1N1CCN(C(=O)[C@@H](c2ccc(Cl)cc2)[C@@H]2CCCN2C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cnc2[nH]ncc2c1N1CCN(C(=O)[C@@H](c2ccc(Cl)cc2)[C@@H]2CCCN2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
4N HCl in dioxane (5 mL) was added to (S)-tert-butyl 2-((S)-1-(4-chlorophenyl)-2-(4-(5-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-2-oxoethyl)pyrrolidine-1-carboxylate (68 mg, 0.13 mmol), and the mixture was stirred at room temperature. After 30 minutes, the solvent was removed under reduced pressure, and the resulting residue was triturated with ether. The solid material was filtered, washed with additional ether (2×2 mL) and dried under high vacuum for 24 hours to provide (S)-2-(4-chlorophenyl)-1-(4-(5-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-2-((S)-pyrrolidin-2-yl)ethanone dihydrochloride (62 mg, 0.12 mmol, 96% yield) as a solid. LCMS (APCI+) m/z 439.1 (M+H)+. NMR (400 Hz, DMSO-d6) δ 9.98 (brs, 1H), 9.06 (s, 1H), 8.23 (s, 1H), 7.49 (d, 2H), 7.43 (d, 2H), 4.56 (d, 1H), 4.03-3.96 (m, 2H), 3.93-3.87 (m, 3H), 3.71-3.65 (m, 1H), 3.64-3.57 (m, 2H), 3.50-3.46 (m, 1H), 3.19-3.13 (m, 2H), 2.31 (s, 3H), 1.97-1.89 (m, 1H), 1.78-1.70 (m, 1H), 1.63-1.52 (m, 2H).
Reaction SMILES: [OH:1][CH:2]([CH:8]([N:15]([CH3:23])[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([O:5]CC)=O.[CH2:24]([NH2:26])[CH3:25]>>[CH2:24]([NH:26][C:3](=[O:5])[CH:2]([OH:1])[CH:8]([N:15]([CH3:23])[C:16]1[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH3:25]
Reactant: CCOC(=O)C(O)C(c1ccccc1)N(C)c1ccc(C)cc1
Reactant: CCN
Product: CCNC(=O)C(O)C(c1ccccc1)N(C)c1ccc(C)cc1
Temperature: 120 °C
Reaction time: 48 h
Yield: 57 %

Procedure:
A mixture of ethyl (2RS,3RS)-2-hydroxy-3-[methyl(4-methylphenyl)amino]-3-phenylpropanoate (Example 12, step 1, 948 mg, 3.03 mmol) and methanolic ethylamine solution (2.0 M in methanol, 25 mL) was stirred at 120° C. in a sealed tube for 48 hours. After cooling, all volatiles were removed under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 0-15% ethyl acetate/hexane) and recrystallized (warm chloroform/hexane/−25° C.) to yield 537 mg (57%) of (2RS,3RS)-N-ethyl-2-hydroxy-3-[methyl(4-methylphenyl)amino]-3-phenylpropanamide as a white solid. MS (ESI) m/z 313 ([M+H]+); HRMS: calculated for C19H24N2O2+H, 313.1911; found (ESI, [M+H]+), 313.1908.
Reaction SMILES: C[Al](C)C.CCCCCCC.[CH2:12]([N:14]([CH2:18][CH3:19])[CH2:15][CH2:16][NH2:17])[CH3:13].[I:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH:26]=[C:25]([C:31](OCC)=[O:32])[C:24]2=[O:36].NC(C1C=CC2C(=CC=CC=2)N=1)=O>ClCCl.O>[CH2:12]([N:14]([CH2:18][CH3:19])[CH2:15][CH2:16][NH:17][C:31]([C:25]1[C:24](=[O:36])[C:23]2[C:28](=[CH:29][CH:30]=[C:21]([I:20])[CH:22]=2)[NH:27][CH:26]=1)=[O:32])[CH3:13]
Reactant: CCN(CC)CCN
Reactant: CCOC(=O)c1c[nH]c2ccc(I)cc2c1=O
Agent: C[Al](C)C
Agent: NC(=O)c1ccc2ccccc2n1
Solvent: CCCCCCC
Solvent: O
Solvent: ClCCl
Product: CCN(CC)CCNC(=O)c1c[nH]c2ccc(I)cc2c1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.8 %

