Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10](/C(/C)=C\SC)[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.O.C(S(O)(=O)=O)(F)(F)F>O>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][C:9]1=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS/C=C(/C)n1c(=O)n(Cc2ccccc2)c2ccccc21
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CO
Solvent: O
Product: O=c1[nH]c2ccccc2n1Cc1ccccc1
Reaction time: 3 h
Yield: 47.4 %

Procedure:
35 mg of 1-benzyl-3-[(1Z)-1-(methylsulfanyl)prop-1-en-2-yl]-1,3-dihydro-2H-benzimidazol-2-one 1 (0.113 mmol) prepared as described in example 2 were solubilised in a solution of MeOH/H2O 1:1 (2 mL). Then, CF3SO3H (2 mL) was added and the solution refluxed under magnetic stirring. After 3 h, H2O was added (5 mL) and the solution was extracted 3×10 mL of CH2Cl2. The resulting solid was finally chromatographed on silica gel (CH2Cl2/AcOEt 8:2) to yield 1-benzyl-1,3-dihydro-2H-benzimidazol-2-one 2 as a white powder (12 mg, 48%). Mp 194° C. (Iitt. G. Vernin, H. Domlog, C. Siv, J. Metzger, J. Heterocyclic Chem., 18, 85 (1981): 198° C.); Rf=0.23 (CH2Cl2/AcOEt 8:2); 1H NMR (200 MHz, CDCl3) δ=5.11 (2H, s, CH2), 6.84-7.35 (9H, m, Ar), 10.08 (1H, brs, NH).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.B(O)(O)[C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:16]1([CH3:19])[CH:17]=[CH:18][C:13]([C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:14][CH:15]=1
Reactant: FC(F)(F)c1cccnc1Cl
Reactant: Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccc(-c2ncccc2C(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a de-gassed mixture of 2-chloro-3-(trifluoromethyl)-pyridine (70.1 mmol), p-tolylboronic acid (70.6 mmol), and 2M Na2CO3 (175.0 mmol), in DME (200 mL) under nitrogen add Pd(PPh3)4 (2.8 mmol). Stir the mixture at 80° C. for overnight, concentrate, extract with EtOAc. Dry over Na2SO4, concentrate under vacuum, pass a silica gel pad to give 2-p-tolyl-3-trifluoromethyl-pyridine.
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1.[Mg].II.[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][C:24]([CH2:29][CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])([CH:27]=[O:28])[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>O1CCCC1>[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][C:24]([CH2:29][CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])([CH:27]([C:2]2[C:6]3[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=3[S:4][CH:3]=2)[OH:28])[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: Fc1ccc2scc(Br)c2c1
Reactant: CC(C)(C)CCC1(C=O)CCN(C(=O)OC(C)(C)C)C1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(C)CCC1(C(O)c2csc3ccc(F)cc23)CCN(C(=O)OC(C)(C)C)C1
Reaction time: 1 h
Yield: 21.6 %

Procedure:
A mixture of 3-bromo-5-fluoro-benzothiophene (0.4 g, 1.73 mmoles), magnesium (0.051 g, 2.1 mmoles) and a few particles of iodine in anhydrous tetrahydrofuran (10 nil) was refluxed for 7 hours, and then cooled in an ice bath. To the reaction mixture was slowly added a solution of 3-(3,3-dimethyl-butyl)-3-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.39 g, 1.38 mmoles) in anhydrous tetrahydrofuran (9 ml). The reaction mixture was stirred at ice bath temperature for one hour and quenched with saturated aqueous ammonium chloride solution. The aqueous solution was extracted into ethylacetate which was washed with brine and dried over anhydrous sodium sulfate. After removal of drying agent, the organic solution was concentrated under reduced pressure. The residue was purified by silica gel chromatography (0 to 20% ethyl acetate in hexane) to yield 3-(3,3-dimethyl-butyl)-3-[(5-fluoro-benzo[b]thiophen-3-yl)-hydroxy-methyl]-pyrrolidine-1-carboxylic acid tert butyl ester as yellow foam (0.13 g, 21%), MS=436 [M+H]+,
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.N1CCCC1.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][C:18]1=[O:26].Cl>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[C:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[NH:17][C:18]1=[O:26]
Reactant: O=C1Cc2ccccc2N1
Reactant: COc1ccc(C=O)cc1Br
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCNC1
Product: COc1ccc(C=C2C(=O)Nc3ccccc32)cc1Br
Temperature: 25 °C
Reaction time: 12 h
Yield: 41 %

