Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:37][CH3:38])[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[CH:16][C:15]([C:18]3[CH:19]=[C:20](/[CH:33]=[N:34]/OC)[C:21]4[S:25][C:24]([NH:26][C:27](=[O:31])[NH:28][CH2:29][CH3:30])=[N:23][C:22]=4[CH:32]=3)=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH2:39].CC#N>CO.[OH-].[Na+].O>[C:33]([C:20]1[C:21]2[S:25][C:24]([NH:26][C:27](=[O:31])[NH:28][CH2:29][CH3:30])=[N:23][C:22]=2[CH:32]=[C:18]([C:15]2[CH:14]=[N:13][C:12]([N:9]3[CH2:8][CH2:7][C:6]([CH2:37][CH3:38])([C:4]([OH:3])=[O:5])[CH2:11][CH2:10]3)=[N:17][CH:16]=2)[CH:19]=1)(=[O:39])[NH2:34]
Reactant: O
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(CC)(C(=O)OCC)CC4)nc3)cc(/C=N/OC)c2s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC#N
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(CC)(C(=O)O)CC4)nc3)cc(C(N)=O)c2s1
Temperature: 65 °C
Yield: 5 %

Procedure:
Ethyl-4-ethyl-1-[5-[2-(ethylcarbamoylamino)-7-[(E)-methoxyiminomethyl]-1,3-benzothiazol-5-yl]pyrimidin-2-yl]piperidine-4-carboxylate (619 mg, 1.147 mmol) 100 was suspended in MeOH (9 mL) and NaOH(aq) (1M, 9 mL), sealed in a microwave vessel, irradiated at 85° C. for 1 h, followed by conventionally heating overnight at 65° C. The reaction was diluted with water (40 mL) and washed with EtOAc (1×50 mL). Acidification of the aqueous phase with HCl(aq) (1M, pH 2) and back extracting with EtOAc (3×60 mL) yielded a waxy solid which was subjected directly to reverse phase chromatography (5-100% H2O/MeCN) yielding 25 mg (5% yield) of the Compound 193 as a by-product to the aldoxime. 1H NMR (DMSO-d6) δ 8.84 (s, 2H), 8.33 (s, 1H), 8.11 (d, J=1.4 Hz, 1H), 8.03 (d, J=1.4 Hz, 1H), 7.71 (s, 1H), 6.87 (t, J=5.4 Hz, 1H), 4.46 (dd, J=9.9, 3.6 Hz, 2H), 3.18 (qd, J=13.2, 4.8 Hz, 4H), 2.06 (d, J=13.4 Hz, 2H), 1.54 (q, J=7.4 Hz, 2H), 1.35 (td, J=13.6, 4.0 Hz, 2H), 1.11 (t, J=7.2 Hz, 3H), 0.81 (t, J=7.5 Hz, 3H). MS: 498.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][S:10]([CH2:13][CH3:14])(=[O:12])=[O:11])[CH:5]=[N:6][CH:7]=1.I[CH:16]([CH3:18])[CH3:17].[H-].[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]([CH:16]([CH3:18])[CH3:17])[S:10]([CH2:13][CH3:14])(=[O:11])=[O:12])[CH:5]=[N:6][CH:7]=1
Reactant: CC(C)I
Reactant: CCS(=O)(=O)NCc1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Product: CCS(=O)(=O)N(Cc1cncc(Br)c1)C(C)C

