Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=[N:20]O)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=3)[N:20]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: ON=C(Cc1ccc(C(F)(F)F)cn1)c1cccc(F)c1
Solvent: ClCCl
Solvent: O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Fc1cccc(C2=NC2c2ccc(C(F)(F)F)cn2)c1
Temperature: 0 °C
Reaction time: 0.12 h
Yield: 80.7 %

Procedure:
To a solution of 1-(3-fluorophenyl)-2-(5-trifluoromethyl-2-pyridinyl)ethanone oxime (3.3 g, 11.06 mmol) in CH2Cl2 (50 ml) was added Et3N (6.2 ml, 44.24 mmol). The solution was cooled to 0° C. and TFAA (1.9 ml, 13.27 mmol) was added dropwise over 30 min. After the addition was complete, the solution was stirred for an additional 5-10 min at 0° C. and then warmed to room temperature. After stirring for 1 hour at ambient temperature, the reaction was judged complete by HPLC and cooled to 0° C. Water (50 ml) was added and the layers were separated. The aqueous layer was extracted with CH2Cl2 (2×5 ml), and the combined organic extracts were dried over MgSO4. After filtration and concentration under reduced pressure, the residue was purified using column chromatography on silica gel (elution with 5-10% EtOAc in hexanes) to afford 2.5 g (81%) of the title compound as a yellow waxy solid.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[CH2:13]([N:15]1[C:21]2[N:22]=[CH:23][C:24]([CH2:26][CH2:27][OH:28])=[CH:25][C:20]=2[C:19](=[O:29])[N:18]([CH3:30])[C:17]2[CH:31]=[CH:32][CH:33]=[N:34][C:16]1=2)[CH3:14].O[C:36]1[CH:37]=[C:38]([C:42]2[CH:47]=[CH:46][C:45]([C:48]([O:50][CH3:51])=[O:49])=[CH:44][CH:43]=2)[CH:39]=[CH:40][CH:41]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[CH2:13]([N:15]1[C:21]2[N:22]=[CH:23][C:24]([CH2:26][CH2:27][O:28][C:40]3[CH:39]=[C:38]([C:42]4[CH:47]=[CH:46][C:45]([C:48]([O:50][CH3:51])=[O:49])=[CH:44][CH:43]=4)[CH:37]=[CH:36][CH:41]=3)=[CH:25][C:20]=2[C:19](=[O:29])[N:18]([CH3:30])[C:17]2[CH:31]=[CH:32][CH:33]=[N:34][C:16]1=2)[CH3:14]
Reactant: CCN1c2ncc(CCO)cc2C(=O)N(C)c2cccnc21
Reactant: COC(=O)c1ccc(-c2cccc(O)c2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCN1c2ncc(CCOc3cccc(-c4ccc(C(=O)OC)cc4)c3)cc2C(=O)N(C)c2cccnc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 42.8 %

Procedure:
A solution of DEAD (84 μL, 0.54 mmol) in THF (0.5 mL) was added over 2 h to an ice-cold solution of 11-ethyl-5,11-dihydro-8-(2-hydroxyethyl)-5-methyl-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one (100 mg, 0.34 mmol), methyl 3′-hydroxy-[1,1′-biphenyl]-4-carboxylate (123 mg, 0.54 mmol) and PPh3 (141 mg, 0.54 mmol) in THF (3.4 mL). The reaction mixture was stirred at 25° C. for 12 h then concentrated under reduced pressure. The residue was purified by flash chromatography (toluene:EtOAc, 85:15) to give the title compound (74 mg, 43% yield) as white gummy solid.
Reaction SMILES: [CH3:1][N:2]([CH3:4])[NH2:3].[CH3:5][O:6][CH2:7]/[CH:8]=[CH:9]/[CH:10]=O>>[CH3:1][N:2]([CH3:4])[N:3]=[CH:10]/[CH:9]=[CH:8]/[CH2:7][O:6][CH3:5]
Reactant: COC/C=C/C=O
Reactant: CN(C)N
Product: COC/C=C/C=NN(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78.2 %

