Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C=CC([C:8]2[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=CC=1.[N:38]1([C:44]2[N:49]=[CH:48][C:47](B(O)O)=[CH:46][CH:45]=2)[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]2[N:24]=[C:20]([CH:17]3[CH2:16][CH2:15][N:14]([C:13]4[N:12]=[CH:11][N:10]=[C:9]([NH2:37])[C:8]=4[C:47]4[CH:48]=[N:49][C:44]([N:38]5[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]5)=[CH:45][CH:46]=4)[CH2:19][CH2:18]3)[N:21]([CH3:36])[CH:22]=2)=[CH:26][C:27]=1[C:32]([F:34])([F:33])[F:35]
Reactant: OB(O)c1ccc(N2CCNCC2)nc1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(F)cc2)CC1
Product: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(N3CCNCC3)nc2)CC1

Procedure:
The title compound was prepared in an analogous manner as 5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine using (6-(piperazin-1-yl)pyridin-3-yl)boronic acid instead of 4-fluorophenylboronic acid. LC-MS: (M+1=582, obsd.=582).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][OH:17])=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O>[Pt].C(O)C>[NH2:1][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][OH:17])=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: O=[N+]([O-])c1cnc2ccccc2c1NCCO
Agent: [Pt]
Solvent: CCO
Product: Nc1cnc2ccccc2c1NCCO

Procedure:
2-[(3-Nitro-4-quinolinyl)amino]ethanol (6 g) was combined with ethanol (200 mL) and platinum on carbon catalyst. The mixture was hydrogenated on a Parr apparatus. This procedure was repeated four additional times using a total of 30 g of starting material. The mixtures from all five hydrogenations were combined and then filtered through a layer of Celite® filter aid to remove the catalyst. The filtrate was concentrated under vacuum to provide crude 2-[(3-amino-4-quinolinyl)amino]ethanol.
Reaction SMILES: [Na+].[I-].[F:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1.[C:13]([O:17][C:18]([N:20]1[CH2:24][CH:23]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH2:22][CH:21]1[CH:33]=[CH:34][N+:35]([O-:37])=[O:36])=[O:19])([CH3:16])([CH3:15])[CH3:14]>CO.CC#N>[C:13]([O:17][C:18]([N:20]1[CH2:24][CH:23]([O:25][Si:26]([C:29]([CH3:30])([CH3:31])[CH3:32])([CH3:28])[CH3:27])[CH2:22][CH:21]1[CH:33]([C:8]1[C:7]2[C:11](=[CH:12][C:4]([F:3])=[CH:5][CH:6]=2)[NH:10][CH:9]=1)[CH2:34][N+:35]([O-:37])=[O:36])=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CC(O[Si](C)(C)C(C)(C)C)CC1C=C[N+](=O)[O-]
Reactant: Fc1ccc2cc[nH]c2c1
Agent: [I-]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC(O[Si](C)(C)C(C)(C)C)CC1C(C[N+](=O)[O-])c1c[nH]c2cc(F)ccc12
Reaction time: 72 h
Yield: 74.2 %

Procedure:
To a solution of CeCl3.7H2O (6.06 g, 40.6 mmol) and NaI (2.44 g, 16.2 mmol) in MeOH (200 mL) was added SiO2 (30 g). The resulting pale yellow solution was evaporated to dryness to afford a fine yellow powder. To this solid was added 6-fluoroindole (6.59 g, 48.7 mmol) and a solution of 77 (15.1 g, 40.6 mmol) in anhydrous CH3CN (150 mL). The heterogeneous reaction mixture was evaporated to dryness and allowed to stand 72 h at ambient temperature. The reaction mixture was diluted with CH2Cl2 and additional silica gel (150 mL) was added. The mixture was concentrated to dryness and the product was eluted by flash silica gel chromatography (15-25% EtOAc/hexanes) to afford 78 (15.3 g, 75%) as an inseparable mixture of diastereomers. Mass spectrum, m/z [508.2] (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=1.[CH:24]([C:27]1[N:31]=[C:30]([CH:32]2[CH2:37][CH2:36][CH2:35][NH:34][CH2:33]2)[O:29][N:28]=1)([CH3:26])[CH3:25].C(N(CC)CC)C>O1CCCC1>[CH:24]([C:27]1[N:31]=[C:30]([CH:32]2[CH2:37][CH2:36][CH2:35][N:34]([C:2]3[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=4)[N:3]=3)[CH2:33]2)[O:29][N:28]=1)([CH3:26])[CH3:25]
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccc(C)cc1
Reactant: CC(C)c1noc(C2CCCNC2)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCC(C(=O)OC)c1c(C)nc(N2CCCC(c3nc(C(C)C)no3)C2)nc1-c1ccc(C)cc1
Yield: 18.6 %

