Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9][CH2:10][C:11]([OH:28])([CH3:27])[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=2)=[O:13])[CH:6]=[CH:7][CH:8]=1.OO.[H-].[OH2:32].[Cl-].[Na+].[OH2:35]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9]([CH2:10][C:11]([OH:28])([CH3:27])[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[C:17]([C:23]([F:24])([F:25])[F:26])[CH:16]=2)=[O:13])(=[O:35])=[O:32])[CH:6]=[CH:7][CH:8]=1
Reactant: O
Reactant: COc1cccc(SCC(C)(O)C(=O)Nc2ccc(C#N)c(C(F)(F)F)c2)c1
Agent: OO
Agent: [Cl-]
Agent: [H-]
Solvent: ClCCl
Product: COc1cccc(S(=O)(=O)CC(C)(O)C(=O)Nc2ccc(C#N)c(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-(3-methoxyphenylthio)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide (29 mg, 0.07 mmol) in dichloromethane (0.18 mL) at −78° C. was added 30% hydrogen peroxide (16 μL, 0.57 mmol) followed by the slow addition of trifluoroacetic an hydride (60 μL, 0.45 mmol). The reaction was stirred at room temperature for 16 h. The reaction was diluted with dichloromethane. Cold water and brine were added, and the reaction was stirred for 20 minutes. The organic layer was separated, dried over magnesium sulfate, filtered and evaporated. Purification by column chromatography (hexane:EtOAc 50:50) yielded 19 mg of desired product. Production of PLM5 was confirmed by 1-H NMR, 13-C NMR, and mass spectral analysis.
Reaction SMILES: N#N.[Cl:3][CH2:4][C:5]1[O:6][CH:7]=[C:8]([C:10](OC)=[O:11])[N:9]=1.CC(C[AlH]CC(C)C)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1COCC1.CC(=O)OCC>[Cl:3][CH2:4][C:5]1[O:6][CH:7]=[C:8]([CH2:10][OH:11])[N:9]=1
Reactant: COC(=O)c1coc(CCl)n1
Agent: CC(C)C[AlH]CC(C)C
Agent: N#N
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCc1coc(CCl)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of methyl 2-(chloromethyl)oxazole-4-carboxylate (Organic Process Research & Development 2001, 5, 37-44) (12.50 g, 71.20 mmol) in THF (400 mL) was treated dropwise at 0° C. with DiBAL-H (242 mL of a 1.0 M solution in THF, 242.0 mmol) and the resulting solution was stirred for 1 h at 0° C. and then allowed to warm to rt. The reaction mixture was carefully poured over a Rochelle's salt solution (600 mL) and EA (250 mL) was added. The mixture was stirred for 1.5 h. The aq. layer was extracted with EA (2×250 mL) and the combined org. layers were dried over MgSO4, filtered and the solvent was removed under reduced pressure. Purification of the residue by FC (1:4 hept-EA) gave the title compound as a yellow oil: TLC: rf (1:4 hept-EA)=0.28. LC-MS-conditions 07: tR=0.39 min; [M+H]+=147.98.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH3:12])([CH3:11])[C:9]#[N:10].[OH-].[Na+].CC([OH:19])(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH3:12])([CH3:11])[C:9]([NH2:10])=[O:19]
Reactant: CC(C)(C)O
Reactant: CC(C)(C#N)c1ccccc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C(N)=O)c1ccccc1Br
Temperature: 100 °C
Reaction time: 40 h

Procedure:
A mixture of 2-(2-bromophenyl)-2-methylpropanenitrile A33 (0.377 g, 1.68 mmol), NaOH (0.135 g, 3.37 mmol) and t-BuOH (4 mL) was stirred in a sealed vessel at 100° C. for 40 hours. The reaction mixture was cooled, diluted with DCM and filtered through Celite. The filtrate solvent was removed in vacuo and the residue was purified by column chromatography (Biotage Isolera, 24 g SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound A34 as a colourless oil (0.192 g, 48%). LCMS-D: rt 3.06 min; m/z 242/244 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:10](Cl)(=[O:14])[CH2:11][CH2:12][CH3:13].N1C=CC=CC=1.O>C(Cl)Cl>[Br:1][C:2]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:10](=[O:14])[CH2:11][CH2:12][CH3:13]
Reactant: CCCC(=O)Cl
Reactant: Nc1cccc(F)c1Br
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CCCC(=O)Nc1cccc(F)c1Br
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.9 %