Procedure:
A mixture of 3-bromo-p-anisaldehyde (1 g, 4.65 mmol), pyrrolidine (1.9 ml, 23.2 mmol) and oxindole (0.62 g, 4.65 mmol) in dimethylformamide (7 ml) was held in a sealed tube at 100° C. for 12 hours. The mixture was cooled to room temperature and poured into 1N hydrochloric acid (100 ml). The precipitate which formed was filtered and washed with water. The precipitate was then dissolved in ethyl acetate (200 ml), the solution washed with brine, dried over magnesium sulfate and then concentrated. The solid obtained was chromatographed (silica, 30-40% ethyl acetate/hexanes) to give 0.63 g (42%) of 3-(3-bromo-4-methoxybenzylidene)-1,3-dihydroindol-2-one as a yellow solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][OH:19])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.F[C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1.Cl>O1CCCC1>[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][O:19][C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)=[CH:15][CH:16]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: OCCc1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1ccc(OCCc2ccc(OCc3ccccc3)cc2)cc1
Temperature: 40 °C

Procedure:
To a suspension of sodium hydride (60%, 2.2 g, 55 mmol) in dry tetrahydrofuran (250 ml) was added a solution of 1-benzyloxy-4-(2-hydroxyethyl)benzene (11.4 g, 50 mmol) in tetrahydrofuran (50 ml). The reaction was heated to 40° C. for 1 hour. 4-Fluorobenzonitrile (6.7 g, 55 mmol) was added and the mixture was heated to reflux for 5 hours, cooled and neutralized with concentrated HCl. The precipitate was filtered, the filtrate was concentrated to dryness and the resulting solid was recrystallized from ethanol (12 g).
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[C:17]([CH3:22])[CH:16]=[C:15]3C(F)(F)F)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[Br:27]C1C2C(=CC=C(O)C=2)N=C(C)C=1>>[Br:27][C:15]1[C:14]2[C:19](=[CH:20][CH:21]=[C:12]([O:11][C@H:8]3[CH2:9][CH2:10][C@H:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:6][CH2:7]3)[CH:13]=2)[N:18]=[C:17]([CH3:22])[CH:16]=1
Reactant: Cc1cc(Br)c2cc(O)ccc2n1
Reactant: Cc1cc(C(F)(F)F)c2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1
Product: Cc1cc(Br)c2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1

Procedure:
Synthesized as per 6-(trans-4-tert-Butyl-cyclohexyloxy)-2-methyl-4-trifluoromethyl-quinoline using 4-Bromo-2-methyl-quinolin-6-ol as starting material. ESI-MS (M+H+): 378.1.
Reaction SMILES: [N:1]#[C:2]Br.[F:4][C:5]1[CH:6]=[C:7]([NH2:21])[C:8]([NH:11][C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=2[CH3:20])=[CH:9][CH:10]=1>C(O)C>[F:4][C:5]1[CH:10]=[CH:9][C:8]2[N:11]([C:12]3[C:13]([CH3:20])=[CH:14][C:15]([CH3:19])=[CH:16][C:17]=3[CH3:18])[C:2]([NH2:1])=[N:21][C:7]=2[CH:6]=1
Reactant: Cc1cc(C)c(Nc2ccc(F)cc2N)c(C)c1
Reactant: N#CBr
Solvent: CCO
Product: Cc1cc(C)c(-n2c(N)nc3cc(F)ccc32)c(C)c1
Temperature: 25 °C
Yield: 97.8 %

