Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S-:2].[Na+].Cl[C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1.ClC1N=CC=CN=1>CN(C=O)C.O>[CH3:1][S:2][C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1
Reactant: C[S-]
Reactant: Clc1nccc(-c2ccccc2)n1
Agent: Clc1ncccn1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1nccc(-c2ccccc2)n1
Reaction time: 0.25 h

Procedure:
To a stirred suspension of sodium methanethiolate (0.35 g) in DMF (5 ml) at 0° C. was added dropvise a solution of 2-chloro-4-phenylpyrimidine (0.86 g, prepared from 2-chloropyrimidine according to the method of D B Harden et al., J. Org. Chem., 1988, 53, 4137) in DMF (5 ml). Stirring was continued at 0° C. for 15 minutes and then the temperature was allowed to rise to room temperature. After a further 2 hours, the reaction mixture was diluted with water and then extracted with ether (×3). The combined ether extracts were washed with water, dried, filtered and evaporated to give 2-methylthio-4-phenylpyrimidine (0.76 g) as a brown solid which was used directly in the next stage.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[NH:8][C:9]2[C:14]([C:15]=1[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N+:23]([O-:25])=[O:24])=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:6].[CH3:26]I.O>CCCCCC.C1COCC1>[CH3:3][O:4][C:5]([C:7]1[N:8]([CH3:26])[C:9]2[C:14]([C:15]=1[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N+:23]([O-:25])=[O:24])=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:6]
Reactant: CI
Reactant: COC(=O)c1[nH]c2ccccc2c1Oc1ccccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)c1c(Oc2ccccc2[N+](=O)[O-])c2ccccc2n1C
Reaction time: 3 h

Procedure:
6.73 g (0.16 mole) of 57% sodium hydride in mineral oil was washed with hexane and suspended in 500 ml of THF. To this was added 43.4 g (0.139 mole) of methyl-3-[o-nitrophenoxy]-indole-2-carboxylate. The mixture was stirred at reflux for 1 hour, then 42.6 g (0.3 mole) of methyl iodide was added and reflux continued for 3 hours. Water (5 ml) was added, the THF removed by distillation and the gummy residue recrystallized from isopropanol to give analytical material as yellow needles, mp. 119°-21°.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=1[CH2:27][CH3:28].[CH3:29][C:30]1([CH3:40])[CH2:34][C:33]2[CH:35]=[CH:36][CH:37]=[C:38]([OH:39])[C:32]=2[O:31]1.[OH-].[K+].CS(C)=O>C(OCC)(=O)C>[CH3:29][C:30]1([CH3:40])[CH2:34][C:33]2[CH:35]=[CH:36][CH:37]=[C:38]([O:39][C:2]3[C:7](=[O:8])[N:6]([CH2:9][C:10]4[CH:15]=[CH:14][C:13]([C:16]5[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=5)=[CH:12][CH:11]=4)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=3[CH2:27][CH3:28])[C:32]=2[O:31]1
Reactant: CCCc1nc(CC)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC1(C)Cc2cccc(O)c2O1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)c(Oc2cccc3c2OC(C)(C)C3)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 150 °C
Reaction time: 12 h
Yield: 39.2 %

Procedure:
A mixture of 4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.45 g), 2,2-dimethyl-2,3-dihydro-1-benzofuran-7-ol (0.25 g), 8 M potassium hydroxide solution (0.19 mL) and dimethyl sulfoxide (8 mL) was stirred at 150° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.21 g, 39%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[C:28]5[C:23](=[CH:24][C:25]([Cl:29])=[CH:26][CH:27]=5)[N:22]([CH3:30])[N:21]=4)[N:18]=3)[N:13](COCC[Si](C)(C)C)[CH:12]=2)=[O:10])[CH2:4][CH2:3]1.FC(F)(F)C(O)=O.C(N)CN>ClCCl>[OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[C:28]5[C:23](=[CH:24][C:25]([Cl:29])=[CH:26][CH:27]=5)[N:22]([CH3:30])[N:21]=4)[N:18]=3)[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)N[C@H]2CC[C@H](O)CC2)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Solvent: ClCCl
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)N[C@H]4CC[C@H](O)CC4)c3n2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 15 h

