Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16](C)[CH:15]=2)=[CH:10][C:9]=1[NH:21][C:22](=[O:34])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]#[N:33])[CH:27]=1)=O)(C)(C)C.[C:36](O)(C(F)(F)F)=O>C(Cl)Cl>[O:34]=[C:22]1[CH2:23][C:24]([C:26]2[CH:27]=[C:28]([CH:29]=[CH:30][CH:31]=2)[C:32]#[N:33])=[N:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:15]=[C:16]([CH3:36])[CH:17]=[CH:18][CH:19]=3)=[CH:10][C:9]=2[NH:21]1
Reactant: Cc1cccc(-c2ccc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c3cccc(C#N)c3)c2)c1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cccc(-c2ccc3c(c2)NC(=O)CC(c2cccc(C#N)c2)=N3)c1

Procedure:
Prepared from {3-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-3′-methyl-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K15) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow powder (145 mg).
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:14](=[O:16])[CH3:15])[CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.CO>C(Cl)(Cl)Cl>[Br:1][CH2:15][C:14]([C:10]1([C:7]2[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=2)[CH2:13][CH2:12][CH2:11]1)=[O:16]
Reactant: CC(=O)C1(c2ccc(Cl)cc2)CCC1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(CBr)C1(c2ccc(Cl)cc2)CCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of bromine (35 ml) in chloroform (150 ml) was added dropwise over 3 hours to a stirred mixture of 1-[1-(4-chlorophenyl)cyclobutyl]ethanone (150 g), chloroform (50 ml) and methanol (235 ml). When the addition was complete, the mixture was stirred at ambient temperature for a further 3 hours, then it was diluted with ice-cold water (750 ml). The product was extracted into dichloromethane (3×200 ml), and the combined extracts were washed with saturated aqueous sodium hydrogen carbonate solution (3×100 ml) and water (100 ml), dried (MgSO4), and the solvents removed in vacuo, to leave 2-bromo-1-[1-(4-chlorophenyl)cyclobutyl]ethanone as an oil which was used without further purification.
Reaction SMILES: [C:1]([O:8]CC)(=O)[C:2]([O:4]CC)=O.[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[N:19]1[C:23]([NH:24][CH2:25][CH3:26])=[C:22]([NH2:27])[CH:21]=[N:20]1>CCOC(C)=O>[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[N:19]1[C:23]2[N:24]([CH2:25][CH3:26])[C:2](=[O:4])[C:1](=[O:8])[NH:27][C:22]=2[CH:21]=[N:20]1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCNc1c(N)cnn1-c1ccc(F)cc1F
Solvent: CCOC(C)=O
Product: CCn1c(=O)c(=O)[nH]c2cnn(-c3ccc(F)cc3F)c21
Temperature: 150 °C

Procedure:
A mixture of diethyl oxalate (5.68 mL, 4.20 mmol) and 1-(2,4-difluorophenyl)-N5-ethyl-1H-pyrazole-4,5-diamine (1.00 g, 4.20 mmol) were heated in an oil bath at 150° C. for 18 h. The reaction mixture was cooled to RT and treated with EtOAc (5 mL) and hexanes (15 mL). The precipitated tan solid was filtered and rinsed with 5 mL of ether to afford 1-(2,4-difluorophenyl)-7-ethyl-1H-pyrazolo[3,4-b]pyrazine-5,6(4H,7H)-dione. MS (ES+): 293.1 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.F[C:16]1[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][C:17]=1[N+:26]([O-:28])=[O:27].C(=O)([O-])[O-].[Na+].[Na+]>CS(C)=O>[CH2:8]([N:5]1[CH2:6][CH2:7][CH:2]([NH:1][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][C:17]=2[N+:26]([O-:28])=[O:27])[CH2:3][CH2:4]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: CS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(NC2CCN(Cc3ccccc3)CC2)c([N+](=O)[O-])c1
Temperature: 90 °C
Reaction time: 12 h
Yield: 98.5 %

