Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4](I)[CH:3]=1.[C:10]([OH:15])(=[O:14])[C:11]([CH3:13])=O.C1N2CCN(CC2)C1>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[CH:13]=[C:11]([C:10]([OH:15])=[O:14])[NH:8][C:5]2=[CH:6][N:7]=1
Reactant: CC(=O)C(=O)O
Reactant: Nc1cnc(Cl)cc1I
Agent: [Pd+2]
Agent: C1CN2CCN1CC2
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Temperature: 107 °C

Procedure:
Route B: A mixture of 6-chloro-4-iodopyridin-3-ylamine (Preparation 106, 0.33 g, 1.30 mmol), pyruvic acid (0.27 mL, 3.89 mmol), DABCO (0.44 g, 3.89 mmol) and palladium acetate (0.015 g, 0.07 mmol) in dry DMF was stirred vigorously and degassed with argon for 15 min. The reaction mixture was heated to 107° C. for 5 h. The reaction mixture was allowed to cool to rt and stirred for 16 h. The volatiles were removed under reduced pressure and the residue partitioned between ethyl acetate (100 mL) and water (50 mL). The layers were separated and the aqueous extracted with ethyl acetate (2×50 mL). The combined organics were extracted with aqueous NaOH (2M, 3×70 mL). The combined aqueous extracts were acidified to pH 4 by careful addition of glacial acetic acid, then extracted with ethyl acetate (3×60 mL). The combined organics were washed with brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo to give the title compound as a brown solid. RT=2.72 min, m/z (ES+)=197 [M+H]+
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=[O:7].[CH3:13]O>S(=O)(=O)(O)O.C(OCC)(=O)C>[OH:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([O:8][CH3:13])=[O:7]
Reactant: CO
Reactant: O=C(O)C=Cc1ccccc1O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: COC(=O)C=Cc1ccccc1O
Temperature: 25 °C
Yield: 91.4 %

Procedure:
To a 250-mL round bottom flask were added, in turn, 5.57 g (33.9 mmol) of 2-hydroxycinnamic acid, 80 mL of methanol, and 6 drops of concentrated sulfuric acid. The resulting clear solution was heated to reflux for 6 hours and then allowed to cool to room temperature. The solvent was removed in vacuo to give a sticky white solid. The solid was dissolved in 80 mL of ethyl acetate, and washed with: 3 40-mL portions of 10% aqueous sodium bicarbonate; 1 40-mL portion of water; and 2 25 mL portions of brine. The organic layer was concentrated in vacuo to give 5.51 g (91.4%) of methyl 2-hydroxycinnamate as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][C:33]=1Br)[N:30]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[N:29]=[C:28]2[NH:43][C:44](=[O:48])[CH2:45][CH2:46][CH3:47].[C:49]([O:52][CH2:53][CH3:54])(=O)[CH3:50]>O.O1CCOCC1.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>[C:2]1([CH2:1][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:25]3[CH:26]=[C:27]4[C:31](=[CH:32][C:33]=3[C:9]3[CH:10]=[CH:11][C:49]([O:52][CH2:53][C:54]5[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=5)=[CH:50][CH:14]=3)[N:30]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[N:29]=[C:28]4[NH:43][C:44](=[O:48])[CH2:45][CH2:46][CH3:47])=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(C)=O
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Br)c(Br)cc12
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccc(OCc4ccccc4)cc3)c(-c3ccc(OCc4ccccc4)cc3)cc12

