Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH3:23][O:24][C:25]1[CH:34]=[C:33]2[C:28]([N:29]=[CH:30][C:31]([S:35][CH2:36][CH2:37][OH:38])=[N:32]2)=[CH:27][CH:26]=1.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])O.[Na+]>ClCCl.CCCCCC.C(OCC)(=O)C>[CH3:23][O:24][C:25]1[CH:34]=[C:33]2[C:28]([N:29]=[CH:30][C:31]([S:35][CH2:36][CH:37]=[O:38])=[N:32]2)=[CH:27][CH:26]=1
Reactant: COc1ccc2ncc(SCCO)nc2c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc2ncc(SCC=O)nc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
Dess-Martin periodinane (10.8 g, 25.4 mmol, 2.0 eq) is added at 0° C. to a stirred solution of 2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethanol (3.0 g, 12.7 mmol, 1.0 eq) in dichloromethane (100 mL). The reaction mixture is stirred 0° C. for 30 minutes then at room temperature for 3 hours. Then a saturated sodium thiosulfate aqueous solution (50 mL) is added, followed by a saturated sodium hydrogen carbonate aqueous solution (50 mL). The resulting mixture is stirred for 30 minutes, then extracted with dichloromethane (3×100 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a crude product that is purified by column chromatography (silica gel, eluent: ethyl acetate:hexane, 1:5, v/v) to afford (7-methoxy-quinoxalin-2-ylsulfanyl)-acetaldehyde as a yellow oil (2.22 g, 75% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.[Br:18][CH2:19][CH2:20][CH2:21]Br>>[Br:18][CH2:19][CH2:20][CH2:21][O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH:9]=[CH:10]2
Reactant: BrCCCBr
Reactant: Oc1ccc2c(ccn2-c2ccc(F)cc2)c1
Product: Fc1ccc(-n2ccc3cc(OCCCBr)ccc32)cc1

Procedure:
In analogy to example 3.1, 1-(4-Fluoro-phenyl)-1H-indol-5-ol and 1,3-dibromopropane were converted to yield 5-(3-Bromo-propoxy)-1-(4-fluoro-phenyl)-1H-indole as colorless solid 61-62° C., MS: 347 (M, 1Br).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N+:21]([O-])=O)[C:18]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30](=[O:37])[NH:31][C:32]([CH3:36])([CH3:35])[CH2:33][OH:34])[CH:25]=4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1>C(OCC)C.[Pd]>[NH2:21][C:19]1[C:18]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30](=[O:37])[NH:31][C:32]([CH3:35])([CH3:36])[CH2:33][OH:34])[CH:25]=2)=[CH:17][C:11]2[C:12]([C:13]([NH:15][CH3:16])=[O:14])=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[O:9][C:10]=2[CH:20]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc([N+](=O)[O-])c(-c3cccc(C(=O)NC(C)(C)CO)c3)cc12
Agent: [Pd]
Solvent: CCOCC
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N)c(-c3cccc(C(=O)NC(C)(C)CO)c3)cc12
Reaction time: 16 h
Yield: 93.5 %

Procedure:
To a solution of 2-(4-fluorophenyl)-5-(3-((1-hydroxy-2-methylpropan-2-yl)carbamoyl)phenyl)-N-methyl-6-nitrobenzofuran-3-carboxamide (108 mg) in ethyl ether (4 mL), was added palladium on carbon (1.137 mg). The mixture was stirred under hydrogen with a balloon for 16 hours. Pd/C was removed by filtration and the filtrate was concentrated to give 6-amino-2-(4-fluorophenyl)-5-(3-((1-hydroxy-2-methylpropan-2-yl)carbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide 103 (95 mg).
