Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9](O)(O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].Cl.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=1[NH:24][C:25](=[O:28])[NH:26][NH2:27]>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=1[NH:24][C:25](=[O:28])[NH:26][N:27]=[C:9]1[C:10](=[O:11])[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[C:7]1=[O:8]
Reactant: COc1ccc(Cl)c(NC(=O)NN)c1
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Agent: Cl
Product: COc1ccc(Cl)c(NC(=O)NN=c2c(=O)c3ccccc3c2=O)c1

Procedure:
ninhydrin, 4-(2-chloro-5-methoxyphenyl)-semicarbazide hydrochloride
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([CH2:9][CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][OH:18])[CH2:13][CH2:12]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].I([O-])(=O)(=O)=[O:21].[Na+]>C(Cl)(Cl)(Cl)Cl.O.C(#N)C.O.[Ru](Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:7]([CH3:8])[CH2:9][CH2:10][C@H:11]1[CH2:12][CH2:13][C@H:14]([C:17]([OH:21])=[O:18])[CH2:15][CH2:16]1)=[O:19])([CH3:3])([CH3:2])[CH3:4]
Reactant: CN(CC[C@H]1CC[C@H](CO)CC1)C(=O)OC(C)(C)C
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CN(CC[C@H]1CC[C@H](C(=O)O)CC1)C(=O)OC(C)(C)C

Procedure:
A solution of 17.1 g (63.1 mmol) of trans-[2-(4-hydroxymethyl-cyclohexyl)-ethyl]-methyl-carbamic acid tert-butyl ester in 60 mL of CCl4, 60 mL of water and 90 mL of acetonitrile were treated with 0.075 g (0.33 mmol, 0.05 eq) of ruthenium (III) chloride-hydrate and 55.4 g (259 mmol, 4.1 eq) of sodium metaperiodate within 30 min. After 6 h the reaction was decanted and washed with CH2Cl2 (×3). The decanted phase was partitioned between CH2Cl2 (×3)/H2O, the organic phase was dried over Na2SO4 and evaporated to yield 17.24 g (96%) of trans-4-[2-(tert-butoxycarbonyl-methyl-amino)-ethyl]-cyclohexanecarboxylic acid, MS: 284 (M−H−).
Reaction SMILES: [OH:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH:4]=O.[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C:16]1[N:17]=[C:18]2[N:22]([C:23]=1[C:24]1[N:25]=[N:26][C:27]([NH:30][NH2:31])=[CH:28][CH:29]=1)[CH:21]=[CH:20][O:19]2.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C(Cl)Cl>[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C:16]1[N:17]=[C:18]2[N:22]([C:23]=1[C:24]1[CH:29]=[CH:28][C:27]3[N:26]([C:4]([CH2:3][C:2]([CH3:7])([OH:1])[CH3:6])=[N:31][N:30]=3)[N:25]=1)[CH:21]=[CH:20][O:19]2
Reactant: NNc1ccc(-c2c(-c3ccc(F)cc3F)nc3occn23)nn1
Reactant: CC(C)(O)CC=O
Solvent: Ic1ccccc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(O)Cc1nnc2ccc(-c3c(-c4ccc(F)cc4F)nc4occn34)nn12
Reaction time: 1 h
Yield: 33.5 %

