Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.Cl.[Cl:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22](Cl)=[O:23])[CH:17]=1>CO.C1COCC1.CCOC(C)=O>[Cl:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:23])[CH:17]=1
Reactant: O=C(Cl)c1cc(Cl)ccn1
Reactant: CC(C)N
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)NC(=O)c1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.5 %

Procedure:
A 0° C. solution of isopropylamine (0.971 mL, 11.30 mmol) and DIEA (1.973 mL, 11.30 mmol) in MeOH (10 mL) and THF (5 mL) was treated with 4-chloropicolinoyl chloride hydrochloride (0.8 g, 3.77 mmol) in one portion, warmed to RT and stirred for 2 h. The mixture was diluted with EtOAc, washed with satd. NaHCO3, then brine and the organic layer was dried over Na2SO4, concentrated to dryness and purified by silica gel chromatography (EtOAc/Hex) to afford 4-chloro-N-isopropylpicolinamide (0.67 g, 90%). 1H NMR (400 MHz, DMSO-d6): δ 8.60 (d, J=5.3 Hz, 1H), 8.56 (d, J=8.4 Hz, 1H), 8.00 (d, J=2.2 Hz, 1H), 7.75 (dd, J=5.3, 2.1 Hz, 1H), 4.10-4.09 (m, 1H), 1.17 (d, J=6.6 Hz, 6H); MS (ESI) m/z: 199.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][C:12]3[CH:18]=[C:17]([O:19][CH2:20][C@@H:21]([NH:23][C:24](=[O:26])[CH3:25])[CH3:22])[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH:5]=[C:6]([F:9])[C:7]=1[OH:8].FC(F)(F)S(O[CH2:33][C:34]([F:37])([F:36])[F:35])(=O)=O>>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][C:12]3[CH:18]=[C:17]([O:19][CH2:20][C@@H:21]([NH:23][C:24](=[O:26])[CH3:25])[CH3:22])[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH:5]=[C:6]([F:9])[C:7]=1[O:8][CH2:33][C:34]([F:37])([F:36])[F:35]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CC(=O)N[C@@H](C)COc1ccc2nc(-c3cc(F)c(O)c(F)c3)oc2c1
Product: CC(=O)N[C@@H](C)COc1ccc2nc(-c3cc(F)c(OCC(F)(F)F)c(F)c3)oc2c1

Procedure:
Using N-((2S)-1-((2-(3,5-difluoro-4-hydroxyphenyl)-1,3-benzoxazol-6-yl)oxy)propan-2-yl)acetamide and 2,2,2-trifluoroethyl trifluoromethanesulfonate, and in the same manner as in Example 5, the title compound was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[N+:10]([O-:12])=[O:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][Cl:22]>C(#N)C>[Cl:22][CH2:21][CH2:20][O:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([N+:10]([O-:12])=[O:11])[CH:5]=1
Reactant: ClCCBr
Reactant: COc1ccc(O)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(OCCCl)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
4-Methoxy-3-nitrophenol (0.8 g, 4.7 mmol) was dissolved in acetonitrile (13 ml). Potassium carbonate (1.63 g, 11.8 mmol) was added, followed by 1-bromo-2-chloroethane (3.93 ml, 47.2 mmol). The reaction was heated and stirred at reflux for 20 h. The reaction was cooled to room temperature, the solid was then filtered off and the solvent evaporated under reduced pressure to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[NH:4][CH3:5].Cl[C:11]([O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=2)=[CH:16][CH:15]=1)=[O:12]>>[F:28][C:27]([F:30])([F:29])[C:24]1[CH:25]=[CH:26][C:21]([O:20][C:17]2[CH:18]=[CH:19][C:14]([O:13][C:11](=[O:12])[N:4]([C:3]3[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=3[Cl:1])[CH3:5])=[CH:15][CH:16]=2)=[N:22][CH:23]=1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: CNc1ccccc1Cl
Product: CN(C(=O)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)c1ccccc1Cl

