Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:5]([NH:7][C:8]1[CH:9]=[N:10][C:11]([O:14][C:15]2[C:16]3[CH:17]4[CH2:25][C:18]4([CH3:26])[CH2:19][O:20][C:21]=3[CH:22]=[CH:23][CH:24]=2)=[CH:12][CH:13]=1)=[O:6])([CH3:4])[NH2:3].Cl[C:28](Cl)([O:30]C(=O)OC(Cl)(Cl)Cl)Cl.C1CCCCC1.C(OCC)(=O)C>ClCCl>[CH3:4][C:2]1([CH3:1])[NH:3][C:28](=[O:30])[N:7]([C:8]2[CH:9]=[N:10][C:11]([O:14][C:15]3[C:16]4[CH:17]5[CH2:25][C:18]5([CH3:26])[CH2:19][O:20][C:21]=4[CH:22]=[CH:23][CH:24]=3)=[CH:12][CH:13]=2)[C:5]1=[O:6]
Reactant: CC(C)(N)C(=O)Nc1ccc(Oc2cccc3c2C2CC2(C)CO3)nc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCCCC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC1(C)NC(=O)N(c2ccc(Oc3cccc4c3C3CC3(C)CO4)nc2)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.1 %

Procedure:
To a solution of 2-methyl-N1-{6-[(1a-methyl-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-7-yl)oxy]-3-pyridinyl}alaninamide (Intermediate 129, 100 mg) in dry dichloromethane (10 ml) TEA (0.177 ml, 1.273 mmol) was added and the reaction mixture was cooled to 0° C. At this point a solution of triphosgene (37.8 mg, 0.127 mmol) in dry dichloromethane (2.5 ml) was slowly added (over 30 minutes) and the reaction mixture was stirred for 1 hour at the same temperature. The reaction was then quenched with water and the two phases were separated. The organic layer was dried over sodium sulphate, filtered and evaporated and the residue was purified by silica gel chromatography (Companion system, with a gradient from cyclohexane/ethyl acetate 8:2 to cyclohexane/ethyl acetate 1:1) to give the title compound as a white solid (40 mg, 0.103 mmol).
Reaction SMILES: [C:1]([O:5][C:6]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][NH:14][C:15]2[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=2[C:17]([NH2:19])=[O:18])[CH2:8][CH2:7]1)(=[O:4])[CH2:2][CH3:3].[CH:30](=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.N1CCCCC1.[OH:44][S:45]([OH:48])(=[O:47])=[O:46]>C(O)C.O>[OH2:4].[OH2:37].[S:45]([OH:48])([OH:47])(=[O:46])=[O:44].[C:1]([O:5][C:6]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][N:14]2[C:15]3[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:17](=[O:18])[NH:19][CH:30]2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:8][CH2:7]1)(=[O:4])[CH2:2][CH3:3]
Reactant: O=Cc1ccccc1
Reactant: CCC(=O)OC1(c2ccccc2)CCN(CCNc2ccccc2C(N)=O)CC1
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Solvent: C1CCNCC1
Product: CCC(=O)OC1(c2ccccc2)CCN(CCN2c3ccccc3C(=O)NC2c2ccccc2)CC1
Reaction time: 1 h

Procedure:
A mixture of 2-[2-(4-propionoxy-4-phenylpiperidino)ethylamino]benzamide (12.55 g), benzaldehyde (3.55 g), piperidine (1.35 g), and absolute ethanol (80 ml) was refluxed for 30 hrs. The solvent was removed on a rotovap. The thick oily product was chromatographed using silica gel and 5% isopropanol in chloroform. The product was isolated and dissolved in 30 ml 95% ethanol The solution was made acid with 4N H2SO4 and then 90 ml H2O was added. After 1 hr, the product was isolated and recrystallized from 850 ml 95% ethanol; yield 8.7 g, m.p. 186°-189° (d).
Reaction SMILES: C(OC([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:22][CH:23]([CH:30]([CH3:32])[CH3:31])[C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])=[O:21])[C:15]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N:14][CH:13]=1)=O)C1C=CC=CC=1>O1CCCC1.C(O)C.[Pd]>[NH2:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:22][CH:23]([CH:30]([CH3:32])[CH3:31])[C:24](=[O:29])[C:25]([F:27])([F:26])[F:28])=[O:21])[C:15]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[N:14][CH:13]=1
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ncc(NC(=O)OCc2ccccc2)c1=O)C(=O)C(F)(F)F
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ncc(N)c1=O)C(=O)C(F)(F)F
Yield: 80.3 %

