Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:8]1[O:12][C:11](=[O:13])[N:10]([CH2:14][CH2:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.[Na].O>C(O)C>[CH2:1]([CH:8]1[O:12][C:11](=[O:13])[N:10]([CH2:14][CH2:15][CH:16]([OH:23])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCN1CC(Cc2ccccc2)OC1=O)c1ccccc1
Agent: B
Agent: [Na]
Solvent: CCO
Solvent: O
Product: O=C1OC(Cc2ccccc2)CN1CCC(O)c1ccccc1
Yield: 0.1 %

Procedure:
5-Benzyl-3-(3-oxo-3-phenylpropyl)-1,3-oxazolidin-2-one (0.31 g, 1 mol) prepared in the above (1) was dissolved in 3 ml of ethanol. To the solution, sodium boron hydride (80 mg, 2 mmol) was added under stirring while chilling with ice. After the resulting solution was stirred to cause reaction at room temperature for 30 minutes, water was added. The obtained solution was extracted with ethyl acetate. The organic portion was sequentially washed with water and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure to obtain 0.31 g of the titled compound as a colorless oil (yield: 100%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:6][CH2:5]1.[C:27](Cl)(=[O:31])[O:28][CH2:29][CH3:30]>>[CH2:29]([O:28][C:27]([N:20]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:4]1([CH2:3][O:2][CH3:1])[CH2:5][CH2:6][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11])[CH2:8][CH2:9]1)=[O:31])[CH3:30]
Reactant: CCOC(=O)Cl
Reactant: COCC1(Nc2ccccc2)CCN(C(=O)OCc2ccccc2)CC1
Product: CCOC(=O)N(c1ccccc1)C1(COC)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 110 °C
Yield: 83.5 %

Procedure:
A mixture of 14.2 parts of (phenylmethyl) 4-(methoxymethyl)-4-(phenylamino)-1-piperidinecarboxylate and 170.2 parts of ethyl carbonochloridate is stirred and refluxed for 16 hours in an oil-bath at 110° C. The reaction mixture is evaporated and the residue is dissolved in 225 parts of trichloromethane. The solution is washed twice with water, dried, filtered and evaporated. The residue is dissolved in methylbenzene and the latter is evaporated again, yielding 14.2 parts (83.5%) of (phenylmethyl) 4-[(ethoxycarbonyl)phenylamino]-4-(methoxymethyl)-1-piperidinecarboxylate as a residue.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:18]([NH2:19])=[CH:17][CH:16]=[C:15]3[C:11]=2/[C:12](=[CH:21]/[C:22]2[NH:23][CH:24]=[CH:25][C:26]=2[O:27][CH3:28])/[C:13](=[O:20])[NH:14]3)=[CH:6][CH:5]=1.[S:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[CH2:35][C:36](Cl)=[O:37]>C([O-])(O)=O.[Na+].C1COCC1>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:18]([NH:19][C:36](=[O:37])[CH2:35][C:31]3[S:30][CH:34]=[CH:33][CH:32]=3)=[CH:17][CH:16]=[C:15]3[C:11]=2/[C:12](=[CH:21]/[C:22]2[NH:23][CH:24]=[CH:25][C:26]=2[O:27][CH3:28])/[C:13](=[O:20])[NH:14]3)=[CH:6][CH:5]=1
Reactant: O=C(Cl)Cc1cccs1
Reactant: COC(=O)c1ccc(-c2c(N)ccc3c2/C(=C/c2[nH]ccc2OC)C(=O)N3)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2c(NC(=O)Cc3cccs3)ccc3c2/C(=C/c2[nH]ccc2OC)C(=O)N3)cc1
Yield: 90.1 %

Procedure:
Using Method M above, (Z)-4-[5-amino-2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-benzoic acid methyl ester (310 mg, 0.8 mmol) (from Example 46 supra) was acylated with 2-thiopheneacetyl chloride (260 mg, 1.6 mmol) (Aldrich) in saturated aqueous NaHCO3 (1.6 mL) and THF (15 mL) at room temperature for 3 h to yield (Z)-4-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl) methylene]-2-oxo-5-[(2-thienylacetyl)amino]-1H-indol-4-yl]-benzoic acid methyl ester (yield 370 mg, 90%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2].[OH:9]O>C(O)(=O)C>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N+:4]=1[O-:9])[CH3:2]
Reactant: CCc1ccccn1
Reactant: OO
Solvent: CC(=O)O
Product: CCc1cccc[n+]1[O-]
Temperature: 80 °C

