Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]([C@H:11]1[N:16](C(OC(C)(C)C)=O)[CH2:15][C@@H:14]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[NH:32][C:33](=[O:53])[C@H:34]([CH:40]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[NH:35][C:36]([O:38][CH3:39])=[O:37])[O:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.[C:57]([OH:63])([C:59]([F:62])([F:61])[F:60])=[O:58]>>[CH2:1]([NH:8][C:9]([C@H:11]1[NH:16][CH2:15][C@@H:14]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[NH:32][C:33](=[O:53])[C@H:34]([CH:40]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[NH:35][C:36]([O:38][CH3:39])=[O:37])[O:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[C:57]([OH:63])([C:59]([F:62])([F:61])[F:60])=[O:58]
Reactant: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](C(=O)NCc2ccccc2)CO1)C(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CN[C@H](C(=O)NCc2ccccc2)CO1)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tert-butyl (2R,5S)-5-(benzylcarbamoyl)-2-[2-(2-{[N-(methoxycarbonyl)-β-phenyl-L-phenylalanyl]amino}phenyl)ethyl]morpholine-4-carboxylate in a 1:1 mixture of CH2Cl2/TFA (0.1 M) was stirred at rt for 1 hr. The reaction mixture was concentrated under reduced pressure and the residue was co-evaporated twice with heptane and triturated in Et2O to afford the desired product as a TFA salt. Alternatively, the TFA salt, after concentration, could be neutralized with aqueous saturated NaHCO3, extracted with EtOAc, dried over Na2SO4, filtered and concentrated and then purified by automated SiO2 flash chromatography system using solvent gradient of 0% to 10% MeOH/CH2Cl2 to afford the desired compound. Alternatively, the free base could be purified by filtration on SCX SPE cartridge made of pTSA-SiO2 eluted first with MeOH to remove non basic impurities and eluted then with 10% NH4OH/MeOH to elute the free base and afford the desired compound after concentration under reduced pressure.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](Br)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:25]([N:27]2[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28]2)=[O:26])=[O:8])[CH2:5][CH2:4]1)#[N:2].[N:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][C:35]=1[CH3:43]>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([C:37]4[CH:38]=[CH:39][N:34]=[C:35]([CH3:43])[CH:36]=4)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:25]([N:27]2[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28]2)=[O:26])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: Cc1cc(B(O)O)ccn1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(Br)cc3Cl)C[C@H]2C(=O)N2CCC(F)(F)C2)CC1
Product: Cc1cc(-c2ccc(S(=O)(=O)[C@@H]3C[C@@H](C(=O)NC4(C#N)CC4)[C@H](C(=O)N4CCC(F)(F)C4)C3)c(Cl)c2)ccn1

Procedure:
The title compound was prepared in analogy to example 196 using (1R,2R,4R)-4-(2-chloro-4-bromo-benzenesulfonyl)-2-(3,3-difluoro-pyrrolidine-1-carbonyl)-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (Example 187 step 4) and 2-picoline-4-boronic acid. Light yellow solid (59%). MS (EI): 577.1 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:21])[C:3]1=[O:28].[C:29]1([CH3:38])[CH:34]=[CH:33][CH:32]=[C:31]([N:35]=[C:36]=[O:37])[CH:30]=1>O1CCCC1>[O:28]=[C:3]1[CH:2]([NH:1][C:36]([NH:35][C:31]2[CH:30]=[C:29]([CH3:38])[CH:34]=[CH:33][CH:32]=2)=[O:37])[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]1[CH2:19][C:20]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:21]
Reactant: NC1N=C(c2ccccc2)c2ccccc2N(CC(=O)c2ccccc2)C1=O
Reactant: Cc1cccc(N=C=O)c1
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)NC2N=C(c3ccccc3)c3ccccc3N(CC(=O)c3ccccc3)C2=O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.5 %

