Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19](O)=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][C@H:23]2[CH2:28][CH2:27][C@H:26]([O:29][CH3:30])[CH2:25][CH2:24]2)[CH:3]=1.[NH3:31]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([NH2:31])=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][C@H:23]2[CH2:28][CH2:27][C@H:26]([O:29][CH3:30])[CH2:25][CH2:24]2)[CH:3]=1
Reactant: N
Reactant: CO[C@H]1CC[C@H](Oc2cc(F)ccc2Nc2ncnc3sc(C(=O)O)c(C)c23)CC1
Product: CO[C@H]1CC[C@H](Oc2cc(F)ccc2Nc2ncnc3sc(C(N)=O)c(C)c23)CC1

Procedure:
Prepared analogously to 1.4 from 0.1 g 4-[4-fluoro-2-(trans-4-methoxycyclohexyloxy)-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid and ammonia (7M in methanol).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.CSC.[CH3:12][C:13]([CH2:17][CH2:18][CH:19]=[C:20]([CH3:28])[CH2:21][CH2:22][CH:23]=[C:24]([CH3:27])[CH2:25][CH3:26])=[CH:14]CO>ClCCl>[Cl:1][CH2:26]/[CH:25]=[C:24](\[CH3:27])/[CH2:23][CH2:22]/[CH:21]=[C:20](\[CH3:28])/[CH2:19][CH2:18][CH:17]=[C:13]([CH3:14])[CH3:12]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCC(C)=CCCC(C)=CCCC(C)=CCO
Solvent: ClCCl
Solvent: CSC
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CCl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 84.8 %

Procedure:
(Note: all temperatures indicated are for the contents of the reaction flask). To a stirred solution of 299 mg (2.24 mmol) of N-chlorosuccinimide in 15 mL of dichloromethane at -30° C. under argon was added 0.18 mL (2.45 mmol) of distilled dimethyl sulfide over 5 minutes. After 10 minutes at -30° C., the reaction was allowed to warm to 0° C. for 10 minutes, followed by cooling to -40° C. A solution of 441.4 mg (1.99 mmol) of 3,7,11-trimethyl-2,6,10-tridecatrien-1-ol in 5 mL of dichloromethane was added dropwise over 10 minutes. The reaction was allowed to warm gradually to 0° C. over 1 hour, and then maintained for 1 hour. After quenching with cold water, the mixture was extracted with hexane and the hexane extract was washed with cold water and cold brine, dried (MgSO4) and evaporated to afford 483 mg of a crude product. Rapid flash chromatography on 20 g of silica gel eluted with 3:97 ethyl acetate:petroleum ether provided 406.5 mg (85%) of a colorless liquid. 13C NMR indicated that this material contained a trace (3%) impurity.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([OH:28])[CH:20]=3)[CH:17]=[N:18][C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH:36](O)[CH3:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([O:28][CH:36]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[F:29])[CH3:37])[CH:20]=3)[CH:17]=[N:18][C:12]=2[CH:11]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(O)c1ccccc1F
Reactant: COC(=O)c1sc(-n2cnc3cc(CO[Si](C)(C)C(C)(C)C)ncc32)cc1O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1sc(-n2cnc3cc(CO[Si](C)(C)C(C)(C)C)ncc32)cc1OC(C)c1ccccc1F

Procedure:
In a similar manner as described for example B31, 5.92 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3H-imidazo[4,5-c]pyridin-3-yl]-3-hydroxythiophene-2-carboxylate, 2.96 mg of 1-(2-fluorophenyl)ethanol, 7.39 g of triphenylphosphine (polymer bound, ˜3 mmol/g) and 6.49 g of di-tert-butyl azodicarboxylate in 200 ml anhydrous dichloromethane yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH:17]([OH:22])[CH2:18][N:19]([CH3:21])[CH3:20])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[C:30](O)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C=O)C>[NH:23]([C:3]1[C:2]([NH:1][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:7][N:6]=[C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH:17]([OH:22])[CH2:18][N:19]([CH3:21])[CH3:20])=[CH:11][CH:10]=2)[N:4]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CN(C)CC(O)COc1ccc(Nc2ncc(N)c(Nc3ccccc3)n2)cc1
Reactant: O=C(O)c1ccccc1
Solvent: CN(C)C=O
Product: CN(C)CC(O)COc1ccc(Nc2ncc(NC(=O)c3ccccc3)c(Nc3ccccc3)n2)cc1
Reaction time: 8 h
Yield: 20.1 %

