Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[CH2:12]([C@@H:19]1[CH2:23][O:22][C:21](=[O:24])[NH:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C>C1(C)C=CC=CC=1>[CH2:12]([C@@H:19]1[CH2:23][O:22][C:21](=[O:24])[N:20]1[C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Agent: CC(C)(C)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(Cc1ccc(Br)cc1)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
2-(4-Bromophenyl)acetic acid (7.85 g, 36.5 mmol) and (R)-4-benzyloxazolidin-2-one (3.23 g, 18.3 mmol) were combined in toluene (30 mL) and triethylamine (10.2 mL, 73.0 mmol). The solution was then heated to 80° C., and a solution of pivaloyl chloride (4.49 mL, 36.5 mmol) in toluene (7.5 mL) was added slowly. The reaction was heated to 110° C. and stirred overnight. The reaction was then cooled, and the toluene solution was washed with 2N HCl, water, 5% Na2CO3, brine and then dried over Na3SO4. After removal of the solvent, the residue was purified by column chromatography to give (R)-4-benzyl-3-(2-(4-bromophenyl)acetyl)oxazolidin-2-one (5.65 g, 83%) as a solid.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].[Si]([O:26][C@H:27]([CH2:39][CH2:40][C:41]1[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=1)[CH2:28][O:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)(C(C)(C)C)(C)C>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.C1(C)C=CC=CC=1>[OH:26][C@H:27]([CH2:39][CH2:40][C:41]1[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=1)[CH2:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([C:2]2[CH:3]=[CH:4][C:5](=[O:9])[N:6]([CH3:8])[CH:7]=2)=[CH:32][CH:31]=1
Reactant: Cn1cc(I)ccc1=O
Reactant: CC(C)(C)[Si](C)(C)O[C@H](CCc1cccnc1)COc1ccc(B(O)O)cc1
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: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cn1cc(-c2ccc(OC[C@H](O)CCc3cccnc3)cc2)ccc1=O

Procedure:
Prepared according to the method described in Example 7c) from 5-iodo-N-methylpyridin-2-one (Example 13a), 0.276 g), ethanol (4 ml), toluene (10 ml), 2M aqueous sodium carbonate (0.58 ml), (2R)-4-[2-(tert-butyldimethylsilanyloxy)-4-pyridin-3-yl-butoxy]benzeneboronic acid (Example 7b), 0.471 g), and tetrakis(triphenylphosphine)palladium(0) (0.03 g). After work up, the residue was purified by column chromatography over silica eluting dichloromethane:methanol (95:5) to give the title compound as a foam (0.191 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:13])=[CH:2]1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:34]=[C:35]([O:39][CH3:40])[C:36]=1[O:37][CH3:38])[C:31](Cl)=[O:32]>>[CH3:40][O:39][C:35]1[CH:34]=[C:30]([CH:29]=[C:28]([O:27][CH3:26])[C:36]=1[O:37][CH3:38])[C:31]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:13])=[CH:2]1)=[O:32]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: COc1cc(C(=O)/C=C/c2c[nH]c3ccccc23)cc(OC)c1OC
Product: COc1cc(C(=O)/C=C/c2cn(C(=O)c3cc(OC)c(OC)c(OC)c3)c3ccccc23)cc(OC)c1OC

Procedure:
Substantially the same procedure as in Example 3 was repeated using Compound 1 (1.69 g) obtained in Example 1 and 3,4,5-trimethoxybenzoyl chloride (2.31 g) except that the obtained crude crystals were recrystallized from a mixed solvent of ethanol and acetone, to give Compound 59 (1.22)
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][CH2:10][CH:11]([CH3:13])[CH3:12])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[N:14]12CCN(CC1)C[CH2:15]2.O>C(#N)C.[C-]#N.C([N+](CC)(CC)CC)C>[Br:1][C:2]1[C:3]([O:9][CH2:10][CH:11]([CH3:13])[CH3:12])=[N:4][C:5]([C:15]#[N:14])=[N:6][CH:7]=1
Reactant: C1CN2CCN1CC2
Reactant: CC(C)COc1nc(Cl)ncc1Br
Agent: CC[N+](CC)(CC)CC
Agent: [C-]#N
Solvent: CC#N
Solvent: O
Product: CC(C)COc1nc(C#N)ncc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.1 %

