Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1C[O:14]CC1.[CH2:16]([O:18][C:19](=[O:37])[CH2:20][C:21]1[C:22]([CH3:36])=[N:23][C:24]2[N:25]([N:28]=[C:29]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:30]=2)[C:26]=1[I:27])[CH3:17].C1(C2ON2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1>C1COCC1>[CH2:16]([O:18][C:19](=[O:37])[CH:20]([C:21]1[C:22]([CH3:36])=[N:23][C:24]2[N:25]([N:28]=[C:29]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:30]=2)[C:26]=1[I:27])[OH:14])[CH3:17]
Reactant: C1CCOC1
Reactant: CCOC(=O)Cc1c(C)nc2cc(C(=O)OCC)nn2c1I
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Agent: [K+]
Product: CCOC(=O)c1cc2nc(C)c(C(O)C(=O)OCC)c(I)n2n1
Reaction time: 0.5 h
Yield: 62.2 %

Procedure:
To a stirred solution of 0.9M KHMDS/THF (39.1 mL, 35.2 mmol) in THF (100 mL) at −78° C. was added a THF (50 mL) solution of ethyl 6-(2-ethoxy-2-oxoethyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (11.3 g, 27.1 mmol) over the course of 5 min. After 30 min, a THF (50 mL) solution of 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (9.20 g, 35.2 mmol) was added to the red reaction mixture and stirring was continued for an additional 30 min at −78° C. Then, the resulting orange reaction mixture was quenched with sat. aq. NH4Cl (50 mL), diluted with EtOAc (200 mL), washed with water (100 mL), brine (100 mL), dried (Na2SO4), filtered and concentrated in vacuo to give a solid. This solid was triturated with small amount of ethyl acetate and solids were filtered, washed with hexanes and dried under high vacuum to afford ethyl 6-(2-ethoxy-1-hydroxy-2-oxoethyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (7.3 g, 16.85 mmol, 62.2% yield) as light yellow solid. 1H NMR (500 MHz, CDCl3) δ 7.33 (s, 1H), 5.75 (d, J=2.1 Hz, 1H), 4.52 (qd, J=7.1, 1.2 Hz, 2H), 4.37-4.30 (m, 2H), 3.57 (d, J=2.4 Hz, 1H), 2.63 (s, 3H), 1.48 (t, J=7.2 Hz, 3H), 1.27 (t, J=7.0 Hz, 3H). LCMS (M+H)=434.1.
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[CH2:9][CH2:10][CH:11]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)[C:12]1[C:20]2[C:15](=[C:16]([CH2:22][S:23][CH3:24])[C:17]([F:21])=[CH:18][CH:19]=2)[NH:14][CH:13]=1)(=O)=O.C(OCC)(=O)C>CN(C=O)C>[Cl:31][C:28]1[CH:27]=[CH:26][C:25]([CH:11]([C:12]2[C:20]3[C:15](=[C:16]([CH2:22][S:23][CH3:24])[C:17]([F:21])=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:9][C:1]#[N:2])=[CH:30][CH:29]=1
Reactant: [C-]#N
Reactant: CSCc1c(F)ccc2c(C(CCOS(C)(=O)=O)c3ccc(Cl)cc3)c[nH]c12
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSCc1c(F)ccc2c(C(CCC#N)c3ccc(Cl)cc3)c[nH]c12
Temperature: 80 °C
Reaction time: 3 h

Procedure:
0.46 g (7.01 mmol) of potassium cyanide were added to 1.55 g (3.50 mmol) of the compound from Example 66A in 32 ml of DMF. The mixture was stirred at 80° C. for 3 h, ethyl acetate was added to the reaction solution, and the mixture was washed twice with water and once with saturated aqueous sodium chloride solution. The combined organic phases were dried over sodium sulfate, the solid was filtered off, and the solvents were removed. The crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 1.00 g (77% of theory) of the target compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13](=[O:14])[NH:12][N:11]3[C:15](=[O:18])[NH:16][N:17]=[C:10]3[C:9]=2[C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:32][C:33]1[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=1>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13](=[O:14])[N:12]([CH2:32][C:33]3[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=3)[N:11]3[C:15](=[O:18])[NH:16][N:17]=[C:10]3[C:9]=2[C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]n2c(=O)[nH]nc2c(-c2ccncc2)c1-c1ccc(Cl)cc1
Reactant: N#Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Cn2c(=O)c(-c3ccc(Cl)cc3)c(-c3ccncc3)c3n[nH]c(=O)n32)cc1
Reaction time: 0.25 h
Yield: 40.1 %