Procedure:
To a stirred solution of a 2.0 M trimethylaluminium solution in heptane (20.8 mL, 41.6 mmol) in anhydrous dichloromethane (350 mL) was added at 0° C., under argon, N,N-diethylethylenediamine (5.78 mL, 41.1 mmol) dropwise. After 10 min, ethyl 6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylate (93) (10.0 g, 31.4 mmol) (Edlin, C.; Eldred, C. D.; Lunniss, C. J.; Redgrave, A. J.; Robinson, J. E.; Woodrow, M. Preparation of aminocarbonylquinoline derivatives as phosphodiesterase type IV (PDE4) inhibitors. Patent WO2005030725, 2005) was added. The mixture was refluxed for 12 h. After cooling to room temperature, water (500 mL) was added and the precipitate was filtered and washed with ethanol (2×100 mL). The filtrate was evaporated under vacuum. The residue was chromatographed (Al2O3, CH2Cl2/EtOH, 94/6, v/v) to give amide 94 (9.70 g, 23.5 mmol) as a beige solid. Yield 81%; Rf (Al2O3, CH2Cl2/EtOH, 94/6, v/v) 0.32; mp 243-245° C.; IR (KBr) ν 1466, 1507, 1551, 1633, 2800-3000, 3062 cm−1; 1H NMR (200 MHz, DMSO-d6) δ 1.23 (t, 6H, J=7.1 Hz), 3.17 (q, 4H, J=7.1 Hz), 3.23 (t, 2H, J=6.8 Hz), 3.71 (q, 2H, J=6.4 Hz), 7.59 (d, 1H, J=8.6 Hz), 8.05 (dd, 1H, J=2.0, 8.6 Hz), 8.51 (d, 1H, J=2.0 Hz), 8.72 (s, 1H), 10.04 (t, 1H, J=5.8 Hz), 10.13 (se, 1H); ESI-MS m/z 413.8 [M+H]+.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].[Li]CCCC.CCCCCC.[CH3:18][O:19][B:20](OC)[O:21][CH3:22]>C1COCC1>[CH3:18][O:19][B:20]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[O:21][CH3:22]
Reactant: COB(OC)OC
Reactant: C#C[Si](C)(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COB(C#C[Si](C)(C)C)OC
Reaction time: 0.25 h

Procedure:
A solution of trimethylsilylacetylene (0.51 mL) in THF (4 mL) was cooled to −78° C. under argon, and then a solution of n-BuLi in n-hexane (1.6 M, 2.25 mL, 3.6 mmol) was added via syringe. The resulting mixture was stirred at the same temperature for 15 min, then trimethylborate (0.4 mL, 3.6 mmol) was added. The cooling bath was removed, and the mixture was stirred at room temperature for 15 min to give a solution of the title compound.
Reaction SMILES: S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+:11].[NH4+].[OH2:13].[CH2:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)(C)(C)C>[C:16]([NH2:11])(=[O:13])[CH:15]=[CH2:14].[CH2:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O
Reactant: [NH4+]
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Solvent: CC(C)(C)O
Solvent: C=Cc1ccccc1
Product: C=CC(N)=O

Procedure:
A copolymer of acrylamide (95.0 wt. %) and styrene (5.0 wt. %) is prepared according to a modification of the procedure of Example 1C using 0.5 wt. % n-C12SH, 0.2 wt. % ammonium persulfate and a solvent medium consisting of 75 wt. % deionized water and 25 wt. % t-butanol. The modification is that the styrene monomer is mixed into the chain transfer agent solution and fed into the reaction flask in that solution. Upon completion of the polymerization, the t-butanol is removed via a steam sparge to afford the product at 17.0% solids in water with a Brookfield Viscosity of 28,000 cps.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([S:21](Cl)(=[O:23])=[O:22])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]>N1C=CC=CC=1>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:9][OH:10])=[CH:3][C:2]=1[NH:1][S:21]([C:15]1[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:13]([O:12][CH3:11])[CH:14]=1)(=[O:23])=[O:22]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Reactant: Nc1cc(CO)ccc1Cl
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2cc(CO)ccc2Cl)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (3-amino-4-chloro-phenyl)-methanol (2.0 g, 12.7 mmol) in pyridine (26 mL) was treated with 3,4-dimethoxybenzenesulfonyl chloride (3.3 g, 1.1 eq). The solution was stirred at RT overnight. The mixture was then partitioned between EA and 3M HCl. The organic layer was washed with brine, dried over MgSO4 and concentrated. The product was recovered as a brownish foam.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[S:4][C:3]=1[C:11]([O-:13])=O.C[Al](C)C.[CH3:18][NH2:19]>C(Cl)Cl>[CH3:18][NH:19][C:11]([C:3]1[S:4][C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])=[CH:6][C:2]=1[NH2:1])=[O:13]
Reactant: CC(C)(C)c1cc(N)c(C(=O)[O-])s1
Reactant: CN
Agent: C[Al](C)C
Solvent: ClCCl
Product: CNC(=O)c1sc(C(C)(C)C)cc1N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 14 %

