Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[N:16]2[C:11]([CH:12]=[N:13][C:14](S(C)=O)=[N:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1.C(N(CC)C(C)C)(C)C.COCC(O)C>>[CH2:1]([C:8]1[N:16]2[C:11]([CH:12]=[N:13][C:14]([NH:33][C:30]3[CH:29]=[CH:28][C:27]([N:24]4[CH2:23][CH2:22][N:21]([CH3:20])[CH2:26][CH2:25]4)=[CH:32][CH:31]=3)=[N:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CS(=O)c1ncc2ccc(Cc3ccccc3)n2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCC(C)O
Product: CN1CCN(c2ccc(Nc3ncc4ccc(Cc5ccccc5)n4n3)cc2)CC1
Yield: 42 %

Procedure:
Into a microwave vial, 7-Benzyl-2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazine (0.120 g, 0.442 mmol), 4-(4-Methyl-piperazin-1-yl)-phenylamine (0.186 g, 0.973 mmol), N,N-Diisopropylethylamine (0.169 mL, 0.973 mmol), and 1-Methoxy-2-propanol (0.50 mL, 5.1 mmol) were added. The reaction was microwaved on 300 watts, 180° C. for 2 hours. The solvent was removed under vacuum. The reaction mixture was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in ACN. The collected fractions were lyophilized to give a yellow solid (74 mg, 42%). LCMS (E/I+) 399.3 (M+H). NMR 1H (DMSO-d6)-9.74 (bs, 1H), 9.21 (s, 1H), 8.83 (s, 1H), 7.64 (d, 2H, J=8.09 Hz), 7.27-7.34 (m, 4H), 7.20 (bs, 1H), 6.96 (d, 2H, J=8.09 Hz), 6.78 (d, 1H, J=4.85 Hz), 6.60 (d, 1H, J=4.85 Hz), 4.27 (s, 2H), 3.74 (d, 2H, J=12.94 Hz), 3.52 (d, 2H, J=12.14 Hz), 3.09-3.24 (m, 2H), 2.77-2.97 (m, 5H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:23][C:5]2[N:6]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[N:17]=3)[C:7]3[CH:8]=[CH:9][C:10]([C:13]#[N:14])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.C(N(C(C)C)CC)(C)C.[CH3:33][N:34]([CH3:38])[C:35](Cl)=[O:36]>ClCCl>[C:13]([C:10]1[CH:9]=[CH:8][C:7]2[N:6]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[N:17]=3)[C:5]3[CH2:23][CH:2]([NH:1][C:35](=[O:36])[N:34]([CH3:38])[CH3:33])[CH2:3][C:4]=3[C:12]=2[CH:11]=1)#[N:14]
Reactant: N#Cc1ccc2c(c1)c1c(n2Cc2cccc(F)n2)CC(N)C1
Reactant: CN(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)C(=O)NC1Cc2c(n(Cc3cccc(F)n3)c3ccc(C#N)cc23)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (±)-2-amino-4-(6-fluoro-pyridin-2-ylmethyl)-1,2,3,4-tetrahydro-cyclopenta[b]indole-7-carbonitrile (70 mg, 0.23 mmol) and diisopropylethylamine (0.35 mmol, 61 μL) in dichloromethane (1 mL) add N,N-dimethylcarbamoyl chloride (0.35 mmol, 32 μL) and stir at room temperature overnight. Load the solution on silica gel and purify by column chromatography (0-100% ethyl acetate/dichloromethane) to obtain the title compound. LCMS 378.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10]C)=[O:9])=[C:4]([NH:14][C:15](OCC)=O)[CH:3]=1.Br.BrC[C:23]([C:25]1[N:26]([CH3:30])[CH:27]=[CH:28][N:29]=1)=[O:24]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([C:6]([CH2:7][C:8]([OH:10])=[O:9])=[C:15]([C:23]([C:25]3[N:26]([CH3:30])[CH:27]=[CH:28][N:29]=3)=[O:24])[NH:14]2)=[CH:12][CH:13]=1
Reactant: Cn1ccnc1C(=O)CBr
Reactant: CCOC(=O)Nc1cc(Cl)ccc1/C=C/C(=O)OC
Agent: Br
Product: Cn1ccnc1C(=O)c1[nH]c2cc(Cl)ccc2c1CC(=O)O

