Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5](Br)=[N:4][CH:3]=1.[O:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][N:20]2[CH:24]=[CH:23][N:22]=[C:21]2[NH2:25])[CH2:14][CH2:13]1>>[Br:1][C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:25][C:21]2[N:20]([CH2:19][CH2:18][N:15]3[CH2:14][CH2:13][O:12][CH2:17][CH2:16]3)[CH:24]=[CH:23][N:22]=2)=[N:4][CH:3]=1
Reactant: Brc1ncc(Br)n2ncnc12
Reactant: Nc1nccn1CCN1CCOCC1
Product: Brc1cnc(Nc2nccn2CCN2CCOCC2)c2ncnn12

Procedure:
Prepared using Intermediate 3 and Intermediate 10 in a manner analogous to the procedure of Example 1, Step 1. 1H NMR (400 MHz, CDCl3) 2.55 (brs, 4H), 2.71-2.80 (m, 2H), 3.68-3.83 (m, 4H), 4.15-4.26 (m, 2H), 6.92 (s, H), 7.05 (s, H), 7.71 (s, H), 8.31 (s, H), 8.58 (s, 1H).
Reaction SMILES: C([Mg]C[SiH](C)C)C1C=CC=CC=1.[Cl-].[CH2:14]([Si:21]([CH2:24]Cl)([CH3:23])[CH3:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Mg].[CH2:27]=[O:28].Cl>C(OCC)C.CCCCCC.C(OCC)C>[CH2:14]([Si:21]([CH3:23])([CH3:22])[CH2:24][CH2:27][OH:28])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C=O
Reactant: C[Si](C)(CCl)Cc1ccccc1
Agent: C[SiH](C)C[Mg]Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: CCOCC
Solvent: CCCCCC
Product: C[Si](C)(CCO)Cc1ccccc1
Yield: 57.2 %

Procedure:
To a solution of benzyldimethylsilylmethyl magnesium chloride, prepared from benzylchloromethyldimethyl silane (Fessenden, R. J., Coon, M. D., J. Med. Chem. Vol. 9 pp. 262-263 (1966)) (1.5 g, 7.55 mmol) and magnesium (0.19 g, 7.9 mmol) in diethyl ether (15 ml), is added paraformaldehyde (0.228 g, 7.6 mmol). Then the mixture is refluxed for 18 hours, cooled to 0° C. and hydrolyzed with 1N HCl (25 ml). The organic layer is washed with water brine and dried over MgSO4. The solution is filtered and solvent removed in vacuo. Chromatography (silica gel, hexane/diethyl ether 70/30) afforded β-(benzyldimethylsilyl)ethanol as an oil (0.84 g, 57% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[CH:6]2.[Cl:19][CH2:20][C:21]1[C:22]([NH:33][CH2:34][CH2:35][CH3:36])=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][C:27]([O:31][CH3:32])=[CH:26][CH:25]=2.Cl.[Cl:38]CC1C(NCCC)=NC2C(C=1)=CC(OC)=CC=2>C1COCC1.CCCCCC.C(Cl)Cl>[ClH:19].[ClH:38].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[C:6]2[CH2:20][C:21]1[C:22]([NH:33][CH2:34][CH2:35][CH3:36])=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][C:27]([O:31][CH3:32])=[CH:26][CH:25]=2
Reactant: CCCc1nc(O)cc2cc(OC)c(OC)cc12
Reactant: CCCNc1nc2ccc(OC)cc2cc1CCl
Agent: Cl
Solvent: ClCCl
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCNc1nc2ccc(OC)cc2cc1Cc1c(O)nc(CCC)c2cc(OC)c(OC)cc12
Temperature: 150 °C
Reaction time: 1.5 h
Yield: 5 %