Procedure:
A solution of cyanogen bromide (2.67 g, 25.2 mmol) in anhydrous ethanol (10 mL) was added at 0° C. to a solution of 4-fluoro-N1-(2,4,6-trimethyl-phenyl)-benzene-1,2-diamine (4.74 g, 19.4 mmol) in anhydrous ethanol (20 mL) under nitrogen. The reaction mixture was warmed up to room temperature for 10 min, then was heated at 155° C. For 40 min with a flow of nitrogen to remove ethanol. Upon cooling to room temperature, the resulting solids were transferred to a separatory funnel via dichloromethane (70 mL), and washed sequentially with 1 N sodium hydroxide (2×35 mL), water and brine. The organic layer was dried over anhydrous sodium sulfate and solvents were removed in vacuo to afford the title compound as a red solid (5.11 g, 98% yield). The purity of this compound was determined to be 95% by LC/MS. 1H NMR (CDCl3, 300 MHz) δ 7.12 (dd, J=9.7, 2.4 Hz, 1H), 7.06 (s, 2H), 6.69 (td, J=9.1, 2.4 Hz, 1H), 6.56 (dd, J=8.5, 4.7 Hz, 1H), 2.38 (s, 3H), 1.98 (s, 6H); 13C NMR (CDCl3, 75 MHz) δ 161.0, 157.9, 154.2, 143.3, 139.9, 137.4, 129.8, 128.8, 107.8 (d, J=10.2 Hz), 106.9 (d, J=25.3 Hz), 103.1 (d, J=25.2 Hz)21.1, 17.5; Mass spec.: 270.17 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=[O:12])=[CH:5]2.CCN(C(C)C)C(C)C.Br[CH:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN1CCCC1=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH:24]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=2)[CH:5]=[C:6]1[C:11]([OH:13])=[O:12])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1cc2cc(Br)ccc2[nH]1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)c1cc2cc(Br)ccc2n1C(c1ccccc1)c1ccccc1
Temperature: 50 °C
Yield: 87.2 %

Procedure:
To 5-bromoindole-2-carboxylic acid (1.024 g, 4.26 mmol) in 1-methyl-2-pyrrolidinone (13 mL) at 0° C. were added iPr2NEt (25.6 mmol), tetrabutylammonium iodide (157 mg, 0.426 mmol) and bromodiphenylmethane (1.20 g, 4.86 mmol). The reaction mixture was heated at 50° C. for 21 h before partitioning between diethyl ether and ice water. After adjusting the pH to 3, the aqueous layer was extracted with diethyl ether. The organic layers were combined, washed with NaH2PO4, dried over MgSO4 and evaporated to dryness. Purification on silica gel column (15% EtOAc in hexane) yielded 1.51 g (87% yield) of the product.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[C:9]2[OH:14])([O-])=O.[H][H]>[Pd].C(O)(C)C>[NH2:1][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[C:9]2[OH:14]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cccc2c(O)cccc12
Agent: [Pd]
Solvent: CC(C)O
Product: Nc1cccc2c(O)cccc12
Reaction time: 2 h
Yield: 95 %

Procedure:
In an autoclave was placed 1.9 g of 5-nitro-1-naphthol, 0.02 g of 5% Pd/C (containing 50% by weight of water), and 50 g of isopropanol, and the hydrogen pressure was set at 0.8 MPa. The reaction was carried out at 50° C. for 2 hours. After the reaction mixture was cooled, the catalyst was filtered off, and the reaction mass thus obtained was analyzed by gas chromatography. As a result, the content of 5-amino-1-naphthol produced was 1.5 g (yield 95%).
Reaction SMILES: CO[C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[F:25])=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH2:27][CH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[F:25][C:19]1[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:18]=1[C:13]1[C:12]([CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([NH:27][CH:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[O:26])=[CH:5][N:6]=2)=[C:16]([CH3:17])[O:15][N:14]=1
Reactant: NC1CCOCC1
Reactant: COC(=O)c1ccc(OCc2c(-c3cc(F)ccc3F)noc2C)nc1
Product: Cc1onc(-c2cc(F)ccc2F)c1COc1ccc(C(=O)NC2CCOCC2)cn1
Yield: 71 %