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 31 from methyl trans-4-chloro-2-(ethoxycarbonylamino)cinnamate (Example 31, step 1) and 2-bromoacetyl-1-methylimidazole hydrobromide*.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]2[N:11]=[C:10]([CH3:12])[C:9]([CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[C:8]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[Cl:29])[N:7]2[CH:30]=1)(=O)[NH2:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1.O>C1COCC1>[C:1]([C:4]1[N:5]=[C:6]2[N:11]=[C:10]([CH3:12])[C:9]([CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[C:8]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[Cl:29])[N:7]2[CH:30]=1)(=[S:40])[NH2:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1nc2nc(C(N)=O)cn2c(-c2ccc(Cl)cc2Cl)c1CNC(=O)OC(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc2nc(C(N)=S)cn2c(-c2ccc(Cl)cc2Cl)c1CNC(=O)OC(C)(C)C
Temperature: 65 °C
Yield: 220.3 %

Procedure:
To a stirred solution of tert-butyl (2-carbamoyl-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidin-6-yl)methylcarbamate (intermediate for Example 62, 150 mg, 0.33 mmol) in THF (10 mL) was added Lawesson's reagent (202 mg, 0.50 mmol). After heating to 65° C. for 20 h, the reaction mixture was poured into H2O (5 mL). The resulting mixture was extracted with EtOAc and the organic layer was washed with satd aq NH4Cl and brine prior to drying over MgSO4. Filtration, concentration under reduced pressure afforded crude tert-butyl (2-carbamothioyl-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidin-6-yl)methylcarbamate (339 mg, 100% crude yield) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.CN(C)C=O.[O:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][CH2:30][NH2:31])[CH2:24][CH2:23]1>CCOCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:31][CH2:30][CH2:29][CH2:28][N:25]1[CH2:26][CH2:27][O:22][CH2:23][CH2:24]1
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Reactant: NCCCN1CCOCC1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccc(Br)cc2/C1=C/NCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
A mixture of 6-bromo-4-(methoxymethylene)-isoquinoline-1,3(2H,4H)-dione (70.5 mg, 0.25 mmole), dimethylformamide (2 mL) and 3-morpholinopropan-1-amine (36.1 mg, 0.25 mmole) is stirred at room temperature for one hour. The reaction mixture is diluted with ether, filtered and washed with fresh ether and dried to give a cream solid, 53.6 mg, (54% yield) MS (ES+): 394.2, (M+H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH:46]=O)[CH:41]=5)[C:36]([F:39])=[CH:37][CH:38]=4)=[O:30])[N:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[C@H:50]12[CH2:56][C@H:53]([NH:54][CH2:55]1)[CH2:52][N:51]2C(OC(C)(C)C)=O.C(O)(=O)C>CS(C)=O>[C@H:50]12[CH2:56][C@H:53]([NH:54][CH2:55]1)[CH2:52][N:51]2[CH2:46][C:42]1[CH:41]=[C:40]([C:35]2[C:36]([F:39])=[CH:37][CH:38]=[C:33]([CH2:32][NH:31][C:29]([C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([C:21]([NH:20][CH2:19][C:10]4[C:11]([NH:12][CH:13]5[CH2:18][CH2:17][O:16][CH2:15][CH2:14]5)=[C:6]5[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]5=[N:8][C:9]=4[CH2:48][CH3:49])=[O:22])[N:24]=3)=[O:30])[CH:34]=2)[CH:45]=[CH:44][CH:43]=1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(C=O)c3)c2)n1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CN4C[C@@H]5C[C@H]4CN5)c3)c2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 18.3 %

