Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:47])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][N:12]2[CH2:18][CH2:17][CH2:16][C@H:15]([N:19]([CH2:26][C:27]3[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([Cl:37])[CH:28]=3)[C:20]3[N:21]=[N:22][N:23]([CH3:25])[N:24]=3)[C:14]3[CH:38]=[C:39]([CH3:46])[C:40]([C:42]([F:45])([F:44])[F:43])=[CH:41][C:13]2=3)[CH2:7][CH2:6]1.[OH-].[Na+]>CO.O.Cl>[Cl:37][C:29]1[CH:28]=[C:27]([CH:32]=[C:31]([C:33]([F:36])([F:34])[F:35])[CH:30]=1)[CH2:26][N:19]([C:20]1[N:21]=[N:22][N:23]([CH3:25])[N:24]=1)[C@H:15]1[CH2:16][CH2:17][CH2:18][N:12]([CH2:11][CH:8]2[CH2:7][CH2:6][CH:5]([CH2:4][C:3]([OH:47])=[O:2])[CH2:10][CH2:9]2)[C:13]2[CH:41]=[C:40]([C:42]([F:43])([F:44])[F:45])[C:39]([CH3:46])=[CH:38][C:14]1=2
Reactant: COC(=O)CC1CCC(CN2CCC[C@H](N(Cc3cc(Cl)cc(C(F)(F)F)c3)c3nnn(C)n3)c3cc(C)c(C(F)(F)F)cc32)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc2c(cc1C(F)(F)F)N(CC1CCC(CC(=O)O)CC1)CCC[C@@H]2N(Cc1cc(Cl)cc(C(F)(F)F)c1)c1nnn(C)n1
Temperature: 60 °C

Procedure:
To a solution of (S)-(4-{5-[(3-Chloro-5-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmethyl}-cyclohexyl)-acetic acid methyl ester (0.1 mmol) in methanol (1 mL), add 4N sodium hydroxide (0.4 mL). Heat the mixture at 60° C. for 3 h. Dilute the cooled mixture with water and 1N HCl to bring the pH to 6-7 and extract with CH2Cl2 (3×15 mL). Combine the organic layers and wash with water and brine, dry over sodium sulfate, filter, and concentrate under reduced pressure to give a residue. Purify the residue by chromatography (elution with 5%-20% methanol in EtOAc) to afford the title compound. MS (ES+): 673 (M+H).
Reaction SMILES: [CH:1]12[CH2:6][CH:4]([CH2:5]1)[CH2:3][N:2]2[C:7]1[CH:12]=[C:11]([N:13]2[CH2:18][C@@H:17]3[CH2:19][C@H:14]2[CH2:15][O:16]3)[CH:10]=[C:9](Cl)[N:8]=1.[F:21][CH:22]([F:40])[O:23][C:24]1[C:25]([NH2:39])=[N:26][CH:27]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH:4]12[CH2:6][CH:1]([CH2:5]1)[N:2]([C:7]1[N:8]=[C:9]([C:28]3[CH:29]=[C:24]([O:23][CH:22]([F:40])[F:21])[C:25]([NH2:39])=[N:26][CH:27]=3)[CH:10]=[C:11]([N:13]3[CH2:18][C@@H:17]4[CH2:19][C@H:14]3[CH2:15][O:16]4)[CH:12]=1)[CH2:3]2
Reactant: CC1(C)OB(c2cnc(N)c(OC(F)F)c2)OC1(C)C
Reactant: Clc1cc(N2C[C@@H]3C[C@H]2CO3)cc(N2CC3CC2C3)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Nc1ncc(-c2cc(N3C[C@@H]4C[C@H]3CO4)cc(N3CC4CC3C4)n2)cc1OC(F)F
Temperature: 120 °C
Yield: 24.6 %

