Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH3:6][Si:7]([C:10]#[CH:11])([CH3:9])[CH3:8].[CH2:12]([O:14][P:15](Cl)[O:16][CH2:17][CH3:18])[CH3:13]>O1CCCC1>[CH3:6][Si:7]([C:10]#[C:11][P:15]([O:16][CH2:17][CH3:18])[O:14][CH2:12][CH3:13])([CH3:9])[CH3:8]
Reactant: CCOP(Cl)OCC
Reactant: C#C[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOP(C#C[Si](C)(C)C)OCC
Temperature: -20 °C

Procedure:
n-Butyllithium (26.02 ml, 1.55M in hexane) was added dropwise over thirty minutes to a stirred solution of trimethylsilylacetylene (5.18 ml) in dry tetrahydrofuran (25 ml), whilst maintaining the temperature below -65° C. After twenty minutes, diethylchlorophosphite (4.71 ml) was added dropwise over twenty minutes, then stirring continued for a further ninety minutes at -65° C. The stirred mixture was allowed to warm to -20° C., quenched by dropwise addition of saturated ammonium chloride solution (10 ml), then allowed to reach room temperature, diluted with water (10 ml) and extracted with chloroform (4×25 ml). The extracts were dried over magnesium sulphate and evaporated under reduced pressure to give diethyl trimethylsilylethynylphosphonite as a brown oil (7.34 g, 83% pure by GC).
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].S(C1C=CC(C)=CC=1)(O[CH2:19][C@H:20]1[O:22][CH2:21]1)(=O)=O>CN(C)C=O>[Br:1][C:2]1[C:7]([O:8][CH2:19][CH:20]2[CH2:21][O:22]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Reactant: Oc1cccnc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1ncccc1OCC1CO1

Procedure:
To a mixture of 25.2 g (0.145 mole) of 2-bromo-3-pyridinol and 30 g (0.22 mole) of potassium carbonate in 80 mL of N,N-dimethylformamide was added 30 g (0.13 mole) of (S)-glycidyl tosylate. The mixture was heated under nitrogen at 55–60° C. for 15 hours. The solvent was then removed in vacuum and replaced with 500 mL of methylene chloride, and the solution was washed with 500 mL of water and with saturated brine, dried over sodium sulfate, filtered and concentrated in vacuum. The residue was column chromatographed on silica gel with methylene chloride as eluant to give 17 g of the (S)-enantiomer of the title compound as a white solid. 1H-NMR (CDCl3): multiplet 8.01 δ (1H); multiplet 7.22 δ (2H); doublet of doublets 4.38 δ (1H); multiplet 4.04 δ (1H); multiplet 3.40 δ (1H); multiplet 2.95 δ (1H); multiplet 2.85 δ (1H).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]([NH:11][C:12]1[NH:13][C:14]2[C:19]([C:20]=1[C:21]([NH2:23])=[O:22])=[CH:18][CH:17]=[C:16]([C:24]1[N:25](C(OC(C)(C)C)=O)[CH:26]=[CH:27][CH:28]=1)[CH:15]=2)=[O:10].[OH-].[Na+].O>ClCCl>[NH2:8][C:9]([NH:11][C:12]1[NH:13][C:14]2[C:19]([C:20]=1[C:21]([NH2:23])=[O:22])=[CH:18][CH:17]=[C:16]([C:24]1[NH:25][CH:26]=[CH:27][CH:28]=1)[CH:15]=2)=[O:10]
Reactant: CC(C)(C)OC(=O)n1cccc1-c1ccc2c(C(N)=O)c(NC(N)=O)[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)Nc1[nH]c2cc(-c3ccc[nH]3)ccc2c1C(N)=O
Reaction time: 0.5 h
Yield: 29 %

Procedure:
Trifluoroacetic acid (0.50 mL, 6.7 mmol) was added to a solution of 2-aminocarbonylamino-6-(1-tert-butoxycarbonylpyrrol-2-yl)indole-3-carboxamide (Compound 4-20, 28 mg, 0.073 mmol) in dichloromethane (0.5 mL) under ice-cooling, and the mixture was stirred for 30 minutes. 2 N Sodium hydroxide aqueous solution (3.5 mL) and water (10 mL) were added to the reaction mixture, and the whole was extracted with ethyl acetate (15 mL). The organic layer was washed with water (5 mL), brine (5 mL), and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (6.0 mg) as an off-white solid (yield 29%).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3](=O)[CH2:4][C:5](=O)[CH3:6].[C:11](#[N:15])[CH2:12][C:13]#[N:14].C[OH:17]>>[OH:17][C:11]1[N:15]=[C:5]([CH3:6])[CH:4]=[C:3]([C:2]([F:10])([F:9])[F:1])[C:12]=1[C:13]#[N:14]
Reactant: CO
Reactant: N#CCC#N
Reactant: CC(=O)CC(=O)C(F)(F)F
Product: Cc1cc(C(F)(F)F)c(C#N)c(O)n1
Yield: 40 %