Procedure:
To a solution of 2-bromo-3-fluoroaniline (2.0 g, 11 mmol) in CH2Cl2 (50 mL) was added butyryl chloride (1.3 g, 13 mmol) and pyridine (1.7 g, 21 mmol) at 0° C. The mixture was stirred at room temperature for 24 h. Water (20 mL) was added and the mixture was extracted with CH2Cl2 (50 mL×3). The organic layers were dried anhydrous over Na2SO4 and evaporated under vacuum to give N-(2-bromo-3-fluorophenyl)butyramide (2.0 g, 73%), which was directly used in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4](=[NH:8])[O:5][CH2:6][CH3:7].N1C(C)=CC=CC=1C.Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4](=[N:8][C:22](=[O:23])[O:24][CH2:25][CH3:26])[O:5][CH2:6][CH3:7]
Reactant: CCOC(=N)c1ccccc1Cl
Reactant: CCOC(=O)Cl
Solvent: Cc1cccc(C)n1
Product: CCOC(=O)N=C(OCC)c1ccccc1Cl

Procedure:
A mixture of 40 g (22 mmol) of ethyl o-chlorobenzimidate and 22.2 g (21 mmol) of 2,6-lutidine in 500 ml of petroleum ether (b.p. 100°-130° C.) is treated with 27.2 g (25 mmol) of ethyl chloroformate and the whole is then heated at reflux temperature for about 16 hours. The precipitated salt is subsequently filtered off, the filtrate is evaporated under reduced pressure and the residue is recrystallized from diethyl ether. In this manner there is obtained ethyl (o-chloro-α-ethoxybenzylidene)carbamate, m.p. 65°-66° C.; 1H--NMR (CDCl3, 60 MHz): 4.02 (q,OCH2CH3), 4.58 (q, OCH2CH3); mass spectrum: 220(100).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH:21]4[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH:6]=[CH:5]1.[C:28](O)(=[O:30])[CH3:29]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:28](=[O:30])[CH3:29])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH:6]=[CH:5]1
Reactant: CC(=O)O
Reactant: NC1CCC(CCN2CCN(c3nccc4ccoc34)CC2)CC1
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4ccoc34)CC2)CC1

Procedure:
The title compound, white solid (30 mg, 41%), MS (ISP) m/z=371.3 [(M+H)+], mp 157° C., was prepared in accordance with the general method of example 6 from 4-[2-(4-furo[2,3-c]pyridin-7-yl-piperazin-1-yl)-ethyl]-cyclohexylamine trihydrochloride (intermediate C) (88 mg, 0.2 mmol) and acetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH:13][C:14](=O)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:9][N:8]=[C:7]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:6]=2[CH:28]=1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[N:13][N:12]=[C:10]3[CH2:9][N:8]=[C:7]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:6]=2[CH:28]=1
Reactant: CCCCCCC(=O)NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Solvent: c1ccncc1
Product: CCCCCCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2

Procedure:
A suspension of 4 parts of 7-chloro-2-(2-enanthylhydrazino)-5-phenyl-3H-1,4-benzodiazepine prepared in Example 31 in 20 parts by volume of pyridine is refluxed for about 3 hours. After evaporation of pyridine, water is added to the residue, whereby 8-chloro-1-hexyl-6-phenyl-4H-s-triazolo [4,3-a] [1,4] benzodiazepine is yielded as crystals. Recrystallization from aqueous acetone yields colorless flakes melting at 75° C to 78° C (sintering).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH2:9]([C:13]1[N:14]=[C:15]([Cl:22])[C:16]2[NH:21][CH:20]=[CH:19][C:17]=2[N:18]=1)[CH2:10][CH2:11][CH3:12]>C1COCC1.CC(OC)(C)C>[CH2:9]([C:13]1[N:14]=[C:15]([Cl:22])[C:16]2[NH:21][CH:20]=[C:19]([I:1])[C:17]=2[N:18]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCCCc1nc(Cl)c2[nH]ccc2n1
Reactant: O=C1CCC(=O)N1I
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CCCCc1nc(Cl)c2[nH]cc(I)c2n1
Reaction time: 0.25 h
Yield: 81.3 %

