Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:13][C:12](=[O:14])[CH:11]=[CH:10][NH:9]2)=[CH:4][CH:3]=1.C([Li])CCC.[Br:20][C:21]1[CH:26]=[C:25]([CH3:27])[C:24]([O:28][CH3:29])=[CH:23][C:22]=1[CH2:30][C:31](Cl)=[O:32].[Cl-].[NH4+]>C1COCC1>[Br:20][C:21]1[CH:26]=[C:25]([CH3:27])[C:24]([O:28][CH3:29])=[CH:23][C:22]=1[CH2:30][C:31]([N:9]1[CH:10]=[CH:11][C:12](=[O:14])[CH2:13][C@H:8]1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:32]
Reactant: COc1cc(CC(=O)Cl)c(Br)cc1C
Reactant: O=C1C=CN[C@H](c2ccc(F)cc2)C1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc(CC(=O)N2C=CC(=O)C[C@H]2c2ccc(F)cc2)c(Br)cc1C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-2-(4-fluoro-phenyl)-2,3-dihydro-1H-pyridin-4-one (80 mg) in THF (1.5 mL) at −78° C. under argon was added n-butyllithium (0.184 mL, 2.5M in hexanes). After ten minutes a solution of (2-bromo-5-methoxy-4-methyl-phenyl)-acetic acid chloride (116 mg) in THF (1 mL) was added. The mixture was stirred at −78° C. for 30 minutes, then at room temperature for 30 minutes. Saturated aqueous ammonium chloride was added and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated to dryness under reduced pressure. Purification of the residue by flash chromatography (hexanes/ethyl acetate gradient) gave (S)-1-[2-(2-bromo-5-methoxy-4-methyl-phenyl)-acetyl]-2-(4-fluoro-phenyl)-2,3-dihydro-1H-pyridin-4-one as a foam. MS (M+H) 433.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:13]([CH3:14])[CH:12]=[CH:11][C:5]2=[N:6][C:7]=1[C@@H:8]([NH2:10])[CH3:9].[N:15]1([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.CC([O-])(C)C.[K+].C([O-])(O)=O.[Na+]>CCOC(C)=O.O1CCOCC1>[NH2:10][C@H:8]([C:7]1[N:6]=[C:5]2[CH:11]=[CH:12][N:13]([CH3:14])[C:4]2=[CH:3][C:2]=1[N:18]1[CH2:19][CH2:20][CH2:21][N:15]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:16][CH2:17]1)[CH3:9]
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1Br
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@H](N)c1nc2ccn(C)c2cc1N1CCCN(C(=O)OC(C)(C)C)CC1
Temperature: 90 °C
Yield: 33.8 %

Procedure:
To a 50 mL pear flask were added (S)-1-(6-bromo-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine (153 mg, 0.602 mmol) and tert-butyl 1,4-diazepane-1-carboxylate (241 mg, 1.20 mmol). After evacuating the flask and flushing it with nitrogen, the flask was charged with dioxane (1.6 mL) and potassium 2-methylpropan-2-olate (1.0 M in THF) (1.32 mL, 1.32 mmol). The mixture was then heated to 90° C. for 1 hour. After cooling, the mixture was worked up with saturated NaHCO3 and EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by preparative HPLC (acid mode, 25-50% ACN/water gradient). The product-containing fractions were combined, neutralized with saturated NaHCO3, concentrated in vacuo to remove ACN, and then extracted with EtOAc. The organic layers were combined, dried over MgSO4, filtered, and concentrated in vacuo to give the title compound (76 mg, 34%). ESI-MS m/z [M+H]+ calc'd for C20H31N5O2, 374. found 374.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=2[S:5][C:6]=1[CH:7]=O.[CH3:13][O:14][C:15](=[O:36])[CH:16]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[CH3:13][O:14][C:15](=[O:36])/[CH:16]=[CH:7]/[C:6]1[S:5][C:4]2[CH:9]=[CH:10][CH:11]=[CH:12][C:3]=2[C:2]=1[Cl:1]
Reactant: O=Cc1sc2ccccc2c1Cl
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)/C=C/c1sc2ccccc2c1Cl
Reaction time: 4 h

