Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:4][C:5]2[CH:12]=[CH:11][C:10]([C:13]([OH:15])=[O:14])=[CH:9][C:6]=2[C:7]=1[CH3:8].[N+](=[CH2:18])=[N-].C(O)(=O)C>CO>[CH3:18][O:14][C:13]([C:10]1[CH:11]=[CH:12][C:5]2[O:4][C:3]([CH2:2][OH:1])=[C:7]([CH3:8])[C:6]=2[CH:9]=1)=[O:15]
Reactant: Cc1c(CO)oc2ccc(C(=O)O)cc12
Reactant: C=[N+]=[N-]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1ccc2oc(CO)c(C)c2c1

Procedure:
A solution of 2-hydroxymethyl-3-methylbenzofuran-5-carboxylic acid (0.69 g) in methanol (250 ml) was treated with an excess of an ethereal solution of diazomethane. The solution was allowed to stand for 11/2 hours at 0° and then the excess of diazomethane was decomposed by dropwise addition of acetic acid until no further effervescence was apparent. The solution was evaporated and the residue was dissolved in ether. The solution was washed with sodium bicarbonate, dried (Na2SO4) and evaporated to give a quantitative yield of 2-hydroxymethyl-3-methylbenzofuran-5-carboxylic acid methyl ester, m.p. 96°-98° (from ethyl acetate/petrol).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1.[Br:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34]Br>CC#N.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][C:6]1[N:7]([CH2:34][C:33]2[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=2[Br:31])[CH:8]=[N:9][CH:10]=1
Reactant: BrCc1ccccc1Br
Reactant: COC(=O)CCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)CCc1cncn1Cc1ccccc1Br
Temperature: 25 °C

Procedure:
To a solution of 3-(1-trityl-1H-imidazol-4-yl)propanoic acid methyl ester (5.0 g, 12.6 mmol) in CH3CN (80 mL) is added a solution of 2-bromobenzylbromide (2.84 g, 11.4 mmol) in CH3CN (20 mL). The resulting clear solution is stirred at ambient temperature over the weekend. The mixture is concentrated and the remaining oil is taken up in 85 mL methanol and heated up at 70° C. for 2 h. Then the mixture is concentrated to give a yellow oil, which is taken up in EtOAc and washed with saturated aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, and concentrated to yield a viscous oil. The crude reaction mixture is subjected to flash chromatography (silica gel) eluting with MeOH:CH2Cl2 to give the desired compound. MS (ESI) m/z 323 (M+H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:10]([C:19]([OH:21])=O)[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH2:35])=[CH:32][CH:31]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C.O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[C:10]([C:19]([NH:35][CH2:34][C:33]3[CH:36]=[CH:37][C:30]([O:29][CH3:28])=[CH:31][CH:32]=3)=[O:21])[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: COc1ccc(CN)cc1
Reactant: CCn1ncc2c(-c3cncc(C)c3)c(C(=O)O)c(-c3ccccc3)nc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CCn1ncc2c(-c3cncc(C)c3)c(C(=O)NCc3ccc(OC)cc3)c(-c3ccccc3)nc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 65.9 %

Procedure:
To a stirred solution of 1-ethyl-4-(5-methyl-3-pyridyl)-6-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (18 mg) and 4-methoxybenzyl amine (10.3 mg) in DMF (1 ml) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (28.6 mg) and N,N-dimethylaminopyridine (9.2 mg). The reaction mixture was stirred at room temperature for 18 hours and at 50° for 5 hours. After cooling, the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with diluted HCl, water, saturated aqueous NaHCO3, water, brine, dried over anhydrous MgSO4 and concentrated in vacuo. The crystalline residue was recrystallized from EtOAc and n-hexane to give 1-ethyl-N-(4-methoxybenzyl)-4-(5-methyl-3-pyridyl)-6-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (15.8 mg) as a colorless crystal.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([NH2:11])=[C:6]([Cl:12])[C:5]=1[NH2:13].C(N(CC)C(C)C)(C)C.[S:24](Cl)(Cl)=O>C(#N)C>[CH3:1][O:2][C:3]([C:4]1[C:5]([NH2:13])=[C:6]([Cl:12])[C:7]2[C:8]([CH:9]=1)=[N:10][S:24][N:11]=2)=[O:14]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1cc(N)c(N)c(Cl)c1N
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc2nsnc2c(Cl)c1N
Temperature: 80 °C
Yield: 56846.2 %

