Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[C:10]([CH3:49])=[C:11]([NH:15][C:16]([C:18]2[C:26]3[N:25]=[C:24]([NH:27][CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])[NH:23][C:22]=3[CH:21]=[C:20]([NH:36][C:37]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[C:45]([F:48])([F:47])[F:46])=[O:38])[CH:19]=2)=[O:17])[CH:12]=[CH:13][CH:14]=1>C(Cl)Cl>[Cl:8][C:9]1[C:10]([CH3:49])=[C:11]([NH:15][C:16]([C:18]2[C:26]3[N:25]=[C:24]([NH:27][CH2:28][C:29]([OH:31])=[O:30])[NH:23][C:22]=3[CH:21]=[C:20]([NH:36][C:37]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[C:45]([F:46])([F:47])[F:48])=[O:38])[CH:19]=2)=[O:17])[CH:12]=[CH:13][CH:14]=1
Reactant: Cc1c(Cl)cccc1NC(=O)c1cc(NC(=O)c2ccccc2C(F)(F)F)cc2[nH]c(NCC(=O)OC(C)(C)C)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(Cl)cccc1NC(=O)c1cc(NC(=O)c2ccccc2C(F)(F)F)cc2[nH]c(NCC(=O)O)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
TFA (1 mL) was added to a solution of tert-butyl N-{4-[(3-chloro-2-methylphenyl)carbamoyl]-6-({[2-(trifluoro methyl)phenyl]carbonyl}amino)-1H-benzimidazol-2-yl}glycinate (95 mg) in methylene chloride (2 mL), and the mixture was stirred for 1 hour at room temperature, and concentrated. The residue was neutralized with 1N aqueous NaOH under ice-cooling and extracted with EtOAc. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified on column chromatography to obtain N-{4-[(3-chloro-2-methylphenyl)carbamoyl]-6-({[2-(trifluoro methyl)phenyl]carbonyl}amino)-1H-benzimidazol-2-yl}glycine (50 mg) as white powder. N-{4-[(3-chloro-2-methylphenyl)carbamoyl]-6-({[2-(trifluoro methyl)phenyl]carbonyl}amino)-1H-benzimidazol-2-yl}glycine (16 mg) was suspended in MeOH. To the suspension was added 2N hydrogen chloride/EtOH solution (1 Eq) to obtain a homogeneous solution. The solvent was removed under reduced pressure. The residue was triturated in diethyl ether, and the precipitate was collected by filtration and dried to obtain the titled compound (12 mg) as white powder.
Reaction SMILES: C([SiH](CC)CC)C.[B].[CH2:9]([CH:16]1[CH2:20][O:19][C:18](=[O:21])[N:17]1[C:22](=[O:51])[CH:23]([O:48][CH2:49][CH3:50])[CH:24]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][N:39](C)[C:40](=O)OC(C)(C)C)[CH:33]=2)=[CH:28][CH:27]=1)O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH2:9]([CH:16]1[CH2:20][O:19][C:18](=[O:21])[N:17]1[C:22](=[O:51])[CH:23]([O:48][CH2:49][CH3:50])[CH2:24][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][NH:39][CH3:40])[CH:33]=2)=[CH:28][CH:27]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(C(=O)N1C(=O)OCC1Cc1ccccc1)C(O)c1ccc(-c2cccc(CN(C)C(=O)OC(C)(C)C)c2)cc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [B]
Solvent: ClCCl
Product: CCOC(Cc1ccc(-c2cccc(CNC)c2)cc1)C(=O)N1C(=O)OCC1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99.6 %

