Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][O:12][N:13]=[C:14]([C:45](=O)[CH2:46]Br)[C:15]([NH:17][CH:18]1[C:43](=[O:44])[N:20]2[C:21]([C:27]([O:29][CH:30]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:28])=[C:22]([CH:25]=[CH2:26])[CH2:23][S:24][C@H:19]12)=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:49][C:50]([NH2:52])=[S:51].C([O-])(=O)C.[Na+]>O1CCCC1.O>[CH2:1]([O:8][C:9]([CH2:11][O:12][N:13]=[C:14]([C:45]1[N:49]=[C:50]([NH2:52])[S:51][CH:46]=1)[C:15]([NH:17][CH:18]1[C:43](=[O:44])[N:20]2[C:21]([C:27]([O:29][CH:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)=[O:28])=[C:22]([CH:25]=[CH2:26])[CH2:23][S:24][C@H:19]12)=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(N)=S
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OCc3ccccc3)C(=O)CBr)[C@H]2SC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OCc3ccccc3)c3csc(N)n3)[C@H]2SC1
Temperature: 35 °C
Reaction time: 4 h
Yield: 82.6 %

Procedure:
To a solution of benzhydryl 7-(2-benzyloxycarbonylmethoxyimino-4-bromo-3-oxobutyramido)-3-vinyl-3-cephem-4-carboxylate (2.5 g) in tetrahydrofuran (25 ml) was added a solution of thiourea (0.78 g) and sodium acetate (0.34 g) in water (10 ml), followed by stirring at 35° C. for 4 hours. The reaction mixture was extracted with ethyl acetate, and the extract was washed with a saturated aqueous sodium chloride and dried over magnesium sulfate. Removal of the solvent gave benzhydryl 7-[2-benzyloxycarbonylmethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (2.0 g).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[ClH:8].Cl.[CH3:10][C:11]1[C:16]([NH2:17])=[CH:15][CH:14]=[CH:13][C:12]=1[NH:18][C:19]1[CH2:23][CH2:22][CH2:21][N:20]=1>>[ClH:8].[CH3:10][C:11]1[C:16]([NH:17][C:5](=[O:7])[CH3:6])=[CH:15][CH:14]=[CH:13][C:12]=1[NH:18][C:19]1[CH2:23][CH2:22][CH2:21][N:20]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(N)cccc1NC1=NCCC1
Agent: Cl
Product: CC(=O)Nc1cccc(NC2=NCCC2)c1C

Procedure:
The title compound (2.5 g) was prepared by the method of Example 17 using acetic anhydride and 3.0 g of the product aniline of Example 45. Structure assignment was supported by the nmr spectrum and by elemental analysis.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][NH2:8])[CH2:2]1.C([O:11][C:12](=O)[C:13]([F:16])([F:15])[F:14])C>CO>[F:14][C:13]([F:16])([F:15])[C:12]([NH:8][CH2:7][CH:3]1[O:4][CH2:5][CH2:6][NH:1][CH2:2]1)=[O:11]
Reactant: CCOC(=O)C(F)(F)F
Reactant: NCC1CNCCO1
Solvent: CO
Product: O=C(NCC1CNCCO1)C(F)(F)F
Temperature: 22 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of morpholin-2-ylmethylamine (3.1 g) in methanol (70 ml) under nitrogen was added an ethereal solution of ethyl-α,α,α-trifluoroacetate (5 ml in 20 ml ether) which had been washed with saturated aqueous sodium bicarbonate, water and brine, and dried. The mixture was stirred for 30 min at 22° C. before removal of all volatiles in vacuo. The residue was dissolved in methanol (10 ml) and the volatiles again removed in vacuo to give the title compound as a white crunchy foam (4.9 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[F:19][C:20]1[C:28]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23]>>[O:15]=[C:13]1[NH:12][C:8]2=[N:9][CH:10]=[CH:11][C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:22](=[O:23])[C:21]4[CH:25]=[CH:26][CH:27]=[C:28]([O:29][C:30]([F:31])([F:32])[F:33])[C:20]=4[F:19])[CH:18]=[CH:17][CH:16]=3)=[C:7]2[NH:14]1
Reactant: O=C(Cl)c1cccc(OC(F)(F)F)c1F
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Product: O=C(Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1)c1cccc(OC(F)(F)F)c1F
Yield: 11.7 %

