Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][CH:3]=1.[CH3:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[C:12]=1B(O)O.CC(C)([O-])C.[K+]>COCCOC.C(O)(C)(C)C.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:11]1([CH3:10])[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[C:12]=1[C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C)c(B(O)O)c(C)c1
Reactant: OCc1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CC(C)(C)O
Product: Cc1cc(C)c(-c2cccc(CO)n2)c(C)c1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 68.4 %

Procedure:
(6-Bromopyridin-2-yl)-methanol (4.23 g, 22.5 mmol) was dissolved in 1,2-dimethoxyethane. Tetrakis(triphenylphosphine)palladium(0) (1.30 g, 1.12 mmol) was added and the reaction stirred for 15 minutes at 50° C. Upon cooling, 2,4,6-trimethylbenzeneboronic acid (3.69 g, 22.5 mmol) in 20 mL 1,2-dimethoxyethane was added to the reaction followed by potassium t-butoxide (5.05 g, 50.0 mmol) in 20 mL of t-butanol. The reaction was heated at 90° C. for 0.5 hr. The solution was cooled and filtered through paper. Flash chromatography (30% ethyl acetate/hexanes) gave the desired product as a white solid (3.50 g, 68% yield).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]2([CH2:21][CH2:20][CH2:19]2)[CH2:16][C:15]2[N:14]=[C:13]([CH:22]([CH3:24])[CH3:23])[C:12]([CH:25]=[O:26])=[C:11]([C:27]3[CH2:28][CH2:29][O:30][CH2:31][CH:32]=3)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:34]1[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][C:35]=1[F:44]>O1CCCC1>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]2([CH2:21][CH2:20][CH2:19]2)[CH2:16][C:15]2[N:14]=[C:13]([CH:22]([CH3:24])[CH3:23])[C:12]([C@H:25]([C:34]3[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][C:35]=3[F:44])[OH:26])=[C:11]([C:27]3[CH2:28][CH2:29][O:30][CH2:31][CH:32]=3)[C:10]1=2)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: Fc1cc(C(F)(F)F)ccc1Br
Reactant: CC(C)c1nc2c(c(C3=CCOCC3)c1C=O)[C@@H](O[Si](C)(C)C(C)(C)C)CC1(CCC1)C2
Solvent: C1CCOC1
Product: CC(C)c1nc2c(c(C3=CCOCC3)c1[C@@H](O)c1ccc(C(F)(F)F)cc1F)[C@@H](O[Si](C)(C)C(C)(C)C)CC1(CCC1)C2

Procedure:
Obtained by starting from (S)-5′-(tert-butyldimethylsilyloxy)-4′-(3,6-dihydro-2H-pyran-4-yl)-2′-isopropyl-6′,8′-dihydro-5′H-spiro[cyclobutane-1,7′-quinoline]-3′-carbaldehyde and 1-bromo-2-fluoro-4-(trifluoromethyl)benzene. Tetrahydrofurane is used instead of toluene.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:19])[N:4]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:5]([CH:8]([CH3:10])[CH3:9])=[CH:6][CH:7]=1.[C:20]1([CH3:30])[CH:25]=[CH:24][CH:23]=[C:22]([S:26](Cl)(=[O:28])=[O:27])[CH:21]=1>C(Cl)Cl>[CH3:30][C:20]1[CH:21]=[C:22]([S:26]([NH:1][C:2]2[C:3](=[O:19])[N:4]([CH2:11][C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[C:5]([CH:8]([CH3:9])[CH3:10])=[CH:6][CH:7]=2)(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)c1ccc(N)c(=O)n1CC(=O)OC(C)(C)C
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Solvent: ClCCl
Product: Cc1cccc(S(=O)(=O)Nc2ccc(C(C)C)n(CC(=O)OC(C)(C)C)c2=O)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 87.5 %

