Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH:4]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=1)[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1)=[N+]=[N-]>N1C=CC=CC=1>[NH2:1][CH:4]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=1)[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1
Reactant: [N-]=[N+]=NC(Cn1ccnc1)c1ccc(Cl)cn1
Solvent: c1ccncc1
Product: NC(Cn1ccnc1)c1ccc(Cl)cn1

Procedure:
A solution of 0.83 g of 1-azido-1-(5-chloro-2-pyridyl)-2-(1H-imidazol-1-yl)ethane in 4 ml of dry pyridine is stirred under a H2S-atmosphere for 3 hours. The reaction mixture is evaporated, the residue is redissolved in 5 ml of dilute acetic acid (acetic acid/water 1/4) and extracted with ethyl acetate. The combined organic phases are evaporated to give the title product as a yellowish oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:15])[CH2:9][CH:10]([OH:14])[CH2:11][CH:12]=[CH2:13])[CH:5]=[CH:6][CH:7]=1>ClCCl.[O-2].[Mn+4].[O-2]>[Br:1][C:2]1[CH:3]=[C:4]([C:8](=[O:15])[CH2:9][CH:10]([OH:14])[CH2:11][CH:12]=[CH2:13])[CH:5]=[CH:6][CH:7]=1
Reactant: C=CCC(O)CC(O)c1cccc(Br)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: C=CCC(O)CC(=O)c1cccc(Br)c1
Reaction time: 4 h
Yield: 82.1 %

Procedure:
A mixture of 1-(3-bromophenyl)hex-5-ene-1,3-diol (2.60 g, 9.59 mmol) and manganese(IV) oxide (9.81 g, 95.9 mmol) in dichloromethane (80 mL) is heated and stirred for 4 h under reflux. The reaction mixture is filtered through a pad of diatomaceous earth and the residue is washed twice with dichloromethane. The filtrate is concentrated under reduced pressure to afford the title compound (2.12 g, 82%). 1H NMR (400 MHz, CDCl3) δ 8.05 (d, 1H, J=1.8 Hz), 7.85 (d, 1H, J=7.5 Hz), 7.69-7.52 (m, 1H), 7.35-7.31 (m, 1H), 5.91-5.82 (m, 1H), 5.18-5.12 (m, 2H), 4.32-4.26 (m, 1H), 3.09-3.00 (m, 2H), 2.39-2.30 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]2[CH:13]=[C:14]([CH2:16][OH:17])[N:15]=[C:5]2[CH:4]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]2[CH:13]=[C:14]([CH:16]=[O:17])[N:15]=[C:5]2[CH:4]=1
Reactant: COc1cc2nc(CO)cn2c2ccccc12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: COc1cc2nc(C=O)cn2c2ccccc12
Temperature: 25 °C
Reaction time: 28 h
Yield: 75.3 %

