Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[O:24][N:23]=[C:22]([C@@H:25]2[CH2:29][CH2:28][CH2:27][N:26]2[C:30](=[O:45])[C:31]([F:44])([F:43])[C:32]2([OH:42])[CH2:37][C:36]([CH3:39])([CH3:38])[CH2:35][C:34]([CH3:41])([CH3:40])[CH2:33]2)[CH:21]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-].[NH4+].[Cl-]>C1COCC1>[F:44][C:31]([F:43])([C:32]1([OH:42])[CH2:33][C:34]([CH3:41])([CH3:40])[CH2:35][C:36]([CH3:39])([CH3:38])[CH2:37]1)[C:30]([N:26]1[CH2:27][CH2:28][CH2:29][C@H:25]1[C:22]1[CH:21]=[C:20]([CH2:19][OH:18])[O:24][N:23]=1)=[O:45]
Reactant: CC1(C)CC(C)(C)CC(O)(C(F)(F)C(=O)N2CCC[C@H]2c2cc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)on2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: CC1(C)CC(C)(C)CC(O)(C(F)(F)C(=O)N2CCC[C@H]2c2cc(CO)on2)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 90.3 %

Procedure:
To a THF (20 mL) solution of the compound (1.784 g) obtained in Example 3-(3), n-Bu4NF (3.4 mL, 1.0 M THF solution) was added and the mixture was stirred at room temperature for 20 minutes. To the reaction mixture, a saturated aqueous solution of NH4Cl was added and the organic layer extracted with AcOEt was dried (MgSO4), filtered and concentrated to give a crude product, which was further purified with neutral silica gel chromatography (AcOEt/hexane) to give the titled compound (1.010 g, colorless solid.)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[N:14]([C:15](OC3C=CC([N+]([O-])=O)=CC=3)=[O:16])[C:13](=[O:27])[NH:12][C:11]([CH3:28])=[C:10]2[C:29]([O:31][CH3:32])=[O:30])[CH:5]=[CH:6][C:7]=1[F:8].[NH2:33][CH2:34][CH2:35][CH2:36][N:37]1[CH:41]=[CH:40][N:39]=[CH:38]1>C(Cl)Cl>[CH3:32][O:31][C:29]([C:10]1[CH:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)[N:14]([C:15](=[O:16])[NH:33][CH2:34][CH2:35][CH2:36][N:37]2[CH:41]=[CH:40][N:39]=[CH:38]2)[C:13](=[O:27])[NH:12][C:11]=1[CH3:28])=[O:30]
Reactant: NCCCn1ccnc1
Reactant: COC(=O)C1=C(C)NC(=O)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1c1ccc(F)c(F)c1
Solvent: ClCCl
Product: COC(=O)C1=C(C)NC(=O)N(C(=O)NCCCn2ccnc2)C1c1ccc(F)c(F)c1
Yield: 83.9 %

Procedure:
A solution of 6-(3,4-difluorophenyl)-4-methyl-5-methoxycarbonyl-1-(4-nitrophenoxy)carbonyl-2-oxo-1,2,3,6-tetrahydro-pyrimidine (100 mg, 0.22 mmol) and 1-(3-aminopropyl)imidazole (40 ml, 0.34 mmol) in CH2Cl2 (10 ml) was stirred at room temperature for 3 hours. The solvent was removed in vacuum. The residue was separated on preparative TLC (CHCl3/MeOH=100/15) to get the title compound (80 mg, 84% yield) as a white solid. Hydrochloride of title compound was made with HCl in ether. Calcd for C20H21N5O4F2+0.3 H2O: C, 54.74%; H, 4.99%; N, 15.89%. Found: C, 54.92%;H, 4.65%; N, 15.77%. M.P. of the salt: 221-224° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:19]([CH3:30])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)=[O:21]>CN(C=O)C.O>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([NH:22][C:20](=[O:21])[CH:19]([O:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH3:30])=[CH:28][CH:27]=1
Reactant: CC(Br)C(=O)Nc1ccc(Cl)cc1
Reactant: Oc1ccnc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(Oc1ccnc2ccccc12)C(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.8 %

