Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]([CH3:29])[CH2:15][CH2:16][C:17]([NH:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][N:24]=[CH:23]2)=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>O1CCCC1>[CH2:7]([N:14]([CH3:29])[CH2:15][CH2:16][CH2:17][NH:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][N:24]=[CH:23]2)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CN(CCC(=O)Nc1ccc2[nH]ncc2c1)Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN(CCCNc1ccc2[nH]ncc2c1)Cc1ccccc1
Temperature: 0 °C
Yield: 48.2 %

Procedure:
Lithium aluminum hydride (107 mg, 2.60 mmol) was added to a solution of N3-benzyl-N1-(1H-indazol-5-yl)-N3-methyl-β-alaninamide (200 mg, 0.973 mmol) in tetrahydrofuran (30 ml) at 0° C., and the resulting mixture was refluxed for one and a half hours. Then, the reaction solution was cooled to 0° C. and a mixture of tetrahydrofuran (10 ml) and water (10 ml) was added thereto, followed by filtration. The filtrate was concentrated and the resulting residue was diluted with chloroform and washed with a 1N-aqueous sodium hydroxide solution and then a saturated aqueous sodium chloride solution. The organic layer was dried over potassium carbonate and distilled under reduced pressure to remove the solvent, and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol=20/1) to obtain N1-benzyl-N3-(1H-indazol-5-yl)-N1-methyl-1,3-propanediamine (138 mg, 72%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]3[CH:17]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]([CH2:30][CH3:31])[CH2:28][CH3:29])=[CH:20][CH:19]=4)[N:15](COCC[Si](C)(C)C)[C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:4][C:3]=1[NH:40][C:41]([NH:43][CH:44]1[CH2:46][CH2:45]1)=[O:42].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]3[CH:17]=[C:16]([C:18]4[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH2:26][N:27]([CH2:28][CH3:29])[CH2:30][CH3:31])=[CH:22][CH:23]=4)[NH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:4][C:3]=1[NH:40][C:41]([NH:43][CH:44]1[CH2:46][CH2:45]1)=[O:42]
Reactant: CCN(CC)CCOc1ccc(-c2cc3c(Oc4ccc(NC(=O)NC5CC5)c(Cl)c4)ncnc3n2COCC[Si](C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCN(CC)CCOc1ccc(-c2cc3c(Oc4ccc(NC(=O)NC5CC5)c(Cl)c4)ncnc3[nH]2)cc1
Reaction time: 3 h
Yield: 68.4 %

Procedure:
1-{2-Chloro-4-[6-[4-(2-diethylaminoethoxy)-phenyl]-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]-phenyl}-3-cyclopropylurea (40 mg, 0.0601 mmol) was dissolved in 1 ml of tetrahydrofuran, and then 0.5 ml (8.3 equivalents) of tetrabutylammonium fluoride (1M tetrahydrofuran solution) was added dropwise and the mixture was refluxed for 2 hours. After returning to room temperature, 3 ml of water was added, the mixture was allowed to stand for 3 hours, and the precipitating crystals were filtered out, washed with water and ether:hexane=1:1 and dried under reduced pressure to obtain 22 mg of the title compound.
Reaction SMILES: [NH2:1][CH:2]1[N:26]([C:27]#[N:28])[CH:5]2[CH:6]([C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([Br:25])[CH:16]=3)[CH:7]=[C:8]3[C:13]([O:12][C:11](=[O:14])[CH:10]=[CH:9]3)=[C:4]2[O:3]1.[C:29](=O)([O-])[O-].[Cs+].[Cs+].CI.CO>CC(C)=O.ClCCl>[NH2:1][CH:2]1[N:26]([C:27]#[N:28])[CH:5]2[CH:6]([C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([Br:25])[CH:16]=3)[CH:7]=[C:8]3[C:13]([O:12][C:11](=[O:14])[C:10]([CH3:29])=[CH:9]3)=[C:4]2[O:3]1
Reactant: COc1cc(C2C=c3ccc(=O)oc3=C3OC(N)N(C#N)C32)cc(Br)c1OC
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CI
Solvent: CC(C)=O
Product: COc1cc(C2C=c3cc(C)c(=O)oc3=C3OC(N)N(C#N)C32)cc(Br)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
2-amino-4-(3-bromo-4,5-dimethoxyphenyl)-3-cyano-8-oxo-4H-oxazolo[4,5-h]chromene (335 mg, 0.75 mmol) and cesium carbonate (270 mg, 0.83 mmol) were diluted in dry acetone (10 mL). Methyl iodide (2M solution in tert-butyl methyl ether, 415 μL, 0.83 mmol) was added and the reaction was stirred at room temperature overnight. Solvent was removed in vacuo and the residue was partitioned between water (20 mL) and EtOAc (60 mL). The aqueous layer was extracted with EtOAc (2×50 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated to a yellow solid. The product was isolated by flash chromatography using a 25S SiO2 system by Biotage, Inc., Charlottesville, Va., using 0 to 1% methanol in dichloromethane to yield 292 mg (85%) 2-amino-4-(3-bromo-4,5-dimethoxyphenyl)-3-cyano-7-methyl-8-oxo-4H-oxazolo[4,5-h]chromene as a light yellow solid. 1H NMR (Acetone-d6) 7.04-6.93 (m, 4H), 6.49 (brs, 2H), 4.83 (s, 1H), 3.86 (s, 3H), 3.76 (s, 3H), 3.39 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Cl[C:25](OCC1C2C=CC=CC=2C2C1=CC=CC=2)=[O:26].ClCCl>CC(C)=O.O>[C:25](=[C:14]([C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)[CH:10]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([NH2:1])[CH:3]=1)[C:11]([OH:13])=[O:12])=[O:26]
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: COc1ccc(C(Cc2ccc([N+](=O)[O-])cc2)C(=O)O)cc1N
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C(C(=O)O)C(=C=O)c2ccc([N+](=O)[O-])cc2)cc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 153.5 %

