Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[C:11]([NH:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH3:38])=[O:12].[CH2:39]([N:41]([CH2:80][CH3:81])[C:42]1[CH:47]=[CH:46][C:45]([NH:48][C:49]([C:51]2[CH:52]=[C:53]([CH:57]=[CH:58][CH:59]=2)[C:54]([OH:56])=O)=[O:50])=[C:44]([C:60]2[CH:65]=[C:64]([C:66](=[O:79])[NH:67][CH2:68][C:69]3[CH:74]=[CH:73][CH:72]=[C:71]([C:75]([F:78])([F:77])[F:76])[CH:70]=3)[CH:63]=[CH:62][N:61]=2)[CH:43]=1)[CH3:40].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:38][O:37][CH2:36][CH2:35][O:34][CH2:33][CH2:32][O:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23][O:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][NH:13][C:11]([C@@H:6]1[CH2:7][CH2:8][CH2:9][CH2:10][N:5]1[CH2:4][CH2:3][N:2]([CH3:1])[C:54](=[O:56])[C:53]1[CH:57]=[CH:58][CH:59]=[C:51]([C:49]([NH:48][C:45]2[CH:46]=[CH:47][C:42]([N:41]([CH2:39][CH3:40])[CH2:80][CH3:81])=[CH:43][C:44]=2[C:60]2[CH:65]=[C:64]([C:66](=[O:79])[NH:67][CH2:68][C:69]3[CH:74]=[CH:73][CH:72]=[C:71]([C:75]([F:76])([F:77])[F:78])[CH:70]=3)[CH:63]=[CH:62][N:61]=2)=[O:50])[CH:52]=1)=[O:12]
Reactant: CNCCN1CCCC[C@H]1C(=O)NCCOCCOCCOCCOCCOCCOCCOCCOC
Reactant: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)O)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)N(C)CCN3CCCC[C@H]3C(=O)NCCOCCOCCOCCOCCOCCOCCOCCOC)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 67.4 %

Procedure:
To a mixture of (S)-1-(2-(methylamino)ethyl)-N-(2,5,8,11,14,17,20,23-octaoxapentacosan-25-yl)piperidine-2-carboxamide (0.145 mmol), 3-((4-(diethylamino)-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)phenyl)carbamoyl)benzoic acid (0.12 mmol, 80 mg) and DIEA (0.6 mmol, 78 mg) in DMF (0.4 mL) was added HATU (0.145 mmol, 55 mg). The mixture was stirred at 60° C. for 1 h and purified by prep. HPLC to give a yellow solid (91 mg, 52%). MS (ES, m/z): 1124.38 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[NH2:5].[OH:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][C:19]=1[O:26][CH3:27]>>[OH:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]2[C:8]3[NH:9][C:10]4[C:15]([C:7]=3[CH2:6][CH:4]([C:3]([O:2][CH3:1])=[O:16])[NH:5]2)=[CH:14][CH:13]=[CH:12][CH:11]=4)=[CH:20][C:19]=1[O:26][CH3:27]
Reactant: COc1cc(C=O)ccc1O
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Product: COC(=O)C1Cc2c([nH]c3ccccc23)C(c2ccc(O)c(OC)c2)N1

Procedure:
The same method but starting from racemic tryptophan methyl ester and 4-hydroxy-3-methoxybenzaldehyde gave the title compound as a cream solid m.p.: 195° C.
Reaction SMILES: [CH:1]([C:4]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)([C:27](=[O:29])[NH2:28])[N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:8][CH:7]([CH2:22][C:23](O)=[O:24])[C:6]1=[O:26])([CH3:3])[CH3:2].[NH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH:1]([C:4]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)([C:27](=[O:29])[NH2:28])[N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[N:8][CH:7]([CH2:22][C:23]([NH:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:24])[C:6]1=[O:26])([CH3:2])[CH3:3]
Reactant: Nc1ccccc1
Reactant: COc1ccc(C(C(N)=O)(C(C)C)N2C(=O)C(CC(=O)O)N=C(c3ccccc3)c3ccccc32)cc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(C(N)=O)(C(C)C)N2C(=O)C(CC(=O)Nc3ccccc3)N=C(c3ccccc3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60.1 %