Procedure:
To the solution of 7-(4-chlorophenyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazine-3,6(2H,5H)-dione (8 mg, 0.023 mmol), prepared as described in Example 9 in DMF (0.3 ml) was added K2CO3 (5 mg, 0.036 mmol) followed by 4-(bromomethyl)benzonitrile (5 mg, 0.025 mmol). After 15 min, the reaction mixture was diluted with ethyl acetate. The resultant solution was then washed with water. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase HPLC to give the title compound, 4-((7-(4-chlorophenyl)-3,6-dioxo-8-(pyridin-4-yl)-2,3-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-5(6H)-yl)methyl)benzonitrile, (4.2 mg, 32%) as a mono trifluoroacetate salt as a yellow foam. MS M+H=454; 1H (CD3OD) δ 8.68(2H), 7.71-7.65(6H), 7.28(2H), 7.20(2H), 5.94(2H).
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[C:5]([NH:24][C:25]1[S:26][CH:27]=[C:28]([C:30](=[N:36][OH:37])[C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:29]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[C:5]([NH:24][C:25]1[S:26][CH:27]=[C:28]([C:30](=[N:36][O:37][CH2:3][CH:2]=[CH2:1])[C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:29]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C=CCBr
Reactant: CCOC(=O)C(=NO)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCON=C(C(=O)OCC)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 4 h
Yield: 86.4 %

Procedure:
Allyl bromide (2.91 g.) was added dropwise to a stirred suspension of ethyl 2-(2-tritylaminothiazol-4-yl)-2-hydroxyiminoacetate (syn isomer, 10 g.), N,N-dimethylformamide (100 ml.) and potassium carbonate (4.54 g.) under ice cooling over 5 minutes, and stirred at the same temperature for 4 hours. After adding water (200 ml.) to the resultant solution, the solution was extracted with diethyl ether twice. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solution was concentrated in vacuo, and the residue was triturated with a solution of n-hexane and diethyl ether. The precipitates were collected by filtration to give ethyl 2-(2-tritylaminothiazol-4-yl)-2-allyloxyiminoacetate (syn isomer, 9.4 g.), mp. 130° to 132° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15]>N1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[CH:13][C:14]([OH:16])=[O:15])([O-:3])=[O:2]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Product: O=C(O)C=Cc1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Yield: 93.3 %

Procedure:
A mixture of 151 g of m-nitrobenzaldehyde, 200 g of pyridine, and 120 g of malonic acid was heated for 3 hours with stirring. The mixture was poured into ice water. The resulting crystalline deposit was collected by filtration, washed with water, and dried, yielding 180 g of m-nitrocinnamic acid having a melting point of 156° C.
Reaction SMILES: C([O:8][C:9](=[O:42])[CH2:10][CH:11]1[O:15][C:14]([CH:16]([NH:21][C:22](=[O:41])[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH3:40])=[O:32])=[CH:26][CH:25]=2)[CH2:17][CH:18]([CH3:20])[CH3:19])=[N:13][CH2:12]1)C1C=CC=CC=1>C1COCC1.CO.[OH-].[Pd+2].[OH-]>[CH3:19][CH:18]([CH3:20])[CH2:17][CH:16]([C:14]1[O:15][CH:11]([CH2:10][C:9]([OH:42])=[O:8])[CH2:12][N:13]=1)[NH:21][C:22](=[O:41])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[CH3:40])=[O:32])=[CH:26][CH:25]=1
Reactant: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)NC(CC(C)C)C2=NCC(CC(=O)OCc3ccccc3)O2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)NC(CC(C)C)C2=NCC(CC(=O)O)O2)cc1
Reaction time: 2 h
Yield: 92 %

