Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[N:15]4[CH2:16][CH2:17][S:18][C:19]([CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])([CH3:21])[CH2:20][C:14]4=[N:13][N:12]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH:31]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[N:32]1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.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>[Si:24]([O:23][CH2:22][C:19]1([CH3:21])[S:18][CH2:17][CH2:16][N:15]2[C:11]([C:8]3([C:5]4[CH:6]=[CH:7][C:2]([C:33]5[NH:32][N:31]=[CH:35][CH:34]=5)=[CH:3][CH:4]=4)[CH2:10][CH2:9]3)=[N:12][N:13]=[C:14]2[CH2:20]1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: CC1(C)OB(c2cc[nH]n2)OC1(C)C
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(Br)cc4)CC3)n2CCS1
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: [K+]
Solvent: O
Solvent: COCCOC
Product: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(-c5ccn[nH]5)cc4)CC3)n2CCS1
Temperature: 25 °C
Yield: 100.9 %

Procedure:
A solution of the compound (300 mg, 0.59 mmol) obtained in Example 16-4), 1H-pyrazole-3-boronic acid pinacol ester (126 mg, 0.65 mmol), tetrakis(triphenylphosphine)palladium(0) (68 mg, 0.06 mmol), and potassium carbonate (163 mg, 1.18 mmol) in 1,2-dimethoxyethane (3 mL) and water (1.5 mL) was stirred at 120° C. for 1 h under microwave irradiation. The reaction mixture was cooled to room temperature, water (3 mL) was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography (ethyl acetate:methanol=70:30) to obtain the title compound (295 mg, quant.) in an orange oily form.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.Br[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].O>CN(C=O)C>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:5]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Oc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1cccnc1
Yield: 32.5 %

Procedure:
To a suspension of 0.22 g of sodium hydride (60% oil dispersion, 5.5 mmol) in 2 mL of DMF was added dropwise a solution of 0.48 g of 3-hydroxypyridine (5.0 mmol) in 2 mL of DMF at room temperature, and the mixture was stirred for an hour. The resulting brown solution was ice-cooled, 0.81 mL of tert-butyl bromoacetate (5.5 mmol) was added, and the mixture was stirred under ice-cooling for an hour followed by stirring at room temperature for 2 hours. After addition of water, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and evaporated. The residue was purified by column chromatography on silica gel (eluent: chloroform:ethyl acetate=5:1), to give 0.34 g of tert-butyl 3-pyridyloxyacetate (Yield: 32.5%) as a clear oil.
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([O:8][C:9]2[CH:10]=[C:11]([C:19]([O:21][CH3:22])=[O:20])[CH:12]=[C:13]([CH:18]=2)[C:14]([O:16][CH3:17])=[O:15])=[CH:6][CH:5]=1)([O-])=O.O1CCCC1.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:18]=[C:13]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=[C:11]([CH:10]=2)[C:19]([O:21][CH3:22])=[O:20])=[CH:23][CH:24]=1
Reactant: COC(=O)c1cc(Oc2ccc([N+](=O)[O-])cc2)cc(C(=O)OC)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COC(=O)c1cc(Oc2ccc(N)cc2)cc(C(=O)OC)c1
Yield: 92.9 %

