Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:12]=[C:13]3[C:19](I)=[CH:18][N:17]([S:21]([C:24]4[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=4)(=[O:23])=[O:22])[C:14]3=[N:15][CH:16]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:31]([Cu])#[N:32]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:12]=[C:13]3[C:19]([C:31]#[N:32])=[CH:18][N:17]([S:21]([C:24]4[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=4)(=[O:23])=[O:22])[C:14]3=[N:15][CH:16]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: N#C[Cu]
Reactant: COc1ccc(-c2cnc3c(n2)c(I)cn3S(=O)(=O)c2ccc(C)cc2)cc1OC
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1ccc(-c2cnc3c(n2)c(C#N)cn3S(=O)(=O)c2ccc(C)cc2)cc1OC
Temperature: 90 °C
Reaction time: 8 h
Yield: 19.5 %

Procedure:
A mixture of 2-(3,4-dimethoxy-phenyl)-7-iodo-5-(toluene-4-sulfonyl)-5H-pyrrolo[2,3-b]pyrazine (380 mg, 0.71 mmol), CuCN (256, 2.8 mmol), bis(dibenzylideneacetone)palladium(0) [Pd2(dba)3] (26 mg, 0.03 mmol), and 1,1′-bis(diphenylphosphino)ferrocene (63 mg, 0.11 mmol) in dioxane (7 mL) was stirred at 90° C. overnight. Additional CuCN (50, 0.56 mmol), Pd2(dba)3 (6 mg, 0.01 mmol), and 1,1′-bis(diphenylphosphino)ferrocene (15 mg, 0.03 mmol) was added to the reaction mixture which was then stirred at 90° C. for 4 h and partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc and the combined organic phases were concentrated. The residue was purified by flash chromatography using 40 g of silica gel and 0-70% EtOAc in hexanes as eluant to afford 60 mg (20%) of 2-(3,4-dimethoxy-phenyl)-5-(toluene-4-sulfonyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonitrile as a white solid and 50 mg (16%) as a yellow solid. MP 233-234° C., M+H 435.
Reaction SMILES: [N:1]1([C:7]2[CH:20]=[CH:19][C:10]([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CN(C)C=O.[C:26]1(C)C(C)=CC=C[CH:31]=1.[C-]#[C-].[Na+].[Na+]>O>[C:13]1([C:11]([C:10]2[CH:9]=[CH:8][C:7]([N:1]3[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]3)=[CH:20][CH:19]=2)([OH:12])[C:26]#[CH:31])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(c1ccccc1)c1ccc(N2CCNCC2)cc1
Reactant: Cc1ccccc1C
Agent: [C-]#[C-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CC(O)(c1ccccc1)c1ccc(N2CCNCC2)cc1

Procedure:
To a 500 mL beaker was added the product from Step 3 (30 g) and anhydrous dimethylformamide (50 mL). Sodium acetylide xylene slurry (22 wt %, 90 g) was dropped to the mixture through addition funnel slowly. The reaction mixture was stirred with a glass stirring bar for 10 minutes. The mixture was poured into water (400 mL). The resulting mixture was extracted with ethyl acetate (200 mL). The recovered top layer was filtered through a silica gel plug using ethyl acetate and methanol mixture as eluent. Solid product was obtained by recrystallization from condensed major fraction. The solid was filtered off and dried in vacuum oven at 60° C. for 3 hours to afford 17 g of 1-phenyl-1-(4-piperazinophenyl)-2-propyn-1-ol.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1F)([O-:3])=[O:2].[F-].[K+].C1OCCOCCOCCOCCOCCOC1.[F:34][C:35]([F:46])([F:45])[CH:36]([C:41]([F:44])([F:43])[F:42])[C:37]([O:39][CH3:40])=[O:38].Cl>S1(CCCC1)(=O)=O.CCOCC>[CH3:40][O:39][C:37](=[O:38])[C:36]([C:5]1[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])([C:35]([F:46])([F:34])[F:45])[C:41]([F:43])([F:42])[F:44]
Reactant: COC(=O)C(C(F)(F)F)C(F)(F)F
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: Cl
Agent: [F-]
Solvent: O=S1(=O)CCCC1
