Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]2=[N:13][CH:14]=[C:15]([C:18]#[N:19])[C:16](=[O:17])[N:5]2[CH2:4]1)[CH3:2]>[Pd].CC1C=CC(C(C)C)=CC=1.C(Cl)Cl>[CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]2=[N:13][CH:14]=[C:15]([C:18]#[N:19])[C:16](=[O:17])[N:5]2[CH:4]=1)[CH3:2]
Reactant: CCC1Cn2c(ncc(C#N)c2=O)-c2ccccc21
Agent: [Pd]
Solvent: ClCCl
Solvent: Cc1ccc(C(C)C)cc1
Product: CCc1cn2c(=O)c(C#N)cnc2c2ccccc12
Yield: 46 %

Procedure:
A stirred mixture of (±)-7-ethyl-6,7-dihydro-4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carbonitrile (3.5 g.) and 10% palladium on carbon (1.5 g.) in p-cymene (50 ml.) was refluxed for 18 hours. The mixture was diluted with methylene chloride and filtered to remove the catalyst. The solvents were removed on a rotary evaporator and the residue crystallized from ethanol to give 1.6 g. (46% yield) of the title compound, m.p. 208°-211°. Successive recrystallizations from toluene and ethanol provided the analytical sample, m.p. 218°-219°.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][CH:7]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:13][CH:12]=1)[CH2:8][CH2:9][CH3:10])=[O:5])#[N:2].N1(CCOC2C=CC(C(N)CCC)=CC=2)CCCC1>>[C:1]([CH2:3][C:4]([NH:6][CH:7]([C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][N:20]2[CH2:23][CH2:24][CH2:22][CH2:21]2)=[CH:15][CH:16]=1)[CH2:8][CH2:9][CH3:10])=[O:5])#[N:2]
Reactant: CCCC(NC(=O)CC#N)c1ccc(OCCN(CC)CC)cc1
Agent: CCCC(N)c1ccc(OCCN2CCCC2)cc1
Product: CCCC(NC(=O)CC#N)c1ccc(OCCN2CCCC2)cc1
Yield: 60 %

Procedure:
The title compound was prepared by using a similar procedure as described for the preparation of 29 except that 1-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)butan-1-amine (27) was used instead of 1-(4-(2-(diethylamino)ethoxy)phenyl)butan-1-amine (25). This produced crude product which was purified by flash silica gel column chromatography, eluting with 5:95 methanol/dichloromethane, to give 31 (140 mg, 60%) as a thick yellow oil: MS (ES+) m/z 330.2 (M+H)+.
Reaction SMILES: CON(C)[C:4]([C@H:6]1[CH2:18][CH2:17][N:9]2[C:10]3[C:15]([CH:16]=[C:8]2[CH2:7]1)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:5].[CH:20]([Mg]Cl)([CH3:22])[CH3:21].[Cl-].[NH4+]>O1CCCC1>[CH:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[CH:16]=[C:8]1[CH2:7][C@@H:6]([C:4]([CH:20]([CH3:22])[CH3:21])=[O:5])[CH2:18][CH2:17][N:9]12
Reactant: CON(C)C(=O)[C@H]1CCn2c(cc3ccccc32)C1
Reactant: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)C(=O)[C@H]1CCn2c(cc3ccccc32)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A stirred solution of 10.0 g (38.7 mmol) of 6,7,8,9-tetrahydro-N-methoxy-N-methyl-pyrido[1,2-a]indole-8(S)-carboxamide in 250 ml of tetrahydrofuran was treated dropwise at 0° C. with 60 ml (120 mmol) of a 2M solution of isopropylmagnesium chloride in tetrahydrofuran. The mixture was stirred at room temperature for 18 hours and poured into 250 ml of saturated ammonium chloride solution. The aqueous phase was washed four times with 100 ml of diethyl ether each time and the combined ethereal extracts were washed with 200 ml of brine, dried over magnesium sulfate and evaporated to dryness. The product was purified by flash chromatography on silica gel using ethyl acetate/petroleum ether (1:3) for the elution to give 4.4 g of isopropyl 6,7,8,9-tetrahydropyrido[1,2-a]indol-8(S)-yl ketone as a white solid of melting point 78°-79° C.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1)=O)(C)(C)C.Br[C:20]1[N:21]([CH3:25])[CH:22]=[CH:23][N:24]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>CCOC(C)=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:25][N:21]1[CH:22]=[CH:23][N:24]=[C:20]1[C:13]1[CH:14]=[CH:15][C:10]([CH2:9][NH2:8])=[CH:11][CH:12]=1
Reactant: Cn1ccnc1Br
Reactant: CC(C)(C)OC(=O)NCc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cn1ccnc1-c1ccc(CN)cc1
Temperature: 90 °C
Yield: 128.2 %

