Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:3]=[C:4]([NH:15][C:16](=[O:20])OCC)[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)#[N:2].[N:21]1([CH2:27][C:28]([NH:30][NH2:31])=O)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C(OCC)(=O)C.O>CN1C(=O)CCC1>[N:21]1([CH2:27][C:28]2[N:2]=[C:1]3[N:31]([C:16]([OH:20])=[N:15][C:4]([C:5]4[CH:6]=[CH:7][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:9][CH:10]=4)=[CH:3]3)[N:30]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: CCOC(=O)NC(=CC#N)c1ccc(C(F)(F)F)cc1
Reactant: NNC(=O)CN1CCOCC1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Oc1nc(-c2ccc(C(F)(F)F)cc2)cc2nc(CN3CCOCC3)nn12
Temperature: 190 °C
Reaction time: 4 h

Procedure:
2.4 g (8.4 mmol) of ethyl {2-cyano-1-[4-(trifluoromethyl)phenyl]ethenyl}carbamate (Example 129A) and 1.34 g (8.4 mmol) of 2-morpholin-4-ylacetohydrazide are dissolved in NMP (12 ml) and stirred in a flask with a calcium chloride drying tube at an oil-bath temperature of 190° C. for 4 h. The reaction mixture is cooled to RT and ethyl acetate (150 ml) and water (100 ml) are added. The organic phase is washed with saturated sodium bicarbonate solution, separated off, dried with magnesium sulphate and concentrated. The residue is chromatographed on silica gel (mobile phase cyclohexane/ethyl acetate 10:1 to 1:1, then with dichloromethane/methanol 100:1). 850 mg (26% of theory) of the product are obtained.
Reaction SMILES: [H-].[Na+].C[C:4]1([CH3:11])[O:8][C@H:7]([CH2:9][OH:10])[CH2:6][O:5]1.[H][H].[CH3:14][O:15][C:16]1[CH:17]=C([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])CCl>CS(C)=O.O1CCCC1.C(OCC)C>[CH3:14][O:15][C:16]1[CH:17]=[C:11]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:4][O:5][CH2:6][C@H:7]([OH:8])[CH2:9][OH:10]
Reactant: COc1ccc(CCl)cc1OC
Reactant: CC1(C)OC[C@@H](CO)O1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CS(C)=O
Product: COc1ccc(COC[C@H](O)CO)cc1OC
Reaction time: 10 h

Procedure:
To the suspension of Sodium hydride (60% oil dispersion, 4.85 g) in dry Dimethyl sulfoxide (100 ml), solution of (R)-(-)-2,2-Dimethyl-1,3-dioxolane-4-methanol (10.68 g) in dry Tetrahydrofuran (30 ml) was added dropwise under Nitrogen atmosphere at room temperature. After evolution of Hydrogen stopped, solution of 3.4-Dimethoxybenzyl chloride (16.42 g) in dry Dimethyl sulfoxide (30 ml) was added dropwise under the same condition. After 10 hrs of stirring, the reaction mixture was diluted with Diethyl ether, washed with water, followed by brine and then dried over Magnesium sulfate, then 1N-Hydrochloric acid (50 ml) and Tetrahydrofuran (100 ml) was added to the residue and stirred for 6 hrs. The reaction mixture was neutralized with Sodium hydrogen carbonate, extracted with Chloroform and dried over Magnesium sulfate. The title compound was obtained after column purification (Hexane+Ethyl acetate 1:2~Ethyl acetate+Acetone (10:1) as oil. Yield: 18.31 g (94%). NMR (CDCl3): 2.16 (1H, br, s), 3.55 (2H, m), 3.67 (2H, m), 3.88 (3H, s), 3.89 (3H, s), 3.92 (1H, m), 4.49 (2H, s). IR (Neat), cm-1 : 3385, 2910, 1505. [α]25D =+1.0° (C=2.0, Chloroform).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:13]2[CH:17]=[CH:16][CH:15]=[CH:14]2)=[C:8]([CH:12]=1)[C:9](O)=[O:10])([O-:3])=[O:2].O>O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:13]2[CH:14]=[CH:15][CH:16]=[CH:17]2)=[C:8]([CH:12]=1)[CH2:9][OH:10])([O-:3])=[O:2]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1-n1cccc1
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(-n2cccc2)c(CO)c1
Yield: 70 %

