Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][CH:10]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.Cl.[NH2:30][OH:31].C(=O)([O-])O.[Na+]>>[CH3:1][C:2]1[CH:7]=[C:6](/[C:8](=[N:30]/[OH:31])/[CH2:9][CH:10]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(C(=O)CC(c2cccc(S(C)(=O)=O)c2)c2ccccc2C)ccn1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(CC(c2cccc(S(C)(=O)=O)c2)c2ccccc2C)=N/O)ccn1

Procedure:
In analogy to example 132, step 6, from 1-(2-methylpyridin-4-yl)-3-(3-(methylsulfonyl)-phenyl)-3-o-tolylpropan-1-one and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a colourless oil, MS (ESI+): m/z=409.3 ([M+H]+).
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:50]=[CH:49][C:16]([C:17]([O:19][C:20]2[CH:27]=[CH:26][C:25]([O:28][C:29](=[O:48])[C:30]3[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][O:43][C:44](=[O:47])[CH:45]=[CH2:46])=[CH:32][CH:31]=3)=[CH:24][C:21]=2[CH:22]=[O:23])=[O:18])=[CH:15][CH:14]=1)(=[O:4])[CH:2]=[CH2:3].CC(C)=[O:53]>>[C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:50]=[CH:49][C:16]([C:17]([O:19][C:20]2[CH:27]=[CH:26][C:25]([O:28][C:29](=[O:48])[C:30]3[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][O:43][C:44](=[O:47])[CH:45]=[CH2:46])=[CH:32][CH:31]=3)=[CH:24][C:21]=2[C:22]([OH:53])=[O:23])=[O:18])=[CH:15][CH:14]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)OCCCCCCOc1ccc(C(=O)Oc2ccc(OC(=O)c3ccc(OCCCCCCOC(=O)C=C)cc3)c(C=O)c2)cc1
Reactant: CC(C)=O
Product: C=CC(=O)OCCCCCCOc1ccc(C(=O)Oc2ccc(OC(=O)c3ccc(OCCCCCCOC(=O)C=C)cc3)c(C(=O)O)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Jones oxidant (CrO3/H2SO4/H2O) (48 ml) was added to a ice-cooled solution of 2,5-di-[4-(6-acryloyloxyhexyloxy)benzoyloxy]benzaldehyde (8.24 g, 12 mmol) in acetone (300 ml) in a dropwise fashion over a period of 30 min. The reaction mixture was stirred overnight at room temperature. The resulting green-orange mixture was filtered off to leave a green precipitate that was washed with 600 ml of ether. The combined organic solutions were washed with water until the orange coloration disappeared (6×250 ml). The colourless organic solution obtained was washed with saturated NaCl solution (2×300 ml), dried over MgSO4 and filtered. Removal of the solvent gave pure 2,5-di-[4-(6-acryloyloxyhexyloxy)benzoyloxy]benzoic acid as a white crystalline material. Yield 8.5 g.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][C@@H:20]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[C:19]4[CH:32]=[CH:33][CH:34]=[CH:35][C:18]=4[C:17]=3[N:16]=2)=[CH:10][CH:9]=1)(=O)=O.[CH3:36][NH:37][CH2:38][CH2:39][CH2:40][CH3:41]>C(N(CC)CC)C>[CH2:38]([N:37]([CH3:36])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][C@@H:20]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[C:19]4[CH:32]=[CH:33][CH:34]=[CH:35][C:18]=4[C:17]=3[N:16]=2)=[CH:10][CH:9]=1)[CH2:39][CH2:40][CH3:41]
Reactant: CCCCNC
Reactant: CS(=O)(=O)OCCc1ccc(Nc2ncc3c(n2)-c2ccccc2[C@H](c2ccc(F)cc2)C3)cc1
Solvent: CCN(CC)CC
Product: CCCCN(C)CCc1ccc(Nc2ncc3c(n2)-c2ccccc2[C@H](c2ccc(F)cc2)C3)cc1

