Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2](F)(F)[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([CH:11]([NH2:13])[CH3:12])=[CH:7][CH:6]=1.FC(F)(F)CO[C:20]1[CH:27]=CC(C#N)=C[CH:21]=1>>[CH:3]1([O:4][C:5]2[N:10]=[CH:9][C:8]([CH:11]([NH2:13])[CH3:12])=[CH:7][CH:6]=2)[CH2:27][CH2:20][CH2:21][CH2:2]1
Reactant: CC(N)c1ccc(OCC(F)(F)F)nc1
Reactant: N#Cc1ccc(OCC(F)(F)F)cc1
Product: CC(N)c1ccc(OC2CCCC2)nc1

Procedure:
The title compound was synthesised according to the procedure described for the synthesis of 1-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]ethanamine, step B, starting from 4-(2,2,2-trifluoroethoxy)benzonitrile. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.28-7.34 (m, 2 H) 6.94-7.00 (m, 2 H) 4.70 (q, J=8.78 Hz, 2 H) 3.95 (q, J=6.53 Hz, 1 H) 1.21 (d, J=6.78 Hz, 3 H). MS (ESI) m/z: 220 [M+H]
Reaction SMILES: [CH2:1]([O:17][C:18]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[C:26]([OH:28])=[O:27])=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].O1CC[CH2:31][CH2:30]1>>[CH2:1]([O:17][C:18]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[C:26]([O:28][CH2:30][CH3:31])=[O:27])=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCOC(=O)C1CCCCC1C(=O)O
Reactant: C1CCOC1
Product: CCCCCCCCCCCCCCCCOC(=O)C1CCCCC1C(=O)OCC
Reaction time: 3 h

Procedure:
A mixture of 1,2-cyclohexanedicarboxylic acid monohexadecyl ester (white solid m.p.=54-55° C.) (8 g) (prepared from 1,2-cyclohexanedicarboxylic anhydride (1 eq), hexadecanol (1 eq), triethylamine (1 eq), in ethyl acetate at room temperature for 24 hours) in 50 ml of tetrahydrofuran was treated with oxalyl choloride (5 g) overnight at room temperature. After solvent removal in vacuuo the resultant acid chloride was dissolved in 50 ml of absolute ethanol, and sodium carbonate (2.2 g) was added. The mixture was stirred for 3 hours, filtered and concentrated in vacuuo. The light yellow liquid product was dissolved in hexane and passed through a pad of silica gel. Solvent removal gave cyclohexane-1,2-dicarboxylic acid monoethyl ester monohexadecyl ester (5.3 g) as a clear colorless liquid which forms a waxy solid when cooled to below room temperature.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[C:4]1=[O:17].[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]2[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=2)[CH:19]=1>>[C:12]([C:11]1[CH:10]=[C:9]([CH:16]=[CH:15][CH:14]=1)[CH2:8][N:5]1[CH2:6][CH2:7][C@H:3]([NH:2][S:30]([C:27]2[CH:26]=[CH:25][C:24]([C:20]3[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=3)=[CH:29][CH:28]=2)(=[O:31])=[O:32])[C:4]1=[O:17])#[N:13]
Reactant: O=S(=O)(Cl)c1ccc(-c2cccnc2)cc1
Reactant: N#Cc1cccc(CN2CC[C@H](N)C2=O)c1
Agent: Cl
Product: N#Cc1cccc(CN2CC[C@H](NS(=O)(=O)c3ccc(-c4cccnc4)cc3)C2=O)c1