Procedure:
Under argon, 3-amino-5-tert-butyl-thiophene-2-carboxylate (2.13 g, 10 mmol) was added to a premixed (15 minutes) methylene chloride (50 mL) solution of trimethylaluminum (5.0 mL, 2.0 M in hexanes) and methylamine (5.0 mL, 2.0 M in THF). The mixture solution was stirred at room temperature for 10 minutes and heated at 41° C. for 3 days. The mixture was cooled and carefully quenched with dilute HCl followed by extraction with methylene chloride. The organic phase was dried over sodium sulfate and concentrated. Column chromatography (hexanes/ethyl acetate) gave 0.3 g of 3-amino-5-tert-butyl-thiophene-2-carboxylic acid methylamide in 14% yield: 1H NMR (300 MHz, CDCl3) δ 6.44 (s, 1H), 5.6 (br, 2H), 5.4 (br, 1H), 3.02 (d, 3H), 1.44 (s, 9H); MS (m/e): 212.9 (M+1).
Reaction SMILES: C([O:8][C:9](=[O:42])[CH:10]([CH2:30][N:31]1[C:39](=[O:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]1=[O:41])[CH:11]([C:16](=[O:29])[NH:17][CH:18]([C:23](=[O:28])[NH:24][CH:25]1[CH2:27][CH2:26]1)[C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:12][CH:13]([CH3:15])[CH3:14])C1C=CC=CC=1.C1CCCCC=1>C(OCC)(=O)C.[Pd]>[CH:25]1([NH:24][C:23]([CH:18]([NH:17][C:16]([CH:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[CH:10]([CH2:30][N:31]2[C:39](=[O:40])[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32]2=[O:41])[C:9]([OH:42])=[O:8])=[O:29])[C:19]([CH3:20])([CH3:21])[CH3:22])=[O:28])[CH2:26][CH2:27]1
Reactant: CC(C)CC(C(=O)NC(C(=O)NC1CC1)C(C)(C)C)C(CN1C(=O)c2ccccc2C1=O)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1=CCCCC1
Product: CC(C)CC(C(=O)NC(C(=O)NC1CC1)C(C)(C)C)C(CN1C(=O)c2ccccc2C1=O)C(=O)O
Yield: 41.1 %

Procedure:
3-(1-Cyclopropylcarbamoyl-2,2-dimethyl-propylcarbamoyl)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-5-methyl-hexanoic acid-1-benzyl ester (3.46 g, 6.02 mmol) was dissolved in ethyl acetate (90 ml) and cyclohexene (10 ml) and the solution was placed under a blanket of argon. 10% palladium on charcoal catalyst (0.75 g) was added and the mixture was heated at reflux for 4 hours. The mixture was cooled and the catalyst was removed by filtration and the filtrate was evaporated to leave a pale yellow foam. Column chromatography (silica gel, gradient elution, 30 to 60% ethyl acetate in hexane) afforded the desired product as a white solid (1.2 g, 41%). 1H-NMR (CD3OD); δ 8.30 (1H, m), 8.08 (1H, m), 7.81 (5H, m), 7.11 (1H, m), 4.11 (0.75H, m), 3.92 (0.25H, m), 3.76 (1 H, m), 3.13-2.85 (2H, br m), 1.72 (1H, m), 1.53 (2H, m), 1.14 (6.7H, s), 1.08 (2.3H, s) and 0.86 (6H, m).
Reaction SMILES: [CH:1]1(/[C:4](/[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:5](/[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][O:19][CH3:20])=[CH:13][CH:12]=2)\[C:6]([O:8]CC)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>CO>[CH:1]1(/[C:4](/[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:5](/[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][O:19][CH3:20])=[CH:13][CH:12]=2)\[C:6]([OH:8])=[O:7])[CH2:3][CH2:2]1
Reactant: CCOC(=O)/C(=C(/c1ccccc1)C1CC1)c1ccc(OCOC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCOc1ccc(/C(C(=O)O)=C(\c2ccccc2)C2CC2)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 75 %