Procedure:
N-Iodosuccinimide (2.09 g, 9.29 mmol) was added portionwise to a stirred solution of 2-butyl-4-chloro-5H-pyrrolo[3,2-d]pyrimidine (1.69 g, 8.06 mmol) in THF (35 mL). The resultant mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with TBME (50 mL) then washed with aqueous sodium thiosulphate solution (50 mL) then saturated aqueous sodium chloride solution (20 mL). The organic phase was dried (Na2SO4), filtered and evaporated. The sample was dissolved in dichloromethane and purified by chromatography on silica using a gradient of 0-100% dichloromethane-cyclohexane over 30 minutes followed by a gradient of 0-100% TBME-cyclohexane followed by 0-20% methanol over 15 minutes. The appropriate fractions were identified by LC-MS then combined and evaporated in vacuo to give the title compound as a yellow solid (2.2 g).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([CH2:20][CH2:21][C:22]#[N:23])[CH2:16][CH2:15]2)=[C:6]2[S:12][CH:11]=[CH:10][C:7]2=[N:8][CH:9]=1)([O-])=O>[Pd].CO>[NH2:1][C:4]1[C:5]([NH:13][C@H:14]2[CH2:15][CH2:16][C@H:17]([CH2:20][CH2:21][C:22]#[N:23])[CH2:18][CH2:19]2)=[C:6]2[S:12][CH:11]=[CH:10][C:7]2=[N:8][CH:9]=1
Reactant: N#CCC[C@H]1CC[C@H](Nc2c([N+](=O)[O-])cnc3ccsc23)CC1
Agent: [Pd]
Solvent: CO
Product: N#CCC[C@H]1CC[C@H](Nc2c(N)cnc3ccsc23)CC1
Reaction time: 2 h

Procedure:
A mixture of 3-{trans-4-[(6-nitrothieno[3,2-b]pyridin-7-yl)amino]cyclohexyl}propanenitrile (63 mg, 0.19 mmol) and 10% palladium on carbon (20 mg) in methanol (1 mL) was hydrogenated under balloon pressure of H2 at room temperature for 2 h. The reaction mixture was filtered and the filtrate was concentrated to give the desired product (48 mg, 84%), which was used directly in the next step. LCMS calculated for C16H21N4S (M+H)+: m/z=301.1. Found: 301.1.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1[C:21]2[N:20]=[C:19]([S:22][CH2:23][C:24]3[C:29]([CH3:30])=[C:28]([CH3:31])[CH:27]=[CH:26][N:25]=3)[NH:18][C:17]=2[CH:16]=[C:15]([CH3:32])[C:14]=1[O:33][CH3:34].[OH-].[Na+]>C(Cl)Cl.O>[CH3:12][C:13]1[C:21]2[N:20]=[C:19]([S:22]([CH2:23][C:24]3[C:29]([CH3:30])=[C:28]([CH3:31])[CH:27]=[CH:26][N:25]=3)=[O:9])[NH:18][C:17]=2[CH:16]=[C:15]([CH3:32])[C:14]=1[O:33][CH3:34]
Reactant: COc1c(C)cc2[nH]c(SCc3nccc(C)c3C)nc2c1C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COc1c(C)cc2[nH]c(S(=O)Cc3nccc(C)c3C)nc2c1C
Temperature: -10 °C
Reaction time: 0.08 h
Yield: 32 %