Procedure:
4-Amino-1-benzylpiperidine (87 g) was added slowly during 20 minutes to a stirred mixture of 2-fluoro-5-methylsulphonyl-nitrobenzene (100 g) and anhydrous sodium carbonate (35 g) in 500 mL DMSO, the internal temperature rose from 20° C. to 50° C. The mixture was stirred at 90° C. for 12 hours, then poured into ice/water and the yellow solid was filtered off, redissolved in dichloromethane, dried and evaporated to give 175 g N-(1-benzylpiperidin-4-yl)-2-nitro-4-methylsulphonylaniline.
Reaction SMILES: Br[C:2]1[C:10]2[S:9][CH:8]=[N:7][C:6]=2[CH:5]=[C:4]([CH3:11])[C:3]=1[OH:12].[Cl:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[C:10]3[S:9][CH:8]=[N:7][C:6]=3[CH:5]=[C:4]([CH3:11])[C:3]=2[OH:12])=[CH:16][CH:15]=1
Reactant: Cc1cc2ncsc2c(Br)c1O
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc2ncsc2c(-c2ccc(Cl)cc2)c1O
Temperature: 110 °C

Procedure:
The reaction mixture of 7-bromo-5-methylbenzo[d]thiazol-6-ol (5D) (90 mg, 0.37 mmol), 4-chlorophenyl boronic acid (86 mg, 0.55 mmol), Pd(PPh3)4 (40 mg, 0.037 mmol), K2CO3 (153 mg, 1.11 mmol) in 1,2-dimethoxyethane (1 ml)/H2O(0.5 ml) was heated at 110° C. in the microwave for 10 min. Then the reaction mixture was diluted with water, extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered, concentrated and purified by silica gel column (0-100% ethyl acetate/hexanes). LCMS-ESI+: calc'd for C14H10ClNOS: 276.0 (M+H+). Found: 276.2 (M+H+).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.S(=O)(=O)(O)O.[CH3:16]O>>[OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH3:16])=[O:9])[CH2:4][CH2:3]1
Reactant: O=C(O)C1CCC(O)CC1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)[C@H]1CC[C@H](O)CC1
Temperature: 60 °C
Reaction time: 10 h

Procedure:
A 250-mL round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was charged with 4-hydroxycyclohexane-1-carboxylic acid (15.7 g, 108.90 mmol, 1.00 equiv) in methanol (90 mL). Sulfuric acid (0.8 mL) was added to the mixture slowly. The resulting solution was stirred for 10 hr at 60° C. The reaction was then quenched by the addition of 200 mL of sodium bicarbonate (sat.). The resulting solution was extracted with 3×200 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting trans-methyl 4-hydroxycyclohexane-1-carboxylate (16.6 g, 96%) was obtained as a light yellow oil.
Reaction SMILES: [I:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([OH:9])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:16]=[C:15](Cl)[CH:14]=[CH:13][N:12]=1.C([O-])([O-])=O.[K+].[K+].O>CC(N(C)C)=O>[Cl:10][C:11]1[CH:16]=[C:15]([O:9][C:5]2[C:6]([CH3:8])=[N:7][C:2]([I:1])=[CH:3][CH:4]=2)[CH:14]=[CH:13][N:12]=1
Reactant: Cc1nc(I)ccc1O
Reactant: Clc1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1nc(I)ccc1Oc1ccnc(Cl)c1
Temperature: 110 °C
Yield: 73.4 %

Procedure:
A mixture of 6-iodo-2-methylpyridin-3-ol (6.8 g, 28.9 mmol), 2,4-dichloropyridine (8.56 g, 57.9 mmol) and K2CO3 (4.00 g, 28.9 mmol) in DMA (50 mL) was heated at 110° C. for 16 h under argon. The mixture was cooled to RT, treated with H2O, extracted with EtOAc (2×) and the combined organics were washed with H2O, then brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford 3-((2-chloropyridin-4-yl)oxy)-6-iodo-2-methylpyridine (7.35 g, 73%) as a white solid. MS (ESI) m/z: 346.9 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:4]=2[C:3]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].F[C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[N+:25]([O-:27])=[O:26]>CS(C)=O>[F:24][C:22]1[CH:21]=[CH:20][C:19]([N+:25]([O-:27])=[O:26])=[C:18]([CH:23]=1)[NH:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:4]=2[C:3]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1c(N)sc2cc(C)ccc12
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Solvent: CS(C)=O
Product: CCOC(=O)c1c(Nc2cc(F)ccc2[N+](=O)[O-])sc2cc(C)ccc12
Yield: 71.2 %