Procedure:
N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(6-fluoro-3′-formyl-3-biphenylyl)methyl]-2,6-pyridinedicarboxamide (50.0 mg. 0.075 mmol) was diluted in DMSO (1.5 mL) and dispensed into a 1 dram vial containing 1,1-dimethylethyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (0.226 mmol) and acetic acid (4.52 mg, 0.075 mmol) and fitted magnetic stir bar. The resulting solution was stirred at room temperature for 4 h. MP-B(OAc)3H (0.753 mmol, 176 mg) was added and the solution was stirred for another 12 h. The polymer reagent was filtered off and to the filtrate was added MeOH (2.0 mL) and 1 drop of concentrated HCl. This solution was heated at 60° C.° for 12 h. Purification was completed via a Gilson HPLC (basic conditions) to afford 10.26 mg (18.4%) of the title compound. LC-MS m/z 746 (M+H)+, 0.69 min (ret time).
Reaction SMILES: C(/C(/[CH:11]=[CH:12]/[C:13](/[C:21]#[N:22])=[C:14](\O)/[C:15]([O:17][CH2:18][CH3:19])=[O:16])=C(/O)\C(OCC)=O)#N.[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C=O.C(OCC)(=O)C>[CH2:23]([N:30]1[CH:11]=[CH:12][C:13]([C:21]#[N:22])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)/C(O)=C(C#N)/C=C/C(C#N)=C(\O)C(=O)OCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C#N)ccn1Cc1ccccc1
Temperature: 95 °C
Yield: 58 %

Procedure:
A solution of (2E,4E,6E)-diethyl 3,6-dicyano-2,7-dihydroxyocta-2,4,6-trienedioate (18 g, 58.8 mmol) in N,N-Dimethylformamide (DMF) (100 mL) and Ethyl acetate (100 mL), was treated with benzylamine (15.44 mL, 141 mmol) and the resultant was heated at 95° C. for 3 hours. The dark mixture was concentrated and purified on silica gel (0-70% ethyl acetate/hexanes) to afford ethyl 1-benzyl-3-cyano-1H-pyrrole-2-carboxylate (8.7 g, 34.1 mmol, 60% yield) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.25-7.45 (m, 3H) 7.11-7.16 (m, 2H) 6.84-6.87 (m, 1H) 6.53-6.58 (m, 1H) 5.59 (s, 2H) 4.37 (q, J=7.04 Hz, 2H) 1.40 (t, J=7.13 Hz, 3H); LCMS (m/z) ES+=255 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[Br:10].[CH3:11][O:12][CH:13]([O:16]C)[CH:14]=[CH2:15].C(N(CC)CC)C>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[Br:10][C:3]1[C:4]([F:9])=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[CH2:15][CH2:14][C:13]([O:12][CH3:11])=[O:16]
Reactant: C=CC(OC)OC
Reactant: Fc1cc(F)c(Br)c(Br)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cc(F)cc(F)c1Br
Temperature: 90 °C