Solvent: CCOCC
Product: COC(=O)C(c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])(C(F)(F)F)C(F)(F)F
Temperature: 25 °C

Procedure:
A mixture of 7.08 g (38.07 mmol) 2,4-dinitrofluorobenzene, 2.43 g (41.88 mmol) KF, and 0.58 g (2.21 mmol) 18-crown-6-ether in 37 mL sulfolane was added 4.00 g (19.04 mmol) methyl 2-(trifluoromethyl)-3,3,3-trifluoropropionate dropwise over about 7 h via syringe pump. After the addition was complete, another 2.43 g KF, 0.58 g 18-Crown-6-ether were added and then 4.00 g Methyl 2-(trifluoromethyl)-3,3,3-trifluoropropionate were added dropwise over 12 h. The next day, repeated additions using same amounts and setting syringe pump addition over 14 h. The following day, the additions were again repeated, this time using half the amounts as above additions and setting syringe pump addition at 12 h. After addition was completed, the reaction mix was cooled to RT and diluted into Et2O and 0.5 N aqueous HCl. The layers were separated, and the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under vacuum. The crude was eluted on a silica gel column with EtOAc/hexanes gradient, to yield the titled compound, as a yellow solid. [See Vlasov et al., J. Org. Chem. USSR (Engl. Trans.), 15:1953-1964 (1979)]
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][NH:15]3)=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH:29]1([NH2:32])[CH2:31][CH2:30]1.CCN(C(C)C)C(C)C>CS(C)=O.CS(C)=O.CO>[CH:29]1([NH:32][C:2]2[N:7]=[C:6]([C:8]([NH:10][C:11]3[CH:19]=[C:18]([C:20]4[CH:28]=[CH:27][CH:26]=[C:25]5[C:21]=4[CH:22]=[CH:23][NH:24]5)[CH:17]=[C:16]4[C:12]=3[CH:13]=[N:14][NH:15]4)=[O:9])[CH:5]=[CH:4][CH:3]=2)[CH2:31][CH2:30]1
Reactant: NC1CC1
Reactant: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1cccc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: CO
Product: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1cccc(NC2CC2)n1
Temperature: 160 °C
Yield: 1.8 %

Procedure:
To a microwave vial was added 2 ml of a solution of 6-chloro-N-[6-(1H-indol-4-yl)-1H-indazol-4-yl]-2-pyridinecarboxamide (350 mg, 0.90 mmol, prepared as described in Example 18) in DMSO (14 ml). Cyclopropylamine (0.018 ml, 0.26 mmol) and DIPEA (0.113 ml) were added and the mixture was heated at 160° C. for 2 h under microwave irradiation. Further cyclopropylamine (0.018 ml, 0.26 mmol) was added and the mixture was heated at 160° C. for 2 h under microwave irradiation. Again, cyclopropylamine (0.018 ml, 0.26 mmol) was added and the mixture was heated at 160° C. for 1 h under microwave irradiation. After this time, cyclopropylamine (0.018 ml, 0.26 mmol) and DIPEA (0.113 ml) were both added to the mixture and it was heated at 160° C. for 2 h under microwave irradiation. The crude reaction mixture was dissolved in DMSO/MeOH (1:1) and purified by Mass Directed Automated Preparative HPLC (Method E). The sample was re-purified by Mass Directed Automated Preparative HPLC (Method E, using Waters Atlantis column 100 mm×19 mm, 5 um). Product-containing fractions were dried under a stream of nitrogen to afford the title compound (1.9 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:14]3[CH:15]=[CH:16][C:17]4[O:21][CH2:20][CH2:19][C:18]=4[CH:22]=3)[CH2:12][O:11][C:10]([NH2:13])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C(CCC)=CC(CCC)=CC=1CCC)(C)(C)C.[CH3:59][O:60][C:61]1[CH:62]=[C:63]([CH:65]=[CH:66][CH:67]=1)[NH2:64]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C.O.C1(C)C=CC=CC=1>[O:21]1[C:17]2[CH:16]=[CH:15][C:14]([C:8]3([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([NH:64][C:63]5[CH:65]=[CH:66][CH:67]=[C:61]([O:60][CH3:59])[CH:62]=5)[CH:3]=4)[CH2:12][O:11][C:10]([NH2:13])=[N:9]3)=[CH:22][C:18]=2[CH2:19][CH2:20]1