Procedure:
This was synthesized by using (S)-4-(6-(4-fluorophenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenethyl methanesulfonate, N-methylbutan-1-amine and triethylamine as described in general procedure 2 to afford the desired product. M.p.=164-166° C. 1H NMR (DMSO-d6) 400 MHz δ 10.65 (brs, 1H), 9.78 (s, 1H), 8.32-8.35 (m, 2H), 7.79 (d, J=8.6 Hz, 2H), 7.51 (t, J=5.0 Hz, 2H), 7.26 (d, J=8.6 Hz, 2H), 7.02-7.08 (m, 5H), 4.46 (t, J=6.2 Hz, 1H), 3.13-3.18 (m, 5H), 2.99-3.03 (m, 3H), 2.79 (d, J=5.0 Hz, 3H), 1.17 (t, J=7.8 Hz, 2H), 1.31 (m, 2H), 1.27-1.32 (m, 3H), 0.91 (t, J=7.4 Hz, 3H) LCMS m/e 481 [M+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][C:15]=2[O:20][C:21]([F:24])([F:23])[F:22])=[CH:10][C:9]=1[NH:25][C:26](OC(C)(C)C)=O)(C)(C)C.C(O)(C(F)(F)F)=O.COC(=N)[C:44]([Cl:47])([Cl:46])[Cl:45]>C(Cl)Cl>[Cl:45][C:44]([Cl:47])([Cl:46])[C:26]1[NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][C:21]([F:23])([F:24])[F:22])=[CH:10][C:9]=2[N:25]=1
Reactant: COC(=N)C(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2OC(F)(F)F)cc1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)Oc1ccccc1-c1ccc2[nH]c(C(Cl)(Cl)Cl)nc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 85 %

Procedure:
(3-tert-Butoxycarbonylamino-2′-trifluoromethoxy-biphenyl-4-yl)-carbamic acid tert-butyl ester (573 mg, 1.22 mmol, as prepared in the previous step) was placed in a mL vial equipped with a magnetic stir bar. DCM (10 mL) and TFA (5 mL) were added, and the mixture stirred at rt for 12 h. The solvent was removed under reduced pressure, and the residue was dissolved in DCM and washed with 2M aq NaOH. The organic extract was dried over MgSO4 and concentrated in vacuo. The residue was dissolved in AcOH (5 mL) and placed in an 8 mL vial equipped with a magnetic stir bar. The mixture was cooled to 0° C., treated with methyl-2,2,2-trichloroacetimidate (0.167 mL, 1.35 mmol) via syringe, and stirred at rt for 3 days. The solvent was removed under reduced pressure. The crude product was purified by column chromatography using a 12-g SiO2 pre-packed column eluting with EtOAc/hexanes, 0:1 to 2:5, v/v over 30 min, yielding 409 mg (85%) of the desired compound. 1H-NMR (400 MHz, d4-MeOH) δ: 7.71-7.77 (m, 2H), 7.52-7.57 (m, 1H), 7.39-7.51 (m, 4H).
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1)=[O:6].O.Cl>C(OCC)C>[Br:13][C:9]1[CH:8]=[C:7]([C:5]([OH:6])([CH3:1])[CH3:4])[CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)c1cccc(Br)c1
Reactant: C[Mg]Br
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: CC(C)(O)c1cccc(Br)c1
Reaction time: 0.5 h