Procedure:
To a solution of 5-bromo-2-chloro-4-isobutoxypyrimidine (2.16 g) and 1,4-diazabicyclo[2.2.2]octane (1.83 g) in acetonitrile (30 mL) was added tetraethylammonium cyanide (1.40 g), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added water at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.71 g) as a colorless oil.
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH2:19][CH:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=1)O)[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CS(Cl)(=O)=O.O>C(Cl)Cl>[Si:1]([O:8][C@H:9]1[CH2:10][N:11]([C:12]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:18])[CH:20]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)[CH2:19]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC[C@@H](CC(O)c1cccc(F)c1)O[Si](C)(C)C(C)(C)C
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)CC1c1cccc(F)c1
Temperature: -60 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (2R)-2-(tert-butyldimethylsilyloxy)-4-(3-fluorophenyl)-4-hydroxybutylcarbamate (I-2) (15.8 g, 38.2 mmol) in DCM (120 mL) at −60° C. under N2 was added TEA (16 mL, 114.6 mmol) and MsCl (3.3 mL, 42.0 mmol). The resulting mixture was stirred at −60° C. for 1 hour. The reaction was poured into water, washed with brine, dried over sodium sulfate, filtered and concentrated to yield (4R)-tert-butyl 4-(tert-butyldimethylsilyloxy)-2-(3-fluorophenyl)pyrrolidine-1-carboxylate (I-3). MS m/z 418.1 (M+23)+.
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].[Cl:5][C:6]([Cl:13])([Cl:12])[CH2:7][CH2:8][C:9](Cl)=[O:10].C(N(CC)CC)C>C1CCCCC1>[Cl:5][C:6]([Cl:13])([Cl:12])[CH2:7][CH:8]1[C:2]([CH3:4])([CH3:3])[CH2:1][C:9]1=[O:10]
Reactant: O=C(Cl)CCC(Cl)(Cl)Cl
Reactant: C=C(C)C
Solvent: CCN(CC)CC
Solvent: C1CCCCC1
Product: CC1(C)CC(=O)C1CC(Cl)(Cl)Cl
Reaction time: 4 h

Procedure:
261 g of isobutylene is injected into a 1 liter autoclave containing 49 g (0.23 mol) of 4,4,4-trichlorobutyric acid chloride in 280 ml of cyclohexane. A solution of 28.3 g (0.28 mol) of triethylamine in 233 ml of cyclohexane is pumped in at 70° C. in the course of 4 hours. The reaction mixture is afterwards held at 70° C. for a further 4 hours. The precipitated hydrochloride of the triethylamine is filtered off; the filtrate obtained is washed with dilute hydrochloric acid and then with water, dried over sodium sulphate and concentration by evaporation. Distillation of the residue yields 2-(2',2',2'-trichloroethyl)-3,3-dimethylcyclobutanone as a clear liquid, b.p. 118°-122° C./14 mm Hg.
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([O:6][C:7](=[O:18])[C:8]([CH:10]1[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[C:11]1=O)=O)[CH3:5]>CCO>[CH2:4]([O:6][C:7]([C:8]1[C:10]2[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[C:11]=2[NH:3][N:2]=1)=[O:18])[CH3:5]
Reactant: NN
Reactant: CCOC(=O)C(=O)C1CCC(C)(C)C1=O
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1n[nH]c2c1CCC2(C)C
Yield: 70.9 %