Procedure:
5-Amino-4-anilino-2-{4-[2-hydroxy-3-(N,N-dimethylamino)propoxy]anilino}pyrimidine (Example 108; 100 mg, 0.25 mmol) and benzoic acid (30 mg, 0.25 mmol) were dissolved in DMF (3 ml). 4-N,N-dimethylaminopyridine (90 mg, 0.74 mmol) and 1-(3-N,N-dimethylaminopropyl-3-ethylcarbodiimide) hydrochloride (72 mg, 0.38 mmol) were added and the solution was stirred overnight. Silica (1 g) was added and volatile material was removed by evaporation. The residue was purified by column chromatography, eluting with 0-10% 2M methanolic ammonia in DCM. Concentration of the appropriate fractions gave the product as a solid (25 mg, 20%). NMR: 2.2 (s, 6H), 2.4 (m, 2H), 3.9 (m, 3H), 6.8 (d, 2H), 7.0 (t, 1H), 7.3 (t, 2H), 7.55 (m, 5H), 7.65 (d, 2H), 7.95 (s, 1H), 8.05 (d, 2H), 8.6 (s, 1H), 9.0 (s, 1H), 8.6 (s, 1H); MS (MH+): 499.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[S:7][C:8]2[C:13]([N:14]=1)=[CH:12][CH:11]=[C:10]([O:15][C:16]1[CH:17]=[C:18]([NH:24][C:25](=[O:37])[C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([C:35]#[N:36])([CH3:34])[CH3:33])[CH:27]=3)[CH:19]=[CH:20][C:21]=1[C:22]#[N:23])[N:9]=2)=[O:4].C(N(CC)CC)C.[CH3:45][N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1>O1CCCC1.C(OCC)(=O)C>[C:35]([C:32]([C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=1)[C:25]([NH:24][C:18]1[CH:19]=[CH:20][C:21]([C:22]#[N:23])=[C:16]([O:15][C:10]2[N:9]=[C:8]3[S:7][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:49]4[CH2:50][CH2:51][N:46]([CH3:45])[CH2:47][CH2:48]4)=[N:14][C:13]3=[CH:12][CH:11]=2)[CH:17]=1)=[O:37])([CH3:34])[CH3:33])#[N:36]
Reactant: CN1CCNCC1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(C#N)c(Oc3ccc4nc(NC(=O)CCl)sc4n3)c2)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN1CCN(CC(=O)Nc2nc3ccc(Oc4cc(NC(=O)c5cccc(C(C)(C)C#N)c5)ccc4C#N)nc3s2)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
N-[3-({2-[(Chloroacetyl)amino][1,3]thiazolo[5,4-b]pyridin-5-yl}oxy)-4-cyanophenyl]-3-(1-cyano-1-methylethyl)benzamide synthesized above was dissolved in tetrahydrofuran (3.0 mL), triethylamine (136 μL, 0.99 mmol) and 1-methylpiperazine (109 μL, 0.99 mmol) were added, and the mixture was stirred at 60° C. for 8 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), washed with water (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/methanol=100/0→80/20), and the obtained solution was concentrated under reduced pressure. The residue was triturated with ethyl acetate/diisopropyl ether/hexane to give the title compound (93 mg, 47%) as a colorless solid.
Reaction SMILES: C(O[C@H]1C2C(=CC(OCCC)=CC=2)[C@@H](N)C1)C=C.[NH2:19][CH:20]([C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]([CH3:32])[CH:26]=1)[CH2:21][C:22]([OH:24])=O.[C:33](O)([C:35]([F:38])([F:37])[F:36])=[O:34].FC(F)(F)C(OC(=O)C(F)(F)F)=O>>[CH3:32][C:27]1[CH:28]=[C:29]([CH3:31])[CH:30]=[C:25]2[C:26]=1[C:22](=[O:24])[CH2:21][CH:20]2[NH:19][C:33](=[O:34])[C:35]([F:38])([F:37])[F:36]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1cc(C)cc(C(N)CC(=O)O)c1
Agent: C=CCO[C@@H]1C[C@H](N)c2cc(OCCC)ccc21
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1cc(C)c2c(c1)C(NC(=O)C(F)(F)F)CC2=O
Temperature: 25 °C
Yield: 71 %

