Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[C:5]=1[NH2:6])([CH3:3])[CH3:2].C[Al](C)C.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([C:32]#[N:33])[CH:23]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:25]=1.C(Cl)Cl>C1(C)C=CC=CC=1.CO>[CH:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[NH:6][C:32]([C:22]1[CH:23]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:25]=[C:20]([O:19][CH3:18])[CH:21]=1)=[NH:33])([CH3:13])[CH3:12]
Reactant: COc1cc(C#N)cc(-c2ccccc2)c1
Reactant: CC(C)c1cccc(C(C)C)c1N
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1cc(C(=N)Nc2c(C(C)C)cccc2C(C)C)cc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.4 %

Procedure:
To a 500 mL 3 neck flask, 2,6-diisopropylaniline (4.99 g, 27.3 mmol) and 100 mL toluene were charged. The mixture was cooled down in ice bath. Trimethylaluminum (20.48 mL, 41.0 mmol) was added dropwise via additional funnel. The reaction mixture was stirring at RT for 2 hours. Then, to the mix, added 5-methoxy-[1,1′-biphenyl]-3-carbonitrile (6.0 g, 28.7 mmol) dissolved in 50 mL toluene. The reaction mixture was heated to 70° C. overnight under a nitrogen atmosphere. The reaction mixture was cooled in an ice bath and poured it into silica gel mixed with DCM and methanol (2:1 ratio of DCM:methanol). The slurry was stirred and filtered and washed with DCM and methanol. The solvent was evaporated. The solid remaining after evaporation of solvent was added to 150 mL hexane and the mixture was stirred. The mixture was filtered and washed with hexane. After removal of solvent, 6.8 g of product was obtained for next step.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:31][CH2:32][CH:33]4[CH2:35][CH2:34]4)[C:15]=3[NH:14][C:13]=2[CH3:36])=[O:11])[CH2:5][CH2:4]1.C([O:40][C@@H:41]([CH3:45])[C:42](Cl)=[O:43])(=O)C>>[CH:33]1([CH2:32][O:31][C:22]2[CH:23]=[CH:24][C:25]([C:27]([F:30])([F:29])[F:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:36])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:42](=[O:43])[C@@H:41]([OH:40])[CH3:45])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:35]1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(C(F)(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Agent: Cl
Product: Cc1[nH]c2c(-c3cc(C(F)(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](NC(=O)[C@H](C)O)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-(trifluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f32) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [ClH:1].[Br:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[C:12]([NH:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]1)=[O:13]>CCOCC.CO>[ClH:1].[Br:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[C:12]([NH:14][CH2:15][CH:16]1[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]1)=[O:13]
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)c2n[nH]c3ccc(Br)cc23)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: O=C(NCC1CCNCC1)c1n[nH]c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
2M HCl in Et2O (1.8 L) was added to a solution of compound tert-butyl 4-(aminomethyl)piperidine-1-carboxylate 11a (0.24 moles) in MeOH (500 mL). The mixture was stirred for 3 hours at room temperature then the resulting solid was filtered and dried to give 5-Bromo-N-(piperidin-4-ylmethyl)-1H-indazole-3-carboxamide hydrochloride 11 b (76% yield).
Reaction SMILES: [CH:1]1([CH:6]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[C:7]([NH:9][C:10]2[CH:11]=[C:12]([CH:24]=[CH:25][CH:26]=2)[CH2:13][C:14]2([C:17]([O:19]C(C)(C)C)=[O:18])[CH2:16][CH2:15]2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.O.C(O)(C(F)(F)F)=O>ClCCl>[CH:1]1([CH:6]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:29][CH:28]=2)[C:7]([NH:9][C:10]2[CH:11]=[C:12]([CH:24]=[CH:25][CH:26]=2)[CH2:13][C:14]2([C:17]([OH:19])=[O:18])[CH2:15][CH2:16]2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)C1(Cc2cccc(NC(=O)C(c3ccc(C(F)(F)F)cc3)C3CCCC3)c2)CC1
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cccc(CC2(C(=O)O)CC2)c1)C(c1ccc(C(F)(F)F)cc1)C1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4.83 g (9.63 mmol) of (+/−)-tert-butyl 1-[3-({cyclopentyl[4-(trifluoromethyl)phenyl]acetyl}-amino)benzyl]cyclopropanecarboxylate were dissolved in 25 ml of dichloromethane and, after addition of a drop of water, 7.5 ml of TFA were added at RT. The reaction mixture was stirred at RT for 2 h and then concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 4:1→2:1). This gave 3.89 g (90.8% of theory) of the target compound.