Procedure:
Hydrazine hydrate (0.229 mL, 4.71 mmol) was added to a stirring room temperature solution of 1 (0.9961 g, 4.71 mmol) in EtOH (4.7 mL, 1 M) under N2. The reaction was then heated to reflux until judged complete by TLC (2 h). The reaction was concentrated and purified by silica gel chromatography (Combiflash column, 70:30:2 Hexanes:CH2Cl2:2N NH3 in EtOH). Only pure fractions were combined and concentrated to obtain 0.6955 g (71.2%) of 2. 1H (CDCl3, 400 MHz): δ 11.04 (1H, broad s), 4.33 (2H, q, J=7.3 Hz), 2.76 (2H, t, J=6.8 Hz), 2.26 (2H, t, J=6.8 Hz), 1.33 (3H, t, J=7.3 Hz), 1.31 (6H, s) ppm. 13C (CDCl3, 100 MHz): δ 168.08, 160.61, 128.73, 127.27, 61.15, 47.22, 38.64, 27.57, 22.00, 14.48 ppm.
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:4][CH2:5][CH2:6][N:7]=1.[CH3:8][S:9](Cl)(=[O:11])=[O:10]>>[CH3:8][S:9]([N:7]1[CH2:6][CH2:5][N:4]=[C:3]1[S:2][CH3:1])(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: CSC1=NCCN1
Product: CSC1=NCCN1S(C)(=O)=O

Procedure:
Starting from 2-(methylthio)-4,5-dihydro-1H-imidazole and methanesulphonyl chloride, the expected product is obtained according to the procedure described in Step C of Example 3.
Reaction SMILES: [NH:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[C:5]([NH2:14])[C:4]=2[N:3]=[CH:2]1.[H-].[Na+].[CH2:17](Br)[CH:18]([CH3:20])[CH3:19]>CN(C)C=O.O>[CH3:17][CH:18]([CH3:20])[CH2:19][N:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[C:5]([NH2:14])[C:4]=2[N:3]=[CH:2]1
Reactant: Nc1nc2ccccc2c2[nH]cnc12
Reactant: CC(C)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Cn1cnc2c(N)nc3ccccc3c21
Temperature: 100 °C

Procedure:
To a stirred suspension of 1.0 g (0.0054 mole) of 1H-imidazo[4,5-c]quinolin-4-amine in 10 mL of N,N-dimethylformamide was added 0.15 g (0.0059 mole) of sodium hydride. To this stirred mixture was added 0.74 g (0.0054 mole) of isobutyl bromide. After 30 minutes the mixture was heated at about 100° C. for one hour. The mixture was cooled to about 20° C., diluted with 20 mL of water, and the solid was separated by filtration. Recrystallization from N,N-dimethylformamide provided the known antiviral agent 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine.
Reaction SMILES: FC(F)(F)S(O[C@@H:7]([C:12]1[CH:13]=[N:14][C:15]([Cl:18])=[CH:16][CH:17]=1)[C:8]([F:11])([F:10])[F:9])(=O)=O.[F:21][CH2:22][CH2:23][N:24]([C@H:32]1[CH2:36][CH2:35][NH:34][CH2:33]1)[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28].C([O-])([O-])=O.[K+].[K+]>C1COCC1>[Cl:18][C:15]1[N:14]=[CH:13][C:12]([C@@H:7]([N:34]2[CH2:35][CH2:36][C@H:32]([N:24]([CH2:23][CH2:22][F:21])[C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30])[CH2:33]2)[C:8]([F:9])([F:10])[F:11])=[CH:17][CH:16]=1
Reactant: O=S(=O)(O[C@@H](c1ccc(Cl)nc1)C(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N(CCF)[C@H]1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CCF)[C@H]1CCN([C@H](c2ccc(Cl)nc2)C(F)(F)F)C1
Temperature: 50 °C
Reaction time: 18 h
Yield: 48.3 %

