Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([C:13]([NH:15][C@H:16]([C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])[CH2:17][CH2:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])(C)(C)C.[C:39]1(OC)[CH:44]=CC=C[CH:40]=1.C(N(CC)CC)C.C(OC(=O)CCC)(=O)CCC>FC(F)(F)C(O)=O.C1C=CC=CC=1.C(Cl)(Cl)Cl>[C:6]([NH:8][C@H:9]([C:13]([NH:15][C@H:16]([C:29]([O:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)=[O:30])[CH2:17][CH2:18][C:19]([O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:20])=[O:14])[CH:10]([CH3:11])[CH3:12])(=[O:7])[CH2:40][CH2:39][CH3:44]
Reactant: COc1ccccc1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: CCCC(=O)OC(=O)CCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCC(=O)N[C@H](C(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of dibenzyl N-(N-tert-butoxycarbonyl-L-valyl)-L-glutamate (1 g) and anisole (0.5 ml) in trifluoroacetic acid (2 ml) was stirred at 0° C. for 1 hour. Evaporation of trifluoroacetic acid under reduced pressure gave a residue which was taken up in benzene. Benzene was distilled off by using high vacuum pump. This operation was repeated three times to leave crude dibenzyl N-L-valyl-L-glutamate, which was dissolved in chloroform (20 ml). To this solution were added triethylamine (3 ml) and butyric anhydride (0.5 ml) and the resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into ice water and the separated organic layer was washed with dilute hydrochloric acid solution, a saturated aqueous solution of sodium bicarbonate and brine respectively. After solvent was evaporated, the residue was recrystallized from petroleum ether to afford dibenzyl N-(N-butanoyl-L-valyl)-L-glutamate (613 mg) as crystals.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[O:4][C:5]([CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)([CH3:9])[CH2:6][C:7]=1[OH:8].[CH3:16][C:17]1[CH:22]=[C:21]([CH3:23])[N:20]2[N:24]=[C:25]([SH:27])[N:26]=[C:19]2[N:18]=1>>[CH:10]1([C:5]2([CH3:9])[O:4][C:3](=[O:15])[C:2]([S:27][C:25]3[N:26]=[C:19]4[N:18]=[C:17]([CH3:16])[CH:22]=[C:21]([CH3:23])[N:20]4[N:24]=3)=[C:7]([OH:8])[CH2:6]2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: Cc1cc(C)n2nc(S)nc2n1
Reactant: CC1(C2CCCC2)CC(O)=C(Cl)C(=O)O1
Product: Cc1cc(C)n2nc(SC3=C(O)CC(C)(C4CCCC4)OC3=O)nc2n1

Procedure:
The title compound was prepared from 3-Chloro-6-cyclopentyl-4-hydroxy-6-methyl-5,6-dihydro-pyran-2-one (described in Step 2 below) and 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-thiol using the coupling method described in Example C(4). 1H NMR (CDCl3): δ 1.54 (s, 3H), 1.55-2.32 (br m, 9H), 2.59 (m 1H), 2.64 (s, 3H), 2.71 (s, 3H), 2.96 (m, 1H), 6.77 (s, 1H). ESIMS: MH+ 375.10, MH− 373.10.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[F:15][C:16]([F:46])([CH:43]([F:45])[F:44])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][N:28]([C:31]3[CH:36]=[CH:35][C:34]([N:37]4[CH:41]=[CH:40][NH:39][C:38]4=[O:42])=[CH:33][CH:32]=3)[CH2:27][CH2:26]2)=[CH:21][CH:20]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:39]1[CH:40]=[CH:41][N:37]([C:34]2[CH:33]=[CH:32][C:31]([N:28]3[CH2:27][CH2:26][N:25]([C:22]4[CH:21]=[CH:20][C:19]([O:18][CH2:17][C:16]([F:15])([F:46])[CH:43]([F:45])[F:44])=[CH:24][CH:23]=4)[CH2:30][CH2:29]3)=[CH:36][CH:35]=2)[C:38]1=[O:42])[CH3:13]
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: O=c1[nH]ccn1-c1ccc(N2CCN(c3ccc(OCC(F)(F)C(F)F)cc3)CC2)cc1
Product: C[C@@H](n1ccn(-c2ccc(N3CCN(c4ccc(OCC(F)(F)C(F)F)cc4)CC3)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 16.3 %