Procedure:
In a 25 mL round-bottomed flask, 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (trans-4-hydroxycyclohexyl)amide (60 mg, 0.108 mmol) was dissolved in dichloromethane (3 mL). Trifluoroacetic acid (0.2 mL, 2.6 mmol) was added and the orange reaction mixture was stirred at room temperature for 15 h. Additional trifluoroacetic acid (0.7 mL) was added and the reaction stirred for an additional 5 h. The reaction mixture was then concentrated under reduced pressure. The resultant crude solid was dissolved in dichloromethane (3 mL) and ethylenediamine (0.20 mL, 2.96 mmol) was added. The light yellow reaction mixture was stirred at room temperature for 20 h. The reaction mixture was concentrated and the residue was precipitated with water. The suspension was stirred for 1 h and the crude solid collected by filtration. The crude solid was sequentially washed with water, dichloromethane, ethyl acetate, and hexanes to afford 28 mg (60%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (trans-4-hydroxy-cyclohexyl)amide as a light yellow solid. MS: [M+H]+=525; 1H NMR (300 MHz, DMSO-d6) δ: 9.08 (s, 2H), 8.40 (s, 1H), 8.43 (d, J=1.0 Hz, 1H), 8.02 (d, J=1.0 Hz, 1H), 8.01 (s, 1H), 7.28 (dd, J=8.6, 2.0 Hz, 1H), 4.45-4.76 (m, 1H), 4.17 (s, 3H), 3.70-3.96 (m, 1H), 3.43-3.59 (m, 1H), 2.07 (d, J=11.1 Hz, 2H), 1.92 (d, J=10.6 Hz, 2H), 1.18-1.55 (m, 4H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[CH:9][C:10]2[CH2:16][CH:15]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:14]3[CH:23]=[CH:24][CH:25]=[CH:26][C:13]=3[CH2:12][C:11]=2[CH:27]=1)(=O)=O.[O:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]1[O:36][CH2:37][CH2:38][C:39]#[C:40][Sn](CCCC)(CCCC)CCCC.[Li+].[Cl-]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[O:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]1[O:36][CH2:37][CH2:38][C:39]#[C:40][C:7]1[CH:8]=[CH:9][C:10]2[CH:16]=[C:15]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:14]3[CH:23]=[CH:24][CH:25]=[CH:26][C:13]=3[CH2:12][C:11]=2[CH:27]=1
Reactant: CCCC[Sn](C#CCCOC1CCCCO1)(CCCC)CCCC
Reactant: CCOC(=O)CC1Cc2ccc(OS(=O)(=O)C(F)(F)F)cc2Cc2ccccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: CCOC(=O)CC1=Cc2ccc(C#CCCOC3CCCCO3)cc2Cc2ccccc21
Reaction time: 1.5 h
Yield: 83.1 %

Procedure:
A mixture of ethyl (±)-10,11-dihydro-3-(trifluoromethanesulfonyloxy)-5H-dibenzo[a,d]cycloheptene-10-acetate (1.34 g, 3.13 mmole), 4-(2-tetrahydropyranyloxy)-1-tributylstannyl-1-butyne (1.66 g, 3.76 mmole), LiCl (398 mg, 9.39 mmole), bis(triphenylphosphine)palladium dichloride (110 mg, 0.094 mmole), and anhydrous dioxane (31 mL) was heated at reflux under argon. After 1.5 hr, the reaction was concentrated to remove most of the dioxane, and the residue was taken up in Et2O (100 mL). 10% KF (50 mL) was added and the mixture was stirred briskly for 0.5 hr. The aqueous layer was removed and the Et2O layer was filtered through a mixture of celite® and MgSO4. The filtrate was concentrated and the residue was chromatographed on silica gel (10% EtOAc/hexanes) to afford the title compound (1.12 g, 83%) as a pale yellow oil: TLC (20% EtOAc/hexanes) Rf 0.40; 1H NMR (400 MHz, CDCl3) δ 7.21-7.30 (m, 1 H), 7.06-7.20 (m, 5 H), 7.00 (d, J=7.8 Hz, 1 H), 4.69 (t, J=3.6 Hz, 1 H), 4.31 (d, J=15.2 Hz, 1H), 4.11-4.23 (m, 2 H), 3.76-3.97 (m, 4 H), 3.59-3.68 (m, 1 H), 3.48-3.57 (m, 1 H), 3.34 (dd, J=15.2, 4.1 Hz, 1H), 2.97 (dd, J=15.2, 9.5 Hz, 1 H), 2.70 (t, J=7.3 Hz, 2 H), 2.65 (dd, J=15.7, 4.8 Hz, 1 H), 2.51 (dd, J=15.7, 9.5 Hz, 1 H), 1.78-1.92 (m, 1H), 1.68-1.78 (m, 1 H), 1.44-1.68 (m, 4 H), 1.27 (t, J=7.1 Hz, 3 H); MS (ES) m/e 455 (M+Na)+.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:12](=[O:30])[C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:15]([N+:27]([O-])=O)[CH:14]=2)=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH3:11])=[O:9].C([O-])(O)=O.[Na+]>CCOC(C)=O>[Br:1][C:2]1[S:3][C:4]([C:12](=[O:30])[C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[C:15]([NH2:27])[CH:14]=2)=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)Cc1cc(C(=O)c2ccc(C#Cc3ccccc3)c([N+](=O)[O-])c2)sc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)Cc1cc(C(=O)c2ccc(C#Cc3ccccc3)c(N)c2)sc1Br
Yield: 92.4 %