Procedure:
To a solution in anhydrous tetrahydrofuran (10 ml) of the compound (392 mg) obtained in Example 1a, a borane-tetrahydrofuran complex (1.0 M, 2.2 ml) was added dropwise under a nitrogen atmosphere. After heating the reaction mixture under reflux for 3 hours, water was added and the mixture was concentrated at reduced pressure. Brine was added to the resulting residue and the mixture was extracted with ethyl acetate. The organic layer was dried with anhydrous sodium sulfate and concentrated at reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; ethyl acetate:dichloromethane=1:19) to give the titled compound (yield, 70%).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([OH:11])=[O:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.CN([Si](C)(C)C)C(=O)C(F)(F)F.Cl[CH2:25][C:26]1[CH:27]=[CH:28][C:29]2[S:34][C:33]3[N:35]=[CH:36][CH:37]=[N:38][C:32]=3[NH:31][C:30]=2[CH:39]=1>C(#N)C>[N:38]1[C:32]2[NH:31][C:30]3[CH:39]=[C:26]([CH2:25][N+:1]45[CH2:8][CH2:7][C:4]([C:9]([O-:11])=[O:10])([CH2:5][CH2:6]4)[CH2:3][CH2:2]5)[CH:27]=[CH:28][C:29]=3[S:34][C:33]=2[N:35]=[CH:36][CH:37]=1
Reactant: O=C(O)C12CCN(CC1)CC2
Reactant: ClCc1ccc2c(c1)Nc1nccnc1S2
Agent: CN(C(=O)C(F)(F)F)[Si](C)(C)C
Solvent: CC#N
Product: O=C([O-])C12CC[N+](Cc3ccc4c(c3)Nc3nccnc3S4)(CC1)CC2
Reaction time: 2 h
Yield: 14.3 %

Procedure:
0.620 g of 1-azabicyclo[2.2.2]octane-4-carboxylic acid was dissolved in 40 ml of acetonitrile. After adding 3.98 g of N-methyl-N-(trimethylsilyl)trifluoroacetamide, the resulting mixture was stirred for 2 hours. Next, 0.998 g of 8-chloromethyl-10H-pyrazino[2,3-b][1,4]benzothiazine was added thereto and the resulting mixture was heated under reflux for 4 hours. After distilling off the solvent under reduced pressure, the residue was dissolved in methanol/dichloromethane. After adding diethyl ether, the mixture was filtered and the residue was purified by High-porous gel chromatography (CHP20P, mfd by Mitsubishi Chemical Industries, 75-150μ) (eluted with methanol/water) to thereby give 0.21 g of the title compound as a yellow powder.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[CH2:12]([Li])CCC.CCCCCC>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:7]([C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:11]=[CH:10][CH:9]=1)=[CH2:12]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Product: C=Cc1cccc([N+](=O)[O-])c1

Procedure:
Treatment of 3-nitrobenzaldehyde (20 g) with methyltriphenylphosphonium bromide (61.5g) and n-butyllithium in hexane (172 mmol), as described in Example 1a, gave 3-ethenylnitrobenzene (10.3 g), δ (360 MHz, CDCl3), 5.44 and 5.59 (2H, 2d, CH2), 6.75 (1H, dd, CH), 7.49 (1H, t, 5-H), 7.70 (1H, dd, 4-H), 8.09 (1H, dd, 6-H) and 8.24 (1H, d, 2-H).
Reaction SMILES: C([O-])([O-])=[O:2].C([O-])([O-])=O.OO.OO.OO.[Na+].[Na+].[Na+].[Na+].[Br:19][CH2:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)=[CH:26][C:27]([C:31]#[N:32])=[N:28]2)=[CH:23][CH:22]=1>O.CC(C)=O>[Br:19][CH2:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25]([C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)=[CH:26][C:27]([C:31]([NH2:32])=[O:2])=[N:28]2)=[CH:23][CH:22]=1
Reactant: N#Cc1cc(-c2ccc(F)cc2)c2ccc(CBr)cc2n1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: NC(=O)c1cc(-c2ccc(F)cc2)c2ccc(CBr)cc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.1 %