Procedure:
To round bottom flask, 3-hydroxy-3-methylbutanal (0.178 g, 1.185 mmol) and 6-(2,4-difluorophenyl)-5-(6-hydrazinylpyridazin-3-yl)imidazo[2,1-b]oxazole (0.3 g, 0.859 mmol) and DCM 5 mL were added. The reaction mixture was stirred at about ambient temperature for about 1 h. Iodobenzene diacetate (0.38 g, 1.18 mmol) was added and was stirred at ambient temperature for overnight. The reaction mixture was quenched with water. The aqueous phase was extracted with DCM and the organic layer was concentrated under reduced pressure. The crude material was purified by silica gel chromatography using DCM/MeOH (90:10). After concentration of the fractions with product, the resulting solid was triturated with ether. The solid was collected by filtration then dried under vacuum at about 60° C. for about 2 days to give the title compound (0.118 g, 33.5%): LC/MS (Table 1, Method g) Rt=1.78 min; MS m/z: 411.2 (M+H)+. 1H NMR (DMSO-d6) δ 8.52 (d, 1H), 8.27 (d, 1H), 8.21 (d, 1H), 7.75 (m, 1H), 7.50-7.40 (m, 1H), 7.34-7.25 (m, 1H), 6.90 (m, 1H), 4.71 (s, 1H), 3.33 (s, 2H), 1.27 (s, 6H)
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:14][CH2:15][C@H:16]3[CH2:21][CH2:20][C@@H:19]([C:22]([F:25])([F:24])[F:23])[CH2:18][CH2:17]3)=[CH:6][C:7]([F:13])=[C:8]([CH:12]=2)[C:9]([OH:11])=O)[CH2:3][CH2:2]1.N1(S(N)(=O)=O)CCC1.[CH:34]1([S:37]([NH2:40])(=[O:39])=[O:38])[CH2:36][CH2:35]1>>[CH:1]1([C:4]2[C:5]([O:14][CH2:15][C@H:16]3[CH2:17][CH2:18][C@@H:19]([C:22]([F:25])([F:23])[F:24])[CH2:20][CH2:21]3)=[CH:6][C:7]([F:13])=[C:8]([CH:12]=2)[C:9]([NH:40][S:37]([CH:34]2[CH2:36][CH2:35]2)(=[O:39])=[O:38])=[O:11])[CH2:3][CH2:2]1
Reactant: O=C(O)c1cc(C2CC2)c(OC[C@H]2CC[C@@H](C(F)(F)F)CC2)cc1F
Reactant: NS(=O)(=O)C1CC1
Agent: NS(=O)(=O)N1CCC1
Product: O=C(NS(=O)(=O)C1CC1)c1cc(C2CC2)c(OC[C@H]2CC[C@@H](C(F)(F)F)CC2)cc1F

Procedure:
Following the procedure as described in Example 218 step 5, and making variations as required to replace trans-4-((5-chloroadamantan-2-yl)oxy)-5-cyclopropyl-2-fluorobenzoic acid with cis-5-cyclopropyl-2-fluoro-4-((4-(trifluoromethyl)cyclohexyl)-methoxy)benzoic acid and to replace azetidine-1-sulfonamide with cyclopropanesulfonamide, the title compound was obtained as colorless solid (0.11 g, 79%): 1H NMR (300 MHz, DMSO-d6) δ 11.82 (s, 1H), 7.13 (d, J=8.3 Hz, 1H), 7.04 (d, J=13.1 Hz, 1H), 4.06 (d, J=7.1 Hz, 2H), 3.11-3.03 (m, 1H), 2.42-2.26 (m, 1H), 2.14 (brs, 1H), 2.06-1.97 (m, 1H), 1.74-1.56 (m, 8H), 1.13-1.09 (m, 4H), 0.91-0.85 (m, 2H), 0.69-0.64 (m, 2H); MS (ES+) m/z 464.1 (M+1); MS (ES−) m/z 462.2 (M−1).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:39]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[O:40]>ClCCl.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:39]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[O:40])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCCCCOC(=O)Cl
Reactant: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OC)c4ccccn4)ccc3n2C)cc1
Yield: 66 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)amide hydrochloride and n-pentyl chloroformate. Yield: 66% of theory, C32H37N7O5 (599.7); Rf value: 0.58 (silica gel; dichloromethane/methanol=9:1); EKA mass spectrum: (M+H)+=600; (M+H+Na)++=311.7; (M+Na)+=622.
Reaction SMILES: [Br:1]Br.Cl.[C:4]([C:7]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)(=[O:6])[CH3:5].CCOCC>C(Cl)Cl>[BrH:1].[Br:1][CH2:5][C:4]([C:7]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]1)=[O:6]
Reactant: CC(=O)C1(c2ccccc2)CCNCC1
Reactant: BrBr
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: Br
Product: O=C(CBr)C1(c2ccccc2)CCNCC1
Reaction time: 8 h
Yield: 196.7 %