Procedure:
A mixture of 1,2-dibromo-3,5-difluorobenzene (4.5 g), 3,3-dimethoxyprop-1-ene (5.1 mL), tetrabutylammonium chloride (4.6 g) and triethylamine (3.5 mL) in N,N-dimethylformamide (50 mL) is purged with nitrogen for 20 minutes. Palladium-(II)-acetate (111 mg) is added and the mixture heated for 16 hours at 90° C. After cooling the mixture is partitioned between aqueous HCl (1 M) and diethyl ether, the organic layer dried (Na2SO4), volatiles evaporated under reduced pressure and the residue purified by column chromatography (silica gel; hexane:ethyl acetate 98:2→80:20) to give the title compound (Yield 3.6 g).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]([CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:29]=[C:28]2[C:23]([C:24]([NH:30][C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=3[F:38])=[N:25][CH:26]=[N:27]2)=[CH:22][C:21]=1[O:39][CH3:40])(O)=[O:14].[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>CN(C)C1C=CN=CC=1.CN(C=O)C>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([NH:30][C:24]2[C:23]3[C:28](=[CH:29][C:20]([O:19][CH2:18][CH2:17][CH2:16][C:13]([N:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)=[O:14])=[C:21]([O:39][CH3:40])[CH:22]=3)[N:27]=[CH:26][N:25]=2)=[C:32]([F:38])[CH:33]=1
Reactant: C1COCCN1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCCC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 46.3 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (94 mg, 4.9 mmol) was added to a mixture of 7-(3carboxypropoxy)4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline (164 mg, 0.4 mmol), morpholine (0.11 g; 1.26 mmol) and 4-dimethylaminopyridine (200 mg, 1.64 mmol) in DMF (5 ml). The reaction mixture was stirred at ambient temperature for 24 hours and the volatiles were removed by evaporation. Water was added to the residue and the aqueous mixture was extracted with methylene chloride (3×30 ml). The extracts were combined and the solvent removed by evaporation. The residue was triturated with ether and the precipitate was collected by filtration. The solid was purified by column chromatography eluting with methylene chloride/methanol/aqueous ammonia (100/8/1). The purified product was triturated with acetone, collected by filtration and dried to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-morpholinocarbonylpropoxy)quinazoline (88 mg, 46%).
Reaction SMILES: [OH:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[OH-].[Na+].[CH2:13](Br)Br>O>[CH2:13]1[O:10][C:9]2[C:2](=[C:3]([CH:6]=[CH:7][CH:8]=2)[CH:4]=[O:5])[O:1]1
Reactant: O=Cc1cccc(O)c1O
Reactant: BrCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=Cc1cccc2c1OCO2
Yield: 42.6 %

Procedure:
(a) A mixture of 2,3-dihydroxybenzaldehyde (6.4 g, 50 mmol) and sodium hydroxide (5 g in 25 ml of water) was added over 110 mins to a refluxing mixture of methylene bromide (17.3 g, 100 mmol), N,N,N-[tri-(C8 to C10 alkyl)]-N-methylammonium chloride (0.5 g; supplied by Aldrich Chemicals under the Trade Name "Adogen" 464) and water (10 ml). The mixture was heated at reflux for a further 5 hr under nitrogen and then steam distilled. The distillate was extracted with dichloromethane. Evaporation of the dried (MgSO4) organic extract gave 2,3-methylenedioxybenzaldehyde (3.2 g, 46%) as a yellow oil. Pmr spectrum (CDCl3 ; δ in ppm): 6.03 (2H,s); 6.66-6.99 (2H,m); 7.02-7.25 (1H,m); 9.97 (1H,s).
Reaction SMILES: Cl[C:2]1[C:3](=[O:29])[N:4]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH:21]C(=O)OC(C)(C)C)=[N:19][CH:20]=2)[C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:30][O:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:21][C:18]1[N:19]=[CH:20][C:15]([CH2:14][N:4]2[C:5](=[O:13])[C:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[C:2]([NH:36][C:35]3[CH:37]=[CH:38][C:32]([O:31][CH3:30])=[CH:33][CH:34]=3)[C:3]2=[O:29])=[CH:16][CH:17]=1
Reactant: COc1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CN2C(=O)C(Cl)=C(c3ccccc3)C2=O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(NC2=C(c3ccccc3)C(=O)N(Cc3ccc(N)nc3)C2=O)cc1
Temperature: 150 °C
Yield: 29.6 %

