Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:21]([CH2:31][OH:32])[C:20]([CH2:33][CH3:34])=[CH:19]1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3].C([O:38]N([C@H]1CN(C(OC(C)(C)C)=O)[C@H](C(O)=O)C=C1C)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)C=C>>[CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[C@H:21]([C:31]([OH:38])=[O:32])[C:20]([CH2:33][CH3:34])=[CH:19]1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCON([C@@H]1C=C(CC)[C@@H](CO)N(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](C(=O)O)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Product: C=CCON([C@@H]1C=C(CC)[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccccc1[N+](=O)[O-]

Procedure:
The title compound was prepared from (2S,5R)-tert-butyl 5-(N-(allyloxy)-2-nitrophenylsulfonamido)-3-ethyl-2-(hydroxymethyl)-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 210, 2.35 g, 4.72 mmol) following the procedure described for Intermediate 19. The title compound was obtained as a tan foam (1.89 g, 78%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[H-].[Na+].[CH3:14][O:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([CH2:23]Br)=[CH:19][CH:18]=1.C([O-])(O)=O.[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:23][C:20]2[CH:21]=[CH:22][C:17]([C:16]([O:15][CH3:14])=[O:25])=[CH:18][CH:19]=2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: Nc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CNc2ccc(Cl)cc2[N+](=O)[O-])cc1
Reaction time: 0.5 h

Procedure:
To 4-chloro-2-nitroaniline (10 mmol, 1.73 g) in DMF (10 mL) was added NaH (11 mmol, 440 mg of 60% suspension in mineral oil). After 30 min the reaction vessel was placed in a water bath and methyl-4-(bromomethyl)benzoate (11 mmol, 2.52 g) was added (exothermic). The reaction mixture was allowed to stand at ambient temperature for 16 h, then poured into saturated NaHCO3, affording an orange precipitate which was filtered, washed with water and dried in vacuo. Purification by flash chromatography on silica eluting with 15% EtOAc in hexanes provided the product as an orange solid. LC-MS (ESI, Method C) 3.79 min, m/z 321.1 (M+1).
Reaction SMILES: C(OC(=O)[N:7]([S:13]([C:16]1[CH:21]=[C:20]([Cl:22])[C:19]([O:23][C:24]2[CH:25]=[N:26][C:27](Cl)=[CH:28][C:29]=2[C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)=[CH:18][C:17]=1[F:37])(=[O:15])=[O:14])[C:8]1[S:9][CH:10]=[CH:11][N:12]=1)(C)(C)C.[F:39][C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][CH:45]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C)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>[Cl:22][C:20]1[C:19]([O:23][C:24]2[CH:25]=[N:26][C:27]([C:44]3[CH:43]=[CH:42][CH:41]=[C:40]([F:39])[CH:45]=3)=[CH:28][C:29]=2[C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)=[CH:18][C:17]([F:37])=[C:16]([S:13]([NH:7][C:8]2[S:9][CH:10]=[CH:11][N:12]=2)(=[O:15])=[O:14])[CH:21]=1
Reactant: CC(C)(C)OC(=O)N(c1nccs1)S(=O)(=O)c1cc(Cl)c(Oc2cnc(Cl)cc2-c2cccnc2)cc1F
Reactant: OB(O)c1cccc(F)c1
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: CN(C)C=O
Solvent: O
Product: O=S(=O)(Nc1nccs1)c1cc(Cl)c(Oc2cnc(-c3cccc(F)c3)cc2-c2cccnc2)cc1F
Reaction time: 0.17 h
Yield: 29.9 %

