Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[CH3:12][CH:13]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[C:20]([CH3:25])[CH:19]=[CH:18]2)[CH3:14].[I:26]I.C1(C)C=CC=CC=1>C(OCC)(=O)C>[I-:26].[F:1][C:2]1[CH:11]=[CH:10][C:9]2[N+:8]3[CH:25]=[C:20]4[CH:19]=[CH:18][C:17]5[CH:16]=[C:15]([CH:13]([CH3:14])[CH3:12])[CH:24]=[CH:23][C:22]=5[N:21]4[C:7]=3[CH:6]=[CH:5][C:4]=2[CH:3]=1
Reactant: II
Reactant: Cc1ccc2cc(C(C)C)ccc2n1
Reactant: Fc1ccc2ncccc2c1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)c1ccc2c(ccc3c[n+]4c5ccc(F)cc5ccc4n32)c1
Product: [I-]

Procedure:
A solution of 88.3 g. of 6-fluoroquinoline, 27.8 g. of 6-(1-methylethyl)quinaldine and 76.2 g. of iodine in 100 ml. of toluene is heated at 95°-100° C. for 5 days, cooled and diluted with 350 ml. of ethyl acetate. The precipitate is collected, pulverized, suspended in 500 ml. of aqueous methanol and recovered by filtration. The solid is suspended in 400 ml. of cold methanol, stirred with 6 ml. of hydrazine and the solid 3-fluoro-10-(1-methylethyl)imidazo[1,2-a:3,4-a']diquinolin-15-ium iodide is collected by filtration; m.p. 305°-307° C., after crystallization from methanol.
Reaction SMILES: O[CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:41]I>C(Cl)(Cl)Cl>[I:41][CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:15]
Reactant: C[C@H](CO)CN1C(=O)COc2ccccc21
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: C[C@H](CI)CN1C(=O)COc2ccccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 80 %