Procedure:
In analogy to the procedure described for the preparation of intermediate A-42, ethanesulfonic acid (5-bromo-pyridin-3-ylmethyl)-amide (intermediate A-11) was reacted with 2-iodopropane in presence of NaH (60% in mineral oil) to give the title compound as white solid after purification by reverse phase HPLC on a Gemini-NX column. MS: 323.1 (M+H+).
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][CH:5]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]=[O:18])=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH2:8]1)[CH3:6].[Cl-].[NH4+]>CCOCC>[CH3:6][CH:5]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]([OH:18])[CH3:1])=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH2:8]1)[CH3:4]
Reactant: CC(C)N1CCCc2cc(C=O)ccc21
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(O)c1ccc2c(c1)CCCN2C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4.9 ml (15 mmol) of a 3.0M ethereal solution of methylmagnesium bromide was diluted with 15 ml of ether. An ethereal solution of 2.0 g (10 mmol) of 1-(1-methylethyl)-1,2,3,4-tetrahydroquinoline-6-carbaldehyde was dropped into the dilution prepared above at room temperature. The obtained mixture was stirred at room temperature for one hour, followed by the addition of an aqueous solution of ammonium chloride. The resulting mixture was extracted with ethyl acetate. The organic phase was washed with a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate and concentrated in a vacuum to give 2.1 g of the title compound as a brown oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([S:11]([NH:14][C:15]3[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:22])(=[O:13])=[O:12])[N:10]=[C:4]2[N:3]=1.[Br:23]N1C(=O)CCC1=O>C(O)(=O)C.C(OC(=O)C)(=O)C>[Br:23][C:7]1[C:2]([CH3:1])=[N:3][C:4]2[N:5]([N:8]=[C:9]([S:11]([NH:14][C:15]3[C:16]([Cl:22])=[CH:17][CH:18]=[CH:19][C:20]=3[Cl:21])(=[O:13])=[O:12])[N:10]=2)[CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccn2nc(S(=O)(=O)Nc3c(Cl)cccc3Cl)nc2n1
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: Cc1nc2nc(S(=O)(=O)Nc3c(Cl)cccc3Cl)nn2cc1Br
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
A suspension of 4.0 g (11 mmol) of 5-methyl-N-(2,6-dichlorophenyl)-1,2,4-triazolo[1,5-a]pyrimidine-2-sulfonamide in 50 ml of glacial acetic acid and 10 ml of acetic anhydride was stirred at 90° C. for 30 minutes. N-Bromosuccinimide (2.4 g, 13 mmol) was added to this hot solution, and the reaction mixture was stirred at 90° C. for 60 minutes. The solution was cooled and poured into 200 ml of ice water. A solid which separated was collected and dried. This crude product was purified by dissolving the sample in methylene chloride, filtering the solution through silica gel and triturating the filtrate with pentane. The desired product was obtained as a solid, mp 215°-216° C. IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: [OH:1][C@H:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][C@@H:12]3[CH3:24])[C:5]=2[C@H:4]([CH3:25])[CH2:3]1.[H-].[Na+].[CH3:28]I>C1COCC1>[CH3:28][O:1][C@H:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][C@@H:12]3[CH3:24])[C:5]=2[C@H:4]([CH3:25])[CH2:3]1
Reactant: CI
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)OC(C)(C)C)C[C@@H]3C)c21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@@H]1C[C@@H](C)c2c1ncnc2N1CCN(C(=O)OC(C)(C)C)C[C@@H]1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.2 %

Procedure:
To a solution of (S)-tert-butyl 4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (0.098 g, 0.28 mmol) in THF (10 mL) were added NaH (60%, 50 mg, 1.25 mmol) and MeI (0.08 mL, 1.28 mmol). The mixture was stirred at room temperature overnight. The solution was removed and the residue was purified by silica gel chromatography, eluting with ethyl acetate to give (S)-tert-butyl 4-((5R,7R)-7-methoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (0.056 g, 55%). 1H NMR (CDCl3, 400 MHz) δ 8.56 (s, 1H), 4.66 (m, 2H), 4.30-3.80 (m, 3H), 3.55 (s, 3H), 3.54-2.90 (m, 4H), 2.25 (m, 1H), 1.98 (m, 1H), 1.49 (s, 9H), 1.24 (d, J=12.4 Hz, 3H), 1.13 (d, J=7.2 Hz, 3H). MS (APCI+) [M+H] +363.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[C:20]1([CH2:26][CH2:27][CH2:28][CH2:29][NH2:30])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC#N>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:30][CH2:29][CH2:28][CH2:27][CH2:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: NCCCCc1ccccc1
Solvent: CC#N
Product: CC(C)(C)N1C(=O)C(NCCCCc2ccccc2)=C(c2ccccc2)S1(=O)=O
Yield: 92.1 %