Procedure:
43 ml (272 mmol) of triethylsilane are added dropwise to a solution of 17 ml (136 mmol) of boron trifluoroetherate in 150 ml of dichloromethane cooled beforehand to 0° C. After stirring for 15 minutes, 10 g (17 mmol) of tert-butyl N-{4′-[3-(4-benzyl-2-oxooxazolidin-3-yl)-2-ethoxy-1-hydroxy-3-oxopropyl]biphenyl-3-ylmethyl}-N-methylcarbamate dissolved in 70 ml of dichloromethane are added dropwise. The reaction medium is stirred from 0° C. to room temperature for 3 hours and then heated at 40° C. for 48 hours, treated with saturated aqueous sodium carbonate solution, extracted with dichloromethane, dried over magnesium sulfate, filtered and concentrated. The residue obtained is purified by chromatography on a column of silica eluted with a dichloromethane/methanol/triethylamine mixture (95/5/0.5). 8 g of 4-benzyl-3-[2-ethoxy-3-(3′-methylaminomethylbiphenyl-4-yl)propionyl]oxazolidin-2-one are obtained in a yield of 13% to 3 g of methyl 2-ethoxy-3-hydroxy-3-(3′-methylaminomethylbiphenyl-4-yl)propionate are obtained in a yield of 51%.
Reaction SMILES: B1([O-])OO1.[OH2:5].[OH2:6].O.O.[Na+].[CH2:10]([C:17]1[O:18][C:19]2[CH:52]=[CH:51][CH:50]=[CH:49][C:20]=2[C:21]=1[C:22]1[CH:48]=[CH:47][C:25]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][S:33][CH2:34][C@H:35]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:36]([OH:38])=[O:37])=[CH:28][CH:27]=2)=[CH:24][CH:23]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)(=O)C.C(OCC)(=O)C>[CH2:10]([C:17]1[O:18][C:19]2[CH:52]=[CH:51][CH:50]=[CH:49][C:20]=2[C:21]=1[C:22]1[CH:23]=[CH:24][C:25]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][S:33]([CH2:34][C@H:35]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:44])[CH3:45])=[O:41])[C:36]([OH:38])=[O:37])(=[O:6])=[O:5])=[CH:28][CH:27]=2)=[CH:47][CH:48]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O
Reactant: CC(C)(C)OC(=O)N[C@@H](CSCc1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1)C(=O)O
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](CS(=O)(=O)Cc1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1)C(=O)O
Temperature: 40 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
Sodium perborate tetrahydrate (320 mg, 2.1 mmol) was added as a solid to a stirred solution of (2R)-3-[4′-(2-benzylbenzofuran-3-yl)biphen-4-ylmethylsulfanyl]-2-tert-butoxycarbonylamino-propionic acid (440 mg, 0.74 mmol) in acetic acid (10 mL) at 40° C. This solution was stirred at 40° C. for 2 hours (HPLC control) and then diluted with ethyl acetate (50 mL), washed with water, brine (2×), dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification of the product by flash column chromatography, using 15% methanol in methylene chloride as eluent, afforded the title compound as a white solid (426 mg, 92%): mp. 202-203° C. Rf 0.40 (20% methanol in dichloromethane). 1H NMR (DMSO-d6, 300 MHz) δ 7.84 (2H, d, J=9 Hz, Ar—H), 7.74 (2H, d, J=9 Hz, Ar—H), 7.60 (4H, m, Ar—H), 7.48 (2H, d, J=9 Hz, Ar—H), 7.29 (5H, m, Ar—H), 7.22 (2H, d, J=8 Hz, Ar—H), 6.58 (1H, br s, NH), 4.51 (2H, s, PhCH2), 4.27 (2H, s, PhCH2S), 4.16 (1H, m, CHN), 3.56 (1H, dd, J=15, 5 Hz, CHHCHN), 3.20 (1H, dd, J=15, 8 Hz, CHHCHN), 1.37 (9H, s, tBu); ESI-LCMS e/z calcd for C36H35NO7S 625.739, found 626 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]([C:6]1[S:10][C:9]([C:11]([OH:13])=[O:12])=[CH:8][CH:7]=1)([CH3:5])[CH3:4].[C:14]([O-])([O-])=O.[K+].[K+].IC.O>CN(C=O)C>[CH3:14][O:12][C:11]([C:9]1[S:10][C:6]([C:3]([CH3:4])([CH3:5])[CH2:2][OH:1])=[CH:7][CH:8]=1)=[O:13]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(CO)c1ccc(C(=O)O)s1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(C(C)(C)CO)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
A solution of 5-(2-hydroxy-1,1-dimethyl-ethyl)-thiophene-2-carboxylic acid (0.495 g, 2.47 mmol) in DMF (12.0 mL) is treated with K2CO3 (0.515 g, 3.73 mmol), iodomethane (0.23 mL, 3.69 mmol), and stirred at rt overnight. The mixture is poured into H2O (25 mL) and extracted with EtOAc (3×25 mL). The combined extracts are washed with H2O, brine, dried over MgSO4, filtered, and concentrated. The residue is loaded onto silica gel and eluted with hexanes using a gradient of 0% to 75% EtOAc to give 5-(2-hydroxy-1,1-dimethyl-ethyl)-thiophene-2-carboxylic acid methyl ester (0.439 g, 83%). MS (ES): 215.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[OH:26])[C:6]([C:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][C:9]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:7].[CH2:27]([N:29]([CH2:34][CH3:35])[CH2:30][CH2:31][CH2:32]Cl)[CH3:28]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH2:32][CH2:31][CH2:30][N:29]([CH2:34][CH3:35])[CH2:27][CH3:28])[C:6]([C:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][C:9]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:7]
Reactant: COc1cc(C(=O)c2c(-c3ccccc3)oc3ccccc23)ccc1O
Reactant: CCN(CC)CCCCl
Product: CCN(CC)CCCOc1ccc(C(=O)c2c(-c3ccccc3)oc3ccccc23)cc1OC

