Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[K+].[CH3:3][N:4]([CH:6]=[O:7])[CH3:5].[CH3:8][CH:9]1[S:14][C:13](=[O:15])[NH:12][N:11]=[C:10]1[C:16]1[CH:17]=[C:18]2C(=[CH:23][CH:24]=1)NC(=O)[C:19]12[CH2:29][CH2:28][CH2:27][CH2:26]1.[CH3:30]I>O>[CH3:30][N:12]1[N:11]=[C:10]([C:16]2[CH:17]=[C:18]3[C:3](=[CH:23][CH:24]=2)[N:4]([CH3:5])[C:6](=[O:7])[C:19]23[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:9]([CH3:8])[S:14][C:13]1=[O:15]
Reactant: CN(C)C=O
Reactant: CI
Reactant: CC1SC(=O)NN=C1c1ccc2c(c1)C1(CCCC1)C(=O)N2
Agent: [H-]
Agent: [K+]
Solvent: O
Product: CC1SC(=O)N(C)N=C1c1ccc2c(c1)C1(CCCC1)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.76 g (19 mmol) washed potassium hydride, 75 ml dry DMF and 3 g (9.5 mmol) 5'-(3,6-dihydro-6-methyl-2-oxo-2H-1,3,4-thiadiazin-5-yl)-spiro-[cyclopentane-1, 3'-[3H]-indol]-2'(1'H)-one (Example 6) were stirred at room temperature during 30mn. 2.8 g (20 mmol) methyliodide were added and the stirring was continued for 1 hr. 150 ml water were added and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate. The crude product was purified by column chromatography on silica (eluent:methylen chloride/methanol: 99.5/0.5).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:15][C:16](=[O:37])[CH2:17][C@@H:18]([NH2:36])[C:19]([NH:21][C@H:22]([C:27](=[O:35])[NH:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1)[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:20])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CO[CH:40]1[CH:44]([C:45]2[CH:50]=[CH:49][C:48]([C:51]3[CH:56]=[CH:55][C:54]([C:57]#[N:58])=[CH:53][CH:52]=3)=[CH:47][CH:46]=2)[CH2:43][CH:42](OC)O1>>[CH2:8]([O:15][C:16](=[O:37])[CH2:17][C@@H:18]([N:36]1[CH:42]=[CH:43][C:44]([C:45]2[CH:50]=[CH:49][C:48]([C:51]3[CH:52]=[CH:53][C:54]([C:57]#[N:58])=[CH:55][CH:56]=3)=[CH:47][CH:46]=2)=[CH:40]1)[C:19]([NH:21][C@H:22]([C:27](=[O:35])[NH:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1)[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:20])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)[C@H](NC(=O)[C@H](N)CC(=O)OCc1ccccc1)C(=O)Nc1ccncc1
Reactant: COC1CC(c2ccc(-c3ccc(C#N)cc3)cc2)C(OC)O1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[C@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccc(-c3ccc(C#N)cc3)cc2)c1)C(=O)Nc1ccncc1
Yield: 42 %