Procedure:
A reaction flask was charged with (S)-4-(3-Hydroxy-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one (2.52 g, 11.4 mmol), triphenylphosphine (6.12 g, 23.3 mmol), imidazole (1.98 g, 29.1 mmol), and iodine (8.88 g, 35.0 mmol) in CHCl3 (30 mL) and stirred at rt for 20 h. The reaction mixture was washed with saturated sodium thiosulfate, dried over Na2SO4, filtered, and concentrated. The product was purified by flash column chromatography (SiO2; n-heptane/EtOAc 3:1) to give the title compound (3.02 g, 80%). 1H NMR (CDCl3) δ 7.07-7.00 (m, 4H), 4.65-4.55 (m, 2H), 3.94 (dd, J=1.7 Hz, J=6.7 Hz, CH2), 3.23-3.14 (m, 2H), 2.18-2.07 (m, 1H), 1.05 (d, J=6.1 Hz, CH3).
Reaction SMILES: [CH2:1]([O:8][C@H](C)C(N[C@H]1C[C@@H](N2C=NC3C2=NC(N2CC[C@@H](NC(NC4C=NC=CC=4)=O)C2)=NC=3NCC(C2C=CC=CC=2)C2C=CC=CC=2)[C@H](O)[C@@H]1O)=O)[C:2]1C=CC=CC=1.[NH2:60][C@@H:61]1[CH2:65][CH2:64][N:63]([C:66]2[N:74]=[C:73]3[C:69]([N:70]=[CH:71][N:72]3[C@@H:75]3[CH2:79][C@H:78]([NH:80][C:81](=[O:92])[C@H](OCC4C=CC=CC=4)C)[C@@H:77]([OH:93])[C@H:76]3[OH:94])=[C:68]([NH:95][CH2:96][CH:97]([C:104]3[CH:109]=[CH:108][CH:107]=[CH:106][CH:105]=3)[C:98]3[CH:103]=[CH:102][CH:101]=[CH:100][CH:99]=3)[N:67]=2)[CH2:62]1.[N:110]1[CH:115]=[CH:114][CH:113]=[CH:112][C:111]=1[CH2:116][NH:117][C:118](=[O:120])O.C1(OC(=O)NC2C=NC=CC=2)C=CC=CC=1>>[C:98]1([CH:97]([C:104]2[CH:105]=[CH:106][CH:107]=[CH:108][CH:109]=2)[CH2:96][NH:95][C:68]2[N:67]=[C:66]([N:63]3[CH2:64][CH2:65][C@@H:61]([NH:60][C:118]([NH:117][CH2:116][C:111]4[CH:112]=[CH:113][CH:114]=[CH:115][N:110]=4)=[O:120])[CH2:62]3)[N:74]=[C:73]3[C:69]=2[N:70]=[CH:71][N:72]3[C@@H:75]2[CH2:79][C@H:78]([NH:80][C:81](=[O:92])[CH2:2][CH2:1][OH:8])[C@@H:77]([OH:93])[C@H:76]2[OH:94])[CH:99]=[CH:100][CH:101]=[CH:102][CH:103]=1
Reactant: C[C@@H](OCc1ccccc1)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](N)C4)nc32)[C@H](O)[C@@H]1O
Reactant: C[C@@H](OCc1ccccc1)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)Nc5cccnc5)C4)nc32)[C@H](O)[C@@H]1O
Reactant: O=C(O)NCc1ccccn1
Agent: O=C(Nc1cccnc1)Oc1ccccc1
Product: O=C(CCO)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)NCc5ccccn5)C4)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound was prepared analogously to (R)-2-benzyloxy-N-((1S,2R,3S,4R)-4-{6-(2,2-diphenyl-ethylamino)-2-[(R)-3-(3-pyridin-3-yl-ureido)-pyrrolidin-1-yl]-purin-9-yl}-2,3-dihydroxy-cyclopentyl)-propionamide (Example 181, step 5), by substituting N-{(1S,2R,3S,4R)-4-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-3-hydroxy-propionamide (Intermediate ZG) for (R)—N-{(1S,2R,3S,4R)-4-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-benzyloxy-propionamide (Example 181, step 4) and pyridin-2-ylmethyl-carbamic acid (Intermediate ZC) for pyridin-3-yl-carbamic acid phenyl ester (Intermediate ZB).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1.Cl.[NH2:13][C@H:14]1[CH2:19][C@@H:18]([OH:20])[C@H:17]([CH3:21])[CH2:16][CH2:15]1.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:20][C@H:18]1[C@H:17]([CH3:21])[CH2:16][CH2:15][C@@H:14]([NH:13][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=2)[CH2:19]1
Reactant: C[C@@H]1CC[C@@H](N)C[C@H]1O
Reactant: CSc1ncc(C#N)c(Cl)n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ncc(C#N)c(N[C@@H]2CC[C@@H](C)[C@H](O)C2)n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a stirring solution of 4-chloro-2-(methylthio)-pyrimidine-5-carbonitrile (310 mg, 1.670 mmol) and (1R,2R,5R)-5-amino-2-methylcyclohexanol hydrochloride (304 mg, 1.837 mmol; synthesis described herein) in DMF (2.4 mL) was added DIEA (0.873 ml. 5.01 mmol). The resulting mixture was stirred at 60° C. for 2 h. LCMS showed the reaction to be complete. The solvent was evaporated under reduced pressure and the residue diluted with 150 mL ethyl acetate and 50 mL water. The layers were separated and the aqueous phase was extracted with 75 mL ethyl acetate. The combined ethyl acetate layers were washed with brine (2×50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to an oil that solidified upon standing to afford 4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-2-(methylthio)pyrimidine-5-carbonitrile (418 mg, 1.503 mmol, 90% yield). MS (ESI) m/z 279.3 [M+1]+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][CH2:11][CH2:12]O)=[CH:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:33]N1C(=O)CCC1=O>C(Cl)Cl>[Br:33][CH2:12][CH2:11][CH2:10][C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][CH:2]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCCCc1csc2ccccc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCCc1csc2ccccc12
Yield: 84.6 %

Procedure:
Compound 80-3 (1.46 g) was dissolved in methylene chloride (20 ml), triphenylphosphine (2.19 g) and N-bromosuccinimide (1.49 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 3 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (1.64 g) as a pale-yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH:12]=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[S:14](N)([NH2:17])(=[O:16])=[O:15]>N1C=CC=CC=1>[CH:12]1[C:3]2[CH:4]=[CH:5][C:6]3[C:11](=[N:10][CH:9]=[CH:8][CH:7]=3)[C:2]=2[NH:1][S:14](=[O:16])(=[O:15])[N:17]=1
Reactant: Nc1c(C=O)ccc2cccnc12
Reactant: NS(N)(=O)=O
Solvent: c1ccncc1
Product: O=S1(=O)N=Cc2ccc3cccnc3c2N1
Yield: 82.1 %