Procedure:
To a solution of 3 (105 mg, 0.298 mmol) in MeOH (3 ml) was added 2N NaOH (1.5 ml), and the mixture was stirred at 80° C. for 24 h. After cooling, 2 N HCl (1.5 ml) was added drop wise under ice cooling, and the whole was extracted with AcOEt, the organic layer was washed with brine, dried over Na2SO4, then concentrated. The residual solid was triturated with hexanes to give 7 (75%). 7: colorless powder; 1H-NMR (CDCl3) δ 0.45 (2H, m), 0.83 (2H, m), 2.73 (1H, m), 3.40 (3H, s), 5.04 (2H, s), 6.73 (2H, d, J=9.0 Hz), 6.89 (2H, m), 6.92 (2H, d, J=9.0 Hz), 7.05-7.14 (3H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:32]=[CH:31][C:23]([C:24]([NH:26][CH2:27][CH2:28][O:29][CH3:30])=[O:25])=[C:22]([F:33])[CH:21]=1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1)=O.Cl.[NH2:35][OH:36].C([O-])(O)=O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:32]=[CH:31][C:23]([C:24]([NH:26][CH2:27][CH2:28][O:29][CH3:30])=[O:25])=[C:22]([F:33])[CH:21]=1)[CH2:9]/[C:10](=[N:35]\[OH:36])/[C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1
Reactant: COCCNC(=O)c1ccc(C(CC(=O)c2ccc(=O)n(C)c2)c2ccccc2Cl)cc1F
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COCCNC(=O)c1ccc(C(C/C(=N\O)c2ccc(=O)n(C)c2)c2ccccc2Cl)cc1F

Procedure:
In analogy to example 151, step 3, 4-(1-(2-chlorophenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxopropyl)-2-fluoro-N-(2-methoxyethyl)benzamide was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound as a colorless foam, MS (ESI+): m/z=486.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]([CH:20]1[CH2:22][CH2:21]1)[C:7](=[O:19])[C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)[CH3:2].[CH2:24]([N:31]1[CH:35]=[C:34]([C:36](O)=[O:37])[CH:33]=[N:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:1]([O:3][C:4](=[O:23])[CH:5]([N:6]([CH:20]1[CH2:22][CH2:21]1)[C:7](=[O:19])[C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15]([F:16])([F:17])[F:18])=[CH:12][CH:13]=1)[C:36]([C:34]1[CH:33]=[N:32][N:31]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:35]=1)=[O:37])[CH3:2]
Reactant: CCOC(=O)CN(C(=O)c1ccc(OC(F)(F)F)cc1)C1CC1
Reactant: O=C(O)c1cnn(Cc2ccccc2)c1
Product: CCOC(=O)C(C(=O)c1cnn(Cc2ccccc2)c1)N(C(=O)c1ccc(OC(F)(F)F)cc1)C1CC1

Procedure:
The title compound, a colorless oil (0.9 g, 41%), was prepared in analogy to intermediate 8A by reaction of [cyclopropyl-(4-trifluoromethoxy-benzoyl)-amino]-acetic acid ethyl ester (intermediate 7B) with 1-benzyl-1H-pyrazole-4-carboxylic acid (Kalla R. V.; Elzein E.; Perry T.; Li X.; Palle V.; Varkhedkar V.; Gimbel A.; Maa T.; Zeng D.; Zablocki J. Journal of Medicinal Chemistry (2006), 49(12), 3682-92).MS: 516.1 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:3]=1[CH2:4][N:5]1[C:10](=[O:11])[CH2:9][NH:8][C:7]2[N:12]=[CH:13][C:14](I)=[CH:15][C:6]1=2.[CH2:22]([O:24][C:25]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)=[O:26])[CH3:23]>>[CH2:22]([O:24][C:25](=[O:26])[C:27]1[CH:32]=[CH:31][C:30]([C:14]2[CH:13]=[N:12][C:7]3[NH:8][CH2:9][C:10](=[O:11])[N:5]([CH2:4][C:3]4[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:2]=4[F:1])[C:6]=3[CH:15]=2)=[CH:29][CH:28]=1)[CH3:23]
Reactant: O=C1CNc2ncc(I)cc2N1Cc1cc(F)ccc1F
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Product: CCOC(=O)c1ccc(-c2cnc3c(c2)N(Cc2cc(F)ccc2F)C(=O)CN3)cc1
Yield: 62 %

