Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:41]=[CH:42][CH:43]=1)[C:8]([NH:10][C:11]1[S:12][C:13]2[CH2:40][CH2:39][CH2:38][CH2:37][C:14]=2[C:15]=1[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)=[O:17])=[O:9])(=[O:4])=[O:3].[C:44]([N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)(=[O:46])[CH3:45]>ClCCl>[C:44]([N:47]1[CH2:52][CH2:51][N:50]([S:2]([C:5]2[CH:6]=[C:7]([CH:41]=[CH:42][CH:43]=2)[C:8]([NH:10][C:11]2[S:12][C:13]3[CH2:40][CH2:39][CH2:38][CH2:37][C:14]=3[C:15]=2[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]3[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=3)=[CH:21][CH:20]=2)=[O:17])=[O:9])(=[O:4])=[O:3])[CH2:49][CH2:48]1)(=[O:46])[CH3:45]
Reactant: CC(=O)N1CCNCC1
Reactant: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(S(=O)(=O)Cl)c4)sc4c3CCCC4)cc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(S(=O)(=O)N5CCN(C(C)=O)CC5)c4)sc4c3CCCC4)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.9 %

Procedure:
A mixture of 300 mg of methyl 4-[2-(4-{[(2-{[3-(chlorosulfonyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate, 181 mg of 1-acetylpiperazine, and 3.0 mL of dichloromethane was stirred at room temperature overnight, and then the reaction mixture was concentrated under reduced pressure. The obtained residue was washed with ethanol and water in this order to obtain 305 mg of methyl 4-{2-[4-({[2-({3-[(4-acetylpiperazin-1-yl)sulfonyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]ethyl}benzoate as a pale yellow solid.
Reaction SMILES: C([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[S:6]1(=[O:29])=[O:28])(C)(C)C.C(=O)([O-])[O-].[K+].[K+].[CH2:36](Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(O)(C(F)(F)F)=O>[CH2:36]([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[S:6]1(=[O:28])=[O:29])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(C)(C)N1C(=O)C(NCCCCc2ccccc2)=C(c2ccccc2)S1(=O)=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: O=C1C(NCCCCc2ccccc2)=C(c2ccccc2)S(=O)(=O)N1Cc1ccccc1
Temperature: 120 °C
Reaction time: 0.08 h
Yield: 54.7 %

Procedure:
2-tert-Butyl-5-phenyl-4-[(4-phenylbutyl)amino]isothiazol-3(2H)-one 1,1-dioxide (Example 1) (0.150 g, 0.36 mmol) was dissolved in TFA (3 ml) and heated in a microwave reactor at 120° C. for 20 mins. The reaction mixture was concentrated and the residue was repeatedly dissolved in DCM and evaporated. The crude product was dissolved in dry MeCN (3 ml) and potassium carbonate (0.251 g, 1.82 mmol) and benzylbromide (0.075 g, 0.44 mmol) was added. The reaction mixture was heated at 120° C. for 15 mins and then at 130° C. for 5 mins in a microwave reactor. The reaction mixture was purified by silica gel column chromatography using a 90:10 mixture of hexane and EtOAc as eluant, to give the title compound (0.088 g, 54%). 1H NMR (500 MHz, CDCl3): δ 7.55-7.49 (m, 4H), 7.48-7.31 (m, 6H), 7.31-7.25 (m, 2H), 7.23-7.17 (m, 1H), 7.11-7.05 (m, 2H), 5.31-5.25 (m, 1H), 4.85 (s, 2H), 2.90-2.82 (m, 2H), 2.50-2.42 (m, 2H), 1.45-1.33 (m, 4H); 13C NMR (125 MHz, CDCl3): δ 159.3, 141.7, 135.6, 134.6, 131.8, 130.0, 129.0, 128.9, 128.9, 128.6, 128.5, 128.5, 126.2, 125.1, 107.0, 44.2, 43.8, 35.4, 29.2, 28.3
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]3[C:15](=[O:19])[NH:16][N:17]([CH3:18])[C:13]=3[NH:12][C:11]3[CH2:20][CH2:21][C:22](=[O:23])[C:10]2=3)[CH:5]=[CH:6][C:7]=1[F:8].Cl[C:25]([O:27][CH3:28])=[O:26].N1C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]3[C:15](=[O:19])[N:16]([C:25]([O:27][CH3:28])=[O:26])[N:17]([CH3:18])[C:13]=3[NH:12][C:11]3[CH2:20][CH2:21][C:22](=[O:23])[C:10]2=3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC(=O)Cl
Reactant: Cn1[nH]c(=O)c2c1NC1=C(C(=O)CC1)C2c1ccc(F)c(Br)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)n1c(=O)c2c(n1C)NC1=C(C(=O)CC1)C2c1ccc(F)c(Br)c1