Procedure:
3-Amino-6 isopropyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone (assumed to be 3.37 mmol), as prepared in the preceding step, and N-methylmbrpholine (1.0 mL, 9.1 mmol) were dissolved in methylene chloride (20 mL) and cooled to 0° C. A solution of m-toluenesulfonyl chloride (0.67 g, 3.5 mmol) in methylene chloride (5 mL) was added and the reaction stirred at ambient temperature for 16 hours. After evaporation in vacuo, the crude product was dissolved in methylene chloride, washed with 10% aqueous citric acid, saturated NaHCO3, and brine, dried over MgSO4, and filtered. The evaporated filtrate gave the title compound (1.24 g, 88%) as a tan solid. 1H NMR (300 MHz, CDCl3) δ 7.65 (m, 2H), 7.58 (br s, 1H), 7.46 (d, 1H, J=7.8 Hz), 7.33 (m, 2H), 6.08 (d, 1H, J=7.9 Hz), 4.69 (s, 2H), 2.67 (m, 1H), 2.38 (s, 3H), 1.41 (s, 9H), 1.22 (s, 3H), 1.19 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[C:19](=[O:20])[N:18]([CH2:21][CH2:22][C:23](O)=[O:24])[C:17](=[O:26])[N:16]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=4)[C:15]=3[CH3:37])=[CH:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2].O1CCCC1.B.[Cl-].[NH4+]>O1CCCC1>[OH:24][CH2:23][CH2:22][CH2:21][N:18]1[C:19](=[O:20])[C:14]([C:13]2[N:9]([C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=3)[N:10]=[CH:11][CH:12]=2)=[C:15]([CH3:37])[N:16]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:35])([F:36])[F:34])[CH:28]=2)[C:17]1=[O:26]
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)c(=O)n(CCC(=O)O)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: B
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)c(=O)n(CCCO)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 74.4 %

Procedure:
To a solution of 3-[5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-4-methyl-2,6-dioxo-3-(3-trifluoromethylphenyl)-2,3-dihydropyrimidin-1(6H)-yl]propanoic acid (prepared in Example 73) (36.2 mg) in tetrahydrofuran (0.5 ml) was added under ice-cooling borane tetrahydrofuran complex (0.1 ml:1.09 M tetrahydrofuran solution), and the resulting mixture was stirred at room temperature for eighteen hours. The reaction mixture was cooled again under ice-cooling and thereto was added borane tetrahydrofuran complex (0.2 ml:1.09 M tetrahydrofuran solution) and the resulting mixture was stirred at room temperature for five hours. To the reaction mixture was added saturated aqueous ammonium chloride solution (2 ml) and the resulting mixture was extracted with ethyl acetate (20 ml×2). The organic layer was washed with water (20 ml) and saturated saline (20 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol) to afford 4-[5-[3-(3-hydroxypropyl)-6-methyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile (26.2 mg).
Reaction SMILES: Cl[C:2]1[S:3][C:4]([N+:10]([O-:12])=[O:11])=[CH:5][C:6]=1[N+:7]([O-:9])=[O:8].[CH2:13]([NH:15][CH2:16][CH3:17])[CH3:14]>CO>[CH2:13]([N:15]([C:2]1[S:3][C:4]([N+:10]([O-:12])=[O:11])=[CH:5][C:6]=1[N+:7]([O-:9])=[O:8])[CH2:16][CH3:17])[CH3:14]
Reactant: CCNCC
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)s1
Solvent: CO
Product: CCN(CC)c1sc([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 68 %