Reactant: COc1cccc(N)c1
Reactant: NC1=NC(c2cccc(Br)c2)(c2ccc3c(c2)CCO3)CO1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CCCc1cc(CCC)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(CCC)c1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cccc(Nc2cccc(C3(c4ccc5c(c4)CCO5)COC(N)=N3)c2)c1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A microwave tube was charged with 4-(3-bromo-phenyl)-4-(2,3-dihydro-benzofuran-5-yl)-4,5-dihydro-oxazol-2-ylamine (Building Block K, 167 mg, 0.467 mmol, 1.0 eq), sodium tert-butoxide (89 mg, 0.933 mmol, 2.0 eq.), 2-di-t-butylphosphino-2′,4′,6′-tri-1-propyl-1,1′biphenyl (18 mg, 0.042 mmol, 0.042 eq.), tris(dibenzylideneacetone)dipalladium (10 mg, 0.012 mmol, 0.025 eq.) and 3-methoxyaniline (115 mg, 0.933 mmol, 2.0 eq.). After three vacuum-nitrogen cycles, toluene was introduced (1 mL), the tube was sealed and stirred at 100° C. for 16 hours. After cooling to room temperature, water (1 mL) and ethyl acetate (1 mL) were added. The organic fraction of the reaction mixture was placed on an SCX column. This was then washed with dichloromethane/methanol. The desired product was obtained by eluting with 2 M ammonia in methanol. Fractions containing the compound were combined and the product purified further using preparative HPLC to yield 53 mg (30% yield) of the title compound as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[F:24][C:25]1[CH:26]=[C:27]([C:35](O)=[O:36])[C:28]2[O:33][CH2:32][O:31][CH2:30][C:29]=2[CH:34]=1>>[Cl:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:35]([C:27]2[C:28]3[O:33][CH2:32][O:31][CH2:30][C:29]=3[CH:34]=[C:25]([F:24])[CH:26]=2)=[O:36])=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c(-c2cccc(Cl)c2)s1
Reactant: O=C(O)c1cc(F)cc2c1OCOC2
Product: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cc(F)cc3c2OCOC3)c(-c2cccc(Cl)c2)s1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-[5-(3-chloro-phenyl)-2-methyl-thiazol-4-yl]-methanone with 6-Fluoro-4H-benzo[1,3]dioxine-8-carboxylic acid. LC-MS (basic): tR=0.92 min; [M+H]+=528.3.
Reaction SMILES: C([O:8][C:9]1[C:10]([O:34][CH3:35])=[CH:11][C:12]2[CH2:21][CH2:20][N:19]3[CH:14]([CH2:15][C:16]4[C:25]([Cl:26])=[CH:24][C:23]([O:27][CH3:28])=[C:22]([O:29][CH2:30][CH2:31][OH:32])[C:17]=4[CH2:18]3)[C:13]=2[CH:33]=1)C1C=CC=CC=1>[Ni]>[OH:8][C:9]1[C:10]([O:34][CH3:35])=[CH:11][C:12]2[CH2:21][CH2:20][N:19]3[CH:14]([CH2:15][C:16]4[C:25]([Cl:26])=[CH:24][C:23]([O:27][CH3:28])=[C:22]([O:29][CH2:30][CH2:31][OH:32])[C:17]=4[CH2:18]3)[C:13]=2[CH:33]=1
Reactant: COc1cc2c(cc1OCc1ccccc1)C1Cc3c(Cl)cc(OC)c(OCCO)c3CN1CC2
Agent: [Ni]
Product: COc1cc2c(cc1O)C1Cc3c(Cl)cc(OC)c(OCCO)c3CN1CC2

Procedure:
A product obtained in Example 16 (0.08 g, 0.16 mmol) was hydrogenated in the present of Raney-Ni. The desired product was obtained following the synthetic procedure described in Example 1, 4 or 7. The crude product was purified by silica chromatography (ethyl acetate/petroleum ether) to give pale yellow powder (0.013 g, 19.9%). mp 184° C. 1HNMR (DMSO-d6) δ: 2.28˜2.56 (3H, m, CH2), 2.71˜2.88 (2H, m, CH2), 3.04˜3.31 (3H, m, CH2 and N—CH), 3.61 (2H, t, OCH2), 3.73 (3H, s, Ar—OCH3), 3.78 (3H, s, Ar—OCH3), 3.94 (2H, m, OCH2), 4.18 (1H, d, CH2), 6.64 (1H, s, ArH), 6.72 (1H, s, ArH), 7.03 (1H, s, ArH).