Procedure:
The title compound is prepared from 3-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)benzonitrile hydrochloride (0.3 g, 1.2 mmol) as in EXAMPLE 24, Part B using 4-pyridin-3-ylbenzenesulfonyl chloride (0.57 g, 2.4 mmol) in place of 6-methoxynaphthalene-2-sulfonyl chloride. The crude product is purified by chromatography (2.5% MeOH/CH2Cl2 to 5% MeOH/CH2Cl2) to obtain a white solid (0.08 g, 0.18 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:14][Mg]Cl>C1COCC1.O>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:11])([F:12])[F:13])=[CH:6][C:3]=1[CH:4]([OH:5])[CH3:14]
Reactant: O=Cc1cc(C(F)(F)F)ccc1Br
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(O)c1cc(C(F)(F)F)ccc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
To a solution of 2-bromo-5-(trifluoromethyl)benzaldehyde (10 g, 39.6 mmol) in THF (40 mL), methyl magnesium chloride (3 M in THF) (26.4 mL, 79.3 mmol) was added at −78° C. dropwise. The reaction was warmed to 25° C. and stirred at this temperature for 1 h under a nitrogen atmosphere. Then the reaction mixture was diluted with water (200 mL) extracted with ethyl acetate (2×200 mL). Organic part was dried over sodium sulfate, filtered and concentrated in vacuum to give the crude compound which was further purified by column chromatography using silica gel (100 to 200 mesh) eluting with 0% to 10% ethyl acetate in hexanes to afford 1-(2-bromo-5-(trifluoromethyl)phenyl)ethanol (10.4 g, 98%) as a clear liquid. MS (ESI, Negative ion) m/z (M−1): 267.0. 1H NMR (400 MHz, DMSO) δ 7.87 (s, 1H), 7.80 (d, J=8.2 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 5.68 (d, J=4.2 Hz, 1H), 5.03-4.94 (m, 1H), 1.32 (d, J=6.3 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:19][C@@H:20]([CH2:25][CH3:26])[C:21]([O:23][CH3:24])=[O:22]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:19][C@@H:20]([CH2:25][CH3:26])[C:21]([O:23][CH3:24])=[O:22])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CC[C@H](N)C(=O)OC
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: Cl
Product: CC[C@H](NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)C(=O)OC

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl (S)-2-aminobutanoate hydrochloride (prepared from (S)-(+)-2-aminobutyric acid (Aldrich) using General Procedure H), the title compound was prepared as a solid (mp=103-106° C.).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH2:10]([O:12][C:13]([CH:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]2[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=2)[NH2:26])=[O:22])[CH2:17][CH2:16]1)=[O:14])[CH3:11]>>[Cl:1][C:2]1[N:7]=[C:6]([NH:26][C:25]2[CH:27]=[CH:28][CH:29]=[C:23]([C:21]([N:18]3[CH2:17][CH2:16][CH:15]([C:13]([O:12][CH2:10][CH3:11])=[O:14])[CH2:20][CH2:19]3)=[O:22])[CH:24]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: CCOC(=O)C1CCN(C(=O)c2cccc(N)c2)CC1
Reactant: Fc1cnc(Cl)nc1Cl
Product: CCOC(=O)C1CCN(C(=O)c2cccc(Nc3nc(Cl)ncc3F)c2)CC1

Procedure:
In a like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 3-[[4-(ethoxycarbonyl)piperidino]carbonyl]aniline were reacted to provide 2-chloro-N4-[3-[[4-(ethoxycarbonyl)piperidino]carbonyl]phenyl]-5-fluoro-4-pyrimidineamine. LCMS: purity: 96%; MS (m/e): 407 (M+).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=2)=[CH:4][NH:3]1.[CH2:19](O)C=C>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[O:1]=[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH:16]=[CH2:19])=[O:13])=[CH:10][CH:9]=2)=[CH:4][NH:3]1
Reactant: CCOC(=O)c1ccc(-c2ccc(=O)[nH]c2)cc1
Reactant: C=CCO
Agent: [Ti+4]
Agent: CC(C)[O-]
Product: C=CCOC(=O)c1ccc(-c2ccc(=O)[nH]c2)cc1

