Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:14])[CH2:11][CH2:12][CH3:13])=[CH:6][CH:5]=1.[BH4-].[Na+]>C(O)C.C1COCC1>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:14])[CH2:11][CH2:12][CH3:13])=[CH:6][CH:5]=1
Reactant: CCCC(=O)c1ccc(C(=O)OC)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCC(O)c1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.6 %

Procedure:
To a solution of 4-butyryl-benzoic acid methyl ester (400 mg, 1.94 mmol) in ethanol (5 mL) and THF (4 mL) is added sodium borohydride (110 mg, 2.9 mmol), the mixture is stirred at room temperature for 2 h. The reaction mixture is quenched by acetic acid (0.5 mL) and water (10 mL), extracted with ethyl acetate. Combined organic layers are washed with brine and dried over sodium sulfate. Concentration and column chromatography on silica gel gives the title compound (370 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][CH2:18][NH2:19])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Br:21][C:22]1[CH:23]=[N:24][C:25](Cl)=[N:26][CH:27]=1.C(N(C(C)C)CC)(C)C.O>CN1CCCC1=O>[C:1]([O:5][C:6](=[O:20])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][CH2:18][NH:19][C:25]2[N:26]=[CH:27][C:22]([Br:21])=[CH:23][N:24]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: Clc1ncc(Br)cn1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCCN)cs1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCCNc2ncc(Br)cn2)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.3 %

Procedure:
2-{[4-(3-Aminopropyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (5.3 g) synthesized in Example 33 and 5-bromo-2-chloropyrimidine (3.24 g) were dissolved in N-methylpyrrolidone (60 mL), diisopropylethylamine (5.8 mL) was added, and the mixture was stirred at room temperature for 8 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=10:1 to 5:1) to give the title compound (5.65 g) as a colorless oil.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[NH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][CH2:12]1>C1COCC1>[C:17]1([CH:14]2[CH2:13][CH2:12][N:11]([CH2:10][CH2:9][CH2:8][NH:7][C:4](=[O:5])[CH2:3][C:2]([CH3:1])=[O:6])[CH2:16][CH2:15]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C=C1CC(=O)O1
Reactant: NCCCN1CCC(c2ccccc2)CC1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)NCCCN1CCC(c2ccccc2)CC1
Reaction time: 1 h
Yield: 104.8 %

Procedure:
Diketene (1.64 mL, 21.3 mmol, 1.50 equiv) was added at 0° C. to a stirred solution of 1-(3-aminopropyl)-4-phenylpiperidine (3.10 g, 14.2 mmol, 1.00 equiv) in anhydrous THF (30 mL) under argon, and stirring was continued at room temperature for 1 hour. The mixture was concentrated to give 4.50 g (100%) of viscous orange oil, which was characterized spectroscopically and used for the next reaction without purification.
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:23][CH3:24])=[O:5])C.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]=[C:33]=[O:34])[CH:27]=1>>[Cl:25][C:26]1[CH:27]=[C:28]([N:32]2[C:4](=[O:5])[C:6]3[CH:7]=[N:8][C:9]4[C:10]([O:23][CH3:24])=[CH:11][CH:12]=[CH:13][C:14]=4[C:15]=3[N:16]([CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)[C:33]2=[O:34])[CH:29]=[CH:30][CH:31]=1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCCC1
Reactant: O=C=Nc1cccc(Cl)c1
Product: COc1cccc2c1ncc1c(=O)n(-c3cccc(Cl)c3)c(=O)n(C3CCCCC3)c12
Yield: 68.8 %

Procedure:
3-(3-Chloro-phenyl)-1-cyclohexyl-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (30 mg) was prepared from 4-cyclohexylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.1 mmol) and 1-chloro-3-isocyanato-benzene (0.15 mmol) following general procedure C. LCMS: m/z 436 [M−1]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](O)=[O:31])[CH2:14][C:13]2[C:8](=[C:9]([O:21][CH3:22])[C:10]([O:19][CH3:20])=[C:11]([O:17][CH3:18])[C:12]=2[O:15][CH3:16])[CH2:7]1)=[O:5])[CH3:2].[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[O:31])[CH2:7][C:8]2[C:13](=[C:12]([O:15][CH3:16])[C:11]([O:17][CH3:18])=[C:10]([O:19][CH3:20])[C:9]=2[O:21][CH3:22])[CH2:14]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(CCCCCCCC(=O)O)Cc2c(c(OC)c(OC)c(OC)c2OC)C1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C1(CCCCCCCC(=O)N2CCOCC2)Cc2c(c(OC)c(OC)c(OC)c2OC)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 93.6 %

