Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][CH2:12][C:13]2([CH2:19][C:20]([OH:22])=[O:21])O>ClCCl>[Cl:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][CH2:12]/[C:13]/2=[CH:19]\[C:20]([OH:22])=[O:21]
Reactant: O=C(O)CC1(O)CCc2c(Cl)cccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)/C=C1\CCc2c(Cl)cccc21
Reaction time: 0.5 h
Yield: 62.3 %

Procedure:
Trifluoroacetic acid (25.1 mL) was added to a stirred, chilled (ice-methanol bath) solution of 2-(4-chloro-1-hydroxy-1-indanyl)acetic acid (10.4 g, 0.05 mol) in dichloromethane (230 mL). After 30 min, the mixture was concentrated in vacuo. Dichloromethane was added to the residue and the mixture was concentrated in vacuo to give 6.5 g (68%) of a white solid. Recrystallization of 0.98 g from acetonitrile: 2-propanol mixtures gave 0.62 g of a white solid: m.p., 233°-234° C.; NMR (DMSO-d6): d12.15 (br, 1H, COOH), 7.30-7.81 (m, 3H, Ar), 6.41 (s, 1H, =CH), 3.00-3.06, 3.19-3.22 (2m's, 4H, 2×CH2), steady-state nOe; irradiation at 6.41 d, observed 19.7% nOe at 7.79.
Reaction SMILES: C[O:2][C:3](=[O:42])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([O:28]CC3C=CC=CC=3)[C:25](Br)=[CH:24][C:23]=2[CH2:37][CH3:38])[C:12]=1[CH2:39][CH2:40][CH3:41].[O:43]1[CH:47]=[CH:46][C:45](B(O)O)=[CH:44]1.C(=O)([O-])[O-].[Na+:55].[Na+]>O1CCCC1.O.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>[OH2:2].[Na+:55].[CH2:37]([C:23]1[CH:24]=[C:25]([CH:45]2[CH2:46][CH2:47][O:43][CH2:44]2)[C:26]([OH:28])=[CH:27][C:22]=1[O:21][CH2:20][CH2:19][CH2:18][O:17][C:13]1[C:12]([CH2:39][CH2:40][CH3:41])=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([O-:42])=[O:2])[CH3:38].[CH2:37]([C:23]1[CH:24]=[C:25]([CH:45]2[CH2:46][CH2:47][O:43][CH2:44]2)[C:26]([OH:28])=[CH:27][C:22]=1[O:21][CH2:20][CH2:19][CH2:18][O:17][C:13]1[C:12]([CH2:39][CH2:40][CH3:41])=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([O-:42])=[O:2])[CH3:38].[Na+:55]
Reactant: CCCc1c(OCCCOc2cc(OCc3ccccc3)c(Br)cc2CC)cccc1Oc1ccccc1C(=O)OC
Reactant: OB(O)c1ccoc1
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: O
Solvent: C1CCOC1
Product: CCCc1c(OCCCOc2cc(O)c(C3CCOC3)cc2CC)cccc1Oc1ccccc1C(=O)[O-]
Temperature: 100 °C
Yield: 65 %