Procedure:
8 g of bromine are added rapidly at RT to a suspension of 11.98 g of 4-acetyl-4-phenylpiperidine hydrochloride in 200 ml of DCM and the reaction mixture is left to stand overnight at RT, with stirring. It is diluted by the addition of 200 ml of ether and the precipitate formed is filtered off and washed with ether to give 17.88 g of the expected product after drying under vacuum.
Reaction SMILES: Cl.[C:2](Cl)(=O)[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.I.[CH:12]1([NH:15][C:16](=[N:19][NH2:20])[NH:17][CH3:18])[CH2:14][CH2:13]1.O>N1C=CC=CC=1>[CH:12]1([NH:15][C:16]2[N:17]([CH3:18])[C:2]([C:3]3[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=3)=[N:20][N:19]=2)[CH2:14][CH2:13]1
Reactant: O=C(Cl)c1ccncc1
Reactant: CNC(=NN)NC1CC1
Agent: Cl
Agent: I
Solvent: c1ccncc1
Solvent: O
Product: Cn1c(NC2CC2)nnc1-c1ccncc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Isonicotinoyl chloride hydrochloride (630 mg, 3.5 mmol) was added to N-cyclopropyl-N′-methylcarbonohydrazonic diamide hydroiodide (900 mg 3.5 mmol) in pyridine (10 ml) and the mixture was stirred at r.t. for 2 h. The mixture was the heated to 160° C. under microwave irradiation for 10 min. Water (50 ml) was added and the mixture was extracted with DCM. The pooled organic phases were dried and concentrated and the desired product was obtained by prep. HPLC. LCMS (M++1) 216
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[OH:14][C@@H:15]([C@H:17]1[C@@H:20]([C:21]#[C:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[NH:19][C:18]1=[O:27])[CH3:16].C(OCC)(=O)C>CN(C)C=O.O>[Si:6]([O:14][C@@H:15]([C@H:17]1[C@@H:20]([C:21]#[C:22][Si:23]([CH3:24])([CH3:26])[CH3:25])[NH:19][C:18]1=[O:27])[CH3:16])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: C[C@@H](O)[C@@H]1C(=O)N[C@@H]1C#C[Si](C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1C(=O)N[C@@H]1C#C[Si](C)(C)C
Reaction time: 1.5 h

Procedure:
Imidazole (0.2 g) and tert-butyldimethylsilyl chloride (0.3 g) are added to a solution of cis-3-[(R)-1-hydroxyethyl]-4-trimethylsilylethynyl-2-azetidinone (0.2 g) in N,N-dimethylformamide (7 ml), and the mixture is stirred at 60° C.-65° C. for 1.5 hours and then poured into a mixture of ethyl acetate (50 ml) and water (50 ml). The organic layer is separated, washed with aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure, and the residue is subjected to silica gel column chromatography to give cis i.e. (3R,4S)-3-[(R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-trimethylsilylethynyl-2-azetidinone as crystals. (0.24 g).
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][CH2:7][NH:6][CH:5]([C:9]([NH:11][C@H:12]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)[CH3:13])=[O:10])[CH2:4]2)[CH2:2]1.C([O-])([O-])=O.[Na+].[Na+].[F:29][C:30]([F:40])([F:39])[C:31]1[CH:38]=[CH:37][C:34]([CH2:35]Br)=[CH:33][CH:32]=1>CC#N>[F:29][C:30]([F:40])([F:39])[C:31]1[CH:38]=[CH:37][C:34]([CH2:35][N:6]2[CH2:7][CH2:8][C:3]3([CH2:2][CH2:1]3)[CH2:4][CH:5]2[C:9]([NH:11][C@H:12]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([O:20][CH2:35][C:34]3[CH:33]=[CH:32][C:31]([C:30]([F:29])([F:39])[F:40])=[CH:38][CH:37]=3)=[O:19])=[CH:16][CH:15]=2)[CH3:13])=[O:10])=[CH:33][CH:32]=1
Reactant: C[C@H](NC(=O)C1CC2(CCN1)CC2)c1ccc(C(=O)O)cc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: C[C@H](NC(=O)C1CC2(CCN1Cc1ccc(C(F)(F)F)cc1)CC2)c1ccc(C(=O)OCc2ccc(C(F)(F)F)cc2)cc1
Temperature: 68 °C
Yield: 72.3 %