Procedure:
To a suspension of 20 mg (93 mmol) of 2,4,5-triamino-3-chloro-benzoic acid methyl ester in 1 ml of acetonitrile, is added 32 ml (0.19 mmol) of N,N-diisopropylethylamine followed by 9 ml (0.13 mmol) of thionyl chloride. The mixture is stirred at 80° C. over the night. Then, 32 ml of N,N-diisopropylethylamine is added again as well as 9 ml of thionyl chloride and the mixture is again stirred for 5 hours at a temperature of 80° C. The solvent is evaporated and the residue is suspended in EtOAc. After filtration, EtOAc is evaporated and 18 mg (73.9 mmol, 80%) of a yellowish-brown solid is obtained. LC/MS: 244/246 (M+1)+.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=1B(O)O>>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=1[C:5]1[C:4]([C:3]([OH:2])=[O:24])=[CH:9][C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Reactant: OB(O)c1cc(Cl)ccc1Cl
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1cc(Cl)ccc1Cl
Yield: 32.3 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with 2,5-dichlorophenylboronic acid (available from Combi-Blocks Inc.; 76 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2′,5′-dichloro-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2-carboxylic acid (32 mg, 32%). 1H NMR (400 MHz, DMSO-d6) δ 13.18 (br s, 1H), 8.56 (s, 1H), 8.50 (s, 1H), 8.34 (s, 1H), 8.29 (d, J=8.0 Hz, 1H), 8.10 (d, J=8.5 Hz, 1H), 7.77 (d, J=7.3 Hz, 1H), 7.54-7.57 (m, 1H), 7.49 (s, 1H), 7.47 (s, 2H).
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[S:12]1[CH2:17][CH2:16][CH:15](O)[CH2:14][CH2:13]1>>[S:12]1[CH2:17][CH2:16][CH:15]([O:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:14][CH2:13]1
Reactant: OC1CCSCC1
Reactant: CCOC(=O)/C(=N\O)C(C)=O
Product: CCOC(=O)/C(=N\OC1CCSCC1)C(C)=O
Yield: 20 %

Procedure:
Ethyl (Z)-2-hydroxyimino-3-oxobutyrate (5.72 g) was reacted with tetrahydro-4H-thiopyran-4-ol as described in Example 4a. method 3 to give the title compound (1.82 g, 20%) as colourless liquid, νmax (film) 2930, 1740, and 1690 cm-1, δH (CDCl3) 1.35 (3H, t), 2.06 (2H,m), 2.21 (2H, m) 2.40 (3H, s), 2.57 (2H, m), 2.82 (2H, m), and 4.37 (3H, q+m), δc (CDCl3) 14.2, 25.2, 25.3 (2C), 32.1 (2C), 62.0, 81.9, 150.5, 161.2 and 192.7. [Mass spectrum, MH+ (260)].
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[CH2:8][C@@H:9]1[O:11][CH2:10]1.CC(C)([O-])C.[K+].O1CCCC1>C(O)(C)(C)C>[O:11]1[CH2:10][CH:9]1[CH2:8][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: ClC[C@H]1CO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: C1CN(CC2CO2)CCO1
Temperature: 25 °C
Yield: 88.7 %

Procedure:
Morpholine 53a (8.712 ml, 0.1 mol) was dissolved in tert-butanol (4.5 ml) under stirring at room temperature, and (R)-(−)-1-chloro-2,3-epoxypropane (8.05 ml, 0.1 mol) was added slowly to the solution at 0° C. in an ice-water bath. Upon completion of the addition, the ice-water bath was removed, and the reaction mixture was allowed to warm up to room temperature and stirred for 24 hours. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was added dropwise with a solution of potassium tert-butoxide in tetrahydrofuran (60 ml, 1.67 mol/L, 100 mmol) while maintaining the temperature below 10° C. in an ice-water bath, gradually turned from light yellow to white turbid solution and stirred for 30 minutes. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was concentrated under reduced pressure, added with water (50 ml), exacted with dichloromethane (100 ml×2). The combined organic extracts were washed with saturated brine (100 ml), dried over anhydrous magnesium sulfate, filtered to remove the drying agent and concentrated under reduced pressure to obtain the title compound 4-oxiranylmethyl-morpholine 53b (12.7 g, yield 88.8%) as a yellow oil.
Reaction SMILES: [CH3:1]/[C:2](=[CH:6]\[CH3:7])/[C:3](O)=[O:4].CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[CH3:24][O:25][C:26](=[O:29])[CH2:27][NH2:28]>C(Cl)Cl>[CH3:24][O:25][C:26](=[O:29])[CH2:27][NH:28][C:3](=[O:4])/[C:2](/[CH3:1])=[CH:6]/[CH3:7]
Reactant: C/C=C(\C)C(=O)O
Reactant: COC(=O)CN
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C/C=C(\C)C(=O)NCC(=O)OC
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 42.6 %