Procedure:
To a solution of 1,1,1-trifluoropentane-2,4-dione (5.8 g, 37.7 mmol) in methanol (20 mL) was added malononitrile (5 g, 75 mmol) and then the mixture was heated to reflux. The mixture was maintained at the same temperature for 12 hours. The resultant mixture was cooled to room temperature, and then filtered. The solid was washed with methanol to give pure 2-hydroxy-6-methyl-4-(trifluoromethyl)nicotinonitrile (3 g, 40%). 1H NMR (300 MHz, d6-DMSO): δ 13.36 (s, 1H), 6.65 (s, 1H), 2.38 (s, 3H).
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([N+:33]([O-])=O)[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[C@@H:17]([O:21][C:22](=[O:24])[CH3:23])[C@H:16]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].O.CC(O)=O>CCOC(C)=O.[Fe]>[C:22]([O:21][C@@H:17]1[C@@H:18]([CH3:20])[CH2:19][N:14]([C:13]2[C:12]([NH2:33])=[CH:11][N:10]=[C:9]3[CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:6][CH2:7][C:8]=23)[CH2:15][C@H:16]1[NH:25][C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])(=[O:24])[CH3:23]
Reactant: CC(=O)OC1CCc2c1ncc([N+](=O)[O-])c2N1C[C@H](C)[C@@H](OC(C)=O)[C@H](NC(=O)OC(C)(C)C)C1
Agent: [Fe]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)OC1CCc2c1ncc(N)c2N1C[C@H](C)[C@@H](OC(C)=O)[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.7 %

Procedure:
A mixture of 4-{(3R,4R,5S)-4-(acetyloxy)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (0.086 g, 0.17 mmol), water (0.10 mL), AcOH (3.0 mL) and iron powder (0.200 g, 3.58 mmol) was stirred at room temperature for 3 h. The reaction mixture was diluted with EtOAc (10 mL), then filtered. The filtrate was concentrated under reduced pressure. EtOAc (20 mL) and aq. Na2CO3 (10 mL) were added to the residue and the mixture was stirred at room temperature for 30 min. The organic layer was separated, dried over Na2SO4, then filtered and concentrated under reduced pressure to give the sub-title compound (80 mg, 92%) as a brown foamy powder. LCMS calc. for C23H35N4O6 (M+H)+: m/z=463.3. Found: 463.3.
Reaction SMILES: C(OC[C@H]1OC(OC)(CO)[C@@H](O)C1)(=O)C1C=CC=CC=1.C(Cl)(=O)C1C=CC=CC=1.[C:30]([O:38][CH2:39][C@@:40]1([O:47][C@H:46]([CH2:48][O:49][C:50](=[O:57])[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH2:45][C@@H:43]1[OH:44])[O:41][CH3:42])(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(OC[C@]1(O[C@H](COC(=O)C2C=CC=CC=2)C[C@@H]1O)OC)(=O)C1C=CC=CC=1>ClCCl.N1C=CC=CC=1>[C:30]([O:38][CH2:39][C:40]1([O:47][C@H:46]([CH2:48][O:49][C:50](=[O:57])[C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH2:45][C@@H:43]1[OH:44])[O:41][CH3:42])(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CO[C@@]1(COC(=O)c2ccccc2)O[C@H](COC(=O)c2ccccc2)C[C@@H]1O
Agent: COC1(CO)O[C@H](COC(=O)c2ccccc2)C[C@@H]1O
Agent: CO[C@]1(COC(=O)c2ccccc2)O[C@H](COC(=O)c2ccccc2)C[C@@H]1O
Solvent: ClCCl
Solvent: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: COC1(COC(=O)c2ccccc2)O[C@H](COC(=O)c2ccccc2)C[C@@H]1O
Temperature: -40 °C
Reaction time: 5 h