Procedure:
Method H was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one and 2-fluoro-3-trifluoromethoxy-benzoyl chloride to afford the title compound (11 mg, 11.7%). 1H-NMR (δ, ppm, DMSO-d6): 6.50 (d, 1H, HPy,5, J=5.9 Hz), 6.91-6.94 (m, 1H, Harom), 7.43-7.46 (m, 3H, Harom), 7.53-7.55 (m, 2H, Harom), 7.70-7.74 (m, 1H, Harom), 7.81 (d, 1H, HPy,6, J=5.9 Hz), 10.70 (s, 1H, NHamide), 11.18 (s, 1H, NHPy7), 11.39 (s, 1H, NHPy9). LC-MS, tR=4.62 minutes, m/z: 449.08 (M+H)+, calculated for C20H13N4O4F4. HRMS (EI): m/z [M+H] calculated for C20H13N4O4F4: 449.0873; found: 449.0879.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12](CC3C=CC(CCC(O)=O)=CC=3)[C:11]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:10]=3[N:9]=2)=[C:4]([O:31][CH2:32]C2CCCC2)[CH:3]=1.ClC1C=CC(C2N(CC3C=C(C=CC=3)C(O)=O)C3C=C(F)C(F)=CC=3N=2)=C(OCC2CCCC2)C=1.[CH3:73][O:74][C:75](=[O:85])[CH2:76][C:77]1[CH:82]=[CH:81][C:80]([CH2:83]Br)=[CH:79][CH:78]=1>>[CH3:73][O:74][C:75](=[O:85])[CH2:76][C:77]1[CH:78]=[CH:79][C:80]([CH2:83][N:12]2[C:11]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[O:31][CH3:32])=[CH:81][CH:82]=1
Reactant: COC(=O)Cc1ccc(CBr)cc1
Reactant: O=C(O)CCc1ccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)cc1
Agent: O=C(O)c1cccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)c1
Product: COC(=O)Cc1ccc(Cn2c(-c3ccc(Cl)cc3OC)nc3cc(F)c(F)cc32)cc1

Procedure:
The title compound was prepared in analogy to Example 19, intermediate b, from 2-(4-chloro-2-methoxy-phenyl)-5,6-difluoro-1H-benzoimidazole (Example 19, intermediate c) and (4-bromomethyl-phenyl)-acetic acid methyl ester (CAS Reg. No. 7398-42-7). Brown sticky solid (15%). MS (Turbo Spray): m/z=457.4 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C@H:13]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][CH2:35]Cl)=[CH:27][CH:26]=3)[C@H:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C@H:13]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][N:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)=[CH:27][CH:26]=3)[C@H:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: ClCCCCOc1ccc([C@H]2c3ccc(OCc4ccccc4)cc3OC[C@H]2c2ccccc2)cc1
Product: c1ccc(COc2ccc3c(c2)OC[C@@H](c2ccccc2)[C@H]3c2ccc(OCCCCN3CCOCC3)cc2)cc1

Procedure:
From (+,−) cis 7-Benzyloxy-4-[4-(4-chlorobutyloxy)-phenyl]-3-phenyl-chroman (300 mg, 0.60 mmol) and morpholine (240 mg, 3 mmol). Reaction time 4 days. The evaporated product was crystallised from ether-petrolether, and further purified by silica column chromatography using methanol-methylene chloride (1+19) as eluent.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][N:3]=1.CO[CH:10](OC)[N:11]([CH3:13])[CH3:12]>CN(C=O)C>[CH3:10][N:11]([CH3:13])/[CH:12]=[CH:1]/[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][N:3]=1
Reactant: COC(OC)N(C)C
Reactant: Cc1ccncn1
Solvent: CN(C)C=O
Product: CN(C)/C=C/c1ccncn1
Temperature: 140 °C
Reaction time: 24 h
Yield: 95.1 %