Procedure:
A solution of 3.52 g (18.3 mmol) of 13 in 50 mL toluene was treated with methyl(triphenylphosphoranylidene)acetate (7.48 g, 21.9 mmol). After 4 h, saturated NaHCO3 solution (50 mL) was added and the mixture extracted with ethyl acetate (2×75 mL). The combined ethyl acetate solution was washed with brine (50 mL), dried (Na2SO4), filtered and evaporated. Purification by flash chromatography on silica gel (5% ethyl acetate/hexane) provided 3.60 g (14.6 mmol, 80%) of the enoate (14).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[S:11][C:10]([N:12]=CN(C)C)=[N:9][C:8]=1[CH3:17])=O.[N+]([O-])(O)=O.[CH3:23][S:24]([C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([NH2:36])=[NH:35])=[CH:29][CH:28]=1)(=[O:26])=[O:25]>CC#N>[NH2:12][C:10]1[S:11][C:7]([C:5]2[CH:4]=[CH:3][N:36]=[C:34]([NH:33][C:30]3[CH:29]=[CH:28][C:27]([S:24]([CH3:23])(=[O:25])=[O:26])=[CH:32][CH:31]=3)[N:35]=2)=[C:8]([CH3:17])[N:9]=1
Reactant: CS(=O)(=O)c1ccc(NC(=N)N)cc1
Reactant: Cc1nc(N=CN(C)C)sc1C(=O)C=CN(C)C
Solvent: O=[N+]([O-])O
Solvent: CC#N
Product: Cc1nc(N)sc1-c1ccnc(Nc2ccc(S(C)(=O)=O)cc2)n1

Procedure:
By condensation of N′-[5-(3-dimethylamino-acryloyl)-4-methyl-thiazol-2-yl]-N,N-dimethyl-formamidine and N-(4-methanesulfonyl-phenyl)-guanidine nitrate. Yellow solid. Anal. RP-HPLC: tR=13.2 min (0-60% MeCN, purity >97%). 1H-NMR (DMSO-d6) δ: 1.98 (s, 3H, CH3), 2.54 (s, 3H, CH3), 7.06 (d, 1H, J=5.5 Hz, pyrimidinyl-H), 7.80 (m, 2H, Ph-H), 8.00 (m, 2H, Ph-H), 8.45 (d, 1H, J=5.5 Hz, pyrimidinyl-H), 10.05 (sbr, 2H, NH2). MS (ESI+) m/z 362.38 [M+H]+ (C15H15N5O2S2 requires 361.44).
Reaction SMILES: [SH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][Cl:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:14][CH2:13][CH2:12][S:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1
Reactant: ClCCBr
Reactant: O=C(O)c1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(O)c1ccc(SCCCl)cc1
Temperature: 40 °C
Reaction time: 7 h
Yield: 55.4 %

Procedure:
4-Mercaptobenzoic acid (65 mmol) and 1-Bromo-2-chloro-ethane (71 mmol) are dissolved in acetone (120 ml) and powdered potassium carbonate (71 mmol) is added. The mixture is warmed up to 40° C. and stirred for 7 hours. After evaporation of the solvent, the residue is extracted with ethyl acetate. The extract is washed with water and dried over sodium sulfate and evaporated. The crude product is suspended in diethylether and the solid filtered of and dried (vacuum). 7.8 g of a white powder with mp. 142-144° C., Rf=0.37 (methylenchlorid/methanol=9/1) is obtained.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)(O)[O-].[Na+].[F:29][C:30]1[CH:31]=[CH:32][C:33]([O:39][CH3:40])=[C:34](B(O)O)[CH:35]=1>CN(C)C=O.O.C(OCC)(=O)C.CC(P(C(C)(C)C)C1[CH-]C=CC=1)(C)C.CC(P(C(C)(C)C)C1[CH-]C=CC=1)(C)C.[Cl-].[Cl-].[Fe+2].[Pd+2]>[F:29][C:30]1[CH:35]=[CH:34][C:33]([O:39][CH3:40])=[C:32]([C:2]2[C:3]3[CH:10]=[C:9]([CH:11]4[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]4)[NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3c(Cl)ncnc3[nH]2)CC1
Reactant: COc1ccc(F)cc1B(O)O
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(C)(C)P(c1ccc[cH-]1)C(C)(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(F)cc1-c1ncnc2[nH]c(C3CCN(C(=O)OC(C)(C)C)CC3)cc12
Temperature: 100 °C

