Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([CH2:20][CH2:21][CH2:22][CH3:23])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:8]=1)=[N+]=[N-]>[Pd]>[NH2:1][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([CH2:20][CH2:21][CH2:22][CH3:23])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:8]=1
Reactant: CCCCC(Cc1ccc(OCCN=[N+]=[N-])cc1)C(=O)OCC
Agent: [Pd]
Product: CCCCC(Cc1ccc(OCCN)cc1)C(=O)OCC
Yield: 100.1 %

Procedure:
In a similar manner to that described in Reference example 1(d), a reaction was carried out using ethyl 3-[4-(2-azidoethoxy)phenyl]-2-butylpropionate (1.62 g), which is the product of Reference example 6(g), and palladium on carbon (5%, 243 mg) and the reaction mixture was treated to afford the title compound (1.49 g) as a syrup.
Reaction SMILES: C([Li])CCC.[CH3:6][S:7]([O:10][CH3:11])(=[O:9])=[O:8].[CH:12]([C:14]1[CH:18]=[C:17]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)[NH:16][C:15]=1[C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)=O.[O:29]1CCC[CH2:30]1>>[CH3:6][S:7]([O:10][CH3:11])(=[O:9])=[O:8].[OH:29][CH2:30][CH:12]([C:14]1[CH:18]=[C:17]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)[NH:16][C:15]=1[C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)[S:7]([CH3:6])(=[O:9])=[O:10]
Reactant: C1CCOC1
Reactant: O=Cc1cc(-c2cccs2)[nH]c1-c1cccs1
Agent: COS(C)(=O)=O
Agent: [Li]CCCC
Product: CS(=O)(=O)C(CO)c1cc(-c2cccs2)[nH]c1-c1cccs1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 43 %

Procedure:
The lithio derivative of methyl methanesulfonate was prepared at -78° C. under argon by the dropwise addition of 0.56 mL of a 1.60M n-butyllithium (0.891 mmol) to a solution of 72 μL (0.85 mmol) of methyl methanesulfonate in 2 mL of anhydrous tetrahydrofuran. After 45 minutes at -78° C., 3-formyl-2,5-dithienylpyrrole (105 mg, 0.41 mmol) in 1 mL of tetrahydrofuran was added dropwise over a 5 minute period to the lithio methyl methanesulfonate solution. The reaction mixture was allowed to stir for 30 minutes at -78° C. After the completion of reaction, it was then quenched with a saturated aqueous ammonium chloride solution. The aqueous layer was extracted three times with 50 mL portions of ethyl acetate and the combined organic layers were washed with water (10 mL×1) and brine (10 mL×1). The organic layer was dried over anhydrous magnesium sulfate, filtered and the solvent was removed under reduced pressure. The crude product was purified on 50 g of silica gel. Elution with hexane-ethyl acetate (5:1), gave 64 mg (43%) of title compound.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.Br[CH2:12][CH2:13][C:14]([OH:16])=[O:15]>O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:6][CH:5]=1
Reactant: O=C(O)CCBr
Reactant: Sc1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCSc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 101 %

Procedure:
8.5 g (0.211 mol) of sodium hydroxide was added to 45 mL of water, 20.0 g (0.106 mol) of 4-bromothiophenol (purchased from Aldrich Chemical Company) was then added and the mixture was cooled to about 0° C. 18.0 g (0.116 mol) of 3-bromopropionic acid (purchased from Aldrich Chemical Company) was added in portions while keeping the temperature below 5° C. The mixture was warmed to room temperature, stirred for 1 h under nitrogen, and was then washed with diethyl ether (3×100 mL). The aqueous layer was acidified with 1N HCl, and then filtered to yield 27.95 g of the title compound of Step A as a solid melting at 101-103° C. 1H NMR (CDCl3): δ2.66 (t,2H), 3.14 (t,2H), 7.2 (m,2H), 7.4 (m,2H).
Reaction SMILES: [C:1]([C:3]1[N:7]([CH2:8][CH2:9][CH3:10])[N:6]=[C:5]([CH3:11])[C:4]=1[NH:12][C:13](=O)[CH3:14])#[N:2].[OH:16]O.O.[OH-].[Na+]>C(O)(=O)C>[CH3:11][C:5]1[C:4]2[N:12]=[C:13]([CH3:14])[N:2]=[C:1]([OH:16])[C:3]=2[N:7]([CH2:8][CH2:9][CH3:10])[N:6]=1
Reactant: OO
Reactant: CCCn1nc(C)c(NC(C)=O)c1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CCCn1nc(C)c2nc(C)nc(O)c21
Temperature: 80 °C
Yield: 66 %