Procedure:
A mixture of 10 g of 4-methylpyrimidine, 38 g of N,N-dimethylformamide dimethylacetal (DMFDMA) and 46.6 g of DMF was stirred in a sealed tube at 140° C. for 24 hours. The reaction solution was cooled and the solvent was distilled off under reduced pressure to provide 15.08 g (yield: 95%) of the title compound as brown crystal.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]#[N:18])=[CH:14][CH:15]=3)[CH2:10][O:9]2)=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.[CH:27](OC)=[O:28]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:27]=[O:28])[C:16]3[C:11](=[CH:12][C:13]([C:17]#[N:18])=[CH:14][CH:15]=3)[CH2:10][O:9]2)=[CH:4][CH:3]=1
Reactant: COC=O
Reactant: N#Cc1ccc2c(c1)COC2c1ccc(F)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ccc2c(c1)COC2(C=O)c1ccc(F)cc1
Temperature: -40 °C
Reaction time: 1 h
Yield: 48.6 %

Procedure:
A solution of 1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile (2.4 g, 10 mmol) in THF (15 mL) was added to a solution of LDA (11 mmol) in THF (25 mL) at −78° C. under an atmosphere of nitrogen. The mixture was allowed to warm to −40° C. during 45 min. Freshly distilled methyl formate (0.75 mL, 12 mmol) was added at this temperature, and stirring was continued for 1 h while warming to 0° C. Then the mixture was poured into ice/saturated ammonium chloride solution, and extracted with Et2O (3×100 mL). The organic extracts were washed with brine, dried and evaporated. Silica gel chromatography (heptane, EtOAc 4:1) of the residue gave the product (1.3 g, 50%). 1H NMR (CDCl3) δ 5.35 (2H, s); 7.10 (2H, t, J=9.0 Hz); 7.50 (1H, dd, J=5.2 and 9.0 Hz); 7.57 (1H, s); 7.60 (1H, d, J=8.0 Hz); 7.70 (1H, d, J=8.0 Hz).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[C:11]2[C:6]=1[CH2:7][CH2:8][CH2:9][CH2:10]2)(=[O:3])[CH3:2].S([O-])([O-])(=O)=[O:18].[Mg+2].[Mn]([O-])(=O)(=O)=O.[K+]>CC(C)=O>[C:1]([NH:4][C:5]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[C:11]2[C:6]=1[C:7](=[O:18])[CH2:8][CH2:9][CH2:10]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(F)c(F)c2c1CCCC2
Reactant: O=S(=O)([O-])[O-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CC(C)=O
Product: CC(=O)Nc1cc(F)c(F)c2c1C(=O)CCC2
Reaction time: 1 h

Procedure:
To a solution of the compound obtained in (6) above (810 mg) in 30 ml of acetone was added 3 ml of 15% aqueous solution of magnesium sulfate. 1.17 gm of potassium permanganate was slowly added to the mixture while stirring. After 1 hour, the reaction product was extracted with chloroform, the extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain 806 mg of the title compound. NMR(CDCl3) δ: 2.05-2.17(2H, m), 2.23(3H, s), 2.68(2H, t, J=5.85 Hz), 3.00(2H, t, J=5.85 Hz), 8.61(1H, dd, J=7.8 Hz,13.2 Hz), 12.1-12.23(1H, br s).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:10])[CH:9]=1)[C:5]#[N:6].[CH3:11][S:12](Cl)(=[O:14])=[O:13]>C(Cl)Cl.N1C=CC=CC=1>[Br:10][C:8]1[CH:9]=[C:2]([NH:1][S:12]([CH3:11])(=[O:14])=[O:13])[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=1
Reactant: N#Cc1cc(N)cc(Br)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc(Br)cc(C#N)c1
Reaction time: 6.5 h
Yield: 88 %

Procedure:
To a stirring solution of 502 mg of 3-amino-5-bromobenzonitrile in 6 mL of CH2Cl2 and 2 mL of pyridine at 0° C. was added 0.2 mL (2.57 mmol) of MsCl at 0° C. The ice bath was removed and stirring was continued at r.t. for 6.5 h. The solution was concentrated and EtOAc and 20 mL of H2O were added. The organic layer was washed with 15 mL of brine and water, dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (35% EtOAc/hexanes) provided 617 mg of N-(3-bromo-5-cyanophenyl)methanesulfonamide as a colorless solid in 88% yield.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=O.[CH3:13][C:14]([S@:17]([NH2:19])=[O:18])([CH3:16])[CH3:15]>ClCCl.S([O-])([O-])(=O)=O.[Cu+2]>[C:14]([S@:17](/[N:19]=[CH:1]/[C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=[O:18])([CH3:16])([CH3:15])[CH3:13]
Reactant: COC(=O)c1cccc(C=O)c1
Reactant: CC(C)(C)[S@](N)=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: COC(=O)c1cccc(/C=N/[S@](=O)C(C)(C)C)c1
Reaction time: 8 h
Yield: 14.3 %