Procedure:
To a microwave vial charged with (1S,4S)-5-(2-(2-azabicyclo[2.1.1]hexan-2-yl)-6-chloropyridin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane (70 mg, 0.24 mmol), 3-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (75.53 mg, 0.26 mmol) and potassium carbonate (66.29 mg, 0.48 mmol) in dioxane/water (5:1, 3.0 mL) was added 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride (3.5 mg, 0.048 mmol) under nitrogen. The vial was sealed and heated by microwave irradiation at 120° C. for 1 h. The reaction mixture was concentrated in vacuo, and resulting residue was purified by PR-HPLC (Basic) to afford 5-[6-(3-azabicyclo[2.1.1]hexan-3-yl)-4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-2-pyridyl]-3-(difluoromethoxy)pyridin-2-amine (24.55 mg, 24.6% yield). LCMS (ESI) [MH]+=416.1; 1H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 1H), 7.91 (s, 1H), 7.15 (t, J=74.0 Hz, 1H), 6.42 (s, 1H), 6.21 (s, 2H), 5.54 (s, 1H), 4.76-4.74 (m, 2H), 4.62 (s, 1H), 3.73 (d, J=6.8 Hz, 1H), 3.63 (d, J=7.6 Hz, 1H), 3.45 (d, J=8.8 Hz, 1H), 3.33 (s, 2H), 3.10 (d, J=10.4 Hz, 1H), 2.88-2.86 (m, 1H), 1.88-1.81 (m, 4H), 1.27-1.26 (m, 2H).
Reaction SMILES: [CH3:1][Si:2]([O:23]C)([O:21]C)[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([Si:15]([CH3:20])([O:18]C)[O:16]C)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(O)(=O)C>CCOCC>[CH3:20][Si:15]([OH:18])([OH:16])[C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:7]=[CH:8][C:3]([Si:2]([CH3:1])([OH:21])[OH:23])=[CH:4][CH:5]=2)=[CH:10][CH:11]=1
Reactant: CO[Si](C)(OC)c1ccc(-c2ccc([Si](C)(OC)OC)cc2)cc1
Solvent: CC(=O)O
Solvent: CCOCC
Product: C[Si](O)(O)c1ccc(-c2ccc([Si](C)(O)O)cc2)cc1
Yield: 32 %

Procedure:
A suspension of 4,4′-bis-(methyldimethoxysilyl)biphenyl (2.4 g, 6.62 mmol) in 5 ml of ether was stirred vigorously with 3 ml of 0.5% acetic acid solution for 32 days. The white suspension was filtered and the solid was washed three times with acetone and ether. The resulting fine white solid was dried for one day under vacuum at room temperature and gave 4,4′bis-(methyldihydroxysilyl)biphenyl in 32% yield (0.65 g, 2.10 mmol). 1H NMR (DMSO-d6, δ, ppm) 7.66 (8H, s); 6.40 (4H, s); 0.19 (6H, s). 13C NMR (DMSO-d6, δ, ppm) 144.7, 139.3, 134.9, 126.6, 0.38. 29Si NMR (DMSO-d6, δ, ppm) −21.22. Anal. Calcd.; For C14H18O4Si2: C, 54.87; H, 5.92; Si, 18.33%. Found: C, 54.82; H, 5.79; Si, 18.80%.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:24][CH:25]([CH3:28])[CH2:26][NH2:27].CC1N(C(N(C)C)=O)C1>N1C=CC=CC=1>[CH3:24][CH:25]([CH3:28])[CH2:26][NH:27][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)nc1)N1Cc2cccn2Cc2ccccc21
Reactant: CC(C)CN
Agent: CC1CN1C(=O)N(C)C
Solvent: c1ccncc1
Product: CC(C)CNc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cn1
Temperature: 100 °C

