Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[C:12]([CH2:13][C:14]([O-:16])=O)=[CH:11][N:10]=[CH:9]2)=[CH:5][C:4]=1[F:19])#[N:2].[Li+].Cl.[NH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[CH:31]=1.O.ON1C2C=CC=CC=2N=N1.C(Cl)CCl.C(N(C(C)C)CC)(C)C>>[OH:36][C:32]1[CH:31]=[C:30]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH2:23][NH:22][C:14](=[O:16])[CH2:13][C:12]2[N:8]([CH2:7][C:6]3[CH:17]=[CH:18][C:3]([C:1]#[N:2])=[C:4]([F:19])[CH:5]=3)[CH:9]=[N:10][CH:11]=2)[CH:35]=[CH:34][CH:33]=1
Reactant: N#Cc1ccc(Cn2cncc2CC(=O)[O-])cc1F
Reactant: NCc1ccccc1-c1cccc(O)c1
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [Li+]
Solvent: O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(Cn2cncc2CC(=O)NCc2ccccc2-c2cccc(O)c2)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of lithium 1-(4-cyano-3-fluorobenzyl)imidazol-5-ylacetate from Step D (143 mg, 0.55 mmol), 2-aminomethyl-3′-hydroxybiphenyl hydrochloride from Example 4, Step H (118 mg, 0.50 mmol), 1-hydroxybenzotriazole hydrate (74 mg, 0.55 mmol), EDC (105 mg, 0.55 mmol), and diisopropylethylamine (129 mg, 1.00 mmol) in dry, degassed DMF (2 mL) was stirred at ambient temperature overnight. The solvent was removed under reduced pressure and the residue was partitioned between sat. aq. NaHCO3 (3 mL) and CHCl3 (5 mL). The aqueous layer was extracted further with CHCl3 (2×5 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography, eluting with a gradient of 3-5% MeOH/0.3-0.5% NH4OH in CHCl3 to give the titled product as a white foam.
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]1[C:9](=[O:10])[C:8]2[C:11]([C:21]([O:23]CC)=[O:22])=[C:12]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[S:13][C:7]=2[N:6]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:5]1=[O:30].O>CO.O1CCCC1>[CH3:3][N:4]1[C:9](=[O:10])[C:8]2[C:11]([C:21]([OH:23])=[O:22])=[C:12]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[S:13][C:7]=2[N:6]([CH2:26][CH:27]([CH3:28])[CH3:29])[C:5]1=[O:30]
Reactant: CCOC(=O)c1c(Cc2ccccc2)sc2c1c(=O)n(C)c(=O)n2CC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(C(=O)O)c(Cc3ccccc3)sc21
Temperature: 50 °C
Reaction time: 16 h
Yield: 71.7 %

Procedure:
1M Sodium hydroxide solution (7.5 ml) was added to a stirred solution of ethyl 1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-6-phenylmethyl-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylate (1.50 g) in methanol (7.5 ml) and tetrahydrofuran (15 ml). After 16 hours, further 1M sodium hydroxide solution (7.5 ml) was added and the solution was stirred at 50° C. for a further 8 hours. Water (100 ml) was added and the solution was washed with ether (100 ml). The aqueous phase was acidified by addition of concentrated hydrochloric acid and then extracted with ethyl acetate (2×100 ml). Undissolved solid in the organic extracts was filtered and dried in vacuo at 50° C. to give the title compound (1.00 g).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[Cl:5][C:6]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([O:15][CH3:16])=[C:9]([Cl:17])[C:7]=1[NH2:8].[N-]=C=O.[CH3:21][NH:22][C:23]1[CH:28]=[C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][N:37]3[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]3)[CH:31]=2)[N:26]=[CH:25][N:24]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:5][C:6]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([O:15][CH3:16])=[C:9]([Cl:17])[C:7]=1[NH:8][C:1](=[O:2])[N:22]([CH3:21])[C:23]1[CH:28]=[C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][N:37]3[CH2:38][CH2:39][N:40]([CH3:43])[CH2:41][CH2:42]3)[CH:31]=2)[N:26]=[CH:25][N:24]=1
