Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]1[CH:34]=[CH:33][C:8]([C:9]([N:11]2[CH2:16][CH2:15][N:14]3[N:17]=[C:18]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)[C:19]([C:20]4[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=4)=[C:13]3[NH:12]2)=[O:10])=[CH:7][CH:6]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CO>[F:32][C:29]1[CH:30]=[CH:31][C:26]([C:18]2[C:19]([C:20]3[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=3)=[C:13]3[NH:12][N:11]([C:9](=[O:10])[C:8]4[CH:7]=[CH:6][C:5]([OH:4])=[CH:34][CH:33]=4)[CH2:16][CH2:15][N:14]3[N:17]=2)=[CH:27][CH:28]=1
Reactant: CC(=O)Oc1ccc(C(=O)N2CCn3nc(-c4ccc(F)cc4)c(-c4ccncc4)c3N2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Product: O=C(c1ccc(O)cc1)N1CCn2nc(-c3ccc(F)cc3)c(-c3ccncc3)c2N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.7 %

Procedure:
A mixture of 2-(4-acetoxybenzoyl)-7-(4-fluorophenyl)-8-(pyridin-4-yl)-1,2,3,4-tetrahydropyrazolo[5,1-c][1,2,4]triazine (65 mg, 0.142 mmol) and potassium carbonate (20 mg, 0.142 mmol) in methanol (1.3 ml) was stirred for 30 minutes at ambient temperature. The mixture was adjusted to pH 6 with an aqueous saturated ammonium chloride solution, and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by chromatography on silica gel (eluent:dichloromethane/methanol; 30/1~20/1), and the obtained amorphous product was crystallized from diisopropyl ether to give 7-(4-fluorophenyl)-2-(4-hydroxybenzoyl)-8-(pyridin-4-yl)-1,2,3,4-tetrahydropyrazolo[5,1-c][1,2,4]triazine (37 mg).
Reaction SMILES: [CH3:1][Si:2]([CH3:29])([CH3:28])[C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:23]=1)[C:6]([NH:8][C:9]1[CH:19]=[CH:18][C:12]([CH:13]=[CH:14][C:15]([OH:17])=[O:16])=[C:11]([F:20])[CH:10]=1)=[O:7].[H][H]>O1CCCC1.CO.[C].[Pd]>[CH3:27][Si:24]([CH3:25])([CH3:26])[C:22]1[CH:21]=[C:5]([CH:4]=[C:3]([Si:2]([CH3:29])([CH3:28])[CH3:1])[CH:23]=1)[C:6]([NH:8][C:9]1[CH:19]=[CH:18][C:12]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[C:11]([F:20])[CH:10]=1)=[O:7]
Reactant: [H][H]
Reactant: C[Si](C)(C)c1cc(C(=O)Nc2ccc(C=CC(=O)O)c(F)c2)cc([Si](C)(C)C)c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: C[Si](C)(C)c1cc(C(=O)Nc2ccc(CCC(=O)O)c(F)c2)cc([Si](C)(C)C)c1
Yield: 75.9 %

Procedure:
Compound 2 (160 mg) was dissolved in a mixed solution of tetrahydrofuran (0.59 ml) and methanol (0.59 ml). Palladium carbon (4.4 mg) was added thereto, and the mixture was stirred in a hydrogen atmosphere for 4.5 hours. After the reaction was over, the reaction mixture was filtered through Celite. The filtrate was condensed and recrystallized with dichloromethane and n-hexane to obtain Compound 7 (122 mg, 76%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:21]2[CH2:25][C@H:24]([CH2:26][N:27]3[CH:31]=[CH:30][N:29]=[N:28]3)[O:23][C:22]2=[O:32])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][C:11]([C:14]2[CH2:18][C@@H:17]([CH2:19][OH:20])[O:16][N:15]=2)=[CH:12][CH:13]=1.Cl.[CH2:34]([N:36]([CH2:42][CH3:43])[CH2:37][CH2:38][C:39](O)=[O:40])[CH3:35].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.CN(C=O)C.C(#N)C.CCOCC>[CH2:34]([N:36]([CH2:42][CH3:43])[CH2:37][CH2:38][C:39]([O:20][CH2:19][C@H:17]1[O:16][N:15]=[C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:7]3[CH:6]=[CH:5][C:4]([N:21]4[CH2:25][C@H:24]([CH2:26][N:27]5[CH:31]=[CH:30][N:29]=[N:28]5)[O:23][C:22]4=[O:32])=[CH:3][C:2]=3[F:1])=[CH:9][N:10]=2)[CH2:18]1)=[O:40])[CH3:35]
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NO[C@H](CO)C3)nc2)c(F)c1
Reactant: CCN(CC)CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCN(CC)CCC(=O)OC[C@@H]1CC(c2ccc(-c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)cn2)=NO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.7 %