Procedure:
In the same manner as in Reference Example 5, starting from 0.44 g of (1S)-1-[(2R)-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 0.48 g of 1-[4-[4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-1-piperazinyl]phenyl]-2(1H,3H)-imidazolone, 0.11 g of 1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-3-[4-[4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-1-piperazinyl]phenyl]-2(1H,3H)-imidazolone was obtained as a colorless powder.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][CH2:20][CH:21]([C:23]([O:25][CH3:26])=[O:24])[N:22]=2)=[CH:14][C:13]=1[CH3:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrCC(Cl)(Cl)Cl.C1CCN2C(=NCCC2)CC1>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][CH:20]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[N:22]=2)=[CH:14][C:13]=1[CH3:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1COC(c2ccc(NC(=O)OCc3ccccc3)c(C)c2)=N1
Agent: ClC(Cl)(Cl)CBr
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COC(=O)c1coc(-c2ccc(NC(=O)OCc3ccccc3)c(C)c2)n1
Yield: 49.2 %

Procedure:
The same operation as in Example (108d) was performed using methyl 2-(4-{[(benzyloxy)carbonyl]amino}-3-methylphenyl)-4,5-dihydro-1,3-oxazole-4-carboxylate obtained in Example (109c) (1.43 g, 3.88 mmol), bromotrichloroethane (414 μL, 4.1 mmol), DBU (628 μL, 4.1 mmol) and dichloromethane (10 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/4, 1/2, 1/1, 2/1) to obtain 0.7 g of the title compound as a colorless solid (49%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:26])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2].[C:27](OC(=O)C)(=[O:29])[CH3:28]>C(N(CC)CC)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:26][C:27](=[O:29])[CH3:28])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1nc(C#N)c2c(ccn2Cc2ccc(F)c(F)c2)c1O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc(C#N)c2c(ccn2Cc2ccc(F)c(F)c2)c1OC(C)=O

Procedure:
Prepared in analogy to that of Example 120(a) from 7-cyano-1-(3,4-difluoro-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, acetic anhydride, and triethyl amine. The title compound, ESI MS (m/z): 400 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3](=[N:6][N+:7]([O-:9])=[O:8])[S:4][CH3:5].C(=O)([O-])[O-].[K+].[K+].[C:16]([O:19]C(=O)C)(=O)[CH3:17]>C(#N)C>[C:16]([N:2]([CH3:1])[C:3](=[N:6][N+:7]([O-:9])=[O:8])[S:4][CH3:5])(=[O:19])[CH3:17]
Reactant: CNC(=N[N+](=O)[O-])SC
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CSC(=N[N+](=O)[O-])N(C)C(C)=O
Reaction time: 3 h
Yield: 92.7 %

Procedure:
To a mixture of 1,2-dimethyl-3-nitroisothiourea (2.93 g), potassium carbonate (4.07 g), and acetonitrile (60 ml) was added acetic anhydride (2.53 g) at room temperature and the mixture was stirred for 3 hour at this temperature. Insoluble materials were removed by filtration and the filtrate was concentrated. Chloroform (100 ml) was added to the residue and the mixture was washed with water twice. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated to give 3.48 g of 1-acetyl-1,2-dimethyl-3-nitroisothiourea.
Reaction SMILES: Br[C:2]1[C:3]([F:17])=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[CH:5]2.C([O-])([O-])=O.[Cs+].[Cs+].[C:24]([Si](C)(C)C)#[C:25][CH2:26][CH3:27].N#N>CCOC(C)=O.O.[Cu]I.CC([O-])=O.CC([O-])=O.[Pd+2].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.[Fe+2].CC(N(C)C)=O>[C:24]([C:2]1[C:3]([F:17])=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[CH:5]2)#[C:25][CH2:26][CH3:27]
Reactant: CCC#C[Si](C)(C)C
Reactant: Fc1c(Br)ccc2c1cnn2C1CCCCO1
Agent: [Cu]I
Agent: [Fe+2]
Agent: [Pd+2]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCC#Cc1ccc2c(cnn2C2CCCCO2)c1F
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 84.7 %