Procedure:
8-Amino-quinoline-7-carbaldehyde 404 (100 mg, 0.58 mmol) and sulfamide (558 mg, 5.81 mmol) in pyridine (2 ml) was heated in a microwave at 140° C. for 2 h. After cooling, the mixture was concentrated in vacuo. The crude residue was dissolved in DCM and neutralised with citric acid. The resulting precipitate was collected by filtration and dried to give the title compound (111 mg, 82%) which was used in the next step without further purification.
Reaction SMILES: I[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[CH:10]=[N:11][C:12](=[O:16])[N:13]([CH3:15])[CH:14]=2)=[CH:4][C:3]=1[CH3:17].[F:18][C:19]1[CH:20]=[CH:21][C:22](B2OC(C)(C)C(C)(C)O2)=[C:23]2[C:27]=1[C@H:26]([O:28][C:29]1[CH:42]=[CH:41][C:32]3[C@H:33]([CH2:36][C:37]([O:39][CH3:40])=[O:38])[CH2:34][O:35][C:31]=3[CH:30]=1)[CH2:25][CH2:24]2.BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:17][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[N:11][C:12](=[O:16])[N:13]([CH3:15])[CH:14]=2)[CH:6]=[C:7]([CH3:8])[C:2]=1[C:22]1[CH:21]=[CH:20][C:19]([F:18])=[C:27]2[C:23]=1[CH2:24][CH2:25][C@H:26]2[O:28][C:29]1[CH:42]=[CH:41][C:32]2[C@H:33]([CH2:36][C:37]([O:39][CH3:40])=[O:38])[CH2:34][O:35][C:31]=2[CH:30]=1
Reactant: Cc1cc(-c2cnc(=O)n(C)c2)cc(C)c1I
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6cnc(=O)n(C)c6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from 5-(4-iodo-3,5-dimethylphenyl)-1-methylpyrimidin-2(1H)-one and methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 14): tR=1.08 min; Mass spectrum (ESI+): m/z=555 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[C:12]1([C:18]2[S:22][C:21](B(O)O)=[CH:20][CH:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[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>[C:12]1([C:18]2[S:22][C:21]([C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[NH:7][C:6](=[O:11])[CH2:5]4)=[CH:20][CH:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)c1ccc(-c2ccccc2)s1
Reactant: O=C1Cc2cc(Br)ccc2N1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C1Cc2cc(-c3ccc(-c4ccccc4)s3)ccc2N1
Temperature: 120 °C
Reaction time: 1 h
Yield: 29.1 %

Procedure:
To a solution of 5-bromooxindole (100 mg, 0.572 mmol) in dioxane/H2O (3 ml/1 ml) was added Pd(PPh3)4 (55 mg, 0.047 mmol), 5-phenylthiophene-2-boronic acid (106 mg, 0.519 mmol) and potassium carbonate (196 mg, 1.42 mmol). The mixture was stirred at 120° C. for 1 hour under microwave irradiation. The residue was extracted with CHCl3, and the organic layer was washed with H2O and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (CHCl3/MeOH) to give 5-(5-phenylthiophen-2-yl)indolin-2-one (44 mg) as a pale yellow solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[O:5]([CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20]O)[CH2:15]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(Cl)(Cl)Cl>[ClH:3].[Cl:3][CH2:20][CH:16]1[CH2:17][CH2:18][CH2:19][N:14]([CH2:13][CH2:12][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:15]1
Reactant: OCC1CCCN(CCOc2ccccc2)C1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cl
Product: ClCC1CCCN(CCOc2ccccc2)C1

Procedure:
A solution of thionyl chloride (1.7 ml) in chloroform (10 ml) was added dropwise with stirring to a solution of 1-(2-phenoxyethyl)piperidin-3-ylmethanol (5.0 g) in chloroform (70 ml) at 0°-5° C. After the addition the mixture was boiled under reflux for 2.5 hours. The solvent was removed under reduced pressure and the residue was triturated with ether and filtered to give 3-chloromethyl-1-(2-phenoxyethyl)piperidine hydrochloride, m.p. 125°-127° C.
Reaction SMILES: CO[CH:3](OC)[C:4](=[N:7][OH:8])[C:5]#[N:6].Cl.[C:12]([NH:16][NH2:17])([CH3:15])([CH3:14])[CH3:13].Cl.N>O.CO>[NH2:6][C:5]1[N:16]([C:12]([CH3:15])([CH3:14])[CH3:13])[N:17]=[CH:3][C:4]=1[N:7]=[O:8]
Reactant: CC(C)(C)NN
Reactant: COC(OC)C(C#N)=NO
Agent: Cl
Agent: N
Solvent: O
Solvent: CO
Product: CC(C)(C)n1ncc(N=O)c1N
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 57.4 %

