Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:4][C:5](Cl)=[N:6][CH:7]=1.[NH2:16][NH2:17]>C1COCC1>[Br:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:4][C:5]([NH:16][NH2:17])=[N:6][CH:7]=1
Reactant: Clc1ccc(-c2cc(Cl)ncc2Br)cc1
Reactant: NN
Solvent: C1CCOC1
Product: NNc1cc(-c2ccc(Cl)cc2)c(Br)cn1
Temperature: 20 °C
Yield: 63.9 %

Procedure:
To a solution of 5-bromo-2-chloro-4-(4-chlorophenyl)pyridine (1.3 g, 4.3 mmol) in THF (10 mL) was added hydrazine (1.4 g, 43 mmol). The reaction mixture was refluxed under argon for 4 days, then allowed to cool to 20° C. and concentrated in vacuo. The residue was purified by using reverse phase preparative HPLC (Conditions: Phenomenex Luna 5μC 18 30×100 mm; Eluted with 0% to 100% B, 10 min gradient, 100% B hold for 5 min, (A=90% H2O, 10% CH3CN, 0.1% trifluoroacetic acid and B=10% H2O, 90% CH3CN, 0.1% trifluoroacetic acid); Flow rate at 40 mL/min, UV detection at 220 nm), followed by basification with 1N aqueous NaOH to pH 12 and extraction with CHCl3 to afford 0.82 g (63%) of the title compound as an off-white solid. LC/MS (method B): retention time=1.47 min, [M+H]+=298.0.
Reaction SMILES: [CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[CH:13][NH:12]4)[CH2:5][C@@H:4]([CH2:18][NH:19][NH2:20])[CH2:3]1.[CH3:21][N:22]=[C:23]=[S:24]>O1CCCC1>[CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[CH:13][NH:12]4)[CH2:5][C@@H:4]([CH2:18][NH:19][NH:20][C:23](=[S:24])[NH:22][CH3:21])[CH2:3]1
Reactant: CN1C[C@H](CNN)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Reactant: CN=C=S
Solvent: C1CCOC1
Product: CNC(=S)NNC[C@@H]1C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]2N(C)C1
Temperature: 0.5 °C
Yield: 74.5 %

Procedure:
1.2 g (0.0043 moles) of 6-methyl-8β-hydrazinomethyl-ergoline are dissolved in 120 ml of dry tetrahydrofuran, the solution is cooled to 0.5° C., and 0.38 g (0.0052 moles) of methyl isothiocyanate are added with stirring. The reaction mixture is stirred for one hour, and the solvent is distilled off in vacuo. The residue is subjected to chromatography on a column packed with 40 g of silica gel; a 100:0.3:20 mixture of chloroform, water and methanol is applied as eluting agent. The eluents which contain a single compound with an Rf value of 0.45 are combined and evaporated, and the dry residue is crystallized from ethanol. 1.1 g (76.8%) of 6-methyl-8β-([N'-methylthiocarbamoyl-hydrazino]-methyl)-ergoline are obtained; m.p.: 220°-221° C., [α]D20 =-45.7° (c=1, in 96% ethanol).
Reaction SMILES: [N+:1]([C:4]1[C:9]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:18][C:19]([O:21]CC)=[O:20])([O-:3])=[O:2].[OH-].[K+].O.Cl>CO>[N+:1]([C:4]1[C:9]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:18][C:19]([OH:21])=[O:20])([O-:3])=[O:2]
Reactant: CCOC(=O)Cc1cccc(Oc2ccccc2F)c1[N+](=O)[O-]
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)Cc1cccc(Oc2ccccc2F)c1[N+](=O)[O-]

Procedure:
A solution of ethyl 2-[2-nitro-3-(2-fluorophenoxy)phenyl]acetate in methanol (50 ml) was added to a solution of potassium hydroxide (20 g) in methanol (50 ml) with stirring under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Water (700 ml) was added to the reaction mixture and the resultant aqueous solution was adjusted to pH 2.0 with conc. hydrochloric acid. The precipitating crystals were collected by filtration, washed with water and recrystallized from a mixture of ethyl acetate and n-hexane (1:1) to give 2-[2-nitro-3-(2-fluorophenoxy)phenyl]acetic acid (31.9 g). mp 144°-146° C.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:10][C:11]1[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=1[NH2:13]>>[NH2:13][C:12]1[CH:14]=[CH:15][C:16]([C:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:9])=[CH:17][C:11]=1[F:10]
Reactant: Nc1ccccc1F
Reactant: O=C(O)c1ccccc1
Product: Nc1ccc(C(=O)c2ccccc2)cc1F
Temperature: 200 °C
Reaction time: 1 h
Yield: 46.4 %