Procedure:
A THF (4.0 ml) suspension of 8-(2-ethoxycarbonyl-4,5,6,7-tetramethoxyindan-2-yl)octanoic acid (114 mg, 0.252 mmols), morpholine (0.110 ml, 1.26 mmols), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (96.6 mg, 0.504 mmols) and 1-hydroxybenzotriazole monohydrate (77.2 mg, 0.504 mmols) was stirred at room temperature for 12 hours. The reaction mixture was concentrated in vacuo, to which was added water. Then, this was extracted with ethyl acetate, and the organic layer was washed with water and a saturated aqueous sodium chloride solution, and then dried. The solvent was evaporated out, and the resulting crude product was purified by silica gel column chromatography (hexane:ethyl acetate=4:1 to 1:1) to obtain the entitled compound (123 mg) as an oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:14])[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][N:6]=1.[H-].[Na+].Br[CH2:18][CH:19]1[CH2:21][CH2:20]1>C1COCC1.CN(C=O)C.CCOC(C)=O>[CH:19]1([CH2:18][O:1][CH2:2][CH2:3][N:4]([CH3:14])[C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][N:6]=2)[CH2:21][CH2:20]1
Reactant: CN(CCO)c1ccc([N+](=O)[O-])cn1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN(CCOCC1CC1)c1ccc([N+](=O)[O-])cn1
Reaction time: 8 h

Procedure:
(2-Hydroxy-ethyl)-methyl-(5-nitro-pyridin-2-yl)-amine (98.5 mg, 0.5 mmol) in THF (10 mL) and DMF (2 mL) was stirred with 60% NaH in oil (32 mg, 0.8 mmol) for 1 hr. The mixture was cooled and to this was added bromomethylcyclopropane (0.685 mg, 5 mmol). The reaction mixture was allowed to stir overnight. The mixture was diluted with EtOAc, extracted with H2O and dried over MgSO4. The EtOAc was filtered, evaporated to dryness and used without further purification. Yield: 82 mg. ES-MS calcd for C12H17N3O3 (m/e) 251.29, obsd 252.1 (M+H).
Reaction SMILES: [ClH:1].Cl.[N+:3]([C:6]1[CH:18]=[CH:17][C:9]([CH2:10][N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:8][CH:7]=1)([O-:5])=[O:4].C(N(CC)CC)C.[Cl:26][CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:29]>C1C=CC=CC=1>[ClH:26].[ClH:1].[N+:3]([C:6]1[CH:18]=[CH:17][C:9]([CH2:10][N:11]2[CH2:16][CH2:15][N:14]([CH2:27][C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:29])[CH2:13][CH2:12]2)=[CH:8][CH:7]=1)([O-:5])=[O:4]
Reactant: O=[N+]([O-])c1ccc(CN2CCNCC2)cc1
Reactant: O=C(CCl)c1ccccc1
Agent: Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(CN1CCN(Cc2ccc([N+](=O)[O-])cc2)CC1)c1ccccc1
Yield: 42 %

Procedure:
A mixture of N-(4-nitrobenzyl)piperazine dihydrochloride (7.73 g, 30 mmol), triethylamine (8.37 ml, 60 mmol) and 2-chloro-1-phenylethanone (6.12 g, 39 mmol) in 100 ml of benzene was refluxed for 5 hours, and then treated according to general preparation 2 to give 5.2 g of compound (IV-4), yield 59.51%, mp 236-238° C. M+ 339.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([NH:21][C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4[O:48][CH3:49])[N:23]=3)=[C:14]3[C:18]=2C[N:16]([CH3:19])[C:15]3=[O:20])[CH:7]=[N:6]1.NC1C([C:57](NC)=[O:58])=C(OC)C(C2C=NN(CCCO)C=2)=CC=1>>[OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([NH:21][C:22]3[C:27]([C:28]([F:30])([F:29])[F:31])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4[O:48][CH3:49])[N:23]=3)=[C:14]([C:15](=[O:20])[NH:16][CH3:19])[C:18]=2[O:58][CH3:57])[CH:7]=[N:6]1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Reactant: CNC(=O)c1c(N)ccc(-c2cnn(CCCO)c2)c1OC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c(OC)c3C(=O)NC)n2)c(OC)c1)OCC

