Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:26]=[CH:25][C:6]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:15]3[N:14]4[CH2:18][CH2:19][CH:20]([CH2:21][C:22]([OH:24])=[O:23])[C:13]4=[CH:12][C:11]=3[CH:10]=2)=[CH:5][C:4]=1[C:27]([F:30])([F:29])[F:28])#[N:2].[Li+].[OH-:32].Cl>O1CCOCC1>[C:1]([C:3]1[CH:26]=[CH:25][C:6]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:15]3[N:14]4[CH2:18][CH2:19][CH:20]([CH2:21][C:22]([OH:24])=[O:23])[C:13]4=[CH:12][C:11]=3[CH:10]=2)=[CH:5][C:4]=1[C:27]([F:29])([F:30])[F:28])(=[O:32])[NH2:2]
Reactant: N#Cc1ccc(COc2ccc3c(c2)cc2n3CCC2CC(=O)O)cc1C(F)(F)F
Reactant: [OH-]
Agent: Cl
Agent: [Li+]
Solvent: C1COCCO1
Product: NC(=O)c1ccc(COc2ccc3c(c2)cc2n3CCC2CC(=O)O)cc1C(F)(F)F
Temperature: 50 °C
Reaction time: 48 h

Procedure:
To a solution of 2-(7-(4-cyano-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid (15.0 mg, 0.036 mmol) in dioxane (1 mL) was added 1 M LiOH (aq) (3.0 mL). The reaction was stirred at 50° C. for 48 h. 1 M HCl (aq) was added until pH=3. The mixture was extracted with EtOAc. The organic extract was dried over MgSO4 and purified by preparative HPLC/MS to give the title compound as a solid (3.1 mg). LCMS m/z=433.4 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.14-2.27 (m, 1H), 2.55 (dd, J=16.23, 8.02 Hz, 1H), 2.63-2.72 (m, 1H), 2.72-2.83 (m, 1H), 3.52-3.63 (m, 1H), 3.90-4.00 (m, 1H), 4.04-4.15 (m, 1H), 5.21 (s, 2H), 6.01 (s, 1H), 6.78 (dd, J=8.72, 2.40 Hz, 1H), 7.07 (d, J=2.27 Hz, 1H), 7.20 (d, J=8.72 Hz, 1H), 7.49-7.60 (m, 2H), 7.75 (d, J=7.83 Hz, 1H), 7.82 (s, 1H), 7.91 (s, 1H), 12.28 (bs, 1H).
Reaction SMILES: COC[O:4][C:5](=[O:14])[C:6]([CH3:13])([CH3:12])[CH2:7][O:8][CH2:9][O:10][CH3:11].CO.[OH-].[Na+].Cl>C(OCC)C>[CH3:11][O:10][CH2:9][O:8][CH2:7][C:6]([CH3:13])([CH3:12])[C:5]([OH:14])=[O:4]
Reactant: COCOCC(C)(C)C(=O)OCOC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Product: COCOCC(C)(C)C(=O)O
Temperature: 25 °C
Reaction time: 96 h
Yield: 111.7 %

Procedure:
To a mixture of 3-methoxymethoxy-2,2-dimethylpropionic acid methoxymethyl ester (16.5 g) and methanol (30 mL), 5 N aqueous sodium hydroxide solution (30 mL) was added, and the resulting mixture was stirred at room temperature for 4 days. Ice was added to the mixture, and at 0° C., 5 N hydrochloric acid (35 mL) and diethyl ether (300 mL) were added thereto. The mixture was shaken and the organic layer was collected. The organic layer was washed with saturated aqueous sodium chloride solution (100 mL) and dried over anhydrous magnesium sulfate. The resulting mixture was filtered and the obtained filtrate was concentrated under reduced pressure to obtain the captioned compound (14.5 g).
Reaction SMILES: [CH3:1][C:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:27])[CH2:10][CH2:11][CH:12]([OH:26])[CH:13]([CH3:25])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:24])[CH2:18][CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])=[CH:3][CH2:4][OH:5].[C:28](OC(=O)C)(=[O:30])[CH3:29]>N1C=CC=CC=1>[C:28]([O:5][CH2:4][CH:3]=[C:2]([CH3:1])[CH2:6][CH2:7][CH:8]=[C:9]([CH3:27])[CH2:10][CH2:11][CH:12]([OH:26])[CH:13]([CH3:25])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:24])[CH2:18][CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])(=[O:30])[CH3:29]
Reactant: CC(C)=CCCC(C)=CCCC(C)C(O)CCC(C)=CCCC(C)=CCO
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCC=C(C)CCC=C(C)CCC(O)C(C)CCC=C(C)CCC=C(C)C
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 74.4 %