Procedure:
To a solution of tert-butyl {5-[(3-chloro-2,5-dioxo-4-phenyl-2,5-dihydro-1H-pyrrol-1-yl)methyl]pyridin-2-yl}carbamate (0.86 mmol, 357 mg) in dry DMF (1.0 mL) was added 4-methoxyaniline (0.96 mmol, 118 mg) and anhydrous potassium carbonate (0.96 mmol, 133 mg) and the reaction mixture was subjected to microwave heating single node at 150° C. for 15 min. The reaction mixture was purified using HPLC (95% 0.1M ammonium acetate buffer:5% CH3CN→5% 0.1M ammonium acetate buffer: 95% CH3CN, 10 min., 25 mL/min.) to give 102 mg (29%) of the title compound. 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 7.62 (dd, J=8.6 Hz, J=2.3 Hz, 1H), 7.21 (bs, 1H), 7.15-7.04 (m, 3H), 6.98-6.93 (m, 2H), 6.62-6.49 (m, 5H), 4.62 (s, 2H), 3.69 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([F:7])=[C:4]([F:6])[F:5].[OH:10][S:11](O)(=[O:13])=[O:12].O=S(=O)=O>>[C:3]1([F:7])([C:2]([F:9])([F:8])[F:1])[S:11](=[O:12])(=[O:10])[O:13][C:4]1([F:6])[F:5]
Reactant: O=S(=O)(O)O
Reactant: FC(F)=C(F)C(F)(F)F
Agent: O=S(=O)=O
Product: O=S1(=O)OC(F)(F)C1(F)C(F)(F)F
Temperature: 50 °C
Yield: 65 %

Procedure:
Using essentially the procedure of Example 1, the reactor was charged with 44.7 g hexafluoropropene, 45.9 g of 67 wt. % oleum and 41.5 g Fluorinert FC-77™. The reaction mixture was heated at 50° C. for 6 hours. The reactor was vented of excess HFP and the sultone layer (95.0 g) was separated and distilled to provide the HFP sultone (45 g, b.p. 48°-52° C., purity 93% by gc). The yield was 65% based on consumed HFP.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH2:15][CH3:16])[CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[N:9]=1.C(N(CCN[C:33]([C:35]1[CH:44]=[N:43][C:42]2[C:37](=[CH:38][CH:39]=[C:40]([I:45])[CH:41]=2)[N:36]=1)=[O:34])CCOC1C(F)=NC=CC=1)C>>[CH2:15]([N:4]([CH2:3][CH2:2][NH:1][C:33]([C:35]1[CH:44]=[N:43][C:42]2[C:37](=[CH:38][CH:39]=[C:40]([I:45])[CH:41]=2)[N:36]=1)=[O:34])[CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[N:9]=1)[CH3:16]
Reactant: CCN(CCN)CCNc1cccc(F)n1
Reactant: CCN(CCNC(=O)c1cnc2cc(I)ccc2n1)CCOc1cccnc1F
Product: CCN(CCNC(=O)c1cnc2cc(I)ccc2n1)CCNc1cccc(F)n1
Yield: 97 %

Procedure:
This compound was prepared, starting from compound 15 (55 mg, 0.24 mmol), according to the procedure developed for compound 10. Reaction time under reflux: 6 h, to give compound 16 (84 mg, 0.16 mmol) as an orange-coloured oil. Yield 97%; Rf (Al2O3, CH2Cl2/EtOH, 98/2, v/v) 0.70; IR (CCl4) ν 1521, 1619, 1685, 2760-3000, 3405 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.09 (t, 3H, J=7.1 Hz), 2.72 (q, 2H, J=7.1 Hz), 2.82 (m, 2H), 3.35 (q, 2H, J=5.7 Hz), 3.63 (q, 2H, J=5.9 Hz), 5.40 (se, 1H), 6.01 (dd, 1H, J=2.3, 8.0 Hz), 6.11 (dd, 1H, J=2.3, 8.0 Hz), 7.30 (q, 1H, 4JH-F=8.0 Hz, J=8.0 Hz), 7.90 (d, 1H, J=8.8 Hz), 8.06 (dd, 1H, J=1.8, 8.8 Hz), 8.34 (se, 1H), 8.58 (d, 1H, J=1.8 Hz), 9.61 (s, 1H); ESI-MS m/z 508.9 [M+H]+.
Reaction SMILES: O.C(OC([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:43]([F:44])=[CH:42][C:18]3[N:19]=[C:20]([C:22]4[C:26]([NH:27][C:28]([N:30]5[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]5)=[O:29])=[CH:25][N:24](C5CCCCO5)[N:23]=4)[NH:21][C:17]=3[CH:16]=2)[CH2:11][CH2:10]1)=O)(C)(C)C>FC(F)(F)C(O)=O>[F:44][C:43]1[C:15]([N:12]2[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]2)=[CH:16][C:17]2[NH:21][C:20]([C:22]3[C:26]([NH:27][C:28]([N:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[O:29])=[CH:25][NH:24][N:23]=3)=[N:19][C:18]=2[CH:42]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc3[nH]c(-c4nn(C5CCCCO5)cc4NC(=O)N4CCCCC4)nc3cc2F)CC1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1c[nH]nc1-c1nc2cc(F)c(N3CCNCC3)cc2[nH]1)N1CCCCC1
Temperature: 22 °C
Reaction time: 48 h
Yield: 74.2 %