Procedure:
To a stirred solution of 6,7-dimethoxy-1-propyl-isoquinolin-3-ol RBO 35134 (250 mg, 1.01 mmol) in THF (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 3-(chloromethyl)-6-methoxy-N-propylquinolin-2-amine free base SLA 28178 (269 mg, 1.01 mmol) followed by a dropwise addition of n-Buli (1.6 M in hexane, 0.65 mL, 1.04 mmol) and the mixture was stirred at 150° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (150 mL) and washed with brine (20 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent EtOAc:MeOH=100:0 to 92:8) followed by a second purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 95:5) provided, after evaporation, 70 mg of 6,7-dimethoxy-4-((6-methoxy-2-(propylamino)quinolin-3-yl)methyl)-1-propylisoquinolin-3-ol as a brown solid. This free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (0.40 mL). The reaction mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum to afford 6,7-dimethoxy-4-((6-methoxy-2-(propylamino)quinolin-3-yl)methyl)-1-propylisoquinolin-3-ol dihydrochloride 52 as a yellow solid (26.6 mg, 5% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH:13]([CH2:14][N:15]([C@@H:23]([C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27][CH:26]=3)[CH3:24])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:12][CH2:11][NH:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl[C:36](=[O:44])[CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40].C1COCC1.[Cl-].[NH4+]>C(N(CC)CC)C>[C:18]([O:17][C:16]([N:15]([CH2:14][CH:13]1[CH2:12][CH2:11][N:10]([C:36](=[O:44])[CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:9][CH:8]1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[C@@H:23]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)[CH3:24])=[O:22])([CH3:19])([CH3:21])[CH3:20]
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCNCC1c1cccc(F)c1)C(=O)OC(C)(C)C
Reactant: CCOC(=O)CCC(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CCC(=O)N1CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c2cccc3ccccc23)C(c2cccc(F)c2)C1
Reaction time: 72 h
Yield: 99.7 %

Procedure:
To a mixture of 139 mg of tert-butyl {[3-(3-fluorophenyl)piperidin-4-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate, 54 mg of ethyl 4-chloro-4-oxobutanoate, and 4.0 mL of THF was added 0.084 mL of triethylamine at room temperature, followed by stirring for 3 days. To the reaction mixture was added a saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate. Then, the organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 177 mg of ethyl 4-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-(3-fluorophenyl)piperidin-1-yl]-4-oxobutanoate as a colorless oily compound. ESI+: 591
Reaction SMILES: CI.[C:3]([O:6][CH2:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18](=[S:25])[NH:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])=[CH:10][CH:9]=1)(=[O:5])[CH3:4].[CH3:26]C(C)([O-])C.[K+]>C1COCC1.COC(C)(C)C>[C:3]([O:6][CH2:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](/[C:18](/[S:25][CH3:26])=[N:19]/[CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])=[CH:10][CH:9]=1)(=[O:5])[CH3:4]
Reactant: CC(=O)OCc1ccc(C(=S)NC[Si](C)(C)C)c2ccccc12
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CS/C(=N\C[Si](C)(C)C)c1ccc(COC(C)=O)c2ccccc12
Reaction time: 0.33 h
Yield: 88.1 %

Procedure:
To a mixed solution of methyl iodide (0.60 g) and (4{[(trimethylsilyl)methyl]carbamothioyl}naphthalen-1-yl)methyl acetate (1.2 g) in THF (30 ml) was added potassium t-butoxide (0.45 g) gradually, and the mixture was stirred for 20 minutes at the same temperature. The mixture was diluted with t-butyl methyl ether and washed with water and a saturated aqueous brine, subsequently dried over magnesium sulfate. After filtering the reaction mixture, the solvent was distilled off under reduced pressure, to obtain {4-[(Z)-(methylsulfanyl){[(trimethylsilyl)methyl]imino}methyl]naphthalen-1-yl}methyl acetate (1.1 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:26])[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:28][N:29]([CH:31](OC)OC)[CH3:30]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18](=[O:26])[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:28][N:29]([CH3:31])[CH3:30])=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)Cc3ccccc3)cc2)CCC1
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CN(C)C=C(C(=O)c1ccc(C2(NC(=O)OC(C)(C)C)CCC2)cc1)c1ccccc1

Procedure:
To a solution of compound 1-3 (5.0 g, 13.7 mmol) in toluene (30 mL) was added DMFDMA (18.15 g, 68.4 mmol) and the mixture was heated at reflux for 4 hours. The TLC showed the starting material was disappeared. The mixture was cooled and the formed white solid was collected. After washed by PE, the solid was dried in vacuum to get the product 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.C([Li])CCC.CN([CH:17]=[O:18])C>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:17]=[O:18]
Reactant: CN(C)C=O
Reactant: Fc1ccc(F)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cc(F)ccc1F
Reaction time: 0.08 h
Yield: 60.4 %

