Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[N:7]([C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=2)[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]=1.CC(C)=[O:24]>>[F:21][C:2]([F:1])([F:20])[C:3]1[N:7]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([OH:24])=[O:13])=[CH:14][CH:15]=2)[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]=1
Reactant: CC(C)=O
Reactant: O=Cc1ccc(-n2c(C(F)(F)F)nc3ccccc32)cc1
Product: O=C(O)c1ccc(-n2c(C(F)(F)F)nc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 4-(2-Trifluoromethyl-benzoimidazol-1-yl)-benzaldehyde (0.58 g, 2 mmol) in acetone (25 mL) was added Jones's reagent (1.0 mL, 2.0 M) at 0° C. After stirring at room temperature for 2 h, the mixture was partitioned between EtOAc and saturated NaHCO3 solution. After usual workup, the crude material was separated by silica gel chromatography (50% Hexane/EtOAc to EtOAc) to afford the intermediate acid 4-(2-Trifluoromethyl-benzoimidazol-1-yl)-benzoic acid as awhile solid (490 mg).
Reaction SMILES: [O:1]=[C:2]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[NH:12][C:11]2=[O:19])[CH2:6][CH2:5]1.[BH4-].[Na+]>CO>[OH:1][CH:2]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:3][N:4]1[CH2:5][CH2:6][CH:7]([N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[NH:12][C:11]2=[O:19])[CH2:8][CH2:9]1
Reactant: O=C(CN1CCC(n2c(=O)[nH]c3ccccc32)CC1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=c1[nH]c2ccccc2n1C1CCN(CC(O)c2ccccc2)CC1
Yield: 67.7 %

Procedure:
1.91 g of the product obtained in Example 24 is dissolved in 30 ml of methanol, and reacted with 1.1 g of sodium borohydride under the same conditions as in Example 7 to obtain 1.62 g of a crude product. Recrystallization of the product from ethanol yields 1.3 g of 1-[2-hydroxy-2-phenyl-1-ethyl]-4-(2-keto-1-benzimidazolinyl)-piperidine.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].C(Cl)(=O)C([Cl:17])=O>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:17])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Chloro-3-nitrobenzoic acid (40.40 g, 0.20 mole) was suspended in DCM (100 mL) containing 3 drops of DMF. Oxalyl chloride (1.5 equivalents, 0.3 mole, 27 mL) was added in small portions and the mixture stirred overnight at room temperature. After refluxing for an additional hour to complete the reaction, volatiles were removed under reduced pressure and the residue was coevaporated twice with hexane to give the title compound as a light yellow solid.
Reaction SMILES: [CH2:1]([C:3]1([CH3:27])[NH:22][C:21]([CH2:24][CH3:25])([CH3:23])[CH2:20][C:5]2([NH:9][C:8](=[O:10])[N:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:6]2=[O:19])[CH:4]1[CH3:26])[CH3:2].[CH2:28]1[O:30][CH2:29]1>CO.Cl>[CH2:1]([C:3]1([CH3:27])[N:22]([CH2:28][CH2:29][OH:30])[C:21]([CH2:24][CH3:25])([CH3:23])[CH2:20][C:5]2([NH:9][C:8](=[O:10])[N:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:6]2=[O:19])[CH:4]1[CH3:26])[CH3:2]
Reactant: CCCCCCCCN1C(=O)NC2(CC(C)(CC)NC(C)(CC)C2C)C1=O
Reactant: C1CO1
Agent: Cl
Solvent: CO
Product: CCCCCCCCN1C(=O)NC2(CC(C)(CC)N(CCO)C(C)(CC)C2C)C1=O
Temperature: 110 °C
Yield: 97.1 %