Procedure:
According to the procedure described in Example 1(c) for the preparation N-(1,7-diaza-4-oxa-8-oxo-tricyclo-[9.6.1.012,17]-octadeca-11(18),12,14,16-tetraen-9S-yl)-3(R)-(3-phenyl-1H-pyrrol-1-yl)sucinnamic acid benzyl ester, crude 3(R)-amino-N-[2,2-dimethyl-1(S)-(pyridin-4-ylcarbamoyl)propyl]succinamic acid benzyl ester trifluoroacetate salt and 4′-(2,5-dimethoxy-tetrahydrofuran-3-yl)-biphenyl-4-carbonitrile were condensed to give 75 mg (42%) of 3(R)-[3-(4′-cyanobiphenyl-4-yl)-1H-pyrrol-1yl]-N-[2,2-dimethyl-1(S)-(pyridin-4-ylcarbamoyl)propyl]succinamic acid benzyl ester as an off-white powder, mp 115-6° C. 1H NMR: δ 8.42 (d, 2H, J=5.6 Hz), 7.72 (s, 2H), 7.58 (s, 2H), 7.50 (d, 2H, J=5.0 Hz), 7.31 (s, 2H), 7.26 (s, 7H), 7.12 (m, 1H), 6.85 (dd, 1H, J=2.5, 2.5 Hz), 6.64 (dd, 1H, J=1.6, 2.8 Hz), 6.25 (m, 1H), 5.20-5.10 (m, 3H), 4.15 (d, 1H, J=8.1 Hz), 3.39 (dd, 1H, J=5.5, 17.3 Hz), 3.25 (dd, 1H, J=7.9, 17.3 Hz), 0.94 (s, 9H). IR (KBr): 3331, 2959, 2225, 1735, 1687, 1655, 1602, 1559, 1511, 1288, 1203, 825cm−1. HRFABMS: Calculated for C35H37N4O4 (M+H+): 640.2924. Found: 640.2908. Anal. Calculated for C39H37N5O4•1.1 EtOAc: C, 70.76; H, 6.27; N, 9.51. Found: C, 70.73; H, 6.19; N, 9.16.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[CH:34][CH:35]=[C:9]23)[CH2:4][CH2:3]1.[C:36]([O:39][C:40]([CH3:45])([CH3:44])[C:41](Cl)=[O:42])(=[O:38])[CH3:37].C(OCC)(=O)C.O>N1C=CC=CC=1>[C:36]([O:39][C:40]([CH3:45])([CH3:44])[C:41]([O:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]#[N:29])=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[CH:34][CH:35]=[C:9]23)[CH2:6][CH2:7]1)=[O:42])(=[O:38])[CH3:37]
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](O)CC2)c2ccnn12
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OC(=O)C(C)(C)OC(C)=O)CC2)c2ccnn12
Reaction time: 2 h

Procedure:
To a solution of 4′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.47 g) in pyridine (3 mL) was added 2-chloro-1,1-dimethyl-2-oxoethyl acetate (0.44 mL) and the mixture was stirred for 2 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.47 g, 79%).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[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:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:47][CH2:48][CH2:49][NH2:50]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([NH:50][CH2:49][CH2:48][OH:47])=[O:42])[CH2:36][CH2:35]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:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: NCCO
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)NCCO)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(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]-piperidin-4-yl}-acetic acid was coupled with 2-hydroxylethylamine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C38H48Cl2N5O4 [(M+H)+] 708.3078, observed 708.3074.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([S:33][C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=3)[NH:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:16][CH:15]=1>ClCCl>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:21]=[C:22]([S:33]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=3)=[O:9])[NH:23][C:24]=2[C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc(-c2nc(Sc3cccc(OC)c3)[nH]c2-c2ccc(OC)cc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(-c2nc(S(=O)c3cccc(OC)c3)[nH]c2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
A solution of 2.164 g of 3-chloroperbenzoic acid (80%) in 150 ml of dichloromethane is added dropwise to a solution of 4.19 g of 4,5-bis(4-methoxyphenyl)-2-(3-methoxyphenylthio)imidazole in 100 ml of dichloromethane. The solution is stirred for 3 hours at room temperature, washed with sodium bicarbonate solution, dried over sodium sulfate, and concentrated to dryness under vacuum. The residue is chromatographed on 150 g of silica gel with acetone/hexane, thus obtaining 3.96 g of 4,5-bis(4-methoxyphenyl)-2-(3-methoxyphenylsulfinyl)imidazole as an amorphous foam.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4]1[C:13]2[C:8](=[C:9]([OH:15])[C:10]([OH:14])=[CH:11][CH:12]=2)[CH2:7][CH:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:5]=1.Cl.C([O:25][CH2:26][CH3:27])C.[C:28](OC(=O)C)(=[O:30])[CH3:29]>>[ClH:1].[C:28]([O:15][C:9]1[C:10]([O:14][C:26](=[O:25])[CH3:27])=[CH:11][CH:12]=[C:13]2[C:8]=1[CH2:7][CH:6]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH:5]=[C:4]2[CH2:3][NH2:2])(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: NCC1=CC(c2ccccc2)Cc2c1ccc(O)c2O
Reactant: CCOCC
Agent: Cl
Product: CC(=O)Oc1ccc2c(c1OC(C)=O)CC(c1ccccc1)C=C2CN
Temperature: 25 °C
Reaction time: 48 h
Yield: 29 %