Procedure:
A solution of 1,4-difluorobenzene (10 g, 87.6 mmol, 1 wt) in THF (175 mL, 17.5 vol) was stirred under nitrogen and cooled to −75 to −78° C. n-Butyllithium (82 mL of 1.6 M solution in hexanes, 131.4 mmol, 1.5 eq) was added to the reaction mixture over approximately 20 minutes while maintaining the temperature at <−65° C. After a further hour, DMF (10.16 mL, 131.4 mmol, 1.5 eq) was added over approximately 10 minutes while maintaining the temperature <−65° C. The reaction mixture was quenched after 10 minutes by the addition of acetic acid (17.5 mL, 1.75 mL) directly followed by water (440 mL, 36.4 vol). This caused the reaction to exotherm to 5° C. The cold bath was then removed, TBME (220 mL, 22 vol) added and the reaction stirred for 5 minutes. The phases were separated and the aqueous phase extracted with TBME (2×220 mL, 22 vol). The organic phases were combined, washed with 0.2 M HCl (220 mL, 22 vol), 2 M Na2CO3 (220 mL, 22 vol) then saturated brine (220 mL, 22 vol), dried over magnesium sulphate (50 g, 5 wt) and concentrated on a rotary evaporator to afford the crude product (11.07 g). Purification by Kugelrohr distillation gave the product as a clear, colourless oil (7.52 g, 60%)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16].C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][CH2:27][CH2:28][CH3:29].Cl>C(#N)C>[CH2:26]([N:11]1[CH2:10][CH2:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([C:15]([F:16])([F:18])[F:17])[CH:4]=2)([OH:14])[CH2:13][CH2:12]1)[CH2:27][CH2:28][CH3:29]
Reactant: Cc1ccc(C2(O)CCNCC2)cc1C(F)(F)F
Reactant: CCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCN1CCC(O)(c2ccc(C)c(C(F)(F)F)c2)CC1

Procedure:
Preparation according to Example 2: 4-[4-methyl-3-(trifluoromethyl)phenyl]piperidin-4-ol (0.5 g, 1.93 mmol), acetonitrile (20 ml), potassium carbonate (0.53 g, 3.8 mmol), 1-bromobutane (0.20 ml, 2.1 mmol). Yield: 0.48 g, 79%. The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 197-198° C. MS m/z (relative intensity, 70 eV) 315 (M+, 7), 272 (bp), 254 (48), 181 (38), 169 (25).
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH3:9])[C:5]([Cl:10])=[C:4]([C:11]([O:13][CH3:14])=[O:12])[CH:3]=1.O1CCOC[CH2:16]1>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]>[Cl:10][C:5]1[N:6]([CH3:9])[C:7](=[O:8])[C:2]([CH3:16])=[CH:3][C:4]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1cc(Br)c(=O)n(C)c1Cl
Reactant: C1COCCO1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: COC(=O)c1cc(C)c(=O)n(C)c1Cl
Temperature: 70 °C
Reaction time: 0.83 h
Yield: 73 %

Procedure:
An oven dried two-necked flask was charged with methyl 5-bromo-2-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (5.79 g, 20.64 mmol), Pd(dppf)2Cl2 (0.82 g, 1.0 mmol) and dioxane (60 mL). The resulting red suspension was purged with argon for 10 min and ZnMe2 (2.0M, 10.3 mL, toluene) was added. The reaction mixture was stirred at 70° C. for 50 min, cooled at room temperature and quenched with MeOH (50 mL) and diluted with EtOAc (100 mL). The mixture was washed with a sat NH4Cl aq. solution, the organic layer was dried (Na2SO4) and concentrated under reduced pressure yielding to a brown residue. The residue was purified by flash chromatography (Biotage system) using a gradient of EtOAc (0-30%) in hexane to afford the title product (3.23 g, 73%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](\[CH3:15])/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[CH3:16][Si:17]([CH3:46])([CH3:45])[C:18]1[CH:19]=[C:20]([CH:38]=[C:39]([Si:41]([CH3:44])([CH3:43])[CH3:42])[CH:40]=1)[C:21](NC1C=CC(C=CC(OCC)=O)=C(F)C=1)=[O:22]>>[CH3:42][Si:41]([CH3:44])([CH3:43])[C:39]1[CH:38]=[C:20]([CH:19]=[C:18]([Si:17]([CH3:46])([CH3:45])[CH3:16])[CH:40]=1)[C:21]([NH:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[C:9](\[CH3:15])/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1)=[O:22]
Reactant: CCOC(=O)/C(C)=C/c1ccc(N)cc1
Reactant: CCOC(=O)C=Cc1ccc(NC(=O)c2cc([Si](C)(C)C)cc([Si](C)(C)C)c2)cc1F
Product: CCOC(=O)/C(C)=C/c1ccc(NC(=O)c2cc([Si](C)(C)C)cc([Si](C)(C)C)c2)cc1
Yield: 27 %