Procedure:
[4-(1-Methyl-1H-imidazol-2-yl-benzyl]-carbamic acid tert-butyl ester: Add 4-(N-tert-Butoxycarbonyl-aminomethyl)phenylboronic acid (1.9 g, 7.4 mmol), 2-bromo-1-methyl-1H-imidazole (800 mg, 5.0 mmol), tetrakis(triphenylphosphine)-palladium(0) (287 mg, 0.25 mmol) and potassium carbonate (860 mg, 6.2 mmol) to a flask containing toluene (10 mL). Heat the mixture in a sealed flask at 90° C. for 16 h. Cool the mixture, dilute with EtOAc (50 mL), filter through Celite®, and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc/methanol (49:50:1) to obtain the desired intermediate (1.2 g, 83%). GC-MS m/z: 287 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([C:9]#[N:10])[C:3]=1[N+:11]([O-:13])=[O:12].[F:14][C:15]([F:26])([F:25])[C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[NH2:1][C:2]1[CH:7]=[C:6]([C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([C:15]([F:26])([F:25])[F:14])[CH:21]=2)[N:5]=[C:4]([C:9]#[N:10])[C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: N#Cc1nc(Cl)cc(N)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1nc(-c2cccc(C(F)(F)F)c2)cc(N)c1[N+](=O)[O-]
Temperature: 150 °C
Yield: 19.3 %

Procedure:
A stirring suspension of 4-amino-6-chloro-3-nitro-pyridine-2-carbonitrile (1.0 g, 5.04 mmol), 3-(trifluoromethyl)phenyl boronic acid (1148 mg, 6.04 mmol) and potassium carbonate (2.08 g, 15.1 mmol) in THF (16 ml) was degassed with nitrogen before the addition of palladium tetrakistriphenylphosphine (582 mg, 0.50 mmol). The resulting suspension was heated to 150° C. for 5 minutes using the ‘Creator’ microwave. The reaction mixture was filtered through celite and concentrated in vacuo. The residual brown oil was columned on silica gel using dichloromethane as eluant to give the title compound as a yellow solid (300 mg).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[Cl:18])[N:14]=[C:13]([N:19]1[CH:23]=[C:22]([C:24]([O:26]CC)=[O:25])[CH:21]=[N:20]1)[NH:12][C:11]2=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][NH:31][CH2:32][CH3:33]>>[CH2:1]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[Cl:18])[N:14]=[C:13]([N:19]1[CH:23]=[C:22]([C:24]([OH:26])=[O:25])[CH:21]=[N:20]1)[N:12]=[C:11]2[N:31]([CH2:32][CH3:33])[CH3:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(Cl)c(Cc4ccccc4)cc3c(=O)[nH]2)c1
Reactant: CCNC
Product: CCN(C)c1nc(-n2cc(C(=O)O)cn2)nc2cc(Cl)c(Cc3ccccc3)cc12