Procedure:
(E)-2-methyl-2-butenoic acid (300 mg, 3.00 mmol) was dissolved in CH2Cl2 (6 mL) and N-methyl morpholine (396 μL, 3.60 mmol) was added to the solution. The reaction mixture was cooled to −15° C. Isobutyl chloroformate (389 μL, 3.00 mmol) was added and stirred at −15° C. for 15 min. Glycine methyl ester hydrochloride (377 mg, 3.00 mmol), CH2Cl2 (4 mL), and N-methyl morpholine (330 μL, 3.00 mmol) were added to the solution. After stirring at −15° C. for 15 min, the reaction mixture was warmed to 24° C. and stirred for 16 h. CH2Cl2 (60 mL) was added to the reaction mixture and the organic layer was washed with 1 N aq HCl (3×20 mL) and 5% aq NaHCO3 (3×20 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was evaporated. The crude product was purified by silica gel column chromatography using 30% and 40% EtOAc/CH2Cl2 to give 11 (219 mg, 43% yield). 1H-NMR (400 MHz, CDCl3) δ 6.47 (m, 1H), 6.37 (bs, 1H), 4.05 (d, J=4.8 Hz, 2H), 3.73 (s, 3H), 1.83 (m, 3H), 1.73 (m, 3H); 13C-NMR (100 MHz, CDCl3) δ 170.8, 169.4, 131.8, 131.2, 52.4, 41.6, 14.0, 12.3; HRMS (ESI) calcd for C8H14NO3 [M+H]+172.0974, found 172.0974.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:12][C:13]([N:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]2=[O:24])=[CH:14][C:15]=1[CH3:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S(O[CH2:42][CH2:43][CH:44]2[CH2:46][CH2:45]2)(=O)=O)=CC=1>CN(C)C=O>[CH2:1]([NH:8][C:9]([C:11]1[S:12][C:13]([N:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:42][CH2:43][CH:44]3[CH2:46][CH2:45]3)=[CH:19][C:18]2=[O:24])=[CH:14][C:15]=1[CH3:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(-n2ccc(O)cc2=O)sc1C(=O)NCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCCC2CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(-n2ccc(OCCC3CC3)cc2=O)sc1C(=O)NCc1ccccc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 58.1 %