Procedure:
To a solution of 4-((1S)-1-(6-azaspiro[2.5]octane-5-carboxamido)ethyl)benzoic acid (D128) (10 mg, 33.1 μmol) in dry MeCN, Na2CO3 (17.5 mg, 165.4 μmol) and 4-(trifluoromethyl)-benzylbromide (24 mg, 99.2 μmol) were added in sequence. The mixture was heated at 68° C. for 18 hrs. The solid was filtered off, MeCN was evaporated and the residue was purified by Biotage SNAP-Si column (10 g) eluting with a mixture DCM/EtOAc from 100/0 to 80/20. Collected fractions after solvent evaporation afforded the title compounds (D129) (14.8 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[O:18]1[CH2:23][CH2:22][CH:21](O)[CH2:20][CH2:19]1.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]([CH:21]2[CH2:22][CH2:23][O:18][CH2:19][CH2:20]2)[C:12]2[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: OC1CCOCC1
Reactant: O=S(=O)(Cc1ccncc1)c1ccc(Cl)cc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccc(Cl)cc1)C(c1ccncc1)C1CCOCC1
Temperature: 25 °C
Yield: 70.8 %

Procedure:
A toluene (5 ml) solution of the 4-(4-chlorophenylsulfonylmethyl)pyridine (70 mg, 0.261 mmol) obtained in Example 119, tetrahydropyran-4-ol (51 μl, 0.538 mmol) and cyanomethylenetri-n-butylphosphorane (129 mg, 0.538 mol) was heated under reflux for 3 days under an argon atmosphere. After cooling to room temperature, the reaction mixture was added with tetrahydropyran-4-ol (51 μl, 0.538 mmol) and cyanomethylenetri-n-butylphosphorane (129 mg, 0.538 mol), followed by heating under reflux for 22 hours under an argon atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was subjected to flash chromatography on a silica gel column, and the fraction obtained from the hexane:ethyl acetate (=1:2) eluate was concentrated under reduced pressure to give the title compound (65 mg, 71%) as a white solid. The resulting solid was washed with hexane-ether and collected by filtration, whereby the title compound was obtained as a white powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:43])[NH:7][C:8]([C:10]1[S:11][C:12]([S:41][CH3:42])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=S)=[CH:26][C:25]=3[CH3:40])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].[NH3:44]>CO.[Hg]=O>[C:1]([O:5][C:6](=[O:43])[NH:7][C:8]([C:10]1[S:11][C:12]([S:41][CH3:42])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH2:44])=[N:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:26][C:25]=3[CH3:40])[CH:21]=[CH:22][CH:23]=2)(=[O:16])=[O:17])[CH:14]=1)=[NH:9])([CH3:3])([CH3:4])[CH3:2]
Reactant: N
Reactant: CCCCCCNC(=S)Nc1ccc(-c2cccc(S(=O)(=O)c3cc(C(=N)NC(=O)OC(C)(C)C)sc3SC)c2)c(C)c1
Agent: O=[Hg]
Solvent: CO
Product: CCCCCCN=C(N)Nc1ccc(-c2cccc(S(=O)(=O)c3cc(C(=N)NC(=O)OC(C)(C)C)sc3SC)c2)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
({4-[4′-(3-Hexyl-thioureido)-2′-methyl-biphenyl-3-sulfonyl]-5-methylsulfanyl-thiophen-2-yl}-imino-methyl)-carbamic acid tert-butyl ester (33 mg, 0.14 mmol. Example 136: step a) was dissolved into ammonia in methanol (2.0 M, 4 mL). To this was added mercury(II) oxide (33.9 mg, 0.16 mmol) and the reaction stirred at RT for 2 hours. Additional mercury(II) oxide (154 mg, 0.08 mmol) was added and the reaction was heated to 40° C. overnight. The reaction was filtered with 0.2 μM disk and washed with EtOAc followed by removal of solvents in vacuo that yielded the title compound which was used without further purification (30 mg). ESI-MS (m/z): Calcd. for C31H41N5O4S3: 644.2 (M+1); found: 644.1.
Reaction SMILES: C([NH:11][C@H:12]([C:16]([NH:18][CH:19]([C:23]([F:53])([F:52])[C:24](=[O:51])[CH:25]([NH:33][C:34](=[O:50])[C@H:35]([CH2:47][O:48][CH3:49])[NH:36][C:37]([O:39]CC1C=CC=CC=1)=O)[CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[CH:20]([CH3:22])[CH3:21])=[O:17])[CH2:13][O:14][CH3:15])(OCC1C=CC=CC=1)=O.[CH2:54](N(CC)CC)C.[C:61](Cl)(=[O:63])[CH3:62]>C(Cl)Cl.[Pd]>[C:61]([NH:11][C@H:12]([C:16]([NH:18][CH:19]([C:23]([F:52])([F:53])[CH:24]([OH:51])[CH:25]([NH:33][C:34](=[O:50])[C@H:35]([CH2:47][O:48][CH3:49])[NH:36][C:37](=[O:39])[CH3:54])[CH2:26][CH:27]1[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1)[CH:20]([CH3:21])[CH3:22])=[O:17])[CH2:13][O:14][CH3:15])(=[O:63])[CH3:62]
Reactant: COC[C@H](NC(=O)OCc1ccccc1)C(=O)NC(CC1CCCCC1)C(=O)C(F)(F)C(NC(=O)[C@H](COC)NC(=O)OCc1ccccc1)C(C)C
Reactant: CCN(CC)CC
Reactant: CC(=O)Cl
Agent: [Pd]
Solvent: ClCCl
Product: COC[C@H](NC(C)=O)C(=O)NC(CC1CCCCC1)C(O)C(F)(F)C(NC(=O)[C@H](COC)NC(C)=O)C(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution was 50 mg of the resultant compound of Example 185 and 20 mg of 10% Pd/C was stirred vigorously under a hydrogen atmosphere. After 30 minutes, the catalyst was filtered off and the filtrate concentrated to give a colorless oil, which was dissolved in 2 ml of CH2Cl2. The solution was cooled to 0° C., 0.03 ml of triethylamine and 0.01 ml of acetyl chloride was added. After 2 hrs, the solution was concentrated and the crude product purified by silica gel column chromatography (5% MeOH/CH2Cl2) to give 16 mg of the desired compound. Mass spectrum: (M+H)+ =565.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH2:9][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:2]1.CCN(C(C)C)C(C)C.[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>C1COCC1>[CH2:7]([O:6][C:4]([CH:3]1[CH2:9][CH2:10][CH2:11][N:1]([C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([F:21])=[CH:23][CH:24]=2)[CH2:2]1)=[O:5])[CH3:8]
Reactant: CCOC(=O)C1CCCNC1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCCN(C(=O)c2ccc(F)cc2)C1
Temperature: 0 °C
Reaction time: 24 h
Yield: 33 %