Procedure:
Nitrogen was bubbled into a solution of 5-bromo-4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (19.7 g, 65.9 mmol; Intermediate 21) and DMA (60 mL). After 5 min, CuI (1.25 g, 6.6 mmol), Pd(OAc)2 (1.48 g, 6.6 mmol), dppf (3.66 g, 6.6 mmol), Cs2CO3 (34.3 g, 105.4 mmol), and but-1-yn-1-yltrimethylsilane (11.6 g, 92.3 mmol; Intermediate 39) were added sequentially with continued N2 bubbling. The resulting mixture was heated at 80° C. for 18 h under N2. The reaction mixture was diluted with EtOAc (900 mL) and H2O (500 mL) and then filtered. The organic layer of the filtrate was separated, and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine (3×100 mL), dried over anhydrous Na2SO4, concentrated, and purified by silica gel chromatography (1:30 EtOAc/petroleum ether) to give the title compound (15.2 g) as a white solid. 1H NMR (DMSO-d6, 400 MHz): δ 8.26 (s, 1H), 7.57 (d, 1H), 7.42 (dd, 1H), 5.87 (dd, 1H), 3.90-3.86 (m, 1H), 3.78-3.71 (m, 1H), 2.48 (q, 2H), 2.40-2.30 (m, 1H), 2.05-1.95 (m, 2H), 1.77-1.71 (m, 1H), 1.59-1.57 (m, 2H), 1.19 (t, 3H); LCMS: 273 (M+H)+.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH3:14])=[O:5])#[N:2].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>>[C:1]([C:3](=[CH:17][N:18]([CH3:20])[CH3:19])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH3:14])=[O:5])#[N:2]
Reactant: CCc1ccccc1NC(=O)CC#N
Reactant: COC(OC)N(C)C
Product: CCc1ccccc1NC(=O)C(C#N)=CN(C)C

Procedure:
As for Example 1, 2-cyano-2'-ethylacetanilide as long needles, m.p. 128°-130° C. (prepared by the procedure described in U.S. Pat. No. 3,116,312), is heated with N,N-dimethylformamide dimethylacetal to yield 2-cyano-3-dimethylamino-2'-ethylacrylanilide as colorless prisms, m.p. 102.5°-104° C.
Reaction SMILES: [CH2:1]([C:3]1([CH:13]=[N:14][S:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])[CH2:12][CH2:11][C:6]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:5][CH2:4]1)[CH3:2].[CH2:21](C1(C#N)CCC2(OCCO2)CC1)[CH3:22].C1(CC2(C=NS(C(C)(C)C)=O)CCC3(OCCO3)CC2)CC1.C([Mg]Br)=C.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH2:1]([C:3]1([CH:13]([NH:14][S:15]([C:17]([CH3:19])([CH3:18])[CH3:20])=[O:16])[CH:21]=[CH2:22])[CH2:4][CH2:5][C:6]2([O:7][CH2:8][CH2:9][O:10]2)[CH2:11][CH2:12]1)[CH3:2]
Reactant: CCC1(C#N)CCC2(CC1)OCCO2
Reactant: CCC1(C=NS(=O)C(C)(C)C)CCC2(CC1)OCCO2
Agent: C=C[Mg]Br
Agent: CC(C)(C)S(=O)N=CC1(CC2CC2)CCC2(CC1)OCCO2
Agent: O=S(=O)([O-])[O-]
Solvent: C1CCOC1
Product: C=CC(NS(=O)C(C)(C)C)C1(CC)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Under argon, 2.00 g (6.64 mmol) of 2-methyl-propane-2-sulfinic acid 1-(8-ethyl-1,4-dioxa-spiro[4.5]dec-8-yl)-methylideneamide (prepared from 8-ethyl-1,4-dioxa-spiro[4.5]decane-8-carbonitrile using the protocol described for the synthesis of 19) were dissolved in 5 mL of absolute tetrahydrofuran. Then, 7.30 mL (7.30 mmol) of vinylmagnesium bromide (1M in tetrahydrofuran) were added dropwise at 0° C. and the reaction mixture was stirred for 17 h at room temperature. Another 16.6 mL (16.6 mmol) of vinylmagnesium bromide (1M in tetrahydrofuran) were added and the mixture stirred for 2 h at room temperature. The reaction mixture was cooled to 0° C. and 15 mL of saturated aqueous sodium sulphate solution were added. The suspension was filtered over celite, the organic layer was dried over magnesium sulphate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 0%→100% ethyl acetate in heptane) to yield 1.30 g of the title compound 57 as mixture of diastereoisomers. Rt=2.19, 2.26 min (Method N). Detected mass: 330.2 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C@@H:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13])([CH3:4])([CH3:3])[CH3:2].Br[CH2:16][C:17]1[CH:26]=[C:25]2[C:20]([CH:21]=[CH:22][N:23]=[C:24]2[Cl:27])=[CH:19][CH:18]=1>>[C:1]([O:5][C:6](=[O:14])[NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([CH2:16][C:17]2[CH:26]=[C:25]3[C:20]([CH:21]=[CH:22][N:23]=[C:24]3[Cl:27])=[CH:19][CH:18]=2)[C:9]1=[O:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1nccc2ccc(CBr)cc12
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(Cc2ccc3ccnc(Cl)c3c2)C1=O
Yield: 80.1 %