Procedure:
To a suspension of 5% Pd/C (1.4 g, 2.2 mmol) in ethanol (12 mL) was added slowly a solution of (S)-benzyl 3-(tert-butoxycarbonyl(2-fluoroethyl)amino)pyrrolidine-1-carboxylate (2.44 g, 21.6 mmol) in methanol (5 mL). The mixture was evacuated and backfilled with nitrogen and then evacuated and backfilled with hydrogen, then stirred under a hydrogen atmosphere for 2 hours. The suspension was filtered through a pad of Celite and washed with a methanol (50 ml). The filtrate was concentrated under reduced pressure to afford (S)-tert-butyl 2-fluoroethyl(pyrrolidin-3-yl)carbamate. To a solution of (S)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethyl trifluoromethanesulfonate (0.97 g, 2.82 mmol) in anhydrous THF (5 mL) was added (S)-tert-butyl 2-fluoroethyl(pyrrolidin-3-yl)carbamate (0.92 g, 3.95 mmol) and K2CO3 (0.59 g, 4.23 mmol). The resulting mixture was heated with stirring at 50° C. for 18 hours. After cooling to ambient temperature the mixture was partitioned between water (12 mL) and ethyl acetate (30 mL). The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure and the residue obtained purified by column chromatography (Biotage 25M; 10% ethyl acetate:hexanes) to afford tert-butyl (S)-1-((R)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-yl(2-fluoroethyl)carbamate (0.58 g, 48%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8]S(C(F)(F)F)(=O)=O)[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.[C:24]1([CH2:30][CH2:31][CH2:32][CH2:33]O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[O:20]1[CH:21]=[CH:22][CH:23]=[C:19]1[C:4]1[C:5]([N+:16]([O-:18])=[O:17])=[C:6]([O:8][CH2:33][CH2:32][CH2:31][CH2:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:7]=[C:2]([NH2:1])[N:3]=1
Reactant: Nc1nc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c(-c2ccco2)n1
Reactant: OCCCCc1ccccc1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1nc(OCCCCc2ccccc2)c([N+](=O)[O-])c(-c2ccco2)n1

Procedure:
From trifluoro-methanesulfonic acid 2-amino-6-furan-2-yl-5-nitro-pyrimidin-4-yl ester, 4-phenyl-1-butanol and DBU in DME. ES-MS ni/e (%): 355 (M+H+, 100).
Reaction SMILES: [CH2:1]([S:5]([C:8]1[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=1)(=[O:7])=[O:6])[CH:2]([CH3:4])[CH3:3].Cl.[CH3:18][C:19]1[O:23][N:22]=[C:21]([C@H:24]([CH2:26][CH:27]([CH3:29])[CH3:28])[NH2:25])[N:20]=1.C(OC(N[C@@H](CC(C)C)C(O)=O)=O)(C)(C)C>>[CH3:28][CH:27]([CH3:29])[CH2:26][C@H:24]([NH:25][C:14]([C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([S:5]([CH2:1][CH:2]([CH3:3])[CH3:4])(=[O:6])=[O:7])[N:13]=1)=[O:16])[C:21]1[N:20]=[C:19]([CH3:18])[O:23][N:22]=1
Reactant: CC(C)CS(=O)(=O)c1cccc(C(=O)O)n1
Reactant: Cc1nc([C@@H](N)CC(C)C)no1
Agent: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Product: Cc1nc([C@H](CC(C)C)NC(=O)c2cccc(S(=O)(=O)CC(C)C)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(isobutylsulfonyl)picolinic acid (Example 330 b) and (S)-5-methyl-α-(2-methylpropyl)-1,2,4-oxadiazole-3-methanamine hydrochloride (which was prepared from (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid (CAN 13139-15-6) in analogy to the procedures described in Example 38 a to e) as starting materials. MS (EI): m/e=395.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH2:17][CH2:18][NH:19][CH:20]2[CH2:25][CH3:26]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:19]3[CH2:18][CH2:17][C:16]4[C:21](=[CH:22][CH:23]=[CH:24][C:15]=4[F:14])[CH:20]3[CH2:25][CH3:26])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CCC1NCCc2c(F)cccc21
Product: CCC1c2cccc(F)c2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-fluoro-1-ethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [Cl:1][CH2:2][C@H:3]1[CH2:7][O:6][S:5](=[O:9])(=[O:8])[O:4]1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][C:18]2=[O:23])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+:28].[K+]>C(#N)C>[K+:28].[Cl:1][CH2:2][C@H:3]([O:4][S:5](=[O:9])(=[O:8])[O-:6])[CH2:7][NH:10][C:11]1[CH:12]=[CH:13][C:14]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][C:18]2=[O:23])=[CH:15][CH:16]=1
Reactant: Nc1ccc(N2CCOCC2=O)cc1
Reactant: O=S1(=O)OC[C@H](CCl)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1COCCN1c1ccc(NC[C@H](CCl)OS(=O)(=O)[O-])cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 126.1 %