Procedure:
A solution of 2-tert-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.150 g, 0.50 mmol), TEA (0.076 g, 0.751 mmol) and 4-phenylbutylamine (0.097 g, 0.65 mmol) in MeCN (3 mL) was heated in a microwave reactor at 120° C. for 10 mins. The mixture was evaporated and the residue was purified by silica gel column chromatography using a 85:15 mixture of heptane and EtOAc as eluant, to give the title compound (0.19 g, 92%) as a solid; 1H NMR (500 MHz, CDCl3): δ 7.52-7.47 (m, 2H), 7.45-7.40 (m, 3H), 7.31-7.26 (m 2H), 7.22-7.17 (m, 1H), 7.08 (d, 2H), 5.26 (t, 1H), 2.88-2.81 (m, 2H), 2.49-7.43 (m 2H), 1.75 (s 9H), 1.48-1.36 (m 4H); 13C NMR (125 MHz, CDCl3) δ 159.9, 141.8, 135.3, 131.9, 129.8, 128.8, 128.6, 128.5, 126.2, 125.3, 107.0, 61.7, 44.1, 35.5, 29.2, 28.4, 27.9; Mass Spectrum: M−H+ 413.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]([C:10]1[S:11][C:12]([S:32][CH3:33])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=3[NH2:31])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[CH3:40][O:41][C:42](=[O:50])[CH2:43][CH2:44][CH2:45][CH2:46][C:47](Cl)=[O:48]>CCOC(C)=O>[CH3:40][O:41][C:42](=[O:50])[CH2:43][CH2:44][CH2:45][CH2:46][C:47](=[O:48])[NH:31][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]([CH3:30])[C:24]=1[C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([S:15]([C:13]2[CH:14]=[C:10]([C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:34])=[NH:9])[S:11][C:12]=2[S:32][CH3:33])(=[O:17])=[O:16])[CH:19]=1
Reactant: COC(=O)CCCCC(=O)Cl
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2N)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)CCCCC(=O)Nc1cccc(C)c1-c1cccc(S(=O)(=O)c2cc(C(=N)NC(=O)OC(C)(C)C)sc2SC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
{[4-(2′-Amino-6′-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (100 mg, 0.19 mmol, Example 25: step c) was dissolved into THF (3 mL). To this was added 5-Chlorocarbonyl-pentanoic acid methyl ester (41.5 mg, 0.23 mmol) and the reaction was stirred at RT for 2 hours. The reaction was dissolved into EtOAc and washed with brine. The combined organic layers were dried (MgSO4) followed by removal of solvents in vacuo resulted in the title compound that was used without further purification. ESI-MS (m/z): Calcd. for C31H37N3O7S3: 660.2 (M+1); found: 660.8.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=3[O:30][CH3:31])[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[Br:32][C:33]1[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[CH:35][C:34]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].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.O>[Br:32][C:33]1[CH:38]=[C:37]([C:39]([F:40])([F:41])[F:42])[CH:36]=[CH:35][C:34]=1[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=3[O:30][CH3:31])[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)c(OC)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1Br
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4Br)nccc3c2)c(OC)c1

Procedure:
A microwave vial was charged with 1-chloro-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (0.075 g, 0.158 mmol), (2-bromo-4-(trifluoromethyl)phenyl)boronic acid (0.064 g, 0.236 mmol), tetrakis(triphenylphosphine)palladium(0) (0.018 g, 0.016 mmol), and potassium carbonate (0.109 g, 0.788 mmol). Dioxane (1.182 ml) and water (0.394 ml) were added, the vial was flushed with argon and sealed, and microwaved at 100° C. for 30 minutes. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified by silica gel chromatography (12 g column, gradient elution 0 to 50% EtOAc:Heptane) to afford 1-(2-bromo-4-(trifluoromethyl)phenyl)-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide as a white solid. m/z (ESI) 664.1 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:22])([CH2:19][CH:20]=[CH2:21])[C:3]([NH:5][N:6]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1)=[O:4].FC(F)(F)C(O)=O>ClCCl>[F:22][C:2]([F:1])([CH2:19][CH:20]=[CH2:21])[C:3]([NH:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:4]
Reactant: C=CCC(F)(F)C(=O)NN1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCC(F)(F)C(=O)NN1CCNCC1