Procedure:
To a solution of 3 (25 mg, 0.05 mmol) in EtOAc (5 mL) was added stannous chloride dihydrate (58 mg, 0.26 mmol). The resulting mixture was refluxed for one hour under N2. The reaction mixture was poured onto ice (5 g), and basified with a saturated NaHCO3 solution to pH 8. The white milky mixture was filtered through a Celite pad to remove tin oxides. The organic layer from the filtrate was dried over MgSO4, filtered, and then concentrated in vacuo. MPLC purification (Hex:EtOAc/4:1) of the crude product gave the desired intermediate methyl (2-bromo-5-(3-amino-4-(phenylethynyl)benzoyl)thiophen-3-yl)acetate as a yellow foam (21 mg, 90%). 1H NMR (400 MHz, CDCl3) δ 7.55 (m, 2H), 7.50 (s, 1H), 7.48 (d, J=1.6 Hz, 1H), 7.38 (m, 3H), 7.17 (m, 2H), 4.40 (brs, 2H), 3.73 (s, 3H), and 3.66 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 186.7, 170.3, 148.1, 143.4, 138.1, 135.9, 135.1, 132.4, 131.8, 129.0, 128.7, 122.9, 122.8, 118.8, 114.5, 112.3, 97.6, 85.3, 52.6, and 35.0; HRMS-ESI calcd C22H16BrNO3S [M+Na] 475.9926. found 475.9923. To a 250 mL flask containing freshly distilled toluene (50 mL) was added methyl (2-bromo-5-(3-amino-4-(phenylethynyl)benzoyl)thiophen-3-yl)acetate (2.93 g, 6.45 mmol) and indium tribromide (1.14 g, 3.22 mmol) under N2. The resulting mixture was refluxed for one hour. The solvent was removed in vacuo. MPLC purification (Hex:EtOAc/4:1) of the crude product gave 4 as a yellow solid (2.50 g, 85%). 1H NMR (400 MHz, CDCl3) δ 9.38 (brs, 1H), 7.98 (s, 1H), 7.69 (d, J=7.8 Hz, 2H), 7.58 (m, 2H), 7.47 (s, 1H), 7.40 (t, J=7.5 Hz, 2H), 7.30 (m, 1H), 6.80 (s, 1H), 3.65 (s, 3H), and 3.59 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 187.4, 170.5, 144.2, 142.3, 136.5, 135.7, 134.9, 133.3, 131.8, 130.9, 129.4, 128.8, 125.9, 121.9, 120.4, 113.5, 100.3, 52.6, and 35.2.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[Cl-].[Cl-].[Cl-].[Al+3].[Br:16]Br.[OH-].[Na+]>C(OCC)(=O)C>[Br:16][C:9]1[C:8]2[CH:7]=[N:6][CH:5]=[CH:4][C:3]=2[C:2]([NH2:1])=[CH:11][CH:10]=1
Reactant: BrBr
Reactant: Nc1cccc2cnccc12
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Nc1ccc(Br)c2cnccc12
Temperature: 80 °C
Reaction time: 2 h
Yield: 69.7 %