Procedure:
As described for example 265f, 6-[3-(2,5-difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (200 mg, 0.56 mmol) was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (170 mg, 71%) which was obtained as a colourless oil. MS: m/e=430.5 [M+H]+.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[NH:13][C:12](=[O:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]1[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1>CN(C)C=O.C(OCC)(=O)C>[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:13]2[C:12](=[O:14])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:4]2=[O:3])=[CH:24][CH:23]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: CCOC(=O)Cn1c(=O)[nH]c(=O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cn1c(=O)n(Cc2ccc(Cl)cc2)c(=O)c2ccccc21
Temperature: 25 °C
Yield: 84.9 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 367 mg) in N,N-dimethylformamide (15 ml) was added a solution of ethyl 2-(1,2,3,4-tetrahydro-2,4-dioxoquinazolin-1-yl)acetate (2.0 g) in N,N-dimethylformamide (35 ml) with stirring at room temperature under nitrogen atmosphere, and the mixture was stirred at the same temperature for 15 minutes. To this mixture was added 4-chlorobenzyl chloride (1.48 g) with stirring at room temperature and the mixture was stirred at the same temperature for 1 hour. The solvent was evaporated in vacuo to give a residue, which was dissolved in ethyl acetate. The ethyl acetate solution was washed with water and dried. Evaporation of the solvent gave a residue, which was washed with n-hexane to afford ethyl 2-[3-(4-chlorobenzyl)-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-1-yl]acetate (2.55 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([OH:15])=[O:14])=[CH:8][CH:7]=[CH:6]2.[C:16](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:7]=[CH:6]2
Reactant: O=C([O-])[O-]
Reactant: COc1ccc2c(C(=O)O)cccc2c1
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COC(=O)c1cccc2cc(OC)ccc12
Temperature: 25 °C
Yield: 90.9 %

Procedure:
A mixture of 9.1 g of 6-methoxynaphthoic acid and 7.2 g of anhydrous potassium carbonate in 45 ml of acetone was heated to 50°-55° C. for 15 minutes, and 4.5 ml of dimethyl sulfate were then slowly dripped in over a period of 15 minutes. The mixture was then heated at reflux for one hour and cooled to room temperature, after which all the acetone was stripped under vacuum. After workup, it was determined that the process resulted in the formation of 8.85 g of methyl 6-methoxynaphthoate having an HPLC purity of 83.3%.
Reaction SMILES: [OH:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1.Br[CH2:37][CH2:38][Cl:39]>C(#N)C>[Cl:39][CH2:38][CH2:37][O:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)[CH:3]=1
Reactant: Oc1cc(-c2cccs2)n[nH]1
Reactant: ClCCBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: ClCCOc1cc(-c2cccs2)n[nH]1
Yield: 29.2 %

Procedure:
5-Hydroxy-3-(2-thienyl)pyrazole (2.49 g), potassium carbonate (3.11 g) and 18-crown-6-ether (0.13 g) is suspended in acetonitrile (31 ml), to which 1-bromo-2-chloroethane (2.15 g) is added drop by drop and the reaction mixture is refluxed for 5 hours by heating. After the reaction is completed, it is extracted with ethyl acetate, washed with aqueous solution of sodium hydrogen carbonate and dried with anhydrous magnesium sulfate. Dichloromethane is added to the residue obtained by distilling off ethyl acetate and the insoluble matter is filtered off. Dichloromethane is added and distilled off to obtain the objective 5-(2-chloroethoxy)-3-(2-thienyl)pyrazole (1.0 g). mp. 134-138° C.
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[C:5]([I:24])=[CH:6][C:7](=[O:23])[N:8]([CH2:10][CH2:11][C@@:12]([CH3:22])([S:18]([CH3:21])(=[O:20])=[O:19])[C:13]([O:15]CC)=[O:14])[CH:9]=1>CC1CCCO1.O.[OH-].[Na+]>[F:3][C:4]1[C:5]([I:24])=[CH:6][C:7](=[O:23])[N:8]([CH2:10][CH2:11][C@@:12]([CH3:22])([S:18]([CH3:21])(=[O:20])=[O:19])[C:13]([OH:15])=[O:14])[CH:9]=1
Reactant: CCOC(=O)[C@@](C)(CCn1cc(F)c(I)cc1=O)S(C)(=O)=O
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CC1CCCO1
Solvent: O
Product: C[C@@](CCn1cc(F)c(I)cc1=O)(C(=O)O)S(C)(=O)=O
Temperature: 70 °C
Reaction time: 2 h
Yield: 44.8 %