Procedure:
To a solution of ethyl 4-(2-oxo-2H-pyridin-5-yl)benzoate (1.24 g, 5.10 mmoles, reference example 36f) in allyl alcohol (50 mL) was added titanium (IV) isopropoxide. The resulting mixture was heated to 70° C. for seven hours at which point more titanium (IV) isopropoxide (3 mL) was added. After 18 hours the heat was removed and 1N HCl solution (50 mL) was added followed by extraction with CH2Cl2 (200 mL). The organic layer was isolated and concentrated to give the title compound in quantitative yield. MS (ion spray) m/z 256 (M+H)+.
Reaction SMILES: CC(C)([O-])C.[Na+].[CH:7]([C:10]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]([CH3:19])[CH3:18])[C:11]=1[NH2:12])([CH3:9])[CH3:8].Br[C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:30]=1[N:29]=[CH:28][CH:27]=[CH:26]2>C1(C)C=CC=CC=1>[CH:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:10]([CH:7]([CH3:9])[CH3:8])[C:11]=1[NH:12][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:30]=1[N:29]=[CH:28][CH:27]=[CH:26]2)([CH3:19])[CH3:18]
Reactant: Brc1cccc2cccnc12
Reactant: CC(C)c1cccc(C(C)C)c1N
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)c1cccc(C(C)C)c1Nc1cccc2cccnc12
Yield: 38 %

Procedure:
Charge a round bottomed flask equipped with a reflux condenser with tris(dibenzylidene acetone)dipalladium(0)(Pd2(dba)3) (0.090 mmol, Aldrich), racemic 2,2′-bis(diphenylphosphine)-1,1′-binaphthyl (rac-BINAP) (0.207 mmol; Fluka division of Aldrich), and sodium tertiary-butoxide (NaOtBu) (4.05 mmol; Aldrich) in toluene (15 mL). To the resulting suspension add 2,6-diisopropylaniline (2.88 mmol) and 8-bromoquinoline (2.88 mmol), and then heat the resulting mixture under reflux overnight. Pump down the reaction mixture to dryness under vacuum, and purify the resulting crude residue by column chromatography on silica gel eluting with 9:1 pentane:diethyl ether (C5H12:Et2O) to give purified (1) in 38% yield.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:19][C:20]1[CH:28]=[C:27]2[C:23]([C:24]([NH:37][C:38](=[O:42])[CH2:39][CH2:40][CH3:41])=[N:25][N:26]2COCC[Si](C)(C)C)=[CH:22][C:21]=1[C:43]1[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=1.C(OCC)(=O)C>O1CCCC1>[Cl:19][C:20]1[CH:28]=[C:27]2[C:23]([C:24]([NH:37][C:38](=[O:42])[CH2:39][CH2:40][CH3:41])=[N:25][NH:26]2)=[CH:22][C:21]=1[C:43]1[CH:44]=[CH:45][C:46]([CH3:49])=[CH:47][CH:48]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)c(-c3ccc(C)cc3)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC(=O)Nc1n[nH]c2cc(Cl)c(-c3ccc(C)cc3)cc12
Yield: 31.3 %

Procedure:
11.4 cm3 of tetrabutylammonium fluoride as a 1M solution in tetrahydrofuran are added to 870 mg of N-[6-chloro-5-(4-methylphenyl)-1-[[2-(trimethylsilyl)ethoxy]-methyl]-1H-indazol-3-yl]butanamide, described previously, in 20 cm3 of tetrahydrofuran. The medium is then refluxed for 20 hours and the mixture is then allowed to return to room temperature and 20 cm3 of ethyl acetate are added; the organic phase is washed with 2×20 cm3 of saturated aqueous sodium hydrogen carbonate solution and then with 2×20 cm3 of saturated aqueous sodium chloride solution. The organic phase is separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and evaporated to dryness under reduced pressure (2 kPa; 45° C.). The residue is taken up in 10 cm3 of diethyl ether, filtered off on a sinter funnel and then dried under reduced pressure (90 Pa; 50° C.) to give 195 mg of N-[6-chloro-5-(4-methylphenyl)-1H-indazol-3-yl]butanamide in the form of a beige-coloured powder.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH2:12]([CH:14]([CH2:19][CH2:20][CH2:21][OH:22])[C:15]([O:17][CH3:18])=[O:16])[CH3:13].CCOCC>ClCCl>[CH2:12]([CH:14]([CH2:19][CH2:20][CH:21]=[O:22])[C:15]([O:17][CH3:18])=[O:16])[CH3:13]
Reactant: CCC(CCCO)C(=O)OC
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CCC(CCC=O)C(=O)OC
Temperature: 20 °C
Reaction time: 2.5 h
Yield: 59323.1 %

