Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:29][N:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37](N2C=CN=C2)=[O:38])=[CH:32][C:31]1=[O:44]>C(Cl)Cl>[CH3:29][N:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37]([N:9]2[CH2:10][CH:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:28])=[O:38])=[CH:32][C:31]1=[O:44]
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: Cn1ccc(NC(=O)n2ccnc2)cc1=O
Solvent: ClCCl
Product: Cn1ccc(NC(=O)N2CC(CC(C)(C)C)C(C#N)(c3ccc(Cl)cc3F)C2c2cccc(Cl)c2F)cc1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (15.8 mg, 0.0373 mmol) and imidazole-1-carboxylic acid (1-methyl-2-oxo-1,2-dihydro-pyridin-4-yl)-amide (76.3 mg, 0.105 mmol) in CH2Cl2 (1.5 mL) was stirred at rt for 1 day. The reaction mixture was then purified by flash column to rac (2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carboxylic acid (1-methyl-2-oxo-1,2-dihydro-pyridin-4-yl)-amide (19.7 mg, 92.1%). HRMS (ES+) m/z Calcd for C29H28Cl2F2N4O2+H [(M+H)+]: 573.1630; Found: 573.1629.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:7](=[O:8])[CH2:6][CH2:5][C@@H:4]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:3]1.[CH3:18][Mg]Br>C(OCC)C>[OH:8][C:7]1([CH3:18])[CH2:6][CH2:5][C@@H:4]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:3][C:2]1([CH3:17])[CH3:1]
Reactant: C[Mg]Br
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCC(=O)C(C)(C)C1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N[C@@H]1CCC(C)(O)C(C)(C)C1
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a solution of (R)-tert-butyl (3,3-dimethyl-4-oxocyclohexyl)carbamate (550 mg, 2.28 mmol) in diethyl ether (15 mL) was added methyl magnesium bromide (3 M, 3.00 mL) at −30° C. to −40° C. under nitrogen. The mixture was stirred at this temperature for 0.5 h and quenched with saturated aqueous ammonium chloride solution (150 mL). The aqueous layer was extracted with ethyl acetate (300 mL×3). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure. The residue was purified silica gel chromatography column (12% ethyl acetate in petroleum ether) to afford the title compound as a yellow oil (520 mg, 5.02 mmol, 88% yield). MS (ESI) m/z 258.2 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4][CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][C:9]2[NH:13][C:14]([CH:17]=O)=[C:15]([CH3:16])[C:8]=2[C:7]1=[O:19])[CH3:2].[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[CH2:30][S:31]([C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[NH:39][C:38](=[O:43])[CH2:37]2)(=[O:33])=[O:32].N1CCCCC1>C(O)C>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[CH2:30][S:31]([C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[NH:39][C:38](=[O:43])/[C:37]/2=[CH:17]\[C:14]1[NH:13][C:9]2[CH2:10][CH2:11][CH2:12][N:6]([CH2:5][CH2:4][N:3]([CH2:20][CH3:21])[CH2:1][CH3:2])[C:7](=[O:19])[C:8]=2[C:15]=1[CH3:16])(=[O:32])=[O:33]
Reactant: CCN(CC)CCN1CCCc2[nH]c(C=O)c(C)c2C1=O
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3c(Cl)cccc3Cl)ccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCN1CCCc2[nH]c(/C=C3\C(=O)Nc4ccc(S(=O)(=O)Cc5c(Cl)cccc5Cl)cc43)c(C)c2C1=O
Temperature: 25 °C
Yield: 79.4 %