Procedure:
To a stirred solution of N-benzyl-5-(4-hydroxy-2-oxopyridin-1(2H)-yl)-3-methylthiophene-2-carboxamide (0.20 g, 0.59 mmol) in N,N-dimethylformamide (4 mL) at ambient temperature was added potassium carbonate (0.082 g, 0.59 mmol), followed by the addition of 2-cyclopropylethyl 4-methylbenzenesulfonate (0.13 g, 0.59 mmol). The reaction mixture was stirred at 70° C. for 2 hours, and then allowed to cool to ambient temperature and partitioned between ethyl acetate (50 mL) and water (25 mL). The organic layer was washed with brine (25 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography eluting with 40% ethyl acetate in hexanes to afford the title compound as a colorless solid (0.14 g, 58%): mp 134-136° C.; 1H NMR (300 MHz, CDCl3) δ 7.52 (d, J=7.8 Hz, 1H), 7.36-7.27 (m, 5H), 6.83 (s, 1H), 6.18 (t, J=5.6 Hz, 1H), 6.06 (dd, J=7.8, 2.6 Hz, 1H), 5.95 (d, J=2.7 Hz, 1H), 4.58 (d, J=5.6 Hz, 2H), 4.02 (t, J=6.6 Hz, 2H), 2.53 (s, 3H), 1.72-1.64 (m, 2H), 0.89-0.73 (m, 1H), 0.55-0.45 (m, 2H), 0.15-0.08 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 167.2, 162.9, 162.3, 139.7, 139.6, 138.0, 134.3, 128.7, 127.8, 127.5, 126.9, 121.9, 103.4, 97.4, 68.8, 43.9, 33.6, 15.9, 7.6, 4.2; MS (ES+) m/z 409.3 (M+1).
Reaction SMILES: [NH2:1][C:2]([CH3:16])([CH2:5][N:6]1[CH:14]=[C:13]2[C:8]([N:9]=[CH:10][C:11]([Br:15])=[CH:12]2)=[N:7]1)[C:3]#[N:4].[F:17][C:18]([F:29])([F:28])[C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[S:24])=[CH:21][CH:20]=1>>[Br:15][C:11]1[CH:10]=[N:9][C:8]2=[N:7][N:6]([CH2:5][C:2]([NH:1][C:23](=[S:24])[C:22]3[CH:21]=[CH:20][C:19]([C:18]([F:17])([F:28])[F:29])=[CH:27][CH:26]=3)([C:3]#[N:4])[CH3:16])[CH:14]=[C:13]2[CH:12]=1
Reactant: CC(N)(C#N)Cn1cc2cc(Br)cnc2n1
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Product: CC(C#N)(Cn1cc2cc(Br)cnc2n1)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(5-bromo-2H-pyrazolo[3,4-b]pyridin-2-yl)-2-methylpropionitrile (35 mg, described in Example 204) and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (30.7 mg, 50%). MS (ES): M/Z [M+H]=484. 1H NMR: (400 MHz, CHLOROFORM-d): 1.99 (s, 3H), 4.94 (d, J=1.6 Hz, 2H), 7.76 (d, J=8.2 Hz, 1H), 7.90 (d, J=8.4 Hz, 2H), 8.20 (s 1H), 8.26 (d, J=2.1 Hz, 1H), 8.37 (s 1H) and 8.74 (d, J=2.1 Hz, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −42.2 (s, 3F).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[C:5]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)=[N:4][N:3]=1.C(O)(=[O:27])C.C(N(C(C)C)CC)(C)C.O>CN1CCCCC1=O>[Cl:24][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[O:22][CH3:23])[CH2:15][NH:14][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([C:12]#[N:13])[CH:7]=2)[C:2](=[O:27])[NH:3][N:4]=1
Reactant: COc1ccc(CNc2nnc(Cl)c3ccc(C#N)cc23)cc1Cl
Reactant: CC(=O)O
Agent: CN1CCCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ccc(CNc2n[nH]c(=O)c3ccc(C#N)cc23)cc1Cl
Temperature: 170 °C
Reaction time: 7 h

Procedure:
1-Chloro-4-(3-chloro-4-methoxybenzyl)amino-6-cyanophthalazine (1.0 g) prepared in Example 1 was dissolved in 10 ml of N-methyl-2-piperidone, followed by the addition of 0.26 ml of acetic acid and 2.1 ml of diisopropylethylamine. The obtained mixture was stirred at 170° C. for 7 hours, followed by the addition of 100 ml of water. The crystals thus precipitated were recovered by filtration.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[NH:22]1[CH:26]=[CH:25][CH:24]=[N:23]1>>[N+:12]([C:11]1[CH:10]=[C:9]2[C:4]([C:5](=[O:21])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:7](=[O:15])[NH:8]2)=[CH:3][C:2]=1[N:22]1[CH:26]=[CH:25][CH:24]=[N:23]1)([O-:14])=[O:13]
Reactant: c1cn[nH]c1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(-n3cccn3)cc2c1=O
Yield: 27 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (30 mg, 0.0943 mmol) is reacted with 1H-pyrazole according to the GPB affording 9.4 mg (27%) of a red powder. Rt=3.64 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[CH3:11])[CH3:2].CO[CH:15](OC)[N:16](C)C>C(Cl)Cl.CN(C=O)C>[CH2:1]([O:3][C:4]([C:5]1[C:6]2[N:7]([N:16]=[CH:15][CH:11]=2)[CH:8]=[CH:9][CH:10]=1)=[O:12])[CH3:2]
Reactant: CCOC(=O)c1cccnc1C
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1cccn2nccc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 74.4 %