Procedure:
20 mg (0.03 mmol) of tert-butyl((5-chloro-4-((6′-chloro-[3,4′-bipyridin]-3′-yl)oxy)-2-fluorophenyl)sulfonyl)(thiazol-2-yl)carbamate was dissolved in 3 mL of N,N-dimethylformamide, and 7 mg (0.05 mmol) of (3-fluorophenyl)boronic acid was added thereto, and then 3.8 mg (10 mol %) of Pd(PPh3)4, 10.6 mg (0.10 mmol) of Na2CO3, and 1 mL of H2O were added thereto. After reacting with microwave reactor at 120° C. for 10 minutes, the solvent was removed, and the remaining material was diluted with ethyl acetate and the organic layer was separated, and washed with saturated sodium chloride. The organic layer was collected, dried with magnesium sulfate to remove water, and concentrated under reduced pressure, and the residue was purified by column chromatography (developing solvent, hexane:ethyl acetate=3:1) to obtain 5 mg (27% yield) of the title compound.
Reaction SMILES: [F:1][CH:2]([F:14])[C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=1.[Br:15]N1C(=O)CCC1=O.O=O>ClC(Cl)(Cl)Cl>[Br:15][C:2]([F:1])([F:14])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]([F:11])([F:12])[F:13])=[CH:7][CH:8]=1
Reactant: FC(F)c1ccc(OC(F)(F)F)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=O
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)Oc1ccc(C(F)(F)Br)cc1
Temperature: 25 °C

Procedure:
A solution of 2.38 g (11.22 mmol) of 1-(difluoromethyl)-4-(trifluoromethoxy)benzene and 6.19 g (34.78 mmol) of N-bromosuccinimide (NBS) in 25 ml of tetrachloromethane is irradiated with exclusion of oxygen using a sun lamp. During this, the solvent reaches its boiling point. It is irradiated under reflux for 48 hours. The mixture is then allowed to cool to room temperature, precipitated succinimide is filtered off, and the filtrate is evaporated to dryness. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane). 1.73 g (5.94 mmol, 53% of theory) of a yellowish oil are obtained.
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:6])[CH2:3][Mg]Cl.[F:13][C:14]([F:23])([F:22])[C:15](=[O:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(OCC)C.C1COCC1>[CH2:19]([O:18][C:16](=[O:17])[C:15]([OH:21])([C:14]([F:13])([F:22])[F:23])[CH2:3][C:2]([CH3:1])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6])[CH3:20]
Reactant: CCOC(=O)C(=O)C(F)(F)F
Reactant: CC(C)(C[Mg]Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)C(O)(CC(C)(C)c1ccccc1)C(F)(F)F
Reaction time: 2 h

Procedure:
To a room temperature solution of 45 mL (22.5 mmol) of a 0.5 M solution of 2-methyl-2-phenylpropylmagnesium chloride in diethyl ether was added 38 g (22.5 mmol) of ethyl trifluoropyruvate in 10 mL of anhydrous THF. The reaction became slightly warm to the touch and a white precipitate quickly developed. After 2 hours, the reaction was diluted with diethyl ether and quenched with 1 N aqueous HCl. The aqueous layer was separated and extracted with ether. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a brown oil. Chromatography on silica gel eluting with hexanes-EtOAc (98:2), afforded the title compound as a clear, colorless oil (4.6 g, 67%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([NH:14][NH2:15])[N:11]=[N:12][CH:13]=1.[C:16]([O-])([O-])(OCC)[CH3:17]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[N:12][N:11]2[C:16]([CH3:17])=[N:15][N:14]=[C:10]2[N:9]=1
Reactant: NNc1nncc(-c2ccccc2F)n1
Reactant: CCOC(C)([O-])[O-]
Product: Cc1nnc2nc(-c3ccccc3F)cnn12

Procedure:
A mixture of 6.15 g. of 5-(o-fluorophenyl)-3-hydrazino-1,2,4-triazine and 50 ml. of ethyl orthoacetate is refluxed for 2.5 hours, cooled and the solid is collected by filtration and washed with hexane and ethanol, giving the desired product as yellow crystals, m.p. 227°-229° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Cl[C:9]1[N:14]=[C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:12]=[C:11]([N:21]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[N:23]=[C:22]2[CH:30]([F:32])[F:31])[N:10]=1.O>CS(C)=O>[F:32][CH:30]([F:31])[C:22]1[N:21]([C:11]2[N:12]=[C:13]([N:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)[N:14]=[C:9]([NH:1][C:2]3[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=3)[N:10]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=1
Reactant: Nc1ccncc1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Solvent: O
Solvent: CS(C)=O
Product: FC(F)c1nc2ccccc2n1-c1nc(Nc2ccncc2)nc(N2CCOCC2)n1
Temperature: 120 °C
Yield: 19.9 %