Procedure:
A mixture of [2-(3-methyl-1-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-4,5-dihydrooxazol-5-yl]-acetic acid benzyl ester (120 mg) and palladium hydroxide (40 mg) in 10 ml of THF and 10 ml of MeOH was shaken on a Parr Apparatus under 30 p.s.i. H2 for 2 h. The mixture was filtered through Celite and the filtrate concentrated under reduced pressure. The residue was suspended in EtOAc and concentrated under reduced pressure. Trituration with hot EtOAc gave 93 mg of the title compound as a light pink solid. MS [M+1]+ 481.3; 1H nmr (400 MHz, DMSO-d6) δ0.77-0.87 (m, 6H), 1.39-1.59 (m, 3H), 2.10-2.33 (m, 4H, including s at 2.21, 3H), 2.40-5.08 (m, 7H, including q at 3.36, J=14.2 Hz, 2H), 6.90 (t, J=7.4 Hz, 1H), 7.08-7.14 (m, 4H), 7.35 (d, J=6.8 Hz, 2H), 7.79 (d, J=8.1 Hz, 1H), 7.95-8.45 (m, 2H), 9.13-9.23 (m, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.Br[CH2:7][CH2:8][N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[N:1]1([CH2:7][CH2:8][N:9]2[C:10](=[O:19])[C:11]3[C:12](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:14])[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: c1c[nH]nn1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCn1ccnn1
Temperature: 15 °C
Reaction time: 8 h

Procedure:
Add 1H-1,2,3-triazole (250 g; 3.51 mol), N-(2-bromoethyl)phthalimide (942 g; 3.52 mol) and 1500 mL of DMF to a 5-L roundbottom flask fitted with a mechanical stirrer, nitrogen inlet and temperature probe. Cool the mixture to 15° C. Stir the mixture until all of the solids are nearly dissolved and then cool in an ice-water bath. Add cesium carbonate (1145 g; 3.51 mol) in portions over 10 min. The reaction mixture exotherms to 21° C. Allow the mixture to stir and come to RT overnight. Pour the reaction mixture into a 12-L flask containing 8 L of ice-water. Stir the suspension for 30 min and then filter and rinse the solid with 3 L of water. Air-dry for 2 h. Recrystallize the mixture of regioisomers from 7 L of absolute ethanol. Isolate the solid by filtration and air-dry. Recrystallize again from 16 L of absolute ethanol. Isolate the solids by filtration and rinse with fresh ethanol (1000 mL). Vacuum-dry the solids at 40° C. to give the title compound, 292.7 g (34%) as a white solid. MS (EI) m/z 243 [M+1]+.
Reaction SMILES: C(C1C=NC(C2C=CC(O[CH2:22][CH2:23][CH2:24][O:25][CH2:26][C:27]([O:30][C:31]([F:48])([F:47])[C:32]([F:46])([F:45])[O:33][C:34]([F:44])([F:43])[C:35]([F:42])([F:41])[O:36][C:37]([F:40])([F:39])[F:38])([F:29])[F:28])=CC=2)=NC=1)CCCCCCC.[CH2:49]([O:54][C:55]1[CH:56]=[N:57][C:58]([C:61]2[CH:66]=[CH:65][C:64]([OH:67])=[CH:63][CH:62]=2)=[N:59][CH:60]=1)[CH2:50][CH2:51][CH2:52][CH3:53]>CN(C)C=O>[CH2:49]([O:54][C:55]1[CH:60]=[N:59][C:58]([C:61]2[CH:62]=[CH:63][C:64]([O:67][CH2:22][CH2:23][CH2:24][O:25][CH2:26][C:27]([O:30][C:31]([F:47])([F:48])[C:32]([F:45])([F:46])[O:33][C:34]([F:43])([F:44])[C:35]([F:41])([F:42])[O:36][C:37]([F:40])([F:39])[F:38])([F:29])[F:28])=[CH:65][CH:66]=2)=[N:57][CH:56]=1)[CH2:50][CH2:51][CH2:52][CH3:53]
Reactant: CCCCCOc1cnc(-c2ccc(O)cc2)nc1
Reactant: CCCCCCCCc1cnc(-c2ccc(OCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)F)cc2)nc1
Solvent: CN(C)C=O
Product: CCCCCOc1cnc(-c2ccc(OCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)F)cc2)nc1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
The title compound was prepared essentially as in Example 1 by combining 3-(2-(2-(2-(trifluoromethoxy)tetrafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)-1-chloropropane (6.1 g, 28.0 mmol, Example 24) with 5-pentyloxy-2-[4-hydroxyphenyl]pyrimidine (3 g, 11.6 mmol) in dimethylformamide and stirring at 120° C. overnight to provide product boiling at 185-190° C. at 0.3 torr (yield of 5.5 g).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[CH:18]=[C:19]([NH:27][CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[C:20]2[N:21]([C:23]([CH3:26])=[N:24][N:25]=2)[N:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34](O)(=O)C.C=O>C1COCC1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[CH:18]=[C:19]([NH:27][CH:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[C:20]2[N:21]([C:23]([CH3:26])=[N:24][N:25]=2)[N:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nnc2c(NC3CCNCC3)cc(-c3cc4ccccc4n3Cc3ccccc3)nn12
Reactant: CC(=O)O
Agent: C=O
Solvent: C1CCOC1
Product: Cc1nnc2c(NC3CCN(C)CC3)cc(-c3cc4ccccc4n3Cc3ccccc3)nn12
Reaction time: 2 h