Procedure:
Using BTMB (1.95 g) and Compound 13a (1.8 g), Compound 13b (910 mg, 27%) was obtained as a yellow solid in the same manner as Compound 2b was synthesized.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.[Cl:37][C:38]1[C:39]([C:48]([F:51])([F:50])[F:49])=[N:40][N:41]([CH2:44][C:45](O)=[O:46])[C:42]=1[CH3:43]>>[Cl:37][C:38]1[C:39]([C:48]([F:50])([F:49])[F:51])=[N:40][N:41]([CH2:44][C:45]([N:34]2[CH2:33][CH2:32][N:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=3)[CH2:36][CH2:35]2)=[O:46])[C:42]=1[CH3:43]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: c1ccc(N2CCNCC2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCN(c2ccccn2)CC1

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(2-Pyridyl)piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (DMSO-d6, 400 MHz) 8.11 (d, 1H), 7.53 (t, 1H), 6.85 (d,1H), 6.65 (t, 1H), 5.37 (s, 2H), 3.59–3.50 (m, 8H), 2.18 (s, 3H) ppm; MS (ES) M+H expected=388.1, found=388.0.
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]([F:17])([F:16])[C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][N:10]=1.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>C(Cl)(Cl)Cl>[C:22]1([O:21][C:19](=[O:20])[NH:15][C:12]2[CH:11]=[N:10][C:9]([C:8]([F:7])([F:16])[F:17])=[CH:14][CH:13]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ccc(C(F)(F)F)nc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=C(Nc1ccc(C(F)(F)F)nc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Pyridine (2.9 mL) was added to a solution of 2-trifluoromethyl-5-aminopyridine (1.95 g) in chloroform (15 mL), the mixture was cooled in ice, and phenyl chloroformate (1.8 mL) was added thereto. The resulting mixture was stirred at room temperature overnight, and the reaction mixture was concentrated under reduced pressure. The residue was washed with isopropyl ether to afford phenyl[6-(trifluoromethyl)pyridin-3-yl]carbamate (2.16 g).
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6](Br)[CH3:7])(=[O:3])[CH3:2].C(OCCBr)(=O)C.[OH:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[N:25]=[CH:24][CH:23]=[CH:22]2>>[C:1]([O:4][CH2:5][CH2:6][CH2:7][O:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[N:25]=[CH:24][CH:23]=[CH:22]2)(=[O:3])[CH3:2]
Reactant: Oc1cccc2cccnc12
Reactant: CC(=O)OCC(C)Br
Agent: CC(=O)OCCBr
Product: CC(=O)OCCCOc1cccc2cccnc12

Procedure:
3-(Quinolin-8-yloxy)propyl acetate (44A) was prepared following a similar procedure as that described in example 39, except 2-bromopropyl acetate for 2-bromoethyl acetate and 8-hydroxyquinoline was used instead of 3-(dimethylamino)phenol in step 1 of example 39.
Reaction SMILES: [CH2:1]([C:6]1[CH:22]=[CH:21][C:9]([C:10]([C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([OH:16])=O)=[O:11])=[CH:8][CH:7]=1)[C:2]([CH3:5])([CH3:4])[CH3:3].S(=O)(=O)(O)O>O>[CH2:1]([C:6]1[CH:22]=[CH:21][C:9]2[C:10](=[O:11])[C:12]3[C:13](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:14](=[O:16])[C:8]=2[CH:7]=1)[C:2]([CH3:3])([CH3:4])[CH3:5]
Reactant: CC(C)(C)Cc1ccc(C(=O)c2ccccc2C(=O)O)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)(C)Cc1ccc2c(c1)C(=O)c1ccccc1C2=O
Temperature: 85 °C
Reaction time: 4 h
Yield: 90.2 %