Procedure:
To 50.46 g (0.234 mmol) of pyridinium chlorochromate, under argon, was added 100 mL of dichloromethane followed, with rapid stirring, by 25.0 g (0.156 mmol) of methyl 2-ethyl-5-hydroxypentanoate in 20 mL of dichloromethane. After stirring at 20° C. for 2.5 h, 15 g of silica gel was added followed by 200 mL of ether. Filtration through a 3.5×40 cm silica gel column (60-200 mesh), eluting with ether and concentration at 40° C. under vacuum gave an oil, which was redissolved in 100 mL of dichloromethane. Washing with 3×100 mL of cold 1N HCl, 3×100 mL of satd. NaHCO3, drying over MgSO4, filtration, concentration at 40° C. and distillation gave methyl 2-ethyl-5-oxopentanoate 14.64 g (59%) product, b.p 104°-105° C. (16 mm Hg).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:10][CH2:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:19]=[C:20]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[N:21]([CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[CH:22]=2)=[CH:14][C:13]=1[CH3:34]>>[N:5]1[C:4]2[NH:8][CH2:9][CH2:10][C:3]=2[C:2]([N:31]2[CH2:30][CH2:29][CH:28]([C:20]3[N:21]([CH2:23][CH2:24][N:25]([CH3:26])[CH3:27])[CH:22]=[C:18]([C:15]4[CH:16]=[CH:17][C:12]([F:11])=[C:13]([CH3:34])[CH:14]=4)[N:19]=3)[CH2:33][CH2:32]2)=[N:7][CH:6]=1
Reactant: Clc1ncnc2c1CCN2
Reactant: Cc1cc(-c2cn(CCN(C)C)c(C3CCNCC3)n2)ccc1F
Product: Cc1cc(-c2cn(CCN(C)C)c(C3CCN(c4ncnc5c4CCN5)CC3)n2)ccc1F

Procedure:
The title compound was prepared according to the procedure described for the preparation of A4 by using 4-chloro-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine coupling with 2-(4-(4-fluoro-3-methyl-phenyl)-2-(piperidin-4-yl)-1H-imidazol-1-yl)-N,N-dimethylethanamine. LC-MS (M+H=450, obsd.=450);
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:40]=[CH:41][CH:42]=1)[C:5]([NH:7][CH2:8][CH2:9][O:10][CH:11]1[CH2:27][CH:26]2[C:14]([CH3:39])([CH:15]3[CH:23]([CH:24]([OH:28])[CH2:25]2)[CH:22]2[C:18]([CH3:37])([CH:19]([CH:29]([CH3:36])[CH2:30][CH2:31][C:32]([O:34]C)=[O:33])[CH2:20][CH2:21]2)[CH:17]([OH:38])[CH2:16]3)[CH2:13][CH2:12]1)=[O:6].[OH-].[Na+].Cl>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:40]=[CH:41][CH:42]=1)[C:5]([NH:7][CH2:8][CH2:9][O:10][CH:11]1[CH2:27][CH:26]2[C:14]([CH3:39])([CH:15]3[CH:23]([CH:24]([OH:28])[CH2:25]2)[CH:22]2[C:18]([CH3:37])([CH:19]([CH:29]([CH3:36])[CH2:30][CH2:31][C:32]([OH:34])=[O:33])[CH2:20][CH2:21]2)[CH:17]([OH:38])[CH2:16]3)[CH2:13][CH2:12]1)=[O:6]
Reactant: COC(=O)CCC(C)C1CCC2C3C(O)CC4CC(OCCNC(=O)c5cccc(Br)c5)CCC4(C)C3CC(O)C12C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(CCC(=O)O)C1CCC2C3C(O)CC4CC(OCCNC(=O)c5cccc(Br)c5)CCC4(C)C3CC(O)C12C
Temperature: 25 °C
Reaction time: 6 h
Yield: 93.7 %