Procedure:
[6-(1-Benzyl-1H-indol-2-yl)-3-methyl-[1,2,4]triazolo[4,3-b]pyridazin-8-yl]-piperidin-4-yl-amine (10 mg; 0.02 mmol) was dissolved in 300 μl THF, treated with glacial acetic acid (3 μl 0.05 mmol) and formaldehyde (7 μl; 0.09 mmol). At least was added STAB (6 mg; 0.03 mmol) and all stirred for 2 hours. The crude reaction mixture was purified by reversed phase under basic conditions.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](=[O:18])[C:11](=[O:17])[C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)[CH2:2]2.[CH:19]1([Mg]Cl)[CH2:23][CH2:22][CH2:21][CH2:20]1>CCOCC>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](=[O:18])[C:11]([CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)([OH:17])[C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)[CH2:2]2
Reactant: Cl[Mg]C1CCCC1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(=O)c1cccs1
Solvent: CCOCC
Product: O=C(O[C@H]1CN2CCC1CC2)C(O)(c1cccs1)C1CCCC1

Procedure:
Prepared using the same method as for Intermediate I-14, but from 20.8 g (0.0784 mol) of 2-oxo-2-thien-2-ylacetic acid (3R)-1-azabicyclo[2.2.2]oct-3-yl ester and cyclopentylmagnesium chloride, 0.08 mol (40 ml of a solution 2M in ether). The oil obtained (15.64 g) was purified by chromatography on silica gel eluting with chloroform/methanol/ammonia 97:3:0.5 to obtain 8.38 g (32%) of a pure product, mixture of diastereomers: I-15a and I-15b. Structure confirmed by 1H-NMR.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[CH:10]=[C:9]1[C:18]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[N:21]=[N:20][C:19]=1[O:30][CH3:31])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:51][N:52]([CH3:56])[CH2:53][CH2:54]O.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1.C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:54][CH2:53][N:52]([CH3:56])[CH3:51])[CH:15]=2)[CH:10]=[C:9]1[C:18]1[CH:23]=[C:22]([C:24]2[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=2)[N:21]=[N:20][C:19]=1[O:30][CH3:31])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1nnc(-c2ccncc2)cc1-c1cc2ccc(O)cc2n1C(=O)OC(C)(C)C
Reactant: CN(C)CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1nnc(-c2ccncc2)cc1-c1cc2ccc(OCCN(C)C)cc2n1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 43 %