Procedure:
Step BM (1). A solution of 3-amino-3-(3,5-dimethylphenyl)propanoic acid (18 g, 0.078 mol) and TFA (72 mL) was stirred at rt for 30 min. Trifluoroacetic anhydride (72 mL) was added and the resulting mixture was heated at reflux for 2 h. After cooling to rt, the reaction was concentrated in vacuo. The crude residue was dissolved in EtOAc and sequentially washed with 1 N NaOH and brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to afford 15 g (71% yield) of N-(4,6-dimethyl-3-oxo-2,3-dihydro-1H-inden-1-yl)-2,2,2-trifluoroacetamide as a white solid. LC-MS (M+H)+=272.09; 1H NMR (500 MHz, CDCl3) δ ppm 7.17 (s, 1H) 7.04 (s, 1H) 6.91 (d, J=6.71 Hz, 1H) 5.52-5.59 (m, 1H) 3.15 (dd, J=18.92, 7.93 Hz, 1H) 2.50 (s, 3H) 2.46 (d, J=3.36 Hz, 1H) 2.40 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([C:10]2[C:15]([N:16](COC)[S:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=3)(=[O:19])=[O:18])=[CH:14][C:13]([Cl:33])=[CH:12][N:11]=2)=[O:9])[CH:5]=[CH:4][CH:3]=1.O>Cl.O1CCOCC1>[NH2:1][C:2]1[N:7]=[C:6]([C:8]([C:10]2[C:15]([NH:16][S:17]([C:20]3[CH:21]=[CH:22][C:23]([C:26]([CH3:28])([CH3:27])[CH3:29])=[CH:24][CH:25]=3)(=[O:18])=[O:19])=[CH:14][C:13]([Cl:33])=[CH:12][N:11]=2)=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1cccc(N)n1)S(=O)(=O)c1ccc(C(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(Cl)cnc2C(=O)c2cccc(N)n2)cc1
Temperature: 25 °C
Yield: 7.5 %

Procedure:
A mixture of N-[2-(6-amino-pyridine-2-carbonyl)-5-chloro-pyridin-3-yl]-4-tert-butyl-N-methoxymethyl-benzenesulfonamide (58.6 mg, 1.03 mmol) in 4 N HCl in dioxane (4 mL) and water (1 mL) was stirred at 90° C. overnight. The reaction mixture was cooled to room temperature, evaporated to dryness, and treated with saturated aqueous NaHCO3 solution until pH 7-8. The mixture was extracted with EtOAc (2×25 mL), dried (anhydrous Na2SO4), and concentrated in vacuo. The obtained residue was purified via column chromatography (SiO2, 70% EtOAc in hexanes) to afford N-[2-(6-amino-pyridine-2-carbonyl)-5-chloro-pyridin-3-yl]-4-tert-butyl-benzenesulfonamide (34.5 mg) in 64% yield. 1H NMR (400 MHz, CDCl3) δ 11.1 (s, 1 H), 8.26 (d, 1 H), 8.18 (d, 1 H), 7.76 (d, 2H), 7.51 (t, 1 H), 7.44 (d, 2H), 7.03 (d, 1 H), 6.66 (d, 1 H), 4.67 (s, 2H), 1.22 (s, 9H); ESMS m/z (relative intensity): 445.1 (M+H)+ (100).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[O:12][C:13]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:31])=[C:14]([C:16]([NH:18][CH2:19][CH:20]([O:23]C)OC)=O)[N:15]=2)[C:8]([CH3:32])=[CH:7][N:6]=1)(=[O:3])[CH3:2].CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>O>[Cl:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:13]1[O:12][C:11]([C:9]2[C:8]([CH3:32])=[CH:7][N:6]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:10]=2)=[N:15][C:14]=1[C:16]1[O:23][CH:20]=[CH:19][N:18]=1
Reactant: COC(CNC(=O)c1nc(-c2cc(NC(C)=O)ncc2C)oc1-c1ccccc1Cl)OC
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Product: CC(=O)Nc1cc(-c2nc(-c3ncco3)c(-c3ccccc3Cl)o2)c(C)cn1
Temperature: 130 °C
Reaction time: 3 h
Yield: 2.6 %