Procedure:
To the solution 500 g (4.7 mol) 2-ethylpyridine in 2.0 L acetic acid is added H2O2 (1586.0 g, 13.900 mol). Then the mixture is heated to 80° C. overnight. After cooling to room RT, the mixture is poured into the crushed ice, and extracted with DCM (8×1.0 L). The DCM layers are combined, washed with saturated Na2SO3 solution, dried over anhydrous Na2SO4. The solvent is removed in vaccuo to afford the title compound.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:18]3[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=3)[N:12]([CH3:20])[N:11]=2)[CH2:6][CH2:5]1)(=O)C.[ClH:21].[OH-].[Na+].C(OCC)(=O)C.Cl>C(OCC)(=O)C>[ClH:21].[F:19][C:15]1[CH:14]=[C:13]2[C:18]([C:10]([CH:7]3[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]3)=[N:11][N:12]2[CH3:20])=[CH:17][CH:16]=1
Reactant: CC(=O)N1CCC(c2nn(C)c3cc(F)ccc23)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cn1nc(C2CCNCC2)c2ccc(F)cc21
Yield: 21 %

Procedure:
A solution of 16.8 g of 3-(1-acetyl-4-piperidinyl)-6-fluoro-1-methyl-1H-indazole and 100 ml of 6N hydrochloric acid was heated under reflux for 4 hrs. The solution was cooled in an ice bath, 50% aqueous sodium hydroxide was added, dropwise, with stirring and the mixture was extracted with ethyl acetate. Concentration of the organic extract gave an oil. The oil was dissolved in ethyl acetate and a saturated solution of ethyl acetate-hydrogen chloride was added. The salt was recrystallized twice from trichloromethane-ether and then from isopropanol (charcoal) to yield 3.0 g (21%) of product, mp 256°-258° C.
Reaction SMILES: [C:1]([OH:9])(=[O:8])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH3:7].[C:10]1([CH3:16])[CH:15]=CC=C[CH:11]=1>>[C:1]([O:9][C:10]([CH3:16])([CH3:15])[CH3:11])(=[O:8])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCC/C=C/C(=O)O
Reactant: Cc1ccccc1
Product: CCCC/C=C/C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
74.79 ml (312 mmol) of 1,2-(di-tert-butyl)trimethylamine were added to a stirred mixture of 5 g (39 mmol) of (E)-2-heptenoic acid in 100 ml of toluene at 80° C. The mixture was stirred under reflux for 30 minutes and then cooled to room temperature. The mixture was washed in sequence with water and saturated sodium bicarbonate solution, then dried over anhydrous magnesium sulphate and filtered. The solvent was removed by evaporation. There were obtained 7.5 g of tert-butyl (E)-2-heptenoate as a yellow oil; MS: m/e 185.0 [M+H].
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH:11]=[CH2:12])[C:8]2[N:7]([S:13]([C:16]3[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:6]=[CH:5][C:4]=2[C:3]=1[CH:23]=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:44](Br)(Br)([Br:46])[Br:45]>C(Cl)Cl>[Br:45][C:44]([Br:46])=[CH:23][C:3]1[C:2]([CH3:1])=[CH:10][C:9]([CH:11]=[CH2:12])=[C:8]2[C:4]=1[CH:5]=[CH:6][N:7]2[S:13]([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:14])=[O:15]
Reactant: C=Cc1cc(C)c(C=O)c2ccn(S(=O)(=O)c3ccc(C)cc3)c12
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C=Cc1cc(C)c(C=C(Br)Br)c2ccn(S(=O)(=O)c3ccc(C)cc3)c12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 5-methyl-1-tosyl-7-vinyl-1H-indole-4-carbaldehyde (50 mg, 0.147 mmol) and PPh3 (116 mg, 0.442 mmol) in DCM (1.5 mL) at 0° C., was added CBr4 (73.3 mg, 0.221 mmol) and the reaction was warmed to room temperature. After 10 minutes the reaction mixture was loaded onto silica gel and was purified by flash chromatography (0-50% EtOAc in heptanes) to provide the title compound. 1H NMR (400 MHz, DMSO-d6) d ppm 7.76-7.91 (m, 2H) 7.43-7.61 (m, 3H) 7.17-7.43 (m, 3H) 6.63-6.70 (m, 1H) 5.59 (dd, J=17.18, 1.26 Hz, 1H) 5.27 (dd, J=10.99, 1.14 Hz, 1H) 2.28-2.35 (m, 3H) 2.18-2.28 (m, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[C:27]2[CH:32]=[CH:31]C(Cl)=CC=2Cl)[O:23][CH2:22][C:21]2[N:16]3[C@@H:17]([CH3:36])[C:18](=[O:35])[NH:19][N:20]=2)[CH2:9]1)=O)(C)(C)C.[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38]>C(Cl)Cl>[F:40][C:39]([F:42])([F:41])[C:37]([OH:43])=[O:38].[NH:8]1[CH2:11][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[CH:27]2[CH2:32][CH2:31]2)[O:23][CH2:22][C:21]2[N:16]3[C@@H:17]([CH3:36])[C:18](=[O:35])[NH:19][N:20]=2)[CH2:9]1
Reactant: C[C@H]1C(=O)NN=C2COc3cc(-c4ccc(Cl)cc4Cl)c(NC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1C(=O)NN=C2COc3cc(C4CC4)c(NC4CNC4)cc3N21
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of 3-[7-(2,4-dichloro-phenyl)-4(S)-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino]-azetidine-1-carboxylic acid tert-butyl ester (Enantiomer 2, SFC (Table 1, Method 12) Rt=8.89 min., 0.280 g, 0.655 mmol) in DCM (9 mL) was added TFA (1.5 mL) and the reaction mixture was stirred for 2 h at ambient temperature. The solution was concentrated in vacuo to give 6-(azetidin-3-ylamino)-7-cyclopropyl-4(S)-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one trifluoroacetic acid (Example #64-2, Enantiomer 2, SFC (Table 1, Method 1) Rt=5.859 min., 0.275 g, 0.624 mmol, 95%). LC/MS (Table 1, Method 4) Rt=1.331 min.; MS m/z: 328 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.CC(C)([O-])C.[K+].Cl[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]([NH:24][CH3:25])=[O:23])[CH:17]=1>CC(N(C)C)=O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([O:8][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([C:22]([NH:24][CH3:25])=[O:23])[CH:17]=2)=[CH:6][CH:7]=1
Reactant: Nc1ccc(O)cn1
Reactant: CNC(=O)c1cc(Cl)ccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CNC(=O)c1cc(Oc2ccc(N)nc2)ccn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.6 %