Procedure:
To a solution of 2-(5-benzyloxycarbonylamino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl)-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide (1.9 g) in tetrahydrofuran (50 mL) and ethanol (50 mL) was added 10% (w/w) palladium on carbon (0.29 g) and the resulting solution was placed under a hydrogen atmosphere (0.75 bar) for 12 h. The catalyst was removed by filtration through diatomaceous earth and the solvent was evaporated. The resulting oil was crystallized from ether. The product was collected and washed with ether:hexane (1:1) to provide 2-(5-amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl)-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide (1.14 g) as a white solid; NMR (DMSO/D2O): 7.38 (m,6), 4.55 (d,1), 4.37 (d,1), 3.98 (m,1), 2.17 (m,1), 0.79 (d,3), 0.72 (d,3).
Reaction SMILES: CS[C:3]1[NH:7][N:6]=[N:5][N:4]=1.[S:8]([O-:13])(O[O-])(=O)=[O:9].[K+].[K+].[CH2:16]1COCC1>O>[CH3:16][S:8]([C:3]1[NH:7][N:6]=[N:5][N:4]=1)(=[O:13])=[O:9]
Reactant: O=S(=O)([O-])O[O-]
Reactant: CSc1nnn[nH]1
Reactant: C1CCOC1
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)c1nnn[nH]1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a stirred solution of 5-(methylthio)-1H-tetrazole (300 mg; Aldrich Chemical Company, Inc., Milwaukee, Wis.) in THF (15 mL) and water (15 mL) was added potassium peroxomonosulfate (Oxone®, DuPont Specialty Chemicals, Deepwater, N.J., USA) (3.18 g). After stirring at room temperature for five days, the reaction mixture was filtered and the filtercake was washed with THF. The filtrate was concentrated under reduced pressure. Crude NMR showed this to be a mixture of desired product and starting material, so the mixture was taken up in methanol and treated with potassium peroxomonosulfate (Oxone®, DuPont Specialty Chemicals, Deepwater, N.J., USA). After stirring at room temperature for five days, the reaction mixture was filtered and the filtercake was washed with methanol. The filtrate was concentrated under reduced pressure to afford 0.400 g of impure (I-11a) as a solid which was used in the next step without purification; m/z 146.9 (M−H)−.
Reaction SMILES: [Cl-].O[C:3]1[C:12]([N+]#N)=[C:11]2[C:6]([CH:7]=[CH:8][N:9]=[CH:10]2)=[CH:5]C=1.[C:15](=[O:18])(O)[O-:16].[Na+].[CH3:20]O>>[CH:10]1[NH:9][CH:8]=[CH:7][C:6]2[C:11]=1[C:12]([C:15]([O:16][CH3:20])=[O:18])=[CH:3][CH:5]=2
Reactant: O=C([O-])O
Reactant: CO
Reactant: N#[N+]c1c(O)ccc2ccncc12
Agent: [Cl-]
Agent: [Na+]
Product: COC(=O)c1ccc2cc[nH]cc1-2
Yield: 50 %