Procedure:
A suspension of 7.6 g (25 mmol) of 1-aminomethyl-5,6-dihydroxy-3-phenyl-3,4-dihydronaphthalene hydrochloride (Example 2B) in 400 mL of acetic anhydride saturated with anhydrous hydrogen chloride was stirred at ambient temperature for 48 h. Approximately 2 L of diethyl ether was added and a solid was collected by filtration and washed with diethyl ether. Crystallization of the crude material (6.7 g) was achieved by dissolving the powder in 400 mL of hot ethanol, adding 100 mL of water, filtering the solution hot and allowing it to cool. The white crystals which formed were filtered and dried to give 2.8 g (29% yield) of 5,6-bis(acetoxy)-1-aminomethyl-3-phenyl-3,4-dihydronaphthalene hydrochloride, m.p. 207°-208° C. 1H NMR (d6 -DMSO) δ: 2.28 (s, 6H), 2.62 (dd, 1H), 2.95 (dd, 1H), 3.7-3.8 (m, 1H), 3.97 (s, 2H), 6.25 (d, 1H), 7.19 (d, 1H), 7.2-7.4 (m, 6H), 8.41 (br s, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:3]2[C:7](=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:9]=1)[CH2:6][CH2:5][CH2:4]2.[F:16][C:17]([F:28])([C:24]([F:27])([F:26])[F:25])[C:18]([F:23])([F:22])[C:19](Cl)=[O:20].[Sn](Cl)(Cl)(Cl)Cl.[OH-].[Na+]>ClC(Cl)C.C(Cl)Cl>[F:25][C:24]([F:26])([F:27])[C:17]([F:16])([F:28])[C:18]([F:22])([F:23])[C:19]([C:9]1[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:7]2[N:3]([C:2]=1[CH3:1])[CH2:4][CH2:5][CH2:6]2)=[O:20]
Reactant: Cc1cc(-c2ccccc2)c2n1CCC2
Reactant: O=C(Cl)C(F)(F)C(F)(F)C(F)(F)F
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: Cc1c(C(=O)C(F)(F)C(F)(F)C(F)(F)F)c(-c2ccccc2)c2n1CCC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5-Methyl-7-phenyl-2,3-dihydro-1H-pyrrolizine (Example 30 c, 1.0 g, 0.005 mol), dissolved in dichloroethane (20 ml) is treated with heptafluorobutyryl chloride (0.83 ml, 1.3 g, 0.0055 mol) at RT and finally tin tetrachloride (0.7 ml, 1,56 g, 0.006 mol) in dichloroethane (5 ml) is added dropwise. The mixture warms to 35° C. and is stirred at RT for 16 h. The GC-MS analysis shows a 60% reaction. The reaction mixture is rendered alkaline with NaOH (25%, 25 ml) in an ice bath and, after addition of CH2Cl2 (25 ml), the organic phase is separated in a separating funnel. The alkali phase is extracted a further two times with dichloromethane (2×20 ml). These CH2Cl2 extracts are combined, dried over Na2SO4 sicc. and evaporated to dryness in vacuo.
Reaction SMILES: Cl.[CH3:2][O:3][NH:4][CH3:5].C(N(CC)CC)C.[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1>C(Cl)Cl>[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([N:4]([O:3][CH3:2])[CH3:5])=[O:19])=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 94 %