Procedure:
(5R)-3-(3-Fluoro-4-{6-[(5S)-5-(hydroxymethyl)-4,5-dihydroisoxazol-3-yl]pyridin-3-yl}phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Example 1, 0.25 g, 0.57 mmol), N,N-diethyl-β-alanine hydrochloride (0.24 g, 1.43 mmol), 4-dimethylaminopyridine (0.02 g, 0.16 mmol), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.25 g, 1.30 mmol) were combined in DMF (4 ml). The suspension was allowed to stir for one hour at room temperature. The mixture was then diluted with acetonitrile:ether (1:1) and filtered. The solids were dissolved in a minimum amount of methanol and purified by chromatography (silica gel, 5 to 20% methanol in dichloromethane). Evaporation of the product containing fractions and trituration of the resulting solid with diethyl ether yielded the title compound as a white solid (70 mg), melting point: 167° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[C:6]([NH:11][S:12]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)(=[O:14])=[O:13])[CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:20](O)=[O:21].Cl.[C:24]([S:43][CH2:44][CH2:45][NH2:46])([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O.CN(C)C=O.C(N(CC)CC)C>[CH3:1][C:2]1[C:10]2[C:5](=[C:6]([NH:11][S:12]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)(=[O:14])=[O:13])[CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:20]([NH:46][CH2:45][CH2:44][S:43][C:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:21]
Reactant: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1c(C(=O)O)[nH]c2c(NS(=O)(=O)c3cccs3)cccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C(=O)NCCSC(c2ccccc2)(c2ccccc2)c2ccccc2)[nH]c2c(NS(=O)(=O)c3cccs3)cccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.5 %

Procedure:
To a mixture of 3-methyl-7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (0.70 g), 2-(tritylthio)ethylamine hydrochloride (0.82 g), 1H-1,2,3-benzotriazol-1-ol (0.34 g), triethylamine (0.35 mL) and N,N-dimethylformamide (15 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.48 g) at 0° C., and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the obtained crystals were filtrated, washed with water and dried. The obtained crystals were subjected to silica gel column chromatography and the title compound (1.36 g, quantitative) was obtained as colorless crystals from a fraction eluted with ethyl acetate. melting point>214° C. (decomposition).
Reaction SMILES: COC1C=CC([CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[NH:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[NH:26][CH:27]=[CH:28][C:21]=23)=[O:13])=CC=1.[F:31][C:32]([F:43])([F:42])[O:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1C=O>>[F:31][C:32]([F:42])([F:43])[O:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[S:15][CH:16]=[CH:17][C:18]=1[NH:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]2[NH:26][CH:27]=[CH:28][C:21]=12)=[O:13]
Reactant: O=Cc1ccccc1OC(F)(F)F
Reactant: COc1ccc(CNCCNC(=O)c2sccc2Nc2ccnc3[nH]ccc23)cc1
Product: O=C(NCCNCc1ccccc1OC(F)(F)F)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid [2-(4-methoxy-benzylamino)-ethyl]amide using 2-(trifluoromethoxy)benzaldehyde instead of 4-methoxy benzaldehyde. LCMS (ESI) 476 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.52 (1H, br. s.) 10.28 (1H, s) 8.05 (1H, t, J=5.64 Hz) 8.01 (1H, d, J=5.42 Hz) 7.77 (1H, d, J=5.42 Hz) 7.58 (1H, dd, J=6.86, 2.17 Hz) 7.47 (1H, d, J=5.42 Hz) 7.25-7.39 (4H, m) 6.80 (1H, d, J=5.47 Hz) 6.42 (1H, dd, J=3.49, 1.93 Hz) 3.76 (2H, s) 3.33-3.42 (2H, m) 2.65 (2H, t, J=6.49 Hz)
Reaction SMILES: Br[C:2]1[C:3]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.CC(C)([O-])C.[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(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[O:25]1[CH2:26][CH2:27][N:22]([C:2]2[C:3]([O:8][CH:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]3)=[N:4][CH:5]=[CH:6][CH:7]=2)[CH2:23][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ncccc2Br)CC1
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ncccc2N2CCOCC2)CC1
Yield: 77.7 %