Procedure:
To about 1 g of crude methyl 6-O-benzoyl-4-deoxy-α,β-D-fructofuranoside (prepared as described in Example 1, Step 6) in dichloromethane (25 mL) containing 4 Å molecular sieves and pyridine (0.28 mL) and maintained at -40° C., benzoyl chloride (0.4 mL) was added and the solution was stirred between -30° to -20° C. for 5 h. The reaction mixture was filtered, diluted with dichloromethane and washed with ice cold 0.5M HCl, sat. aqueous NaHCO3 solution, dried over magnesium sulfate and evaporated. Final purification was effected by chromatography on a column of silica gel. The yields of the separated anomers were 0.582 g of methyl 4-deoxy-1,6-di-O-benzoyl-α-D-fructofuranoside and 0.200 g of methyl 4-deoxy-1,6-di-O-benzoyl-β-D-fructofuranoside.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[C:12]([NH:14][C@H:15]([C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=1)[CH3:16])=[O:13].O[Li:31].O>>[F:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[C:12]([NH:14][C@H:15]([C:17]1[CH:18]=[CH:19][C:20]([C:21]([O-:23])=[O:22])=[CH:25][CH:26]=1)[CH3:16])=[O:13].[Li+:31]
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)C2CCCCN2Cc2cccc(F)c2)cc1
Reactant: [Li]O
Solvent: O
Product: C[C@H](NC(=O)C1CCCCN1Cc1cccc(F)c1)c1ccc(C(=O)[O-])cc1
Product: [Li+]

Procedure:
The title compound (E3) (50 mg) was prepared according to the general procedure for esters hydrolysis starting from methyl 4-((1S)-1-(1-(3-fluorobenzyl)piperidine-2-carboxamido)ethyl)benzoate (D20) (54 mg). (LiOH H2O: 1.75 eq; reaction time: 3 hrs)
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][CH2:15]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:37]>ClCCl>[Br:37][CH2:15][CH2:14][CH2:13][C:3]1[N:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:6][C:2]=1[CH3:1]
Reactant: Cc1oc(-c2ccccc2)nc1CCCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1oc(-c2ccccc2)nc1CCCBr
Temperature: 0 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
Alcohol 1-4 (3 g, 13.8 mmol) was dissolved in dichloromethane (200 mL) and cooled to 0° C. under N2 atmosphere. Triphenylphosphine (4.35 g, 16.6 mmol) was added followed by CBr4 (5.5 g, 16.6 mol) in small portions. Reaction temperature was allowed to equilibrate to 23° C. over 8 hours. 20 g of SiO2 gel was added and solvent removed in vacuo. The dried silica gel was placed in a filter and washed with 10% EtOAc/Hexanes. The filtrate was reduced to minimum volume and chromatographed with 5-10% EtOAc/Hexanes to give 3.5 g of the product 1-5 as a clear oil (90% yield). M+1=280.0/282.1.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([NH:10][C:11]3[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])[N:8]([CH3:9])[C:4]=2[C:3]=1[C:21]([NH2:23])=[O:22].[C:24]1(C)[CH:29]=CC(S(O)(=O)=O)=C[CH:25]=1.CC(C)=O.C(=O)(O)[O-].[Na+]>CCOC(C)=O>[Cl:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([Cl:17])[C:11]=1[NH:10][C:7]1[N:8]([CH3:9])[C:4]2=[C:3]3[C:2](=[CH:20][CH:19]=[C:5]2[N:6]=1)[NH:1][C:24]([CH3:29])([CH3:25])[NH:23][C:21]3=[O:22]
Reactant: Cn1c(Nc2c(Cl)cccc2Cl)nc2ccc(N)c(C(N)=O)c21
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: Cn1c(Nc2c(Cl)cccc2Cl)nc2ccc3c(c21)C(=O)NC(C)(C)N3
Temperature: 25 °C
Reaction time: 1 h
Yield: 333.1 %