Procedure:
To stirred polyphosphoric acid (125 g) at 90° C. was added benzoic acid (18.32 g) and 2-fluoroaniline (8.33 g) and the bath temperature was raised to 200° C. for 1 hour. The heating bath was removed and the stirred mixture was treated cautiously with water (60 ml). The mixture was stirred at 140-160° C. for 1 hour, the heating bath was removed, and 3M hydrochloric acid was added (50 ml). The mixture was poured into water (750 ml) and filtered through diatomaceous earth with a dichloromethane wash. The filtrate was made basic with 15% sodium hydroxide and the mixture was again filtered through diatomaceous earth with a dichloromethane wash. The combined dichloromethane extracts were washed (saturated aqueous sodium hydrogen carbonate), dried, filtered, and evaporated. Chromatography, with ether/hexanes (gradient, 10/90 to 50/50) as the eluent, followed by recrystallization from hexanes, yielded the title compound as a light yellow solid (7.48 g). M.p. 83-85° C.; MS: 216 (M+H); NMR (400 MHz): 6.27 (brs, 2H), 6.80 (t, 1H, J=8.6), 7.36 (q, 1H, J=8.4, 1.9), 7.41 (q, 1H, J=12.4, 1.9), 7.49-7.51 (m, 2H) 7.60-7.63 (m, 3H); EA: C13H10FNO requires C, 72.55; H, 4.68; N, 6.51%; found: C, 72.51; H, 4.82; N, 6.42%.
Reaction SMILES: [C:1](=[O:6])([O:4][CH3:5])OC.C[O-].[Na+].[NH2:10][C:11]1[CH:15]=[C:14]([CH3:16])[O:13][N:12]=1.Cl>C(OCC)(=O)C.O>[CH3:16][C:14]1[O:13][N:12]=[C:11]([NH:10][C:1](=[O:6])[O:4][CH3:5])[CH:15]=1
Reactant: COC(=O)OC
Reactant: Cc1cc(N)no1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)Nc1cc(C)on1

Procedure:
Dimethyl carbonate (2.38 g) and sodium methoxide (0.30 g) are added to 3-amino-5-methylisoxazole (0.49 g), and the resultant mixture is stirred at 100° C for 3 hours. After cooling, the reaction mixture is combined with water (15 ml), adjusted to pH 1 with a small amount of c. hydrochloric acid and shaken twice with ethyl acetate. The organic layer is washed with water, dried over anhydrous sodium sulfate and evaporated to remove the solvent. The resulting light yellow crystals (0.52 g) are chromatographed on a column of silica gel, whereby methyl N-(5-methyl-3-isoxazolyl)carbamate is obtained as crystals melting at 136.0° to 137.0° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=2)[C:35]([NH2:37])=[O:36])O1.C([O-])([O-])=O.[Na+].[Na+]>O.O1CCOCC1.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>[CH3:23][O:22][C:14]1[CH:13]=[C:12]([NH:11][C:4]2[C:5]3[N:10]=[CH:9][S:8][C:6]=3[N:7]=[C:2]([C:32]3[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=3)[C:35]([NH2:37])=[O:36])[N:3]=2)[CH:17]=[C:16]([O:18][CH3:19])[C:15]=1[O:20][CH3:21]
Reactant: COc1cc(Nc2nc(Cl)nc3scnc23)cc(OC)c1OC
Reactant: CC1(C)OB(c2cccc(C(N)=O)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(Nc2nc(-c3cccc(C(N)=O)c3)nc3scnc23)cc(OC)c1OC
Temperature: 97 °C
Reaction time: 16 h
Yield: 28.9 %