Procedure:
The product from Example 1 (0.1 g) in methylene chloride (10 mL) was stirred overnight with methyl chloroformate (0.04 mL) and pyridine (0.06 mL). The reaction mixture was evaporated under reduced pressure and the residue was chromatographed on silica gel eluting with 5% ethanol/methylene chloride to provide 0.038 g of the title compound. 1H NMR (DMSO-d6) δ 2.32 (t, 2H), 2.72 (m, 2H), 3.65 (s, 3H), 3.7 (s, 3H), 4.72 (s, 1H), 7.11 (m, 1H), 7.22 (t, 1H), 7.32 (dd, 1H), 10.80 (s, 1H); MS (ESI+) m/z 438 (M+H)+; Anal. Calcd for C18H15N3BrFO4: C, 49.54; H, 3.44; N, 9.63. Found: C, 49.69; H, 3.27; N, 9.72.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:30][C@@H:31]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[O:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23](O)=[O:24])=[C:19]([S:26][CH:27]([CH3:29])[CH3:28])[CH:18]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:45]1[CH:50]=[CH:49][CH:48]=[C:47]([S:51]([NH2:54])(=[O:53])=[O:52])[CH:46]=1.C1CCN2C(=NCCC2)CC1.Cl>CN(C)C=O.C(OCC)(=O)C>[CH:27]([S:26][C:19]1[CH:18]=[C:17]([C:14]2[CH:13]=[CH:12][C:11]([CH2:10][CH2:9][N:8]([CH2:30][C@@H:31]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[O:32][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][O:34]3)[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:16][CH:15]=2)[CH:22]=[CH:21][C:20]=1[C:23]([NH:54][S:51]([C:47]1[CH:46]=[N:45][CH:50]=[CH:49][CH:48]=1)(=[O:53])=[O:52])=[O:24])([CH3:28])[CH3:29]
Reactant: CC(C)Sc1cc(-c2ccc(CCN(C[C@H](OC3CCCCO3)c3ccccc3)C(=O)OC(C)(C)C)cc2)ccc1C(=O)O
Reactant: NS(=O)(=O)c1cccnc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)Sc1cc(-c2ccc(CCN(C[C@H](OC3CCCCO3)c3ccccc3)C(=O)OC(C)(C)C)cc2)ccc1C(=O)NS(=O)(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of 4′-[2-[(tert-butoxycarbonyl)[(2R)-2-phenyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]amino]ethyl]-3-(isopropylthio)-4-biphenylcarboxylic acid (500 mg) in N,N-dimethylformamide (5 ml) was added N,N′-carbonyldiimidazole (157 mg) and stirred at room temperature for 30 minutes. To the mixture were added 3-pyridinesulfonamide (153 mg) and 1,8-diazabicyclo[5.4.0]-7-undecene (145 μl) and stirred at room temperature for 3 hours. The reaction mixture was poured into 0.1N hydrochloric acid and ethyl acetate and the organic layer was separated. The organic layer was washed with water and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified with silica gel column chromatography to give tert-butyl [2-[3′-(isopropylthio)-4′-[[(3-pyridylsulfonyl)amino]carbonyl]-4-biphenylyl]-ethyl][(2R)-2-phenyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]carbamate (613 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3](=[O:22])[CH2:4][N:5]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@:7]2([CH2:20][CH2:19][CH2:18][NH:17][CH2:16]2)[C:6]1=[O:21].CN(C)C(=O)CN1C[C@@H](C2C=CC=CC=2)[C@@]2(CCCNC2)C1=O.[CH2:47]([O:54][CH2:55][C@@H:56]([NH:60][C:61](=[O:73])[C:62]([NH:65][C:66]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:67])([CH3:64])[CH3:63])[C:57](O)=[O:58])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C(#N)C>[CH2:47]([O:54][CH2:55][C@@H:56]([NH:60][C:61](=[O:73])[C:62]([NH:65][C:66](=[O:67])[O:68][C:69]([CH3:72])([CH3:71])[CH3:70])([CH3:64])[CH3:63])[C:57]([N:17]1[CH2:18][CH2:19][CH2:20][C:7]2([C:6](=[O:21])[N:5]([CH2:4][C:3]([N:2]([CH3:23])[CH3:1])=[O:22])[CH2:9][CH:8]2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:16]1)=[O:58])[C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](COCc1ccccc1)C(=O)O
Reactant: CN(C)C(=O)CN1C[C@H](c2ccccc2)[C@]2(CCCNC2)C1=O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)C(=O)CN1C[C@@H](c2ccccc2)[C@@]2(CCCNC2)C1=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)CN1CC(c2ccccc2)C2(CCCN(C(=O)[C@@H](COCc3ccccc3)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C2)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A racemic mixture of (4R,5S)—N,N-dimethyl-2-(1-oxo-4-phenyl-2,7-diazaspiro[4.5]decan-2-yl)acetamide and (4S,5R)—N,N-Dimethyl-2-(1-oxo-4-phenyl-2,7-diazaspiro[4.5]decan-2-yl)acetamide (Intermediate 1D) (193 mg; 0.612 mmol) was solubilised in acetonitrile (3 ml). (R)-3-Benzyloxy-2-(2-tert-butoxycarbonylamino-2-methylpropionylamino)-propionic acid (Intermediate 3A) (233 mg; 0.612 mmol) was treated with DIPEA (0.427 ml; 2.448 mmol) and ®T3P (50% in EtOAc), (0.714 ml; 1.224 mmol). The mixture was stirred at RT for 2 hours and concentrated in vacuo. The crude residue was solubilised in ethyl acetate and washed with water (3×50 ml). The organics were washed with brine, dried with magnesium sulfate, filtered and concentrated to yield the title compound.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:19](=[O:20])[O:18][CH:17]([C:21]([F:24])([F:23])[F:22])[N:16]=2)=[CH:11][CH:10]=1.[Br:25][C:26]1[S:27][CH:28]=[C:29]([CH:31]=[CH:32][N+:33]([O-:35])=[O:34])[CH:30]=1>C1(C)C=CC=CC=1.Cl.CCOCC>[Br:25][C:26]1[S:27][CH:28]=[C:29]([CH:31]([C:17]2([C:21]([F:22])([F:24])[F:23])[N:16]=[C:15]([C:12]3[CH:11]=[CH:10][C:9]([Cl:8])=[CH:14][CH:13]=3)[C:19](=[O:20])[O:18]2)[CH2:32][N+:33]([O-:35])=[O:34])[CH:30]=1
Reactant: O=C1OC(C(F)(F)F)N=C1c1ccc(Cl)cc1
Reactant: O=[N+]([O-])C=Cc1csc(Br)c1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C1OC(C(C[N+](=O)[O-])c2csc(Br)c2)(C(F)(F)F)N=C1c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A solution of triethylamine (0.30 g, 3 mmol) in toluene is added to a solution of 4-(p-chlorophenyl)-2-(trifluoromethyl)-3-oxazolin-5-one (10.00 g, 38 mmol) and 2-bromo-4-(2-nitrovinyl)thiophene (8.98 g, 32 mmol) in toluene at 0° C. The reaction mixture is warmed to room temperature and diluted with dilute hydrochloric acid and ether. The organic layer is separated, dried over MgSO4, concentrated in vacuo, diluted with hexane, stirred at reflux, cooled to room temperature and decanted to obtain a clear solution. The solution is concentrated in vacuo and chromatographed to give the title product.
Reaction SMILES: Br[C:2]1[C:6]([Br:7])=[CH:5][S:4][CH:3]=1.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C(O)C.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>[Br:7][C:6]1[C:2]([C:13]2[CH:14]=[CH:15][C:10]([O:9][CH3:8])=[CH:11][CH:12]=2)=[CH:3][S:4][CH:5]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Brc1cscc1Br
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: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2cscc2Br)cc1
Temperature: 75 °C
Reaction time: 13 h
Yield: 30.5 %