Procedure:
31.2 g of N-methoxymethanamine hydrochloride and 91.2 ml of triethylamine in 500 ml of DCM is cooled in an ice bath, and then 56 g of 4-chlorobenzoyl chloride are added slowly and the mixture is left to stir at AT for 4 hours. A mixture of ice/water is added, the mixture is extracted with DCM, the organic phase is washed with a buffer solution pH=2 and dried over Na2SO4, and the solvent is evaporated off under vacuum. 60 g of the expected compound are obtained.
Reaction SMILES: [Na].O[CH:3]=[C:4]1[CH2:8][CH2:7][O:6][C:5]1=[O:9].[C:10]1([CH2:16][CH2:17][NH2:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([CH2:16][CH2:17][NH:18][CH:3]=[C:4]2[CH2:8][CH2:7][O:6][C:5]2=[O:9])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NCCc1ccccc1
Reactant: O=C1OCCC1=CO
Agent: [Na]
Product: O=C1OCCC1=CNCCc1ccccc1
Yield: 74.9 %

Procedure:
Using 3-hydroxymethylenedihydrofuran-2-one sodium salt (50 mmol) and 2-phenylethylamine (55 mmol) and proceeding according to the abovementioned method A1, 3-(2-phenylethylamino)methylenedihydrofuran-2-one (8.14 g, efficiency: 75%) is produced in the form of a white powder.
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].C(N(CC)CC)C.[CH2:12]([CH:17]1[C:21](O)([CH3:22])[CH:20]=[CH:19][C:18]1=[O:24])[CH2:13][CH2:14][CH2:15][CH3:16]>C1(C)C=CC=CC=1>[CH2:12]([C:17]1[C:18](=[O:24])[CH2:19][CH:20]([S:3][C:1](=[O:4])[CH3:2])[C:21]=1[CH3:22])[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCC1C(=O)C=CC1(C)O
Reactant: CC(O)=S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCC1=C(C)C(SC(C)=O)CC1=O
Reaction time: 1 h
Yield: 100.4 %

Procedure:
Into the same flask as used in Example 1, thioacetic acid (35 g) and triethylamine (7 g) were charged, and 2-n-pentyl-3-hydroxy-3-methyl-4-cyclopentenone (18.2 g) was dropwise added thereto at a temperature of 20° to 35° C. for 1 hour. Thereafter, the reaction mixture was stirred at a temperature of 40° to 60° C. for 3 hours. After completion of the reaction, the mixture was diluted with toluene (50 ml) and treated in the same manner as in Example 50 to obtain 2-n-pentyl-3-methyl-4-acetylthio-2-cyclopentenone (24.1 g). Yield, 94%. nD20 1.5146.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.CC(N(C)C)=O.[OH-].[Na+].Cl[C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=1>C1(C)C=CC=CC=1.O>[CH3:23][C:20]1[CH:19]=[CH:18][C:17]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][C:33]3[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=3)=[CH:3][CH:4]=2)([C:9]([F:10])([F:11])[F:12])[C:13]([F:14])([F:15])[F:16])=[CH:22][CH:21]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: Cc1ccc(C(c2ccc(O)cc2)(C(F)(F)F)C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1ccc(C(c2ccc(Oc3ccc([N+](=O)[O-])cc3)cc2)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 0 °C