Procedure:
N,N-Dimethylhydrazine (10.90 mL, 0.14 mol) was added dropwise over 15 min to (E)-4-methoxy-2-butenal (13.06 g, 0.13 mol) while cooling the reaction with an ice bath. The bath was then removed and the mixture stirred for 1.5 h at ambient temperature. Calcium chloride (20 g) was added to the reaction, let set for 15 min, and the product decanted. Distillation (bp 102°-110° C., 25 mm Hg) of the oil through a 10 cm Vigreaux column provided pure (E)-4-methoxy-2-butenal N,N-dimethylhydrazone (17) (14.45 g, 78%): IR (neat) 2850, 2820, 1560, 1465, 1445, 1375, 1270, 1120, 1030, 970 cm-1 ; 1H NMR (CDCl3) δ 2.80 (s, 6H), 3.26 (s, 3H), 3.93 (dd, 2H, J=6.2, 1.2 Hz), 5.74 (dt, 1H, J=15.8, 6.2 Hz), 6.31 (ddt, 1H, J=15.8, 8.9, 1.2 Hz), 6.92 (d, 1H, J=8.9 Hz); Anal. calcd for C7H14N2O: C 59.05, H 10.07, N 19.52; found C 59.13, H 9.92, N 19.70.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].[CH2:8]([O:12][CH:13]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:14]=[O:15])[CH2:9][CH2:10][CH3:11]>C(O)CCC>[CH2:17]([O:16][CH:13]([O:12][CH2:8][CH2:9][CH2:10][CH3:11])[CH:14]([OH:15])[C:2]([C:1]([O:5][CH2:6][CH3:7])=[O:4])=[CH2:3])[CH2:18][CH2:19][CH3:20]
Reactant: CCCCOC(C=O)OCCCC
Reactant: C=CC(=O)OCC
Solvent: CCCCO
Product: C=C(C(=O)OCC)C(O)C(OCCCC)OCCCC

Procedure:
400 mmoles ethyl acrylate and 70 g (355 mmoles) of 95.5% by weight dibutoxyethanal in butanol were reacted using the method of example 1 to form 4,4-dibutoxy-2-ethoxycarbonyl-3-hydroxy-1-butene as a liquid which distilled at 120° C. under 0.4 mbar.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[O:18][CH2:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[CH3:21][C:22]1[S:26][C:25]([C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=2)[CH:30]=O)=[N:24][CH:23]=1>>[CH2:19]([O:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([F:17])[C:11]=1[CH:2]1[N:1]([CH2:30][C:29]2[CH:32]=[CH:33][CH:34]=[C:27]([C:25]3[S:26][C:22]([CH3:21])=[CH:23][N:24]=3)[CH:28]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1)[CH3:20]
Reactant: Cc1cnc(-c2cccc(C=O)c2)s1
Reactant: CCOC(=O)C(C)CC(N)c1c(F)cccc1OCC
Product: CCOc1cccc(F)c1C1CC(C)C(=O)N1Cc1cccc(-c2ncc(C)s2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2-ethoxy-6-fluorophenyl)-2-methylbutanoate with 3-(5-methylthiazol-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.92 min.; [M+H]+: 425.02 g/mol.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:22]3[C:13](=[CH:14][C:15]4[O:20][CH2:19][CH2:18][O:17][C:16]=4[CH:21]=3)[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:23][C:24](O)=[O:25].[F:27][C:28]1[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=1[NH2:30].C(N(CC)CC)C.C(OC1C=CC2C(=CC=CC=2)N1C(OCC)=O)C>C(Cl)(Cl)Cl.C(OCC)(=O)C>[F:27][C:28]1[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=1[NH:30][C:24](=[O:25])[CH2:23][N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]2([C:22]3[C:13](=[CH:14][C:15]4[O:20][CH2:19][CH2:18][O:17][C:16]=4[CH:21]=3)[O:12][CH2:11]2)[C:2]1=[O:1]
Reactant: Nc1ccccc1F
Reactant: O=C(O)CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2ccccc21
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C(CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2ccccc21)Nc1ccccc1F
Temperature: 25 °C
Yield: 11.9 %