Procedure:
1.9 g of 4-benzyloxyphenylboronic acid, 1.63 g of sodium carbonate in 20 cm3 of distilled water and 500 mg of tetrakis(triphenylphosphine)palladium are added to 1.35 g of N-[5,6-dibromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described in Example 70, in 100 cm3 of dioxane. The mixture is refluxed for 18 hours, the temperature is then allowed to return to room temperature to add 100 cm3 of ethyl acetate and 100 cm3 of water, and the reaction medium is filtered through a sinter funnel packed with Celite. The organic phase is separated out after settling of the phases has taken place, washed with 100 cm of saturated aqueous sodium chloride solution, separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 50° C.). The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 4.5 cm), eluting with a cyclohexane/ethyl acetate mixture (70/30 by volume). The fractions containing the expected product are combined, evaporated under reduced pressure (2 kPa; 50° C.) and dried (90 Pa; 50° C.) to give 1.96 g of N-[5,6-bis[4-(phenylmethoxy)phenyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide in the form of an orange-coloured oil in a purity of 70%, which product is used without further modification in the following step.
Reaction SMILES: [S:1]([C:5]1[CH:11]=[C:10]([SH:12])[C:9]([Cl:13])=[CH:8][C:6]=1[NH2:7])(=[O:4])(=[O:3])[NH2:2].[C:14](Cl)(=O)[CH3:15]>O1CCOCC1>[CH3:14][C:15]1[NH:2][S:1](=[O:3])(=[O:4])[C:5]2[CH:11]=[C:10]([SH:12])[C:9]([Cl:13])=[CH:8][C:6]=2[N:7]=1
Reactant: CC(=O)Cl
Reactant: Nc1cc(Cl)c(S)cc1S(N)(=O)=O
Solvent: C1COCCO1
Product: CC1=Nc2cc(Cl)c(S)cc2S(=O)(=O)N1

Procedure:
A mixture of 2-sulfamoyl-4-mercapto-5-chloroaniline, prepared as described in Example 13, Step A-3 (0.02 mole) and acetyl chloride (0.022 mole) in 75 ml. of dioxane is heated under reflux for 24 hours. The solution is concentrated to dryness in vacuo and the residue dissolved in 75 ml. of ethanol and treated with 75 ml. of concentrated ammonium hydroxide in the cold. Thereafter the solution is heated under reflux for three hours and concentrated to dryness in vacuo. The residue is suspended in 100 ml. of water acidified with hydrochloric acid and the product, following recrystallization from dimethylformamide-water, melts at 304°-305° C.
Reaction SMILES: Cl.[F:2][C:3]([F:20])([F:19])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13](CC#N)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[OH-:21].[Na+].[O:23]1[CH2:28][CH2:27]OCC1>>[F:2][C:3]([F:20])([F:19])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:27][C:28]([OH:23])=[O:21])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1
Reactant: C1COCCO1
Reactant: [OH-]
Reactant: N#CCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: Cl
Agent: [Na+]
Product: O=C(O)Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 110 °C
Yield: 90 %

Procedure:
Concentrated hydrochloric acid (37%, 1 mL) is added to a solution of (4′-trifluoromethyl-biphenyl-4-yl)-acetonitrile (0.290 g, 1.11 mmol) in [1,4]dioxane (2 mL), heated at 110° C. for six hours, cooled to room temperature and adjust pH to 3 using 5.0 N sodium hydroxide, extracted with ethyl acetate three times. Organics are dried over sodium sulfate, filtered and concentrated to provide 0.280 g (11.0 mmol, 90%) of title compound.
Reaction SMILES: [CH3:1][NH:2][NH2:3].[Cl:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH:15]=[O:16])[CH2:10][C:9](=[CH:17]O)[C:8]2=O.C(O)(=O)C>CO>[Cl:4][C:5]1[CH:14]=[CH:13][C:12]2[N:11]([CH:15]=[O:16])[CH2:10][C:9]3[CH:17]=[N:3][N:2]([CH3:1])[C:8]=3[C:7]=2[CH:6]=1
Reactant: CNN
Reactant: O=CN1CC(=CO)C(=O)c2cc(Cl)ccc21
Solvent: CC(=O)O
Solvent: CO
Product: Cn1ncc2c1-c1cc(Cl)ccc1N(C=O)C2
Reaction time: 1.5 h
Yield: 61.7 %

