Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)O1.Cl[C:18]1[N:19]=[C:20]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][C@@H:29]2[CH3:34])[C:21]2[CH2:26][N:25]([CH3:27])[CH2:24][C:22]=2[N:23]=1>>[CH3:27][N:25]1[CH2:26][C:21]2[C:20]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][C@@H:29]3[CH3:34])=[N:19][C:18]([C:9]3[CH:10]=[CH:11][C:12]([NH2:13])=[CH:14][CH:15]=3)=[N:23][C:22]=2[CH2:24]1
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1CN(C)C2
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Product: C[C@H]1COCCN1c1nc(-c2ccc(N)cc2)nc2c1CN(C)C2
Yield: 72 %

Procedure:
Step 2 Method as intermediate 5, using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline and (S)-4-(2-chloro-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)-3-methylmorpholine. The crude reaction mixture was partitioned between water and EtOAc, the phases separated and the organic layer dried over magnesium sulphate, filtered and the solvent removed in vacuo. The residue was purified by flash chromatography (0-15% MeOH/DCM), to yield a pale yellow oil (477 mg, 72%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Cl[C:17]1[N:22]=[C:21]([CH3:23])[CH:20]=[C:19]([N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[N:18]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:17]2[N:22]=[C:21]([CH3:23])[CH:20]=[C:19]([N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[N:18]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: Cc1cc(N2CCCC2)nc(Cl)n1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Product: COc1cc(Nc2nc(C)cc(N3CCCC3)n2)ccc1-n1cnc(C)c1
Yield: 91 %

Procedure:
The title compound was prepared from 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine (61 mg, 0.30 mmol) and 2-chloro-4-methyl-6-pyrrolidin-1-yl-pyrimidine (65 mg, 0.33 mmol) in analogous manner as described in example 90. It was obtained in 91% yield as a light brown solid. MS ISP (m/e): 365.2 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.21 (s, 1H), 8.10 (s, 1H), 7.62 (s, 1H), 7.27 (d, 1H), 7.15 (d, 1H), 7.00 (s, 1H), 5.86 (s, 1H), 3.79 (s, 3H), 3.45 (br m, 4H), 2.19 (s, 3H), 2.14 (s, 3H), 1.94 (br m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[NH:11][CH:12]=[CH:13][C:6]=12.[Cl-].[NH4+]>O1CCCC1.CO.[Zn]>[NH:11]1[C:7]2=[N:8][CH:9]=[CH:10][C:5]([O:4][C:3]3[CH:14]=[CH:15][C:16]([NH2:18])=[CH:17][C:2]=3[F:1])=[C:6]2[CH:13]=[CH:12]1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
To a suspension of 4-(2-fluoro-4-nitrophenoxy)-1H-pyrrolo[2,3-b]pyridine (300 mg, 1.1 mmol) in tetrahydrofuran (5 mL) and methanol (10 mL), were added zinc powder (350 mg, 5.5 mmol) and ammonium chloride (294 mg, 5.5 mmol). The mixture was stirred at rt overnight. The mixture was filtered through a pad of Celite®, rinsed with methanol. The filtrate was concentrated. The product was purified by flash column chromatography (silica gel, 1–5% MeOH in CH2Cl2) to afford the desired product (205 mg, 77%) as an off-white solid. MS(ESI+) m/z 244 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:14]2[O:15][C:16]([CH2:19][CH2:20][C:21](=[O:23])[CH3:22])=[CH:17][CH:18]=2)=[C:4]([CH2:9][C:10]([O:12]C)=[O:11])[CH:5]=[C:6]([OH:8])[CH:7]=1.[OH-].[Na+].Cl>C(#N)C>[OH:1][C:2]1[C:3]([C:14]2[O:15][C:16]([CH2:19][CH2:20][C:21](=[O:23])[CH3:22])=[CH:17][CH:18]=2)=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:6]([OH:8])[CH:7]=1
Reactant: COC(=O)Cc1cc(O)cc(O)c1-c1ccc(CCC(C)=O)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CC(=O)CCc1ccc(-c2c(O)cc(O)cc2CC(=O)O)o1
Temperature: 60 °C
Reaction time: 3 h
Yield: 52.2 %