Procedure:
Same procedure as EXAMPLE 101D, but using (2-oxopyrrolidin-3-(R)-yl)carbamic acid tert-butyl ester (312 mg, 1.56 mmol) and 7-bromomethyl-1-chloroisoquinoline (440 mg, 1.72 mmol) as the starting materials. The crude product is purified by column chromatography on silica with 50-100% ethyl acetate/hexanes. The product fractions are combined and concentrated to give the product as a pale yellow powder (471 mg. 1.25 mmol).
Reaction SMILES: [C:1]1([CH2:7][OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)[N:11]=1>>[CH2:7]([O:8][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)[N:11]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCc1ccccc1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Product: Cc1cc(Nc2cc3ccccc3c(OCc3ccccc3)n2)n[nH]1

Procedure:
Similar procedure as described in example 10 was used, starting from phenyl-methanol and (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give (1-benzyloxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS: m/e 331 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([CH:20]([C:22]3[O:23][C:24]4[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][C:25]=4[N:26]=3)[OH:21])[C:13]([O:18][CH3:19])=[CH:14][C:15]=2[CH3:17])[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.O=[Mn]=O>[C:31]([C:28]1[CH:29]=[CH:30][C:24]2[O:23][C:22]([C:20]([C:12]3[C:13]([O:18][CH3:19])=[CH:14][C:15]([CH3:17])=[C:16]4[C:11]=3[CH:10]=[CH:9][N:8]4[C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])=[O:21])=[N:26][C:25]=2[CH:27]=1)#[N:32]
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(O)c1nc2cc(C#N)ccc2o1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(=O)c1nc2cc(C#N)ccc2o1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
tert-Butyl-4-((5-cyanobenzo[d]oxazol-2-yl)(hydroxy)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (163 mg, 0.376 mmol) was dissolved in DCM (3.76 mL) and MnO2 (327 mg, 3.76 mmol) was added. The reaction mixture was stirred at rt for 15 h. The reaction mixture was filtered through Celite® and washed three times with DCM. The filtrate was evaporated to dryness to give the title compound. MS (ESI+) m/z 432.16 (M+H).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([F:25])[C:22](OC)=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>[Cl-].[Na+].O>[CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([F:25])[C:22]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1c(F)cc2c3c(cccc13)C(=O)N(OCc1ccccc1)C2=O
Reactant: C1CCNC1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: O=C1c2cccc3c(N4CCCC4)c(F)cc(c23)C(=O)N1OCc1ccccc1

Procedure:
A solution of 48 mg (0.14 mmol) of 2-benzyloxy-5-fluoro-6-methoxy-benzo[de]isoquinoline-1,3-dione (from Example Y3) in 1 mL of pyrrolidine was refluxed for 1 hour and poured into 15 mL of brine. The precipitate was isolated and washed with water until washings were colorless. The solid was dried to yield 32 mg of the title compound.
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][CH2:7][CH2:6][C@H:5]1[C:9]([O:11]CC=C)=O)[CH:2]=[CH2:3].[C-]#[N:16].[Na+]>N.CO>[CH2:1]([N:4]1[CH2:8][CH2:7][CH2:6][C@H:5]1[C:9]([NH2:16])=[O:11])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)[C@@H]1CCCN1CC=C
Reactant: [C-]#N
Agent: N
Agent: [Na+]
Solvent: CO
Product: C=CCN1CCC[C@H]1C(N)=O