Procedure:
This compound was prepared according to the method C from methyl 2-(2-chloro-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (0.095 g; 0.285 mmol), 3-isopropyl-5-(piperidin-3-yl)-1,2,4-oxadiazole (0.167 g; 0.856 mmol) and triethyl amine (0.200 mL; 1.43 mmol) in tetrahydrofuran (2 mL). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2-30%) in heptane furnished 0.026 g (18%) of the titled compound as a colorless oil.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].CC([O-])(C)C.[K+].[F:13][C:14]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:15]=1F.[Cl-].[Na+]>O.C1(C)C=CC=CC=1.CS(C)=O>[F:13][C:14]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:15]=1[O:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:6]
Reactant: OCCCCO
Reactant: Fc1cc(F)c(F)cc1F
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: OCCCCOc1cc(F)c(F)cc1F
Reaction time: 18 h

Procedure:
To a mixture of 1,4-butanediol (15 g, 0.17 mol) and t-BuOK (8.0 g, 0.071 mol) were added 1,2,4,5-tetrafluorobenzene (5.0 g, 33 mmol) and DMSO (50 g) at 60° C. After being stirred at this temperature for 18 h, toluene (200 mL), water (50 mL) and sodium chloride (10 g) were added to the reaction mixture. The layers were separated and the organic layer was concentrated in vacuo giving the title compound. This material was used directly in the next step.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[CH:13]([CH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14].[Cl-].[NH4+]>CCCCCC.C1(C)C=CC=CC=1.C(OCC)(=O)C.O1CCCC1>[OH:14][CH:13]([CH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: Brc1cccnc1
Reactant: O=CC1CCOCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OC(c1cccnc1)C1CCOCC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 87.8 %

Procedure:
To toluene (2.2 mL), n-butyllithium (a 2.77 mol/L solution in hexane, 0.82 mL, 2.28 mmol) was added under a nitrogen atmosphere at −60° C. To this, a solution of 3-bromopyridine (200 μL, 2.08 mmol) in toluene (0.73 mL) was slowly added dropwise at the same temperature and the mixture was stirred at −78° C. for 15 minutes. To this suspension, tetrahydrofuran (0.73 mL) was slowly added dropwise and the mixture was stirred at the same temperature for 15 minutes. Then, 4-formyltetrahydropyran (285 mg, 2.50 mmol) was added thereto. Over 1 hour, the reaction mixture was heated to −15° C. Then, a saturated aqueous ammonium chloride solution was added to the reaction mixture, and extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol=19/1) to give 3-[hydroxy(tetrahydropyran-4-yl)methyl]pyridine (Compound CW) (353 mg, yield: 88%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:13]2=[N:14][C:15]3[N:16]([CH3:23])[C:17](=[O:22])[NH:18][C:19](=[O:21])[C:20]=3[N:12]2[CH:11]=[C:10]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O.[CH3:31][CH2:32][O:33]C(C)=O>OS(O)(=O)=O.C(OC(=O)C)(=O)C>[C:32]([C:11]1[N:12]2[C:13](=[N:14][C:15]3[N:16]([CH3:23])[C:17](=[O:22])[NH:18][C:19](=[O:21])[C:20]=32)[N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[C:10]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:33])[CH3:31]
Reactant: CCOC(C)=O
Reactant: COc1ccccc1-n1c(-c2ccccc2)cn2c3c(=O)[nH]c(=O)n(C)c3nc12
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COc1ccccc1-n1c(-c2ccccc2)c(C(C)=O)n2c3c(=O)[nH]c(=O)n(C)c3nc12
Temperature: 25 °C
Yield: 39 %