Procedure:
5-(2-Diethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 1j (60 mg, 0.21 mmol) and 5-(2,6-dichloro-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one 64c (67 mg, 0.19 mmol) were dissolved in 3 ml of ethanol, and added with 52 μl of piperidine the solution at room temperature. Upon completion of the addition, the reaction mixture was heated to reflux for 2 hours. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled to room temperature, and filtered. The filter cake was washed with anhydrous ethanol (3 ml×2) and dried to obtain the title compound (Z)-2-((5-(2,6-dichlorobenzylsulfonyl)-2-oxoindolin-3-ylidene)methyl)-5-(2-(diethylamino)ethyl)-3-methyl-5,6,7,8-tetrahydro pyrrolo[3,2-c]azepin-4(1H)-one 70 (95 mg, yield 79%) as an orange solid.
Reaction SMILES: [NH2:1][C:2]([CH3:15])([CH2:13]C)[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[CH2:16]=O>CCOCC>[CH2:16]=[N:1][C:2]([CH3:15])([CH3:13])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4]
Reactant: C=O
Reactant: CCC(C)(N)C(=O)OCc1ccccc1
Solvent: CCOCC
Product: C=NC(C)(C)C(=O)OCc1ccccc1
Reaction time: 4 h
Yield: 106.7 %

Procedure:
To benzyl 2-amino-2-methylbutyrate (12.96 g) was dropped at room temperature 37% formalin (7.62 g), and the mixture was stirred for 4 h. The reaction mixture was dissolved in ether and washed with water. The organic phase was dried over magnesium sulfate, filtered and evaporated to get the captioned compound (13.7 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][NH:13][C:12]1=[O:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24](I)[CH3:25]>[Ag]=O.CN(C)C=O>[CH2:24]([N:13]1[CH2:14][C@@H:15]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[C:12]1=[O:23])[CH3:25]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)[C@@H]1CNC(=O)N1C(=O)OCc1ccccc1
Agent: O=[Ag]
Solvent: CN(C)C=O
Product: CCN1C[C@@H](C(=O)OC(C)(C)C)N(C(=O)OCc2ccccc2)C1=O
Yield: 59.4 %

Procedure:
9.6 g of tert.-butyl (4S)-3-benzyloxycarbonyl-2-oxo-imidazolidine-4-carboxylate, 14.0 g of silver oxide, 46.8 g of ethyl iodide and 200 ml of dimethylformamide are treated in the same manner as described in Example 1-(2). 6.2 g of tert.-butyl (4S)-1-ethyl-3-benzyloxycarbonyl-2-oxo-imidazolidine-4-carboxylate are obtained as colorless crystals.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1)[CH2:4][CH2:5][OH:6].C(N(CC)C(C)C)(C)C.[C:24]([C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][C:34]=1[O:35][CH:36]([CH3:38])[CH3:37])[C:29](O)=[O:30])#[N:25].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][C@H:3]([NH:2][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][C:34]([O:35][CH:36]([CH3:38])[CH3:37])=[C:26]([C:24]#[N:25])[CH:27]=2)[CH2:4][CH2:5][OH:6])=[CH:13][CH:12]=1
Reactant: N[C@H](CCO)Cc1ccc(Br)cc1
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(C(=O)N[C@H](CCO)Cc2ccc(Br)cc2)cc1C#N
Reaction time: 0.05 h
Yield: 78.7 %

Procedure:
To a suspension of (3S)-3-Amino-4-(4-bromophenyl)-1-butanol hydrochloride (1.80 g, 6.42 mmol) in dry DMF (32 mL) was added N,N-diisopropylethyl amine (2.49 g, 19.3 mmol) and the resultant clear solution was stirred for 3 min. 3-Cyano-4-[(1-methylethyl)oxy]benzoic acid (1.45 g, 7.06 mmol) and HBTU (2.68 g, 7.06 mmol) were added and the reaction was stirred at rt under nitrogen. After 1.5 h, the reaction mixture was quenched with water (50 mL) and extracted with EtOAc (3×30 mL). The extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (75% EtOAc/hexanes) to give 2.18 g (78%) of the title compound as a white solid. LC/MS (ES) m/e 431.2 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:16](=O)[CH:15]2[CH:10]([N:11]([CH3:18])[CH2:12][CH2:13][CH2:14]2)[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([N:8]1[CH2:16][CH:15]2[CH:10]([N:11]([CH3:18])[CH2:12][CH2:13][CH2:14]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCCC2C(=O)N(Cc3ccccc3)C(=O)C21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCCC2CN(Cc3ccccc3)CC21