Procedure:
7-Hydroxy-8-isoquinolinediazonium chloride (0.50 g, 2.4 mmol) and sodium bicarbonate (302 mg, 3.6 mmol) in anhydrous methanol (650 ml) is irradiated with a 275 watt sunlamp at 0° C. for 3 hours. The reaction mixture is evaporated to dryness under vacuum. The crude residue is dissolved in water and the product is extracted in methylene chloride. The combined organic extracts are dried over magnesium sulfate, filtered and concentrated under reduced pressure to provide the product as an orange solid (210 mg) in 50% yield.
Reaction SMILES: [CH3:1][N:2]1[CH:6]2[CH2:7][CH:8]([OH:10])[CH2:9][CH:3]1[CH2:4][CH2:5]2.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl>[CH3:1][N:2]1[C@@H:6]2[CH2:7][CH:8]([O:10][S:19]([CH3:18])(=[O:21])=[O:20])[CH2:9][C@H:3]1[CH2:4][CH2:5]2
Reactant: CS(=O)(=O)Cl
Reactant: CN1C2CCC1CC(O)C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1[C@@H]2CC[C@H]1CC(OS(C)(=O)=O)C2
Reaction time: 1 h
Yield: 62.9 %

Procedure:
Tropine (14.2 g, 100 mmol) was dissolved in CH2Cl2 (210 ml) and triethylamine (23 ml, 160 mmol) was added. Methanesulfonyl chloride (9.3 ml, 120 mmol) was added rapidly dropwise which caused the methylene chloride solution to reflux gently. The mixture was stirred one hour further; then extracted with cold 0.5 molar sodium hydroxide, water, and brine, dried by filtration through phase separating paper and concentrated to yield 13.8 g (65%) of title product as a yellow solid. NMR 4.88 (t, J=5 Hz, 1H), 3.10-3.05 (m, 2H), 2.94 (s, 3H), 2.22 (s, 3H), 2.20-2.10 (m, 2H), 2.02-1.88 (m, 6H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([S:19]([NH:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])(=[O:21])=[O:20])=[CH:16][CH:17]=2)[C:12]([NH:28][C:29]([NH2:31])=[NH:30])=[N:11][CH:10]=1.[H-].[Na+].[C:34](OC(=O)CCNS(C1C=C2C(C(Cl)=CN=C2Cl)=CC=1)(=O)=O)([CH3:37])([CH3:36])[CH3:35]>COCCOC.CCOC(C)=O>[C:34]([O:26][C:25](=[O:27])[CH2:24][CH2:23][NH:22][S:19]([C:15]1[CH:14]=[C:13]2[C:18]([C:9]([Cl:8])=[CH:10][N:11]=[C:12]2[NH:28][C:29]([NH2:31])=[NH:30])=[CH:17][CH:16]=1)(=[O:20])=[O:21])([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)CCNS(=O)(=O)c1ccc2c(Cl)cnc(Cl)c2c1
Reactant: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)NCCC(=O)O)cc12
Agent: [H-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)CCNS(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Temperature: 30 °C