Procedure:
To a solution of tert-butyl 4-((3-bromopyridin-2-yl)oxy)piperidine-1-carboxylate (see PREPARATION P20.4; 4 g, 11.2 mmol), morpholine (1.46 g, 16.8 mmol), Pd2(dba)3 (513 mg, 0.56 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) (349 mg, 0.56 mmol), sodium tert-butoxide (t-BuONa) (2.15 g, 22.4 mmol) then the reaction mixture was stirred at 90° C. for overnight. The mixture was left to reach room temperature, then the reaction mixture was filtered through a pad of CELITE® and the filter cake was washed with CH2Cl2 (3×20 mL). The combined filtrates were evaporated in vacuo and the residue was purified by column chromatography to give the product (3.1 g, 8.7 mmol, yield 70%). ESI-MS (M+1): 364 calc. for C19H29N3O4 363.
Reaction SMILES: C(OC([N:7]1[CH2:11][C@@H:10]([S:12][C:13]2[C@H:19]([CH3:20])[C@H:18]3[N:15]([C:16](=[O:24])[C@@H:17]3[C@H:21]([OH:23])[CH3:22])[C:14]=2[C:25]([O:27]CC=C)=[O:26])[CH2:9][C@H:8]1[CH2:31][O:32][CH2:33][C:34]([NH:36][C:37]([NH2:39])=[O:38])=[O:35])=O)C=C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1CCOCC1.C(O)=O>O1CCCC1.O.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.C(OCC)(=O)C>[OH:23][C@@H:21]([C@H:17]1[C:16](=[O:24])[N:15]2[C@@H:18]1[C@@H:19]([CH3:20])[C:13]([S:12][C@@H:10]1[CH2:11][NH:7][C@H:8]([CH2:31][O:32][CH2:33][C:34]([NH:36][C:37]([NH2:39])=[O:38])=[O:35])[CH2:9]1)=[C:14]2[C:25]([OH:27])=[O:26])[CH3:22]
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](COCC(=O)NC(N)=O)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: O=CO
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](COCC(=O)NC(N)=O)C3)[C@H](C)[C@H]12
Yield: 50.1 %