Procedure:
Into a 1 liter egg plant-shaped flask, 66.24 g (0.2 moles) of dimethyl 5-(4-nitrophenoxy)isophthalate of the first intermediate compound, 6.39 g of a 10% palladium-active charcoal, 440 ml of tetrahydrofuran and 220 ml of ethanol were placed, and the resultant mixture was stirred for 24 hours under the atmosphere of hydrogen. The reaction fluid was filtered with Celite, and the filtrate was concentrated under a reduced pressure. Hexane was added to the concentrated fluid, and formed precipitates were separated by filtration. The obtained white solid substance was dried at 50° C. for 1 day under a reduced pressure, and 55.96 g of the second intermediate compound was obtained (the yield: 93%).
Reaction SMILES: [CH2:1]([O:4][C:5]([CH:7]1[C:12](=[O:13])[CH:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][S:9][CH2:8]1)=[O:6])[CH:2]=[CH2:3].C([O-])([O-])=O.[K+].[K+].Br[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[C:32]([F:39])[CH:31]=1.CCCCCC.CCOC(C)=O>CC(C)=O>[CH2:1]([O:4][C:5]([C:7]1([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[C:32]([F:39])[CH:31]=2)[C:12](=[O:13])[CH:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][S:9][CH2:8]1)=[O:6])[CH:2]=[CH2:3]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1F
Reactant: C=CCOC(=O)C1CSCC(NC(=O)OC(C)(C)C)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: CCCCCC
Product: C=CCOC(=O)C1(Cc2ccc([N+](=O)[O-])c(F)c2)CSCC(NC(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-tert-butoxycarbonylamino-4-oxo-tetrahydro-thiopyran-3-carboxylic acid allyl ester (2.55 g, 8.08 mmol) in acetone (150 mL) was added K2CO3 (3.38 g, 24.2 mmol) and 4-bromomethyl-2-fluoro-1-nitro-benzene (2.12 g, 8.9 mmol) and the reaction mixture was stirred at 25° C. for 16 h. After dilution with water the product is extracted with EtOAc. Combined extracts were washed with brine, dried over MgSO4 and evaporated. The product obtained as a light yellow solid was suitable for use in the next step: TLC (hexane-EtOAc 1:3) Rf=0.26; HPLC RtA=2.31 min; ESIMS [M+NH4]+=486.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[CH3:14][NH:15][CH3:16].C1COCC1>C(Cl)Cl>[CH3:14][N:15]([CH3:16])[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3]
Reactant: CNC
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
A solution of 3-(chlorosulfonyl)benzoic acid (152 mg, 0.689 mmol) in methylene chloride (2 mL) was treated with 2.0 M dimethylamine in THF (1.137 mL, 2.274 mmol), and the mixture was stirred overnight at room temperature. The reaction was quenched with 1 N HCl, and extracted 3× with EtOAc. The combined organic phases were washed with 1 N HCl followed by brine, then dried over sodium sulfate and concentrated in-vacuo to yield the title compound (138 mg, 0.602 mmol, 87% yield). MS (ESI+)=230.18, (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl[CH2:12][CH2:13][OH:14].C(=O)([O-])[O-].[K+].[K+].C>C(C(C)=O)C.CO>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:12][CH2:13][OH:14])([O-:3])=[O:2]
Reactant: OCCCl
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CO
Product: O=[N+]([O-])c1cccc(OCCO)c1
Reaction time: 8 h

Procedure:
A mixture of m-nitrophenol (28 g, 0.2 mole), 2-chloroethanol (53.6 ml, 0.8 mole), and potassium carbonate (110.4 g, 0.8 mole) in 300 ml methyl ethyl ketone was kept at reflux temperature with stirring overnight. The solid was filtered and dissolved in water. The filtrate was concentrated and some wolid was crystallized from 2-propanol/isopropyl ether. This light-brown solid was collected and weighed 22.78 g (62%). The mother liquor was concentrated and redissolved in toluene/ethyl acetate and extracted with the above aqueous solution. The aqueous layer was further extracted with fresh toluene/ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate, filtered, and concentrated to give a second crop of 6.46 g (17.6%). The second crop was dissolved in methanol, stirred with charcoal, filtered, evaporated, and crystallized from 2-propanol/isopropyl ether to give a pure sample. The sample was dried under vacuum at room temperature overnight, mp 85°-86° C.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([NH:9][C:10]([C:12]1[N:13]([C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:14][CH2:15][NH:16][CH:17]=1)=[O:11])([CH3:8])([CH3:7])[CH3:6].[CH:24](O)=[O:25]>>[C:5]([NH:9][C:10]([C:12]1[N:13]([C:18](=[O:23])[C:19]([F:22])([F:20])[F:21])[CH2:14][CH2:15][N:16]([CH:24]=[O:25])[CH:17]=1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: O=CO
Reactant: CC(C)(C)NC(=O)C1=CNCCN1C(=O)C(F)(F)F
Solvent: O=S(Cl)Cl
Product: CC(C)(C)NC(=O)C1=CN(C=O)CCN1C(=O)C(F)(F)F