Procedure:
Reaction of 3-(3-methoxy-4-hydroxybenzoyl)-2-phenyl benzofuran with 3-diethylaminopropyl chloride according to the procedure of Example 1 gives the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH2:16])=[O:15])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:17][CH2:18][O:19][C:20]([CH:22]1[C:27](=O)[CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:21]>>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH:16][C:23]2[CH2:24][CH2:25][CH2:26][CH2:27][C:22]=2[C:20]([O:19][CH2:18][CH3:17])=[O:21])=[O:15])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C1CCCCC1=O
Reactant: CCOC(=O)c1cc(NC(N)=O)ccc1Cl
Product: CCOC(=O)C1=C(NC(=O)Nc2ccc(Cl)c(C(=O)OCC)c2)CCCC1

Procedure:
using ethyl 2-chloro-5-ureidobenzoate and ethyl cyclohexanone-2-carboxylate there is obtained ethyl 2-chloro-5-{3-[2-(ethoxycarbonyl)-1-cyclohexen-1-yl]ureido}-benzoate, m.p. 119°-122° C.,
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([CH:47]=[CH:48][CH:49]=2)[C:43]([O:45]C)=O)=[N:8]1.O.[OH-].[Li+].[CH3:53][C@H:54]([NH2:61])[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O1CCCC1.O1CCCC1.O>[C:55]1([C@@H:54]([NH:61][C:43]([C:42]2[CH:47]=[CH:48][CH:49]=[C:40]([C:9]3[C:10]4[C:15](=[CH:14][CH:13]=[C:12]([C:16]5[N:20]=[CH:19][N:18]([C:21]([C:22]6[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=6)([C:28]6[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=6)[C:34]6[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=6)[N:17]=5)[CH:11]=4)[N:7]([CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)[N:8]=3)[CH:41]=2)=[O:45])[CH3:53])[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: COC(=O)c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: C[C@H](N)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](NC(=O)c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1)c1ccccc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 80.9 %