Procedure:
334 g (1 mol) of 2-(4-hydroxyphenyl)-2-(4-methylphenyl)hexafluoropropane, 1.2 dm3 of dimethylacetamide, 200 cm3 of toluene and 44 g of sodium hydroxide were refluxed until it was no longer possible to separate off any water of reaction using a water separator. The toluene was then removed by distillation, 164.4 g (1.1 mol) of 4-chloronitrobenzene were added, and the mixture was refluxed for 48 hours. After the mixture had been cooled to about 0° C., the solid was filtered off, washed with about 100 cm3 of dimethylacetamide and discarded. As much of the dimethylacetamide as possible was removed from the filtrate by vacuum distillation. The oily residue was taken up in 800 cm3 of methanol, a yellow solid precipitating out. The solid was separated off and dried. After the mother liquor had been worked up, a total of 325 g (71% of theory) of a yellow solid were obtained.
Reaction SMILES: ClC1C=CC(OC)=NC=1.[Br:10][C:11]1[CH:12]=[C:13]([OH:36])[CH:14]=[CH:15][C:16]=1[N:17]1[C@@H:21]([CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[C@H:20]([CH3:31])[C:19]([C:32]([F:35])([F:34])[F:33])=[N:18]1.[Cl:37][C:38]1[C:39]([N:46]2[CH2:51][CH2:50][C@H:49](O)[C@H:48]([CH3:53])[CH2:47]2)=[CH:40][C:41]([O:44][CH3:45])=[N:42][CH:43]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C>C1COCC1>[Br:10][C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][C:16]=1[N:17]1[C@@H:21]([CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[C@H:20]([CH3:31])[C:19]([C:32]([F:33])([F:34])[F:35])=[N:18]1)[O:36][C@@H:49]1[CH2:50][CH2:51][N:46]([C:39]2[C:38]([Cl:37])=[CH:43][N:42]=[C:41]([O:44][CH3:45])[CH:40]=2)[CH2:47][C@H:48]1[CH3:53]
Reactant: COc1cc(N2CC[C@H](O)[C@H](C)C2)c(Cl)cn1
Reactant: C[C@@H]1C(C(F)(F)F)=NN(c2ccc(O)cc2Br)[C@H]1CO[Si](C)(C)C(C)(C)C
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: COc1ccc(Cl)cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(N2CC[C@@H](Oc3ccc(N4N=C(C(F)(F)F)[C@@H](C)[C@@H]4CO[Si](C)(C)C(C)(C)C)c(Br)c3)[C@H](C)C2)c(Cl)cn1
Temperature: 25 °C
Reaction time: 59 h
Yield: 90.1 %

Procedure:
A3E. 4-((3R,4R)-4-(3-Bromo-4(4S,5R)-5-(((tert-butyldimethylsilyl)oxy)methyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl)phenoxy)-3-methylpiperidin-1-yl)-5-chloro-2-methoxypyridine: To a stirred solution of 3-bromo-4-((4S,5R)-5-(((tert-butyldimethylsilyl)oxy)methyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl)phenol (10.2 mg, 0.022 mmol), (3R,4S)-1-(5-chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-ol (81I, 11 mg, 0.042 mmol) and triphenylphosphine (13 mg, 0.049 mmol) in THF (0.2 mL) at rt was added di-tert-butylazodicarboxylate (11 mg, 0.047 mmol). The resulting solution was stirred at rt for 59 h and then evaporated The residue was chromatographed (SiO2, 96/4 CHCl3/Ether) to afford 4-((3R,4R)-4-(3-bromo-4-((4S,5R)-5-(((tert-butyldimethylsilyl)oxy)methyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl)phenoxy)-3-methylpiperidin-1-yl)-5-chloro-2-methoxypyridine (14 mg, 66% yield) as a colorless oil: LC-MS [M+H] 705, 707, 709.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([C:7]2[CH:8]=[CH:9][C:10]([CH3:18])=[C:11]([CH:17]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:2]1.C(O)(=O)[C@H]([C@@H](C(O)=O)O)O.CN(C)CCCN=C=NCC.[CH3:40][C:41]1[N:42]=[C:43]([C:49]2[CH:54]=[CH:53][C:52]([C:55]([F:58])([F:57])[F:56])=[CH:51][CH:50]=2)[S:44][C:45]=1[C:46](O)=[O:47]>C(OCC)(=O)C.C(OCC)C>[CH2:15]([O:14][C:12](=[O:13])[C:11]1[CH:17]=[C:7]([C@H:3]2[CH2:4][CH2:5][CH2:6][N:1]([C:46]([C:45]3[S:44][C:43]([C:49]4[CH:50]=[CH:51][C:52]([C:55]([F:58])([F:56])[F:57])=[CH:53][CH:54]=4)=[N:42][C:41]=3[CH3:40])=[O:47])[CH2:2]2)[CH:8]=[CH:9][C:10]=1[CH3:18])[CH3:16]
Reactant: CCOC(=O)c1cc([C@H]2CCCNC2)ccc1C
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc([C@H]2CCCN(C(=O)c3sc(-c4ccc(C(F)(F)F)cc4)nc3C)C2)ccc1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 94.6 %