Procedure:
m-Chloroperbenzoic acid, 91% (0.53 g, 0.0028 mol) dissolved in CH2Cl2 (25 ml) and cooled to -10° C. was added under stirring to 4,6-dimethyl-5-methoxy-2-[[(3,4-dimethyl-2-pyridinyl)methyl]thio]-1H-benzimidazole (0.91 g, 0.0028 mol) dissolved in CH2CI2 (50 ml) maintaining the temperature at -5° C. Stirring was continued at -5° C. for 5 min and then NaOH (0.34 g, 0.0085 mol) dissolved in water (25 ml) was added under vigorous stirring. The two phases were separated and the aqueous phase was washed with CH2Cl2 (10 ml). More CH2Cl2 (50 ml) was added to the aqueous phase, the pH was adjusted to 9.5 by adding 2M HCl and after stirring the phases were separated. The organic phase was dried (Na2SO4), filtered and the solvent was evaporated off giving an oil which was crystallized from CH3CN (15 ml) yielding the desired product (0.3 g, 32%), m.p. 161° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[C:17]([NH:22][CH2:23][C:24]4(C)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[N:16]=3)[C:12]([Cl:31])=[CH:11][N:10]=2)[CH2:4][CH2:3]1.[CH3:32][C:33]1([CH:38]=O)[O:37][CH2:36][CH2:35][O:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.O>[Cl:31][C:12]1[C:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([NH:22][CH2:23][CH:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[N:16]=2)=[CH:14][C:9]([NH:8][C@H:5]2[CH2:6][CH2:7][C@H:2]([NH:1][CH2:32][C:33]3([CH3:38])[O:37][CH2:36][CH2:35][O:34]3)[CH2:3][CH2:4]2)=[N:10][CH:11]=1
Reactant: CC1(C=O)OCCO1
Reactant: CC1(CNc2nc(-c3cc(N[C@H]4CC[C@H](N)CC4)ncc3Cl)ccc2F)CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC1(CN[C@H]2CC[C@H](Nc3cc(-c4ccc(F)c(NCC5CCOCC5)n4)c(Cl)cn3)CC2)OCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N2′-(trans-4-aminocyclohexyl)-5′-chloro-5-fluoro-N6-((4-methyltetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine (21 mg, 0.048 mmol) in DCM (1.0 ml) was added 2-methyl-1,3-dioxolane-2-carbaldehyde (synthesized following the procedure reported in Org. Lett., 2009, 11, 3542-3545), sodium triacetoxyborohydride (20.51 mg, 0.097 mmol). The reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed sequentially with water and brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by reverse phase HPLC and lyophilized to give 12 mg off-white powder of the title compound as its TFA salt. LCMS (m/z): 534.1 (MH+), retention time=0.62 min.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[NH:19][N:18]=3)=[CH:15][N:16]=[C:11]2[N:10]([C:30]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CS(O[CH2:54][CH2:55][CH:56]1[CH2:60][O:59][C:58]([CH3:62])([CH3:61])[O:57]1)(=O)=O.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:54][CH2:55][CH:56]4[CH2:60][O:59][C:58]([CH3:62])([CH3:61])[O:57]4)[N:18]=3)=[CH:15][N:16]=[C:11]2[N:10]([C:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3n[nH]c4ccc(OC(F)F)cc34)nc12
Reactant: CC1(C)OCC(CCOS(C)(=O)=O)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3nn(CCC4COC(C)(C)O4)c4ccc(OC(F)F)cc34)nc12
Temperature: 65 °C

Procedure:
To a solution of N-tert-butyl-2-(5-(difluoromethoxy)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (100 mg, 0.156 mmol) in DMF (5 mL) was added 2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl methanesulfonate (42 mg, 0.187 mmol) followed by K2CO3 (65 mg, 0.468 mmol). The mixture was heated at 65° C. for 2 hours. After cooling to room temperature, the mixture was poured into water, filtered, the filter cake washed with water and dried to give N-tert-butyl-2-(5-(difluoromethoxy)-1-(2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide. The crude product was used in the next step without purification. MS: (M+H)+=771.0.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][C:12]([NH2:14])=[O:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C[O:16][C:17](=O)[C:18]([C:20]1[C:30]2=[C:31]3[C:26](=[CH:27][CH:28]=[CH:29]2)[CH2:25][CH2:24][CH:23]([CH2:32][OH:33])[N:22]3[CH:21]=1)=O>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[C:12](=[O:13])[NH:14][C:17](=[O:16])[C:18]=3[C:20]3[C:30]4=[C:31]5[C:26](=[CH:27][CH:28]=[CH:29]4)[CH2:25][CH2:24][CH:23]([CH2:32][OH:33])[N:22]5[CH:21]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: NC(=O)Cc1c[nH]c2cc(F)ccc12
Reactant: COC(=O)C(=O)c1cn2c3c(cccc13)CCC2CO
Product: O=C1NC(=O)C(c2cn3c4c(cccc24)CCC3CO)=C1c1c[nH]c2cc(F)ccc12