Procedure:
A suspension of 3.0 g of methyl 3-formylbenzoate, 2.25 g of (R)-2-methyl-2-propanesulfinamide, and 6.0 g of copper (II) sulfate in 50 ml of dichloromethane was stirred overnight. The reaction mixture was filtered over Celite and the solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 700 mg of methyl 3-[(E)-{[(R)-tert-butylsulfinyl]imino}methyl]benzoate.
Reaction SMILES: C([O:8][C:9](=[O:24])[CH2:10]/[CH:11]=[CH:12]/[CH2:13][C:14]([O:16]CC1C=CC=CC=1)=[O:15])C1C=CC=CC=1>[OH-].[Na+]>[C:14]([OH:16])(=[O:15])[CH2:13]/[CH:12]=[CH:11]/[CH2:10][C:9]([OH:24])=[O:8]
Reactant: O=C(C/C=C/CC(=O)OCc1ccccc1)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C/C=C/CC(=O)O
Yield: 34.7 %

Procedure:
A suspension of 1.62 grams (5.00 mmoles) of dibenzyl-trans-hex-3-ene-1,6-dioate in 25 ml of 10% sodium hydroxide solution is heated to reflux for 12 hours. At the end of this time the reaction mixture is cooled and extracted twice, each with 15 ml of chloroform. The aqueous phase is acidified with dilute hydrochloric acid and extracted three times with 50 ml portions of ether. The ether extracts are combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Recrystallization of the yellowish residual oil from aqueous methanol yields 0.25 gram of trans-hex-3-ene-1,6-dioic acid, m.p.=197°-198° C. (Lit. m.p.=199°). The melting point of a mixture of the reaction product and an authentic sample obtained from Aldrich Chemical Co. remains unchanged.
Reaction SMILES: C([Sn](=O)CCCC)CCC.C[Si]([N:15]=[N+:16]=[N-:17])(C)C.FC(F)(F)C(C1C=CC(C#N)=CC=1)=CC1C=CC2C(C)(C)CCC(C)(C)C=2C=1.[F:46][C:47]([F:74])([F:73])[C:48]([C:65]1[CH:72]=[CH:71][C:68]([C:69]#[N:70])=[CH:67][CH:66]=1)=[CH:49][C:50]1[C:59]([CH3:60])=[CH:58][C:57]2[C:56]([CH3:62])([CH3:61])[CH2:55][CH2:54][C:53]([CH3:64])([CH3:63])[C:52]=2[CH:51]=1>C1(C)C=CC=CC=1>[F:46][C:47]([F:73])([F:74])[C:48]([C:65]1[CH:66]=[CH:67][C:68]([C:69]2[NH:70][N:17]=[N:16][N:15]=2)=[CH:71][CH:72]=1)=[CH:49][CH:50]1[C:59]([CH3:60])=[CH:58][C:57]2[C:56]([CH3:62])([CH3:61])[CH2:55][CH2:54][C:53]([CH3:64])([CH3:63])[C:52]=2[CH2:51]1
Reactant: Cc1cc2c(cc1C=C(c1ccc(C#N)cc1)C(F)(F)F)C(C)(C)CCC2(C)C
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CC1(C)CCC(C)(C)c2cc(C=C(c3ccc(C#N)cc3)C(F)(F)F)ccc21
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: CC1=CC2=C(CC1C=C(c1ccc(-c3nnn[nH]3)cc1)C(F)(F)F)C(C)(C)CCC2(C)C
Temperature: 110 °C
Yield: 49 %