Procedure:
N-[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-β-alanine trifluoroacetate ##STR14## Guanidine hydrochloride (140 mg, 1.46 mmol was added in one portion to a stirred suspension of NaH (35 mg, 80% dispersion by wt in mineral oil, 1.17 mmol) in DME (8.0 mL) and the mixture was heated at 30° C. under N2 for 30 min. N-[(1,4-Dichloro-7-isoquinolinyl)sulphonyl]-β-alanine t-butyl ester (150 mg, 0.37 mmol) was added and the mixture heated at 90° C. for 18 h. The cooled mixture was diluted with EtOAc, washed with water, brine, dried (MgSO4) and evaporated in vacuo. The residue was purified by column chromatography upon silica gel using CH2Cl2 -MeOH-0.880NH3 (97:3:0.3 to 95:5:0.5) as eluant to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-β-alanine t-butyl ester (75 mg, 0.175 mmol) as a yellow foam
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][NH:10][CH:9]=2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl.CN([CH:21]=[O:22])C>C(Cl)Cl>[CH:21]([C:9]1[NH:10][CH:11]=[CH:12][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)=[O:22]
Reactant: Cc1ccc(-c2cc[nH]c2)cc1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc(-c2cc[nH]c2C=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Following a standard procedure (Balasubramanian, T. et al, J. Org. Chem. 2000, 65, 7919-7929), a solution of 7 (472 mg, 3.00 mmol) in DMF (0.96 mL) and CH2Cl2 (30 mL) under argon was cooled to 0° C. and then POCl3 (340 μL, 3.60 mmol) was added dropwise. After 1 h, the flask was warmed to room temperature and stirred overnight (˜18 h). The reaction was quenched at 0° C. with 2.5 M NaOH (25 mL). The mixture was poured into water (50 mL), extracted with CH2Cl2, and the combined organic layers were washed with water, brine, dried (NaSO4), and concentrated. The residue was chromatographed [silica, CH2Cl2/ethyl acetate (9:1)] to give a brown solid. 1H NMR spectroscopy showed two regioisomers in ˜13:1 ratio. Cooling of the solution (ethyl acetate/hexanes) at ˜−16° C. resulted in precipitation of an orange solid, which proved to be a single regioisomer (354 mg, 64%): mp 149-150° C.; 1H NMR δ 2.41 (s, 3H), 6.42-6.44 (m, 1H), 7.10-7.13 (m, 1H), 7.26 (d, J=8.0 Hz, 2H), 7.40 (d, J=8.0 Hz, 2H), 9.63-9.64 (m, 1H), 9.52-9.78 (br, 1H); 13C NMR δ 21.4, 111.6, 126.2, 128.9, 129.3, 129.7, 130.9, 137.7, 137.9, 180.2; FAB-MS obsd 186.0907, calcd 186.0919 (C12H11NO).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[NH:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)[N:3]=1.C([Sn](CCCC)CCCC)CCC.[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>[Pd]>[N:12]1[C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[NH:9][C:8]=1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][N:30]=2)[N:3]=1
Reactant: c1ccncc1
Reactant: Brc1cccc(-c2nc3ccccc3[nH]2)n1
Agent: [Pd]
Agent: CCCC[Sn](CCCC)CCCC
Product: c1ccc(-c2cccc(-c3nc4ccccc4[nH]3)n2)nc1

Procedure:
In Scheme 3, the starting material is 2-bromo-6-carboxyl pyridine 7. Addition of an ortho-substituted aniline derivative 2 using BOP chemistry generates 2-bromo-6-benzimidazolyl pyridine 8. A tributyl-tin activated pyridine 11 is added to 8 in the presence of a palladium catalyst to yield 2-benzimidazolyl-6-pyridyl pyridine 6.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][CH2:13][C:14]([N:16]([CH:25]([CH3:27])[CH3:26])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)=[O:15]>C(O)C.O>[F:8][C:5]1[CH:6]=[CH:7][C:2]([NH:12][CH2:13][C:14]([N:16]([CH:25]([CH3:27])[CH3:26])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:15])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: COc1ccc(N(C(=O)CN)C(C)C)cc1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Solvent: O
Solvent: CCO
Product: COc1ccc(N(C(=O)CNc2ccc(F)cc2[N+](=O)[O-])C(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43 %