Procedure:
19.2 g (0.08 mol) of crude 6-benzyl-1-methyl-5,7-dioxooctahydropyrrolo[3,4-b]pyridine are reduced with 6.1 g (0.16 mol) of lithium aluminum hydride in absolute tetrahydrofuran in accordance with the working instructions of Example 1c.
Reaction SMILES: [SH:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[Br:10]Br>C(OCC)(=O)C>[Br:10][C:8]1[C:3]2=[N:4][CH:5]=[CH:6][CH:7]=[C:2]2[S:1][N:9]=1
Reactant: N#Cc1ncccc1S
Reactant: BrBr
Solvent: CCOC(C)=O
Product: Brc1nsc2cccnc12
Temperature: 25 °C

Procedure:
To a solution of 3-mercaptopicolinonitrile (1.05 g, 7.72 mmol) in ethyl acetate (30 mL), bromine (3.00 g, 18.90 mmol) was added dropwise at 0° C. The reaction mixture was allowed to warm to room temperature and then refluxed for 3 h. The reaction mixture was concentrated under reduced pressure. Trituration with hexanes:methylene chloride (1:1 mixture) gave 3-bromoisothiazolo[4,5-b]pyridine, as light brown solid which was carried forward without further purification. MW=215 confirmed by LC-MS, tr=15.89 min (Method Y) MH+=216.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[N:13]([CH2:14][CH3:15])[N:12]=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH:10]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([N:35]([CH3:43])[CH2:36][CH2:37][C:38]([O:40]CC)=[O:39])=[O:34])=[CH:29][CH:28]=1>>[CH:1]1([CH:7]([NH:26][C:27]2[CH:28]=[CH:29][C:30]([C:33]([N:35]([CH3:43])[CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:34])=[CH:31][CH:32]=2)[C:9]2[N:13]([CH2:14][CH3:15])[N:12]=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Reactant: CCn1nc(-c2ccc(C(F)(F)F)cc2)cc1C(O)C1CCCCC1
Product: CCn1nc(-c2ccc(C(F)(F)F)cc2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 20 %

Procedure:
Using cyclohexyl{1-ethyl-3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-5-yl}methanol (0.6 g) synthesized in Example 56(3) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.48 g) synthesized in Example 2(2) and in the same manner as in Example 1(7), the title object compound (0.19 g, 19%) was obtained as a white solid.
Reaction SMILES: [Si]([O:8][C@@H:9]([C:23]1[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=1)[CH2:10][N:11]1[CH2:16][CH2:15][CH2:14][C@H:13]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:12]1)(C(C)(C)C)(C)C.C(=O)(O)[O-].[Na+].Cl.[NH2:37][OH:38]>CC(O)C.C(OCC)(=O)C>[OH:8][C@H:9]([C:23]1[CH:24]=[CH:25][C:26](/[C:29](=[N:37]/[OH:38])/[NH2:30])=[CH:27][CH:28]=1)[CH2:10][N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:12]1
Reactant: NO
Reactant: CCOC(=O)C[C@H]1CCCN(C[C@@H](O[Si](C)(C)C(C)(C)C)c2ccc(C#N)cc2)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CCOC(=O)C[C@@H]1CCCN(C[C@H](O)c2ccc(/C(N)=N/O)cc2)C1
Temperature: 75 °C
Yield: 120.6 %