Procedure:
A solution of 4-(2,2-difluoropent-4-enamido)-1-(t-butoxycarbonyl)piperazine (Example 16, step b) (5.0 g, 16.4 mmol) in 10 ml dichloromethane was treated with 2 ml trifluoroacetic acid. The reaction was concentrated after 24 hours, basified to pH 9 using 4N sodium hydroxide and extracted into dichloromethane. The organic extracts were dried (MgSO4) and concentrated to give 4-(2,2-difluoropent-4-enamido)piperazine as a yellow oil. δH (250 MHz, CDCl3) 2.83-3.01 (6H, m), 3.59-3.63 (2H, t, J=10 Hz), 3.67-3.71 (2H, t, J=10 Hz), 5.23 (1H, s), 5.27-5.30 (1H, d, J=7.5 Hz), 5.79-5.95 (1H, m).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](Cl)=[CH:5][N:4]=1)#[N:2].[F-:10].[K+]>CN1CCCC1=O.C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([F:10])=[CH:5][N:4]=1)#[N:2]
Reactant: [F-]
Reactant: N#Cc1ccc(Cl)cn1
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(F)cn1
Yield: 48.2 %

Procedure:
A mixture of 2-cyano-5-chloropyridine (1 g, 7.22 mmol) and potassium fluoride (1.26 g, 21.68 mmol) in 1-methyl-2-pyrrolidinone (25 mL) was heated at reflux for 18 hours. After cooling, the reaction was diluted with ethyl acetate and extracted with water and brine. The organic solvents were then removed in vacuo. Silica gel chromatography of the residue afforded 425 mg (48%) of 2-cyano-5-fluoropyridine.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[C:12]([N:17]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]=2[NH:10][C:9]1=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[Br:38]Br>C(O)(=O)C.O>[CH2:1]([N:8]1[C:16]2[C:15]([Br:38])=[CH:14][N:13]=[C:12]([N:17]([CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:11]=2[NH:10][C:9]1=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrBr
Reactant: O=c1[nH]c2c(N(Cc3ccccc3)Cc3ccccc3)nccc2n1Cc1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]c2c(N(Cc3ccccc3)Cc3ccccc3)ncc(Br)c2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 107.6 %

Procedure:
1-benzyl-4-dibenzylamino-1,3-dihydro-imidazo[4,5,c]pyridine-2-one (1 g, 2.4 mmol) was suspended in 20 mL of acetic acid then sodium acetate (195 mg, 2.4 mmol) was added followed by bromine (456 mg, 2.85 mmol) dropwise. The mixture was stirred at room temperature for 15 minutes. A heavy precipitate was formed. The mixture was diluted in water (50 mL) and the solid was filtered and washed with water. It was then diluted in ethyl acetate (20 mL), dried over magnesium sulfate and the solvent was removed in vacuo to give 1.29 g of the title compound as a light orange solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12](B(O)O)[N:13]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)[C:30]([F:33])([F:32])[F:31]>>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:30]([F:33])([F:32])[F:31])[N:13]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2c(OCc3ccccc3)cccc21
Reactant: C[Si](C)(C)C(F)(F)F
Product: CC(C)(C)OC(=O)n1c(C(F)(F)F)cc2c(OCc3ccccc3)cccc21

Procedure:
[4-(Benzyloxy)-1-(tert-butoxycarbonyl)-1H-indol-2-yl]boronic acid and trimethyl(trifluoromethyl)silane were combined to give tert-butyl 4-(benzyloxy)-2-(trifluoromethyl)-1H-indole-1-carboxylate, which was debenzylated via ammonium formate transfer hydrogenation to give tert-butyl 4-hydroxy-2-(trifluoromethyl)-1H-indole-1-carboxylate.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20](Cl)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:35][N:36]1[C:40]2[CH:41]=[C:42]([Sn](CCCC)(CCCC)CCCC)[S:43][C:39]=2[C:38]([CH3:57])=[N:37]1>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([C:42]2[S:43][C:39]3[C:38]([CH3:57])=[N:37][N:36]([CH3:35])[C:40]=3[CH:41]=2)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2c(s1)c(C)nn2C
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1nn(C)c2cc(-c3nc(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)c(F)c4c3C(=O)N(C(=O)OC(C)(C)C)C4)sc12
Temperature: 90 °C