Procedure:
Prepared analogously to Compound 1B replacing Compound 1C with 6-amino-3-[1-(3-hydroxypropyl)-1H-pyrazol-4-yl]-2-methoxy-N-methyl benzamide (Compound 30C). 1H NMR (CD3OD, 400 MHz): δ 8.31 (s, 1H), 8.17 (s, 1H), 8.00 (s, 1H), 7.92 (d, J=8.4 Hz, 1H), 7.84 (d, J=8.6 Hz, 1H), 7.67 (d, J=8.6 Hz, 1H), 6.96 (t, J=2.0 Hz, 1H), 6.70 (d, J=8.3 Hz, 1H), 4.33 (t, J=6.8 Hz, 2H), 3.99 (m, 4H), 3.90 (s, 3H), 3.66 (s, 3H), 3.58 (t, J=6.3 Hz, 2H), 3.19 (d, J=21.5 Hz, 2H), 2.92 (s, 3H), 2.11 (m, 2H), 1.22 (t, J=7.1 Hz, 6H). MS (ESI): m/z=722.53 [M+H]+. HPLC: tR=3.63 min (ZQ3: polar—5 min).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N+:13]([O-])([OH:15])=[O:14].O>C(O)(=O)C>[N+:13]([C:11]1[C:2](=[O:1])[NH:3][C:4]2[C:9]([C:10]=1[OH:12])=[CH:8][CH:7]=[CH:6][CH:5]=2)([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: Oc1cc(O)c2ccccc2n1
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]c2ccccc2c(O)c1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 83 %

Procedure:
To a mixture of 1.45 g (9.00 mmol) of 2,4-dihydroxyquinoline (Aldrich) in 10 mL of glacial acetic acid was added 2.5 mL of HNO3 (69-71%). The mixture was heated at 90° C. for 5 min to become a red solution, then a precipitate was observed in the solution. The mixture was cooled to room temperature, then was added 40 mL of water and the mixture was stirred for 20 min. The mixture was filtered and washed with water, dried to leave 1.54 g (83%) of title compound as a yellow solid, mp 216° C. (decomposed, lit: Buckle, D. R., et al., J. Med. Chem. 18:726-732 (1975), 216° C.). 1H NMR (CDCl3 +DMSO-d6), 7.013 (t, 1, J=7.5), 7.105 (d, 1, J=7.5), 7.396 (t, 1, J=7.2), 7.877 (d, 1, 7.8), 11.72 (mb 1).
Reaction SMILES: C(O[CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=2)[C:14]([N:22]2[C:26]([C:27]3[C:35]4[C:30](=[CH:31][CH:32]=[C:33]([F:36])[CH:34]=4)[N:29]([CH3:37])[CH:28]=3)=[N:25][NH:24][C:23]2=[O:38])=[CH:13]1)C1C=CC=CC=1.[C:39]1(=[O:49])[NH:43][C:42](=[O:44])[C:41]2=[CH:45][CH:46]=[CH:47][CH:48]=[C:40]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[F:21][C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][CH:18]=1)[N:12]([CH2:11][CH2:10][CH2:9][N:43]1[C:39](=[O:49])[C:40]3[C:41](=[CH:45][CH:46]=[CH:47][CH:48]=3)[C:42]1=[O:44])[CH:13]=[C:14]2[N:22]1[C:23](=[O:38])[NH:24][N:25]=[C:26]1[C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([F:36])[CH:34]=2)[N:29]([CH3:37])[CH:28]=1
Reactant: Cn1cc(-c2n[nH]c(=O)n2-c2cn(CCCOCc3ccccc3)c3ccc(F)cc23)c2cc(F)ccc21
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1cc(-c2n[nH]c(=O)n2-c2cn(CCCN3C(=O)c4ccccc4C3=O)c3ccc(F)cc23)c2cc(F)ccc21
Reaction time: 8 h
Yield: 69.9 %