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and N-methylethanamine in step E. MS (ESI): predicted mass calcd. for C22H20ClN5O2, 421.9
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][NH:10][CH:9]=2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl.CN([CH:21]=[O:22])C>C(Cl)Cl>[CH:21]([C:9]1[NH:10][CH:11]=[CH:12][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([I:1])=[CH:7][CH:6]=1)=[O:22]
Reactant: CN(C)C=O
Reactant: Ic1ccc(-c2cc[nH]c2)cc1
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1[nH]ccc1-c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4 (5.15 g, 19.1 mmol) in DMF (6.1 mL) and CH2Cl2 (140 mL) under argon was cooled to 0° C. and then POCl3 (2.11 mL, 22.6 mmol) was added dropwise. After 1 h, the flask was warmed to room temperature and stirred overnight. The reaction was quenched at 0° C. with 2.5 M NaOH (100 mL). The mixture was poured into water (500 mL), extracted with CH2Cl2, and the combined organic layers were washed with water, brine, dried (Na2SO4), and the solvent was removed in vacuo. 1H NMR spectroscopy showed two regioisomers in a 6:1 ratio. The minor isomer exhibited signals at δ 7.21 and 7.39 ppm, compared with signals at δ 6.42 and 7.14 for the major isomer. The most downfield signal (7.39 ppm) is assigned to the proton adjacent to a formyl group, which occurs in the 2-formyl-4-aryl substituted pyrrole. Recrystallization from ethyl acetate afforded an orange solid corresponding to the major aidehyde (2.25 g). The mother liquor was concentrated and purified by flash column chromatography [silica, hexanes/ethyl acetate (3:1)]. The first fraction corresponded to the major aldehyde (1.25 g). The total yield of the title compound was 3.50 g (62%): mp 153-154° C.; 1H NMR δ 6.42 (m, 1H), 7.14 (m, 1H), 7.22 (m, 2H), 7.76 (m 2H), 9.59 (s, 1H), 10.72 (br, 1H); 13C NMR δ 93.5, 104.3, 111.4, 125.8, 128.6, 130.8, 133.1, 137.8, 179.4; FAB-MS obsd 296.9663, calcd 296.9651; Anal. Calcd for C10H8INO: C, 44.5; H, 2.7; N, 4.7. Found: C, 44.4; H, 2.7; N, 4.6.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C@@H:4]([C:5]#[CH:6])[C@H:3]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].C=O.[CH:17](NC(C)C)(C)C.Cl>O.[Cu](Br)Br.O1CCOCC1>[CH3:1][C:2]1([CH3:14])[C@@H:4]([CH:5]=[C:6]=[CH2:17])[C@H:3]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: C#C[C@H]1[C@@H](C(=O)OC(C)(C)C)C1(C)C
Reactant: CC(C)NC(C)C
Agent: Br[Cu]Br
Agent: C=O
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: C=C=C[C@H]1[C@@H](C(=O)OC(C)(C)C)C1(C)C
Temperature: 80 °C

Procedure:
A mixture of 131 g of tert.-butyl (1R,cis) 2,2-dimethyl-3-ethynyl-cyclopropane-carboxylate, 32 g of paraformaldehyde, 111 ml of diisopropylamine, 31 g of copper bromide and 1,300 ml of dioxane was heated at 80° C. for 161/2 hours and was cooled to 20° C. and diluted with water. The mixture was adjusted to a pH of 1 with aqueous N hydrochloric acid and was extracted with methylene chloride. The organic phase was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with a 1-1 hexane-methylene chloride mixture yielded 44 g of tert.-butyl (1R,cis) 2,2-dimethyl-3-(1,2-propadienyl)-cyclopropane-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:13]=[CH:14][CH:15]=2)[N:5]=[CH:6][C:7]=1[C:8]([O:10]CC)=[O:9].O>C1COCC1>[Cl:1][C:2]1[C:3]2[N:4]([CH:13]=[CH:14][CH:15]=2)[N:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)c1cnn2cccc2c1Cl
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cnn2cccc2c1Cl
Temperature: 55 °C
Reaction time: 1 h

Procedure:
Dissolved ethyl 4-chloropyrrolo[1,2-b]pyridazine-3-carboxylate (Preparation 2 from Step 5B, 2 g, 8.90 mmol) in THF (12 mL) and added water (2 mL) followed by monohydrated lithium hydroxide (0.747 g, 17.81 mmol) and the resulting yellow mixture was sonicated to give a fine dispersion followed by heating to 55° C. and stirring vigorously for one hour. After removing the organics under vacuum, the resulting residue was dissolved in ˜50 mL of water and 6 N aqueous HCl added until acidic giving a yellow slurry of the product. The product was extracted with ethyl acetate, washed with brine, dried over Na2SO4, decanted and conc. in vacuo to afford 1.8 g (˜quant.) of a yellow solid as the title compound. LCMS (condition B): m/z=197.1, 199.0. HPLC (condition B): Retention time=2.59 min.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:18]([CH3:31])=[CH:19][C:20]([CH:27]4[CH2:30][CH2:29][CH2:28]4)=[C:21]([CH:26]=3)[C:22]([NH:24][NH2:25])=[O:23])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].CS(O)(=O)=O.C(O[C:40](OCC)(OCC)[CH2:41][CH3:42])C>O1CCOCC1.C(OCC)(=O)C>[CH:27]1([C:20]2[C:21]([C:22]3[O:23][C:40]([CH2:41][CH3:42])=[N:25][N:24]=3)=[CH:26][C:17]([C:15]([N:12]3[CH2:11][CH2:10][CH:9]([C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=4)[CH2:14][CH2:13]3)=[O:16])=[C:18]([CH3:31])[CH:19]=2)[CH2:30][CH2:29][CH2:28]1
Reactant: CCOC(CC)(OCC)OCC
Reactant: Cc1cc(C2CCC2)c(C(=O)NN)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Agent: CS(=O)(=O)O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2C2CCC2)o1
Temperature: 110 °C
Reaction time: 0.33 h
Yield: 78.8 %