Procedure:
To a mixture of 3,4-dibromothiophene (Scheme I, 1) (5 g, 20.7 mmol), 4-methoxyphenylboronic acid (Scheme I, 2, X1=4-methoxyphenyl) (3.14 g, 20.7 mmol), sodium carbonate (4.38 g, 41.3 mmol), toluene (100 mL), in a mixture of ethanol (60 mL) and water (40 mL) was added Pd(PPh3)4 (2.02 g, 1.75 mmol) under nitrogen. The mixture was stirred at 75° C. for 13 h, poured into water (60 mL), and extracted with ethyl acetate (60 mL×3). The organic extracts were dried over anhydrous magnesium sulfate (10 g), evaporated, and purified by column chromatography on silica gel (petroleum ether/ethyl acetate=150:1) to give 3-bromo-4-(4-methoxyphenyl)thiophene (Scheme 1, 2, X1=4-methoxyphenyl) (1.7 g, yield 30.6%). 1H NMR (DMSO-d6 400 MHz): δ 7.84 (d, J=3.2 Hz, 1H), 7.64 (d, J=3.2 Hz, 1H), 7.42 (d, J=8.8 Hz, 2H), 6.97 (d, J=8.8 Hz, 2H), 3.78 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1>CN(C=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:22][C:21]2[CH:24]=[CH:25][C:18]([F:17])=[CH:19][CH:20]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Fc1ccc(CBr)cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCc2ccc(F)cc2)cc1
Temperature: 100 °C
Reaction time: 48 h
Yield: 95.9 %