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[C:11]([N+:16]([O-])=O)[C:12]([O:14][CH3:15])=[CH:13][C:8]=2[CH2:7][N:6]([CH2:19][CH3:20])[CH2:5][C:4]1=[O:21])[CH3:2].C(O)C.C(OCC)(=O)C>[Pd]>[NH2:16][C:11]1[C:12]([O:14][CH3:15])=[CH:13][C:8]2[CH2:7][N:6]([CH2:19][CH3:20])[CH2:5][C:4](=[O:21])[N:3]([CH2:1][CH3:2])[C:9]=2[CH:10]=1
Reactant: CCN1CC(=O)N(CC)c2cc([N+](=O)[O-])c(OC)cc2C1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCN1CC(=O)N(CC)c2cc(N)c(OC)cc2C1
Yield: 73.7 %

Procedure:
1,4-Diethyl-7-methoxy-8-nitro-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (0.50 g, 0.0017 mol) was hydrogenated in a solution of Ethanol (40 mL, 0.7 mol), Ethyl acetate (40 mL, 0.4 mol;) and 10% Pd/C (10:90, Palladium:carbon black, 0.05 g) for 12 hrs. The reaction was filtered and the filtrate evaporated to give an oil. This was chromatographed on Alumina (12 g) and eluded with DCM/EtOH (20-1) to give 8-Amino-1,4-diethyl-7-methoxy-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one as an oil (0.33 g, 74%). LCMS (m/e) 264 (M+1); 1H-NMR (DMSO, 400 MHz) δ 6.76 (s, 1H), 6.61 (s, 1H), 5.75 (s, 1H), 4.86 (s, 2H), 3.77 (s, 3H), 3.72-70 (q, 2H, J=6.06 Hz), 3.38 (s, 2H), 2.89 (s, 2H), 1.05-01 (t, 3H, J=7.07 Hz).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH2:15])=[CH:12][CH:11]=1.C(N(CC)C(C)C)(C)C>O>[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH:15][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=2)=[CH:12][CH:11]=1
Reactant: Fc1cccc(F)n1
Reactant: NCc1ccc(Cl)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Fc1cccc(NCc2ccc(Cl)cc2)n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 67.9 %

Procedure:
To 2,6-difluoro-pyridine (20, 3.80 g, 33.0 mmol) in 20.0 mL ofN-methylpyrrolidone, 4-chloro-benzylamine (21, 5.6 mL, 46.0 mmol) and N,N-diisopropylethylamine (10.0 mL, 57.4 mmol) were added. The reaction was stirred at 90° C. overnight, then poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with 25% ethyl acetate in hexane. Appropriate fractions were combined and the solvents removed under vacuum, and the resulting material was washed with ethyl acetate/hexane to provide the desired compound as a white solid (22, 5.30 g).
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([N:22]2[CH2:26][C:25]([O:27][C:28]3[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=3[F:35])=[CH:24][C:23]2=[O:36])[C:9]([NH:11]C2C=CN(CC(O)(C)C)N=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)C(C)C)(C)C.[CH3:70][O:71][C:72](=[O:80])[C:73]1[CH:78]=[CH:77][C:76](N)=[N:75][CH:74]=1>ClCCl>[CH3:70][O:71][C:72](=[O:80])[C:73]1[CH:78]=[CH:77][C:76]([NH:11][C:9](=[O:10])[C@@H:8]([N:22]2[CH2:26][C:25]([O:27][C:28]3[C:29]([F:35])=[CH:30][CH:31]=[CH:32][C:33]=3[F:34])=[CH:24][C:23]2=[O:36])[CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:75][CH:74]=1
Reactant: COC(=O)c1ccc(N)nc1
Reactant: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCCC2)N2CC(Oc3c(F)cccc3F)=CC2=O)n1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC(=O)[C@H](CC2CCCCC2)N2CC(Oc3c(F)cccc3F)=CC2=O)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 39.2 %

Procedure:
A solution of (S)-3-cyclohexyl-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid (prepared in Example 36, 90 mg, 0.25 mmol) in dichloromethane (10 mL) was treated with bromotripyrrolidinophosphonium hexafluorophosphate (138 mg, 0.30 mmol), N,N-diisopropylethylamine (95 mg, 0.74 mmol) and 6-aminonicotinic acid methyl ester (45 mg, 0.30 mmol). The reaction mixture was stirred at 25° C. for 18 h under nitrogen. The reaction mixture was diluted with dichloromethane, washed with 2N aqueous hydrochloric acid, saturated sodium bicarbonate solution, a saturated sodium chloride solution and dried over magnesium sulfate. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g; 0% to 100% ethyl acetate/hexanes) to afford 6-{(S)-3-cyclohexyl-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionylamino}-nicotinic acid methyl ester (49 mg, 40%) as a white solid: LR-ES-MS m/z calculated for C26H27F2N3O5 [M]+ 499, observed [M+H]+ 500; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.85-1.35 (m, 6H) 1.49-1.88 (m, 7H) 3.86 (s, 3H) 4.31 (d, J=18.3 Hz, 1H) 4.63 (d, J=18.3 Hz, 1H) 5.03 (m, 1H) 5.07 (s, 1H) 7.30-7.52 (m, 3H) 8.16 (d, J=9.1 Hz, 1H) 8.28 (dd, J=9.1, 2.4 Hz, 1H) 8.87 (d, J=2.4 Hz, 1H) 11.32 (s, 1H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].C[O:8][C:9](=[O:21])[CH2:10][C:11]1[C:12]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[C:13]=2[S:14][CH:15]=1.Cl[CH2:23][C:24]1[CH:28]=[C:27]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[O:26][N:25]=1>C(#N)C.ClCCl>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([C:27]2[O:26][N:25]=[C:24]([CH2:23][O:20][C:16]3[C:13]4[S:14][CH:15]=[C:11]([CH2:10][C:9]([OH:8])=[O:21])[C:12]=4[CH:19]=[CH:18][CH:17]=3)[CH:28]=2)=[CH:34][CH:33]=1
Reactant: ClCc1cc(-c2ccc(Cl)cc2)on1
Reactant: COC(=O)Cc1csc2c(O)cccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: ClCCl
Product: O=C(O)Cc1csc2c(OCc3cc(-c4ccc(Cl)cc4)on3)cccc12
Reaction time: 20 h
Yield: 38 %

Procedure:
Cesium carbonate (0.31 g, 90 mmol) was added to a stirred solution of compound 77B from the preceding step (0.14 g, 0.63 mmol) and commercially available 3-chloromethyl-5-(4-chloro-phenyl)-isoxazole (0.14 g, 0.63 mmol) in 15-20 mL of acetonitrile at room temp. After 20 hours the mixture was stripped of solvent in vacuo. The residue was dissolved in dichloromethane and filtered through a short column of Celite® over silica gel, eluting with several column volumes of solvent. The filtrate was stripped of solvent in vacuo, and the residue recrystallized from DMF to afford 0.1 g (38% yield) of the title compound as a snow-white solid; mp 155-156° C. Calc for C21H16ClNO4S: C, 60.94; H, 3.90; N, 3.38. found: C, 60.67; H, 3.72; N, 3.41. Step 4. Preparation of {7-[5-(4-Chloro-phenyl)-isoxazol-3-ylmethoxy]-benzo[b]thiophen-3-yl}-acetic acid (Compound 77D)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]3[CH:17]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[CH:20][CH:19]=4)[N:15]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:4][C:3]=1[NH2:41].[CH:42]1([NH:45][C:46](=O)[O:47]C2C=CC=CC=2)[CH2:44][CH2:43]1.O>CS(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]3[CH:17]=[C:16]([C:18]4[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH2:26][CH2:27][N:28]([CH2:29][CH3:30])[CH2:31][CH3:32])=[CH:22][CH:23]=4)[N:15]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:38])([CH3:39])[CH3:40])[C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:4][C:3]=1[NH:41][C:46]([NH:45][CH:42]1[CH2:44][CH2:43]1)=[O:47]
Reactant: O=C(NC1CC1)Oc1ccccc1
Reactant: CCN(CC)CCCOc1ccc(-c2cc3c(Oc4ccc(N)c(Cl)c4)ncnc3n2COCC[Si](C)(C)C)cc1
Solvent: O
Solvent: CS(C)=O
Product: CCN(CC)CCCOc1ccc(-c2cc3c(Oc4ccc(NC(=O)NC5CC5)c(Cl)c4)ncnc3n2COCC[Si](C)(C)C)cc1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
After dissolving the 2-chloro-4-[6-[4-(3-diethylaminopropoxy)phenyl]-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]phenylamine synthesized in Production Example 160-2 in 0.6 ml of dimethylsulfoxide, 23 mg of phenyl cyclopropylcarbamate was added and the mixture was stirred at 80° C. for 1.5 hours. After further adding 75 mg of phenyl N-cyclopropylcarbamate and stirring at 100° C. for 5 hours, 70 mg of the same reagent was added prior to stirring overnight. The mixture was then returned to room temperature, water was added, and liquid separation and extraction were performed with an ethyl acetate: tetrahydrofuran (5:1) mixed solvent. The organic layer was dried over sodium sulfate, concentrated and subjected to NH silica gel column chromatography (hexane-ethyl acetate) to obtain 18 mg of the title compound.