Procedure:
A mixture of 2-{3-[3-(5-benzyloxy-4-bromo-2-ethylphenoxy)propoxy]-2-propylphenoxy}-benzoic acid methyl ester (3.00 g, 4.73 mmol), furan-3-boronic acid (1.06 g, 9.47 mmol), tetrakis(triphenylphosphine)palladium(0) (0.54 g, 0.47 mmol), and 2 M aqueous sodium carbonate solution (20 mL) in tetrahydrofuran (40 mL) was heated at 100° C. for 48 h. The mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was separated, washed once with water, once with saturated sodium chloride solution, dried (sodium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel, 10% ethyl acetate/90% hexane) of the residue provided 1.9 g (65%) of the title compound as a yellow oil. 1H NMR (CDCl3) δ 7.88 (dd, J=8, 2 Hz, 1H), 7.87 (s, 1H), 7.40 (m, 7H), 7.26 (s 1H), 7.05 (m, 2H), 6.80 (d, J=9 Hz, 1H), 6.76 (d, J=2 Hz, 1H), 6.67 (d, J=9 Hz, 1H), 6.60 (s, 1H), 6.43 (d, J=9 Hz, 1H), 5.11 (s, 2H), 4.18 (m, 4H), 3.83 (s, 3H), 2.66 (t, J=8 Hz, 2H), 2.62 (q, J=7 Hz, 2H), 2.30 (quintet, J=6 Hz, 2H), 1.57 (hextet, J=8 Hz, 2H), 1.20 (t, J=7 Hz, 3H), 0.92 (t, J=7 Hz, 3H); MS ES+ m/z=621 (p+1); IR (CHCl3, cm−1) 3000, 1727, 1603, 1461.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]=[C:9]([CH2:13][C:14](O)=[O:15])[C:10]([OH:12])=[O:11].[OH-].[Na+]>O>[O:15]=[C:14]1[N:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:8][CH:9]([C:10]([OH:12])=[O:11])[CH2:13]1
Reactant: Nc1ccccc1
Reactant: C=C(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C1CC(=O)N(c2ccccc2)C1
Temperature: 110 °C
Yield: 97.2 %

Procedure:
A mixture of aniline (3.26 g; 34.68 mmol) and 2-methylenesuccinic acid (5.47 g; 41.62 mmol) in water (10 ml) was heated in a sealed tube at 110° C. for 30 hours. After cooling to room temperature, 6N NaOH (13 mL) was added and the resulting precipitate was filtered off. The filtrate was acidified with 6N hydrochloric acid to pH 1 and the resulting precipitate was filtered, washed with water, and dried to yield 6.92 g (97%) of 5-oxo-1-phenypyrrolidine-3-carboxylic acid as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[C:19]4[CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28][C:20]=4[N:21]([CH2:24][O:25][CH2:26][CH3:27])[C:22]=3[CH:23]=2)[C:11](=[O:39])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CCO.CCOCC>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[C:19]4[CH2:31][NH:30][CH2:29][CH2:28][C:20]=4[N:21]([CH2:24][O:25][CH2:26][CH3:27])[C:22]=3[CH:23]=2)[C:11](=[O:39])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOCn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: CCOCn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CNCC2
Temperature: 60 °C
Yield: 62.9 %