Procedure:
A mixture of commercially available 8-(2-methoxyphenyl)-1-methyl-7-phenyl-1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione (5, 200 mg, 0.516 mmol) in concentrated H2SO4 (0.103 mL) and acetic anhydride (1.29 mL) was refluxed for 2 h. The reaction was cooled to room temperature, poured into 10 mL of water, and extracted with CH2Cl2 (2×10 mL). The organic extracts were dried over MgSO4 and evaporated under reduced pressure. Purification by column chromatography on silica gel using a gradient CH2Cl2:EtOAc from 5:1 to 1:1 afforded the desired compound as a white solid (88 mg, 39% yield). 1H NMR (500 MHz, DMSO-d6): δ=11.03 (s, 1H), 7.54 (d, J=7.9 Hz, 1H), 7.42 (t, J=7.8 Hz, 1H), 7.30-7.37 (m, 5H), 7.08 (d, J=7.9 Hz, 1H), 7.02 (t, J=7.8 Hz, 1H), 3.60 (s, 3H), 3.30 (s, 3H), 2.46 (s, 3H); 13C NMR (100 MHz, DMSO-d6, CDCl3): δ=187.6, 154.4, 153.6, 153.0, 150.6, 146.8, 135.7, 131.4, 130.7, 129.8, 129.6, 127.5, 126.4, 121.2, 120.6, 120.1, 112.5, 101.0, 55.5, 29.6, 28.8; IR (film): ν=3160, 3050, 1668, 1490, 1292, 1211, 1023, 751, 555 cm−1; HRMS (ESI): m/z: calcd for C23H19N5O4Na+: 452.1335, found: 452.1338.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].CCN(C(C)C)C(C)C.[CH2:30]([N:37]=[C:38]=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCOCC1>[CH2:30]([NH:37][C:38](=[O:39])[NH:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Reactant: O=C=NCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CNC(=O)NCc1ccccc1)NC(c1ccccc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 93 %

Procedure:
A solution of 0.2 mmol rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and 0.28 mmol of DIPEA in 2 ml of dioxane was treated with 0.2 mmol of benzylisocyanate. The mixture was stirred at room temperature for 48 hours, concentrated and diluted with diethyl ether. The solid was filtered off, dissolved in dichloromethane and extracted 2 times with a diluted solution of citric acid. The organic phase was dried and concentrated. The residue was triturated with diethyl ether to give the title compound as a colorless solid. Yield=93%.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:13])[CH:5]=[CH:6][C:7]2=[O:12].[Br:14]Br>>[CH:10]1[CH:11]=[C:2]([OH:1])[C:3]2[C:4]([C:5]([Br:14])=[CH:6][C:7](=[O:12])[C:8]=2[CH:9]=1)=[O:13]
Reactant: O=C1C=CC(=O)c2c(O)cccc21
Reactant: BrBr
Product: O=C1C=C(Br)C(=O)c2c(O)cccc21

Procedure:
Step 1 in the above Scheme B may be, for example, carried out according to Tietze, et al., Chem. Eur. J., 2007, 13, 9939-9947. For example, to 5-hydroxynaphthalene-1,4-dione dissolved in an appropriate solvent is added bromine to give 3-bromojuglone in Step 1.
Reaction SMILES: Cl[C:2]([C@H:4]1[C@@H:6](/[CH:7]=[C:8](\[Cl:13])/[C:9]([F:12])([F:11])[F:10])[C:5]1([CH3:15])[CH3:14])=[O:3].[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:18]=1[CH2:19][OH:20].N1C=CC=CC=1.C1(C)C=CC=CC=1>C(OCC)C>[Cl:13]/[C:8](/[C:9]([F:12])([F:11])[F:10])=[CH:7]\[C@@H:6]1[C@H:4]([C:2]([O:20][CH2:19][C:18]2[C:21]([F:25])=[CH:22][CH:23]=[CH:24][C:17]=2[Cl:16])=[O:3])[C:5]1([CH3:15])[CH3:14]
Reactant: OCc1c(F)cccc1Cl
Reactant: CC1(C)[C@H](/C=C(\Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC1(C)[C@H](/C=C(\Cl)C(F)(F)F)[C@@H]1C(=O)OCc1c(F)cccc1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 55.4 %

