Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[C:2]([CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][N:15]2[CH2:22][CH2:21][CH2:20][N:19]([C:23]3[N:27]([CH2:28][C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)[C:26]4[CH:36]=[CH:37][CH:38]=[CH:39][C:25]=4[N:24]=3)[CH2:18][CH2:17][CH2:16]2)=[CH:9][CH:8]=1)([OH:4])=[O:3].Cl.[CH:41](O)([CH3:43])[CH3:42]>>[F:35][C:32]1[CH:33]=[CH:34][C:29]([CH2:28][N:27]2[C:26]3[CH:36]=[CH:37][CH:38]=[CH:39][C:25]=3[N:24]=[C:23]2[N:19]2[CH2:20][CH2:21][CH2:22][N:15]([CH2:14][CH2:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][C:2]([O:4][CH:41]([CH3:43])[CH3:42])=[O:3])=[CH:12][CH:11]=3)[CH2:16][CH2:17][CH2:18]2)=[CH:30][CH:31]=1
Reactant: CC(C)O
Reactant: O=C(O)CCc1ccc(CCN2CCCN(c3nc4ccccc4n3Cc3ccc(F)cc3)CCC2)cc1
Agent: Cl
Agent: [Na]
Product: CC(C)OC(=O)CCc1ccc(CCN2CCCN(c3nc4ccccc4n3Cc3ccc(F)cc3)CCC2)cc1

Procedure:
A solution of 5-[2-[4-(2-carboxyethyl)phenyl]ethyl]-1-[1(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-1,5-diazacyclooctane sodium salt (163 mg) in an isopropanol solution saturated with HCl was refluxed for 4 hours. The solvent was removed under reduced pressure, and the residue was dissolved in methylene chloride (20 ml). The solution was washed with a saturated aqueous NaHCO3 solution and brine. The organic layer was dried over anhydrous MgSO4. The solvent was removed under reduced pressure, and the residue was purified by medium pressure liquid column chromatography on a silica gel column using a mixture of methylene chloride, diethyl ether and methanol (1:1:0.25) as eluent to give 1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-5-[2-[4-(2-isopropoxycarbonylethyl)phenyl]ethyl]-1,5-diazacyclooctane (123mg) as a colorless oily liquid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:23][CH2:24][CH2:25][CH3:26])=[C:7]([C:9]2[NH:10][C:11](=[O:22])[C:12]3[N:17]([CH3:18])[N:16]=[C:15]([CH2:19][CH2:20][CH3:21])[C:13]=3[N:14]=2)[CH:8]=1.[OH-].[Na+].C(O)C[OH:31].O>CS(C)=O>[OH:31][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:23][CH2:24][CH2:25][CH3:26])=[C:7]([C:9]2[NH:10][C:11](=[O:22])[C:12]3[N:17]([CH3:18])[N:16]=[C:15]([CH2:19][CH2:20][CH3:21])[C:13]=3[N:14]=2)[CH:8]=1
Reactant: CCCOc1ccc(CCl)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Reactant: OCCO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCCOc1ccc(CO)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Temperature: 100 °C
Yield: 2 %

Procedure:
To a solution of 5-(5-chloromethyl-2-n-propoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one (0.5 g, 0.0013 mol) in dimethyl sulphoxide (10 ml) was added sodium hydroxide (0.26 g, 0.0065 mol) and ethylene glycol (0.41 g, 0.0065 mol). The reaction mixture was heated at 100° C. for 6 hours, allowed to cool and poured into water (50 ml), then the aqueous mixture extracted with ethyl acetate (3>30 ml). The combined extracts were filtered, dried (Na2SO4) and evaporated under vacuum to provide an oil which was purified by chromatography on silica gel (6g), using a methanol in dichloromethane elution gradient (0-3%) methanol). The solid product was crystallised from hexane-ethyl acetate to afford the title compound as a white solid (2%), m.p. 174°-175° C. Found: C,63.97; H,6.66; N,15.57. C19H24N4O3 requires C,64.03; H,6.79; N,15.72%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12]/[CH:13]=[CH:14]/[C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)[CH:9](O)[CH3:10])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:44](C(OCC)=O)=NC(OCC)=O.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12]/[CH:13]=[CH:14]/[C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)[CH:9]([NH2:44])[CH3:10])=[CH:4][CH:3]=1
Reactant: CC(O)C(C/C=C/c1ccc2ccccc2c1)c1ccc(Cl)cc1
Reactant: CCOC(=O)N=NC(=O)OCC
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(N)C(C/C=C/c1ccc2ccccc2c1)c1ccc(Cl)cc1