Procedure:
To a mixture of Ethyl nipecotate (2 g, 12.72 mmol) in THF (25 ml, 0.5M) was added DIEA (4.79 ml, 27.99 mmol). The reaction mixture was cooled to 0° C. and 4-Fluoro-benzoyl chloride (2.5 g-15.76 mmol) was slowly added. The reaction was to go up to R.T and stirred for 24 h. The solution was concentrated and DCM was added following by HCl 1N. The aqueous phase was separated and organic phase was extracted twice with HCl 1N and twice with water, dried over Na2SO4, filtered and concentrated to afford 1.15 g (33%) of 1-(4-Fluoro-benzoyl)-piperidine-3-carboxylic acid ethyl ester as a colorless oil which can be used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:3]=1[C:4]([NH2:6])=[O:5].[CH3:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([CH3:30])[C:21]=1[O:22][CH2:23][CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)[CH:17]=O.S([O-])(O)=O.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[CH3:30][C:20]1[CH:19]=[C:16]([C:17]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([F:11])=[CH:8][C:7]=3[F:12])[N:1]=2)[CH:15]=[C:14]([CH3:13])[C:21]=1[O:22][CH2:23][CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: Cc1cc(C=O)cc(C)c1OCCN1CCCC1
Reactant: NC(=O)c1c(N)cc(F)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cc(-c2nc3cc(F)cc(F)c3c(=O)[nH]2)cc(C)c1OCCN1CCCC1
Temperature: 145 °C
Reaction time: 16 h