Procedure:
To a mixture of 3,7,11,15,19-pentamethyl-2,6,14,18-eicosatetraene-1,10-diol (3.75 g) in pyridine (1 ml) while cooling with ice, acetic anhydride (1.53 g) is dropwise added in 15 minutes, and then stirring is continued for 40 minutes. The reaction mixture is poured into ice water and extracted with ether. The ether extract is washed with water, dried and evaporated. The residue (3.9 g) is purified by chromatography on silica gel (40 g) using benzene to give 1-acetoxy-3,7,11,15,19-pentamethyl-2,6,14,18-eicosatetraen-10-ol (3.1 g).
Reaction SMILES: [CH3:1][S-:2].[Na+].[O:4]=[S:5]1(=[O:35])[C:11]2[CH:12]=[C:13]([O:17][CH3:18])[C:14](Br)=[CH:15][C:10]=2[N:9]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[C:8](=[O:26])[C:7]([CH2:31][CH2:32][CH2:33][CH3:34])([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:6]1>CN(C=O)C>[O:4]=[S:5]1(=[O:35])[C:11]2[CH:12]=[C:13]([O:17][CH3:18])[C:14]([S:2][CH3:1])=[CH:15][C:10]=2[N:9]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[C:8](=[O:26])[C:7]([CH2:31][CH2:32][CH2:33][CH3:34])([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:6]1
Reactant: CCCCC1(CCCC)CS(=O)(=O)c2cc(OC)c(Br)cc2N(c2ccc(Cl)cc2)C1=O
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCC1(CCCC)CS(=O)(=O)c2cc(OC)c(SC)cc2N(c2ccc(Cl)cc2)C1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 96.4 %

Procedure:
Sodium methanethiolate (0.43 g, 6.08 mmol) was added to a solution of 1,1-dioxo-3,3-dibutyl-4-oxo-5-(4-chlorophenyl)-7-bromo-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 96; 0.66 g, 1.22 mmol) in anhydrous DMF (11 ml) under nitrogen. The reaction mixture was stirred at room temperature for 72 hours. The solvent was evaporated under reduced pressure and the residue was extracted with trichloromethane/water. The organic layer was separated, washed with brine, dried and evaporated under reduced pressure. The crude product was purified by column chromatography using DCM as eluent to give the title compound 0.6 g (96%). NMR (500 MHz) 0.80–1.0 (m, 6H), 1.10–1.6 (m, 10H), 1.70–2.0 (m, 2H), 2.28 (s, 3H), 3.37–3.70 (m, 2H), 4.04 (s, 3H), 6.65 (s, 1H), 7.25–7.30 (m, 2H), 7.35–7.42 (m, 3H); m/z 510.4.
Reaction SMILES: Cl[CH:2]([O:7][CH2:8][CH:9]=[CH2:10])[CH2:3][CH2:4][CH2:5][CH3:6].[NH:11]1[CH:15]=[N:14][CH:13]=[N:12]1>>[N:11]1([CH:2]([O:7][CH2:8][CH:9]=[CH2:10])[CH2:3][CH2:4][CH2:5][CH3:6])[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: c1nc[nH]n1
Reactant: C=CCOC(Cl)CCCC
Product: C=CCOC(CCCC)n1cncn1

