Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[Cl:12].[N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15](B(O)O)[CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[Cl:12][C:7]1[C:6]2[C:11](=[C:2]([C:15]3[CH:14]=[N:13][C:22]4[C:17]([CH:16]=3)=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:3]=[CH:4][CH:5]=2)[N:10]=[CH:9][CH:8]=1
Reactant: OB(O)c1cnc2ccccc2c1
Reactant: Clc1ccnc2c(Br)cccc12
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
Product: Clc1ccnc2c(-c3cnc4ccccc4c3)cccc12
Yield: 41.6 %

Procedure:
Pd(PPh3)4 (0.0581 g) was added to a solution of the obtained 8-bromo-4-chloroquinoline (0.242 g), 3-quinolineboronic acid (0.163 g), and an aqueous sodium carbonate solution (2 M, 1.5 mL) in ethylene glycol dimethyl ether (3.0 mL) in a nitrogen atmosphere, and the mixture was stirred at 85° C. for 3 hours. The reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with brine and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by neutral silica gel column chromatography (chloroform/methanol) to obtain 4′-chloro-3,8′-biquinoline (0.114 g) as a white solid. Compound (117) was obtained as a pale yellow solid (yield based on 6 steps: 37%) according to Example 3(3) using the obtained 4′-chloro-3,8′-biquinoline instead of compound (3b) and 4-cyano-3-(4-hydroxycyclohexylamino)phenylboronic acid pinacol ester instead of 4-cyano-3-(ethylamino)phenylboronic acid pinacol ester.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:7][CH:6]=1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[S:28]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:7][CH:6]=1)([CH3:27])(=[O:30])=[O:29]
Reactant: CC(C)(C)OC(=O)CCc1ccc(CCCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCc1ccc(CCCOS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
With a 4.82 g (18.3 mmols) portion of t-butyl 3-[4-(3-hydroxypropyl)phenyl]propionate were admixed 5.09 ml (36.6 mmols) of triethylamine, 2.84 ml (36.6 mmols) of methanesulfonyl chloride and 50 ml of methylene chloride. The mixture was stirred at room temperature for 12 hours, concentrated and then diluted with benzene. The benzene layer was washed with saturated aqueous solution of NaCl, dried over Na2SO4 and concentrated, giving 6.29 g (yield 100%) of t-butyl 3-[4-(3-mesyloxypropyl)phenyl]propionate in the form of an oil. This product was used for the subsequent reaction without purification.
Reaction SMILES: [OH-].[K+].S([O-])([O-])(=O)=O.[Na+].[Na+].[C:10]1([NH:16][N:17]=[CH:18][C:19]2[CH:20]=[CH:21][C:22]3[N:23]([CH2:32][CH3:33])[C:24]4[C:29]([C:30]=3[CH:31]=2)=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:34]([CH:36]1[O:38][CH2:37]1)Cl>[O-]S([O-])(=O)=O.[Na+].[Na+]>[O:38]1[CH2:37][CH:36]1[CH2:34][N:16]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[N:17]=[CH:18][C:19]1[CH:20]=[CH:21][C:22]2[N:23]([CH2:32][CH3:33])[C:24]3[C:29]([C:30]=2[CH:31]=1)=[CH:28][CH:27]=[CH:26][CH:25]=3
Reactant: CCn1c2ccccc2c2cc(C=NNc3ccccc3)ccc21
Reactant: ClCC1CO1
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Agent: [Na+]
Product: CCn1c2ccccc2c2cc(C=NN(CC3CO3)c3ccccc3)ccc21
Temperature: 25 °C
Yield: 78.5 %