Procedure:
To a round-bottom flask was added a solution of 5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-methylbenzohydrazide (compound 230.4, 150 mg, 0.360 mmol, 1.00 equiv) in dioxane (5 mL). MeSO3H (7 mg, 0.07 mmol, 0.20 equiv), and 1,1,1-triethoxypropane (190 mg, 1.08 mmol, 3.00 equiv) were added to the reaction. The resulting solution was stirred for 20 min at 110° C., then cooled to room temperature and diluted with 50 mL of ethyl acetate. The organic layer was washed with 2×20 mL of water, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product (200 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (64.0% CH3CN up to 76.0% in 6 min, up to 100.0% in 4 min, down to 64.0% in 1 min); Detector, Waters 2489 254&220 nm. The fractions containing pure compound were combined and lyophilized to yield 129 mg (79%) of the title compound as a white solid. m/z (ES+) 455 (M+H)+. 1H-NMR (300 MHz, CD3OD, ppm): δ 7.73-7.67 (m, 3H), 7.52-7.48 (m, 3H), 5-4.94 (m, 1H), 4.25-4.20 (m, 1H), 3.60-3.58 (m, 1H), 3.33-3.24 (m, 1H), 3.05-2.97 (m, 4H), 2.49 and 2.30 (2 singlets, amide rotamers, CH3, 3H), 2.39-2.34 (m, 2H), 2.19-1.91 (m, 4H), 1.88-1.66 (m, 4H), 1.49-1.42 (t, 3H).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10](SC)[N:9]=2)=[CH:6][C:5]([CH2:17][N:18]2[CH2:23][CH2:22][N:21]([S:24]([CH3:27])(=[O:26])=[O:25])[CH2:20][CH2:19]2)=[CH:4][N:3]=1.CCO>[Ni]>[F:1][C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[CH:10][N:9]=2)=[CH:6][C:5]([CH2:17][N:18]2[CH2:19][CH2:20][N:21]([S:24]([CH3:27])(=[O:26])=[O:25])[CH2:22][CH2:23]2)=[CH:4][N:3]=1
Reactant: CSc1nc(C)nc(-c2cc(CN3CCN(S(C)(=O)=O)CC3)cnc2F)n1
Agent: [Ni]
Solvent: CCO
Product: Cc1ncnc(-c2cc(CN3CCN(S(C)(=O)=O)CC3)cnc2F)n1
Temperature: 70 °C

Procedure:
Raney nickel (76 mg, 1.297 mmol) water suspension was added to a mixture of 2-(2-fluoro-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-4-methyl-6-(methylthio)-1,3,5-triazine (107 mg, 0.259 mmol) in EtOH (5.00 mL, 86 mmol) and the mixture was heated under nitrogen at 70° C. for 1.5 h. The resulting mixture was passed through a short plug of Celite® (diatomaceous earth). The filter cake was washed with MeOH (3×10 mL). The combined organic phases were concentrated to give the crude product, which was used directly in the next step without purification.
Reaction SMILES: C[Al](C)C.[CH2:5]([N:7]1[C:12](=[O:13])[CH:11]=[C:10]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:9]=[C:8]1[CH2:20][C:21]([O:23]CC)=O)[CH3:6].[F:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1.S([O-])([O-])(=O)=O.[K+].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[CH2:5]([N:7]1[C:12](=[O:13])[CH:11]=[C:10]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[N:9]=[C:8]1[CH2:20][C:21]([NH:31][C:30]1[CH:32]=[CH:33][C:27]([F:26])=[CH:28][CH:29]=1)=[O:23])[CH3:6]
Reactant: Nc1ccc(F)cc1
Reactant: CCOC(=O)Cc1nc(N2CCOCC2)cc(=O)n1CC
Agent: C[Al](C)C
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCn1c(CC(=O)Nc2ccc(F)cc2)nc(N2CCOCC2)cc1=O
Temperature: 80 °C