Procedure:
A mixture of 0.048 g (0.51 mmol) of 4-aminopyridine and 0.095 g (0.26 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole in DMSO (1.5 mL) was heated at 120° C. for 1 hr. The reaction mixture was cooled to room temperature and water was added. The solid was collected by filtration and washed with water to give 0.022 g (20% yield) of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-(4-pyridinyl)-1,3,5-triazin-2-amine: mp (MeOH) 222-224° C.; 1H NMR (DMSO-d6) δ 10.30 (br s, 1H), 8.59-8.46 (m, 3H), 7.91-7.86 (m, 4H), 7.55-7.44 (m, 2H), 3.88 (br s, 4H), 3.77-3.76 (m, 4H); HRMS (FAB+) MNa+ Calcd. for C20H18F2N8NaO: m/z 447.1466. Found: m/z 447.1464; HRMS (FAB+) MH+ Calcd. for C20H19F2N8NO: m/z 425.1644. Found: m/z 425.1629.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1.Cl.[O-:23][C:24]#[N:25].[Na+]>>[NH:1]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)[C:24]([NH2:25])=[O:23]
Reactant: N#C[O-]
Reactant: Nc1ccc2c(c1)C(=Cc1c[nH]c3ncccc13)C(=O)N2
Agent: Cl
Agent: [Na+]
Product: NC(=O)Nc1ccc2c(c1)C(=Cc1c[nH]c3ncccc13)C(=O)N2
Temperature: 0 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
A mixture of 5-amino-3-[(7-azaindol-3-yl)methylene]-2-oxindole (2.773 g, 10 mmol) in ice water (20 ml) are added 5N HCl (2 ml, 10 mmol) under stirring. Then the mixture was heated to 70°14 80° C., sodium cyanate (0.715 g, 11 mmol) was added portionwise and the stirring was continued for further 4 h at this temperature. After cooling the raw product was extracted with CHCl3, the organic layer washed to neutrality with saline solution, dried and evaporated in vacuo. The residue was chromatographed on silica gel using CHCl3 --MeOH mixtures as eluant to give pure title compound in about 50% yield.
Reaction SMILES: [NH:1]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C@@H:2]([C:14]([N:16]([CH3:49])[C@H:17]([C:35]([NH:37][CH2:38][C:39]([O:41]CC1C=CC=CC=1)=[O:40])=[O:36])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:34])[NH:23][S:24]([C:27]1[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=1)(=[O:26])=[O:25])=[O:15])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([C:10]([F:13])([F:12])[F:11])=[O:9].C(OCC)C>CO>[NH:1]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C@@H:2]([C:14]([N:16]([CH3:49])[C@H:17]([C:35]([NH:37][CH2:38][C:39]([OH:41])=[O:40])=[O:36])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:34])[NH:23][S:24]([C:27]1[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=1)(=[O:25])=[O:26])=[O:15])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([C:10]([F:12])([F:11])[F:13])=[O:9]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@@H](C(=O)NCC(=O)OCc2ccccc2)N(C)C(=O)[C@@H](CCCCNC(=O)C(F)(F)F)NC(=O)OC(C)(C)C)cc1
Solvent: CO
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@@H](C(=O)NCC(=O)O)N(C)C(=O)[C@@H](CCCCNC(=O)C(F)(F)F)NC(=O)OC(C)(C)C)cc1
Reaction time: 1.5 h
Yield: 94 %