Procedure:
49.60 g (416.9 mmol) of thionyl chloride was added over 40 min at 20° C. to a solution of 96.94 g (347.1 mmol) of 1-trifluoroacetyl-1,4,5,6-tetrahydropyrazine-2-carboxylic acid tert-butylamide in 465.9 g (10.1 mol) of formic acid. After a reaction time of 2 hours at 20° C., the mixture was concentrated on a rotary evaporator at 60° C. and 80 mbar and the brownish-black residue was taken up with 400 ml of ethyl acetate and 400 ml of water. The aqueous phase was washed again with twice 250 ml of ethyl acetate and the combined organic extracts were dried over 50.1 g of sodium sulfate. After filtration, the solution was concentrated on a rotary evaporator and the viscous residue was stirred with 250 ml of diisopropyl ether. The precipitated solid was filtered off, washed with twice 100 ml of diisopropyl ether and dried. The yield was 96.76 g (91 %) of colorless crystals. The melting point of the title compound was: 158.4° to 160.3° C. Other data concerning the title compound was:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][N:5]1[N:9]=[N:8][C:7]([NH2:10])=[N:6]1.[CH:12]1[C:25]2[CH:24]([C:26](Cl)=[O:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[O:17][C:16]=2[CH:15]=[CH:14][CH:13]=1>>[CH3:1][O:2][C:3](=[O:11])[CH2:4][N:5]1[N:9]=[N:8][C:7]([NH:10][C:26]([CH:24]2[C:25]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[O:17][C:18]3[C:23]2=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:27])=[N:6]1
Reactant: COC(=O)Cn1nnc(N)n1
Reactant: O=C(Cl)C1c2ccccc2Oc2ccccc21
Product: COC(=O)Cn1nnc(NC(=O)C2c3ccccc3Oc3ccccc32)n1

Procedure:
The title compound, white solid, m.p. 243-244° and MS: (neg. ions): m/e=364.0 (M+−H) was prepared in accordance with the general method of example 1 from (5-amino-tetrazol-2-yl)-acetic acid methyl ester and 9H-xanthene-9-carbonyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:13])[CH:12]=1)[CH:5]([OH:9])[C:6]([OH:8])=O.Cl.N[C@H](C([C:20]1([NH2:35])[C:26](=[O:27])[N:25]([CH3:28])[C:24]2[CH:29]=[CH:30][CH:31]=[CH:32][C:23]=2[N:22]([CH3:33])[C:21]1=[O:34])=O)C>>[F:13][C:11]1[CH:10]=[C:4]([CH:5]([OH:9])[C:6]([NH:35][C@H:20]([C:26]([NH:35][CH:20]2[C:21](=[O:34])[N:22]([CH3:33])[C:23]3[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=3[N:25]([CH3:28])[C:26]2=[O:27])=[O:27])[CH3:21])=[O:8])[CH:3]=[C:2]([F:1])[CH:12]=1
Reactant: C[C@H](N)C(=O)C1(N)C(=O)N(C)c2ccccc2N(C)C1=O
Reactant: O=C(O)C(O)c1cc(F)cc(F)c1
Agent: Cl
Product: C[C@H](NC(=O)C(O)c1cc(F)cc(F)c1)C(=O)NC1C(=O)N(C)c2ccccc2N(C)C1=O