Procedure:
Compound 261 (20 mg, 0.063 mmol) obtained in Example 261 was dissolved in acetonitrile (2.0 mL), and aqueous 4 mol/L sodium hydroxide solution (2.0 mL, 4.0 mmol) was added thereto and stirred at 60° C. for 3 hours. 3 mol/L hydrochloric acid (4.0 mL) was added to the reaction solution, and extracted twice with chloroform (50 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated away under reduced pressure. The resulting residue was purified through preparative thin-layer chromatography (methanol/chloroform=1/6) to obtain Compound 262 (10 mg, 52%).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]3[C:13](=[C:14]([C:15]4[CH:20]=[C:19]([CH3:21])[C:18]([OH:22])=[C:17]([CH3:23])[CH:16]=4)[C:4]=2[C:3]=1[CH3:24])[CH:12]=[CH:11][CH:10]=[CH:9]3.[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1>[CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]3[C:13](=[C:14]([C:15]4[CH:20]=[C:19]([CH3:21])[C:18]([O:22][C:25](=[O:27])[CH3:26])=[C:17]([CH3:23])[CH:16]=4)[C:4]=2[C:3]=1[CH3:24])[CH:12]=[CH:11][CH:10]=[CH:9]3
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(-c2c3ccccc3cc3sc(C)c(C)c23)cc(C)c1O
Solvent: c1ccncc1
Product: CC(=O)Oc1c(C)cc(-c2c3ccccc3cc3sc(C)c(C)c23)cc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.8 %

Procedure:
To a solution of 4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenol (24.0 g, 72.2 mmol) in pyridine (200 mL) at 0C under nitrogen was added dropwise acetic anhydride (8.9 mL, 93.9 mmol) over a period of 10 min. After 45 min at 0C, the reaction mixture was placed in the freezer for 18 h, then removed and stirred for 2 h in an ice bath that was allowed to warm to room temperature. The reaction mixture was poured onto water (1 L) and acidified with 10% hydrochloric acid to a pH of 1. The resulting mixture was extracted with diethyl ether (1 L), which was washed with 10% hydrochloric acid (1 L), twice with water (1 L), brine (700 mL), and dried (MgSO4). Concentration under reduced pressure and chromatography with petroleum ether:ethyl acetate (97:3) gave the title compound as a cream solid (22.4 g, 79%): NMR (CDCl3): δ 8.26 (s, 1H), 7.87 (d, 1H), 7.58 (d, 1H), 7.44-7.40 (m, 1H), 7.33-7.29 (m, 1H), 7.07 (s, 2H), 2.42 (s, 3H), 2.41 (s, 3H), 2.23 (s, 6H), 1.67 (s, 3H); MS(EI): [M+] 374; Anal. Calc. for C24H22O2S: C, 76.97, H, 5.92, N, 0.00. Found: C, 76.17, H, 5.75, N, 0.22.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([CH3:14])([CH3:13])[C:6]([O:8]CC(C)C)=[O:7].[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1[O-:23].[Na+].C1(C)C=CC=CC=1>CS(C)=O>[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1[O:23][CH2:2][CH2:3][CH2:4][C:5]([CH3:14])([CH3:13])[C:6]([OH:8])=[O:7]
Reactant: Cc1ccc(C)c([O-])c1
Reactant: CC(C)COC(=O)C(C)(C)CCCCl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: Cc1ccc(C)c(OCCCC(C)(C)C(=O)O)c1
Yield: 80 %

Procedure:
subsequently reacting said 2-methylpropyl 5-chloro-2,2-dimethylpentanoate with sodium 2,5-dimethylphenolate under reflux in a solvent comprising a mixture of from 10 parts (V/V) toluene/1 part (V/V) dimethylsulfoxide to 5 parts (V/V) toluene/1 part (V/V) dimethylsulfoxide, hydrolyzing the resulting ester, and thereafter acidifying the mixture and isolating 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid;
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@H:10]([CH:14]([CH3:16])[CH3:15])[C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1.[Cl:19]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:19][C:7]1[CH:8]=[C:3]([C:2]([F:17])([F:18])[F:1])[CH:4]=[CH:5][C:6]=1[NH:9][C@H:10]([CH:14]([CH3:16])[CH3:15])[C:11]([OH:13])=[O:12]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)[C@@H](Nc1ccc(C(F)(F)F)cc1)C(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)[C@@H](Nc1ccc(C(F)(F)F)cc1Cl)C(=O)O