Procedure:
In the same manner as in Starting Material Synthesis Example 4 and using ethyl 2-amino-6-methylbenzo[b]thiophene-3-carboxylate (4.5 g), 2,4-difluoronitrobenzene (3.1 g) and dimethyl sulfoxide, ethyl 2-(5-fluoro-2-nitroanilino)-6-methylbenzo[b]thiophene-3-carboxyiate (5.1 g) was obtained.
Reaction SMILES: [CH3:1][N:2]([S:4]([NH:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[CH:11]2)(=[O:6])=[O:5])[CH3:3].[CH3:17][N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1>>[CH3:3][N:2]([S:4]([NH:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[C:21]1[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH:20]=1)(=[O:6])=[O:5])[CH3:1]
Reactant: CN1CCC(=O)CC1
Reactant: CN(C)S(=O)(=O)Nc1ccc2[nH]ccc2c1
Product: CN1CC=C(c2c[nH]c3ccc(NS(=O)(=O)N(C)C)cc23)CC1
Yield: 72.8 %

Procedure:
Beginning with 1.17 gm (4.89 mMol) 5-(N,N-dimethylamino)sulfonylamino-1H-indole and 0.78 mL (6.4 mMol) 1-methyl-4-piperidone, 1.19 gm (72.6%) of the title compound were recovered as a pale yellow powder.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6](Br)[CH:7]=1.[Cl-].[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:14]=1[CH2:15][Zn+]>O1CCCC1.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[Br:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6]([CH2:15][C:14]2[C:13]([Cl:12])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:21])[CH:7]=1
Reactant: Clc1cccc(Cl)c1C[Zn+]
Reactant: N#Cc1ncc(Br)cc1Br
Agent: [Pd]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ncc(Cc2c(Cl)cccc2Cl)cc1Br
Temperature: 85 °C

Procedure:
A solution of the product of EXAMPLE 1A (4.52 g, 15.34 mmol) in tetrahydrofuran (75 mL) was treated with palladium tetrakis(triphenylphosphine) (0.887 g, 0767 mmol) and 2,6-dichlorobenzyl zinc chloride (46 mL, 0.5M in tetrahydrofuran). The mixture was heated at 85° C. for 1 hour. After cooling to ambient temperature, the mixture was diluted with water and extracted with ethyl acetate. The organics were washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. Purification by silica gel chromatography (0-100% ethyl acetate in hexanes) provided the title compound. MS (LC-MS) m/z 342 (M+H)+.
Reaction SMILES: [N:1]([O-])=[O:2].[Na+].C(O)(=O)C.[N+:9]([C:12]1[CH:30]=[CH:29][C:15]([CH2:16][O:17][C:18]([N:20]2[CH2:25][CH2:24][NH:23][CH:22]([C:26]([OH:28])=[O:27])[CH2:21]2)=[O:19])=[CH:14][CH:13]=1)([O-:11])=[O:10]>O>[N+:9]([C:12]1[CH:13]=[CH:14][C:15]([CH2:16][O:17][C:18]([N:20]2[CH2:25][CH2:24][N:23]([N:1]=[O:2])[CH:22]([C:26]([OH:28])=[O:27])[CH2:21]2)=[O:19])=[CH:29][CH:30]=1)([O-:11])=[O:10]
Reactant: O=C(O)C1CN(C(=O)OCc2ccc([N+](=O)[O-])cc2)CCN1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=NN1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1C(=O)O
Reaction time: 1 h

Procedure:
The H2O (300 mL) solution of NaNO2 (cont. 98.5%) (6.66 g) was added to the acetic acid (864 mL) solution of piperazine-1,3-dicarboxylic acid 1-(4-nitrobenzyl) ester (26.72 g) under a nitrogen atmosphere at 0° C. for 0.5 h and stirred for 1 h. In addition, the H2O (132 mL) solution of NaNO2 (cont. 98.5%) (2.41 g) was added to the solution at 0° C. for 0.5 h and stirred for 1 h. The solution was concentrated under reduced pressure and H2O (500 mL) was added to the residue. The solution was extracted with AcOEt (5 times) and organic layer was washed with brine. The mixture was dried over MgSO4, filtered and concentrated under reduced pressure to afford crude 4-nitrosopiperazine-1,3-dicarboxylic acid 1-(4-nitrobenzyl) ester as pale brown amorphous (27.83 g (gross), 25.77 g (net), 88.2%).
Reaction SMILES: N1C(C)=CC(C)=CC=1C.[CH3:10][N:11]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([C:19]2[CH:29]=[C:28]([O:30][C:31]3[CH:36]=[CH:35][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:33][CH:32]=3)[C:22]3[CH2:23][CH:24]([CH2:26]O)[O:25][C:21]=3[CH:20]=2)=[O:18])=[N:12]1.CCN(S(F)(F)[F:47])CC>C(Cl)Cl>[CH3:10][N:11]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([C:19]2[CH:29]=[C:28]([O:30][C:31]3[CH:36]=[CH:35][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:33][CH:32]=3)[C:22]3[CH2:23][CH:24]([CH2:26][F:47])[O:25][C:21]=3[CH:20]=2)=[O:18])=[N:12]1
Reactant: Cn1ccc(NC(=O)c2cc(Oc3ccc(S(C)(=O)=O)cc3)c3c(c2)OC(CO)C3)n1
Reactant: CCN(CC)S(F)(F)F
Solvent: Cc1cc(C)nc(C)c1
Solvent: ClCCl
Product: Cn1ccc(NC(=O)c2cc(Oc3ccc(S(C)(=O)=O)cc3)c3c(c2)OC(CF)C3)n1
Reaction time: 8 h
Yield: 18.4 %

Procedure:
A solution of 2,4,6-collidine (0.0311 mL, 0.235 mmol) and 2-hydroxymethyl-4-(4-methanesulfonyl-phenoxy)-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (200) (50 mg, 0.11 mmol) in CH2Cl2 (3 mL) was cooled to −15° C. DAST (0.0307 mL, 0.235 mmol) was added drop wise. The mixture was stirred at −15° C. to room temperature overnight, then quenched with MeOH at 0° C., concentrated, and purified by column chromatography eluting with 25-75% EtOAc in hexanes to give a white solid (9 mg, 18% yield). 1H NMR (400 MHz, CDCl3) δ 8.48 (s, 1 H) 7.78-8.03 (m, 2 H) 7.20-7.34 (m, 2 H) 7.02-7.20 (m, 3 H) 6.77 (d, J=2.27 Hz, 1 H) 5.01-5.19 (m, 1 H) 4.42-4.78 (m, 2 H) 3.79 (s, 3H) 3.25 (dd, J=16.55, 9.73 Hz, 1 H) 3.08 (s, 3 H) 2.99-3.06 (m, 1 H); LCMS for C21H20FN3O5S m/z 446.00 (M+H+).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.[CH2:12](I)[CH2:13][CH2:14][CH3:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH2:12]([O:6][C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][C:7]=1[O:8][CH3:9])[CH:2]=[O:1])[CH2:13][CH2:14][CH3:15]
Reactant: CCCCI
Reactant: COc1ccc(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCOc1cc(C=O)ccc1OC
Temperature: 25 °C

Procedure:
Isovanillin (6.00 g, 39.4 mM), butyl iodide (5.7 ml, 49.3 mM), and anhydrous potassium carbonate (6.8 g, 49.3 mM) were dissolved in dried dimethylformamide (50 ml) and stirred at room temperature for one night, then the solution was diluted with ethyl acetate (300 ml) and washed with water. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed in vacuo to obtain a residue as a light yellow oil. The residue was purified by flash chromatography (SiO2: eluted by 20% ethyl acetate/hexane solution). The solvent was removed in vacuo and the resultant product was dried to obtain 3-butoxy-4-methoxy-3-benzaldehyde 8.09 g (yield 99.0%) as a light yellow oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][CH2:27][CH2:28][CH3:29])=[O:25])=[C:19]([Cl:30])[CH:18]=3)=[N:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:31][CH3:32].C(=O)([O-])[O-].[K+].[K+].[SH:39][C:40]1[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=1.O>CN(C)C=O>[Cl:30][C:19]1[CH:18]=[C:17]([O:16][C:10]2[C:9]3[C:14](=[CH:15][C:6]([O:5][CH2:4][CH2:3][CH2:2][S:39][C:40]4[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=4)=[C:7]([O:31][CH3:32])[CH:8]=3)[N:13]=[CH:12][N:11]=2)[CH:22]=[CH:21][C:20]=1[NH:23][C:24]([NH:26][CH2:27][CH2:28][CH3:29])=[O:25]
Reactant: Sc1ccncc1
Reactant: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OCCCBr)c(OC)cc23)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OCCCSc4ccncc4)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
A starting compound (N-(4-{[7-(3-bromopropoxy)-6-methoxy-4-quinazolinyl]oxy}-2-chlorophenyl)-N′-propyl-urea, 80 mg), potassium carbonate (138 mg), and 4-mercaptopyridine (22 mg) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give 60 mg (yield 72%) of the title compound.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=O)[CH2:9]1)(=[O:7])[CH3:6].[Cl-].[Al+3].[Cl-].[Cl-].[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:5]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([C:25]2[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=2)=[O:16])[CH2:9]1)(=[O:7])[CH3:6]
Reactant: Fc1ccccc1
Reactant: CC(=O)N1CCCC(C(=O)O)C1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Product: CC(=O)N1CCCC(C(=O)c2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Thionyl chloride (2.12 ml, 32.1 mmol) was added to fluorobenzene solution (20 ml) of 1-acetyl-3-piperidinecarboxylic acid (5.00 g, 29.2 mmol) under ice-cooling, which was stirred at room temperature for 30 minutes. Aluminum chloride (9.74 g, 73.0 mmol) was added to the solution, which was stirred at 90° C. for 1 hour. The reaction mixture was poured in ice, and extraction was conducted using ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, saturated sodium hydrogencarbonate solution, and again saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then the solvent was distilled out under reduced pressure. The resulting oily substance was purified by silica gel column chromatography (development solvent; hexane:ethyl acetate=1:1), to give (1-acetyl-3-piperidinyl)(4-fluorophenyl)methanone (4.93 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH2:16])=[O:8])[N:6]=1.[C:24]1([C:34](O)=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH:16][C:34]([C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][CH:25]=2)=[O:35])=[O:8])[N:6]=1
Reactant: O=C(O)c1cccc2ccccc12
Reactant: NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(N)sc1-c1cccc(F)c1
Product: Nc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc3ccccc23)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [2-Amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,2S,5R)-2-aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-methanone with Naphthalene-1-carboxylic acid. LC-MS (basic): tR=0.83 min; [M+H]+=487.4.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].[CH:26](O)([CH3:28])[CH3:27]>>[C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]([C:18]1[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:26]([CH3:28])[CH3:27])=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)O
Reactant: CC(C)(C)OC(=O)NC(C(=O)c1ccc(O)cc1)c1ccc(Cl)cc1
Product: CC(C)Oc1ccc(C(=O)C(NC(=O)OC(C)(C)C)c2ccc(Cl)cc2)cc1

Procedure:
The title compound was prepared from rac-[1-(4-chloro-phenyl)-2-(4-hydroxy-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester and isopropanol in analogy to Example 9c): MS (ISP): 404.4 (M+H)+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][C:21]1[O:25][N:24]=[C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:22]=1[C:32]1[N:36]2[CH2:37][C:38]3[C:43]([C:35]2=[N:34][N:33]=1)=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=3.O[CH2:46][C:47]1[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl>[CH3:20][C:21]1[O:25][N:24]=[C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:22]=1[C:32]1[N:36]2[CH2:37][C:38]3[C:43]([C:35]2=[N:34][N:33]=1)=[CH:42][C:41]([O:44][CH2:46][C:47]1[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=1)=[CH:40][CH:39]=3
Reactant: Cc1onc(-c2ccccc2)c1-c1nnc2n1Cc1ccc(O)cc1-2
Reactant: OCc1cccnc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1onc(-c2ccccc2)c1-c1nnc2n1Cc1ccc(OCc3cccnc3)cc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.6 %

Procedure:
Under nitrogen atmosphere, triphenylphosphine bound resin (0.41 g, 0.45 mmol, 1.12 mmol/g) was swelled in dichloromethane for 30 minutes. 3-(5-Methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindol-8-ol (0.1 g, 0.30 mmol) (prepared by Example 3 step (a)), 3-hydroxymethylpyridine (44 μl, 0.45 mmol, 1.5 eq.) and diethyl azodicarboxylate (71 μl, 0.45 mmol, 1.5 eq.) were added and the reaction was stirred at room temperature overnight. The resin was filtered off and washed with dichloromethane, methanol and diethyl ether. The combined organics were concentrated in vacuo. The residue was purified firstly by alumina chromatography, eluting with 1% methanol/dichloromethane, and secondly by silica chromatography, using dichloromethane→5% methanol/dichloromethane as the eluant, to afford the title compound (21 mg, 16%). 1H NMR (400 MHz, CDCl3) δ 8.70–8.69 (1H, m), 8.61–8.59 (1H, m), 7.80 (1H, dt, J=7.8, 2.1 Hz), 7.59 (1H, d, J=2.4 Hz), 7.54–7.52 (2H, m), 7.46–7.33 (4H, m), 7.18 (1H, d, J=8.4 Hz), 7.02 (1H, dd, J=8.4, 2.4 Hz), 5.16 (2H, s), 3.96 (2H, s), 2.70 (3H, s). m/z (ES+) 422 (M+H)+.
Reaction SMILES: [NH:1]([C:3]([C:5]1[N:10]=[C:9]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=[CH:7][CH:6]=1)=O)[NH2:2].[CH:22]1([NH:25][CH:26]=O)[CH2:24][CH2:23]1.C1(N)CC1.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[CH:22]1([N:25]2[CH:26]=[N:2][N:1]=[C:3]2[C:5]2[N:10]=[C:9]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:8]=[CH:7][CH:6]=2)[CH2:24][CH2:23]1
Reactant: O=CNC1CC1
Reactant: NNC(=O)c1cccc(NC(=O)OCc2ccccc2)n1
Agent: NC1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: O=C(Nc1cccc(-c2nncn2C2CC2)n1)OCc1ccccc1
Temperature: 100 °C
Yield: 29.4 %

Procedure:
To a sealable flask containing benzyl 6-(hydrazinecarbonyl)pyridin-2-ylcarbamate (1.97 g, 6.89 mmol, 1.0 eq) was added N-cyclopropyl formamide (1.8 mL, 20.7 mmol, 3.0 eq), cyclopropylamine (1.4 mL, 20.7 mmol, 3.0 eq), toluene (0.2 M), and trifluoracetic acid (0.511 mL, 6.89 mmol, 1.0 eq). The flask was sealed and heated to 100° C. for 24 hours. The reaction mixture was concentrated under reduced pressure to provide a yellow oil, which was purified by flash chromatography (Rf=0.44 in 10% methanol/ethyl acetate, gradient flash: 3%→10% methanol in ethyl acetate). The product, which consisted of a mixture of the desired compound with cyclopropyl formamide, was suspended in acetonitrile, sonicated, and the resultant suspension filtered to provide benzyl 6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-ylcarbamate (680 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5]O[CH2:3][CH2:2]1.Cl[C:8]1[C:13]([Br:14])=[CH:12][N:11]=[C:10]([CH2:15][OH:16])[CH:9]=1.ClC1C(O)=NC=CC=1Cl>>[N:1]1([C:8]2[C:13]([Br:14])=[CH:12][N:11]=[C:10]([CH2:15][OH:16])[CH:9]=2)[CH2:6][CH2:5][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: OCc1cc(Cl)c(Br)cn1
Agent: Oc1nccc(Cl)c1Cl
Product: OCc1cc(N2CCCC2)c(Br)cn1

Procedure:
Substituting pyrrolidine (7.4 ml) for morpholine and 4-chloro-5-bromo-2-hydroxymethylpyridine (4 g) for 3,4-dichloro-2-hydroxypyridine and using corresponding molar proportions of the other reagents in the method of Example 3D gave 4-pyrrolidino-5-bromo-2-hydroxymethylpyridine. 2.28 g, m.p. 108°-10° C., from ether.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([NH:11]C(=O)C3C=CC=CC=3)[S:8][C:5]2=[N:6][CH:7]=1.[OH-].[Na+]>OS(O)(=O)=O>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([NH2:11])[S:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(Nc1nc2cc(Br)cnc2s1)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Nc1nc2cc(Br)cnc2s1
Yield: 97.4 %

Procedure:
A solution of N-(6-bromothiazolo[5,4-b]pyridin-2-yl)benzamide III (2.0 g, 5.98 mmol) in 70% H2SO4 (10.0 mL) was heated to 140° C. for 1 h. After the completion of the reaction (TLC monitoring), the reaction mixture was poured onto crushed ice, basified with 30% aqueous NaOH solution till pH 8.0 and extracted with EtOAc (3×150 mL). The combined organics was washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to obtain the desired product (1.34 g, 98%). 1H NMR (400 MHz, DMSO-d6): δ 7.85 (d, J=2.0 Hz, 1H), 8.05 (br s, 2H) and 8.18 (d, J=2.0 Hz, 1H).