Procedure:
To a solution of the product from Example 1 (80 mg, 0.189 mmol) in dry THF (10 mL) was added phthalimide (42 mg, 0.28 mmol) and triphenylphosphine (74 mg, 0.28 mmol). The mixture was cooled on an ice bath and diethyl azodicarboxylate (44 μL, 0.28 mmol) was added. The reaction mixture was allowed to reach room temperature and was then stirred overnight. Concentration and silica gel chromatography (dichloromethane-methanol, 99:1/98:2/95:5) gave 73 mg (70%) of the sub-title compound.
Reaction SMILES: [CH2:1]([NH:6][C:7]1[N:8]=[CH:9][NH:10][C:11]=1[C:12]#[N:13])[CH2:2][CH2:3][CH2:4][CH3:5].[C:14]([NH:22][NH2:23])(=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)CCC.O>[CH2:1]([NH:6][C:7]1[N:8]=[CH:9][NH:10][C:11]=1[C:12]1[NH:23][N:22]=[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:13]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCNc1nc[nH]c1C#N
Reactant: NNC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Solvent: O
Product: CCCCCNc1nc[nH]c1-c1nc(-c2ccccc2)n[nH]1
Temperature: 170 °C
Reaction time: 14 h
Yield: 15.1 %

Procedure:
The mixture of 4-(pentylamino)-1H-imidazole-5-carbonitrile (200 mg, 1.12 mmol), benzohydrazide (229 mg, 1.68 mmol) and potassium carbonate (100 mg, 0.72 mmol) in 1-butanol (6 ml) in a sealed tube was stirred at 170° C. for 14 hours. The reaction was diluted with water and extracted with EtOAc three times. The combined organic layers was dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by preparative LCMS (method A) to yield the desired product (50 mg, 17% yield). LCMS calculated for C16H21N6 (M+H): 297.2. found 297.1.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[CH:3]=1.[CH2:8]([O:10][C:11](=[O:24])[C:12](=[CH:20]OCC)[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=O)[CH3:9]>C(O)(=O)C>[CH3:7][C:4]1[C:3]2[C:2](=[N:1][C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:12]([C:11]([O:10][CH2:8][CH3:9])=[O:24])[CH:20]=2)[O:6][N:5]=1
Reactant: Cc1cc(N)on1
Reactant: CCOC=C(C(=O)OCC)C(=O)C(=O)OCC
Solvent: CC(=O)O
Product: CCOC(=O)c1cc2c(C)noc2nc1C(=O)OCC
Temperature: 25 °C
Reaction time: 65 h
Yield: 40.8 %

Procedure:
5-Amino-3-methylisoxazole (12.25 g, 0.125 mol) and diethyl(ethoxymethylene)oxalacetate (33.55 g, 0.138 mol) are dissolved in 200 mL glacial acetic acid under an N2 atmosphere. The solution is heated to reflux for two hours, then stirred at room temperature for 65 hours. The solution is poured into ice water, causing the precipitation of a red solid. The solid is collected by filtration, redissolved in 175 mL glacial acetic acid and reprecipitated with the addition of ice. The resulting yellow solid is collected by filtration and air dried, giving 14.20 g of product, yield 40.8%, having melting point 95°-99° C. A small amount is recrystallized from hexanes/ethyl acetate, melting point 100°-101° C.
Reaction SMILES: ClS([N:5]=[C:6]=[O:7])(=O)=O.O[C:9]([CH3:19])([CH3:18])[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11]>C1(C)C=CC=CC=1>[C:6]([C:9]([CH3:19])([CH3:18])[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11])(=[O:7])[NH2:5]
Reactant: CC(C)(O)C(=O)c1ccccc1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: Cc1ccccc1
Product: CC(C)(C(N)=O)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60 %

Procedure:
A solution of chlorosulfonyl isocyanate in toluene was added to a solution of 2-hydroxy-2-methyl propiophenone in anhydrous toluene at 0° C. The mixture was stirred at room temperature for 1.5 hours then the resulting precipitate was collected. The precipitate was taken up in dioxane, cooled to 0°, then triturated with water. Prior to extraction with ether the dioxane solution was stirred overnight at room temperature. Extracted ether phase was treated with aqueous sodium bicarbonate until neutral, dried over sodium sulfate, and concentrated to leave a clear colorless oil. Upon trituration with petroleum ether the oil crystallized to leave a white solid. After drying the solid, 2-carbamoyl-2-methyl propiophenone was obtained in 60% yield. This carbamate was heated at 180° C. under a weak vacuum to form the imine. The carbamate melted at 120° C., was stirred at 180° C. for 30-50 minutes, then solidified upon cooling. The crude product was recrystallized from benzene/cyclohexane to give a 73% yield of the desired product with mp. 106°-108.5° C. (lit. 111-111.5). The product was confirmed by NMR, MS, and IR analysis. ##STR15##
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1.[OH-].[Na+]>>[F:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:16][CH2:15][CH2:14][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=3)=[CH:30][CH:29]=2)=[CH:26][CH:27]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Reactant: Oc1ccc(-c2ccc(F)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(-c3ccc(F)cc3)cc2)cc1)C(=O)O