Procedure:
4.06 g of (2RS,3SR,5E)-3-(4-chlorophenyl)-6-(2-naphthyl)-5-hexen-2-ol was dissolved in 30 ml of tetrahydrofuran, and 4.77 g of triphenylphosphine, 2.89 ml of diethyl azodicarboxylate and 4.77 g of diphenylphosphoryl azide were added under cooling with ice with stirring, followed by stirring at room temperature for 30 minutes. The reaction solution was evaporated to dryness under reduced pressure. Then, the residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/1→30/1). The obtained azide product was heated and refluxed together with 3.2 g of triphenylphosphine in 100 ml of 10% water-containing tetrahydrofuran. The reaction solution was evaporated to dryness under reduced pressure. Then, the residue was purified by silica gel column chromatography (methylene chloride/methanol=50/1→20/1) to obtain 2.30 g of the above-identified compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].[C:10]1([CH3:20])[CH:15]=CC(S(O)(=O)=O)=C[CH:11]=1.CC(=C)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:10]([CH3:20])([CH3:15])[CH3:11])[C:3]=1[OH:9]
Reactant: Cc1ccc(O)c(C)c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C=C(C)C
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(O)c(C(C)(C)C)c1
Yield: 2443.9 %

Procedure:
To a 1 liter flask equipped with a condenser, over-head stirrer, and gas inlet tube was added 2,4-dimethylphenol (200 g, 1.64 m.), toluene (400 ml), and p-toluenesulfonic acid (10 g). After heating this solution to reflux, isobutylene was added continuously for 14 hrs. Upon cooling, the solution was washed twice with water (400 ml), dried (MgSO4), and the solvent evaporated to afford a dark brown liquid. GC confirmed that this liquid was about 72% product. Distillation afforded 253 g (86.6%) of clear product which was shown to be 97% pure by GC.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH:9][C:10]([NH2:12])=[O:11])=[CH:7][C:6]([C:13]2[C:21]3[C:20]([NH:22][C@H:23]([C:25]4[N:30]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[C:29](=[O:37])[C:28]5=[C:38]([CH3:41])[CH:39]=[CH:40][N:27]5[N:26]=4)[CH3:24])=[N:19][CH:18]=[N:17][C:16]=3[N:15](COCC[Si](C)(C)C)[CH:14]=2)=[CH:5][N:4]=1.FC(F)(F)C(O)=O.N>>[CH3:1][O:2][C:3]1[C:8]([NH:9][C:10]([NH2:12])=[O:11])=[CH:7][C:6]([C:13]2[C:21]3[C:20]([NH:22][C@H:23]([C:25]4[N:30]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[C:29](=[O:37])[C:28]5=[C:38]([CH3:41])[CH:39]=[CH:40][N:27]5[N:26]=4)[CH3:24])=[N:19][CH:18]=[N:17][C:16]=3[NH:15][CH:14]=2)=[CH:5][N:4]=1
Reactant: COc1ncc(-c2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)cc1NC(N)=O
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: COc1ncc(-c2c[nH]c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)cc1NC(N)=O
Yield: 40.9 %

Procedure:
(S)-1-(2-Methoxy-5-(4-((1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyridin-3-yl)urea (60 mg, 0.08 mmol, 86% purity) was treated with trifluoroacetic acid (2.0 ml, 26.0 mmol) and a solution of ammonia (7N in methanol, 5.0 ml, 35.0 mmol) according to the method described in Example 27. The residue was purified using SP1® Purification System (reverse phase, 0% to 100% water-methanol/acetonitrile 1:1) to obtain 18 mg (43% yield) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7](I)[CH:6]=[CH:5][C:3]=1[NH2:4].[N:10]1[NH:11][C:12](=[O:16])[CH:13]=[CH:14][CH:15]=1.C([O-])([O-])=O.[K+].[K+].OC1C=CC=C2C=1N=CC=C2>CS(C)=O.[Cu]I>[NH2:4][C:3]1[CH:5]=[CH:6][C:7]([N:11]2[C:12](=[O:16])[CH:13]=[CH:14][CH:15]=[N:10]2)=[CH:8][C:2]=1[F:1]
Reactant: O=c1cccn[nH]1
Reactant: Nc1ccc(I)cc1F
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: Nc1ccc(-n2ncccc2=O)cc1F
Temperature: 25 °C