Procedure:
Following General Procedure I above using 3,5-difluoromandelic acid (Lancaster) and the product from Example 8-R, the title compound was prepared as an amorphous white solid. Purification was by L.C. 2000 eluting with straight EtOAc then flash chromatography eluting with CH2Cl2/Acetone (4:1 gradient to 3:1). Rf=0.39 and 0.34 (EtOAc).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[NH:12]1[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:15]2[CH:14]=[CH:13]1>ClCCl>[NH:12]1[C:16]2=[N+:17]([O-:9])[CH:18]=[CH:19][CH:20]=[C:15]2[CH:14]=[CH:13]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1cnc2[nH]ccc2c1
Solvent: ClCCl
Product: [O-][n+]1cccc2cc[nH]c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
A solution of 3-chloroperbenzoic acid (224.3 g) in dichloromethane (1500 mL) was cooled to 0° C. To this a solution of 1H-pyrrolo[2,3-b]pyridine (59.1 g) in dichloromethane (500 mL) was added dropwise over 30 minutes. The reaction mixture was stirred at room temperature for 1 hour. The solution was concentrated, diluted with methanol (1500 mL) and treated with 10% potassium carbonate in water (300 mL). The slurry was filtered and the filtrate was evaporated to dryness. The residue was chromatographed on neutral alumina with 20% methanol in dichloromethane to give the title compound as a tan solid (47.0 g). MS: 135 (MH+). 1HNMR (CDCl3): δ 13.1 (s, 1H), 8.2 (d, 1H), 7.65 (d, 1H), 7.4 (d, 1H), 7.0 (m, 1H), 6.55 (d, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[C:10]([O:14][C:15](=[O:31])[N:16]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[CH3:30])[C:17](=[O:22])[CH2:18][CH2:19][C:20]#[CH:21])([CH3:13])([CH3:12])[CH3:11]>>[C:10]([O:14][C:15](=[O:31])[N:16]([C:17](=[O:22])[CH2:18][CH2:19][C:20]#[C:21][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1)[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[CH3:30])([CH3:13])([CH3:11])[CH3:12]
Reactant: FCc1cccc(Br)n1
Reactant: C#CCCC(=O)N(C(=O)OC(C)(C)C)c1ccc(F)cc1C
Product: Cc1cc(F)ccc1N(C(=O)CCC#Cc1cccc(CF)n1)C(=O)OC(C)(C)C
Yield: 79.7 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)pyridine (150 mg, 0.79 mmol, Example 190(E)) and (4-fluoro-2-methyl-phenyl)-pent-4-ynoyl-carbamic acid tert-butyl ester (241 mg, 0.79 mmol, 188(B)). Reaction time: 3 hours. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 260 mg (0.63 mmol, 79%) of [5-(6-fluoromethyl-pyridin-2-yl)-pent-4-ynoyl]-(4-fluoro-2-methyl-phenyl)-carbamic acid tert-butyl ester as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([F:9])[CH2:5][N:4]1[C:10]([C:12]1[N:13]=[C:14]([CH3:23])[S:15][C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:11].[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][C:32]=2[C:34](O)=[O:35])[CH:27]=[CH:26][CH:25]=1>>[F:9][CH:6]1[CH2:5][N:4]([C:10]([C:12]2[N:13]=[C:14]([CH3:23])[S:15][C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:11])[CH:3]([CH2:2][NH:1][C:34]([C:32]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:33]=2[N:24]=[CH:25][CH:26]=[CH:27]3)=[O:35])[CH2:8][CH2:7]1
Reactant: O=C(O)c1cccc2cccnc12
Reactant: Cc1nc(C(=O)N2CC(F)CCC2CN)c(-c2ccccc2)s1
Product: Cc1nc(C(=O)N2CC(F)CCC2CNC(=O)c2cccc3cccnc23)c(-c2ccccc2)s1

Procedure:
The final product N-((5-fluoro-1-(2-methyl-5-phenylthiazole-4-carbonyl)piperidin-2-yl)methyl)quinoline-8-carboxamide was prepared by following general procedure A using (2-(aminomethyl)-5-fluoropiperidin-1-yl)(2-methyl-5-phenylthiazol-4-yl)methanone and quinoline-8-carboxylic acid. The NMR of desired product indicated the presence of two rotamers in 1/2 ratio. 1H NMR (DMSO-d6, 400 MHz) δ 11.02-10.99 (m, 0.33H), 10.73-10.70 (m, 0.67H), 9.05-9.03 (m, 0.33H), 8.98-8.97 (m, 0.67H), 8.62-8.59 (m, 1.33H), 8.52-8.50 (M, 0.67 h), 8.24-8.19 (m, 1H), 7.81-7.74 (m, 1.33H), 7.72-7.68 (m, 0.67H), 7.47-7.43 (m, 0.67H), 7.34-7.32 (m, 2.33H), 7.19-7.10 (m, 2H), 5.08-4.67 (m, 2H) 3.98-3.34 (m, 4H), 2.65 (s, 1H), 2.23 (s, 2H), 2.12-1.69 (m, 2.67H), 1.41-1.39 (m, 1.33H). MS (ESI) 489 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C@H:19]3[CH2:23][CH2:22][CH2:21][NH:20]3)=[CH:13][CH:12]=2)[N:4]=[C:5]2[C:10]=1[CH:9]=[CH:8][CH:7]=[CH:6]2.Br[CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29]>>[CH3:31][O:30][C:28](=[O:29])[CH2:27][CH2:26][CH2:25][N:20]1[CH2:21][CH2:22][CH2:23][C@@H:19]1[CH2:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([N:3]2[C:2]([Cl:1])=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[CH:9]3)=[N:4]2)=[CH:16][CH:15]=1
Reactant: COC(=O)CCCBr
Reactant: Clc1c2ccccc2nn1-c1ccc(OC[C@H]2CCCN2)cc1
Product: COC(=O)CCCN1CCC[C@@H]1COc1ccc(-n2nc3ccccc3c2Cl)cc1
Yield: 80.7 %