Procedure:
To a solution of 4-hydroxyquinoline (100 mg, 0.69 mmol) in anhydrous DMF under N2 was added K2CO3 (286 mg, 2.10 mmol) and a solution of 2-bromo-N-(4-chlorophenyl)propanamide (218 mg, 0.83 mmol) in DMF. The reaction mixture was stirred for 12 h at room temperature before being diluted with water (50 mL) and extracted with chloroform (3×50 mL). The combined organic extracts were dried over anhydrous MgSO4, filtered, concentrated in vacuo and purified by flash chromatography using ethyl acetate/n-hexane (a gradient of 10%) to furnish 114 (207 mg, 92% yield) as a white solid. mp. 170-172° C., 1H NMR (CDCl3, 400 MHz) δ 1.83 (d, J=6.4 Hz, 3H), 5.06 (q, J=6.8, 13.6 Hz, 1H), 6.76 (d, J=5.6 Hz, 1H), 7.28 (d, J=8.4 Hz, 2H), 7.46 (d, J=8.4 Hz, 2H), 7.61 (t, J=8.0 Hz, 1H), 7.77 (t, J=7.6 Hz, 1H), 8.09 (d, J=7.2 Hz, 1H), 8.26 (d, J=8.4 Hz, 1H), 8.76 (d, J=5.6 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 18.72, 75.83, 102.05, 122.27, 121.32, 121.58, 126.61, 129.34, 129.60, 130.34, 130.51, 135.40, 149.74, 151.48, 159.47, 169.20; ESI-HRMS for C18H16N2O2Cl (M+H)+calcd. 327.0900. found 327.0901.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:5]2[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CO[CH:31]1[CH2:35][CH2:34][CH:33](OC)O1>C(O)(=O)C>[CH2:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([N:1]3[CH:31]=[CH:35][CH:34]=[CH:33]3)=[CH:10][CH:9]=2)[C:5]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[C:6]1[C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC1CCC(OC)O1
Reactant: CCOC(=O)c1c(-c2ccccc2)c2cc(N)ccc2n1Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)c1c(-c2ccccc2)c2cc(-n3cccc3)ccc2n1Cc1ccccc1
Yield: 95.1 %

Procedure:
A solution of ethyl 5-amino-1-benzyl-3-phenyl-1H-indole-2-carboxylate (0.74 g, 2 mmol), 2,5-dimethoxytetrahydrofuran (0.40 g, 3 mmol) in acetic acid was heated to 90° C. for 3 h. The reaction was cooled and concentrated. The residue was then purified by flash silica gel chromatography (hexanes/ethyl acetate 5/1) to afforded 0.8 g (95%) of ethyl 1-benzyl-3-phenyl-5-(1H-pyrrol-1-yl)-1H-indole-2-carboxylate as an off-white solid: 1H NMR (CDCl3) δ 0.97 (t, J=7.1 Hz, 3 H), 4.11 (q, J=7.1 Hz, 2 H), 5.84 (s, 2 H), 6.30 (t, J=2.1 Hz, 2 H), 7.01 (t, J=2.1 Hz, 2 H), 7.10-7.50 (m, 13 H); MS (ESI) m/z 421 (MH+); HRMS calcd for C28H25N2O2: 421.1917; found (ESI+): 421.1903; Anal. calcd for C28H24N2O2: C, 79.98; H, 5.75; N, 6.66. Found: C, 80.03; H, 5.67; N, 6.49.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]([O:14]C)=[O:13])=[N:10][CH:11]=1)[CH:3]([OH:5])[CH3:4].Cl>O.[OH-].[Li+]>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]([OH:14])=[O:13])=[N:10][CH:11]=1)[CH:3]([OH:5])[CH3:4]
Reactant: COC(=O)c1ccc(C(O)C(C)O)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CC(O)C(O)c1ccc(C(=O)O)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 5-(1,2-dihydroxypropyl)-2-pyridinecarboxylate (5 mg) in water (0.1 ml), 1N lithium hydroxide (50 μl) was added at room temperature. After stirring for 1 hour at room temperature, the reaction mixture was neutrized with 1N HCl. The solution was applied to a Diaion HP20 (Mitsubishikasei trademark) column and eluted with methanol-water (1:1) to give 5-(1,2-dihydroxypropyl)-2-pyridinecarboxylic acid: white amorphous powder; molecular formula C9H11NO4 ; LRFAB-MS m/z 196 [M-H]- ; 1H-NMR (D3O) δ 8.74 (1H, d, J=2.2 Hz), 8.47 (1H, d, J=8.1 Hz), 8.28 (1H, dd, J=8.1 and 2.2 Hz), 4.88 (1H, d,J=4.3 Hz), 4.12 (1H, dq, J=6.5 and 4.3 Hz), 1.21 (3H, d,J=6.5 Hz).
Reaction SMILES: Br[C:2]1[CH:22]=[N:21][C:5]2[N:6]([C:17](=[O:20])[NH:18][CH3:19])[C@@H:7]([CH3:16])[CH2:8][N:9]([C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])[C:4]=2[CH:3]=1.[CH:23]1([N:26]2[CH:30]=[C:29](B3OC(C)(C)C(C)(C)O3)[CH:28]=[N:27]2)[CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[CH:23]1([N:26]2[CH:30]=[C:29]([C:2]3[CH:22]=[N:21][C:5]4[N:6]([C:17](=[O:20])[NH:18][CH3:19])[C@@H:7]([CH3:16])[CH2:8][N:9]([C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])[C:4]=4[CH:3]=3)[CH:28]=[N:27]2)[CH2:25][CH2:24]1
Reactant: CC1(C)OB(c2cnn(C3CC3)c2)OC1(C)C
Reactant: CNC(=O)N1c2ncc(Br)cc2N(C(=O)OC(C)C)C[C@@H]1C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: CNC(=O)N1c2ncc(-c3cnn(C4CC4)c3)cc2N(C(=O)OC(C)C)C[C@@H]1C
Temperature: 80 °C