Procedure:
5-Aminoisoquinoline (5.50 g, 38.1 mmol) and aluminium trichloride (15.1 g, 113 mmol) were combined and heated at 80° C. in a 3-necked flask equipped with a dropping funnel, stirrer bar, needle and sintered glass tube. Bromine (3.04 g, 19.05 mmol) was dripped onto the sintered glass funnel and the vapour diffused onto the complex over a period of 2 hours. Heating was continued for 2 hours. The suspension was added portionwise to crushed ice and the solution basified with concentrated NaOH solution. The aqueous layer was extracted with ethyl acetate (4×100 mL) and the layers were separated. The organic layers were combined, dried (Na2SO4), filtered and the filtrate was concentrated to give a grey solid. The grey solid was subjected to column chromatography (hexanes:ethyl acetate, 3:1) to provide the title compound (2.96 g, 35%). MS (ESI+) m/z 225 (M+H)+; MS (ESI−) m/z 223 (M−H−; 1H NMR (CDCl3, 300 MHz) δ 4.22 (br s, 2H), 6.83 (d, J 8.1, 1H), 7.25 (s, 1H), 7.54 (d, J 5.8, 1H), 7.61 (d, J 8.1, 1H), 8.59 (d, J 5.8, 1H), 9.56 (s, 1H).
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].[Br:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1>C(N(CC)CC)C>[Br:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](=[O:13])[C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:10][CH:9]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: C#CCCCC
Solvent: CCN(CC)CC
Product: CCCCC#CC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The following were stirred at ambient temperature for about 2 hours 30 minutes, 49 ml of 1-hexyne, 75 ml of triethylamine, 40 mg of cuprous iodide, 40 mg of bis triphenylphosphine palladium dichloride and 9 g of parabromobenzoyl chloride.
Reaction SMILES: C([C:4]1[S:8][C:7]2[S:9][C:10]([C:12]([C:14]3[CH:15]=[C:16]([CH:20]([CH2:24][CH3:25])[C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:11][C:6]=2[CH:5]=1)(O)=O.Cl.C(#N)C>N1C2C(=CC=CC=2)C=CC=1.[Cu]>[S:9]1[C:7]2[S:8][CH:4]=[CH:5][C:6]=2[CH:11]=[C:10]1[C:12]([C:14]1[CH:15]=[C:16]([CH:20]([CH2:24][CH3:25])[C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=1)=[O:13]
Reactant: CCC(C(=O)O)c1cccc(C(=O)c2cc3cc(C(=O)O)sc3s2)c1
Agent: [Cu]
Agent: Cl
Solvent: c1ccc2ncccc2c1
Solvent: CC#N
Product: CCC(C(=O)O)c1cccc(C(=O)c2cc3ccsc3s2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 56.7 %

Procedure:
2-{3-(5-Carboxy-thieno[2,3-b]thien-2-yl)carbonyl-phenyl}butyric acid (15.6 g) and copper powder (1 g) are suspended in quinoline (150 cc) and heated at 195°-200° C. for 20 minutes, and then at the boil for 10 minutes. After cooling, ice (300 g) and a 12N concentrated aqueous solution of hydrogen chloride (100 cc) are added to the reaction mixture, which is extracted three times with methylene chloride (total 600 cc). The combined methylene chloride solutions are washed three times with distilled water (total 300 cc), and then extracted twice with a 2N aqueous solution of sodium hydroxide (total 400 cc) and three times with distilled water (total 600 cc). The combined aqueous alkaline phases are acidified to pH 1 by the addition of a 12N concentrated aqueous solution of hydrogen chloride and extracted three times with methylene chloride (total 450 cc). The combined methylene chloride solutions are washed three times with distilled water (total 300 cc), dried over anhydrous sodium sulphate in the presence of decolourizing charcoal (5 g), filtered and evaporated. The residue obtained (9.3 g) is dissolved in boiling acetonitrile (70 cc). After cooling, starting the crystallization and standing for 1 hour at 4° C., the resulting crystals are filtered off, washed once with iced acetonitrile (15 cc) and dried under reduced pressure (20 mm Hg) at a temperature of about 20° C., in the presence of potassium hydroxide pellets. Crude 2-{3-(thieno[2,3-b]thien-2-yl)carbonyl-phenyl}butyric acid (7.8 g), melting at 143° C., is thus obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[N:13][CH:12]=[CH:11][N:10]=2)=[CH:4][C:3]=1[C@:15]1([CH2:34][F:35])[CH2:20][C@@H:19]([C:21]([F:24])([F:23])[F:22])[O:18][C:17]([NH:25]C(=O)C2C=CC=CC=2)=[N:16]1.N12CCCN=C1CCCCC2>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[N:13][CH:12]=[CH:11][N:10]=2)=[CH:4][C:3]=1[C@:15]1([CH2:34][F:35])[CH2:20][C@@H:19]([C:21]([F:23])([F:24])[F:22])[O:18][C:17]([NH2:25])=[N:16]1
Reactant: O=C(NC1=N[C@](CF)(c2cc(Oc3cnccn3)ccc2F)C[C@@H](C(F)(F)F)O1)c1ccccc1
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: NC1=N[C@](CF)(c2cc(Oc3cnccn3)ccc2F)C[C@@H](C(F)(F)F)O1
Temperature: 60 °C
Reaction time: 1 h
Yield: 56.6 %

