Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[NH:6][CH:5]=[C:4]([C:9]([NH:11][CH2:12][CH2:13][OH:14])=[O:10])[CH:3]=1.IC.[C:17](=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Br:1][C:2]1[C:7](=[O:8])[N:6]([CH3:17])[CH:5]=[C:4]([C:9]([NH:11][CH2:12][CH2:13][OH:14])=[O:10])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(NCCO)c1c[nH]c(=O)c(Br)c1
Agent: [K+]
Solvent: CS(C)=O
Solvent: CI
Product: Cn1cc(C(=O)NCCO)cc(Br)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-bromo-N-(2-hydroxyethyl)-6-oxo-1,6-dihydropyridine-3-carboxamide (400 mg, 1.532 mmol), iodomethane (0.114 mL, 1.839 mmol), and potassium carbonate (212 mg, 1.532 mmol) in DMSO (5 mL) was stirred at room temperature overnight. The reaction mixture was subsequently filtered and purified via preparative HPLC, eluting with a gradient of 1-30% ACN in H2O (containing 10 mM NH4HCO3) to give the title compound.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[OH:17])=[N:8][C:7]=2[CH:18]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.Cl[CH:33]([F:35])[F:34]>O>[F:34][CH:33]([F:35])[O:17][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:11]=1[C:9]1[O:10][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:19])([F:1])[F:20])=[CH:18][C:7]=2[N:8]=1
Reactant: Oc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Reactant: FC(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)Oc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 0.50 g of 4-[5-(trifluoromethyl)benzoxazole-2-yl]pyridin-3-ol, 1.23 g of potassium carbonate and 14 ml of DMF was stirred while heating at 70° C. for three hours with chlorodifluoromethane gas injected. By stopping injection of gas, the mixture was cooled to room temperature and allowed to stand overnight. Water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.11 g of 2-(3-difluoromethoxypyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 126”).
Reaction SMILES: S([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)([O-])(=O)=O.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.CCOCC.[C:23]1(C)[CH:28]=CC=[CH:25][CH:24]=1>>[CH2:9]1[C:8]2[C:7](=[CH:6][CH:5]=[CH:11][CH:10]=2)[C:23]([CH2:24][CH2:25][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:28]1
Reactant: Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: C1CCNCC1
Solvent: CCOCC
Product: C1=C(CCN2CCCCC2)c2ccccc2C1
Yield: 99 %

Procedure:
The crude tosylate prepared as described in part B above (41.5 g, 0.13 M) and piperidine (28 g, 0.33 M) in 200 ml toluene are heated under reflux overnight. Ether is added to the warm reaction mixture until crystals begin forming. After cooling, the solid is removed by filtration and washed several times with ether. The filtrate and washes are combined and the solvents removed in vacuo. The oily residue is dissolved in ether, a small amount of insoluble material is removed by filtration, and the ether is removed from the filtrate leaving 29.7 g (99%) of brown oil. The sample is purified by distillation at reduced pressure recovering 86% as a yellow oil boiling 115°/0.05 mm. to 130°/0.1 mm.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([NH2:16])=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=1.[H-].[Na+].Cl[CH2:22][CH2:23][S:24](Cl)(=[O:26])=[O:25].O>C1COCC1.CCCCCC>[F:18][C:2]([F:1])([F:17])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:11]3=[N:16][S:24](=[O:26])(=[O:25])[CH2:23][CH2:22][N:12]3[CH:13]=[CH:14][CH:15]=2)=[CH:8][CH:9]=1
Reactant: O=S(=O)(Cl)CCCl
Reactant: Nc1ncccc1-c1ccc(OC(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: O=S1(=O)CCN2C=CC=C(c3ccc(OC(F)(F)F)cc3)C2=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.2 %