Procedure:
The title compound was prepared from product from 3-chloro-2-[4-((R)-1-pyrrolidin-2-ylmethoxy)-phenyl]-2H-indazole (0.4 g, 1.1 mmol) and methyl 4-bromobutyrate (0.25 g, 1.4 mmol) using the procedure of step 7 of the Example 5 to provide the title compound (0.38 g, 79%).
Reaction SMILES: [F:1][CH2:2][C:3]([CH2:17][F:18])([CH3:16])[C:4](=[O:15])[CH:5](Br)[O:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.N1C=[CH:22][N:21]=[N:20]1.[C:24](#[N:26])C>>[F:1][CH2:2][C:3]([CH2:17][F:18])([CH3:16])[C:4](=[O:15])[CH:5]([O:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)[N:21]1[CH:22]=[N:26][CH:24]=[N:20]1
Reactant: c1c[nH]nn1
Reactant: CC#N
Reactant: CC(CF)(CF)C(=O)C(Br)Oc1ccc(Cl)cc1
Product: CC(CF)(CF)C(=O)C(Oc1ccc(Cl)cc1)n1cncn1
Temperature: 50 °C
Yield: 71 %

Procedure:
190 g (0.557 mol) of 3,3-bisfluoromethyl-1-bromo-1-(4-chlorophenoxy)-butan-2-one and 90 g (1.3 mols) of triazole were introduced into 800 ml of acetonitrile, the mixture was heated at 50° C. for 5 hours, the solvent was distilled off under a waterpump vacuum, the residue was taken up in one liter of methylene chloride and washed twice with 1,000 ml of water each time, the organic phase was dried over sodium sulphate and the solvent was distilled off. The residue was taken up in 500 ml of diisopropyl ether and the precipitate was filtered off. The mother liquor was distilled. 130.5 g (71% of theory) of 3,3-bisfluoromethyl-1-(4-chlorophenoxy)-1-(1,2,4-triazol-1-yl)-butan-2-one of boiling point 160°-66° C./0.2 mm Hg were obtained. ##STR76##
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.[C:6]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:9])C=C.O1CC[CH2:17][CH2:16]1>>[CH:2]12[CH2:1][CH:5]([CH:16]=[CH:17]1)[CH2:4][CH:3]2[C:6]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: C1CCOC1
Reactant: C1=CCC=C1
Reactant: C=CC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)C1CC2C=CC1C2
Yield: 90.7 %

Procedure:
In a reactor, cyclopentadiene (66 g) and tetrahydrofuran solvent (500 g) were charged, and the mixture was stirred homogeneously. To the reaction mixture, tert-butyl acrylate (128 g) was added, and the resultant mixture was stirred at a temperature between −30° C. and 60° C. for about 10 hours to carry out the reaction. When the reaction was completed, the solvent was removed by using a rotary evaporator, and the residue was distilled under reduced pressure to obtain 176 g (yield: 90%) of tert-butyl 5-norbornene-2-carboxylate represented by chemical formula VIIa.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][CH:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[CH2:31]=O>>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][CH:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][CH2:22][N:21]([CH3:31])[CH2:20][CH2:19]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1
Reactant: C=O
Reactant: O=C(NC(COCC1CCNCC1)c1ccccc1F)c1ccc2c(Cl)c[nH]c2c1
Product: CN1CCC(COCC(NC(=O)c2ccc3c(Cl)c[nH]c3c2)c2ccccc2F)CC1

Procedure:
Using alkylation method B, 3-chloro-N-[1-(2-fluoro-phenyl)-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide (250 mg, 0.58 mmol) and paraformaldehyde (174 mg, 5.8 mmol) afforded, after purification (SiO2: 10:2:2:1 DCM:EtOAc:hexane:isopropylamine), 160 mg (63%) of the title compound.
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[C:4](=[S:16])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1[Si:12]([CH3:15])([CH3:14])[CH3:13])[CH3:2].[CH3:19]I>>[CH2:17]([N:3]([CH2:1][CH3:2])[C:4](=[S:16])[C:5]1[CH:10]=[CH:9][C:8]([CH3:19])=[C:7]([F:11])[C:6]=1[Si:12]([CH3:13])([CH3:15])[CH3:14])[CH3:18]
Reactant: CCN(CC)C(=S)c1cccc(F)c1[Si](C)(C)C
Reactant: CI
Product: CCN(CC)C(=S)c1ccc(C)c(F)c1[Si](C)(C)C

