Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9](=[O:25])[CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17]C(OC(C)(C)C)=O)[CH:12]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[OH-].[Na+]>Cl>[NH2:17][C:13]1[CH:12]=[C:11]([CH2:10][C:9]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[CH:5]=2)=[O:25])[CH:16]=[CH:15][N:14]=1
Reactant: Cc1cc(C)cc(C(=O)Cc2ccnc(NC(=O)OC(C)(C)C)c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(C)cc(C(=O)Cc2ccnc(N)c2)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 77.8 %

Procedure:
2N-hydrochloric acid (50 mL) was added to 1-(3,5-dimethylphenyl)-2-(2-tert-butoxycarbonylamino-4-pyridyl)ethanone (12 g, 36 mmol) and the mixture was stirred at 100° C. for 1 hour. After the reaction mixture was cooled to room temperature, an 8N aqueous solution of sodium hydroxide (15 mL) was added and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated. The residue was recrystallized from ethyl acetate to obtain 6.8 g of the title compound (28 mmol, yield 77%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH:14]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:15]([NH:17][OH:18])=[O:16])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[OH:25]OS([O-])=O.[K+]>CO.C1COCC1.O>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([S:12]([CH:14]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:15]([NH:17][OH:18])=[O:16])(=[O:25])=[O:13])=[CH:10][CH:11]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)C(C(=O)NO)C2CCCCC2)cc1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC#CCOc1ccc(S(=O)(=O)C(C(=O)NO)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of 2-{[4-(2-butynyl oxy)phenyl]sulfinyl}-2-cyclohexyl-N-hydroxyacetamide (180 mg, 0.52 mmol) in MeOH/THF at room, oxone (5.0 g, excess) was added in water (20 ml). Reaction mixture was stirred at room temperature for 6 hrs and filtered. Methanol-THF layer was concentrated and extracted with chloroform. The organic layer was washed well with water, dried, filtered and concentrated. The product was purified by silica gel column chromatography by eluting it with 4:1 ethyl acetate; hexane and 2-{[4-(2-butynyloxy) phenyl]sulfonyl}-2-cyclohexyl-N-hydroxyacetamide was isolated as a white solid. mp: 191° C.; Yield: 45 mg (24%); MS: 366.3 (M+H)+; 1H NMR (300 MHz, DMSO-d6): δ0.95-1.12 (band, 5H), 1.58 (m, 5H), 1.85 (t, J=2.22 Hz, 3H), 2.05 (m, 1H), 3.63 (d, J=9.1 Hz, 1H), 4.87 (d, J=2.34 Hz, 2H), 7.16 (d, J=9 Hz, 2H), 7.76 (d, J=9 Hz, 2H), 9.01 (s, 11H), 10.7 (s, 1H).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C@@H:9]2[C@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[N:3]1[CH:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1.Cl.O1CCOCC1>CO>[NH:14]1[CH2:13][CH2:12][CH:11]([N:3]2[C@@H:4]3[C@H:9]([CH2:8][CH2:7][CH2:6][CH2:5]3)[CH2:10][C:2]2=[O:1])[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2C(=O)C[C@H]3CCCC[C@@H]32)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C1C[C@H]2CCCC[C@@H]2N1C1CCNCC1
Temperature: 25 °C