Procedure:
The title product was prepared from 2-chlor-N-methylaniline and 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate, preparative HPLC (method C) (48%, light yellow oil). HPLC-MS m/z=423.1 (M+1), Rt: 4.98 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][C:6]2[C:7](=[O:17])[C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([O:32][CH2:33][CH2:34][CH2:35][NH:36][CH3:37])[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]>C(N(CC)CC)C>[CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][C:6]2[C:7](=[O:17])[C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][N:36]([CH3:37])[CH2:35][CH2:34][CH2:33][O:32][C:26]3[CH:27]=[CH:28][C:29]([O:30][CH3:31])=[C:24]([O:23][CH3:22])[CH:25]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)C(=O)C(=O)N(CCCCl)CC2
Reactant: CNCCCOc1ccc(OC)c(OC)c1
Solvent: CCN(CC)CC
Product: COc1ccc(OCCCN(C)CCCN2CCc3cc(OC)c(OC)cc3C(=O)C2=O)cc1OC

Procedure:
The title compound is prepared from 3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-1,2-dion-3-yl)-1-chloropropane, N-[3-(3,4-dimethoxyphenyloxy)-propyl]-methylamine and triethylamine analogously to Example 6.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[C:7]1([C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([CH3:17])[C:14](O)=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CN(C)C=O.ClCCl>[C:7]1([C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([CH3:17])[C:14]([Cl:4])=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C(=O)O)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C(=O)Cl)(c1ccccc1)c1ccccc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
52.08 g (0.33 mol) of oxalyl chloride are slowly added dropwise at 20° C. to a suspension of 25.0 g (0.11 mol) of 2,2-diphenylpropionic acid, 100 mL of dichloromethane, and 4 drops of dimethylformamide. The mixture is stirred for 1 hour at 20° C. and 0.5 hour at 50° C. The solvent is distilled off and the residue remaining is used in the next step without any further purification.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]#[CH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Br)C=C.[OH-].[K+].C[N+]1([O-])CC[O:21][CH2:20][CH2:19]1>[N+](CCCC)(CCCC)(CCCC)CCCC.[Cl-].O=[Os](=O)(=O)=O.O.C(Cl)Cl>[C:1]1([CH2:7][CH2:8][C:9]#[C:10][CH2:19][CH:20]=[O:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: C#CCCc1ccccc1
Agent: O=[Os](=O)(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Solvent: C=CCBr
Product: O=CCC#CCCc1ccccc1

Procedure:
Reaction of 4-phenyl-1-butyne (5; commercially available from Lancaster Synthesis, Windham, N.H.) with allyl bromide under phase-transfer conditions (CH2Cl2, n-Bu4NCl, water, KOH), selective oxidation of the alkene moiety using catalytic OsO4/pyr and stoichiometric N-methylmorpholine-N-oxide, and oxidative cleavage of the resultant diol using NalO4 affords 6-phenyl-hex-3-ynal (6). Lithiation of phosphine oxide 7 [Katritzky, Alan R., Feng, Daming, Lang, Hengyuan J.Org.Chem., volume 62(12) page 4131 (1997)], Wittig condensation with 6, and heating of the intermediate dienyne (not shown) with p-toluenesulfonic acid in ethanol affords enyne 8. Asymmetric dihydroxylation of 8 with AD mix α (Aldrich Chemical Co., Milwaukee) and methanesulfonamide [Sharpless, K. B., Amberg, W., Bennani, Y. Crispino, G. A.; Hartung, J; Jeong, K. S.; Kwong, H.-L.; Morikawa, K.; Wang, Z.-M.; Xu, D. Zhang, X.-L. J. Org. Chem., volume 57, page 2768 (1992)], followed by selective reduction with H2 over Pd/BaSO4, affords β-hydroxy lactone 9. Sequental treatment of 9 with CH3SO2Cl/NEt3 and diisobutylaluminum hydride (DIBAL-H) provides lactol 10. Sodium borohydride reduction, K2CO3 treatment, and oxidation of the resulting β-hydroxyepoxide with the Dess-Martin reagent produces the epoxyaldehyde 11, Wittig olefination of 11 and known ylide 12 [Zamboni, R.; Milettee, S.; Rokach, J. Tetrahedron Lett., volume 24, page 4899 (1983)] followed by saponification of the resulting methyl ester with LiOH in dimethoxyethane (DME)/water yields 2.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6](Cl)[CH:7]=1.[C:11]([C:13]1[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=1)#[CH:12].C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C.[OH-].[NH4+].[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]([C:12]#[C:11][C:13]2[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=2)[CH:5]=[N:4][C:3]=1[C:9]#[N:10]
Reactant: N#Cc1ncc(Cl)cc1Cl
Reactant: C#Cc1ccc(C(=O)OCC)cc1
Agent: [Cu]I
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2cnc(C#N)c(Cl)c2)cc1
Temperature: 25 °C