Procedure:
The title compound was prepared from the compound of Example 74 and 3.0 eq MeI according to General Method A and recrystallized from cold hexanes/ethyl acetate to give 2.5 g of the title compound, an 82% yield. m.p. 96-97° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].S([O-])(=O)(=O)C.[CH2:22]([N:24]([CH:27](O)[CH2:28][CH3:29])[CH2:25][CH3:26])[CH3:23]>CN(C=O)C.O>[CH2:22]([N:24]([CH2:25][CH3:26])[CH2:27][CH2:28][CH2:29][O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH3:23]
Reactant: CCC(O)N(CC)CC
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: CS(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CCCOc1cccc([N+](=O)[O-])c1
Temperature: 80 °C

Procedure:
To a stirred solution of 3-nitrophenol (2 mmol) in DMF (6 mL) at rt, solid potassium carbonate (4 mmol) was added. A solution of the mesylate of N,N-diethylaminopropanol (2.2 mmol) in DMF (2 mL) was then added to the reaction mixture and heated to 80° C. until completion, according to General Procedure Q1, as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was then treated with cold H2O (15 mL), and extracted with EtOAc (2×15 mL). The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of the solvent in vacuuo afforded the desired N,N-diethyl-N-[3-(3-nitrophenoxy)propyl]amine. The crude product was used directly for further transformation.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([O:26][CH2:27][CH3:28])[C:22]([O:24][CH3:25])=[O:23])=[CH:16][CH:15]=2)[CH2:3][CH2:2]1.[CH:29]([N-]C(C)C)(C)C.[Li+].CI.Cl>O1CCCC1.O>[CH3:29][C:21]([O:26][CH2:27][CH3:28])([CH2:20][C:17]1[CH:16]=[CH:15][C:14]([O:13][CH2:12][CH2:11][N:4]2[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[O:1][CH2:2][CH2:3]2)=[CH:19][CH:18]=1)[C:22]([O:24][CH3:25])=[O:23]
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(Cc1ccc(OCCN2CCOc3ccccc32)cc1)C(=O)OC
Agent: Cl
Agent: [Li+]
Solvent: CI
Solvent: O
Solvent: C1CCOC1
Product: CCOC(C)(Cc1ccc(OCCN2CCOc3ccccc32)cc1)C(=O)OC
Temperature: -78 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of methyl 3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoate (0.6 g, 1.5 mmol) obtained in example 2 in dry tetrahydrofuran (5 mL) was added lithium diisopropyl amide (5.25 μL, 0.5 mL solution in THF/hexane) at −78° C. After stirring for 1 h at −78° C., methyl iodide (0.75 mL) was added and the reaction mixture was allowed to warm to room temperature (ca 25° C.) and stirred for further 20 h at the same temperature. Water (20 mL) was added, acidified with 1 N hydrochloric acid and extracted with ethyl acetate (2×25 mL). The combined ethyl acetate layer was washed with water (25 mL), brine (25 mL), dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure to afford the title compound (0.5 g, 80%) as an oil.
Reaction SMILES: ON1[C:6](=O)[CH2:5][CH2:4][C:3]1=[O:8].C1CCCCC1.C(=O)=[O:16].O=O.[C:20]([OH:23])(=[O:22])[CH3:21]>O.O.O.O.C([O-])(=O)C.[Co+2].C([O-])(=O)C>[C:20]([OH:23])(=[O:22])[CH2:21][CH2:6][CH2:5][CH2:4][C:3]([OH:8])=[O:16]
Reactant: O=C=O
Reactant: O=C1CCC(=O)N1O
Reactant: CC(=O)O
Agent: [Co+2]
Agent: CC(=O)[O-]
Agent: O=O
Solvent: C1CCCCC1
Solvent: O
Product: O=C(O)CCCCC(=O)O
Temperature: 80 °C
Reaction time: 6 h
Yield: 56 %

Procedure:
In this example, a solution of 0.1191 g (1.03 mmol) of N-hydroxysuccinimide, 1.0074 g (9.5 mmol) of cyclohexane and 0.1330 g (0.53 mmol) of cobalt acetate tetrahydrate in 40 ml of acetic acid was heated to 80° C. in a Parr Hastelloy reactor with temperature and pressure transducer. After the temperature reached 80° C., 745 psi of CO2 was introduced into the reactor, then 120 psi of O2 was added slowly to the reactor. The mixture was stirred under pressure for six hours at 80° C., then the pressure was released, and the mixture was cooled to room temperature. The mixture solution was extracted with ethyl acetate then washed with a saturated NaCl solution in water and, dried over Na2SO4 to get adipic acid in 56% yield, with analyses by GC-MS and NMR. At 100 to 120° C., the yield was about 40 to 60% adipic acid.