Procedure:
Following the procedure of Example 2, allyl 1-chloropentyl ether (3 g) and 1,2,4-triazole (3.8 g) were reacted to give the title compound as a colourless oil, which was purified by distillation.
Reaction SMILES: [CH3:1][C:2](=[CH2:30])[C:3]([N:5]1[C@@:9]2([CH2:13][CH2:12][N:11]([C@@H:14]([C:19]([O:21]CC3C=CC=CC=3)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]2=[O:29])[CH2:8][CH2:7][CH2:6]1)=[O:4].[OH-].[Na+].O>CO>[CH3:30][C:2](=[CH2:1])[C:3]([N:5]1[C@@:9]2([CH2:13][CH2:12][N:11]([C@@H:14]([C:19]([OH:21])=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]2=[O:29])[CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: C=C(C)C(=O)N1CCC[C@]12CCN([C@H](CC(C)C)C(=O)OCc1ccccc1)C2=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=C(C)C(=O)N1CCC[C@]12CCN([C@H](CC(C)C)C(=O)O)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
To a solution of 15 (65 mg, 0.16 mmol) in methanol (2.5 ml) were added aq. NaOH (1.6 ml, 1N) and H2O (1.6 ml) and the mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated at reduced pressure, and the residue was partitioned between H2O (20 ml) and DCM (20 ml). The aqueous phase was acidified to pH=2 with aq HCl (10 ml, 0.1 N) and extracted with DCM (3×20 ml). The combined organic phases were washed with brine (25 ml), dried (Na2SO4) and concentrated at reduced pressure to afford 18 (44 mg, 85%) as a white solid. HPLC [Column Novapack C18 (Waters), 3.9×150 mm, Φ=1 ml/min, λ=214 nm, eluent: ACN/0.05% TFA, (25/75)] Rt=6.38 min.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])[C:6]([OH:8])=O.Cl.Cl.[CH3:23][O:24][C:25](=[O:34])[C@H:26]([CH2:28][C:29]1[N:33]=[CH:32][NH:31][CH:30]=1)[NH2:27].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[CH3:23][O:24][C:25](=[O:34])[C@H:26]([CH2:28][C:29]1[N:33]=[CH:32][NH:31][CH:30]=1)[NH:27][C:6](=[O:8])[CH:5]([CH2:4][C:3]1[CH:17]=[CH:18][CH:19]=[CH:20][C:2]=1[F:1])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16]
Reactant: O=C(O)C(Cc1ccccc1F)Cc1ccccc1F
Reactant: COC(=O)[C@@H](N)Cc1c[nH]cn1
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)C(Cc1ccccc1F)Cc1ccccc1F
Yield: 71.8 %

Procedure:
In 30 ml of N,N-dimethylformamide were suspended 1.8 g of bis(2-fluorobenzyl)acetic acid and 1.9 g of L-histidine methyl ester dihydrochloride, and to the suspension were successively added 1.68 ml of diphenylphosphoryl azide and 2.9 ml of triethylamine with stirring under ice-cooling. The mixture was still stirred for 16 hours. The reaction mixture was evaporated under reduced pressure, and to the residue was added a 5% aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=1) to obtain 2.0 g of N- bis(2-fluorobenzyl)acetyl-L-histidine methyl ester having an Rf1 value of 0.76 as a white powder.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH2:7][S:8][CH3:9])=[C:4]([C:10]([O:12][CH3:13])=[O:11])[CH:3]=1.[F:14][C:15]([F:26])([F:25])[C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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>[CH3:9][S:8][CH2:7][C:5]1[O:6][C:2]([C:19]2[CH:20]=[CH:21][C:16]([C:15]([F:26])([F:25])[F:14])=[CH:17][CH:18]=2)=[CH:3][C:4]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1cc(Br)oc1CSC
Reactant: OB(O)c1ccc(C(F)(F)F)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: O
Solvent: COCCOC
Product: COC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)oc1CSC
Reaction time: 8 h
Yield: 75.7 %