Procedure:
To a solution of (2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)acetic acid (0.53 g, 1.50 mmol), 2-fluoroaniline (0.2 mL, 2.1 mmol) and triethylamine (0.5 mL, 3.5 mmol) in chloroform (30 mL) was added 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (0.48 g, 1.94 mmol). The reaction mixture was heated at reflux for 26 h, allowed to cool to ambient temperature, diluted with ethyl acetate and washed sequentially with water, 10% w/v hydrochloric acid, water, 10% w/v aqueous sodium hydroxide, water and brine. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography and eluted with ethyl acetate/hexanes (1/3) to afford N-(2-fluorophenyl)-2-(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)acetamide (0.08 g, 12%): mp 117-119° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.24-8.22 (m, 1H), 8.05-7.90 (m, 1H), 7.33-6.95 (m, 6H), 6.50-6.47 (m, 1H), 6.33-6.30 (m, 1H), 4.94-4.89 (m, 1H), 4.68-4.49 (m, 4H), 4.17-4.09 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 178.2, 164.6, 155.2, 144.7, 141.3, 138.4, 131.9, 129.1, 125.6, 124.9, 121.8, 120.4, 115.0, 114.8, 111.7, 108.9, 99.4, 80.0, 64.6, 63.8, 58.0, 45.1; MS (ES+) m/z 446.8 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C:17]3[CH2:16][CH2:15][C:14]4[C:9](=[CH:10][CH:11]=[C:12]([O:21][CH3:22])[CH:13]=4)[C:8]=3[CH2:7][CH2:6][C:5]=2[CH:4]=1>[Pd]>[CH3:22][O:21][C:12]1[CH:11]=[CH:10][C:9]2[C:8]3[C:17](=[C:18]4[C:5](=[CH:6][CH:7]=3)[CH:4]=[C:3]([O:2][CH3:1])[CH:20]=[CH:19]4)[CH:16]=[CH:15][C:14]=2[CH:13]=1
Reactant: COc1ccc2c(c1)CCC1=C2CCc2cc(OC)ccc21
Agent: [Pd]
Product: COc1ccc2c(ccc3c4ccc(OC)cc4ccc23)c1
Temperature: 200 °C
Yield: 34.7 %

Procedure:
Under an argon gas flow, 70 g (0.24 mol) of 2,8-dimethoxy-5,6,11,12-tetrahydrochrysene and 50 g of Pd/C were charged into a 5 L round bottom flask equipped with a condenser, and heated at 200° C. for 1 h. Thereafter, the obtained reaction mixture was heated to 300° C. and sublimated. The resultant reaction product was recrystallized with acetic acid, thereby obtaining 24 g of the aimed product (yield: 35%).
Reaction SMILES: [NH2:1][C:2]([C:4]1[C:5]([F:32])=[C:6]([CH:28]=[CH:29][C:30]=1[F:31])[O:7][CH2:8][C:9]1[O:13][N:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20]C(=O)OC(C)(C)C)=[CH:16][CH:15]=2)[N:10]=1)=[O:3].O1CCOCC1.[ClH:39]>>[ClH:39].[NH2:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]2[N:10]=[C:9]([CH2:8][O:7][C:6]3[C:5]([F:32])=[C:4]([C:2]([NH2:1])=[O:3])[C:30]([F:31])=[CH:29][CH:28]=3)[O:13][N:12]=2)=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2noc(COc3ccc(F)c(C(N)=O)c3F)n2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: NC(=O)c1c(F)ccc(OCc2nc(-c3ccc(N)cc3)no2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
tert-Butyl N-[4-(5-[3-(aminocarbonyl)-2,4-difluorophenoxy]methyl-1,2,4-oxadiazol-3-yl)phenyl]carbamate (300 mg, 0.67 mmol, 1 equiv.) was dissolved in 4N HCl in dioxane (7 ml, 28 mmol, 42 equiv.) and the reaction mixture was stirred at r.t. overnight. Volatiles were removed under reduced pressure, the residue was triturated with dry Et2O and the solid formed was filtered and rinsed with dry Et2O. The crude product (200 mg) was taken-up in EtOH (2 ml) and was triturated with 2N HCl in Et2O solution (0.3 ml) and dry Et2O. The white solid was filtered and washed with dry Et2O, to give 110 mg of the desired product (43% yield). HPLC-MS (method 1): m/z 347 [M+H-HCl]+, Rt=2.98 min.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]2[O:29][C:28]([C:30](OCC)=[O:31])=[CH:27][C:26]=2[CH:35]=1>C1COCC1>[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]2[O:29][C:28]([C:30]([C:19]3[C:14]([F:13])=[N:15][CH:16]=[CH:17][CH:18]=3)=[O:31])=[CH:27][C:26]=2[CH:35]=1
Reactant: Fc1ccccn1
Reactant: CCOC(=O)c1cc2cc(OC)ccc2o1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1ccc2oc(C(=O)c3cccnc3F)cc2c1
Reaction time: 0.5 h