Procedure:
A solution of 14.6 g (64 mmol) of the product of Step A in 700 ml of chloroform was vigorously stirred while 60 g of activated manganese dioxide were added thereto and the mixture was then stirred at room temperature for 28 hours. The mixture was filtered and the filter was throughly washed with chloroform. The filtrate was evaporated to dryness under reduced pressure and the residue was crystallized from ethyl acetate to obtain 10.9 g (75% yield) of 5-methoxyimidazo[1,2-a]quinolin-2-carboxaldehyde in the form of a white crystalline solid melting at 195°-196° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13]O)=[CH:9][N:8]=1.C(N(C(C)C)CC)(C)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C([N:58]1[CH:62]=[C:61]([CH2:63][C:64]2[CH:69]=[CH:68][C:67]([C:70]#[N:71])=[CH:66][CH:65]=2)[N:60]=[CH:59]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:60]2[C:61]([CH2:63][C:64]3[CH:69]=[CH:68][C:67]([C:70]#[N:71])=[CH:66][CH:65]=3)=[CH:62][N:58]=[CH:59]2)=[CH:9][N:8]=1
Reactant: N#Cc1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Reactant: OCc1ccc(-c2ccccn2)nc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(Cc2cncn2Cc2ccc(-c3ccccn3)nc2)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(pyrid-2-yl)-5-hydroxymethyl-pyridine (269 mg, 1.33 mmol) and diisopropylethylamine (0.464 mL, 2.66 mmol) in dichloromethane (7 mL) at -78° C. is added trifluoromethanesulfonic anhydride (0.224 mL, 1.33 mmol) and the mixture stirred at -78° C. for 1 hour. To this mixture is added a solution of 1-trityl-4-(4-cyanobenzyl)-imidazole (566 mg, 1.33 mmol) in dichloromethane (5 mL). The mixture is allowed to warm to ambient temperature and stirred for 2 hours. The solvent is evaporated in vacuo. The residue is dissolved in methanol (50 mL), heated at reflux for 1 hour, and the solvent is evaporated in vacuo. The residue is partitioned between dichloromethane and sat. aq. NaHCO3 solution. The organic layer is dried, (Na2SO4) and the solvent evaporated in vacuo. The residue is chromatographed to afford the title compound.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:6]([C:9]1[CH:10]=[CH:11][C:12]2[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14][C:13]=2[CH:20]=1)([O-:8])=[O:7].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>>[N+:6]([C:9]1[CH:10]=[CH:11][C:12]2[CH2:18][CH2:17][CH:16]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:15][CH2:14][C:13]=2[CH:20]=1)([O-:8])=[O:7]
Reactant: O=C1CCc2ccc([N+](=O)[O-])cc2CC1
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc2c(c1)CCC(N1CCCC1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Pyrrolidine (0.85 g, 12 mmol) and 2-nitro-5,6,8,9-tetrahydro-benzocyclohepten-7-one (2.05 g, 10 mmol) were mixed in 1,2-dchloroethane (35 mL) and then treated with NaBH(OAc)3 (3.18 g, 15 mmol) and AcOH (0.60 g, 10 mmol). The mixture was stirred at ambient temperature under a N2 atmosphere overnight. The reaction mixture was quenched with saturated NaHCO3, and the product was extracted with EtOAc (3×30 mL). The organic layers were combined and dried over NaSO4. The solvent was evaporated and the residue was purified by flash column chromatography eluting with CH2Cl2/DMA=1/1 (DMA=CH2Cl2/MeOH/30% NH3=80/19/1) to afford 1-(2-nitro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl)pyrrolidine, a yellow oil (2.2 g, 85%); MS (m/e): 261 (M+H+).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=3[OH:21])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[OH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O>>[OH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=3[OH:21])[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1O
Reactant: Cc1ccc(-c2cccc(-c3cccc(Br)n3)n2)c(O)c1
Product: Cc1ccc(-c2cccc(-c3cccc(-c4ccccc4O)n3)n2)c(O)c1
Yield: 68 %

Procedure:
6-(2-Hydroxyphenyl)-6′-(2-hydroxy-4-methylphenyl)-2,2′-bipyridine was prepared from 6-bromo-6′-(2-hydroxy-4-methylphenyl)-2,2′-bipyridine and 2-hydroxyphenylboronic acid in 68% yield using method F; δH [2 H6]-DMSO 13.55,(1H, b), 13.39,(1H, b), 8.38-8.32,(4H, m), 8.30-8.20,(4H, m), 8.13,(3H, d,), 8.03,(1H, d), 7.37,(1H, t), 7.00,(2H, m), 6.81,(2H, m), 2.30,(3H, s); MS 355 (MH)+; HPLC retention time (system 1) 4.34 minutes.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([CH3:21])[CH3:20])[C:14]=1[NH:22][C:23](=[O:39])[CH2:24][NH:25][CH:26]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:12]>CCOC(C)=O>[CH3:12][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([CH3:20])[CH3:21])[C:14]=1[NH:22][C:23](=[O:39])[CH2:24][N:25]([CH:26]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:8]([NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:9])[CH3:10]
Reactant: O=C=Nc1ccccc1
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CNC(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CN(C(=O)Nc1ccccc1)C(c1ccccc1)c1ccccc1
Reaction time: 48 h