Procedure:
(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 173, Step A was treated with 4′-Fluoro-biphenyl-4-ol from Step B under the Standard Procedure J. The compound thus obtained was allowed to react under Standard hydrolysis procedure C (NaOH) to give the title compound. MS(ES) for C25H25FO5 [M+NH4]+: 442, [M+Na]+: 447.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)[N:11]=1>>[CH3:26][C:24]1[NH:23][N:22]=[C:21]([NH:20][C:12]2[N:11]=[C:10]([O:8][C:4]3[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][CH:5]=3)[C:19]3[C:14]([CH:13]=2)=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:25]=1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Reactant: Cc1cccc(O)c1
Product: Cc1cccc(Oc2nc(Nc3cc(C)[nH]n3)cc3ccccc23)c1

Procedure:
Similar procedure as described in example 10 was used, starting from 3-methyl-phenol and (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give (5-methyl-1H-pyrazol-3-yl)-(1-m-tolyloxy-isoquinolin-3-yl)-amine. LC-MS m/e 331(MH+).
Reaction SMILES: [Cl-].[CH2:2]([O:6][C:7]1[C:12]2[C:13]([O:16][CH2:17][CH:18]3[CH2:23][CH2:22][NH2+:21][CH2:20][CH2:19]3)=[N:14][O:15][C:11]=2[CH:10]=[CH:9][CH:8]=1)[CH:3]([CH3:5])[CH3:4].[O:24]1[C:26]2([CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH2:25]1.C(N(CC)C(C)C)(C)C>C(O)C>[CH2:2]([O:6][C:7]1[C:12]2[C:13]([O:16][CH2:17][CH:18]3[CH2:23][CH2:22][N:21]([CH2:25][C:26]4([OH:24])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH2:20][CH2:19]3)=[N:14][O:15][C:11]=2[CH:10]=[CH:9][CH:8]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: C1CC2(CCO1)CO2
Reactant: CC(C)COc1cccc2onc(OCC3CC[NH2+]CC3)c12
Agent: [Cl-]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)COc1cccc2onc(OCC3CCN(CC4(O)CCOCC4)CC3)c12
Yield: 67.7 %

Procedure:
A solution of 4-{[(isobutoxy-1,2-benzisoxazol-3-yl)oxy]methyl}piperidinium chloride (40.9 mg, 0.120 mmol, EXAMPLE 8, step 4), 1,6-dioxaspiro[2.5]octane (30.4 mg, 0.266 mmol, Phosphorus and Sulfur and Related Elements 1984, 19, 113) and N,N-diisopropylethylamine (0.10 mL, 0.58 mmol) in ethanol (1 mL) was stirred overnight at room temperature. Solvent was evaporated, and the residual oil was purified by NH gel column chromatography (hexane/ethyl acetate 4:1) to give 34.0 mg (68%) of the title compound as a colorless oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:9]=[C:10]([CH2:14][C:15](O)=[O:16])[CH:11]=[CH:12][CH:13]=1.[Cl-].[NH4+]>CCOCC>[F:7][C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][OH:16])[CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)Cc1cccc(F)c1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Product: OCCc1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a stirred suspension of lithium aluminium hydride (25 g, 0.65 mol) in dry ether (300 ml) at 0° C. was added dropwise 3-fluorophenylacetic acid (50 g, 0.32 mol, Lancaster Synthesis). After the addition the mixture was heated to reflux for 2 hours, then stirred overnight at room temperature. Saturated aqueous ammonium chloride (200 ml) was added and the mixture was filtered and the solids washed with ether. The ether layer was separated, dried over anhydrous magnesium sulphate and evaporated. Distillation of the residue afforded 2-(3-fluorophenyl)ethanol (43.05 g, 95%), bp 91°-94° at 2 mmHg, NMR δ 7.3 (1H, m), 7.05-6.9 (3H, m), 3.85 (2H,t), 2.85 (2H,t), 2.0 (1H,s).
Reaction SMILES: O[C@@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][C:9]#[N:10])[CH2:4][CH2:3]1.N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:35]I>ClCCl>[I:35][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][C:9]#[N:10])[CH2:4][CH2:3]1
Reactant: II
Reactant: N#CC[C@H]1CC[C@@H](O)CC1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: N#CC[C@H]1CC[C@H](I)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.3 %