Procedure:
To a mixture of ethyl 2-((R)-1-((S)-2-(tert-butyldimethylsilyloxy)-2-(4-cyanophenyl)ethyl)piperidin-3-yl)acetate (940 mg, 2.183 mmol) and sodium bicarbonate (733 mg, 8.73 mmol) in 2-propanol (50 mL) was added hydroxylamine hydrochloride (303 mg, 4.37 mmol). The reaction mixture was heated at 75° C. overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated NaCl. The organic layer was dried MgSO4, filtered, and concentrated to yield 920 mg of ethyl 2-((S)-1-((R)-2-hydroxy-2-(4-((Z)—N′-hydroxycarbamimidoyl)phenyl)ethyl)piperidin-3-yl)acetate. (M+H)=464; HPLC RT=1.57 minutes. 1H NMR (400 MHz, CDCl3) δ ppm 9.48 (1H, s), 7.55 (2H, d), 7.24 (2H, d), 5.68 (1H, s), 4.74 (1H, m), 4.00 (2H, q), 2.73 (1H, m), 2.65 (1H, m), 2.38 (1H, dd), 2.20 (1H, dd), 2.13 (2H, t), 2.00 (1H, m), 1.80 (3H, m), 1.58 (1H, m), 1.48 (1H, m), 1.38 (1H, m), 1.13 (3H, t), 1.0 (1H, m), 0.85 (9H, s), 0.00 (3H, s), −0.15 (3H, s).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[C:21]([C:22]([F:25])([F:24])[F:23])=[C:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:19][N:18]=3)[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].[NH2:32][CH2:33][C:34]([CH3:37])([OH:36])[CH3:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[C:21]([C:22]([F:25])([F:24])[F:23])=[C:20]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[O:19][N:18]=3)[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:32][CH2:33][C:34]([OH:36])([CH3:37])[CH3:35])=[O:4]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3noc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: CC(C)(O)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(O)CNC(=O)C(O)c1ccc(-c2noc(-c3noc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 52.9 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-IX, 30 mg, 0.070 mmol), 1-amino-2-methylpropan-2-ol (9.30 mg, 0.104 mmol), HATU (34.4 mg, 0.090 mmol), and 4-methylmorpholine (28.1 mg, 0.278 mmol) were added to DMF (1 mL). This was stirred for 1 h and then was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention=11.9 min) to provide (R/S)-2-hydroxy-N-(2-hydroxy-2-methylpropyl)-2-(4-(5-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (20 mg, 0.037 mmol, 52.6% yield): LCMS=503.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.11-8.20 (2 H, m), 7.54-7.85 (7 H, m), 5.17 (1 H, s), 3.25 (2 H, s), 1.17 (3 H, s), 1.15 (3 H, s); HPLC peak RT=8.7 min (Method A).
Reaction SMILES: C(O)(C)(C)C.N.C([O:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]1([CH3:30])[CH2:25][CH2:24][CH2:23][C:22]2([O:29][CH2:28][CH2:27][O:26]2)[CH2:21][O:20]1)C1C=CC=CC=1.[Na]>O1CCCC1>[CH2:28]1[CH2:27][O:26][C:22]2([CH2:21][O:20][C:19]([CH2:18][CH2:17][CH2:16][CH2:15][OH:14])([CH3:30])[CH2:25][CH2:24][CH2:23]2)[O:29]1
Reactant: CC1(CCCCOCc2ccccc2)CCCC2(CO1)OCCO2
Agent: N
Agent: [Na]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: CC1(CCCCO)CCCC2(CO1)OCCO2
Temperature: 78 °C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
t-Butyl alcohol (8.88 g, 0.12 mol) is added to freshly distilled ammonia (360 ml) cooled to 78° C. in an argon atmosphere. The cooling bath is removed and 2-(4'-benzyloxybutyl)-6,6-ethylenedioxy-2-methyloxepane (6.7 g, 0.02 mol) in tetrahydrofuran (90 ml) is added. Freshly cut sodium metal (1.0 g, 0.04 mol) is added in small pieces and the resulting blue solution is stirred for 30 minutes. The reaction is quenched by adding ether (350 ml) followed by water (5 ml). The ammonia is evaporated at room temperature and the ether phase is washed with satd. NaCl (300 ml). The aqueous phase is extracted with ether (5×100 ml). The ether phases are combined, dried (MgSO4) and the solvents are removed under reduced pressure to give 6,6-ethylenedioxy-2-(4'-hydroxybutyl)-2-methyloxepane (13) (4.88 g, 99%): nmr (CDCl3) δ1.18 (s, 3H, CH3), 1.30 (s, 1H, OH), 3.42 (s, 2H, --O--CH2), 3.60 (m, 2H, HO--CH2 --CH2) 3.98 (s, 4H, ketal).
Reaction SMILES: [O:1]1[CH2:7][CH2:6][CH2:5][O:4][C:3]2[CH:8]=[C:9](B(O)O)[CH:10]=[CH:11][C:2]1=2.Cl[C:16]1[C:25]([N:26]([CH:28]([CH3:30])[CH3:29])[CH3:27])=[N:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:31]([O:33][CH3:34])=[O:32])[CH:22]=2)[N:17]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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>[O:1]1[CH2:7][CH2:6][CH2:5][O:4][C:3]2[CH:8]=[C:9]([C:16]3[C:25]([N:26]([CH:28]([CH3:30])[CH3:29])[CH3:27])=[N:24][C:23]4[C:18](=[CH:19][CH:20]=[C:21]([C:31]([O:33][CH3:34])=[O:32])[CH:22]=4)[N:17]=3)[CH:10]=[CH:11][C:2]1=2
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Reactant: OB(O)c1ccc2c(c1)OCCCO2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3ccc4c(c3)OCCCO4)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
To a solution of 3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-ylboronic acid (200.0 mg, 1.03 mmol in dioxane (5.0 mL) was added methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (Scheme I, 150.0 mg, 0.52 mmol), K3PO4 (325.9 mg, 1.54 mmol) and Pd(PPh3)4 (29.7 mg, 0.03 mmol) and water (3 drops) with stirring for 1 h at 90° C. in an oil bath maintained with an inert atmosphere of nitrogen. The reaction mixture was concentrated under vacuum to give a residue, which was purified by a silica gel column with 1% ethyl acetate in petroleum ether to afford methyl 2-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate as a light yellow solid (140.0 mg, 63%).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1>[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: OB(O)c1ccco1
Reactant: Nc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1ccccc1-c1ccco1