Procedure:
A mixture of 9.06 g of 2,5-difluoro-nitrobenzene (60 mmol) and 12.64 g of 2-amino-N-isopropyl-N-(4-methoxy-phenyl)-acetamide (60 mmol, 1.0 equiv) were combined in 225 mL of 2:1 ethanol/water and heated to reflux under nitrogen and stirred vigorously overnight (approx. 16 hrs.). The resulting slurry was cooled to ambient temperature, filtered and washed with 2:1 water/ethanol. The wet solid was dissolved in methylene chloride, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was triturated with hexane, filtered and washed with hexane. The product was dried under high vacuum to provide 9.32 g of the title compound as an orange solid. 1H NMR (300 MHz, CDCl3) d 7.89 (dd, 1H, J=3.1, 9.3), 7.12 (m, 3H), 6.99 (m, 2H), 6.35 (dd, 1H, J=4.8, 9.2), 5.03 (m, 1H), 3.89 (s, 3H), 3.57 (s, 2H), 1.09 (d, 6H, J=6.8); low resolution MS (ESI)m/e 362 (MH+).
Reaction SMILES: [O:1]=[C:2]1[CH2:5][C:4]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:3]1.OO.[OH-].[Na+].O.O.O.O.O.S([O-])([O-])(=[O:29])=S.[Na+].[Na+]>CO.O.C(OCC)(=O)C>[O:29]=[C:2]1[CH2:3][C:4]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:5][O:1]1
Reactant: O=S([O-])([O-])=S
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)C2
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)COC(=O)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
567 ml solution of 37.8 g tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate in methanol was cooled on ice water, and 43 g of 30% aqueous hydrogen peroxide was added dropwise thereinto. 63 ml of 1 N aqueous sodium hydroxide was added dropwise thereto, and the mixture was stirred at room temperature for 2 hr. 1000 ml ethyl acetate, 600 ml water and 100 ml saturated aqueous sodium thiosulfate pentahydrate were added thereto, and the organic layer was recovered. The extracted solution was washed with brine, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was evaporated to give 28.4 g of tert-butyl 3-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([CH2:7][C:8]([OH:10])=O)[N:3]=1.[CH2:11]([C@@H:18]1[NH:23][CH2:22][CH2:21][N:20]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH:33]([F:35])[F:34])[CH:25]=2)[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([C@H:18]1[CH2:19][N:20]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH:33]([F:35])[F:34])[CH:25]=2)[CH2:21][CH2:22][N:23]1[C:8](=[O:10])[CH2:7][C:4]1[N:3]=[C:2]([CH3:1])[NH:6][N:5]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Cc1nc(CC(=O)O)n[nH]1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC(F)F
Product: COc1ccc(N2CCN(C(=O)Cc3n[nH]c(C)n3)[C@@H](Cc3ccccc3)C2)cc1OC(F)F

Procedure:
Prepared by the method outlined for Example 189 using (5-methyl-1H-[1,2,4]triazol-3-yl)-acetic acid and (S)-3-benzyl-1-(3-difluoromethoxy-4-methoxy-phenyl)-piperazine (Example 69, Compound 157) as starting materials. Product as an oil. LC/MS (Method B) 2.57 min, [M+1]+ 472. Potency class A.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[CH:6][NH:5][N:4]=1.[OH:8][C:9]1[C:13](C)=CNN=1.S(Cl)(Cl)=[O:16].[Na]>C(O)CO>[OH:8][CH2:9][CH2:13][O:16][CH2:2][C:3]1[CH:7]=[CH:6][NH:5][N:4]=1
Reactant: Cc1c[nH]nc1O
Reactant: ClCc1cc[nH]n1
Reactant: O=S(Cl)Cl
Agent: [Na]
Solvent: OCCO
Product: OCCOCc1cc[nH]n1