Procedure:
To a solution of 6.0 g of 7,9-diethyl-6,7,9-trimethyl-3-octyl-1,3,8-triazaspiro[4.5]decane-2,4-dione (Compound 5) obtained as described in Example 4, in 40 ml of methanol were added 3 drops of concentrated hydrochloric acid and 3.5 g of ethylene oxide. The mixture was heated at 110° C for 24 hours in a sealed tube and then concentrated to give 6.5 g of Compound 118 as an oil. This product had an Rf value of 0.33 on thin layer chromatography on a 0.25 mm thick layer of silica gel (Kieselgel 60F 254, available from Merck & Co.; eluent, benzene containing 5% of triethylamine).
Reaction SMILES: [CH3:1][N:2]1[C:7]([NH2:8])=[N:6][C:4](=[O:5])[CH2:3]1.[Cl:9][C:10]1[S:11][CH:12]=[C:13]([N:15]=[C:16]=[O:17])[CH:14]=1.O>CN(C=O)C.C1(C)C=CC=CC=1>[Cl:9][C:10]1[S:11][CH:12]=[C:13]([NH:15][C:16]([N:8]=[C:7]2[NH:6][C:4](=[O:5])[CH2:3][N:2]2[CH3:1])=[O:17])[CH:14]=1
Reactant: O=C=Nc1csc(Cl)c1
Reactant: CN1CC(=O)N=C1N
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1ccccc1
Product: CN1CC(=O)NC1=NC(=O)Nc1csc(Cl)c1
Temperature: 80 °C
Yield: 30.6 %

Procedure:
To a stirred suspension of 2.5 g (22.5 mM) of creatinine in 30 ml of anhydrous DMF was added a solution of 2.87 g (18 mM) of 2-chloro-4-thienyl isocyanate in 20 mls toluene. The resulting mixture was heated at 80° C. for 3.5 hrs., cooled, and poured into a mixture of 250 ml of water and 50 ml toluene. The precipitate was collected and recrystallized from ethyl acetate to give 1.5 g of the above urea as a tan solid, m.p. 198°-200° C.
Reaction SMILES: [CH3:1][N:2]([CH3:10])/[N:3]=[C:4](\[CH3:9])/[C:5]([F:8])([F:7])[F:6].C([N-]C(C)C)(C)C.[Li+].CCCCCCC.O1CCCC1.C(C1C=CC=CC=1)C.[F:39][CH2:40]/[C:41](=[N:50]/[S@@:51]([C:53]([CH3:56])([CH3:55])[CH3:54])=[O:52])/[C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([CH3:48])[C:43]=1[F:49].C[Al](C)C.NN>C1COCC1.C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:10])/[N:3]=[C:4](\[C:5]([F:8])([F:7])[F:6])/[CH2:9][C:41]([NH:50][S@@:51]([C:53]([CH3:56])([CH3:55])[CH3:54])=[O:52])([C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([CH3:48])[C:43]=1[F:49])[CH2:40][F:39]
Reactant: Cc1cccc(/C(CF)=N\[S@](=O)C(C)(C)C)c1F
Reactant: C/C(=N\N(C)C)C(F)(F)F
Agent: CC(C)[N-]C(C)C
Agent: C[Al](C)C
Agent: NN
Solvent: C1CCOC1
Solvent: CCCCCCC
Solvent: CCc1ccccc1
Product: Cc1cccc(C(CF)(C/C(=N/N(C)C)C(F)(F)F)N[S@](=O)C(C)(C)C)c1F
Reaction time: 0.5 h
Yield: 180.9 %

Procedure:
To a solution of (E)-1,1-dimethyl-2-(1,1,1-trifluoropropan-2-ylidene)hydrazine (2.256 g, 14.63 mmol) in dry THF (20 mL) at −78° C. were added n,n,n′,n′-tetramethylethylenediamine (2.190 ml, 14.63 mmol) and lithium diisopropylamide, 2.0m heptane/tetrahydrofuran/ethylbenzene (7.32 ml, 14.63 mmol) and stirred at this temperature for 30 min. A solution of (R,E)-N-(2-fluoro-1-(2-fluoro-3-methylphenyl)ethylidene)-2-methylpropane-2-sulfinamide (2.0 g, 7.32 mmol) in toluene (12 mL) at −78° C. was treated with trimethylaluminum, 2.0m solution in toluene (3.66 ml, 7.32 mmol) for 10 min and added dropwise to the solution containing the hydrazine at −78° C. The resulting mixture was stirred at this temperature for 1.5 h. The mixture was quenched with saturated NH4Cl, and extracted with EtOAc. The combined organics were dried over Na2SO4, filtered, concentrated and chromatographed on silica gel using 0-50% EtOAc/hexanes to afford a bright yellow oil as (R)-N-((Z)-4-(2,2-dimethylhydrazono)-1,5,5,5-tetrafluoro-2-(2-fluoro-3-methylphenyl)pentan-2-yl)-2-methylpropane-2-sulfinamide (5.66 g, 77% yield, combined). MS m/z=427.9 [M+H]+. Calculated for C18H26F5N3OS: 427.17.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C.C(=O)([O-])[O-].[Cs+].[Cs+]>[CH2:13]([O:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[CH:8]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Brc1ccc2cc(OCc3ccccc3)ccc2c1
Reaction time: 24 h