Procedure:
Beginning with 2-(6-fluoro-1H-indol-3-yl)acetamide and (4-hydroxymethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)oxoacetic acid methyl ester, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([B:6]2[O:14][C:11]([CH3:13])([CH3:12])[C:8]([CH3:10])([CH3:9])[O:7]2)[CH:3]=[N:2]1.Br[CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1>>[O:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH:17]1[CH2:16][N:2]1[CH:3]=[C:4]([B:6]2[O:7][C:8]([CH3:9])([CH3:10])[C:11]([CH3:13])([CH3:12])[O:14]2)[CH:5]=[N:1]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: BrCC1CCCCO1
Product: CC1(C)OB(c2cnn(CC3CCCCO3)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The title compound was prepared from pyrazole-4-boronic acid pinacol ester and 2-(bromomethyl)tetrahydro-2H-pyran according to Method AC (stirred in a sealed vial at r.t. for 16 h, then heating to 80° C. for 4 h before addition of further 2-(bromomethyl)-tetrahydro-2H-pyran, and heating to 80° C. for a further 2 days) and was isolated as a brown gum (75%). LCMS (ES+) 293 (M+H)+, RT 3.41 minutes (Method 1).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=[O:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[Li]C(C)(C)C.[B:18](OC(C)C)([O:23]C(C)C)[O:19]C(C)C.[Cl-].[NH4+].S([O-])(O)(=O)=O.[K+]>C1COCC1>[OH:19][B:18]([OH:23])[C:2]1[S:1][C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=[O:11])=[CH:9][C:4]=2[CH:3]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: O=C(O)c1ccc2sccc2c1
Agent: O=S(=O)([O-])O
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(O)c1ccc2sc(B(O)O)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Benzothiophene-5-carboxylic acid (2 g, 11.2 mmol, 1 eq) was dissolved in anhydrous THF (50 mL). To the solution was added dropwise tert-BuLi petane solution (1.7M, 20 mL, 3 eq) at −78° C. for 5 minutes under nitrogen atmosphere. The reaction mixture was allowed to warm to room temperature, stirred for 30 minutes, and cooled to −78° C. again, followed by an addition of triisopropyl borate (3.97 mL, 1.5 eq). The reaction was then allowed to warm to room temperature and stirred at that temperature for one hour. To the reaction mixture was added saturated aqueous ammonium chloride (50 mL) and 10% aqueous potassium hydrogensulfate solution (50 mL) to adjust pH to 2. After the mixture was stirred at room temperature for 30 minutes, it was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The upper solution was decanted, concentrated, and the residue was suspended in Hexane/CHCl3/MeOH (40:4:1). The solid was filtered, rinsed with hexane. 2-(dihydroxyboryl)-1-benzothiophene-5-carboxylic acid was obtained as a grayish solid in amount of 1.325 g (53%).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[CH2:21][CH2:20][N:10]3[C:11]4[N:19]=[CH:18][CH:17]=[CH:16][C:12]=4[NH:13][CH2:14][CH2:15][CH:9]3[CH2:8]2)=[CH:4][CH:3]=1.[CH:24]1([C:28](Cl)=[O:29])[CH2:27][CH2:26][CH2:25]1>ClCCl>[CH:24]1([C:28]([N:13]2[CH2:14][CH2:15][CH:9]3[CH2:8][N:7]([CH2:6][C:5]4[CH:22]=[CH:23][C:2]([F:1])=[CH:3][CH:4]=4)[CH2:21][CH2:20][N:10]3[C:11]3[N:19]=[CH:18][CH:17]=[CH:16][C:12]2=3)=[O:29])[CH2:27][CH2:26][CH2:25]1
Reactant: Fc1ccc(CN2CCN3c4ncccc4NCCC3C2)cc1
Reactant: O=C(Cl)C1CCC1
Solvent: ClCCl
Product: O=C(C1CCC1)N1CCC2CN(Cc3ccc(F)cc3)CCN2c2ncccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of the product of Example 64C (97 mg, 0.31 mmol) in dichloromethane (2 mL) was added to cyclobutanecarbonyl chloride (0.048 mL, 0.42 mmol). The resulting, turbid solution was stirred at room temperature for 12 hours, and then the reaction was quenched by the addition of 20% Na2CO3 (1 mL). After 30 minutes, the mixture was made basic (pH˜9) by addition of 1 MNaOH (˜0.2 mL), diluted with water (3 mL) and extracted with CHCl3 (3×2 mL). The combined organic phases were dried over K2CO3 and concentrated: 1H NMR (300 MHz, CD3OD) δ ppm 1.58-2.02 (m, 5H), 2.06-2.44 (m, 4H), 2.68-3.26 (m, 6H), 3.42-3.65 (m, 3H), 3.96-4.47 (m, 2H), 6.82-7.11 (m, 3H), 7.17-7.58 (m, 3H), 8.08-8.32 (m, 1H); MS (DCI) m/z 395 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:12])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.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.[S:46]1[C:50]([C:51]2[N:55]3[CH2:56][CH2:57][NH:58][CH2:59][C:54]3=[N:53][N:52]=2)=[N:49][CH:48]=[N:47]1>CN(C)C=O.C(Cl)Cl>[F:1][C:2]1[C:3]([CH3:12])=[C:4]([C:5]([N:58]2[CH2:57][CH2:56][N:55]3[C:51]([C:50]4[S:46][N:47]=[CH:48][N:49]=4)=[N:52][N:53]=[C:54]3[CH2:59]2)=[O:7])[CH:8]=[CH:9][C:10]=1[F:11]