Procedure:
A mixture of 3-[4-(trifluoromethoxy)phenyl]pyridin-2-amine (350 mg) in dehydrated THF (5 mL) was added to a mixture of sodium hydride (60%, 275 mg) and 2-chloroethanesulfonyl chloride (673 mg) in dehydrated THF (5 mL) under ice-cooling. The reaction mixture was stirred at room temperature overnight, and water and hexane were added. The resulting precipitate was collected by filtration, and washed with water and diisopropyl ether to give the title compound (333 mg) as a white solid. The obtained solid was crystallized from THF, acetonitrile and diisopropyl ether to give a white solid.
Reaction SMILES: [C:1]([OH:11])(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[Br:12]Br.P(Cl)(Cl)Cl>C(OCC)(=O)C>[Br:12][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[C:1]([OH:11])=[O:10]
Reactant: BrBr
Reactant: CCCCCCCCC(=O)O
Solvent: ClP(Cl)Cl
Solvent: CCOC(C)=O
Product: CCCCCCCC(Br)C(=O)O
Yield: 90.4 %

Procedure:
To a mixture of nonanoic acid (20 g, 126 mmol) and bromine (24.3 g 152 mmol) was added phosphorous trichloride (5.2 g, 38 mmol) slowly over 0.5 hour. The mixture was refluxed for 3 days and then diluted with ethyl acetate (200 mL). The organic phase was washed with aqueous saturated NaHSO3 (3×), separated, dried over anhydrous sodium sulfate, and the solvent removed in vacuo to yield 27.0 g of the title compound as a brown oil. 1H NMR (CDCl3, 60 MHz) δ0.70 (m, 3H), 1.20 (m, 9H), 1.90 (m, 3H), 4.13 (m, 1H), 10.80 (br s, 1H).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:23]([C:24](OC)=[O:25])=[C:22]([CH:28]([CH3:30])[CH3:29])[N:21]=[C:20]3[NH:31][CH:32]=[CH:33][C:19]=23)=[CH:14][CH:13]=1.O.C(OCC)(=O)C>C1(C)C=CC=CC=1>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:23]([CH2:24][OH:25])=[C:22]([CH:28]([CH3:30])[CH3:29])[N:21]=[C:20]3[NH:31][CH:32]=[CH:33][C:19]=23)=[CH:14][CH:13]=1
Reactant: COC(=O)c1c(C(C)C)nc2[nH]ccc2c1-c1ccc(F)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)c1nc2[nH]ccc2c(-c2ccc(F)cc2)c1CO
Reaction time: 1 h

Procedure:
100 ml of a 1.5 M solution of diisobutylaluminum hydride in toluene are added slowly at -78° C. under argon to a suspension of 15.6 g (50 mmol) of the compound from Example VI in 700 ml of toluene, which leads to a clear solution. After 1 h, 40 ml of 1.5 M diisobutylaluminum hydride solution are added at the same temperature and the mixture is stirred for a further hour. It is warmed to 0°-5° C. using a water bath and stirred at this temperature for 1 h. 150 ml of water and 100 ml of ethyl acetate are cautiously added, and the mixture is stirred at room temperature for 1 h and filtered off with suction using kieselguhr. The phases are separated, the aqueous phase is extracted with ethyl acetate and the combined organic phases are washed with saturated sodium chloride solution. The solution is dried over sodium sulphate, concentrated to dryness in vacuo and the residue which remains is thoroughly stirred in dichloromethane.
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2](OCC)=O.[CH2:11]([O:18][CH2:19][C:20]([O:22]CC)=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H-].[Na+].Br.[CH3:28][O:29][CH2:30][CH2:31][N:32]1[CH2:36][CH2:35][N:34]=[C:33]1[NH2:37]>>[CH2:11]([O:18][C:19]1[C:20](=[O:22])[N:34]2[CH2:35][CH2:36][N:32]([CH2:31][CH2:30][O:29][CH3:28])[C:33]2=[N:37][C:2]=1[C:1]([O:8][CH2:9][CH3:10])=[O:7])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: COCCN1CCN=C1N
Reactant: CCOC(=O)COCc1ccccc1
Agent: Br
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCN2CCOC
Yield: 12.4 %

