Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[N:4](C2CCCCO2)[N:3]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[CH:27]=[C:26](B(O)O)[CH:25]=[CH:24]2.ClCCl.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl>COCCOC.CO>[CH3:19][O:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[CH:27]=[C:26]([C:2]1[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=3)[NH:4][N:3]=1)[CH:25]=[CH:24]2
Reactant: COc1ccc2cc(B(O)O)ccc2c1
Reactant: N#Cc1ccc2c(c1)c(Br)nn2C1CCCCO1
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2cc(-c3n[nH]c4ccc(C#N)cc34)ccc2c1
Temperature: 45 °C
Yield: 48 %

Procedure:
The title compound was prepared as described in Example 161, using 3-bromo-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (0.500 g, 1.6 mmol), in ethylene glycol dimethyl ether (30 mL), 6-methoxynaphthalene-2-boronic acid (0.395 g, 2.0 mmol), [1,1′-bis(diphenyl phosphino-ferrocene] complex with dichloromethane (1:1) (0.133 g, 0.16 mmol) and potassium phosphate (3.5 g, 16.3 mmol). Solvent was removed using a rotary evaporator and purification of the residue by column chromatography (silica gel, 20% ethyl acetate/hexanes) gave a solid. Methanol (50 mL) and aqueous 6 N hydrochloric acid (50 mL) were added to the solid and the mixture was heated at 45° C. for 5 h. One half of the methanol was evaporated, water was added and the solid filtered and dried in a vacuum oven to afford the title compound (0.230 g, 47% yield over 2 steps): ES-MS (m/z) 300 [M+1]+.
Reaction SMILES: [C:1]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[C:19]([C:22](=[O:27])C(Cl)(Cl)Cl)=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[CH:3][CH:2]=1.CS(C)=O.[NH2:38][CH2:39][C:40]1[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=1>C(#N)C>[C:1]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:2]=[CH:3][C:4]([CH2:7][N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[C:19]([C:22]([NH:38][CH2:39][C:40]4[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=4)=[O:27])=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[CH:5][CH:6]=1
Reactant: NCc1cccnc1
Reactant: O=C(c1ccc2n1Cc1ccccc1N(Cc1ccc(-c3ccccc3)cc1)C2)C(Cl)(Cl)Cl
Solvent: CC#N
Solvent: CS(C)=O
Product: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1N(Cc1ccc(-c3ccccc3)cc1)C2
Yield: 12 %

Procedure:
To a solution of 10-(1,1′-biphenyl-4-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine of Step A (0.93 g, 2.65 mmol) and N,N-dimethylaniline (0.51 mL, 3.98 mmol) in dry dichloromethane (30 mL) at 0° C. under nitrogen was added dropwise trichloroacetyl chloride (0.33 mL, 2.92 mmol). The ice bath was removed and the reaction mixture stirred at room temperature for 19 hours. The reaction mixture was then quenched by the addition of 2 M sodium hydroxide (30 mL) then partitioned between additional dichloromethane (75 mL) and 2 M sodium hydroxide (75 mL). The separated organic phase was washed with 2 M sodium hydroxide (75 mL) and water (75 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to give a yellow syrup (2.12 g). Purification by flash chromatography using a solvent gradient of 1-5% ethyl acetate in hexane afforded 1-{10-[(1,1′-biphenyl)-4-ylmethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-yl}-2,2,2-trichloroethanone (0.88 g, 67%) as a cream foam. To a solution of 1-{10-[(1,1′-biphenyl)-4-ylmethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-yl}-2,2,2-trichloroethanone (0.4 g, 0.807 mmol) and dimethyl sulfoxide (0.29 mL, 4.034 mmol) in dry acetonitrile (5 mL) at room temperature under nitrogen was added 3-(aminomethyl)pyridine (0.17 mL, 1.613 mmol) and the reaction mixture was heated to reflux for 2 days. The cooled mixture was concentrated in vacuo, the semi-solid residue dissolved in ethyl acetate (50 mL), filtered and concentrated in vacuo to afford a dark brown syrup. Purification by flash chromatography using a solvent gradient of 0.5 to 3% methanol in dichloromethane afforded an orange semi-solid that was crystallized from dichloromethane/hexane to give the title compound (0.047 g, 12%) as a cream solid, m.p. 161-165° C. (dec.).
Reaction SMILES: Cl.[CH3:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.Cl[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([C:31]([OH:33])=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O>[CH3:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3([C:31]([OH:33])=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:22][CH:21]=2)=[CH:12][CH:11]=1
Reactant: C[C@@H]1CCCN1CCc1ccc(B(O)O)cc1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H]1CCCN1CCc1ccc(-c2ccc(C3(C(=O)O)CCCC3)cc2)cc1
Temperature: 150 °C