Procedure:
To 35 ml of carbon tetrachloride are added 2.81 g (10.0 mmol) of (R)-2-(4-trifluoromethylphenylamino)-3-methylbutanoic acid and 1.33 g (9.96 mmol) of N-chlorosuccinimide, and the mixture is heated to reflux for 1 hour. The mixture is worked up by partition between ether/water. The layers are separated and the aqueous phase is extracted with ether (2×). The combined organic extracts are washed with water and with brine, dried over magnesium sulfate, filtered and evaporated, giving (R)-2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanoic acid.
Reaction SMILES: [CH2:1]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[C:17](=[O:19])[NH:16][CH2:15][CH2:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:28][CH2:29][F:30].[H-].[Na+]>C(OCC)(=O)C>[CH2:20]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[C:17](=[O:19])[N:16]([CH2:28][CH2:29][F:30])[CH2:15][CH2:14]2)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C1NCCc2cccc(N(Cc3ccccc3)Cc3ccccc3)c21
Reactant: FCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C1c2c(cccc2N(Cc2ccccc2)Cc2ccccc2)CCN1CCF

Procedure:
1.06 g (3.095 mmol) 8-dibenzylamino-3,4-dihydro-2H-isoquinolin-1-one are combined with 1.5 ml (12 mmol) 1-bromo-2-fluoro-ethane and at ambient temperature 780 mg (19.50 mmol) sodium hydride are added batchwise over a period of 30 h. The reaction mixture is diluted with ethyl acetate and extracted with sodium hydrogen carbonate solution. The organic phases are dried and the solvent is eliminated in vacuo. The crude product is purified by column chromatography. The carrier used is silica gel and the eluant used is dichloromethane, to which 5% of a mixture of 90% methanol and 10% saturated aqueous ammonia solution have been added.
Reaction SMILES: [I-].ClC1C=CC=C[N+]=1C.[CH2:10]([OH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:18]1([CH2:24][C:25](O)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CCCC)CCCC)CCC>C(OCC)C>[C:18]1([CH2:24][C:25]([O:17][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)Cc1ccccc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCOCC
Solvent: CCCCN(CCCC)CCCC
Product: O=C(Cc1ccccc1)OCc1ccccc1
Yield: 97 %

Procedure:
To a suspended ethyl ether (2 ml) solution of 2-chloro-1-methylpyridinium iodide (306 mg, 1.2 mmol) was added a mixture of benzyl alcohol (108 mg, 1.0 mmol), phenylacetic acid (136 mg, 1.0 mmol) and tri-n-butylamine (444 mg, 2.4 mmol) in ethyl ether (2 ml), and the resulting mixture was refluxed for 3 hours. After evaporation of the solvent, the residue was separated by silica gel column chromatography, and benzyl phenylacetate was isolated in 97% yield.
Reaction SMILES: [C:1]([NH:4][C@@H:5]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:18]3[C:23]([CH:24]=[C:25]4[C:30]=2[CH:29]=[CH:28][CH:27]=[CH:26]4)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=1)[C:6]([O:8]C)=[O:7])(=[O:3])[CH3:2].O.[OH-].[Li+]>C1COCC1.O.O>[C:1]([NH:4][C@@H:5]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[C:18]3[C:23]([CH:24]=[C:25]4[C:30]=2[CH:29]=[CH:28][CH:27]=[CH:26]4)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][CH:16]=1)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: COC(=O)[C@H](Cc1ccc(-c2c3ccccc3cc3ccccc23)cc1)NC(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N[C@@H](Cc1ccc(-c2c3ccccc3cc3ccccc23)cc1)C(=O)O
Reaction time: 16 h
Yield: 90 %