Procedure:
0.5 mL of water is added to a solution of 380 mg of 4-{6-fluoro-2-[4-[(piperidine-1-carbonyl)amino]-1-(tetrahydropyran-2-yl)-1H-pyrazol-3-yl]-3H-benzimidazol-5-yl}piperazine-1-carboxylic acid tert-butyl ester in solution in 2 mL of trifluoroacetic acid. The reaction medium is stirred at 22° C. for 48 hours. The reaction medium is concentrated under vacuum in a rotary evaporator. The reaction crude is purified by flash chromatography on an Intelliflash apparatus on an Analogix RS-40 cartridge. The elution is carried out with pure dichloromethane and then with dichloromethane containing 5% of ammoniacal methanol. 195 mg of N-[3-(5-fluoro-6-piperazin-1-yl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-piperidine-1-carboxamide are obtained in the form of a yellow solid. 1H NMR (400 MHz, DMSO-d6, δ in ppm): from 1.48 to 1.68 (m, 6H); 3.23 (m, 4H); 3.30 (m, 4H); 3.47 (m, 4H); 7.24 (d, J=8.0 Hz, 1H); 7.48 (d, J=11.5 Hz, 1H); 8.01 (s, 1H). ES mass spectrum: m/z=413 MH+, m/z=328 (M+H—C5H11N)+, m/z=227.9 (M+CH3CN+2H)2+/2 (base peak). Remark: the acetonitrile explaining the m/z=227.9 peak is in the mobile phase.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=1)=[O:4].[N+:13]([C:16]1[C:17]([C:21]([NH2:23])=[O:22])=[N:18][NH:19][CH:20]=1)([O-:15])=[O:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:12][C:8]1[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:19]2[CH:20]=[C:16]([N+:13]([O-:15])=[O:14])[C:17]([C:21]([NH2:23])=[O:22])=[N:18]2)[CH:11]=[CH:10][CH:9]=1
Reactant: NC(=O)c1n[nH]cc1[N+](=O)[O-]
Reactant: O=C(CCl)Nc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1nn(CC(=O)Nc2cccc(F)c2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 68.7 %

Procedure:
A mixture of 2-chloro-N-(3-fluorophenyl)acetamide (0.65 g, 3.46 mmol), 4-nitro-1H-pyrazole-3-carboxamide (0.54 g, 3.46 mmol) and potassium carbonate (0.57 g, 4.13 mmol) in dimethylformamide (10 ml) was stirred at room temperature for 48 hours. The mixture was evaporated and the residue partitioned between ethyl acetate and water. The organic phase was separated, washed, dried and then concentrated to yield 1-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-4-nitro-1H-pyrazole-3-carboxamide (730 mg, 69% yield).
Reaction SMILES: N1C2C=CC=CC=2N=C1C1C2C(=CC(C(O)=O)=CC=2)NN=1.[OH:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([C:32]2[CH:40]=[C:39]3[C:35]([C:36]([CH:41]=O)=[N:37][NH:38]3)=[CH:34][CH:33]=2)=[O:31])=[CH:25][CH:24]=1.[F:43][C:44]1[C:49]([F:50])=[CH:48][C:47]([NH2:51])=[C:46]([NH2:52])[CH:45]=1>>[F:43][C:44]1[C:49]([F:50])=[CH:48][C:47]2[NH:51][C:41]([C:36]3[C:35]4[C:39](=[CH:40][C:32]([C:30]([NH:29][C:26]5[CH:25]=[CH:24][C:23]([OH:22])=[CH:28][CH:27]=5)=[O:31])=[CH:33][CH:34]=4)[NH:38][N:37]=3)=[N:52][C:46]=2[CH:45]=1
Reactant: Nc1cc(F)c(F)cc1N
Reactant: O=Cc1n[nH]c2cc(C(=O)Nc3ccc(O)cc3)ccc12
Agent: O=C(O)c1ccc2c(-c3nc4ccccc4[nH]3)n[nH]c2c1
Product: O=C(Nc1ccc(O)cc1)c1ccc2c(-c3nc4cc(F)c(F)cc4[nH]3)n[nH]c2c1