Procedure:
According to Process F, a mixture of {1-[Isopropyl-(4-methoxy-phenyl)-carbamoylmethyl]-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl}-acetic acid (200 mg, 0.400 mmol), prepared as in Intermediate 29, aniline (0.033 mL, 0.356 mmol), and bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (167 mg, 0.356 mmol) in anhydrous DCM (3 mL) is treated with diisopropylethylamine (0.170 mL, 0.978 mmol) and stirred at ambient temperature under nitrogen. After 1.5 hrs., the solvent is removed in vacuo and the residue is purified by chromatography on flash grade silica gel using 60% ethyl acetate in n-hexane. Fractions containing the product are combined, concentrated in vacuo and triturated with n-hexane. After removing the solvent in vacuo, the product is dried overnight at ambient temperature under high vacuum to provide the title compound (123 mg, 0.214 mmol) as a white solid. The product is lyophilized from acetonitrile/water. 1H NMR (300 MHz, d6-DMSO) δ=0.86-0.96 (m, 6H); 3.14 (d, J=6.9 Hz, 2H); 3.77 (S, 3H); 4.03-6.12 (M, 2H); 4.23 (D, J=16.8 HZ, 1H); 4.59-6.73 (M, 1H); 6.97-7.08 (M, 3H); 7.15-7.32 (M, 6H); 7.36-7.66 (M, 9H); 10.15 (S, 1H). MS (FAB): [M+H]+ =575.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:18]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[CH:16]=C(C=C)[CH:14]=3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:27][CH:28]([OH:30])[CH3:29].[OH2:31]>>[OH:30][C@@H:28]([C:29]1[CH:14]=[C:13]([C:10]2[CH:11]=[CH:12][C:7]([O:6][C:5]3[CH:25]=[CH:26][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:8][CH:9]=2)[N:18]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[CH:16]=1)[CH2:27][OH:31]
Reactant: CC(C)O
Reactant: C=Cc1cc(C(=O)OC)nc(-c2ccc(Oc3ccc(F)cc3)cc2)c1
Reactant: O
Product: COC(=O)c1cc([C@H](O)CO)cc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Reaction time: 3 h

Procedure:
To a suspension of methyl 6-(4-(4-fluorophenoxy)phenyl)-4-vinylpicolinate (0.309 g, 0.884 mmol) in 10 mL 1:1 iPrOH/H2O was added AD-Mix α (1.205 g). The reaction was stirred for 3 h then partitioned between 50 mL EtOAc and 25 mL water. The organics were separated, dried over MgSO4, filtered, and concentrated in vacuo to give crude (S)-methyl 4-(1,2-dihydroxyethyl)-6-(4-(4-fluorophenoxy)phenyl)picolinate which was used in the next step without further purification (LC/MS: m/z=384.1 [M+H]+).
Reaction SMILES: [C:1](=[O:4])([O-])[O-:2].[NH2:5][C:6]1[C:7]([CH3:19])=[C:8](Br)[C:9]2[O:14][C:13]([CH3:16])([CH3:15])[CH:12]=[CH:11][C:10]=2[CH:17]=1.C(N(C(C)C)CC)(C)C>CC(N(C)C)=O>[C:1](=[O:4])([OH:2])[NH2:5].[NH2:5][C:6]1[C:7]([CH3:19])=[CH:8][C:9]2[O:14][C:13]([CH3:15])([CH3:16])[CH:12]=[CH:11][C:10]=2[CH:17]=1
Reactant: Cc1c(N)cc2c(c1Br)OC(C)(C)C=C2
Reactant: O=C([O-])[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Cc1cc2c(cc1N)C=CC(C)(C)O2
Product: NC(=O)O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
After a carbonate resin (0.80 mmol/g, 10 g, 8.0 mmol) of formula 2 was mixed with dimethylacetamide (DMA, 50 mL) by shaking at room temperature for 10 min, 6-amino-8-bromo-2,2,7-trimethyl-2H-benzopyran (4.29 g, 16.0 mmol) and diisopropylethyl amine (DIPEA; 5.17 mg, 40.0 mmol) were successively added thereto and mixed by shaking at 25° C. for 15 hrs. After the reaction was completed, the reaction mixture was subjected to filtration and repeatedly washed with DMF, DCM, DCM/MeOH and MeOH, to obtain a solid resin (Formula 4-10; 12.2 g). (ATR-FTIR; carbamate: 1725 cm−1)
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].[CH2:16](N(CC)CC)C.[F:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[F:33])[C:27](Cl)=[O:28].C(OCC)(=O)C>C(Cl)Cl>[F:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[F:33])[C:27](=[O:28])[CH2:16][NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Reactant: CCN(CC)CC
Reactant: COC(=O)c1[nH]c2cc(Cl)ccc2c1N
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1[nH]c2cc(Cl)ccc2c1NCC(=O)c1ccc(F)c(F)c1