Procedure:
To a solution of Example 1C (200 mg, 0.6 mmol) in N,N-dimethylformamide (8 mL), was added a solution of sodium bicarbonate (0.118 g, 1.404 mmol) in 0.5 mL water followed by 5-fluoro-2-methoxyphenylboronic acid (204 mg, 1.2 mmol). The mixture was degassed with nitrogen and [1,1′-bis(di tert butyl phosphino)ferrocene]palladium(II) dichloride (21 mg, 0.033 mmol) was added. The mixture was heated under microwave conditions (Biotage Initiator) at 100° C. for 1 hour. The mixture was diluted with ethyl acetate and filtered through diatomaceous earth. The organic layer was washed with water and brine, dried over sodium sulfate, filtered, concentrated and purified by column chromatography (silica gel, 40% ethyl acetate-hexane) to afford the title compound. LCMS: 427.21 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH:17]([OH:28])[C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)([CH2:14][CH2:15][CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1(C)C=CC=CC=1.[O-2].[Mn+4].[O-2]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH2:14][CH2:15][CH3:16])([C:17]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)=[O:28])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC1(C(O)c2ccc3ccccc3n2)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CCCC1(C(=O)c2ccc3ccccc3n2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 100 °C
Yield: 64.8 %

Procedure:
To a solution of 4-(hydroxy-quinolin-2-yl-methyl)-4-propyl-piperidine-1-carboxylic acid tert-butyl ester (190 mg, 0.5 mmol) in toluene (5 mL) was added manganese (IV) oxide (activated, 260 mg, 3.0 mmol). The reaction mixture was heated at 100° C. for 3 hours, then cooled to room temperature and filtered through Celite, rinsing with EtOAc. The filtrate was concentrated and purified by flash chromatography (0% to 20% EtOAc in hexanes) to provide 124 mg (67%) of 4-propyl-4-(quinoline-2-carbonyl)-piperidine-1-carboxylic acid tert-butyl ester as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1.[CH2:23]([N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][C:27]1=[O:36])[C:24]#[CH:25].C(O)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:25]#[C:24][CH2:23][N:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=[CH:28][C:27]3=[O:36])[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1
Reactant: Cc1nnc2n1-c1sc(I)cc1C(c1ccccc1Cl)=NC2
Reactant: C#CCn1c(=O)ccc2ccccc21
Solvent: ClCCl
Solvent: CCO
Product: Cc1nnc2n1-c1sc(C#CCn3c(=O)ccc4ccccc43)cc1C(c1ccccc1Cl)=NC2

Procedure:
The title compound was prepared by reacting 4-(2-chlorophenyl)-2-iodo-9-methyl-6H thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine with 1-(2-propynyl)-2(1H)quinolinone [ref. A. Lindquist et al., Acta Pharm. Suecica, 9,99 (1972)]as described in EXAMPLE 37. It was isolated by chromatography over 50 g of silica gel using 5% (v/v) of ethanol in methylene chloride and was further purified by rechromatography over 50 g of silica gel using tetrahydrofuran. Crystallization from ethyl acetate/methanol gave off-white crystals of 1-{3-[4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl] 2-propynyl}-2(1H)-quinolinone with m.p. 162-165°. These crystals contained according to analytical data 0.5 molar amounts of water.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13](OS(C(F)(F)F)(=O)=O)=[CH:12][C:11]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10][C:9]=2[O:27][CH:28]([CH3:30])[CH3:29])=[CH:4][CH:3]=1.[CH:31]1(B(O)O)[CH2:33][CH2:32]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH:31]1([C:13]2[CH:12]=[C:11]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:10]=[C:9]([O:27][CH:28]([CH3:29])[CH3:30])[C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:33][CH2:32]1
Reactant: CCOC(=O)c1cc(OC(C)C)c(-c2ccc(F)cc2)c(OS(=O)(=O)C(F)(F)F)c1
Reactant: OB(O)C1CC1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(OC(C)C)c(-c2ccc(F)cc2)c(C2CC2)c1
Yield: 96.1 %