Procedure:
A mixture of 2-(2-acetamido-5-methylpyridin-4-yl)-5-(2-chlorophenyl)-N-(2,2-dimethoxyethyl)-1,3-oxazole-4-carboxamide (0.226 g, 0.492 mmol) and Eaton's Reagent (7.7 wt % phosphorus pentoxide solution in methanesulfonic acid, 1.2 mL) was allowed to stir at 130° C. for 3 hr. Water was added to the reaction mixture and the solution was extracted with EtOAc. The organic solutions were combined, washed with brine and aqueous sat. NaHCO3, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography to give N-{4-[5′-(2-chlorophenyl)-2,4′-bi-1,3-oxazol-2′-yl]-5-methylpyridin-2-yl}acetamide (Compound I-10) (0.005 g, 2%). LCMS (FA): m/z=395 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[F:17])[CH2:7][N:6]1[C:18]([N:20]([CH3:22])[CH3:21])=[O:19].C(N(CC)CC)C.Cl[C:37]([O:39][CH3:40])=[O:38]>C(Cl)Cl>[Cl:16][C:14]1[CH:13]=[CH:12][C:11]([F:17])=[C:10]([C:8]2[CH2:7][N:6]([C:18]([N:20]([CH3:22])[CH3:21])=[O:19])[C:5]([CH2:4][CH2:3][CH2:2][NH:1][C:37](=[O:38])[O:39][CH3:40])([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:9]=2)[CH:15]=1
Reactant: CN(C)C(=O)N1CC(c2cc(Cl)ccc2F)=CC1(CCCN)c1ccccc1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)NCCCC1(c2ccccc2)C=C(c2cc(Cl)ccc2F)CN1C(=O)N(C)C
Reaction time: 8 h

Procedure:
To 20 mg (0.05 mmol) of amine 20-2 in CH2Cl2 was added 21 μL (0.15 mmol) of triethylamine and 5.8 μL (0.10 mmol) of methyl chloroformate. After stirring overnight the reaction was partitioned between EtOAc and 10% KHSO4, the organic phase was washed with saturated NaHCO3, brine, dried over MgSO4, and concentrated by rotary evaporation. The residue was purified by column chromatography on silica gel with EtOAc/hexanes to provide 22-1 as a white solid. Data for 22-1: 1HNMR (500 MHz, d6-DMSO) δ 7.6 (m, 1H), 7.5-7.1 (m, 8H), 6.2 (s, 1H), 4.95 (m, 1H), 4.7 (m, 1H), 3.55 (s, 3H), 3.0 (m, 2H), 2.7 (s, 6H), 2.7-2.5 (m, 1H), 2.05 (m, 1H), 1.4 (m, 2H) ppm. HRMS (ES) calc'd M+H for C24H27ClFN3O3: 460.1798. Found: 460.1797.
Reaction SMILES: [NH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][N:4]=1)[NH2:2].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>>[CH:13](=[N:2][NH:1][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][N:4]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NNC1=NCCc2ccccc21
Reactant: O=Cc1ccccc1
Agent: Cl
Product: C(=NNC1=NCCc2ccccc21)c1ccccc1