Procedure:
To a solution of 96 (80 mg, 0.20 mmol) in THF/water, 2:1 (3 mL) was added lithium hydroxide monohydrate (17 mg, 0.40 mmol) and the resulting suspension was allowed to stir for 16 h. The reaction mixture was diluted with water (30 mL) and the THF was removed by evaporation. The aqueous layer was washed with DCM (40 mL) to remove unreacted starting material. The aqueous phase was acidified with 10% HCl and the resulting precipitate was extracted with DCM (3×40 mL). The combined organics were dried and evaporated to yield the title compound (69 mg, 0.18 mmol, 90%) as a white solid. Mp 76° C. [α]D20 +29.7 (c. 0.1, EtOH). 1H NMR (CDCl3, 300 MHz): δ 8.47 (s, 1H, ArH10″); 8.02 (d, J=8.4 Hz, 2H, ArH3″ and ArH6″); 7.59 (d, J=8.7 Hz, 2H, ArH8″ and ArH1″); 7.45 (m, 2H, ArH4″ and ArH5″); 7.35 (m, 6H, ArH2″ and ArH7″, 4×ArH″); 6.27 (d, J=6.6 Hz, 1H, NH); 5.00 (m, 1H, H2); 3.39 (dd, J=4.8, 12.9 Hz, 1H, H3a); 3.26 (dd, J=6.3, 14.4 Hz, 1H, H3b); 2.07 (s, 3H, COCH3). Mass Spectrum (ES, +ve) m/z 383 (70%) [MH+]. HRMS calcd for C25H22NO3 384.1600, found 384.1610.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[C:21]1([C:27]2[N:28]=[CH:29][NH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>CS(C)=O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:30]4[CH:31]=[C:27]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[N:28]=[CH:29]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: c1ccc(-c2c[nH]cn2)cc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C(O)c1cn(C2CC2)c2c(F)c(-n3cnc(-c4ccccc4)c3)c(F)cc2c1=O
Yield: 56.5 %

Procedure:
A mixture of 2.8 g (10 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 4.3 g (30 mmol) of 4-phenylimidazole, 20 ml of triethylamine and 100 ml of DMSO is refluxed for 3 hours. It is allowed to cool, poured into a water/ice mixture and adjusted to pH 5 to give a precipitate, which is filtered off and washed with water. The solid is dried under vacuum to give 2.3 g of 1-cyclopropyl-6,8-difluoro-7-(4-phenylimidazol-1-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid melting at 286°-288° C.
Reaction SMILES: BrC1C=CC=C2C=1C(C1C(O)=CC3OCOC=3C=1)[C:5](=[O:16])N2CCCCC.[Br:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]([CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[C:35]2=[O:48])=[C:30]([OH:49])[CH:29]=1>>[Br:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2([CH2:5][OH:16])[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]([CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[C:35]2=[O:48])=[C:30]([OH:49])[CH:29]=1
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Reactant: CCCCCN1C(=O)C(c2ccc(Br)cc2O)c2ccccc21
Product: CCCCCN1C(=O)C(CO)(c2ccc(Br)cc2O)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 1E, and making non-critical variations to replace 4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with 3-(4-bromo-2-hydroxyphenyl)-1-pentyl-1,3-dihydro-2H-indol-2-one, the title compound was obtained: Rf=0.5 (EtOAc/Hexanes, ¼).
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]([NH:14][C:15]([C:17]1[CH:22]=[C:21]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])[C:20](Br)=[CH:19][N:18]=1)=[O:16])([CH3:13])[C:7]1[N:11]=[C:10]([CH3:12])[O:9][N:8]=1)(=[O:4])=[O:3].[Br-].[CH:31]1([Zn+])[CH2:33][CH2:32]1>C1COCC1>[CH3:1][S:2]([CH2:5][C:6]([NH:14][C:15]([C:17]1[CH:22]=[C:21]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])[C:20]([CH:31]2[CH2:33][CH2:32]2)=[CH:19][N:18]=1)=[O:16])([CH3:13])[C:7]1[N:11]=[C:10]([CH3:12])[O:9][N:8]=1)(=[O:4])=[O:3]
Reactant: Cc1nc(C(C)(CS(C)(=O)=O)NC(=O)c2cc(OCC(F)(F)F)c(Br)cn2)no1
Reactant: [Zn+]C1CC1
Agent: [Br-]
Solvent: C1CCOC1
Product: Cc1nc(C(C)(CS(C)(=O)=O)NC(=O)c2cc(OCC(F)(F)F)c(C3CC3)cn2)no1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 11 %

Procedure:
To a solution of 5-Bromo-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid [2-methanesulfonyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide (Example 84c, 60 mg, 120 μmol) in dry THF (0.5 ml) under an argon atmosphere was added tetrakis(tripehylphosphine) palladium(0) (13.8 mg, 12.0 μmol) followed by cyclopropylzinc(II) bromide solution 0.5M in THF (527 μl, 263 μmol). The reaction mixture was then stirred at 100° C. under microwave radiation for 90 min. The reaction mixture was concentrated in vacuo. The residue was dissolved in ethylacetate and solution was extracted with an 1.0M aqueous solution of sodium bicarbonate. The organic phase was dried over sodium sulfate and evaporated down to dryness. The crude material was purified by preparative HPLC to yield the title compound (5.9 mg, 11%) as white solid. MS (ESI, m/z): 463.4 (M+H+).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>C(#N)C>[O:13]1[CH2:14][CH2:15][N:10]([C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[C:5]#[N:6])[CH2:11][CH2:12]1
Reactant: C1COCCN1
Reactant: N#Cc1cccc(F)c1
Solvent: CC#N
Product: N#Cc1cccc(N2CCOCC2)c1
Temperature: 110 °C
Reaction time: 72 h
Yield: 26.6 %