Procedure:
A solution of Boc-D-Lys(Tfa)-NMeArg(Tos)-Gly-OBzl (11.00 g, 13.5 mmol) in methanol (200 ml) was placed in a Parr shaker bottle, purged with N2 for 10 minutes, and treated with 10% palladium on carbon catalyst (10% Pd/C, 3.6 g). The shaker bottle was further purged with 7 pressurization-evacuation cycles, repressurized, and allowed to shake 90 minutes, during which time the calculated amount of hydrogen was consumed. The catalyst was removed by filtration through a bed of Celite and the filtrate was concentrated under reduced pressure yielding a solid. Trituration with refluxing ethyl ether (75 ml) gave pure product (9.18 g, 94%) as a colorless solid. DCI-MS: [M+H]=724.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8]([N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]2[C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)=[O:9])[CH2:2]1.C=O.[C:32](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[CH3:32][N:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8]([N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]2[C:20]2[CH:21]=[CH:22][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:24][CH:25]=2)=[O:9])[CH2:2]1
Reactant: O=C(N[C@@H]1CCCNC1)N1CCc2ccccc2C1c1ccc(C(F)(F)F)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CN1CCC[C@@H](NC(=O)N2CCc3ccccc3C2c2ccc(C(F)(F)F)cc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N—((R)-piperidin-3-yl)-1-(4-(trifluoromethyl)phenyl)-3,4-dihydro-isoquinoline-2(1H)-carboxamide (30 mg, 74 μmol, example 24) in DCE (0.5 mL) was added formaldehyde (28 μL, 372 mol). The resulting mixture was stirred at RT for 1 h and then sodium triacetoxyborohydride (16 mg, 74 μmol) was added. The mixture was then stirred at RT for 4 h. Then, saturated NaHCO3 (0.4 mL) was added and the mixture was extracted with EtOAc (2×3 mL). The combined organic extracts were dried over MgSO4 and concentrated. The residue was purified by silica gel flash column chromatography (0%-10% MeOH (2M NH3)/EtOAc) to give the title compound as an off-white solid. MS (ESI, positive ion) m/z: 418 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[N:6]3[N:13]=[C:14]([CH2:16][OH:17])[CH:15]=[C:5]3[C:4]=2[CH:3]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[N:6]3[N:13]=[C:14]([CH2:16][O:17][C:18](=[O:20])[CH3:19])[CH:15]=[C:5]3[C:4]=2[CH:3]=1
Reactant: O=c1[nH]c2ccc(Cl)cc2c2cc(CO)nn12
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCc1cc2c3cc(Cl)ccc3[nH]c(=O)n2n1

Procedure:
2.50 g (0.01 mole) of 9-chloro-2-(hydroxymethyl)pyrazolo[1,5-c]quinazolin-5(6H)-one and 1.02 g of acetic anhydride in 50 ml pyridine are stirred for 12 hours then refluxed for 30 minutes. The reaction is evaporated; the residue is taken up in chloroform, washed with dilute aqueous sodium bicarbonate, with water and dried. The solvent is evaporated to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:19]3[C:14](=[C:15]([CH:20]=C)[CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.[O:30]1CCOCC1.I([O-])(=O)(=O)=O.[Na+]>O=[Os](=O)(=O)=O.O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH:20]=[O:30])[C:14]=3[CH:13]=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C1COCCO1
Reactant: C=Cc1cccc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: Cc1cccc(C)n1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(C=O)cccc32)cc1
Reaction time: 0.33 h
Yield: 99 %

Procedure:
The experimental for Intermediate 5 Batch 1 was followed using OsO4 (27 mg, 0.11 mmol), 1-[(4-methylphenyl)sulfonyl]-4-vinyl-1H-indole (0.321 g, 1.08 mmol; Intermediate 4), 2,6-lutidine (0.251 mL, 0.23 mmol), dioxane (12 mL), sodium periodate (0.924 g, 4.32 mmol) and water (4 mL). The mixture was stirred for 20 min. and partitioned between 2M aqueous HCl (25 mL) and DCM (25 mL). The organic layer was dried, filtered, combined with Intermediate 5 Batch 1, and concentrated to give a total yield of 390 mg, 99% of a black solid. MS (ESI+) for C16H13NO3S m/z 300 (M+H)+.
Reaction SMILES: B1C2CCCC1CCC2.[CH:10]([C:12]1[CH:13]=[CH:14][C:15]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)=[C:16]([CH:19]=1)[C:17]#[N:18])=[CH2:11].[O-:31]S([O-])=O.[Na+].[Na+]>C1COCC1>[OH:31][CH2:11][CH2:10][C:12]1[CH:13]=[CH:14][C:15]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=2)=[C:16]([CH:19]=1)[C:17]#[N:18]
Reactant: O=S([O-])[O-]
Reactant: C=Cc1ccc(Oc2cccc(C(F)(F)F)c2)c(C#N)c1
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1cc(CCO)ccc1Oc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.4 %