Procedure:
To the commercially available 6-bromo-naphthalene-2-ol (1) (1 equi.) and benzyl bromide (2) (1 equi.) in DMF (3mL/mmole), cesium carbonate (1.25 equi.) was added at room temperature. The reaction mixture was stirred at that temperature for 24 h, quenched with water, extracted with ethyl acetate:hexane (1:1), washed with brine, over MgSO4, and concentrated in vacuo.
Reaction SMILES: COC1C=C(N)C(N)=CC=1.CO[C:13]1[C:26]([O:27][CH3:28])=[CH:25][C:16]2[NH:17][C:18]([CH2:20][CH2:21][CH2:22][NH:23][CH3:24])=[N:19][C:15]=2[CH:14]=1>>[CH3:28][O:27][C:26]1[CH:13]=[CH:14][C:15]2[N:19]=[C:18]([CH2:20][CH2:21][CH2:22][NH:23][CH3:24])[NH:17][C:16]=2[CH:25]=1
Reactant: CNCCCc1nc2cc(OC)c(OC)cc2[nH]1
Agent: COc1ccc(N)c(N)c1
Product: CNCCCc1nc2ccc(OC)cc2[nH]1

Procedure:
Prepared from 4-methoxy-benzene-1,2-diamine in analogy to the methods described for [3-(5,6-dimethoxy-1H-benzoimidazol-2-yl)-propyl]-methyl-amine.
Reaction SMILES: [O:1]=[C:2]1[C:8]2([CH2:12][CH2:11][CH2:10][CH2:9]2)[NH:7][CH2:6][CH2:5][C@@H:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]1[CH2:19][C:20]([O:22]CC1C=CC=CC=1)=[O:21]>CO.[Pd]>[O:1]=[C:2]1[C:8]2([CH2:9][CH2:10][CH2:11][CH2:12]2)[NH:7][CH2:6][CH2:5][C@@H:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]1[CH2:19][C:20]([OH:22])=[O:21]
Reactant: O=C(CN1C(=O)C2(CCCC2)NCC[C@H]1c1ccccc1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C(O)CN1C(=O)C2(CCCC2)NCC[C@H]1c1ccccc1