Procedure:
Reaction of the adduct of diethyl oxalate (16.95 g, 0.116 mol), ethyl benzyloxyacetate (22.53 g, 0.116 mol) and sodium hydride (5.10 g of a 60% dispersion in mineral oil, 0.127 mol) with 1-(2-methoxyethyl)-4,5-dihydro-1H-imidazol-2-amine hydrobromide (26.0 g, 0.116 mol) as described for intermediate 1 gave 5.37 g (12% yield) of the title ester as a clear oil. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.31 (3H, t, J=7.1 Hz, CH3), 3.38 (3H, s, OCH3), 3.61 (4H, s, 2×CH2), 3.84 (2H, t, J=8.9 Hz, CH2), 4.14 (2H, t, J=8.9 Hz, CH2), 4.32 (2H, q, J=7.1 Hz, OCH2), 5.09 (2H, s, OCH2), 7.3-7.38 (3H, m, aromatics), 7.49 (2H, m, aromatics). MS (ESI+) m/e 374 [M+H+].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[C:13]([NH2:16])[N:14]=[CH:15][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)[CH3:20].[OH-].[Na+].C(Cl)Cl>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[C:13]([NH:16][C:25](=[O:26])[C:24]3[CH:28]=[CH:29][C:21]([CH2:19][CH3:20])=[CH:22][CH:23]=3)[N:14]=[CH:15][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(N)ncc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCc1ccc(C(=O)Nc2ncc3c(n2)CCN(C(=O)OC(C)(C)C)C3)cc1
Reaction time: 2 h
Yield: 83.5 %

Procedure:
2-Amino-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester 501 mg (2.0 mmol) was added at 0° C. to a solution of 4-ethylbenzoic acid chloride 296 μl (2.0 mmol) in pyridine (25 ml) and stirring was performed for 2 h at 0° C. and then overnight at RT under nitrogen as inert gas. After the addition of aqueous 1 M NaOH (40 ml) and stirring for 20 minutes, CH2Cl2 (50 ml) was added and the aqueous phase extracted with CH2Cl2 (3×20 ml). The combined organic phases were dried over Na2SO4. After filtration and removal of the solvent, purification was performed by means of column chromatography and the product 2-(4-ethyl-benzoylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester 640 mg (1.67 mmol, 84% of theoretical) was obtained.
Reaction SMILES: N1C=[CH:4][CH:3]=[C:2]1[C:6](Cl)=O.[CH3:9][N:10]([CH3:18])[C:11]([C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)=[O:12]>>[CH3:9][N:10]([CH3:18])[C:11]([C:13]1[N:14]([CH2:6][CH2:2][CH2:3][CH3:4])[CH:15]=[CH:16][CH:17]=1)=[O:12]
Reactant: O=C(Cl)c1ccc[nH]1
Reactant: CN(C)C(=O)c1ccc[nH]1
Product: CCCCn1cccc1C(=O)N(C)C

Procedure:
Likewise, by the method of part B of this Preparation, pyrrole-2-carbonyl chloride, obtained as described by R. J. Boatman et al., in J. Org. Chem. 41, p. 3050 (1976), is converted into N,N-dimethylpyrrole-2-carbox-amide, m.p. 100.5°-102° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:10]=1[O:11][C:12]1[CH:13]=[C:14]([O:23][CH3:24])[CH:15]=[CH:16][C:17]=1[CH2:18]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][N:26]([CH2:30][CH2:31]Cl)[CH2:27][CH2:28][Cl:29]>>[ClH:29].[CH2:1]([O:8][C:9]1[C:10]2[O:11][C:12]3[C:17]([C:18]4([CH2:31][CH2:30][N:26]([CH3:25])[CH2:27][CH2:28]4)[C:19]=2[CH:20]=[CH:21][CH:22]=1)=[CH:16][CH:15]=[C:14]([O:23][CH3:24])[CH:13]=3)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(CCCl)CCCl
Reactant: COc1ccc2c(c1)Oc1c(cccc1OCc1ccccc1)C2
Product: COc1ccc2c(c1)Oc1c(OCc3ccccc3)cccc1C21CCN(C)CC1
Product: Cl