Procedure:
(R)-ethyl 5-(3-piperidinyl)-2-methylbenzoate-D-tartaric acid (Example 9; 2.13 g, 5.36 mmol) was dissolved in 100 mL ethyl acetate and washed with 100 mL saturated aqueous NaHCO3. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The resultant oil was taken up in 20 mL CH2Cl2 and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide (2.05 g, 10.72 mmol) and 4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-carboxylic acid (1.69 g, 5.90 mmol) were added. The reaction was stirred at ambient temperature under nitrogen for 72 h. The reaction was diluted with 200 mL diethyl ether and washed with water (100 mL), saturated aqueous NaHCO3 (2×100 mL), 0.5 N HCl (2×100 mL), water (100 mL), and brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure to yield (R)-2-methyl-5-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carbonyl]-piperidin-3-yl}-benzoic acid ethyl ester (2.62 g, 95%) as a clear oil.
Reaction SMILES: [N:1]1([C:7]2[S:8]C=C(CO)[N:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CO>C(Cl)(Cl)Cl>[NH2:11][C:7]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[S:8]
Reactant: OCc1csc(N2CCOCC2)n1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: NC(=S)N1CCOCC1
Yield: 65 %

Procedure:
Using the procedure of Example 9C but replacing 2-(N,N-dimethylamino)-4-(hydroxymethyl)thiazole with 2-(4-morpholinyl)-4-(hydroxymethyl)thiazole provided, after silica gel chromatography using 1% methanol in chloroform, the desired compound, Rf 0.54 (4% methanol in chloroform), in 65% yield. 1H NMR (CDCl3) δ0.97 (d, J=7 Hz, 3H), 1.00 (d, J=7 Hz, 3H), 2.25 (m, 1H), 3.50 (dd, J=5, 4 Hz, 2H), 3.76 (s, 3H), 3.84 (dd, J=5, 4 Hz, 2H), 4.67 (dd, J=9, 5 Hz, 1H), 7.63 (br d, 1H), 8.02 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([S:14][C:15]2[CH:20]=[C:19]([O:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH:18]=[C:17](Br)[CH:16]=2)=[CH:9][C:8]=1[CH3:27])[CH3:2].[CH2:29]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)[C:30]#[CH:31]>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([S:14][C:15]2[CH:16]=[C:17]([C:31]#[C:30][CH2:29][N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH:18]=[C:19]([O:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH:20]=2)=[CH:9][C:8]=1[CH3:27])[CH3:2]
Reactant: C#CCN1CCOCC1
Reactant: CCOC(=O)COc1cc(C)c(Sc2cc(Br)cc(OCC(C)C)c2)cc1C
Product: CCOC(=O)COc1cc(C)c(Sc2cc(C#CCN3CCOCC3)cc(OCC(C)C)c2)cc1C

Procedure:
The title product was prepared from [4-(3-Bromo-5-isobutoxy-phenylsulfanyl)-2,5-dimethyl-phenoxy]-acetic acid ethyl ester (400 mg; 0.86 mmol) and 4-prop-2-ynyl-morpholine
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([C:12]([OH:14])=O)=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[N:15]1([C:12]([C:9]2[O:10][C:11]3[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=3[CH:8]=2)=[O:14])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C1CCNCC1
Reactant: COc1cccc2cc(C(=O)O)oc12
Product: COc1cccc2cc(C(=O)N3CCCCC3)oc12