Procedure:
A mixture of 4-nitrophenol (1.39 g, 10 mmol), potassium carbonate (1.38 g, 10 mmol) and 4-fluorobenzyl bromide (1.89 g, 10 mmol) in 20 ml of anhydrous DMF was stirred at 100° C. for 2 days. After cooling to room temperature, the reaction mixture was poured into 200 ml of ice-water with stirring. The solid was filtered and washed with water and dried to give 2.37 g (96%) of 1-nitro-4-(4-fluorobenzyloxy)-benzene as yellow solids.
Reaction SMILES: [NH2:1][CH2:2][P:3](=[O:6])([OH:5])[OH:4].O.[C:8]([OH:12])(=[O:11])[CH:9]=O>[Pd]>[NH2:1][CH2:2][P:3](=[O:4])([OH:6])[OH:5].[CH2:9]([NH:1][CH2:2][P:3]([OH:5])([OH:4])=[O:6])[C:8]([OH:12])=[O:11]
Reactant: O=CC(=O)O
Agent: [Pd]
Agent: NCP(=O)(O)O
Solvent: O
Product: O=C(O)CNCP(=O)(O)O

Procedure:
Aminomethylphosphonic acid was reductively alkylated with glyoxylic acid hydrate under catalytic hydrogenation conditions in the manner described in Example 2, except that the catalyst used was palladium metal (0.05 g), and the pH of the initial reaction mixture was 4.5. A 27% conversion of aminomethylphosphonic acid was obtained with a 93.7% selectivity to glyphosate.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]2[CH2:28][N:27]([C:29](=[O:31])[CH3:30])[CH2:26][CH2:25][C:9]=2[N:10]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:24][CH:23]=[N:22][CH:21]=3)=[CH:16][CH:15]=2)[N:12]=1)(=O)=O.[CH3:34][NH:35][CH2:36][CH:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[OH:38]>CS(C)=O>[OH:38][CH:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:36][N:35]([CH3:34])[C:7]1[C:8]2[CH2:28][N:27]([C:29](=[O:31])[CH3:30])[CH2:26][CH2:25][C:9]=2[N:10]=[C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[O:24][CH:23]=[N:22][CH:21]=3)=[CH:18][CH:19]=2)[N:12]=1
Reactant: CNCC(O)c1ccccc1
Reactant: CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(OS(=O)(=O)C(F)(F)F)c2C1
Solvent: CS(C)=O
Product: CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(N(C)CC(O)c3ccccc3)c2C1
Reaction time: 8 h
Yield: 64.6 %