Procedure:
2-Fluoro4-iodoaniline (0.5 g, 2.10 mmol) was combined with 2H-Pyridazin-3-one (0.243 g, 2.53 mmol), CuI (0.06 g, 0.315 mmol), K2CO3 (0.32 g, 2.31 mmol), and 8-hydroxyquinoline (0.046 g, 0.315 mmol) in DMSO (3 mL). The mixture was degassed with a stream of argon and then heated at reflux for 23 h before cooling to RT. 10% aq. NH4OH and EtOAc were added, and the mixture was filtered through a plug of layered celite and decolorizing charcoal, eluting with EtOAc. The filtrate was concentrated under reduced pressure. Purification of the crude product by mplc revealed A (0.16 g, 37%) as a yellow solid. MS: APCI (AP+): 206.1 (M)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]=[CH:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=[O+][O-].P(OCC)(OCC)OCC.[C:29]([C:33]1[CH:38]=[CH:37][C:36]([C:39]2[NH:40][C:41]3[C:46]([NH2:47])=[CH:45][N:44]=[CH:43][C:42]=3[N:48]=2)=[CH:35][CH:34]=1)([CH3:32])([CH3:31])[CH3:30].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CO>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][N:47]([C:46]2[C:41]3[N:40]=[C:39]([C:36]4[CH:37]=[CH:38][C:33]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:34][CH:35]=4)[NH:48][C:42]=3[CH:43]=[N:44][CH:45]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CC=CC1
Reactant: CC(C)(C)c1ccc(-c2nc3cncc(N)c3[nH]2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CCOP(OCC)OCC
Agent: O=[O+][O-]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)c1ccc(-c2nc3c(N4CCN(C(=O)OCc5ccccc5)CC4)cncc3[nH]2)cc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 2.5 %

Procedure:
2,5-Dihydro-pyrrole-1-carboxylic acid benzyl ester 6 was dissolved in DCM (5 ml) and MeOH (2 ml). It was cooled to −78° C. and treated with ozone until it was blue in color. Triethyl phosphite (246 mg, 1.48 mmol) was added and the solution was allowed to stir for 5 minutes. 2-(4-tert-Butyl-phenyl)-1H-imidazo[4,5-c] pyridin-7-ylamine 4 (266 mg, 1.00 mmol) was added followed by sodium triacetoxyborohydride (538 mg, 2.54 mmol). This mixture was allowed to stir for 18 hours. Mass spectroscopy showed no starting material left after this time, and the solvent was removed under vacuum. The crude was taken up in ethyl acetate and washed with a saturated sodium bicarbonate solution, brine, dried over MgSO4, and the crude was purified by HPLC (Method E), yielding the title product 7 (12 mg (2.5%), 0.026 mmol). 1H NMR (DMSO-d6): δ 8.88 (bs, 1H), 8.23 (d, J=8.5 Hz, 2H), 7.96 (s, 1H), 7.68 (d, J=8.5 Hz, 2H), 7.38 (m, 5H), 5.15 (s, 2H), 1.33 (s, 9H). MS (ESI-POS): [M+H]+=470; MS(ESI-NEG):[M−H]−=468.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH:18]3[CH2:23][CH2:22][N:21]([C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)[C:13](=[O:30])[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+].C(COC)OC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[C:2]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH:18]3[CH2:23][CH2:22][N:21]([C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)[C:13](=[O:30])[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C1CN(S(=O)(=O)c2ccc(I)cc2)CCN1CC1CCN(c2ccncc2)CC1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: O=C1CN(S(=O)(=O)c2ccc(-c3ccccc3)cc2)CCN1CC1CCN(c2ccncc2)CC1
Yield: 58.6 %