Procedure:
A solution of 3,5-dichloropicolinonitrile (commercially available) (1.0 eq.), ethyl 4-ethynylbenzoate (commercially available) (1.0 eq.), trans-dichlororbis(triphenylphosphine)palladium (II) (10 mol %), copper (I) iodide (20 mol %), and triethylamine (5.0 eq.) in DMF (0.3 M) was stirred at 50° C. for 3 hours. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate and 10% aqueous ammonium hydroxide. The two phases were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vacuo. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-20% ethyl acetate in hexane to give ethyl 4-((5-chloro-6-cyanopyridin-3-yl)ethynyl)benzoate as a white solid.
Reaction SMILES: [C:1]([N:8]([CH3:14])[C@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:48]([O:55][C:56]([N:58]1[CH2:62][CH:61]([C:63](=[O:71])[NH:64][C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)[CH:60]2[N:72]([C:75](=[O:84])[CH:76]([NH2:83])[CH:77]3[CH2:82][CH2:81][CH2:80][CH2:79][CH2:78]3)[CH2:73][CH2:74][CH:59]12)=[O:57])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>CN1C(=O)CCC1.CCOCC>[CH2:48]([O:55][C:56]([N:58]1[CH2:62][CH:61]([C:63](=[O:71])[NH:64][C:65]2[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=2)[CH:60]2[N:72]([C:75](=[O:84])[CH:76]([NH:83][C:11](=[O:13])[CH:9]([N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH3:14])[CH3:10])[CH:77]3[CH2:82][CH2:81][CH2:80][CH2:79][CH2:78]3)[CH2:73][CH2:74][CH:59]12)=[O:57])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: NC(C(=O)N1CCC2C1C(C(=O)Nc1ccccc1)CN2C(=O)OCc1ccccc1)C1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: CC(C(=O)NC(C(=O)N1CCC2C1C(C(=O)Nc1ccccc1)CN2C(=O)OCc1ccccc1)C1CCCCC1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 88 %

Procedure:
A solution of Boc-N(Me)Ala-OH (155 mg, 0.76 mmol) in NMP (5 mL) was cooled to 0° C. and treated with HATU (290 mg, 0.76 mmol) and DIPEA (0.15 mL, 0.87 mmol) followed in 15 min by the addition of 40 (366 mg, 0.73 mmol). The reaction mixture was allowed to warm to ambient temperature. After 18 h, the solution was diluted with Et2O, washed with H2O, 1M HCl, H2O, saturated aqueous NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated to afford 41 (443 mg) as a white foam that was used without further purification. Mass spectrum, m/z [690.8] (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:39]1[CH:44]=[CH:43][C:42]([CH:45]([NH2:47])[CH3:46])=[CH:41][CH:40]=1>>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:10]=[CH:11][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](=[O:22])[NH:47][CH:45]([C:42]3[CH:43]=[CH:44][N:39]=[CH:40][CH:41]=3)[CH3:46])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:13][CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Reactant: CC(N)c1ccncc1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)NC(C)c4ccncc4)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Yield: 41 %

Procedure:
According to the procedure in Example 385F, the title compound was prepared using 4-(4-tert-butoxycarbonylamino-phenylsulfanyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzoic acid (prepared in Example 385E) and (RS)-1-pyridin-4-yl-ethylamine: yield 41%.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[O:10]1[CH:14]=[CH:13][CH2:12][CH2:11]1>C(C(C)=O)C>[O:10]1[CH2:14][CH2:13][CH2:12][CH:11]1[N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8]
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: C1=COCC1
Solvent: CCC(C)=O
Product: O=c1[nH]c(=O)n(C2CCCO2)cc1F
Yield: 56 %