Procedure:
To a stirred solution of methylmagnesium bromide (60 mL of a 3.0 M solution in diethyl ether) at 0° C. was added dropwise a solution of 3-bromoacetophenone (29.8 grams) in 75 mL of diethyl ether. Once the addition was complete, the mixture was stirred for 0.5 hours and poured into water. The aqueous phase was acidified with 1M hydrochloric acid and extracted with three portions of diethyl ether. The combined ether layers were washed with saturated sodium bicarbonate, concentrated to afford 30.4 grams of the title compound. 1H NMR δ7.72 (br s, 1), 7.49 (d, 1, J=7.8), 7.37 (d, 1, J=7.9), 7.25 (dd, 1, J=7.8, 7.9), 4.19 (s, 1), 1.50 (br s, 6).
Reaction SMILES: Cl[C:2]1[CH:9]=[C:8]([C:10]2[C:11]([C:15]([F:18])([F:17])[F:16])=[N:12][NH:13][CH:14]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[S-2:19].[Na+].[Na+].O>CN(C)C=O>[SH:19][C:2]1[CH:9]=[C:8]([C:10]2[C:11]([C:15]([F:18])([F:17])[F:16])=[N:12][NH:13][CH:14]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: [S-2]
Reactant: N#Cc1ccc(-c2c[nH]nc2C(F)(F)F)cc1Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2c[nH]nc2C(F)(F)F)cc1S
Temperature: 25 °C
Yield: 97.6 %

Procedure:
5.0 g (18.4 mmol) of 2-chloro-4-(3-trifluoromethylpyrazolyl)benzonitrile in N,N-dimethylformamide was stirred together with 1.86 g (23.9 mmol) of sodium sulfide at 120° C. for 30 minutes. The reaction mixture was cooled to room temperature, mixed with 100 ml of water, washed with 30 ml of ethyl acetate, and the aqueous layer was adjusted at pH 5-6 with citric acid, and extracted with 50 ml of ethyl acetate twice. The ethyl acetate layers were combined, washed with 50 ml of water twice and dried over anhydrous magnesium sulfate. The ethyl acetate was distilled off under reduced pressure to obtain 2-mercapto-4-(3-trifluoromethylpyrazolyl)benzonitrile (yield 97.6%) as a pale yellow powder, which was used in Example 1 (2) as the starting material.
Reaction SMILES: C([Mg]Cl)(C)C.C1COCC1.[CH3:11][C:12]1([CH3:24])[O:16][C@@H:15]([CH2:17][N:18]2[CH:22]=[C:21](I)[CH:20]=[N:19]2)[CH2:14][O:13]1.CO[B:27]1[O:31][C:30]([CH3:33])([CH3:32])[C:29]([CH3:35])([CH3:34])[O:28]1>>[CH3:11][C:12]1([CH3:24])[O:16][C@@H:15]([CH2:17][N:18]2[CH:22]=[C:21]([B:27]3[O:31][C:30]([CH3:33])([CH3:32])[C:29]([CH3:35])([CH3:34])[O:28]3)[CH:20]=[N:19]2)[CH2:14][O:13]1
Reactant: COB1OC(C)(C)C(C)(C)O1
Reactant: CC1(C)OC[C@H](Cn2cc(I)cn2)O1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC1(C)OC[C@H](Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)O1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 52.6 %

Procedure:
Isopropylmagnesium chloride in THF (2.0 M, 6.91 mL, 13.82 mmol) was added to a solution of 1-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-4-iodo-1H-pyrazole (Compound 5F, 2.13 g, 6.91 mmol) in THF (60 mL, 800 mmol) at rt. After 10 minutes, the mixture was treated with 2-Methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.40 mL, 20.74 mmol) and stirred for an additional 20 minutes at rt. The reaction was then quenched with sat. NH4Cl and the mixture was concentrated in vacuo to a solid. The crude product was dissolved in DCM, washed with water (2×), dried with sodium sulfate, filtered and concentrated in vacuo to a clear oil. The crude material was purified using a Teledyne ISCO Combiflash® Rf system [20% EtOAc/hexanes] to afford 1.12 g of the title compound (53%). 1H NMR (400 MHz, CD3OD) δ 7.74 (s, 1H), 7.50 (s, 1H), 4.36-4.44 (m, 1H), 4.21-4.34 (m, 2H), 4.05 (dd, J=6.3, 8.6 Hz, 1H), 3.73 (dd, J=5.9, 8.7 Hz, 1H), 1.31 (d, J=8.6 Hz, 6H), 1.25 (s, 12H). MS (ESI): m/z 309.00 [M+H]+. UPLC: tR=1.42 min (UPLC-TOF: polar—3 min).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][C@@H:8]([CH2:15][OH:16])[CH2:9][C@H:10]([CH3:14])[CH2:11][CH2:12][CH3:13])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[S:25](Cl)([C:28]1[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=1)(=[O:27])=[O:26].Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6](=[O:17])[CH2:7][C@@H:8]([CH2:15][O:16][S:25]([C:28]1[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=1)(=[O:27])=[O:26])[CH2:9][C@H:10]([CH3:14])[CH2:11][CH2:12][CH3:13])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCC[C@@H](C)C[C@H](CO)CC(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC[C@@H](C)C[C@H](COS(=O)(=O)c1ccc(C)cc1)CC(=O)OC(C)(C)C
Yield: 91.1 %