Procedure:
In a 30 mL sealed cap glass tube, tert-butyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (150 mg, 0.301 mmol), 1,3-dimethyl-5-(tributylstannyl)-1H-thieno[3,2-c]pyrazole (265 mg, 0.601 mmol) and tetrakis(triphenylphosphine) palladium(0) (174 mg, 0.150 mmol) were dissolved in toluene (5 mL). The cap was sealed and the reaction mixture was heated at 90° C. in an oil bath for 2 hours. The mixture was concentrated to give the intermediate, tert-butyl 6-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-4-(1,3-dimethyl-1H-thieno[3,2-c]pyrazol-5-yl)-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate. The intermediate was dissolved in TFA (5 mL) and the reaction mixture was stirred for 2 hours. The mixture was concentrated, dissolved in DMSO (5 mL), and purified via preparatory HPLC eluting with a gradient of 15-65% ACN (0.035% TFA) and H2O (0.05% TFA). The pure fractions were combined, evaporated to a minimal volume, and lyophilized to give a TFA salt of the title compound as a white solid (95 mg, 72%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.48 (br s, 2H), 1.43-2.03 (m, 6H), 2.33 (s, 3H), 3.83 (br s, 1H), 3.90 (s, 3H), 4.28 (br s, 1H), 4.39-4.51 (m, 2H), 7.09 (d, J=5.81 Hz, 1H), 7.79 (br s, 3H), 8.61 (s, 1H), 9.22 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C20H23FN6OS, 415. found, 415.
Reaction SMILES: C([O:8][C:9]1[C:40]([CH3:41])=[CH:39][C:12]([CH2:13][C@@H:14]([CH2:18][C:19](=[O:38])[N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[CH2:32][CH2:31][C:30]4[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=4[NH:28][C:27]3=[O:37])[CH2:22][CH2:21]2)[C:15]([OH:17])=[O:16])=[CH:11][C:10]=1[O:42][CH3:43])C1C=CC=CC=1.[H][H]>C(N(CC)CC)C.CO.[Pd]>[OH:8][C:9]1[C:40]([CH3:41])=[CH:39][C:12]([CH2:13][C@@H:14]([CH2:18][C:19](=[O:38])[N:20]2[CH2:21][CH2:22][CH:23]([N:26]3[CH2:32][CH2:31][C:30]4[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=4[NH:28][C:27]3=[O:37])[CH2:24][CH2:25]2)[C:15]([OH:17])=[O:16])=[CH:11][C:10]=1[O:42][CH3:43]
Reactant: COc1cc(C[C@@H](CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(C)c1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1cc(C[C@@H](CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(C)c1O
Reaction time: 3 h

Procedure:
A suspension of 7.60 g (12.98 mmol) (S)-2-(4-benzyloxy-3-methoxy-5-methyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-butanoic acid and 0.76 g 10% Pd/C in 2 mL triethylamine and 150 mL MeOH was hydrogenated at RT and 2620 hPa hydrogen pressure for 16 h. To complete the reaction a further 0.38 g 10% Pd/C were added and the mixture was again hydrogenated for 3 h at RT. The catalyst was filtered off through Celite and the filtrate was concentrated by evaporation i.vac. The product was further reacted without purification.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].N[C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([N+:27]([O-:29])=[O:28])[CH:21]=1.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[OH:26][C:23]1[CH:24]=[CH:25][C:20]([NH:13][C:12]2[C:11]3[C:10](=[CH:9][CH:8]=[C:6]4[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]4=3)[N:14]=[CH:15][N:16]=2)=[CH:21][C:22]=1[N+:27]([O-:29])=[O:28]
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Reactant: Nc1ccc(O)c([N+](=O)[O-])c1
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#Cc1nc2ccc3ncnc(Nc4ccc(O)c([N+](=O)[O-])c4)c3c2s1
Yield: 60 %