Procedure:
A mixture of potassium hydroxide powder (KOH, 85%, 198 g, 3 mol,) and anhydrous sodium sulfate (Na2SO4, 51 g, 0.369 mol) was added in three stages to a mixture of 9-ethyl-3-carbazolecarboxaldehyde N-phenylhydrazone (313.4 g, 1 mol) and epichlorohydrin (1.5 mol), while keeping the reaction mixture at 20-25° C. In the first stage, 33 g of Na2SO4 and 66 g of KOH were added initially. In the second stage, 9.9 g of Na2SO4 and 66 g of KOH were added 1 hour into the reaction. In the third stage, 9.9 g of Na2SO4 and 66 g of KOH were added 2 hours into the reaction. The reaction mixture was stirred vigorously at 35-40° C. until the starting hydrazone disappeared (approximately 3-4 hours). Subsequently, the mixture was cooled to room temperature and any remaining solids were removed by filtration. The liquid organic phase was treated with diethyl ether and washed with distilled water until the washed water had a neutral pH. The organic layer was dried over anhydrous magnesium sulfate, treated with activated charcoal, and filtered. The solvent and excess epichlorohydrin were removed by evaporation in a rotary evaporator. The residue was recrystallized from a mixture of toluene and 2-propanol in a 1:1 volume ratio. The crystals formed upon standing were filtered off and washed with 2-propanol to give 290 g of product (78.5% yield). The melting point of the product was found to be 136-137° C. (recrystallized from toluene). The 1H-NMR spectrum (250 MHz) of the product in CDCl3 was characterized by the following chemical shifts (δ, ppm): 8.35 (s, 1H, 4-HHt); 8.14 (d, J=7.8 Hz, 1H, 1-HHt); 7.93 (d, J=7.6 Hz, 1H, 2-HHt); 7.90 (s, 1H, CH═N); 7.54-7.20 (m, 8H, Ph, Ht); 6.96 (t, J=7.2 Hz, 1H, 4-HPh); 4.37 (m, 3H, CH2CH3, one of the NCH2 protons); 4.04 (dd, J1=4.3 Hz, J2=16.4 Hz, 1H, next of the NCH2 protons); 3.32 (m, 1H, CH); 2.88 (dd, 1H, part of the ABX system, cis-HA of CH2O, JAX=2.6 Hz, JAB=4.9 Hz); 2.69 (dd, 1H, part of the ABX system, trans-HB of CH2O, JBX=4.0 Hz); and 1.44 (t, J=7.2 Hz, 3H, CH3). An elemental analysis yielded the following results in weight percent C 78.32, H 6.41, and N 11.55, which compared with calculated values for C24H23N3O in weight percent of C 78.02, H 6.28, and N 11.37.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([OH:6])(=[O:5])=[O:4].Cl[C:10](Cl)(Cl)C(Cl)=O.C(=O)(OC)OC>>[F:1][C:2]([F:8])([F:7])[S:3]([O:6][CH3:10])(=[O:5])=[O:4]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: COC(=O)OC
Product: COS(=O)(=O)C(F)(F)F
Temperature: 90 °C
Yield: 90.5 %

Procedure:
17.74 g (0.1182 mol) of trifluoromethanesulfonic acid are introduced into a round-bottomed flask fitted with a reflux condenser. 21.41 g (0.1177 mol) of trichloroacetyl chloride are added over the course of 2 minutes with constant stirring. 10.60 g (0.1177 mol) of dimethyl carbonate are then added over the course of 5 minutes without cooling the mixture. The reaction mixture warms slightly and is heated at 80-100° C. for 7 hours in an oil bath (temperature in the oil bath) with stirring until the evolution of gas ceases. After cooling to room temperature, the mixture is distilled under atmospheric pressure, giving 17.48 g (yield: 90.5%) of methyl trifluoromethanesulfonate as a transparent, colourless liquid (boiling range 98-100° C.).
Reaction SMILES: [C:1]1([C:7]2[C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][N:10]=[C:9]([NH:18][CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>C(O)C.O>[C:1]1([C:7]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=[C:9]([NH:18][CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cnc(NCc2cccs2)nc1-c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cnc(NCc2cccs2)nc1-c1ccccc1
Yield: 97.6 %

Procedure:
Ethyl 4-phenyl-2-[(thiophen-2-ylmethyl)amino]pyrimidine-5-carboxylate (1.70 g, 5 mmol) was dissolved in ethanol (10 ml). To the solution potassium hydroxide (0.56 g, 10 mmol) dissolved in 10 ml of water was added and the mixture was refluxed for 3 hours. The solvent was distilled off in vacuum, the residue was dissolved in water (35 ml), acidified to pH=3 with 10% hydrochloric acid. The precipitated white crystals were filtered off, washed with water (2×20 ml) and dried. 1.52 g (92%) of the title acid was obtained, m.p.: 212-213° C.; [M+H]+ 312.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:43][CH2:42][C:41](=[O:44])[CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:38]3[CH2:43][CH2:42][C:41](=[O:44])[CH2:40][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(=O)CC1