Procedure:
Into 30 ml of methyl ethyl ketone were suspended 1.3 g of 5-fluorouracil. To this suspension were added 1.4 g of 2,3-dihydrofuran and the mixture was reacted in an autoclave for 2 hours at 180° C. After completion of the reaction, the reaction liquid was treated in the same manner as described in Example 1 whereby 0.38 g of the starting 5-fluorouracil was recovered as a substance insoluble in chloroform and 1.12 g of 1-(2-tetrahydrofuryl)-5-fluorouracil were obtained. The yield of the end product was 79% based on the consumed 5-fluorouracil.
Reaction SMILES: [CH3:1][C:2]1[CH:25]=[C:24]([N+:26]([O-])=O)[CH:23]=[C:22]([CH3:29])[C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:6]=1>C(O)C.CCOC(C)=O.[Pd]>[NH2:26][C:24]1[CH:23]=[C:22]([CH3:29])[C:3]([O:4][C:5]2[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([S:12]([C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)(=[O:14])=[O:13])[CH:6]=2)=[C:2]([CH3:1])[CH:25]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Oc1ccc(O)c(S(=O)(=O)c2ccc(F)cc2)c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc(N)cc(C)c1Oc1ccc(O)c(S(=O)(=O)c2ccc(F)cc2)c1
Reaction time: 4 h
Yield: 98.9 %

Procedure:
To a solution of 4-(2,6-dimethyl-4-nitro-phenoxy)-2-(4-fluoro-benzenesulfonyl)-phenol (11.4 g, 27.4 mmol) in a mixture of ethanol (200 mL) and EtOAc (200 mL) was added catalyst (10% Pd/C, 2.29 g). The mixture was hydrogenated under 45 psi at RT for 4 h. The mixture was filtered through Celite and concentrated to give the title compound of Step D (10.5 g) as a tan solid. The title product of Step D was used in the next step with no further purification. MS (APCl−) Calc.:387.1, Found: 386.2 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=[O:14])[C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:10][C:9]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH2:25]([O:14][C:12]1[C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:10][C:9]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:13]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)c1cc(-c2ccccc2)c(-c2ccc(Cl)cc2)[nH]c1=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(-c2ccccc2)c(-c2ccc(Cl)cc2)nc1OCc1ccccc1
Temperature: 55 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 6-(4-chlorophenyl)-5-(phenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (500 mg, 1.47 mmol) from Step D in DMF (6 mL) was added benzyl bromide (0.22 mL, 1.91 mmol) and then cesium carbonate (622 mg, 1.91 mmol). The reaction was stirred at 55° C. for 4 h and was then diluted with water and extracted twice with methylene chloride. The organic layers were washed with a portion of brine and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give a 4:1 mixture of the crude products. The products were separated by flash column chromatography on silica gel eluted with a gradient of 5 to 10% ethyl acetate in hexanes to first yield the desired higher Rf O-alkylation title product. HPLC/MS: 430 (M+1); Rt=4.9 min;
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[CH:10]=[CH:9][N+:8]([O-:11])=[C:7]([CH3:12])[C:6]=1[CH3:13]>CS(C)=O.O>[CH3:1][O:2][C:5]1[CH:10]=[CH:9][N+:8]([O-:11])=[C:7]([CH3:12])[C:6]=1[CH3:13]
Reactant: C[O-]
Reactant: Cc1c(Cl)cc[n+]([O-])c1C
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc[n+]([O-])c(C)c1C
Reaction time: 8 h