Procedure:
A solution of 2-amino-5-hydroxypyridine (0.968 g, 8.79 mmol) in DMA (15 mL) was treated with potassium tert-butoxide (0.987 g, 8.79 mmol), stirred at RT for 3 h, treated with 4-chloro-N-methylpicolinamide (1.5 g, 8.79 mmol) and stirred at RT for 2 days. The mixture was concentrated to dryness, treated with water, extracted with EtOAc (3×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc, MeOH/DCM) to afford 4-((6-aminopyridin-3-yl)oxy)-N-methylpicolinamide (1.3 g, 61%). 1H NMR (400 MHz, DMSO-d6): δ 8.75 (m, 1H), 8.46 (d, J=5.6 Hz, 1H), 7.82 (d, J=2.9 Hz, 1H), 7.34 (d, J=2.6 Hz, 1H), 7.30 (dd, J=8.9, 3.0 Hz, 1H), 7.10 (dd, J=5.6, 2.7 Hz, 1H), 6.53 (d, J=8.9 Hz, 1H), 6.07 (s, 2H), 2.77 (d, J=4.8 Hz, 3H); MS (ESI) m/z: 245.1 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5](O)=[O:6].C(Cl)CCl.C1C=CC2N(O)N=[N:22][C:20]=2C=1.Cl.CN>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([NH:22][CH3:20])=[O:6]
Reactant: O=C(O)c1ccc(O)c(Br)c1
Reactant: On1nnc2ccccc21
Agent: CN
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: CNC(=O)c1ccc(O)c(Br)c1
Reaction time: 16 h