Procedure:
Methylhydrazine (52.5 g) was dropwise to a mixture of 6-chloro-1-formyl-3-hydroxymethylene-4-oxo-1,2,3,4-tetrahydroquinoline (276 g) and acetic acid (13 ml) in methanol (2.76 liters) at 10° C. to 12° C. over a period of 10 minutes. After being stirred for 1.5 hours at the same temperature, the resulting precipitate was collected by filtration, washed with methanol and dried to give 8-chloro-4,5-dihydro-5-formyl-1-methyl-1H -pyrazolo[4,3-c]quinoline (174 g).
Reaction SMILES: [C:1]([NH:5][C:6]1[NH:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1)([O:3][CH3:4])=[O:2].[Cl:15][S:16](O)(=[O:18])=[O:17]>>[Cl:15][S:16]([C:13]1[CH:12]=[CH:11][C:9]2[N:10]=[C:6]([NH:5][C:1]([O:3][CH3:4])=[O:2])[NH:7][C:8]=2[CH:14]=1)(=[O:18])=[O:17]
Reactant: O=S(=O)(O)Cl
Reactant: COC(=O)Nc1nc2ccccc2[nH]1
Product: COC(=O)Nc1nc2ccc(S(=O)(=O)Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
A solution of 2-carbomethoxyamino-benzimidazole (5.0 g, 0.026 mole) in chlorosulfonic acid (35.00 mL) was stirred at 0° C. for 30 min. and at room temperature for 3 hr. The resulting dark colored reaction mixture was carefully poured into an ice-water mixture (200 mL) and stirred at room temperature for 30 min. The resulting precipitate was filtered and washed throughly with cold water (500 ml). The solid was dried overnight under high vacuum in a desiccator over NaOH pallets to yield the desired compound (5.9 g. 78%) as a grey powder. 1H NMR (DMSO-d6) 3.89 (s, 3H), 7.55 (d, 1H, J=8.4 Hz.) 7.65 (d, 1H, J=8.4 Hz), 7.88 (s, 1H).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])(=O)=O.[C-:16]#[N:17].[Na+].O.[CH3:20]S(C)=O>C1OCCOCCOCCOCCOCCOC1>[F:14][C:9]([F:15])([C:10]([F:13])([F:12])[F:11])[CH2:8][CH2:7][CH2:6][CH2:20][C:16]#[N:17]
Reactant: CS(=O)(=O)OCCCC(F)(F)C(F)(F)F
Reactant: [C-]#N
Reactant: CS(C)=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na+]
Solvent: O
Product: N#CCCCCC(F)(F)C(F)(F)F
Temperature: 100 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
1-Methanesulfonyloxy-4,4,5,5,5-pentafluoropentane (138 g, 538.62 mmol) was dissolved in dimethyl sulfoxide (1000 ml). Sodium cyanide (55.57 g, 1.077 mol) and 18-crown-6 (2.85 g, 10.77 mmol) were added to the solution followed by stirring for 2 hours at 100° C. After cooling to room temperature, water was added to the reaction mixture, which was then extracted twice with ether. The combined organic layers were washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. The solvent was distilled off to give 5,5,6,6,6-pentafluorohexanecarbonitrile (108 g, Yield 100%).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)[CH2:5][CH2:4]1)[CH3:2]>C(Cl)Cl.CO>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCN(Cc2ccc([N+](=O)[O-])cc2)CC1
Solvent: ClCCl
Solvent: CO
Product: CCN1CCN(Cc2ccc(N)cc2)CC1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 11.1 but using 1-ethyl-4-(4-nitro-benzyl)-piperazine (Step 12.2): ESI-MS: 220.1 [M+H]+; TLC: Rf=0.08 (DCM/MeOH+1% NH3aq, 9:1).
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[N:11]1[C:18](Cl)=[N:17][C:15](Cl)=[N:14][C:12]=1[Cl:13]>CCOCC.C1C=CC=CC=1>[Cl:13][C:12]1[N:14]=[C:15]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:17]=[C:18]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:11]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Brc1ccccc1
Agent: II
Agent: [Mg]
Solvent: CCOCC
Solvent: c1ccccc1
Product: Clc1nc(-c2ccccc2)nc(-c2ccccc2)n1
Reaction time: 8 h
Yield: 134.2 %