Procedure:
In a manner analogous to the method described in example 3, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was reacted with piperidin-4-one (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C34H39Cl2N4O3 [(M+H)+] 621.2394, observed 621.2395.
Reaction SMILES: C[Mg]Br.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([C:18]2[N:22]3[CH2:23][CH2:24][CH2:25][C@:26]([O:32][C:33]4[CH:38]=[C:37]([F:39])[C:36]([F:40])=[C:35]([F:41])[CH:34]=4)(C(OCC)=O)[C:21]3=[N:20][N:19]=2)[CH:9]=[CH:10][C:11]=1[C:12]1[O:16][C:15]([CH3:17])=[N:14][CH:13]=1>C1COCC1.C(OCC)(=O)C.[Cl-].[NH4+]>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([C:18]2[N:22]3[CH2:23][CH2:24][CH2:25][C@@:26]([C:6]([OH:5])([CH3:7])[CH3:11])([O:32][C:33]4[CH:38]=[C:37]([F:39])[C:36]([F:40])=[C:35]([F:41])[CH:34]=4)[C:21]3=[N:20][N:19]=2)[CH:9]=[CH:10][C:11]=1[C:12]1[O:16][C:15]([CH3:17])=[N:14][CH:13]=1
Reactant: CCOC(=O)[C@@]1(Oc2cc(F)c(F)c(F)c2)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(-c2nnc3n2CCC[C@]3(Oc2cc(F)c(F)c(F)c2)C(C)(C)O)ccc1-c1cnc(C)o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 129.4 %

Procedure:
To a mixture of methylmagnesium bromide (1 M THF solution, 6.81 mL) in THF (6 mL) was added a mixture of ethyl (8R)-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-8-(3,4,5-trifluorophenoxy)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxylate (1 g) in THF (6 mL) at 0° C., and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate and saturated aqueous ammonium chloride solution, the mixture was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate) to give the title compound (0.63 g) as a solid.
Reaction SMILES: Br[CH2:2][CH:3]([N:8]=[C:9]=[O:10])[CH2:4][CH:5]([CH3:7])[CH3:6].[NH3:11].O>COCCOC>[NH2:11][C:9]1[O:10][CH2:2][CH:3]([CH2:4][CH:5]([CH3:7])[CH3:6])[N:8]=1
Reactant: CC(C)CC(CBr)N=C=O
Reactant: N
Solvent: O
Solvent: COCCOC
Product: CC(C)CC1COC(N)=N1
Reaction time: 0.25 h

Procedure:
21 g (0.1 mole) of 1-bromomethyl-3-methyl-butyl-isocyanate were added dropwise within 1 hour, at 8°-11° C, to a mixture of 25 ml of concentrated ammonia, 25 ml of water and 7 ml of 1,2-dimethoxyethane. Stirring was continued for 15 minutes at 12°-14° C, and then working up was carried out as described in Example 1. 11.6 g (82 percent of the theory) of oily 2-amino-4-isobutyl-2-oxazoline were obtained, which had been previously dissolved and reprecipitated from a mixture of isopropyl ether and hexane and finally evaporated in a high vacuum.
Reaction SMILES: Br[CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3.[CH3:18][S-:19].[Na+]>CN(C)C=O>[CH3:15][C:13]1[CH:14]=[C:5]2[CH2:4][CH:3]([CH2:2][S:19][CH3:18])[O:17][C:6]2=[C:7]2[C:12]=1[NH:11][C:10](=[O:16])[CH:9]=[CH:8]2
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CBr)C2
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSCC1Cc2cc(C)c3[nH]c(=O)ccc3c2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.1 %

Procedure:
A solution of 2-bromomethyl-5-methyl-2,3,6,7-tetrahydrofuro-[2,3-f]quinoline-7-one (2.942 g) in dimethylformamide (120 ml) was combined with aqueous 15% sodium thiomethoxide (9.4 ml), and stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure. Water was added to the residue, and extracted with chloroform. The chloroform extract was washed with diluted hydrochloric acid, diluted caustic soda and water in this order, and dried. The resultant material was crystallized from tetrahydrofuran to obtain 2.355 g of the title compound as colorless prisms (mp. 203°-206° C.) (yield: 90.1%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1.[Br:12]NC(=O)CCC(N)=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][Br:12])=[N:7][C:6]=2[CH:11]=1
Reactant: NC(=O)CCC(=O)NBr
Reactant: Cc1nc2cc(Br)ccc2s1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1nc2cc(Br)ccc2s1
Temperature: 75 °C
Yield: 63.1 %