Procedure:
A solution of 8.9 g (0.042 mol) 2-chloro-3,5-dinitrothiophene, 6.2 g (0.084 mol) diethylamine and 100 ml methanol was heated under reflux for 1/2 hour. The reaction mixture was evaporated under reduced pressure, washed with water and extracted with ether. The ether extracts were dried and evaporated to give an oil. The oil was chromatographed on silica gel (30% ether-hexane eluant) to give 7.0 g of product as an amber oil. Elemental analysis for C8H11N3O4S showed: %S, calc. 13.05, found 13.05.
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C@@:13]1([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[F:31])[CH2:18][O:17][C@@H:16]([CH:19]2[CH2:21][CH2:20]2)[CH2:15][C@H:14]1[CH2:22][OH:23]>ClCCl>[CH:19]1([C@@H:16]2[O:17][CH2:18][C@@:13]([NH:12][C:10]([NH:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[S:11])([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[F:31])[C@H:14]([CH2:22][OH:23])[CH2:15]2)[CH2:21][CH2:20]1
Reactant: N[C@@]1(c2ccc(F)cc2F)CO[C@@H](C2CC2)C[C@H]1CO
Reactant: O=C(N=C=S)c1ccccc1
Solvent: ClCCl
Product: O=C(NC(=S)N[C@@]1(c2ccc(F)cc2F)CO[C@@H](C2CC2)C[C@H]1CO)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Benzoyl isothiocyanate (0.540 mL, 4.02 mmol) was added drop-wise to a solution of rel-[(2R,4R,5S)-5-amino-2-cyclopropyl-5-(2,4-difluorophenyl)tetrahydro-2H-pyran-4-yl]methanol (C20) (1.20 g, 4.23 mmol) in dichloromethane (45 mL). After the reaction mixture had stirred at room temperature for 15 hours, it was partitioned between aqueous hydrochloric acid (0.1 M, 20 mL) and dichloromethane (35 mL). The organic layer was washed with saturated aqueous sodium bicarbonate solution (25 mL) and with saturated aqueous sodium chloride solution (25 mL), then dried over sodium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 45% ethyl acetate in heptane) provided the product as a white solid. Yield: 1.69 g, 3.78 mmol, 89%. LCMS m/z 447.2 [M+H+]. 1H NMR (400 MHz, CD3CN) δ 11.64 (br s, 1H), 9.28 (br s, 1H), 7.89-7.93 (m, 2H), 7.64-7.69 (m, 1H), 7.52-7.58 (m, 2H), 7.44-7.58 (br m, 1H), 6.86-6.99 (m, 2H), 3.48-3.86 (br m, 2H), 3.35-3.47 (m, 1H), 3.01 (ddd, J=11.3, 7.6, 2.7 Hz, 1H), 2.89-3.0 (br m, 1H), 2.3-2.6 (br m, 1H), 1.96-2.03 (m, 1H), 1.7-1.9 (br m, 1H), 0.90-1.00 (m, 1H), 0.44-0.53 (m, 2H), 0.34-0.40 (m, 1H), 0.26-0.31 (m, 1H).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:28]=[CH:27][C:15]([C:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]=[O:26])=[CH:21][CH:20]=2)=[O:17])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(OC1C=CC(C(OC)=O)=CC=1)CCCCCCCC=C.[OH-].[K+].C(Cl)(=O)C(Cl)=O.OC1C=CC(C=O)=CC=1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C>[CH2:1]([O:11][C:12]1[CH:28]=[CH:27][C:15]([C:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]=[O:26])=[CH:21][CH:20]=2)=[O:17])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10]
Reactant: CCCCCCCCCCOc1ccc(C(=O)Oc2ccc(C=O)cc2)cc1
Agent: C=CCCCCCCCCOc1ccc(C(=O)OC)cc1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Product: C=CCCCCCCCCOc1ccc(C(=O)Oc2ccc(C=O)cc2)cc1

Procedure:
Synthesized as described above for compound 10. Quantities: 3 (12.0 g, 41.3 mmol), KOH (3.62 g, 64.7 mmol), oxalyl chloride (12 mL, 0.15 mol), p-hydroxybenzaldehyde (5.25 g, 43.0 mmol), triethylamine (35 mL, 0.25 mol), DMAP (0.25 g, 2.0 mmol). Yield 5.6 g (36%). 1H NMR: δH (CDCl3; 300 MHz): 1.27-1.57 (10 H, m, CH2), 1.85 (2 H, m, O—CH2—CH2), 2.07 (2 H, m, CH2═CH—CH2), 4.07 (2 H, t, 3J=6.6 Hz, O—CH2), 4.99 (2 H, m, CH2═CH), 5.84 (1 H, m, CH2═CH), 7.00 (2 H, d, 3J=9.0 Hz, Ar—H), 7.42 (2 H, d, 3J=8.5 Hz, Ar—H), 7.98 (2 H, d, 3J=8.6 Hz, Ar—H), 8.16 (2 H, d, 3J=9.0 Hz, Ar—H), 10.03 (1 H, s, COH). 13C NMR: δC (CDCl3; 75 MHz): 26.4, 29.3, 29.4, 29.5, 29.7, 29.8, 34.2, 68.8, 114.6, 114.8, 121.2, 123.0, 131.6, 132.8, 134.3, 139.5, 156.3, 164.3, 164.6, 191.4.
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[CH:27]=[CH:26][CH:25]=[CH:24][C:9]=1[C:10]([NH:12][C:13]1[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:11].[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[C:28]([NH:7][C:8]1[CH:27]=[CH:26][CH:25]=[CH:24][C:9]=1[C:10]([NH:12][C:13]1[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:11])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCOC(=O)c1ccccc1NC(=O)c1ccccc1N
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1ccccc1NC(=O)c1ccccc1NC(=O)c1ccccc1
Reaction time: 0.08 h
Yield: 62 %