Procedure:
A mixture of ethyl 4′-fluoro-2-isopropoxy-6-(((trifluoromethyl)sulfonyl)oxy)biphenyl-4-carboxylate (1.67 g), cyclopropylboronic acid (0.955 g), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (228 mg), a 2 M aqueous sodium carbonate solution (5.56 mL), tris(dibenzylideneacetone)dipalladium(0) (238 mg), and toluene (15 mL) was stirred at 100° C. for 2 hours in an argon atmosphere. The reaction mixture was filtered, and then, the filtrate was poured to water, followed by extraction with ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (1.22 g).
Reaction SMILES: [CH:1]1([C:5]2[C:13]([C:14]3[NH:18][C:17]([O:19][CH3:20])=[N:16][N:15]=3)=[CH:12][C:8]([C:9]([OH:11])=O)=[C:7]([CH3:21])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.Cl.[F:23][C:24]1([C:28]2[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=2)[CH2:27][NH:26][CH2:25]1.CC1NC(C2C=C(C=CC=2C)C(O)=O)=C(C)N=1.Cl.N1CC(C2C=CC(C#N)=CC=2)C1>>[CH:1]1([C:5]2[C:13]([C:14]3[NH:18][C:17]([O:19][CH3:20])=[N:16][N:15]=3)=[CH:12][C:8]([C:9]([N:26]3[CH2:25][C:24]([C:28]4[CH:29]=[CH:30][C:31]([C:32]#[N:33])=[CH:34][CH:35]=4)([F:23])[CH2:27]3)=[O:11])=[C:7]([CH3:21])[CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: N#Cc1ccc(C2(F)CNC2)cc1
Reactant: COc1nnc(-c2cc(C(=O)O)c(C)cc2C2CCC2)[nH]1
Agent: Cc1nc(C)c(-c2cc(C(=O)O)ccc2C)[nH]1
Agent: Cl
Agent: N#Cc1ccc(C2CNC2)cc1
Product: COc1nnc(-c2cc(C(=O)N3CC(F)(c4ccc(C#N)cc4)C3)c(C)cc2C2CCC2)[nH]1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 5, except 4-cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoic acid (compound 89.9) and 4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride (compound 43.4) were used in place of 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7) and 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2), respectively. m/z (ES+) 446 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 13.64-13.05 (br, 1H), 7.96 (d, J=8.0 Hz, 2H), 7.76 (d, J=8.0 Hz, 2H), 7.56 (s, 1H), 7.41 (s, 1H), 4.61-4.38 (m, 4H), 4.19 (m, 1H), 3.92 (s, 3H), 2.42 (s, 3H), 2.16 (m, 1H), 2.02 (m, 1H), 1.89 (m, 1H), 1.75 (m, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][S:8][C:7]2[CH:11]=[C:12]([N+:15]([O-])=O)[CH:13]=[CH:14][C:6]1=2.O.NN>CO.[Ni]>[CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][S:8][C:7]2[CH:11]=[C:12]([NH2:15])[CH:13]=[CH:14][C:6]1=2
Reactant: CN(C)CCN1CCSc2cc([N+](=O)[O-])ccc21
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: CN(C)CCN1CCSc2cc(N)ccc21
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
A dark mixture of N,N-dimethyl-2-(7-nitro-2H-benzo[b][1,4]thiazin-4(3H)-yl)ethanamine (1.0 g, 3.74 mmol) in methanol (10 mL) under an argon atmosphere was treated with Raney Nickel (˜0.22 g, 3.74 mmol) and hydrazine hydrate (1.82 mL, 37.4 mmol). The reaction was transferred to a pre-heated oil bath at 65° C. After 50 minutes, the mixture was allowed to cool to room temperature and then poured over a pad of Celite. The Celite pad was rinsed with methanol (20 mL). The filtrate was concentrated, and the crude material was subjected to a short column on silica gel (1:9 (2M NH3 in MeOH):CH2Cl2). The resulting brown residue was carried on to the next step. 1H-NMR (DMSO-d6) δ 6.49 (d, J=9.0 Hz, 1H), 6.27-6.23 (m, 2H), 4.42 (brs, 2H), 3.40-3.30 (m, 2H), 3.18 (t, J=7.2 Hz, 2H), 2.98-2.94 (m, 2H), 2.36 (t, J=7.2 Hz, 2H), 2.16 (s, 6H); ESI-MS (m/z, %): 238 (MH+, 100), 193 (56), 147 (58).
Reaction SMILES: [Br-].[CH2:2]([O:4][C:5](=[O:10])[CH2:6][CH2:7][CH2:8][Zn+])[CH3:3].Cl[C:12]1[N:17]=[C:16]([Cl:18])[CH:15]=[C:14]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:13]=1>C1COCC1.[CH2-]C1C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd+]>[Cl:18][C:16]1[CH:15]=[C:14]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:13]=[C:12]([CH2:8][CH2:7][CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:10])[N:17]=1
Reactant: CCOC(=O)CCC[Zn+]
Reactant: Clc1cc(N2CCOCC2)nc(Cl)n1
Agent: Cl[Pd+]
Agent: [Br-]
Agent: [CH2-]c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)CCCc1nc(Cl)cc(N2CCOCC2)n1
Temperature: 60 °C
Reaction time: 48 h
Yield: 33 %