Procedure:
To a flask having an inner volume of 25 ml and equipped with a stirring device, a thermometer and a reflux condenser were charged, 2.97 g (20 mmol) of 3,3-dimethoxy-2-hydroxyiminopropionitrile with a purity of 96.9% by weight synthesized in the same manner as in Example 1, 2.70 g (21 mmol) of t-butylhydrazine hydrochloride with a purity of 97% by weight, 1.4 ml of water, 6 ml of methanol and 1.3 ml (15 mmol) of conc. hydrochloric acid, and the mixture was reacted at 60 to 62° C. for 3 hours. After completion of the reaction, 5 ml of water was added to the mixture and the mixture was cooled up to 10° C. Then, 2.3 ml (37.9 mmol) of 28% by weight aqueous ammonia was gradually added dropwise to the mixture, and the resulting mixture was stirred for 30 minutes while maintaining the liquid temperature to 5° C. or lower. Precipitated crystals were collected by filtration, and then, the crystals were washed with 1.2 ml of cold water and 1.2 ml of cold methanol, and dried under reduced pressure to obtain 1.93 g of 5-amino-1-t-butyl-4-nitrosopyrazole (Isolation yield: 55.2%) as reddish orange solid with a purity of 96.2% by weight (absolute calibration curve method by high performance liquid chromatography).
Reaction SMILES: [N:1]1([C:8]([NH:10][C@@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][O:20][C:21](=[O:36])[C@@H:22]([NH2:35])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:26][CH:25]=1>C(OCC)(=O)C.CCCCCC>[CH3:19][O:20][C:21](=[O:36])[CH:22]([NH:35][C:12](=[O:14])[CH:11]([NH:10][C:8]([N:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1)=[O:9])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[CH:26][CH:25]=1
Reactant: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)C(Cc1ccc(OC(C)(C)C)cc1)NC(=O)C(CC(C)C)NC(=O)N1CCCCCC1
Yield: 81.2 %

Procedure:
A solution of the product from Example Z (2(S)-[(azepane-1-carbonyl)-amino]-4-methyl-pentanoic acid) (0.20 g, 0.78 mmol) and 2(S)-amino-3-(4-tert-butoxy-phenyl)-propionic acid methyl ester (Bachem, 0.247 g, 0.86 mmol) were coupled according to the procedure described in Example 42. The residue was passed through a plug of silica gel eluting with 70% ethyl acetate/hexane. The material obtained was purified by crystallization from hot hexane/ethyl acetate to give the title compound as a white solid (0.31 g, 81%), mp=96-99° C.
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]([CH2:11][CH2:12][O:13][CH2:14][CH3:15])[C:9]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[O:29][C:30]1[CH:31]=[N:32][C:33]([CH3:36])=[CH:34][CH:35]=1)[NH2:25].CN1CCCC1=O.C(=O)([O-])O.[Na+]>O>[CH2:14]([O:13][CH2:12][CH2:11][N:10]1[C:3]2[C:2]([NH:25][C:24]3[CH:26]=[CH:27][C:28]([O:29][C:30]4[CH:31]=[N:32][C:33]([CH3:36])=[CH:34][CH:35]=4)=[C:22]([CH3:21])[CH:23]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:8]=[C:9]1[C:16]1[O:17][CH:18]=[CH:19][CH:20]=1)[CH3:15]
Reactant: Cc1ccc(Oc2ccc(N)cc2C)cn1
Reactant: CCOCCn1c(-c2ccco2)cc2ncnc(Cl)c21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOCCn1c(-c2ccco2)cc2ncnc(Nc3ccc(Oc4ccc(C)nc4)c(C)c3)c21
Temperature: 140 °C
Reaction time: 2 h
Yield: 63.8 %