Procedure:
Pyridine (43 μL, 0.54 mmol) was added to a stirred solution of aniline 21 (50 mg, 0.18 mmol) in DCM (0.9 mL) at room temperature under nitrogen atmosphere. After 5 min, benzoylchloride 3 (22.5 μL, 0.198 mmol) was added and the reaction was stirred for 2 h before being diluted with DCM and washed with HCl (3×, aq, 1M), NaHCO3 (aq, sat), and brine. The organic phase was dried over Na2SO4, concentrated and purified by column chromatography (toluene:acetone 100:0→98:2) to give benzamide 23a in 62% yield (36 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:17](O)=[O:18])=[CH:11][C:10]=1[OH:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[CH2:30][N:31]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.CN.C(N(CC)C(C)C)(C)C>CN(C=O)C.O.C(OCC)(=O)C>[C:24]([O:23][C:21](=[O:22])[NH:20][C@H:16]([C:17](=[O:18])[NH:31][CH3:30])[CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([OH:28])[CH:11]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)c(O)c1)C(=O)O
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CNC(=O)[C@H](Cc1ccc(OCc2ccccc2)c(O)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
(S)-3-(4-benzyloxy-3-hydroxy-phenyl)-2-tert-butoxycarbonylamino-propionic acid (1.23 mmol) was dissolved in DMF (5 ml). EDCI (2 mmol) was added followed by HOBT (1 mmol) and methylamine hydrochloride (2 mmol). N,N-Diisopropylethylamine (2 mmol) was added and the solution was stirred at room temperature for 5 hours. The solution was diluted with water and ethyl acetate. The ethyl acetate extract was washed with dil HCl, with water and with brine. Drying (MgSO4) and evaporation gave the crude product which crystallised from ethyl acetate-hexane (1:1). [(S)-2-(4-Benzyloxy-3-hydroxy-phenyl)-1-methylcarbamoyl-ethyl]-carbamic acid tert-butyl ester was obtained as a white solid, 348 mg; HPLC/MS retention time 5.22 min, m/z 401 (MH+).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][NH:3][C:2]1=[O:7].[H-].[Na+].Br[CH2:11][C:12]([O:14][CH3:15])=[O:13]>CN(C=O)C>[O:7]=[C:2]1[N:3]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH2:4][CH2:5][CH2:6][O:1]1
Reactant: O=C1NCCCO1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CN1CCCOC1=O
Reaction time: 8 h
Yield: 19.6 %

Procedure:
A solution of 0.20 g (2.0 mmol) of 1,3-oxazinan-2-one from step A above in 2 mL of anhydrous DMF was added to a 10 mL round bottom flask containing 0.13 g (3.2 mmol) of a 60% sodium hydride suspension in mineral oil under an atmosphere of nitrogen. After stirring for 10 min 0.37 g (2.4 mmol) of methyl bromoacetate was added in one portion and the reaction mixture was allowed to stir overnight. The reaction mixture was then quenched with 5 mL of a saturated aqueous ammonium chloride solution and then diluted with 20 mL of water. The resulting suspension was extracted with ethyl acetate (3×10 mL) and the combined organics were washed with water (2×3 mL), brine (1×3 mL) and dried over magnesium sulfate. The mixture was filtered, evaporated and purified by silica gel chromatography eluting with a 5% methanol in ethyl acetate mixture to afford the title compound as a clear oil (0.068 g, 20%). 1HNMR (500 MHz, CDCl3) δ: 4.28 (t, J=5.4 Hz, 2H), 4.03 (s, 2H), 3.70 (s, 3H), 3.36 (t, J=6.2 Hz, 2H), 2.08-2.04 (m, 2H). LC-MS: m/z (ES) 174 (MH)+.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[N:8]=[CH:7][C:6]([C:9]([CH3:16])=[CH:10][C:11]([O:13]CC)=[O:12])=[CH:5][CH:4]=1.[OH-].[Na+]>C1COCC1.CCO>[F:17][C:2]([F:1])([F:18])[C:3]1[N:8]=[CH:7][C:6]([C:9]([CH3:16])=[CH:10][C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C=C(C)c1ccc(C(F)(F)F)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(=CC(=O)O)c1ccc(C(F)(F)F)nc1
Temperature: 60 °C
Yield: 90.9 %