Procedure:
To alcohol 103 (1.98 g, 8.1 mmol) in CH2Cl2 (40 mL) at room temperature was added triethylamine (2.4 g, 0.024 mol), DMAP (20 mg) and tosyl chloride (2.3 g, 0.012 mol). After 14 hours 1N HCl was added and the two layers separated. The aqueous phase was extracted with ether and the combined organic phases dried (MgSO4) and concentrated. Flash chromatography (95% hexane/EtOAc) gave tosylate 104 as an oil (2.94 g, 91%). 13C NMR (100 MHz; CDCl3) 171.60, 144.92, 133.07, 130.02, 128.12, 80.80, 72.15, 39.73, 38.09, 37.89, 32.67, 29.71, 28.22, 21.83, 20.10, 19.54, 14.49.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Cl:5][CH2:6][CH2:7][C:8](Cl)=[O:9].[C:11]1([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(=S)=S>[Cl:5][CH2:6][CH2:7][C:8]([C:14]1[CH:15]=[CH:16][C:11]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:12][CH:13]=1)=[O:9]
Reactant: COC(=O)CCCCCc1ccccc1
Reactant: O=C(Cl)CCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: COC(=O)CCCCCc1ccc(C(=O)CCCl)cc1
Reaction time: 0.17 h

Procedure:
17.2 g of AlCl3, 18.5 ml of CS2 and 3.6 ml of β-chloro-propionyl chloride are placed in a stirring flask with a reflux condenser. 7.06 g of methyl 6-phenylcaproate are allowed to drop into this mixture at room temperature within 10 minutes (rinsing is carried out with 4 ml of CS2). The reaction mixture is subsequently stirred for a further 15 minutes, warmed slightly and then cooled. The reaction mixture is then pipetted into a stirred mixture of ice, water and ether. The organic phase is washed neutral with bicarbonate solution and water. After drying over MgSO4 the solvent is removed, 10.2 g of crystalline product identified as methyl p-[β-chloropropionyl]-6-phenyl-caproate are obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:18]3[C:13](=[N:14][CH:15]=[N:16][C:17]=3[NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[NH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.Cl.[N:28]1([C:33](N)=[NH:34])C=CC=N1>CN(C=O)C>[Cl:26][C:22]1[CH:21]=[C:20]([NH:19][C:17]2[N:16]=[CH:15][N:14]=[C:13]3[NH:12][N:11]=[C:10]([NH:9][C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][NH:1][C:33]([NH2:34])=[NH:28])[CH:4]=4)[C:18]=23)[CH:25]=[CH:24][CH:23]=1
Reactant: NCc1cccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)c1
Reactant: N=C(N)n1cccn1
Agent: Cl
Solvent: CN(C)C=O
Product: N=C(N)NCc1cccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)c1
Temperature: 25 °C
Reaction time: 65 h

