Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[O:8][CH:7]1[CH2:6][CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[CH2:3][CH2:2]2.[NH3:19]>>[CH2:12]([O:11][C:9]([N:4]1[CH2:5][CH2:6][CH:7]([OH:8])[CH:1]([NH2:19])[CH2:2][CH2:3]1)=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(OCc1ccccc1)N1CCC2OC2CC1
Reactant: N
Product: NC1CCN(C(=O)OCc2ccccc2)CCC1O

Procedure:
3 g benzyl 8-oxa-4-azabicyclo[5.1.0]octane-4-carboxylate in 70 mL 30% aqueous ammonia was stirred at 65° C. in a sealed vessel overnight. The reaction was extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate filtered and concentrated to yield 3.1 g of the desired product. (M+H)+: 265
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:12][C:13]([C:15]2[CH:16]=[C:17]([C:23]3[C:28]([F:29])=[CH:27][C:26]([O:30][CH3:31])=[C:25]([Cl:32])[C:24]=3[F:33])[C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)=[O:14])[CH2:10][CH2:9][CH:8]([CH3:11])[CH2:7][CH2:6]1)=[O:4].[OH-].[Na+].O1CCOCC1>O>[Cl:32][C:25]1[C:24]([F:33])=[C:23]([C:17]2[C:18]([O:21][CH3:22])=[CH:19][CH:20]=[C:15]([C:13]([NH:12][C:5]3([C:3]([OH:4])=[O:2])[CH2:10][CH2:9][CH:8]([CH3:11])[CH2:7][CH2:6]3)=[O:14])[CH:16]=2)[C:28]([F:29])=[CH:27][C:26]=1[O:30][CH3:31]
Reactant: COC(=O)C1(NC(=O)c2ccc(OC)c(-c3c(F)cc(OC)c(Cl)c3F)c2)CCC(C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(C(=O)NC2(C(=O)O)CCC(C)CC2)cc1-c1c(F)cc(OC)c(Cl)c1F
Temperature: 80 °C
Reaction time: 6 h
Yield: 75.5 %

Procedure:
150 mg of 1-[(3′-Chloro-2′,6′-difluoro-6,4′-dimethoxy-biphenyl-3-carbonyl)-amino]-4-methyl-cyclohexanecarboxylic acid methyl ester and 25 mg NaOH were dissolved using 5 ml of dioxane and 0.5 ml of water. The mixture was stirred at 80° C. for 6 h. Then, 15 ml of water were added, the dioxane evaporated and acidified to pH=3 using aqueous NaHSO4-solution. The mixture was stirred for 30 minutes at room temperature. The product was then isolated by filtration and dried in vacuo to yield 110 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11](Cl)=[O:12])[CH2:8]2)=[CH:4][CH:3]=1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>O1CCCC1.O>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11]([N:20]3[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]3)=[O:12])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)N1CC(Oc2ccc(Br)cc2)C1
Reactant: CN1CCNCC1
Solvent: O
Solvent: C1CCOC1
Product: CN1CCN(C(=O)N2CC(Oc3ccc(Br)cc3)C2)CC1
Reaction time: 2 h
Yield: 84.7 %

Procedure:
A solution of 2.9 g (0.01 mole) of 3-(4-bromophenoxy)-1-azetidinecarbonyl chloride in 15 ml of tetrahydrofuran was treated while stirring with 1 g (0.01 mole) of 1-methylpiperazine and stirred for 2 hr. The paste-like slurry was diluted with water and the solid was collected by filtration (4 g, wet). Recrystallization from benzene/ligroin yielded 3.0 g of white crystalline product, m.p. 91°-95° C. The solid and 1.16 g of fumaric were dissolved in isopropanol by boiling until a clear solution was obtained. Upon cooling, the precipitated salt was collected by filtration to yield 3 g (63.8%) of fine white crystals, m.p. 197°-198° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:17]3[CH2:18][CH:19]([CH2:21][CH2:22][C:23]([N:25]4[CH2:30][CH2:29][N:28]([C:31]5[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][N:32]=5)[CH2:27][CH2:26]4)=O)[O:20][C:15]4[C:16]3=[C:11]([CH:12]=[CH:13][CH:14]=4)[C:10]=2[CH3:38])=[CH:5][CH:4]=1.Cl>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:17]3[CH2:18][CH:19]([CH2:21][CH2:22][CH2:23][N:25]4[CH2:26][CH2:27][N:28]([C:31]5[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][N:32]=5)[CH2:29][CH2:30]4)[O:20][C:15]4[C:16]3=[C:11]([CH:12]=[CH:13][CH:14]=4)[C:10]=2[CH3:38])=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2c(C)c3cccc4c3n2CC(CCC(=O)N2CCN(c3cc(C)ccn3)CC2)O4)cc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2c(C)c3cccc4c3n2CC(CCCN2CCN(c3cc(C)ccn3)CC2)O4)cc1