Procedure:
To a solution of tert-butyl 7-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-5-(ethoxymethyl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (120 mg, 0.20 mmol) in EtOH (2 mL) was added 1 N HCl in Et2O (1 mL). The reaction was stirred at 60° C. until complete. The solvent was concentrated and the residue was purified by preparative HPLC (Phenomenex Luna C18 (2), 250×50 mm, 15 micron, H2O with 0.05% TFA and CH3CN with 0.05% TFA) to give 4-(benzyloxy)-1-(5-(ethoxymethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one as a white solid (54 mg, 73%). The free base was converted to the HCl salt to give the title compound (35 mg, 65%) as a white powder: mp 148-149° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.12 (s, 2H), 7.66 (d, J=2.0 Hz, 1H), 7.59-7.56 (m, 2H), 7.49-7.37 (m, 5H), 7.08-7.05 (m, 1H), 6.14-6.12 (m, 1H), 5.99 (d, J=2.5 Hz, 1H), 5.57 (s, 2H), 5.17 (s, 2H), 4.38 (m, 2H), 3.55 (m, 2H), 3.45-3.40 (m, 2H), 3.13 (m, 2H), 1.08-1.05 (m, 3H); ESI MS m/z 430 [M+H]+; HPLC (Method A)>99% (AUC), tR=12.8 min.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH2:26][CH2:27][CH2:28][CH3:29])[CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[N:12]([O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:11]([CH3:25])([CH3:24])[CH2:10]2)[N:5]=[C:4]([N:30]([CH2:48][CH2:49][CH2:50][CH3:51])[CH:31]2[CH2:36][C:35]([CH3:38])([CH3:37])[N:34]([O:39][CH:40]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]3)[C:33]([CH3:47])([CH3:46])[CH2:32]2)[N:3]=1.[NH:52]1[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH:40]1([O:39][N:34]2[C:33]([CH3:47])([CH3:46])[CH2:32][CH:31]([N:30]([CH2:48][CH2:49][CH2:50][CH3:51])[C:4]3[N:5]=[C:6]([N:8]([CH2:26][CH2:27][CH2:28][CH3:29])[CH:9]4[CH2:10][C:11]([CH3:24])([CH3:25])[N:12]([O:17][CH:18]5[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]5)[C:13]([CH3:15])([CH3:16])[CH2:14]4)[N:7]=[C:2]([N:52]4[CH2:57][CH2:56][O:55][CH2:54][CH2:53]4)[N:3]=3)[CH2:36][C:35]2([CH3:37])[CH3:38])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]1
Reactant: C1COCCN1
Reactant: CCCCN(c1nc(Cl)nc(N(CCCC)C2CC(C)(C)N(OC3CCCCC3)C(C)(C)C2)n1)C1CC(C)(C)N(OC2CCCCC2)C(C)(C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCCCN(c1nc(N2CCOCC2)nc(N(CCCC)C2CC(C)(C)N(OC3CCCCC3)C(C)(C)C2)n1)C1CC(C)(C)N(OC2CCCCC2)C(C)(C)C1
Yield: 55 %

Procedure:
A mixture of 10.0 g (13.7 mmol) of 2-chloro-4,6-bis[N-(1-cyclohexyloxy-2,2,6,6-tetramethylpiperidin-4-yl)-n-butylamino]-1,3,5-triazine (see Example 75), 1.43 g (16.4 mmol) of morpholine, 0.8 g of sodium hydroxide, and 30 g of toluene is heated at reflux for four hours. Water is collected in a Dean-Stark trap. The liquid phase is decanted and residual solids are washed with toluene. The combined organic solutions are dried over magnesium sulfate and concentrated to give a viscous oil. Purification by HPLC (Waters Prep. 500 A, 29:1 heptane:ethyl acetate) affords 5.9 g (55% yield) of the title compound, a white powder, m.p. 159°-63° C.
Reaction SMILES: [F:1][C:2](=[CH2:6])[C:3](Cl)=[O:4].[Br:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([Br:17])[C:15]=1[OH:16])[C:11]#[N:12].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2](=[CH2:6])[C:3]([O:16][C:15]1[C:14]([Br:17])=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[Br:7])=[O:4]
Reactant: N#Cc1cc(Br)c(O)c(Br)c1
Reactant: C=C(F)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(F)C(=O)Oc1c(Br)cc(C#N)cc1Br
Reaction time: 0.5 h
Yield: 55.7 %

Procedure:
10 g (0.092 mol) α-fluoroacryloyl chloride (obtained in accordance with example 1c) were added dropwise, at a temperature of 5° C., with stirring and in the course of 5 minutes, to a solution of 24.8 g (0.09 mol) of 3,5-dibromo-4-hydroxybenzonitrile and 9.1 g (0.09 mol) of triethylamine in 200 ml of anhydrous methylene dichloride, and the reaction mixture was then stirred for a further 30 minutes at the same temperature. The solid formed was filtered off and washed with 20 ml of anhydrous methylene dichloride. After 0.005 g of hydroquinone monomethyl ether had been added, the volatile constituents in the mixture of filtrate and wash solution were removed by distillation, and the residue was recrystallized from boiling n-heptane. 17.5 g (55% of theory) of 2,6-dibromo-4-cyanophenyl α-fluoroacrylate were obtained, melting point 135° to 138° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:3][CH:2]=1.[CH3:13][S:14][C:15](SC)=[C:16]([C:19]#[N:20])[C:17]#[N:18].O1CCOCC1.[H-].[Na+]>C(O)(=O)C>[C:17]([C:16]([C:19]#[N:20])=[C:15]([C:2]1[CH:3]=[C:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=[CH:6][N:1]=1)[S:14][CH3:13])#[N:18]
Reactant: CCOC(=O)Cc1ccncc1
Reactant: CSC(SC)=C(C#N)C#N
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CCOC(=O)Cc1ccnc(C(SC)=C(C#N)C#N)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 50.1 %