Procedure:
A mixture of 200 mg (0.537 mmol) of 3-(3aminomethyl-phenylamino)-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine (water content: 1.79%; see Step 90.5), 79 mg (0.539 mmol) of 1H-pyrazole-1-carbamidine monohydrochloride and 2 ml of DMF is stirred at RT for 65 hours and then concentrated by evaporation under a high vacuum. Crystallization of the residue from diethyl ether, filtration and washing the filter residue with diethyl ether yield 4-(3-chlorophenylamino)-3-(3-{guanidino-methyl}-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine.1.05 hydrochloride having a water content of 1.76%; m.p. 270° C. (decomp.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:13]=[C:12]([C:14]#[N:15])[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1N.N([O-])=O.[Na+].[BrH:22]>O.[Cu]Br>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:13]=[C:12]([C:14]#[N:15])[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[Br:22]
Reactant: Br
Reactant: COC(=O)c1cc(C#N)c(C(=O)OC)cc1N
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cc(C#N)c(C(=O)OC)cc1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 7 %

Procedure:
To a suspension of 2-amino-5-cyano-terephthalic acid dimethyl ester (11.6 g, 49.5 mmol) in hydrobromic acid (20 ml, 48%) at 0° C. was added an aqueous solution of sodium nitrite (55 mmol, 11 ml, 5M). The reaction mixture was stirred at 0° C. for 30 minutes. Copper (I) bromide (7.1 g, 49.5 mmol) was added as a solution in hydrobromic acid (10 ml, 48%) and the reaction mixture stirred at 0° C. for 10 min before heating at 65° C. for 1 hour. The reaction mixture was cooled to room temperature, diluted with water (50 ml) and the resultant mixture extracted with ethyl acetate (3×20 mL). The aqueous fraction was filtered to recover un-reacted 2-amino-5-cyano-terephthalic acid dimethyl ester (7.1 g). The combined organic fractions were washed with brine (20 ml), dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-50% ethyl acetate in cyclohexane) to yield the title compound as a brown solid (1.0 g, 7%). 1H NMR (CDCl3, 400 MHz) 8.43 (1H, s), 8.19 (1H, s), 4.04 (3H, s), 4.00 (3H, s).
Reaction SMILES: [CH:1]1([NH:7][C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[CH:13]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C=O)C>C(O)C.[Ni]>[NH2:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[CH2:11][NH:10][C:8]([NH:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:9]
Reactant: O=C(NCc1cccc([N+](=O)[O-])c1)NC1CCCCC1
Agent: [Ni]
Solvent: CN(C)C=O
Solvent: CCO
Product: Nc1cccc(CNC(=O)NC2CCCCC2)c1
Reaction time: 2 h
Yield: 84.1 %

Procedure:
1-Cyclohexyl-3-(3-nitro-benzyl)-urea (4 g) was suspended in ethanol (70 ml) and Raney nickel (2 g) was added. Under stirring aqueous hydrazine solution (2.5 ml, 80%) was added. DMF was added (50 ml) and the reaction mixture was stirred for additional 2 h and filtered. The solution was evaporated i.v. affording the title compound (3 g, Rf=0.43 DCM/ethanol 19:1).
Reaction SMILES: [N+:1]([C:4]1[N:8]2[CH:9]=[C:10]([S:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=[CH:12][C:7]2=[N:6][CH:5]=1)([O-])=O.[H][H]>[Pd].O1CCOCC1>[NH2:1][C:4]1[N:8]2[CH:9]=[C:10]([S:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=[CH:12][C:7]2=[N:6][CH:5]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cnc2ccc(Sc3ccccc3)cn12
Agent: [Pd]
Solvent: C1COCCO1
Product: Nc1cnc2ccc(Sc3ccccc3)cn12

Procedure:
A solution of 0.542 gm. (0.002 mole) of 3-nitro-6-phenylthioimidazo [1,2-a] pyridine in 20 ml. of dioxane is reduced at 40 psi. under a hydrogen atmosphere with 0.500 g. of 5% palladium on carbon as catalyst. When the uptake of hydrogen is complete, the catalyst is removed by filtration. The filtrate is evaporated in vacuo to yield 3-amino-6-phenylthioimidazo [1,2-a] pyridine.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][N:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.CC(C)([O-])C.[K+].F[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([N+:27]([O-:29])=[O:28])=[CH:19][CH:18]=1>CS(C)=O>[N+:27]([C:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17]([N:1]2[C:5]3[CH:6]=[CH:7][N:8]=[CH:9][C:4]=3[N:3]=[CH:2]2)=[CH:18][CH:19]=1)([O-:29])=[O:28]
Reactant: c1cc2nc[nH]c2cn1
Reactant: O=[N+]([O-])c1ccc(F)c2ccccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(-n2cnc3cnccc32)c2ccccc12
Temperature: 60 °C