Procedure:
1 g of 2,3-dihydro-5-(4-methoxyphenyl)-6-methyl-2-[3-(4-(4-methylpyridin-1-yl)piperazin-1-yl) -3-oxopropyl]pyrrolo[1,2,3-de]-1,4-benzoxazine (prepared according to Example 6)) was dissolved in 15 ml of anhydrous tetrahydrofuran under a nitrogen atmosphere. 12 ml of a 1 molar borane-tetrahydrofuran complex were added to the solution. The reaction mixture was stirred and heated to reflux for 2 hours. 25 ml of a 6N hydrochloric acid solution were then added and the reaction mixture was stirred for 24 hours. The precipitate formed was dissolved in water which was rendered alkaline (pH=12), and the solution was extracted with dichloromethane. The organic extracts were dried and evaporated. The crude product remaining was purified by column chromatography using dichloromethane containing 2% ethanol as an eluent. The purified title compound was poured into 3N isopropanolic hydrochloric acid solution for conversion into its dihydrochloride salt. 0.6 g of 2,3-dihydro-5-(4-methoxyphenyl)-6-methyl-2-[3-(4-(4-methylpyridin-2-yl)piperazin-1-yl)propyl]pyrrolo[1,2,3-de]-1,4-benzoxazine. 2HCl.0.7H2O was obtained as yellow crystals having a melting point of 248° to 249° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:9]=[CH:8][C:6]([OH:7])=[CH:5][C:4]=1[OH:10].Cl.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18]Cl.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(N(CC)CC)C>[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[O:10][C:4]2[CH:5]=[C:6]([OH:7])[CH:8]=[CH:9][C:3]=2[N:2]=1
Reactant: Nc1ccc(O)cc1O
Reactant: ClCc1ccccn1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: CCN(CC)CC
Product: Oc1ccc2nc(-c3ccccn3)oc2c1

Procedure:
4-Aminoresorcinol hydrochloride (2.0 g, 12.4 mL), picolinyl chloride hydrochloride (2.4 g, 13.6 mM), triethylamine (2.8 g, 27.2 mM) and pyridinium-p-toluenesulfonate (PPTS, 800 mg, 3.2 mM) were refluxed in xylenes (50 mL) for about 72 hours. The reaction mixture was concentrated and the residue dissolved in ethyl acetate (200 mL) and washed with H2O (3×150 mL). The combined aqueous layer was back extracted with ethyl acetate (200 mL) and the combined organic layer was dried over MgSO4. Filtration and concentration provided 1.0 g. Filtration through a silica gel column eluted with 4% methanol/methylene chloride provided an orange solid, 0.32 g; m.p., 100-103° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:7][C:8]=1Cl.[CH3:15][CH:16]([CH3:18])[O-:17].[Na+].O>CS(C)=O>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:7][C:8]=1[O:17][CH:16]([CH3:18])[CH3:15]
Reactant: O=[N+]([O-])c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)Oc1ccc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
To a chilled (5° C.) solution of 118 g (0.5 mole) of 3-(trifluoromethyl)-4-chloronitrobenzene in 100 ml of dimethyl sulfoxide (DMSO) was added dropwise a solution containing 41 g (0.5 mole) of sodium isopropoxide in 300 ml of dimethyl sulfoxide. The dark reaction mixture was stirred at ambient temperature for one hour, poured into water and extracted with ether. The ether extracts were washed with water, dried and concentrated. Recrystallization of the residual liquid from hexane gave 115.5 g (92.7%) of white crystalline solid; m.p. 34°-36°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.[Br:13]Br>C(Cl)Cl.C1COCC1>[Br:13][C:3]1[C:2]([CH3:1])=[CH:12][C:6]2[NH:7][C:8](=[O:11])[CH2:9][O:10][C:5]=2[CH:4]=1
Reactant: BrBr
Reactant: Cc1ccc2c(c1)NC(=O)CO2
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cc2c(cc1Br)OCC(=O)N2
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
To a suspension of 6-methyl-2H-1,4-benzoxazin-3(4H)-one (10.0 g, 61.3 mmol) in DCM (200 mL) and THF (200 mL) at 0° C. was added bromine (15.0 g, 93.7 mmol) dropwise. The reaction mixture was stirred at this temperature for 30 minutes, then filtered. The solid was washed with Et2O (200 mL) to give the title compound (11.95 g, 80%) as a white solid that was used without further purification. δH (CDCl3) 8.95 (1H, s), 7.16 (1H, s), 6.70 (1H, s), 4.59 (2H, s), 2.31 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([O:10]C)=[CH:6][C:4]=1[NH2:5].[F:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[O:22]C)C(O)=O>>[F:12][C:13]1[CH:14]=[C:15]([C:1]2[O:2][C:3]3[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:4]=3[N:5]=2)[CH:19]=[CH:20][C:21]=1[OH:22]
Reactant: COc1ccc(OC)c(N)c1
Reactant: COc1ccc(C(=O)O)cc1F
Product: Oc1ccc2oc(-c3ccc(O)c(F)c3)nc2c1