Procedure:
A mixture of 0.16 g of 10-[(6-chloro-3-pyridinyl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine, 40 mg of pyridine and 2 ml of 2-methylpropylamine is stirred and heated at 100° C. in a sealed vessel for 1 hour. To the mixture is added 0.2 ml of N,N-dimethylpropyleneurea and the mixture is heated at 110° C. for 7 hours. The volatiles are removed under vacuum and 10 ml of 0.5N NaOH is added to the residue. The mixture is filtered and the solid washed with water and then hexane. The solid is dissolved in ethyl acetate and the solution washed with 0.5N NaOH, brine and dried (Na2 SO4). The solution is filtered through a thin pad of hydrous magnesium silicate and the filtrate concentrated to dryness. The residue is triturated with diisopropylether-hexane to give 0.18 g of white solid; mass spectrum (CI) 361 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([F:31])=[C:16]([C@@:18]2([CH3:30])[N:26]=[C:25]([NH2:27])[C:21]3([CH2:24][CH2:23][CH2:22]3)[S:20](=[O:29])(=[O:28])[CH2:19]2)[CH:17]=1>>[NH2:27][C:25]1[C:21]2([CH2:24][CH2:23][CH2:22]2)[S:20](=[O:28])(=[O:29])[CH2:19][C@:18]([C:16]2[CH:17]=[C:12]([NH:11][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)=[O:10])[CH:13]=[CH:14][C:15]=2[F:31])([CH3:30])[N:26]=1
Reactant: C[C@@]1(c2cc(N)ccc2F)CS(=O)(=O)C2(CCC2)C(N)=N1
Reactant: O=C(O)c1ccc(Cl)cn1
Product: C[C@@]1(c2cc(NC(=O)c3ccc(Cl)cn3)ccc2F)CS(=O)(=O)C2(CCC2)C(N)=N1
Yield: 50324.7 %

Procedure:
Prepared from 5-chloropicolinic acid (48.6 mg, 308 μmol, Eq: 1.2) and (R)-7-(5-amino-2-fluoro-phenyl)-7-methyl-5,5-dioxo-5λ6-thia-8-aza-spiro[3.5]non-8-en-9-ylamine (80 mg, 257 mmol, Eq: 1.00) as described for example 2 (method b) to give the title compound (70 mg, 155 mmol, 60.4% yield) as a light yellow foam. MS (ISP): m/z=451.4 [(M+H)+] and 453.2 [(M+2+H)+].
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[CH2:18]([O:20][C:21]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH3:30])=[CH:24][C:22]=1[NH2:23])[CH3:19].Cl.[OH-].[Na+]>O.C(O)C>[CH2:18]([O:20][C:21]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH3:30])=[CH:24][C:22]=1[NH:23][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1)[CH3:19]
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: CCOc1ccc(OCC)c(N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOc1ccc(OCC)c(Nc2cc(C(F)(F)F)nc(-c3cccnc3)n2)c1
Yield: 17.9 %

Procedure:
A mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol), 2,5-diethoxyaniline (52 mg, 0.290 mmol) and 2N HCl (150 μl) in water:ethanol (3:1, 10 ml) was refluxed for 24 h. The mixture was cooled to room temperature and basified with aqueous 2N NaOH to pH 10-12. The resulting precipitate was filtered and isolated as a yellow solid (14 mg, 18%). 1H NMR (CDCl3): 9.67 (s, 1H), 8.74-8.71 (m, 2H), 7.93 (s, 1H), 7.64 (s, 1H), 7.43-7.39 (m, 1H), 6.91 (s, 1H), 6.86 (d, J=9.3 Hz, 1H), 6.65 (dd, J=2.7, 8.7 Hz, 1H), 4.13-4.04 (m, 4H), 1.47-1.42 (m, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:13](=O)[CH2:14][CH3:15])=[C:6](OS(C)(=O)=O)[CH:7]=1.[CH3:17][NH:18][NH2:19].C([O-])(=O)C.[NH4+]>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]2[C:5]([C:13]([CH2:14][CH3:15])=[N:19][N:18]2[CH3:17])=[CH:4][CH:3]=1
Reactant: CCC(=O)c1ccc(Br)cc1OS(C)(=O)=O
Reactant: CNN
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: ClCCl
Product: CCc1nn(C)c2cc(Br)ccc12
Temperature: 135 °C
Yield: 77.1 %