Reactant: O=C(Cl)Cl
Reactant: CNc1cc(Nc2cccc(CN3CCN(C)CC3)c2)ncn1
Reactant: COc1cc(OC)c(Cl)c(N)c1Cl
Agent: O=C([O-])O
Agent: [N-]=C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: COc1cc(OC)c(Cl)c(NC(=O)N(C)c2cc(Nc3cccc(CN4CCN(C)CC4)c3)ncn2)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Phosgene (20% in toluene, 1 mL, 2.0 mmol, 2.4 equiv) is added to a solution of 2,6-dichloro-3,5-dimethoxyaniline (221 mg, 1.0 mmol, 1.2 equiv) in dioxane (2.5 mL), under an argon atmosphere. The mixture is heated to reflux, stirred for 1 h, allowed to cool to RT, and concentrated in vacuo. The resulting isocyanate is added to a solution of N-methyl-N′-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-pyrimidine-4,6-diamine (Step 2.1) (259 mg, 0.83 mmol) in toluene (5 mL), at reflux and under an argon atmosphere. The reaction mixture is stirred at reflux for 3 h, allowed to cool to RT, and diluted with DCM and a saturated aqueous solution of NaHCO3. The aqueous layer is separated and extracted with DCM. The organic phase is washed with brine, dried (Na2SO4), filtered and concentrated. Purification of the crude product by silica gel column chromatography (DCM/MeOH+1% NH3aq, 95:5) affords the title compound as a yellow solid: ESI-MS: 560.0/562.0 [MH]+; tR=3.26 min (purity: 99%, system 1); TLC: Rf=0.37 (DCM/MeOH+1% NH3aq, 9:1).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([NH:33][CH2:34][CH2:35][NH:36][S:37]([C:40]2[C:41]3[CH:42]=[CH:43][N:44]=[CH:45][C:46]=3[CH:47]=[C:48](Br)[CH:49]=2)(=[O:39])=[O:38])[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:20][CH:19]=1>C1(C)C=CC=CC=1.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>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([NH:33][CH2:34][CH2:35][NH:36][S:37]([C:40]2[C:41]3[CH:42]=[CH:43][N:44]=[CH:45][C:46]=3[CH:47]=[C:48]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:49]=2)(=[O:39])=[O:38])[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:20][CH:19]=1
Reactant: COc1ccc(C(NCCNS(=O)(=O)c2cc(Br)cc3cnccc23)c2ccc(OC)cc2)cc1
Reactant: OB(O)c1ccccc1
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: [Cs+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C(NCCNS(=O)(=O)c2cc(-c3ccccc3)cc3cnccc23)c2ccc(OC)cc2)cc1
Temperature: 100 °C
Yield: 57.6 %

Procedure:
Add tetrakis(triphenylphosphine)palladium (0.816 g, 0.706 mmol) to a degassed mixture of phenylboronic acid (0.1.72 g, 14.1 mmol), cesium carbonate (9.20 g, 3.5928.2 mmol), and 7-bromo-isoquinoline-5-sulfonic acid (2-{[bis-(4-methoxy-phenyl)-methyl]-amino}-ethyl)-amide (3.93 g, 7.06 mmol) in toluene (75.0 mL) and water (100.0 mL). Warm to 100° C. for 2 hours, and cool to room temperature. Dilute with toluene (100 mL), separate layers, wash sequentially with water and brine, then dry with anhydrous MgSO4, filter and evaporate. Apply the residue to a cation exchange cartridge, wash the cartridge with methanol, and then elute with 2M methanolic ammonia. Evaporation affords the title compound (2.25 g, 58%). 1H NMR (DMSO): δ9.56 (s, 1H), 8.78(d, J=1.8 Hz, 1H), 8.70(d, J=6.2 Hz, 1H), 8.75(d, J=2.0 Hz, 1H), 8.45 (d, J=6.2 Hz, 1H), 7.91(d of t J1=1.3 Hz, J=7.0 Hz, 2H), 7.62(t of t, J1=1.7 Hz, J2=7.4 Hz, 2H), 7.53 (t of t, J1=1.3 Hz, J2=7.4 Hz, 1H), 7.04 (d of t, J1=1.7 Hz, J2=8.8 Hz, 4H), 6.72 (d of t, J1=1.7 Hz, J2=8.8 Hz, 4H), 4.44 (s, 1H), 3.68(s, 6H), 3.01 (t, J=6.1 Hz, 2H), 2.35 (t, J=5.9 Hz, 2H). LCMS: m/z 554 (M+H)+, 552(M−H).