Procedure:
Suspend the 3-amino-2-carbmethoxy-6-chloroindole (1.15 g, 5.2 mmol) in methylene chloride (80 mL) and add triethylamine (0,497 mL, 5.5 mmol). Addthe 3,4-difluorobenzoyl chloride (0.692 mL, 5.5 mmol) and stir for 30 minutes at room temperature to produce a precipitate. Dilute the reaction with ethyl acetate, rinse with water, dry over magnesium sulfate, filter and concentrate in vacuo to yield the title compound.
Reaction SMILES: O=[CH:2][CH:3]([C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=1[CH3:14])[C:4]#[N:5].O.[NH2:16][NH2:17].C(O)(=O)C.Cl>C1C=CC=CC=1.O>[CH3:14][C:7]1[CH:8]=[C:9]([CH3:13])[CH:10]=[C:11]([CH3:12])[C:6]=1[C:3]1[CH:2]=[N:17][NH:16][C:4]=1[NH2:5]
Reactant: Cc1cc(C)c(C(C#N)C=O)c(C)c1
Reactant: NN
Agent: Cl
Solvent: O
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: Cc1cc(C)c(-c2cn[nH]c2N)c(C)c1
Temperature: 25 °C
Yield: 10.3 %

Procedure:
A mixture of 3-oxo-2-(2,4,6-trimethyl-phenyl)-propionitrile (2.300 g, 12.3 mmol), hydrazine hydrate (0.93 g) and glacial acetic acid (1.55 ml) in 20 ml benzene was heated at reflux for 4.5 hours. Reaction mixture was cooled to room temperature and 50 ml of 18.5% HCl in water was added. The benzene layer was separated and reextracted with 18.5% HCl. The aqueous layer were combined and neutralized with ammonium hydroxide and stirred at rt. overnight. Precipitate formed and was filtered to yield the title compound (0.256 g) as a yellow solid. The benzene layer was concentrated and purified through silica gel column using 5% methanol in chloroform as eluent to give an additional 1.450 g of the title compound; 1H NMR (CDCl3) ä 7.24(s, 1H), 6.95(s, 2H), 4.75(brs, 2H), 2.32(s, 3H), 2.13(s, 6H) ppm.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=1.CN1CCCC1=O>O>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[C:20]([C:25]([F:26])([F:27])[F:28])[CH:19]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Oc1ccc(Br)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc(COc2ccc(Br)cc2C(F)(F)F)cc1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
Potassium carbonate (25.8 g) and 1-(chloromethyl)-4-methoxybenzene (14.4 mL) were added to a mixture of 4-bromo-2-(trifluoromethyl)phenol (15 g) and N-methyl pyrrolidone (100 mL) at room temperature, and the mixture was stirred at 90° C. for 3 hours. After the reaction mixture was cooled to room temperature, water was added thereto, then extraction thereof was performed using EtOAc, and the extract was washed with water. The organic layer was dried over MgSO4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex:EtOAc=9:1 to 6:1), whereby 4-bromo-1-[(4-methoxybenzyl)oxy]-2-(trifluoromethyl)benzene (22 g) was obtained as a colorless oil.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](Cl)=[O:8])[CH2:2][CH3:3].[NH2:14][C:15]1[CH:23]=[N:22][CH:21]=[CH:20][C:16]=1[C:17]([NH2:19])=[O:18].C(N(CC)CC)C>C(#N)C>[CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH:14][C:15]1[CH:23]=[N:22][CH:21]=[CH:20][C:16]=1[C:17]([NH2:19])=[O:18])=[O:8])[CH2:2][CH3:3]
Reactant: CCCOc1ccccc1C(=O)Cl
Reactant: NC(=O)c1ccncc1N
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCOc1ccccc1C(=O)Nc1cnccc1C(N)=O