Procedure:
Potassium hydroxide (669 mg, 7.7 mmol) was added to a solution of ethyl (2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoate (691 mg, 1.55 mmol) in 2-methyltetrahydrofuran:water (2:1 22.5 mL) and the solution was stirred at 70° C. for 2 h. The reaction was diluted with 1 N aq NaOH (50 mL). The organics were separated and the aqueous layer was washed with EtOAc (2×50 mL), and acidified to a pH of 3 using 3 M aqueous HCl. The aqueous layer was extracted with EtOAc (3×60 mL), dried (MgSO4), filtered and concentrated to afford a yellow-white solid (290 mg, 44.8%). MS (LCMS) m/z 418.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.53 (s, 3H) 2.08-2.20 (m, 1H) 2.36-2.48 (m, 1H) 3.13 (s, 3H) 3.79-4.02 (m, 2H) 7.03 (d, J=6.05 Hz, 1H) 7.96 (d, J=4.29 Hz, 1H) 13.82 (br. s., 1H).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[O:28]1[CH2:33][CH2:32][CH:31]([CH2:34][C:35](O)=[O:36])[CH2:30][CH2:29]1>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:35](=[O:36])[CH2:34][CH:31]5[CH2:32][CH2:33][O:28][CH2:29][CH2:30]5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: O=C(O)CC1CCOCC1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: O=C(CC1CCOCC1)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (126 mg, 92%), MS (ISP) m/z=457.4 [(M+H)+], mp 222.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (132 mg, 0.3 mmol) and tetrahydropyran-4-yl-acetic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=4)[CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.C(N(S(F)(F)[F:35])CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([F:35])[CH2:9][N:10]2[CH2:11][CH2:12][CH:13]([N:16]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=4)[CH2:19][CH2:18][CH2:17]3)[CH2:14][CH2:15]2)=[CH:6][CH:7]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: COc1ccc2c(c1)N(C1CCN(CC(O)c3ccc(F)cc3)CC1)CCC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc2c(c1)N(C1CCN(CC(F)c3ccc(F)cc3)CC1)CCC2
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 1-{1-[2-(4-fluorophenyl)-2-hydroxyethyl]piperidin-4-yl}-7-methoxy-1,2,3,4-tetrahydroquinoline (250 mg) in methylene chloride (5 ml) was cooled to −78° C. and diethylaminosulfur trifluoride (DAST, 0.1 ml) was added thereto. Then the reaction solution was stirred at the same temperature for 45 min. After the completion of the reaction, saturated sodium bicarbonate was added to the reaction solution, which was then allowed to warm to room temperature under stirring. The reaction solution was extracted with ethyl acetate and the organic layer was dried over magnesium sulfate. After evaporating the solvent, the resulting residue was purified by silica gel column chromatography (hexane/hexane system) to give 1-{1-[2-(4-fluorophenyl)-2-fluoroethyl]piperidin-4-yl}-7-methoxy-1,2,3,4-tetrahydroquinoline as an oil. This product was dissolved in ethyl acetate. After adding hydrochloric acid, the resulting salt was recrystallized from ethanol/ether to give the title compound (60 mg) (yield: 24%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:33]3[CH:38]=[CH:37][C:36]([CH:39]=O)=[CH:35][CH:34]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=4[F:29])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12.[CH3:41][O:42][CH2:43][CH2:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:33]3[CH:34]=[CH:35][C:36]([CH2:39][N:48]4[CH2:49][CH2:50][N:45]([CH2:44][CH2:43][O:42][CH3:41])[CH2:46][CH2:47]4)=[CH:37][CH:38]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:27])([F:28])[F:26])=[CH:21][C:20]=4[F:29])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12
Reactant: COc1cc(-c2nn(-c3ccc(C=O)cc3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Reactant: COCCN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Product: COCCN1CCN(Cc2ccc(-n3nc(-c4ccc(NC(=O)c5ccc(C(F)(F)F)cc5F)c(OC)c4)c4c(N)ncnc43)cc2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 22.1 %