Procedure:
3-Chloromethylpyrazole, prepared by reacting 3-hydroxy-methylpyrazole with thionyl chloride, is reacted with the sodium salt of ethylene glycol to give 3-(2-hydroxyethoxymethyl)-pyrazole. Treatment of 3-(2-hydroxyethoxymethyl)pyrazole with thionyl chloride gives 3 -(2-chloroethoxymethylpyrazole.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[N:12]2[CH:13]=[C:14]([O:17][C@H:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C@@H:21]([NH2:28])[CH2:20][CH2:19]3)[CH:15]=[CH:16][C:11]2=[N:10][N:9]=1.ClC(Cl)(Cl)C[O:32][C:33](=[O:58])[NH:34][C:35]1[N:39]([C:40]2[CH:41]=[N:42][N:43]([CH2:45][CH2:46]OC3CCCCO3)[CH:44]=2)[N:38]=[C:37]([C:54]([CH3:57])([CH3:56])[CH3:55])[CH:36]=1.C[CH2:62][N:63](C(C)C)[CH:64](C)C>O1CCOCC1>[CH:33]([OH:58])=[O:32].[C:54]([C:37]1[CH:36]=[C:35]([NH:34][C:33]([NH:28][C@@H:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C@H:18]([O:17][C:14]3[CH:15]=[CH:16][C:11]4[N:12]([C:8]([N:3]5[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]5[CH3:1])=[N:9][N:10]=4)[CH:13]=3)[CH2:19][CH2:20]2)=[O:58])[N:39]([C:40]2[CH:41]=[N:42][N:43]([CH2:45][CH2:46][N:63]([CH3:64])[CH3:62])[CH:44]=2)[N:38]=1)([CH3:55])([CH3:56])[CH3:57]
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cnn(CCOC3CCCCO3)c2)n1
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Reactant: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cnn(CCN(C)C)c4)c4ccccc43)cn12
Product: O=CO
Temperature: 80 °C
Reaction time: 8 h
Yield: 162.3 %

Procedure:
A mixture of Intermediate 81d (240 mg, 0.64 mmol), Intermediate 108b (325 mg, 0.64 mmol) and DIPEA (221 μL, 1.27 mmol) in dioxane (6 mL) was stirred at 80° C. overnight. After cooling, the reaction mixture was partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-10% MeOH in DCM to afford the title compound (377 mg, 80%). LCMS (Method 4): Rt 3.48 min, m/z 737 [MH+].
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])[CH:6]=[C:5]2[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][NH2:35])[CH:29]=1>C1(C)C=CC=CC=1.C(O)(C)(C)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][NH:12][C:7]1[CH:6]=[C:5]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:35][CH2:34][C:30]3[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=3)[CH:3]=2)[N:8]=1
Reactant: NCc1cccnc1
Reactant: COc1ccccc1CNc1cc(-c2cccnc2)c2cc(Cl)ccc2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: COc1ccccc1CNc1cc(-c2cccnc2)c2cc(NCc3cccnc3)ccc2n1
Temperature: 130 °C
Reaction time: 16 h