Procedure:
To a solution of ethyl 3-(6-(trifluoromethyl)pyridin-3-yl)but-2-enoate (2.9 g, 11 mmol) in EtOH/THF 1/1 (34 mL) was added 1M NaOH (aq.) (34 mL). The resulting mixture was heated at 60° C. for 1 h after which the reaction mixture was allowed to cool to rt. The volatiles were evaporated and the remaining water phase neutralized with 1 M HCl(aq.). The title compound (2.4 g, 10 mmol, 91%), which precipitated as a white solid, was filtered off and dried under vacuum at 55° C. over night. This material was used directly in the next step, without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([N:12]1[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)[CH2:14][CH2:13]1)[N:8]([C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=1[O:36][CH3:37])[C@@H:7]2[CH2:38][C:39]([OH:41])=[O:40].C[O-].[Na+]>C(#N)C.C(O)C>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([N:12]1[CH2:13][CH2:14][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)[CH2:16][CH2:17]1)[N:8]([C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=1[O:36][CH3:37])[CH:7]2[CH2:38][C:39]([OH:41])=[O:40]
Reactant: COc1cccc(N2CCN(C3=Nc4c(F)cccc4[C@@H](CC(=O)O)N3c3cc(C(F)(F)F)ccc3OC)CC2)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC#N
Product: COc1cccc(N2CCN(C3=Nc4c(F)cccc4C(CC(=O)O)N3c3cc(C(F)(F)F)ccc3OC)CC2)c1
Temperature: 25 °C
Yield: 108.4 %

Procedure:
(R)-{8-Fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-(2-methoxy-5-trifluoromethylphenyl)-3,4-dihydroquinazolin-4-yl}acetic acid (50 g) is dissolved in acetonitrile (500 ml) and treated with sodium methoxide (30% strength in methanol, 32.4 ml) and then stirred under reflux for 60 h. After cooling to room temperature, the mixture is concentrated to one half in vacuo, then it is adjusted to pH 7.5 using hydrochloric acid (20% strength, ca. 20 ml), MIBK (200 ml) is added and it is readjusted to pH 7 using hydrochloric acid (20% strength). The phases are separated, and the organic phase is dried over sodium sulphate and concentrated in a rotary evaporator to give a hard foam. The residue is dissolved in ethanol (150 ml) and concentrated, then again dissolved in ethanol (150 ml) and concentrated. A total of 54.2 g of (±)-{8 fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-(2-methoxy-5-trifluoromethylphenyl)-3,4-dihydroquinazolin-4-yl}acetic acid are thus obtained in quantitative yield as an amorphous solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:10]2[C:5](=[C:6]3[CH:16]=[CH:15][CH:14]=[CH:13][C:7]3=[CH:8][C:9]=2[O:11][CH3:12])[NH:4][CH2:3]1.[CH2:18](I)[CH3:19]>>[CH3:1][C:2]1([CH3:17])[C:10]2[C:5](=[C:6]3[CH:16]=[CH:15][CH:14]=[CH:13][C:7]3=[CH:8][C:9]=2[O:11][CH3:12])[NH:4][CH2:3]1.[CH2:18]([N:4]1[C:5]2[C:10](=[C:9]([O:11][CH3:12])[CH:8]=[C:7]3[CH:13]=[CH:14][CH:15]=[CH:16][C:6]3=2)[C:2]([CH3:17])([CH3:1])[CH2:3]1)[CH3:19]
Reactant: CCI
Agent: COc1cc2ccccc2c2c1C(C)(C)CN2
Product: CCN1CC(C)(C)c2c(OC)cc3ccccc3c21

Procedure:
The 4-methoxybenzoindoline 25 was synthesized as described above in Example 6. Compound 25 was alkylated by the general amino group alkylation procedure described in Example 3 employing ethyl iodide as the alkylating agent to give the N-ethyl-3,3-dimethyl-4-methoxybenzoindoline intermediate 28 (1HNMR: CD3Cl d 7.90 (d, 1H, J=8.7 Hz), 7.68 (d, 1H, J=8.1 Hz), 7.32 (bt, 1H, J=7.5 Hz), 7.22 (bt, 1H, J=6.9 Hz), 6.69 (s, 1H), 3.83 (s, 3H), 3.52 (q, 2H J=7.5 Hz), 3.38 (s, 2H), 1.46 (s, 6H), 1.27 (t, 3H, J=7.5 Hz). Subsequent methoxy group deprotection of compound 28 by the general boron tribromide procedure described in Example 1 yielded the N-ethyl-3,3-dimethyl-4-hydroxy-benzoindoline 29.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]([C:8](=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=1)=[CH:5]OC.[NH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1>>[CH3:1][O:2][C:3](=[O:18])[C:4]([C:8](=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=1)=[CH:5][NH:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1
Reactant: Nc1cccnc1
Reactant: COC=C(C(=O)OC)C(=O)c1ccc(C)c(C)c1
Product: COC(=O)C(=CNc1cccnc1)C(=O)c1ccc(C)c(C)c1