Procedure:
tert-butyl 4-[(3aR,7aS)-2-oxooctahydro-1H-indol-1-yl]piperidine-1-carboxylate was dissolved in MeOH (25 mL) and 4M HCl/dioxane (5 mL) was added. The mixture stirred at room temperature then concentrated in vacuo to give the tile compound. MS (M+1): 223.26
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].C(N(CC)CC)C.[OH:13][CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=O>CO>[NH2:4][C:3]1[O:13][CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:2]=1[C:1]#[N:5]
Reactant: N#CCC#N
Reactant: O=C(CO)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: CO
Product: N#Cc1c(-c2ccc(F)cc2)coc1N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of malononitrile (0.31 g, 4.65 mmol) and triethylamine (0.65 ml, 4.65 mmol) in methanol (5 ml) was added drop-wise to a stirred suspension of 2-hydroxy-4′-fluoroacetophenone (0.65 g, 4.22 mmol) in methanol (16 ml) under a nitrogen atmosphere at ambient temperature. When the addition was complete, the mixture was stirred for 18 hr at ambient temperature. The solvent was then removed in vacuo, water (50 ml) was then added to the residue and the mixture was extracted with dichloromethane (3×50 ml). The combined extracts were dried (MgSO4) and the solvent removed in vacuo to give the crude 2-amino-4-(4′-fluorophenyl)-3-furonitrile which was partially purified by flash chromatography (silica) eluting with dichloromethane and ethyl acetate (1:1). This gave a 3.5:1 mixture of the product and 2-hydroxy-4′-fluoroacetophenone (0.60 g), which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)[C:3]=1[C:4]#[N:5].[CH3:16][N+:17]([CH3:19])=[CH2:18].[I-]>CN(C=O)C>[CH3:16][N:17]([CH2:19][C:14]1[N:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[C:3]=2[C:4]#[N:5])[CH:11]=[N:12][C:13]=1[CH3:15])[CH3:18]
Reactant: C=[N+](C)C
Reactant: Cc1cn(-c2cccc(F)c2C#N)cn1
Agent: [I-]
Solvent: CN(C)C=O
Product: Cc1ncn(-c2cccc(F)c2C#N)c1CN(C)C
Yield: 46 %

Procedure:
As described for example 84b, 2-fluoro-6-(4-methyl-imidazol-1-yl)-benzonitrile was reacted with Eschenmoser's salt in DMF for 7 h at 90° C. Evaporation of the solvent, aqueous workup and chromatography (SiO2, dichloromethane:methanol=100:0 to 97:3) afforded the title compound as a light yellow solid (yield: 46%). 1H-NMR (400 MHz, DMSO): δ=1.94 (s, 6H), 2.17 (s, 3H), 3.23 (s, 2H), 7.61-7.67 (m, 2H), 7.86 (s, 1H), 7.86-7.96 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:22]=[CH:21][C:10]([C:11]([NH:13][CH2:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[O:12])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:23][S:24]([CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)(=[O:26])=[O:25].[C:33]1(=O)[CH2:37][CH2:36][CH2:35][CH2:34]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH:33]1([N:30]2[CH2:29][CH2:28][CH:27]([S:24]([CH2:23][C:3]3[N:4]=[C:5]([C:7]4[CH:8]=[CH:9][C:10]([C:11]([NH:13][CH2:14][C:15]5[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=5)=[O:12])=[CH:21][CH:22]=4)[O:6][C:2]=3[CH3:1])(=[O:25])=[O:26])[CH2:32][CH2:31]2)[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)C1CCNCC1
Reactant: O=C1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)C1CCN(C2CCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
A solution of 4-[5-methyl-4-[(piperidine-4-sulfonyl)methyl]-1,3-oxazol-2-yl]-N-(pyridin-3-ylmethyl)benzamide (300 mg, 0.66 mmol, 1.00 equiv), cyclopentanone (84 mg, 1.00 mmol, 1.51 equiv) and acetic acid (60 mg, 1.00 mmol, 1.51 equiv) in 1,2-dichloroethane (10 mL) was stirred at room temperature for 4 h. Sodium triacetoxyborohydride (420 mg, 1.98 mmol, 3.00 equiv) was added and the resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum and the residue was eluted with water/acetonitrile (95:5-20:80) on a C18 column to give 240 mg (70%) of 4-[4-[(1-cyclopentylpiperidine-4-sulfonyl)methyl]-5-methyl-1,3-oxazol-2-yl]-N-(pyridin-3-ylmethyl)benzamide as a colorless solid. LC-MS- (ES, m/z): 523 [M+H]+, 262; 1HNMR (400 MHz, CD3OD, ppm) δ 8.60 (s, 1H), 8.48 (d, 1H), 8.11 (d, 2H), 7.99 (d, 2H), 7.89 (d, 1H), 7.45 (m, 1H), 4.65 (s, 2H), 4.46 (s, 2H), 3.49 (d, 2H), 3.37 (t, 1H), 3.02 (t, 1H), 2.58-2.55 (m, 2H), 2.51 (s, 3H), 2.37 (d, 2H), 2.06-1.96 (m, 4H), 1.83-1.70 (m, 2H), 1.69-1.51 (m, 4H).
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([OH:46])([C:22]3[N:23]=[CH:24][N:25](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:26]=3)[CH:19]([CH3:21])[CH3:20])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)=[O:5])[CH3:2].Cl.N1C=CC=CC=1>>[CH2:1]([NH:3][C:4]([C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([OH:46])([C:22]3[N:23]=[CH:24][NH:25][CH:26]=3)[CH:19]([CH3:21])[CH3:20])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)c1cccc(-c2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2)c1
Agent: Cl
Solvent: c1ccncc1
Product: CCNC(=O)c1cccc(-c2ccc(C(O)(c3c[nH]cn3)C(C)C)cc2)c1
Yield: 27.7 %