Procedure:
The procedure used was based on the method of Jones et al, AD 229453, September 1959. A stirred mixture of magnesium turnings (24.3 g, 0.935 mol) and a crystal of iodine in ether (150 ml), was added a solution of bromobenzene (155.3 g, 0.985 mol) in ether (100 ml) under a nitrogen atmosphere over a period of 3.75 hr at such a rate as to maintain a gentle reflux. Thereafter, the mixture was refluxed for 2.5 hr. The Grignard reagent thus prepared was then cooled and transferred to an addition funnel and added with stirring to a solution of cyanuric chloride (70 g, 0.38 mol) in benzene (500 ml) at 4°-15° C. (ice bath cooling) over a period of 1.25 hr. After stirring overnight the mixture was refluxed for 4 hr, cooled, and filtered. The filtrate was evaporated to dryness using a Rinco evaporator yielding 136.5 g of crude product mixture. This mixture was distilled in vacuo at 0.007 mm. The desired product, bp 140°-152° C., 63.5 g(62% yield), was crystallized three times from heptane yielding pure 2-chloro-4,6-diphenyl-s-triazine, 46.1 g (45% yield), mp 136°-138° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][OH:10])=[C:6]([OH:8])[CH:7]=1.Br[CH2:12][CH:13]([CH3:15])[CH3:14]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][OH:10])=[C:6]([O:8][CH2:12][CH:13]([CH3:15])[CH3:14])[CH:7]=1
Reactant: OCc1ccc(Cl)cc1O
Reactant: CC(C)CBr
Product: CC(C)COc1cc(Cl)ccc1CO

Procedure:
The title compound was prepared from 5-chloro-2-(hydroxymethyl)phenol (PREPARATION 7) and 1-bromo-2-methylpropane according to the procedure for the preparation of Example 111, part A. 1H NMR (400 MHz, CDCl3): δ 1.04 (6H, d, J=6.8 Hz), 2.07-2.17 (1H, m), 2.29 (1H, s), 3.75 (2H, d, J=6.4 Hz), 4.65 (2H, d, J=4.8 Hz), 6.83 (1H, d, J=2.0 Hz), 6.90 (1H, dd, J=2.0 Hz, 8.0 Hz), 7.20 (1H, d, J=8.0 Hz).
Reaction SMILES: [NH:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])OC1=O.CN(C)C=O.[NH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([NH:27][C:28]2[N:32]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[C:31]3[CH:41]=[CH:42][CH:43]=[CH:44][C:30]=3[N:29]=2)[CH2:23][CH2:22]1>O>[NH2:1][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:4]([NH:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([NH:27][C:28]2[N:32]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[C:31]3[CH:41]=[CH:42][CH:43]=[CH:44][C:30]=3[N:29]=2)[CH2:23][CH2:22]1)=[O:11]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccccc1C(=O)NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reaction time: 3 h
Yield: 80 %

Procedure:
To a stirred and hot (50° C.) mixture of 4.1 parts of 2H-3,1-benzoxazine-2,4(1H)-dione and 31.5 parts of N,N-dimethylformamide was added dropwise a solution of 9.4 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-amine in 31.5 parts of N,N-dimethylformamide at 50° C. Upon completion, stirring was continued for 3 hours at 50° C. Water was added and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was crystallized from acetonitrile, yielding 9.8 parts (80%) of 2-amino-N-[2-[4-[[1-[(4-fluorophenyl)-methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]-ethyl]benzamide; mp. 171.7° C. (intermediate 157).
Reaction SMILES: C([O:5][C:6]([CH2:8][N:9]([S:17]([C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([Cl:30])[CH:26]=2)[CH:21]=1)(=[O:19])=[O:18])[CH2:10][CH:11]=[CH:12][C:13]([O:15][CH3:16])=[O:14])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[C:6]([CH2:8][N:9]([S:17]([C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([Cl:30])[CH:26]=2)[CH:21]=1)(=[O:19])=[O:18])[CH2:10][CH:11]=[CH:12][C:13]([O:15][CH3:16])=[O:14])([OH:7])=[O:5]
Reactant: COC(=O)C=CCN(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc2cc(Cl)ccc2c1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C=CCN(CC(=O)O)S(=O)(=O)c1ccc2cc(Cl)ccc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.3 %