Procedure:
To a stirred solution of 5-chloro-N-(3,4,5-trimethoxyphenyl)thiazolo[5,4-d]pyrimidin-7-amine (337 mg, 0.95 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (190 mg, 1.15 mmol) and Na2CO3 (347 mg, 3.27 mmol) in 2 mL of water and 50 mL of dioxane was added Pd(PPh3)4 (100 mg, 0.086 mmol) in one portion at room temperature under nitrogen. Then the mixture was stirred at 97° C. for 16 hours under nitrogen. The solvent was evaporated at 40° C. at reduced pressure and the residue was purified by silica gel chromatography (silica gel 200-300 mesh, eluting with a mixture of petroleum ether and ethyl acetate (1:2)) to give a crude product. It was purified by preparative HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 ml/inj, flow rate: 20 ml/min; wavelength: 214 nm and 254 nm; the gradient conditions are: 20% acetonitrile/80% water (0.1% TFA V/V) initially, and then proceed to 45% acetonitrile/55% water (0.1% TFA V/V) in a linear fashion after just 9 min.) to give 3-(7-(3,4,5-trimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzamide (120 mg, 27.4%) as a solid. 1H NMR (300 MHz, DMSO): δ 10.10 (s, 1H), 9.43 (s, 1H), 8.93 (s, 1H), 8.58 (d, 1H, J=8.1 Hz), 8.03-8.00 (m, 2H), 7.65-7.60 (m, 3H), 7.50 (brs, 1H), 3.87 (s, 3H), 3.71 (s, 3H), 3.30 (s, 3H). LC-MS: 438 [M+H]+, tR=1.43 min. HPLC: 99.77% at 214 nm, 99.84% at 254 nm, tR=5.68 min.
Reaction SMILES: [CH2:1]([O:3][C:4]1([C:7]2[CH:23]=[CH:22][C:10]([O:11][Si](C(C)C)(C(C)C)C(C)C)=[CH:9][C:8]=2[CH:24]([CH3:26])[CH3:25])[CH2:6][CH2:5]1)[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:1]([O:3][C:4]1([C:7]2[CH:23]=[CH:22][C:10]([OH:11])=[CH:9][C:8]=2[CH:24]([CH3:25])[CH3:26])[CH2:6][CH2:5]1)[CH3:2]
Reactant: CCOC1(c2ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc2C(C)C)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC1(c2ccc(O)cc2C(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
To a solution of [4-(1-ethoxycyclopropyl)-3-isopropyl-phenoxy]-triisopropyl-silane (Intermediate 99, 360.0 mg, 0.96 mmol) in 3 mL THF at 0° C. was added tetrabutylammonium fluoride (625.0 mg, 2.39 mmols, 2.4 mL of a 1M solution in THF). The solution was stirred at 0° C. for 30 minutes and then quenched by the addition of H2O. The mixture was extracted with EtOAc and the combined organic layers were washed with H2O and saturated aqueous NaCl before being dried (MgSO4) and concentrated under reduced pressure. The title compound (180 mg, 86%) was isolated from the residue by column chromatography (4-10% EtOAc-hexanes) as a colorless solid.
Reaction SMILES: C[N:2]([CH:4]=[N:5][C:6]([C:8]1([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:16][CH:15]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=O)C.O.[NH2:30]N>C(O)(=O)C>[N:24]1([CH2:23][CH2:22][CH2:21][O:20][C:17]2[CH:18]=[CH:19][C:14]([C:8]3([C:6]4[N:5]=[CH:4][NH:2][N:30]=4)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)=[CH:15][CH:16]=2)[CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: NN
Reactant: CN(C)C=NC(=O)C1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Solvent: O
Solvent: CC(=O)O
Product: c1nc(C2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)n[nH]1
Temperature: 100 °C
Yield: 24.5 %

Procedure:
N-[(dimethylamino)methylene]-4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carboxamide (0.15 g, 0.39 mmol), hydrazine hydrate (0.048 mL, 0.98 mmol) and acetic acid (1 mL) were combined and heated at 100° C. for 1.5 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in dichloromethane (100 mL) and washed with 10% aqueous sodium carbonate (20 mL). The organic was dried over sodium sulphate and evaporated to provide a clear oil. This was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (92:8:0.8 to 90:10:1) to produce a clear oil which was triturated with diethyl ether (3 mL), a white solid was isolated as the title compound (0.034 g, 24%). 1H NMR (400 MHz, CDCl3) δ 1.82-1.95 (m, 4H), 2.0-2.10 (m, 2H), 2.30 (m, 2H), 2.60-2.70 (m, 2H), 2.70-2.80 (m, 6H), 3.62 (t, 2H), 3.89 (m, 2H), 3.95 (t, 2H), 6.80 (d, 2H), 7.20 (d, 2H), 7.95 (d, 1H). HRMS ESI+ m/z 357.2279 [MH]+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[O:12][CH2:11][C:10]3([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[N:9]=2)=[CH:4][CH:3]=1.C([O-])(C)(C)C.[K+].[CH3:24][CH:25]1[CH2:29][CH2:28][CH2:27][N:26]1[CH2:30][CH2:31][CH2:32][OH:33].C(OCC)(=O)C>O1CCCC1>[CH3:24][CH:25]1[CH2:29][CH2:28][CH2:27][N:26]1[CH2:30][CH2:31][CH2:32][O:33][C:2]1[N:7]=[CH:6][C:5]([C:8]2[O:12][CH2:11][C:10]3([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(C2=NC3(CCCCC3)CO2)cn1
Reactant: CC1CCCN1CCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1CCCN1CCCOc1ccc(C2=NC3(CCCCC3)CO2)cn1
Temperature: 60 °C
Reaction time: 0.35 h
Yield: 55 %