Procedure:
1-(2,5-Difluorobenzyl)-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (600 mg) was reacted with 4-ethoxycarbonyl phenyl boronic acid as in General Procedure 4A to give the title compound as an off-white solid (62% yield). M.p. 201-203° C., LCMS: m/z=424.20 (M+H+), 1H-NMR (DMSO-d6, 400 MHz) δ 1.32 (t, J=7.0 Hz, 3H), 3.99 (s, 2H), 4.32 (q, J=7.0 Hz, 2H), 5.26 (s, 2H), 7.03-7.09 (m, 1H), 7.11-7.19 (m, 1H), 7.33 (s, 1H), 7.34-7.38 (m, 1H), 7.39 (s, 1H), 7.67 (d, J=7.0 Hz, 2H), 6.8 Hz, 2H), 8.10 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:20][CH2:19][C:18]3[C@:13]([CH2:31][O:32][CH2:33][CH2:34][OH:35])([CH2:14][C:15]4[CH:23]=[N:22][N:21]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)[C:16]=4[CH:17]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:36][C@@H:37]1[CH2:41][CH2:40][NH:39][CH2:38]1>>[F:30][C:27]1[CH:28]=[CH:29][C:24]([N:21]2[C:16]3[CH:17]=[C:18]4[C@:13]([CH2:31][O:32][CH2:33][CH2:34][OH:35])([CH2:14][C:15]=3[CH:23]=[N:22]2)[CH2:12][N:11]([S:8]([C:5]2[CH:6]=[N:7][C:2]([N:39]3[CH2:40][CH2:41][C@@H:37]([F:36])[CH2:38]3)=[CH:3][CH:4]=2)(=[O:9])=[O:10])[CH2:20][CH2:19]4)=[CH:25][CH:26]=1
Reactant: F[C@@H]1CCNC1
Reactant: O=S(=O)(c1ccc(Cl)nc1)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(COCCO)C1
Product: O=S(=O)(c1ccc(N2CC[C@@H](F)C2)nc1)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(COCCO)C1

Procedure:
The title compound was prepared by the method of Example 20 using 2-[(R)-6-(6-chloropyridine-3-sulfonyl)-1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalene-4a-ylmethoxy]-ethanol and (R)-3-fluoropyrrolidine. 1H NMR (400 MHz, CHCl3-d): δ 8.55 (d, 1H), 7.78 (dd, 1H), 7.51-7.40 (m, 3H), 7.15 (t, 2H), 6.41 (d, 1H), 6.28 (s, 1H), 5.40 (d, 1H), 4.26 (d, 1H), 3.91 (s, 2H), 3.74-3.61 (m, 6H), 3.55 (d, 1H), 3.48 (d, 1H), 3.21 (d, 1H), 3.13 (d, 1H), 2.49-2.38 (m, 2H), 2.21 (d, 1H), 2.07 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:7](=[O:19])[NH:6][C:5]2=[O:20].[H-].[Na+].[Br:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[C:26]([F:32])[CH:25]=1.O>CN(C)C=O>[Br:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:6]2[C:5](=[O:20])[C:4]3[C:9](=[CH:10][C:11]([Cl:12])=[C:2]([Cl:1])[CH:3]=3)[N:8]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:7]2=[O:19])=[C:26]([F:32])[CH:25]=1
Reactant: CCOC(=O)Cn1c(=O)[nH]c(=O)c2cc(Cl)c(Cl)cc21
Reactant: Fc1cc(Br)ccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cn1c(=O)n(Cc2ccc(Br)cc2F)c(=O)c2cc(Cl)c(Cl)cc21
Yield: 92.5 %