Procedure:
A reaction vial was charged with (S)-isopropyl 7-bromo-3-methyl-4-(methylcarbamoyl)-3,4-dihydropyrido[2,3-b]pyrazine-1 (2H)-carboxylate (0.015 g, 0.04 mmol), 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.2 M solution in 1,4-dioxane, 0.40 mL, 0.080 mmol), potassium carbonate (1.0 M solution in water, 0.120 mL, 0.120 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (0.02 M solution in 1,2-dichloroethane, 0.200 mL, 0.004 mmol). The reaction was purged with nitrogen and heated to 80° C. on a heater shaker overnight. The reaction was diluted with ethyl acetate and washed with brine. The combined organic layers were concentrated under a stream of nitrogen. The crude product was purified by mass triggered preparatory HPLC. The product-containing fractions were combined and concentrated to afford (S)-isopropyl 7-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-4-(methylcarbamoyl)-3,4-dihydropyrido[2,3-b]pyrazine-1(2H)-carboxylate. MS (ESI, pos. ion) m/z 399 [M+H]+.
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([N:6]1[CH2:10][CH2:9][N:8]=[C:7]1SC)=[O:5].[NH2:17][N:18]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>O>[N:18]1([N:17]2[C:2]3[C:3](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:4](=[O:5])[N:6]3[CH2:10][CH2:9][N:8]=[C:7]23)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: NN1CCCCCC1
Reactant: CSC1=NCCN1C(=O)c1ccccc1F
Solvent: O
Product: O=C1c2ccccc2N(N2CCCCCC2)C2=NCCN12
Yield: 76 %