Procedure:
To a solution prepared by diluting 41.6 g (2.0 eq.) of a 28% aqueous solution of sodium methoxide with 200 mL of dimethylsulfoxide, a liquid containing 17.0 g of 4-chlor-2,3-dimethylpyridine-1-oxide dissolved in dimethylsulfoxide (70 mL) was added dropwise. The mixture was allowed to react for 3 hours at 40 to 50° C., and then was left to stand overnight at room temperature. 15 mL of water was added to the reaction liquid, and the mixture was concentrated, to obtain a residue in the form of a black paste. Subsequently, the residue was dissolved in 500 mL of water, and then the aqueous solution was extracted three times with 670 mL of chloroform. The extract was dried over anhydrous magnesium sulfate, and then was concentrated to dryness under reduced pressure, to obtain 37.2 g of 4-methoxy-2,3-dimethylpyridine-1-oxide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:6]([O:12][CH3:13])=[CH:5][C:4]=1[O:14][CH3:15].O.O.[Sn](Cl)(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH3:13][O:12][C:6]1[CH:5]=[C:4]([O:14][CH3:15])[C:3]([O:2][CH3:1])=[CH:8][C:7]=1[NH2:9]
Reactant: COc1cc(OC)c([N+](=O)[O-])cc1OC
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(OC)c(OC)cc1N
Yield: 54.3 %

Procedure:
1,2,4-Trimethoxy-5-nitro-benzene (1.20 g, 5.63 mmol) and tin chloride dihydrate (3.81 g, 16.9 mmol) in ethyl acetate (50 mL) was stirred at 65-70° C. for 20 h. The reaction was cooled, carefully neutralized with sodium bicarbonate and was filtered through Celite. The organic phase was washed with brine, dried (sodium sulfate) and was evaporated. Purification by flash chromatography (SiO2) eluted with 3:7 ethyl acetate:hexanes provided 2,4,5-trimethoxy-phenylamine (0.56 g, 54% yield) as a tan solid. 1H-NMR (DMSO-d6, 500 MHz) 6.57 (s, 1H), 6.37 (s, 1H), 3.70 (s, 3H), 3.65 (s, 3H), 3.63 (s, 3H) ppm; HPLC (Method A) 2.163 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([O:9][CH2:10][C@H:11]2[CH2:14][CH2:13][N:12]2C(OCC2C=CC=CC=2)=O)=[CH:5][CH:4]=1>CCO.[Pd]>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([O:9][CH2:10][C@H:11]2[CH2:14][CH2:13][NH:12]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(OC[C@H]2CCN2C(=O)OCc2ccccc2)cn1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(OC[C@H]2CCN2)cn1
Reaction time: 16 h
Yield: 94.5 %

Procedure:
6-methoxy-3-(1-Cbz-2-(R)-azetidinylmethoxy)pyridine from Example 119c (300 mg, 0.91 mmol) was combined with 10% Pd/C (50 mg) in 30 mL of EtOH, and the mixture was stirred under an H2 atmosphere for 16 hours. The mixture was filtered and concentrated. The crude free base was converted to the salt by treatment with p toluenesulfonic acid in ethyl acetate. The mixture was concentrated, the residue was triturated with ether, and the product was recrystalized from ethyl acetate/ether to give 167 mg (33.9%) of the title compound: mp 139-142° C.; 1H NMR (D2O 300 MHz) δ 2.39 (s, 6H), 2.60-2.70 (m, 2H), 2.98 (s, 3H), 4.04-4.15 (m, 2H), 4.36 (d, J=4.5, 2H), 4.95 (s, 1H), 7.08 (d, J=9.0, 1H), 7.36 (d, J=8.0, 4H), 7.68 (d, J=8.0, 4H), 7.75 (dd, J=3.5, 9.5, 1H), 7.91 (d, J=3.0, 1H); MS (DCI/NH3) m/e 195 (M+H)+. Anal. calcd. for C10H14N2O2.2C7H8O3S: C, 53.52 H, 5.61N, 5.20. Found: C, 53.24 H, 5.68; N, 5.07. [α]D +3.55(c 1, MeOH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]3[CH:13]=[N:14][C:15]([N:18]4[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]4)=[N:16][CH:17]=3)[CH2:11][O:10][CH2:9]2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]3[CH:13]=[N:14][C:15]([N:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)=[N:16][CH:17]=3)[CH2:9][O:10][CH2:11]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(C3(c4ccc(F)cc4)COC3)cn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1ccc(C2(c3cnc(N4CCNCC4)nc3)COC2)cc1
Yield: 100 %