Procedure:
A solution of benzyl [(9S)-11-oxo-9-phenyl-6,10-diazaspiro[4.6]undec-10-yl]acetate from Step B (0.190 g, 0.484 mmol) in methanol (10 mL) was passed through an H-Cube™ continuous flow hydrogenation reactor at 50 Bar of H2 using a Pd/C catalyst at ambient temperature. The solution was concentrated in vacuo to yield the title compound. MS: m/z=303 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.[CH2:23](O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(Cl)CCl>CN(C)C1C=CN=CC=1.CCOCC>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:10]([O:12][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C1(C)CCCCC1
Reactant: OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)OCc1ccccc1)C1(C)CCCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 2-dram vial containing a small stirbar was charged with (R)-2-(tert-butoxycarbonylamino)-2-(1-methylcyclohexyl)acetic acid (10d) (11 mg, 0.04 mmol), CH2Cl2 (1 mL), 4-dimethylaminopyridine (2 mg, 0.02 mmol, 0.5 equiv), benzyl alcohol (20 μL, 0.2 mmol, 5 equiv), and EDC (20 mg, 0.1 mmol, 2.5 equiv). The solution was stirred at room temperature for 3 h, and then diluted with 10 mL Et2O. The mixture was washed with water (2×10 mL), saturated aqueous NaHCO3 (10 mL), and brine (10 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (7:1 hexanes/Et2O) and analyzed by chiral HPLC analysis: (AS-H, 1 mL/min, 2% IPA/hexanes, 210 nm): tR(minor)=6.84 min, tR(major)=8.13 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[C:63]1([NH:69][CH2:70][C@H:71]2[CH2:75][CH2:74][CH2:73][NH:72]2)[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:72]1[CH2:73][CH2:74][CH2:75][C@@H:71]1[CH2:70][NH:69][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: c1ccc(NC[C@H]2CCCN2)cc1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(Nc1ncnc2cc(C(=O)N3CCC[C@@H]3CNc3ccccc3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and (R)-2-(phenylaminomethyl)-pyrrolidine in DMSO at ambient temperature.
Reaction SMILES: [CH3:1]CN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CO.[CH3:34][C:35]([Si:38]([C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[O:39][CH2:40][C@@H:41]([NH:46][C:47]([O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:48])[CH2:42][C:43]([OH:45])=[O:44])([CH3:37])[CH3:36]>CN(C=O)C.[Cl-].[Na+].O>[CH3:37][C:35]([Si:38]([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)([C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[O:39][CH2:40][C@@H:41]([NH:46][C:47]([O:49][CH2:50][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)=[O:48])[CH2:42][C:43]([O:45][CH3:1])=[O:44])([CH3:34])[CH3:36]
Reactant: CC(C)(C)[Si](OC[C@H](CC(=O)O)NC(=O)OCc1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: COC(=O)C[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 90.1 %

Procedure:
In a 1000 ml round-bottomed flask (3S)-4-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-3-({[(phenylmethyl)oxy]carbonyl}amino)butanoic acid D2 (15 g) was dissolved in DMF (200 ml). To this solution DIPEA (28.8 ml, 165 mmol) and TBTU (11.46 g, 35.7 mmol) were added and the solution left under stirring at room temperature for 20 minutes. After this time to the brown solution MeOH (11 ml) was added and the mixture left under stirring at room temperature for 30 minutes. The reaction mixture was transferred into a separatory funnel containing brine (600 ml) and extracted with EtOAc (5×200 ml). The organic phases were washed with water (3×100 ml), dried (Na2SO4) and evaporated under vacuum to give an orange oil. This material was purified by column chromatography on silica gel (flash master, Cy/EtOAc from 100/0 to 80/20) to give the title compound D3 (13.9 g) as a yellow solid. MS: (ES/+) m/z: 506 (M+1). C29H35NO5Si requires 505. 1H NMR (400 MHz, CDCl3-d6) δ (ppm): 7.69-7.29 (m, 15 H), 5.4-5.26 (m, 1 H), 5.11 (m, 2 H), 4.25-4.14 (m, 1 H), 3.82-3.68 (m, 2H), 3.64 (s, 3 H), 2.79-2.52 (m, 2 H), 1.08 (s, 9 H).
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cc2cccnc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(Cc2cccnc2)cc1

Procedure:
A solution of 3-(4'-nitrobenzyl)pyridine of Preparation 7 (7.924 g, 0.0370 mole) in methanol (100 ml) is shaken with 5% Pd on carbon and hydrogen in a Parr apparatus. Hydrogen uptake is complete within 45 min. The catalyst is removed by filtration through sintered glass. The solvent is removed under reduced pressure. The crystalline residue is recrystallized from methylene chloride-hexane with a first crop of 5.229 g; a second crop of 0.492 g; a third crop of 0.480 g; and a fourth crop of 0.137 g (total 6.338 g, 0.0347 mole, 94%). Recrystallization from CH2Cl2 -hexane gives colorless crystals of the titled product with a melting point of 121°-123° C.; IR (nujol) peaks are observed at 3400, 3300, 3200, 1640, 1610, 1590, 1575, 1515, 1480, 845, 800, and 710 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]2[CH:30]=[C:31]([CH3:39])[C:32]3[N:36]=[C:35]([CH3:37])[NH:34][C:33]=3[CH:38]=2)[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:37][C:35]1[NH:34][C:33]2[CH:38]=[C:29]([O:28][C:24]3[N:25]=[CH:26][N:27]=[C:22]([N:17]4[CH2:18][CH2:19][CH:14]([N:10]5[CH2:9][CH2:8][C:7]6[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=6[NH:12][C:11]5=[O:13])[CH2:15][CH2:16]4)[CH:23]=3)[CH:30]=[C:31]([CH3:39])[C:32]=2[N:36]=1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: Cc1nc2c(C)cc(Oc3cc(Cl)ncn3)cc2[nH]1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4cc(C)c5nc(C)[nH]c5c4)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.16 g (0.59 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 0.15 g (0.55 mmol) 6-(6-chloro-pyrimidin-4-yloxy)-2,4-dimethyl-1H-benzimidazole and 0.21 mL (1.2 mmol) DIPEA were combined in 2.0 mL DMF and stirred overnight at RT. The reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined and the acetonitrile was evaporated down. The residue was made alkaline with 4N aqueous sodium hydroxide solution, the precipitate formed was suction filtered, washed with water and dried under HV.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([F:36])=[CH:11][C:12]([NH:29][CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[C:13]([CH:28]=1)[C:14]([NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=1)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:38](OC1C=CC([N+]([O-])=O)=CC=1)=[O:39].CCN(C(C)C)C(C)C.C1CCN2C(=NCCC2)CC1>C1COCC1>[CH2:1]([O:8][C:9]1[CH:28]=[C:13]2[C:12](=[CH:11][C:10]=1[F:36])[N:29]([CH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)[C:38](=[O:39])[N:16]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=1)[C:14]2=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CNC(=O)c2cc(OCc3ccccc3)c(F)cc2NC2CCOCC2)cc1OC
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(Cn2c(=O)c3cc(OCc4ccccc4)c(F)cc3n(C3CCOCC3)c2=O)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
A mixture of 1.0 g of the compound obtained in Step 4.5, 1.223 g of 4-nitrophenyl chloroformate and 0.915 g of DIEA in 15 ml of THF is irradiated in a microwave field for 15 minutes at 80° C. 0.616 g of DBU is then added and the mixture is stirred for 1 hour at room temperature. The reaction medium is evaporated under reduced pressure. The residue is taken up in EtOAc and washed twice with saturated aqueous NaHCO3 solution, then with aqueous 1M KHSO4 solution and then with water. The organic phase is dried over Na2SO4 and filtered, and the filtrate is evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with a DCM/EtOAc mixture from (100/0, v/v) to (60/40, v/v) to give 0.74 g of the expected product.
Reaction SMILES: O[CH:2]([CH:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].II>>[CH2:2]([C:8]1[C:9](=[O:13])[CH2:10][CH2:11][CH:12]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCC(O)C1CCCC1=O
Agent: II
Product: CCCCCCC1=CCCC1=O
Yield: 84.8 %

Procedure:
In a 30 ml four-neck flask fitted with a thermometer, a reflux condenser and a stirrer were placed 2-(1-hydroxyhexyl)cyclopentanone (20 g) synthesized in Reference Example 2 and iodine (5 mg), followed by 6 hours of the reaction at 150° C. The crude product was purified by column chromatography (hexane/ethyl acetate: 95/5) to obtain 15.3 g of 2-hexyl-2-cyclopentenone (GC purity: 99.1%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]2.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:21][C:22]1[N:27]=[C:26](Cl)[CH:25]=[CH:24][N:23]=1.CCOC(C)=O>CS(C)=O>[Cl:21][C:22]1[N:27]=[C:26]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]3)[CH:25]=[CH:24][N:23]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: O=C(O)c1cccc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=C(O)c1cccc2cc(Oc3ccnc(Cl)n3)ccc12
Temperature: 25 °C

Procedure:
To a solution of 6-hydroxy-1-naphthoic acid (10.0 g, 53.1 mmol) in DMSO (60 mL) was added Cs2CO3 (51.9 g, 159.4 mmol). Bubbling was evident. The mixture was stirred at RT for 5 min, at which time 2,4-dichloropyrimidine (15.8 g, 16.3 mmol) was added. The reaction was stirred at RT and monitored by LCMS for the disappearance of starting material. EtOAc (1.0 L) was added, and the reaction was filtered to remove solid Cs2CO3. The mixture was extracted with 2N aqueous NaOH. The aqueous layer was washed with EtOAc, then acidified with 6N aqueous HCl to provide a white suspension. Filtration yielded a white solid.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[F:19][C:20]([F:29])([F:28])[C:21]1([CH2:26][OH:27])[CH2:25][CH2:24][NH:23][CH2:22]1>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([N:23]3[CH2:24][CH2:25][C:21]([CH2:26][OH:27])([C:20]([F:28])([F:29])[F:19])[CH2:22]3)=[O:17])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: OCC1(C(F)(F)F)CCNC1
Agent: Cl
Product: O=C(c1ccc(C2CC2)c(OCC2CC2)n1)N1CCC(CO)(C(F)(F)F)C1
Yield: 36.4 %

Procedure:
In analogy to the procedure described in Example 127 e), 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 3 c, 20 mg, 85.7 μmol) was reacted with (3-(trifluoromethyl)pyrrolidin-3-yl)methanol hydrochloride (CAN 1260812-78-9, 21.2 mg, 103 μmol) to obtain the title compound (12 mg, 36%) as colorless liquid, MS (EI): m/e=385.3 [MH+].
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[N:23]([CH3:27])[N:24]=[CH:25][CH:26]=4)=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3]1.[CH:28](OCC)=[O:29].[O-]CC.[Na+].Cl>C(O)C>[OH:29][CH:28]=[C:10]1[C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[N:23]([CH3:27])[N:24]=[CH:25][CH:26]=4)=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: Cn1nccc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Reactant: CCOC=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cn1nccc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Temperature: 78 °C
Yield: 61.2 %

Procedure:
2-Methyl-2H-pyrazole-3-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.142 g, 0.394 mmol) and ethyl formate (0.095 mL, 1.18 mmol) were dissolved in anhydrous ethanol (4.73 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (0.181 mL, 1.97 mmol). This reaction mixture was heated at 78° C. for 1 h, producing a black oil. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCl(aq) causing the formation of a pale orange precipitate. The suspension was filtered yielding an orange solid as the pure 2-Methyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.093 g, 0.241 mmol, 61%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([C@H:13]([OH:15])[CH3:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:16][N:17]1[C:21](S(C)(=O)=O)=[N:20][N:19]=[C:18]1[C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:16][N:17]1[C:21]([O:15][C@@H:13]([C:10]2[N:11]=[N:12][N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=3)[N:9]=2)[CH3:14])=[N:20][N:19]=[C:18]1[C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1
Reactant: Cn1c(-c2ncccn2)nnc1S(C)(=O)=O
Reactant: Cc1cccc(-n2nnc([C@@H](C)O)n2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cccc(-n2nnc([C@@H](C)Oc3nnc(-c4ncccn4)n3C)n2)c1
Temperature: 65 °C
Reaction time: 15 h
Yield: 72.9 %

Procedure:
A mixture of (1R)-1-[2-(3-methylphenyl)-2H-tetrazol-5-yl]ethanol (251 mg, 1.23 mmol), 2-[4-methyl-5-(methylsulfonyl)-4H-1,2,4-triazol-3-yl]pyrimidine (239 mg, 1.00 mmol) and cesium carbonate (911 mg, 2.80 mmol) in N,N-dimethylformamide (10 mL) was stirred at 65° C. for 15 h. After cooling to room temperature, the product was partitioned between ethyl acetate (300 mL) and water (50 mL). The organic layer was washed with water (3×50 mL) and brine (50 mL), and dried over sodium sulfate. The solvent was concentrated in vacuo. Flash chromatography (silica gel, 2-3% methanol in dichloromethane) yielded the title compound (265 mg, 73%, oil).