Procedure:
Methanesulfonic acid 5-bromo-2-propionyl-phenyl ester (2.00 g, 6.51 mmol) was combined with methylhydrazine (0.69 mL, 13 mmol) and ammonium acetate (1.30 g, 16.9 mmol) in xylenes (12 mL). The reaction mixture was heated to 135° C. for 18 hours using a Dean Stark apparatus. The reaction was cooled to room temperature, diluted with dichloromethane (50 mL), and washed with water (50 mL) and 1N aqueous hydrochloric acid (50 mL). The organic extracts were dried over magnesium sulfate and concentrated. The crude product was purified by chromatography on silica gel eluting with 4:1 hexanes/ethyl acetate to yield 1.20 g of 6-bromo-1-methyl-3ethyl-1H-indazole (75% yield). 1H NMR (400 MHz, CDCl3) δ 1.35 (t, 3, J=7.7), 2.94 (q, 2, J=7.7), 3.95 (s, 3), 7.18 (dd, 1, J=8.5, 1.5), 7.50 (d, J=0.8), 7.52 (dd, 1, J=8.5, 0.6). 13C NMR (100 MHz, CDCl3) δ 13.66, 20.29, 35.21, 111.82, 120.61, 121.35, 121.60, 123.05, 141.68, 147.08. IR 2970, 2935, 1609, 1506, 1458, 1223, 1047, 819, 805 cm-1. Analysis calculated for C10H11BrN2 : C, 50.23; H, 4.64; N, 11.72. Found: C, 50.14; H, 4.57; N, 11.46.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]1[O:37][C:10]([CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)([CH2:11][CH2:12][CH:13]([N+:25]([O-])=O)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[O:9][CH2:8]1.[O-]S([O-])(=O)=O.[Mg+2]>O1CCCC1>[CH2:8]1[O:9][C:10]([CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)([CH2:11][CH2:12][CH:13]([NH2:25])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[O:37][CH2:7]1
Reactant: COc1ccc(CC(CCC2(CCc3ccc(Cl)cc3)OCCO2)[N+](=O)[O-])cc1OC
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccc(CC(N)CCC2(CCc3ccc(Cl)cc3)OCCO2)cc1OC

Procedure:
To a suspension of 16.5 g (0.43 mole) of LiAlH4 in 500 ml of dry tetrahydrofuran was added dropwise a solution of 65 g (0.14 mole) of 1-(3',4'-dimethoxyphenyl)-7-(4'-chlorphenyl)-2-nitroheptan-5-one ethylene ketal in a minimum amount of dry tetrahydrofuran. After the addition the reaction mixture was refluxed gently for 2 hrs. The excess LiAlH4 was decomposed with saturated MgSO4 solution. The inorganic salts were filtered off and washed with ether. The organic layer was extracted twice with water, dried over anh MgSO4, filtered and concentrated under reduced pressure to 250 ml. This was used in the next step.
Reaction SMILES: [CH:1]([NH:3][N:4]1[C:13]2[CH:12]=[C:11]3[O:14][CH2:15][O:16][C:10]3=[CH:9][C:8]=2[C:7](=[O:17])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]1)=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:29](I)[CH3:30]>>[CH2:29]([N:3]([CH:1]=[O:2])[N:4]1[C:13]2[CH:12]=[C:11]3[O:14][CH2:15][O:16][C:10]3=[CH:9][C:8]=2[C:7](=[O:17])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]1)[CH3:30]
Reactant: CCI
Reactant: CCOC(=O)c1cn(NC=O)c2cc3c(cc2c1=O)OCO3
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1cn(N(C=O)CC)c2cc3c(cc2c1=O)OCO3