Procedure:
2-(3-amino-4-methoxyphenyl)-3-(4-nitrophenyl) propionic acid (6.20 g, 19.6 mmol) was dissolved in a mixed solvent of acetone (50 mL) and water (50 mL), and was gradually added with an acetone solution (50 mL) of 9-fluorenylmethyl chloroformate (5.08 g, 19.6 mmol) over 30 minutes in a drop-wise manner at 0° C. The mixture was heated to room temperature, and further stirred for 3 hours. The mixture was then added with dichloromethane (200 mL) and water (300 mL). The separated aqueous phase was extracted with dichloromethane (150 mL) three times. The extracts were mixed with the first organic phase, and washed twice with a saturated brine (150 mL). The organic phase was dried over sodium sulfate, evaporated under reduced pressure so as to remove the solvent, to thereby obtain N-fluoronylmethoxy carbonyl-2-(3-amino-4-methoxyphenyl)-3-(4-nitrophenyl) propionic acid (yield: 10.3 g, yield ratio: 97%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[Br:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([NH:20][NH2:21])=[O:19])=[CH:16][CH:15]=1>C(O)(=O)C>[Br:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([NH:20][N:21]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=3)[NH:7][C:6]2=[O:11])=[O:19])=[CH:16][CH:15]=1
Reactant: NNC(=O)c1ccc(Br)cc1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: CC(=O)O
Product: O=C1Nc2ccc(I)cc2C1=NNC(=O)c1ccc(Br)cc1
Temperature: 100 °C
Yield: 82 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 4-bromobenzohydrazide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 193 mg of the title compound (82%) as a yellow solid in 99.6% purity by HPLC (Rt: 6.03, gradient of 10 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:16]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=2)[NH:15][C:14]([O:25][CH3:26])=[N:13][C:12]=1[CH2:27][CH3:28])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:30]([O:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=1)=[O:31]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([O:8][C:9]([C:11]1[CH:16]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=2)[N:15]([C:30]([O:32][C:33]2[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=2)=[O:31])[C:14]([O:25][CH3:26])=[N:13][C:12]=1[CH2:27][CH3:28])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCC1=C(C(=O)OCc2ccccc2)C(c2ccc(F)c(F)c2)NC(OC)=N1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC1=C(C(=O)OCc2ccccc2)C(c2ccc(F)c(F)c2)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(OC)=N1
Reaction time: 12 h
Yield: 51.9 %