Procedure:
5-Benzyloxy-3-methoxyxanthene is reacted with N-methyldi-(2-chloroethyl)amine using the method described in Example 1 to give 4-benzyloxy-6-methoxy-1'-methylxanthene-9-spiro-4'-piperidine hydrochloride which is used without further purification.
Reaction SMILES: [C:1]1([S:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([S:17][CH2:18][C:19]#[CH:20])=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.O.C1(C)C=CC(S(O)(=O)=[O:30])=CC=1>COCCOC>[C:1]1([S:7]([O:10][C:11]2[CH:12]=[CH:13][C:14]3[S:17][CH:18]=[C:19]([CH2:20][OH:30])[C:15]=3[CH:16]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C#CCSc1ccc(OS(=O)(=O)c2ccccc2)cc1
Solvent: O
Solvent: COCCOC
Product: O=S(=O)(Oc1ccc2scc(CO)c2c1)c1ccccc1
Reaction time: 2 h
Yield: 187.8 %

Procedure:
The compound (3) (65.47 g, 183 mmol) obtained in above (2) was dissolved in 1,2-dimethoxyethane (1.6L) and the solution was refluxed for 4 hours. To the solution were added water (64 ml) and p-toluenesulfonic acid monohydrate (19.2 g, 100 mmol) and refluxing was continued for 2 hours. The reaction mixture was concentrated under reduced pressure. After water (200 ml) was added to the resulting oil, the mixture was extracted with ethyl acetate (300 ml). The organic layer was washed with aqueous sodium hydrogen carbonate and water, dried over anhydrous magnesium sulfate and then the solvent was distilled off under reduced pressure to provide 60.18 g of the title compound (4) as oil. Crude yield: 103%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[C:5]([NH:7][C:8]1[CH:9]=[C:10]([NH:15][C:16]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[N:24]=[CH:23][CH:22]=[CH:21]3)=[O:17])[CH:11]=[CH:12][C:13]=1[CH3:14])=[O:6].[N:31]1([CH2:37][CH2:38]Cl)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[N:31]1([CH2:37][CH2:38][O:1][C:2]2[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=2)[C:5]([NH:7][C:8]2[CH:9]=[C:10]([NH:15][C:16]([C:18]3[CH:19]=[C:20]4[C:25](=[CH:26][CH:27]=3)[N:24]=[CH:23][CH:22]=[CH:21]4)=[O:17])[CH:11]=[CH:12][C:13]=2[CH3:14])=[O:6])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: ClCCN1CCCCC1
Reactant: Cc1ccc(NC(=O)c2ccc3ncccc3c2)cc1NC(=O)c1cccc(O)c1
Product: Cc1ccc(NC(=O)c2ccc3ncccc3c2)cc1NC(=O)c1cccc(OCCN2CCCCC2)c1
Yield: 55 %