Reaction SMILES: [OH-].[Na+].[OH:3][CH:4]([C:6]1[CH:7]=[C:8]([C:24]([O:26]C)=[O:25])[CH:9]=[C:10]2[C:15]=1[O:14][C:13]([N:16]1[CH2:21][CH2:20][O:19][C@H:18]([CH3:22])[CH2:17]1)=[CH:12][C:11]2=[O:23])[CH3:5].O.Cl>CO>[OH:3][CH:4]([C:6]1[CH:7]=[C:8]([C:24]([OH:26])=[O:25])[CH:9]=[C:10]2[C:15]=1[O:14][C:13]([N:16]1[CH2:21][CH2:20][O:19][C@H:18]([CH3:22])[CH2:17]1)=[CH:12][C:11]2=[O:23])[CH3:5]
Reactant: COC(=O)c1cc(C(C)O)c2oc(N3CCO[C@H](C)C3)cc(=O)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(O)c1cc(C(=O)O)cc2c(=O)cc(N3CCO[C@H](C)C3)oc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
NaOH (3.56 mL, 7.11 mmol) was added to a stirred suspension of methyl 8-(1-hydroxyethyl)-2-((R)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxylate (988 mg, 2.84 mmol) in MeOH (10 mL)/water (10 mL). The resulting mixture was stirred at RT for 1 hour then acidified to pH 2-3 with a 2N aq. HCl (7.68 mL, 7.68 mmol). The resulting precipitate was collected by filtration, washed with diethyl ether and dried to afford 8-(1-hydroxyethyl)-2-((R)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxylic acid (900 mg, 95%) as a grey solid, which was used without further purification. Mass Spectrum: M+H+ 334.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][C:6]1([CH3:16])[CH:11]2[CH2:12][CH:7]1[CH2:8][CH:9]=[C:10]2[CH2:13][CH2:14][OH:15].C(N(CC)CC)C>ClCCl>[CH3:2][C:1]([O:15][CH2:14][CH2:13][C:10]1[C@H:11]2[C:6]([CH3:16])([CH3:5])[C@H:7]([CH2:12]2)[CH2:8][CH:9]=1)=[O:3]
Reactant: CC1(C)C2CC=C(CCO)C1C2
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCCC1=CC[C@H]2C[C@@H]1C2(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
50 g of acetyl chloride (=0.64 mole) were slowly added dropwise to a solution of 100 g of (-)-nopol (=0.6 mole) and 130 ml of triethylamine (=0.93 mole) in 600 ml of dichloromethane while cooling in ice at a temperature of 5° to 10° C. The reaction mixture was subsequently stirred at 5° to 10° C. for a further 20 minutes. The reaction mixture was then further stirred without cooling until it had warmed to room temperature. To work up the reaction mixture, it was stirred into 800 ml of ice-water. The organic phase was separated, the aqueous phase was washed with 100 ml of dichloromethane, and the combined organic phases were washed to neutrality with saturated aqueous sodium bicarbonate solution and dried over sodium sulfate. The residue after removal of the dichloromethane by distillation was 130 g of crude product, from which (-)-nopyl acetate was isolated by fractional distillation. 