Procedure:
A mixture of 4-ethoxy-4-oxo-butylzinc bromide (50 mL 0.5M in THF, 25 mmol), 2,4-dichloro-6-morpholinopyrimidine (4.68 g, 20.0 mmol) and trans-benzyl(chloro)bis(triphenylphosphine)palladium(II) (0.15 g, 0.2 mmol) in THF (total volume 80 mL) was stirred at 60° C. for 2 days. After routine workup, flash chromatography purification was performed to obtain 4-chloro-2-(4-ethoxy-4-oxo-butyl)-6-morpholinopyrimidine as a white solid (2.073 g, 6.60 mmol, 33.0%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:32])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=4[CH3:23])[CH2:14][C:13](=[O:24])[NH:12][CH:11]3[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=3)[C:5]2=[CH:4][CH:3]=1.[CH3:33][O:34][CH:35]([Si:37]([CH3:40])([CH3:39])[CH3:38])[CH3:36].[H-].[Li+].[C:43]([O:47][C:48](=[O:53])[NH:49][CH2:50][CH2:51]Br)([CH3:46])([CH3:45])[CH3:44]>CN(C)C=O>[C:43]([O:47][C:48]([NH:49][CH2:50][CH2:51][N:12]1[C:13](=[O:24])[CH2:14][CH:15]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[CH3:23])[C:10]2([C:5]3[C:6](=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[NH:8][C:9]2=[O:32])[CH:11]1[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=1)=[O:53])([CH3:46])([CH3:45])[CH3:44].[CH3:33][O:34][CH:35]([Si:37]([CH3:40])([CH3:39])[CH3:38])[CH3:36]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: Cc1ccc(F)cc1C1CC(=O)NC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: COC(C)[Si](C)(C)C
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: Cc1ccc(F)cc1C1CC(=O)N(CCNC(=O)OC(C)(C)C)C(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 14.3 %

Procedure:
In a manner similar to the method described in example 152a, racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (0.45 g, 0.75 mmol) was reacted with LiH (0.15 g, 18.8 mmol) and (2-bromo-ethyl)-carbamic acid tert-butyl ester (1.0 g, 4.52 mmol) in N,N-dimethyl-formamide (3 mL), a catalytic amount of KI to give racemic (2′S,3S,4′R)-1′-[(tert-butoxycarbonylamino)ethyl]-6-chloro-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane as a yellow solid (80 mg).
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]2[CH2:11][CH:10]([CH2:12][OH:13])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(=O)(O)(O)O.C1(N=C=NC2CCCCC2)CCCCC1>CS(C)=O>[C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]2[CH2:11][CH:10]([CH:12]=[O:13])[CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=P(O)(O)O
Solvent: CS(C)=O
Product: O=CC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.9 %