Procedure:
To a solution of 2-amino-4,6-difluoro-benzamide (0.80 g, 4.60 mmol) and 3,5-dimethyl-4-(2-pyrrolidin-1-yl-ethoxy)-benzaldehyde (1.14 g, 4.60 mmol) in N,N-dimethylacetamide (60 mL) were added sodium hydrogen sulfite (58.5 wt %, 1.25 g, 6.9 mmol) and p-toluenesulfonic acid monohydrate (3.50 g, 18.4 mmol). The reaction mixture was stirred at 145° C. for 16 hours under nitrogen atmosphere, then cooled to room temperature. Solvent was evaporated under reduced pressure. Water (50 mL) was added, followed by saturated aqueous sodium bicarbonate solution (15 mL). The mixture was extracted with CH2Cl2 (2×100 mL) and washed with water. The organic phase was evaporated and the residue was washed with hexane/ether (90:10, 100 mL). The solid was filtered and dried under vacuum to give the title compound as a brown solid. Yield: 1.48 g (80%). MP 234-235° C. 1H NMR (400 MHz, DMSO-d6): δ 12.36 (s, 1H), 7.90 (s, 1H), 7.32 (m, 2H), 3.91 (t, J=4 Hz, 2H), 2.83 (t, J=4 Hz, 2H), 2.55 (s, 4H), 2.31 (s, 6H), 1.70 (s, 4H).
Reaction SMILES: [C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:8]2[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[N:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)=O.CN([CH:29]=[O:30])C>O.ClCCl.[OH-].[Na+]>[C:15]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:12]([CH3:13])=[C:11]([CH:29]=[O:30])[C:10]([CH3:14])=[N:9]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1cc(C)n(C(c2ccccc2)c2ccccc2)n1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: Cc1nn(C(c2ccccc2)c2ccccc2)c(C)c1C=O
Temperature: 100 °C

Procedure:
To a hot solution of 1-(diphenylmethyl)-3,5-dimethyl-(1H)-pyrazole (25.0 g) in DMF (22 ml) was added phosphoryl chloride (8.87 ml) dropwise with stirring under nitrogen and the resulting mixture heated at 100° C. for 3 hr. It was cooled, diluted with water and dichloromethane and basified with 50% sodium hydroxide with ice/water cooling. It was extracted with dichloromethane, the organic extracts washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography over silica, eluting with ethyl acetate/i-hexane (1:19) followed by ethyl acetate to give the sub-title compound as a solid (12.61 g).
Reaction SMILES: Br[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.C[Li].C([Li])(C)(C)C.[C:20](=[O:22])=[O:21].Cl>CCOCC>[OH:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([C:20]([OH:22])=[O:21])[CH:11]=[CH:10]2
Reactant: O=C=O
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: Cl
Agent: [Li]C
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: O=C(O)c1ccc2cc(O)ccc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
To a slurry of 5.00 g (22.4 mmol, Aldrich) of 6-bromo-2-naphthol in 150 ml of dry ether at -78° was added dropwise, 16 ml (1.4M in ether, 22 mmol, Aldrich) of methyllithium solution over 10 minutes. The reaction mixture was stirred for 10 minutes, then 28 ml (1.8M in pentane, 50 mmol, Aldrich) of t-butyllithium solution was added dropwise over 15 minutes. The resulting slurry was stirred at -78° for 30 minutes then at 0° for 15 minutes. The reaction mixture was re-cooled to -78°, added into 100 g of crushed dry ice via cannula, and allowed to warm to room temperature over about ~2 hours, then added to 200 ml of 1M aqueous HCl solution and extracted with 100 ml of ethyl acetate. The organic extract was separated, washed with an additional 200 ml of H2O and concentrated in vacuo to give a pale yellow solid. The crude material was dissolved in 125 ml of warm, saturated aqueous NaHCO3 solution and extracted with two 50 ml portions of ethyl acetate. The aqueous phase was acidified to pH 1 with concentrated HCl. The solid which precipitated was collected on a Buchner funnel then dried under vacuum at 110° to afford 2.95 g (70%) of title compound as an off-white powder, m.p. 237°-241°.
Reaction SMILES: Br[C:2]1[C:3]([F:20])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[CH:13]=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:19]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C@:27]([OH:31])([C:29]#[CH:30])[CH3:28]>>[F:20][C:3]1[C:2]([C:30]#[C:29][C@@:27]([OH:31])([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=2)[CH3:28])=[CH:19][C:6]2[C:7]3[N:8]([CH:13]=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=3)[CH:9]3[CH2:12][CH:11]([C:5]=2[CH:4]=1)[CH2:10]3
Reactant: C#C[C@@](C)(O)c1ccccn1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1C1CC2C1
Product: C[C@@](O)(C#Cc1cc2c(cc1F)C1CC(C1)n1cc(C(N)=O)nc1-2)c1ccccn1

Procedure:
Similar to as described in General Procedure F, reaction of 10-bromo-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide with (R)-2-(pyridin-2-yl)but-3-yn-2-ol gave the titled compound.