Procedure:
100 mg 6-hydroxy-2-(3-methoxy-6-pyridin-4-yl-pyridazin-4-yl)-indole-1-carboxylic acid tert-butyl ester and 175 mg triphenylphosphine are dissolved in 7 mL toluene and 2 mL THF. After dropwise addition of 84 μL 2-dimethylaminoethanol and 123 μL diethyl azodicarboxylate, the reaction mixture is stirred at room temperature for 5 hours. The solvent is removed in vacuo and the residue is dissolved in dichloromethane. The organic phase is washed with water and the aqueous phase is extracted twice with dichloromethane. The combined organic phases are dried over MgSO4 and concentrated in vacuo. Purification by HPLC afforded 35 mg (43%) 6-(2-dimethylaminoethoxy)-2-(3-methoxy-6-pyridin-4-yl-pyridazin-4-yl)-indole-1-carboxylic acid tert-butyl ester.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[O:27][N:26]=[C:25]([CH3:28])[C:24]=4[NH:29][C:30]([O:32][C@@H:33]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH3:34])=[O:31])=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])C.[Li+].[OH-].CCOC(C)=O>O1CCOCC1>[CH3:28][C:25]1[C:24]([NH:29][C:30]([O:32][C@@H:33]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH3:34])=[O:31])=[C:23]([C:20]2[CH:21]=[CH:22][C:17]([C:14]3[CH:13]=[CH:12][C:11]([C:6]4([C:4]([OH:5])=[O:3])[CH2:10][CH2:9][CH2:8][CH2:7]4)=[CH:16][CH:15]=3)=[CH:18][CH:19]=2)[O:27][N:26]=1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)O[C@H](C)c4ccccc4)cc3)cc2)CCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CCCC4)cc3)cc2)c1NC(=O)O[C@H](C)c1ccccc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
1-{4′-[3-methyl-4-((R)-1-phenyl-ethoxycarbonylamino)-isoxazol-5-yl]-biphenyl-4-yl}-cyclopentanecarboxylic acid ethyl ester (0.060 g, 0.11 mmol) in 1,4-dioxane (2 mL) was treated with 1N aqueous LiOH (1 mL), and the reaction was stirred at 60° C. overnight. Acidic work-up, followed by silica gel chromatography (0-50% EtOAc in hexanes) gave the title compound.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[C:9](Cl)(=[O:19])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH-].[Na+].S(=O)(=O)(O)O>O>[C:9]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])(=[O:19])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CCCCCCCCCC(=O)Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCC(=O)N1CCC[C@H]1C(=O)O
Yield: 92.7 %

Procedure:
Proline (manufactured by Ajinomoto Co., Inc., 34.54 g) was dissolved in water (100 g), and decanoyl chloride (manufactured by Tokyo Chemical Industry Co., Ltd., 52.01 g) and 25% aqueous sodium hydroxide solution were added while adjusting to pH 12. The mixture was neutralized with 75% sulfuric acid, and the aqueous layer was removed. Water and ethyl acetate were further added, and the aqueous layer was removed. Ethyl acetate was evaporated under reduced pressure to give decanoyl proline (68.12 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11](C(O)=O)=[CH:10][C:9]=2[S:16][C:17]([F:20])([F:19])[F:18])=[CH:4][CH:3]=1.O>C(CN)O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:12][CH:11]=[CH:10][C:9]=2[S:16][C:17]([F:19])([F:18])[F:20])=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(SC(F)(F)F)c(-c2ccc(Cl)cc2)[nH]1
Solvent: O
Solvent: NCCO
Product: FC(F)(F)Sc1cc[nH]c1-c1ccc(Cl)cc1
Temperature: 160 °C
Reaction time: 5 h
Yield: 25.6 %

Procedure:
A mixture of 5-(p-chlorophenyl)-4-[(trifluoromethyl)thio]pyrrole-2-carboxylic acid (0.5 g, 0.00155 mol) in ethanolamine (1.5 mL) is stirred at 160° C. for five hours, cooled to room temperature overnight with stirring, poured into water and extracted with ether. The combined organic extracts are washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a yellow syrup. Flash chromatography of the syrup using silica gel and a 1:4 ethyl acetate/hexanes solution gives the title product as an off-white solid (0.11 g, mp 59°-64° C.) which is identified by 1HNMR and 19FNMR spectral analyses.
Reaction SMILES: C=O.[CH3:3][N:4]([CH2:9][C:10]#[CH:11])[CH2:5][CH2:6][C:7]#[N:8].C([C:14]1[CH:23]=[CH:22][C:21]2[NH:20][C:19](=[O:24])[C:18]3[NH:25][CH:26]=[CH:27][C:17]=3[C:16]=2[CH:15]=1)#C.[CH2:28]([C:30]([O-:32])=[O:31])[CH3:29]>O1CCOCC1.[Cu](I)I>[C:7]([CH2:6][CH2:5][N:4]([CH3:3])[CH2:9][C:10]#[C:11][C:14]1[CH:23]=[CH:22][C:21]2[NH:20][C:19](=[O:24])[C:18]3[NH:25][CH:26]=[CH:27][C:17]=3[C:16]=2[CH:15]=1)#[N:8].[CH2:28]([C:30]([O-:32])=[O:31])[CH3:29]
Reactant: C#CCN(C)CCC#N
Reactant: C#Cc1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Agent: I[Cu]I
Agent: C=O
Agent: CCC(=O)[O-]
Solvent: C1COCCO1
Product: CN(CC#Cc1ccc2[nH]c(=O)c3[nH]ccc3c2c1)CCC#N
Temperature: 110 °C
Yield: 7.6 %