Procedure:
6-Acetyl-2-(4-(oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl trifluoromethanesulfonate (35 mg, 0.07 mmol, Example 26a) in DMSO (1 mL) dispensed in a library plate. 2-(methylamino)-1-phenylethanol (10.58 mg, 0.07 mmol) was added and it was left to shake overnight at 80° C. before filtered and purified by preparative HPLC to yield 1-(4-((2-hydroxy-2-phenylethyl)(methyl)amino)-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanone (21.9 mg, 63%).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:15]1[CH:19]=[C:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[N:17]=[C:16]1[C@H:24]([NH2:35])[CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:36](Cl)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(#N)C.C(OCC)(=O)C.O>[CH2:36]([NH:35][C@@H:24]([C:16]1[N:15]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:19]=[C:18]([C:20]([CH3:22])([CH3:23])[CH3:21])[N:17]=1)[CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: ClCc1ccccc1
Reactant: CC(C)(C)c1cn(Cc2ccccc2)c([C@H](N)Cc2c[nH]c3ccccc23)n1
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cn(Cc2ccccc2)c([C@@H](Cc2c[nH]c3ccccc23)NCc2ccccc2)n1
Temperature: 23 °C
Reaction time: 1 h
Yield: 5 %

Procedure:
Triethylamine (0.83 ml; 0.006 mol) is added at 23° C. to a solution containing (1R)-1-(1-benzyl-4-tert-butyl-1H-imidazol-2-yl)-2-(1H-indol-3-yl)ethanamine (0.7 g; 0.002 mol; prepared under experimental conditions similar to those previously and using suitable starting reagents and reaction products) in 15 ml of acetonitrile. The mixture is stirred for one hour at 23° C. then benzyl chloride (0.23 ml; 0.002 mol) is added. Stirring is maintained for 16 hours. The reaction mixture is concentrated using a rotary evaporator and the oil obtained is taken up in ethyl acetate and water. The aqueous phase is extracted with ethyl acetate and washed with water then with a saturated solution of sodium chloride. The solvents are evaporated off under vacuum. After purification on a silica column (eluent: AE-heptane/7-3), a deep beige-coloured solid is obtained in the form of a paste (yield of 5%). Free base. Melting point: 60-62° C.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].FC(S(O[C:15]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=2)[N:18]=[C:17]([CH2:29][C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:31])[N:16]=1)(=O)=O)(F)F.[NH2:38][C:39]1[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=1>C1COCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:28][O:27][C:23]1[CH:22]=[C:21]([C:19]2[N:18]=[C:17]([CH2:29][C:30]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[O:31])[N:16]=[C:15]([NH:38][C:39]3[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=3)[CH:20]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: Nc1cccnc1
Reactant: COc1cccc(-c2cc(OS(=O)(=O)C(F)(F)F)nc(CC(=O)N3CCOCC3)n2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: COc1cccc(-c2cc(Nc3cccnc3)nc(CC(=O)N3CCOCC3)n2)c1
Temperature: 25 °C

Procedure:
A round bottom flask, oven dried and kept under N2 atmosphere is charged with Cs2CO3 (1.4 eq), Pd(OAc)2 (5 mol %), and S-(−)-BINAP (7.5 mol %). The flask is purged with N2 for about 5-10 min and a solution of compound 9 (1 eq) in dry THF is added via a syringe, followed by 3-aminopyridine (2 eq) in one portion. The flask is equipped with a reflux condenser, purged again with N2 for 5 min and the reaction mixture is refluxed overnight. The reaction mixture is cooled down to room temperature and the solvent is evaporated under reduced pressure. The residue is washed with water (×2) and triturated with methanol to afford the desired 2-[6-(3-methoxyphenyl)-4-(3-pyridylamino)pyrimidin-2-yl]-1-morpholin-4-ylethan-1-one 10.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.[N+:13]([CH:15](S(C1C=CC(C)=CC=1)(=O)=O)[CH2:16][CH3:17])#[C-:14].C([O-])([O-])=O.[K+].[K+]>CO>[CH2:16]([C:15]1[N:13]=[CH:14][O:8][C:7]=1[C:6]1[CH:9]=[CH:10][C:3]([C:2]([F:11])([F:12])[F:1])=[CH:4][CH:5]=1)[CH3:17]
Reactant: [C-]#[N+]C(CC)S(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCc1ncoc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 88.3 %