Procedure:
A mixture of 4-chloro-5-(2-ethoxyethyl)-6-(2-furyl)-5H-pyrrolo[3,2-d]pyrimidine (76 mg), 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (67 mg) and 1-methyl-2-pyrrolidinone (1.5 mL) was stirred at 140° C. for 2 hrs, poured into water (8 mL) and adjusted to pH 8 with saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate (20 mL×2) and the organic layers were combined and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=1:1→0:1). The object fraction was concentrated under reduced pressure. Diisopropyl ether-hexane was added to the residue, and the solid was collected by filtration and dried under reduced pressure at 60° C. to give the title compound (78 mg).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6](=[CH:12][CH:13]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=O.[N+:19]([CH2:22][CH3:23])([O-:21])=[O:20].C(N)C1C=CC=CC=1>C1(C)C=CC=CC=1>[N+:19]([C:22]([CH3:23])=[CH:1][C:3]1[CH:4]=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6](=[CH:12][CH:13]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([O-:21])=[O:20]
Reactant: CCOC(=O)c1ccc(C=O)cc1C(=O)OCC
Reactant: CC[N+](=O)[O-]
Solvent: Cc1ccccc1
Solvent: NCc1ccccc1
Product: CCOC(=O)c1ccc(C=C(C)[N+](=O)[O-])cc1C(=O)OCC

Procedure:
A mixture of one equivalent of diethyl 4-methylphthalate, two equivalents of N-bromosuccinimide and carbon tetrachloride is irradiated with a 500 W tungsten lamp for three hours. The mixture is filtered and the solution is shaken with excess sodium carbonate solution. Evaporation of the organic phase gives diethyl 4-formylphthalate. This aldehyde is combined with excess nitroethane, toluene and a catalytic amount of benzyl amine. The mixture is heated on a steam bath for 48 hours and evaporated in vacuo to give diethy 4-(2-nitropropen-1-yl)phthalate.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]2[O:12][CH2:13][O:14][C:8]=2[CH:7]=1)[CH:3]=[O:4].C1O[C:18]2C=CC=C[C:17]=2[O:16]1.O=CC(=C)C.C(OC(=O)C)(=O)C>>[C:17]([O:4][CH:3]=[C:2]([CH3:1])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]2[O:12][CH2:13][O:14][C:8]=2[CH:7]=1)(=[O:16])[CH3:18]
Reactant: CC(C=O)Cc1ccc2c(c1)OCO2
Reactant: c1ccc2c(c1)OCO2
Agent: C=C(C)C=O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OC=C(C)Cc1ccc2c(c1)OCO2

Procedure:
The production process (B) comprises the steps of (3) reacting 1,2-methylenedioxybenzene, methacrolein and acetic anhydride with each other to produce 1-acetoxy-2-methyl-3-(3,4-methylenedioxyphenyl)-1-propene; and (2) subjecting the obtained 1-acetoxy-2-methyl-3-(3,4-methylenedioxyphenyl)-1-propene to hydrolysis reaction or to transesterification reaction with an alcohol, followed by subjecting the resulting reaction mixture to distillative purification, to thereby adjust a content of 1-acetyl-3,4-methylenedioxybenzene as a by-product in the 2-methyl-3-(3,4-methylenedioxyphenyl)propanal to from 50 to 3000 ppm.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[C:15]([C:21]#[N:22])=[N:16][CH:17]=[C:18]([F:20])[CH:19]=1.[I:23]I.C(=O)=O.CC(C)=O>C1COCC1>[F:13][C:14]1[C:15]([C:21]#[N:22])=[N:16][CH:17]=[C:18]([F:20])[C:19]=1[I:23]
Reactant: II
Reactant: N#Cc1ncc(F)cc1F
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: N#Cc1ncc(F)c(I)c1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 21.1 %

Procedure:
THF (42 mL) and diisopropylamine (5.6 ml, 39.27 mmol) were combined and cooled at 0° C. then n-butyllithium (17.3 ml, 2.5 M in hexane) was added dropwise at 0° C., and stirred for another 30 minutes. The mixture was then cooled in a dry ice/acetone bath to about −78° C. and a solution of 3,5-difluoropicolinonitrile (5 g, 35.7 mmol) in THF (25 mL) was slowly added. After 30 minutes a solution of I2 (9 g, 35.7 mmol) in THF (35 mL) was added. The reaction was stirred for another 40 minutes at −78° C. in the dry ice/acetone bath, then warmed slightly and quenched with 50 mL sodium thiosulfate solution (10% aq) followed by dilution with water and EtOAc (300 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to a residue which was purified by silica column chromatography eluting with petroleum ether-ethyl acetate (5:1) to give 3,5-difluoro-4-iodopicolinonitrile as a solid (2 g, 21% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.58 (s, 1H).
Reaction SMILES: [C:1]1([C:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[OH:19]O>C(Cl)Cl>[C:1]1([C:7]23[O:19][CH:8]2[CH2:9][CH2:10][CH2:11][CH2:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1=C(c2ccccc2)CCCC1
Reactant: OO
Solvent: c1ccncc1
Solvent: ClCCl
Product: c1ccc(C23CCCCC2O3)cc1
Reaction time: 6 h
Yield: 90.7 %