Procedure:
Sodium percarbonate (2.98 g, 9.50 mmol, 3.0 equiv.) in water (52.8 ml) was added dropwise to a solution of 7-(bromomethyl)-4-(4-fluorophenyl)quinoline-2-carbonitrile (2-1, 1.08 g, 3.17 mmol, 1.0 equiv.) in acetone (106 ml) and the reaction stirred for 1 hour at rt. The reaction was quenched with saturated KH2PO4 and the mixture was extracted with EtOAc (3×). The combined organic fractions were dried (MgSO4), filtered, and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel chromatography (120 g SiO2, 0-100% EtOAc/hexanes) to afford 7-(bromomethyl)-4-(4-fluorophenyl)quinoline-2-carboxamide (3-1, 650 mg, 57%) as a white solid. LRMS m/z (M+H)+ 359.05 found, 359.19 required.
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-:4])[CH3:3].[Na+].[Br-].C1([PH+](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:27]([O:29][C:30]([C:32]1[NH:33][C:34]([CH:38]=O)=[CH:35][C:36]=1[CH3:37])=[O:31])[CH3:28].C1C[O:43][CH2:42][CH2:41]1>>[CH2:27]([O:29][C:30]([C:32]1[NH:33][C:34]([CH:38]=[CH:41][C:42]([O:4][C:2]([CH3:5])([CH3:3])[CH3:1])=[O:43])=[CH:35][C:36]=1[CH3:37])=[O:31])[CH3:28]
Reactant: CC(C)(C)[O-]
Reactant: C1CCOC1
Reactant: CCOC(=O)c1[nH]c(C=O)cc1C
Agent: [Br-]
Agent: [Na+]
Agent: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)c1[nH]c(C=CC(=O)OC(C)(C)C)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
Sodium tert-butoxide (1.37 g, 14.3 mmol) was added to the dry tert-butoxycarbonylmethyl)triphenylphosphonium bromide (6.56 g, 14.3 mmol) in THF (anhydrous, 30 mL) under nitrogen. The mixture was stirred at room temperature for 30 minutes. To the mixture was added 5-formyl-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (2.36 g, 13 mmol) in THF (35 mL). The mixture was then stirred at room temperature under nitrogen for overnight. The solid was filtered off and the filtrate was concentrated followed by column chromatograph (10% EtOAc in hexane) to give 2.95 g (81%) of 5-(2-tert-butoxycarbonyl-vinyl)-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester. 1H NMR (300 MHz, DMSO-d6) δ 11.85 (br s, 1H, NH), 7.35 (d, J=15.7 Hz, 1H), 6.73 (s, 1H), 6.41 (d, J=15.7 Hz, 1H), 4.23 (q, J=7.1 Hz, 2H, OCH2), 2.22 (s, 3H, CH3), 1.44 (s, 9H, 3×CH3), 1.28 (t, J=7.1 Hz, 3H, OCH2CH3). MS 279 [M+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.Br[CH:24]([CH2:28]Br)[C:25]([NH2:27])=[O:26]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:9][CH2:10][N:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=3)[CH:24]([C:25]([NH2:27])=[O:26])[CH2:28]2)[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)C(Br)CBr
Reactant: COc1ccc(CNCCNc2cccc(Cl)c2)cc1OC
Product: COc1ccc(CN2CCN(c3cccc(Cl)c3)CC2C(N)=O)cc1OC

Procedure:
In a manner similar to Preparation 1, react N-(3-chlorophenyl)-N'-[(3,4-dimethoxyphenyl)methyl]-1,2-ethanediamine (13.3 g, 41 mmol) with 2,3-dibromopropanamide (19.1 g, 166 mmol) to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1[S:18][C:5]2[N:6]=[C:7]3[CH:14]=[CH:13][C:12]([C:15]([NH2:17])=O)=[CH:11][N:8]3[C:9](=[O:10])[C:4]=2[C:3]=1[CH3:19].P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[CH3:1][C:2]1[S:18][C:5]2[N:6]=[C:7]3[CH:14]=[CH:13][C:12]([C:15]#[N:17])=[CH:11][N:8]3[C:9](=[O:10])[C:4]=2[C:3]=1[CH3:19]
Reactant: Cc1sc2nc3ccc(C(N)=O)cn3c(=O)c2c1C
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1sc2nc3ccc(C#N)cn3c(=O)c2c1C
Yield: 94.2 %

Procedure:
From 1.0 g (0.0037 mol) of 2,3-dimethyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxamide (Example 36), 50 ml of phosphorus oxychloride and 50 ml of chloroform and refluxing on a steam bath for eighteen hours, following the procedure of Example 27, there is obtained 0.89 g of 2,3-dimethyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carbonitrile; mp 306°-307° C. after recrystallization from glacial acetic acid.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([NH:10][C:11]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([O:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH2:29])[CH:24]=3)=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)=[O:12])[CH3:9].Cl[C:31]([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:32]>O1CCCC1>[CH2:8]([NH:10][C:11]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([O:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:31](=[O:32])[O:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH:24]=3)=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)=[O:12])[CH3:9]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCNC(=O)n1ccc2cc(Oc3ccnc(N)c3)ccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)Oc4ccccc4)c3)ccc21
Temperature: 0 °C
Yield: 109.8 %