Procedure:
To a stirred a solution of 9-BBN (10.37 mL, 5.19 mmol) in dry THF (30 mL) was added dropwise a solution of 5-ethenyl-2-{[3-(trifluoromethyl)phenyl]oxy}benzonitrile (1 g, 3.46 mmol) in THF (30 mL) under nitrogen at 0° C. for 0.5 h. The mixture was then allowed to warm to room temperature and stirring continued for 2 h. Na2SO3 was added to quench the reaction. Purification via flash chromatography then afforded the title compound (546 mg, 1.777 mmol, 51.4% yield).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]=[C:9]([O:12][CH3:13])[C:8](=[O:14])[NH:7][C:6]=2[N:5]=[CH:4][N:3]=1.[C:15](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[Cl:1][C:2]1[C:11]2[N:10]=[C:9]([O:12][CH3:13])[C:8](=[O:14])[N:7]([CH3:15])[C:6]=2[N:5]=[CH:4][N:3]=1
Reactant: COc1nc2c(Cl)ncnc2[nH]c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1nc2c(Cl)ncnc2n(C)c1=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 77.4 %

Procedure:
To a 100 mL round bottomed flask was added 4-chloro-6-methoxypteridin-7(8H)-one (2.09 g, 9.8 mmol, 1.0 equiv) and anhydrous N,N-dimethylformamide (10 mL). Anhydrous potassium carbonate (6.8 g, 49 mmol, 5 equiv) was added in one portion to the reaction flask followed by the drop wise addition of iodomethane (2.09 g, 15 mmol, 1.5 equiv) over the course of 1 minute. The reaction was then vigorously stirred at room temperature. LC/MS analysis at 14 hours indicated the reaction was complete. The reaction mixture was then passed through a glass-sintered funnel and the recovered solids were washed with N,N-dimethylformamide (1×10 mL) and dichloromethane (3×15 mL) to give a dark brown filtrate. The solvent was evaporated at reduced pressure and the resulting powder was redissolved in dichloromethane (200 mL) and washed with saturated sodium chloride solution (200 mL). The organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield 1.72 g (pale brown powder, 77% yield) of 4-chloro-6-methoxy-8-methylpteridin-7(8H)-one as the desired material. 1H NMR (400 MHz, DMSO-d6): δ 8.76 (s, 1H), 4.04 (s, 3H), 3.56 (s, 3H). MS (EI) for C8H7ClN4O2: 227 (MH+).
Reaction SMILES: [C:1]([C:3]1[C:4](B(O)O)=[CH:5][C:6]([O:9][CH3:10])=[N:7][CH:8]=1)#[N:2].Br[C:15]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:16]=1[C:17]#[N:18]>>[Cl:23][C:21]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([C:4]2[CH:5]=[C:6]([O:9][CH3:10])[N:7]=[CH:8][C:3]=2[C:1]#[N:2])[CH:22]=1
Reactant: N#Cc1ccc(Cl)cc1Br
Reactant: COc1cc(B(O)O)c(C#N)cn1
Product: COc1cc(-c2cc(Cl)ccc2C#N)c(C#N)cn1

Procedure:
600 mg (purity 89%, 3.0 mmol) of 5-cyano-2-methoxypyridin-4-ylboronic acid and 649 mg (3.0 mmol) of 2-bromo-4-chlorobenzonitrile in the presence of [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride/dichloromethane monoadduct were reacted according to General Method 2A. After aqueous work-up, the crude product was triturated with water and then with cyclohexane/ethyl acetate (7:3), and the solid was filtered off and dried under high vacuum. Yield: 399 mg (purity 94%, 46% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1F.C([O-])([O-])=O.[K+].[K+].[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][OH:25]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:25][CH2:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=1
Reactant: OCc1ccccn1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(OCc2ccccn2)c(Cl)c1
Temperature: 65 °C
Reaction time: 8 h
Yield: 77.1 %