Procedure:
The above acetamide (16 g, 0.085 mol) is added in portions with stirring at 80° C. to a solution prepared by adding 24 ml of 30% hydrogen peroxide to 200 ml water containing 6 g (0.015 mol) of sodium hydroxide. After stirring at 80° C. for five hours, the mixture is cooled, acidified with acetic acid, and filtered to give 11.6 g (66%) of the title compound, mp 196°-198° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:18]=[CH:17][C:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:8][CH:7]=1>CO.[Pd]>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]1[CH:18]=[CH:17][C:9]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccco2)cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(C2CCCO2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.9 %

Procedure:
To a solution of tert-butyl 4-(furan-2-yl)benzoate (400 mg, 1.64 mmol) in methanol (20 mL) was added palladium on carbon (10%, 100 mg). After stirring for 24 hours at room temperature under hydrogen atmosphere, the mixture was filtered. And the filtrate was concentrated in vacuo to give tert-butyl 4-(tetrahydrofuran-2-yl)benzoate (350 mg, 86%) as a white solid. LRMS (M+H+) m/z: calcd 248.14. found 248. 1H NMR (300 MHz, CD3OD): δ 7.94-7.85 (m, 2H), 7.44-7.28 (m, 2H), 4.95-4.93 (m, 1H), 3.60-3.56 (m, 2H), 2.73-2.68 (m, 2H), 1.77-1.73 (m, 2H), 1.68 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:15][CH:14]=[C:13]([CH2:16][O:17][C:18]3[CH:23]=[C:22]([C:24]4[N:28]([CH2:29]C5C=CC(OC)=CC=5)[C:27](C)=[N:26][N:25]=4)[CH:21]=[CH:20][C:19]=3[CH3:39])[C:8]=2[C:9]([Cl:12])=[N:10][CH:11]=1)=[O:5])[CH3:2].FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1.S(=O)(=O)(O)O>>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:15][CH:14]=[C:13]([CH2:16][O:17][C:18]3[CH:23]=[C:22]([C:24]4[N:28]([CH3:29])[CH:27]=[N:26][N:25]=4)[CH:21]=[CH:20][C:19]=3[CH3:39])[C:8]=2[C:9]([Cl:12])=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc(Cl)c2c(COc3cc(-c4nnc(C)n4Cc4ccc(OC)cc4)ccc3C)csc12
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCOC(=O)c1cnc(Cl)c2c(COc3cc(-c4nncn4C)ccc3C)csc12
Temperature: 25 °C
Reaction time: 42 h

Procedure:
A mixture of 4-chloro-3-{5-[4-(4-methoxy-benzyl)-5-methyl-4H-[1,2,4]triazol-3-yl]-2-methyl-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (85 mg; 0.151 mmol) (from Example 58 supra) with trifluoroacetic acid (1.0 mL; 13 mmol), anisole (100 μL; 0.92 mmol) (Aldrich) and sulfuric acid (50 μL; 0.94 mmol) was stirred at room temperature for 42 hours. The mixture was concentrated. The residue was diluted with dichloromethane and concentrated again. The residue was then diluted with dichloromethane and methanol and washed with saturated aqueous sodium bicarbonate solution and water. The aqueous phases were backwashed with a mixture of dichloromethane and methanol. The two organic phases were combined, dried over sodium sulfate and concentrated. The crude material was purified by flash chromatography (12 g column; EtOAc followed by a gradient to 60:40 EtOAc: methanol) to give 4-chloro-3-[2-methyl-5-(methyl-4H-[1,2,4]triazol-3-yl)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester. (Yield 56.3 mg, 84.20%).
Reaction SMILES: [N:1]1([C:6]2[C:7]3[N:8]([C:16]([C:19]([O:21]CC)=[O:20])=[CH:17][N:18]=3)[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=2)[CH:5]=[N:4][CH:3]=[N:2]1.C1COCC1.[OH-].[Na+].Cl>O.C(O)C>[N:1]1([C:6]2[C:7]3[N:8]([C:16]([C:19]([OH:21])=[O:20])=[CH:17][N:18]=3)[CH:9]=[C:10]([C:12]([F:14])([F:15])[F:13])[CH:11]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CCOC(=O)c1cnc2c(-n3cncn3)cc(C(F)(F)F)cn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1cnc2c(-n3cncn3)cc(C(F)(F)F)cn12
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.3 %