Procedure:
Excess phenylisocyanate (0.44 g) was added to a mixture of the product from Example 4 (0.60 g) in 100 mL EtOAc at room temperature. After sitting for a short period of time at room temperature, the solvent was removed in vacuo. EtOAc was added to the residue and allowed to sit 2 days at room temperature. The ethyl acetate was removed on the rotary evaporator. The residual solid was slurried in hexane/EtOAc, 1/1 and collected by filtration. (0.82 g) (100%). NMR (CDCl3) δ 1.06 (12H, d), δ 2.66 (2H, m), δ 4.24 (2H, s), δ 6.44 (1H, bs), δ 6.9-7.5 (18H, m), δ 7.93 (1H, bs). IR (KBr) 3391, 2964, 1648, 1531, 1444, 752, 700 cm-1.
Reaction SMILES: Br[C:2]1[NH:22][C:5]2=[N:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=3)[N:9]=[C:4]2[CH:3]=1.[Cl:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[C:30](=[O:34])[N:31]([CH3:33])[CH3:32]>>[Cl:23][C:24]1[CH:25]=[C:26]([C:2]2[NH:22][C:5]3=[N:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]4[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=4)[N:9]=[C:4]3[CH:3]=2)[CH:27]=[CH:28][C:29]=1[C:30]([N:31]([CH3:33])[CH3:32])=[O:34]
Reactant: CN(C)C(=O)c1ccc(B(O)O)cc1Cl
Reactant: COc1cc(CCc2cnc3[nH]c(Br)cc3n2)cc(OC)c1
Product: COc1cc(CCc2cnc3[nH]c(-c4ccc(C(=O)N(C)C)c(Cl)c4)cc3n2)cc(OC)c1

Procedure:
The compound was prepared by using procedures analogous to those described for the synthesis of Example 53, Step 2 starting from 6-bromo-2-[2-(3,5-dimethoxyphenyl)ethyl]-5H-pyrrolo[2,3-b]pyrazine and 3-chloro-4-(dimethylcarbamoyl)phenylboronic acid (from Combi-Blocks). LCMS calculated for C25H26ClN4O3 (M+H)+: m/z=465.2. Found 465.1.
Reaction SMILES: [C:1]1([CH2:13][C:14]([NH2:16])=[O:15])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.[O:17]1CCOCC1>O.[Pd]>[C:1]1([C:13](=[O:17])[C:14]([NH2:16])=[O:15])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1
Reactant: NC(=O)Cc1cn2c3c(cccc13)CCC2
Reactant: C1COCCO1
Agent: [Pd]
Solvent: O
Product: NC(=O)C(=O)c1cn2c3c(cccc13)CCC2
Yield: 96 %

Procedure:
To a solution of (5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)acetamide (0.30 g, 1.31 mmol) in dioxane (6 mL) and water (2 mL) was added 10% palladium on carbon (0.060 g), followed by the careful addition of NaH2PO2.H2O (0.60 g, 5.67 mmol) and the reaction was brought to reflux under nitrogen. After 3 hours an additional 0.60 g of NaH2PO2.H2O was added and the reaction was heated at reflux for another 6 hrs. The mixture was cooled, filtered through a pad of Celite, and washed well with ethyl acetate (100 mL). The solution was concentrated under reduced pressure and the residue triturated with water (20 mL). The resulting suspension was filtered and the recovered solid dried under reduced pressure to provide 0.27 g (96%) of the title compound as a white solid.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:11][O:12][C:13](=[O:26])[CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].[C:27](Cl)(=[O:41])/[CH:28]=[CH:29]/[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>C1COCC1>[CH2:19]([O:18][C:16]([N:15]([CH2:14][C:13]([O:12][CH3:11])=[O:26])[C:27](=[O:41])/[CH:28]=[CH:29]/[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)CNC(=O)OCc1ccccc1
Reactant: CCCCCCCCCCC/C=C/C(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCCCCCC/C=C/C(=O)N(CC(=O)OC)C(=O)OCc1ccccc1
Temperature: -70 °C
Yield: 66.2 %