Procedure:
Substantially the same procedure as in Example 219 was repeated using a starting material, 7-Methoxybenzofuran-2-carboxylic acid, and piperidine to give 2-piperidinocarbonyl-7-methoxybenzofuran (Compound 319a). Successively, it was formylated to give 2-piperidinocarbonyl-4-formyl-7-methoxybenzofuran (Compound 319b), then compound 319b was reacted with methylamine hydrochloride to give compound 319 as a white solid.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].CC1(C)CCCC(C)(C)N1.[CH3:16][N:17]1[CH2:23][CH2:22][CH2:21][CH2:20]C[C:18]1=[O:24].Cl[C:26]1[CH:31]=[CH:30]C=[CH:28][C:27]=1[O:32][CH3:33].C(I)C>CCCCCC.O1CCCC1>[CH2:3]([C:2]1([C:1]2[CH:30]=[CH:31][CH:26]=[C:27]([O:32][CH3:33])[CH:28]=2)[CH2:20][CH2:21][CH2:22][CH2:23][N:17]([CH3:16])[C:18]1=[O:24])[CH3:4]
Reactant: CN1CCCCCC1=O
Reactant: [Li]CCCC
Reactant: COc1ccccc1Cl
Agent: CC1(C)CCCC(C)(C)N1
Solvent: CCI
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCC1(c2cccc(OC)c2)CCCCN(C)C1=O
Reaction time: 0.5 h

Procedure:
a solution of butyl lithium (0.05 mole) in hexane (31.25 ml) was treated with 2,2,6,6-tetramethylpiperidine (8.5 ml), followed by dry tetrahydrofuran ("THF"; 100 ml) under an inert atmosphere at 0° C. The mixture was treated with a solution of N-methylcaprolactam (6.25 ml, 50 mM) in THF (20 ml) and stirred for 30 minutes. A solution of butyl lithium (0.05 mole) in hexane (31.25 ml), was added and the mixture stirred for 15 minutes. A solution of o-chloroanisole (6.2 ml) in THF (20 ml) was added slowly, the mixture stirred for 1.5 hours and treated with ethyl iodide (5.15 ml). After one hour, the reaction was quenched with water (100 ml) and the solvents removed under reduced pressure. The residue was partitioned between 2 N HCl (200 ml) and toluene (250 ml). The organic layer was washed with brine, dried and the solvents removed under reduced pressure, to give 3-ethylhexahydro-3-(3 -methoxyphenyl)-1-methyl-2H-azepin-2-one (5.5 g) b.p. 140°/0.1 mm. Recrystallisation from diisopropyl ether gave pure title compound (5.0 g) m.p. 68°-69° C., identical with authentic material.
Reaction SMILES: C[NH:2][C:3](=[O:22])[CH:4]([C:17](=[O:21])[CH2:18][NH:19][CH3:20])[CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1>CO.[OH-].[Na+].CO.O.[H][H]>[CH3:20][NH:19][CH2:18][C:17]([CH:4]([CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)[C:3]([NH2:2])=[O:22])=[O:21]
Reactant: CNCC(=O)C(CCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)C(=O)NC
Reactant: [H][H]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CNCC(=O)C(CCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)C(N)=O
Reaction time: 1 h
Yield: 90 %

Procedure:
N-Methylglycylbiotinamide methyl ester was hydrolyzed in a mixture of 31 mL MeOH and 10 mL of 1N NaOH at room temperature with stirring for 1 hour. The mixture was diluted with 50 mL 50% MeOH/water and neutralized with cation exchange resin, hydrogen form (AG MP-50, BioRad). The solution was filtered, the resin washed (3×50 mL) with 50% MeOH/water, and the solvents removed by rotary evaporation to yield 1.6 g (90%) of N-methylglycylbiotinamide acid as an off-white solid. 1H-NMR. (Ref. Wilbur, D. S., Bioconj. Chem., v8 pp572-584)