Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][NH:9][CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][C:13](=[O:21])[O:12]1.C(O)(=O)C>CCOC(C)=O>[OH:12][CH2:11][C:20]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:14][C:13]([N:9]([CH3:10])[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:21]
Reactant: O=C1Cc2ccccc2CO1
Reactant: CNNC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CN(NC(=O)OC(C)(C)C)C(=O)Cc1ccccc1CO
Temperature: 100 °C

Procedure:
N-(t-Butoxycarbonyl)-N′-methylhydrazine (100 mmol) (Lenman, et al., J. Chem. Soc. Perkin Trans., 1997, 16, 2297-2312; Dutta, et al., J. Chem. Soc. Perkin Trans., 1986, 1655-1664) was added to 3-isochromanone (7.4 g, 50 mmol) (Cheng, et al., J. Heterocyclic Chem., 1995, 32, 73) in a sealed tube followed by 0.2 mL of acetic acid and heated for 12 h at 100° C. The reaction mixture was diluted with EtOAc (100 mL), washed with water (50 mL),1 M HCl (50 mL), brine (50 mL) and dried (Na2SO4). The desired alcohol 2-[2-[2-(Hydroxymethyl)phenyl]-1-oxoethyl]-2-methylhydrazinecarboxylic acid, 1,1-dimethylethyl ester was purified by flash chromatography (silica) using 50% EtOAc in hexane as eluent. MS (ESI) 295 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][CH:9]=[O:10].C[Si](C)(C)[C:13]([F:16])([F:15])[F:14]>C1COCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:14][C:13]([F:16])([F:15])[CH:9]([OH:10])[CH2:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=CCCc1ccccn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC(CCc1ccccn1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 61.4 %

Procedure:
A solution of 760 mg (5.6 mmol) of 3-pyridin-2-ylpropionaldehyde in 3 mL of THF was treated with 13.6 mL (6.8 mmol, 1.2 eq.) of trimethyl(trifluoromethyl)silane (0.5 M solution in THF) and 0.06 mL (0.06 mmol) of tetrabutylammonium fluoride (1.0 M solution in THF) at 0° C. The resulting mixture was stirred at 0° C. for 10 minutes, and quenched with 1 N HCl solution. After stirring for 5 minutes, the pH of the reaction mixture was adjusted to 9 with saturated NaHCO3 solution, and the product was extracted into ether. The ethereal layer was washed with water and brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography to give 706 mg (61%) of 1,1,1-trifluoro-4-pyridin-2-ylbutan-2-ol as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:14])([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)[CH:3]([F:5])[F:4].[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[F:1][C:2]([F:14])([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][Br:15])=[CH:9][CH:8]=1)[CH:3]([F:4])[F:5]
Reactant: Cc1ccc(OC(F)(F)C(F)F)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)C(F)(F)Oc1ccc(CBr)cc1
Temperature: 25 °C

Procedure:
A solution of 4-(1,1,2,2-tetrafluoroethoxy)toluene (6.73 g, 32.3 mmol), N-bromosuccinimide (5.75 g, 32.3 mmol) and 2,2-azobis(isobutyronitrile) (0.2 g) in carbon tetrachloride (30 ml) was heated under reflux for 0.5 hr. After cooling the reaction solution to room temperature, the white precipitate as removed by filtration and the precipitate was washed with diethyl ether. The solvent of the collected filtrate was evaporated under reduced pressure to give a crude product of 4-(1,1,2,2-tetrafluoroethoxy)benzyl bromide as a pale-yellow liquid.
Reaction SMILES: [OH:1][C@@:2]1([C:36]([F:39])([F:38])[F:37])[C:14]2[CH:13]=[C:12]([O:15][CH2:16][CH2:17][CH2:18][C:19]([OH:22])([CH3:21])[CH3:20])[CH:11]=[C:10]([C:23]3[CH:24]=[N:25][N:26]([C:28]([CH3:35])([CH3:34])[C:29]([O:31]CC)=[O:30])[CH:27]=3)[C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[OH-].[Na+].Cl>C(O)C>[OH:1][C@@:2]1([C:36]([F:38])([F:39])[F:37])[C:14]2[CH:13]=[C:12]([O:15][CH2:16][CH2:17][CH2:18][C:19]([OH:22])([CH3:21])[CH3:20])[CH:11]=[C:10]([C:23]3[CH:24]=[N:25][N:26]([C:28]([CH3:34])([CH3:35])[C:29]([OH:31])=[O:30])[CH:27]=3)[C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: CCOC(=O)C(C)(C)n1cc(-c2cc(OCCCC(C)(C)O)cc3c2-c2ccccc2[C@]3(O)C(F)(F)F)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(O)CCCOc1cc(-c2cnn(C(C)(C)C(=O)O)c2)c2c(c1)[C@@](O)(C(F)(F)F)c1ccccc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.6 %

Procedure:
Ethyl 2-{4-[(9R)-9-hydroxy-2-(4-hydroxy-4-methylpentyloxy)-9-(trifluoromethyl)-9H-fluoren-4-yl]-1H-pyrazol-1-yl}-2-methylpropionate (218 mg) was dissolved in ethanol (2.2 ml), 4N aqueous sodium hydroxide (320 μl) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was neutralized with 1N hydrochloric acid, and extracted with ethyl acetate (twice). The obtained organic layer was washed successively with water (twice) and saturated brine. The obtained organic layer was dried over anhydrous magnesium sulfate, the insoluble material was filtered off, and the solvent in the filtrate was evaporated to give the title compound (179 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:22])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>O1CCCC1>[NH2:1][C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:22])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:20])[F:21])[CH:13]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(Nc1cccc([N+](=O)[O-])c1)c1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Product: Nc1cccc(NC(=O)c2cccc(C(F)(F)F)c2)c1
Temperature: 25 °C
Yield: 65.7 %

Procedure:
To a solution of N-(3-nitrophenyl)-3-(trifluoromethyl)benzamide (30.0 g, 96.7 mmol) in tetrahydrofuran (300 mL) was slowly added with heating under reflux aqueous sodium hydrosulfite (97.8 g, 562 mmol) solution (500 mL), and the obtained two-layer solution was vigorously stirred with heating under reflux for 2 days. After cooling the reaction solution to room temperature, the aqueous layer was separated and extracted with ethyl acetate (150 mL×2). The organic layer separated earlier was diluted with ethyl acetate (350 mL), and washed with saturated aqueous sodium hydrogen carbonate solution (150 mL×2) and saturated brine (100 mL). The collected organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (150 mL×2) and saturated brine (150 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (17.8 g, 66%) as a pale-brown solid.
Reaction SMILES: [C:1]([CH:4]([CH2:17][CH2:18][CH2:19][CH:20]([OH:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:5][CH2:6][CH2:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1)(=[O:3])[CH3:2].[C:27](OC(=O)C)(=[O:29])[CH3:28]>C(OCC)C>[C:1]([CH:4]([CH2:17][CH2:18][CH2:19][CH:20]([O:26][C:27](=[O:29])[CH3:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([OH:14])=[O:13])=[CH:15][CH:16]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCC(O)CCCC(CCCc1ccc(C(=O)O)cc1)C(C)=O
Solvent: CCOCC
Product: CCCCCC(CCCC(CCCc1ccc(C(=O)O)cc1)C(C)=O)OC(C)=O
Temperature: 60 °C

Procedure:
A mixture of 4-(4-acetyl-8-hydroxytridecyl)benzoic acid (9.0 g., 0.025 mole) and acetic anhydride (6.1 g., 0.06 mole) is heated at 60° C. for 18 hours. The mixture is then cooled and dissolved in 80 ml. ethyl ether. The solution is extracted with an ice-cold solution of 8 g. sodium hydroxide in 150 ml. water. The basic solution is separated and acidified with concentrated hydrochloric acid. The oily acid which separates is taken up in ether, washed with water, and dried over sodium sulfate. The ether is evaporated to leave the oily crude product.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:47]([NH:49][S:50]([N:53]([CH2:55][CH:56](OC)[O:57]C)[CH3:54])(=[O:52])=[O:51])=[O:48])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][C:24]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[CH:25][C:19]=2[O:18][CH2:17][C@H:16]([N:34]([CH3:46])[CH2:35][CH2:36][N:37](C)[C:38](=O)OC(C)(C)C)[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(Cl)Cl.O.C(O)(C(F)(F)F)=O>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:47]([NH:49][S:50]([N:53]([CH3:54])[CH2:55][CH:56]=[O:57])(=[O:51])=[O:52])=[O:48])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][C:24]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[CH:25][C:19]=2[O:18][CH2:17][C@H:16]([N:34]([CH3:46])[CH2:35][CH2:36][NH:37][CH3:38])[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(CN(C)S(=O)(=O)NC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N(C)CCN(C)C(=O)OC(C)(C)C)COc1cc(OCc2ccccn2)ccc1-3)OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CNCCN(C)[C@H]1COc2cc(OCc3ccccn3)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)NS(=O)(=O)N(C)CC=O)cc3n2C1
Temperature: 40 °C

Procedure:
tert-butyl {2-[[(7R)-14-cyclohexyl-11-[({[(2,2-dimethoxyethyl)(methyl)amino]-sulfonyl}amino)carbonyl]-3-(pyridin-2-ylmethoxy)-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocin-7-yl](methyl)amino]ethyl}methylcarbamate was dissolved in DCM/H2O/TFA (8:1:3, 15 mM). The mixture was warmed to 40° C. After 30 min all volatiles were evaporated in vacuo and the residual material was coevaporated twice with toluene. The remaining yellow oil was used in the next reaction without further purification.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH:6]=[CH:5][N:4]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N:27]=[C:28]=[O:29])[CH:22]=1>>[F:19][C:20]([F:30])([F:31])[C:21]1[CH:22]=[C:23]([NH:27][C:28]([NH:16][C:13]2[CH:14]=[CH:15][C:10]([O:9][C:7]3[CH:6]=[CH:5][N:4]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:8]=3)=[CH:11][CH:12]=2)=[O:29])[CH:24]=[CH:25][CH:26]=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: Nc1ccc(Oc2ccnc(C(F)(F)F)c2)cc1
Product: O=C(Nc1ccc(Oc2ccnc(C(F)(F)F)c2)cc1)Nc1cccc(C(F)(F)F)c1
Reaction time: 4 h

Procedure:
The title compound is prepared as described in Example 102 but using 4-(2-trifluoromethyl-pyridin-4-yloxy)-phenylamine (Example 108) and α,α,α-trifluoro-m-tolyl-isocyanate. The reaction mixture is stirred for 4 h. The title compound is obtained as a white solid: ES-MS: 441.8 [M+H]+; single peak at tR=9.44 min (System 2); Rf=0.38 (CH2Cl2/Et2O, 90/10).
Reaction SMILES: C(O)=O.C(OC([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:20])[CH:18]=2)[CH:13]=[C:12]1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2([CH3:34])[N:32]=[C:31]([NH2:33])[CH2:30][O:29][CH2:28]2)[CH:22]=1)=O)(C)(C)C.Cl>O1CCOCC1>[ClH:20].[Cl:20][C:17]1[CH:18]=[C:19]2[C:14]([CH:13]=[C:12]([C:21]3[CH:22]=[C:23]([C:27]4([CH3:34])[CH2:28][O:29][CH2:30][C:31]([NH2:33])=[N:32]4)[CH:24]=[CH:25][CH:26]=3)[NH:11]2)=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)n1c(-c2cccc(C3(C)COCC(N)=N3)c2)cc2ccc(Cl)cc21
Agent: Cl
Solvent: O=CO
Solvent: C1COCCO1
Product: CC1(c2cccc(-c3cc4ccc(Cl)cc4[nH]3)c2)COCC(N)=N1
Reaction time: 7 h

Procedure:
A mixture of 2-[3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-6-chloro-indole-1-carboxylic acid tert-butyl ester formate (12 mg, 0.02 mmol) and hydrochloric acid in dioxane (4M) was left at room temperature for 7 hours. For the workup, the solution was evaporated at reduced pressure and the residue dried at high vacuum to yield the (RS)-5-[3-(6-chloro-1H-indol-2-yl)-phenyl]-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine hydrochloride as an amorphous brown material. MS (ISP): m/z=340.1 [M+H]+.
Reaction SMILES: [C:1]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([CH3:26])=[C:11]([CH:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)[CH:12]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:3][CH:2]([CH3:4])[C:1]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([CH3:26])=[C:11]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:12]=1)=[O:5]
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCNCC1
Reaction time: 2 h
Yield: 78.5 %

Procedure:
Into a solution of tert-butyl 4-[5-(isobutyrylamino)-2-methylphenyl]-1-piperidinecarboxylate (335 mg, 0.930 mmol) in CH2Cl2 (10.0 mL) was added TFA (10.0 mL) at room temperature. The reaction mixture was stirred for 2 h and concentrated in vacuo. The residue was dissolved in 20 mL of CHCl3/i-PrOH (3:1) and was basified with 5% KOH solution (10 mL). The aqueous layer was extracted with CHCl3/i-PrOH (3:1, 3×10 mL). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give 2-methyl-N-[4-methyl-3-(4-piperidinyl)phenyl]propanamide (190 mg, 78.0%).
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]2[O:17][CH2:16]2)=[CH:11][CH:10]=1)([CH3:3])[CH3:2].[NH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH2:32][CH2:33][C:34](=[O:37])[NH:35][N:36]=2)=[CH:27][C:26]=1[Cl:38]>>[CH:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]([OH:17])[CH2:16][NH:20][CH2:21][CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH2:32][CH2:33][C:34](=[O:37])[NH:35][N:36]=3)=[CH:27][C:26]=2[Cl:38])=[CH:11][CH:10]=1)([CH3:3])[CH3:2]
Reactant: CC(C)OCCOCc1ccc(OCC2CO2)cc1
Reactant: NCCCOc1ccc(C2=NNC(=O)CC2)cc1Cl
Product: CC(C)OCCOCc1ccc(OCC(O)CNCCCOc2ccc(C3=NNC(=O)CC3)cc2Cl)cc1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-isopropoxyethoxymethyl)phenoxy]-2,3-epoxypropane and 6-[4-(3-aminopropoxy)-3-chloro-phenyl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:33])[C:3]([NH:5][C@@H:6]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[C:7]([NH:9][C@@H:10]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:11]([C@@:13]1([CH3:16])[CH2:15][O:14]1)=[O:12])=[O:8])=[O:4].[O:34]1[CH2:38][CH2:37][CH2:36][C@@H:35]1[C:39](O)=[O:40].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][C@H:6]([NH:5][C:3](=[O:4])[C@@H:2]([NH:1][C:39]([C@H:35]2[CH2:36][CH2:37][CH2:38][O:34]2)=[O:40])[CH3:33])[C:7]([NH:9][C@@H:10]([CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:11]([C@@:13]2([CH3:16])[CH2:15][O:14]2)=[O:12])=[O:8])=[CH:26][CH:27]=1
Reactant: O=C(O)[C@H]1CCCO1
Reactant: COc1ccc(C[C@H](NC(=O)[C@H](C)N)C(=O)N[C@@H](Cc2ccccc2)C(=O)[C@@]2(C)CO2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C[C@H](NC(=O)[C@H](C)NC(=O)[C@H]2CCCO2)C(=O)N[C@@H](Cc2ccccc2)C(=O)[C@@]2(C)CO2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 57.2 %

Procedure:
To (S)-2-((S)-2-aminopropanamido)-3-(4-methoxyphenyl)-N-((S)-1-((R)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)propanamide (0.412 mmol assumed) was added a mixture of (R)-tetrahydrofuran-2-carboxylic acid (57 mg, 0.494 mmol), HATU (187 mg, 0.494 mmol), and DMF (3 mL). The mixture was cooled to 0° C. and DIEA (0.352 mL, 2.06 mmol) was added. The reaction mixture was stirred at ambient temperature for 15 min then quenched with sodium bicarbonate (sat.), extracted with ethyl acetate (2×), dried with sodium sulfate, filtered, and concentrated. Purification by column chromatography (3:1 DCM/ethyl acetate+0-10% methanol) provided (R)-N-((S)-1-(((S)-3-(4-methoxyphenyl)-1-(((S)-1-((R)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)amino)-1-oxopropan-2-yl)amino)-1-oxopropan-2-yl)tetrahydrofuran-2-carboxamide (130 mg, 57%) as a colorless amorphous solid. 1H NMR (400 MHz, DMSO-d6): δ 8.46 (d, J=7.6 Hz, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.54 (d, J=8.0 Hz, 1H), 7.31-7.20 (m, 5H), 7.08 (d, J=8.4 Hz, 1H), 6.77 (d, J=8.4 Hz, 1H), 4.59-4.54 (m, 1H), 4.48-4.42 (m, 1H), 4.21-4.16 (m, 2H), 3.80-3.69 (m, 5H), 3.18 (d, J=5.2 Hz, 1H), 2.98 (d, J=6.4 Hz, 1H), 2.95-2.86 (m, 2H), 2.73-2.59 (m, 2H), 2.05-1.99 (m, 1H), 1.80-1.66 (m, 3H), 1.11 (d, J=7.2 Hz, 3H). MS (EI) for C30H37N3O7, found 552.3 (MH+).
Reaction SMILES: [C:1]1([NH:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[N:13]([O-])=[O:14].[Na+]>O>[C:1]1([N:7]([C:8]([CH3:11])([CH3:10])[CH3:9])[N:13]=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)Nc1ccccc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(C)(C)N(N=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Phenyl-t-butylamine (6 g, 0.04 mol) was treated with conc.HCl (5 ml) and a solution of NaNO2(6.4 g, 2.4 eq.) in 20 ml of water was added slowly. The resulting mixture was stirred for 2 hr at r.t. to produce an oily layer which was extracted with EtOAc, washed with brine, and dried over Na2SO4.Yield 6 g (85%). This nitrosoamine was used for the next step without further purification.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([NH2:15])[CH:14]=1)[NH:11][C:10]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:9]2)C.[O:23]=[S:24]1(=[O:31])[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1>>[C:16]1([C:10]2[NH:11][C:12]3[C:8]([CH:9]=2)=[CH:7][C:6]([CH2:5][C:4]([OH:3])=[O:22])=[CH:14][C:13]=3[NH:15][CH:27]2[CH2:28][CH2:29][S:24](=[O:31])(=[O:23])[CH2:25][CH2:26]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)Cc1cc(N)c2[nH]c(-c3ccccc3)cc2c1
Reactant: O=C1CCS(=O)(=O)CC1
Product: O=C(O)Cc1cc(NC2CCS(=O)(=O)CC2)c2[nH]c(-c3ccccc3)cc2c1

Procedure:
2-(2-Phenyl-7-amino-1H-indol-5-yl)acetic acid ethyl ester prepared as an intermediate in the process of Example 31 and 1,1-dioxo-tetrahydro-thiopyran-4-one were reacted according to the same procedures as Step B of Example 1 and Example 30 to give the title compound.
Reaction SMILES: C[C:2]([CH3:5])([O-])[CH3:3].[K+].[C:7]([O:11][C:12]([N:14]1[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)=[O:13])([CH3:10])([CH3:9])[CH3:8].[Cl-].[Li+]>O1CCCC1>[C:7]([O:11][C:12]([N:14]1[C@H:15]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:25][CH:26]=2)[CH2:16]/[C:17](=[CH:12]\[N:14]([CH:15]([CH3:20])[CH3:16])[CH:2]([CH3:5])[CH3:3])/[C:18]1=[O:19])=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC(=O)N1C(=O)CC[C@H]1Cc1ccc(-c2ccccc2)cc1
Agent: [Cl-]
Agent: [K+]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)N(/C=C1\C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1=O)C(C)C
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of potassium tert-butoxide (2.8 eq, 2.8 mmol, 1 M solution in THF) and N,N,N′N′-tetramethylformamidinium chloride (18, R6=Me, R7=Me) (3 eq, 3 mmol) are stirred at 60° C. for 1 h. The mixture is then cooled to room temperature. The mixture is then diluted with tetrahydrofuran to a total volume of 5 ml. (S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (8-a, R1=Boc) (1 eq, 1 mmol) and lithium chloride (1 eq, 1 mmol) is then added to the mixture. The mixture is then stirred at room temperature for 3 h. The volatiles are removed under reduced pressure. Ethyl acetate (20 ml) is added to the mixture. The phases are separated and the organic phase washed with saturated sodium carbonate solution (2×20 ml) and brine (20 ml). The organic phase is dried (Na2SO4) and concentrated under reduced pressure to afford (R)-5-biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) or a salt thereof. The solutions are analysed by TLC (50% ethyl acetate in hexane). RF 0.21 (salt of 7-a, R1=Boc, R6=Me, R7=Me); RF 0.27 (7-a, R1=Boc, R6=Me, R7=Me); RF 0.68 (8-a, R1=Boc).
Reaction SMILES: [CH:1]([CH:4]1[CH2:9][CH2:8][C:7](B2OC(C)(C)C(C)(C)O2)=[CH:6][CH2:5]1)([CH3:3])[CH3:2].Br[C:20]1[O:24][N:23]=[C:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:21]=1[CH3:30].C(=O)([O-])[O-].[K+].[K+].CC#N>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH:1]([CH:4]1[CH2:9][CH2:8][C:7]([C:20]2[O:24][N:23]=[C:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:21]=2[CH3:30])=[CH:6][CH2:5]1)([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1noc(Br)c1C
Reactant: CC(C)C1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1noc(C2=CCC(C(C)C)CC2)c1C
Reaction time: 1 h

Procedure:
To a 2-5 mL microwave vial was added [2-(4-isopropylcyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane] (282 mg, 1.127 mmol), ethyl 5-bromo-4-methylisoxazole-3-carboxylate (Intermediate A) (264 mg, 1.127 mmol), PdCl2(dppf) (82 mg, 0.113 mmol), potassium carbonate (467 mg, 3.38 mmol), MeCN (2 mL) and water (0.667 mL). The vial was evacuated with nitrogen, sealed and placed in the microwave at 80° C. for 1 hr. The resulting mixture was diluted with EtOAc and water and the layers were separated. The organics were dried over MgSO4, filtered and concentrated under reduced pressure to give a brown oil, crude. The crude material was adsorbed onto silica and purification by chromatography eluting with 0-10% EtOAc in iso-hexane afforded the title compound;
Reaction SMILES: [CH:1]1([SH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].F[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1>C(#N)C.O>[CH:1]1([S:6][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: SC1CCCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=[N+]([O-])c1ccc(SC2CCCC2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 32.1 %

Procedure:
Cyclopentanethiol (1.0 g) (available from Aldrich) was dissolved in acetonitrile (10 ml) and potassium carbonate (1.35 g) was added. After 5 min, 1-fluoro-4-nitrobenzene (1.38 g) (available from Aldrich) was added and the mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with ether. The organic layer was washed with 1M aqueous sodium hydroxide (20 ml), water (20 ml), and 1M aqueous hydrochoric acid (20 ml). The organic layer was separated and the solvent evaporated in vacuo to give the title compound as a yellow liquid (0.7 g).
Reaction SMILES: [O:1]=[C:2]1[CH2:8][O:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[O:4][CH2:3]1.[CH3:13]S(C)(=O)=C.[H-].[Na+].[I-].C[S+](C)(C)=O>CS(C)=O>[O:1]1[CH2:13][C:2]21[CH2:3][O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[O:7][CH2:8]2
Reactant: C=S(C)(C)=O
Reactant: O=C1COc2ccccc2OC1
Agent: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Solvent: CS(C)=O
Product: c1ccc2c(c1)OCC1(CO2)CO1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-Oxo-3,4-dihydro-2H-1,5-benzodioxepin (1.64 g.; 10 millimoles) from Example 1, Step C, is added slowly with stirring during 15 minutes at ambient temperature to a solution of dimethyloxosulfonium methylide prepared under nitrogen from 15 millimoles of sodium hydride, 15 millimoles of trimethyloxosulfonium iodide, and 30 mls. of dimethyl sulfoxide. The mixture is stirred for 24 hours at ambient temperature and then 2 hours at 45°-50° C. The mixture is cooled and poured onto 50 g. of ice and repeatedly extracted with diethyl ether. The ethereal extract is washed with water, dried over anhydrous magnesium sulfate and evaporated. The crude product is crystallized from methanol to afford the 3,4-dihydro-2H-1,5-benzodioxepin-3-spiro-2'-oxirane identical with the product prepared from 3-hydroxy-3-aminomethyl-3,4-dihydro-2H-1,5-benzodioxepin as described in Example 57, Step A.