Procedure:
To a stirred solution of methyl 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}benzoate (0.400 g, 0.619 mmol) in a tetrahydrofuran/water mixture (2.50 mL/1.00 mL) was added lithium hydroxide monohydrate (0.0780 g, 1.86 mmol) and the mixture heated at 60° C. for 21 h. To this mixture was added tetrahydrofuran (2.00 mL), (S)-(−)-α-methylbenzylamine (0.240 mL, 1.86 mmol), 1-hydroxybenzotriazole hydrate (0.251 g, 1.86 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.356 g, 1.86 mmol). This mixture was stirred for 18 h at ambient temperature. After the mixture was extracted with ethyl acetate (2×), the combined organic extracts were washed with aqueous saturated sodium bicarbonate, followed by brine, dried over anhydrous sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography with 30–60% ethyl acetate/hexanes gave the title compound (0.368 g, 81% yield). ES-MS (m/z) 493 [M+1(−Tr)]+
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH2:28][NH:27][CH2:26]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH2:28][N:27]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[C:9]([F:17])[C:10]=1[F:16])[CH2:26]2
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)c(F)c2c1=O
Reactant: Fc1ccc2c(c1)CNC2
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3Cc4ccc(F)cc4C3)c(F)c(F)c2c1=O
Yield: 37 %

Procedure:
210 mg of 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 106 mg of 5-fluoroisoindoline, 213 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 108 mg of the target compound.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][O:5][CH2:6][CH2:7][Si:8]([CH3:11])([CH3:10])[CH3:9].[CH:12]1([C:18]([C:20]2[C:21]3[CH:28]=[CH:27][NH:26][C:22]=3[N:23]=[CH:24][N:25]=2)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C[SiH](C)C>CN(C)C=O.C1(C(C2C3C=CNC=3N=CN=2)=O)CCCCC1.O>[CH:12]1([C:18]([C:20]2[C:21]3[CH:28]=[CH:27][N:26]([CH2:4][O:5][CH2:6][CH2:7][Si:8]([CH3:11])([CH3:10])[CH3:9])[C:22]=3[N:23]=[CH:24][N:25]=2)=[O:19])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=C(c1ncnc2[nH]ccc12)C1CCCCC1
Agent: C[SiH](C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc2c(C(=O)C3CCCCC3)ncnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 985.1 %

Procedure:
Cyclohexyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)methanone (50.0 mg, 0.218 mmol) in N,N-dimethylformamide (1 mL) was mixed with sodium hydride (60 wt % dispersion in mineral oil, 9.6 mg, 0.24 mmol) and [2-(chloromethoxy)ethyl]trimethylsilane (42.5 μL, 0.240 mmol) under cooling with ice and stirred for 30 minutes while the temperature was gradually raised to room temperature. Separately, cyclohexyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)methanone (500 mg, 2.18 mmol) in N,N-dimethylformamide (5 mL) was mixed with sodium hydride (60 wt % dispersion in mineral oil, 96 mg, 2.4 mmol) and (chloromethoxy)ethyl]trimethylsilane (425 μL, 2.40 mmol) under cooling with ice and stirred for 30 minutes while the temperature was gradually raised to room temperature. After addition of water, the reaction solution and the previously obtained reaction solution were extracted with ethyl acetate, respectively, and the organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residues were combined and purified by silica gel column chromatography (hexane/ethyl acetate=5/1 (v/v)) to give the title compound as a pale yellow oil (850 mg, yield 99%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[O:21][CH2:22][CH2:23][CH2:24][CH2:25]Cl)=[CH:16][CH:15]=1.C(OCC)(=O)C>CN(C=O)C>[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)[O:21][CH:22]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[CH2:23][CH2:24][CH3:25])=[CH:16][CH:15]=1
Reactant: C1CNCCN1
Reactant: Fc1ccc(C(OCCCCCl)c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCC(OC(c1ccc(F)cc1)c1ccc(F)cc1)N1CCNCC1
Reaction time: 72 h
Yield: 30 %