Procedure:
A mixture of 38 mg (0.11 mmol) of 5-amino-2-(2,6-dichlorophenylamino)-3-methyl-3H-benzimidazole-4-carboxylic acid amide (Example 7), 3 mg (0.02 mmol) p-toluenesulfonic acid, and 2 mL (27 mmol) of acetone was stirred at room temperature for 1 h, then heated to reflux for 1.5 h. The reaction was cooled and poured into a mixture of saturated aqueous sodium bicarbonate and EtOAc. The aqueous phase was extracted with EtOAc, the combined organics were extracted with saturated aqueous sodium bicarbonate, brine, dried (MgSO4), treated with activated carbon, filtered, and concentrated in vacuo to afford 26 mg of an orange solid. The crude product was chromatographed over silica gel to afford 20 mg (47%) of title compound 17, mp 238-239° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][CH3:13])=[N:10][C:9]2[C:4](=[CH:5][C:6]([CH3:15])=[C:7]([CH3:14])[CH:8]=2)[N:3]=1.Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18].N1C=CC=CC=1>ClCCl>[CH3:13][O:12][C:11]1[C:2]([NH:1][C:17](=[O:18])[O:19][CH2:20][CH3:21])=[N:3][C:4]2[C:9](=[CH:8][C:7]([CH3:14])=[C:6]([CH3:15])[CH:5]=2)[N:10]=1
Reactant: COc1nc2cc(C)c(C)cc2nc1N
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)Nc1nc2cc(C)c(C)cc2nc1OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.7 %

Procedure:
2-Amino-3-methoxy-6,7-dimethylquinoxaline (2.34 g, 11.5 mmol) and ethyl chloroformate (2.50 g, 23.0 mmol) were dissolved in dichloromethane (50 ml) at room temperature and thereto pyridine (1.82 g, 23.0 mmol) was added. The mixture was stirred at room temperature for 12 hours and concentrated under the reduced pressure to remove the solvent, and purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (3:1) mixture and concentration gave 2.65 g of the titled compound (yield, 84%).
Reaction SMILES: ON[C:3](=[NH:37])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[C:14]3[C:15](=[O:32])[N:16]([C:19]4[CH:24]=[CH:23][C:22]([N:25]5[CH:30]=[CH:29][CH:28]=[CH:27][C:26]5=[O:31])=[CH:21][CH:20]=4)[CH2:17][CH2:18][C:13]=3[C:12]([C:33]([F:36])([F:35])[F:34])=[N:11]2)[CH:5]=1.[OH-:38].[Na+].OO>ClCCl>[O:32]=[C:15]1[C:14]2[N:10]([C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([NH2:37])=[O:38])[N:11]=[C:12]([C:33]([F:34])([F:36])[F:35])[C:13]=2[CH2:18][CH2:17][N:16]1[C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]2=[O:31])=[CH:21][CH:20]=1
Reactant: N=C(NO)c1cccc(-n2nc(C(F)(F)F)c3c2C(=O)N(c2ccc(-n4ccccc4=O)cc2)CC3)c1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: ClCCl
Product: NC(=O)c1cccc(-n2nc(C(F)(F)F)c3c2C(=O)N(c2ccc(-n4ccccc4=O)cc2)CC3)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The product from Example 116, part A (0.05 g) was dissolved in dichloromethane (10 mL). To this was added sodium hydroxide (1N, 5 mL), hydrogen peroxide (3 mL), and tetrabutylammonium-hydroxide (0.01 g). The reaction mixture was stirred at rt for 24 h and concentrated. Quenched with water (50 mL) and the organics extracted with ethylacetate (2×50 mL), dried (MgSO4) and concentrated. The crude was purified via prep HPLC to a colorless solid. ESI mass spectrum 494(M+H) and 492(M−H).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7](=[O:17])[N:8]([NH:13]C(C)=O)[C:9]([SH:12])=[N:10][N:11]=1)([OH:3])=[O:2].[C:18](O)(=[O:20])[CH3:19]>>[C:18]([O:3][C:1](=[O:2])[CH3:4])(=[O:20])[CH3:19].[C:1]([CH2:4][CH2:5][C:6]1[C:7](=[O:17])[N:8]([NH2:13])[C:9]([SH:12])=[N:10][N:11]=1)([OH:3])=[O:2]
Reactant: CC(=O)O
Reactant: CC(=O)Nn1c(S)nnc(CCC(=O)O)c1=O
Product: CC(=O)OC(C)=O
Product: Nn1c(S)nnc(CCC(=O)O)c1=O