Procedure:
To a solution of allyl (4R,5S,6S)-3-[(2S,4S)-1-allyloxycarbonyl-2-{(ureidocarbonylmethyl)oxymethyl}pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.23 g) in a mixture of tetrahydrofuran (11.5 ml) and water (2.3 ml) were added triphenylphosphine (23 mg), morpholine (0.12 ml), formic acid (0.05 ml), and tetrakis(triphenylphosphine)palladium(0) (26 mg) successively with stirring under ice-cooling. The mixture was stirred at the same temperature for 1 hour and at ambient temperature for 2 hours, and poured into a mixture of ethyl acetate (50 ml) and water (50 ml). The aqueous layer was separated and washed 2 times with ethyl acetate (50 ml). This aqueous layer was concentrated in vacuo to remove the organic solvent. The residue was chromatographed on nonionic adsorption resin, "Diaion HP-20" (made by Mitsubishi Chemical Industries) (10 ml), eluting in turn with water, and a mixture of acetone and water (5:95 V/V). The fractions containing the desired compound were collected and lyophilized to give (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[(2S,4S)-2-{(ureidocarbonylmethyl)oxymethyl}pyrrolidin-4-yl]thio-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (0.09 g).
Reaction SMILES: C([O:8][P:9]([N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([C:28]2[C:29](=[O:47])[NH:30][C:31](=[O:46])[C:32]=2[C:33]2[C:41]3[C:36](=[CH:37][C:38]([N+:42]([O-:44])=[O:43])=[CH:39][CH:40]=3)[N:35]([CH3:45])[CH:34]=2)=[CH:20]1)(=[O:18])[O:10]CC1C=CC=CC=1)C1C=CC=CC=1.C1CC=CCC=1>C1COCC1.C(O)C.[Pd]>[CH3:45][N:35]1[C:36]2[C:41](=[CH:40][CH:39]=[C:38]([N+:42]([O-:44])=[O:43])[CH:37]=2)[C:33]([C:32]2[C:31](=[O:46])[NH:30][C:29](=[O:47])[C:28]=2[C:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:19]([P:9](=[O:8])([OH:18])[OH:10])[CH:20]=2)=[CH:34]1
Reactant: Cn1cc(C2=C(c3cn(P(=O)(OCc4ccccc4)OCc4ccccc4)c4ccccc34)C(=O)NC2=O)c2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Solvent: C1=CCC=CC1
Product: Cn1cc(C2=C(c3cn(P(=O)(O)O)c4ccccc34)C(=O)NC2=O)c2ccc([N+](=O)[O-])cc21
Temperature: 37.5 °C
Yield: 53.6 %

Procedure:
A solution of {3-[4-(1-methyl-6-nitro-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl]-indol-1-yl}-phosphonic acid dibenzyl ester (50 mg, 0.08 mmol) (from step a) above) in a mixture of THF/ethanol (3 ml/6 ml) was treated with 10% Pd/C (75 mg) and 1,4-cyclohexadiene (0.5 ml) and warmed to 35-40° C. for 2 hr. The reaction was cooled, filtered through celite and evaporated to dryness. Crystals were obtained from THF/hexane to yielding 20 mg of {3-[4-(1-methyl-6-nitro-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl]-indol-1-yl}-phosphonic acid. (Yield 55 %)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])[C:8]([CH:20]([NH:22][C:23]1[N:31]=[CH:30][N:29]=[C:28]3[C:24]=1[N:25]=[CH:26][N:27]3C1CCCCO1)[CH3:21])=[CH:7]2.C([O-])(O)=O.[Na+]>>[N:31]1[C:23]([NH:22][CH:20]([C:8]2[N:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])[C:10](=[O:12])[C:11]3[C:6]([CH:7]=2)=[CH:5][CH:4]=[CH:3][C:2]=3[CH3:1])[CH3:21])=[C:24]2[C:28]([NH:27][CH:26]=[N:25]2)=[N:29][CH:30]=1
Reactant: Cc1ccccc1-n1c(C(C)Nc2ncnc3c2ncn3C2CCCCO2)cc2cccc(C)c2c1=O
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1-n1c(C(C)Nc2ncnc3[nH]cnc23)cc2cccc(C)c2c1=O
Reaction time: 2 h
Yield: 54.1 %

Procedure:
8-Methyl-3-(1-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-ylamino)ethyl)-2-o-tolylisoquinolin-1(2H)-one 4105 (180 mg, 0.36 mmol) was dissolved in MeOH(HCl) (50 mL) and stirred for 2 h. Aqueous NaHCO3 solution was added to the reaction mixture and the pH value was adjusted to 9. The mixture was then filtered and the filtrate was concentrated in vacuo to afford the desired product, 3-(1-(9H-purin-6-ylamino)ethyl)-8-methyl-2-o-tolylisoquinolin-1(2H)-one (4106, compound 191 in Table 4) (80 mg, 54% yield) as a yellow solid.
Reaction SMILES: [ClH:1].[CH3:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[CH2:4].N(C(C1C=CC2C(=CC=C(C(C)(N=C=O)C)C=2)C=1)(C)C)=C=O.[O-]C#N.[Na+].N1C=CC=CC=1>C(Cl)Cl.[Cl-].[Zn+2].[Cl-].O>[CH3:4][C:3]([Cl:1])([CH3:2])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C=C(C)c1ccccc1
Reactant: Cl
Agent: CC(C)(N=C=O)c1ccc2cc(C(C)(C)N=C=O)ccc2c1
Agent: N#C[O-]
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(Cl)c1ccccc1
Temperature: 4 °C

Procedure:
α,α-Dimethylbenzylchloride was prepared by passing a stream of dry hydrogen chloride gas through a solution of methylene dichloride (750 ml.) and α-methylstyrene (500 g, 4.2 moles) at 4° C. The reaction and work-up were employed for the paration of 2,6-bis(1-isocyanato-1-methylethyl)naphthalene described in Example 4. The resulting monochloride was dissolved in 750 ml. methylene dichloride and was added to a cooled (4° C.) catalyst solution previously prepared from anhydrous, 90% sodium cyanate (389 g,5.39 moles), pyridine (50 ml., 0.633 mole), zinc chloride (39.15 g,0.28 mole) and 1 ml. H2O in 1075 ml methylene dichloride.
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[CH:9][C:8]([C:11]2([CH3:16])[O:15][CH2:14][CH2:13][O:12]2)=[CH:7][CH:6]=1.[CH2:17](Br)[CH:18]=[C:19]([CH3:21])[CH3:20].[Cl-].[NH4+]>O1CCCC1.O.BrCCBr>[CH3:16][C:11]1([C:8]2[CH:9]=[CH:10][C:5]([CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:6][CH:7]=2)[O:15][CH2:14][CH2:13][O:12]1
Reactant: CC(C)=CCBr
Reactant: CC1(c2ccc(Br)cc2)OCCO1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: BrCCBr
Solvent: O
Solvent: C1CCOC1
Product: CC(C)=CCc1ccc(C2(C)OCCO2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.7 %