Procedure:
A solution of 10.0 g (42.0 mmoles) of the product of Example 1 in 50 ml of N-amino-homopiperidine was heated at reflux for 10 minutes. Upon cooling, a white, crystalline solid formed. The mixture was diluted with water (100 ml) and the solid was collected, washed with water, and air-dried to give 9.03 g of 10-(hexahydro-1H-azepin-1-yl)-2,10-dihydroimidazo[2,1-b]quinazolin-5(3H)-one. Melting point 206°-208° C. Total yield 76%.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[O:40]=[C:41]1[N:45]([CH2:46][C:47]2[N:48]=[C:49]([C:52]3[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=3)[S:50][CH:51]=2)[C:44](=[O:58])[CH2:43][N:42]1[C@@H:59]([C@@H:63]([CH3:66])[CH2:64][CH3:65])[C:60](O)=[O:61].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[O:40]=[C:41]1[N:45]([CH2:46][C:47]2[N:48]=[C:49]([C:52]3[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=3)[S:50][CH:51]=2)[C:44](=[O:58])[CH2:43][N:42]1[C@@H:59]([CH:63]([CH3:66])[CH2:64][CH3:65])[C:60]([NH:1][C@@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)=[O:61]
Reactant: CC[C@H](C)[C@@H](C(=O)O)N1CC(=O)N(Cc2csc(-c3cccnc3)n2)C1=O
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCC(C)[C@@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccc(-c2ccccn2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)N1CC(=O)N(Cc2csc(-c3cccnc3)n2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
A solution containing the product from Example 2C (0.030 g, 0.056 mmol) in THF (0.5 mL) was treated with the product from Example 57C (0.036 g, 0.073 mmol), DEPBT (0.025 g, 0.085 mmol), and N,N-diisopropylethylamine (0.049 mL, 0.282 mmol), stirred at 25° C. for 1 hour, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-100% ethyl acetate/dichloromethane, followed by elution with 0-5% methanol in ethyl acetate to give the title compound (0.044g, 86% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.67 (d, J=6.62 Hz, 3 H), 0.73 (t, J=7.35 Hz, 3 H), 0.90 (m, 12 H), 1.25 (m, 1 H), 1.52 (m, 2 H), 1.75 (m, 1 H), 2.69 (m, 3 H), 3.15 (m, 1 H), 3.50 (s, 3 H), 3.78 (m, 2 H), 4.16 (m, 3 H), 4.67 (d, J=6.62 Hz, 1 H), 4.78 (m, 2 H), 6.67 (d, J=9.93 Hz, 1 H), 6.96 (m, 3 H), 7.07 (m, 2 H), 7.22 (d, J=8.09 Hz, 2 H), 7.31 (m, 1 H), 7.51 (dd, J=7.91, 4.96 Hz, 1 H), 7.64 (s, 1 H), 7.86 (m, 6 H), 8.24 (m, 1 H), 8.64 (m, 2 H), 9.08 (d, J=1.84 Hz, 1 H).
Reaction SMILES: CO[C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]([O:13][CH3:14])=[CH:8][N:9]=2)[N:4]=1.P(Cl)(Cl)([Cl:17])=O>CN(C)C=O>[Cl:17][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]([O:13][CH3:14])=[CH:8][N:9]=2)[N:4]=1
Reactant: COc1cnc2ccc(OC)nc2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cnc2ccc(Cl)nc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 64.5 %

Procedure:
A mixture of 2,7-dimethoxy-[1,5]naphthyridine (5.0 g, 26.29 mmol, 1.0 eq) and phosphorus oxychloride (4.9 mL, 52.58 mmol, 2.0 eq) in N,N-dimethylformamide (100 mL) is stirred at 0° C. for 1 hour then at 80° C. for 1 hour. The reaction mixture is cooled to 0° C., quenched with 10 mL of saturated sodium acetate aqueous solution and then stirred at 30° C. for 30 minutes. The mixture is extracted with ethyl acetate (3×60 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a crude that is purified by column chromatography (silica gel, eluent: ethyl acetate:petroleum ether, 1:6, v/v) to afford 2-chloro-7-methoxy-[1,5]naphthyridine as a yellow solid (3.3 g, 64% yield).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][S:5][CH2:6][CH2:7][CH:8]([O:29][CH3:30])[CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].ClC1C=CC=C(C(OO)=[O:39])C=1>ClCCl>[CH3:30][O:29][CH:8]([CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:7][CH2:6][S:5]([CH2:4][CH2:3][CH2:2][OH:1])=[O:39]
Reactant: CCCCCCCCCCCCCCCCCCOCC(CCSCCCO)OC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCOCC(CCS(=O)CCCO)OC
Yield: 92.7 %

Procedure:
In 20 ml of dichloromethane is dissolved 1.52 g of 3-methoxy-4-octadecyloxybutyl 3-hydroxypropyl sulfide, to which a solution of 0.61 g of m-chloroperbenzoic acid in 8 ml of dichloromethane is added dropwise with stirring under ice cooling. Thereafter, the mixture is stirred at room temperature for 30 minutes to complete the reaction. The reaction mixture is then washed with an aqueous sodium bisulfite solution, an aqueous sodium bicarbonate solution and then water and dried. The solvent is distilled off under reduced pressure and the residue is purified by silica gel column chromatography to obtain 1.46 g of the captioned compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[O:11])[CH:6]=[CH:7][C:8]=1[OH:9].[OH-].[Na+].[CH2:14](I)[CH3:15]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH2:14][CH3:15])[CH:10]=[O:11]
Reactant: COc1cc(C=O)ccc1O
Reactant: CCI
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOc1ccc(C=O)cc1OC
Reaction time: 15 h
Yield: 68.8 %