Procedure:
3-Fluorobenzonitrile (4.35 g, 36.0 mmol) was dissolved in acetonitrile (40 ml), and morpholine (110 ml, 1.25 mol) was added thereto followed by stirring at 110° C. for 3 days and nights. The reaction mixture was concentrated to give oily substances which were then purified by silica gel chromatography (eluent: chloroform) to give the title compound (1.80 g, 27%) as oily substances.
Reaction SMILES: CC(C[AlH]CC(C)C)C.[OH:10][CH2:11][CH2:12][CH:13]1[CH2:17][CH:16]([N:18]2[C:22]3[N:23]=[C:24]([S:37][CH2:38]CC)[N:25]=[C:26]([NH:27][CH:28]4[CH2:30][CH:29]4[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:21]=3[N:20]=[N:19]2)[CH:15]([OH:41])[CH:14]1[OH:42].C(OCC)(=O)C>C1(C)C=CC=CC=1>[OH:10][CH2:11][CH2:12][CH:13]1[CH2:17][CH:16]([N:18]2[C:22]3[N:23]=[C:24]([S:37][CH3:38])[N:25]=[C:26]([NH:27][CH:28]4[CH2:30][CH:29]4[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:21]=3[N:20]=[N:19]2)[CH:15]([OH:41])[CH:14]1[OH:42]
Reactant: CCCSc1nc(NC2CC2c2ccccc2)c2nnn(C3CC(CCO)C(O)C3O)c2n1
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CSc1nc(NC2CC2c2ccccc2)c2nnn(C3CC(CCO)C(O)C3O)c2n1
Temperature: 4 °C
Reaction time: 0.5 h

Procedure:
DIBAL-H® (1.5M solution in toluene, 20 ml) was added to an ice-cooled solution of the product of Example 11, step a) (2.00 g) in toluene (30 ml) and the solution stirred at this temperature for 30 minutes before adding ethyl acetate (2 ml). The solution was washed with water and concentrated. The residue (1.8 g) was taken into ethanol and cooled to 4° C. before adding 3-chloroperoxybenzoic acid (50-55%, 2.5 g) and allowing the reaction to stir at room temperature for 18 hours. The solution was washed with aqueous sodium metabisulfite solution (3×10 ml) then dried and concentrated. Purification (SiO2, ether:isohexane, 80:20, as eluent) afforded the subtitle compound (1.8 g).
Reaction SMILES: [NH2:1][C@@H:2]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].[Na+:22]>[Pd]>[Na+:22].[F:12][C:9]1[CH:10]=[CH:11][C:6]([C@H:2]([NH:1][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:3]([O-:5])=[O:4])=[CH:7][CH:8]=1
Reactant: N[C@H](C(=O)O)c1ccc(F)cc1
Reactant: O=Cc1ccccc1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Product: O=C([O-])[C@@H](NCc1ccccc1)c1ccc(F)cc1
Temperature: 15 °C
Reaction time: 4 h
Yield: 92 %