Procedure:
To a solution of 2.27 g (8.96 mmoles) of 1-diphenylmethyl-3-hydroxymethylazetidine in 30 ml of dimethylsulfoxide are added 586 mg (0.67 equivalent) of phosphoric acid and 4.25 g (2.3 equivalents) of dicyclohexylcarbodiimide, and the mixture is stirred at room temperature overnight. The insoluble materials are filtered off, and the filtrate is alkalified with an aqueous sodium carbonate solution and extracted with ethyl acetate. The extract is reextracted three times with 14.9% aqueous sodium hydrogensulfite solution. The extract is alkalified with 10% aqueous sodium hydroxide solution and extracted with methylene chloride. The extract is dried and evaporated to yield 1.281 g of crude light yellow syrupy 1-diphenylmethyl-3-formylazetidine in 56.9% yield.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[CH:4][C:5]([NH:8][NH:9][C:10](=O)[CH2:11][C:12]2[C:13]([CH3:22])=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)=[N:6][CH:7]=1.BrC1C(C2C=CC(Cl)=CC=2)=CC2N(C(CC3C=NC(C(F)(F)F)=CC=3)=NN=2)C=1>C(O)(=O)C.FC(C1C=CC=CC=1)(F)F>[Br:1][C:2]1[C:3]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[CH:4][C:5]2[N:6]([C:10]([CH2:11][C:12]3[C:13]([CH3:22])=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=3)=[N:9][N:8]=2)[CH:7]=1
Reactant: Cc1nc(C(F)(F)F)ccc1CC(=O)NNc1cc(-c2ccc(Cl)cc2)c(Br)cn1
Agent: FC(F)(F)c1ccc(Cc2nnc3cc(-c4ccc(Cl)cc4)c(Br)cn23)cn1
Solvent: FC(F)(F)c1ccccc1
Solvent: CC(=O)O
Product: Cc1nc(C(F)(F)F)ccc1Cc1nnc2cc(-c3ccc(Cl)cc3)c(Br)cn12
Yield: 63.3 %

Procedure:
The title compound (61 mg, 60%) as a white powder was prepared from N′-(5-bromo-4-(4-chlorophenyl)pyridin-2-yl)-2-(2-methyl-6-(trifluoromethyl)pyridin-3-yl)acetohydrazide (100 mg, 0.20 mmol) in glacial acetic acid (0.6 mL) and (trifluoromethyl)benzene (1.8 mL) by the procedures analogous to those described for 6-bromo-7-(4-chlorophenyl)-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine (Example 56D). LC/MS (method B): retention time=1.83 min, [M+H]+=481.0.
Reaction SMILES: Cl[CH2:2][C:3]1[O:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.[C:10]([O-:13])(=[O:12])[CH3:11].C([N+]1C=CN(C)C=1)C>CC#N>[C:10]([O:13][CH2:2][C:3]1[O:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)[O-]
Reactant: O=Cc1ccc(CCl)o1
Agent: CC[n+]1ccn(C)c1
Solvent: CC#N
Product: CC(=O)OCc1ccc(C=O)o1

Procedure:
In a round flask, 2 mL of methyl cyanide (acetonitrile) as an organic solvent was introduced, 0.145 g (1 mmol) of 5-chloromethylfurfural (CMF, compound I) was dissolved in the organic solvent, 0.170 g (1 mmol) of 1-ethyl-3-methylimidazolium acetate was added to the solution, and then the mixed solution was reacted at normal pressure and room temperature for 5 minutes. After the reaction, the reaction product was extracted by the addition of a small amount of water (5 mL) and ethyl acetate (added twice by 20 mL) to obtain an organic layer. The obtained organic layer was concentrated under reduced pressure to obtain light yellow liquid 5-acetoxymethylfurfural (AcHMF, compound II). The yield thereof is 36%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[OH-].[K+].[I-].[Na+].[CH3:17][N:18]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[C:19](=[O:24])[CH2:20][CH2:21][CH2:22]Cl.[Na+].[Cl-]>CS(C)=O>[CH3:17][N:18]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[C:19]([CH2:20][CH2:21][CH2:22][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2)=[O:24]
Reactant: O=C1CCc2cc(O)ccc2N1
Reactant: CN(C(=O)CCCCl)C1CCCCC1
Agent: [Cl-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Product: CN(C(=O)CCCOc1ccc2c(c1)CCC(=O)N2)C1CCCCC1
Reaction time: 4.5 h

Procedure:
3.2 Grams of 6-hydroxy-3,4-dihydrocarbostyril, 0.9 g of potassium hydroxide, 3.2 g of sodium iodide and 5.0 g of N-methyl-N-(4-chlorobutyryl)cyclohexylamine are added to 50 ml of dimethylsulfoxide, and the mixture is agitated at 70° to 80° C. for 4.5 hours. After the reaction, the reaction solution is poured into 400 ml of saturated NaCl solution and the precipitated crystals are filtered out and washed with water. The thus obtained crude crystals are then recrystallized from benzene-petroluem ether to obtain 2.9 g of 6-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]-3,4-dihydrocarbostyril in the form of colorless needlelike crystals with melting point of 144°-146° C.