Reaction SMILES: [C:1]1([O:11][CH2:12][CH2:13][CH2:14][N:15]2[C:23]3[C:18](=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH3:30])[CH:20]=[CH:21][CH:22]=3)[CH:17]=[C:16]2[C:31](=O)CC(OCC)=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C([N:54](CC)CC)C>O1CCCC1.ClCCl.C(OCC)(=O)C.O>[C:1]1([O:11][CH2:12][CH2:13][CH2:14][N:15]2[C:23]3[C:18](=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH3:30])[CH:20]=[CH:21][CH:22]=3)[CH:17]=[C:16]2[C:31]#[N:54])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCN(CC)CC
Reactant: CCOC(=O)CC(=O)c1cc2c(-c3ccccc3C)cccc2n1CCCOc1cccc2ccccc12
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1ccccc1-c1cccc2c1cc(C#N)n2CCCOc1cccc2ccccc12
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a cooled (0° C.) solution of EXAMPLE 168A (880 mg) in tetrahydrofuran (10 mL) and dichloromethane (2 ml) and triethylamine (2 ml) was added, followed by the addition of trifluoroacetic anhydride (2 ml) dropwise. After the addition, the mixture was stirred for 3 hours at 0° C. After this time the mixture was diluted with ethyl acetate (200 mL) and water (80 mL). The aqueous layer was extracted with ether twice. The combined extracts were washed with water (×3), brine and dried over Na2SO4. Evaporation of solvent gave crude product.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[C:15]([F:17])[C:14]([C:18]3[CH2:19][CH2:20][S:21](=[O:25])(=[O:24])[CH2:22][CH:23]=3)=[C:13]([F:26])[CH:12]=2)[CH2:6]1)=[N+:2]=[N-:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:46][C:47]1NN=N[N:48]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1.CO>[O:25]=[S:21]1(=[O:24])[CH2:20][CH:19]=[C:18]([C:14]2[C:15]([F:17])=[CH:16][C:11]([N:7]3[CH2:6][C@H:5]([CH2:4][N:1]4[N:2]=[N:3][C:47]([CH3:46])=[N:48]4)[O:9][C:8]3=[O:10])=[CH:12][C:13]=2[F:26])[CH2:23][CH2:22]1
Reactant: Cc1nnn[nH]1
Reactant: [N-]=[N+]=NC[C@@H]1CN(c2cc(F)c(C3=CCS(=O)(=O)CC3)c(F)c2)C(=O)O1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nnn(C[C@H]2CN(c3cc(F)c(C4=CCS(=O)(=O)CC4)c(F)c3)C(=O)O2)n1
Temperature: 0 °C
Reaction time: 4 h
Yield: 56.7 %

Procedure:
(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-5-(hydroxymethyl)-oxazolidin-2-one (WO 01/81350 A1) (0.50 g, 1.39 mmol), triphenylphosphine (0.55 g, 2.1 mmol), and 5-methyl-1H-tetrazole (0.18 g, 2.14 mmol) were dissolved in dry tetrahydrofuran (5 ml), and cooled on an ice-water bath. Diisopropylazodicarboxylate (0.41 ml, 2.58 mmol) was added dropwise and the mixture was stirred at 0° C. for 4 hours. Methanol (3 ml) was added, followed by evaporation of the solvent under reduced pressure and purification by flash column chromatography on silica gel with 10% acetonitrile in dichloromethane. The material obtained after chromatography was precipitated from dichloromethane with diethyl ether to give the title compound (0.335 g).