Procedure:
In a similar manner to Example 1 a) reaction of 2-propoxybenzoyl chloride (0.99 g), 3-aminoisonicotinamide (0.69 g) and triethylamine (0.51 g) in acetonitrile (15 ml) afforded a crude product (1.45 g) which was recrystallised from methanol to afford 3-(2-propoxybenzamido)isonicotinamide, 0.73 g, m.p. 214°-7° C.
Reaction SMILES: [CH3:1]/[CH:2]=[CH:3]/[C:4]([CH:6]1[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][CH:8]=[C:7]1[CH3:14])=[O:5].[CH3:15][N:16]([CH2:18][CH2:19][OH:20])[CH3:17].CN(C)C(=N)N(C)C>>[CH3:15][N:16]([CH3:17])[CH2:18][CH2:19][O:20][CH:2]([CH3:1])[CH2:3][C:4]([CH:6]1[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][CH:8]=[C:7]1[CH3:14])=[O:5]
Reactant: CN(C)CCO
Reactant: C/C=C/C(=O)C1C(C)=CCCC1(C)C
Agent: CN(C)C(=N)N(C)C
Product: CC1=CCCC(C)(C)C1C(=O)CC(C)OCCN(C)C
Yield: 32 %

Procedure:
A solution of α-damascone (6.44 g; 33.5 mmol), N,N-dimethylaminoethanol (30.25 ml; 301 mmol) and tetramethylguanidine (TMG) (0.77 g; 6.70 mmol) was heated at 70° C. for 15 h. Afterward, the excess of N,N-dimethylaminoethanol was distilled at ca. 60° C./10 to 2 mbar. The crude product was diluted in diethyl ether (Et2O) and this mixture was extracted with 5% aqueous HCl and washed with water and saturated aqueous NaCl. The combined aqueous phases were basified using aqueous NaOH and extracted twice with ether to recover the crude product in the organic phases. The organic phases were still washed with water and brine, then dried over Na2SO4 and concentrated. Bulb-to-bulb distillation of the crude product (100-125° C./0.05 mbar) afforded 2.94 g of the desired pure product (yield: 32%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14])(=O)=O.[Cl:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C([O-])([O-])=O.[Na+].[Na+].CCOCC>C1(C)C=CC=CC=1.C(O)C.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>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:23][CH:22]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCOC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)C1=C(c2ccc(Cl)cc2)CCCC1

Procedure:
To a solution of EXAMPLE 8A (2.88 g, 10 mmol), 4-chlorophenylboronic acid (1.88 g, 12 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.578 g, 0.5 mmol) in toluene (40 ml) and ethanol (10 ml) was added 2N Na2CO3 (10 mL). The mixture was stirred at reflux overnight. The mixture was diluted ether (300 mL) and washed with water, brine and dried over Na2SO4. After evaporation of solvent, the residue was loaded on a column and eluted with 3% ethyl acetate in hexane to give title compound.
Reaction SMILES: C(O[C:6](=O)[NH:7][C@@H:8]([CH2:28][CH2:29][CH2:30][CH2:31][OH:32])[CH2:9][O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(C)(C)C.Cl.C(=O)[CH2:36][CH:37]([CH3:39])[CH3:38].C(O)(=O)C.C([BH3-])#N.[Na+]>O1CCOCC1.CO>[Si:11]([O:10][CH2:9][C@@H:8]([NH:7][CH2:6][CH2:36][CH:37]([CH3:39])[CH3:38])[CH2:28][CH2:29][CH2:30][CH2:31][OH:32])([C:24]([CH3:26])([CH3:27])[CH3:25])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)CC=O
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCO)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CC(C)CCN[C@@H](CCCCO)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Material from Step 4 (9.8 g, 20.78 mmol) was dissolved in a solution of 4 M HCl (51.9 mL, 208 mmol) in dioxane. The reaction mixture was stirred at room temperature for 1 hour. It was concentrated in vacuo, then dichloromethane was added and concentrated again in vacuo. The residue (1.75 g, 4.29 mmol) was dissolved in methanol (30 mL), and isovaleraldehyde (0.35 mL, 4.50 mmol) and acetic acid (0.25 mL, 4.29 mmol) were added. The reaction mixture was stirred at room temperature for 30 minutes. Sodium cyanoborohydride (0.323 g, 5.15 mmol) was then added to the mixture and it was stirred at room temperature overnight. The reaction mixture was concentrated, and partitioned between EtOAc and saturated aqueous NaHCO3 and extracted with EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to yield the title compound, which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]([CH3:27])[C:17]3[NH:22][C:21](=[O:23])[O:20][C:19]([CH3:25])([CH3:24])[C:18]=3[CH:26]=2)=[CH:4][CH:3]=1.[OH:28]O>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]([CH3:27])[C:17]3[NH:22][C:21](=[O:23])[O:20][C:19]([CH3:24])([CH3:25])[C:18]=3[CH:26]=2)=[O:28])=[CH:6][CH:7]=1
Reactant: Cc1ccc(SCCCCOc2cc(C)c3c(c2)C(C)(C)OC(=O)N3)cc1
Reactant: OO
Product: Cc1ccc(S(=O)CCCCOc2cc(C)c3c(c2)C(C)(C)OC(=O)N3)cc1