Procedure:
To a stirred solution of 3-bromo-4-hydroxybenzoic acid (Commercial eg Aldrich) (2.0 g), EDC (2.65 g), HOBT (1.41 g) and TEA (6.2 ml) in DCM (60 ml) was added methylamine hydrochloride (1.87 g). This was stirred at 25-30 C for 16 h. The solvent was removed under reduced pressure. The residue was dissolved in water and extracted with ethyl acetate. The organics were dried (sodium sulphate) and concentrated in vacuo to yield the title compound, 0.57 g
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:22])[C:5]2=[C:6]([CH2:8][C@H:9]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[Br:21])[NH:10]/[C:11]/2=[N:12]\[OH:13])[N:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:30]1[CH2:34][CH2:33][O:32][C:31]1=[O:35]>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([CH3:22])[C:5]2=[C:6]([CH2:8][C@H:9]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[Br:21])[NH:10]/[C:11]/2=[N:12]\[O:13][CH:30]2[CH2:34][CH2:33][O:32][C:31]2=[O:35])[N:7]=1
Reactant: O=C1OCCC1Br
Reactant: Cc1nc(N)nc2c1/C(=N/O)N[C@@H](c1ccc(F)cc1Br)C2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1nc(N)nc2c1/C(=N/OC1CCOC1=O)N[C@@H](c1ccc(F)cc1Br)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.7 %

Procedure:
To a solution of (R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one oxime (0.3 mmol, 109 mg) in DMF (2.0 mL) was added Cs2CO3 (0.45 mmol, 146 mg) and 3-bromodihydrofuran-2(3H)-one (0.36 mmol, 33.6 μL). The reaction mixture was stirred overnight at r.t. and LCMS shows completion of the reaction. The reaction mixture was poured on crushed ice and the resultant solid was filtered and dried to afford 3-((Z)—((R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)dihydrofuran-2(3H)-one (105 mg, 78%) as off white solid. MS (ES). [M+H] calculated for C18H18BrFN5O3, 450.05; found 450.30.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([O:21]C)=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1)(=O)=O.[CH3:23][O:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27][NH2:28]>>[CH3:23][O:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27][NH:28][CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1
Reactant: COc1ccccc1CN
Reactant: COC(=O)c1ccnc(-c2cn(CCOS(C)(=O)=O)cn2)c1
Product: COc1ccccc1CNCCn1cnc(-c2cc(C(=O)O)ccn2)c1
Yield: 19 %

Procedure:
The title compound was prepared in 19% yield from methyl 2-(1-{2-[(methylsulfonyl)oxy]ethyl}-1H-imidazol-4-yl)pyridine-4-carboxylate (PREPARATION 6) and 2-methoxybenzylamine according to the procedure for the preparation of Example 58. 1HNMR (400 MHz, DMSO): δ 2.91 (2H, t, J=5.9 Hz), 3.72 (2H, s), 3.75 (3H, s), 4.13 (2H, t, J=6.0 Hz), 6.88 (1H, t, J=7.4 Hz), 6.95 (1H, d, J=8.2 Hz), 7.20 (1H, t, J=8.8 Hz), 7.25 (1H, d, J=7.4 Hz), 7.56 (1H, dd, J=6.4 and 1.4 Hz), 7.75 (1H, s), 7.82 (1H, s), 8.28 (1H, s), 8.59 (1H, d, J=5.0 Hz). [M+H] Calc'd for C19H20N4O3, 353. Found, 353.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:15])=[C:4](I)[C:5]([O:11][CH2:12][CH3:13])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH3:16][N:17]([CH3:35])[C:18]([C:20]1[CH:25]=[CH:24][C:23](B2OC(C)(C)C(C)(C)O2)=[CH:22][N:21]=1)=[O:19].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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:8]([C:6]1[C:5]([O:11][CH2:12][CH3:13])=[C:4]([C:23]2[CH:24]=[CH:25][C:20]([C:18]([N:17]([CH3:35])[CH3:16])=[O:19])=[N:21][CH:22]=2)[C:3]([CH3:15])=[C:2]([Cl:1])[CH:7]=1)(=[O:10])[CH3:9]
Reactant: CN(C)C(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CCOc1c(C(C)=O)cc(Cl)c(C)c1I
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOc1c(C(C)=O)cc(Cl)c(C)c1-c1ccc(C(=O)N(C)C)nc1
Temperature: 95 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
To a mixture of 1-(5-chloro-2-ethoxy-3-iodo-4-methylphenyl)ethanone (0.69 g, 2.0 mmol) and N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxamide (0.68 g, 2.4 mmol) in 1,4-dioxane (10 mL), potassium carbonate (0.56 g, 4.1 mmol) in water (3 mL, 200 mmol) was added. The reaction was bubbled with N2. Tetrakis(triphenylphosphine)palladium(0) (0.24 g, 0.20 mmol) was added and N2 was bubbled. Reaction was stirred overnight at 95° C. The reaction was diluted with water, extracted with EtOAc. The combined organic layers were dried over MgSO4, concentrated and purified on silica gel (eluting with 0 to 90% EtOAc in hexanes) to give the desired product (0.6 g, 82%). LCMS calculated for C19H22ClN2O3 (M+H)+: m/z=361.1; Found: 361.0.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8](/[CH:13]=[C:14]3\[S:15][C:16]4[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=4[NH:18][C:19]\3=[O:20])=[CH:9][NH:10]2)=[CH:6][CH:5]=1)(O)=[O:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:37][CH2:38][CH2:39][N:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1>CN(C)C=O>[N:40]1([CH2:39][CH2:38][NH:37][C:1]([C:4]2[CH:12]=[C:11]3[C:7]([C:8](/[CH:13]=[C:14]4\[S:15][C:16]5[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=5[NH:18][C:19]\4=[O:20])=[CH:9][NH:10]3)=[CH:6][CH:5]=2)=[O:2])[CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: NCCN1CCCC1
Reactant: O=C1Nc2ccccc2S/C1=C\c1c[nH]c2cc(C(=O)O)ccc12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C1Nc2ccccc2S/C1=C\c1c[nH]c2cc(C(=O)NCCN3CCCC3)ccc12
Temperature: 40 °C
Yield: 47.8 %