Procedure:
At 0° C. a solution of n-BuLi (0.73 ml, 1.17 mmol) is added to diisopropylamine (0.18 ml, 1.3 mmol). The mixture is stirred for 30 minutes at the same temperature before the resulting solution is added dropwise to a solution 2-fluoropyridine (0.1 ml, 1.17 mmol) in THF (3 ml) at −78° C. After stirring for one hour ethyl 5-methoxy-benzofuran-2-carboxylate (0.25 g, 1.17 mmol) in THF (4 ml) is added and stirring is continued for 2 hours at the same temperature. The reaction mixture is allowed to reach room temperature before quenching with saturated aqueous ammonium chloride solution. The product is extracted with ethyl acetate. Chromatography on silicagel gives the title compound, m.p. 130-134° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].C(N(CC)C(C)C)(C)C.[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(OCC)C>[N+:1]([C:4]1[CH:5]=[C:6]([NH:7][S:26]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:28])=[O:27])[CH:8]=[CH:9][CH:10]=1)([O-:3])=[O:2]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: O=[N+]([O-])c1cccc(NS(=O)(=O)c2ccccc2)c1
Reaction time: 16 h
Yield: 86 %

Procedure:
To 6.17 g (44.7 mmol) of 3-nitroaniline and 8.41 mL (48.2 mmol) of N,N-diisopropylethylamine in 150 mL of anhydrous diethyl ether was added 5.14 mL (40.2 mmol) of benzenesulfonyl chloride. The mixture was heated to reflux under nitrogen with stirring for 16 h, cooled and the resulting two-phase mixture scratched to crystallize the insoluble oil. After decanting the ether layer, the derived solid was dissolved in 300 mL of dichloromethane and the solution washed with 2 N HCl (3×200 mL), saturated NaHCO3 (200 mL), brine (200 mL), dried (Na2SO4) and concentrated to give 9.62 g (86%) of the title compound as a light tan solid. 1H-NMR (300 MHz, CDCl3) δ 7.96 (m, 2 H), 7.86 (m, 2 H), 7.41-7.63 (m, 5 H), and 7.30 (br s, 1 H). Mass spectrum (MALDI-TOF, gentisic acid matrix) calcd. for C12H10N2O4S: 301.0 (M+Na). Found: 301.1.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]([NH2:14])=[NH:13])(=[O:10])=[O:9].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.CN(C=O)C>[NH2:13][C:12]1[NH:14][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[S:8](=[O:10])(=[O:9])[N:11]=1
Reactant: N=C(N)NS(=O)(=O)c1cnccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: NC1=NS(=O)(=O)c2cnccc2N1