Procedure:
To a mixture of 0.74 g 3-amino-1,3-dihydro-1-phenacyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 5 ml tetrahydrofuran, was added a solution of 0.27 g 3-tolyl isocyanate in 3 ml tetrahydrofuran, and the resulting mixture was stirred at room temperature for four hours. The solvent was distilled off from the reaction mixture, and the residue was recrystallized from a mixture of toluene and n-hexane, thus giving 0.78 g of 1-[2,3-dihydro-2-oxo-1-phenacyl-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(3-tolyl)urea.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][C:16]2=[O:26])=[CH:11][CH:10]=1)=O)(C)(C)C.[C:27]([OH:33])([C:29]([F:32])([F:31])[F:30])=[O:28]>C(Cl)Cl>[F:30][C:29]([F:32])([F:31])[C:27]([OH:33])=[O:28].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][C:16]2=[O:26])=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-n2c(=O)[nH]c3ccccc3c2=O)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(-n2c(=O)[nH]c3ccccc3c2=O)cc1
Reaction time: 1 h
Yield: 99 %

Procedure:
To a chilled suspension of (tert-butoxy)-N-[4-(2,4-dioxo(1,3-dihydroquinazolin-3-yl))phenyl]carboxamide (0.35 g, 1 mmol) in CH2Cl2 (2 mL) was added neat TFA (2 mL). The resulting solution was stirred cold for 1 hr, concentrated in vacuo, azeotroped with heptane and dried to give desired compound (0.376 g, 99%) as the mono TFA salt. ES-MS (M+H)+=254.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Br[CH:10]([CH:14]([CH3:16])[CH3:15])[C:11]([OH:13])=[O:12].O(C1C=C(C=CC=1)CBr)C1C=CC=CC=1>>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C@H:10]([C:11]([OH:13])=[O:12])[CH:14]([CH3:16])[CH3:15])=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: CC(C)C(Br)C(=O)O
Agent: BrCc1cccc(Oc2ccccc2)c1
Product: CC(C)[C@H](Nc1ccc(F)cc1)C(=O)O

Procedure:
The acid, N-(4-fluorophenyl)valine is prepared as above from 4-fluoroaniline and α-bromoisovaleric acid and then reacted with m-phenoxybenzyl bromide, as above, to yield the m-phenoxybenzyl ester of N-(4-fluorophenyl)valine. nmr (CDCl3) δ centered at 0.90 [m, 6, (CH3)2CH], 2.0 [m, 1, (CH3)2CH], 3.80 ##STR23## and 5.15 ppm (s, 2, ArCH2O). IR (film) 3400 m-1 (NH).
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1([CH:15]2[CH2:20][NH:19][CH2:18][C:17]3[S:21][CH:22]=[CH:23][C:16]2=3)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>C(O)(C)C>[CH2:1]([N:19]1[CH2:20][CH:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:16]2[CH:23]=[CH:22][S:21][C:17]=2[CH2:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(C2CNCc3sccc32)cc1
Reactant: ClCc1ccccc1
Agent: Cl
Solvent: CC(C)O
Product: c1ccc(CN2Cc3sccc3C(c3ccccc3)C2)cc1
Yield: 52 %

Procedure:
Benzyl chloride is condensed with 4-phenyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine (Example 3), according to the procedure of Example 8. Hydrochloride; M.p. = 185° C (isopropanol); Yield: 52%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:27])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]([CH3:26])=[CH2:25])[C:5]2=[CH:4][CH:3]=1.[CH3:28][O:29][CH:30]([Si:32]([CH3:35])([CH3:34])[CH3:33])[CH3:31].[C:36]([O:40][C:41](=[O:44])[CH2:42]Br)([CH3:39])([CH3:38])[CH3:37].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:27])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:42][C:41]([O:40][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:44])[CH:11]3[C:24]([CH3:26])=[CH2:25])[C:5]2=[CH:4][CH:3]=1.[CH3:28][O:29][CH:30]([Si:32]([CH3:35])([CH3:34])[CH3:33])[CH3:31]
Reactant: C=C(C)C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: CC(C)(C)OC(=O)CBr
Agent: COC(C)[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=C(C)C1N(CC(=O)OC(C)(C)C)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 79 %