Procedure:
A solution of lithium bis(trimethylsilyl)amide (44.8 ml, 1M solution) in anhydrous THF (50 ml) was cooled to −70° C. under argon in a dry flask with stirring. To the solution was added Cbz glycine methyl ester (10.0 g) in THF (20 mL) dropwise while maintaining the reaction temperature at −70° C. After 30 min stirring at −70° C., a solution of the (E)-tetradec-2-enoyl chloride (12.1 g) in THF (10 mL) was added slowly at −70° C. The reaction mixture was stirred at −70° C. for 1 hr and then allowed to warm up to 0° C. The reaction was quenched with aqueous citric acid solution (5%, 300 ml) and warmed up to room temperature. The crude product was extracted with ethyl acetate (500 ml). The ethyl acetate phase was washed with DI water twice and dried with sodium sulfate. The solvent was removed under vacuum to yield oily residue, which was purified by silica gel column chromatography. Pure product was obtained after column purification as a clear oil (12.8 g, 66.2% yield). Proton NMR(CDCl3) δ 0.88 (t, 3H), 1.26 (m, 16H), 1.43 (m, 2H), 2.22 (m, 2H), 3.67 (s, 3H), 4.53 (s, 2H), 5.24 (s, 2H), 6.94 (d, 1H), 7.05 (td, 1H). 7.36 (m, 5H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14](=[O:17])[CH2:15]Br)=[CH:4][CH:3]=1.[C:18]([O-:21])(=[O:20])[CH3:19].[K+]>O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14](=[O:17])[CH2:15][O:21][C:18](=[O:20])[CH3:19])=[CH:4][CH:3]=1
Reactant: CC(=O)[O-]
Reactant: Cc1ccc(-c2ccccc2C(=O)CBr)cc1
Agent: [K+]
Solvent: O
Product: CC(=O)OCC(=O)c1ccccc1-c1ccc(C)cc1
Temperature: 100 °C
Yield: 33.3 %

Procedure:
A solution of 1.44 g (4.98 mmol) of 4'-methyl-2-(bromoacetyl)-1,1'-biphenyl in 3.0 mL of polyethyleneglycol-400 was added to a solution of 500 mg of potassium acetate in 3.0 mL of polyethyleneglycol-400. The suspension was heated at 100° C. for 30 minutes, then cooled and diluted with 100 mL of water. The resultant mixture was extracted with ether; the combined ether extracts were diluted with an equal volume of hexane and washed with water. The organic layer was separated, dried over magnesium sulfate, filtered, and the solvent was removed under vacuum to yield an oil which was purified by silica chromatography, eluting with hexane/ethyl acetate (8:1) to give 444 mg (1.66 mmol,33%) of product as an oil. 1H NMR (200 MHz,CDCl3): 2.06 (s,3H), 2.39 (s,3H), 4.46 (s,2H), 7.23 (s,4H), 7.3-7.6 (m,4H).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([NH:20][C:21]#[N:22])=[N:9][C:10]2[CH:19]=[CH:18]C=[C:16]3[C:11]=2C=CC=[N:15]3)=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=1)[CH3:26].CN(C)C=O.C(N(CC)CC)C>O1CCCC1>[CH2:25]([O:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([NH:9][C:10]3[CH:11]=[CH:16][N:15]=[CH:18][CH:19]=3)=[N:20][C:21]#[N:22])=[CH:23][CH:24]=2)=[O:36])=[CH:30][CH:29]=1)[CH3:26]
Reactant: N#CNC(=Nc1cccc2ncccc12)NCc1ccc(N)cc1
Reactant: CCOc1ccc(N=C=O)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOc1ccc(NC(=O)Nc2ccc(CNC(=NC#N)Nc3ccncc3)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 85 %

Procedure:
N-(4-Amino-benzyl)-N′-cyano-N″-quinolin-5-yl-guanidine (100 mg, 0.380 mmol) and 1-ethoxy-4-isocyanato-benzene (61 mg,, 0.39 mmol) were dissolved in and mixture of N,N-dimethylformamide (2.0 mL).and tetrahydrofuran (1.0 mL). Triethylamine (0.060 mL, 0.390 mmol) was added. The reaction mixture was shaken at room temperature for 12 hours. The solvent was removed in vacuo to give the title compound (yield=85%). 1H NMR (DMSO-d6, ppm): 8.34 (br, s, 2H); 7.41-7.21 (m, 10H); 6.82-6.76 (m, 2H); 4.43 (s, 2H); 3.93 (dq, 2H); 1.28 (dt, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]([OH:15])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:16][CH2:17][C:18]1[CH:23]=[C:22]([CH:24]=[CH2:25])[C:21]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[C:20]([F:31])[CH:19]=1.CCOC(OC(OCC)=O)=O.CCCCCC.CCOC(C)=O>CN(C=O)C>[F:31][C:20]1[CH:19]=[C:18]([CH:23]=[C:22]([CH:24]=[CH2:25])[C:21]=1[NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH2:17][NH:16][C:13](=[O:15])[C:12]#[C:11][C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:10][CH:9]=1
Reactant: C=Cc1cc(CN)cc(F)c1NS(C)(=O)=O
Reactant: CC(C)(C)c1ccc(C#CC(=O)O)cc1
Agent: CCOC(=O)OC(=O)OCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=Cc1cc(CNC(=O)C#Cc2ccc(C(C)(C)C)cc2)cc(F)c1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 68.8 %