Procedure:
By the reaction in the same manner as in Example 4-(iii) using N-ethyl-4′-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl][1,1′-biphenyl]-3-carboxamide (4.00 g) and pyridine hydrochloride (1.14 g), the title compound (664 mg) was obtained as a colorless amorphous powder.
Reaction SMILES: CC(C)([O-])C.[Na+].CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.Cl[C:41]1[C:50]2[C:45](=[CH:46][C:47]([F:51])=[CH:48][CH:49]=2)[N:44]=[C:43]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][N:53]=2)[C:42]=1[CH3:58].[CH3:59][C:60]1([CH3:80])[O:79][CH2:78][C:63]2([C:71]3[C:66](=[CH:67][C:68]([N:72]4[CH2:77][CH2:76][O:75][CH2:74][CH2:73]4)=[CH:69][CH:70]=3)[NH:65][CH2:64]2)[CH2:62][O:61]1>CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C1(C)C=CC=CC=1>[F:51][C:47]1[CH:46]=[C:45]2[C:50]([C:41]([N:65]3[C:66]4[C:71](=[CH:70][CH:69]=[C:68]([N:72]5[CH2:77][CH2:76][O:75][CH2:74][CH2:73]5)[CH:67]=4)[C:63]4([CH2:62][O:61][C:60]([CH3:80])([CH3:59])[O:79][CH2:78]4)[CH2:64]3)=[C:42]([CH3:58])[C:43]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][N:53]=3)=[N:44]2)=[CH:49][CH:48]=1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Cl
Reactant: CC1(C)OCC2(CNc3cc(N4CCOCC4)ccc32)CO1
Agent: CC(C)(C)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC2(COC(C)(C)OC2)c2ccc(N3CCOCC3)cc21
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
To a microwave vial was added sodium tert-butoxide (0.035 g, 0.37 mmol), ruphos (8.6 mg, 0.018 mmol), 4-chloro-7-fluoro-3-methyl-2-(pyridin-2-yl)-quinoline (0.053 g, 0.19 mmol), 2,2-dimethyl-6′-morpholinospiro[[1,3]dioxane-5,3′-indoline] (0.056 g, 0.18 mmol), and XPhos pre-catalyst (0.014 g, 0.018 mmol) in toluene (1.2 mL). The suspension was deoxygenated with argon for 5 min and stirred at 100° C. for 90 min under microwave irradiation. Purification by column chromatography (eluting with a gradient of 10-60% EtOAc in hexanes) gave 1′-(7-fluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-yl)-2,2-dimethyl-6′-morpholinospiro[[1,3]dioxane-5,3′-indoline] as a yellow solid. Mass Spectrum (ESI) m/e=541.3 (M+1).
Reaction SMILES: [CH2:1]([N:3]([CH2:30][CH3:31])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([N+:15]([O-])=O)=[CH:12][CH:13]=2)[CH:8]=[C:7]1[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1)[CH3:2].I.CS[C:35]([C:37]1[S:38][CH:39]=[CH:40][CH:41]=1)=[NH:36]>C(O)C.C(OCC)C.[Pd]>[CH2:1]([N:3]([CH2:30][CH3:31])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:35]([C:37]3[S:38][CH:39]=[CH:40][CH:41]=3)=[NH:36])=[CH:12][CH:13]=2)[CH:8]=[C:7]1[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1)[CH3:2]
Reactant: CCN(CC)CCn1c(Cc2ccc(OC(F)(F)F)cc2)cc2cc([N+](=O)[O-])ccc21
Reactant: CSC(=N)c1cccs1
Agent: [Pd]
Agent: I
Solvent: CCOCC
Solvent: CCO
Product: CCN(CC)CCn1c(Cc2ccc(OC(F)(F)F)cc2)cc2cc(NC(=N)c3cccs3)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.1 %