Procedure:
In a manner similar to the method described in example 55c, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-isopropenyl-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (3 g, 5.64 mmol) prepared in example 116a was reacted with bromo-acetic acid tert-butyl ester and cesium carbonate in N,N-dimethyl-formamide to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-isopropenyl-2,3-dihydro-1′-[(tert-butoxycarbonyl)methyl]-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane as a white foam (Yield: 2.98 g, 79%).
Reaction SMILES: [Br:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]([C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][C:19](OC)=[O:20])[CH2:14][CH2:13]2)[CH:9]2[CH2:11][CH2:10]2)=[O:7])=[C:4]([F:25])[CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Br:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]([CH:9]2[CH2:11][CH2:10]2)[C@H:12]2[CH2:13][CH2:14][C@H:15]([CH2:18][CH2:19][OH:20])[CH2:16][CH2:17]2)=[O:7])=[C:4]([F:25])[CH:3]=1
Reactant: COC(=O)C[C@H]1CC[C@H](N(C(=O)c2ccc(Br)cc2F)C2CC2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(c1ccc(Br)cc1F)N(C1CC1)[C@H]1CC[C@H](CCO)CC1

Procedure:
To a solution of methyl 2-(trans-4-(4-bromo-N-cyclopropyl-2-fluorobenzamido)cyclohexyl)acetate (0.050 g, 0.12 mmol) in THF (2 mL) was added lithium aluminum hydride (1.0 M solution in THF) (0.15 ml, 0.15 mmol) at 0° C. The reaction was quenched with saturated NH4Cl (10 mL) after 30 minutes. The mixture was extracted with EtOAc twice. The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by prep TLC eluting with 5% MeOH—CH2Cl2 and 50% EtOAc-hexane. The desired alcohol product was obtained as a white solid (15 mg). MS: 386 (M+1), C18H23BrFNO2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][C:19]([CH3:21])=[C:18]([C:22]([OH:24])=O)[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:25])[CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH:38]1[CH2:42][CH2:41][N:40]=[C:39]1[C:43]1[CH:48]=[CH:47][C:46]([CH2:49][CH2:50][NH:51][CH3:52])=[CH:45][CH:44]=1.CCN(C(C)C)C(C)C>ClCCCl.CN(C=O)C>[NH:40]1[CH2:41][CH2:42][N:38]=[C:39]1[C:43]1[CH:44]=[CH:45][C:46]([CH2:49][CH2:50][N:51]([CH3:52])[C:22]([C:18]2[CH:17]=[C:16]([CH2:15][N:13]([S:10]([C:6]3[C:5]([CH3:25])=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=3[CH3:9])(=[O:11])=[O:12])[CH3:14])[O:20][C:19]=2[CH3:21])=[O:24])=[CH:47][CH:48]=1
Reactant: CNCCc1ccc(C2=NCCN2)cc1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)c(C)o2)c(C)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)N(C)CCc3ccc(C4=NCCN4)cc3)c(C)o2)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)-2-methylfuran-3-carboxylic acid (82 mg, 0.22 mmol) was dissolved in DCE (1 mL) and CDI (72 mg, 0.33 mmol) was added. The reaction was stirred at ambient temperature for 2 h and 0.5 mL of this solution was added to a flask containing 2-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]-N-methylethanamine 0.3 HCl (34 mg, 0.11 mmol) and DIPEA (0.076 mL, 0.44 mmol) in DMF (2 mL). The reaction was stirred at ambient temperature for 3 days, then heated in a microwave at 120° C., 250 psi, 200 W for 2×20 min. The reaction was concentrated and diluted with DCM, then washed with water and saturated brine, and dried over MgSO4. The filtrate was shaken with Ambersep and PL-MIA resins, then filtered. The solvent was removed in vacuo and a portion of the crude product purified using prep method C.
Reaction SMILES: C(O[C:4](=[O:22])[C:5]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:8]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:7][C:6]=1[CH3:21])C.[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1.C[Al](C)C.[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:29][C:4](=[O:22])[C:5]2[C:10]([C:11]([F:12])([F:14])[F:13])=[CH:9][C:8]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:7][C:6]=2[CH3:21])=[CH:26][CH:25]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1c(C)cc(N2CCOCC2)cc1C(F)(F)F
Agent: C[Al](C)C
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1cc(N2CCOCC2)cc(C(F)(F)F)c1C(=O)NCc1ccc(Cl)cc1
Temperature: 110 °C
Yield: 80 %