Procedure:
Piperazine (4.31 g, 50 mmol) was dissolved in 40 mL of anhydrous DMF and stirred with K2CO3 powder (2.76 g, 20 mmol) and KI (100 mg, 0.6 mmol) for 0.5 h. To this turbid solution, 1-[bis(4-fluorophenyl)methoxy]-4-chlorobutane (2, 1.55 g, 5 mmol) in 10 mL of DMF was added slowly. The reaction mixture was stirred for 72 h at 60°-70°. The turbid reaction mixture was poured into 200 mL of ethyl acetate, washed with sat. NaCl solution (60 mL×5), dried over MgSO4 and evaporated to dryness. The crude oil was applied to a silica gel column for purification. Elution with CHCl3:MeOH (93:7) afforded the desired mono-alkylated product 3 (540 mg, 1.5 mmol, 30%) as a slightly yellow oil. 1H NMR (CDCl3): δ 1.55-1.69 (4H, m), 2.31 (2H, t, J=7.5), 2.39 (4H, br s), 2.88 (4H, t, J=4.8), 3.43 (2H, t, J=6.0), 5.28 (1H, s), 6.98-7.02 (4H, m), 7.25-7.29 (4H, m). mp (bis oxalate salt): 215°-218° C. Anal. C25H30N2O9F2) C, H, N.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]([CH2:14][C:15]#[CH:16])[C:4](=[O:17])[C:3]=1[CH3:18].[CH3:19][NH:20][CH3:21]>O1CCCC1.CCOCC>[CH3:19][N:20]([CH3:21])[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]([CH2:14][C:15]#[CH:16])[C:4](=[O:17])[C:3]=1[CH3:18]
Reactant: CNC
Reactant: C#CCn1c(-c2ccccc2)nc(Cl)c(C)c1=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: C#CCn1c(-c2ccccc2)nc(N(C)C)c(C)c1=O
Temperature: 25 °C

Procedure:
To an ice cooled solution of 1.5 g (3.8 mmol) 6-chloro-5-methyl-2-phenyl-3-propargyl-4(3H)-pyrimidinone in 4 mL of tetrahydrofuran, was added 22 mL (99 mmol) of 4.5M dimethylamine in ether portionwise (2-4 mL) over a period of 7 days. The reaction mixture was allowed to warm and stir at room temperature after each addition. The progress of the reaction was followed by gas chromatography and proceeded to 80% completion. The solvent was removed in vacuo and the residue was taken up in ether and washed twice with water. The organic layer was dried over MgSO4 and concentrated to yield 1.15 g crude solid product. Flash column chromatography on silica gel (gradient elution 25-30% ethyl acetate-hexane) afforded pure 6-dimethylamino-5-methyl-2-phenyl-3-propargyl-4(3H)-pyrimidinone (compound 23), as a white solid. 1H-NMR (CDCl3)δ2.2 (3H, s); 2.35 (1H, t); 3.5 (6H, s); 4.6 (2H, d); 7.65 (3H, m); 7.75 (2H, m).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].O.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:19]([F:24])([F:23])C([O-])=O.[Na+]>CN(C)C=O>[F:23][CH:19]([F:24])[O:10][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[F:1]
Reactant: O=C([O-])C(F)(F)Cl
Reactant: N#Cc1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(OC(F)F)c(F)c1
Temperature: 110 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
To a mixed solution of 3-fluoro-4-hydroxybenzonitrile (3.10 g) in N,N-dimethylformamide (31 ml)/water (3.1 ml) were successively added cesium carbonate (10.3 g) and sodium chlorodifluoroacetate (7.93 g). After stirring at 110° C. for 2 hr, the reaction mixture was partitioned by adding toluene and water. The aqueous layer was extracted with toluene, and the combined organic layer was washed with water. The organic layer was dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure to give the title compound (4.09 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1B1OC(C)(C)C(C)(C)O1.Br[C:18]1[CH:19]=[C:20]2[CH2:26][N:25]([C@@H:27]([CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[CH:42]=3)[CH2:28][N:29]3[C:37](=[O:38])[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:30]3=[O:39])[C:24](=[O:48])[C:21]2=[N:22][CH:23]=1.C(N(CC)C(C)C)(C)C.O1CCOCC1.O>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:18]1[CH:19]=[C:20]2[CH2:26][N:25]([C@@H:27]([CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[CH:42]=3)[CH2:28][N:29]3[C:37](=[O:38])[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:30]3=[O:39])[C:24](=[O:48])[C:21]2=[N:22][CH:23]=1
Reactant: Cn1ncc(Cl)c1B1OC(C)(C)C(C)(C)O1
Reactant: O=C1c2ccccc2C(=O)N1C[C@H](Cc1cccc(F)c1)N1Cc2cc(Br)cnc2C1=O
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(Cl)c1-c1cnc2c(c1)CN([C@@H](Cc1cccc(F)c1)CN1C(=O)c3ccccc3C1=O)C2=O
Temperature: 110 °C
Reaction time: 0.67 h
Yield: 28.3 %