Reaction SMILES: [CH3:1][Si](C)(C)[N-][Si](C)(C)C.[K+].[CH:11]([C:13]12[CH2:20][CH2:19][C:16]([C:21]([O:23][CH3:24])=[O:22])([CH2:17][CH2:18]1)[CH2:15][CH2:14]2)=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.CCOC(C)=O>[CH:11]([C:13]12[CH2:20][CH2:19][C:16]([C:21]([O:23][CH3:24])=[O:22])([CH2:17][CH2:18]1)[CH2:15][CH2:14]2)=[CH2:1]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COC(=O)C12CCC(C=O)(CC1)CC2
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CC12CCC(C(=O)OC)(CC1)CC2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of methyltriphenylphosphonium bromide (9.1 g, 12.8 mmol) in THF (50 ml) at 0° C. was added potassium hexamethyldisilazide (0.5M in toluene, 48.6 ml), dropwise over 5 min. The resulting mixture was allowed to warm up to room temperature over 1 h, then cooled again to 0° C. and treated with methyl 4-formylbicyclo[2.2.2]octane-1-carboxylate (4-1) (Chapman, N. B. et al. J. Org. Chem., 1970, 35, 917) (2.5 g, 12.8 mmol). The reaction mixture was stirred at room temperature for 18 h then diluted with EtOAc (350 ml). The organic phase was washed with aqueous HCl (1 N), saturated aqueous sodium bicarbonate, and brine, then dried (Na2SO4) and concentrated in vacuo. The resulting solid was purified by flash silica gel chromatography, eluting with a gradient 0-4% EtOAc/hexanes. The resulting methyl 4-vinylbicyclo[2.2.2]octane-1-carboxylate (4-2) was isolated as a clear, colorless oil.
Reaction SMILES: [CH2:1]([CH:3]1[N:8]([C:9]([C:11]2[C:12]([NH:20][CH2:21][C:22]3[O:23][CH:24]=[CH:25][CH:26]=3)=[N:13][C:14]([CH:17]([CH3:19])[CH3:18])=[N:15][CH:16]=2)=[O:10])[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1)[CH3:2].C(OCC)(=O)C.[ClH:40]>>[ClH:40].[ClH:40].[CH2:1]([CH:3]1[CH2:4][NH:5][CH2:6][CH2:7][N:8]1[C:9]([C:11]1[C:12]([NH:20][CH2:21][C:22]2[O:23][CH:24]=[CH:25][CH:26]=2)=[N:13][C:14]([CH:17]([CH3:19])[CH3:18])=[N:15][CH:16]=1)=[O:10])[CH3:2]
Reactant: CCC1CN(C(=O)OC(C)(C)C)CCN1C(=O)c1cnc(C(C)C)nc1NCc1ccco1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCC1CNCCN1C(=O)c1cnc(C(C)C)nc1NCc1ccco1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
tert-Butyl 3-ethyl-4-({4-[(2-furylmethyl)amino]-2-isopropylpyrimidin-5-yl}carbonyl)piperazine-1-carboxylate (100 mg) was dissolved in 4 M hydrogen chloride-ethyl acetate solution (3 ml), and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added and the precipitate was collected by filtration to give the object compound (74 mg).