Procedure:
A mixture of (±)-cis-1-chlorocarbonyl-3-(Z-2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-2,2-dimethylcyclopropane (0.82 g), 2-chloro-6-fluorobenzyl alcohol (1.0 g), pyridine (0.275 g) and dry toluene (50 ml) was stirred at the ambient temperature (ca. 25° C.) for a period of 6 hours and then kept for a further period of 72 hours without stirring. The mixture was diluted with diethyl ether (350 ml) and the resultant mixture washed with water, with dilute aqueous sodium carbonate solution, and then dried over anhydrous magnesium sulphate. The solvents were evaporated and the residual oil purified by preparative thick layer chromatography using silica gel plates and diethyl ether as eluent. The oil which was obtained was then distilled to yield 2-chloro-6-fluorobenzyl(±)-cis-3-(Z-2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-2,2-dimethylcyclopropane carboxylate (0.67 g) b.p. 150°/0.05 mm Hg.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([NH:30][C@H:31]2[CH2:36][CH2:35][C@H:34]([OH:37])[CH2:33][CH2:32]2)=[CH:26][C:25]=1[C:38]([F:41])([F:40])[F:39])([O-:23])=[O:22].[H-].[Na+].O1CCCC1>ClCCl.CN(C)C=O>[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([NH:30][C@H:31]2[CH2:36][CH2:35][C@H:34]([O:37][CH2:2][C:3]([N:5]3[CH2:10][CH2:9][N:8]([C:11]4[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=4)[CH2:7][CH2:6]3)=[O:4])[CH2:33][CH2:32]2)=[CH:26][C:25]=1[C:38]([F:39])([F:40])[F:41])([O-:23])=[O:22]
Reactant: O=C(CCl)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Reactant: O=[N+]([O-])c1ccc(N[C@H]2CC[C@H](O)CC2)cc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(CO[C@H]1CC[C@H](Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)N1CCN(c2ccc(C(F)(F)F)cc2)CC1

Procedure:
2-Chloro-1-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-ethanone (26 mg, 0.09 mmol, prepared in accordance with Example 4), trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexanol (26 mg, 0.09 mmol, prepare in accordance with Example 5), and sodium hydride (10 mg, 60% in oil, 0.26 mmol) were placed under an inert atmosphere. Tetrahydrofuran (1 mL) was added under stirring. Next, dimethylformamide (300 μL) was added under stirring. The resulting mixture was stirred for 40 min at room temperature and then diluted with dichloromethane (5 mL). The mixture was washed with water (5 mL) and then washed with saturated aqueous sodium hydrogencarbonate (5 mL). The organic phase was collected, dried over magnesium sulfate, filtered, and concentrated under vacuum. The crude product was purified by preparative HPLC. Following lyophilization of the fractions of interest, the desired product was isolated as a yellow solid (21 mg, 43% yield). The structure was confirmed using Protocol II-A. Calculated mass=575; observed mass=575; HPLC retention time=4.51 min.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:11]([NH:13][C@@H:14]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[C:15]([O:17]C)=[O:16])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+].CO>C(OCC)(=O)C.O>[CH2:1]([O:8][CH2:9][C@H:10]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:11]([NH:13][C@@H:14]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)[C:15]([OH:17])=[O:16])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(C[C@H](NC(=O)[C@H](COCc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1
Reaction time: 5 h

Procedure:
To crude (S)-methyl 2-((S)-3-(benzyloxy)-2-((tert-butoxycarbonyl)amino) propanamido)-3-(4-methoxyphenyl)propanoate (3.39 mmol assumed) was added aqueous lithium hydroxide (5 mL of a 2 N solution) and methanol (5 mL). The reaction mixture was stirred for 5 h then diluted with ethyl acetate and water, washed with ethyl acetate (1×), acidified with citric acid, extracted with DCM, washed with brine, dried with sodium sulfate, filtered, and concentrated to provide (S)-2-((S)-3-(benzyloxy)-2-((tert-butoxycarbonyl)amino)propanamido)-3-(4-methoxyphenyl)propanoic acid as an amorphous off-white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:11][C:12]#[N:13])[CH:8]=2)[CH:3]=[CH:2]1.[BH4-].[Na+]>CC(O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:11][C:12]#[N:13])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: N#CC=C(c1ccccc1)c1ccc2cc[nH]c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: N#CCC(c1ccccc1)c1ccc2cc[nH]c2c1
Temperature: 25 °C