Procedure:
Ethyl 5-[ethyl(formyl)amino]-5,8-dihydro-8-oxo-1,3-dioxolo-[4,5-g]quinoline-7-carboxylate [V; R and R" are C2H5 ] was prepared from 5 g of ethyl 5-(formylamino)-5,8-dihydro-8-oxo-1,3-dioxolo[4,5-g]quinoline-7-carboxylate (Example 3), 4.5 g of potassium carbonate and 3.7 ml of ethyl iodide according to the procedure of Example 6. There was obtained 3.2 g of ethyl 5-[ethyl(formyl)amino]-5,8-dihydro-8-oxo-1,3-dioxolo[4,5-g]-quinoline-7-carboxylate, colorless granules, m.p. 218°-221° C. when recrystallized from ethanol.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:11][CH3:12])[C:5]([O:9][CH3:10])=[C:6]([Cl:8])[CH:7]=1.[CH:13]1([CH:18]([OH:21])[CH:19]=[CH2:20])[CH2:17][CH2:16][CH2:15][CH2:14]1.C(=O)(O)[O-].[Na+]>CN1CCCC1=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:8][C:6]1[CH:7]=[C:2]([CH2:20][CH2:19][C:18]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:21])[CH:3]=[C:4]([CH2:11][CH3:12])[C:5]=1[O:9][CH3:10]
Reactant: C=CC(O)C1CCCC1
Reactant: CCc1cc(Br)cc(Cl)c1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCc1cc(CCC(=O)C2CCCC2)cc(Cl)c1OC
Temperature: 140 °C
Yield: 80.6 %

Procedure:
A mixture of 5-bromo-1-chloro-3-ethyl-2-methoxy-benzene (2 g, 8 mmol), 1-Cyclopentyl-2-propen-1-ol (1.31 g, 10.4 mmol), dichlorobis(triphenylphosphine)palladium (II) (110 mg, 0.16 mmol), and sodium bicarbonate (0.81 g, 9.6 mmol) in N-methylpyrrolidinone (15 mL) was heated to 140° C. under N2 for 5 h. The reaction mixture was partitioned between 1N HCl and EtOAc. The organic layer was washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated to a black oil. The oil was purified by flash column chromatography (0% to 10% EtOAc in hexanes) to give the desired product (1.9 g, 82%). 1H NMR (400 MHz, CDCl3): δ 1.20 (t, J=7.6 Hz, 3H), 1.53-1.81 (m, 8H), 2.65 (q, J=7.6 Hz, 2H), 2.74 (m, 2H), 2.79-2.87 (m, 3H), 3.81 (s, 3H), 6.90 (s, 1H), 7.03 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].[H-].[Na+].[F:19][C:20]([F:30])([F:29])[C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1.O>COCCOC>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:16])[CH:10]([CH2:25][C:24]1[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:29])[F:30])=[CH:28][CH:27]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
To a solution of ethyl 3-(2,4-difluorophenyl)-3-oxopropionate (9 g, 39.4 mmol) in 1,2-dimethoxyethane (50 ml) was added sodium hydride (60% in oil, 1.58 g, 39.4 mmol) under ice-cooling and the mixture was stirred at room temperature for 30 min. To the reaction solution was dropwise added a solution of 4-trifluoromethylbenzyl bromide (9.43 g, 39.4 mmol) in 1,2-dimethoxyethane (50 ml) and the reaction solution was stirred at room temperature for 3 hrs. The reaction solution was poured into water (200 ml) and extracted with ethyl acetate (200 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced-pressure. The residue was purified by silica gel column chromatography (toluene:hexane=1:1-toluene) and recrystallized from diisopropyl ether-hexane to give ethyl 3-(2,4-difluorophenyl)-3-oxo-2-((4-(trifluoromethyl)phenyl)methyl)propionate (11.6 g, 77%).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[Cl:29][C:30]1[CH:39]=[C:38]2[C:33]([C:34]([NH:40][NH2:41])=[CH:35][CH:36]=[N:37]2)=[CH:32][CH:31]=1>>[Cl:29][C:30]1[CH:39]=[C:38]2[C:33]([C:34]([N:40]3[C:5]([C:7]4[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]5[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]6[CH2:24][CH2:25][CH2:26][CH2:27]6)(=[O:22])=[O:21])[CH:15]=5)[N:8]=4)=[CH:4][CH:3]=[N:41]3)=[CH:35][CH:36]=[N:37]2)=[CH:32][CH:31]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(=O)(=O)N3CCCC3)c2)ccc1=O
Reactant: NNc1ccnc2cc(Cl)ccc12
Product: O=c1ccn(-c2cccc(S(=O)(=O)N3CCCC3)c2)nc1-c1ccnn1-c1ccnc2cc(Cl)ccc12