Procedure:
2-(6-chloropyridin-3-yl)-3-oxa-1-azaspiro[4.5]dec-1-ene ax49 (0.109 g, 0.76 mmol, 1 eq) and potassium tert-butanolate (0.102 g, 0.91 mmol, 1.2 eq) are added to a cold (0° C.) solution of 3-(2-methylpyrrolidin-1-yl)propan-1-ol (0.2 g, 0.8 mmol, 1.05 eq) in tetrahydrofuran (4 ml). The mixture is stirred under microwave irradiation (150 W) at 60° C. for 21 min. Ethyl acetate is then added. The organic layer is washed with a saturated solution of sodium hydrogenocarbonate, dried over magnesium sulfate and the solvent is removed under vacuum to give 0.227 g of yellow oil. The oil is purified over silica (eluent: dichloromethane/methanol/ammonia 97:2.7:0.3) to give 0.149 g of 2-{6-[3-(2-methylpyrrolidin-1-yl)propoxy]pyridin-3-yl}-3-oxa-1-azaspiro[4.5]dec-1-ene 16 as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([O:17]CC)=O)=[N:4][CH:5]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1.Cl[C:21](=[O:28])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[CH2:8]([C:6]1[CH:7]=[C:2]2[C:3]([C:15]([OH:17])=[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:21](=[O:28])[NH:1]2)=[N:4][CH:5]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)CC(=O)Cl
Reactant: CCOC(=O)c1ncc(Cc2ccccc2)cc1N
Product: CCOC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 3-amino-5-benzylpyridine-2-carboxylate and ethyl 3-chloro-3-oxopropionate employing methods similar to those described in Example 1, Steps 9-10. The product was obtained as a white solid: 1H NMR (d6-DMSO) δ 10.72 (1H, br s), 8.24 (1H, br s), 7.36-7.23 (6H, m), 4.14 (2H, q, J=7 Hz), 4.06 (2H, s), 1.22 (3H, t, J=7 Hz); ES+ MS: 325 (M+H+, 75), 347 (M+Na+, 26); Anal. Calcd for C18H16N2O4: C, 53.61; H, 3.99; N, 6.94. Found: C, 53.40; H, 3.92; N, 6.92.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:24])=[C:4]([C:8]2[N:9]=[C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:25][C:26]1[CH:27]=[C:28]([S:31](Cl)(=[O:33])=[O:32])[S:29][CH:30]=1>>[NH2:19][C:15]1[N:14]=[C:13]([C:12]2[S:11][C:10]([C:20]([CH3:21])([CH3:23])[CH3:22])=[N:9][C:8]=2[C:4]2[C:3]([F:24])=[C:2]([NH:1][S:31]([C:28]3[S:29][CH:30]=[C:26]([CH3:25])[CH:27]=3)(=[O:33])=[O:32])[CH:7]=[CH:6][CH:5]=2)[CH:18]=[CH:17][N:16]=1
Reactant: Cc1csc(S(=O)(=O)Cl)c1
Reactant: CC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(N)n2)s1
Product: Cc1csc(S(=O)(=O)Nc2cccc(-c3nc(C(C)(C)C)sc3-c3ccnc(N)n3)c2F)c1