Reaction SMILES: [CH2:1]([CH:3]1[CH2:7][O:6]C[O:4]1)[CH3:2].[CH2:8](O)C(O)CC.C[Si]([C:18]1[NH:23][C:22](=[O:24])[N:21]([Si](C)(C)C)[C:20](=[O:29])[C:19]=1[F:30])(C)C.FC1C(=O)NC(=O)NC=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.CO>[OH:6][CH2:7][CH:3]([O:4][N:23]1[CH:18]=[C:19]([F:30])[C:20](=[O:29])[N:21]([CH3:8])[C:22]1=[O:24])[CH2:1][CH3:2]
Reactant: CCC(O)CO
Reactant: C[Si](C)(C)c1[nH]c(=O)n([Si](C)(C)C)c(=O)c1F
Reactant: CCC1COCO1
Agent: O=C([O-])O
Agent: O=c1[nH]cc(F)c(=O)[nH]1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCC(CO)On1cc(F)c(=O)n(C)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Ethyl-1,3-dioxolane (10 ml) prepared from butane-1,2-diol was added to bis(trimethylsilyl)-5-fluorouracil prepared from 5-fluorouracil (10 g) as in Example 1. To the mixture was added dropwise a solution of anhydrous stannic chloride (6 ml) in chloroform (15 ml) over one hour under cooling in an ice bath followed by stirring at room temperature for one hour. The reaction mixture was poured into methanol (100 ml) containing sodium bicarbonate (30 g), and after removing the resulting precipitate, the filtrate was evaporated under reduced pressure. The residue was dissolved in water (10 ml), purified by column chromatography with use of Amberlite XAD-4 (Rohm and Haas Co.), and treated with benzene to give 6.9 g of crystalline 1-(1-hydroxymethylpropyloxy)-methyl-5-fluorouracil.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][S:7]([CH2:10][C:11](O)=O)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[F:16][C:17]1[CH:24]=[CH:23][C:20](C=O)=[CH:19][CH:18]=1>>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][S:7](/[CH:10]=[CH:11]/[C:20]2[CH:23]=[CH:24][C:17]([F:16])=[CH:18][CH:19]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(O)CS(=O)(=O)Cc1ccc(Br)cc1
Reactant: O=Cc1ccc(F)cc1
Product: O=S(=O)(/C=C/c1ccc(F)cc1)Cc1ccc(Br)cc1
Yield: 82 %

Procedure:
A solution of 4-bromobenzyl sulfonylacetic acid (0.01 mol) and 4-fluorobenzaldehyde (0.01 mol) was subjected to Procedure 1, Part B. The title compound was obtained in 82% yield.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12]2[CH:11]=[C:10]([N+:13]([O-])=O)[CH:9]=[C:8]([C:16]([O:18][CH3:19])=[O:17])[C:7]=2[CH:6]=[N:5]1)[CH3:3]>C(O)C.[Pd]>[NH2:13][C:10]1[CH:9]=[C:8]([C:16]([O:18][CH3:19])=[O:17])[C:7]2[CH:6]=[N:5][N:4]([CH:2]([CH3:1])[CH3:3])[C:12]=2[CH:11]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])cc2c1cnn2C(C)C
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1cc(N)cc2c1cnn2C(C)C

Procedure:
Methyl 1-(1-methylethyl)-6-nitro-1H-indazole-4-carboxylate (1.39 g, 5.28 mmol) was dissolved in ethanol (70 mL) and hydrogenated using an H-Cube instrument (full H2 mode and 10% Pd/C). The solvent was removed in vacuo and the residue was purified via silica gel chromatography (eluent: 0% to 40% gradient; EtOAc:Hex). The product was obtained as 1.05 g (85%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.58 (d, J=6.57 Hz, 6H), 4.00 (s, 5H), 4.70 (dt, J=13.39, 6.69 Hz, 1H), 6.80 (s, 1H), 7.37 (d, J=2.02 Hz, 1H), 8.30 (s, 1H). LCMS(ES) [M+H]+234.0
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C@H:3]([CH3:18])[CH:4]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]=[CH2:17])=[CH:12][CH:11]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].COCCOC.[Cl:27][C:28]([Cl:33])(Cl)[C:29](Cl)=[O:30].ClCCl>C(OCC)C.[Cu].[Zn]>[Cl:27][C:28]1([Cl:33])[C:29](=[O:30])[CH2:17][CH:16]1[C:13]1[CH:12]=[CH:11][C:10]([CH:4]([C@@H:3]([CH3:18])[C:2]([F:1])([F:19])[F:20])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:15][CH:14]=1