Procedure:
A mixture of methyl 5-bromo-2-[(methylsulfanyl)methyl]furan-3-carboxylate (5.3 g), 4-(trifluoromethyl)phenylboronic acid (4.6 g), tetrakis(triphenylphosphine)palladium(0) (1.2 g), 2N aqueous sodium carbonate solution (24 mL) and 1,2-dimethoxyethane (50 mL) was stirred overnight with refluxing under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 20% ethyl acetate/hexane) to give the title compound (5.0 g, 75%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([CH:9]=C)=[CH:6][C:7]=1[CH3:8].C[N+]1([O-])CC[O:15]CC1>CC#N.O.O=[Os](=O)(=O)=O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([CH:9]=[O:15])=[CH:6][C:7]=1[CH3:8]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=Cc1cc(C)c(Cl)nn1
Agent: O=[Os](=O)(=O)=O
Solvent: CC#N
Solvent: O
Product: Cc1cc(C=O)nnc1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 89.9 %

Procedure:
To a white suspension of 3-chloro-6-ethenyl-4-methylpyridazine (34.1 mg, 0.221 mmol), NaIO4 (189 mg, 0.882 mmol), 4-methylmorpholine N-oxide (28.4 mg, 0.243 mmol) in CH3CN (3 mL) and water (1.5 mL) was added OsO4 (0.013 mL, 2.206 μmol), and the mixture was stirred at room temperature for 3 days. The reaction was monitored by LCMS and starting material was observed. The reaction mixture was heated at 60° C. overnight and no more starting material was observed. Solvents were evaporated in vacuo and the residue was partitioned between EtOAc and water. The aqueous layer was extracted with additional EtOAc. The combined organic phases were washed with water, dried with over anhydrous MgSO4, filtered and concentrated under reduced pressure to give 31.1 mg of the title compound as a white solid. It will be used in the next step without prior purification.
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].Cl.Cl.[NH:25]1[CH2:65][CH2:64][CH2:63][C@H:26]1[C:27]([NH:29][C@H:30]([C:42]([N:44]1[CH2:62][CH2:61][CH2:60][C@H:45]1[C:46]([NH:48][C@H:49]([C:57]([NH2:59])=[O:58])[CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:47])=[O:43])[CH2:31][C:32](=[O:41])[O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:28].CN1CCOCC1.C(P(=O)(OCC)OCC)#N>CC(N(C)C)=O>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([N:25]1[CH2:65][CH2:64][CH2:63][C@H:26]1[C:27]([NH:29][C@H:30]([C:42]([N:44]1[CH2:62][CH2:61][CH2:60][C@H:45]1[C:46]([NH:48][C@H:49]([C:57]([NH2:59])=[O:58])[CH2:50][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)=[O:47])=[O:43])[CH2:31][C:32](=[O:41])[O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:28])=[O:12])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8]
Reactant: N=C(N)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)[C@@H]1CCCN1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CC(=O)N(C)C
Product: N=C(N)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(N)=O
Reaction time: 4 h

Procedure:
To a stirred solution of Z-Arg.HCl (5.17 g, 15 mmoles) in dimethylacetamide (25 mL) at 25° C. was added a solution of HCl.Pro-Asp(OBzl)-Pro-Phe-NH2 and N-methylmorpholine (1.65 mL, 15 mmoles) in dimethylacetamide (25 mL). To the resulting solution, diethyl cyanophosphonate (2.45 g, 15 mmoles) and N-methylmorpholine (1.65 mL, 15 mmoles) were added and the mixture stirred for 4 hours. The reaction was quenched by the addition of 10% aqueous acetic acid (10 mL) and the solvents were removed on a rotary evaporator under reduced pressure. The resulting solid was triturated with 10% potassium carbonate and then with water and filtered.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:37])[C:7](=[CH2:36])[CH2:8][C@H:9]([OH:35])[C@@H:10]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:11][C@@H:12]([CH:24]([CH3:26])[CH3:25])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH3:4]>O1CCCC1.[Pd]>[CH2:1]([NH:5][C:6](=[O:37])[CH:7]([CH3:36])[CH2:8][C@H:9]([OH:35])[C@@H:10]([NH:27][C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH2:11][C@@H:12]([CH:24]([CH3:25])[CH3:26])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C=C(C[C@H](O)[C@H](C[C@H](Cc1ccc(C(C)(C)C)cc1)C(C)C)NC(=O)OC(C)(C)C)C(=O)NCCCC
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCNC(=O)C(C)C[C@H](O)[C@H](C[C@H](Cc1ccc(C(C)(C)C)cc1)C(C)C)NC(=O)OC(C)(C)C