Procedure:
To a mixture of ethyl 4-pyridylacetate (46.7 g, 0.28 mol), 3,3-bis(methylthio)-2-cyanoacrylonitrile (47.6 g, 0.28 mol) and p-dioxane (300 ml) cooled in an ice bath was added 60% NaH (11.2 g, 0.28 mol) over 30 minutes. The mixture was slowly warmed to room temperature over 2 hours and was stirred at ambient temperature for 4 hours. The mixture was poured into ice-water, acidified with acetic acid and the resulting precipitate was collected by filtration and washed with water. The product was recrystallized from cyclohexane and dried at 70°-75° C. in high vacuum to afford 40.3 g (50%) of ethyl 2-(2,2-dicyano-1-methylthioethenyl)-4-pyridylacetate as orange crystals, m.p. 148°-152° C.
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[N:9]=[C:8]([CH2:10][O:11][N:12]=[C:13]([C:20]2[N:24]([CH3:25])[N:23]=[N:22][N:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=[CH:6][CH:5]=1.[H-].[Na+].I[CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>CN(C=O)C.[Cl-].[Na+].O>[CH:29]1([O:1][N:2]=[CH:3][C:4]2[N:9]=[C:8]([CH2:10][O:11][N:12]=[C:13]([C:20]3[N:24]([CH3:25])[N:23]=[N:22][N:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:7]=[CH:6][CH:5]=2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: Cn1nnnc1C(=NOCc1cccc(C=NO)n1)c1ccccc1
Reactant: IC1CCCCC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nnnc1C(=NOCc1cccc(C=NOC2CCCCC2)n1)c1ccccc1
Temperature: 45 °C
Reaction time: 0.17 h
Yield: 43 %

Procedure:
To a stirred solution of N-({6-[(hydroxyimino)methyl]pyridin-2-yl}methoxy)-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (0.2 g, 0.593 mmol, 1 eq.) in 2.5 ml of dry DMF, was added NaH (0.024 g, 0.623 mmol, 1.05 eq.) in one portion. After 10 mins, 1-iodocyclohexane (0.130 g, 0.623 mmol, 1.05 eq.) was added rapid dropwise. Stirring was continued for 20 hrs and warmed at 45° C. for 4 hrs. “brine” was added and the reaction was extracted with EtOAc (2×75 ml). The combined organic layers were washed with water (2×), dried over MgSO4 and evaporated. The residue was purified by chromatography on silica gel to give N-[(6-{[(cyclohexyloxy)imino]methyl}pyridin-2-yl)methoxy]-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (0.107 g, 41% yield) as a colourless viscous oil.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:18][O:17][C:16]([CH3:20])([CH3:19])[O:15][CH2:14]2)(=O)=O)=CC=1.[CH:21]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH3:20][C:16]1([CH3:19])[O:15][CH2:14][CH:13]([CH2:12][NH:26][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[CH2:18][O:17]1
Reactant: Cc1ccc(S(=O)(=O)OCC2COC(C)(C)OC2)cc1
Reactant: NC1CCCC1
Product: CC1(C)OCC(CNC2CCCC2)CO1
Temperature: 80 °C
Yield: 93.8 %