Procedure:
0.640 ml of a 2M solution of trimethylaluminium in toluene, and then, after stirring for 40 minutes at ambient temperature, a solution of 190 mg of ethyl [1-ethyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate in 6 ml of toluene are successively added, dropwise, to a solution of 0.13 ml of 4-fluoroaniline in 4 ml of toluene. The reaction mixture is heated at 80° C. for 4 hours, cooled using an ice bath and run into water. A 1M solution of potassium sulphate and ethyl acetate are then added, and the organic phase is extracted, washed again with a 1M solution of potassium phosphate and then dried over magnesium phosphate, filtered and, finally, concentrated under reduced pressure. After purification by silica column chromatography, eluent: 980101 then 960202 CH2Cl2/CH3CN/MeOH, 60 mg of 2-[1-ethyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]-N-(4-fluorophenyl)acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: COC1C=CC([C@@H]2O[C@H]2C(N)=O)=CC=1.NC1C=CC=CC=1S.N[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30][CH:31]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1)[CH:32]([OH:36])[C:33]([NH2:35])=[O:34].Cl>CO.ClC1C=CC=CC=1>[OH:36][C@H:32]1[C:33](=[O:34])[NH:35][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[S:30][C@H:31]1[C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1
Reactant: COc1ccc(C(Sc2ccccc2N)C(O)C(N)=O)cc1
Agent: COc1ccc([C@@H]2O[C@H]2C(N)=O)cc1
Agent: Cl
Agent: Nc1ccccc1S
Solvent: CO
Solvent: Clc1ccccc1
Product: COc1ccc([C@@H]2Sc3ccccc3NC(=O)[C@@H]2O)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 19.6 %

Procedure:
A mixture of (2R,3S)-3-(4-methoxyphenyl)-2,3-epoxypropionamide (15.46 g) and chlorobenzene (309 ml) is refluxed with heating under nitrogen atmosphere. When the reflux is started, a solution of 2-aminothiophenol (11.02 g) and ferric chloride hexahydrate (2.16 mg) in methanol (0.1 ml) is added immediately to the reaction mixture, and the mixture is stirred at the same temperature for 5 minutes to give a reaction mixture containing 3-(2-aminophenylthio)-2-hydroxy-3-(4-methoxyphenyl)propionamide (24.24 g) [(2S,3S)/(2S,3R)=91.3/8.7]. A quarter of the mixture is obtained, and 35% hydrochloric acid (1.04 g) is added thereto. The mixture is refluxed for 13 hours to remove the solvent. The remaining chlorobenzene is evaporated from the mixture, and methanol (25 ml) is added to the residue. The mixture is refluxed for one hour, allowed to cool to room temperature, and further cooled at 3° C. overnight. The precipitated crystals are collected by filtration, washed with chilled methanol, and dried at 50° C. to give (2S,3S)-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one (4.49 g).
Reaction SMILES: CN(C)C=O.Cl[C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]#[C:16][CH3:17])[N:10]=[CH:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:24][CH:25]1[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]1>C(OCC)(=O)C>[CH2:14]([O:13][C:11]1[CH:12]=[C:7]([N:27]2[CH2:28][CH2:29][CH2:30][CH:25]([CH3:24])[CH2:26]2)[N:8]=[CH:9][N:10]=1)[C:15]#[C:16][CH3:17]
Reactant: CC#CCOc1cc(Cl)ncn1
Reactant: CC1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC#CCOc1cc(N2CCCC(C)C2)ncn1
Temperature: 80 °C
Reaction time: 4 h
Yield: 73.9 %

Procedure:
Into 2 ml of N,N-dimethylformamide was resolved 183 mg of 4-chloro-6-(2-butynyloxy)pyrimidine, 166 mg of potassium carbonate and 99 mg of 3-methylpiperidine was added therein, and the mixture was stirred for 4 hours at 80° C. The reaction mixture was cooled to near room temperature, ethyl acetate was added therein, and the mixture was washed with a saturated sodium chloride aqueous solution three times. The organic layers were dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 181 mg of 4-(2-butynyloxy)-6-(3-methylpiperidino) pyrimidine (hereinafter, referred to as Compound (19)).
Reaction SMILES: [C:1]1(=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[CH2:2]1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH:16]=O>CCO.N1CCCCC1>[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH:16]=[C:2]1[C:1](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:10]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: O=C1CC(=O)c2ccccc21
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1C(=Cc2ccc(Cl)c(Cl)c2)C(=O)c2ccccc21
Yield: 85 %