Procedure:
To a solution of 30.4 g (0.2 mole) of vanilline, 12 g (0.3 mole) of sodium hydroxide and 300 ml of water, then 37.4 g (0.24 mole) of ethyl iodide are added. The reaction mixture is heated to boiling for 15 hours, then cooled and extracted with benzene. The extract is evaporated. The crude residue is dissolved in 110 ml of a 25% aqueous sodium hydroxide solution, clarified with activated charcoal and made alkaline to pH 12. The precipitated crystals are filtered, washed with water and dried. Thus 24.8 g of 3-methoxy-4-ethoxy-benzaldehyde are obtained, yield 69%, m.p.: 65°-67° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([CH3:10])[CH:3]=1.[N:11]1[CH:16]=[C:15](B(O)O)[CH:14]=[N:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:8][C:6]1[CH:7]=[C:2]([C:15]2[CH:16]=[N:11][CH:12]=[N:13][CH:14]=2)[CH:3]=[C:4]([CH3:10])[C:5]=1[OH:9]
Reactant: OB(O)c1cncnc1
Reactant: Cc1cc(Br)cc(C)c1O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: Cc1cc(-c2cncnc2)cc(C)c1O
Reaction time: 0.25 h
Yield: 20 %

Procedure:
4-Bromo-2,6-dimethylphenol (0.5 g, 2.5 mmol) was dissolved in dimethoxyethane/water (2:1). pyrimidin-5-ylboronic acid (0.37 g, 2.8 mmol), Pd(dppf)Cl2 (0.02 g, 0.13 mmol) and sodium carbonate (0.79 g, 7.5 mmol) were added thereto, followed by reacting in microwave reactor at 120° C. for 15 minutes. After the completion of the reaction, the reaction mixture was added with water, and extracted with ethyl acetate. The obtained organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 2,6-dimethyl-4-(pyrimidin-5-yl)phenol (0.1 g, 20%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[C:4]=1[C:5]#[N:6].[I:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24].C(N(CC)CC)C>>[I:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23]([N:16]1[CH2:17][CH2:18][CH:13]([CH2:12][O:11][C:7]2[CH:8]=[CH:9][CH:10]=[C:3]([F:2])[C:4]=2[C:5]#[N:6])[CH2:14][CH2:15]1)=[O:24]
Reactant: O=C(Cl)c1cccc(I)c1
Reactant: N#Cc1c(F)cccc1OCC1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Product: N#Cc1c(F)cccc1OCC1CCN(C(=O)c2cccc(I)c2)CC1
Yield: 95 %

Procedure:
A mixture of 2-fluoro-6-(piperidin-4-ylmethoxy)-benzonitrile hydrochloride (200 mg; 0.7 mmol) (Example 123, Step 3) was stirred at room temperature with 3-iodobenzoyl chloride (187 mg; 0.7 mmol) and triethylamine (0.3 mL; 2.1 mmol) for 16 hours. Reaction was cooled and quenched with dilute HCl and mixture extracted with ethyl acetate (2×20 mL). Combined organics washed with water, saturated sodium bicarbonate, brine and dried over Na2SO4. Crude solid was obtained as 2-[1-(3-iodo-benzoyl)-piperidin-4-ylmethoxy]-6-fluoro-benzonitrile. (310 mg; 95% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([F:21])[CH:14]=1.C([O-])([O-])=O.[Na+].[Na+].[OH-].[Na+]>C(O)C.C1C=CC=CC=1.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>[F:21][C:15]1[CH:14]=[C:13]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:20]=[CH:19][C:16]=1[C:17]#[N:18]
Reactant: N#Cc1ccc(Br)cc1F
Reactant: COc1ccc(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: CCO
Solvent: c1ccccc1
Product: COc1ccc(-c2ccc(C#N)c(F)c2)cc1
Temperature: 25 °C
Yield: 92 %