Procedure:
To a stirring solution of 5-(benzyloxycarbonyl)-1,6-dihydro-2-methoxy-4-ethyl-6-(3,4-difluorophenyl)pyrimidine (17.0 g, 44.0 mmol) and 4-dimethylaminopyridine (7.00 g, 57.3 mmol) in CH2Cl2 (200 mL) was added 4-nitrophenyl chloroformate as a powder (11.5 g, 57.1 mmol) at room temperature. The reaction mixture was stirred for 12 h and then the solvent was removed in vacuo. The residue was purified by chromatography (EtOAc/Hexane, 1/9 to 3/7), giving 5-(benzyloxycarbonyl)-4-ethyl-1,6-dihydro-2-methoxy-6-(3,4-difluorophenyl)-1-[(4-nitrophenyloxy)carbonyl]pyrimidine as a colorless viscous oil (12.6 g, 50%). 1H NMR d 1.24 (t, J=7.2 Hz, 3H), 2.81-2.98 (m, 3H), 3.97 (s, 3H), 5.14 (ABq, A=5.08, B=5.20, J=12.3 Hz, 2H), 6.28 (s, 3H), 7.03-7.29 (m, 8H), 7.35 (d, J=9.2 Hz, 2H), 8.26 (d, J=9.2 Hz, 2H).
Reaction SMILES: [CH:1]1[C:10]2[C:9]3([C:15]([O:17]CC)=[O:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH:8]3[CH2:7][O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C[Si](C)(C)[O-].[K+]>C1COCC1>[CH:1]1[C:10]2[C:9]3([C:15]([OH:17])=[O:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH:8]3[CH2:7][O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C12CCCCC1COc1ccccc12
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(O)C12CCCCC1COc1ccccc12
Yield: 98.4 %

Procedure:
A solution of the compound from Example 69 (4.9 g, 18.6 mmol) and potassium trimethylsilanolate (4.5 g) in 75 ml THF was refluxed for 23 hours. Workup as previously described gave the title compound as a white solid (4.25 g).
Reaction SMILES: CC1C=C(C)N([C:8]([CH:10]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:17][C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])N=1.[CH2:24]([C:26]1[O:30][C:29]([NH2:31])=[N:28][N:27]=1)[CH3:25].CC(C)=O>CN(C=O)C>[CH2:24]([C:26]1[O:30][C:29]([NH:31][C:8]([CH:10]2[C:11]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:9])=[N:28][N:27]=1)[CH3:25]
Reactant: Cc1cc(C)n(C(=O)C2c3ccccc3Oc3ccccc32)n1
Reactant: CCc1nnc(N)o1
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCc1nnc(NC(=O)C2c3ccccc3Oc3ccccc32)o1
Temperature: 25 °C
Reaction time: 6 h
Yield: 41.7 %

Procedure:
500.5 mg (1.64 mmol) (3,5-dimethylpyrazol-1-yl)-(9H-xanthen-9-yl)-methanone and 186.8 mg (1.64 mmol) 5-ethyl-[1,3,4]oxadiazol-2-ylamine were suspended in 1.5 ml DMF and stirred for 6 h at 130°. The reaction mixture was allowed to cool to room temperature and 5 ml of acetone were added. After stirring for 5 min, the product was filtered, washed with acetone and dried in vaccuo to yield 219.5 mg of 9H-xanthene-9-carboxylic acid (5-ethyl-[1,3,4]oxadiazol-2-yl)-amide as a white solid, m.p. 256-257° C. and MS: m/e=321.2 (M+)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][S:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:24]([O:26][C:27](=[O:47])[CH:28]([C:32]1[CH:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][CH:33]=1)[CH:29]([CH3:31])[CH3:30])[CH3:25]>>[CH2:24]([O:26][C:27](=[O:47])[CH:28]([C:32]1[CH:33]=[CH:34][C:35]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[CH2:14][S:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:4][CH:3]=2)=[CH:36][CH:37]=1)[CH:29]([CH3:31])[CH3:30])[CH3:25]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CSCCc1ccccc1
Reactant: CCOC(=O)C(c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(C)C
Product: CCOC(=O)C(c1ccc(-c2ccc(-c3onc(C)c3CSCCc3ccccc3)cc2)cc1)C(C)C