Procedure:
To a solution of 2-chloro-1-fluoro-4-nitro-benzene (8.75 g, 50 mmol) in dry Acetone (100 ml) was added 10.0 g of K2CO3 and 5.45 g of 2-pyridylmethanol (50 mmol). The reaction mixture was then stirred at 65° C. overnight. Filtration and concentration gave a solid which was recrystallized to give the desired product as a white solid (10.2 g).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:41])[N:10]([CH:12]([C:14](=[O:40])[NH:15][CH:16]([C:21]([N:23]1[CH2:27][CH2:26][CH:25]2[NH:28][CH2:29][CH:30]([O:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[C:34]([F:39])[CH:33]=3)[CH:24]12)=[O:22])[C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:51][N:52]=[C:53]=[O:54]>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:41])[N:10]([CH:12]([C:14](=[O:40])[NH:15][CH:16]([C:21]([N:23]1[CH2:27][CH2:26][CH:25]2[N:28]([C:53](=[O:54])[NH:52][CH3:51])[CH2:29][CH:30]([O:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[C:34]([F:39])[CH:33]=3)[CH:24]12)=[O:22])[C:17]([CH3:19])([CH3:18])[CH3:20])[CH3:13])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C(=O)NC(C(=O)N1CCC2NCC(Oc3ccc(F)c(F)c3)C21)C(C)(C)C)N(C)C(=O)OCc1ccccc1
Reactant: CN=C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)N1CC(Oc2ccc(F)c(F)c2)C2C1CCN2C(=O)C(NC(=O)C(C)N(C)C(=O)OCc1ccccc1)C(C)(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 91.3 %

Procedure:
A solution containing 35 (228 mg, 0.4 mmol), DIPEA (104 mg, 0.8 mmol) in DCM (5 mL) was cooled to 0° C. Methyl isocyanate (35 mg, 0.6 mmol) was added. After 3 h, the reaction mixture was warmed to ambient temperature, diluted with DCM, washed successively with saturated aqueous NaHCO3, 1N HCl, and brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford the crude 40 (230 mg) which was used without further purification. Mass spectrum, m/z [630.1] (M+H)+.
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[Cl:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22](=[O:26])[N:21]([C:27]1[C:28]([CH:33]=O)=[CH:29][CH:30]=[N:31][CH:32]=1)[CH2:20][CH2:19]2.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>C(Cl)Cl.CO>[Cl:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22](=[O:26])[N:21]([C:27]1[CH:32]=[N:31][CH:30]=[CH:29][C:28]=1[CH2:33][N:39]1[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]1)[CH2:20][CH2:19]2
Reactant: O=Cc1ccncc1N1CCc2cc(Cl)ccc2C1=O
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CN1CCN(Cc2ccncc2N2CCc3cc(Cl)ccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.4 %

Procedure:
NaBH(OAc)3 (84 mg, 0.4 mmol) was added into a solution of 5-(6-chloro-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-pyridine-4-carbaldehyde (28.6 mg, 0.1 mmol) and 1-methyl-piperazine (10 mg 0.1 mmol) in DCM and MeOH (10 mL, 1:1). The reaction mixture was stirred at RT overnight before it was poured into ice-water (10 mL) and extracted with EtOAc (2×10 mL). The organic layers were washed with brine, dried over anhy. MgSO4, filtered and concentrated in vacuo to give a crude product which was then purified by prep-HPLC to give title compound (7.2 mg, 16%) as a white solid. MS: 371.1 (M+H+).
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:14]2=[N:15][C:16]([OH:19])=[CH:17][CH:18]=[C:13]2[N:12]=[N:11]1.O>C(O)(=O)C>[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:14]2=[N:15][C:16]([OH:19])=[C:17]([Br:1])[CH:18]=[C:13]2[N:12]=[N:11]1
Reactant: BrBr
Reactant: Oc1ccc2nnn(-c3ccccc3F)c2n1
Solvent: O
Solvent: CC(=O)O
Product: Oc1nc2c(cc1Br)nnn2-c1ccccc1F
Yield: 91.2 %

Procedure:
Bromine (0.10 ml, 2 mmol) was added to a stirred solution of 3-(2-fluorophenyl)-5-hydroxy-1,2,3-triazolo[4,5-b]pyridine (0.23 g, 1.0 mmol) in glacial acetic acid (5 ml) at room temperature. After 4 h the solution was poured into water (150 ml). The precipitate was collected, dissolved in 10% methanol-dichloromethane (100 ml), dried (Na2SO4), filtered and concentrated to give 3-(2-fluorophenyl)-5-hydroxy-6-bromo-1,2,3-triazolo[4,5-b]pyridine (0.282 g, 91%) as a beige solid. δH (360 MHz; CDCl3) 7.42-7.47 (2H, m), 7.60-7.71 (2H, m) and 8.48 (1H, s); m/z (ES+) 309, 311 (M+H+).