Procedure:
To a stirring suspension of 3-(1H-indol-6-yl)-3-phenyl-acrylonitrile XII (1.3 g, 5.3 mmol) in 2-propanol (30 ml), NaBH4 (1.3 g, 34 mmol) was added portionwise over 30 min. The mixture was heated at reflux for 110 hours while occasionally adding 2-propanol to maintain the original volume. The mixture was cooled to room temperature and concentrated. The residue was partitioned between Et2O and H2O. The organic layer was separated, washed with brine, dried over MgSO4, filtered and evaporated. The crude 3-(1H-indol-6-yl)-3-phenyl-propionitrile (1.2 g, 90% pure) was used without further purification for the next reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]([C:11]([NH2:13])=[O:12])[NH2:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.O.[C:15]1([C:21]([CH:23]=O)=O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:11](=[O:12])[N:13]=[C:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:23]=[N:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=CC(=O)c1ccccc1
Reactant: NC(=O)N(N)c1cc(Cl)cc(Cl)c1
Solvent: O
Solvent: C1COCCO1
Product: O=c1nc(-c2ccccc2)cnn1-c1cc(Cl)cc(Cl)c1
Yield: 42.2 %

Procedure:
In 50 ml of dioxane was dissolved 2.20 g of 2-(3,5-dichlorophenyl)semicarbazide followed by addition of 1.52 g of phenylglyoxal monohydrate, and the mixture was refluxed for 5 hours. The reaction mixture was then concentrated and the residue was recrystallized from acetonitrile to provide 1.34 g of the title compound. m.p. 160-161° C.
Reaction SMILES: CC1C=CC(C(O[C@H]([C@@H](OC(=O)C2C=CC(C)=CC=2)C(O)=O)C(O)=O)=O)=CC=1.C[O:30][C:31](=[O:70])[CH2:32][CH:33]1[C:42]2[C:37](=[C:38]([F:43])[CH:39]=[CH:40][CH:41]=2)[N:36]=[C:35]([N:44]2[CH2:49][CH2:48][N:47]([C:50]3[CH:55]=[CH:54][CH:53]=[C:52]([O:56][CH3:57])[CH:51]=3)[CH2:46][CH2:45]2)[N:34]1[C:58]1[CH:63]=[C:62]([C:64]([F:67])([F:66])[F:65])[CH:61]=[CH:60][C:59]=1[O:68][CH3:69].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[F:43][C:38]1[CH:39]=[CH:40][CH:41]=[C:42]2[C:37]=1[N:36]=[C:35]([N:44]1[CH2:45][CH2:46][N:47]([C:50]3[CH:55]=[CH:54][CH:53]=[C:52]([O:56][CH3:57])[CH:51]=3)[CH2:48][CH2:49]1)[N:34]([C:58]1[CH:63]=[C:62]([C:64]([F:67])([F:66])[F:65])[CH:61]=[CH:60][C:59]=1[O:68][CH3:69])[C@@H:33]2[CH2:32][C:31]([OH:70])=[O:30]
Reactant: COC(=O)CC1c2cccc(F)c2N=C(N2CCN(c3cccc(OC)c3)CC2)N1c1cc(C(F)(F)F)ccc1OC
Agent: Cc1ccc(C(=O)O[C@@H](C(=O)O)[C@@H](OC(=O)c2ccc(C)cc2)C(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1cccc(N2CCN(C3=Nc4c(F)cccc4[C@@H](CC(=O)O)N3c3cc(C(F)(F)F)ccc3OC)CC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.6 %

Procedure:
(2R,3R)-2,3-Bis[(4-methylbenzoyl)oxy]succinic acid-methyl{8-fluoro-2-[4-(3-methoxyphenyl)-piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate (1:1 salt) (170 g) are suspended in ethyl acetate (850 ml) and shaken with saturated aqueous sodium bicarbonate solution (850 ml) until both phases are clear (ca. 5 min.). The phases are separated, and the solvent of the organic phase is replaced at normal pressure with 1,4-dioxane up to a final temperature of 99° C. (a total of 2.55 l of solvent is distilled off and 2.55 l of 1,4-dioxane are employed in portions). The mixture is cooled to room temperature and stirred at room temperature for 18 h with 1N sodium hydroxide solution (525 ml). Subsequently, the pH is adjusted to 7.5 using concentrated hydrochloric acid (ca. 35 ml), MIBK (850 ml) is added, then the pH is readjusted to 7.0 using concentrated hydrochloric acid (ca. 10 ml). The phases are separated, and the organic phase is dried over sodium sulphate and concentrated. The residue is dissolved in ethanol (350 ml) and concentrated, then again dissolved in ethanol (350 ml) and concentrated at 50° C. A total of 91.6 g of (R)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-(2-methoxy-5-trifluoromethylphenyl)-3,4-dihydroquinazolin-4-yl}acetic acid are thus obtained as an amorphous solid, corresponding to 91.6% of theory.
Reaction SMILES: [C:1]1([C:7]([O:9][Si](C)(C)C)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:16]=1[S:22][CH:23]([C:27](O)=[O:28])[C:24](O)=[O:25]>>[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:16]=1[S:22][C:23]1[C:24](=[O:25])[O:9][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:8][C:27]=1[OH:28]
Reactant: C=C(O[Si](C)(C)C)c1ccccc1
Reactant: Cc1cccc(C)c1SC(C(=O)O)C(=O)O
Product: Cc1cccc(C)c1Sc1c(O)cc(-c2ccccc2)oc1=O