Procedure:
A solution of (S)-α-amino-4-fluorobenzeneacetic acid (1.00 kg, 5.91 moles) in aqueous sodium hydroxide (1M, 5.91 L) was filtered and added to 10% palladium-on-carbon (25 g). A solution of benzaldehyde (941 g, 8.87 moles) was added and the batch was stirred under hydrogen (50 psi) for 4 hours. The batch was filtered and the filtrate was evaporated to residue under vacuum, then flushed with ethanol (2×3 L). The residue was slurried in boiling ethanol (1.5 L), then cooled to 15° C. The slurry was filtered and the filter cake was washed with cold ethanol (2×500 mL), then dried under vacuum at 55° C. to give 1.83 kg (92% yield) of (S)-4-fluoro-α-[(phenylmethyl)-amino]benzeneacetate sodium salt.
Reaction SMILES: Cl[CH2:2][CH:3]([C:5]1[N:6]([CH3:10])[CH:7]=[CH:8][CH:9]=1)[OH:4].[CH3:11][NH2:12].[BH4-].[Na+]>CO.O>[CH3:11][NH:12][CH2:2][CH:3]([C:5]1[N:6]([CH3:10])[CH:7]=[CH:8][CH:9]=1)[OH:4]
Reactant: CN
Reactant: Cn1cccc1C(O)CCl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CNCC(O)c1cccn1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-chloro-1-(1-methyl-1H-pyrrol-2-yl)ethanol (Croce, P. D.; Ferraccioli, R.; Ritieni, A. Synthesis, 1990, 212-213) (2.05 g) is dissolved in methanol (40 mL) and added dropwise to a 2.0 M solution of methylamine in methanol (65 mL) at 0° C. The reaction mixture is stirred at 0° C. for 1 h and then allowed to warm to room temperature. The reaction mixture is stirred at room temperature for 18 h and then cooled to 0° C. Sodium borohydride (0.738 g) in H2O (40 mL) is added dropwise. The reaction mixture is stirred at 0° C. for 30 min and then allowed to warm to room temperature. The reaction mixture is stirred at room temperature for 18 h. An additional 0.738 g (19.5 mmol) of sodium borohydride is added and the reaction mixture is stirred at room temperature for 18 h. The reaction is quenched with a 1 N HCl solution and then concentrated in vacuo to remove methanol. The aqueous layer is adjusted to pH 12 with a 2 N NaOH solution and extracted with CH2Cl2 (4×100 mL). The combined organic layers are dried (MgSO4), filtered, and concentrated in vacuo. The resulting yellow oil is crystallized from ethyl acetate to yield 0.772 g of the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.IC.[C:25](=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[N:16]([CH3:25])[CH:17]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: CCCCC(CC(=O)c1ccc(=O)[nH]c1)c1ccc(Br)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: CCCCC(CC(=O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1

Procedure:
In analogy to example 161, step 1, 5-[3-(4-bromo-phenyl)-heptanoyl]-1H-pyridin-2-one was reacted with iodomethane in the presence of potassium carbonate to give the title compound as a colorless solid, MS (ESI+): m/z=376.2 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH:7]([CH2:11][CH3:12])[C:8]([OH:10])=[O:9])(=[O:3])[CH3:2].[Si:17]([O:24][C@H:25]1[CH2:34][C@H:33](O)[C@H:32]2[C:27]([CH:28]=[CH:29][C@H:30]([CH3:53])[C@@H:31]2[CH2:36][CH2:37][C@H:38]2[O:43][C:42](=[O:44])[CH2:41][C@H:40]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[CH2:39]2)=[CH:26]1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>>[Si:17]([O:24][C@H:25]1[CH2:34][C@H:33]([O:9][C:8](=[O:10])[CH:7]([O:6][C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[C:1](=[O:3])[CH3:2])[CH2:11][CH3:12])[C@H:32]2[C:27]([CH:28]=[CH:29][C@H:30]([CH3:53])[C@@H:31]2[CH2:36][CH2:37][C@H:38]2[O:43][C:42](=[O:44])[CH2:41][C@H:40]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:47])[CH3:48])[CH2:39]2)=[CH:26]1)([C:20]([CH3:21])([CH3:22])[CH3:23])([CH3:19])[CH3:18]
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Reactant: CCC(Oc1ccccc1C(C)=O)C(=O)O
Product: CCC(Oc1ccccc1C(C)=O)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 89 %

Procedure:
A procedure similar to that described in Example 1, above, was followed, but using 0.81 g of (2RS)-2-(2-acetylphenoxy)butyric acid and 1.0 g of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give 1.22 g of the title compound as a colorless foam.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH:5]=[CH:6][C:7]1[S:15][C:14]2[C:13]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[N:12][C:11]([Cl:22])=[N:10][C:9]=2[CH:8]=1)[CH3:2]>C(OCC)(=O)C.C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][C:7]1[S:15][C:14]2[C:13]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[N:12][C:11]([Cl:22])=[N:10][C:9]=2[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
To as solution of 3-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-acrylic acid ethyl ester (2 g) in ethyl acetate (100 mL) was added a suspension of Pd/C (200 mg) in ethanol (10 mL). The flask was flushed with nitrogen and then a hydrogen balloon was fitted. The reaction mixture was stirred at room temperature for 16 h. The mixture was then filtered through Celite and the filtrate concentrated to give 3-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)propionic acid ethyl ester as a yellow solid (1.83 g).