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 4-[4-(3-amino-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinamine (80 mg, 0.233 mmol) and 4-methyl-2-thiophenesulfonyl chloride (50 mg, 0.256 mmol), the title compound was obtained as a white solid (59 mg, 47% yield). MS (ESI): 504 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:13]=[N:14][C:15]([OH:18])=[CH:16][CH:17]=2)[CH:6]=1)[CH3:2].[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=1[C:28]1[C:32]([CH2:33]O)=[C:31]([CH:35]([CH3:37])[CH3:36])[O:30][N:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:13]=[N:14][C:15]([O:18][CH2:33][C:32]3[C:28]([C:22]4[C:21]([Cl:20])=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:27])=[N:29][O:30][C:31]=3[CH:35]([CH3:37])[CH3:36])=[CH:16][CH:17]=2)[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc(Oc2ccc(O)nc2)c1
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CCOC(=O)c1cccc(Oc2ccc(OCc3c(-c4c(Cl)cccc4Cl)noc3C(C)C)nc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 41.1 %

Procedure:
To a suspension of 3-(6-hydroxy-pyridin-3-yloxy)-benzoic acid ethyl ester (0.20 g, 0.77 mmol), [3-(2,6-dichloro-phenyl)-5-isopropyl-isoxazol-4-yl]-methanol (0.22 g, 0.77 mmol), triphenylphosphine (0.242 g, 0.92 mmol) in benzene (10 ml) was added dropwise diisopropyldiazenedicarboxylate (0.202 g, 1.00 mmol). The reaction mixture was stirred at room temperature for 4 h and concentrated under reduced pressure. The resulting residue was further purified by column chromatography using silica (eluent hexanes-ethyl acetate 5:1) to give 0.167 g (41%) of 3-{6-[3-(2,6-dichloro-phenyl)-5-isopropyl-isoxazol-4-ylmethoxy]-pyridin-3-yloxy}-benzoic acid ethyl ester as colorless oil.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.CSC.[N+:12]([C:15]1[CH:16]=[C:17](/[C:21](/[CH3:25])=[CH:22]/[CH2:23]O)[CH:18]=[CH:19][CH:20]=1)([O-:14])=[O:13]>ClCCl>[Cl:1][CH2:23]/[CH:22]=[C:21](/[C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=1)\[CH3:25]
Reactant: O=C1CCC(=O)N1Cl
Reactant: C/C(=C\CO)c1cccc([N+](=O)[O-])c1
Solvent: CSC
Solvent: ClCCl
Product: C/C(=C\CCl)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
To a solution of N-chlorosuccinimide (52.3 g, 0.39 mol) in dichloromethane (800 ml) at 0° C. was added dropwise over 1 h dimethylsulfide (27.9 ml, 0.38 mol). To the mixture was added dropwise over 30 min at 0° C. a solution of (E)-3-(3-nitrophenyl)-2-buten-1-ol (Preparation 2, 72 g, 0.373 mol) in dichloromethane (200 ml). The mixture was warmed to room temperature over 1 h, then poured onto brine (500 ml). The layers were separated, and the aqueous layer extracted with ether (500 ml). The organic extracts were combined, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica column chromatography, eluting with 10:1 hexane/ethyl acetate, then as a gradient up to 4:1 hexane/ethyl acetate. Appropriate fractions were combined and concentrated in vacuo to give the title compound as a very pale yellow solid (69 g, 88%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH:11]=2)=[C:7]([NH2:9])[CH:8]=1.Cl.[N:23]1([CH2:29][CH2:30][O:31][C:32]2[CH:40]=[CH:39][C:35]([C:36](Cl)=O)=[CH:34][CH:33]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH:11]=2)=[C:7]([NH:9][CH2:36][C:35]2[CH:34]=[CH:33][C:32]([O:31][CH2:30][CH2:29][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:40][CH:39]=2)[CH:8]=1
Reactant: O=C(Cl)c1ccc(OCCN2CCCCC2)cc1
Reactant: COc1ccc(C2=Cc3ccc(OC)cc3CC2)c(N)c1
Agent: Cl
Product: COc1ccc2c(c1)CCC(c1ccc(OC)cc1NCc1ccc(OCCN3CCCCC3)cc1)=C2
Yield: 18.7 %

Procedure:
Synthesized from 5-methoxy-2-(6-methoxy-3,4-dihydronaphthalen-2-yl)phenylamine (341 mg) and 4-(2-piperidin-1-ylethoxy)benzoyl chloride hydrochloride (990 mg) according to an analogous synthetic method to Example 110, the title compound (113 mg) was obtained.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[N:13]=[C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)[C:11]([CH:25]=[O:26])=[CH:10][N:9]=1.C[Li].[C:29](=O)([O-])O.[Na+]>O1CCCC1.CCOCC>[OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[N:13]=[C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)[C:11]([C@@H:25]([OH:26])[CH3:29])=[CH:10][N:9]=1
Reactant: COc1ccc(CNc2nc(N3CCC[C@H]3CO)ncc2C=O)cc1Cl
Reactant: O=C([O-])O
Agent: [Li]C
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(CNc2nc(N3CCCC3CO)ncc2[C@H](C)O)cc1Cl