Procedure:
The title compound was prepared by Method A using 1-phenyl-1-(trimethylsilyloxy)ethylene (1.95 g, 10.14 mmol) and diethyl ester of [(2,6-dimethylphenyl)thio]propanedioic acid (2.0 g, 6.8 mmol). m.p. 248°-249° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.47 (s, 6H), 6.75 (s, 1H), 7.08 (m, 3H), 7.39 (m, 3H), 7.78 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][CH2:5][NH:6][C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.Cl[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[CH:21][C:20]=1[CH3:35].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C.O>[CH3:1][O:2][C:3](=[O:16])[CH2:4][CH2:5][NH:6][C:7](=[O:15])[C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:27][CH:26]=3)=[CH:21][C:20]=2[CH3:35])=[CH:12][CH:13]=1
Reactant: COC(=O)CCNC(=O)c1ccc(O)cc1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)ccc1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: COC(=O)CCNC(=O)c1ccc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2C)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 56.9 %

Procedure:
To a solution of 3-(4-hydroxy-benzoylamino)-propionic acid methyl ester (0.11 g, 0.49 mmol) and 4-chloromethyl-3-methyl-4′-trifluoromethyl-biphenyl (0.12 g, 0.41 mmol) in acetonitrile (4 mL) is added Cs2CO3 (0.20 g, 0.61 mmol). The mixture is stirred at RT for 12 h. The mixture is diluted with water and extracted with EtOAc. The organics are dried with MgSO4, and the crude material is purified by flash chromatography to yield 0.11 g (58%) of the title compound.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]([CH:17]=[O:18])=[C:15]([CH:19]([CH3:21])[CH3:20])[CH:14]=[C:13]2[C:8]=1[C:9](=[O:24])[CH2:10][C:11]([CH3:23])([CH3:22])[O:12]2)(=O)=O.[C:27]1(B(O)O)[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Cl-].[NH4+]>O1CCOCC1.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:27]1([C:7]2[C:16]([CH:17]=[O:18])=[C:15]([CH:19]([CH3:21])[CH3:20])[CH:14]=[C:13]3[C:8]=2[C:9](=[O:24])[CH2:10][C:11]([CH3:22])([CH3:23])[O:12]3)[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]=1
Reactant: OB(O)C1=CCCCC1
Reactant: CC(C)c1cc2c(c(OS(=O)(=O)C(F)(F)F)c1C=O)C(=O)CC(C)(C)O2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Solvent: C1COCCO1
Product: CC(C)c1cc2c(c(C3=CCCCC3)c1C=O)C(=O)CC(C)(C)O2
Temperature: 25 °C

Procedure:
A solution of 365 mg (930 μmol) of 6-formyl-7-isopropyl-2,2-dimethyl-4-oxo-3,4-dihydro-2H-chromen-5-yl trifluoromethanesulfonate (Example 19A), 152 mg (1.20 mmol) of cyclohex-1-en-1-ylboronic acid, 75 mg (60 μmol) of tetrakis(triphenylphosphine)palladium and 334 mg (1.57 mmol) of potassium phosphate in 5.5 ml of degassed dioxane is stirred at 100° C. overnight. After cooling to room temperature, ammonium chloride solution is added and the mixture is extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate, the solvent is then removed under reduced pressure and the residue is purified by column chromatography on silica gel (mobile phase:cyclohexane/ethyl acetate 20:1).