Procedure:
Dibutyl tin oxide (15.1 mg, 10% mol) and trimethylsilyl azide (0.16 ml, 1.22 mmol), are added successively to a solution of the (E) compound 4-[1-trifluoromethyl-2-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)-1-ethenyl]benzonitrile (0.24 g, 0.60 mmol) in anhydrous toluene (1.25 ml). The reaction medium is heated for 16 hours at reflux (110° C.) under an atmosphere of argon and with magnetic stirring. The mixture is purified by flash chromatography on silica (eluent CH2Cl2 then MeOH:CH2Cl2=5:95) to obtain, after evaporation and washing with pentane and drying, 0.13 g of a white solid, compound (E) 5-[4-[1-trifluoromethyl-2-(5,6,1,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)-1-ethenyl]phenyl]-1H-tetrazole (compound CB63237) (yield=49%).
Reaction SMILES: C([O:3][P:4]([CH2:9][NH:10][C:11](=[O:38])[CH2:12][CH2:13][C:14]([CH3:37])=[CH:15][CH2:16][C:17]1[C:18]([O:30]CC[Si](C)(C)C)=[C:19]2[C:23](=[C:24]([CH3:28])[C:25]=1[O:26][CH3:27])[CH2:22][O:21][C:20]2=[O:29])(=[O:8])[O:5]CC)C.C[Si](Br)(C)C.N1C(C)=CC=CC=1C>C(#N)C>[OH:30][C:18]1[C:17]([CH2:16][CH:15]=[C:14]([CH3:37])[CH2:13][CH2:12][C:11]([NH:10][CH2:9][P:4](=[O:3])([OH:8])[OH:5])=[O:38])=[C:25]([O:26][CH3:27])[C:24]([CH3:28])=[C:23]2[C:19]=1[C:20](=[O:29])[O:21][CH2:22]2
Reactant: CCOP(=O)(CNC(=O)CCC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)OCC
Agent: C[Si](C)(C)Br
Solvent: CC#N
Solvent: Cc1cccc(C)n1
Product: COc1c(C)c2c(c(O)c1CC=C(C)CCC(=O)NCP(=O)(O)O)C(=O)OC2
Reaction time: 8 h
Yield: 9 %

Procedure:
To a solution of ({6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoylamino}-methyl)-phosphonic acid diethyl ester (40 mg, 0.07 mmol) in acetonitrile (1 mL) was added TMSBr (91 μL, 0.7 mmol) followed by 2,6-lutidine (81.5 μL, 0.7 mmol). The reaction was allowed to proceed overnight when it was completed as judged by LCMS. The reaction mixture was quenched with MeOH and concentrated to dryness. The residue was purified by preparative reverse-phase HPLC to afford 2.6 mg (9%) of desired product as a white solid. 1H NMR (300 MHz, CD3OD) δ 1.67 (s, 3H), 2.17 (m, 5H), 2.30-2.46 (m, 2H), 2.80-2.86 (m, 2H), 3.55 (m, 2H), 3.82 (s, 3H), 5.26 (s, 3H) ppm; 31P (121.4 MHz, CD3OD) δ 10.27 ppm; MS (m/z) 412 [M−H]−, 414 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([NH:8][C:9]2[C:10](=[CH:14][C:15]([Br:18])=[CH:16][CH:17]=2)[C:11](O)=O)=[CH:6][CH:5]=[N:4]1)[CH3:2].O=P(Cl)(Cl)[Cl:21].[NH4+].[OH-]>>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:10]([C:11]([Cl:21])=[C:6]2[CH:5]=[N:4]1)=[CH:14][C:15]([Br:18])=[CH:16][CH:17]=3)[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCn1nccc1Nc1ccc(Br)cc1C(=O)O
Agent: [NH4+]
Agent: [OH-]
Product: CCn1ncc2c(Cl)c3cc(Br)ccc3nc21
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A mixture of N-(1-ethylpyrazol-5-yl)-5-bromoanthranilic acid (12.6 g) and POCl3 (30 ml) was refluxed overnight. The reaction mixture was poured into ice-water (500 ml), stirred for 20 minutes, and then NH4OH was added until a pH of 8-10 was obtained. The mixture was stirred for 0.5 hours and then the solid which formed was collected by filtration. The solid was dissolved in CH2Cl2, dried over MgSO4 and purified by column chromatography on silica gel eluting with 30% hexane/ethyl acetate to afford 6.5 g of 1-ethyl-4-chloro-6-bromo-1H-pyrazolo[3,4-b]quinoline, m.p. 117°-118° C.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[CH:20]=[CH:19][CH:18]=[CH:17][C:4]=1[CH2:5][CH:6]([NH:13][CH2:14][CH2:15][CH3:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:21](OCC)(OCC)(OCC)[CH3:22]>>[ClH:1].[CH3:21][C:22]1[N:13]([CH2:14][CH2:15][CH3:16])[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][C:4]2[CH:17]=[CH:18][CH:19]=[CH:20][C:3]=2[N:2]=1
Reactant: CCCNC(Cc1ccccc1N)c1ccccc1
Reactant: CCOC(C)(OCC)OCC
Agent: Cl
Product: CCCN1C(C)=Nc2ccccc2CC1c1ccccc1