Procedure:
Under an atmosphere of nitrogen to a solution of a 7.11 g of (R)-4-chloromethyl-[1,3,2]dioxathiolane 2,2-dioxide (MW=156.59; 1.38 eq.) in 95 mL of acetonitrile were added 6.34 g of 4-(4-aminophenyl)-morpholin-3-one (APMO) (MW=192.22; 1 eq.) and 3.29 g (MW=138.21; 0.72 eq.) of potassium carbonate. The reaction mixture was stirred for 24 h at room temperature. Then the resulting suspension was cooled to 0° C. After stirring for at least 2 h at this temperature, the product was isolated by filtration and the filter cake was washed with 50 mL of acetonitrile. After drying in vacuo at 30° C., 12.09 g of the crystalline title compound (MW=402.90) were isolated. Yield=91.0%.
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: COc1ccc([Mg]Br)cc1
Reactant: N#Cc1cccc(-c2ccncc2C=O)c1
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: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:28]=[CH:27][C:17]([CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])=[C:16]([F:29])[CH:15]=1.[I:30]I>C1COCC1>[Cl:13][C:14]1[CH:28]=[CH:27][C:17]([CH2:18][O:19][Si:20]([C:23]([CH3:24])([CH3:25])[CH3:26])([CH3:22])[CH3:21])=[C:16]([F:29])[C:15]=1[I:30]
Reactant: II
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(Cl)cc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)[Si](C)(C)OCc1ccc(Cl)c(I)c1F
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of diisopropylamine (3.09 mL, 21.8 mmol) in THF (60 mL) under at 0° C. was added n-butyllithium (6.83 mL, 20.0 mmol) dropwise over 5 min. After 10 min, the reaction mixture was cooled to −78° C., and a solution of (4-chloro-2-fluorobenzyloxy)(tert-butyl)dimethylsilane (5.00 g, 18.2 mmol) in THF (15 mL) was added slowly over 5 min. After 2 h at −78° C., a solution of iodine (5.54 g, 21.8 mmol) in THF (25 mL) was added over 10 min. After a further 20 min at −78° C., the reaction mixture was warmed to RT and was quenched with sodium thiosulfate, followed by water (100 mL). The separated aqueous solution was extracted with diethyl ether (2×60 mL). The combined organic phases were washed with saturated aqueous solution of sodium bicarbonate, and brine. The resulting organic solution was then dried over magnesium sulfate and concentrated under reduced pressure. Flash chromatography on silica gel (dichloromethane: hexane=10:90) gave (4-chloro-2-fluoro-3-iodobenzyloxy)(tert-butyl)dimethylsilane as colorless oil. 1H NMR (300 MHz, CDCl3) δ ppm 7.30 (1H, t, J=7.5 Hz), 7.17 (1H, d, J=7.1 Hz), 4.65 (2H, s), 0.75-0.85 (9H, m), 0.01 (6 H, s)
Reaction SMILES: C(O[C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:27]=[C:26]3[C:21]([C:22]([NH2:28])=[N:23][CH:24]=[N:25]3)=[CH:20][CH:19]=2)[C:13](=[O:29])[CH:12]1[CH2:30][O:31][CH3:32])=[O:10])C1C=CC=CC=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[Cl:64][C:65]1[S:69][C:68]([O:70][CH2:71]C(O)=O)=[CH:67][CH:66]=1>CN(C=O)C>[NH2:28][C:22]1[C:21]2[C:26](=[CH:27][C:18]([CH2:17][N:14]3[CH2:15][CH2:16][N:11]([C:9](=[O:10])[CH2:71][O:70][C:68]4[S:69][C:65]([Cl:64])=[CH:66][CH:67]=4)[C@@H:12]([CH2:30][O:31][CH3:32])[C:13]3=[O:29])=[CH:19][CH:20]=2)[N:25]=[CH:24][N:23]=1
Reactant: O=C(O)COc1ccc(Cl)s1
Reactant: COCC1C(=O)N(Cc2ccc3c(N)ncnc3c2)CCN1C(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC[C@H]1C(=O)N(Cc2ccc3c(N)ncnc3c2)CCN1C(=O)COc1ccc(Cl)s1
Reaction time: 16 h