Procedure:
A mixture 0.25 g of 4-chloro-3-pyridylsulfonylguanidine (Preparation 14) and 0.25 g of potassium carbonate in 5 cm3 of dioxane/DMF (80/20) is heated at reflux for 24 hours.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[Br:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[CH3:31])[C:25](O)=O>>[Br:21][C:22]1[CH:23]=[C:24]([C:25]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:17]([F:19])([F:20])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)[N:16]=2)[CH:28]=[CH:29][C:30]=1[CH3:31]
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Reactant: Cc1ccc(C(=O)O)cc1Br
Product: Cc1ccc(-c2nc(Cn3ccc4c(C(F)(F)F)c(C#N)ccc43)no2)cc1Br

Procedure:
Synthesized as described in Example 72 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 3-bromo-4-methylbenzoic acid: MS (ESI): m/z 461 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Cl[CH2:16][C:17]1[NH:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][CH2:13][N:12]([CH2:16][C:17]2[NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]=2)[CH2:11][CH2:10]1
Reactant: COc1ccccc1C1CCNCC1
Reactant: ClCc1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1C1CCN(Cc2nc3ccccc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 24.1 %

Procedure:
A mixture of 4-(2-methoxyphenyl)piperidine (0.2 g, 1.06 mmol), 2-chloromethyl-benzimidazole (186, 1.1 mmol) and Cs2CO3 (0.36 g, 0.36 mmol) in DMF (8 mL) were stirred at room temperature for 18 hours. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (20 mL). The organic layer was washed with brine (2×30 mL) and dried over MgSO4, filtered and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography eluting with 5% methanol in dichloromethane to give the title compound (82 mg, 25%). 1H NMR (CDCl3, 300 MHz) δ 1.69 (m, 4H), 2.19 (m, 2H), 2.87(m, 1H), 2.96 (m, 2H), 3.75 (s, 2H), 3.77 (s, 3H), 6.92 (m, 2H), 7.15 (m, 4H), 7.45 (m, 1H), 7.55 (m, 1H), 12.26 (s, 1H). MS (DCI-NH3) m/z 322 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:10][C:6]=1[C:7](Cl)=[O:8].[NH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1>>[F:1][C:2]([F:21])([F:20])[CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:10][C:6]=1[C:7]([NH:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)=[O:8]
Reactant: NCc1ccccn1
Reactant: O=C(Cl)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Product: O=C(NCc1ccccn1)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F

Procedure:
contacting the resultant 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid chloride with 2-aminomethylpyridine, whereby there is formed 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-pyridylmethyl)benzamide;
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[CH:4]([N:16]1[CH2:21][CH2:20][N:19](S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)[CH:18]([CH2:34][CH3:35])[CH2:17]1)[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].SC1C=CC(O)=CC=1.Cl>CN(C=O)C>[CH3:1][O:2][C:3](=[O:36])[CH:4]([N:16]1[CH2:21][CH2:20][NH:19][CH:18]([CH2:34][CH3:35])[CH2:17]1)[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1
Reactant: CCC1CN(C(Cc2ccc3ccccc3c2)C(=O)OC)CCN1S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: Oc1ccc(S)cc1
Solvent: CN(C)C=O
Product: CCC1CN(C(Cc2ccc3ccccc3c2)C(=O)OC)CCN1
Temperature: 25 °C
Reaction time: 6 h
Yield: 80 %