Procedure:
90 ml of Ethanolic hydrogen chloride is added dropwise to a stirred suspension of 9.00 g of 2-amino-α-phenyl-N-propylphenethylamine in 90 ml of triethyl orthoacetate. After complete addition, the mixture is refluxed for 2 hours. The ethanol is slowly distilled from the mixture and additional ethanolic hydrogen chloride (50 ml) is added. The mixture is then distilled to a volume of 20-30 ml. 100 ml of ether is added causing precipitation of the hydrochloride salt. The salt is collected, washed with ether (100 ml) and dried to give white crystals, mp 272°-275° C. of 4,5-dihydro-2-methyl-4-phenyl-3-propyl-3H-1,3-benzodiazepine hydrochloride.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:12]2[N:13]([CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)[N:14]=[C:15]3[C:11]=2[CH2:10][CH2:9][NH:8][CH2:17][CH2:16]3)=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C3CCCCC3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Reactant: OB(O)c1ccc(Cl)cc1
Product: Clc1ccc(-c2c3c(nn2C2CCCCC2)CCNCC3)cc1
Yield: 52.7 %

Procedure:
The title compound (48 mg) was prepared as in Example 177, Steps C and D, using 129 mg of 2-cyclohexyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 177, Step B) and 173 mg of 4-chlorophenylboronic acid. MS (ESI): exact mass calculated for C19H24ClN3, 329.17. found, m/z 330.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.60-7.53 (m, 2H), 7.36-7.27 (m, 2H), 3.94-3.83 (m, 1H), 3.43-3.36 (m, 2H), 3.34-3.26 (m, 2H), 3.2-3.12 (m, 2H), 2.80-2.72 (m, 2H), 1.98-1.76 (m, 6H), 1.67 (br s, 1H), 1.32-1.17 (m, 3H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][OH:7].[Cl:8][C:9]1[C:14](Cl)=[N:13][CH:12]=[CH:11][N:10]=1>>[Cl:8][C:9]1[C:14]([O:7][CH2:6][C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[N:13][CH:12]=[CH:11][N:10]=1
Reactant: Clc1nccnc1Cl
Reactant: OCc1ccco1
Product: Clc1nccnc1OCc1ccco1
Yield: 68 %

Procedure:
The title compound was prepared according to the procedure described in Example 1, Step 1, starting from 2-furanmethanol (4.18 g, 42.7 mmol), 2,3-dichloropyrazine (2.05 g, 13.8 mmol) and KO-t-BuO (1.82 g, 16.2 mmol). The product, which was obtained as a yellowish oil in 68% yield, was used directly in the next step.
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:6]([O:8][CH3:9])=[O:7])[CH2:5][CH2:4]1.ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O>ClCCl.CC1(C)N([O])C(C)(C)CCC1>[CH:2]([C:3]1([C:6]([O:8][CH3:9])=[O:7])[CH2:5][CH2:4]1)=[O:1]
Reactant: COC(=O)C1(CO)CC1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Solvent: ClCCl
Product: COC(=O)C1(C=O)CC1
Temperature: -5 °C
Reaction time: 0.33 h
Yield: 120.5 %