Procedure:
A mixture of (R)-4-(2-(2-methylpyrrolidin-1-yl)ethyl)phenylboronic acid hydrochloride (300 mg, 1.113 mmol), 1-(4-chlorophenyl)cyclopentanecarboxylic acid (300 mg, 1.335 mmol), Na2CO3 (472 mg, 4.45 mmol), and dichlorobis(p-dimethylaminophenyldi-tert-butylphosphine)palladium (7.88 mg, 0.011 mmol) in 1,4-dioxane (6 mL) and H2O (1.2 mL) was heated under microwave irradiation at 150° C. for 10 min. The mixture was concentrated. The residue was purified by HPLC to give the title compound. LCMS m/z=378.3 [M+H]+.
Reaction SMILES: [CH3:1][N:2](CC1C2C(=CC=CC=2)C=CC=1C)[C:3](=[O:23])[C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[CH:8][C:7]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[N:6][CH:5]=1.[Cl:36][C:37]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][C:38]=1[CH2:39]Br>>[Cl:36][C:37]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][C:38]=1[CH2:39][N:2]([CH3:1])[C:3](=[O:23])[C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[CH:8][C:7]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[N:6][CH:5]=1
Reactant: COc1ccc(Cl)c(CBr)c1
Reactant: Cc1ccccc1-c1cc(N2CCOCC2)ncc1C(=O)N(C)Cc1c(C)ccc2ccccc12
Product: COc1ccc(Cl)c(CN(C)C(=O)c2cnc(N3CCOCC3)cc2-c2ccccc2C)c1

Procedure:
The parent compound was obtained as a white solid in comparable yields according to the procedures described above for the preparation of N-methyl-N-(2-methyl-naphthalen-1-ylmethyl)-6-morpholin-4-yl-4-o-tolyl-nicotinamide (Example 19) using 2-chloro-5-methoxy-benzyl bromide instead of 1-chloromethyl-2-methylnaphthalene in step b).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([Br:21])[C:19]=1[OH:20])[CH:5]=[C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)[NH:8][C:7]1=[O:16].[CH3:22]C(C)([O-])C.[K+].C1OCCOCCOCCOCCOCCOC1.ClC[CH2:48][C:49]([CH3:54])([CH3:53])[C:50]([O-:52])=[O:51]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([Br:21])[C:19]=1[O:20][CH2:22][O:52][C:50](=[O:51])[C:49]([CH3:54])([CH3:53])[CH3:48])[CH:5]=[C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)[NH:8][C:7]1=[O:16]
Reactant: O=C1Nc2ccc(Cl)cc2C1=Cc1cc(Br)c(O)c(Br)c1
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(CCCl)C(=O)[O-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)C(=O)OCOc1c(Br)cc(C=C2C(=O)Nc3ccc(Cl)cc32)cc1Br
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 44.1 %