Procedure:
A solution of methyl 4-[(tert-butoxycarbonylmethyl)(6-chloro-naphthalene-2-sulfonyl)amino]-2-butenoate (22.7 g) in toluene (30 ml) was combined with trifluoroacetic acid (30 ml) and stirred at room temperature for 1.5 hours. The reaction mixture was concentrated and the resultant residue was crystallized from ether-hexane to obtain methyl 4-[carboxymethyl(6-chloro-naphthalene-2-sulfonyl)amino]-2-butenate (19.35 g) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Cl:19][C:20]1[C:25]([F:26])=[CH:24][CH:23]=[C:22]([F:27])[C:21]=1/[CH:28]=[CH:29]/[C:30](O)=[O:31]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:30](=[O:31])/[CH:29]=[CH:28]/[C:21]3[C:22]([F:27])=[CH:23][CH:24]=[C:25]([F:26])[C:20]=3[Cl:19])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: O=C(O)/C=C/c1c(F)ccc(F)c1Cl
Product: CC(=O)c1ccc(Cn2cc(NC(=O)/C=C/c3c(F)ccc(F)c3Cl)cn2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-(2-chloro-3,6-difluoro-phenyl)-acrylic acid.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][N:14]=2)[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=[C:8]([NH:24][C:25]([NH:27][C:28]2[C:33]([CH:34]([CH3:36])[CH3:35])=[CH:32][CH:31]=[CH:30][C:29]=2[CH:37]([CH3:39])[CH3:38])=[O:26])[C:7]1=[O:40])#[N:2].C(=O)([O-])[O-:42].[Na+].[Na+].OO.O>CO.CC(C)=O>[NH2:2][C:1]([CH2:3][CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][N:14]=2)[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=[C:8]([NH:24][C:25]([NH:27][C:28]2[C:29]([CH:37]([CH3:39])[CH3:38])=[CH:30][CH:31]=[CH:32][C:33]=2[CH:34]([CH3:36])[CH3:35])=[O:26])[C:7]1=[O:40])=[O:42]
Reactant: COc1cccc(-c2c(NC(=O)Nc3c(C(C)C)cccc3C(C)C)c(=O)n(CCCC#N)c3ncccc23)c1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CO
Product: COc1cccc(-c2c(NC(=O)Nc3c(C(C)C)cccc3C(C)C)c(=O)n(CCCC(N)=O)c3ncccc23)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of N-[1-(3-cyanopropyl)-4-(3-methoxyphenyl)-l,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea (100 mg, 0.19 mmol) in methanol-acetone (3 ml) were added 10% aqueous sodium carbonate solution (1 ml) and 30% hydrogen peroxide (1 ml), and the mixture was stirred at room temperature for three hours. The mixture was poured into water, and extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The residue was concentrated under reduced pressure, and purified by preparative thin layer chromatography to give the title compound (96 mg, 0.17 mmol).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH2:15][C:16]([NH2:18])=[S:17]>>[CH3:1][O:2][C:3]([C:4]1[N:15]=[C:16]([NH2:18])[S:17][C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:14]
Reactant: NC(N)=S
Reactant: COC(=O)C(=O)C(Cl)c1ccccc1
Product: COC(=O)c1nc(N)sc1-c1ccccc1

Procedure:
prepared by reaction of 3-chloro-2-oxo-3-phenyl-propionic acid methyl ester with thiourea. LC-MS: tR=0.77 min; [M+H]+=235.1.
Reaction SMILES: [B][B][B][B][B][B][B][B][B][B].[NH2:11][C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:19]=2[N:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)[N:14]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)[N:13]=1.[CH3:49][O:50][C:51]1[CH:64]=[CH:63][C:54]([CH2:55][N:56]2[CH2:60][C:59](=O)[CH2:58][C:57]2=[O:62])=[CH:53][CH:52]=1>CO.C(Cl)Cl>[CH3:48][O:47][C:44]1[CH:43]=[CH:42][C:41]([CH2:40][N:14]2[C:15]3=[N:16][CH:17]=[C:18]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:19]([N:21]4[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26]4)=[C:20]3[C:12]([NH:11][CH:59]3[CH2:58][C:57](=[O:62])[N:56]([CH2:55][C:54]4[CH:53]=[CH:52][C:51]([O:50][CH3:49])=[CH:64][CH:63]=4)[CH2:60]3)=[N:13]2)=[CH:46][CH:45]=1
Reactant: COc1ccc(CN2CC(=O)CC2=O)cc1
Reactant: COc1ccc(Cn2nc(N)c3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(-c4ccccc4)cnc32)cc1
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(CN2CC(Nc3nn(Cc4ccc(OC)cc4)c4ncc(-c5ccccc5)c(N5CCN(C(=O)OC(C)(C)C)CC5)c34)CC2=O)cc1
Temperature: 48 °C
Reaction time: 20 h
Yield: 71.4 %