Procedure:
To a solution of (cis-4-hydroxycyclohexyl)acetonitrile (2.50 g, 18.0 mmol) in dichloromethane (80 mL) at 0° C. was added 1H-imidazole (1.47 g, 21.6 mmol), triphenylphosphine (5.65 g, 21.6 mmol), and followed by iodine (5.47 g, 21.6 mmol) in several portions over a period of 45 min. The resulting suspension was gradually allowed to warm to room temperature. After stirring at room temperature overnight, the mixture was partitioned between Et2O (100 mL) and water (100 mL). The organic layer was washed with saturated Na2SO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (0-20% ethyl acetate/hexanes) to give the desired product as white solid (1.0 g, 22%). 1H NMR (400 MHz, CDCl3) δ 4.04 (m, 1H), 2.50-2.38 (m, 2H), 2.24 (d, J=6.1 Hz, 2H), 1.99 (m, 2H), 1.77 (m, 3H), 1.22 (m, 2H) ppm.
Reaction SMILES: [H-].[Na+].[CH:3]1([N:8]([C:14]2[C:19]([CH:20]=O)=[CH:18][N:17]=[C:16]([S:22][CH3:23])[N:15]=2)[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:7][CH2:6][CH2:5][CH2:4]1.O>CCCCCC.C1C=CC=CC=1>[CH:3]1([N:8]2[C:14]3[N:15]=[C:16]([S:22][CH3:23])[N:17]=[CH:18][C:19]=3[CH:20]=[C:9]2[C:10]([O:12][CH3:13])=[O:11])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COC(=O)CN(c1nc(SC)ncc1C=O)C1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)c1cc2cnc(SC)nc2n1C1CCCC1
Temperature: 70 °C
Reaction time: 1 h
Yield: 34.7 %

Procedure:
Sodium hydride (3.85 g, 167 mmol) (freshly washed with hexane) was added to a solution of compound 226 (12.95 g, 41.9 mmol) in benzene (150 mL). The reaction was stirred at 70° C. After 1 h, the reaction contents were poured into water (300 mL) and extracted with ethyl acetate (2×100 mL). The combined organics were washed with brine, dried over MgSO4, and concentrated in vacuo. Silica gel chromatography (gradient elution 0 to 50% ethyl acetate in hexanes) afforded compound 227 (4.24 g, 34.8% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([N:19]3[CH2:28][CH2:27][C:22]4(OCC[O:23]4)[CH2:21][CH2:20]3)(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1.C1COCC1>Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([S:16]([N:19]3[CH2:20][CH2:21][C:22](=[O:23])[CH2:27][CH2:28]3)(=[O:17])=[O:18])=[CH:14][CH:15]=2)=[O:7])=[CH:29][CH:30]=1
Reactant: O=C(NCc1ccc(S(=O)(=O)N2CCC3(CC2)OCCO3)cc1)c1ccc(Cl)cc1
Agent: Cl
Solvent: C1CCOC1
Product: O=C1CCN(S(=O)(=O)c2ccc(CNC(=O)c3ccc(Cl)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
4-chloro-N-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-ylsulfonyl)benzyl]benzamide 7c (2.7 g, 5.99 mmol) was suspended in 6 N HCl (40 ml) and THF added until a clear solution was obtained (about 40 ml). The reaction mixture was stirred at room temp overnight and THF was removed in vacuo. The resulting suspension was diluted with cold water (50 ml), aged for 1 h at room temp and filtered. The filter residue was dried under high vacuum for several hours to yield 2.0 g (82%) of ketone 4-chloro-N-{4-[(4-oxo-1-piperidinyl)sulfonyl]benzyl}benzamide 7d as colourless powder in >90% purity (LC-MS).