Procedure:
A solution of 3-(3,5-dibromo-4-hydroxy-benzylidene)-2-oxo-2,3-dihydro-5-chloro-1 H-indole (0.43 g, 1.0 mmol) in dry acetonitrile (20 mL) under nitrogen was treated with potassium tert-butoxide (0.12 g, 1.1 mmol) at room temperature. The resulting orange heterogenous mixture was treated with 18-crown-6 (0.053 g, 0.20 mmol) and stirred for 15 minutes before adding chloromethylpivalate (0.40 mL, 2.8 mmol). The reaction was heated to seventy degrees celsius, stirred for three hours then filtered while hot. The filtrate was allowed to cool to room temperature and stirred overnight. The resulting solids were collected on a filter, washed with acetonitrile and dried under vacuum to provide the title compound (0.24 g, 44%) as a mixture of E/Z isomers. 1H NMR (DMSO-d6): (mixture of E/Z isomers) δ10.93 (s, 1H), 10.87(s, 1H), 8.85 (s, 2H), 8.09 (s, 2H), 7.94 (s, 1H), 7.84 (d, 1H), 7.67 (s, 1H), 7.32-7.39 (m, 3H), 6.96 (d, 1H), 6.91 (d, 1H), 5.91 (s, 2H), 5.88 (s, 2H), 1.23 (s, 9H), 1.22 (s, 9H). MS (ES-): 542 (60) (M−1). Anal. Calcd for C21H18NO4ClBr2: C, 46.40; H, 3.34; N, 2.58. Found: C, 46.33; H, 3.30; N, 2.55.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]([F:35])([F:34])[C:9]1[CH:33]=[CH:32][C:12]([O:13][C:14]2[CH:31]=[CH:30][C:17]([O:18][CH:19]([CH3:29])[C:20]([O:27][CH3:28])=[CH:21][C:22](OCC)=[O:23])=[CH:16][CH:15]=2)=[CH:11][CH:10]=1.[H-].O>CCOCC>[F:7][C:8]([F:34])([F:35])[C:9]1[CH:10]=[CH:11][C:12]([O:13][C:14]2[CH:31]=[CH:30][C:17]([O:18][CH:19]([CH3:29])[C:20]([O:27][CH3:28])=[CH:21][CH2:22][OH:23])=[CH:16][CH:15]=2)=[CH:32][CH:33]=1
Reactant: CCOC(=O)C=C(OC)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: COC(=CCO)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reaction time: 0.17 h

Procedure:
To a slurry of LiAlH4 (400 mg) in anhydrous ether (20 ml) is added dropwise at 0°, a solution of ethyl 4-[4-(4-trifluoromethylphenoxy)phenoxy]-3-methoxy-2-pentenoate (1.2 g) in ether (10 ml). After addition is complete, the reaction mixture is stirred for about 10 minutes. Excess hydride is decomposed with wet ether and water. After filtration, the filtrate is concentrated to give the alcohola, 4-[4-(4-trifluoromethylphenoxy)phenoxy]-3-methoxy-2-penten-1-ol.
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]([F:20])([F:19])[O:9][C:10]1[CH:18]=[CH:17][C:13]([CH:14]=[N:15][OH:16])=[CH:12][CH:11]=1.[NH2:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[CH2:27])=[CH:24][CH:23]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[F:7][C:8]([F:19])([F:20])[O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]2[CH2:27][CH:26]([C:25]3[CH:28]=[CH:29][C:22]([NH2:21])=[CH:23][CH:24]=3)[O:16][N:15]=2)=[CH:12][CH:11]=1
Reactant: C=Cc1ccc(N)cc1
Reactant: ON=Cc1ccc(OC(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Nc1ccc(C2CC(c3ccc(OC(F)(F)F)cc3)=NO2)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 61.2 %