Procedure:
The title compound was prepared in substantially the same manner as described in Example 1, from 2,5-dimethoxyaniline, and 3-fluoro-4-methoxybenzoic acid and was obtained as a white solid, m.p. 262–268° C.; MS m/e 244 (M−H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:15][CH2:14][CH2:13][C:12]3[S:11][C:10]([C:16]([NH2:18])=[O:17])=[N:9][C:8]=3[C:6]=2[CH:7]=1.[CH3:19][C:20]([CH3:24])([C:22]#[CH:23])[OH:21]>>[OH:21][C:20]([CH3:24])([CH3:19])[C:22]#[C:23][C:2]1[CH:3]=[CH:4][C:5]2[O:15][CH2:14][CH2:13][C:12]3[S:11][C:10]([C:16]([NH2:18])=[O:17])=[N:9][C:8]=3[C:6]=2[CH:7]=1
Reactant: NC(=O)c1nc2c(s1)CCOc1ccc(Br)cc1-2
Reactant: C#CC(C)(C)O
Product: CC(C)(O)C#Cc1ccc2c(c1)-c1nc(C(N)=O)sc1CCO2

Procedure:
9-Bromo-4,5-dihydro-[1]benzoxepino[5,4-d]thiazole-2-carboxamide (0.15 g) was reacted with dimethyl ethynyl carbinol similar to as described in Procedure E to afford 56.9 mg of 9-(3-hydroxy-3-methyl-but-1-ynyl)-4,5-dihydro-[1]benzoxepino[5,4-d]thiazole-2-carboxamide following reverse phase hplc purification. MS (Q1) 329 (M)+. 1H NMR (400 MHz, DMSO) δ 8.57 (d, J=2.1 Hz, 1H), 8.39 (s, 1H), 7.84 (s, 1H), 7.27 (dd, J=8.3, 2.1 Hz, 1H), 7.01 (d, J=8.3 Hz, 1H), 5.40 (s, 1H), 4.34 (t, J=4.9 Hz, 2H), 3.41 (t, J=4.9 Hz, 2H), 1.49 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:13]=[CH:14][C:15]3[S:19][CH:18]=[C:17]([CH3:20])[C:16]=3[C:21]=2[CH:22]=[O:23])[N:4]=1.[Mn]([O-])(=O)(=O)=[O:25].[K+]>CC(C)=O.O>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][C:12]2[C:21]([C:22]([OH:25])=[O:23])=[C:16]3[C:17]([CH3:20])=[CH:18][S:19][C:15]3=[CH:14][CH:13]=2)[N:6]=1
Reactant: COc1cc(OC)nc(Oc2ccc3scc(C)c3c2C=O)n1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COc1cc(OC)nc(Oc2ccc3scc(C)c3c2C(=O)O)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 74.7 %