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using 5-(4-bromo-phenyl)-3-methyl-4-phenethylsulfanylmethyl-isoxazole and 3-methyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-butyric acid ethyl ester.
Reaction SMILES: [C:1]([CH2:4][CH:5]([S:15]([OH:18])(=[O:17])=[O:16])[CH2:6][NH:7][C:8](=[O:14])/[CH:9]=[CH:10]\[C:11]([OH:13])=O)([OH:3])=[O:2].CC(N(C)C)=O.C[Si](N[Si](C)(C)C)(C)C>[Cl-].[Cl-].[Zn+2].C1(C)C=CC=CC=1>[O:13]=[C:11]1[CH:10]=[CH:9][C:8](=[O:14])[N:7]1[CH2:6][CH:5]([S:15]([OH:18])(=[O:17])=[O:16])[CH2:4][C:1]([OH:3])=[O:2]
Reactant: O=C(O)/C=C\C(=O)NCC(CC(=O)O)S(=O)(=O)O
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Solvent: CC(=O)N(C)C
Product: O=C(O)CC(CN1C(=O)C=CC1=O)S(=O)(=O)O
Reaction time: 6 h
Yield: 74.8 %

Procedure:
(Z)-4-(3-carboxy-2-sulfopropylamino)-4-oxobut-2-enoic acid (450 mg, 1.60 mmol) in mixture of 10 ml of dry DMA and 50 ml of dry toluene was heated. After the temperature reached at 80° C., HMDS (hexamethyldisilazane, 1.80 ml, 8.63 mmol,) and ZnCl2 (3.2 ml, 1.0 M in diethyl ether) were added. The mixture was continued heated to 115˜125° C. and toluene was collected through Dean-Stark trap. The reaction mixture was fluxed at 120° C. for 6 h. During this period, 2×20 ml of dry toluene was added to keep the mixture volume around 8˜10 ml. Then the mixture was cooled, 1 ml of 1:10 HCl (conc)/CH3OH was added, evaporated, purified on SiO2 chromatography eluted with 1:5:0.01 CH3OH/CH2Cl2/HAc to afford 315 mg (75%) of the title product. 1H NMR (DMF-d7) 6.96 (s, 2H), 4.04 (dd, 1H, J=4.3, 13.8 Hz), 3.47 (m, 1H), 3.23 (dd, 1H, J=7.4, 14.7 Hz), 2.99 (dd, 1H, J=3.3, 16.8 Hz), 2.35 (dd, 1H, J=8.1, 16.9 Hz); 13C NMR 173.58, 172.18, 135.54, 54.61, 40.24, 32.43, ESI MS m/z− 261.70 (M−H).
Reaction SMILES: [Cl-].[C:2]([C:6]1[CH:7]=[C:8]([CH:16]=[C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:18]=1[OH:19])[CH2:9][N+]1C=CC=CC=1)([CH3:5])([CH3:4])[CH3:3].[OH-].[Na+].[N+:26]([CH2:29][CH2:30][CH3:31])([O-:28])=[O:27].O>C(O)C>[CH2:30]([CH:29]([N+:26]([O-:28])=[O:27])[CH2:9][C:8]1[CH:16]=[C:17]([C:20]([CH3:21])([CH3:23])[CH3:22])[C:18]([OH:19])=[C:6]([C:2]([CH3:4])([CH3:3])[CH3:5])[CH:7]=1)[CH3:31]
Reactant: CC(C)(C)c1cc(C[n+]2ccccc2)cc(C(C)(C)C)c1O
Reactant: CCC[N+](=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCC(Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)[N+](=O)[O-]
Reaction time: 3 h
Yield: 97.6 %

Procedure:
A solution of 16.7 grams of 3,5-di-tert.butyl-4-hydroxybenzylpyridinium chloride in 50 milliliters of ethanol was added dropwise in 15 minutes to a slurry of 2.0 grams of sodium hydroxide and 13.4 grams of 1-nitropropane (200% excess) in 50 milliliters of ethanol. The reaction mixture as stirred for 3 hours and was then poured into 600 milliliters of water. The oil which precipitated was separated by extraction with hexane. The extract was evaporated to give 15.0 grams (98% of theory) of 1-ethyl-2-(3,5-di-tert.butyl-4-hydroxyphenyl)-1-nitroethane which melted at 55°-60° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH:9]([OH:13])[CH:10]([CH3:12])[CH3:11])[CH:3]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9](=[O:13])[CH:10]([CH3:11])[CH3:12])[CH:3]=1
Reactant: CC(C)C(O)c1cc(Br)ccc1O
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC(C)C(=O)c1cc(Br)ccc1O
Temperature: 40 °C
Yield: 17 %