Procedure:
A mixture of (4-tert-Butylphenyl)propynoic acid (step 2 of Example 11, 0.16 mmol, 33.0 mg) and N-(4-aminomethyl-2-fluoro-6-vinylphenyl)methanesulfonamide (step 6 of Example 2, 0.19 mmol, 39.20 mg), DEPC (1.2 eq, 0.19 mmol, 29.13 μl), TEA (2 eq, 0.32 mmol, 44.60 μl) in DMF under an Ar atmosphere was stirred at room temperature for 12 h. Upon completion, as determined by TLC, the reaction solution was extracted by EtOAc (150 ml×3) and the organic phase was washed with H2O, dried (Na2SO4), filtered and concentrated. After silica gel column chromatography (n-hexane/EtOAc=2:1), 3-(4-tert-butylphenyl)propynoic acid 3-fluoro-4-methanesulfonylamino-5-vinylbenzylamide (49.5 mg, 0.11 mmol, 72.25%) was isolated.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[F:22][C:23]1([CH3:27])[CH2:26][NH:25][CH2:24]1>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:25]3[CH2:26][C:23]([F:22])([CH3:27])[CH2:24]3)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: CC1(F)CNC1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: Cl
Product: CC1(F)CN(C(=O)c2ccc(N3CC(F)(F)C3)c(OCC3CC3)n2)C1
Yield: 24 %

Procedure:
In analogy to the procedure described in Example 127 e), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b, 20 mg, 70.4 μmol) was reacted with 3-fluoro-3-methylazetidine hydrochloride (CAN 1427379-42-7, 10.6 mg, 84.4 μmol) to obtain the title compound (6 mg, 24%) as off-white solid, MS (ESI): m/e=356.2 [MH+].
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]1[C:13]3[S:19][C:18]([C:20]([OH:22])=O)=[CH:17][C:14]=3[NH:15][N:16]=1)=[CH:6]2.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[F:53][C:54]1[CH:59]=[CH:58][C:57]([N:60]2[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]2)=[CH:56][CH:55]=1>CN(C)C=O.C(OCC)(=O)C.CO>[F:53][C:54]1[CH:55]=[CH:56][C:57]([N:60]2[CH2:65][CH2:64][N:63]([C:20]([C:18]3[S:19][C:13]4[C:12]([C:7]5[NH:8][C:9]6[C:5]([CH:6]=5)=[CH:4][C:3]([CH2:2][OH:1])=[CH:11][CH:10]=6)=[N:16][NH:15][C:14]=4[CH:17]=3)=[O:22])[CH2:62][CH2:61]2)=[CH:58][CH:59]=1
Reactant: O=C(O)c1cc2[nH]nc(-c3cc4cc(CO)ccc4[nH]3)c2s1
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(c1cc2[nH]nc(-c3cc4cc(CO)ccc4[nH]3)c2s1)N1CCN(c2ccc(F)cc2)CC1
Reaction time: 0.17 h
Yield: 58.4 %

Procedure:
To a solution of 3-(5-hydroxymethyl-1H-indol-2-yl)-1H-thieno[3,2-c]pyrazole-5-carboxylic acid [124 mg, 0.396 mmol, Example (37)] in dimethyl formamide (5 mL) is added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (91 mg, 0.474 mmol) and 1-hydroxybenzotriazole (54 mg, 0.399 mmol). After stirring for 10 minutes, to it is added diisopropylethylamine (0.138 mL) and 1-(4-fluorophenyl)piperazine (79 mg, 0.438 mmol). The resulting yellow solution mixture is stirred at room temperature overnight. The reaction mixture is diluted in ethyl acetate (60 mL) and washed with water (3×10 mL), brine and dried over sodium sulfate. Purification by chromatography on silica gel (50% ethyl acetate/heptane then ethyl acetate) gave solid. The solid is redissolved in methanol and triturated with water to give [4-(4-fluoro-phenyl)-piperazin-1-yl]-[3-(5-hydroxymethyl-1H-indol-2-yl)-1H-thieno[3,2-c]pyrazol-5-yl]-methanone [110 mg, 56%, Example (38)] as cream solid, mp=156-158° C.; 1H NMR [(CD3)2SO)]: δ 13.490 (1H, s), 11.59 (1H, s), 7.563 (2H), 7.356 (1H), 7.109-6.985 (5H, m), 6.648 (1H), 5.004 (1H, t, OH), 4.553 (2H, d, OCH2), 3.856 (4H, br s), 3.208 (4H, br peak); LC/MS: 476 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1I.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[C:16]([C:28]2[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(-c2ccccc2C(=O)NCCc2c[nH]c3ccc(Cl)cc23)cc1
Yield: 94 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-methoxybiphenyl-2-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.075 g; 0.176 mmol), 4-methoxyphenylboronic acid (0.028 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) furnished 0.067 g (94%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-methoxybiphenyl-2-carboxamide as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:8]=[CH:7]2.[Se](=O)=[O:19]>C(Cl)Cl>[C:12]1([C:9]2[CH:8]=[CH:7][C:6]3[C:11](=[C:2]([CH:1]=[O:19])[CH:3]=[CH:4][CH:5]=3)[N:10]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1cccc2ccc(-c3ccccc3)nc12
Reactant: O=[Se]=O
Solvent: ClCCl
Product: O=Cc1cccc2ccc(-c3ccccc3)nc12
Temperature: 140 °C
Reaction time: 5 h
Yield: 43.3 %

Procedure:
8.46 g of 8-methyl-2-phenylquinoline [compare Atwell, G.J. et al., J. Med. Chem. 32, 396-401 (1989)] are mixed with 8.9 g (80 mmol) of selenium dioxide and heated first to 140° C. with stirring, then to 160° C. for 5 hours. The mixture is cooled, a further 2.5 g of selenium dioxide are added and the mixture is stirred at 160° C. for 2.5 hours. It is cooled, stirred with methylene chloride, the solid is filtered off and the filtrate is concentrated. The mixture obtained is purified by flash chromatography on silica gel using toluene/hexane 1:1 and toluene. 3.9 g of beige colored crystals of melting point 100°-102° C. are obtained.
Reaction SMILES: C(N=C=NCCCN(C)C)C.C1C=CC2N(O)N=NC=2C=1.[OH:22][C:23]1[CH:40]=[CH:39][C:26]([NH:27][C:28]2[CH:36]=[C:35]([F:37])[C:34]([F:38])=[CH:33][C:29]=2[C:30]([OH:32])=O)=[CH:25][CH:24]=1.Cl.[CH2:42]([O:49][NH2:50])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(N(CC)CC)C>ClCCl.CCOCC>[OH:22][C:23]1[CH:24]=[CH:25][C:26]([NH:27][C:28]2[CH:36]=[C:35]([F:37])[C:34]([F:38])=[CH:33][C:29]=2[C:30]([NH:50][O:49][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:32])=[CH:39][CH:40]=1
Reactant: NOCc1ccccc1
Reactant: O=C(O)c1cc(F)c(F)cc1Nc1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C(NOCc1ccccc1)c1cc(F)c(F)cc1Nc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
1-Ethyl-3-(3′-dimethylaminopropyl)carbodiimide (EDCI, 0.22 g, 1.1 mmol) and HOBt (0.17 g, 1.1 mmol) were added to a solution of crude 2-(4-hydroxyanilino)-4,5-difluoro-benzoic acid (Example M, 0.265 g, 1.00 mmol) in 70 mL of dichloromethane at 0° C. After 1 hour, O-benzylhydroxylamine hydrochloride (0.176 g, 1.1 mmol), and triethylamine (0.15 mL, 1.1 mmol) were added, and the reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with 100 mL of ether and washed with water and 0.1N HCl, water, and brine, dried over sodium sulfate. Solvents were evaporated to give 0.35 g of the title compound as a crude solid.