Procedure:
A solution of tert-butyl 4-(5-(3-(4-fluorophenyl)oxetan-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate (22 mg, 0.05 mmol) in DCM (1 mL) was treated with TFA (0.5 mL) at 60° C. for 3 h and then concentrated under reduced pressure. The residue (30 mg, crude, yellow solid, 100% yield) was directly used into the next step without further purification. MS (ES+) C17H19FN4O requires: 314. found 315 [M+H]+; purity: 87% (UV254).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]3([O:26][C:27](=[O:28])[C:5]=2[CH:4]=1)[CH2:13][CH2:12][N:11]([C:14]([C:16]1([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[CH2:18][CH2:17]1)=[O:15])[CH2:10]3.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+]>O1CCCC1.O>[OH:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]3([O:26][C:27](=[O:28])[C:5]=2[CH:4]=1)[CH2:13][CH2:12][N:11]([C:14]([C:16]1([C:19]2[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=2)[CH2:17][CH2:18]1)=[O:15])[CH2:10]3
Reactant: COc1ccc2c(c1)C(=O)OC21CCN(C(=O)C2(c3ccc(C)cc3)CC2)C1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C2(C(=O)N3CCC4(C3)OC(=O)c3cc(O)ccc34)CC2)cc1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
To a solution of 5-methoxy-1′-{[1-(4-methylphenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one (40 mg, 0.0001 mol) in tetrahydrofuran (2 mL, 0.02 mol) was added L-Selectride® in tetrahydrofuran (1.0 M, 0.53 mL) and the resulting solution was heated to 120° C. for 50 minutes using microwave irradiation. To the reaction mixture was added a few drops of water to quench the reaction. Then the reaction mixture was concentrated and about. 3 mL of concentrated HCl aqueous solution was added to dissolve the residue. The resulting solution was stirred at rt for 2 h. The crude product was purified using prep-HPLC. LCMS: m/z 364.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:7][CH2:8][NH2:9])=[CH:4][S:5][CH:6]=1.[CH2:10]1[O:18][CH:11]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[OH:18][CH:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:10][NH:9][CH2:8][CH2:7][C:3]1[C:2]([Br:1])=[CH:6][S:5][CH:4]=1
Reactant: c1ccc(C2CO2)cc1
Reactant: NCCc1cscc1Br
Product: OC(CNCCc1cscc1Br)c1ccccc1

Procedure:
N-(2-hydroxy-2-phenylethyl) 4-bromo-thiophene-3-ethylamine was prepared from 4-bromothiophene-3-ethylamine and styrene oxide by the method described in Example 1(b) and recrystallised from cyclohexane (m.p. 75°).
Reaction SMILES: C[O:2][C:3](=[O:42])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]([N:14]2[CH2:18][C@@H:17]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C@@:16]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[F:33])([C:24]#[N:25])[C@H:15]2[C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:35]=2[F:41])=[O:13])=[CH:6][CH:5]=1.[Li+].[OH-]>C1COCC1.CO>[Cl:40][C:37]1[CH:38]=[CH:39][C:34]([C@@H:15]2[C@:16]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[F:33])([C:24]#[N:25])[C@H:17]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:18][N:14]2[C:12]([NH:11][CH2:10][C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:42])=[O:2])=[CH:9][CH:8]=2)=[O:13])=[C:35]([F:41])[CH:36]=1
Reactant: COC(=O)c1ccc(CNC(=O)N2C[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2ccc(Cl)cc2F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)C[C@@H]1CN(C(=O)NCc2ccc(C(=O)O)cc2)[C@H](c2ccc(Cl)cc2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
To a mixture of rac-4-({[(2S,3S,4S)-2,3-bis-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-methyl)-benzoic acid methyl ester (105.0 mg, 0.17 mmol) in THF/MeOH (1.8 mL/0.6 mL) was added 4 N LiOH (0.6 mL), and the reaction mixture was stirred at rt for 2 hrs. The reaction mixture was concentrated and quenched with 2 N H2SO4, extracted with EtOAc, and washed with water, brine. The organic phase was separated, and dried over Na2SO4. The mixture was then concentrated and purified by RP-HPLC to give rac-4-({[(2S,3S,4S)-2,3-bis-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-methyl)-benzoic acid (100.1 mg, 97.6%). HRMS (ES+) m/z Calcd for C31H29Cl2F2N3O3+H [(M+H): 600.1627; Found: 600.1628.