Procedure:
Prepared analogously to Example 2 from 6-[4-(4-methyl-phenylmercapto)-butoxy]-4,4,8-trimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: FC(F)(F)[C:3]1C=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C(O[CH2:17][CH3:18])(=[O:15])C#C.[N+:19](C)([O-:21])=[O:20]>>[N+:19]([CH2:17][CH3:18])([O-:21])=[O:20].[CH3:7][C:6]1[CH:5]=[C:4]([CH3:3])[O:15][N:8]=1
Reactant: C#CC(=O)OCC
Reactant: C[N+](=O)[O-]
Reactant: Nc1ccc(C(F)(F)F)cc1
Product: CC[N+](=O)[O-]
Product: Cc1cc(C)on1

Procedure:
By substituting 5-amino-1,3-benzodioxole for 4-(trifluoromethyl)aniline in a, and then substituting the appropriate substituted propiolic ester for ethyl propiolate and/or the appropriate stubstituted nitromethane for nitroethane in a, the identical process gives 4-(1,3-benzodioxol-5-aminocarbonyl)-3-methylisoxazole, 4-(1,3-benzodioxol-5-aminocarbonyl)-3-cyclopropylisoxazole, 4-(1,3-benzodioxol-5-aminocarbonyl])-3,5-dimethylisoxazole, 4-(1,3-benzodioxol-5-aminocarbonyl)-3-cyclopropyl-5-methylisoxazole, and 4-(1,3-benzodioxol-5-aminocarbonyl)-5-(2-chlorophenyl)-3-methylisoxazole, and 4-(1,3-benzodioxol-5-aminocarbonyl)-5-(2-chlorophenyl)-3-cyclopropylisoxazole.
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15](Br)[CH:16]=3)[CH2:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH:21]1([N:24]2[C:33]3[C:28](=[CH:29][C:30]([F:48])=[C:31]([Sn](CCCC)(CCCC)CCCC)[C:32]=3[CH3:34])[C:27](=[O:49])[C:26]([C:50]([O:52][CH2:53][CH3:54])=[O:51])=[CH:25]2)[CH2:23][CH2:22]1.C(OCC)(=O)C.Cl>CN(C)C=O.[Ag-]=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>[CH:21]1([N:24]2[C:33]3[C:28](=[CH:29][C:30]([F:48])=[C:31]([C:15]4[CH:16]=[C:17]5[C:12](=[CH:13][CH:14]=4)[CH2:11][N:10]([S:7]([C:4]4[CH:5]=[CH:6][C:1]([CH3:20])=[CH:2][CH:3]=4)(=[O:9])=[O:8])[CH2:18]5)[C:32]=3[CH3:34])[C:27](=[O:49])[C:26]([C:50]([O:52][CH2:53][CH3:54])=[O:51])=[CH:25]2)[CH2:22][CH2:23]1
Reactant: Cc1ccc(S(=O)(=O)N2Cc3ccc(Br)cc3C2)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1c(F)cc2c(=O)c(C(=O)OCC)cn(C3CC3)c2c1C
Agent: O=[Ag-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C2CC2)c2c(C)c(-c3ccc4c(c3)CN(S(=O)(=O)c3ccc(C)cc3)C4)c(F)cc2c1=O
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
In 25 ml of N,N-dimethylformamide was dissolved 2.30 g of 2-(p-toluenesulfonyl)-5-bromoisoindoline, and 1.51 g of silver (I) oxide and 0.75 g of tetrakis(triphenylphosphine)palladium (0) were added to the solution, after which the resulting mixture was stirred at 100° C. for five minutes under a nitrogen atmosphere. Subsequently, to this reaction mixture was added 1.54 g of ethyl 1-cyclopropyl-6-fluoro-8-methyl-7-tributylstannyl-1,4-dihydro-4-oxoquinoline-3-carboxylate dissolved in 5 ml of N,N-dimethylformamide, and resulting mixture was stirred at 100° C. for 15 minutes. The reaction mixture was added to a mixed solvent of 50 ml of ethyl acetate and 100 ml of water, and the pH was adjusted to 2 with 2N hydrochloric acid, after which insolubles were removed by