Procedure:
To a mixture of ethyl 8-(1H-1,2,4-triazol-1-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carboxylate (320 mg), THF (4 mL) and ethanol (4 mL) was added 2N aqueous sodium hydroxide solution (0.98 mL), and the mixture was stirred at room temperature 3 hr. The reaction mixture was acidified with 1N hydrochloric acid, water was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from THF/hexane to give the title compound (270 mg).
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:12]3[CH2:14][O:13]3)[CH:9]=2)[C:4](=[O:15])[O:3]1.Cl.[N:17]1([C:23](=[O:36])[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH:35]=[N:34][N:33]=[N:32]3)=[CH:27][CH:26]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.CCN(C(C)C)C(C)C>CCO>[OH:13][CH:12]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[C:4](=[O:15])[O:3][CH:2]([CH3:1])[CH2:11]2)[CH2:14][N:20]1[CH2:19][CH2:18][N:17]([C:23](=[O:36])[CH2:24][C:25]2[CH:26]=[CH:27][C:28]([N:31]3[CH:35]=[N:34][N:33]=[N:32]3)=[CH:29][CH:30]=2)[CH2:22][CH2:21]1
Reactant: O=C(Cc1ccc(-n2cnnn2)cc1)N1CCNCC1
Reactant: CC1Cc2cc(C3CO3)ccc2C(=O)O1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC1Cc2cc(C(O)CN3CCN(C(=O)Cc4ccc(-n5cnnn5)cc4)CC3)ccc2C(=O)O1

Procedure:
A sealed tube containing 3-methyl-6-(oxiran-2-yl)-3,4-dihydro-1H-isochromen-1-one (72 mg, 35 mmol), 1-(piperazin-1-yl)-2-[4-(1H-tetrazol-1-yl)phenyl]ethanone hydrochloride (109 mg, 0.35 mmol), DIEA (0.2 mL) and EtOH (3 mL) was heated to 80 C for 12 hours. The excess solvent was removed and the crude product purified via MPLC (35% EtOAc/Hex-60% EtOAc/Hex) to give 6-[1-hydroxy-2-(4-{[4-(1H-tetrazol-1-yl)phenyl]acetyl}piperazin-1-yl)ethyl]-3-methyl-3,4-dihydro-1H-isochromen-1-one. LC-MS (IE, m/z): 477 [M+1]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([NH2:18])=[O:17].[Cl:19][C:20]1[C:21]([CH3:27])=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23].C(O)(=O)C.[OH-].[Na+]>CN(C=O)C.O>[Cl:19][C:20]1[C:21]([CH3:27])=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH:23][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([NH2:18])=[O:17]
Reactant: Cc1c(N)cccc1Cl
Reactant: COc1cc2ncc(C(N)=O)c(Cl)c2cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2ncc(C(N)=O)c(Nc3cccc(Cl)c3C)c2cc1OC
Temperature: 100 °C
Yield: 80.7 %