Procedure:
A mixture of 4-chloro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (150 mg, 0.63 mmol), 2-[(2S)-2-(3-bromo-7-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (150 mg, 0.32 mmol), bis(tri-t-butylphosphine)palladium (30 mg, 0.06 mmol) and N,N-diisopropylethylamine (0.16 mL, 0.95 mmol) in 1,4-dioxane (5.0 mL, 64 mmol) and water (0.5 mL, 30 mmol) was stirred at 110° C. for 40 min at microwave. Direct purification on prep.—HPLC (pH=10) afforded 48 mg (29% yield) of the desired intermediate as white solid. LC-MS found: 530.1 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:10][C@H:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N:19]2[CH2:24][CH2:23][O:22][CH:21]([CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:20]2)[CH:14]=1)[CH3:12])C1C=CC=CC=1.[H][H]>[Pd].CO>[C:30]([O:29][C:27](=[O:28])[NH:26][CH2:25][C@@H:21]1[O:22][CH2:23][CH2:24][N:19]([C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([CH:11]([NH2:10])[CH3:12])[CH:14]=2)[CH2:20]1)([CH3:32])([CH3:31])[CH3:33]
Reactant: [H][H]
Reactant: C[C@H](NC(=O)OCc1ccccc1)c1cccc(N2CCOC(CNC(=O)OC(C)(C)C)C2)c1
Agent: [Pd]
Solvent: CO
Product: CC(N)c1cccc(N2CCO[C@@H](CNC(=O)OC(C)(C)C)C2)c1
Yield: 89 %

Procedure:
The mixture of (S)-(1-{3-[2-(tert-butoxycarbonylaminomethyl)-morpholin-4-yl]-phenyl}-ethyl)-carbamic acid benzyl ester (600 mg, 1.3 mmol), palladium on C (10 wt %) (300 mg), and methanol (10 ml) was put onto hydrogenator and shaken at 50 psi of hydrogen for 2 days and one night. The mixture was filtered through Celite pad and washed with methanol. The filtrate was concentrated under vacuum. The sticky oil (89% yield) was used for next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([B:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]2)=[C:6]([CH3:19])[CH:5]=1.C1C(=O)N([Br:28])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([B:10]2[O:11][C:12]([CH3:18])([CH3:17])[C:13]([CH3:15])([CH3:16])[O:14]2)=[C:6]([CH2:19][Br:28])[CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(CBr)c1
Temperature: 25 °C
Yield: 103 %

Procedure:
The solution of 3-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (3.71 g, 13.4 mmol), NBS (2.39 g, 13.4 mmol), and AIBN (235 mg) in CCl4 (20 ml) was heated at 80° C. for 14 hours. The mixture was cooled to 25° C., and was filtered and washed with CCl4. The solution was concentrated under reduced pressure, and was diluted with EtOAc. The solution was washed with water and brine and was dried with Na2SO4. Concentration gave 3-Bromomethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (4.9 g).
Reaction SMILES: [OH:1][C:2]1[C:6]([CH3:7])=[C:5]([CH3:8])[O:4][N:3]=1.[N+](=[CH2:11])=[N-]>CCOCC>[CH3:11][N:3]1[C:2](=[O:1])[C:6]([CH3:7])=[C:5]([CH3:8])[O:4]1
Reactant: C=[N+]=[N-]
Reactant: Cc1onc(O)c1C
Solvent: CCOCC
Product: Cc1on(C)c(=O)c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-hydroxy-4,5-dimethylisoxazole (7 g, 62 mmol) in ether (50 mL) was added diazomethane until a persistent yellow colour was obtained. The reaction was stirred for another 30 min at room temperature. The ether was evaporated off and the residue purified by column chromatography on silica gel using ether as eluent. 4 g of the desired material was obtained.