Procedure:
To a solution of N-((4S,6S)-4-(2-fluoro-5-(pyrazin-2-yloxy)phenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (85 mg, 0.173 mmol) in MeOH (690 μL) was added 1,8-diazabicyclo-[5.4.0]undec-7-ene (77 μL, 0.518 mmol) dropwise. The reaction mixture was stirred at 60° C. for 1 h, then at 80° C. for another hour. After cooling to room temperature, the crude material was purified by reverse-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 110 Å, 150×30 mm, 0.1% TFA in CH3CN/H2O, gradient 10% to 70% over 30 min. The fractions were combined and concentrated. It was partitioned between DCM and saturated NaHCO3. The aqueous layer was back extracted with DCM and the combined organic was dried (Na2SO4) and concentrated to provide (4S,6S)-4-(2-fluoro-5-(pyrazin-2-yloxy)phenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (38 mg, 0.098 mmol, 56.7% yield) as white solid. MS m/z=389 [M]+. Calculated for C16H13F5N4O2: 388.29.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:30](=[O:31])[N:29]([CH3:32])[C:12]2[N:13]([CH3:28])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:24]=[C:23]([CH2:25][OH:26])[N:22]([CH3:27])[N:21]=1)=[CH:16][CH:15]=3.[C:33](Cl)(=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:30](=[O:31])[N:29]([CH3:32])[C:12]2[N:13]([CH3:28])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:24]=[C:23]([CH2:25][O:26][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[N:22]([CH3:27])[N:21]=1)=[CH:16][CH:15]=3
Reactant: Cn1nc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)cc1CO
Reactant: CC(C)(C)C(=O)Cl
Product: Cn1nc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)cc1COC(=O)C(C)(C)C

Procedure:
The process is carried out as indicated in Example 70 above, with the compound from Example 82, 3-(2,4-dichlorophenyl)-6-(5-hydroxymethyl-1-methyl-1H-pyrazol-3-yl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one, and pivaloyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:27]([F:30])([F:29])[F:28])[O:13][N:12]=[C:11]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([C:24]([OH:26])=[O:25])=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(Cl)(=O)C(Cl)=O.O[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=1.C([O-])([O-])=O.[K+].[K+]>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:27]([F:28])([F:30])[F:29])[O:13][N:12]=[C:11]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([C:24]([O:26][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=4)=[O:25])=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Reactant: Oc1ccccn1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Oc1ccccn1)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
To a stirred suspension of 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-1-naphthalenecarboxylic acid (prepared according to the procedure described in WO 2007/079162, 1.50 g, 3.30 mmol) in dichloromethane (15 mL) at room temperature was added oxalyl chloride (0.58 mL, 6.60 mmol) followed by one drop of N,N-dimethylformamide. The reaction mixture was stirred at room temperature for 2 h and then concentrated under vacuum. The residue was dissolved in dichloromethane (10 mL) and added to a stirred suspension of 2-hydroxypyridine (0.38 g, 3.96 mmol) and K2CO3 (1.37 g, 9.90 mmol) in dichloromethane (15 mL) at room temperature. The resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered through a short pad of Celite® diatomaceous filter aid, and the pad was rinsed with dichloromethane. The combined filtrate was concentrated and the residue was purified by column chromatography on silica gel using hexane/EtOAc as eluent to provide the title product as a yellow solid (0.80 g, 46% yield).
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]1[C@@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][NH:12][CH2:11]1)(C(C)(C)C)(C)C.O[C@@H:22]([CH2:33][CH:34]1[CH2:37][CH2:36][CH2:35]1)[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>>[CH:9]([C@@H:10]1[C@@H:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:13][N:12]([C@H:22]([CH2:33][CH:34]2[CH2:37][CH2:36][CH2:35]2)[C:23]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:24])[CH2:11]1)=[O:8]
Reactant: O=C(OCc1ccccc1)[C@@H](O)CC1CCC1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CNC[C@@H]1c1ccccc1
Product: O=C[C@H]1CN([C@H](CC2CCC2)C(=O)OCc2ccccc2)C[C@@H]1c1ccccc1