98 g of (-)-nopyl acetate with a boiling point of 117°-119° C. (10 mm Hg) and a refractive index nD20 =1.4722 were obtained.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:8][CH2:7][N:6]1[S:9]([C:12]1[N:16]2[C@:17]([CH3:42])([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]4[CH:37]=[N:38][CH:39]=[N:40][CH:41]=4)=[CH:32][CH:31]=3)[C:18](=[O:28])[N:19]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)[C:15]2=[N:14][CH:13]=1)(=[O:11])=[O:10])=O.[NH3:43]>>[Cl:27][C:22]1[CH:21]=[C:20]([N:19]2[C:15]3=[N:14][CH:13]=[C:12]([S:9]([N:6]4[CH2:7][CH2:8][C@H:5]4[C:3]([NH2:43])=[O:2])(=[O:11])=[O:10])[N:16]3[C@:17]([CH3:42])([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]4[CH:37]=[N:38][CH:39]=[N:40][CH:41]=4)=[CH:32][CH:31]=3)[C:18]2=[O:28])[CH:25]=[C:24]([Cl:26])[CH:23]=1
Reactant: COC(=O)[C@@H]1CCN1S(=O)(=O)c1cnc2n1[C@](C)(Cc1ccc(-c3cncnc3)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1
Reactant: N
Product: C[C@@]1(Cc2ccc(-c3cncnc3)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(S(=O)(=O)N3CC[C@H]3C(N)=O)n21
Temperature: 50 °C

Procedure:
(S)-1-[(R)-7-(3,5-Dichloro-phenyl)-5-methyl-6-oxo-5-(4-pyrimidin-5-yl-benzyl)-6,7-dihydro-5H-imidazo[1,2-α]imidazole-3-sulfonyl]-azetidine-2-carboxylic acid methyl ester (0.025 g, 0.04 mmol) was dissolved in 2.0 M methanolic ammonia solution (5 mL) in a sealed tube and heated to 50° C. for 48 h. The reaction was cooled to room temperature and the volatiles were removed in vacuo. The resultant residue was purified by silica gel chromatography to afford 0.018 g of the title compound (612.1, M+H).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[N:7][CH:8]=1.S(Cl)([Cl:23])=O>C(Cl)(Cl)Cl>[Cl:23][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[N:7][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1ccc(OCCc2ccc(CO)cn2)cc1
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccc(OCCc2ccc(CCl)cn2)cc1
Yield: 96.7 %

Procedure:
To a solution of 5-hydroxymethyl-2-[2-(4-nitrophenoxy)ethyl]pyridine (9.4 g) in chloroform (100 ml) was added thionyl chloride (7.0 g) and the mixture was stirred under reflux for 30 minutes. After cooling, the reaction mixture was washed with saturated aqueous solution of sodium bicarbonate and then water, dried over magnesium sulfate and concentrated under reduced pressure to obtain 5-chloromethyl-2-[2-(4-nitrophenoxy)ethyl]pyridine (9.7 g, yield: 85%). The compound was recrystallized from ethyl acetate-hexane to obtain colorless needles, m.p. 77°-78° C.