Procedure:
Using the same procedure as for the synthesis of 3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid in Example 53(a), step (ii), N-(4-hydroxyphenyl)-3-formyl-1H-indazole-6-carboxamide and 4,5-difluoro 1,2-phenylenediamine gave 3-(5,6-difluoro-1H-benzoimidazol-2-yl)-N-(4-hydroxyphenyl)1H-indazole-6-carboxamide as a tan solid. 1H NMR (DMSO-d6) δ 13.99 (1H, s), 13.27 (1H, s), 10.21 (1H, s), 9.25 (1H, s), 8.52 (1H, d, J=8.7 Hz), 8.21 (1H, s), 7.85 (1H, d, J=9.0 Hz), 7.80 (1H, t, J=9.8 Hz), 7.55 (2H, d, J=8.7 Hz), 7.47 (1H, t, J=9.8 Hz), 6.75 (2H, d, J=8.7 Hz). MS (APCI positive) 406. The starting material was prepared as follows: To a solution of 3-formyl-1H-indazole-6-carboxylic acid (1.6 g, 8.4 mmol) and 4 aminophenol (1.8 g, 16.8 mmol) in dry dimethylformamide (35 mL) was added HATU (3.8 g, 16.8 mmol) followed by triethylamine (1.4 mL, 10.1 mmol). The reaction was stirred at room and monitored by TLC and LC/MS. After two hours the reaction was complete. The solvent was removed by vacuum and the product was purified by flash column chromatography using ethyl acetate: petroleum ether 1:1 to pure ethyl acetate. N-(4-Hydroxyphenyl)-3-formyl-1H-indazole-6-carboxamide was isolated as a tan colored solid. 1H NMR (DMSO-d6) δ 6.79 (2H, d, 8.9 Hz), 759 (2H, d, 8.9 Hz), 7.94 (1H, d, 9.8 Hz), 8.24 (1H, d, 8.2 Hz), 8.31 (1H, s), 9.31 (1H, br s), 10.27 (2H, s). MS (APCI pos) 282.1.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C([O-])([O-])=O.[Na+].[Na+].[CH3:19][O:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1>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>[CH3:19][O:20][C:21]1[CH:26]=[C:25]([C:2]2[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:24]=[CH:23][CH:22]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: CCOC(=O)c1ccccc1Br
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: CCOC(=O)c1ccccc1-c1cccc(OC)c1
Temperature: 100 °C

Procedure:
To a stirred solution of ethyl 2-bromobenzoate (13.7 g, 59.8 mmol) and tetrakis(triphenylphosphine)palladium(0) (3.46 g, 3.0 mmol) in 1,2-dimethoxyethane (600 mL) was added 2 M aq. Na2CO3 (60 mL, deoxygenated). 3-Methoxyphenylboronic acid (10.0 g, 65.8 mmol) was added in 1,2-dimethoxyethane (80 mL) and the mixture was heated to 100° C. for 36 hours, under argon atmosphere. The mixture was cooled, diluted with water (1 L) and extracted with EtOAc (2×800 mL). The combined organic extracts were washed with sat. aq. NaHCO3, then brine, then dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography, eluting with a gradient of 0-10% EtOAc in hexane, to give the titled product as a colorless oil.