Procedure:
90 g (0.3 mole) of this 2-(4-neopentylbenzoyl)-benzoic acid were introduced into 900 g of 100 percent strength sulfuric acid at 60° C. and then stirred for 4 hours at 85° C. The reaction mixture was then poured into a mixture of 1,500 g of water and 500 g of ice, and the stirred mixture was cooled. The precipitated crystals of neopentylanthraquinone were filtered off, washed neutral with dilute sodium hydroxide solution and water, dried, and distilled at 240° C./0.5 mbar. 75.3 g (89%) of 2-neopentylanthraquinone (mp. 93.8° C.) were obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.C(NCBr)(O[C:18](C)([CH3:20])[CH3:19])=O>>[C:8]([C:6]1[CH:5]=[C:4]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH:3]=[C:2]([C:18]([CH3:20])=[CH2:19])[CH:7]=1)#[N:9]
Reactant: CC(C)(C)OC(=O)NCBr
Reactant: CS(=O)(=O)Nc1cc(Br)cc(C#N)c1
Product: C=C(C)c1cc(C#N)cc(NS(C)(=O)=O)c1

Procedure:
N-(3-cyano-5-(prop-1-en-2-yl)phenyl)methanesulfonamide was synthesized from N-(3-bromo-5-cyanophenyl)methanesulfonamide following the general procedure as described for the Cbz protected Boc aminomethyl bromide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([F:15])([F:14])[CH:10]([CH2:16][N:17]=[N+]=[N-])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([F:14])([F:15])[CH:10]([CH2:16][NH2:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(F)(F)C(CN=[N+]=[N-])C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(F)(F)C(CN)C1
Reaction time: 2 h

Procedure:
A mixture of 3-azidomethyl-4,4-difluoro-piperidine-1-carboxylic acid tert-butyl ester (1.1 mmol, 300 mg) and 10% palladium on carbon (60 mg) in EtOAc (8 mL) was stirred under an atmosphere of H2 for 2 hrs, filtered through celite, and concentrated to provide 3-aminomethyl-4,4-difluoro-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:12]([NH:14][C@@H:15](C)[CH2:16][OH:17])=[O:13])[CH:5]=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32].[NH2:33][C@@H](C)CO>>[NH2:33][C:16]([CH2:15][NH:14][C:12](=[O:13])[C:11]1[CH:19]=[CH:20][C:21]([CH3:22])=[C:9]([N:6]2[C:7](=[O:8])[C:2]([Br:1])=[C:3]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[F:32])[N:4]=[CH:5]2)[CH:10]=1)=[O:17]
Reactant: C[C@H](N)CO
Reactant: Cc1ccc(C(=O)N[C@@H](C)CO)cc1-n1cnc(OCc2ccc(F)cc2F)c(Br)c1=O
Product: Cc1ccc(C(=O)NCC(N)=O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Br)c1=O