Procedure:
To a solution of 2-[3-ethyl-4-(2-nitro-benzenesulfonyl)-piperazin-1-yl]-3-naphthalen-2-yl-propionic acid methyl ester, 33, (4.1 g, 8.0 mmol) in anhydrous DMF (40 mL) is added potassium carbonate (6.7 g, 48.2 mmol) and 4-mercaptophenol (3.0 g, 24.1 mmol). The reaction mixture is stirred for six hours at room temperature, cooled in a ice bath and the pH adjusted to ˜3 with 1M HCl. The reaction mixture is extracted with Et2O (4×100 mL), the organic layers combined and extracted with 1M HCl (100 mL). The organic layers are then discarded. The aqueous layers were combined and cooled in ice bath and pH was adjusted to ˜10 with K2CO3. The aqueous layer is extracted with EtOAc (4×125 mL) and dried over Na2SO4. The combined organic layers are concentrated in vacuo to afford 2.1 g (80% yield) of the desired product. 1H NMR (CDCl3, δ): 7.84–7.75 (m, 3H), 7.70 (s, 1H), 7.50–7.38 (m, 2H), 7.35 (dd, J=8.3, 1.7 Hz, 1H), 3.60(s, 3H), 3.55–3.50 (m, 1H), 3.30–3.24 (m, 1H), 3.18–3.08 (m, 1H), 3.05–2.75 (m, 5H), 2.70–2.55 (m, 1H), 2.50 (dd, J=10.4, 4.1 Hz, 1H), 2.04 (t, J=10.4 Hz, 1H), 1.52–1.32 (M, 2H), 1.00 (t, J=8.3 Hz, 3H); 13C NMR, δ 171.8, 135.9, 133.7, 132.4, 128.1, 128.0, 127.9, 127.8, 126.1, 125.6, 120.8, 70.0, 57.3, 54.3, 52.9, 51.3, 46.4, 35.7, 27.5, 10.6.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][N:33]=2)[C:28]([CH:35]=O)=[CH:27]1.N1CCCCC1>CO>[NH:26]1[C:34]2=[N:33][CH:32]=[CH:31][CH:30]=[C:29]2[C:28](/[CH:35]=[C:7]2\[O:8][C:4]3[C:3]([CH2:12][N:13]4[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]4)=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=3[C:6]\2=[O:9])=[CH:27]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Solvent: C1CCNCC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4ncccc24)C3=O)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 58.3 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.100 g, 0.287 mmol) obtained in Example A16, Step 1 in methanol (1 mL) was added with 7-aza-1H-indole-3-carboxaldehyde (0.0502 g, 0.344 mmol) and piperidine (0.00244 g, 0.0287 mmol), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was cooled to room temperature, and then the precipitated solid was collected by filtration to obtain tert-butyl (Z)-4-({2-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0798 g, 58%).
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[NH:13][N:12]=2)[C:7]([F:19])=[CH:6][C:3]=1[C:4]#[N:5].[F:20][C:21]1[CH:26]=[CH:25][C:24]([C@@H:27]([NH2:29])[CH3:28])=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C>CCCCO>[CH:16]1([C:14]2[NH:13][N:12]=[C:11]([NH:10][C:8]3[C:7]([F:19])=[CH:6][C:3]([C:4]#[N:5])=[C:2]([NH:29][C@H:27]([C:24]4[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=4)[CH3:28])[N:9]=3)[CH:15]=2)[CH2:18][CH2:17]1
Reactant: C[C@H](N)c1ccc(F)cc1
Reactant: N#Cc1cc(F)c(Nc2cc(C3CC3)[nH]n2)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1C#N)c1ccc(F)cc1
Temperature: 140 °C
Yield: 51.6 %