Procedure:
A mixture of 4-chloro-6,7-dimethoxy-3-quinolinecarboxamide (0.046 g, 0.17 mmol), 3-chloro-2-methylaniline (25 μl, 0.21 mmol) and acetic acid (40 μl) in DMF (0.8 ml) was heated at 100° C. for 4.5 h. After cooling the reaction mixture was diluted with water (15 ml) and made alkaline with 1 M NaOH. The precipitate was collected by filtration, rinsed with water and dried to give the title compound (51 mg, 79%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:21]([O-])=O)=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([NH:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:7]=1.C([O-])=O.[NH4+]>CCO.[Pd]>[NH2:21][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][C:6]=1[NH:8][C@@H:9]1[CH2:10][CH2:11][C@H:12]([C:15]([NH:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(F)ccc2[N+](=O)[O-])CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(F)ccc2N)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of cis-4-(5-fluoro-2-nitrophenylamino)-N-isopropylcyclohexanecarboxamide (123 mg, 0.380 mmol) in EtOH (5 mL) was added ammonium formate (240 mg, 3.80 mmol) and 10% palladium on carbon (40.5 mg, 0.038 mmol). The reaction was stirred at RT for 1 hour. The reaction mixture was filtered through Celite® brand filter aid (washed with MeOH), concentrated, and redissolved in DCM (10 mL). The solution was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated to afford cis-4-(2-amino-5-fluorophenylamino)-N-isopropylcyclohexanecarboxamide as a purple oil that crystallized upon standing. The diamine was dissolved in THF (5 mL), cooled to 0° C., and 4-fluorobenzoyl isothiocyanate (97 mg, 0.534 mmol) was added. The reaction was stirred at 0° C. for 15 minutes, and then DIPEA (0.100 mL, 0.573 mmol) and EDC (110 mg, 0.573 mmol) were added, and the reaction was stirred for 1 hour at 60° C. The reaction mixture was concentrated, adsorbed onto a plug of silica gel, and purified by column chromatography, eluting with 0-100% EtOAc in DCM, to provide (E)-4-fluoro-N-(6-fluoro-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide as an off-white powder (137 mg, 81% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09 (d, J=6.7 Hz, 6H), 1.55-1.80 (m, 4H), 2.04-2.12 (m, 2H), 2.53 (br. s., 1H), 2.68-2.82 (m, 2H), 3.94-4.08 (m, 1H), 4.86 (br. s., 1H), 7.02-7.12 (m, 1H), 7.25 (dd, J=8.9 Hz, 8.9 Hz, 2H), 7.53 (dd, J=8.8, 4.9 Hz, 1H), 7.60 (dd, J=9.5, 1.9 Hz, 1H), 7.70 (d, J=7.4 Hz, 1H), 8.32 (dd, J=8.8, 5.9 Hz, 2H), 12.82 (s, 1H). MS, m/z (C24H26F2N4O2): calcd, 440.2. found, 440.7 [M+H].
Reaction SMILES: [CH3:1][S-:2].[Na+].Br[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13]>CO>[CH3:1][S:2][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: C[S-]
Reactant: O=C(O)CCCCCCCBr
Agent: [Na+]
Solvent: CO
Product: CSCCCCCCCC(=O)O

Procedure:
Sodium thiomethoxide (942 mg, 13.44 mmol) was added to a solution of 8-bromooctanoic acid (500 mg, 2.24 mmol) in methanol (5.6 mL), and the mixture was heated under reflux overnight. The reaction mixture was concentrated under reduced pressure, adjusted to pH 1 by adding 1 N hydrochloric acid and then extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1) to give 8-(methylthio)octanoic acid as a colorless oily substance (426.5 mg, 100%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13](Cl)=[O:14])=[CH:4][CH:3]=1.[B-](F)(F)(F)F.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.N1C=CC=CC=1.Cl.[C:45]1([CH:51]([C@H:53]2[CH2:57][CH2:56][CH2:55][NH:54]2)[OH:52])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>C(#N)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:54]2[CH2:55][CH2:56][CH2:57][C@@H:53]2[CH:51]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[OH:52])=[O:14])=[CH:4][CH:3]=1
Reactant: OC(c1ccccc1)[C@H]1CCCN1
Reactant: Cc1ccc(-c2oncc2C(=O)Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: c1ccncc1
Solvent: CC#N
Product: Cc1ccc(-c2oncc2C(=O)N2CCC[C@@H]2C(O)c2ccccc2)cc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To a solution of 5-(4-methylphenyl)isoxazole-4-carbonyl chloride (22 mg, 0.11 mmol) in acetonitrile (5 mL) was added o-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) (45 mg, 0.14 mmol, 1.3 eq.), pyridine (34 μL, 0.42 mmol, 4 eq.), and phenyl[(2R)-pyrrolidin-2-yl]methanol hydrochloride (25 mg, 0.12 mmol, 1.1 eq.). The reaction mixture was stirred at ambient temperature for 20 h and at 40° C. for an additional 2 h. The solvent was removed, and the residue was purified by preparative reverse-phase HPLC to yield the product as a white solid. HRMS (ESI, pos. ion) m/z calcd for C22H22N2O3: 362.1630, found 362.1625.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH2:17][NH:16][CH2:15][CH2:14]2)=[O:10].[CH3:21][O:22][CH2:23][CH2:24][O:25][CH2:26][C:27](O)=[O:28].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.C(N(CC)CC)C>[CH3:21][O:22][CH2:23][CH2:24][O:25][CH2:26][C:27]([N:16]1[CH2:15][CH2:14][C:13]2[C:18](=[CH:19][CH:20]=[C:11]([C:9]([NH:8][O:7][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)=[O:10])[CH:12]=2)[CH2:17]1)=[O:28]
Reactant: O=C(NOC1CCCCO1)c1ccc2c(c1)CCNC2
Reactant: COCCOCC(=O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COCCOCC(=O)N1CCc2cc(C(=O)NOC3CCCCO3)ccc2C1
Reaction time: 8 h