Reactant: C=Cc1ccc(C(C(=O)OCC)[C@@H](C)C(F)(F)F)cc1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: [Cu]
Agent: [Zn]
Solvent: COCCOC
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)C(c1ccc(C2CC(=O)C2(Cl)Cl)cc1)[C@@H](C)C(F)(F)F
Reaction time: 8 h

Procedure:
3.83 g (13.38 mmol) of ethyl (3R)-4,4,4-trifluoro-3-methyl-2-(4-vinylphenyl)butanoate were dissolved in 50 ml of diethyl ether, and 2.67 g (20.74 mmol) of zinc-copper couple and 6.5 ml of 1,2-dimethoxyethane were added in succession. 4 ml (36.1 mmol) of trichloroacetyl chloride were then slowly added dropwise to the suspension obtained. The reaction solution was then heated under reflux and stirred overnight. After addition of dichloromethane, the reaction mixture was washed successively with water and saturated sodium chloride solution. The organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product obtained was purified chromatographically on silica gel (mobile phase: cyclohexane/ethyl acetate 4:1). This gave 4.57 g (86% of theory) of the title compound in the form of a yellowish oil which was used without further characterization in subsequent reactions.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:12]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[N:11]=[C:10]([C:21]3[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=3)[C:4]=2[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][CH2:36][OH:37].O>CN(C=O)C>[Cl:1][C:2]1[C:3]2[N:12]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[N:11]=[C:10]([C:21]3[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=3)[O:27][CH2:35][CH2:36][OH:37])[C:4]=2[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: OCCBr
Reactant: COc1ncc(Cl)c2c1c(-c1cccc(O)c1)nn2-c1c(F)cccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ncc(Cl)c2c1c(-c1cccc(OCCO)c1)nn2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-(7-chloro-1-(2,6-difluorophenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)phenol (30 mg), potassium carbonate (7 mg) and 2-bromoethanol (21 μL) in DMF (3 mL) was stirred at 70° C. for 5 hr. The mixture was allowed to be cooled to room temperature, potassium carbonate (107 mg) and 2-bromoethanol (55 μL) were added thereto, and the mixture was stirred overnight at 7° C. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (15 mg).
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:21]=[CH:20][C:9]3[O:10][CH2:11][C:12]4[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=4[C:14](=[O:15])[C:8]=3[CH:7]=2)=[N:4][N:3]=[N:2]1.C(O)C.[BH4-].[Na+].Cl>O>[NH:4]1[C:5]([C:6]2[CH:21]=[CH:20][C:9]3[O:10][CH2:11][C:12]4[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=4[CH:14]([OH:15])[C:8]=3[CH:7]=2)=[N:1][N:2]=[N:3]1
Reactant: O=C1c2ccccc2COc2ccc(-c3nnn[nH]3)cc21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OC1c2ccccc2COc2ccc(-c3nnn[nH]3)cc21

Procedure:
Suspend 1 gm. of 2-(1H-tetrazol-5-yl)-6,11-dihydro-11-oxodibenz[b,e]oxepin in 100 cc. of absolute ethanol and add excess sodium borohydride in portions. Dilute the resulting solution with water and acidify with aqueous conc. hydrochloric acid. Separate the solids by filtration. Crystallize from ethyl acetate to obtain the title product (m.p. 335° C.).