Reactant: Cc1c(C(=O)O)ccc(F)c1F
Reactant: c1nsc(-c2nnc3n2CCNC3)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c(C(=O)N2CCn3c(nnc3-c3ncns3)C2)ccc(F)c1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3,4-Difluoro-2-methylbenzoic acid (I68)(124 mg, 0.720 mmol) was dissolved in dry N,N-dimethylformamide (DMF) (4.7 mL) before treating with HATU (274 mg, 0.720 mmol) and DIPEA (0.252 mL, 1.441 mmol) and stirring for 15 mins at RT, under argon before adding 3-(1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine (I115)(100 mg, 0.480 mmol) and stirring for a further 18 hours. LCMS confirmed that the desired material was present and that no start material was left. The reaction was worked up by diluting with DCM (50 ml), washing with water (50 ml). The aqueous layer was extracted with DCM (2×30 ml). The combined extracts were washed with brine (30 ml), dried (Na2SO4), filtered and evaporated to afford a pale pink gum. The product was purified on a SNAP 50 g cartridge, eluting with 0-10% MeOH in DCM, the desired fractions were collected and the solvent was evaporated to afford a dark orange gum. Due to presence of residual DMF the crude gum product was diluted with DCM (30 ml), washed with brine (2×20 ml), dried (Na2SO4), filtered and evaporated to afford an orange foam. The foam triturated with n-hexane to afford a pale orange solid. Liquers were removed and the residue was triturated again with n-Hexane. Liquers were removed and the solid was dried overnight in the vac oven at 40° C. to afford desired product in 146 mg as a pale orange solid.
Reaction SMILES: [Cl:1][C:2]([Cl:18])=[CH:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]([Cl:16])[C:9]([O:10][CH2:11][CH2:12]O)=[C:8]([Cl:17])[CH:7]=1.CS(Cl)(=O)=O.[N-:24]=[N+:25]=[N-:26].[Na+]>C(Cl)Cl.CS(C)=O.O>[Cl:1][C:2]([Cl:18])=[CH:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]([Cl:16])[C:9]([O:10][CH2:11][CH2:12][N:24]=[N+:25]=[N-:26])=[C:8]([Cl:17])[CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: OCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CS(C)=O
Product: [N-]=[N+]=NCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.3 %

Procedure:
A mixture of 1.0 gram (0.003 mole) of 2-(4-(3,3-dichloroprop-2-enyloxy)-2,6-dichlorophenoxy)ethan-1-ol, 0.33 gram (0.0033 mole) of TEA and 0.37 gram (0.0032 mole) of methanesulfonyl chloride in 10 mL of methylene chloride was stirred at ambient temperature for two hours. The reaction mixture was diluted with 25 mL of methylene chloride and was washed first with 25 mL of water followed by 10 mL of a saturated aqueous sodium chloride solution. The organic phase was dried with magnesium sulfate, filtered and the filtrate concentrated under reduced pressure leaving an oil, which solidified upon standing. The solid was dissolved in 10 mL of DMSO to which 0.32 gram (0.005 mole) of sodium azide was added. The reaction mixture stirred at ambient temperature for about 18 hours at which time the reaction mixture was heated at 60° C. for one hour. The mixture was allowed to cool to ambient temperature, diluted with 25 mL of water and extracted with two 25 mL portions of ethyl acetate. The combined extracts were washed with 20 mL of an aqueous saturated sodium chloride solution, dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure providing 0.86 gram of the subject compound as a foam. The NMR spectrum was consistent with the proposed structure.