Procedure:
Using an analogous procedure to that described in Example 7, N-[3-(3-hydroxybenzamido)-4-methylphenyl]quinoline-6-carboxamide was reacted with 2-piperidinoethyl chloride to give the title compound in 55% yield; NMR Spectrum: (DMSOd6) 1.39 (m, 2H), 1.49 (s, 4H), 2.2 (s, 3H), 2.42 (s, 4H), 2.65 (t, 2H), 4.15 (t, 2H), 7.15 (m, 1H), 7.26 (d, 1H), 7.41 (t, 1H), 7.55 (m, 2H), 7.62 (m,2H),7.86 (s, 1H), 8.12 (d, 1H), 8.24 (m, 1H), 8.52 (m, 1H), 8.61 (s, 1H), 8.99 (d, 1H), 9.89 (s, 1H), 10.48 (s, 1H); Mass Spectrum: M+H+ 509.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:26])[C:15]2[C:20]([NH:21][CH:22]([CH3:24])[CH3:23])=[CH:19][CH:18]=[C:17]([Cl:25])[N:16]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)=O)C.CO.C1(C)C=CC=CC=1>ClCCl>[CH3:26][N:14]([CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[C:15]1[C:20]([NH:21][CH:22]([CH3:24])[CH3:23])=[CH:19][CH:18]=[C:17]([Cl:25])[N:16]=1
Reactant: CC(C)Nc1ccc(Cl)nc1N(C)C1CCN(Cc2ccccc2)CC1
Agent: CC(Cl)OC(=O)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: CC(C)Nc1ccc(Cl)nc1N(C)C1CCNCC1

Procedure:
1-Benzyl-4-[N-methyl-N-(3-isopropylamino-6-chloro-2-pyridinyl)amino]piperidine (EXAMPLE 184, 1.60 g, 4.84 mmol) is dissolved in dichloromethane (0.2M) and cooled to 0°. 1-Chloroethyl-chloroformate (0.57 ml, 5.32 mmol) is added dropwise. The mixture is allowed to warm to 20°-25°, then refluxed one half hour. The solvent is removed to one third volume, 15 ml methanol is added and the mixture is refluxed 2 hr. Extraction with chloroform, drying the extract over sodium sulfate and removal of the solvent gives the crude product. Flash column chromatography (silica gel, 100 g; methanol/chloroform (10/90)) gives the title compound, NMR (300 MHz, CD3OD) 6.88, 3.49, 3.23, 2.87, 2.50, 1.95, 1.70 and 1.12δ.
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]([CH3:22])[CH2:7][CH:8]([NH:18][C:19](=[O:21])[CH3:20])[C:9]1[S:10][C:11]([C:14]#[C:15][CH2:16][OH:17])=[CH:12][CH:13]=1)(=[O:3])[CH3:2].[Cl:23][C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1.C(OC(N=NC(OCC)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[C:1]([O:4][CH2:5][C@H:6]([CH3:22])[CH2:7][CH:8]([NH:18][C:19](=[O:21])[CH3:20])[C:9]1[S:10][C:11]([C:14]#[C:15][CH2:16][O:17][C:27]2[CH:28]=[CH:29][C:24]([Cl:23])=[CH:25][CH:26]=2)=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(=O)NC(C[C@@H](C)COC(C)=O)c1ccc(C#CCO)s1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)NC(C[C@@H](C)COC(C)=O)c1ccc(C#CCOc2ccc(Cl)cc2)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.1 %