Procedure:
To a stirred solution of N-chlorosuccinimde (0.634 mmol, 85 μL) and pyridine (4 μL) in 2.5 mL of chloroform was added p-trifluoromethoxybenzaldehyde oxime (130 mg, 0.634 mmol). The reaction was heated at 50° C. for 3 h. 4-Aminostyrene (0.793 mmol, 93 μL) was then added followed by a solution of triethylamine (0.666 mmol, 93 μL) dissolved in 0.5 mL of CHCl3 dropwise. The reaction was stirred at 50° C. for 3 h. The cooled solution was diluted with chloroform (15 mL) and washed with water (2×10 mL). The organic phase was then dried over MgSO4, filtered and concentrated. The residue was purified via radial chromatography using a 2:1 hexane/EtOAc solution as the eluent (Rf=0.18) to afford 4-[3-(4-trifluoromethoxyphenyl)-4,5-dihydro-isoxazol-5-yl]-phenylamine (125 mg; 61%). 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J=8.2 Hz, 2H), 7.25 (d, J=8.2 Hz, 2H), 7.17 (d, J=8.2 Hz, 2H), 6.68 (d, J=8.2 Hz, 2H), 5.65 (dd, J=10.9, 8.9 Hz, 1H), 3.55-3.75 (bs, 2H), 3.67 (dd, J=16.8, 10.9 Hz, 1H), 3.30 (dd, J=16.8, 8.9 Hz, 1H); EIMS 322 (M+).
Reaction SMILES: [Br:1][C:2]1[S:17][C:5]2[N:6]([CH3:16])[C:7](=[O:15])[N:8]([CH2:11][CH2:12][CH2:13][OH:14])[C:9](=[O:10])[C:4]=2[C:3]=1[CH2:18][Br:19].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.[CH2:37]1[CH2:42][O:41][CH:40]=[CH:39][CH2:38]1.O>C(Cl)Cl>[Br:1][C:2]1[S:17][C:5]2[N:6]([CH3:16])[C:7](=[O:15])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:40]3[CH2:39][CH2:38][CH2:37][CH2:42][O:41]3)[C:9](=[O:10])[C:4]=2[C:3]=1[CH2:18][Br:19]
Reactant: C1=COCCC1
Reactant: Cn1c(=O)n(CCCO)c(=O)c2c(CBr)c(Br)sc21
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: O
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(CBr)c(Br)sc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.2 %

Procedure:
To a solution of 6-bromo-5-(bromomethyl)-3-(3-hydroxypropyl)-1-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (2.5 g, 6.1 mmol) and PPTS (153 mg, 0.61 mmol) in DCM (25 mL) at 0° C. was added DHP (2.00 g, 24.5 mmol) dropwise. The reaction was stirred at RT for 18 h, poured into water (30 mL) and extracted with DCM (2×20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (4:1) to give 6-bromo-5-(bromomethyl)-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (1.7 g, 56.7% yield) as a yellow oil.
Reaction SMILES: [CH:1](=[N:8][N:9]1[CH:13]=[CH:12][N:11]([N:14]=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]1=[S:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][B-:24]([F:27])([F:26])[F:25].[CH3:28][O+](C)C>C(Cl)Cl>[F:23][B-:24]([F:27])([F:26])[F:25].[CH:15](=[N:14][N+:11]1[CH:12]=[CH:13][N:9]([N:8]=[CH:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:10]=1[S:22][CH3:28])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: S=c1n(N=Cc2ccccc2)ccn1N=Cc1ccccc1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CSc1n(N=Cc2ccccc2)cc[n+]1N=Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3.06 g of 1,3-bis(benzylideneamino)-1,3-dihydro-2H-imidazole-2-thione in 100 ml of absolute methylene chloride are treated with 1.47 g of trimethyloxonium tetrafluoroborate. The mixture is stirred at room temperature for 3 hours and the resulting precipitate is removed by filtration under suction. From the filtrate, by the addition of diethyl ether, there is precipitated a additional portion of the desired product which, together with the first portion, is washed once with water, once with cold methanol and three times with diethyl ether and subsequently reprecipitated from acetonitrile/diethyl ether. There is obtained colorless 1,3-bis(benzylideneamino)-2-(methylthio)imidazolium tetrafluoroborate of melting point 215°-220° (decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:5][C:4]=1B(O)O.Br[C:18]1[N:19]=[CH:20][C:21]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[N:22][C:23]=1[Cl:24]>C(OCC)(=O)C.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>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:5][C:4]=1[C:20]1[C:21]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[N:22][C:23]([Cl:24])=[CH:18][N:19]=1
Reactant: COc1ccc(CNc2cnc(Br)c(Cl)n2)cc1
Reactant: COc1ccc(OC(F)(F)F)cc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: COc1ccc(CNc2nc(Cl)cnc2-c2cc(OC(F)(F)F)ccc2OC)cc1
Temperature: 80 °C

