Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>CS(C)=O.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: C1COCCN1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=C(Nc1ccc(Oc2ccnc(N3CCOCC3)n2)c2ccccc12)c1cc(F)cc(N2CCOCC2)c1
Temperature: 80 °C
Yield: 47.2 %

Procedure:
A mixture of 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide (0.1 mmol) and morpholine (0.087 ml, 1.0 mmol) in DMSO (0.5 ml) is heated at 80° C. for 6 h. The resulting mixture is diluted with CH2Cl2 (2 ml), washed with 0.01 N NaOH, and dried over sodium sulfate. After evaporation to dryness, the residue is purified by column chromatography on silica gel (50% EtOAc in hexane) to give 3-fluoro-5-morpholin-4-yl-N-{4-[(2-morpholin-4-ylpyrimidin-4-yl)oxy]-1-naphthyl}benzamide as a white solid (25 mg). Mp: 104-106° C.; 1H NMR (300 MHz, CDCl3) δ 3.26 (bs, 4H), 3.64 (bs, 8H), 3.87 (bs, 4H), 6.07 (d, J=4.5 Hz, 1H), 6.77 (d, J=11.7 Hz, 1H), 7.07 (d, J=7.5 Hz, 1H), 7.32 (bs, 2H), 7.52-7.59 (m, 2H), 7.89-8.00 (m, 3H), 8.12-8.19(m, 2H); MS: 530 (M+1).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:33]2[CH:38]=[CH:37][C:36]([S:39]([NH2:42])(=[O:41])=[O:40])=[CH:35][CH:34]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.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>[CH:18]1([N:9]2[C:10]3[CH:15]=[CH:14][N:13]=[C:12]([O:16][CH3:17])[C:11]=3[C:7]([C:33]3[CH:38]=[CH:37][C:36]([S:39]([NH2:42])(=[O:41])=[O:40])=[CH:35][CH:34]=3)=[N:8]2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: COc1nccc2c1c(OS(=O)(=O)C(F)(F)F)nn2C1CCCC1
Reactant: CC1(C)OB(c2ccc(S(N)(=O)=O)cc2)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: O
Solvent: COCCOC
Product: COc1nccc2c1c(-c1ccc(S(N)(=O)=O)cc1)nn2C1CCCC1
Yield: 96.1 %

Procedure:
A solution of 1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (150 mg) obtained in Step C of Example 12, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (145 mg), tetrakis(triphenylphosphine)palladium(0) (47.4 mg) and 2M aqueous sodium carbonate solution (1.03 mL) in DME (10 mL) was heated overnight with reflux under nitrogen atmosphere. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (147 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[Cl:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=1[F:23]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:19]3[CH:20]=[CH:21][C:22]([F:23])=[C:17]([Cl:16])[CH:18]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1ccc(F)c(Cl)c1

Procedure:
The title compound, MS: m/e=347.2 (M+H+), was prepared in accordance with the general method of example 7 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 3-chloro-4-fluoro-benzene boronic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[S:11][C:7]=2[C:6]([C:16]([OH:18])=[O:17])=[CH:5][CH:4]=1.[CH:19]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[C:21](O)[CH:20]=1.CN(C1C=CC=CN=1)C.Cl.CN(C)CCCN=C=NCC>ClCCl>[N+:25]([C:24]1[CH:19]=[CH:20][C:21]([O:17][C:16]([C:6]2[C:7]3[S:11][C:10]([C:12]([F:13])([F:14])[F:15])=[N:9][C:8]=3[C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:18])=[CH:22][CH:23]=1)([O-:27])=[O:26]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COc1ccc(C(=O)O)c2sc(C(F)(F)F)nc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2sc(C(F)(F)F)nc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 74.6 %

Procedure:
A suspension of 4-methoxy-2-trifluoromethylbenzothiazole-7-carboxylic acid (140 mg) in dichloromethane (10ml) was treated with p-nitrophenol (72 mg), dimethylaminopyridine (catalytic) and 1-(3-dimethylaminopropyl)-3-ethyl carbodimide hydrochloride (150 mg). The mixture was stirred at room temperature for 12 hours and the reaction washed with water (10 ml). The organic layer was separated, dried over magnesium sulphate (5 g) and evaporated in vacuo. Purification by flash chromatography (eluent 50% ethyl acetate/hexane) yielded the title compound as an off-white solid (150 mg). TLC Rf 0.13 (50% ethyl acetate in heptane).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[C:12]([CH:15]([C:17]([OH:19])=O)[F:16])[CH:13]=[CH:14][C:8]=2[CH:7]=1)=[O:5])[CH3:2].C(Cl)(=O)C(Cl)=O.[NH4+:26].[OH-]>C(Cl)Cl.CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[C:12]([CH:15]([C:17](=[O:19])[NH2:26])[F:16])[CH:13]=[CH:14][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2ccc(C(F)C(=O)O)cc2s1
Reactant: [NH4+]
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccc(C(F)C(N)=O)cc2s1
Reaction time: 0.33 h

Procedure:
To a slurry of 6-(carboxy-fluoro-methyl)-benzo[b]thiophene-2-carboxylic acid ethyl ester (400 mg, 1.42 mmol) in DCM (10 mL) was added oxalyl chloride (0.148 mL, 1.70 mmol) and 2 drops of DMF. After 20 min, the resultant solution was added to a solution of NH4OH (0.9 mL, 7.08 mmol) in DCM (5 mL) dropwise. After 1 h, the solvent was removed in vacuo and the solid was triturated with MeOH and H2O. The white solid was filtered and used without further purification. 1H NMR (DMSO-d6) δ 8.20 (s, 1H), 8.11 (s, 1H), 8.04 (d, J=8.2 Hz, 1H), 7.91 (br s, 1H), 7.62 (br d, J=2.4 Hz, 1H), 7.51 (d, J=8.2 Hz, 1H), 5.94 (d, J=45.7 Hz, 1H), 4.33 (q, J=7.2 Hz, 2H), 1.31 (t, J=7.2 Hz, 3H). cal'd 282 (MH+), exp 282 (MH+).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]([O:16][C:17]([N:19]1[C@@H:24]([CH:25]=[O:26])[CH2:23][O:22][C@@H:21]([CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[C:12]([O:16][C:17]([N:19]1[C@@H:24]([C@@H:25]([OH:26])[C@@H:8]([N+:9]([O-:11])=[O:10])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:23][O:22][C@@H:21]([CH2:27][CH2:28][CH:29]2[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]2)[CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1C[C@H](CCC2CCCCC2)OC[C@@H]1C=O
Reactant: O=[N+]([O-])CCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](CCC2CCCCC2)OC[C@@H]1[C@@H](O)[C@H](Cc1ccccc1)[N+](=O)[O-]
Temperature: 0 °C
Yield: 63.8 %

Procedure:
Add 1-phenyl-2-nitroethane (91 mg, 0.61 mmol) to a solution of 2-(S)-(2-cyclohexylethyl)-5-(R)-formylmorpholine-4-carboxylic acid tert-butyl ester (164 mg, 0.50 mmol) in dry tetrahydrofuran (6 mL). Cool to 0° C. and add tetrabutylammonium fluoride (0.25 mL of a 1 M solution in tetrahydrofuran, 0.25 mmol) and refrigerate the solution overnight. Dilute with ethyl acetate, wash with cold saturated aqueous sodium chloride (50 mL), dry (sodium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 2.5:97.5 ethyl acetate:dichloromethane) to give the desired compound as a white foam (152 mg, 63%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][C:5]2([CH3:14])[CH3:13].C[Si]([C:19]#[CH:20])(C)C.C([O-])([O-])=O.[K+].[K+]>C(N(CC)CC)C.CO.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>[C:19]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][C:5]2([CH3:14])[CH3:13])#[CH:20]
Reactant: C#C[Si](C)(C)C
Reactant: CC1(C)CCC(=O)c2ccc(Br)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CO
Product: C#Cc1ccc2c(c1)C(C)(C)CCC2=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution (flushed for 15 minutes with a stream of argon) of 13.55 g (53.8 mmol) of 6-bromo-3,4-dihydro-4,4-dimethyl-naphthalen-1(2H)-one (Compound H) in 280 ml of triethylamine was added 1.87 g (2.66 mmol) of bis(triphenylphosphine)palladium(II) chloride and 0.53 g (2.66 mmol) of cuprous iodide. The solution mixture was flushed with argon for 5 minutes and then 100 ml (938.7 mmol) of trimethylsilyl acetylene was added. The reaction mixture was sealed in a pressure tube and placed in a preheated oil bath (100° C.) for 24 hours. The reaction mixture was then filtered through celite, washed with Et2O and the filtrate concentrated in vacuo to give crude 6-(2-trimethylsilyl)ethynyl-3,4-dihydro-4,4-dimethyl-naphthalen-1(2H)-one. To a solution of this crude TMS-acetylenic compound in 50 ml of methanol was added 2.8 g (20.3 mmol) of K2CO3. The mixture was stirred for 8 hours at ambient temperature and then filtered. The filtrate was concentrated in vacuo, diluted with Et2O (100 ml), washed with water (10 ml), 10% HCl (10 ml) and brine (10 ml), dried over MgSO4 and concentrated in vacuo. Purification by column chromatography (silica, 10% EtOAc-hexane) yielded the title compound as a white solid.
Reaction SMILES: ClC(Cl)(Cl)C(O)=O.S(=O)(=O)(O)O.[N+:13]([C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[O:22][CH2:21][CH2:20][C:19]2=[O:26])([O-:15])=[O:14].[N-:27]=[N+]=[N-].[Na+]>>[N+:13]([C:16]1[CH:25]=[CH:24][C:23]2[O:22][CH2:21][CH2:20][C:19](=[O:26])[NH:27][C:18]=2[CH:17]=1)([O-:15])=[O:14]
Reactant: O=C1CCOc2ccc([N+](=O)[O-])cc21
Reactant: [N-]=[N+]=[N-]
Agent: O=C(O)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C1CCOc2ccc([N+](=O)[O-])cc2N1
Temperature: 70 °C
Yield: 22 %

Procedure:
Trichloroacetic Acid (39 g, 0.24 mol), Sulfuric acid (3 mL, 0.05 mol), and 6-Nitro-chroman-4-one (5.000 g, 0.026 mol) were combined and heated to 70° C. Sodium azide (3.36 g, 0.052 mol) was added slowly. The resulting solution was heated for 2 h, poured onto ice. Title compound isolated as a beige solid in 22% yield. 95% purity, LCMS: 209.15 (M+1) 1H NMR (400 MHz, DMSO, d6) δ 10.13, (s, 1H), 8.06 (dd, J=1.5 Hz, 1H), 7.85-7.82 (m, 1H), 7.15 (d, J=8.8 Hz, 1H), 4.47-4.44 m, 2H), 2.88-2.85 (m, 2H).
Reaction SMILES: [Cl:1]C1C=C2C(C=CN2)=CC=1.C(O[C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([C:24]([NH2:26])=[O:25])[CH:19]=[C:18]2[N:27]=[C:28]=[O:29])C=C>>[Cl:1][C:23]1[CH:22]=[C:21]2[C:17]([C:18]([N:27]=[C:28]=[O:29])=[CH:19][N:20]2[C:24]([NH2:26])=[O:25])=[CH:16][CH:15]=1
Reactant: Clc1ccc2cc[nH]c2c1
Reactant: C=CCOc1ccc2c(c1)c(N=C=O)cn2C(N)=O
Product: NC(=O)n1cc(N=C=O)c2ccc(Cl)cc21

Procedure:
was prepared from 6-chloroindole using the protocol described for steps B-E in scheme A4 for the preparation of 5-allyloxy-3-isocyanato-indole-1-carboxylic acid amide.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10](=[O:12])[CH3:11])=[CH:4][C:3]=2[O:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:28]1([CH2:34][S:35][CH:36]([C:40](O)=[O:41])[C:37](O)=[O:38])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[O:9]1[C:8]2[CH:7]=[CH:6][C:5]([C:10]3[O:12][C:37](=[O:38])[C:36]([S:35][CH2:34][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[C:40]([OH:41])[CH:11]=3)=[CH:4][C:3]=2[O:2][CH2:1]1
Reactant: O=C(O)C(SCc1ccccc1)C(=O)O
Reactant: CC(=O)c1ccc2c(c1)OCO2
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1oc(-c2ccc3c(c2)OCO3)cc(O)c1SCc1ccccc1

Procedure:
The title compound was prepared by Method A using 3',4'-(methylenedioxy)acetophenone (0.871 g, 5.31 mmol), lithium bis(trimethylsilyl)amide (0.977 g, 5.84 mmol), chlorotrimethylsilane (0.741 mL, 5.84 mmol), THF (58 mL), and diethyl ester of [(phenylmethyl)thio]propanedioic acid (1.00 g, 3.54 mmol). m.p. dec. 170° C.; 1H NMR (400 MHz, DMSO-d6) δ 3.98 (s, 2 H), 6.13 (s, 2 H), 6.61 (s, 1 H), 7.05 (d, 2 H), 7.27 (m, 7 H).
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]=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:20])(C)(C)C.CC1(C)O[C:27](=[O:29])[CH:26]=[C:25]([C:30]2[S:31][CH:32]=[CH:33][CH:34]=2)O1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:14]1([C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:25]([C:30]4[S:31][CH:32]=[CH:33][CH:34]=4)[CH2:26][C:27](=[O:29])[NH:20][C:9]=3[CH:10]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cc1N
Reactant: CC1(C)OC(=O)C=C(c2cccs2)O1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccs2)=Nc2ccc(-c3ccccc3)cc2N1
Yield: 59.5 %

Procedure:
Prepared from (3-amino-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G9) (69 mg, 0.243 mmol) and 2,2-dimethyl-6-thiophen-2-yl-[1,3]dioxin-4-one (Example J1) (54 mg, 0.257 mmol) according to the general procedure K. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a brown solid (46 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[CH:13]([OH:17])[C:14]([OH:16])=O.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1O>C1(C)C(C)=CC=CC=1>[O:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[C:14]1[CH:13]([C:3]1[CH:4]=[C:5]([O:8][C:9]([F:10])([F:11])[F:12])[CH:6]=[CH:7][C:2]=1[F:1])[OH:17]
Reactant: Nc1ccccc1O
Reactant: O=C(O)C(O)c1cc(OC(F)(F)F)ccc1F
Solvent: Cc1ccccc1C
Product: OC(c1nc2ccccc2o1)c1cc(OC(F)(F)F)ccc1F

Procedure:
A mixture of (2-fluoro-5-trifluoromethoxyphenyl)hydroxyacetic acid (prepared according to 72C) (2.4 g), ortho-aminophenol (1.03 g) in xylene (25 mL) is refluxed for 4 h with a Dean-Stark apparatus and concentrated under reduced pressure. Purification by chromatography on silica gel (gradient dichloromethane/methanol/ammonia from 100/0/0 to 98/2/0.5) to afford the pure benzoxazol-2-yl(2-fluoro-5-trifluoromethoxyphenyl)methanol.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([NH:11][C:12]2[C:16]3[CH:17]=[CH:18][C:19]([OH:21])=[CH:20][C:15]=3[O:14][C:13]=2[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=2)=[O:23])=[O:10])[CH2:5][CH2:4]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]>CN(C)C=O.O>[C:44]([O:43][C:41]([CH2:40][O:21][C:19]1[CH:18]=[CH:17][C:16]2[C:12]([NH:11][C:9]([C@H:6]3[CH2:5][CH2:4][C@H:3]([N:2]([CH3:32])[CH3:1])[CH2:8][CH2:7]3)=[O:10])=[C:13]([C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=3)=[O:23])[O:14][C:15]=2[CH:20]=1)=[O:42])([CH3:47])([CH3:46])[CH3:45]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CN(C)[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3cc(O)ccc23)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3cc(OCC(=O)OC(C)(C)C)ccc23)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Trans-3-[4-(dimethylamino)cyclohexylcarbonylamino]-6-hydroxy-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (90 mg) obtained in Example 151 is dissolved in N,N-dimethylformamide (2 ml), and thereto are added cesium carbonate (110 mg) and t-butyl bromoacetate (35.5 μl). The mixture is stirred at room temperature for 12 hours, and further stirred at 50° C. for 2.5 hours. The reaction solution is allowed to stand for cooling, and diluted with water, and extracted with ethyl acetate. The organic layer is concentrated under reduced pressure, and the resulting residue is purified by NH-silica gel column chromatography (eluent: hexane/ethyl acetate=1/1, then ethyl acetate) to give the title compound (21 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([C:12]2[C:16]([Cl:17])=[C:15]([O:18][CH:19]([F:21])[F:20])[N:14]([CH3:22])[N:13]=2)=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:30][O:31][NH2:32]>C1(C)C=CC=CC=1.O>[CH3:30][O:31][NH:32][C:4](=[O:5])[C:3]1[CH:7]=[C:8]([C:12]2[C:16]([Cl:17])=[C:15]([O:18][CH:19]([F:21])[F:20])[N:14]([CH3:22])[N:13]=2)[C:9]([F:11])=[CH:10][C:2]=1[Cl:1]
Reactant: CON
Reactant: Cn1nc(-c2cc(C(=O)Cl)c(Cl)cc2F)c(Cl)c1OC(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CONC(=O)c1cc(-c2nn(C)c(OC(F)F)c2Cl)c(F)cc1Cl
Reaction time: 4 h

Procedure:
A solution of 8.4 g (22 mmol) of 2-chloro-5-(4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazol-3-yl)-4-fluorobenzoyl chloride in 150 ml of toluene was treated with 34 g (0.24 mol) of potassium carbonate, and 16 g (48 mmol) of a 25% strength aqueous methoxyamine hydrochloride solution was subsequently added dropwise. After the reaction mixture had been stirred for 4 hours, it was diluted with 0.5 l of water. The organic phase was then separated off, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and finally concentrated. Yield: 8.3 g.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:10][CH:11]=[CH2:12])=[O:9])=[CH:4][C:3]=1[N+:13]([O-])=O.CO>[Fe].O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:10][CH:11]=[CH2:12])=[O:9])=[CH:4][C:3]=1[NH2:13]
Reactant: C=CCS(=O)c1ccc(N)c([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CO
Solvent: O
Product: C=CCS(=O)c1ccc(N)c(N)c1

Procedure:
2 G. of 1-amino-2-nitro-4-(prop-2-en-1-ylsulfinyl)-benzene is treated for four hours in a refluxing mixture of 160 ml. methanol and 40 ml. water with 4 g. iron powder (added in two portions) and 1 g. ferrous sulfate. The mixture is filtered, and the filtrate concentrated. The residue is dissolved in chloroform and washed with water, then the solvent evaporated affording 1,2-diamino-4-(prop-2-en-1-ylsulfinyl)benzene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].[NH2:27][C:28]1[S:29][CH:30]=[C:31]([C:33]([CH3:36])([CH3:35])[CH3:34])[N:32]=1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1>CC(N(C)C)=O.C(OCC)(=O)C>[C:33]([C:31]1[N:32]=[C:28]([NH:27][C:17]([C:16]2[CH:20]=[CH:21][C:13]([O:12][C:11]3[CH:10]=[C:9]4[C:4]([CH:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:6][CH2:7][O:8]4)=[CH:3][C:2]=3[Cl:1])=[CH:14][CH:15]=2)=[O:18])[S:29][CH:30]=1)([CH3:36])([CH3:35])[CH3:34]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Reactant: CC(C)(C)c1csc(N)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4nc(C(C)(C)C)cs4)cc3)c(Cl)cc21
Temperature: 50 °C
Yield: 64.7 %

Procedure:
4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (53 mg, 0.141 mmol) and 2-amino-4-tert-butylthiazole (44.0 mg, 0.281 mmol) in DMA were treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53.9 mg, 0.281 mmol) followed by 1-hydroxy-7-azabenzotriazole (19.1 mg, 0.141 mmol) at ambient temperature. The reaction was heated to 50° C. for 14 hours. The reaction was diluted with ethyl acetate, washed with 1 N HCl, saturated aqueous bicarbonate, and brine. The ethyl acetate layer was dried with sodium sulfate and the product purified on SP1 (20 to 65% Ethyl acetate/hexane) to provide the desired compound (47 mg).
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:8][O:7][CH2:6][CH2:5][N:4]1[C:9]1[N:14]=[C:13]([NH:15][CH3:16])[N:12]=[C:11]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19](F)[CH:18]=2)[CH:10]=1)[CH3:2].[NH2:26][NH2:27]>CC#N>[CH2:1]([C@@H:3]1[CH2:8][O:7][CH2:6][CH2:5][N:4]1[C:9]1[N:14]=[C:13]([NH:15][CH3:16])[N:12]=[C:11]([C:17]2[CH:24]=[C:23]3[C:20]([C:21]([NH2:22])=[N:26][NH:27]3)=[CH:19][CH:18]=2)[CH:10]=1)[CH3:2]
Reactant: NN
Reactant: CC[C@@H]1COCCN1c1cc(-c2ccc(C#N)c(F)c2)nc(NC)n1
Solvent: CC#N
Product: CC[C@@H]1COCCN1c1cc(-c2ccc3c(N)n[nH]c3c2)nc(NC)n1
Yield: 28.5 %

Procedure:
4-[6-[(3R)-3-Ethyl-4-morpholinyl]-2-(methylamino)-4-pyrimidinyl]-2-fluorobenzonitrile (0.464 g, 1.359 mmol) was taken up in CH3CN (5 mL) followed by the addition of hydrazine (0.171 mL, 5.44 mmol) and Hunig's (1.899 mL, 10.87 mmol) in a 20 mL microwave vial. The reaction was irradiated at 150° C. for 1 hour. The reaction mixture was then concentrated and the resulting residue was purified using reverse phase HPLC (5-30% CH3CN/H2O, 0.1% TFA). Fractions were combined and diluted with EtOAc. The organics were washed with saturated NaHCO3 solution (2×) that was back extracted with EtOAc (×1). The organics were combined and dried over Na2SO4. The product was taken up in 2 mL H2O and lyophilized to afford the title compound (137 mg) as a white fluffy powder. LC-MS (ES) m/z=354 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.89 (t, 3H), 1.60-1.82 (m, 2H), 2.83 (d, J=4.0 Hz, 3H), 3.10 (d, J=2.3 Hz, 1H), 3.43 (d, J=2.5 Hz, 1H), 3.52 (dd, J=11.5, 2.9 Hz, 1H), 3.84 (d, J=11.4 Hz, 1H), 3.89 (dd, J=11.2, 3.2 Hz, 1H), 4.03 (q, J=7.1 Hz, 1H), 4.14-4.26 (m, 1H), 4.29-4.38 (m, 1H), 5.38 (s, 2H), 6.55 (bs, 2H), 7.59 (d, J=8.6 Hz, 1H), 7.71 (d, J=8.6 Hz, 1H), 7.97 (bs, 1H), 11.50 (bs, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:12])[CH:10]=[CH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:13]([NH:21][NH2:22])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)(C)C>[C:13]([NH:21][NH:22][CH2:11][CH2:10][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:12])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C=CC(=O)OCc1ccccc1
Reactant: NNC(=O)c1ccccc1
Solvent: CC(C)O
Product: O=C(CCNNC(=O)c1ccccc1)OCc1ccccc1
Temperature: 25 °C
Yield: 50.1 %

Procedure:
Benzylacrylate (1.13 ml, 7.34 mmol) was added to a stirred suspension of benzoylhydrazine (285) (1.0 g, 7.34 mmol) in isopropanol (28 ml). The mixture was refluxed for 20 h, cooled to room temperature then concentrated. The residue was purified by flash chromatography (20% EtOAc in CH2Cl2) to afford 259 (1.098 g, 50%) as an oil which crystallized on standing: mp 65° C.; IR (KBr) 3283, 1723, 1644, 1316, 1201, 1156; 1H NMR (CDCl3) δ 8.32-8.18 (1H, m), 7.81-7.70 (2H, m), 7.57-7.23 (8H, m), 5.36-4.92 (1H, brm), 5.11 (2H, s), 3.26 (2H, t, J=6.5), 2.59 (2H, t, J=6.5); 13C NMR (CDCl3) δ 172.12, 167.27, 135.65, 132.54, 131.66, 128.45, 128.10, 128.06, 126.84, 66.31, 47.33, 33.31; Anal. Calcd for C17H18N2O3: C, 68.44; H, 6.08; N, 9.39. Found: C, 68.42; H, 6.10; N, 9.38. MS (ES +) 321 (M+Na, 38%), 299 (M++1, 100).
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[C:9]([CH:10]3[C:15]([C:16]#[N:17])=[C:14]([CH:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)[NH:13][C:12]4=[N:24][NH:25][CH:26]=[C:11]34)=[CH:8][CH:7]=[CH:6][C:5]=12.C(N(C(C)C)CC)(C)C.Cl.[N:37]1([C:42](N)=[NH:43])C=CC=N1>CO>[N:1]1[O:2][N:3]=[C:4]2[C:9]([CH:10]3[C:15]([C:16]#[N:17])=[C:14]([CH:18]4[CH2:19][CH2:20][N:21]([C:42](=[NH:37])[NH2:43])[CH2:22][CH2:23]4)[NH:13][C:12]4=[N:24][NH:25][CH:26]=[C:11]34)=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: N=C(N)n1cccn1
Reactant: N#CC1=C(C2CCNCC2)Nc2n[nH]cc2C1c1cccc2nonc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: N#CC1=C(C2CCN(C(=N)N)CC2)Nc2n[nH]cc2C1c1cccc2nonc12
Reaction time: 8 h
Yield: 59.5 %

Procedure:
To a solution of 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine (1.5 g) in MeOH (30 mL) was added diisopropylethylamine (4.2 g), and 1H-pyrazole-1-carboxamidine hydrochloride (0.96 g) at room temperature and the mixture was stirred overnight. The precipitated crystals were collected by filtration to give the title compound (1.0 g) as yellow crystals.