Procedure:
A mixture of 4-(trifluoromethyl)benzaldehyde (3.60 mL, 27.0 mmol), 1-(1-isocyanopropylsulfonyl)-4-methylbenzene (6.02 g, 27.0 mmol), and K2CO3 (4.47 g, 32.4 mmol) in MeOH (100 mL) was heated to reflux. After 1.5 hr the reaction mixture was cooled to ambient temperature, and the volatiles evaporated at reduced pressure. The residue was partitioned between Et2O (100 mL) and H2O (100 mL). The separated aqueous phase was extracted with Et2O. The combined organic extract was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. Chromatography on silica gel (Analogix® Intelliflash 280™; SF40-150 g column; 10% to 30% EtOAc/hexanes eluant, 30 min) afforded 5.75 g (88%) of the title compound as a pale yellow oil. 1H NMR (300 MHz, DMSO-d6) δ 8.44 (s, 1H), 7.90-7.78 (m, 4H), 2.79 (q, J=7.5, 2H), 1.23 (t, J=7.5, 3H). MS (DCI+) m/z 242 (M+H).
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[OH:17][NH3+:18]>C(O)C>[C:1]1([C:7](=[N:18][OH:17])[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)c1ccccc1
Reactant: [NH3+]O
Agent: [Cl-]
Solvent: CCO
Product: ON=C(Cc1ccccc1)c1ccccc1
Yield: 24.1 %

Procedure:
A mixture of 1,2-diphenylethanone (19.6 g, 100 mmol) and hydroxyl ammonium chloride (13.9 g, 200 mmol) in absolute ethanol (200 ml) was heated at reflux for 4 h. The solvent was evaporated in vacuo and the residue extracted with dichloromethane (2×100 ml). The combined organic phases were washed with water (2×50 ml) and brine (10 ml) and dried (MgSO4). The solvent was evaporated in vacuo and the residue left for crystallisation. The crystallised product was suspended in n-heptane/diethylether 20/1 and the precipitate collected to give 5.1 g of 1,2-diphenylethanone oxime.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:18])OCC(Cl)(Cl)Cl)[N:7]([CH3:19])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:20]1([C:26]2[N:30]=[C:29]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[S:28][N:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([N:34]2[CH2:35][CH2:36][N:31]([C:29]3[S:28][N:27]=[C:26]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:30]=3)[CH2:32][CH2:33]2)=[O:18])[N:7]([CH3:19])[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: Cn1nc(C(C)(C)C)cc1NC(=O)OCC(Cl)(Cl)Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cn1nc(C(C)(C)C)cc1NC(=O)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 70 °C
Reaction time: 15 h
Yield: 74.7 %

Procedure:
A mixture of 2,2,2-trichloroethyl (3-tert-butyl-1-methyl-1H-pyrazol-5-yl)carbamate (294 mg, 0.895 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and diisopropylethylamine (0.156 ml, 0.895 mmol) in dimethylsulfoxide (2.7 ml) was stirred at 70° C. for 15 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 258 mg (74.8%) of the desired product as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)=[O:4].Cl[C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([OH:25])[CH:21]=2)[N:16]=1.C([O-])([O-])=O.[Na+].[Na+]>>[OH:25][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([C:8]1[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=1)[CH:24]=[CH:23]2
Reactant: Oc1ccc2nc(Cl)ccc2c1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1ccc(-c2ccc3cc(O)ccc3n2)cc1

Procedure:
Scheme 1, step 1, starting from 4-(methoxycarbonyl)phenylboronic acid and 2-chloroquinolin-6-ol, using Na2CO3 instead of TEA.
Reaction SMILES: [C:1]1([C:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(O)=[O:14].[Na+].OOS([O-])=O.[K+].O>C(#N)C.O>[C:1]1([C:7]23[O:14][CH:8]2[CH2:9][CH2:10][CH2:11][CH2:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C([O-])O
Reactant: C1=C(c2ccccc2)CCCC1
Agent: O=S([O-])OO
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: c1ccc(C23CCCCC2O3)cc1
Reaction time: 2 h
Yield: 83 %

Procedure:
To a solution of phenyl cyclohexene (79 mg, 0.5 mmol) in a mixture of acetonitrile (4.5 ml) and water (2 drops) were added first finely crushed NaHCO3 (168 mg, 2 mmol) and oxone (307 mg, 0.5 mmol) then the catalyst (0.05 mmol). The resulting yellow suspension was allowed to react at RT, under good stirring. TLC was used to follow the reaction which indicated that the reaction was finished in 2 h. Water (3 ml) was added to the reaction mixture followed by extraction into methylene dichloride. The organic extracts were combined and dried over anhydrous sodium sulphate. Concentration on a rotary evaporator gave a material which was purified on a column using 2% ethyl acetate:petrol mixture as eluent to give the desired compound as a colourless oil. (72 mg, 83% yield, 70% e.e).