Procedure:
A mixture of 1.5 g (5 mmol) of (2,2-dimethyl-1,3-dioxan-5-yl)methyl 4-methylbenzenesulfonate and 10 mL (101 mmol) of cyclopentylamine is heated for 12 hours at 80° C. The medium is concentrated under reduced pressure and then taken up in 200 mL of Et2O, washed with water (2×50 mL), dried over Na2SO4 and concentrated under reduced pressure. 1 g of N-[(2,2-dimethyl-1,3-dioxan-5-yl)methyl]cyclopentanamine is obtained in the form of an oil, which is used in the following step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:15])[NH:12]C(=O)N[C:9]2=[O:14])=[CH:4][CH:3]=1.[OH-:16].[Na+].Cl>O>[NH2:12][C:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)([CH3:15])[C:9]([OH:16])=[O:14]
Reactant: [OH-]
Reactant: CC1(c2ccc(Br)cc2)NC(=O)NC1=O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(N)(C(=O)O)c1ccc(Br)cc1
Temperature: 145 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
A mixture of 5-(4-bromo-phenyl)-5-methyl-imidazolidine-2,4-dione (4.0 g, 14.9 mmol) and 3 N NaOH (50 mL) was heated in a sealed tube at 145° C. for two days, then diluted with water (100 mL) The solution was adjusted to pH=4 with 6 N HCl carefully and subsequently stirred at room temperature for 2 hours. The precipitate was filtered off, washed with water. The collected white solid was dried under vacuum to give the product (2.5 g, 65%). m/z 243.7, 245.7 (M+H)+.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:9][CH2:8][N:7]([C@H:10]([C:12]2[CH:17]=[CH:16][C:15](B3OC(C)(C)C(C)(C)O3)=[CH:14][CH:13]=2)[CH3:11])[C:6](=[O:27])[NH:5]1.I[C:37]1[CH:42]=[CH:41][N:40]([CH3:43])[C:39](=[O:44])[CH:38]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:9][CH2:8][N:7]([C@H:10]([C:12]2[CH:13]=[CH:14][C:15]([C:37]3[CH:42]=[CH:41][N:40]([CH3:43])[C:39](=[O:44])[CH:38]=3)=[CH:16][CH:17]=2)[CH3:11])[C:6](=[O:27])[NH:5]1
Reactant: Cn1ccc(I)cc1=O
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)NC1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C[C@@H](c1ccc(-c2ccn(C)c(=O)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)NC1=O
Yield: 54.4 %

Procedure:
To a solution of (S)-4-(2-hydroxy-2-methylpropyl)-4-phenyl-1-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)tetrahydropyrimidin-2(1H)-one (170 mg, 0.36 mmol) and 4-iodo-1-methylpyridin-2(1H)-one (100 mg, 0.43 mmol) in dry 1,4-dioxane (5 mL) was added 2M aq Cs2CO3 (1 mL) and Pd(PPh3)Cl2 (21.4 mg, 0.03 mmol). After addition, the mixture was heated to reflux for 2 h under N2 atmosphere. The solid was filtered off and diluted with water (30 mL) and EtOAc (30 mL). The mixture was extracted with EtOAc (3×40 mL), and the combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by prep TLC to afford (S)-4-(2-hydroxy-2-methylpropyl)-1-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-4-phenyltetrahydropyrimidin-2(1H)-one (90 mg, yield: 54.4%). 1H NMR (CDCl3): 0.661 (s, 3H), 1.23 (s, 3H), 1.49-1.50 (m, 3H), 1.98-2.02 (m, 2H), 2.05-2.13 (m, 1H), 2.17-2.18 (m, 2H), 2.60-2.63 (m, 1H), 2.74-2.78 (m, 1H), 3.57 (s, 3H), 5.87-5.92 (m, 1H), 6.35-6.37 (m, 1H), 6.71-6.72 (d, 1H), 7.18-7.22 (m, 2H), 7.23-7.25 (m, 1H), 7.30-7.32 (m, 2H), 7.33-7.37 (m, 5H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[OH:18])[N:3]=1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(N(CC)CC)C>C(Cl)Cl>[N:19]1([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])[N:3]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1
Reactant: C1CNCCN1
Reactant: Oc1ccccc1-c1nc(Cl)c2ccccc2n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Oc1ccccc1-c1nc(N2CCNCC2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.9 %