Procedure:
To a suspension of ethyl 2-(6,7-dichloro-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-1-yl)acetate (2.0 g) in N,N-dimethylformamide (50 ml) was added sodium hydride (60% in mineral oil, 288 mg) at room temperature with stirring and the mixture was stirred at the same temperature for 1 hour. To this mixture was added 4-bromo-2-fluorobenzyl bromide (1.93 g) at room temperature with stirring and the mixture was stirred at the same temperature for 2 hours. The solvent was removed to give a residue, which was poured into water. The resulting precipitates were collected by filtration and washed with n-hexane to give ethyl 2-[3-(4-bromo-2-fluorobenzyl)-6,7-dichloro-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-1-yl]acetate (2.94 g).
Reaction SMILES: Br[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[N:5]=[C:4]([CH2:15][CH2:16][CH3:17])[CH:3]=1.[CH3:18][C:19]1[C:23](B(O)O)=[C:22]([CH3:27])[O:21][N:20]=1.C([O-])([O-])=O.[K+].[K+].[I-].[Na+]>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.O1CCOCC1>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([N:6]2[C:2]([C:23]3[C:19]([CH3:18])=[N:20][O:21][C:22]=3[CH3:27])=[CH:3][C:4]([CH2:15][CH2:16][CH3:17])=[N:5]2)=[CH:8][CH:9]=1
Reactant: Cc1noc(C)c1B(O)O
Reactant: CCCc1cc(Br)n(-c2ccc(OC)cc2)n1
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: [I-]
Solvent: C1COCCO1
Product: CCCc1cc(-c2c(C)noc2C)n(-c2ccc(OC)cc2)n1
Temperature: 150 °C
Yield: 58.9 %

Procedure:
5-Bromo-1-(4-methoxyphenyl)-3-propyl-1H-pyrazole (287 mg, 0.97 mmol), 3,5-dimethylisoxazol-4-ylboronic acid (274 mg, 1.94 mmol), K2CO3 (806 mg, 5.83 mmol), sodium iodide (291 mg, 1.94 mmol) and Pd(PPh3)4 (90 mg, 0.08 mmol) were mixed with degassed dioxane (1 mL) and degassed H2O (1 mL) under nitrogen in a microwave vial. The reaction was heated at 150° C. for 20 min. The crude mixture was diluted with CH2Cl2 and washed with water. The organic phase was separated from the water phase, dried using a phase separator and evaporated. The crude product was purified on silica column (CH2Cl2:Et2O, 90:10) to give 4-(1-(4-methoxyphenyl)-3-propyl-1H-pyrazol-5-yl)-3,5-dimethylisoxazole (178 mg, 59%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][C@H:2]1[CH2:7][OH:8].[C:9]([Si:13]([CH3:16])([CH3:15])Cl)([CH3:12])([CH3:11])[CH3:10].N1C=CN=C1>ClCCl>[Si:13]([O:8][CH2:7][C@@H:2]1[CH2:3][O:4][CH2:5][CH2:6][NH:1]1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC[C@@H]1COCCN1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1COCCN1
Yield: 90 %

Procedure:
(3R)-Morpholine-3-methanol (84.8 mg, 0.72 mmol), t-butyldimethylchlorosilane (0.11 g, 0.72 mmol), and imidazole (59.1 mg, 0.87 mmol) were allowed to react in 1 mL of dichloromethane at room temperature for 2 hours. The reaction product was purified by silica gel chromatography (dichloromethane:methanol:acetone=15:1:0.5) to obtain (3S)-3-(t-butyldimethylsilyloxy)methylmorpholine (0.15 g, 92%) as a colorless oil.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]2[CH:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]3[O:21][C:4]=2[CH:3]=1.C(N1CC=CC(O)C1)(OC(C)(C)C)=[O:23].BrC1C=C(OC)C=CC=1O>>[OH:23][C:7]1[CH:2]=[CH:3][C:4]2[O:21][CH:9]3[CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13][CH:8]3[C:5]=2[CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CC=CC(O)C1
Reactant: CC(C)(C)OC(=O)N1CCC2c3ccc(O)cc3OC2C1
Agent: COc1ccc(O)c(Br)c1
Product: CC(C)(C)OC(=O)N1CCC2c3cc(O)ccc3OC2C1

Procedure:
Tert-butyl 6-hydroxy-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate was synthesized as described for tert-butyl 7-hydroxy-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate starting N-boc-3-hydroxy-1,2,3,6-tetrahydropyridine and 2-bromo-4-methoxyphenol.