Procedure:
To a solution of indan-1,3-dione (1a) (960 mg, 6.6 mmol) in EtOH (8.2 mL) was added 3,4-dichlorobenzaldehyde (b) (1.3 g 7.2 mmol) followed by piperidine (3 drops). The reaction mixture was heated to reflux for 30 min. After cooling the reaction was diluted with EtOH (8 mL) and the precipitate was filtered. The resulting solid was triturated twice with EtOH and dried under high vacuum to give 2-(3,4-dichloro-benzylidene)-indane-1,3-dione (1c) (1.7 g, 82% yield).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Si:8](Cl)(Cl)(Cl)[Cl:9].Cl>>[Cl:9][Si:8].[C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cl[Si](Cl)(Cl)Cl
Agent: Cl
Solvent: Oc1ccccc1
Product: [Si]Cl
Reaction time: 1.5 h

Procedure:
One mol of fine granular hydrated silica, 1 mol of phenol and 1 mol of silicon tetrachloride are slowly added simultaneously while agitating for 1 to 2 hours; hydrogen chloride is evolved and the reaction is complete in 2 to 8 hours, thereby producing a phenol chlorosilicon acid reaction product. To this resinous product, 1 mol of 2-toluenesulphonic acid is slowly added while agitating for 1 to 2 hours; the reaction is complete in 2 to 8 hours, thereby producing toluene sulphonic acid phenol silicon acid resinous product, a white granular product.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1COCC1.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>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: COc1ccccc1B(O)O
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: C1CCOC1
Solvent: COCCOC
Product: COc1ccccc1-c1ccc(C=O)cc1
Temperature: 85 °C
Yield: 91.8 %

Procedure:
To a stirred degassed solution of 4-bromobenzaldehyde (218 mg, 1.18 mmol) and 2-methoxybenzeneboronic acid (188 mg, 1.24 mmol) in DME/THF (5 mL, 4:1) were added a 2 M Na2CO3 solution (1.6 mL) and Pd(PPh3)4 (63 mg, 0.055 mmol). The reaction mixture was flushed with argon and maintained under argon while being heated at 85° C. overnight. The mixture was then cooled and diluted with EtOAc (25 mL) and water (25 mL). The aqueous layer was washed with EtOAc (2×10 mL) and the combined organic extracts dried (Na2SO4), filtered and concentrated. Purification of the resultant oil by column chromatography with silica gel (Hexanes/Et2O, 80:20) afforded the title compound (230 mg, 92%) as a clear oil. 1H NMR (CDCl3) δ 3.84 (s, 3H), 7.01-7.09 (m, 2H), 7.33-7.39 (m, 2H), 7.71 (d, 2H, J=6 Hz), 7.93 (d, 2H, J=6 Hz), 10.05 (s, 1H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([NH:17][S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1)(=[O:20])=[O:19])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:8][C:5]1[CH:6]=[CH:7][C:2]2[N:17]([S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=3)(=[O:19])=[O:20])[CH:15]([CH3:16])[C:10]3[C:9](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:3]=2[CH:4]=1
Reactant: COc1cccc(S(=O)(=O)NC(C)c2ccccc2-c2cc(F)ccc2F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(S(=O)(=O)N2c3ccc(F)cc3-c3ccccc3C2C)c1
Yield: 23.7 %

Procedure:
The title compound was prepared from N-[1-(2′,5′-difluoro-1,1′-biphenyl-2-yl)ethyl]-3-methoxybenzenesulfonamide (440 mg, 1.1 mmol), anhydrous N,N-dimethylformamide (2 mL), and potassium carbonate (301 mg, 2.2 mmol) according to the procedure and in the same manner as described in Example 105, step d. The product was purified by preparative liquid chromatography on a Biotage® 40 Mi column of prepacked silica gel (90 g), eluting with a gradient of 30%-50% methyl tert-butyl ether in hexane (35 min), to afford the desired compound (100 mg, 24%) as a white solid;