Procedure:
A mixture of 4-(4-iodobenzenesulfonyl)-1-[1-(4-pyridyl)-4-piperidylmethyl)-2-piperazinone (216 mg), phenylboronic acid (98 mg), tetrakis(triphenylphosphine)palladium (46 mg), 1M sodium carbonate solution (1.2 ml) and dimethoxyethane (10 ml) was refluxed for 2 hours and cooled, and to the reaction solution was added ethyl acetate. The mixture was washed with water and saturated brine, dried and concentrated, and the residue was purified with silica gel column chromatography (acetone:methanol=9:1→1:1) and washed with water to give colorless crystals of 4-[(1,1′-biphenyl)-4-ylsulfonyl]-1-[1-(4-pyridyl)-4-piperidylmethyl]-2-piperazinone (115 mg), which were dissolved in ethanol and a solution of 4N hydrochloric acid in ethyl acetate. The solution was concentrated under reduced pressure to give amorphous of the title compound.
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[C:3]1=O.[NH2:19][C:20]([NH2:22])=[S:21].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(O)C>[F:15][C:14]([F:17])([F:16])[C:11]1[CH:12]=[CH:13][C:8]([CH:4]2[C:3]3[N:19]=[C:20]([NH2:22])[S:21][C:2]=3[CH2:7][CH2:6][CH2:5]2)=[CH:9][CH:10]=1
Reactant: NC(N)=S
Reactant: O=C1C(Br)CCCC1c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1nc2c(s1)CCCC2c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
The diastereomer mixture of 2-bromo-6-(4-trifluoromethylphenyl)cyclohexanone (500 mg) was dissolved in ethanol (10 mL). Thiourea (130 mg) was added and the mixture was stirred at room temperature overnight. A sodium bicarbonate solution and ethyl acetate were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration, and then the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (394 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10](B2OC(C)(C)C(C)(C)O2)[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])([O-:3])=[O:2].Br[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1>O1CCOCC1>[N+:1]([C:4]1[CH:11]=[C:10]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])([O-:3])=[O:2]
Reactant: Brc1ccccn1
Reactant: CC1(C)OB(c2ccc(C=O)c([N+](=O)[O-])c2)OC1(C)C
Solvent: C1COCCO1
Product: O=Cc1ccc(-c2ccccn2)cc1[N+](=O)[O-]

Procedure:
The title compound was prepared by the procedure as described in Example 101 (Step C) using 2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde and 2-bromopyridine in dioxane (reflux).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([OH:17])[CH:11]=1.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC(C)=O>[CH3:7][O:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:12]([O:17][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:11]=1
Reactant: COC(=O)c1ccc(O)c(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Yield: 122.9 %

Procedure:
Potassium carbonate (6.5 g; 47 mmol) was added to a solution of 3,4-dihydroxybenzoic acid methyl ester (2.6 g; 15.7 mmol) and benzyl bromide (5.37 g; 31.4 mmol) in acetone (100 ml). The reaction mixture was refluxed for 12 hrs. After the removal of the solvent under reduced pressure, the residue was partitioned between ethyl acetate (150 ml) and water (50 ml). The ethyl acetate layer was washed with water (50 ml) and dried over anhydrous magnesium sulfate. Removal of the solvent under reduced pressure provided 3.36 g of 3,4-Dibenzyloxy benzoic acid methyl ester (Yield=86.6%)
Reaction SMILES: [CH2:1]([NH2:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].[CH2:9]([N:27]=[C:28]=[O:29])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>>[CH2:9]([NH:27][C:28]([NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][NH2:8])=[O:29])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: NCCCCCCN
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Product: CCCCCCCCCCCCCCCCCCNC(=O)NCCCCCCN