Procedure:
To a solution of 2-bromoaniline (137 mg, 0.80 mmol) in THF (4.0 ml) was added 2-furanboronic acid (89 mg, 0.80 mmol), tetrakis-(triphenylphosphine)palladium (0) (92 mg, 0.08 mmol) and sodium carbonate solution (2M, 2.0 ml, 4.0 mmol). The mixture was heated in a sealed tube using a microwave reactor (20 W) at 130° C. for 25 min. This procedure was carried out 5 times and the reaction mixtures were combined. The mixture was separated and the aqueous layer extracted with EtOAc. The combined organic layers were dried and evaporated in vacuo. The residue was purified by flash chromatography on silica (eluant pet. ether:EtOAc 85:15) to give a brown oil; yield 211 mg, 33%.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].C(O)C.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([N:36]=[C:37]=[S:38])=[O:35])=[CH:30][CH:29]=1>C1(C)C=CC=CC=1>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([NH:36][C:37]([NH:4][C:3]2[CH:5]=[CH:6][C:7]([O:9][C:10]3[C:19]4[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]=[CH:12][CH:11]=3)=[CH:8][C:2]=2[Cl:1])=[S:38])=[O:35])=[CH:30][CH:29]=1
Reactant: O=C(N=C=S)c1ccc(Cl)cc1
Reactant: COc1cc2nccc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(Cl)cc4)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 4-chloro-1-benzenecarbonyl isothiocyanate was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (49 mg, yield 61%).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][O:3][CH2:4][CH2:5][OH:6].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(Cl)Cl>[O:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[O:7][CH2:1][CH2:2][O:3][CH2:4][CH2:5][OH:6]
Reactant: C1CCOCC1
Reactant: OCCOCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: OCCOCCOC1CCCCO1
Reaction time: 8 h
Yield: 56.7 %

Procedure:
To 800 mL of CH2Cl2 were added diethylene glycol (57 mL, 0.6 mol) and p-toluenesulfonic acid monohydrate (5.7 g, 30 mmol) successively. Then tetrahydropyran (27.4 mL, 0.3 mol) was added dropwise at 0° C. The reaction mixture was stirred overnight and quenched with H2O, extracted with CH2Cl2, washed with H2O and brine successively, concentrated through rotary evaporation, and subjected to silica gel chromatography using CH2Cl2/MeOH as the eluent to afford compound 28 (32.5 g, 0.17 mol, 57% yield) as a clear oil: 1H NMR (500 MHz, CDCl3) δ 4.59 (t, J=4.0 Hz, 1H), 3.85-3.80 (m, 2H), 3.68-3.64 (m, 4H), 3.59-3.55 (m, 3H), 3.48-3.44 (m, 1H), 2.98 (br, 1H), 1.81-1.76 (m, 1H), 1.71-1.65 (m, 1H), 1.59-1.46 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21](O)=[O:22])[CH:16]=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[CH:26]([NH2:29])([CH3:28])[CH3:27]>>[CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]([NH:29][CH:26]([CH3:28])[CH3:27])=[O:22])[CH:16]=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: CC(C)N
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(C=CC(=O)O)c2)=C(C)C1=O
Product: COC1=C(OC)C(=O)C(Cc2cccc(C=CC(=O)NC(C)C)c2)=C(C)C1=O
Yield: 34.4 %