Procedure:
600 mg of methyl 4-{3-[2-(3-bromobenzoylamino)ethoxy]-7,12-dihydroxy-10,13-dimethylhexadecahydrocyclopenta[a]phenanthren-17-yl}pentanoate are dissolved in 19 ml of methanol and 4.6 ml of a 1N aqueous NaOH solution are added. The mixture is stirred at RT for 6 hours, then poured into 150 ml of a 2N aqueous HCl solution and extracted 4 times using 150 ml of MTB each time. The extract is dried over Na2SO4 and the solvent is removed in vacuo. 550 mg of a viscous oil are obtained, which are employed further as such.
Reaction SMILES: [C:1]([C:3]1[N:7]=[CH:6][N:5]([C@@H:8]2[O:20][C@H:19]([CH2:21][O:22]C(=O)C)[C@@H:14]([O:15]C(=O)C)[C@H:9]2[O:10]C(=O)C)[N:4]=1)#[N:2].C(N(CC)CC)C.S.C(N)=[S:35]>C(O)C>[C@@H:8]1([N:5]2[CH:6]=[N:7][C:3]([C:1](=[S:35])[NH2:2])=[N:4]2)[O:20][C@H:19]([CH2:21][OH:22])[C@@H:14]([OH:15])[C@H:9]1[OH:10]
Reactant: NC=S
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc(C#N)n2)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: S
Solvent: CCO
Solvent: CCN(CC)CC
Product: NC(=S)c1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)n1
Reaction time: 2 h

Procedure:
A mixture of 3-cyano-1-(2,3,5-tri-O-acetyl-β -D-ribofuranosyl)-1,2,4-triazole (8.0 g., 22.7 mmole), triethylamine (14.0 ml.) and ethanol (200 ml.) was stirred at 25° while hydrogen sulfide gas was passed into the solution for 2 hrs. The solvent was removed and the residue was treated with a solution of sodium methoxide (600 mg.) in methanol (150 ml.) for three hours at 25°. After the solution was neutralized with Bio-Rad AG 50W-X2(H), it as filtered, and the solvent was removed. Crystallization of the product from aqueous ethanol provided 4.5 g. (76.0%) of the thiocarboxamide with M.P. 173-175°.
Reaction SMILES: Br[C:2]1[C:11]([CH3:12])=[C:10]([O:13][CH3:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[O:15][CH3:16].[F:17][C:18]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>C1CCCCC1.CCOC(C)=O>[CH3:16][O:15][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([O:13][CH3:14])=[C:11]([CH3:12])[C:2]=1[C:20]([C:19]1[CH:23]=[CH:24][C:25]([C:27]([F:28])([F:29])[F:30])=[CH:26][C:18]=1[F:17])=[O:21]
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1F
Reactant: COc1c(C)c(Br)c(OC)c2ccccc12
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: COc1c(C)c(C(=O)c2ccc(C(F)(F)F)cc2F)c(OC)c2ccccc12