Procedure:
Methyl 1-(hydroxymethyl)cyclopropanecarboxylate (16.0 g, 123.07 mmol) is dissolved in dichloromethane (320 mL) and the mixture is cooled to −5° C. Trichloroisocyanuric acid (29.1 g, 125.5 mmol) is added portionwise followed by the addition of TEMPO (1.9 g, 12.3 mmol). The reaction mixture is stirred at −5° C. for 20 min, allowed to warm to RT, and stirred for 20 min. The mixture is filtered through a pad of CELITE® and diluted with dichloromethane (500 mL). The solution is washed with saturated Na2CO3 (300 mL), 1 N HCl (300 mL), brine (300 mL), and saturated ammonium chloride (3×200 mL). The organic portion is dried over MgSO4, filtered, and concentrated under reduced pressure to obtain 19 g of the title compound, still containing dichloromethane (theoretical 15.75 g). The material is used as is in the next reaction. 1H NMR (400 MHz, CDCl3); δ 1.7-1.6 (m, 4H), 3.81 (s, 3H), 10.38 (s, 1H).
Reaction SMILES: C([N:8]1[C:16]2[C:15]3=[N:17][N:18]=[CH:19][N:14]3[C:13](=[O:20])[N:12]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:11]=2[N:10]=[CH:9]1)C1C=CC=CC=1.Cl>C(O)(=O)C.[OH-].[Pd+2].[OH-]>[CH2:21]([N:12]1[C:11]2[N:10]=[CH:9][NH:8][C:16]=2[C:15]2=[N:17][N:18]=[CH:19][N:14]2[C:13]1=[O:20])[CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCn1c(=O)n2cnnc2c2c1ncn2Cc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CC(=O)O
Product: CCCCCn1c(=O)n2cnnc2c2[nH]cnc21
Reaction time: 8 h
Yield: 65.8 %

Procedure:
To a mixture of 9-benzyl-6-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[3,4-i]purin-5-one (0.25 g, 0.74 mmol) in acetic acid (20 mL) was added palladium hydroxide (0.20 g, 1.4 mmol) under N2. The mixture was shaken under H2 at 60 psi overnight. Since the reaction was not complete, more palladium hydroxide (0.2 g, 1.4 mmol) and concentrated HCl (1 mL) were added. The resulting mixture was shaken under H2 at 60 psi overnight. The reaction solution was filtered and the filtrate was concentrated under vacuum to provide the product as a white solid (0.12 g, 65.6%). LCMS calculated for C11H15N6O (M+H): 247.1; found: 247.1.
Reaction SMILES: [CH2:1]([C:3]1[C:8](/[CH:9]=[CH:10]/[O:11]C)=[CH:7][CH:6]=[CH:5][C:4]=1[C:13]1[N:17]=[C:16]([C:18]2[CH:19]=[CH:20][C:21]([CH2:26][CH:27]([CH3:29])[CH3:28])=[C:22]([CH:25]=2)[C:23]#[N:24])[S:15][N:14]=1)[CH3:2].Cl>O1CCCC1>[CH2:1]([C:3]1[C:8]([CH2:9][CH:10]=[O:11])=[CH:7][CH:6]=[CH:5][C:4]=1[C:13]1[N:17]=[C:16]([C:18]2[CH:19]=[CH:20][C:21]([CH2:26][CH:27]([CH3:28])[CH3:29])=[C:22]([CH:25]=2)[C:23]#[N:24])[S:15][N:14]=1)[CH3:2]
Reactant: CCc1c(/C=C/OC)cccc1-c1nsc(-c2ccc(CC(C)C)c(C#N)c2)n1
Agent: Cl
Solvent: C1CCOC1
Product: CCc1c(CC=O)cccc1-c1nsc(-c2ccc(CC(C)C)c(C#N)c2)n1
Temperature: 70 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
To a solution of 5-(3-{2-ethyl-3-[(E)-2-(methyloxy)ethenyl]phenyl}-1,2,4-thiadiazol-5-yl)-2-(2-methylpropyl)benzonitrile (D61) (500 mg) in tetrahydrofuran (THF) (20 mL) stirred under nitrogen at room temperature was added 2M hydrochloric acid (1.239 mL). The reaction mixture was stirred at 70° C. for 2 h. After cooling the reaction, the solution was condensed under reduced pressure to give 5-{3-[2-ethyl-3-(2-oxoethyl)phenyl]-1,2,4-thiadiazol-5-yl}-2-(2-methylpropyl)benzonitrile (D62) (483 mg), which was used directly in the next step without further purification. MS (ES): C23H23N3OS requires 389. found 390.1 (M+H+).