Procedure:
A mixture of 200 mg N-(tetrahydro-2H-pyran-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide, 0.045 ml 2-(2-methoxyethoxy)acetic acid, 111 mg HOBt, 276 mg EDC, 0.603 ml triethylamine and 7 ml DMF is stirred overnight. The reaction mixture is quenched with 3 ml water and 5 ml dichloromethane. The organic phase is separated, the water phase extracted with 2 ml dichloromethane. The combined organic phases are dried and evaporated. 335 ml of yellow oil is obtained, which is further purified by preparative HPLC-methods.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([N:23]([CH:25]([CH3:27])[CH3:26])[CH3:24])[CH2:19][C@H:18]2[C:28]([O:30]CC)=[O:29])[C:13]1=[O:33])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>Cl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([N:23]([CH:25]([CH3:27])[CH3:26])[CH3:24])[CH2:19][C@H:18]2[C:28]([OH:30])=[O:29])[C:13]1=[O:33])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: Cl
Product: CC(C)N(C)[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](C(=O)O)C1
Temperature: 55 °C
Reaction time: 20 h
Yield: 840.6 %

Procedure:
Example 1, Alternative Step 9f: The aminoester 6 (9.76 g, 2.12 mmol) was dissolved in 2N HCl (80 mL), then heated to ˜55° C. under inert atmosphere. The reaction was stirred for 20 h, then cooled to room temperature. The reaction solution was washed twice with toluene (25 mL portions), neutralized to pH 6-7 by the addition of KOH pellets, then extracted eight times with methylene chloride (100 mL portions). The combined extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure to 50 mL total volume. The concentrated solution was then slowly added to methyl tert-butyl ether (300 mL) over 15 min in an addition funnel with vigorous stirring. The resulting white slurry was stirred at ambient temperature for Ih, then cooled to 0° C. and stirred for 1 h. The product was filtered, and washed twice with methyl tert-butyl ether (25 mL portions). Water from the wet cake was removed by azeotropic distillation with acetonitrile (300 mL). The product was dried under reduced pressure to provide (1R,2S,5R)-2-((3S)-3-Benzyloxycarbonylamino-2-oxo-pyrrolidin-1-yl)-5-(isopropyl-methyl-amino)-cyclohexanecarboxylic acid 7, (7.69 g, 84% yield) as a white foam. 1H-NMR: (400 MHz, 50° C., CDCl3) δ 7.44-7.32 (m, 5H), 6.10 (broad s, 1H), 5.19 (app s, 2H), 4.42 (dd, J=15.6, 7.8 Hz, 1H), 4.29-4.23 (m, 1H), 3.68-3.60 (m, 2H), 3.33-3.27 (m, 2H), 3.20 (broad s, 1H), 2.99 (broad s, 1H), 2.51 (s, 3H), 2.49-2.45 (m, 3H), 2.33-2.31 (m, 1H), 2.00 (ddd, J=9.0, 8.6, 3.9 1H), 1.95-1.78 (m, 2H), 1.36-1.21 (m, 6H). LCMS: m/z 432.20 [Calc: C23H34N3O5 432.25].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:20])([CH3:19])[CH2:9][NH:10][C:11]2[N:12]=[N:13][C:14]([CH:17]=[CH2:18])=[CH:15][CH:16]=2)=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pd]>[CH2:17]([C:14]1[N:13]=[N:12][C:11]([NH:10][CH2:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)([CH3:20])[CH3:19])=[CH:16][CH:15]=1)[CH3:18]
Reactant: C=Cc1ccc(NCC(C)(C)c2ccc(F)cc2)nn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCc1ccc(NCC(C)(C)c2ccc(F)cc2)nn1
Yield: 10 %

Procedure:
The isolated product from Step 1 was dissolved in ethanol (10 mL) and transferred to a 20 dram vial. Palladium (10% on carbon, 10 mg) was then added, and the reaction was stirred under 60 psi of hydrogen for 3 days. The reaction was then filtered, concentrated, and purified by reverse phase column chromatography to afford 3 mg (10%) of 6-ethyl-N-(2-(4-fluorophenyl)-2-methylpropyl)pyridazin-3-amine as a clear oil, m/z=274 [M+H].
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Cl:17][CH2:18][C:19]([OH:21])=[O:20].Cl>CN(C=O)C.C(O)(C)C>[ClH:17].[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:18][C:19]([OH:21])=[O:20])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: O=C(O)CCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: O=C(O)COC1CCN(Cc2ccccc2)CC1
Reaction time: 4 h
Yield: 20.1 %