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][NH:12][S:13]([C:16]1[C:17]2[CH:18]=[CH:19][N:20]=[CH:21][C:22]=2[CH:23]=[CH:24][CH:25]=1)(=[O:15])=[O:14])CC1C=CC=CC=1.[H][H]>C(O)C.[C].[Pd]>[CH3:1][NH:2][CH2:10][CH2:11][NH:12][S:13]([C:16]1[C:17]2[CH:18]=[CH:19][N:20]=[CH:21][C:22]=2[CH:23]=[CH:24][CH:25]=1)(=[O:15])=[O:14]
Reactant: [H][H]
Reactant: CN(CCNS(=O)(=O)c1cccc2cnccc12)Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CNCCNS(=O)(=O)c1cccc2cnccc12
Yield: 63.6 %

Procedure:
In 100 ml of ethanol was dissolved 2.0 g of N-[2-(N-methyl-N-benzylamino)ethyl]-5-isoquinolinesulfonamide, i.e., Compound (65) as obtained in Example 16, and to the solution was added 0.2 g of 10% palladium-carbon. Then the solution was vigorously stirred at a temperature of 20° C. to 25° C. in a hydrogen stream of 2.0 to 2.5 atm. for 5 hours. After the palladium-carbon was separated from the reaction solution by filtration, the reaction solution was concentrated to dryness to give 0.95 g of N-(2-methylaminoethyl)-5-isoquinolinesulfonamide, i.e., Compound (14) in a yield of 64%.
Reaction SMILES: N1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](CO)=C1.C(N(CC)CC)C.[C:19](Cl)(=[O:26])C1C=CC=CC=1.[OH2:28]>CN(C1C=CN=CC=1)C>[C:3]([O:26][CH3:19])(=[O:28])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O
Reactant: OCc1c[nH]c2ccccc12
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccccc1
Temperature: 0 °C
Yield: 42 %

Procedure:
To an oven dried flask that cooled under argon was added the (1H-indol-3-yl)methanol (1.0 grams, 6.8 mmol, 0.1M in dry dichloromethane, purchased from Fisher Scientific, stored over 4 angstrom molecular sieves) and DMAP (0.083 grams, 0.68 mmol). While stirring at 0° C., triethyl amine (2.0 mL, 14.3 mmol, purchased from Fisher Scientific) was added followed by benzoyl chloride (0.96 mL, 8.2 mmol, purchased from Fisher Scientific). Once the reaction was complete it was diluted with water, and the organic layer removed. The aqueous layer was then washed with dichloromethane twice and the organic material combined. The organic material was dried with sodium sulfate, filtered, and concentrated. Purification using a Teledyne ISCO on silica support (hexanes/ethyl acetate gradient) afforded the desired 1-benzoyl-1H-indol-3-yl)methyl benzoate. 42% yield. 1H-NMR δ8.42 (d, 1H), 8.02 (dd, 2H), 7.76 (m, 3H), 7.62 (dd, 1H), 7.54 (m, 3H), 7.47-7.37 (m, 5H), 5.50 (s, 2H).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:18])[C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])=[N:6][CH:7]=1.[F:19][C:20]1([F:39])[O:24][C:23]2[CH:25]=[C:26]([CH3:38])[C:27](B3OC(C)(C)C(C)(C)O3)=[CH:28][C:22]=2[O:21]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C(#N)C.O>[F:39][C:20]1([F:19])[O:24][C:23]2[CH:25]=[C:26]([CH3:38])[C:27]([C:2]3[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:18])[C:10]4[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=4[F:17])=[N:6][CH:7]=3)=[CH:28][C:22]=2[O:21]1