Procedure:
29 grams 1,6-hexanediamine (0.25 mole) was reacted with 20 gms (0.068 mole) octadecyl isocyanate as in Example 2. Yield: 25.5 gms, melting point 123°-168°C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.CN(C)C=O.[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[C:21]([CH2:23]Br)=[O:22]>O>[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[C:21]([CH2:23][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)=[O:22]
Reactant: O=C(CBr)c1ccc2ccccc2c1
Reactant: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cn1ccnc1)c1ccc2ccccc2c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred, ice-cooled slurry of 35 g. of imidazole in 25 ml. of dimethylformamide is added 24.9 g. of bromomethyl 2-naphthyl ketone. The mixture is stirred for 2 hours at 0° C., and then allowed to come to room temperature and stirred overnight. The solution is poured into water and the resulting sticky solid filtered off, washed with water and dissolved in benzene. Thereafter the resultant benzene solution is dried (azeotroped) to afford 1-(2-naphthoylmethyl)imidazole which is converted to its hydrochloride acid addition salt by addition of ethereal hydrogen chloride until precipitation is complete. The salt is crystallized by the addition of ethyl acetate and the resulting solid recrystallized from methanol/acetone to yield colorless needles of 1-(2-naphthoylmethyl)imidazole hydrochloride, m.p. 226°-228.5° C. (decomp.).
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]2[CH2:9][CH2:10][N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:5]2=[N:4][CH:3]=1.[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][C:27]=1[F:35])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl-].[Li+]>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29]([C:2]2[C:7](=[O:8])[N:6]3[CH2:9][CH2:10][N:11]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:5]3=[N:4][CH:3]=2)=[CH:28][C:27]=1[F:35])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=c1c(Br)cnc2n1CCN2c1ccccc1
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: C1COCCO1
Product: O=c1c(-c2ccc(OCc3ccccc3)c(F)c2)cnc2n1CCN2c1ccccc1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A suspension of 6-bromo-1-phenyl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one (0.075 g, 0.257 mmol), 4-(benzyloxy)-3-fluorophenylboronic acid (0.076 g, 0.308 mmol), Pd(PPh3)4 (0.015 g, 0.013 mmol) and lithium chloride (0.044 g, 1.03 mmol) in dioxane (2 mL) and 2M aqueous Na2CO3 was stirred at 100° C. for 30 minutes. The reaction mixture was cooled to room temperature and then partitioned between EtOAc and H2O. The layers were separated and the aqueous layer was re-extracted with EtOAc (1×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by flash column chromatography, eluting with 10:1 CH2Cl2/EtOAc. The product was obtained (84 mg; 79%) as a pale tan solid. 1H-NMR (400 MHz, DMSO-d6) δ 8.04 (s, 1H), 7.82 (m, 2H), 7.61 (dd, 1H), 7.50-7.31 (m, 8H), 7.25 (t, 1H), 7.14 (t, 1H), 5.21 (s, 2H), 4.20 (m, 4H). LRMS (APCI pos) m/e 414 (M+1).
Reaction SMILES: C12(COC3C(C4CC4)=CC(C(O)=O)=C(F)C=3)CC3CC(CC(C3)C1)C2.[CH:26]1([C:29]2[C:30]([O:39][CH2:40][C:41]34[CH2:50][CH:45]5[CH2:46][CH:47]([CH2:49][C:43]([O:51][C:52](=[O:57])[C:53]([F:56])([F:55])[F:54])([CH2:44]5)[CH2:42]3)[CH2:48]4)=[CH:31][C:32]([F:38])=[C:33]([CH:37]=2)[C:34](O)=[O:35])[CH2:28][CH2:27]1.C([CH:60]1[CH2:63][N:62]([S:64]([NH2:67])(=[O:66])=[O:65])[CH2:61]1)#N.N1(S(N)(=O)=O)CCC1>>[F:56][C:53]([F:54])([F:55])[C:52]([O:51][C:43]12[CH2:49][CH:47]3[CH2:46][CH:45]([CH2:50][C:41]([CH2:40][O:39][C:30]4[CH:31]=[C:32]([F:38])[C:33]([C:34](=[O:35])[NH:67][S:64]([N:62]5[CH2:63][CH2:60][CH2:61]5)(=[O:66])=[O:65])=[CH:37][C:29]=4[CH:26]4[CH2:27][CH2:28]4)([CH2:48]3)[CH2:42]1)[CH2:44]2)=[O:57]
Reactant: N#CC1CN(S(N)(=O)=O)C1
Reactant: O=C(O)c1cc(C2CC2)c(OCC23CC4CC(C2)CC(OC(=O)C(F)(F)F)(C4)C3)cc1F
Agent: NS(=O)(=O)N1CCC1
Agent: O=C(O)c1cc(C2CC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(C2CC2)c(OCC23CC4CC(C2)CC(OC(=O)C(F)(F)F)(C4)C3)cc1F