Procedure:
Allyl (S)-1-allyl-2-pyrrolidinecarboxylate (2.5 g, 12.8 mmol; and NaCN (64 mg, 1.3 mmol) in 50 ml 9M ammonia in methanol were stirred at 35° C. for 27 h. GLC showed a complete conversion. After evaporation the residue was dissolved in Et2O and washed with brine. Drying (Na2SO4), evaporation and recrystallization gave 1.6 g.(81%) of the title amide identical with the one made in Example 8A.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[C:12](=[O:28])[N:13]([CH:20]1[CH2:25][CH2:24][C:23](=[O:26])[NH:22][C:21]1=[O:27])[C:14]2=[O:19])C)(C)(C)C.[ClH:30].CCOCC>C(Cl)Cl>[ClH:30].[O:27]=[C:21]1[CH:20]([N:13]2[C:12](=[O:28])[C:11]3[C:15](=[CH:16][CH:17]=[CH:18][C:10]=3[CH2:9][NH:7][CH3:6])[C:14]2=[O:19])[CH2:25][CH2:24][C:23](=[O:26])[NH:22]1
Reactant: CN(Cc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CNCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
To a stirred solution of [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-methyl-carbamic acid t-butyl ester (8.1 g, 20.2 mmol) in methylene chloride (80 mL), was added 2N HCl/ether (25 mL). The mixture was stirred at room temperature overnight. The mixture was filtered, washed with CH2Cl2 (20 mL), and dried to afford 2-(2,6-dioxo-piperidin-3-yl)-4-methylaminomethyl-isoindol-1,3-dione hydrochloride (5.3 g, 77%) as an off white solid: 1H NMR (DMSO-d6) δ 11.17 (s, 1H), 9.64 (s, 2H), 8.11-7.91 (m, 3H), 5.22-5.15 (dd, J=4.9 and 12.5 Hz, 1H), 4.55 (s, 2H), 2.98-2.84 (m, 1H), 2.64-2.50 (m, 2H), 2.60 (s, 3H), 2.08-2.03 (m, 1H); 13C NMR (DMSO-d6) δ 172.69, 169.60, 167.22, 166.51, 136.40, 134.86, 131.45, 130.65, 129.20, 123.88, 48.89, 45.66, 32.39, 30.84, 21.96.
Reaction SMILES: [I:1]Cl.[CH2:3]1[C:11]2[C:6](=[CH:7][C:8]([NH2:12])=[CH:9][CH:10]=2)[CH2:5][O:4]1.C(=O)(O)[O-].[Na+]>ClCCl.CO>[I:1][C:9]1[CH:10]=[C:11]2[C:6]([CH2:5][O:4][CH2:3]2)=[CH:7][C:8]=1[NH2:12]
Reactant: Nc1ccc2c(c1)COC2
Reactant: ClI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Nc1cc2c(cc1I)COC2
Reaction time: 1 h

Procedure:
Dropwise, add a 1.0 M solution of iodine monochloride (64 mmol) to a solution of 1,3-dihydro-isobenzofuran-5-ylamine (64 mmol) in dichloromethane (200 mL), methanol (50 mL) and sodium bicarbonate (96 mmol). After stirring for 1 h, quench the reaction with aqueous sodium metabisulfite (100 mL). Separate the organic phase and wash the aqueous with dichloromethane (2×100 mL). Combine the organics and dry over sodium sulfate. Filter the reaction and remove solvent under vacuum. Chromatograph (0-20% ethyl acetate/hexane) the crude mixture over silica gel to give the title compound as a tan solid. 1H NMR (CDCl3, 400 MHz): δ 4.10 (bs, 2H), 4.97 (s, 4H), 6.63 (s, 1H), 7.49 (s, 1H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[F:11])=[O:3].[F:12][C:13]([F:20])([F:19])[C:14](OCC)=[O:15].C[O-].[Na+]>CCOCC.CO>[F:11][C:5]1[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:4]=1[C:2](=[O:3])[CH2:1][C:14]([C:13]([F:20])([F:19])[F:12])=[O:15]
Reactant: CC(=O)c1cc(F)ccc1F
Reactant: CCOC(=O)C(F)(F)F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: O=C(CC(=O)C(F)(F)F)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
28.5 g of 2,5-difluoroacetophenone and 26 g of ethyl trifluoroacetate were stirred in 400 ml of anhydrous ether and cooled in an ice bath. 42 ml of 25 wt % sodium methoxide in methanol was then added over 5 minutes. After stirring 1 hour at room temperature, the reaction mixture was extracted with water, the water acidified and extracted with methylene chloride to give 42 g of 1-(2,5-difluorophenyl)-3-(trifluoromethyl)propane-1,3-dione.
Reaction SMILES: [Cl:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[H-].[Na+].[CH3:13][Si:14]([CH3:21])([CH3:20])[CH2:15][CH2:16][O:17][CH2:18]Cl>CN(C=O)C>[CH3:13][Si:14]([CH3:21])([CH3:20])[CH2:15][CH2:16][O:17][CH2:18][N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[Cl:1]
Reactant: Clc1nc2ccccc2[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1c(Cl)nc2ccccc21
Reaction time: 1.5 h
Yield: 60.5 %