Procedure:
In a manner similar to that of Example 4, condensation of 1-hydrazino-3,4-dihydroisoquinoline (7 g.) and benzaldehyde (5.5 g.) and treatment of the reaction mixture with hydrochloric acid gave a solid, which was recrystallized from ethanol-ether, affording 1-(2-benzylidenehydrazino)-3,4-dihydroisoquinoline (I: X=C6H5, X'=Y=Y'=Z=Z'=H) hydrochloride (11.6 g., m.p. 226°-228° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:14][C:15]([NH2:17])=[S:16])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]1.Br[CH:19]1[CH2:24][CH2:23][CH2:22][CH:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])[C:20]1=O>>[F:1][C:2]1[CH:3]=[C:4]([NH:14][C:15]2[S:16][C:19]3[CH2:24][CH2:23][CH2:22][CH:21]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[O:31][CH3:32])[C:20]=3[N:17]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]1
Reactant: Cc1cn(-c2ccc(NC(N)=S)cc2F)cn1
Reactant: COc1ccccc1C1CCCC(Br)C1=O
Product: COc1ccccc1C1CCCc2sc(Nc3ccc(-n4cnc(C)c4)c(F)c3)nc21

Procedure:
The title compound was prepared from [3-fluoro-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea (45 mg, 0.18 mmol) and crude 2-bromo-6-(2-methoxy-phenyl)-cyclohexanone (153 mg, 0.50 mmol) using in analogous manner the procedure described in example 1b). Obtained as a light-yellow solid (14 mg, 18%). MS ISP (m/e): 435.4 [(M+H)+]. mp 227-230° C.
Reaction SMILES: [CH2:1]([CH:5]([CH:12]=[CH2:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH2:2][CH2:3][CH3:4].[C:14]([O-])(=[O:16])[CH3:15].C(OC(=O)C)(=O)C>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:14]([O:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH:12]=[CH2:13])(=[O:16])[CH3:15]
Reactant: CC(=O)[O-]
Reactant: C=CC(CCCC)CCCCCO
Agent: CN(C)c1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: C=CC(CCCC)CCCCCOC(C)=O
Yield: 93 %

Procedure:
6- Butyloct-7-en-1-ol (800 mg, 4.34 mmol) was converted to the acetate in a standard procedure with acetic anhydride, pyridine and 4-dimethylaminopyridine (DMAP). Subsequent purification by PMLPC yielded 914 mg (93%) of 6-butyloct-7-en-1-yl acetate.
Reaction SMILES: C(OC(=O)NC1(C2C=CC(C3C(C4C=CC=CC=4)=CC4N(CCC#N)C(=O)COC=4N=3)=CC=2)CCC1)(C)(C)C.[O:40]=[C:41]1[CH2:46][O:45][C:44]2[N:47]=[C:48]([C:57]3[CH:62]=[CH:61][C:60]([C:63]4([NH:67][C:68](=[O:74])[O:69][C:70]([CH3:73])([CH3:72])[CH3:71])[CH2:66][CH2:65][CH2:64]4)=[CH:59][CH:58]=3)[C:49]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)=[CH:50][C:43]=2[NH:42]1.[F:75][CH:76]([F:79])[CH2:77]I>>[C:70]([O:69][C:68](=[O:74])[NH:67][C:63]1([C:60]2[CH:61]=[CH:62][C:57]([C:48]3[C:49]([C:51]4[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=4)=[CH:50][C:43]4[N:42]([CH2:77][CH:76]([F:79])[F:75])[C:41](=[O:40])[CH2:46][O:45][C:44]=4[N:47]=3)=[CH:58][CH:59]=2)[CH2:64][CH2:65][CH2:66]1)([CH3:71])([CH3:73])[CH3:72]
Reactant: FC(F)CI
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)CO4)cc2)CCC1
Agent: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(CCC#N)C(=O)CO4)cc2)CCC1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(CC(F)F)C(=O)CO4)cc2)CCC1