Procedure:
A mixture of 2-methyl-4-morpholin-4-yl-6-(trifluoromethyl)-benzoic acid ethyl ester (0.27 g, 0.85 mmol), 4-chlorobenzylamine (1.21 g, 8.51 mmol) and trimethylaluminium (2M in toluene) (2.98 ml, 5.96 mmol) in toluene (9 ml) is heated at 110° C. for 4 d. After completion of the reaction (monitored by TLC), a 2M aqueous solution of sodium hydroxide is carefully added and the mixture is extracted with ethyl acetate (2×15 ml). The combined organic layers are washed with 2M aqueous solution of sodium hydroxide (10 ml), brine (10 ml) and dried over sodium sulfate. The solvent is evaporated to get the crude product, which is purified by column chromatography (silica gel, 30% ethyl acetate/cyclohexane) to afford N-[(4-chlorophenyl)-methyl]-2-methyl-4-morpholin-4-yl-6-(trifluoromethyl)-benzamide (example 19) (0.28 g, 0.68 mmol, 80%). [M+H]+ 413.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:9]([CH2:11][CH3:12])[CH3:10]>>[CH3:10][CH:9]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:11][CH3:12]
Reactant: Nc1ccccc1
Reactant: CCC(C)Br
Product: CCC(C)Nc1ccccc1

Procedure:
N-(1-methylpropyl)aniline was prepared from aniline and 2-bromobutane using the same method as in Example 2ii).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[N:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[S:14][CH:15]=1.[NH2:20][CH2:21][CH2:22][OH:23]>ClCCl>[F:17][C:16]([F:19])([F:18])[C:13]1[S:14][CH:15]=[C:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH2:2][NH:20][CH2:21][CH2:22][OH:23])[N:12]=1
Reactant: NCCO
Reactant: FC(F)(F)c1nc(-c2ccccc2OCCBr)cs1
Solvent: ClCCl
Product: OCCNCCOc1ccccc1-c1csc(C(F)(F)F)n1
Temperature: 80 °C

Procedure:
A mixture of 4-[2-(2-bromoethoxy)phenyl]-2-(trifluoromethyl)-1,3-thiazole (C5) (115 mg, 0.327 mmol) and 2-aminoethanol (0.197 mL, 3.26 mmol) was heated to 80° C. for 3 hours. After cooling to room temperature, the reaction was diluted with dichloromethane and washed with 0.5 N aqueous sodium hydroxide solution, then with water. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo, yielding the title compound as a white solid. Yield: 113 mg, quantitative. 1H NMR (400 MHz, CDCl3) δ 2.88 (dd, J=5.2, 5.1 Hz, 2H), 3.15 (dd, J=5, 5 Hz, 2H), 3.68 (br dd, J=5, 5 Hz, 2H), 4.25 (dd, J=5, 5 Hz, 2H), 7.03 (br d, J=8.3 Hz, 1H), 7.08-7.12 (m, 1H), 7.33-7.38 (m, 1H), 8.18 (s, 1H), 8.21 (br d, J=7.9 Hz, 1H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13])=[O:2].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([Mg]Br)=[CH:21][CH:20]=1>C1COCC1>[OH:2][CH:1]([C:22]1[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=1)[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13]
Reactant: N#Cc1cccc(-c2ccncc2C=O)c1
Reactant: COc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2cnccc2-c2cccc(C#N)c2)cc1

Procedure:
To the solution of 3-(3-formyl-pyridin-4-yl)-benzonitrile (30 mg, 0.15 mmol) in THF (1.5 mL) at −78° C. was added 0.5 M 4-methoxyphenylmagnesium bromide in THF (0.6 mL). The reaction mixture was quenched with ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash chromatography eluted with 5% methanol in dichloromethane to yield 3-{3-[hydroxy-(4-methoxy-phenyl)-methyl]-pyridin-4-yl}-benzonitrile as white crystals.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[H-].[Na+].[N+](C1C=CC([O:20][C:21]([N:23]2[CH2:26][CH:25]([O:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[F:40])=[CH:30][N:29]=3)[CH2:24]2)=O)=CC=1)([O-])=O>CN(C=O)C>[CH3:1][C:2]1[N:7]=[N:6][C:5]([NH:8][C:21]([N:23]2[CH2:24][CH:25]([O:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[F:40])=[CH:30][N:29]=3)[CH2:26]2)=[O:20])=[CH:4][CH:3]=1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CC(Oc2ccc(-c3ccccc3F)cn2)C1
Reactant: Cc1ccc(N)nn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)N2CC(Oc3ccc(-c4ccccc4F)cn3)C2)nn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49 %