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][CH:6]=1.C([BH3-])#N.[Na+]>>[C:11]([C:8]1[CH:9]=[CH:10][C:5]([CH2:4][NH:3][O:2][CH3:1])=[CH:6][CH:7]=1)#[N:12]
Reactant: CON=Cc1ccc(C#N)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CONCc1ccc(C#N)cc1
Yield: 75 %

Procedure:
Reduction of 4-cyanobenzaldehyde O-methyloxime with sodium cyanoborohydride as described in the preparation of compound 3-B gave the title hydroxylamine as a clear oil (75% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 3.48 (3H, s, OCH3), 4.09 (2H, s, NCH2), 7.48 (2H, m, aromatics), 7.63 (2H, m, aromatics). The hydrochloride salt was obtained as a white solid: mp 168° C. (dec.). Anal. calcd. for C9H10N2O—HCl: C, 54.41; H, 5.58; N, 14.10. Found: C, 54.44; H, 5.62; N, 13.94.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[NH:6][C:5](=[O:10])[C:4]=1[CH2:11][NH:12][C:13]([C:15]1[C:23]2[C:18](=[N:19][C:20]([N:24]3[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]3)=[CH:21][CH:22]=2)[N:17]([CH:37]([CH3:41])[CH2:38][O:39][CH3:40])[C:16]=1[CH3:42])=[O:14].Cl>CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[NH:6][C:5](=[O:10])[C:4]=1[CH2:11][NH:12][C:13]([C:15]1[C:23]2[C:18](=[N:19][C:20]([N:24]3[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]3)=[CH:21][CH:22]=2)[N:17]([CH:37]([CH3:41])[CH2:38][O:39][CH3:40])[C:16]=1[CH3:42])=[O:14]
Reactant: COCC(C)n1c(C)c(C(=O)NCc2c(OC)cc(C)[nH]c2=O)c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)nc21
Agent: Cl
Solvent: CO
Product: COCC(C)n1c(C)c(C(=O)NCc2c(OC)cc(C)[nH]c2=O)c2ccc(N3CCNCC3)nc21
Reaction time: 2 h
Yield: 24.7 %

Procedure:
To tert-butyl 4-(3-(((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-1-(1-methoxypropan-2-yl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-6-yl)piperazine-1-carboxylate (crude, used directly from last step). was added saturated hydrochloride solution in methanol (5 ml) at 0° C. The reaction mixture was allowed to room temperature and stirred for 2 hours. The reaction mixture was concentrated and purified by preparative HPLC (Mobile phase A: water with 0.05% ammonia solution; Mobile phase B: MeCN; column temperature: 30° C. Gradient: 30-60% B 10 min) to give a N-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-(1-methoxypropan-2-yl)-2-methyl-6-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (23 mg, 24.7%, two steps.). LRMS (M+1H) m/z: calcd 482.26. found 483. 1H NMR (400 MHz, CDCl3) δ: 1.59-1.62 (d, J=7.2 Hz, 3H), 2.21 (s, 3H), 2.71 (s, 3H), 2.96-3.01 (m, 4H), 3.23 (s, 3H), 3.40-3.43 (m, 4H), 3.81-3.88 (m, 4H), 4.10-4.14 (m, 1H), 4.61-4.63 (d, J=5.6 Hz, 2H), 5.91 (s, 1H), 6.41-6.44 (d, J=8.8 Hz, 1H), 7.41-7.45 (m, 1H), 7.90-7.93 (d, J=8.8 Hz, 1H).
Reaction SMILES: [CH2:1]([N:3]([CH2:27][CH3:28])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[N:13]=[CH:12][C:11]([NH:14][C:15]([C:17]2[C:25]3[C:24](=O)[CH2:23][CH2:22][CH2:21][C:20]=3[NH:19][N:18]=2)=[O:16])=[CH:10][CH:9]=1)[CH3:2].[CH3:29][N:30]([CH:32](N(C)C)[N:33](C)C)C.C(O)(=O)C.C(N)=N.[Na+].[Cl-].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([N:3]([CH2:27][CH3:28])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[N:13]=[CH:12][C:11]([NH:14][C:15]([C:17]2[C:25]3[C:24]4[N:33]=[CH:32][N:30]=[CH:29][C:23]=4[CH2:22][CH2:21][C:20]=3[NH:19][N:18]=2)=[O:16])=[CH:10][CH:9]=1)[CH3:2]
Reactant: CN(C)C(N(C)C)N(C)C
Reactant: CCN(CC)CCCOc1ccc(NC(=O)c2n[nH]c3c2C(=O)CCC3)cn1
Agent: N=CN
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCO
Solvent: CC(=O)O
Product: CCN(CC)CCCOc1ccc(NC(=O)c2n[nH]c3c2-c2ncncc2CC3)cn1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