Procedure:
4-Bromo-2-(1-hydroxy-2-methylpropyl)phenol (4.88 g, 19.9 mmol) was dissolved in DCM (50 mL) then manganese dioxide (2.44 g, 23.8 mmol) was added. After stirring for about 2 h at ambient temperature another portion of manganese dioxide (2.44 g, 23.8 mmol) was added then the mixture was heated to about 40° C. After about 2 d the mixture was filtered then evaporated and the residue purified by flash chromatography on silica gel with 9:1 Heptane/EtOAc as an eluent to give the title compound (0.82 g, 17%): LC/MS (Table 1, Method a) Rt, =3.38 min; MS m/z: 241.1 (M−H)−.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:18]=[C:17]([C:19]3[C:23]4[CH2:24][C:25]([CH3:30])([CH3:29])[CH2:26][C:27](=[O:28])[C:22]=4[S:21][C:20]=3[N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:16]=[CH:15][N:14]=2)[CH:8]=1)(=O)=O.[NH2:39][CH:40]1[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41]1.CC(C)([O-])C.[K+]>O1CCOCC1.CC(O)=O.CC(P(C(C)(C)C)C1C(C2[C-]=CC=CC=2)=CC=CC=1)(C)C.[Pd]>[CH3:29][C:25]1([CH3:30])[CH2:24][C:23]2[C:19]([C:17]3[CH:16]=[CH:15][N:14]=[C:13]([C:9]4[CH:8]=[C:7]([NH:39][CH:40]5[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41]5)[CH:12]=[CH:11][CH:10]=4)[CH:18]=3)=[C:20]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[S:21][C:22]=2[C:27](=[O:28])[CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Reactant: CC1(C)CC(=O)c2sc(N3CCOCC3)c(-c3ccnc(-c4cccc(OS(=O)(=O)C(F)(F)F)c4)c3)c2C1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1[c-]cccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CC1(C)CC(=O)c2sc(N3CCOCC3)c(-c3ccnc(-c4cccc(NC5CCN(C(=O)OC(C)(C)C)C5)c4)c3)c2C1
Yield: 65.5 %

Procedure:
A mixture of Example 360 (115 mg, 0.20 mmol), 3-amino-1-(tert-butoxy-carbonyl)pyrrolidine (76 mg, 0.41 mmol), potassium tert-butoxide (32 mg, 0.28 mmol) and acetato(2′-di-tert-butylphosphino-1,1′-biphenyl-2-yl)palladium(II) (20 mg, 0.043 mmol) in 1,4-dioxane (2.0 mL) was heated in a sealed tube at 100° C., under microwave irradiation, for 2 h. The solvent was removed in vacuo and the residue was purified by column chromatography (SiO2, 0-100% EtOAc/heptane) to give the title compound (79 mg, 65%) as an off-white solid. δH (CDCl3) 8.73 (1H, d, J 5.1 Hz), 7.75 (1H, s), 7.38 (1H, s), 7.35-7.23 (3H, m), 6.74-6.68 (1H, m), 4.25-4.12 (1H, m), 4.00-3.88 (1H, m), 3.84-3.73 (1H, m), 3.72-3.64 (4H, m), 3.58-3.43 (2H, m), 3.37-3.20 (1H, m), 3.07-2.99 (4H, m), 2.53 (2H, s), 2.45 (2H, s), 2.31-2.17 (1H, m), 2.01-1.89 (1H, m), 1.47 (9H, s), 1.05 (6H, s). LCMS (ES+) 603.2 (M+H)+.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[C:6]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[CH:7]=C[CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C([N:19](CC)CC)C.[I-].[K+].ClCCCN1C(C)(C)C2C=CC=CC=2S1(=O)=O>CN(C=O)C>[N:11]1([C:6]2[C:5]3[C:10](=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:9]=[N:19][CH:7]=2)[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]1
Reactant: CCN(CC)CC
Reactant: c1cc2c(c(N3CCNCC3)c1)CCCC2
Agent: CC1(C)c2ccccc2S(=O)(=O)N1CCCCl
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc2c(N3CCNCC3)cncc2c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 43 %