Procedure:
To a solution of (Z)-2-[(6-carboxyindol-3-yl)methylene]-2H-1,4-benzothiazin-3(4H)-one (0.5 g, 1.5 mmol) in dry N,N-dimethylformamide (30 ml), 1,1′-carbonyldiimidazol (0.24 g, 1.5 mmol) was added under nitrogen atmosphere, and the mixture was heated at 40° C. for 1 h. Then N-(2-aminoethyl)pyrrolidine (0.34 g, 2.98 mmol) was added and the mixture heated at the same temperature for an additional time of 20 h. The reaction was allowed to cool to room temperature and the solvent removed under reduced pressure. The residue was treated with water and the yellow precipitate was crystallized from N,N-dimethylformamide/water to yield 0.31 g (48%) of the entitled product.
Reaction SMILES: CC([O-])(C)C.[K+].[Br:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][N:12]=[CH:11]2.[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1>C1COCC1>[Br:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:23][C:22]1[CH:25]=[CH:26][C:19]([O:18][CH3:17])=[CH:20][CH:21]=1)[N:12]=[CH:11]2
Reactant: COc1ccc(CCl)cc1
Reactant: Brc1ccc2[nH]ncc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(Cn2ncc3cc(Br)ccc32)cc1
Reaction time: 0.5 h

Procedure:
To a suspension of KOtBu (8.13 g, 72.4 mmol) in THF (60 mL) was added 5-bromo-1H-indazole (12.98 g, 65.9 mmol) in THF (60 mL). After 30 min, 4-methoxybenzyl chloride (9.38 mL, 69.2 mmol) was added (neat) and the resulting pale yellow solution was stirred 48 h. The reaction was quenched by addition of saturated NH4Cl solution, and the mixture was extracted with EtOAc. Evaporation of the organic phase followed by column chromatography of the residue on silica gel, eluting with 1/9-EtOAc/heptane, afforded the title compound, which was recrystallized from toluene/heptane (1/5) to afford the title compound as colorless cubes (7.65 g, 37%). Also recovered from the chromatography was 5-bromo-2-(4-methoxybenzyl)-2H-indazole (8.0 g, 38%)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:9][CH2:10][CH:11]=O)[CH:8]=1)([O-:3])=[O:2].[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH2:19][CH2:18]2.[BH4-].[Na+]>CO>[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH2:11][CH2:10][CH2:9][N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[N:6]1)[CH2:19][CH2:18]2
Reactant: COc1ccc2c(c1)CCN2
Reactant: O=CCCn1cc([N+](=O)[O-])cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(c1)CCN2CCCn1cc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(4-nitro-1H-pyrazol-1-yl)propanal (200 mg, 1.18 mmol) in MeOH (12.0 mL), 5-methoxyindoline (176 mg, 1.18 mmol) was added. This reaction mixture was stirred at rt for 1 h, then NaBH4 (121 mg, 3.20 mmol) was added and stirred for another 30 min at rt. The reaction mixture was quenched with water and extracted with EtOAc (2×). The combined org. layers were dried (MgSO4), filtered and the solvent was removed under reduced pressure to yield 5-methoxy-1-(3-(4-nitro-1H-pyrazol-1-yl)propyl)indoline, which was used in the next step without further purification. LC-MS conditions B: tR=0.56 min, [M+H]+=303.15.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=1)[CH:9]=[CH:8]2)=[O:4].[C:24]([C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25]>>[C:24]([C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([CH2:14][N:10]3[C:11]4[C:7](=[CH:6][C:5]([C:3]([OH:2])=[O:4])=[CH:13][CH:12]=4)[CH:8]=[CH:9]3)=[CH:16][CH:17]=2)(=[O:36])=[O:35])=[CH:30][CH:29]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: COC(=O)c1ccc2c(ccn2Cc2ccc([N+](=O)[O-])cc2)c1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cn3ccc4cc(C(=O)O)ccc43)cc2)cc1