Procedure:
0.6 g of 5-(4,6-dimethoxypyrimidin-2-yl)oxy-4-formyl-3-methylbenzothiophene was dissolved in 80 ml of acetone. While stirring the solution at room temperature, 0.6 g of potassium permanganate dissolved in 10 ml of water was dropwise added thereto over a period of 15 minutes, and the mixture was further stirred at room temperature for 4 hours. It was then concentrated under reduced pressure to remove acetone, and then a saturated sodium bicarbonate aqueous solution was added thereto to make the mixture alkaline. The mixture was extracted with ethyl acetate, and then the aqueous layer was precipitated with 10% hydrochloric acid. The precipitated crystals were collected by filtration and washed with water to obtain 0.47 g (yield: 76%) of the desired compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:9]([CH3:25])[C:10]2[N:15]=[C:14]3[S:16][C:17]([NH:19][C:20]([CH:22]4[CH2:24][CH2:23]4)=[O:21])=[N:18][C:13]3=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][C:28]=1[C:36]([F:39])([F:38])[F:37]>CN(C)C=O.C(OCC)(=O)C>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([NH:1][C:2]2[CH:3]=[C:4]([N:9]([CH3:25])[C:10]3[N:15]=[C:14]4[S:16][C:17]([NH:19][C:20]([CH:22]5[CH2:23][CH2:24]5)=[O:21])=[N:18][C:13]4=[CH:12][CH:11]=3)[CH:5]=[CH:6][C:7]=2[F:8])=[O:35])=[CH:29][C:28]=1[C:36]([F:37])([F:38])[F:39]
Reactant: CN(c1ccc(F)c(N)c1)c1ccc2nc(NC(=O)C3CC3)sc2n1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(c1ccc(F)c(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)c1)c1ccc2nc(NC(=O)C3CC3)sc2n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 71.1 %

Procedure:
N-{5-[(3-Amino-4-fluorophenyl)(methyl)amino][1,3]thiazolo[5,4-b]pyridin-2-yl}cyclopropanecarboxamide (120 mg, 0.34 mmol) produced in Example 1(x) was dissolved in N,N-dimethylformamide (1.5 mL), 1-chloro-4-isocyanato-2-(trifluoromethyl)benzene (89 mg, 0.40 mmol) was added, and the mixture was stirred at room temperature for 6 hr. The reaction mixture was diluted with ethyl acetate (10 mL), and washed successively with saturated aqueous sodium hydrogen carbonate solution (10 mL) and saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/hexane=50/50→100/0), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (140 mg, 72%) as a colorless powder.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=[O:15])[CH2:6][CH2:5]2.[CH3:19][C:20](OC(C)=O)=[O:21]>N1C=CC=CC=1>[C:20]([O:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=[O:15])[CH2:6][CH2:5]2)(=[O:21])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Solvent: c1ccncc1
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(C(=O)O)O2
Temperature: 40 °C
Reaction time: 8 h

Procedure:
6-Hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (5.0 g, 19.99 mmol) was dissolved in pyridine (18 mL) and Ac2O added (10 mL) in one portion. The exothermic reaction warmed to 40° C., was let cool to room temperature and stirred overnight. The crude reaction mixture was quenched with 100 mL H2O, stirred for 1 h followed by additional 100 mL H2O and 1 h of stirring. A fine white precipitate of 6-acetoxy-2,5,7,8-tetramethylchroman-2-carboxylic acid was formed and collected by filtration (4.544 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[CH2:35][N:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1)[CH2:6][C:7]1[C:8]2[CH:29]=[CH:28][C:27]([O:30]C)=[CH:26][C:9]=2[S:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:14][CH:13]=1)#[N:2].C(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>ClC(Cl)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[CH2:35][N:36]1[CH2:37][CH2:38][CH2:39][CH2:40]1)[CH2:6][C:7]1[C:8]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][C:9]=2[S:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)=[CH:14][CH:13]=1)#[N:2]
Reactant: COc1ccc2c(Cc3ccc(CN4CCCC4)c(C#N)c3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: CCS
Product: N#Cc1cc(Cc2c(-c3ccc(OCCN4CCCC4)cc3)sc3cc(O)ccc23)ccc1CN1CCCC1
Reaction time: 1 h
Yield: 67.6 %