Procedure:
In a pressure tube, a mixture of the product from step A (1 equivalent), 2-methoxy-5-trifluoromethoxyphenylboronic acid (1.6 equivalents) and Pd(PPh3)4 (0.04 equivalents) in toluene (4 ml/mmol of product from step A), ethanol (0.2 ml/mmol of product from step A) and aqueous K2CO3 (2M, 2 ml/mmol of product from step A) is heated to 80° C. for 16 hours. The mixture is diluted with ethyl acetate, and the organic fraction washed with NaOH (2M, 20 mL/mmol of product from step A) and brine (3×20 ml/mmol of product from step A), then dried (MgSO4), filtered and the solvent removed under reduced pressure. Chromatography of the residue provides (3-(2-methoxy-5-trifluoromethoxyphenyl)-6-chloropyrazin-2-yl)[(4-methoxyphenyl)methyl]amine.
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6]([OH:8])=[O:7])[NH2:2].[CH3:13][CH:14]([CH3:18])C(O)=O.[CH:19](=O)[CH2:20]C=O.Cl.[OH-].[Na+]>CCO>[CH2:19]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:11]([CH3:12])=[C:3]([N:1]2[CH:18]=[CH:14][CH:13]=[N:2]2)[CH:4]=1)[CH3:20]
Reactant: O=CCC=O
Reactant: CC(C)C(=O)O
Reactant: Cc1ccc(C(=O)O)cc1NN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1ccc(C)c(-n2cccn2)c1
Temperature: 25 °C
Yield: 47.2 %

Procedure:
A solution of 3-hydrazino-4-methyl benzoic acid (See U.S. provisional application 60/570,284) (1.0 g, 4.93 mmol), malonaldehyde(bismethylacetate) (0.82 mL, 4.93 mmol), and concentrated HCl (1 mL) in EtOH (20 mL) was heated to reflux for 4 h. After cooling to room temperature, the reaction was poured into ice water, neutralized with 2N NaOH, and extracted with CH2Cl2 (3×). The organic layers were dried over Na2SO4, filtered and concentrated to afford 4-methyl-3-pyrazol-1-yl-benzoic acid ethyl ester (536 mg, 47%) as a yellow oil. A solution of the pyrazole (536 mg, 2.33 mmol) and bromine (0.167mL, 3.26 mmol) in CHCl3 (15 mL) was refluxed for 4.5 h then cooled and concentrated. Chromatography (1:1 EtOAc/hexanes) yielded 3-(4-bromo-pyrazol-1-yl)-4-methyl-benzoic acid ethyl ester (0.739 g, 99%). The bromopyrazole (366 mg, 1.18 mmol) was dissolved in dioxane (2 mL) and flushed with N2. 1-Methyl-5-tributylstannanyl-1H-imidazole (366 mg, 0.986 mmol) was added to the reaction flask in dioxane (0.5 mL) then the flask was purged with N2. After Pd(PPh3)4 (85 mg, 0.074 mmol) was added, the reaction was heated to 100° C. in a sealed tube. The reaction mixture was stirred with a 10% KF solution for 30 min then diluted with EtOAc. The layers were separated and the aqueous layer extracted with EtOAc (3×). The organic layers were combined, dried over Na2SO4, and concentrated. The resulting residue was purified by chromatography on silica gel (5% MeOH/CH2Cl2) to give 4-methyl-3-[4-(3-methyl-3H-imidazol-4-yl)-pyrazol-1-yl]-benzoic acid ethyl ester (81 mg, 22%).
Reaction SMILES: CO[CH2:3][CH2:4]OC.C(S(C1N(C2C=CC=CC=2)N=NN=1)(=O)=O)C.[CH2:23]([CH:26]1[CH2:30][CH2:29][CH:28]([CH:31]2[CH2:36][CH2:35][CH:34]([CH:37]=O)[CH2:33][CH2:32]2)[CH2:27]1)[CH2:24][CH3:25].C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1COCC1>[CH:37](/[CH:34]1[CH2:35][CH2:36][CH:31]([CH:28]2[CH2:29][CH2:30][CH:26]([CH2:23][CH2:24][CH3:25])[CH2:27]2)[CH2:32][CH2:33]1)=[CH:3]\[CH3:4]
Reactant: CCCC1CCC(C2CCC(C=O)CC2)C1
Reactant: COCCOC
Agent: CCS(=O)(=O)c1nnnn1-c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: C/C=C/C1CCC(C2CCC(CCC)C2)CC1
Temperature: -70 °C