Procedure:
Tetrahydrofuran (20 ml) and triethylamine (2.70 ml, 19.4 mmol) were added to N1-ethyl-5-(2-amino-4-pyridyl)oxy-1H-1-indolecarboxamide (1.91 g, 6.45 mmol, Production example 27-1); phenyl chloroformate (1.79 ml, 14.2 mmol) was added thereto at 0° C. while stirred; and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was partitioned between ethyl acetate and water; the organic layer was concentrated to yield a mixture (2.95 g) of phenyl N-(4-(1-(ethylamino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamate and phenyl N-(4-(1-(ethylamino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)-N-(phenoxycarbonyl)carbamate. A portion of 0.454 g of the mixture was dissolved in N,N-dimethylformamide (5 ml); and 4-(1-pyrrolidinyl)piperidine (0.522 g, 3.39 mmol) was added; and the reaction mixture was stirred for 5 hours. The reaction mixture was partitioned between ethyl acetate and water; the organic layer was concentrated to yield a solid; the obtained solid was washed with hexane:diethyl ether=1:1 to yield the title compound as crystals (205 mg, 0.43 mmol). MS Spectrum (ESI): 477 (M+1), 953 (2M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1.CC(N(C)C)=O>C(Cl)Cl>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: O=C(O)c1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2)cc1
Reaction time: 24 h
Yield: 94 %

Procedure:
10 g of 4-nitrobenzoic acid chloride are slowly introduced into 7.4 g of 4-aminobenzoic acid and 36 ml of dimethylacetamide while maintaining the temperature at less than 25° C. After stirring for 24 hours, 50 ml of methylene chloride are added at 10° C. in order to precipitate the desired product. After washing with water and drying, 14.5 g of product are isolated.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[CH3:21][CH:22]([NH2:26])[CH2:23][CH2:24][CH3:25].C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][C:15](=[O:17])[NH:26][CH:22]([CH3:21])[CH2:23][CH2:24][CH3:25])=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Reactant: CCCC(C)N
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CCCC(C)NC(=O)COc1ccc(C[C@H](OC)C(=O)O)cc1

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and 1-methyl-butylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C17H25NO5 [M−H]−: 322.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])=[N:9]2)=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28](=[O:34])[CH:29]=[CH:30][C:31](O)=[O:32])[CH3:26].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl.O>[CH2:25]([O:27][C:28](=[O:34])[CH:29]=[CH:30][C:31]([N:22]1[CH2:23][CH2:24][N:19]([C:6]2[C:5]3[C:10](=[CH:11][C:2]([CH3:1])=[CH:3][CH:4]=3)[N:9]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])[N:7]=2)[CH2:20][CH2:21]1)=[O:32])[CH3:26]
Reactant: CCOC(=O)C=CC(=O)O
Reactant: Cc1ccc2c(N3CCNCC3)nc(-c3ccccc3O)nc2c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)C=CC(=O)N1CCN(c2nc(-c3ccccc3O)nc3cc(C)ccc23)CC1
Reaction time: 0.33 h
Yield: 91 %

Procedure:
To 2-(7-methyl-4-piperazin-1-yl-quinazolin-2-yl)-phenol (787 mg, 2.46 mmol) in 8 mL of CH2Cl2 at room temperature was added sequentially but-2-enedioic acid monoethyl ester (531 mg, 3.69 mmol), triethylamine (686 μL, 4.92 mmol), BOP (1.63 g, 3.69 mmol). The reaction mixture was stirred for 20 min and diluted with water and CH2Cl2. The organic layer was separated and dried over Na2SO4, and the solvent was removed under reduced pressure to give an oil. The residue was subjected to purification by normal phase LC using 10-100% EtOAc-hexanes to give 4-{4-[2-(2-Hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazin-1-yl}-4-oxo-but-2-enoic acid ethyl ester (1.00 g, 91% yield). LC/MS: m/z 447.3 (M+H)+ at 2.93 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]2[C@H:15]([CH3:16])[CH2:14][CH2:13][C@H:12]([C:17]([OH:19])=O)[CH2:11]2)[CH:3]=1.CCN(C(C)C)C(C)C.[NH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]2[C@H:15]([CH3:16])[CH2:14][CH2:13][C@H:12]([C:17]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:19])[CH2:11]2)[CH:3]=1
Reactant: CNc1nc(Cl)cc(N2C[C@@H](C(=O)O)CC[C@H]2C)n1
Reactant: Nc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNc1nc(Cl)cc(N2C[C@@H](C(=O)Nc3ccccc3)CC[C@H]2C)n1
Temperature: 0 °C
Yield: 63 %