Procedure:
To a solution of 2-(4-chloroquinazolin-2-yl)phenol (2.0 g, 7.8 mmol) in CH2Cl2 at 0° C. was rapidly added a solution of piperazine (2.01 g, 23.4 mmol) and triethylamine (2.17 mL, 15.6 mmol) in 10 mL CH2Cl2. The reaction was warmed to room temperature and stirred for 5 hours. The reaction was quenched with 25 mL of water and extracted with (3×15) mL of CH2Cl2. The organic layer was dried over Na2SO4, filtered, and concentrated to afford 2-(4-(piperazin-1-yl)quinazolin-2-yl)phenol (1.98 g, 83%). LC/MS: m/z 307.3 (M+H)+ at 1.47 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) δ 8.43 (d, J=10.1 Hz, 1H), 8.04 (d, J=8.3 Hz, 1H), 7.85 (m, 2H), 7.53 (m, 1H), 7.38 (m, 1H), 6.95 (m, 2H), 3.85 (t, J=4.8 Hz, 4H), 2.94 (t, J=4.8 Hz, 4H) ppm.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][S:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].O[N:16]1[C:20](=[O:21])[CH2:19][CH2:18][C:17]1=[O:22].CN(C)CCCN=C=NCC.C(OCC)(=O)C>ClCCl>[CH2:19]1[C:20](=[O:21])[N:16]([O:13][C:12]([CH2:11][CH2:10][CH2:9][S:8][S:7][C:2]2[N:1]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:14])[C:17](=[O:22])[CH2:18]1
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)CCCSSc1ccccn1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(CCCSSc1ccccn1)ON1C(=O)CCC1=O
Reaction time: 2 h
Yield: 76.6 %

Procedure:
Compound 11a (1.10 g, 4.8 mmol) and N-hydroxysuccinimide (0.64 g, 5.5 mmol) were dissolved in dichloromethane (50 mL). The solution was magnetically stirred as 1-[3-(dimethylamino)propyl]-3 ethylcarbodiimide (1.05 g, 5.5 mmol) was added. After 2 h, ethyl acetate (150 mL) was added and the solution was transferred to a separatory funnel and washed consecutively with 0.5 M HCl (30 mL) and saturated sodium chloride (20 mL). The organic layer was dried over anhydrous sodium sulfate, and then the solvent was removed under vacuum. The residue was taken up in a minimum volume of ethyl acetate and was purified by silica chromatography using a mobile phase of hexanes:ethyl acetate:acetic acid (2.5:1:0.02, v/v/v). Fractions containing pure product were combined and solvent was removed to give N-succinimidyl 4-(2-pyridyldithio)butanoate (SPDB, 3a) (1.2 g, 76% yield). 1H NMR (CDCl3): δ 2.12-2.19 (2H, m), 2.78-2.87 (6H, m), 2.91 (2H, t, J=7.0), 7.06-7.12 (1H, m), 7.62-7.71 (2H, m), 8.48 (1H, d, 4.4 Hz). MS (M+Na+) Found: 348.8 Calculated: 349.4.
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl.[NH:11]1[CH2:14][CH:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:12]1.Cl[C:24]1[O:25][C:26]2[C:27](=[C:29]([C:41]#[N:42])[C:30]([CH3:40])=[C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:32]=2[F:33])[N:28]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[C:41]([C:29]1[C:27]2[N:28]=[C:24]([N:11]3[CH2:14][CH:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])[CH2:12]3)[O:25][C:26]=2[C:32]([F:33])=[C:31]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:30]=1[CH3:40])#[N:42]
Reactant: CC(C)(C)OC(=O)NC1CNC1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(Cl)nc2c1C#N
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1c(-c2ccccc2)c(F)c2oc(N3CC(NC(=O)OC(C)(C)C)C3)nc2c1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
Diisopropylethylamine (787 μl, 4.63 mmol) and tert-butyl azetidin-3-ylcarbamate hydrochloride (483 mg, 2.31 mmol) were added to a dichloromethane (20 ml) solution of 2-chloro-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-cabonitrile (I-130) (553 mg, 1.93 mmol), followed by stirring at room temperature for 30 minutes. With cooling with ice, aqueous 10% citric acid solution (10 ml) was added to the reaction liquid, followed by extraction with chloroform (50 ml), then the organic layer was washed with saturated brine (50 ml). After drying over anhydrous sodium sulfate and concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate=2:1) to obtain the entitled compound (815 mg, 100%) as a colorless oily substance.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>>[Si:14]([O:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1cccc(-c2ccccn2)c1
Product: CC(C)(C)[Si](C)(C)Oc1cccc(-c2ccccn2)c1