Procedure:
1-Benzyl-4-hydroxypiperidine (10 g) in dry DMF (50 ml) was added dropwise to a stirred suspension of sodium hydride (5 g, 50% dispersion in mineral oil) in dry DMF (50 ml) at 20° under an atmosphere of nitrogen. The suspension was stirred at 20° for 4 hours, then 2-chloroacetic acid (4.95 g) in DMF (50 ml) was added slowly in two equal portions with a 2 hour interval between each. The resulting thick slurry was stirred at 20° for 24 hours. Isopropanol (75 ml) was added and the slurry was acidified to pH 6 with 2 N hydrochloric acid then concentrated in vacuo. The aqueous residue was adjusted to pH 10 with sodium hydroxide solution and extracted with chloroform (3×100 ml). The aqueous layer was separated, acidified to pH 3 with 2 N hydrochloric acid and extracted with chloroform (3×100 ml). The organic extracts were again discarded and the aqueous phase was concentrated to half volume, filtered and the filtrate evaporated in vacuo to give 2-(1-benzylpiperidin-4-oxy)acetic acid, hydrochloride (3 g), characterised by n.m.r.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[N:16]3)=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[C:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O)(=[O:23])[CH3:22]>>[C:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[N:16]3)=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1)(=[O:23])[CH3:22]
Reactant: O=C(Nc1ccc2cccnc2c1)c1ccc(Br)cc1
Reactant: CC(=O)c1ccccc1B(O)O
Product: CC(=O)c1ccccc1-c1ccc(C(=O)Nc2ccc3cccnc3c2)cc1

Procedure:
Using the procedure outlined in Example 58, the title compound was prepared from 4-bromo-N-quinolin-7-ylbenzamide (Example 82) (50 mg, 0.153 mmol) and 2-acetyl-phenylboronic acid (28 mg, 0.17 mmol) as an off -white solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 8.92 (dd, 1H), 8.21 (d, 1H), 8.20 (s, 1H), 8.14 (d, 1H), 8.10 (dd, 1H), 7.86 (d, 1H), 7.63 (dd, 1H), 7.57 (td, 1H), 7.48 (m, 3H), 7.40 (dd, 1H), 7.35 (dd, 1H), 3.85 (s, 3H).
Reaction SMILES: [CH3:1][CH2:2][CH2:3]Br.[Mg].Cl[SiH:7]1[CH2:12][CH2:11][CH:10]([C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][CH2:20][C:21]3[CH:26]=[C:25]([F:27])[C:24]([F:28])=[C:23]([F:29])[CH:22]=3)[CH2:15][CH2:14]2)[CH2:9][CH2:8]1>C1COCC1>[F:29][C:23]1[CH:22]=[C:21]([CH2:20][CH2:19][C@H:16]2[CH2:17][CH2:18][C@H:13]([C@H:10]3[CH2:11][CH2:12][Si@H:7]([CH2:1][CH2:2][CH3:3])[CH2:8][CH2:9]3)[CH2:14][CH2:15]2)[CH:26]=[C:25]([F:27])[C:24]=1[F:28]
Reactant: CCCBr
Reactant: Fc1cc(CC[C@H]2CC[C@H](C3CC[SiH](Cl)CC3)CC2)cc(F)c1F
Agent: [Mg]
Solvent: C1CCOC1
Product: CCC[Si@H]1CC[C@H]([C@H]2CC[C@H](CCc3cc(F)c(F)c(F)c3)CC2)CC1

Procedure:
2.5 g (20 mmol) of n-propyl bromide was dripped into a mixture of 0.5 g (21 mmol) of magnesium and 50 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 50 ml THF solution of 7.8 g (20 mmol) of 1-chloro-4-(trans-4-(2-(3,4,5-trifluorophenyl) ethyl) cyclohexyl)-1-silacyclohexane. The silacyclohexane rings of the reacted mixture thus obtained were a mixture of trans isomers and cis isomers. After a conventional after treatment, they were separated by means of chromatography to obtain 6.1 g (yield 80%) of trans-4-(trans-4-(2-(3,4,5-trifluorophenyl) ethyl) cyclohexyl)-1-n-propyl-1-silacyclohexane.