Procedure:
150 mg of N-tert-butoxycarbonyl-2-methylene-4-(S)-hydroxy-5-(S)-amino-7(S)-isopropyl-8-(p-tert-butyl-phenyl)-octanoic acid (N-butyl)amide (diastereoisomer I) are hydrogenated in the presence of 150 mg of 10% Pd/C in 20 ml of tetrahydrofuran for 2 hours at room temperature and under normal pressure. The reaction mixtures is filtered and concentrated by evaporation. The residue is purified by means of FC (50 g of silica gel, dichloromethane/diethyl ether=8:2). The title compound is obtained in the form of a diastereoisomeric mixture: Rf (dichloromethane/diethyl ether=8:2)=0.18.
Reaction SMILES: C([Li])(C)(C)C.CCCCC.Br[C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH2:20][CH3:21])=[N:16][CH:17]=1.[C:22]([Si:26]([CH3:38])([CH3:37])[O:27][CH2:28][CH:29]=[N:30][S@@:31]([C:33]([CH3:36])([CH3:35])[CH3:34])=[O:32])([CH3:25])([CH3:24])[CH3:23]>C1COCC1>[C:22]([Si:26]([CH3:38])([CH3:37])[O:27][CH2:28][C@H:29]([NH:30][S@@:31]([C:33]([CH3:36])([CH3:35])[CH3:34])=[O:32])[C:12]1[CH:17]=[N:16][C:15]([O:18][CH2:19][CH2:20][CH3:21])=[CH:14][CH:13]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CCCOc1ccc(Br)cn1
Reactant: CC(C)(C)[S@@](=O)N=CCO[Si](C)(C)C(C)(C)C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCCOc1ccc([C@H](CO[Si](C)(C)C(C)(C)C)N[S@](=O)C(C)(C)C)cn1
Reaction time: 0.5 h