Procedure:
The title compound was prepared from 1-(4-nitro-benzyl)-1H-indole-5-carboxylic acid methyl ester and 4-tert-butylbenzene sulfonyl chloride followed the procedure of Example 3 Step 2 as a light brown solid: 1H NMR (DMSO-d6) δ 1.24 (s, 9H), 5.33 (s, 2H), 6.59 (d, J=3.2 Hz, 1H), 7.02 (d, J=8.7 Hz, 2H), 7.07 (d, J=8.7 Hz, 2H), 7.45 (d, J=8.7 Hz, 1H), 7.51-7.54 (m, 3H), 7.65 (d, J=8.5 Hz, 2H), 7.69 (d, J=1.7 Hz, 1H), 8.21 (d, J=1.3 Hz, 1H), 10.23 (br s, 1H), 12.39 (br s, 1H); MS (ESI) m/z 463 (MH+), 461 ([M−H]−); HRMS calcd for C26H26N2O4S: 463.1690; found (ESI+): 463.1681.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH:9][C:10]1[C:15]([CH:16]=O)=[C:14]([CH3:18])[N:13]=[C:12]([S:19][CH3:20])[N:11]=1)[CH3:8].[C:21](#[N:25])[CH2:22][C:23]#[N:24]>C(O)C>[CH2:7]([N:9]1[C:10]2[N:11]=[C:12]([S:19][CH3:20])[N:13]=[C:14]([CH3:18])[C:15]=2[CH:16]=[C:22]([C:23]#[N:24])[C:21]1=[NH:25])[CH3:8]
Reactant: N#CCC#N
Reactant: CCNc1nc(SC)nc(C)c1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCn1c(=N)c(C#N)cc2c(C)nc(SC)nc21
Temperature: 70 °C

Procedure:
Potassium carbonate (0.539 g, 3.90 mmol) was added to a suspension of 4-(ethylamino)-6-methyl-2-(methylthio)pyrimidine-5-carbaldehyde (0.413 g, 1.95 mmol) from above, and malononitrile (0.194 g, 2.93 mmol) in absolute ethanol (15.0 mL) and heated to 70° C. After one h, the reaction was allowed to cool to room temperature and concentrated in vacuo. The residue was diluted with ethyl acetate (50 mL) and washed with saturated NaHCO3 (50 mL), and brine. The organic phase was separated and concentrated in vacuo. The residue was precipitated with ethyl acetate and hexanes to give 8-ethyl-7-imino-4-methyl-2-(methylthio)-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile as a brown solid that was used in the subsequent step without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]([CH2:13]O)[CH:10]=[CH:11][CH:12]=1.P(Br)(Br)[Br:16]>C1COCC1>[Br:16][CH2:13][C:9]1[CH:8]=[C:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: OCc1cccc(-c2cnccn2)c1
Reactant: BrP(Br)Br
Solvent: C1CCOC1
Product: BrCc1cccc(-c2cnccn2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.3 %

Procedure:
To a stirred solution of (3-(pyrazin-2-yl)phenyl)methanol (200 mg, 1.08 mmol) in THF (5 mL), PBr3 (349 mg, 1.29 mmol) was added dropwise at 0° C. and stirred for 10 min. Then, the reaction mixture was refluxed for 3 h. The mixture was cooled to rt, poured into ice-cold saturated aqueous NaHCO3 solution (5 mL) and extracted with ethyl acetate (2×). The combined organic layers were washed with brine and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to yield the title compound (200 mg, 75%). [TLC Rf=0.54 (ethyl acetate/hexane 50:50)].