Procedure:
A mixture of 4-methoxyphenylboronic acid (4.56 g, 30.0 mmol) in ethanol (20 mL) was added to a solution of 4-bromo-2-fluorobenzonitrile (5.00 g, 25.0 mmol) and tetrakis(triphenylphosphine)palladium (578 mg, 0.50 mmol) in benzene (50 mL). The resulting mixture was treated with a 2.0 M aqueous solution of Na2CO3 (25 mL, 50 mmol) and heated briefly at reflux, then at 65° C. overnight. The mixture was cooled to room temperature and treated with 6.0 M aqueous NaOH. The aqueous phase was separated and extracted with ether. First the original organic phase and then the ethereal wash were filtered through diatomaceous earth. The collection flask was changed and the solids remaining atop the diatomaceous earth were washed through with EtOAc. The ethereal wash was concentrated and refiltered as before. The combined EtOAc rinses were combined and concentrated to provide the title compound as a yellow powder (92% yield). 1HNMR (300 MHz, d6-DMSO) δ 3.82 (s, 3 H), 7.07 (d, 2 H), 7.72 (dd, 1 H), 7.79 (d, 2 H), 7.85 (dd, 1 H), 7.95 (dd, 1 H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CS(O[CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]2[O:25][N:24]=[C:23]([CH:26]([CH3:28])[CH3:27])[N:22]=2)[CH2:17][CH2:16]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:14][CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[O:25][N:24]=[C:23]([CH:26]([CH3:28])[CH3:27])[N:22]=3)[CH2:17][CH2:16]2)=[CH:6][N:7]=1
Reactant: Oc1ccc(Br)nc1
Reactant: CC(C)c1noc(N2CCC(COS(C)(=O)=O)CC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1noc(N2CCC(COc3ccc(Br)nc3)CC2)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 80.3 %

Procedure:
A mixture of 6-bromo-3-pyridinol (1 g, 5.75 mmol), {1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl methanesulfonate (prepared as in Example 100, Steps 1-4, 1.74 g, 5.75 mmol), potassium carbonate (1.59 g, 11.49 mmol), and DMF (15 mL) stirred at 80° C. overnight. The mixture was cooled to room temperature, charged with water (100 mL), and was extracted with EtOAc. The organics were dried over MgSO4, filtered, and concentrated. The crude product was purified by chromatography on a silica gel column using 0 to 50% EtOAc/hexane to give 1.76 g (80%) of 2-bromo-5-[({1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl)oxy]pyridine as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.03 (d, 1H, J=3.1 Hz), 7.36 (d, 1H, J=8.7 Hz), 7.07 (dd, 1H, Ja=8.7 Hz, Jb=3.1 Hz), 4.21 (dd, 2H, Ja=11.0 Hz, Jb=2.1 Hz), 3.84 (d, 2H, J=6.3 Hz), 3.09 (m, 2H), 2.94-2.83 (m, 1H), 2.12-1.98 (m, 1H), 1.92 (d, 2H, J=12.2 Hz), 1.36-1.53 (m, 2H), 1.28 (d, 6H, J=7.0 Hz); LRMS (ESI), m/z 381/383 (M+H).
Reaction SMILES: [CH2:1]([C:3]([C:7]1[C:12]2[N:13]([CH3:17])[C:14](=[O:16])[NH:15][C:11]=2[CH:10]=[CH:9][CH:8]=1)(O)[CH2:4][CH3:5])[CH3:2].Cl>C(O)C.[Pd]>[CH2:1]([CH:3]([C:7]1[C:12]2[N:13]([CH3:17])[C:14](=[O:16])[NH:15][C:11]=2[CH:10]=[CH:9][CH:8]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(O)(CC)c1cccc2[nH]c(=O)n(C)c12
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCC(CC)c1cccc2[nH]c(=O)n(C)c12
Temperature: 50 °C
Reaction time: 3 h
Yield: 54 %

Procedure:
A mixture of 7-(1-ethyl-1-hydroxypropyl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (6.00 g, 25.6 mmol) and 6N HCl (20 mL) in ethanol (100 mL) was stirred at 50° C. for 3 h. The mixture was concentrated in vacuo, and the resulting residue was dissolved in ethyl acetate, washed with aqueous potassium carbonate. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to give pale yellow oil, which was used in the next reaction without further purification. MS Calcd.: 216. Found: 217 (M+H). The crude material was dissolved in ethanol (150 mL). This solution was treated with 10% palladium on carbon (50% wet; 1.00 g), purged with hydrogen, and stirred under 5 atoms hydrogen for 7 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The residue was crystallized from ethanol/diethylether to afford the title compound as colorless crystals (3.02 g, 54%). mp 130-132° C.