Procedure:
The title compound was prepared using a procedure similar to that used in Step 2 of the synthesis of 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-N-[(1S)-2-hydroxy-1-methylethyl]-4-methylbenzamide by substituting glycineamide HCl for (S)-(+)-2-amino-1-propanol. 1H NMR (CD3OD/400 MHz) δ8.32 (s, 1H), 7.95 (m, 1H), 7.80 (s, 1H), 7.61 (q, 1H, J=8.4 Hz), 7.53 (d, 1H, J=8.0 Hz), 7.01 (m, 2H), 5.58 (m, 2H), 4.01 (s, 2H), 2.20 (s, 3H). ESHRMS m/z 507.0474 (M+H calculated for C21H18BrF2N4O4 requires 507.0474).
Reaction SMILES: C(OC([N:8]([CH2:15][CH2:16][CH2:17][N:18]1[C:22]([C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[CH:25][CH:24]=2)=[CH:21][S:20][C:19]1=[N:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1)[CH2:9][C:10](OCC)=[O:11])=O)(C)(C)C.Cl.[CH2:44]([NH2:46])[CH3:45].C(N(C(C)C)CC)(C)C.N=C=N>ClCCl.CN(C)C=O>[CH2:44]([NH:46][C:10](=[O:11])[CH2:9][NH:8][CH2:15][CH2:16][CH2:17][N:18]1[C:22]([C:23]2[CH:24]=[CH:25][C:26]([N:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)=[CH:27][CH:28]=2)=[CH:21][S:20][C:19]1=[N:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1)[CH3:45]
Reactant: CCOC(=O)CN(CCCn1c(-c2ccc(N3CCOCC3)cc2)csc1=Nc1ccc(F)cc1)C(=O)OC(C)(C)C
Reactant: CCN
Agent: Cl
Agent: N=C=N
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)CNCCCn1c(-c2ccc(N3CCOCC3)cc2)csc1=Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was synthesized by combinatorial chemistry technique. That is, to a solution of the compound obtained in Example 329 (2) in dichloromethane (43.8 μmol/ml) (1 ml) were added a solution of ethylamine hydrochloride in N,N-dimethylformamide (35.0 μmol/ml) (1 ml), a solution of diisopropylethylamine (35.0 μmol/ml) (1 ml) and a suspension of carbodiimide resin in dichloromethane (79.2 mg/ml, manufactured by Argonaut) (1 ml), and the mixture was stirred at room temperature overnight. The reaction mixture was filtered, and the filter cake was washed twice with dichloromethane (1 ml), and the filtrate was washed with a saturated aqueous sodium hydrogen carbonate solution (2 ml), and then washed twice with water (2 ml). The organic layer was passed through a filter containing magnesium sulfate, and the filter was washed twice with dichloromethane (1 ml), and the filtrate was concentrated. To the residue was added a 90% trifluoroacetic acid (2 ml), and the mixture was stirred at room temperature for 2 hours, and concentrated. The residue was dissolved in dichloromethane (2 ml), and excess amount of ion-exchange resin (Dowex 1-X8, OH-type) was added thereto, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, and the filter cake was washed twice with dichloromethane (1 ml), and the filtrate was concentrated to give the title compound (6 mg).
Reaction SMILES: [CH2:1]([C@H:4]([C@H:11]([OH:18])[C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])[C:5]([O:7][CH:8]([CH3:10])[CH3:9])=[O:6])[CH:2]=[CH2:3].CCN(C(C)C)C(C)C.Br[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH3:37])=[CH:31][CH:30]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CC#N.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:36]([O:35][C:32]1[CH:33]=[CH:34][C:29](/[CH:3]=[CH:2]/[CH2:1][C@H:4]([C@H:11]([OH:18])[C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])[C:5]([O:7][CH:8]([CH3:10])[CH3:9])=[O:6])=[CH:30][CH:31]=1)[CH3:37]
Reactant: CCOc1ccc(Br)cc1
Reactant: C=CC[C@@H](C(=O)OC(C)C)[C@H](O)C(=O)OC(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOc1ccc(/C=C/C[C@@H](C(=O)OC(C)C)[C@H](O)C(=O)OC(C)C)cc1
Temperature: 25 °C
Yield: 97.9 %

Procedure:
To a solution of diisopropyl (2R,3S)-2-allyl-3-hydroxybutanedioate (3.0 g; 11.6 mmol; 1.0 eq.) and DIEA (3.86 mL; 28.9 mmol; 2.4 eq.) in CH3CN (30.0 mL) was added 4-bromophenetole (2.0 mL; 13.9 mmol; 1.2 eq.). To this solution was added a mixture of tri-o-tolylphosphine (0.35 g; 1.16 mmol; 0.1 eq.) and palladium(II) acetate (0.03 g; 0.12 mmol; 0.01 eq.) in CH3CN (3.0 mL) which was sonicated before the addition to the reaction mixture. The reaction was stirred under argon at reflux for 2.5 h, cooled to RT and the solvents were evaporated under reduce pressure. The resulting residue was then taken up in EtOAc and washed with an aqueous saturated solution of NaCl. Evaporation of the solvent gave an oil (4.3 g). Purification by chromatography (SiO2, gradient from 20/80 EtOAc/c-hex to 100/0 EtOAc/c-hex) gave the title product as a colorless oil (4.41 g, 100%). M+(ESI): 379.3. 1H NMR (CDCl3, 300 MHz) δ 7.14 (d, J=8.6 Hz, 2H), 6.70 (d, J=8.6 Hz, 2H), 6.46 (d, J=15.6 Hz, 1H), 6.00-5.86 (m, 1H), 5.05-4.83 (m, 2H), 4.13 (dd, J=7.0 Hz, J=3.0 Hz, 1H), 3.90 (q, J=7.0 Hz, 2H), 3.10 (d, J=7.2 Hz, 1H), 2.89-2.78 (m, 1H), 2.70-2.55 (m, 1H), 2.52-2.35 (m, 1H), 1.27 (t, J=7.0 Hz, 3H), 1.22-1.00 (m, 12H).