Procedure:
A mixture of N1-{4-[4-amino-1-(4-formylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-2-fluoro-4-(trifluoromethyl)benzamide (Intermediate 2) (0.075 g, 0.14 mmol), 1-(2-methoxyethyl)-piperazine (0.039 g, 0.27 mmol), and sodium triacetoxyborohydride (0.087 g, 0.41 mmol) in dichloroethane (1.4 mL) was shaken at room temperature for 3 days. Additional portions of 1-(2-methoxyethyl)-piperazine (0.10 mL) and sodium triacetoxyborohydride (0.089 g, 0.41 mmol) were added and the reaction mixture was shaken for 16 h. 1N NaOH (1 mL) was added and the resulting solution was extracted with two portions of dichloromethane (2 mL each). The combined organic portions were concentrated to afford a brown solid which was purified by preparative RP-HPLC (Rainin C18, 8 μm, 300 Å, 25 cm; 20-80% acetonitrile-0.05 M ammonium acetate over 25 min, 21 mL/min); the fraction eluting from 16.9-20.2 min was collected, concentrated, and lyopholized to afford N1-{4-[4-amino-1-(4-{[4-(2-methoxyethyl)piperazino]methyl}phenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-2-fluoro-4-(trifluoromethyl)benzamide as a white solid (0.021 g, 0.031 mmol): 1H NMR (d6-DMSO, 400 MHz): δH 9.94 (1H, s), 8.34-8.37 (2H, m), 8.14-8.17 (1H, m), 7.98-8.02 (1H, m), 7.89 (1H, d, J=10.4 Hz), 7.74-7.76 (1H, m), 7.34-7.64 (6H, m), 3.96 (3H, s), 3.51 (2H, s), 3.31-3.43 (2H, m), 3.22 (3H, s), and 2.41-2.45 (10H, m); RP-HPLC (Hypersil C18, 5 μm, 100 Å, 15 cm; 5%-100% acetonitrile-0.1 M ammonium acetate over 15 min, 1 mL/min). Rt 11.24 min.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[C:7]([O:14][CH3:15])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[NH2:38][C:39]1[CH:40]=[C:41]([CH:45]2[CH2:49][CH2:48][CH2:47][N:46]2[C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH:42]=[CH:43][CH:44]=1>CN(C=O)C.O>[C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH:38][C:39]2[CH:40]=[C:41]([CH:45]3[CH2:49][CH2:48][CH2:47][N:46]3[C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH:42]=[CH:43][CH:44]=2)=[O:11])=[C:7]([O:14][CH3:15])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1cccc(N)c1
Reactant: COc1cc(C(C)(C)C)ccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(C)(C)C)ccc1C(=O)Nc1cccc(C2CCCN2C(=O)OC(C)(C)C)c1
Reaction time: 17 h
Yield: 34.8 %

Procedure:
To a solution of 4-tert-butyl-2-methoxy-benzoic acid (0.05 g) in DMF (1.5 mL) at room temperature, was added in order, 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (0.046 g), 1-hydroxy-benzotriazole (0.033 g) and 15 min. later, (±)-2-(3-aminophenyl)-1-(tert-butyloxycarbonyl)-pyrrolidine (0.05 g). The reaction mixture was allowed to stir for 17 h and then poured into water. The aqueous mixture was extracted with ethyl acetate twice. The combined organic layer was washed with brine, dried (sodium sulfate) and evaporated in vacuo to afford an amber oil. Suction silica gel chromatography eluting with ethyl acetate in hexane (from 30% to 100%, in 10% increments) gave desired product as an amber solid (0.03 g).