Procedure:
2-bromo-1.4-dimethoxy-3-methylnaphthalene (300 mg, 1.07 mmol) and commercially available 2-fluoro-4-trifluoromethyl-benzoylchloride (265 mg. 1.17 mmol) were treated according to general procedure 12.1. The resulting yellow oil was purified through flash chromatography (Cyclohexane:EtOAc 10:1). The product was obtained as a yellow oil. Rf(Cyclohexane:EtOAc 10:1)=0.50. Yield=175 mg (42%).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][O:6][C:7]1[C:15]2[CH:14]=[C:13]([C:16]3[O:20][C:19](=[O:21])[NH:18][N:17]=3)[O:12][C:11]=2[CH:10]=[CH:9][CH:8]=1.I[CH:23]([CH3:25])[CH3:24]>>[CH3:24][CH:23]([O:21][C:19]1[O:20][C:16]([C:13]2[O:12][C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([O:6][CH2:5][O:4][CH3:3])[C:15]=3[CH:14]=2)=[N:17][N:18]=1)[CH3:25]
Reactant: COCOc1cccc2oc(-c3n[nH]c(=O)o3)cc12
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Product: COCOc1cccc2oc(-c3nnc(OC(C)C)o3)cc12
Yield: 86.2 %

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 117 using sodium hydride (0.28 g), 5-(4-(methoxymethyloxy)benzo(b)furan-2-yl)-2,3-dihydro-1,3,4-oxadiazol-2-one (1.5 g) and 2-iodopropane (1.1 g), the title compound (1.5 g) was obtained as brown crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([N:23]=[C:24]=[O:25])[CH3:22]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:24]([NH:23][CH2:21][CH3:22])=[O:25])[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN=C=O
Reactant: CC(C)(C)OC(=O)NC[C@H]1CCN(CCCCCN)C1
Solvent: ClCCl
Product: CCNC(=O)NCCCCCN1CC[C@H](CNC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
5-((3R)-3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)-pentylamine (2.0 g) was dissolved in methylene chloride (20 ml) and a solution of ethyl isocyanate (0.55 ml) in methylene chloride was dropwise added under ice-cooling. The mixture was stirred at room temperature for 0.25 hr, and the reaction mixture was concentrated under reduced pressure to give (3R)-3-tert-butoxycarbonylaminomethyl-1-(5-(3-ethylureido)pentyl)pyrrolidine.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[CH3:10][NH:11][CH:12]1[CH2:16][CH2:15][C:14]2([CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]2)[CH2:13]1.CCN(CC)CC>CCO>[Cl:1][C:2]1[N:7]=[C:6]([N:11]([CH3:10])[CH:12]2[CH2:16][CH2:15][C:14]3([CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:17]3)[CH2:13]2)[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: CNC1CCC2(CCCN(C(=O)OC(C)(C)C)C2)C1
Reactant: Clc1ncc(Cl)c(Cl)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN(c1nc(Cl)ncc1Cl)C1CCC2(CCCN(C(=O)OC(C)(C)C)C2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
To a solution of 2,4,5-trichloropyrimidine (355.7 g, 1.94 mmol) and tert-butyl 2-(methylamino)-7-azaspiro[4.5]decane-7-carboxylate (403.2 g, 1.50 mmol) in EtOH (10 mL) was added Et3N (315.5 mg, 3.12 mmol). After addition, the reaction mixture was stirred at rt overnight and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/8) to give the title compound as yellow oil (470 mg, 75.4%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[C:5]([C:16]#[N:17])=[C:4]([S:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:32]1[O:33][CH2:34][CH2:35][CH:36]=1)CCC>O1CCOCC1.CN(C=O)C.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>[NH2:1][C:2]1[N:7]=[C:6]([C:32]2[O:33][CH2:34][CH2:35][CH:36]=2)[C:5]([C:16]#[N:17])=[C:4]([S:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[N:3]=1
Reactant: N#Cc1c(OS(=O)(=O)C(F)(F)F)nc(N)nc1SCCc1ccccn1
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCCO1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: N#Cc1c(SCCc2ccccn2)nc(N)nc1C1=CCCO1
Temperature: 100 °C
Yield: 8.5 %