Procedure:
Decaborane (0.014 g, 0.12 mmol) was added to a solution of tert-butyl 4-(3-amino-1-(4-methoxybenzyl)-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.20 g, 0.39 mmol) and 1-(4-methoxybenzyl)pyrrolidine-2,4-dione (0.10 g, 0.47 mmol) in MeOH (3 mL) and DCM (0.5 mL) and stirred at 48° C. (oil bath) for 20 hours. The solvent was removed. The resulting residue was dissolved in ethyl acetate (20 mL), washed with saturated NaHCO3 (10 mL), dried (sodium sulfate) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (hexane:ethyl acetate=1:1) to give tert-butyl 4-(1-(4-methoxybenzyl)-3-(1-(4-methoxybenzyl)-5-oxopyrrolidin-3-ylamino)-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.20 g, 70%) as a solid. LCMS (APCI+) m/z 718(M+H)+.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH3:6][C:7]([CH3:23])([CH3:22])[C:8](=[O:21])[CH2:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])=[O:11].C(O)C>ClCCl>[Cl:4][CH:9]([C:8](=[O:21])[C:7]([CH3:23])([CH3:22])[CH3:6])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])=[O:11]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(C)(C)C(=O)CC(=O)Nc1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(C)C(=O)C(Cl)C(=O)Nc1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
Sulfuryl chloride (54.1 g, 0.4 mol) was added dropwise with vigorous stirring over a 60 minute period to a solution of N-[4,4-dimethyl-3-oxopentanoyl]-2,4-dichloroaniline, prepared as above (109 g, 0.378 mol) in dichloromethane (600 mL) at -10° C. The reaction mixture was maintained at this temperature for 3 hours after the addition had been completed. After this time, the mixture was allowed to warm to 0° C. and ice (approximately 50 mL) was added, with stirring. The organic layer was separated and washed with 50% saturated aqueous sodium chloride solution (2×500 mL), then dried over magnesium sulfate. Evaporation of the solvent afforded a brown oil which was stirred with ethanol (150 mL) to induce crystallization of the product. The resultant mixture was stored at 0° C. overnight. The solid product was removed by filtration, washed with cold ethanol and dried to afford N-[2-chloro-4,4,-dimethyl-3-oxopentanoyl]-2,4-dichloroaniline (104.2 g, 85.4% yield) as a white crystalline solid which melted at 64.5°-65.5° C. The structure of this compound was confirmed by mass spectroscopy and by 1H and 13C NMR spectroscopy.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.Br[CH:13]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15].CCN(C(C)C)C(C)C>C(#N)C>[CH2:17]([O:16][C:14](=[O:15])[CH:13]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:18]
Reactant: CC(=O)Nc1cccc(N)c1
Reactant: CCOC(=O)C(Br)c1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(Nc1cccc(NC(C)=O)c1)c1ccccc1
Temperature: 100 °C
Yield: 85.9 %

Procedure:
N-(3-Aminophenyl)acetamide (371 mg, 2.47 mmol), ethyl 2-bromo-2-phenylacetate (0.29 mL, 1.64 mmol), and DIPEA (0.43 mL, 2.47 mmol) are dissolved in acetonitrile (5 mL). The reaction is heated under MW irradiation at 100° C. for 30 minutes. Conversion complete by UPLC/MS-UV. Acetonitrile is evaporated and the crude residue is purified by flash chromatography (DCM/EtOAc=8/2) to obtain intermediate I92 as a colorless oil (440 mg, 86% yield).