Procedure:
3-[3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]acrylic acid (55 mg, 0.16 mmol) obtained in Example 36 and isopropylamine (0.016 ml, 0.18 mmol) were used, and a method similar to that described in Example 24 was employed to obtain the title compound (21 mg, 0.055 mmol, yield 34%).
Reaction SMILES: C[O-].[Na+].O.Cl.[OH:6][C:7]1[C:8]([CH3:24])=[C:9]([CH3:23])[C:10]2[O:15][C@:14]([CH3:20])([CH2:16][C:17]([OH:19])=[O:18])[CH2:13][CH2:12][C:11]=2[C:21]=1[CH3:22]>CO>[OH:6][C:7]1[C:8]([CH3:24])=[C:9]([CH3:23])[C:10]2[O:15][C@@:14]([CH3:20])([CH2:16][C:17]([OH:19])=[O:18])[CH2:13][CH2:12][C:11]=2[C:21]=1[CH3:22]
Reactant: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CC(=O)O)O2
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1c(C)c2c(c(C)c1O)CC[C@](C)(CC(=O)O)O2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
This crude enriched (R)-ester (1.1 g) was dissolved in MeOH (8 mL) and treated with NaOMe (2.7 mL of a 25 wt % solution in MeOH, 12 mmol). This solution was heated at reflux for 24 h when H2O (2 mL) was added to the hot solution and reflux was maintained for an additional 30 min. The solution was cooled to room temperature, 1M HCl (15 mL) was added, and the mixture was stirred vigorously for 1 h. The solid was isolated by filtration, washed with H2O (2×5 mL), and air-dried overnight to give 0.70 g (70% yield; essentially 1:1/(R):(S), Method A) of (R,S)-acid of Formula (XI) as a brown solid.
Reaction SMILES: [CH2:1]([N:4]([CH2:18][CH2:19][CH3:20])[CH:5]1[CH2:17][CH2:16][C:8]2[C:9]3[CH:10]=[CH:11][NH:12][C:13]=3[CH:14]=[CH:15][C:7]=2[CH2:6]1)[CH2:2][CH3:3].P(Cl)(Cl)(Cl)=O.[OH-].[Na+].CN(C)[C:30](=[O:33])[CH2:31][CH3:32]>>[CH2:18]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:17][CH2:16][C:8]2[C:9]3[C:10]([C:30](=[O:33])[CH2:31][CH3:32])=[CH:11][NH:12][C:13]=3[CH:14]=[CH:15][C:7]=2[CH2:6]1)[CH2:19][CH3:20]
Reactant: CCCN(CCC)C1CCc2c(ccc3[nH]ccc23)C1
Reactant: CCC(=O)N(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CCCN(CCC)C1CCc2c(ccc3[nH]cc(C(=O)CC)c23)C1
Temperature: 80 °C
Yield: 100 %

Procedure:
A mixture of dipropyl-(6,7,8,9-tetrahydro-3H-benzo[e]indol-7-yl)amine (70 mg, 0.26 mmol) and phosphorous oxychloride (48 μL, 80 mg, 0.52 mmol) in N,N-dimethyl propionamide (250 μL) was heated at 80° C. for 6 hours. After cooling 5M sodium hydroxide was added and the mixture was heated again for 0.5 hour. After cooling, the mixture was extracted 3 times with ethyl acetate, dried (magnesium sulfate), filtered and evaporated to yield a residue to which 99% ethanol was added. This was then evaporated to dryness. A few repetions of the last procedure yielded a residue of 86 mg (100%) of the product.: