Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([OH:9])[CH3:8].CCN(CC)CC.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([O:9][S:18]([CH3:17])(=[O:20])=[O:19])[CH3:8]
Reactant: CC(O)c1ccccn1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(OS(C)(=O)=O)c1ccccn1
Reaction time: 1.17 h
Yield: 105.3 %

Procedure:
To a stirred solution of 1-pyridin-2-yl-ethanol (156 mg, 1.27 mmol) (Mandal, S. K. et al. J. Org. Chem. 2003, 68, 4600-4603) and Et3N (0.27 mL, 1.94 mmol) in CH2Cl2 (5 mL) was added methanesulphonyl chloride (0.11 mL, 1.29 mmol) and the solution was stirred for 70 minutes. The solution was diluted with CH2Cl2 (20 mL) and washed with saturated aqueous NaHCO3 (2×15 mL) and brine (1×15 mL). The combined aqueous phase was extracted with CH2Cl2 (1×15 mL). The combined organic phase was dried (Na2SO4), filtered and concentrated under reduced pressure to give crude methanesulphonic acid 1-pyridin-2-yl-ethyl ester as a yellow oil (269 mg, 100%). 1H NMR (CDCl3) δ 1.77 (d, 3H, J=6.6 Hz), 2.94 (s, 3H), 5.79 (q, 1H, J=6.6 Hz), 7.28 (ddd, 1H, J=7.4, 7.1, 1.3 Hz), 7.47 (d, 1H, J=7.9 Hz), 7.76 (td, 1H, J=7.6, 1.7 Hz), 8.61 (d, 1H, J=4.9 Hz).
Reaction SMILES: C[O:2][C:3](=[O:37])[C:4]([CH3:36])([CH3:35])[CH2:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[NH:17][C:16]3[CH:18]=[C:19]([C:22]4[O:23][C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[CH3:33])=[N:25][N:26]=4)[CH:20]=[CH:21][C:15]=3[N:14]=2)=[C:8]([CH3:34])[CH:7]=1.[OH-].[Na+].Cl>C1COCC1.CO.O>[CH3:12][C:10]1[CH:11]=[C:6]([CH2:5][C:4]([CH3:36])([CH3:35])[C:3]([OH:37])=[O:2])[CH:7]=[C:8]([CH3:34])[C:9]=1[C:13]1[NH:17][C:16]2[CH:18]=[C:19]([C:22]3[O:23][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[N:25][N:26]=3)[CH:20]=[CH:21][C:15]=2[N:14]=1
Reactant: COC(=O)C(C)(C)Cc1cc(C)c(-c2nc3ccc(-c4nnc(-c5ccccc5C)o4)cc3[nH]2)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccccc1-c1nnc(-c2ccc3nc(-c4c(C)cc(CC(C)(C)C(=O)O)cc4C)[nH]c3c2)o1
Reaction time: 4 h

Procedure:
Dissolve 3-{3,5-dimethyl-4-[6-(5-o-tolyl-[1,3,4]oxadiazol-2-yl)-1H-benzoimidazol-2-yl]-phenyl}-2,2-dimethyl-propionic acid methyl ester (286 mg, 0.578 mmol) in THF (2.9 mL)/MeOH (2.9 mL). Add 1 N NaOH (2.9 mL) and stir for 4 h. Add NaOH (102 mg, 2.55 mmol) in water (1 mL). Upon disappearance of the ester by LC/MS, concentrate the reaction. Acidify to pH 1.5 by addition of 1 N HCl (5.4 mL). Collect the solid by filtration and dry at 40° C. in a vacuum oven. Triturate the solid with DCM to afford the title compound as a white solid: (M+H)+ 481.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](Br)=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:7]=[CH:6]2.[F:18][C:19]([F:24])([F:23])C([O-])=O.[Na+]>[Cu]I.CN(C)C=O>[CH3:1][O:2][C:3]1[C:4]([C:19]([F:24])([F:23])[F:18])=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:7]=[CH:6]2
Reactant: COC(=O)c1cccc2c(Br)c(OC)ccc12
Reactant: O=C([O-])C(F)(F)F
Agent: [Cu]I
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c(C(F)(F)F)c(OC)ccc12
Reaction time: 5 h
Yield: 76 %

Procedure:
Using the same general procedure as in Comparative Example A, one molar proportion of methyl 6-methoxy-5-bromo-1-naphthoate (MMBN) was reacted with 1.7 molar proportions of sodium trifluoroacetate in the presence of 2 molar proportions of CuI and molar proportions of N,N-dimethylformamide (DMF), with an additional 0.95 molar proportion of sodium trifluoroacetate being added during the course of the reaction. The total reaction time was 5 hours. After workup, the desired methyl 6-methoxy-5-trifluoromethyl-1-naphthoate (MMTN) was isolated in a 76% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:9]2=O)=[CH:5][CH:4]=1>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6](=[CH:5][CH:4]=1)[CH2:7][CH:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9]2
Reactant: CCOC(=O)C1Cc2ccc(OC)cc2C1=O
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)C1Cc2ccc(OC)cc2C1

Procedure:
32.0 g (0.145 mol) of ethyl 6-methoxy-indan-1-one-2-carboxylate [cf. H. O. House, C. B. Hudson, J. Org. Chem. 35 (1970) 3, 647-651] are hydrogenated with 20 bar of H2 at 50° C. for 5 h in 180 ml of MeOH in the presence of 5 g of palladium/carbon (5% strength) as a catalyst. The catalyst is filtered off, the methanol is stripped off in vacuo and the residue is distilled in a bulb tube furnace.
Reaction SMILES: C[O:2][C:3](=[O:41])[C:4]1[CH:9]=[C:8]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH:7]=[CH:6][C:5]=1/[CH:15]=[CH:16]/[C:17]1[CH:22]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:20]=[C:19]([C:27]2[C:28]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[N:29][CH:30]=[CH:31][CH:32]=2)[CH:18]=1>[Li+].[OH-].CO.C1COCC1>[CH2:34]([O:33][C:28]1[C:27]([C:19]2[CH:18]=[C:17](/[CH:16]=[CH:15]/[C:5]3[CH:6]=[CH:7][C:8]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:9][C:4]=3[C:3]([OH:41])=[O:2])[CH:22]=[C:21]([C:23]([CH3:24])([CH3:26])[CH3:25])[CH:20]=2)=[CH:32][CH:31]=[CH:30][N:29]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COC(=O)c1cc(NS(C)(=O)=O)ccc1/C=C/c1cc(-c2cccnc2OCc2ccccc2)cc(C(C)(C)C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)c1cc(/C=C/c2ccc(NS(C)(=O)=O)cc2C(=O)O)cc(-c2cccnc2OCc2ccccc2)c1

Procedure:
step a—A solution of 199 (0.042 g) in 1 N LiOH (1 mL), MeOH (1 mL) and THF (1 mL) was stirred at 50° C. for 3 h, cooled and concentrated in vacuo. The solution was acidified and extracted with EtOAc. The extracts were washed with brine, dried, filtered and evaporated to afford 2-{(E-2-[3-(2-benzyloxy-pyridin-3-yl)-5-tert-butyl-phenyl]-vinyl}-5-methanesulfonylamino-benzoic acid (199a).
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=1[O:19][Si](C(C)(C)C)(C)C)[CH:12]=[CH:13][CH2:14][OH:15])(C(C)(C)C)(C)C.Cl>C(Cl)Cl.O=[Mn]=O>[CH:16]1[C:11](/[CH:12]=[CH:13]/[CH:14]=[O:15])=[CH:10][C:9]([OH:8])=[C:18]([OH:19])[CH:17]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C=CCO)cc1O[Si](C)(C)C(C)(C)C
Agent: O=[Mn]=O
Agent: Cl
Solvent: ClCCl
Product: O=C/C=C/c1ccc(O)c(O)c1
Temperature: 20 °C
Reaction time: 24 h
Yield: 53.9 %

Procedure:
3,4-Bis-(t-butyldimethylsilyloxy)cinnamyl alcohol (7.88 g, 20 mmol) was dissolved in 1000 mL CH2Cl2, 17.2 g activated MnO2 (200 mmol) were added and the mixture was vigorously stirred for 24 h at 20° C. MnO2 was filtered off and the filtrate was taken to dryness. To the obtained 3,4-bis(tBDMS)caffeoyl aldehyde 250 mL of CHCl3 was added followed by addition of n-Bu4NF monohydrate (11.6 g, 40 mmol). The mixture was stirred at 20° C. for 30 min and worked up with 300 mL of 5% HCl. Chloroform layer was separated, washed with H2O, dried with Na2SO4 and taken to dryness. The residue was purified on a silica gel column, eluent MeOH—CHCl3, 1:4+1% AcOH. The solvents were evaporated and the crystalline residue was washed with CHCl3 to give caffeoyl aldehyde (1.77 g, 54%). M.p. 200 -202° C., λmax 222, 239, 249, 342 nm. 1H-NMR (δ, ppm): 6.54 (dd, 1H, J 7.7 and 15.8 Hz, Hα), 6.91 (d, 1H, J 8.2 Hz, H5), 7.12 (br.d, 1H, J 8.2 Hz, H6), 7.21 (br.s, 1H, H2), 7.52 (d, 1H, J 15.8 Hz, H), 9.62 (d, 1H, J 7.7 Hz, CHO).
Reaction SMILES: [C:1]([CH:4]([O:6][C:7]1[N:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]=1)[CH3:5])([OH:3])=O.[Na].[CH3:19][OH:20]>>[CH2:19]([O:20][C:1]([CH:4]([O:6][C:7]1[N:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]=1)[CH3:5])=[O:3])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(Oc1ncn(-c2ccccc2)n1)C(=O)O
Reactant: CO
Agent: [Na]
Product: CC(Oc1ncn(-c2ccccc2)n1)C(=O)OCc1ccccc1

Procedure:
A 5.5 g portion of the compound of Example 22 was added to 50 ml of methanol containing 0.54 g of sodium, and the mixture was heated briefly to reflux. It was then cooled and the solvent was removed under vacuum. To it was added 75 ml of toluene, 2.6 ml of benzyl chloride and 2.3 g of triethylamine, and the mixture was heated under reflux for 22 hours. It was then cooled, poured over ice-water, and extracted with ethyl acetate. The extract was washed with water and with saturated brine, and was dried with sodium sulfate and phase separation paper. It was then evaporated under vacuum, and the residue was recrystallized from ethanol-water to obtain 2.5 g of the desired product, m.p. 78°-80°.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[Br:11][CH2:12][CH2:13][C:14](Cl)=[O:15]>>[Br:11][CH2:12][CH2:13][C:14]([N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1)=[O:15]
Reactant: c1ccc2c(c1)CCNC2
Reactant: O=C(Cl)CCBr
Product: O=C(CCBr)N1CCc2ccccc2C1

Procedure:
from 3,4-dihydro-1H-isoquinoline and 3-bromopropanoyl chloride
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH3:8].[CH:9]1([NH:15][C:16]2[C:17]([NH2:22])=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.O>CN(C=O)C>[CH:9]1([NH:15][C:16]2[C:17]([NH:22][CH3:8])=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Nc1ccccc1NC1CCCCC1
Reactant: CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CNc1ccccc1NC1CCCCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 39 %

Procedure:
Potassium carbonate (2.45 g, 17.7 mmol) and iodomethane (0.81 ml, 13.0 mmol) were added to a solution of N-cyclohexyl-benzene-1,2-diamine from Example E26.2 (2.25 g, 11.8 mmol) in DMF (10 ml). The mixture was stirred for 6 h at room temperature then poured into water and extracted with EtOAc. The organic layer was washed with water then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 5% EtOAc:95% hexane) to yield the title compound (950 mg, 39%).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([N:16]3[N:20]=[N:19][C:18]([CH2:21][CH3:22])=[N:17]3)[C@@H:13]([OH:23])[C@H:12]2[OH:24])=[C:4]([NH:25][CH2:26][CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:3]=1.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].C1(C(C2C=CC=CC=2)CNC2N=C(NCCN3CCCCC3)N=C3C=2N=CN3[C@@H]2C[C@H](N3C=C(CO)C=N3)[C@@H](O)[C@H]2O)C=CC=CC=1.[C:94]([NH:101][C@@H:102]1[CH2:106][CH2:105][NH:104][CH2:103]1)([O:96][C:97]([CH3:100])([CH3:99])[CH3:98])=[O:95]>>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[C:97]([O:96][C:94](=[O:95])[NH:101][C@@H:102]1[CH2:106][CH2:105][N:104]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[C@@H:11]3[CH2:15][C@H:14]([N:16]4[N:20]=[N:19][C:18]([CH2:21][CH3:22])=[N:17]4)[C@@H:13]([OH:23])[C@H:12]3[OH:24])=[C:4]([NH:25][CH2:26][CH:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:3]=2)[CH2:103]1)([CH3:100])([CH3:98])[CH3:99]
Reactant: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(Cl)nc43)[C@H](O)[C@@H]2O)n1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Agent: OCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NCCN5CCCCC5)nc43)[C@H](O)[C@@H]2O)c1
Solvent: O=C(O)C(F)(F)F
Product: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)OC(C)(C)C)C5)nc43)[C@H](O)[C@@H]2O)n1

Procedure:
This compound is prepared from (1R,2S,3R,5S)-3-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(5-ethyl-tetrazol-2-yl)-cyclopentane-1,2-diol (BA6) using a procedure analogous to that of (1R,2S,3R,5S)-3-[6-(2,2-diphenyl-ethylamino)-2-(2-piperidin-1-yl-ethylamino)-purin-9-yl]-5-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentane-1,2-diol trifluoroacetate (Example 46) replacing 1-(2-amino-ethyl)piperidine with (3R)-(+)-3-(BOC-amino)pyrrolidine. MS (ES+) m/e 696 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12](/[CH:13]=[CH:14]/[C:15]([F:18])([F:17])[F:16])[C:11](=[O:19])[N:10]([CH2:20][C:21](O)=[O:22])[N:9]=2)=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[C:38](=[O:52])([O:40][CH2:41][CH:42]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[Cl:51])[CH2:43][NH2:44])[NH2:39]>CN(C=O)C>[C:38](=[O:52])([O:40][CH2:41][CH:42]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[Cl:51])[CH2:43][NH:44][C:21](=[O:22])[CH2:20][N:10]1[C:11](=[O:19])[N:12](/[CH:13]=[CH:14]/[C:15]([F:18])([F:17])[F:16])[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[N:9]1)[NH2:39]
Reactant: O=C(O)Cn1nc(-c2ccc(Cl)cc2)n(/C=C/C(F)(F)F)c1=O
Reactant: NCC(COC(N)=O)c1ccccc1Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: NC(=O)OCC(CNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(/C=C/C(F)(F)F)c1=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 47 mg (135 μmol) of the compound of Example 33A, 34 mg (176 μmol) of EDC and 24 mg (176 μmol) of HOBt in 1 ml of DMF was stirred at RT for 1 h, and 34 mg (149 μmol) of the compound of Example 15A were then added. The mixture was stirred at RT for 16 h and then separated directly by preparative HPLC [Method 9] into its components. This gave 28 mg (37% of theory) of the title compound.
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[C:3](=[O:5])[CH3:4].[CH2:7]([O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Ba+2].[OH-]>CCO>[CH2:7]([O:14][C:15]1[CH:16]=[CH:17][C:18]([CH:19]=[CH:4][C:3](=[O:5])[CH:2]([CH3:6])[CH3:1])=[CH:21][CH:22]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: CC(=O)C(C)C
Agent: [Ba+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)C(=O)C=Cc1ccc(OCc2ccccc2)cc1

Procedure:
The title compound was prepared as described in the General Method 2 using 81.1 g (942 mmol) of 3-methyl-butan-2-one, 100 g (474 mmol) of 4-benzyloxybenzaldehyde, 10 g of anhydrous barium hydroxide and 500 mL of EtOH.
Reaction SMILES: C(OC([NH:8][C:9]1([C:12]([NH:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:13])[CH2:11][CH2:10]1)=O)(C)(C)C.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[NH2:8][C:9]1([C:12]([NH:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:13])[CH2:11][CH2:10]1
Reactant: CCOC(=O)CNC(=O)C1(NC(=O)OC(C)(C)C)CC1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CNC(=O)C1(N)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.7 %

Procedure:
To 680 mg of compound 22 were added 10 ml of trifluoroacetic acid and 0.5 g of anisole. The mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. To the residue was added aqueous potassium carbonate and pH was adjusted over 10. The mixture was saturated with sodium chloride and extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The procedure gave 410 mg of compound 23.
Reaction SMILES: [CH:1]12[O:6][CH:2]1[CH2:3][CH2:4][CH2:5]2.Br[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([O:16][CH3:17])[CH:9]=1>>[CH3:15][O:14][C:12]1[CH:13]=[C:8]([C@@H:2]2[CH2:3][CH2:4][CH2:5][C@H:1]2[OH:6])[CH:9]=[C:10]([O:16][CH3:17])[CH:11]=1
Reactant: C1CC2OC2C1
Reactant: COc1cc(Br)cc(OC)c1
Product: COc1cc(OC)cc([C@@H]2CCC[C@H]2O)c1

Procedure:
Preparation 19 is prepared from cyclopentene oxide and 1-bromo-3,5-dimethoxybenzene in a manner similar to preparation 10. 1H NMR (CDCl3): 6.41 (s, 2H), 6.33(s, 1H), 4.15 (dd, J=7.5 Hz, 1H), 3.78 (s, 6H), 2.81 (dd, J=9.2 Hz, 1H), 2.1 (m, 2H), 1.9-1.5 (m, 6H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:28]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[CH3:29])[S:5][C:6]=1[CH:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[N:11]([Si](C(C)C)(C(C)C)C(C)C)[CH:10]=1)[OH:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(#N)C>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][N:28]([CH3:29])[C:4]2[S:5][C:6]([C:7]([C:9]3[C:17]4[C:12](=[N:13][CH:14]=[CH:15][CH:16]=4)[NH:11][CH:10]=3)=[O:8])=[CH:2][N:3]=2)=[CH:32][CH:33]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(O)c2sc(N(C)Cc3ccc(Cl)cc3)nc2Cl)c2cccnc21
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CN(Cc1ccc(Cl)cc1)c1ncc(C(=O)c2c[nH]c3ncccc23)s1
Temperature: 40 °C
Reaction time: 2 h
Yield: 22.2 %

Procedure:
A mixture of {4-chloro-2-[(4-chloro-benzyl)-methyl-amino]-thiazol-5-yl}-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol (552, 1 g, 2 mmol), triethylsilane (2 mL, 12 mmol), and trifluoroacetic acid (1 mL, 13 mmol) in acetonitrile (10 mL) was stirred at 40° C. for 2 hours. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with sodium bicarbonate and brine, and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with methanol in dichloromethane to provide the desired compound as a yellow solid (P-0178, 0.17 g, 30%). MS (ESI) [M+H+]+=383.09.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH2:16])(C)(C)C.C(O[C:23](=[O:39])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][N:30]=[C:29]([C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)[CH:28]=1)=O)(C)(C)C>>[N:30]1[CH:31]=[CH:32][C:27]([C:25]2[CH2:24][C:23](=[O:39])[NH:16][C:9]3[CH:10]=[C:11]([Cl:15])[C:12]([CH3:14])=[CH:13][C:8]=3[N:7]=2)=[CH:28][C:29]=1[C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccnc(-c2cccnc2)c1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Product: Cc1cc2c(cc1Cl)NC(=O)CC(c1ccnc(-c3cccnc3)c1)=N2

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-methyl-phenyl)-carbamic acid tert-butyl ester (Example J22) (102 mg, 0.4 mmol) and 3-[2,3′]bipyridinyl-4-yl-3-oxo-propionic acid tert-butyl ester (Example K57) (119 mg, 0.4 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (120 mg).
Reaction SMILES: C(OC1C(=O)C=C(C)OC=1)C1C=CC=CC=1.FC(F)CN.Cl.C(N(CC)CC)C.OC1C(=O)C=CN(CC(F)(F)F)C=1C.C([O:51][C:52]1[C:53](=[O:63])[CH:54]=[C:55]([CH3:62])[N:56]([CH2:58][CH:59]([F:61])[F:60])[CH:57]=1)C1C=CC=CC=1>CO.[Pd].N1C=CC=CC=1>[F:61][CH:59]([F:60])[CH2:58][N:56]1[CH:57]=[C:52]([OH:51])[C:53](=[O:63])[CH:54]=[C:55]1[CH3:62]
Reactant: Cc1cc(=O)c(OCc2ccccc2)cn1CC(F)F
Agent: [Pd]
Agent: Cc1c(O)c(=O)ccn1CC(F)(F)F
Agent: Cc1cc(=O)c(OCc2ccccc2)co1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1cc(=O)c(O)cn1CC(F)F
Yield: 58 %

Procedure:
In a similar manner as described in example 4(a), 5-(benzyloxy)-1-(2,2-difluoroethyl)-2-methylpyridin-4(111)-one (2.20 g) was prepared from a mixture of 5-(benzyloxy)-2-methyl-4H-pyran-4-one (3.00 g, 13.8 mmol), difluoroethylamine (2.48 g, 55.2 mmol), triethylamine hydrochloride (5.58 g, 55.2 mmol) and pyridine (15 mL). Yield=58%; 1H NMR (90 MHz, MeOD-D4) δ (ppm): 7.53 (s, 1H), 7.27-7.45 (m, 5H), 6.36 (s, 1H), 5.56-6.77 (tt, J=54.9, 3.6 Hz, 1H), 5.04 (s, 2H), 4.24-4.60 (td, J=14.9, 2.7, 2H) and 2.36 (s, 3H); MS m/z 280 [M+1]+. (b) In a similar manner as described in example 1(b), 1-(2,2-difluoroethyl)-5-hydroxy-2-methylpyridin-4(111)-one (230 mg) was prepared from 5-(benzyloxy)-1-(2,2-difluoroethyl)-2-methylpyridin-4(1H)-one (500 mg, 1.80 mmol) with 10% Pd/C (wet, 50 mg) in methanol (40 mL) under hydrogen at 15 psi pressure in a Parr apparatus for 27 minutes. Yield=99%; 1H NMR (MeOD-D4, 90 MHz) δ (ppm): 7.46 (s, 1H), 6.37 (s, 1H), 5.62-6.83 (tt, J=54.9, 3.6 Hz, (1H), 4.26-4.60 (td, J=15.3, 2.4 Hz, 2H) and 2.38 (s, 3H); MS m/z 190 [M+1]+.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]=[CH:17][CH:16]=[CH:15]4)[N:9]=[N:10][C:5]2=[N:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:28]([O:30][CH2:31][CH3:32])=[CH2:29])CCC>CN(C=O)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>[CH2:31]([O:30][C:28]([C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]=[CH:17][CH:16]=[CH:15]4)[N:9]=[N:10][C:5]2=[N:4][CH:3]=1)=[CH2:29])[CH3:32]
Reactant: Fc1cc2ncccc2cc1Cn1nnc2ncc(Br)nc21
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=C(OCC)c1cnc2nnn(Cc3cc4cccnc4cc3F)c2n1
Temperature: 100 °C

Procedure:
A mixture of 6-(6-bromo-[1,2,3]triazolo[4,5-b]pyrazin-1-ylmethyl)-7-fluoro-quinoline (2.0 g, 5.57 mmol), Pd(Ph3P)4 (0.64 g, 0.56 mmol) and tributyl(1-ethoxyvinyl)stannane (4.02 g, 11.14 mmol) in DMF (50 mL) was purged with nitrogen and then heated at 100° C. for 7 h. After removal of the solvent under reduced pressure, the residue was diluted with DCM, washed sequentially with aqueous KF and water, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel with gradient (DCM:MeOH=50:1) to give the title compound as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.11 (s, 1H), 8.93 (d, 1H), 8.40 (d, 1H), 8.15 (d, 1H), 7.83 (d, 1H), 7.54 (m, 1H), 6.22 (s, 2H), 5.50 (d, 1H), 4.73 (d, 1H), 4.02 (q, 2H), 1.40 (t, 3H). LCMS (method E): [MH]+=351, tR=5.42 min.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[OH:8][C:9]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]1>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[OH:8][C:9]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:12][NH:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CC(O)(c2ccccc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OC1(c2ccccc2)CNC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
1 ml of trifluoroacetic acid is added to a solution containing 50 mg (0.19 mmol) of tert-butyl 3-hydroxy-3-phenylazetidine-1-carboxylate dissolved in 4 ml of dichloromethane. The reaction medium is stirred at ambient temperature for 3 hours and then concentrated. The crude product obtained is purified by silica gel chromatography (eluent 90/10 dichloromethane/methanol). 36 mg in the form of a white powder are obtained with a yield of 68%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6])#[CH:2].Br[CH2:11][CH2:12][P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:3]1[CH:4]=[C:5]([NH:6][CH2:11][CH2:12][P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])[CH:7]=[CH:8][CH:9]=1)#[CH:2]
Reactant: CCOP(=O)(CCBr)OCC
Reactant: C#Cc1cccc(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#Cc1cccc(NCCP(=O)(OCC)OCC)c1
Yield: 7.2 %

Procedure:
3-Ethynyl aniline (2.36 g, 22.1 mmol), diethyl 2-bromoethylphosphonate (5.41 g, 22.1 mmol) and potassium carbonate (3.1 gm, 22.1 mmol) were heated at 90° C. in anhydrous acetonitrile (40 mL) for 26 h. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel, eluting with 1:1 ethyl acetate:hexanes followed by 97:3 methylene chloride:methanol to provide diethyl 2-(3-ethynylphenylamino)ethylphosphonate (450 mg) as a yellow oil. 1H NMR (CDCl3) δ 7.15 (t, 1H), 6.83 (d, 1H), 6.70 (br s, 1H), 6.60 (m, 1H), 4.10 (m, 4H), 3.41 (m, 2H), 3.00 (s, 1H), 2.10 (m, 2H), 1.35 ppm (m, 6H). MW=281 confirmed by LC-MS, tr=11.65 min (Method Y) MH+=282.
Reaction SMILES: [C:1]([O-:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([O-:6])=[O:5].[NH4+:9].[NH4+].N>>[NH2:9][CH:2]([C:1]([O-:8])=[O:7])[CH2:3][C:4]([O-:6])=[O:5].[NH4+:9].[NH4+:9]
Reactant: O=C([O-])/C=C\C(=O)[O-]
Agent: N
Agent: [NH4+]
Product: NC(CC(=O)[O-])C(=O)[O-]

Procedure:
reacting the diammonium maleate with the excess ammonia at an elevated temperature in a range of about 40 degrees C. to about 200 degrees C., at an elevated pressure in a range of about 275 psig to about 1000 psig, and for a time period of about 30 minutes to about 5 hours, to produce diammonium D,L-aspartate;