Procedure:
5-Aza-benzimidazole (312 mg, 2.62 mmol, 1 equiv.) in 5 mL anhydrous DMSO was treated with potassium tert-butoxide (294 mg, 2.62 mmol, 1.0 equiv.) at room temperature. When the mixture was completely homogeneous, 4-fluoro-1-nitro-naphthalene (500 mg, 2.62 mmol, 1 equiv.) was added in one portion and the mixture was heated to 60° C. for 0.5 h. The reaction was allowed to cool, then quenched with dilute aqueous NaHCO3 solution. The product was extracted with a mixture of EtOAc, THF and acetone. The organic extracts were washed with water and brine, then dried (Na2SO4), filtered and the solvents removed in vacuo. 1H NMR revealed a 1:1 ratio of regioisomers. The products were purified by column chromatography on SiO2 using EtOAc/MeOH eluent mixtures. 1-(4-Nitro-naphthalen-1-yl)-1H-imidazo[5,4-c]pyridine was isolated at high Rf and 1-(4-nitro-naphthalen-1-yl)-1H-imidazo[4,5-c]pyridine at lower Rf, and overlapping fractions were in between. The overall yield was 357 mg (47%). Each nitro-naphthalene from above (˜100 mg, 0.4 mmol) was separately dissolved in 10 mL EtOAc and 5 mL of MeOH. Ammonium formate was then added (100 mg, 1.6 mmol or 4 equiv.) and 10% palladium-on-carbon (˜60 mg). The mixture was stirred for 0.5 h at 50° C., then allowed to cool, filtered through diatomaceous earth and the solvents were removed in vacuo to afford ˜80 mg of each naphthyl-amine 5a and 5b, which could be coupled with anilines or pyrazolamines to form ureas by the procedures described in Examples 2-4 above.
Reaction SMILES: [F:1][C@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:18]([CH3:25])[N:19]=[CH:20][C:21]=2[N+:22]([O-])=O)[O:4][CH2:3]1.BrC1SC(NC(=O)OC(C)(C)C)=C(C(=O)NC2C=NN(C)C=2[C@@H]2CC[C@@H](NC(OC(C)(C)C)=O)[C@@H](F)CO2)N=1.C(OC([NH:72][C:73]1[S:77][C:76]([C:78]2[CH:83]=[CH:82][CH:81]=[C:80]([F:84])[C:79]=2[F:85])=[N:75][C:74]=1[C:86](O)=[O:87])=O)(C)(C)C>>[NH2:72][C:73]1[S:77][C:76]([C:78]2[CH:83]=[CH:82][CH:81]=[C:80]([F:84])[C:79]=2[F:85])=[N:75][C:74]=1[C:86]([NH:22][C:21]1[CH:20]=[N:19][N:18]([CH3:25])[C:17]=1[C@@H:5]1[CH2:6][CH2:7][C@@H:8]([NH2:9])[C@@H:2]([F:1])[CH2:3][O:4]1)=[O:87]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2cccc(F)c2F)nc1C(=O)O
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Agent: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1
Product: Cn1ncc(NC(=O)c2nc(-c3cccc(F)c3F)sc2N)c1[C@@H]1CC[C@@H](N)[C@@H](F)CO1