Procedure:
The title compound was prepared from 3-(R)-(t-butyldimethylsilyloxymethyl)-4-(S)-phenyl pyrrolidine (from EXAMPLE 1, Step E) and 2-(S)-hydroxy-3-(cyclobutyl)propanoic acid, benzyl ester (from EXAMPLE 25, Step A) using procedures analogous to those described in EXAMPLE 1, Steps G-I. For the title compound: 1H NMR (300 MHz) δ 1.542.08 (m, 8H), 2.31 (m, 1H), 2.75 (t, J=8.6 Hz, 1H), 2.96 (m, 1H), 3.11-3.35 (m, 4H), 3.56 (q, J=7.9 Hz, H3), 5.16 (s, 2H), 7.19-7.39 (m, 10H), 9.63 (d, J=2.2 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:11])[N:4]([CH3:10])[C:5](=[O:9])[NH:6][C:7]=1[NH2:8].[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.C([BH3-])#N.[Na+]>O.C(O)(=O)C>[NH2:8][C:7]1[NH:6][C:5](=[O:9])[N:4]([CH3:10])[C:3](=[O:11])[C:2]=1[NH:1][CH2:17][C:16]1[CH:19]=[CH:20][C:13]([Cl:12])=[CH:14][CH:15]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: Cn1c(=O)[nH]c(N)c(N)c1=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cn1c(=O)[nH]c(N)c(NCc2ccc(Cl)cc2)c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 41.7 %

Procedure:
To a solution of 5,6-diamino-3-methylpyrimidine-2,4(1H,3H)-dione (0.8 g, 5.13 mmol) in water (10 mL) and acetic acid (0.5 mL) was added 4-chlorobenzaldehyde (0.72 g, 5.14 mmol), the mixture was stirred at room temperature for 5 h. The mixture was cooled to 0° C., sodium cyanoborohydride (0.3 g, 4.76 mmol) was added and the resulting mixture was stirred at room temperature overnight. The mixture was concentrated and filtered, and the filter cake was washed with methanol, dried in vacuo to give 6-amino-5-(4-chlorobenzylamino)-3-methylpyrimidine-2,4(1H,3H)-dione (0.6 g, 42.9% yield) as yellow solid. LCMS MH+ 281.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][NH2:12])=[CH:5][CH:4]=1.[ClH:13].NCCC1C=CC(OC)=C2C=1[CH2:19][C:20](=[O:28])[NH:21]2>>[ClH:13].[NH2:12][CH2:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]2[C:5]=1[CH2:19][C:20](=[O:28])[NH:21]2
Reactant: COc1ccc(CCN)c2c1NC(=O)C2
Reactant: COc1ccc(CCCN)cc1
Agent: Cl
Product: COc1ccc(CCCN)c2c1NC(=O)C2

Procedure:
Using 50 g of p-methoxyphenylpropylamine for the starting material of Example 1 gives 4-(3-aminopropyl)-7-methoxy-2(3H)-indolone hydrochloride. This material (3 g) was converted to the base and alkylated using methyl formate-formaldehyde at reflux to give 4-(3-dimethylaminopropyl)-7-methoxy-2(3H)-indolone hydrochloride and, after treatment with boron tribromide in methylene chloride at -20°, 4-(3-dimethylaminopropyl)-7-hydroxy-2(3H)-indolone hydrobromide.