Procedure:
Mixed anhydride of acetic acid and 6-(2-carboxyethyl)-3-mercapto-4-acetamino-1,2,4-triazin-5-one. The vacuum dried (55° C., 0.05 mm, 4 hours) product obtained from the reaction of acetic anhydride and 6-(2-carboxyethyl)-3-mercapto-4-amino-1,2,4-triazin-5-one at 145° C. (bath temperature) for 8 hours as described in Example 1 (but not reacted with t-butanol) is separated. Mp. 95°-100° C.; dec. 130° C. Insoluble in water, alcohol, and t-butyl alcohol; soluble in acetone, chloroform, and acetonitrile. Anal. Calcd. for C14H20O5N4S: N, 20.59; S, 11.76. Found: N, 20.56; S, 11.68.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH:7]([C:12]([OH:14])=[O:13])[CH2:8][C:9]([OH:11])=[O:10])=[CH:3][CH:2]=1.[CH2:15](O)[CH3:16].[C:18]1(C)C=CC=C[CH:19]=1.OS(O)(=O)=O>O>[C:4]1([CH:7]([CH2:8][C:9]([O:11][CH2:15][CH3:16])=[O:10])[C:12]([O:14][CH2:18][CH3:19])=[O:13])[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: O=C(O)CC(C(=O)O)c1ccccc1
Reactant: Cc1ccccc1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)CC(C(=O)OCC)c1ccccc1
Temperature: 115 °C

Procedure:
A mixture of 50 g of DL-phenylsuccinic acid (0.257 mol), 90 mL (1.59 mol) of ethanol, 46 mL of toluene and 0.39 g of concentrated H2SO4 was heated to 115° C. An azeotropic mixture of ethanol, toluene and water was distilled over a column of 10 cm. When the distillation stopped the same amounts of ethanol and toluene was added. To obtain a complete conversion this was repeated twice. The resulting oil was distilled at 114° C. (2·10−2 mbar); yield 60.82 g (95%), purity 100%
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:18]([CH3:43])=[CH:19][C:20]([CH:39]4[CH2:42][CH2:41][CH2:40]4)=[C:21]([C:23]4[NH:38][C:26]5[CH2:27][N:28](C(OC(C)(C)C)=O)[CH2:29][CH2:30][C:25]=5[N:24]=4)[CH:22]=3)=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2]>ClCCl.FC(F)(F)C(O)=O.Cl.O>[CH:39]1([C:20]2[C:21]([C:23]3[NH:38][C:26]4[CH2:27][NH:28][CH2:29][CH2:30][C:25]=4[N:24]=3)=[CH:22][C:17]([C:15]([N:12]3[CH2:11][CH2:10][CH:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)[CH2:14][CH2:13]3)=[O:16])=[C:18]([CH3:43])[CH:19]=2)[CH2:40][CH2:41][CH2:42]1
Reactant: Cc1cc(C2CCC2)c(-c2nc3c([nH]2)CN(C(=O)OC(C)(C)C)CC3)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C2CCC2)c(-c2nc3c([nH]2)CNCC3)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Yield: 47.1 %

Procedure:
A solution of tert-butyl 2-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-methylphenyl)-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate (406.2, 600 mg, 0.620 mmol, 1.00 equiv, 60%) in dichloromethane (3 mL) and trifluoroacetic acid (1.5 mL) was stirred for 3 h at 25° C., then diluted with 5 mL of hydrochloric acid (3 mol/L) and 10 mL of water. The resulting mixture was washed with 3×20 mL of ethyl acetate and the pH was then adjusted to ˜9 with sodium hydroxide (aq, 3 M). The resulting mixture was extracted with 4×20 mL of dichloromethane. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to yield 140 mg (37%) of the title compound as a brown solid.
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:16]([N:23]1[CH2:28][CH2:27][N:26]([C:10]([C@@H:9]2[CH2:13][CH2:14][CH2:15][N:8]2[C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])=[O:12])[CH2:25][CH2:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCN(Cc2ccccc2)CC1
Yield: 90.1 %

Procedure:
A solution of N-Boc-L-proline 0.645 g (3 mmol), 1-benzylpiperazine 0.528 g (3 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) 1.152 g (6 mmol) and catalytic amount of 4-(dimethylamino) pyridine in methylene chloride (50 ml) was stirred at room temperature overnight. The reaction mixture was concentrated and applied to flash column chromatography using methylene chloride and methanol (100:5) as eluents to give 1.01 g of desired product in 90% yield.
Reaction SMILES: Br[C:2]1[C:6]2[C:7](=[O:11])[NH:8][CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.[N:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C([O-])([O-])=O.[Na+].[Na+].Cl>CC(=O)OCC.C1(C)C=CC=CC=1.C(O)C>[N:12]1[CH:17]=[CH:16][C:15]([C:2]2[C:6]3[C:7](=[O:11])[NH:8][CH:9]=[CH:10][C:5]=3[O:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: O=c1[nH]ccc2occ(Br)c12
Reactant: OB(O)c1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=c1[nH]ccc2occ(-c3ccncc3)c12
Temperature: 130 °C
Yield: 43.4 %