Procedure:
Following the procedure for tert-butyl(1-(4-(1-(2-cyanoethyl)-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate, tert-butyl 1-(4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutylcarbamate (100 mg, 0.212 mmol) was reacted with 1,1-difluoro-2-iodoethane (122 mg, 0.636 mmol) to afford the title compound (85 mg. 1H NMR (500 MHz, CDCl3): 7.42 (1H, s), 7.24-7.30 (7H, m), 7.17-7.19 (2H, m), 6.11 (1H, tt), 5.05 (1H, br), 4.92 (s, 2H), 4.28 (dt, 2H), 2.44-2.49 (m, 4H), 2.05 (m, 1H), 1.81 (m, 1H), 1.2-1.43 (br, 9H).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[O:3].[C:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)(=[O:8])[CH3:7].C(=O)([O-])[O-].[K+:19].[K+].[OH-].[K+]>>[OH:3][CH:2]([CH2:7][C:6](=[O:8])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[C:1]([O-:5])=[O:4].[K+:19]
Reactant: O=CC(=O)O
Reactant: CC(=O)c1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Product: O=C(CC(O)C(=O)[O-])c1ccccn1

Procedure:
The condensation of glyoxylic acid with the 2-acetylpyridine 4 is carried out according to an aldolization in a basic medium (potassium carbonate) (Scheme 3) (Coates and McKillop, 1992). This step was optimized from 31% to 65% by simply increasing the number of equivalents of the base to 3 eq., whereas the yield from this condensation drops in a more basic medium of potassium hydroxide (Coates and McKillop, 1992). The potassium 2-hydroxy-4-oxo-4-(pyridin-2-yl)butanoate 5 obtained subsequently becomes cyclized, at the reflux of acetic acid in the presence of hydrazine monohydrate, so as to form the intermediate 6 which becomes dehydrated in situ so as to give the 6-(pyridin-2-yl)-2H-pyridazin-3-one 7 with an overall yield of 65%.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][S:12][CH2:13][CH2:14][NH2:15])[CH:6]=1)[CH3:3].I.[CH3:17][N:18]1[CH2:22][C:21](=[O:23])[N:20]=[C:19]1SC.C(N(CC)CC)C>C(O)C>[CH3:3][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][S:12][CH2:13][CH2:14][NH:15][C:19]2[N:18]([CH3:17])[CH2:22][C:21](=[O:23])[N:20]=2)[CH:6]=1)[CH3:1]
Reactant: CN(C)Cc1ccnc(CSCCN)c1
Reactant: CSC1=NC(=O)CN1C
Agent: I
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN(C)Cc1ccnc(CSCCNC2=NC(=O)CN2C)c1