Procedure:
(6-Chloro-4-pyridin-3-yl-quinolin-2-yl)-(2-methoxy-benzyl)-amine (185 mg, 0.492 mmol) was dissolved in 5 mL toluene and 1 mL tert. butanol. Argon was bubbled through the solution for 2 minutes to remove oxygen. 3-Picolylamine (160 mg, 1.48 mmol), sodium tert.-butylate (95 mg, 0.99 mmol), palladium acetate (6 mg, 0.027 mmol) and 2-dicyclohexyl-phosphino-2′,4′,6′-triisopropylbiphenyl (X-Phos, 23 mg, 0.05 mmol) were added. The reaction mixture was stirred in a sealed tube at 130° C. for 16 h. The solvent was evaporated and the residue purified by flash chromatography on silica gel (dichloromethane/methanol 100:0->90:10 gradient). The title compound was obtained as a yellow foam (105 mg, 47%), MS: m/e=448.3 (M+H+).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][NH:12][C:13](OC(C)(C)C)=O)=[C:7]([N+:20]([O-:22])=[O:21])[CH:6]=1)(=[O:4])=[O:3].[C:23]1(=O)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30]C=2)[CH2:26][CH2:25][CH2:24]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)(C(F)(F)F)=O.ClCCl>[C:13]1(=[N:12]/[NH:11][C:8]2[CH:9]=[CH:10][C:5]([S:2]([NH2:1])(=[O:3])=[O:4])=[CH:6][C:7]=2[N+:20]([O-:22])=[O:21])/[CH2:30][CH2:29][CH2:28][C:27]2[C:32]/1=[CH:23][CH:24]=[CH:25][CH:26]=2
Reactant: O=C1CCCc2ccccc21
Reactant: CC(C)(C)OC(=O)NNc1ccc(S(N)(=O)=O)cc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccc(N/N=C2\CCCc3ccccc32)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A room temperature solution of Example 73A (145 mg, 0.44 mmol) in 1:1 TFA/dichloromethane (10 mL) was stirred for 4 hours and concentrated. The concentrate was dissolved in ethanol (2 mL), treated with 3,4-dihydro-1(2H)-naphthalenone (8.2 mg, 0.06 mmol) and pyridinium p-toluenesulfonate (2 mg, 0.008 mmol), heated to reflux, stirred for 2 hours, cooled to room temperature, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 4% methanol/dichloromethane to provide the desired product. MS (ESI(−)) m/e 359 (M−H)−.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][C:9]1=[O:17])([CH3:4])([CH3:3])[CH3:2].CC(N=P(N1CCCC1)(N1CCCC1)N1CCCC1)(C)C.Cl[CH2:41][C:42]1[N:46]([CH2:47][CH2:48][CH:49]([CH3:51])[CH3:50])[C:45]2[CH:52]=[CH:53][C:54]([C:56]#[N:57])=[CH:55][C:44]=2[N:43]=1>C(Cl)Cl.CCOCC>[C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([CH2:41][C:42]2[N:46]([CH2:47][CH2:48][CH:49]([CH3:51])[CH3:50])[C:45]3[CH:52]=[CH:53][C:54]([C:56]#[N:57])=[CH:55][C:44]=3[N:43]=2)[C:9]1=[O:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)CCn1c(CCl)nc2cc(C#N)ccc21
Reactant: CC(C)(C)OC(=O)Cn1c(=O)[nH]c2ccccc21
Agent: CC(C)(C)N=P(N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)CCn1c(Cn2c(=O)n(CC(=O)OC(C)(C)C)c3ccccc32)nc2cc(C#N)ccc21
Reaction time: 0.42 h
Yield: 209.8 %

Procedure:
(2-Oxo-2,3-dihydro-benzoimidazol-1-yl)-acetic acid tert-butyl Ester (399 mg, 1.61 mmol) in CH2Cl2 (15 ml) was trreated with BTPP and then treated with 2-chloromethyl-1-(3-methyl-butyl)-1H-benzoimidazole-5-carbonitrile (400 mg, 1.53 mmol). The reaction was stirred for 25 min then the mixture was diluted with ether and washed with water. The organic layer was dried over MgSO4, concentrated and the residue purified by column chromatography with gradient elution using first 1:1 EtOAc in hexanes then 2:1 EtOAc in hexanes to give 1.52 g (99%) of {3-[5-Cyano-1-(3-methyl-butyl)-1H-benzoimidazol-2-ylmethyl]-2-oxo-2,3-dihydro-benzoimidazol-1-yl}-acetic acid tert-butyl ester as a white solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:3]1.[F:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([Cl:18])=[O:17]>C(Cl)(Cl)Cl>[ClH:18].[CH:7]1([N:4]2[CH2:5][CH2:6][CH:2]([NH:1][C:16](=[O:17])[C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[F:13])[CH2:3]2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=C(Cl)c1ccccc1F
Reactant: NC1CCN(C2CCCCC2)C1
Solvent: ClC(Cl)Cl
Product: Cl
Product: O=C(NC1CCN(C2CCCCC2)C1)c1ccccc1F

Procedure:
To 19.5 g. (0.117 mole) of 3-amino-1-cyclohexylpyrrolidine in 100 ml. of chloroform was added dropwise 11.6 g. (0.074 mole) of o-fluorobenzoyl chloride in 100 ml. of chloroform. The solution was concentrated in vacuo and the residue partitioned between ethyl acetate containing 10% isopropyl ether and dilute hydrochloric acid. The acid layer was made basic with dilute sodium hydroxide and extracted with chloroform. The chloroform solution was dried over sodium sulfate, concentrated and the residue crystallized twice from ligroin. The yield was 13 g. (82%); m.p. at 204°-206°C.