Procedure:
To a stirred solution of 290 mg (0.72 mmol) trifluoromethanesulfonic acid 2-amino-5-cyano-6-(2-pyridin-2-yl-ethylsulfanyl)-pyrimidin-4-yl ester in 10 ml dioxane and 2 ml DMF under argon at room temperature were added 283 mg (0.79 mmol) tributyl-(4,5-dihydro-furan-2-yl)-stannane and 50 mg (0.07 mmol) bis(triphenylphosphine)palladium(II) chloride. The reaction mixture was heated at 100° C. for 1 h, then cooled to room temperature and partitioned between water and ethyl acetate. The organic phase was dried over sodium sulfate and concentrated in vacuo. Flash chromatography (ethyl acetate then 5/95 methanol/ethyl acetate) followed by trituration in ether afforded 20 mg (9%) 2-amino-4-(4,5-dihydro-furan-2-yl)-6-(2-pyridin-2-yl-ethylsulfanyl)-pyrimidine-5-carbonitrile as a light brown crystalline solid. ES-MS m/e (%): 348 (M+Na+, 30), 326 (M+H+, 100).
Reaction SMILES: [C:1]([N:4]([CH2:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=1)[CH2:5][C:6]1[N:7]=[N:8][N:9]([CH2:11][Si](C)(C)C)[CH:10]=1)(=[O:3])[CH3:2].C1COCC1.[Li+].[OH-]>CO>[C:1]([N:4]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:25][CH:26]=1)[CH2:5][C:6]1[N:7]=[N:8][N:9]([CH3:11])[CH:10]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(CN(Cc2cn(C[Si](C)(C)C)nn2)C(C)=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)N(Cc1ccc(C(=O)O)cc1)Cc1cn(C)nn1
Reaction time: 8 h

Procedure:
A solution of methyl 4-{[acetyl({1-[(trimethylsilyl)methyl]-1H-1,2,3-triazol-4-yl}methyl)amino]methyl}benzoate (101 mg, 0.270 mmol), THF (809 uL) and MeOH (270 uL) was treated with aqueous LiOH (270 uL, 0.809 mmol, 3M in water). The reaction immediately turned red and was stirred overnight. The reaction was quenched with 2M aq. HCl and extracted with EtOAc 2×. The combined organic layers were washed with brine, dried (MgSO4) and concentrated to afford the protosilylated carboxylic acid as a yellow oil. MS: cal'd 361 (MH+), exp 361 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]([CH2:13][OH:14])[CH2:11][O:10][C:9]1([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].Cl[C:24]1[C:28]2[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:27]=2[O:26][N:25]=1>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH:12]([CH2:13][O:14][C:24]2[C:28]3[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:27]=3[O:26][N:25]=2)[CH2:11][O:10][C:9]1([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1ccc2onc(Cl)c2c1
Reactant: CC(C)(C)OC(=O)N1C(CO)COC1(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C(COc2noc3ccc(Cl)cc23)COC1(C)C

Procedure:
A solution of 6.94 g of 3-tert-butoxycarbonyl-4-hydroxymethyl-2,2-dimethyloxazolidine in 28 ml of tetrahydrofuran is added to a solution of 6.02 g of potassium tert-butoxide in 28 ml of tetrahydrofuran at 10°-15° C., and they are subjected to reaction at the same temperature for two hours. Subsequently, this reaction mixture is added under reflux to a solution of 5.64 g of 3,5-dichloro-1,2-benzoisoxazole in 28 ml of tetrahydrofuran and they are refluxed for a further one hour. The reaction mixture is cooled and thereafter the solvent is removed by distillation under reduced pressure, after which ethyl acetate and water are added to the residue obtained, and after shaking, the organic layer is separated. The separated organic layer is washed with a saturated saline solution and dried over anhydrous magnesium sulfate, after which the solvent is removed by distillation under reduced pressure. The crystals obtained are recrystallized from n-hexane to obtain 8.41 g of colorless, crystalline 3-[(3-tert-butoxycarbonyl-2,2-dimethyloxazolidin-4-yl)methoxy]-5-chloro-1,2-benzoisoxazole having a melting point of 117°-118° C.