Procedure:
To a solution of 5-Bromo-2-methyl-benzothiazole (1.0 g, 4.385 mmol) in CCl4 (15 mL) is added N-bromosuccinamide (1.1 g, 6.140 mmol) and azobisisobutyronitrile (0.029 g, 0.175 mmol) at room temperature reaction. The reaction mixture is heated to 75° C. for 16 hours. Reaction mixture is cooled to room temperature, filtered and the solvent evaporated in vacuo to give the crude material, which is then purified by flash chromatography using 3.5% ethyl acetate in hexane as an eluent to afford the title compound (0.85 g). 1H NMR (400 MHz, DMSO-d6) δ: 5.12 (s, 2H), 7.68-7.71 (dd, J1=1.92 Hz, J2=8.76 Hz, 1H), 7.95 (d, J=8.6 Hz, 1H), 8.43 (d, J=1.92 Hz, 1H). LC-MS (m/z): [M+H]=308.2.
Reaction SMILES: C(O[C:4]([CH2:6][N:7]1[C:12](=[O:13])[C:11]([C:14](=[O:17])[NH:15][CH3:16])=[CH:10][C:9]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[N:8]1)=[O:5])C.[NH2:26][CH2:27][CH2:28][OH:29]>CO>[OH:29][CH2:28][CH2:27][NH:26][C:4]([CH2:6][N:7]1[C:12](=[O:13])[C:11]([C:14](=[O:17])[NH:15][CH3:16])=[CH:10][C:9]([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)=[N:8]1)=[O:5]
Reactant: CCOC(=O)Cn1nc(-c2ccc(OC)cc2)cc(C(=O)NC)c1=O
Reactant: NCCO
Solvent: CO
Product: CNC(=O)c1cc(-c2ccc(OC)cc2)nn(CC(=O)NCCO)c1=O
Yield: 91 %

Procedure:
In methanol, 2-ethoxycarbonylmethyl-6-(4-methoxyphenyl)-4-methylcarbamoyl-2H-pyridazin-3-one and 2-aminoethanol were heated under reflux for 4 hours. Post-treatments were conducted as in Example 43, whereby the title compound was obtained in a yield of 91.0%.
Reaction SMILES: [F:1][C:2]([F:15])=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14].[CH3:16][C:17]1[CH:22]=[CH:21][C:20](O)=[CH:19][CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[C:2]([F:15])[F:1])=[CH:19][CH:18]=1
Reactant: Cc1ccc(O)cc1
Reactant: OCCCCCCCCCCC=C(F)F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(OCCCCCCCCCCC=C(F)F)cc1
Yield: 37.2 %

Procedure:
A solution of 1.0 gram (0.0045 mole) of 12,12-difluoro-11-dodecen-1-ol (prepared in Example 5), 0.49 gram (0.0045 mole) of 4-methylphenol, 1.2 grams (0.0045 mole) of triphenylphosphine, and 0.79 gram (0.0045 mole) of diethyl azodicarboxylate in 25 ml of tetrahydrofuran was stirred, and the progress of the reaction was monitored by gas chromatographic analysis. Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure to a residue. The residue was dissolved in 25 ml of diethyl ether, and a solid precipitate was removed by filtration. The filtrate was concentrated under reduced pressure to a residual solid. The solid was subjected to column chromatography on silica gel. Elution was accomplished using methylene chloride. The appropriate fractions were combined and concentrated under reduced pressure yielding 0.52 gram of 12,12-difluoro-11-dodecenyl 4-methylphenyl ether. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([NH:8][C:9](=O)[CH:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.O1CCCC1.O.[OH-].[Na+]>O1CCCC1>[CH2:1]([NH:8][CH2:9][CH:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[CH3:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C(=O)NCc1ccccc1)c1ccc(O)cc1
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(CNCc1ccccc1)c1ccc(O)cc1
Yield: 52.3 %