Procedure:
To a mixture of 10.2 g of magnesium turnigns, 300 ml of tetrahydrofuran and a few pieces of iodine, was added 3.8 g of 1,2-dibromoethane with stirring under a stream of nitrogen. Additionally, a solution of 93.0 g of 2-(p-bromophenyl)-2-methyl-1,3-dioxolane dissolved in 300 ml of tetrahydrofuran was dropped while keeping the temperature at 50°-55° C. After dropping, the reaction mixture was stirred for 30 minutes, and cooled to room temperature. A solution of 66.0 g of prenyl bromide in 100 ml of tetrahydrofuran was then dropped to the reaction mixture while keeping the reaction temperature at 50°-55° C., which was allowed to stand for overnight at room temperature. A solution of 20 g of ammonium chloride in 50 ml of water was added. The organic layer was decanted, concentrated and dissolved in ethyl ether. The ethereal solution was washed with water, dried, concentrated and distilled to give 69.1 g of 2-methyl-2-(p-prenylphenyl)-1,3-dioxolane, b.p. 106-107 °C/0.10 mmHg.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C:8]1[CH:9]=[C:10]([CH:36]=[CH:37][CH:38]=1)[CH:11]=[C:12]1[CH2:17][CH2:16][N:15]([C:18](=O)[CH2:19][NH:20][C:21]([NH:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]=[C:26]([CH3:34])[CH:25]=2)=[O:22])[CH2:14][CH2:13]1.CCOC(C)=O.C([O-])(O)=O.[Na+]>C1COCC1.CO>[CH3:7][C:8]1[CH:9]=[C:10]([CH:36]=[CH:37][CH:38]=1)[CH:11]=[C:12]1[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][NH:20][C:21]([NH:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]=[C:26]([CH3:34])[CH:25]=2)=[O:22])[CH2:16][CH2:17]1
Reactant: Cc1cccc(C=C2CCN(C(=O)CNC(=O)Nc3cc(C)nc4ccccc34)CC2)c1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cccc(C=C2CCN(CCNC(=O)Nc3cc(C)nc4ccccc34)CC2)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a suspension of LiAlH4 (100 mg, 2.6 mmol) in THF (40 mL) is added a solution of crude 1-{2-[4-(3-methyl-benzylidene)-piperidin-1-yl]-2-oxo-ethyl}3-(2-methyl-quinolin-4-yl)-urea (1 mmol) in THF (10 mL) and the mixture is stirred at room temperature for 15 h. The suspension is poured slowly into EtOAc (200 mL) and MeOH (10 mL) and, subsequently, sat. NaHCO3 (dropwise, total of 1.5 mL) is added. The precipitate is filtered off and washed with MeOH (2×20 mL). The filtrate is dried (Na2SO4), filtered and evaporated. The residue is purified by flash chromatography (SiO2, CH2Cl2-MeOH, 10:1) to provide the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4](=[O:8])(=[O:7])[CH2:3][CH:2]1[C:9]([O:11][CH3:12])=[O:10].[C:13]([NH:20][CH2:21][CH:22]=O)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:17][C:16]([O:15][C:13]([NH:20][CH2:21][CH2:22][N:1]1[CH2:6][CH2:5][S:4](=[O:7])(=[O:8])[CH2:3][CH:2]1[C:9]([O:11][CH3:12])=[O:10])=[O:14])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)NCC=O
Reactant: COC(=O)C1CS(=O)(=O)CCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COC(=O)C1CS(=O)(=O)CCN1CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 15.7 %

Procedure:
To a stirred solution of methyl 3-thiomorpholinecarboxylate 1,1-dioxide (D16; 1.08 g, 5.6 mmol) in 14 ml of anhydrous 1,2-dichloroethane was added N-boc-2-aminoacetaldehyde (1.1 g, 6.7 mmol) and acetic acid (0.316 ml, 5.6 mmol). After 30 min. sodium triacetoxyborohydride (1.78 g, 8.4 mmol) was added and the solution stirred at room temperature. Additional aliquots of N-boc-2-aminoacetaldehyde and sodium triacetoxyborohydride (1.0 g, 4.7 mmol) were added and the reaction continued overnight. The solvent was removed under reduced pressure and the residue was purified by SCX column, followed by chromatography (silica, cyclohexane:ethyl acetate 70:30 to 1:1) and again SCX, to give 295 mg of the target compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][O:14][C:15]=2[CH3:16])=[O:10])=[CH:4][CH:3]=1.[I:17][CH2:18][CH2:19][CH2:20]I.C(=O)([O-])[O-].[K+].[K+]>>[I:17][CH2:18][CH2:19][CH2:20][O:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][O:14][C:15]=2[CH3:16])=[O:10])=[CH:4][CH:3]=1
Reactant: ICCCI
Reactant: Cc1oncc1C(=O)Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1oncc1C(=O)Nc1ccc(OCCCI)cc1
Reaction time: 4 h