Procedure:
(2R)-Acetylamino-2-methyl-4-[5-(3-hydroxypropynyl)thiophen-2-yl]butyl acetate (285 mg, 0.88 mmol) obtained in Example 52(a) and 4-chlorophenol (136 mg, 1.06 mmol) were dissolved in anhydrous tetrahydrofuran (5 ml), and then azodicarboxylic acid diethylester (230 mg, 1.32 mmol) and triphenylphosphine (346 mg, 1.32 mmol) were added thereto in an ice bath followed by stirring for 4 hours at room temperature. Into the reaction mixture was poured water, and the resulting solution was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on a silica gel column (elution solvent; hexane:ethyl acetate=2:1-1:3) to give (2R)-acetylamino-2-methyl-4-{5-[3-(4-chlorophenoxy)propynyl]thiophen-2-yl}butyl acetate (195 mg, 51% yield) as a yellow oil. This product was dissolved in 6 ml of a mixture solvent (tetrahydrofuran:methanol:water=1:1:1), and lithium hydroxide monohydrate (370 mg, 8.82 mmol) was added thereto followed by stirring for 6 hours at 50° C. The reaction solution was poured into water, extracted with dichloromethane, and after the dichloromethane layer was dried over anhydrous sodium sulfate, the solvent was evaporated in vacuo. The residue (175 mg, 0.50 mmol) was dissolved in ethyl acetate (5 ml), and oxalic acid (45 mg, 0.50 mmol) was added thereto to precipitate crystals. The crystals were filtered off to afford the title compound (198 mg, 86% yield) as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C@:9]1([CH2:28][F:29])[CH2:14][C@@H:13]([C:15]([F:18])([F:17])[F:16])[O:12][C:11]([NH:19]C(=O)C2C=CC=CC=2)=[N:10]1.[Cl:30][C:31]1[CH:36]=[C:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:34]=[C:33](Cl)[N:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[Cl:30][C:31]1[N:32]=[C:33]([O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C@:9]3([CH2:28][F:29])[CH2:14][C@@H:13]([C:15]([F:17])([F:16])[F:18])[O:12][C:11]([NH2:19])=[N:10]3)[CH:4]=2)[CH:34]=[C:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:36]=1
Reactant: Clc1cc(-c2ccccc2)cc(Cl)n1
Reactant: O=C(NC1=N[C@](CF)(c2cc(O)ccc2F)C[C@@H](C(F)(F)F)O1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: NC1=N[C@](CF)(c2cc(Oc3cc(-c4ccccc4)cc(Cl)n3)ccc2F)C[C@@H](C(F)(F)F)O1
Temperature: 100 °C
Yield: 2.9 %

Procedure:
In round-bottomed flask were added N-((4S,6S)-4-(2-fluoro-5-hydroxyphenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (225 mg, 0.543 mmol), 2,6-dichloro-4-phenylpyridine (146 mg, 0.652 mmol), cesium carbonate (230 mg, 0.706 mmol) in DMSO (1358 μl). The flask was heated in 100° C. oil bath for 7 h. After cooling to RT, the reaction mixture was partitioned between EtOAc and water. The aqueous layer was back extracted with EtOAc (2×) and the combined organics was dried (Na2SO4) and concentrated. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0% to 50% EtOAc in hexane, followed 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 15 min, then neutralized with saturated NaHCO3 and extracted with DCM, to provide (4S,6S)-4-(5-((6-chloro-4-phenylpyridin-2-yl)oxy)-2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (8 mg, 0.016 mmol, 2.96% yield) as a off-white solid.
Reaction SMILES: [C:1](Cl)(=[O:6])/[C:2](=[CH:4]/[CH3:5])/[CH3:3].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1.Cl>C(Cl)Cl>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]2[C:11]=1[CH:4]([CH3:5])[CH:2]([CH3:3])[C:1]2=[O:6]
Reactant: C/C=C(\C)C(=O)Cl
Reactant: COc1ccc(OC)cc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(OC)c2c1C(=O)C(C)C2C
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.4 %