Procedure:
Dissolve N-benzyl-2-(4-hydroxy-phenyl)-propionamide (13.25 g, 51.9 mmol) in anhydrous tetrahydrofuran (100 mL) and add via a cannula to borane-tetrahydrofuran complex (10M in tetrahydrofuran, 300 mL, 300 mmol) under nitrogen. Heat the reaction to reflux for 18 h under nitrogen. Cool the reaction to 0° C. and quench with 6 M hydrochloric acid. Concentrate the tetrahydrofuran on a rotary evaporator to give the crude product. Add water (50 mL) and tetrahydrofuran (30 mL) to the crude product and heat the reaction to reflux for 1 h. Cool the reaction to room temperature and adjust the pH to pH=8 with 5 N sodium hydroxide. Add brine (200 mL) and extract with ethyl acetate (3× 200 mL). Dry the ethyl acetate extracts over magnesium sulfate, filter, and concentrate on a rotary evaporator to give the crude product. Purify the crude product by flash chromatography on silica gel eluting with 0.7% concentrated ammonium hydroxide/7% ethanol/chloroform to yield 6.55 g (52%) of 4-(2-benzylamino-1-methyl-ethyl)-phenol: HPLC (30/70 to 90/10 ACN/(0.1% TFA in water) Zorbax SB-Phenyl Column 4.6 mm×15 cm×5 micron: Retention time: 3.08 minutes, Purity: 99.6%; mass spectrum (ion spray): m/z=242.1 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([OH:12])=O)[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19].O[N:21]=[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][O:31][CH2:32][CH2:33][OH:34])[CH:25]=1)[NH2:23]>>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:12][N:23]=[C:22]([C:24]3[CH:25]=[C:26]([CH:27]=[CH:28][CH:29]=3)[CH2:30][O:31][CH2:32][CH2:33][OH:34])[N:21]=2)[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19]
Reactant: NC(=NO)c1cccc(COCCO)c1
Reactant: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Product: COCc1cc(-c2nc(-c3cccc(COCCO)c3)no2)ccc1-c1ccccc1C

Procedure:
The title compound was obtained following procedure described for example 54 step 1 but starting from Intermediate 28 (200 mg; 0.73 mmol) and Intermediate 76 (153 mg; 0.73 mmol). Purification by column chromatography (EtOAc:cHex from 10:90 to 50:50) gave the title compound as a colorless oil. 1H NMR (DMSO-d6, 300 MHz) δ 8.32 (d, J=1.5 Hz, 1H), 8.17 (dd, J=7.9, 1.8 Hz, 1H), 8.10 (bs, 1H), 8.06-8.02 (m, 1H), 7.60-7.59 (m, 1H), 7.42 (d, J=7.9 Hz, 1H), 7.36-7.26 (m, 3H), 7.15-7.13 (m, 1H), 4.69 (t, J=5.4 Hz, 1H), 4.22 (d, J=12.7 Hz, 1H), 4.16 (d, J=12.7 Hz, 1H), 3.61-3.51 (m, 4H), 3.25 (s, 3H), 2.03 (s, 3H). LC/MS (Method B): 431.3 (M+H)+. HPLC (Method A) Rt 5.50 min (Purity: 96.9%).
Reaction SMILES: FC1C=CC2N(C(CC3N(C)C=CN=3)=C(C3C=CC(F)=CC=3)N=2)C=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:33]=[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]3[C:40]=2[CH:41]=O)=[CH:28][CH:27]=1.[CH3:43][C:44]1[O:48][N:47]=[CH:46][N:45]=1>>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]2[N:33]=[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]3[C:40]=2[CH2:41][C:46]2[N:45]=[C:44]([CH3:43])[O:48][N:47]=2)=[CH:30][CH:31]=1
Reactant: Cc1ncno1
Reactant: O=Cc1c(-c2ccc(Cl)cc2)nc2ccccn12
Agent: Cn1ccnc1Cc1c(-c2ccc(F)cc2)nc2ccc(F)cn12
Product: Cc1nc(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)no1