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-[3-(pyrrolidine-1-sulfonyl)-phenyl]-1H-pyridazin-4-one (A-29) and (7-chloro-quinolin-4-yl)-hydrazine according to the method described for example 91. MS: M=533.1 (M+H)+
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][C:17](=[O:19])[CH3:18])=[CH:11][C:10]=1[O:20][CH3:21])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].[C:30](Cl)(=[O:32])[CH3:31].C(OCC)C.CCCCCC>C1COCC1>[Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][C:17](=[O:19])[CH2:18][C:30](=[O:32])[CH3:31])=[CH:11][C:10]=1[O:20][CH3:21])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CC(=O)Cl
Reactant: COc1cc(C=CC(C)=O)ccc1O[Si](C)(C)C(C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cc(C=CC(=O)CC(C)=O)ccc1O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 34.3 %

Procedure:
A solution of 1-(4'-t-butyldimethylsilyloxy-3'-methoxyphenyl)-1-butene-3-one (12.8 g, 41.8 mmol) in THF (50 mL) is cooled to -78° C. under an argon atmosphere. Lithium di-isopropyl amide (83.5 mmol, in 50 mL THF) is slowly added to the reaction mixture. The reaction is stirred at -78° C. for 30 minutes. Acetyl chloride (16.4 g, 209 mmol) dissolved in THF (20 mL) is then added to the reaction over a 30 minute period. The reaction is quenched with aqueous HCl. The layers are separated, and the aqueous layer is washed with ethyl acetate. The combined organic layers are washed with saturated aqueous sodium bicarbonate, dried over MgSO4, and evaporated to give a red oil. Flash chromatography (ethyl ether/hexane 2:8) afford 5.0 g (34%) of 1-(4'-t-butyldimethylsilyloxy-3'-methoxyphenyl)-1-hexene-3,5-dione, mp=81°-85° C.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:11])=[N:9][CH:10]=1)[CH3:3].ClC1C=C(C=CC=1)C(OO)=[O:17].C(OCC)(=O)C>ClCCl>[CH3:3][CH:2]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:11])=[N+:9]([O-:17])[CH:10]=1)[CH3:1]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(OC(C)C)cn1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1ccc(OC(C)C)c[n+]1[O-]
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 217.2 %

Procedure:
5-(1-Methylethoxy)-2-methylpyridine (227 mg, 0.661 mmol) was dissolved in dichloromethane (7.5 mL). The resultant mixture was added with 3-chloroperoxybenzoic acid (408 mg, 0.733 mmol) under ice-cold conditions, and stirred at 0° C. for 45 minutes. The reaction solution was added with ethyl acetate, a saturated aqueous solution of sodium metabisulfite, and an aqueous solution of sodium hydrogen carbonate, and then extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (ethyl acetate) and 5-(1-methylethoxy)-2-methylpyridine 1-oxide (240 mg, yield 6%) was obtained as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][C:11]([I:14])=[C:10]([CH:15]=[O:16])[C:9]2=[O:17])=[CH:4][CH:3]=1.[OH:18]P([O-])(O)=O.[Na+].CC(=CC)C.Cl([O-])=O.[Na+]>C1COCC1.[OH-].[Na+].CCOC(C)=O.O.C(O)(C)(C)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:13]=[CH:12][C:11]([I:14])=[C:10]([C:15]([OH:18])=[O:16])[C:9]2=[O:17])=[CH:6][CH:7]=1
Reactant: O=Cc1c(I)ccn(-c2ccc(F)cc2)c1=O
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1c(I)ccn(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.4 %