Procedure:
To a solution of (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-formylpyrimidine (91.0 mg) in tetrahydrofuran (20 ml) is added 1.10 M solution of methyl lithium in ether (1.1 ml) at −78° C., and the mixture is reacted for 10 minutes, and thereto is added aqueous sodium hydrogen carbonate solution. The reaction mixture is extracted with ethyl acetate to give crude (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-(1-hydroxyethyl)pyrimidine, MS (m/z): 393 (MH30).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].Cl[C:14]([F:19])([F:18])C([O-])=O.[Na+].[OH-].[Na+]>CN(C)C=O.O>[F:18][CH:14]([F:19])[O:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=C([O-])C(F)(F)Cl
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc(OC(F)F)ccc1[N+](=O)[O-]
Temperature: 125 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
To a solution of 5-hydroxy-2-nitrobenzaldehyde (500 mg) in N,N-dimethylformamide (4.3 mL) were added sodium chlorodifluoroacetate (456 mg), sodium hydroxide (120 mg) and water (0.060 mL) at room temperature, and the mixture was stirred at 125° C. for one hour. The reaction mixture was cooled to room temperature, diluted with water and then extracted with ethyl acetate. The organic layer was washed successively with water and saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (240 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[C:11](=[O:22])[NH:12][N:13]=[C:14]([C:16]2[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=2)[CH:15]=1.[Br:23]N1C(=O)CCC1=O>CC(C)=O>[Br:23][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]=1[C:10]1[C:11](=[O:22])[NH:12][N:13]=[C:14]([C:16]2[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=2)[CH:15]=1
Reactant: Cn1cc(-c2cc(-c3cc4ccccc4[nH]3)c(=O)[nH]n2)cn1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(C)=O
Product: Cn1cc(-c2cc(-c3[nH]c4ccccc4c3Br)c(=O)[nH]n2)cn1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
30 mg of 4-(1H-Indol-2-yl)-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one is dissolved in 4 ml of acetone and 22 mg of N-bromosuccinimide is added. The solution is stirred at RT for 20 min and the product is purified by preparative RP-HPLC eluting with a gradient of 0-100% acetonitrile in water (+0.01% trifluoroacetic acid). Yield 14 mg. LC-MS (ES+) 370/372 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH:8]=[C:7]([C:9]2[CH:10]=[C:11]3[NH:17][CH:16]=[CH:15][C:12]3=[N:13][CH:14]=2)[CH:6]=[N:5]1.[CH2:18]([O:20][C:21](=[O:24])[CH2:22]Br)[CH3:19].ClCCl>CN(C)C=O>[CH2:18]([O:20][C:21](=[O:24])[CH2:22][N:17]1[C:11]2[C:12](=[N:13][CH:14]=[C:9]([C:7]3[CH:6]=[N:5][N:4]([CH3:3])[CH:8]=3)[CH:10]=2)[CH:15]=[CH:16]1)[CH3:19]
Reactant: Cn1cc(-c2cnc3cc[nH]c3c2)cn1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)Cn1ccc2ncc(-c3cnn(C)c3)cc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 42.5 %

Procedure:
In a N2 charged round bottom flask, Sodium Hydride, 60%, (41 mg, 1.01 mmol) was suspended in dimethylformamide (2.5 mL). The solution was maintained under N2 and cooled to 0° C. for 10 minutes. Next, 6-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-b]pyridine (200 mg, 1.01 mmol) was dissolved in dimethylformamide (2.5 mL) and added to the cooled solution dropwise. The solution was allowed to stir at 0° C. for an additional 10 minutes. Finally, Bromo-acetic acid ethyl ester (123 uL, 1.11 mmol) was slowly added to the reaction vessel. The reaction was allowed to equilibrate back to room temperature, while stirring for 2 hours. Finally, the solution was transferred to a separatory funnel with dichloromethane (75 mL) and washed with water (2×75 mL). The organic layer was dried over Na2SO4, concentrated down and purified by flash chromatography (0-10% Methanol/dichloromethane step gradient) to afford the title compound (122 mg, 43% yield). MS m/z=285 [M+H+]+