Procedure:
A1Cl3 (64 g, 0.48 mol) and CH2Cl2 (250 ml) (dried with magnesium sulfate) were placed under an argon atmosphere in a 500 ml three necked round bottomed flask fitted with a magnetic stirring apparatus, an addition funnel, an inner thermometer and a reflux condenser. A mixture of tigloyl chloride (33) (42 g, 0.35 mol) and 1,4-dimethoxybenzene (48.4 g, 0.35 mol, dissolved in CH2Cl2 (75 ml)) was added over a period of 1 h at −10° C. under vigorous stirring. After 2 h stirring at −2° C. to −5° C. the mixture was allowed to come to ambient temperature and was stirred overnight. The dark red mixture was then refluxed for 2 h, after cooling to ambient temperature the reaction mixture was poured carefully onto a mixture of concentrated HCl (300 ml) and ice (500 g). Then the resulting yellow mixture was transferred to a separation funnel, the lower CH2Cl2 layer was isolated and the aqueous layer extracted with diethyl ether (3×100 ml). The combined organic layers were dried over magnesium sulfate, filtered, and the solvents removed under reduced pressure to give a dark brown liquid. This residue was distilled using a 15 cm Vigreux column to obtain an orange-yellow light viscous liquid (110-115° C., 0.8 mbar). The liquid was purified via column chromatography [(SiO2, 25×9 cm) eluent: cyclohexane:ethylacetate (1:1)] to afford 2,3-dimethyl-4,7-dimethoxy-1-indanone (36) (9.53 g, 12%), Rf 0.35 (cyclohexane:ethylacetate (5:1)) as an orange liquid. The liquid was found to be a mixture of the two isomers of 4,7-dimethoxy-2,3-dimethyl-1-indanone (36a to 36b approximately 4:1).
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([N:18]([CH2:21][CH3:22])CC)C.COCCO[CH2:28][CH2:29]OC.Cl>O>[C:22]1([CH2:21][NH:18][C:2]2[CH:10]=[C:9]([Cl:11])[C:8]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[C:28]2[C:29](=[CH:10][CH:2]=[CH:3][CH:4]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: COCCOCCOC
Reactant: CS(=O)(=O)c1cc(C(=O)O)c(Cl)cc1Cl
Reactant: CCN(CC)CC
Agent: Cl
Solvent: O
Product: CS(=O)(=O)c1cc(C(=O)O)c(NCc2cccc3ccccc23)cc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2,4-Dichloro-5-methylsulfonylbenzoic acid (5.4 g.; 0.02 mole), 1-aminomethylnaphthylene (3.2 g.; 0.02 mole), and triethylamine (4 ml.) are added to diglyme (50 ml.). The resulting solution is refluxed with stirring for 4 hours. The reaction solution is cooled to room temperature and is slowly added to a solution of concentrated hydrochloric acid (10 ml.) in water (150 ml.) The aqueous layer is decanted from the viscous oil that separates. This viscous oil is dissolved in ethanol (25 ml.) and the resulting solution is poured into water. The tan colored solid which precipitates is collected and dried, yield 5.5 g. (70%). After several recrystallizations from acetonitrile, the 2-(1-naphthylmethyl)amino-4-chloro-5-methylsulfonylbenzoic acid melts at 242°-246° C. (dec. with eff.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:25][C@@H:24]([CH3:26])[N:11]2[C:12]3[CH:13]=[C:14]([C:20]([F:23])([F:22])[F:21])[C:15](Br)=[CH:16][C:17]=3[CH2:18][C@@H:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27]I.C[Li].O>C(OC)(C)(C)C.C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:25][C@@H:24]([CH3:26])[N:11]2[C:12]3[CH:13]=[C:14]([C:20]([F:23])([F:22])[F:21])[C:15]([CH3:27])=[CH:16][C:17]=3[CH2:18][C@@H:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3cc(Br)c(C(F)(F)F)cc3N21
Reactant: CI
Agent: [Li]C
Solvent: O
Solvent: COC(C)(C)C
Solvent: CCOCC
Product: Cc1cc2c(cc1C(F)(F)F)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Temperature: 0 °C
Yield: 67.5 %

Procedure:
(4R,10aR)-8-Bromo-4-methyl-7-trifluoromethyl-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indole-2-carboxylic acid tert-butyl ester (0.38 g, 0.8 mmol) and methyl iodide (0.25 g, 1.6 mmol) were dissolved in tert-butylmethylether (3 mL). A solution of methyl lithium in diethylether (0.66 mL, 1.6 M) was added with cooling (0° C.) and stirring. The mixture was stirred for ½ h at 0° C., water (25 mL) was added and the mixture was extracted with diethylether (2×20 mL). Organic phases were pooled, dried with MgSO4 and the solvent was removed in vacuo. Chromatography on silica gel (n-hexane/diethylether 4:1) yielded the title product as light yellow oil (0.20 g, 63%).