Procedure:
Prepared from VII and 4-amino-2-nitrophenol. Flash chromatography eluent (DCM-EtOAc, 5:5). Yield: 60%; brown solid; mp>260° C.; IR (KBr) νmax/cm−1 3334, 3081, 2926, 2225, 1627, 1591, 1569, 1525, 1465, 1419, 1395, 1305, 1237, 1171, 1132, 1070, 966, 930, 834, 819; 1H NMR (300 MHz, DMSO-d6) δ 8.52 (d, 1H, J=8.7 Hz), 8.28 (m, 1H), 8.03 (m, 1H), 7.75 (d, 1H, J=8.7 Hz), 7.61 (m, 1H), 7.15 (d, 1H, J=9.0 Hz); HRMS calcd for C16H9N6O3S (M+H+): 365.0457, found 365.0441.
Reaction SMILES: [C:1]([O:5][C:6](=[O:47])[NH:7][CH:8]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][C:36](=[O:46])[NH:37][O:38]CC3C=CC=CC=3)=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:19])[CH3:18])[CH2:13][CH2:12]1)=[O:10])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6](=[O:47])[NH:7][CH:8]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:29]=[CH:30][C:31]([CH2:34][CH2:35][C:36](=[O:46])[NH:37][OH:38])=[CH:32][CH:33]=2)=[CH:23][CH:22]=1)[C:9]([N:11]1[CH2:12][CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16]1)=[O:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: [H][H]
Reactant: CC(=O)N1CCN(C(=O)C(Cc2ccc(Oc3ccc(CCC(=O)NOCc4ccccc4)cc3)cc2)NC(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CO
Product: CC(=O)N1CCN(C(=O)C(Cc2ccc(Oc3ccc(CCC(=O)NO)cc3)cc2)NC(=O)OC(C)(C)C)CC1
Yield: 103.3 %

Procedure:
Palladium on BaSO4 (5%, 0.4 g) was added to a degassed solution of the benzyl hydroxamate 20 (0.9 g) in MeOH (75 mL) and the suspension was treated with hydrogen at atmospheric pressure for 6 h. The suspension was filtered over a Celite® bed and concentrated to yield the desired hydroxamate 21 (˜0.8 g, quantitative yield). 1H NMR (400 MHz, DMSO-d6): 10.38 (s, 1H), 8.72 (s, 1H), 7.24 (d, J=8.0 Hz, 2H), 7.16 (d, J=8.8 Hz, 2H), 6.88 (d, J=7.6 Hz, 2H), 6.83 (d, J=8.4 Hz, 2H), 4.58 (m, 1H) 3.10-3.45 (m, 8H), 2.76-2.85 (m, 4H), 2.24 (t, J=7.2 Hz, 2H), 2.00 (s, 3H), 1.32 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([N:21]([CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])[CH3:22])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[Li+].[OH-]>CO.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([N:21]([CH2:23][C:24]([OH:26])=[O:25])[CH3:22])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CN(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(OCC#Cc2ccc(Cl)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(CC(=O)O)S(=O)(=O)c1ccc(OCC#Cc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a solution of tert-butyl [[(4-{[3-(4-chlorophenyl)-2-propynyl]oxy}phenyl)sulfonyl](methyl)amino]acetate (0.331 g, 0.736 mmol in methanol/THF was added 1.23 mL (3.5 eq) of a 1.0 N solution of LiOH and the reaction was stirred at room temp overnight. The solvent was removed in vacuo and the residue was suspended in water, adjusted to pH to 3 with 2N HCl. The resulting solid was rinsed with ether and dried in vacuo to afford 0.27 g (89%) of [[(4-{[3-(4-chlorophenyl)-2-propynyl]oxy}phenyl)sulfonyl](methyl)amino]acetic acid. Electrospray Mass Spec 392.1 (M+H)+