Procedure:
To a clear solution of 2-methyl-nicotinic acid ethyl ester (50.6 g, 306 mmol) in anhydrous methylene chloride (200 mL) was added Omesitylenesulfonylhydroxylamine (73 g, 337 mmol; prepared according to a literature procedure described in Krause; J. G., Synthesis 1972, 140); in portions at 0° C. The solution obtained was stirred at 0° C. for 15 min, and then at rt for 1 h. Concentration under reduced pressure gave a yellow solid. After the solid was dissolved in anhydrous DMF (300 mL), N,N-dimethylformamide dimethyl acetal (122 mL, 918 mmol) was added at 0° C. The mixture was stirred at 0° C. for 15 min, and then at 90° C. for 3 h. The reaction mixture was concentrated under reduced pressure, mixed with H2O (200 mL), and extracted with Et2O (3×180 mL). The combined organic solutions were washed sequentially with brine (50 mL), 1N aqueous HCl (50 mL), and brine (50 mL), and dried over Na2SO4. Filtration through a SiO2 column, which was then eluted with 30% EtOAc in heptane, gave compound 777A (43.3 g, 74%) as a yellow solid. HPLC: 80% at 3.20 min (retention time) plus 20% corresponding methyl ester at 2.83 min (retention time) (YMC S5 ODS-A column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 191 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)[CH2:2][CH:3]=[CH2:4].O.CC[O:16]CC>C1COCC1.[Cl-].[Na+].O>[OH:16][CH2:4][CH2:3][CH2:2][CH2:1][C:5]1[CH:6]=[CH:7][C:8]([C:9]#[N:10])=[CH:11][CH:12]=1
Reactant: C=CCCc1ccc(C#N)cc1
Reactant: CCOCC
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(CCCCO)cc1
Temperature: 0 °C

Procedure:
4-(3-Butenyl)benzonitrile (from step (i) above, 10.8 g, 69 mmol) was dissolved in dry THF (140 mL) and was cooled to 0° C. BH3—Me2S complex (20 mL, 2 M) was added dropwise over 45 minutes at 0° C. and, after 7 hours, water (70 mL) and NaBO3—4H2O (25 g) were added and the mixture was stirred overnight before dilution with ether (700 mL) and brine (satd., 250 mL). After separation, the aqueous phase was extracted with ether (2×200 mL) and the combined extracts were dried, filtered and evaporated to give crude sub-title compound. Purification by flash chromatography on SiO2 (300 g) with heptane:EtOAc (3:1 to 1:1) gave the sub-title compound (6.99 g).
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[CH:2]=[CH2:3].[C:10]1([CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[O:21])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N12CCC(CC1)C(O)C2>CCOCC>[OH:21][CH:20]([C:2](=[CH2:3])[C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH2:19][CH2:18][CH2:17][CH2:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: O=CCCCCc1ccccc1
Agent: OC1CN2CCC1CC2
Solvent: CCOCC
Product: C=C(C(=O)OC(C)(C)C)C(O)CCCCc1ccccc1
Reaction time: 384 h
Yield: 89.8 %

Procedure:
t-Butyl acrylate (6.7 g, 46 mmol), 5-phenyl pentanal (3.7 g, 23 mmol) and 3-quinuclidinol (0.38 g, 3 mmol) are combined and stirred under N2. After 24 hours stirring is halted and the resulting solution is allowed to sit at ambient temperature for 16 days. TLC analysis (30% ether in petroleum ether) showed that the reaction is nearly complete. The product is purified by column chromatography (silica, 20% ether in petroleum ether) to yield t-butyl 2-(1-hydroxy-5-phenylpentyl)acrylate (6 g, 45%): 1H NMR (300 MHz, CDCl3) δ 7.29-7.24 (m, 2H), 7.18-7.14 (m, 3H), 6.10 (d, J=1.1 Hz, 1H), 5.67 (s, 1H), 4.33 (q, J=6.7 Hz, 1H), 2.74 (d, J=6.7 Hz, 1H), 2.61 (t, J=7.6 Hz, 2H), 1.70-1.53 (m, 4H), 1.50 (s, 9H), 1.50-1.32 (m, 2H); 13C NMR (75.5 MHz, CDCl3) δ 165.93, 143.91, 142.51, 128.32, 128.20, 125.57, 123.82, 81.35, 71.79, 36.17, 35.82, 31.26, 28.04, 25.54; MS (EI) m/e 291 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C@H:17]3[CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19][N:18]3[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].N1C(C)=CC=CC=1C.[Si](OS(C(F)(F)F)(=O)=O)(C(C)(C)C)(C)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([C@H:17]3[CH2:22][NH:21][CH2:20][CH2:19][N:18]3[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:16])[CH2:13][CH2:14]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)N2CCN(c3ccc(Cl)c(Cl)c3)CC2)C1
Agent: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)OC(=O)N1CCNC[C@@H]1C(=O)N1CCN(c2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C