Procedure:
6.5 g (0.03 mol) of 5-methylisoxazole-4-carboxylic acid (4-hydroxyphenyl)amide are dissolved in 57 ml (0.5 mol) of 1,3-diiodopropane and 26.2 g (0.19 mol) of finely ground potassium carbonate are added with intensive stirring. The reaction is complete after approximately 4 h. Working up is carried out by means of filtration, concentration and chromatography on silica gel by means of ethyl acetate/petroleum ether 1:1 with addition of 1% glacial acetic acid. The yield of the process was 6.7 g.
Reaction SMILES: [F:1][C:2]([F:29])([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=1)[C:3]1[N:12]=[C:11](SC)[C:10]2[C:5](=[C:6]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][C:16]3=[O:21])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.ClC1C=CC=C(C(OO)=O)C=1.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+].[CH3:53][C:54]1[NH:58][N:57]=[C:56]([NH2:59])[CH:55]=1>C(Cl)Cl.C1COCC1>[F:1][C:2]([F:29])([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=1)[C:3]1[N:12]=[C:11]([NH:59][C:56]2[CH:55]=[C:54]([CH3:53])[NH:58][N:57]=2)[C:10]2[C:5](=[C:6]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][C:16]3=[O:21])[CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: CSc1nc(C(F)(F)c2ccc(F)cn2)nc2c(N3CCOCC3=O)cccc12
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cc(Nc2nc(C(F)(F)c3ccc(F)cn3)nc3c(N4CCOCC4=O)cccc23)n[nH]1
Reaction time: 0.5 h
Yield: 19.9 %

Procedure:
To 4-(2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazolin-8-yl)morpholin-3-one (180 mg, 0.428 mmol) in DCM (5 mL) at 0° C. was added 3-chloroperbenzoic acid (70%, 158 mg, 0.64 mmol) and the mixture was stirred for 30 min. The mixture was diluted with DCM and then aq sodium thiosulfate was added, followed by saturated aq sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure. To the residue were added THF (3 mL) and 5-methyl-1H-pyrazol-3-amine (124 mg, 1.28 mmol) and the mixture was stirred at rt for 5 min. A precipitate formed which was collected by filtration and then purified by preparative HPLC (Varian C-18 reverse phase column, eluted with gradient of solvent B=0.05% formic acid/ACN and solvent A=5% ACN/0.05% formic acid/H2O) to afford 4-(2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-8-yl)morpholin-3-one (40 mg, 20%). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.21 (s, 3H) 3.65 (d, J=4.52 Hz, 2H) 3.85-3.93 (m, 2H) 4.18 (s, 2H) 6.20 (s, 1H) 7.63-7.71 (m, 1H) 7.82 (d, J=7.16 Hz, 1H) 7.93-8.05 (m, 2H) 8.57-8.73 (m, 2H) 10.84 (br s, 1H) 12.24 (br s, 1H); LC-MS (ESI) m/z 470 (M+H)+.
Reaction SMILES: ClCC(OC)=O.[CH2:7]([C:9]1[O:10][C:11]2[CH:31]=[CH:30][CH:29]=[CH:28][C:12]=2[C:13]=1[C:14]([C:16]1[CH:27]=[CH:26][C:19]([O:20][CH2:21][C:22](OC)=[O:23])=[CH:18][CH:17]=1)=[O:15])[CH3:8].O.[NH3:33]>>[CH2:7]([C:9]1[O:10][C:11]2[CH:31]=[CH:30][CH:29]=[CH:28][C:12]=2[C:13]=1[C:14]([C:16]1[CH:27]=[CH:26][C:19]([O:20][CH2:21][C:22]([NH2:33])=[O:23])=[CH:18][CH:17]=1)=[O:15])[CH3:8]
Reactant: CCc1oc2ccccc2c1C(=O)c1ccc(OCC(=O)OC)cc1
Reactant: N
Agent: COC(=O)CCl
Solvent: O
Product: CCc1oc2ccccc2c1C(=O)c1ccc(OCC(N)=O)cc1

Procedure:
According to the Procedure B of Example 1, the intermediate of the Example 3 was reacted with methyl chloroacetate. The resulting product methyl 4-(2-ethyl-benzofuroyl) phenoxyacetate (Compound 11) was treated with concentrated ammonia water 28%) 100 ml and was stirred under ice-cooled condition for three hours. The white powder thus obtained, after drying was recrystallized from methanol.