Procedure:
To (3S,6R)-1-[6-chloro-2-(methylamino)-4-pyrimidinyl]-6-methyl-3-piperidinecarboxylic acid (880 mg, 3.09 mmol) in CH2Cl2 (15 mL) at room temperature was added Hunig's base (1.62 mL, 9.27 mmol, 3 equiv) and aniline (0.56 mL, 6.18 mmol, 2 equiv), and the resulting mixture was chilled in an ice bath. To this stirred solution was added HATU (1.29 g, 3.40 mmol, 1.1 equiv) in one portion. The resulting suspension was stirred in the ice bath for 45 minutes. LCMS showed conversion complete. The mixture was filtered, and the filtrate was concentrated in vacuo. Silica gel column chromatography with gradient elution of 1% EtOAc in CHCl3 to 35% EtOAc in CHCl3 gave 700 mg of the title compound. LC-MS (ES) m/z=360 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:34]=[CH:33][C:18]([NH:19][CH2:20][C:21]3[CH:30]=[C:29]4[C:24]([CH:25]=[CH:26][C:27]([C:31]#[N:32])=[CH:28]4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:35](OC(=O)C)(=[O:37])[CH3:36].C(OCC)(=O)C>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([N:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][C:27]([C:31]#[N:32])=[CH:26][CH:25]=4)[CH:30]=3)[C:35](=[O:37])[CH3:36])=[CH:33][CH:34]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCc3ccc4ccc(C#N)cc4c3)cc2)CC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)N(Cc1ccc2ccc(C#N)cc2c1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
7-[[4-[(1-t-Butoxycarbonyl-4-piperidyl)oxy]anilino]methyl]-2-naphthalenecarbonitrile obtained in Reference Example 2 (150 mg) was dissolved in 1 ml of pyridine, 268 mg of acetic anhydride and 10 mg of 4-dimethylaminopyridine were added to the solution, and the mixture was stirred at room temperature for 15 hours. Ethyl acetate was added to the reaction solution. The mixture was washed with 10% citric acid aqueous solution and saturated sodium bicarbonate aqueous solution in that order, dried over anhydrous sodium sulfate, and then evaporated. By recrystallizing the resulting residue from ethanol, 139 mg of N-[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]phenyl]-N-[(7-cyano-2-naphthyl)methyl]acetamide was obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[C:5]2[CH:14]=[C:15]([NH2:20])[C:16]([CH3:19])=[C:17]([CH3:18])[C:4]=2[O:3]1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32](O)=[O:33])=[CH:26][CH:25]=1>>[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([NH:20][C:15]2[C:16]([CH3:19])=[C:17]([CH3:18])[C:4]3[O:3][C:2]([CH3:21])([CH3:1])[CH:6]([C:7]4[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][CH:12]=4)[C:5]=3[CH:14]=2)=[O:33])=[CH:26][CH:25]=1
Reactant: Cc1ccc(C2c3cc(N)c(C)c(C)c3OC2(C)C)cc1
Reactant: COc1ccc(CCC(=O)O)cc1
Product: COc1ccc(CCC(=O)Nc2cc3c(c(C)c2C)OC(C)(C)C3c2ccc(C)cc2)cc1
Yield: 64 %