Procedure:
Then, 2-(3-hydroxyphenyl)pyridine is treated with tert-butyldimethylsilyl chloride (TBDMSCl) to protect the OH group with a tert-butyldimethylsilyl group and give 2-(3-tert-butyldimethylsilyloxyphenyl)pyridine according to scheme (3).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.[H-].[Na+].Br[CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[N:25].O>CN(C=O)C>[C:24]([CH2:23][CH2:22][CH2:21][CH2:20][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([CH3:1])=[C:3]1[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)#[N:25]
Reactant: N#CCCCCBr
Reactant: Cc1c(-c2cccnc2)[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(-c2cccnc2)n(CCCCC#N)c2ccccc12
Reaction time: 0.5 h

Procedure:
A solution of 3-methyl-2-(3-pyridyl)indole (2.09 g) in 12 ml of DMF is added to a suspension of 0.528 g of 50% sodium hydride (dispersion in mineral oil) in 6 ml of DMF at 0°. The mixture is stirred at 0° for 0.5 hour and is treated with a solution of 1.78 g of 5-bromovaleronitrile in 4 ml of DMF. This mixture is stirred at room temperature overnight and is poured into 125 ml of water. This is extracted with 2×50 ml of ether, the extract is washed with 3×20 ml of water and dried over MgSO4 to give 1-(4-cyanobutyl)-3-methyl-2-(3-pyridyl)-indole as an oil.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:18][CH3:19])=[C:7]([CH:17]=1)[O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13])=[O:2].O1CCCC1.[BH4-].[Na+]>O>[OH:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([O:18][CH3:19])=[C:7]([CH:17]=1)[O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13]
Reactant: COc1ccc(C=O)cc1Oc1cccc(C#N)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CO)cc1Oc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
In a 40 mL vial equipped with a stir bar was placed (16) (1.09 g, 4.27 mmol), tetrahydrofuran (10 mL), water (10 mL) and sodium borohydride (485 mg, 12.8 mmol). The mixture was stirred at room temperature for 2 hours and then quenched with water (60 mL). After extractions with ethyl acetate (3×50 mL), the organic portions were combined, washed with brine (75 mL), dried (MgSO4), concentrated. The resulting solid was dried in a high vacuum oven for 5 hours at 45° C. and 945 mg (86% yield) of (17) was isolated.
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](O)=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([O:15][C:16]1[CH:17]=[C:18]([CH2:19][OH:20])[CH:22]=[CH:23][CH:24]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCOc1cccc(C(=O)O)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOc1cccc(CO)c1

Procedure:
The title compound is prepared by the procedure of Example 21 using 20.0 g of product from Example 23, 200 ml of dry tetrahydrofuran and 7.94 g of lithium aluminum hydride. The product, 18.82 g, is obtained as colorless crystals.