filtration. The organic layer formed was separated, washed with a saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure. The residue obtained was purified by a column chromatography (eluent: toluene:ethyl acetate=3:1), and diethyl ether was thereafter added thereto, after which the crystals formed were collected by filtration, to obtain 0.55 g of colorless, crystalline ethyl 1-cyclopropyl-6-fluoro-8-methyl-7-[2-(p-toluenesulfonyl)isoindolin-5-yl]-1,4-dihydro-4-oxoquinoline-3-carboxylate.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH2:10][C@H:9]1[C:24]([OH:26])=O)=[O:7])(C)(C)C.[Cl:27][C:28]1[CH:33]=[C:32]([N:34]=C=O)[CH:31]=[C:30]([Cl:37])[CH:29]=1.[N:38]1[C:47]2[C:42](=[CH:43][C:44]([NH2:48])=[CH:45][CH:46]=2)[CH:41]=[CH:40][CH:39]=1>>[Cl:23][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[Cl:22])[CH2:15][O:14][N:13]=[C:11]1[CH2:12][N:8]([C:6]([NH:34][C:32]2[CH:33]=[C:28]([Cl:27])[CH:29]=[C:30]([Cl:37])[CH:31]=2)=[O:7])[C@H:9]([C:24]([NH:48][C:44]2[CH:43]=[C:42]3[C:47](=[CH:46][CH:45]=2)[N:38]=[CH:39][CH:40]=[CH:41]3)=[O:26])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CC(=NOCc2ccc(Cl)c(Cl)c2)C[C@H]1C(=O)O
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Reactant: Nc1ccc2ncccc2c1
Product: O=C(Nc1ccc2ncccc2c1)[C@@H]1CC(=NOCc2ccc(Cl)c(Cl)c2)CN1C(=O)Nc1cc(Cl)cc(Cl)c1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylic acid, 1,3-dichloro-5-isocyanatobenzene, and 6-quinolinamine the title compound was obtained in 66% purity by LC/MS. MS(ESI+): m/z=617.2.
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]2[C:5]([C:6]3[CH2:7][CH2:8][CH2:9][C:10](=[O:16])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[C:17]([Si](C)(C)C)([F:20])([F:19])[F:18].[F-].[Cs+]>C1COCC1>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]2[C:5]([C:6]3[CH2:7][CH2:8][CH2:9][C:10]([C:17]([F:20])([F:19])[F:18])([OH:16])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1
Reactant: O=C1CCCc2c1[nH]c1c(Cl)c(Cl)ccc21
Reactant: C[Si](C)(C)C(F)(F)F
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Product: OC1(C(F)(F)F)CCCc2c1[nH]c1c(Cl)c(Cl)ccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 19.8 %

Procedure:
7,8-Dichloro-2,3,4,9-tetrahydro-1H-carbazol-1-one (0.2 g, 0.78 mmol) was dissolved in anhydrous THF (5 mL), cooled to 0° C., and CF3TMS (1.2 mL, 8.7 mmol) followed by CsF (0.36 mg, 2.3 mmol) were added and stirred for 30 min. at 0° C. The reaction mixture was slowly warmed to room temperature and stirred for an additional 2 h, quenched with saturated NH4Cl and extracted with EtOAc (3×20 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to give the crude compound which was purified by column chromatography [EtOAc-hexane (1:4) as eluant] to provide the title compound as a yellow syrup (0.05 g, 19%). 1H NMR (500 MHz, CDCl3, δ in ppm) 8.32 (bs, 1H), 7.38 (d, J=8.5 Hz, 1H), 7.21 (d, J=8.5 Hz, 1H), 2.85-2.81 (m, 1H), 2.73-2.70 (m, 1H), 2.68 (s, 1H), 2.29-2.24 (m, 1H), 2.13-2.11 (m, 2H), 2.03-2.01 (m, 1H).