Procedure:
Compound 9 (75 mg, 0.172 mmol) was dissolved in anhydrous ethanol (5 mL) in a dry argon purged flask. Palladium, 10wt % on activated carbon (18.3 mg, 0.0172 mmol) is quickly added and the atmosphere from the flask evacuated by vacuum pump and replaced with hydrogen from a balloon. The atmosphere is evacuated from the flask and replaced with hydrogen twice more and the mixture stirred under a hydrogen atmosphere at room temperature. After 3 hours, thin layer chromatography (2M NH3 in MeOH:CH2Cl2, 2.5:97.5) shows complete conversion to 10, which is utilized without isolation. The mixture is filtered through a pad of celite to remove insolubles, the pad washed with anhydrous ethanol (5 mL) and the ethanolic solution of the amine 10 is charged to a small, argon purged flask fitted with a magnetic stirbar. Thiophene-2-carboximidothioic acid methyl ester hydroiodide (63.8 mg, 0.224 mmol) is added to the flask and the reaction was stirred under argon at ambient temperature for 45 hours. The solution was diluted with diethyl ether (100 ml) and cooled in an ice bath. No precipitate formed thus the solvent was evaporated. The residue was purified using silica gel column chromatography (2M NH3 in MeOH:CH2Cl2, 2.5:97.5 to 5:95) to afford a pale yellow residue 11 (47 mg, 53.0%). 1H NMR (MeOD) δ 0.98 (t, 6H, J=7.1 Hz), 2.47-2.56 (2×m, 6H), 4.13 (t, 2H, J=7.1 Hz), 4.24 (s, 2H), 6.24 (s, 1H), 6.84 (dd, 1H, J=8.4, 1.6 Hz), 7.09-7.13 (m, 2H), 7.17-7.24 (m, 2H), 7.33-7.39 (m, 3H), 7.56 (d, 1H, J=5.2 Hz), 7.64 (d, 1H, J=3.7 Hz); ESI-MS (m/z, %): 515 (MH+, 100%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1.[Cl:14][C:15]1[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17]Br>>[Cl:14][C:15]1[C:22]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][N:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1
Reactant: N#Cc1ccnc(-c2c[nH]cn2)c1
Reactant: FC(F)(F)c1cccc(CBr)c1Cl
Product: N#Cc1ccnc(-c2cn(Cc3cccc(C(F)(F)F)c3Cl)cn2)c1

Procedure:
The title compound was prepared from 2-(1H-imidazol-4-yl)pyridine-4-carbonitrile (PREPARATION 4) and 2-chloro-3-(trifluoromethyl)benzyl bromide according to the procedure for the preparation of Example 43, part A using room temp. [M+H] Calc'd for C17H10ClF3N4, 363. Found, 363.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][O:14][C:13]2[CH:17]=[C:18]([S:21]([N:24](CC3C=CC(OC)=CC=3)[C:25]3[S:26][CH:27]=[CH:28][N:29]=3)(=[O:23])=[O:22])[CH:19]=[CH:20][C:12]1=2)[CH2:3][OH:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][O:14][C:13]2[CH:17]=[C:18]([S:21]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)(=[O:22])=[O:23])[CH:19]=[CH:20][C:12]1=2)[CH2:3][OH:4]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccccc2C(O)CO)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1nccs1)c1ccc2c(c1)OCCN2c1ccccc1C(O)CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 5.5 %

Procedure:
To a solution of 4-(2-(1,2-dihydroxyethyl)phenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (300 mg, 0.585 mmol) in DCM (5 mL) was added TFA (0.7 mL, Spectrochem) at 0° C. The reaction mixture was stirred at ambient temperature for 2 h. After completion, the reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (10 mL) and extracted with DCM (2×10 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material which was purified by prep HPLC to obtain 4-(2-(1,2-dihydroxyethyl)phenyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (14 mg, 5.9%) as a white solid. m/z (ESI) 434.0 (M+H)+. 1H NMR (400 MHz, DMSO) δ 12.48 (s, 1H), 7.61 (d, J=5.0 Hz, 1H), 7.37 (d, J=4.5 Hz, 2H), 7.23 (t, J=7.7 Hz, 1H), 7.16 (d, J=4.3 Hz, 1H), 7.11 (s, 1H), 7.05 (d, J=8.6 Hz, 1H), 6.71 (d, J=4.2 Hz, 1H), 6.05 (d, J=8.5 Hz, 1H), 5.16 (s, 1H), 4.66 (d, J=25.7 Hz, 2H), 4.34 (q, J=10.8, 10.3 Hz, 2H), 3.77 (t, J=8.3 Hz, 1H), 3.68-3.45 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:15])[CH2:11][C:12](=[O:14])[CH3:13].CN(C)N>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]([C:11]1[C:10](=[O:15])[CH:11]=[C:12]([CH3:13])[O:14][C:12]=1[CH3:13])=[O:15]
Reactant: CC(=O)CC(=O)Nc1cccc(C)c1C
Agent: CN(C)N
Solvent: Cc1ccccc1
Product: Cc1cc(=O)c(C(=O)Nc2cccc(C)c2C)c(C)o1
Temperature: 60 °C
Reaction time: 8 h
Yield: 126.8 %

Procedure:
A mixture of 10.3 g (50 m mol) of N-(2,3-dimethylphenyl)-3-oxo-butanamide, 4.50 g (75 m mol) of N,N-dimethylhydrazine and 60 ml of toluene was stirred for 8 hours at 60° C. Then, unreacted N,N-dimethylhydrazine and the resulting water together with about 10 ml of toluene were distilled off outside the reaction system. 10.5 g (125 m mol) of diketene was added dropwise to the remaining solution over a period of 5 minutes, while refluxing. The mixture was further refluxed for 2 hours and cooled to room temperature. The resulting crystals were filtered, washed and dried to obtain 8.63 g (yield 64%) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:19][C:18]([C:20]#[N:21])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:23][OH:24].[OH-].[K+]>C(O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:19][C:18]([C:20](=[N:23][OH:24])[NH2:21])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NO
Reactant: N#Cc1ccc(-c2ccc(OCc3ccccc3)cc2)o1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: NC(=NO)c1ccc(-c2ccc(OCc3ccccc3)cc2)o1

Procedure:
A mixture of 30 g (0.11 mole) of 5-(p-benzyloxyphenyl)-2-furonitrile, 8.3 g (0.12 mole) of hydroxylamine hydrochloride, 8 g (0.12 mole) of KOH and 330 ml of absolute ethanol was refluxed for 11/2 hours, cooled in an ice bath and filtered. The solid obtained was recrystallized from 95% ethanol to yield 19 g (56%). An analytical sample was obtained by drying a sample in the vacuum pistol at the temperature of refluxing CHCl3, m.p. 145°-146°.
Reaction SMILES: Cl[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1.[NH:22]1[CH2:27][CH2:26][CH:25]([C:28]#[N:29])[CH2:24][CH2:23]1>CS(C)=O.O>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[NH:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:3]2[C:2]([N:22]3[CH2:27][CH2:26][CH:25]([C:28]#[N:29])[CH2:24][CH2:23]3)=[N:7][CH:6]=[CH:5][N:4]=2)=[CH:10][CH:11]=1
Reactant: Clc1nccnc1Oc1ccc(Nc2ccccn2)cc1
Reactant: N#CC1CCNCC1
Solvent: O
Solvent: CS(C)=O
Product: N#CC1CCN(c2nccnc2Oc2ccc(Nc3ccccn3)cc2)CC1
Reaction time: 8 h

Procedure:
In a 50 mL round-bottomed flask was placed N-(4-(3-chloropyrazin-2-yloxy)-phenyl)pyridin-2-amine (0.2376 g, 0.7954 mmol) in DMSO. Piperidine-4-carbonitrile (0.4363 g, 3.977 mmol) was added and the temperature was brought to 80° C. to stir overnight. The reaction mixture was diluted with water (10 mL) and extracted with DCM (3×10 mL). The organic extract was washed with water (3×10 mL), satd sodium chloride solution (3×10 mL), dried with magnesium sulfate, filtered, and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage™ pre-packed silica gel column (25M), eluting with a gradient of 1% to 5% methanol in DCM, to provide 1-(3-(4-(pyridin-2-ylamino)-phenoxy)pyrazin-2-yl)piperidine-4-carbonitrile. MS (ESI, pos. ion) m/z: 373.1 (M+1). IC50 (uM) 0.006048.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[Na+].[CH2:6]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[CH3:7].Cl>O.CCOCC>[CH2:6]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([N+:1]([O-:4])=[O:2])[CH:9]=1)[CH3:7]
Reactant: CCc1ccc(O)cc1
Reactant: O=[N+]([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CCc1ccc(O)c([N+](=O)[O-])c1
Reaction time: 72 h
Yield: 95 %

Procedure:
To a stirred mixture of 130 ml of water, 130 ml of ether, 7.66 g of sodium nitrate and 10.0 g of 4-ethylphenol was added 13 ml of concentrated hydrochloric acid, and the reaction was continued at room temperature for 3 days. To the reaction mixture was added 300 ml of water and the mixture was extracted with 500 ml of ether. The extract was washed with water, then a brine and dried with anhydrous sodium sulfate. The drying agent was filtered off and the solvent was distilled away under reduced pressure to give 13.0 g of 4-ethyl-2-nitrophenol.
Reaction SMILES: CC1C=CC(S(OCC2(C)CC3C=C(Cl)C=C(OS(C(F)(F)F)(=O)=O)C=3O2)(=O)=O)=CC=1.S1C=CC(B(O)O)=C1.C(=O)([O-])[O-].[K+].[K+].C(C1C=CC=CC=1B1OC(C)(C)C(C)(C)O1)(C)C.CC1C=CC(S(O[CH2:75][C:76]2([CH3:91])[CH2:80][C:79]3[CH:81]=[C:82]([Cl:90])[CH:83]=[C:84]([C:85]4[CH:89]=[CH:88][S:87][CH:86]=4)[C:78]=3[O:77]2)(=O)=O)=CC=1.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[N-:103]=[N+:104]=[N-:105].[Na+]>C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[N:103]([CH2:75][C:76]1([CH3:91])[CH2:80][C:79]2[CH:81]=[C:82]([Cl:90])[CH:83]=[C:84]([C:85]3[CH:89]=[CH:88][S:87][CH:86]=3)[C:78]=2[O:77]1)=[N+:104]=[N-:105]
Reactant: Cc1ccc(S(=O)(=O)OCC2(C)Cc3cc(Cl)cc(-c4ccsc4)c3O2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: CC(C)c1ccccc1B1OC(C)(C)C(C)(C)O1
Solvent: ClCCl
Product: CC1(CN=[N+]=[N-])Cc2cc(Cl)cc(-c3ccsc3)c2O1

Procedure:
Treatment of (±)-(5-chloro-2-methyl-7-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (5.00 g, 10.0 mmol), thiophene-3-boronic acid (1.92 g, 15.0 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.82 g, 1.0 mmol), and potassium carbonate (2.76 g, 20.0 mmol) generally according to the procedure described for Intermediate 35 provided (±)-(5-chloro-2-methyl-7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate. Treatment of the tosylate with sodium azide (2.00 g, 30.7 mmol) generally according to the procedure described for Intermediate 98 gave (±)-2-(azidomethyl)-5-chloro-2-methyl-7-thien-3-yl-2,3-dihydro-1-benzofuran. Treatment of the azide with sulfided platinum on carbon (0.250 g, 5 wt. %) generally according to the procedure described for Example 1 afforded 0.7 g (22%0 of (±)-(5-chloro-2-methyl-7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methylamine as a white solid, hydrochloride salt. mp 295-298° C. (dec); Anal. calcd. for C14H14ClNOSHCl: C, 53.17; H, 4.78; N, 4.43. Found: C, 52.80; H, 4.74; N, 4.24.
Reaction SMILES: C([O:8][C:9](=[O:24])[CH2:10][CH2:11][C:12]#[C:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)C1C=CC=CC=1.[Li+].[OH-]>>[F:21][C:20]([F:22])([F:23])[C:17]1[CH:16]=[CH:15][C:14]([C:13]#[C:12][CH2:11][CH2:10][C:9]([OH:24])=[O:8])=[CH:19][CH:18]=1
Reactant: O=C(CCC#Cc1ccc(C(F)(F)F)cc1)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)CCC#Cc1ccc(C(F)(F)F)cc1

Procedure:
In analogy to the procedure described for example 1 e], 5-(4-trifluoromethyl-phenyl)-pent-4-ynoic acid benzyl ester was treated with LiOH to obtain the title compound as off-white solid.