Procedure:
2-(4-(Dimethylaminomethyl)pyrid-2-ylmethylthio)ethylamine (2.25 g), 1-methyl-2-methylthio-imidazolin-4-one hydroiodide (2.71 g) and triethylamine (2.18 g) were refluxed in ethanol (50 ml) for 6 hours.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]=[C:10]=[O:11].[OH:12][C:13]1[N:17]=[C:16]([S:18][CH2:19][CH2:20][CH2:21][CH3:22])[S:15][N:14]=1>C(OC(C)C)(C)C>[CH3:8][NH:9][C:10]([N:14]1[C:13](=[O:12])[N:17]=[C:16]([S:18][CH2:19][CH2:20][CH2:21][CH3:22])[S:15]1)=[O:11]
Reactant: CCCCSc1nc(O)ns1
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: CC(C)OC(C)C
Product: CCCCSc1nc(=O)n(C(=O)NC)s1
Temperature: 20 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
0.5 ml of triethylamine and 4.78 g of methyl isocyanate were added to a solution of 95 g of 3-hydroxy-5-n-butylthio-1,2,4-thiadiazole in 50 ml of isopropyl ether and the mixture was stirred for 2 hours at 20° C and was vacuum filtered. The recovered precipitate was washed with isopropyl ether and dried to obtain 11.2 g of 2-(N-methylcarbamoyl)-5-n-butylthio-1,2,4-thiadiazole-3-one melting at 102° C.
Reaction SMILES: [C:1]([Li])(C)(C)C.[CH3:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[N:13]=[C:14]([CH2:16][CH2:17][CH3:18])[NH:15][C:8]=12.CI>C1COCC1>[CH2:6]([C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[N:13]=[C:14]([CH2:16][CH2:17][CH3:18])[NH:15][C:8]=12)[CH3:1]
Reactant: CCCc1nc2nccc(C)c2[nH]1
Reactant: [Li]C(C)(C)C
Solvent: CI
Solvent: C1CCOC1
Product: CCCc1nc2nccc(CC)c2[nH]1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
tert-Butyllithium (0.978 mL, 1.7M/pentane) was added to a cooled (-78° C.) THF (5 mL) solution of 7-methyl-2-propylimidazo[4,5-b]pyridine (97 mg, 0.554 mmol). After 2 hour the reaction was warmed to 0° C. for 1 minute then cooled back to -78° C. MeI (0.172 mL) was added, the mixture was stirred at -78° C. for 1 hour then warmed to 0° C. for 1 minute and then quenched (NH4OH). Extractive workup and purification (SiO2, 2% MeOH/EtOAc) gave 85 mg of 7-ethyl-2-propylimidazo[4,5-b]pyridine which was converted to the title compound as outlined in Example 7, Part B. 1H NMR (250 MHz, CD3OD) δ 8.28 (d, 1H, J=6 Hz), 7.72-7.65 (m, 2H), 7.62-7.54 (m, 2H), 7.22 (d, 1H, J=6 Hz), 7.17-7.08 (AB q, 4H), 5.61 (s, 2H), 3.12 (q, 2H, J=9 Hz), 2.89 (t, 2H, J=9 Hz), 1.80-1.63 (m, 2H), 1.41 (t, 3H, J=9 Hz), 0.99 (t, 3H, J=9 Hz).
Reaction SMILES: [C:1]([Si:5]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[CH:13]=1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[Br:20]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:19][C:14]1[CH:13]=[C:12]([CH:17]=[C:16]([CH3:18])[CH:15]=1)[O:11][CH2:10][CH2:9][O:8][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C)cc(OCCO[Si](C)(C)C(C)(C)C)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(CBr)cc(OCCO[Si](C)(C)C(C)(C)C)c1

Procedure:
To a solution of tert-butyl-[2-(3,5-dimethyl-phenoxy)-ethoxy]-dimethylsilane (2.22 g, 7.91 mmol) in carbon tetrachloride (50 mL) under nitrogen was added N-bromosuccinimide (1.57 g, 8.70 mmol) and benzoyl peroxide (0.38 g, 1.58 mmol). The resulting mixture was heated at reflux for 3 hours with simultaneous illumination by a sun lamp. The precipitate was filtered off and the filtrate was concentrated under reduced pressure. The crude material (3.99 g) was purified by column chromatography (silica gel 230-400 mesh; 1/0 to 4/1 hexanes/EtOAc as eluent) to give [2-(3-bromomethyl-5-methyl-phenoxy)-ethoxy]-tert-butyl-dimethyl-silane as a light yellow oil. Yield: 2.17 g (75%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5](=[CH:11][C:12]#[N:13])[CH2:6][C:7]([O:9][CH3:10])=[O:8]>CO.[Pd]>[CH3:10][O:9][C:7](=[O:8])[CH2:6][CH:5]([CH2:11][C:12]#[N:13])[CH2:4][C:3]([O:2][CH3:1])=[O:14]
Reactant: COC(=O)CC(=CC#N)CC(=O)OC
Agent: [Pd]
Solvent: CO
Product: COC(=O)CC(CC#N)CC(=O)OC
Temperature: 25 °C
Reaction time: 96 h
Yield: 52.1 %

Procedure:
To a solution of crude 3-cyanomethylene-pentanedioic acid dimethyl ester (403 g) in methanol (500 mL), 5% Pd—C was added and the mixture was stirred at room temperature for 4 days. The Pd—C was removed by filtration and the filtrate was concentrated under reduced pressure to give crude 3-cyanomethyl-pentanedioic acid dimethyl ester (212 g). The residue was purified by distillation to obtain 3-cyanomethyl-pentanedioic acid dimethyl ester (bp 130-150° C., 133 Pa) as a yellow oil. 1H NMR (200 MHz, CDCl3) δ ppm 2.46-2.61 (m, 5 H) 2.62-2.78 (m, 4 H) 3.71 (s, 6 H).