Procedure:
To a solution of di-tert-butyl (2R)-2-{[4-(3,4-dichlorophenyl)piperazin-1-yl]carbonyl}piperazine-1,4-dicarboxylate and 2,6-lutidine in dichloromethane at ice bath temperature under argon was added TBDMSOTf (total of 0.4 mL added following the reaction by tlc and lc-ms until complete. The ice-bath was removed and the reaction quenched with saturated aqueous ammonium chloride at ambient temperature. The mixture was partitioned between water and dichloromethane and the organic layer washed with brine and concentrated at reduced pressure. The residue was dissolved in THF and cooled to ice bath temperature. Water (0.5 mL) was added, followed by TBAF (1M in THF) drop-wise. The mixture was again warmed to ambient temperature and partitioned between dichloromethane and water. The organic phase was dried (MgSO4), filtered and concentrated. The residue (647 mg) was purified by silica gel chromatography on an Isco Companion (40 g column), eluting with 0-10% methanol in dichloromethane to give the title intermediate (204 mg). A further amount of impure compound (48 mg) was also isolated.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]#[N:11])=[CH:4][C:3]=1[N+:12]([O-])=O.CO>[Fe].O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]#[N:11])=[CH:4][C:3]=1[NH2:12]
Reactant: N#CCSc1ccc(N)c([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CO
Solvent: O
Product: N#CCSc1ccc(N)c(N)c1
Reaction time: 2 h

Procedure:
4.1 G. of 1-amino-2-nitro-4-cyanomethylthiobenzene in 60 ml. of methanol and 12 ml. of water is treated with 1.25 g. of ferrous sulfate and 3.3 g. of iron powder at reflux. After 2 hours, 1.25 g. of ferrous sulfate and 3.3 g. of iron powder are added and heating is continued for four hours. The mixture is poured into 600 ml. of hot tetrahydrofuran and filtered. 1,2-Diamino-4-cyanomethylthiobenzene is obtained from the filtrate by evaporation.
Reaction SMILES: C(OC(=O)C1C=CC(NC(=O)C(N2C3C=C(F)C(F)=CC=3N=C2C2C=CC(Cl)=CC=2)C2CCCCC2)=CC=1)C.[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]2[N:51]([CH:52]([CH:56]3[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]3)[C:53]([OH:55])=O)[C:50]3[CH:62]=[CH:63][CH:64]=[CH:65][C:49]=3[N:48]=2)=[CH:43][CH:42]=1.[CH3:66][O:67][C:68]([C:70]1([O:73][C:74]2[CH:79]=[CH:78][C:77]([NH2:80])=[C:76]([F:81])[CH:75]=2)[CH2:72][CH2:71]1)=[O:69]>>[CH3:66][O:67][C:68]([C:70]1([O:73][C:74]2[CH:79]=[CH:78][C:77]([NH:80][C:53](=[O:55])[CH:52]([N:51]3[C:50]4[CH:62]=[CH:63][CH:64]=[CH:65][C:49]=4[N:48]=[C:47]3[C:44]3[CH:45]=[CH:46][C:41]([Cl:40])=[CH:42][CH:43]=3)[CH:56]3[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]3)=[C:76]([F:81])[CH:75]=2)[CH2:72][CH2:71]1)=[O:69]
Reactant: O=C(O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2ccccc21
Reactant: COC(=O)C1(Oc2ccc(N)c(F)c2)CC1
Agent: CCOC(=O)c1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1
Product: COC(=O)C1(Oc2ccc(NC(=O)C(C3CCCCC3)n3c(-c4ccc(Cl)cc4)nc4ccccc43)c(F)c2)CC1

Procedure:
The title compound was prepared in analogy to example 22, intermediate d), from [2-(4-chloro-phenyl)-benzoimidazol-1-yl]-cyclohexyl-acetic acid (Ex. 39/40, int. b) and 1-(4-amino-3-fluoro-phenoxy)-cyclopropanecarboxylic acid methyl ester to give the product as a light yellow foam (21%).