Procedure:
Using 2,2,6,7-tetramethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine obtained Reference Example 139 and 3-(4-methoxyphenyl)propionic acid, the title compound was obtained in the same manner as in Reference Example 359. Yield 64%. Melting point: 149-150° C. (ethyl acetate-hexane).
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([CH3:6])[CH3:5].[CH3:7][N:8]1[C:16]2[N:15]=[C:14]([Cl:17])[NH:13][C:12]=2[C:11](=[O:18])[NH:10][C:9]1=[O:19].CCN(C(C)C)C(C)C.O>CN(C)C=O>[CH3:7][N:8]1[C:16]2[N:15]=[C:14]([Cl:17])[N:13]([CH2:2][CH:3]=[C:4]([CH3:6])[CH3:5])[C:12]=2[C:11](=[O:18])[NH:10][C:9]1=[O:19]
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]c(Cl)nc21
Reactant: CC(C)=CCBr
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
5.87 mL of 1-bromo-3-methyl-2-butene is added to 10.56 g of 3-methyl-8-chloroxanthine and 17 mL of Hünig base in 100 mL of N,N-dimethylformamide. The reaction mixture is stirred for approximately 10 minutes at ambient temperature and then combined with 800 mL of water. The light-colored precipitate formed is suction filtered, washed with ethanol and diethyl ether and dried. Yield: 10.56 g (81% of theory); mass spectrum (ESI+): m/z=269, 271 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:3]=1[C:4]([NH:6][CH:7]([C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH2:19][CH2:20][CH3:21])(=[O:18])=[O:17])=[CH:12][CH:11]=1)[CH:8]=O)=[O:5].[CH3:27][O:28][CH2:29][C@H:30]1[CH2:34][CH2:33][CH2:32][NH:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:3]=1[C:4]([NH:6][CH:7]([C:10]1[CH:11]=[CH:12][C:13]([S:16]([CH2:19][CH2:20][CH3:21])(=[O:18])=[O:17])=[CH:14][CH:15]=1)[CH2:8][N:31]1[CH2:32][CH2:33][CH2:34][C@@H:30]1[CH2:29][O:28][CH3:27])=[O:5]
Reactant: COC[C@H]1CCCN1
Reactant: CCCS(=O)(=O)c1ccc(C(C=O)NC(=O)c2ccc(Cl)cc2Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCCS(=O)(=O)c1ccc(C(CN2CCC[C@@H]2COC)NC(=O)c2ccc(Cl)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,4-dichloro-N-{2-oxo-1-[4-(propylsulphonyl)phenyl]-ethyl}benzamide (135 mg, 0.33 mmol) in 1,2-dichloroethane (5 mL) under nitrogen was added (R)-2-(methoxymethyl)pyrrolidine (81 □L, 0.66 mmol) followed by sodium triacetoxyborohydride (138 mg, 0.65 mmol) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched by addition of satd. NaHCO3(aq) and the product extracted into ethyl acetate (×2). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated. One diastereoisomer of the title compound was isolated in pure form following preparative HPLC. 1H NMR δ (400 MHz, CDCl3) δ 1.00 (3H, t, J=7.4 Hz), 1.32-1.40 (1H, m), 1.52-1.59 (2H, m), 1.71-1.82 (4H, m), 1.96-2.04 (1H, m), 2.37-2.42 (1H, m), 2.87 (1H, br s), 3.00 (3H, s), 3.03-3.07 (2H, m), 3.21-3.35 (3H, m), 5.15-5.19 (1H, m), 7.34 (1H, dd, J=1.9, 8.3 Hz), 7.47 (1H, d, J=1.9 Hz), 7.59-7.61 (3H, m), 7.87 (2H, d, J=8.3 Hz), 8.31 (1H, d, J=5.3 Hz); m/z (ES+) 515 (M+H), 513 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:15]1[C:16]([O:29][C:30]2[CH:35]=[CH:34][C:33](OC)=[CH:32][CH:31]=2)=[N:17][C:18]([C:21]2[CH:22]=[N:23][CH:24]=[C:25](SC)[CH:26]=2)=[N:19][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:38][O:39]C1C=CC(O)=CC=1.CSC1C=C(B(O)[OH:56])C=NC=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:15]1[C:16]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([OH:56])[CH:31]=2)=[N:17][C:18]([C:21]2[CH:22]=[N:23][CH:24]=[C:25]([O:39][CH3:38])[CH:26]=2)=[N:19][CH:20]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1ccc(Oc2nc(-c3cncc(SC)c3)ncc2NC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Reactant: COc1ccc(O)cc1
Reactant: CSc1cncc(B(O)O)c1
Product: COc1cncc(-c2ncc(NC[C@@H]3CCCN3C(=O)OC(C)(C)C)c(Oc3cccc(O)c3)n2)c1

Procedure:
The title compound was prepared in a same manner to Compound 1g in Example 1. Using an adaptation of the method described in Procedure A-D, substituting 3-Hydroxy-phenol for 4-Methoxyphenol in Procedure A and substituting 5-Methoxy-pyridin-3-yl boronic acid for Compound 1f in Procedure D, the title Compound 10a was obtained. MS: m/z 494.2 (M+H)+.