Procedure:
Following the procedure for Example 111 starting from tert-butyl N-[(3S,4R,7S)-3-fluoro-7-(2-methyl-4-nitro-pyrazol-3-yl)oxepan-4-yl]carbamate (Intermediate 88), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 5-(tert-butoxycarbonylamino)-2-(2,3-difluorophenyl)thiazole-4-carboxylic acid (Example 25) gave 181 as the hydrochloride salt as a pale pink solid (30 mg, 38% over three steps). 1H NMR (400 MHz, d6-DMSO) δ 9.42 (s, 1H), 8.54-8.41 (m, 4H), 7.96-7.89 (m, 1H), 7.67 (s, 1H), 7.50-7.39 (m, 3H), 5.28 (m, 1H), 4.84 (d, J=10.4 Hz, 1H), 4.33-4.17 (m, 1H), 4.11-3.99 (m, 1H), 3.78 (s, 3H), 3.74-3.52 (m, 1H), 2.16-1.81 (m, 4H). LCMS (ES+) m/z 467 (M+1).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:6]=[C:5]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:4]=1.O.[OH-].[Na+].Cl[C:23]([O:25][CH2:26][C:27]([Cl:30])([Cl:29])[Cl:28])=[O:24]>CCOC(C)=O>[Cl:28][C:27]([Cl:30])([Cl:29])[CH2:26][O:25][C:23]([NH:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:6]=[C:5]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:4]=1)=[O:24]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
A mixture of 5-amino-3-t-butyl-1-p-tolylpyrazole hydrochloride (300 g, 1.13 mol), water (0.9 L), EtOAc (2.1 L) and NaOH (117 g, 2.84 mol) was stirred between 5-15° C. for 30 min. To this mixture, 2,2,2-trichloroethyl chloroformate (342 g, 1.58 mol) was added over 1 h between 5-15° C. The mixture was stirred at room temperature for 2 h, and then the aqueous layer was separated from the EtOAc layer. The EtOAc layer was washed with brine (2×0.9 L) and dried over MgSO4 (60 g). The EtOAc layer was collected by filtration. To this solution, heptane was added. A part of the solution was removed by distillation. The product was crystallized from the solution, collected by filtration and dried in vacuum oven to constant weight. Yield: 409 g, 90%. 1H NMR (CDCl3) δ 7.40 (d, 2H), 7.30 (d, 2H), 6.40 (s, 1H), 4.80 (s, 2H), 2.40 (s, 3H), 1.40 (s, 9H). MS (EI) m/z 404 (M+).
Reaction SMILES: [C:1]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:6])[CH2:2][C:3]([O-:5])=O.CN1CCOCC1.P(Cl)(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.[F:39][C:40]([F:49])([F:48])[C:41]1[CH:42]=[C:43]([NH2:47])[CH:44]=[CH:45][CH:46]=1>C1COCC1>[CH2:8]([O:7][C:1](=[O:6])[CH2:2][C:3]([NH:47][C:43]1[CH:44]=[CH:45][CH:46]=[C:41]([C:40]([F:39])([F:48])[F:49])[CH:42]=1)=[O:5])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=C([O-])CC(=O)OCc1ccccc1
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: O=C(CC(=O)OCc1ccccc1)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
mono-Benzyl malonate (10 g) was dissolved in THF (100 ml), 4-methylmorpholine and cooled to −22° C. prior to the slow addition of diphenyl chlorophosphate (14 ml) and 3-trifluoromethyl-phenylamine (19 ml). After the reaction was warmed to rt overnight, it was heated to gently reflux for 0.5 h. After the reaction was cooled to rt, the solid was filtered off. The filtrate was concentrated. EtOAc was added along with 1N HCl solution. The organic layer was washed with NaHCO3 solution (aq) and brine, dried (MgSO4), filtered, and concentrated. Flash chromatography of the resulting residue gave N-(3-trifluoromethyl-phenyl)-malonamic acid benzyl ester (8.0 g): 1H NMR (CDCl3, δppm, 300 mHz) 3.56 (s, 2H), 5.26 (s, 2H), 7.40 (m, 7H), 7.75 (d, 1H), 7.83 (s, 1H), 9.43 (s, br, 1H).