Procedure:
To a solution of 6-Methyl-pyridazin-3-ylamine (60 mg, 0.55 mmol, [Cas. No 18591-82-7]) in DMF (3 mL) at 0° C. was added sodium hydride (20 mg, 0.5 mmol, 60% disp. in mineral oil). After stirring at 0° C. for 15 min. a solution of 3-[5-(2-Fluoro-phenyl)-pyridin-2-yloxy]-azetidine-1-carboxylic acid 4-nitro-phenyl ester (102 mg, 0.25 mmol) in DMF (4 mL) was added dropwise. After stirring for 16 hrs at ambient temperature the reaction mixture was concentrated in vacuo, diluted with ethyl acetate (50 mL) and washed sequentially with sat. aqueous sodium hydrogen carbonate solution (2×50 mL) then sat. sodium chloride solution (50 mL). Mixture dried over magnesium sulphate and filtered. Filtrate solvents were removed in vacuo and the residue was purified by flash chromatography (40% ethyl acetate in DCM) to give the title compound (48 mg, 49%)
Reaction SMILES: CC([C:4]1[CH:9]=[C:8](C(C)C)[CH:7]=[C:6](C(C)C)[C:5]=1[CH2:16][C:17]([C:19]1[C:20]([CH:33]([CH3:35])[CH3:34])=[C:21]([O:28][S:29](=[O:32])(=[O:31])[NH2:30])[C:22]([CH:25]([CH3:27])[CH3:26])=[CH:23][CH:24]=1)=[O:18])C.C(C1C=C(C(C)C)C=C(C(C)C)C=1C[Mg]Br)(C)C.C([Mg]Cl)C1C=CC=CC=1>>[C:5]1([CH2:16][C:17]([C:19]2[C:20]([CH:33]([CH3:35])[CH3:34])=[C:21]([O:28][S:29](=[O:31])(=[O:32])[NH2:30])[C:22]([CH:25]([CH3:27])[CH3:26])=[CH:23][CH:24]=2)=[O:18])[CH:6]=[CH:7][CH:8]=[CH:9][CH:4]=1
Reactant: CC(C)c1cc(C(C)C)c(CC(=O)c2ccc(C(C)C)c(OS(N)(=O)=O)c2C(C)C)c(C(C)C)c1
Agent: CC(C)c1cc(C(C)C)c(C[Mg]Br)c(C(C)C)c1
Agent: Cl[Mg]Cc1ccccc1
Product: CC(C)c1ccc(C(=O)Cc2ccccc2)c(C(C)C)c1OS(N)(=O)=O

Procedure:
This compound was prepared in the same manner as the title compound of Example 5, except that 2,4,6-triisopropylbenzyl magnesium bromide was replaced with benzylmagnesium chloride (commercially available), mp 150°-152° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9]O)[CH:5]=[CH:4][CH:3]=1.[C:11]1(=[O:21])[NH:15][C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[CH3:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][N:15]2[C:14](=[O:16])[C:13]3=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]3[C:11]2=[O:21])[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(CCO)n1
Reactant: O=C1NC(=O)c2ccccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(CCN2C(=O)c3ccccc3C2=O)n1
Reaction time: 8 h
Yield: 66.9 %

Procedure:
45.6 g (262 mmol) of diethyl azadicarboxylate (DEAD) was added dropwise to a solution of 30.0 g (219 mmol) of 2-(6-methyl-2-pyridyl)ethanol, 38.6 g (262 mmol) of phthalimide and 68.6 g (262 mmol) of triphenylphosphine in 300 ml of tetrahydrofuran at a temperature of 15° to 25° C. The mixture was stirred overnight. Water was added to the mixture. After extraction with ethyl acetate, the organic layer was washed with water. After extraction with 2N hydrochloric acid, a 3N sodium hydroxide solution was added to the aqueous layer at 0° C. to make it alkaline. White crystals thus formed were collected by filtration to give 39.04 g (yield: 67%) of the intended compound.
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[N:8]=[C:7]([CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[S:18][C:14]=3[C:13](=[O:25])[N:12]([CH:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]3)[C:11]2=[O:39])[O:6][N:5]=1.[ClH:40]>C(Cl)Cl.O1CCOCC1>[ClH:40].[CH3:1][S:2][CH2:3][C:4]1[N:8]=[C:7]([CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[S:18][C:14]=3[C:13](=[O:25])[N:12]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:11]2=[O:39])[O:6][N:5]=1
Reactant: CSCc1noc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CSCc1noc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)n1