Procedure:
1g (4.02 mmol) of the crude 2-(3,4-Dimethyl-benzoyl)-3-methoxy-acrylic acid methyl ester and 0.38 g (4.02 mmol) of 3-aminopyridine were heated neat at 100° C. for 2 h. The product crystallized upon cooling the reaction to rt to yield 1.12 g of 2-(3,4-Dimethyl-benzoyl)-3-(pyridin-3-ylamino)-acrylic acid methyl ester as brown crystalline solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:19]([O:18][C:16](=[O:17])[NH:15][CH2:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)OCc2ccccc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCC1CCNCC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 3 (4.4 g, 13 mmol) in 90 ml of methylene chloride was added 45 ml of TFA. After stirring at room temperature for 24 hours, the solvents were removed in vacuo and the residue partitioned between chloroform and 10% Na2CO3. The organics were dried over MgSO4, filtered, and the solvent removed in vacuo to give the title compound.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH3:16].[Cl:17][C:18]1[N:19]=[C:20]([C:26](O)=[O:27])[NH:21][C:22]=1[CH:23]([CH3:25])[CH3:24].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[Cl:17][C:18]1[N:19]=[C:20]([C:26]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]2[O:15][CH3:16])=[O:27])[NH:21][C:22]=1[CH:23]([CH3:25])[CH3:24]
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Reactant: CC(C)c1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)c1nc(Cl)c(C(C)C)[nH]1

Procedure:
The same operation as in Example (1g) was performed using tert-butyl cis(±)-4-amino-3-methoxypiperidine-1-carboxylate obtained by the method described in Example (1e) (0.50 g, 2.17 mmol), 4-chloro-5-(propan-2-yl)-1H-imidazole-2-carboxylic acid obtained in Example (35f) (0.30 g, 1.59 mmol), WSC hydrochloride (0.92 g, 4.80 mmol) and HOBT (0.22 g, 1.63 mmol), to obtain 0.60 g of the title compound as a white foamy substance (94%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[Cl:11][C:12]1[CH:17]=[C:16]([NH:18][C:19]2[C:24]([NH2:25])=[C:23]([Cl:26])[N:22]=[CH:21][N:20]=2)[CH:15]=[CH:14][N:13]=1>N1C=CC=CC=1.O.C(OCC)(=O)C>[Cl:26][C:23]1[C:24]([NH:25][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)=[C:19]([NH:18][C:16]2[CH:15]=[CH:14][N:13]=[C:12]([Cl:11])[CH:17]=2)[N:20]=[CH:21][N:22]=1
Reactant: Nc1c(Cl)ncnc1Nc1ccnc(Cl)c1
Reactant: O=C(Cl)c1cccc(F)c1
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(Nc1c(Cl)ncnc1Nc1ccnc(Cl)c1)c1cccc(F)c1
Reaction time: 12 h
Yield: 62.1 %

Procedure:
3-Fluorobenzoyl chloride (1.3 mL, 10.7 mmol) was added dropwise to a suspension of N4-(2-chloro-4-pyridyl)-6-chloro-4,5-pyrimidine diamine (2.5 g, 9.8 mmol) in pyridine (50 mL) over 5 minutes in a nitrogen atmosphere at 0 to 5° C., and the mixture was stirred as such for 12 hours. The reaction solution was diluted with water and ethyl acetate (100 mL). The organic layer was washed with 1N hydrochloric acid (×1). After the 1N hydrochloric acid layer was extracted with ethyl acetate (×2), the combined organic layers were washed with a saturated aqueous sodium bicarbonate solution (×1), dried over anhydrous sodium sulfate and concentrated. The residue was suspended in diethyl ether, and the solid was collected by filtration and washed with diethyl ether, to give the title compound (2.3 g, 62%) as a colorless solid.