Procedure:
A 1.7 M solution of tert-butyllithium in pentane (15.2 mL, 25.8 mmol) was added drop wise to a stirring solution of 5-bromo-2-propoxypyridine IM3 (2.54 g, 11.8 mmol) dissolved in dry THF (29.4 mL) at −78° C. under Ar. The solution was subsequently stirred at this temperature for 30 min. A solution of (R)-2-methyl-propane-2-sulfinic acid [2-(tert-butyl-dimethyl-silanyloxy)ethylidene]-amide IM49 (3.26 g, 11.8 mmol) in dry THF (15 mL) was then added drop wise at −78° C. and the solution was stirred at this temperature for 30 min. The cooling bath was removed and the mixture was allowed to reach room temperature overnight. The mixture was quenched with saturated aqueous NH4Cl solution (75 mL) and EtOAc (150 mL). The phases were separated and the organic layer was washed with brine and then dried over MgSO4. Flash chromatography (silica, 10-100% EtOAc in heptanes) gave (R)-2-Methyl-propane-2-sulfinic acid [(R)-2-(tert-butyl-dimethyl-silanyloxy)-1-(6-propoxy-pyridin-3-yl)-ethyl]amide, the fastest eluding isomer, as a clear oil (2.33 g, 48%) sufficiently pure for the next step. Diastereomeric excess >95% based on 1H NMR.
Reaction SMILES: [C:1]([C:5]([NH:7][C@@H:8]([C@@H:12]([C:14]1[O:18][N:17]=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][C:20]=2[Cl:29])[N:15]=1)[CH3:13])[C:9](O)=[O:10])=[O:6])([CH3:4])([CH3:3])[CH3:2].[NH:30]1[CH2:37][CH2:36][CH2:35][C@H:31]1[C:32]([NH2:34])=[O:33].C1C=NC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[C:1]([C:5]([NH:7][C@@H:8]([C@@H:12]([C:14]1[O:18][N:17]=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][C:20]=2[Cl:29])[N:15]=1)[CH3:13])[C:9]([N:30]1[CH2:37][CH2:36][CH2:35][C@H:31]1[C:32]([NH2:34])=[O:33])=[O:10])=[O:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H](c1nc(-c2ccc(S(C)(=O)=O)cc2Cl)no1)[C@H](NC(=O)C(C)(C)C)C(=O)O
Reactant: NC(=O)[C@@H]1CCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](c1nc(-c2ccc(S(C)(=O)=O)cc2Cl)no1)[C@H](NC(=O)C(C)(C)C)C(=O)N1CCC[C@H]1C(N)=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To the crude acid from Step D (0.15 g, 0.33 mmol) in 5 mL of dichloromethane was added L-prolineamide (0.057 g, 0.49 mmol), HOAt (0.090 g, 0.66 mmol), N,N-diisopropylethylamine (0.17 mL, 0.99 mmol) and HATU (0.25 g, 0.66 mmol). After stirring at room temperature for 12 h, the reaction was diluted with dichloromethane. The organic phase was washed sequentially with two portions of 0.5N aqueous sodium bicarbonate solution and saturated aqueous brine, dried over sodium sulfate, and evaporated in vacuo. Purification by HPLC (YMC Pro-C18 column, gradient elution, 10-90% acetonitrile/water with 0.1% TFA) afforded the title compound. LC/MS 556.2 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][F:4].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[C:15]3[N:19]([C:20](=[O:22])[CH:21]=2)[C:18]2[CH:23]=[CH:24][CH:25]=[CH:26][C:17]=2[NH:16]3)=[CH:9][CH:8]=1>>[F:4][CH2:3][CH2:2][N:16]1[C:17]2[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=2[N:19]2[C:20](=[O:22])[CH:21]=[C:13]([C:10]3[CH:9]=[CH:8][C:7]([O:6][CH3:5])=[CH:12][CH:11]=3)[CH:14]=[C:15]12
Reactant: COc1ccc(-c2cc(=O)n3c(c2)[nH]c2ccccc23)cc1
Reactant: FCCBr
Product: COc1ccc(-c2cc(=O)n3c4ccccc4n(CCF)c3c2)cc1