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].[N+:6]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][CH2:14][CH2:13][C:12]2=O)([O-:8])=[O:7].C(O)C>O>[N+:6]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][CH2:14][CH2:13][C:12]2=[N:2][OH:3])([O-:8])=[O:7]
Reactant: NO
Reactant: O=C1CCOc2ccc([N+](=O)[O-])cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1ccc2c(c1)C(=NO)CCO2
Reaction time: 0.42 h

Procedure:
A solution of 79 g (1.14 mole) of hydroxylamine hydrochloride in 770 ml of H2O, contained in a 2 l. Erlenmeyer flask, was treated with 619 ml of 10% NaOH, 150 g (0.78 mole) of 6-nitro-4-chromanone and enough ethanol (750 ml) to produce a solution at the boiling point. The reaction mixture was boiled for 25 min., cooled to 50° over 2 hrs., and filtered. The filtrate was refrigerated overnight and filtered. The tan crystalline solid was washed with 200 ml of ethanol and dried, m.p. 173°-178°. Yield: 60 g (37%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][C@H:6]1[CH2:11][N:10]([S:12]([C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Cl:25])[CH:21]=3)[CH:16]=2)(=[O:14])=[O:13])[CH2:9][C@H:8]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[NH:7]1)=[O:4].C(N(CC)C(C)C)(C)C.[Br:40][C:41]1[CH:49]=[CH:48][C:44]([C:45](Cl)=[O:46])=[CH:43][CH:42]=1.O>ClCCl>[CH3:30][O:29][C:27]([CH2:26][C@H:8]1[CH2:9][N:10]([S:12]([C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Cl:25])[CH:21]=3)[CH:16]=2)(=[O:13])=[O:14])[CH2:11][C@H:6]([CH2:5][C:3]([O:2][CH3:1])=[O:4])[N:7]1[C:45](=[O:46])[C:44]1[CH:48]=[CH:49][C:41]([Br:40])=[CH:42][CH:43]=1)=[O:28]
Reactant: COC(=O)C[C@H]1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)C[C@H](CC(=O)OC)N1
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C[C@H]1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)C[C@H](CC(=O)OC)N1C(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
In dichloromethane (8 ml), the trans-2,6-bis(methoxycarbonylmethyl)-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine (79.7 mg) was dissolved. Under ice cooling, N,N-diisopropylethylamine (68.0 μl) and a solution of 4-bromobenzoyl chloride (51.0 mg) in dichloromethane (2 ml) were added to the resulting solution, followed by stirring at room temperature for 5.5 hours. Water was added to the reaction mixture to separate the organic layer. The organic layer was washed with saturate aqueous NaCl solution, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (n-hexane:ethyl acetate=l:1), whereby the title compound (113 mg, 98%) was obtained as pale yellow amorphous powder.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:23])([CH3:22])[C@@H:11]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:12]=C)(=[O:7])=[O:6].O=O.[O:26]=[O+][O-].CSC>ClCCl.C(O)C>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:22])([CH3:23])[C@@H:11]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH:12]=[O:26])(=[O:6])=[O:7]
Reactant: C=C[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCCl
Reactant: O=[O+][O-]
Agent: O=O
Solvent: ClCCl
Solvent: CSC
Solvent: CCO
Product: CC(C)(COS(=O)(=O)CCCCl)[C@H](C=O)OCc1ccccc1
Yield: 60 %

Procedure:
Following the general procedure for the preparation of aldehydes from alkenes of Description 11, (3S)-2,2-dimethyl-3-(phenylmethoxy)pent-4-enyl (3-chloropropyl]sulfonate (11a) (25.0 g, 69.3 mmol) dissolved in a mixture of 300 mL of dichloromethane (DCM) and 40 mL of ethanol was treated with a mixture of oxygen and ozone (O2/O3). Upon completion of the reaction, 10.6 mL (9.0 g, 138 mmol) of dimethyl sulfide (DMS) was added. After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) (EtOAc/Hxn=1:6) as eluent to provide 15.0 g (60% yield) of the title compound (11b) as a colorless oil. Rf=0.22 (EtOAc/Hxn=1:6). 1H NMR (400 MHz, CDCl3): δ=1.10 (s, 6H), 2.26-2.33 (m, 2H), 3.23-3.29 (m, 2H), 3.65 (d, J=2.8 Hz, 1H), 3.63-3.68 (m, 2H), 4.03 (d, J=9.6 Hz, 1H), 4.15 (d, J=8.8 Hz, 1H), 4.50 (d, J=11.2 Hz, 1H), 4.68 (d, J=11.2 Hz, 1H), 7.30-7.39 (m, 5H), 9.73 (d, J=2.8 Hz, 1H) ppm. MS (ESI) m/z 385.03 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: ClC1C(C(C2[CH:11]=[N:12][N:13](C)C=2C2C=CC(C)=CC=2)=O)=C(Cl)N=CN=1.C(N(CC)C(C)C)(C)C.N1CC[C@H](N2CCCCC2)C1.Cl[C:45]1[C:50]([C:51]([C:53]2[CH:54]=[N:55][N:56]([CH3:65])[C:57]=2[C:58]2[CH:63]=[CH:62][C:61]([CH3:64])=[CH:60][CH:59]=2)=O)=[C:49]([N:66]2[CH2:70][CH2:69][C@H:68]([N:71]3[CH2:76][CH2:75][CH2:74][CH2:73][CH2:72]3)[CH2:67]2)[N:48]=[CH:47][N:46]=1.CNN>C(#N)C>[CH3:11][N:12]1[C:45]2=[N:46][CH:47]=[N:48][C:49]([N:66]3[CH2:70][CH2:69][C@H:68]([N:71]4[CH2:72][CH2:73][CH2:74][CH2:75][CH2:76]4)[CH2:67]3)=[C:50]2[C:51]([C:53]2[CH:54]=[N:55][N:56]([CH3:65])[C:57]=2[C:58]2[CH:59]=[CH:60][C:61]([CH3:64])=[CH:62][CH:63]=2)=[N:13]1
Reactant: Cc1ccc(-c2c(C(=O)c3c(Cl)ncnc3Cl)cnn2C)cc1
Reactant: Cc1ccc(-c2c(C(=O)c3c(Cl)ncnc3N3CC[C@H](N4CCCCC4)C3)cnn2C)cc1
Agent: C1CCN([C@H]2CCNC2)CC1
Agent: CNN
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccc(-c2c(-c3nn(C)c4ncnc(N5CC[C@H](N6CCCCC6)C5)c34)cnn2C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
To a mixture of (4,6-dichloropyrimidin-5-yl)[1-methyl-5-(4-methylphenyl)-1H-pyrazol-4-yl]methanone (C5) (7.3 g, 21 mmol) and N,N-diisopropylethylamine (13.56 g, 104.9 mmol) in acetonitrile (100 mL) was added 1-[(3S)-pyrrolidin-3-yl]piperidine (4.8 g, 31 mmol), and the resulting reaction mixture was stirred at room temperature for 3 hours. To this solution of {4-chloro-6-[(3S)-3-(piperidin-1-yl)pyrrolidin-1-yl]pyrimidin-5-yl}[1-methyl-5-(4-methylphenyl)-1H-pyrazol-4-yl]methanone (C7) was added drop-wise a solution of methylhydrazine (12.1 g, 262 mol) in acetonitrile (20 mL). After being stirred overnight at room temperature, the reaction mixture was concentrated in vacuo and partitioned between dichloromethane (100 mL) and water (100 mL). The aqueous layer was extracted with dichloromethane (2×100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated; purification via silica gel chromatography (Gradient: 10% to 50% ethyl acetate in petroleum ether) afforded the product as a white solid. Yield: 8.64 g, 18.9 mmol, 90% yield. LCMS m/z 457.3 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.39-1.49 (br m, 2H), 1.53-1.73 and 2.00-2.25 (br multiplets, presumed 8H), 2.31 (s, 3H), 2.32-2.45 (br m, 2H), 2.56-2.68 (br m, 1H), 2.90-3.16 (v br m, 1H), 3.26-3.78 (br m, 3H), 3.87 (s, 3H), 4.00 (s, 3H), 7.16 (br AB quartet, JAB=8 Hz, ΔνAB=26 Hz, 4H), 7.66 (s, 1H), 8.29 (s, 1H).
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].I[C:10]1[CH:36]=[CH:35][C:13]2[N:14]([CH2:17][C:18]3[CH:34]=[CH:33][C:21]4[N:22]=[C:23]([NH:25][C@@H:26]5[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]5[OH:32])[S:24][C:20]=4[CH:19]=3)[CH:15]=[N:16][C:12]=2[CH:11]=1.[NH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][C:38]1=[O:43]>CS(C)=O.[Cu](I)I>[OH:32][C@@H:27]1[CH2:28][CH2:29][CH2:30][CH2:31][C@H:26]1[NH:25][C:23]1[S:24][C:20]2[CH:19]=[C:18]([CH2:17][N:14]3[C:13]4[CH:35]=[CH:36][C:10]([N:37]5[CH2:42][CH2:41][CH2:40][CH2:39][C:38]5=[O:43])=[CH:11][C:12]=4[N:16]=[CH:15]3)[CH:34]=[CH:33][C:21]=2[N:22]=1
Reactant: O=C1CCCCN1
Reactant: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(I)ccc43)cc2s1
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C1CCCCN1c1ccc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Temperature: 125 °C
Yield: 2.1 %

Procedure:
To a stirred mixture of copper iodide (23 mg, 0.12 mmol) and tripotassium phosphate (190 mg, 0.90 mmol) in DMSO (3 mL) were added (1R,2R)-2-((6-((5-iodo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (150 mg, 0.30 mmol) from Step 5 of Example 183 and piperidin-2-one (200 mg, 2.02 mmol). The mixture was flushed with argon and heated in a sealed reaction vessel at 125° C. for 15 h. The reaction mixture was cooled to rt and filtered, and the filtrate was purified directly by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the stationary phase to afford 1-(1-((2-(((1R,2R)-2-Hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-5-yl)piperidin-2-one (3 mg, 7%) as a solid. 1H NMR (500 MHz, DMSO-d6) δ 8.31 (br s, 1H), 7.69 (br s, 1H), 7.62 (s, 1H), 7.44-7.53 (m, 2H), 7.30 (d, J=8.4 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H), 7.08 (d, J=8.9 Hz, 1H), 5.45 (s, 2H), 3.62 (t, J=5.4 Hz, 2H), 3.51 (br s, 1H), 3.37-3.46 (m, 2H), 2.36-2.43 (m, 2H), 2.06 (m, 1H), 1.82-1.93 (m, 5H), 1.61-1.70 (m, 2H), 1.20-1.36 (m, 4H); LCMS (ESI) m/z 476 (M+H)+.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.N1C2C(=CC=CC=2)C=CC=1.[N+:16]([C:19]1[C:20](=O)[NH:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=1)([O-:18])=[O:17].C(=O)(O)[O-].[Na+]>O>[Cl:3][C:20]1[C:19]([N+:16]([O-:18])=[O:17])=[CH:24][CH:23]=[C:22]([C:25]([F:28])([F:27])[F:26])[N:21]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c(C(F)(F)F)ccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccc2ncccc2c1
Product: O=[N+]([O-])c1ccc(C(F)(F)F)nc1Cl
Temperature: 140 °C
Yield: 87 %

Procedure:
To phosphorous oxychloride (11 ml, 117 mmol) was added quinoline (8.4 ml, 70 mmol) followed by 3-nitro-6-trifluoromethyl-2(1H)-pyridone (24.0 g, 115 mmol), and the resulting solution heated at 140° C. for 18 h. The solution was then cooled to 100° C., when water (50 ml) was carefully added. After cooling to room temperature, saturated sodium bicarbonate (200 ml) was added and the mixture extracted with ethyl acetate (2×200 ml). The extracts were dried (MgSO4) and concentrated, and the residue purified by silica chromatography to give the product as a brown oil (22.7 g, 0.1 mol, 87% yield).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:4])([CH3:3])[CH3:2].S(Cl)(Cl)=O.[CH2:18]([NH:20][CH2:21][CH3:22])[CH3:19]>C(Cl)Cl>[CH2:18]([N:20]([CH2:21][CH3:22])[C:7](=[O:9])[C:6]1[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=1[C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:19]
Reactant: CC(C)(C)c1ccccc1C(=O)O
Reactant: CCNCC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCN(CC)C(=O)c1ccccc1C(C)(C)C
Temperature: 0 °C

Procedure:
A solution of 2-tert-butylbenzoic acid (4.0 g, 22.5 mmol) in thionyl chloride (8.2 mL, 112 mmol) was stirred at RT for 2 h, then was concentrated three times from carbon tetrachloride to remove all traces of excess thionyl chloride. A solution of diethylamine (4.93 g, 67.4 mmol) in CH2Cl2 (10 mL) was added dropwise over 10 min to an ice water-cooled solution of the crude acid chloride in CH2Cl2 (35 mL). Ten min after addition was complete, the reaction was partitioned between ether and 10% HCl. The ether phase was then washed with sat aq NaHCO3, then was dried (MgSO4), and concentrated to afford a quantitative yield of N,N-diethyl-2-tert-butyl-benzamide as an off-white solid. m.p. 38.5°-40.5° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH2:5][CH2:6][CH2:7][C:8](=[O:17])[C:9]=2[C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>[Pd].CCOCC>[CH3:1][C:2]1[NH:3][C:4]2[CH:5]=[CH:6][CH:7]=[C:8]([OH:17])[C:9]=2[C:10]=1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Cc1[nH]c2c(c1-c1ccccc1)C(=O)CCC2
Agent: [Pd]
Solvent: CCOCC
Product: Cc1[nH]c2cccc(O)c2c1-c1ccccc1

Procedure:
An amount of 22.5 g (0.1 mole) of 4,5,6,7-tetrahydro-2-methyl-3-phenyl-1H-4indolone and 5 g of palladium on charcoal were heated for six hours to 200° C. After cooling, ether was added under stirring, and the mixture was filtered. The ether filtrate was evaporated, and the residue was chromatographed on silicagel (solvent: toluene).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[C:23]([O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=1)(=[O:25])[CH3:24].Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:31]([C:30]2[CH:29]=[CH:28][C:27]([O:26][C:23](=[O:25])[CH3:24])=[CH:35][CH:34]=2)=[O:32])=[CH:20][CH:21]=1
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)c4ccc(OC(C)=O)cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 7 h
Yield: 72.3 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (110 mg) and commercially available 4-acetoxybenzoic acid (207 mg) were dissolved in N,N-dimethylformamide (6 ml), 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (223 mg) was added, and the admixture was stirred at room temperature for 7 hours. The reaction mixture was then purified in the same manner as described in Example 51 to obtain 123 mg of the title compound (yield: 72%).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:9]([O:11][CH3:12])=[O:10].[CH3:19][C:20]1[O:24][N:23]=[C:22]([C:25]2[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=2)[N:21]=1>C(#N)C>[CH3:19][C:20]1[O:24][N:23]=[C:22]([C:25]2[CH:26]=[C:27]([CH:28]=[CH:29][CH:30]=2)[O:31][CH:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([O:11][CH3:12])=[O:10])[N:21]=1
Reactant: Cc1nc(-c2cccc(O)c2)no1
Reactant: COC(=O)C(Br)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)C(Oc1cccc(-c2noc(C)n2)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
11.5 g (33.5 mmol) of caesium carbonate and 7.67 g (35.2 mmol) of methyl 2-bromo-2-phenylacetate are added to a solution of 5.90 g (33.5 mmol) of 3-(5-methyl-1,2,4-oxadiazol-3-yl)phenol in 50 ml of acetonitrile. The reaction mixture is stirred at room temperature for 24 hours, then filtered, and the filtrate is evaporated, giving methyl [3-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]-2-phenylacetate as a yellowish oil; ESI 325.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:20][CH2:19][C:18]3[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=3[NH:16][C:15]2=[O:25])[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[NH:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH2:20][CH2:19][C:18]3[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=3[NH:16][C:15]2=[O:25])[CH2:12][CH2:13]1
Reactant: O=C1Nc2ccccc2CCN1C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: O=C1Nc2ccccc2CCN1C1CCNCC1
Reaction time: 8 h
Yield: 67.9 %

Procedure:
3-(1-Benzyl-piperidin-4-yl) 1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one (100 mg, 0.3 mmol) in methanol (5 mL) was flushed with nitrogen, and treated with palladium on charcoal (10%, 10 mg). The flask was flushed with hydrogen and allowed to stir under an atmosphere of hydrogen overnight. The reaction was flushed with nitrogen, filtered through celite, and concentrated. Column chromatography gave 50 mg (68%) of the desired material. LC/MS: tR=1.07 min, 246.26 (MH)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14](=[O:24])[NH:15][CH2:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[N:21][CH:22]=3)[CH:11]=[C:10]([C:25](O)=[O:26])[CH:9]=2)=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[F:51][C:52]1([F:56])[CH2:55][NH:54][CH2:53]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[F:51][C:52]1([F:56])[CH2:55][N:54]([C:25]([C:10]2[CH:11]=[C:12]([C:14]([NH:15][CH2:16][C:17]3[CH:22]=[N:21][C:20]([CH3:23])=[N:19][CH:18]=3)=[O:24])[CH:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)[CH:9]=2)=[O:26])[CH2:53]1
Reactant: FC1(F)CNC1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)NCc3cnc(C)nc3)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(C(=O)NCc3cnc(C)nc3)cc(C(=O)N3CC(F)(F)C3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4′-methyl-5-((2-methylpyrimidin-5-yl)methylcarbamoyl)biphenyl-3-carboxylic acid (11 mg, 0.030 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (12 mg, 0.061 mmol), 1-hydroxybenzotriazole hydrate (4.7 mg, 0.030 mmol), CH2Cl2 (2 mL) were added 3,3-difluoroazetidine (4.2 mg, 0.046 mmol) and N,N-diisopropylethylamine (11 μL, 0.061 mmol). The mixture was stirred at room temperature overnight, and then concentrated in vacuo. The residue was purified by preparative HPLC (100×21.2 mm C18 column, 30-70% MeCN/water[10 mM Et2NH]) to afford a white foam.