Procedure:
DME (1,2-dimethoxyethane; 80 ml) and 5-(ethylsulfonyl)-1-phenyl-1H-tetrazole (4.62 g) were added to 4-(3-propylcyclopentyl)cyclohexanecarboaldehyde (3.29 g) obtained in the second step in Example 3, in a reaction vessel under an atmosphere of nitrogen, and the mixture was cooled to −70° C., and then KHMDS (Potassium Hexamethyldisilazide; 20%, in a THF solution) (23.9 ml) was added dropwise. The reaction solution was warmed to room temperature, and was extracted with diethyl ether after the addition of water (50 ml). The resulting organic layer was washed with water and dried over anhydrous sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate/n-heptane= 1/9 by volume) and then purified by means of a preparative HPLC system, Model PLC-561 made by GL Sciences Inc. to give (E)-1-(prop-1-enyl)-4-(3-propylcyclopentyl)cyclohexane (2.0 g).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1.[CH3:12][N:13]1C(=O)CCC1>>[C:12]([C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1)#[N:13]
Reactant: CN1CCCC1=O
Reactant: Brc1ccc2ccncc2c1
Product: N#Cc1ccc2ccncc2c1
Temperature: 25 °C

Procedure:
A solution of 7-bromoisoquinoline (1.80 g, 8.65 mmol) and cuprous cyanide (1.16 g, 12.97 mmol) in N-methyl pyrrolidinone (17 mL) was heated to 200° C. for 2 h. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water. The aqueous phase was back-extracted with additional ethyl acetate and the combined organic layers were washed with saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure to yield 7-cyano-isoquinoline (770 mg): 1H NMR (300 MHz, CDCl3) δ 9.35 (s, 1H), 8.70 (d, J=5 Hz, 1H), 8.40 (s, 1H), 7.95 (d, J=8 .Hz, 1H), 7.84 (d, J=8 Hz, 1H), 7.73 (d, J=5 Hz, 1H); ESI MS m/z 155 [M+H]+.
Reaction SMILES: Cl.[CH3:2][C@@:3]1([C:8]([O:10][CH3:11])=[O:9])[CH2:7][CH2:6][CH2:5][NH:4]1.[Cl:12][C:13]1[CH:14]=[C:15]([S:20](Cl)(=[O:22])=[O:21])[CH:16]=[C:17]([Cl:19])[CH:18]=1.C(N(C(C)C)CC)(C)C>C1COCC1.C(Cl)Cl>[Cl:19][C:17]1[CH:16]=[C:15]([S:20]([N:4]2[CH2:5][CH2:6][CH2:7][C@@:3]2([CH3:2])[C:8]([O:10][CH3:11])=[O:9])(=[O:21])=[O:22])[CH:14]=[C:13]([Cl:12])[CH:18]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Reactant: COC(=O)[C@]1(C)CCCN1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)[C@]1(C)CCCN1S(=O)(=O)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
2-methyl-(L)-proline, methyl ester hydrochloride (95 gm, 52.9 mmol) was dissolved in a mixture (1:1) of dry THF and CH2Cl2 (250 mL). A solution of 3,5-dichlorobenzenesulfonyl chloride (13.0 gm, 52.9 mmol) in dry CH2Cl2 (20 mL) was added. The reaction was cooled in an ice bath and diisopropylethylamine (20.5 gm, 158.6 mmol) was added. The ice bath was removed and the reaction mixture was stirred overnight at rt. The reaction was concentrated and dried to a tan solid (18.68 gm). This solid was purified on a Biotage 40M chromatography system eluted with 10% EtOAc in hexanes to yield N-(3,5-dichlorobenzenesulfonyl)-2-methyl-(L)-proline, methyl ester as a pure white solid (16.8 gm, 85% yield).