Procedure:
1.1 g (5.2 mmol) of 1-(5-tetralinyl)piperazine, 1.5 ml of triethylamine and a trace of potassium iodide were added to a solution of 1.64 g (6.0 mmol) of 2-(3-chloroprop-1-yl)-3,3-dimethyl-2,3-dihydro-1,2-benzoisothiazole 1,1-dioxide in 40 ml of DMF. The reaction mixture was stirred at 100° C. for four hours and then poured in ice-water, and the resulting precipitate was filtered off with suction. Purification took place by recrystallization from isopropanol to result in 1 g (43%) of the product (melting point 140° C.).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C@@H:9]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]3[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=3[CH:36]=2)[CH2:8][N:7]1[S:37]([C:40]1[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=1)(=[O:39])=[O:38])=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([C@@H:10]2[C@@H:9]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:8][N:7]([S:37]([C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)(=[O:38])=[O:39])[C@H:6]([CH2:4][OH:3])[CH2:11]2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)[C@@H]1C[C@H](c2ccc(OC)cc2)[C@@H](OCc2ccc3c(c2)N(CCCOC)CCO3)CN1S(=O)(=O)c1ccc(C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](CO)C[C@@H]3c3ccc(OC)cc3)cc21

Procedure:
Similar to example 1, 0.45 g of (2S,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidine-2-carboxylic acid ethyl ester are reacted with lithium aluminium hydride to afford the title compound as a yellow oil. Rf=0.3 (EtOAc-heptane 2:1); Rt=4.82.
Reaction SMILES: C([Mg]Br)(C)C.[F:6][C:7]([F:38])([F:37])[C:8]1[CH:9]=[C:10]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:11][N:12]([CH3:29])[C:13](=[O:28])[C:14]1[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])=[CH:18][C:17](I)=[N:16][CH:15]=1.[CH:39](=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.[Cl-].[NH4+]>O1CCCC1.O>[F:6][C:7]([F:38])([F:37])[C:8]1[CH:9]=[C:10]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:11][N:12]([CH3:29])[C:13](=[O:28])[C:14]1[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])=[CH:18][C:17]([CH:39]([OH:46])[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[N:16][CH:15]=1
Reactant: Cc1ccccc1-c1cc(I)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=Cc1ccccc1
Agent: CC(C)[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccccc1-c1cc(C(O)c2ccccc2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 57 %

Procedure:
To 1.8 ml of a 1 M solution of isopropyl magnesium bromide in tetrahydrofuran (1.8 mmol) a solution of 500 mg (0.865 mmol) N-(3,5-bis-trifluoromethyl-benzyl)-6-iodo-N-methyl-4-o-tolyl-nicotinamide (Example 4) in 10 ml tetrahydrofuran was added dropwise at 40° C. After 2 h 0.116 ml (I1.15 mmol) benzaldehyde were added. The reaction mixture was allowed to warm to room temperature over night. Addition of water and saturated aqueous ammonium chloride solution was followed by extraction with three portions of ethyl acetate. The combined organic extracts were dried with sodium sulfate and concentrated. Column chromatography afforded 274 mg (57%) of the title compound as an off-white foam.
Reaction SMILES: Br[C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[CH3:8].[Li]CCCC.CN([CH:17]=[O:18])C.C>C(OCC)C.CCCCCC>[CH3:8][C:3]1[S:4][CH:5]=[C:6]([CH3:7])[C:2]=1[CH:17]=[O:18]
Reactant: Cc1csc(C)c1Br
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: Cc1csc(C)c1C=O
Temperature: -78 °C
Reaction time: 4 h

Procedure:
A solution of 3-bromo-2,4-dimethylthiophene, B8, (5.9 g, 0.031 mol) in 200 mL of diethyl ether was cooled to -78° C., and a solution of n-BuLi (25.0 mL, 1.6M) in hexanes was added dropwise. When the addition was complete, the reaction was stirred at -78° C. for 4 h. TLC analysis indicated very little conversion so reaction mixture was warmed slowly to -25° C. Then a solution of DMF (4.5 g, 0.062 mol) in 25 mL of ether was cannulated into the reaction mixture which was allowed to warm to ambient temperature and was stirred overnight. The reaction was quenched with water and extracted twice with diethyl ether. The organic extracts were combined, washed with twice with water and then brine and dried (MgSO4). The solution was filtered and concentrated to provide an amber oil which was dissolved in hexane. The solution was treated with charcoal, filtered through Dicalite, and concentrated to give 2,4-dimethylthiophene-3-carboxaldehyde, C,8, which was used directly in the next step. ##STR60##