Procedure:
To a solution of 4-(4-amino-quinazoline-7-ylmethyl)-2-methoxymethyl-3-oxo-piperazine-1-carboxylic acid benzyl ester, EXAMPLE 75, (0.69 g, 2.29 mmol) in 9 mL of DMF is added N,N-diisopropylethyl amine (0.89 g, 6.87 mmol), TBTU (0.76 g, 2.36 mmol), and 5-chloro-2-thienyloxyacetic acid, EXAMPLE 24, (0.40 g, 2.08 mmol). The solution is stirred for 16 hours. After this time the solution is concentrated. The crude material is purified by RP-HPLC eluting with a gradient of 10% CH3CN/H2O (0.1% TFA) to 80% CH3CN/H2O (0.1% TFA). The product fractions are lyophilized to give product as a white solid (1.0 g, 1.57 mmol). 1H NMR (d6-DMSO, 300 MHz) δ9.70 (bs, 2H), 8.78 (s, 1H), 8.29 (m, 1H), 7.55 (m, 2H), 6.72 (m, 1H), 6.22 (m, 1H), 4.80 (m, 4H), 3.78 (m, 4H), 3.59 (m, 3H), 3.31 and 3.2 (s, 3H rotational isomers).MS (ion spray) M+H=476. Elemental Analysis: C21H22ClN5O4S.1.4CF3CO2H cal: C=45.03%, H=3.68%, N=11.04%; found C=44.98%, H=3.71%, N=11.02%.
Reaction SMILES: N[CH:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[BrH:13].N([O-])=O.[Na+]>O>[Br:13][CH:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:10]([OH:12])=[O:11]
Reactant: NC(Cc1ccccc1)C(=O)O
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)C(Br)Cc1ccccc1
Temperature: -10 °C

Procedure:
15.0 g (165 mmol) of DL-phenylalanine and 37.8 g (317 mmol) were dissolved in 80 ml of water. 25 ml of conc. HBr in water were added at room temperature, and the reaction solution was then cooled to −10° C. While stirring at −10° C., 7.77 g (112 mmol) of sodium nitrite were added in portions over a period of 1 h, and the reaction solution was then stirred at 0° C. for 6 h. The reaction solution was extracted with diethyl ether (4×60 ml), the combined organic phases were dried over magnesium sulfate, and the solvent was removed in vacuo. Yield: 18.0 g (86%) of yellow oil
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:13][CH2:14][CH3:15])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].CC1(C)C(C)(C)OB([C:24]2[CH:36]=[CH:35][C:27]([CH2:28][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[CH:26][CH:25]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>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>[CH2:14]([NH:13][C:4]1[C:5]([CH3:12])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:11]=[C:2]([C:24]2[CH:25]=[CH:26][C:27]([CH2:28][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[CH:35][CH:36]=2)[CH:3]=1)[CH3:15]
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)cc2)OC1(C)C
Reactant: CCNc1cc(Br)cc(C(=O)OC)c1C
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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCNc1cc(-c2ccc(CN3CCOCC3)cc2)cc(C(=O)OC)c1C
Temperature: 100 °C
Yield: 98.7 %

Procedure:
To a stirred solution of methyl 5-bromo-3-(ethylamino)-2-methylbenzoate (600 mg, 2.2 mmol) and 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]morpholine (1.0 g, 3.3 mmol) in dioxane (5 mL), aqueous 2M Na2CO3 solution (3.96 mL, 7.93 mmol) was added and solution was purged with argon for 15 min. Then Pd(PPh3)4 (255 mg, 0.22 mmol) was added and argon was purged again for 15 min. Reaction mass was heated at 100° C. for 4 h. On completion, reaction mixture was diluted with water and extracted with 10% MeOH/DCM (3 times). Combined organic layer was dried over sodium sulphate. Removal of the solvent under reduced pressure followed by column chromatographic purification afforded the desired compound (800 mg, 98%).