Reaction SMILES: [B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.C(N(CC)C(C)C)(C)C.[F:32][C:33]([F:74])([F:73])[C:34]1([C:69]([F:72])([F:71])[F:70])[C:38](=[O:39])[N:37]([C@@H:40]([CH2:44][CH:45]([CH3:47])[CH3:46])[C:41](O)=[O:42])[C:36](=[O:48])[N:35]1[CH2:49][C:50]1[CH:55]=[CH:54][C:53]([NH:56][C:57]([NH:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=2[CH3:66])=[O:58])=[C:52]([O:67][CH3:68])[CH:51]=1.[NH2:75][C@H:76]([C:83]1[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=1)[CH2:77][C:78]([O:80][CH2:81][CH3:82])=[O:79]>CN(C=O)C>[F:72][C:69]([F:70])([F:71])[C:34]1([C:33]([F:74])([F:73])[F:32])[C:38](=[O:39])[N:37]([C@@H:40]([CH2:44][CH:45]([CH3:46])[CH3:47])[C:41]([NH:75][C@H:76]([C:83]2[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=2)[CH2:77][C:78]([O:80][CH2:81][CH3:82])=[O:79])=[O:42])[C:36](=[O:48])[N:35]1[CH2:49][C:50]1[CH:55]=[CH:54][C:53]([NH:56][C:57]([NH:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=2[CH3:66])=[O:58])=[C:52]([O:67][CH3:68])[CH:51]=1
Reactant: CCOC(=O)C[C@H](N)c1ccccc1
Reactant: COc1cc(CN2C(=O)N([C@@H](CC(C)C)C(=O)O)C(=O)C2(C(F)(F)F)C(F)(F)F)ccc1NC(=O)Nc1ccccc1C
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C[C@H](NC(=O)[C@H](CC(C)C)N1C(=O)N(Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)C(C(F)(F)F)(C(F)(F)F)C1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.2 %

Procedure:
1.89 g (5.77 mmol) of TOTU and 932 μL of N,N-diisopropylethylamine were added at 0° C. to a solution of 3.57 g (5.77 mmol) of (S)-2-(4,4-bis(trifluoromethyl)-3-(4-(3-(2-methylphenyl)ureido)-3-methoxybenzyl)-2, 5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetic acid (prepared from (S)-2-(4,4-bis(trifluoromethyl)-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetic acid and 4-(3-(2-methylphenyl)ureido)-3-methoxybenzyl chloride as described in Example 18f) and 1.11 g (5.77 mmol) of ethyl (S)-3-amino-3-phenylpropionate in 30 mL of absolute DMF. After stirring at room temperature for 1 hour, DMF was removed in vacuo, the residue was taken up in ethyl acetate and the ethyl acetate solution was washed successively with an aqueous KHSO4K2SO4 solution, a saturated NaHCO3 solution and water. After drying the organic phase over sodium sulfate and filtering, the solvent was removed in vacuo and the residue was chromatographed over silica gel using ethyl acetate/heptane (2/3). After concentration of the product fractions, 3.26 g (71%) of the title compound were obtained.