Reactant: O=C(Nc1cnc(Br)cn1)c1c(F)cccc1F
Reactant: Cc1cc2c(cc1B1OC(C)(C)C(C)(C)O1)OC(F)(F)O2
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc2c(cc1-c1cnc(NC(=O)c3c(F)cccc3F)cn1)OC(F)(F)O2
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 76486.1 %

Procedure:
Palladium tetrakis-triphenylphosphine (23 mg, 20 μmol) was added to a degassed solution of bromide 17 (129 mg, 0.4 mmol) and boronate 14 (117 mg, 0.4 mmol) in dioxane:acetonitrile:water (9:9:2, 2.0 mL) and potassium phosphate (125 mg, 0.6 mmol). The resulting mixture was heated under argon at 80° C. with stiffing for 1.5 hours. The mixture was then cooled, extracted with dichloromethane (3×7 mL), dried with sodium sulfate and concentrated under reduced pressure. Flash chromatography (ISCO system, silica, 0-30% ethyl acetate in hexane) provided 10 (124 g, 78%) as a crystalline solid: LRESIMS 406.1 [M+H]+, calcd. for C19H12F4N3O3 406.1.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][C@@H:12]([CH3:16])[CH2:11]2)=[CH:6][C:5]=1[O:17][CH2:18][CH3:19].[NH:20]1[CH:24]=[CH:23][N:22]=[C:21]1[C:25]1[C:33]2[C:28](=[N:29][CH:30]=[CH:31][CH:32]=2)[N:27]([CH2:34][C:35](O)=[O:36])[N:26]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CCOC(C)=O.CN(C=O)C>[NH:20]1[CH:24]=[CH:23][N:22]=[C:21]1[C:25]1[C:33]2[C:28](=[N:29][CH:30]=[CH:31][CH:32]=2)[N:27]([CH2:34][C:35]([N:13]2[CH2:14][CH2:15][N:10]([C:7]3[CH:8]=[CH:9][C:4]([Cl:3])=[C:5]([O:17][CH2:18][CH3:19])[CH:6]=3)[CH2:11][C@@H:12]2[CH3:16])=[O:36])[N:26]=1
Reactant: O=C(O)Cn1nc(-c2ncc[nH]2)c2cccnc21
Reactant: CCOc1cc(N2CCN[C@@H](C)C2)ccc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(N2CCN(C(=O)Cn3nc(-c4ncc[nH]4)c4cccnc43)[C@@H](C)C2)ccc1Cl
Temperature: 30 °C

Procedure:
The title compound was prepared following Protocol A. To a vial containing (S)-1-(4-chloro-3-ethoxyphenyl)-3-methylpiperazine dihydrochloride (70 mg, 0.21 mmol) was added 2-(3-(1H-imidazol-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)acetic acid (51 mg, 0.21 mmol), HBTU (81 mg, 0.21 mmol), DMF (0.7 mL), and DIPEA (0.15 mL, 0.87 mmol). The reaction mixture was maintained at 30° C. for 24 h. The solution was diluted with EtOAc (30 mL) and washed with 1N HCl (2×10 mL) and sat. aq. NaCl (2×10 mL). The organic phase was dried over MgSO4 and concentrated in vacuo. The resulting residue was purified by preparative HPLC (20→95% gradient of MeCN—H2O with 0.1% TFA) and the pure fractions lyophilized to afford the indicated compound (11 mg, 11% yield): MS (ES) [M+H]+expected 480.2, found 480.5; 1H NMR (CDCl3, 400 MHz) δ 9.94 (br s, 1H), 8.79 (dd, J=1.6, 8.0, 1H), 8.55 (dd, J=1.6, 4.4, 1H), 7.19-7.26 (m, 4H), 6.37-6.43 (m, 2H), 5.40 (br s, 2H), 2.78-4.81 (m, 10H), 4.07 (q, J=6.8, 2H), 1.46 (t, J=6.8, 3H).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[C:8]([C:18]2[S:19][CH:20]=[C:21]([CH2:23][C:24]([OH:26])=O)[N:22]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[O:60]1[CH2:65][CH2:64][CH:63]([CH2:66][NH2:67])[CH2:62][CH2:61]1>CN(C=O)C.O>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[C:8]([C:18]2[S:19][CH:20]=[C:21]([CH2:23][C:24]([NH:67][CH2:66][CH:63]3[CH2:64][CH2:65][O:60][CH2:61][CH2:62]3)=[O:26])[N:22]=2)[CH:7]=[N:6]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: NCC1CCOCC1