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7]C)=[O:5].C[O-].[Na+].CC1C=CC=C[C:18]=1[O:23]C.C(Cl)(=O)C.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCl>[CH3:18][O:23][C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: CCOC(=O)c1cccnc1Cl
Reactant: COc1ccccc1C
Agent: C[O-]
Agent: Cl
Agent: [Al+3]
Solvent: ClCCl
Solvent: CC(=O)Cl
Product: COC(=O)c1cccnc1OC

Procedure:
Methyl 2-methoxynicotinate was synthesized from ethyl 2-chloronicotinate with sodium methoxide as described in Example 34. A 100 mL dry flask was charged with 2-methylanisole (7.92 g, 65 mmol), acetyl chloride (5.1 mL, 71 mmol), aluminum chloride (9.45 g, 71 mmol) and 40 mL of anhydrous dichloromethane. The reaction mixture was kept at reflux for 2 h, then poured into 15 mL of HCl (3 N) and extracted with 100 mL ether. The organic layer was further washed with sodium bicarbonate to pH 6-7, then further washed with brine and dried over sodium sulfate. The solvent was evaporated and the residue was dried under high vacuum to yield the intermediate (10.0 g, 93.85%). A 100 mL dry flask was charged with methyl 2-methoxynicotinate (2.50 g, 15 mmol), 10 mL anhydrous DMF and NaH (0.9 g, 22.5 mmol, 60% in oil). The intermediate (2.58 g, 15.7 mmol) in 3 mL anhydrous DMF was added and the reaction was stirred for 2 hours. The mixture was poured into 120 mL of water with 3 mL AcOH. The yellow solid was further wash with water and passed through a column (hexane:EtOAc 3:1) to give the methoxy intermediate (3.4 g, 75.7%). A 50 mL flask was charged with the methoxy intermediate (1.0 g, 3.3 mmol) and pyridine hydrogen chloride (4.0 g, 33 mmol) and heated to 190° C. for 3 h. The mixture was poured into a sodium bicarbonate solution and the solid was collected by filtration, washed with EtOAc and MeOH (20 mL each) to give 2-(4-hydroxy-3-methylphenyl)-4H-pyrano[2,3-b]pyridine-4-one (0.58 g, 69.4%). MS (ES) m/z: 254.0 (M+1); Mp. 300-302° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:10]([O-])=O)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[Sn](Cl)Cl.[CH3:16][CH2:17][O:18]C(C)=O>>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:17](=[O:18])[CH3:16])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: CCOC(C)=O
Reactant: COc1ncc(Br)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Product: COc1ncc(Br)cc1NC(C)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 5-bromo-2-methoxy-3-nitro-pyridine (Stage 63.1.4, 450 mg, 1.93 mmol) and tin dichloride (1.465 mg, 7.72 mmol) in EtOAc (30 ml) was refluxed for 3 h. The reaction mixture was evaporated to dryness and then quenched with cold 3 M aqueous NaOH (50 ml) and CH2Cl2 (50 ml) and stirred for 3 h at rt. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with 30 ml sat. aqueous NaHCO3, dried over Na2SO4, filtered and evaporated. The crude product was dry loaded on silica gel and purified by MPLC (CH2Cl2/MeOH 0% to 4%) to give after evaporation the title compound as an off-white solid (HPLC: tR 2.72 min (Method A); M+H=245, 247 MS-ES).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:15](O)=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:15][OH:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCNCC1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCC1(c2ccc(Cl)cc2)CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Took 3.0 g of 4-(4-chloro-phenyl)-piperidine-4-carboxylic acid hydrochloride (10.9 mmol, 1.00 equiv.) and 20 mL dry THF in a 250 mL round bottom flask fitted with a stir bar, reflux condenser, and N2 inlet. The resulting slurry was cooled in an ice water bath, followed by the addition of 825 mg LiAlH4 in several small portions. The ice bath was removed and the mixture allowed to stir overnight at room temperature under N2. The reaction was carefully quenched with a small amount of aqueous NaOH and allowed to stir for several hours. The solids were removed by vacuum filtration and discarded; the mother liquor was concentrated under vacuum and purified by normal phase HPLC (MeOH-DCM as the eluent). MS (ES) M+H expected=226.7, found=226.1
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[N:3]=1.Cl.[CH:19]12[NH:26][CH:23]([CH2:24][CH2:25]1)[CH2:22][O:21][CH2:20]2.C(N(CC)CC)C>ClCCl>[Cl:8][C:6]1[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[N:3]=[C:2]([N:26]2[CH:19]3[CH2:25][CH2:24][CH:23]2[CH2:22][O:21][CH2:20]3)[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(-c2nc(Cl)cc(Cl)n2)cc1
Reactant: C1CC2COCC1N2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(-c2nc(Cl)cc(N3C4CCC3COC4)n2)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 86 %