Procedure:
A solution of tert-butyl 4-[1-({3-[(methylsulfanyl)methyl]-1,2,4-oxadiazol-5-yl}methyl)-2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate (715 mg; compound B11) in DCM (15 ml) is reacted with a solution of hydrogen chloride in 1,4-dioxane (3 ml, 4.0 M) according to the procedure described in example B28 to afford the title compound as a solid.
Reaction SMILES: [Mg].C(I)C.C[Si](C)(C)[O:7][C:8]1[CH:13]=[CH:12][C:11](Br)=[CH:10][C:9]=1[C:15]1([CH3:20])[O:19]CCO1.[CH3:23][Si:24](Cl)([CH3:26])[CH3:25].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>O1CCCC1.CCCCCC.CCOC(C)=O.CC(C)=O.O>[OH:7][C:8]1[CH:13]=[CH:12][C:11]([Si:24]([CH3:26])([CH3:25])[CH3:23])=[CH:10][C:9]=1[C:15](=[O:19])[CH3:20]
Reactant: CC1(c2cc(Br)ccc2O[Si](C)(C)C)OCCO1
Reactant: C[Si](C)(C)Cl
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Mg]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(=O)c1cc([Si](C)(C)C)ccc1O
Yield: 66 %

Procedure:
A mixture of 321 mg (13.2 mmol) of magnesium, 0.07 ml of ethyl iodide and 1.32 ml of dry tetrahydrofuran was refluxed. After cooling, the mixture was diluted with 3.96 ml of dry tetrahydrofuran and refluxed. To the mixture was added dropwise a solution 4.0 g of crude 2-(2-trimethylsilyloxy-5-bromophenyl)-2-methyl-1,3-dioxolane, obtained as above, in 9.6 ml of tetrahydrofuran and the reaction mixture was refluxed for 2 hours. After cooling, 1.68 ml (13.2 mmol) of trimethylsilyl chloride was added and refluxed for 3 hours. Water was added to the reaction mixture. The mixture was extracted with ether. The extract was washed with water and sat.aq.NaCl, dried over anhyd.Na2SO4 and evaporated. To the residue was added 72 ml of acetone, 10.8 ml (600 mmol) of water and 0.46 g (1.8 mmol) of PPTS. The mixture was refluxed for 3 hours and evaporated. The residue was dissolved in ether. The solution was washed with water, aqueous sodium bicarbonate solution and sat.aq.NaCl, dried over anhyd.Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel [eluent: n-hexane-AcOEt (20:1)] to 1.66 g of pale yellow liquid (yield 67%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][CH:8]2[NH:14][C:13](=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:2]1.F[B-](F)(F)F.[CH3:21][O+](C)C>C(Cl)Cl>[O:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][CH:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:21])=[N:14]2)=[CH:2]1
Reactant: O=C1CCCCC(CCc2ccoc2)N1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC1=NC(CCc2ccoc2)CCCC1

Procedure:
The product of Example 170 is reacted with trimethyloxonium tetrafluoroborate in CH2Cl2 by the method of Example 3 to produce the title material.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O>CCO.[Pd]>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:3][C:2]=1[F:1]
Reactant: CCOC(=O)C(C)c1ccc([N+](=O)[O-])c(F)c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(C)c1ccc(N)c(F)c1
Reaction time: 1 h
Yield: 88.1 %

Procedure:
A suspension of ethyl 2-(3-fluoro-4-nitrophenyl)propanoate (8.3 g, 34.41 mmol) and Pd/C (10% Pd) in EtOH (170 mL) was hydrogenated for 1 h under a hydrogen atmosphere (2.5 bar, 22° C.). The suspension was removed by filtration, concentrated under vacuum and purified by column chromatography (SiO2, ethyl acetate/hexane 1:5) to obtain ethyl 2-(4-amino-3-fluorophenyl)propanoate (6.4 g, 77%).