Reactant: COc1ccc(-c2c(-c3nc(CC(=O)O)cs3)cnn2C(C)(C)C)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2c(-c3nc(CC(=O)NCC4CCOCC4)cs3)cnn2C(C)(C)C)cc1
Yield: 93.3 %

Procedure:
A solution of the compound (780 mg, 2.10 mmol) obtained in step 13, HATU (958 mg, 2.52 mmol), DIEA (0.439 ml, 2.52 mmol) and (tetrahydro-2H-pyran-4-yl)methanamine (290 mg, 2.52 mmol) in DMF (10 mL) was stirred at room temperature for 14 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine and dried, and the solvent was evaporated under reduced pressure to give the title compound (918 mg, 1.959 mmol, 93%) as a white powder.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:25][CH2:24][N:23]([C:26](=[O:32])[CH2:27][NH:28]CCO)[CH2:22][CH2:21]3)[CH:17]=[CH:16][C:15]=2[NH:33][C:34]([C:36]2[NH:37][CH:38]=[C:39]([C:41]#[N:42])[N:40]=2)=[O:35])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1.[BH-](OC(C)=O)(OC(C)=O)[O:44][C:45]([CH3:47])=O.[Na+].C=O>CO>[C:3]([OH:5])([C:2]([F:7])([F:6])[F:1])=[O:4].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:21][CH2:22][N:23]([C:26](=[O:32])[C:27]([CH3:2])([NH2:28])[CH2:47][CH2:45][OH:44])[CH2:24][CH2:25]3)[CH:17]=[CH:16][C:15]=2[NH:33][C:34]([C:36]2[NH:37][CH:38]=[C:39]([C:41]#[N:42])[N:40]=2)=[O:35])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1
Reactant: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCN(C(=O)CNCCO)CC3)cc2C2=CCCCC2)n1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC(N)(CCO)C(=O)N1CCC(c2ccc(NC(=O)c3nc(C#N)c[nH]3)c(C3=CCCCC3)c2)CC1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 113.8 %

Procedure:
A solution of 4-cyano-1H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-{1-[2-(2-hydroxy-ethylamino)-acetyl]-piperidin-4-yl }-phenyl)-amide trifluoroacetic acid salt (as prepared in Example 44, step (c), 50.0 mg, 0.085 mmol) in MeOH (3 mL) was treated with Na(OAc)3BH (39.5 mg, 0.19 mmol) and 37% aqueous formaldehyde (8.2 μL, 0.10 mmol). The mixture was stirred at room temperature for 5.5 h, and the solvents were removed in vacuo. Reverse phase HPLC (C-18 column) (10% to 50% acetonitrile in water with 0.1% TFA over 30 min) afforded the title compound (19.5 mg, 47%) as a white solid. H-NMR (CD3OD; 400 MHz): δ 8.12 (d, 1H, J=8.4 Hz), 8.02 (s, 1H), 7.19 (dd, 1H, J=8.4, 2.0 Hz), 7.09 (d, 1H, J=2.0 Hz), 5.84-5.79 (m, 1H), 4.72-4.64 (m, 1H), 4.39-4.23 (m, 2H), 3.84-3.79 (m, 1H), 3.31-3.21 (m, 1H), 3.03-2.94 (m, 6H), 2.92-2.80 (m, 2H), 4H), 2.00-1.90 (m, 2H), 1.90-1.76 (m, 5H), 1.78-1.59 (m, 2H). LC-MS (ESI, m/z): Calcd. for C27H34N6O3 491.3 (M+H), found 491.2.