Procedure:
In a 250 mL round-bottomed flask was placed 4,6-dichloro-2-(4-nitrophenyl)pyrimidine (59, 192 mg, 0.711 mmol) in dichloromethane (8 mL) to give a colorless solution. 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (33, 106 mg, 0.711 mmol) was added and the solution was cooled to 0° C. Triethylamine (0.297 mL, 2.133 mmol) was added slowly and the mixture was allowed to slowly warm to room temperature, and stirred for 16 hours at room temperature. The mixture was heated under reflux for 2 hours, diluted with dichloromethane and washed with saturated NaHCO3. The organic phase was dried over MgSO4, filtered and concentrated. the crude product was applied to a silica gel column and eluted with 5-40% EtOAc in hexanes to give the title compound (212 mg, 86%). The sample was identical to the same compound prepared according to Scheme 16. HRMS: For [M+H]+ mass error=0.1 mDa or 0.39 ppm.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([C:15]([OH:17])=O)=[N:6][O:7][C:8]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.C(Cl)CCl.O/[N:42]=[C:43](/[C:45]1[CH:62]=[CH:61][C:48]([CH2:49][N:50]2[CH2:53][CH:52]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:51]2)=[CH:47][CH:46]=1)\[NH2:44]>C(#N)C>[CH:1]1([C:4]2[C:5]([C:15]3[O:17][N:44]=[C:43]([C:45]4[CH:46]=[CH:47][C:48]([CH2:49][N:50]5[CH2:51][CH:52]([C:54]([O:56][C:57]([CH3:58])([CH3:60])[CH3:59])=[O:55])[CH2:53]5)=[CH:61][CH:62]=4)[N:42]=3)=[N:6][O:7][C:8]=2[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(/C(N)=N/O)cc2)C1
Reactant: O=C(O)c1noc(-c2ccccc2)c1C1CC1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CC#N
Product: CC(C)(C)OC(=O)C1CN(Cc2ccc(-c3noc(-c4noc(-c5ccccc5)c4C4CC4)n3)cc2)C1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 4-cyclopropyl-5-phenylisoxazole-3-carboxylic acid (22 mg, 0.096 mmol), HOBt (26.5 mg, 0.173 mmol), and diisopropylethylamine (0.067 mL, 0.384 mmol) in acetonitrile (1 mL) was added EDC (43.2 mg, 0.226 mmol) and (Z)-tert-butyl 1-(4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate (Int.1, 29.3 mg, 0.096 mmol). The reaction mixture was stirred at 80° C. for 2 h. The reaction mixture was concentrated, and the residue was purified by preparative HPLC to give tert-butyl 1-(4-(5-(4-cyclopropyl-5-phenylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][N:5]1[C:9](=[O:10])[N:8]([CH:11]2[CH2:13][CH2:12]2)[C:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[N:6]1.[C:25]1([CH3:32])[C:30]([OH:31])=[CH:29][CH:28]=[CH:27][CH:26]=1>C(#N)C.[Cu].[Cu]=O>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:7]2[N:8]([CH:11]3[CH2:13][CH2:12]3)[C:9](=[O:10])[N:5]([CH2:4][C:3]3[CH:21]=[CH:22][CH:23]=[CH:24][C:2]=3[O:31][C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:32])[N:6]=2)=[CH:15][CH:16]=1
Reactant: O=c1n(Cc2ccccc2Br)nc(-c2ccc(Cl)cc2)n1C1CC1
Reactant: Cc1ccccc1O
Agent: O=[Cu]
Agent: [Cu]
Solvent: CC#N
Product: Cc1ccccc1Oc1ccccc1Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Temperature: 85 °C
Reaction time: 16 h

Procedure:
100 mg (0.25 mmol) of the compound from Example 99A, 53 mg (0.49 mmol) of o-cresol and 91 mg (0.74 mmol) of 4-N,N-dimethylaminopyridine were dissolved in 5 ml of acetonitrile, and 39 mg (0.62 mmol) of copper powder and 49 mg (0.62 mmol) of copper(II) oxide were added. The mixture was stirred at 85° C. for 16 h. For work-up, the mixture was cooled to RT and filtered through silica gel, and the residue was rinsed with a little ethyl acetate. The filtrate was concentrated under reduced pressure and the crude product was then purified chromatographically [Method 19]. This gave 25 mg (23% of theory) of the target compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[CH:7]=[C:6]2[CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C[O:25][C:26](=[O:37])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH2:34][CH2:35]Cl>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[CH:7]=[C:6]2[CH:18]1[CH2:23][CH2:22][N:21]([CH2:35][CH2:34][O:33][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[C:26]([OH:37])=[O:25])[CH2:20][CH2:19]1
Reactant: COC(=O)c1ccccc1OCCCl
Reactant: COc1ccc2c(c1)c(C1CCNCC1)cn2Cc1cccs1
Product: COc1ccc2c(c1)c(C1CCN(CCOc3ccccc3C(=O)O)CC1)cn2Cc1cccs1

Procedure:
This compound was prepared following the procedure described in example 13 (part D) starting with 2.4 g (7.4 mmol) of 5-methoxy-3-piperidin-4-yl-1-thiophen-2-ylmethyl-1H-indole and 1.8 g (8 mmol) of 2-(2-chloro-ethoxy)-benzoic acid methyl ester. After standard work-up, 1.3 g (36% of yield) of the expected acid were obtained.