Procedure:
General experimental procedure (E) for N-alkylation reaction with 1-bromo-2-fluoroethane was followed. Reaction was performed on a 10.0 mg scale of 3-(4-methoxyphenyl)-1-oxo-1H,5H-pyrido[1,2-a]benzimidazole. Isolated 3.8 mg (33%) of T626 as a white solid. 1H NMR (CDCl3): δ 8.84 (1H, d, J=8.0 Hz), 7.62 (2H, m), 7.45 (1H, m), 7.31 (2H, m), 6.97 (2H, m), 6.54 (1H, s), 6.28 (1H, s), 4.90 (1H, t, J=4.8 Hz), 4.79 (1H, t, J=4.8 Hz), 4.52 (1H, t, J=4.8 Hz), 4.46 (1H, t, J=4.8 Hz), 3.84 (3H, s); MS: 337 (M+H+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([C:21]([NH:23][CH2:24][C:25]3[C:26](=[O:33])[NH:27][C:28]([CH3:32])=[CH:29][C:30]=3[CH3:31])=[O:22])[C:12]3[CH:17]=[N:16][N:15]([CH:18]([CH3:20])[CH3:19])[C:13]=3[N:14]=2)=[CH:5][CH:4]=1.[CH3:34][N:35]([CH3:41])[CH2:36][CH2:37][CH2:38][NH:39][CH3:40]>CN(C=O)C>[CH3:31][C:30]1[CH:29]=[C:28]([CH3:32])[NH:27][C:26](=[O:33])[C:25]=1[CH2:24][NH:23][C:21]([C:11]1[C:12]2[CH:17]=[N:16][N:15]([CH:18]([CH3:20])[CH3:19])[C:13]=2[N:14]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([CH2:2][N:39]([CH2:38][CH2:37][CH2:36][N:35]([CH3:41])[CH3:34])[CH3:40])=[CH:8][CH:7]=2)[CH:10]=1)=[O:22]
Reactant: CNCCCN(C)C
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CBr)cc3)nc3c2cnn3C(C)C)c(=O)[nH]1
Solvent: CN(C)C=O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN(C)CCCN(C)C)cc3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
6-(4-(Bromomethyl)phenyl)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1 equiv.) was suspended in DMF and N1,N1,N3-trimethylpropane-1,3-diamine (5 equiv.) was added to it. The reaction mixture was stirred at room temperature for overnight. On completion of reaction, solvent was removed under reduced pressure and residue was purified by prep. HPLC chromatography to provide the desired compound (30% yield). LCMS: 544.25 (M+1)+; HPLC: 99.96% (@ 254 nm) (Rt;4.732); 1H NMR (DMSO-d6, 400 MHz) δ 11.55 (bs, 1H), 10.14-9.80 (m, 1H), 8.95 (bs, 1H), 8.40-8.35 (m, 3H), 8.22-8.19 (m, 1H), 7.75-7.69 (m, 2H), 5.91 (s, 1H), 5.35-5.32 (m, 1H), 4.42 (d, 2H, J=3.6 Hz), 3.08-2.98 (m, 6H), 2.80-2.62 (m, 8H), 2.23 (s, 3H), 2.13 (s, 3H), 2.07 (m, 2H), 1.55 (d, 6H, J=6.4 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH:15]=[CH:14][C:13]([C:18](=[O:27])[CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)([CH3:17])[CH2:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[F:28][C:29]([Si](C)(C)C)([F:31])[F:30].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[F:28][C:29]([F:31])([F:30])[C:18]([C:13]1([CH3:17])[CH:14]=[CH:15][C:16]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[N:9]=[CH:10][C:11]=2[CH2:12]1)([OH:27])[CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC1(C(=O)CCc2ccccc2)C=Cc2c(cnn2-c2ccc(F)cc2)C1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC1(C(O)(CCc2ccccc2)C(F)(F)F)C=Cc2c(cnn2-c2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29 %

Procedure:
To a THF (1 mL) solution of Example 202 (7 mg, 0.019 mmol) and trifluoromethyl trimethylsilane (28 μL, 6.6 eq) at 0° C. was added a 1 M THF solution of tetrabutylammonium fluoride (128 μL, 6.7 eq). The mixture was slowly warmed to room temperature overnight. HPLC showed only about 10% conversion. Additional trifluoromethyl trimethylsilane (374 μL) was added and the reaction was completed in 1 h. The mixture was concentrated and purified by reverse-phase HPLC (80 to 100% solvent B gradient) to give the title compound (2.4 mg, 29%) as a 1:1 mixture of two isomers. MS found: (M+H)+=431.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.[CH3:11][S:12](Cl)(=[O:14])=[O:13].C(N(CC)CC)C.Cl>C1(C)C=CC=CC=1>[CH3:11][S:12]([O:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1)(=[O:14])=[O:13]
Reactant: CSc1ccc(CO)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CSc1ccc(COS(C)(=O)=O)cc1
Temperature: 10 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
In a sulfonating flask, 50 g (0.32 mol) of 4-methylthiobenzyl alcohol and 46.3 g (0.32 mol) of methylsulfonyl chloride are dissolved in 250 ml of toluene and, with cooling at 10° C., 32.5 g (0.32 mol) of triethylamine are added dropwise. The reaction mixture is then heated to room temperature and stirred overnight. 400 ml of 2N hydrochloric acid are then added to the reaction solution slowly and with cooling. The phases are separated and the organic phase is washed with water, dried over MgSO4 and concentrated in a rotary evaporator. 60 g (80%) of 4-methylthiobenzyl alcohol methanesulfonate are obtained in the form of a yellow oil.