Procedure:
The title compound was prepared according to Method C and the experimentals described for compound 199 from 2-(4-chlorophenyl)imidazo[1,2-a]pyridine-3-carbaldehyde and 5-methyl-1,2,4-oxadiazole. M/e+ 325 for C17H14ClN4O (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 8.22 (d, J=6.9 Hz, 1H), 7.91 (d, J=8.4 Hz, 2H), 7.66 (d, J=8.8 Hz, 1H), 7.47 (d, J=8.4 Hz, 2H), 7.23 (m, 1H), 6.88 (t, J=6.9 Hz, 1H), 4.42 (d, J=0.7 Hz, 2H), 2.56 (s, 3H) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].[CH2:17](Br)[CH2:18][CH2:19][CH3:20]>>[CH2:17]([N:11]1[CH2:10][CH2:9][N:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([N+:14]([O-:16])=[O:15])[CH:4]=2)[CH2:13][CH2:12]1)[CH2:18][CH2:19][CH3:20]
Reactant: Cc1ccc(N2CCNCC2)cc1[N+](=O)[O-]
Reactant: CCCCBr
Product: CCCCN1CCN(c2ccc(C)c([N+](=O)[O-])c2)CC1

Procedure:
Beginning with 1-(4-methyl-3-nitro-phenyl)-piperazine and 1-butylbromide, the title compound was recovered by the procedure described in Example 2. MS m/z (rel. intensity, 70 eV) 277 (M+, 23), 234 (bp), 191 (17), 70 (64), 56 (33).
Reaction SMILES: C([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][C:13]3[C:24]4[C:18]5([CH2:30][CH:21]([C:22](=[O:29])[C:23]=4[C:25]([F:28])([F:27])[F:26])[CH2:20][CH2:19]5)[CH2:17][C:14]=32)=[N:9]1)C1C=CC=CC=1.Cl.[H][H]>O1CCOCC1.[Pd]>[F:27][C:25]([F:26])([F:28])[C:23]1[C:22](=[O:29])[C@H:21]2[CH2:30][C@@:18]3([C:24]=1[C:13]1[CH:12]=[CH:11][C:10]4[NH:9][N:8]=[CH:16][C:15]=4[C:14]=1[CH2:17]3)[CH2:19][CH2:20]2
Reactant: O=C1C(C(F)(F)F)=C2c3ccc4nn(Cc5ccccc5)cc4c3CC23CCC1C3
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Product: O=C1C(C(F)(F)F)=C2c3ccc4[nH]ncc4c3C[C@@]23CC[C@@H]1C3
Reaction time: 0.75 h

Procedure:
To a solution of 2-benzyl-6-(trifluoromethyl)-2,9,10,11-tetrahydro-8,10a-methanoazuleno[2,1-e]indazol-7(8H)-one (0.820 g, 2.00 mmol) in 50 mL of dioxane was added 12N aqueous HCl (0.170 mL, 2.00 mmol) followed by 30% palladium on carbon (0.250 g) and the stirred mixture was hydrogenated under balloon pressure of hydrogen. After 45 minutes, additional 30% palladium on carbon (0.090 g) was added. After hydrogenating for an additional 1 hour, the mixture was filtered through a pad of silica gel, washing with EtOAc. The filtrate was washed with 5% aqueous NaHCO3 and the aqueous phase was back-extracted with EtOAc. The combined organic layers were diluted with Et2O and hexanes and washed with water and brine. The organic phase was concentrated under vacuum and the residue was chromatographed on silica gel (elution with 1:4 to 1:1 EtOAc/hexanes) to yield (rac)-(8R,10aS)-6-(trifluoromethyl)-3,9,10,11-tetrahydro-8,10a-methanoazuleno[2,1-e]indazol-7(8H)-one as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[N:6][CH:7]=1.Cl[C:26]1[C:31]([C:32]([OH:34])=[O:33])=[CH:30][N:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>C(O)C>[C:32]([C:31]1[CH:30]=[N:29][CH:28]=[CH:27][C:26]=1[N:21]1[CH2:20][CH2:19][CH:18]([CH2:17][NH:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[O:24])[CH2:23][CH2:22]1)([OH:34])=[O:33]
Reactant: O=C(Nc1ccc(Cl)cn1)c1ccccc1NCC1CCNCC1
Reactant: O=C(O)c1cnccc1Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(Nc1ccc(Cl)cn1)c1ccccc1NCC1CCN(c2ccncc2C(=O)O)CC1

Procedure:
Using a similar procedure to that described in Example 52, N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (100 mg, 0.29 mmol), 4-chloronicotinic acid (91 mg, 0.58 mmol), triethylamine (59 mg, 0.58 mmol), and ethanol (5 mL) yielded, after RPHPLC purification, 45 mg (33%) of the title compound as a trifluoroacetate salt.