Procedure:
A portion of 2-chloro-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoronicotinonitrile (Method 1; 0.8 g, 2.8 mmol) and (S)-1-(4-fluorophenyl)ethanamine (0.8 g, 5.6 mmol) were added to a solution of n-BuOH (4 ml) and DIEA (0.5 g, 3.7 mmol) in a sealed tube. The reaction was heated to 140° C. for 48 hrs, then cooled to 25° C. and concentrated. The resulting residue was purified by column chromatography (DCM-MeOH=50:1) to give the title compound (0.55 g, 50%). 1H NMR (400 MHz, CDCl3) δ 8.44 (br s, 1H), 7.37-7.33 (m, 2H), 7.27 (d, J=9.6 Hz, 1H), 7.07-7.03 (m, 2H), 6.11 (s, 1H), 5.24-5.20 (m, 2H), 1.87-1.83 (m, 1H), 1.60 (d, J=6.2 Hz, 3H), 1.01-0.98 (m, 2H), 0.79-0.65 (m, 2H). MS: Calcd.: 380. Found: [M+H]+ 381.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[O:21][C:20]([NH:22][CH2:23][C:24]5[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=5)=[N:19][N:18]=4)[CH:15]=3)[N:10]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:9]=2)[N:3]=1.[CH:42]([NH2:45])([CH3:44])[CH3:43]>CS(C)=O>[CH:42]([NH:45][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[O:21][C:20]([NH:22][CH2:23][C:24]5[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=5)=[N:19][N:18]=4)[CH:15]=3)[N:10]([S:32]([C:35]3[CH:36]=[CH:37][C:38]([CH3:39])=[CH:40][CH:41]=3)(=[O:33])=[O:34])[CH:9]=2)[N:3]=1)([CH3:44])[CH3:43]
Reactant: CC(C)N
Reactant: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3nccc(Cl)n3)cn4S(=O)(=O)c3ccc(C)cc3)o2)cc1
Solvent: CS(C)=O
Product: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3nccc(NC(C)C)n3)cn4S(=O)(=O)c3ccc(C)cc3)o2)cc1
Temperature: 110 °C
Reaction time: 12 h
Yield: 42.5 %

Procedure:
To a solution of 5-(3-(4-chloropyrimidin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-oxadiazol-2-amine (500 mg, 0.85 mmol) in DMSO (5 mL) was added isopropylamine (60 mg, 1.02 mmol). The mixture was stirred at 110° C. for 12 h. The reaction was quenched with ice cold H2O and was extracted with EtOAc. The combined organic layers were dried, filtered and concentrated. The residue was purified with flash chromatography (basic alumina, eluting with 30-40% EtOAc in Hex) to give 5-(3-(4-(isopropylamino)pyrimidin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-oxadiazol-2-amine (220 mg, 52%). MS (ESI, pos. ion) m/z: 609.6 (M+1); 1H-NMR (400 MHz, DMSO-d6): δ 9.07 (s, 1H), 8.39 (s, 1H), 8.23 (m, 1H), 8.12 (d, J=8 Hz, 1H), 8.00 (d, J=8 Hz, 2H), 7.85 (d, J=8.4 Hz, 1H), 7.79-7.57 (m, 5H), 7.43 (d, J=8 Hz, 2H), 7.312 (d, J=8 Hz, 3H), 6.90 (d, J=8 Hz, 2H), 4.38 (m, 3H), 3.72 (s, 3H), 2.32 (s, 3H), 1.17 (d, J=6.4 Hz, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]([NH2:14])=O)[NH:9]2)=[CH:5][C:4]=1[CH3:15].P(Cl)(Cl)(Cl)=O.C(Cl)(Cl)Cl>O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]#[N:14])[NH:9]2)=[CH:5][C:4]=1[CH3:15]
Reactant: COc1cc2[nH]c(C(N)=O)cc2cc1C
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1cc2[nH]c(C#N)cc2cc1C
Reaction time: 1 h
Yield: 62.3 %

Procedure:
A mixture of 202 mg of 6-methoxy-5-methyl-1H-indole-2-carboxamide (1 mmol), 0.47 mL of phosphorus oxychloride (5 mmol) and 3 mL of chloroform was refluxed for 2 hs. Then cooled solution was poured into 10 mL of water and stirred for 1 hr. After separation the organic layer was dried over sodium sulfate and concentrated. The residue was purified on silica gel column using hexane-ethyl acetate 5:1 to afford 116 mg of 6-methoxy-5-methyl-1H-indole-2-carbonitrile. 1H NMR (600 MHz, CDCl3): δ 8.26 (br, 1H), 7.37 (s, 1H), 7.06 (s, 1H), 6.76 (s, 1H), 3.88 (s, 1H), 2.28 (s, 3H).