Procedure:
A reaction tube was charged with 3-bromofuro[3,2-c]pyridin-4(5H)-one (1000 mg, 4.67 mmol) and a mixture of 1 mL of ethanol and 1 mL of toluene under argon. To this mixture, pyridin-4-ylboronic acid (574 mg, 4.67 mmol) and a 2 M solution of Na2CO3 (743 mg, 7.01 mmol) were added followed by the addition of tetrakis-(triphenylphoshine)palladium (540 mg, 0.467 mmol). The reaction mixture was heated in a Cem microwave at about 130° C. for about 30 min. After completion of the reaction, EA was added followed by the addition of 2 N HCl. The mixture was extracted twice with EtOAc. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography to give the title compound as dark yellow solid (430 mg, 43.4%).
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][S:7]([CH:10]([C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=1)[CH3:11])(=[O:9])=[O:8].C[Li].[CH3:27]C(C)=O.F[C:32](F)(F)[C:33]([OH:35])=O>C1COCC1.C(OCC)C>[Br:18][C:15]1[CH:14]=[CH:13][C:12]([C:10]([S:7]([NH2:6])(=[O:8])=[O:9])([C:33]([OH:35])([CH3:32])[CH3:27])[CH3:11])=[CH:17][CH:16]=1
Reactant: CC(C)=O
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(CNS(=O)(=O)C(C)c2ccc(Br)cc2)c(OC)c1
Agent: [Li]C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(O)C(C)(c1ccc(Br)cc1)S(N)(=O)=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Under inert gas, 2.58 g of N-(2,4-dimethoxybenzyl)-1-(4-bromophenyl)ethanesulfonamide was initially charged in 40 ml of THF, and then, at a temperature of −78° C., 7.90 ml of a 1.6 N methyllithium solution in diethyl ether were added dropwise and the mixture was stirred at constant temperature for 10 minutes. Subsequently, 2.47 ml of acetone were added. After stirring for 15 minutes, the reaction solution was admixed with 0.96 ml of trifluoroacetic acid and allowed to warm up to room temperature. After the removal of the solvent under reduced pressure, the residue was dissolved in 50 ml of dichloromethane, 10 ml of trifluoroacetic acid were added and the mixture was stirred at room temperature for 1 hour. 100 ml of methanol were added to the reaction solution and the solvent was concentrated by rotary evaporation. The crude product was purified by filtration through a silica gel column. The column was washed through with ethyl acetate until no further product eluted. The eluate was concentrated by rotary evaporation and the residue (2.01 g) was used in the next reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Cl[C:28]1[N:33]=[C:32]([Cl:34])[C:31]([C:35]([F:38])([F:37])[F:36])=[CH:30][N:29]=1.C(Cl)Cl>CC(N(C)C)=O>[Cl:34][C:32]1[C:31]([C:35]([F:37])([F:36])[F:38])=[CH:30][N:29]=[C:28]([NH:1][C:2]2[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:7])=[CH:4][CH:3]=2)[N:33]=1
Reactant: Nc1ccc(C(=O)OCc2ccccc2)cc1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: O=C(OCc1ccccc1)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
10 g (44 mmol) benzyl 4-aminobenzoate are dissolved in 200 mL DMA, 8 mL Hünig base (0.97 eq) are added and 10.4 g (48.21 mmol) 2,4-dichloro-5-trifluoromethylpyrimidine, dissolved in 50 mL DMA, are added dropwise at RT to this solution. The reaction mixture is stirred at 60° C. overnight, then combined with 300 mL DCM and extracted with water (3 times 300 mL). The organic phase is dried and the solvent is eliminated in vacuo. The crude product is combined with 100 mL MeOH, digested and left to stand for 2 h. Then it is stirred for 10 min, the precipitate is filtered off and washed with MeOH. Finally the crude product is again suspended in MeOH, filtered off, washed with a little MeOH and dried in the vacuum dryer at 60° C. 8.5 g A-2a are obtained.