A mixture of 4-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid [6-(3-diethylamino-propoxy)-pyridin-3-yl]-amide (192 mg, 0.50 mmol) and tris(dimethylamino)methane (181 mg, 1.25 mmol) is stirred in a pressure reactor at 60° C. for 5 hours. After cooling, the reaction mixture is dissolved in ethanol (5 mL), treated with formamidine acetate (1.00 g, 9.6 mmol), and stirred in a pressure reactor at 110° C. for 18 hours. The reaction mixture is poured into 10% NaCl (50 mL), treated with 1 M sodium carbonate to pH 11 and extracted with chloroform (40 mL). The extract is dried over sodium carbonate, and the solvent is evaporated under reduced pressure. The residue is triturated with diethyl ether to give pure crystalline 5,7-dihydro-6H-pyrazolo[3,4-h]quinazoline-9-carboxylic acid [6-(3-diethylamino-propoxy)-pyridin-3-yl]-amide. 1H NMR (CD3OD) t, J=7.1 Hz, 6H), 1.98 (m, 2H), 2.61 (q, J=7.1 Hz, 4H), 2.69 (m, 2H), 3.10 (m, 2H), 3.16 (m, 2H), 4.32 (t, J=6.2 Hz, 2H), 6.84 (dd, J=8.8 and 0.5 Hz, 1H), 8.17 (dd, J=8.9 and 2.7 Hz, 1H), 8.51 (dd, J=2.7 and 0.5 Hz, 1H), 8.65 (s, 1H), 9.09 (s, 1H) MW 421.507; MS (M+H)+ 422.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[CH3:17].C([Sn](CCCC)(CCCC)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)CCC.CN(C=O)C.[F-].[K+]>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.O>[CH3:17][C:3]1[CH:4]=[C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)[CH:6]=[CH:7][C:2]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: Cc1cc(-c2nc3ccccc3o2)ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(-c2nc3ccccc3o2)ccc1-c1ccccn1
Temperature: 100 °C

Procedure:
Polyphosphoric acid (100 mL) was added to a beaker containing 2-aminophenol (17.7 g, 162 mmol) and 4-bromo-3-methylbenzoic acid (13.6 g, 64 mmol). The mixture was heated at 200° C. for 1 h, then poured into ice water (1 L) and allowed to stand overnight. The mixture was filtered and dried to afford 2-(4-bromo-3-methyl(phenyl))-benzoxazole as a colorless solid. A solution of 2-(4-bromo-3-methyl(phenyl))-benzoxazole (670 mg, 2.3 mmol), 2-(tributylstannyl)pyridine (850 mg, 2.3 mmol), Pd(Ph3P)4 (270 mg, 0.23 mmol) and DMF (23 mL) was degassed with bubbling argon for 15 min. The reaction mixture was heated at 100° C. for 8 h. The reaction was cooled to rt, and KF (500 mg) and H2O (250 mL) were added. The mixture was extracted with MTBE (3×50 mL), and the combined organic extracts were washed with water (2×20 mL), brine (1×20 mL), dried (MgSO4), and concentrated to afford an oil. Purification of the oil by flash chromatography on silica gel (EtOAc:hexanes 1:2) afforded the desired 2-(3-methyl-4-pyridin-2-ylphenyl)-1,3-benzoxazole as a colorless solid: 1H NMR (CDCl3, 300 MHz) δ 8.91 (d, 1H), 8.52 (t, 1H), 8.19 (s, 1H), 8.15 (d, 1H), 7.97 (br t, 1H), 7.89 (d, 1H), 7.70–7.72 (m, 1H), 7.61 (d, 1H), 7.51–7.54 (m, 1H), 7.30–7.33 (m, 2H), 2.45 (s, 3H), MS (ESI) 287 (M+H)+.
Reaction SMILES: ClC1C=CC(SCC(O)=O)=NC=1.C[O:14][C:15](=[O:25])[CH2:16][S:17][C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][N:19]=1>>[Cl:24][C:23]1[C:18]([S:17][CH2:16][C:15]([OH:25])=[O:14])=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)CSc1ncccc1Cl
Agent: O=C(O)CSc1ccc(Cl)cn1
Product: O=C(O)CSc1ncccc1Cl
Yield: 97 %

Procedure:
(3-Chloro-pyridin-2-ylsulfanyl)-acetic acid (19) was synthesized according to the procedure used for compound 15. Starting with 0.69 g (3.2 mmol) of corresponding ester 18 the target 19 was obtained as a white solid (0.63 g) in 97% yield.