Procedure:
In a 50 mL flask equipped with a magnetic stirrer, 7.9 g (50 mmol) of 1-phenylcyclohexene and 63 mg (0.25 mmol, 0.5 mol %) of MTO are dissolved in 1.5 Molar CH2Cl2 and to this solution is added 0.48 mL (6 mmol, 12 mol %) of pyridine followed by 7.6 mL (75 mmol; 1.5 equivalents) of 30% aqueous H2O2 added dropwise from a syringe (circa 5-10 minutes). During the H2O2 -addition the temperature is kept at 20-25° C. by applying an external cooling bath. The reaction is complete after 6 h and the aqueous phase is seperated and discarded. The remaining H2O2 in the yellow organic phase is decomposed to O2 and H2O by stirring with a catalytic amount of MnO2 (circa 10 mg). After the yellow color has completely disappeared the mixture is dried over Na2SO4, concentrated, and purified by filtration through a short column of silica gel which has been deactivated with NEt3. The column is washed with hexane/CH2Cl2 and concentration of the eluate affords 7.9 g (91%) of 1-phenyl-1,2-epoxycyclohexane as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH2:7][N:8]([C:22](=[O:26])[C@H:23]([CH3:25])[NH2:24])[CH:9]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[Na+].C(O)(=O)C.O=[C:38]([CH2:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:39]([O:41][CH2:42][CH3:43])=[O:40]>C(O)C.[Ni]>[C:1]([O:5][C:6](=[O:27])[CH2:7][N:8]([C:22](=[O:26])[C@H:23]([CH3:25])[NH:24][CH:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:44][CH2:45][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)[CH:9]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[CH2:11][CH2:10]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: COc1cc2c(cc1OC)C(N(CC(=O)OC(C)(C)C)C(=O)[C@H](C)N)CC2
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Agent: [Ni]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(CCc1ccccc1)N[C@@H](C)C(=O)N(CC(=O)OC(C)(C)C)C1CCc2cc(OC)c(OC)cc21
Yield: 33.3 %

Procedure:
L-Alanyl-N-(5,6-dimethyloxyindan-1-yl)glycine tert-butyl ester (4.0 g) is dissolved in 80 ml of ethanol, and 0.77 g of sodium acetate, 4.0 g of acetic acid, 4.0 g of ethyl 2-oxo-4-phenyl-butyrate, 12 g of molecular sieve 3A and 6.0 g of Raney nickel are added. Thereafter, the reaction and treatment are carried out as in Example 2 to give 2.0 g of N-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-N-(5,6-dimethoxyindan-1-yl)glycine tert-butyl ester as slightly yellow oil.
Reaction SMILES: [Cl:1][CH:2]([F:16])[C:3]([F:15])([F:14])[O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1.[CH2:17]([NH2:25])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH2:24].[OH-:26].[K+]>C(Cl)CCl>[Cl:1][CH:2]([F:16])[C:3]([F:15])([F:14])[O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][NH:25][C:9](=[O:10])[C:8]2[CH:7]=[CH:6][C:5]([O:26][C:3]([F:14])([F:15])[CH:2]([F:16])[Cl:1])=[CH:13][CH:12]=2)=[O:10])=[CH:7][CH:6]=1
Reactant: [OH-]
Reactant: NCCCCCCCN
Reactant: O=C(Cl)c1ccc(OC(F)(F)C(F)Cl)cc1
Agent: [K+]
Solvent: ClCCCl
Product: O=C(NCCCCCCCNC(=O)c1ccc(OC(F)(F)C(F)Cl)cc1)c1ccc(OC(F)(F)C(F)Cl)cc1

Procedure:
m.p. 153°-154° C., 16.0 g., was prepared as in Example 16 using 4-(2-chloro-1,1,2-trifluoroethoxy)benzoyl chloride (from 23.0 g. of the corresponding acid as in Example 16) in 150 ml. of ethylene dichloride, 5.8 g. of 1,7-heptanediamine, 200 ml. of 10% aqueous potassium hydroxide solution, 500 ml. of ethylene dichloride and recrystallization from acetonitrile using decolorizing charcoal.