Procedure:
To a solution of 2-chloro-1H-benzo[d]imidazole (1 g, 6.6 mmol.) in dry DMF (10 mL) was added sodium hydride (60%, 0.26 g, 6.5 mmol.) at room temperature under nitrogen atmosphere. 2-(trimethylsilyl)ethoxymethyl chloride (SEMCl, 1.14 g, 6.8 mmol.) was added dropwise after the solution stirred for 1.5 h. The resulting mixture stirred overnight and then quenched with water and extracted with ethyl acetate (30 mL×3). The combined organic layers was washed with water, dried over sodium sulfate and concentrated to give a residue. The residue was purified by column chromatography to give 1-((2-(trimethylsilyl)ethoxy)methyl)-2-chloro-1H-benzo[d]imidazole (1.13 g, 60.8%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[C:21]3[CH:22]=[CH:23][S:24][C:20]=3[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C@H:13]2[CH3:25])(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(O)(=O)C.C(Cl)(Cl)Cl.[Br:34]N1C(=O)CCC1=O>C(Cl)Cl.CCCCCC>[Br:34][C:23]1[S:24][C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C@@H:13]([CH3:25])[N:12]([S:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)(=[O:11])=[O:10])[C:21]=2[CH:22]=1
Reactant: COc1ccc(S(=O)(=O)N2c3ccsc3-c3ccccc3[C@H]2C)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: CCCCCC
Product: COc1ccc(S(=O)(=O)N2c3cc(Br)sc3-c3ccccc3[C@H]2C)cc1
Temperature: 23 °C
Reaction time: 0.08 h
Yield: 98.6 %

Procedure:
A solution of (5R)4-[(4-methoxyphenyl)sulfonyl]-5-methyl-4,5-dihydrothieno[3,2-c]isoquinoline (12.7 g, 34 mmol) in 1:1 acetic acid-chloroform (300 mL) was treated with N-bromosuccinimide (6.1 g, 34 mmol) at −10° C. After ca. 5 min., the cooling bath was removed and the mixture was warmed to 23° C. After 18 h the resulting solution was poured into water (1.2 L) and extracted with methylene chloride (4×400 mL). The organic solution was washed with 25% aqueous potassium hydroxide and brine (1 L each), dried (K2CO3), and concentrated in vacuo to give the crude product (15.5 g) as a green solid which was loaded onto a column of silica gel (100 g) in warm 25% methylene chloride-hexane. Flash chromatography eluting 25-, then 50-, and then 75% methylene chloride-hexane gave the title compound (15.1 g, 98%, m.p. 136-38° C.) as a white solid. [α]D=+219.4. 1H NMR (400 MHz) δ 1.21 (d, J=7 Hz, CHCH3), 3.64 (s, 3H, OCH3), 5.40 (m, 1H, CHCH3), 6.69 (d, J=9 Hz, 2H, ArH), 6.98 (d, J=7.5 Hz, 1H, ArH), 7.08 (m, 1H, ArH), 7.14 (m, 1H, ArH), 7.16-7.23 (overlapping m, 3H, ArH), 7.36 (s, 1H, ArH). MS (ESI) m/z 450 [M+H]+ Analysis calc. for C19H16BrNO3S2: C, 50.67: H, 3.58; N, 3.11. Found: C, 50.68; H, 3.37; N, 3.04
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:10]2[CH:14]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:12]=[N:11]2)[CH:6]=[CH:7][C:8]=1[OH:9])#[N:2].Br[C:21]([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:9][C:8]1[CH:7]=[CH:6][C:5]([N:10]2[CH:14]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:12]=[N:11]2)=[CH:4][C:3]=1[C:1]#[N:2])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)Br
Reactant: CCOC(=O)c1cnn(-c2ccc(O)c(C#N)c2)c1
Product: CCOC(=O)c1cnn(-c2ccc(OC(C)(C)C)c(C#N)c2)c1

Procedure:
The same reaction and treatment as in Example 5 using ethyl 1-(3cyano-4-hydroxyphenyl)pyrazole-4-carboxylate and 1-bromo-1,1-dimethylethane gives ethyl 1-(4-tert-butoxy-3-cyanophenyl)pyrazole-4-carboxylate.