Procedure:
Following the procedure as described in Example 230 and making variations as required to replace 4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with 5-cyclopropyl-2-fluoro-4-((3-(2,2,2-trifluoroacetoxy)adamantan-1-yl)methoxy)benzoic acid and to replace 3-cyanoazetidine-1-sulfonamide with azetidine-1-sulfonamide, the title compound was obtained as colorless solid (0.22 g, 47%): 1H NMR (300 MHz, DMSO-d6) δ 11.62 (s, 1H), 7.17 (d, J=8.3 Hz, 1H), 6.95 (d, J=12.9 Hz, 1H), 4.05 (t, J=7.7 Hz, 4H), 3.79 (s, 2H), 2.32 (br s, 2H), 2.19-2.14 (m, 8H), 2.06-2.00 (m, 1H), 1.70-1.59 (m, 6H), 0.95-0.88 (m, 2H), 0.70-0.65 (m, 2H); MS (ES+) m/z 575.1 (M+1); MS (ES−) m/z 573.1 (M−1).
Reaction SMILES: C(OC([N:8]1[CH2:26][CH2:25][C@@H:11]2[N:12]([CH3:24])[C:13]3[C:14]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:16]([OH:19])=[CH:17][C:18]=3[C@@H:10]2[CH2:9]1)=O)(C)(C)C.Br[CH2:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1.C([O-])([O-])=O.[K+].[K+]>>[CH3:24][N:12]1[C:13]2[C:14]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:16]([O:19][CH2:28][C:29]3[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=3)=[CH:17][C:18]=2[C@@H:10]2[CH2:9][NH:8][CH2:26][CH2:25][C@H:11]12
Reactant: CN1c2c(cc(O)cc2C(F)(F)F)[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]21
Reactant: BrCc1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CN1c2c(cc(OCc3ccncc3)cc2C(F)(F)F)[C@@H]2CNCC[C@@H]21

Procedure:
The title compound was prepared by following the general Method C as a light yellow solid (56 mg, 57%) from (4aS,9bR)-8-hydroxy-5-methyl-6-trifluoromethyl-1,3,4,4a,5,9b-hexahydro-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester (Example 71, 100 mg, 0.27 mmol), 4-bromomethyl-pyridine (141 mg, 0.56 mmol) and K2CO3 (156 mg, 1.12 mmol). MS (ESI): 364 (base, M+H).
Reaction SMILES: [F:1][C:2]1[C:3]([C:32]([F:35])([F:34])[F:33])=[C:4]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[C:20]4[CH2:21][N:22](C(OC(C)(C)C)=O)[CH2:23][CH2:24][C:19]=4[NH:18][N:17]=3)=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[ClH:36]>C(Cl)Cl.CCOCC>[ClH:36].[F:1][C:2]1[C:3]([C:32]([F:35])([F:33])[F:34])=[C:4]([CH:8]2[CH2:9][CH2:10][N:11]([C:14]([C:16]3[C:20]4[CH2:21][NH:22][CH2:23][CH2:24][C:19]=4[NH:18][N:17]=3)=[O:15])[CH2:12][CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(C(=O)N3CCC(c4cccc(F)c4C(F)(F)F)CC3)c2C1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(c1n[nH]c2c1CNCC2)N1CCC(c2cccc(F)c2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
To a solution of tert-butyl 3-(4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-6,7-dihydro-H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (31, 0.148 g, 0.30 mmol) in CH2Cl2 (2 mL) was added HCl (2 mL, 2.0 N solution in Et2O). The mixture stirred at ambient temperature for 18 h, was diluted with Et2O (30 mL), and the resulting solids were collected by filtration to give (4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone hydrochloride (32) as a white solid (0.097 g, 75%): 1H NMR (300 MHz, DMSO-d6) δ 9.46-9.20 (m, 2H), 7.74-7.61 (m, 1H), 7.46 (d, J=8.1 Hz, 1H), 7.37-7.25 (m, 1H), 4.70-4.44 (m, 2H), 4.34-4.22 (m, 2H), 3.50-3.10 (m, 4H), 2.93-2.76 (m, 3H), 1.86-1.60 (m, 4H); ESI MS m/z 468 [M+H]+.