Procedure:
1-(4-fluorophenyl)-4-iodo-2-oxo-1,2-dihydropyridine-3-carbaldehyde (8 g, 23 mmol) and sodium phosphate monobasic (8 g, 58.4 mmol) were stirred vigorously in a mixture of THF (35 mL), tert-butanol (35 mL), and water (35 mL) at 0° C. 2-Methyl-2-butene (2.0 M in THF 36.1 mL, 72.2 mmol) was added to the reaction mixture, followed by sodium chlorite (4.8 g, 53.7 mmol). The ice bath was removed and the reaction mixture was warmed to RT and stirred vigorously for 1 h. 1N HCl (20 mL) was added. The mixture was stirred for 5 min. The solids were collected by filtration and washed with water, EtOAc, and ether. The layers of the filtrate were separated, the aqueous layer was extracted with EtOAc, and the combined organics were dried over MgSO4 and concentrated in vacuo. The resulting solid was suspended in EtOAc, filtered, and washed with EtOAc and ether to yield additional product. The pale yellow solids (8.22 g) were combined, dissolved in a minimal amount of 1N aqueous NaOH, treated with EtOAc, and stirred vigourously for 5 min. The layers were separated, and the aqueous layer was washed with EtOAc. The aqueous layer was acidified to pH 1 with conc HCl. The pale yellow solid that precipitated out of solution was collected by filtration, washed with water, EtOAc, and ether, and dried under vacuum to afford 1-(4-fluorophenyl)-4-iodo-2-oxo-1,2-dihydropyridine-3-carboxylic acid (5.4 g, 64.5% yield). 1H NMR (400 MHz, DMSO-d6): δ 13.5 (s, 1 H), 7.43-7.47 (m, 3 H), 7.30-7.35 (m, 2 H), 6.76 (d, J=7.2 Hz, 1 H).
Reaction SMILES: [OH:1][C:2]1([CH3:15])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].[CH2:18](Br)[CH:19]=[CH2:20]>CN(C=O)C>[CH2:20]([O:1][C:2]1([CH3:15])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)[CH:19]=[CH2:18]
Reactant: CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOC1(C)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.7 %

Procedure:
To a mixture of tert-butyl 4-hydroxy-4-methylpiperidine-1-carboxylate (4.30 g, 20.0 mmol) in DMF (50 mL) at 0° C. was added NaH (60 wt %) (1.60 g, 39.9 mmol). The mixture was then stirred at rt for 2 h. At this time allyl bromide (8.64 mL, 100 mmol) was added slowly over the course of 5 min. The reaction mixture was stirred at rt for 3 h. It was then cooled to 0° C. and quenched with sat. aq. ammonium chloride. The reaction mixture was extracted with ether. The organic phase was dried over MgSO4, filtered and concentrated to obtain a colorless oil, which was then purified by biotage, eluting with 0-25% EtOAc/hexane to isolate 3.1 g (61%) of tert-butyl 4-(allyloxy)-4-methylpiperidine-1-carboxylate as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 6.02-5.90 (m, 1H), 5.32 (dd, J=17.2, 1.7 Hz, 1H), 5.16 (dd, J=10.4, 1.4 Hz, 1H), 3.94-3.88 (m, 2H), 3.73 (br. s., 2H), 3.19 (br. s., 2H), 1.78 (d, J=13.1 Hz, 2H), 1.53-1.42 (m, 11H), 1.21 (s, 3H).