Procedure:
3-[3-Cyano-4-[(1-pyrrolidinyl)methyl]benzyl]-6-methoxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophene (60 mg, 0.11 mmol) in dichloroethane (4 mL) at 0° C. under argon was treated with ethanethiol (0.1 mL) and aluminum chloride (100 mg) for 3 h before quenching with saturated aqueous sodium bicarbonate solution (10 mL). The stirring was allowed to continue for 1 h at ambient temperature. The resulting mixture was diluted with saturated aqueous sodium bicarbonate solution (50 mL) and extracted with dichloromethane (50 mL×3). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Chromatography with Et3N:MeOH:EtOAc (5:5:90) afforded the title compound as a white foam (40 mg, 68%).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])=[C:12]([S:32]([CH3:35])(=[O:34])=[O:33])[CH:11]=1>>[CH3:30][C:29]1[C:24]([N:21]2[CH2:22][CH2:23][N:18]([C:16]([C:13]3[CH:14]=[CH:15][C:10]([N:7]4[C@@H:3]([CH2:2][OH:1])[CH2:4][CH2:5][C:6]4=[O:8])=[CH:11][C:12]=3[S:32]([CH3:35])(=[O:34])=[O:33])=[O:17])[CH2:19][CH2:20]2)=[N:25][CH:26]=[C:27]([CH3:31])[CH:28]=1
Reactant: O=C1CC[C@H](CO)N1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)CC[C@@H]4CO)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 42.5 %

Procedure:
Using (R)-5-hydroxymethylpyrrolidin-2-one (409 mg) and (4-bromo-2-methanesulfonylphenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (1.53 g) described in Preparation Example 112 and by the reaction and treatment in the same manner as in Example 1, (R)-1-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-3-methanesulfonylphenyl}-5-hydroxymethylpyrrolidin-2-one (700 mg) was obtained. Using the obtained (R)-1-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-3-methanesulfonylphenyl}-5-hydroxymethylpyrrolidin-2-one (700 mg) and methyl tosylate (0.21 mL) and by the reaction and treatment in the same manner as in Example 36, the title compound (319 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[CH:19]1([C:22]#[C:23][C:24]2[CH:25]=[CH:26][C:27]([C:30](O)=[O:31])=[N:28][CH:29]=2)[CH2:21][CH2:20]1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:30]([C:27]3[CH:26]=[CH:25][C:24]([C:23]#[C:22][CH:19]4[CH2:21][CH2:20]4)=[CH:29][N:28]=3)=[O:31])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Reactant: O=C(O)c1ccc(C#CC2CC2)cn1
Product: C[C@]1(c2cc(NC(=O)c3ccc(C#CC4CC4)cn3)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 5-cyclopropylethynyl-pyridine-2-carboxylic acid (CAS1174322-62-3, WO2009091016) following procedure I yielded the title compound as a white solid. MS (ISP): m/z=429.3 [M+H]+.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:20]=1[C:21](=[CH:29]O)[C:22](=[O:28])[NH:23]2>>[CH3:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:20]=1[C:21](=[CH:29][NH:17][C:14]1[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[CH:16][CH:15]=1)[C:22](=[O:28])[NH:23]2
Reactant: Cc1cccc2c1C(=CO)C(=O)N2
Reactant: Nc1ccc(OCCCN2CCCCC2)cc1
Product: Cc1cccc2c1C(=CNc1ccc(OCCCN3CCCCC3)cc1)C(=O)N2
Yield: 49.6 %

Procedure:
In a manner similar to that described in Example 231, 4-(3-Piperidin-1-yl-propoxy)-phenylamine (0.61 g, 1.3 equiv.) and 4-methyl-3-hydroxymethylene-1,3-dihydro-indol-2-one (0.35 g, 2 mmol, 1 equiv.) are reacted to give the named compound as a yellow solid (388 mg, 49%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1)=[O:4].[H-].[Na+].Cl[C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[N:23]=[C:22]([NH2:30])[N:21]=1.O>CC(N(C)C)=O>[NH2:30][C:22]1[N:23]=[C:24]([C:26]([F:29])([F:27])[F:28])[CH:25]=[C:20]([O:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][NH:5][C:3](=[O:4])[C:2]([F:15])([F:16])[F:1])=[CH:8][CH:9]=2)[N:21]=1
Reactant: Nc1nc(Cl)cc(C(F)(F)F)n1
Reactant: O=C(NCc1ccc(CO)cc1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Nc1nc(OCc2ccc(CNC(=O)C(F)(F)F)cc2)cc(C(F)(F)F)n1
Temperature: 90 °C

Procedure:
322 mg (1.38 mmol) 2,2,2-trifluoro-N-(4-hydroxymethyl-benzyl)-acetamide is dissolved in 2 mL dry dimethylacetamide under argon atmosphere, and 50 mg (2.1 mmol) NaH is added. 136 mg (0.69 mmol) 4-chloro-6-(trifluoromethyl)pyrimidin-2-amine 24 is then added and the solution stirred at 90° C. over night. 1 mL water is added carefully to quench all excess NaH and the mixture poured into 50 mL 0.5 N HCl. The crude product is extracted with ethyl acetate, the combined organic phases washed with brine and dried over MgSO4. After evaporation of the solvent, the product is purified by flash column chromatography (gradient ethyl acetate: cyclohexane from 1:1 to 3:1).
Reaction SMILES: [C:1]([C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:27])[CH2:10][C:11]([CH3:26])([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=3)[O:12]2)=[CH:7][C:6]=1[OH:28])([CH3:4])([CH3:3])[CH3:2].[C:29](OC(=O)C)(=[O:31])[CH3:30]>N1C=CC=CC=1>[C:29]([O:28][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:5]=1[C:1]([CH3:4])([CH3:2])[CH3:3])[O:12][C:11]([CH3:26])([CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)[CH2:10][C:9]2=[O:27])(=[O:31])[CH3:30]
Reactant: CC1(COc2ccc([N+](=O)[O-])cc2)CC(=O)c2cc(O)c(C(C)(C)C)cc2O1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1cc2c(cc1C(C)(C)C)OC(C)(COc1ccc([N+](=O)[O-])cc1)CC2=O
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A mixture of 1.7 g of 7-t-butyl-6-hydroxy-2-methyl-2-(4-nitrophenoxymethyl)chroman-4-one (prepared as described in Preparation 53), 1 ml of acetic anhydride and 10 ml of pyridine was allowed to stand for 1 day at room temperature. The reaction mixture was then poured into ice-water, stirred for 2 hours and extracted with benzene. The benzene extract was washed with 3N aqueous hydrochloric acid, water, a saturated aqueous solution of sodium bicarbonate and water in that order, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was recrystallized from a mixture of benzene and ethyl acetate (about 10:1 by volume) to give the title compound, melting at 82°-84° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:14])([C:10]([F:13])([F:12])[F:11])[C:5]([O:7]CC)=O.[C:15](#[N:17])[CH3:16]>C1COCC1>[F:14][C:4]([F:3])([C:10]([F:11])([F:12])[F:13])[C:5](=[O:7])[CH2:16][C:15]#[N:17]
Reactant: CC#N
Reactant: CCOC(=O)C(F)(F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCC(=O)C(F)(F)C(F)(F)F
Temperature: 50 °C

Procedure:
A stirred suspension of sodium hydride (15.6 g of a 60% dispersion in mineral oil, 0.39 mol) in THF (100 mL) was heated to 50° C. To this was added a mixture of ethyl 2,2,3,3,3-pentafluoropropanoate (25 g, 0.13 mol) and dry acetonitrile (5.3 g, 0.13 mol), dropwise, and the resulting colorless suspension was heated at 50° C. for 4 h. After cooling to rt the reaction mixture was concentrated under reduced pressure and the residue poured into water (100 mL) and extracted with diethyl ether (100 mL). The aqueous layer was separated, acidified to pH 2 with aqueous 2 M HCl and extracted with diethyl ether (2×200 mL). The combined diethyl ether layers were dried over magnesium sulfate then concentrated under reduced pressure to afford 4,4,5,5,5-pentafluoro-3-oxopentanenitrile an orange oil (17 g) which was used in the next step without further purification.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH3:8][C:9]([CH3:11])=[CH2:10]>>[CH2:10]([CH:3]1[C:4](=[O:5])[O:6][C:1](=[O:7])[CH2:2]1)[C:9](=[CH2:8])[CH3:11]
Reactant: O=C1C=CC(=O)O1
Reactant: C=C(C)C
Product: C=C(C)CC1CC(=O)OC1=O

Procedure:
reacting maleic anhydride with 2-methylpropene to yield β-methallylsuccinic anhydride;