Procedure:
31 mg (0.35 mmol) of para-formaldehyde, 35 mg (0.42 mmol) of 3-(methyl-prop-2-ynyl-amino)-propionitrile and 7 mg (0.04 mmol) of copper iodide are added to a suspension of 98 mg (0.35 mmol) of 8-ethynyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in 3 ml of anhydrous dioxan, then the mixture is heated at 110° C. for 6 hours. The raw reaction product is then filtered, and the filtrate is evaporated. The residue is triturated with methanol, then the new filtrate is evaporated. The product is recrystallized from methanol to give 10 mg (8%) of 8-{3-[(2-cyano-ethyl)-methyl-amino]-prop-1-ynyl}-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in the form of a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][C:6]([CH:15]=[O:16])=[CH:5][C:4]=1[CH3:17].[OH-:18].[Na+]>[Ag-]=O>[CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][C:6]([C:15]([OH:18])=[O:16])=[CH:5][C:4]=1[CH3:17]
Reactant: COc1c(C)cc(C=O)cc1-c1ccccc1
Reactant: [OH-]
Agent: O=[Ag-]
Agent: [Na+]
Product: COc1c(C)cc(C(=O)O)cc1-c1ccccc1
Yield: 89 %

Procedure:
The title compound was prepared according to the procedure in Example 6, step 3 using 6-methoxy-5-methyl-biphenyl-3-carbaldehyde (1.53 g, 6.77 mmol), silver (I) oxide (1.56 g, 6.77 mmol) and NaOH (2.71 g, 67.7 mmol) to give 1.46 g (89%) of the title compound as a white solid, mp 165-168° C. 1H NMR (DMSO-d6) δ 2.34 (s, 3 H), 3.36 (s, 3 H), 7.38-7.55 (m, 5 H), 7.71 (d, 1 H), 7.81 (dd, 1 H). IR (KBr) 3400, 2950, 1700, 1600 and 1410 cm-1. mass spectrum (EI), m/z 242 (M+). Anal. Calcd. for C15H14O3.0.2 H2O: C, 73.27; H, 5.91; N, 0.00. Found: C, 73.21; H, 5.93; N, 0.17.
Reaction SMILES: [NH:1]([C:8]1[CH:17]=[N:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[C@H:20]1[CH2:24][CH2:23][O:22][CH2:21]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:2]1([NH:1][C:8]2[CH:17]=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][C@@H:20]4[CH2:24][CH2:23][O:22][CH2:21]4)[CH:14]=3)[N:9]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@H]1CCOC1
Reactant: Oc1ccc2nc(Nc3ccccc3)cnc2c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1ccc(Nc2cnc3cc(O[C@@H]4CCOC4)ccc3n2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a THF solution at 0° C. under argon is added 2-anilino-6-quinoxalinol (0.23 g, 0.97 mmol), (S)-(+)-3-hydroxytetrahydrofuran (0.086 mL, 1.3 mmol), and triphenylphosphine (0.31 g, 1.2 mmol). DEAD (0.18 mL, 1.2 mmol) is added portionwise. The reaction is allowed to warm to room temperature and stirred for 1.5 hours. The mixture is concentrated and partitioned between EtOAc and H2O. The organic layer is washed with H2O, brine, dried (MgSO4), and concentrated. The resulting yellow oil is chromatographed (50% EtOAc/hexanes) and taken up in Et2O/IPA (isopropanol). HCl/Et2O solution is added dropwise and the resulting red-orange powder is dried in vacuo. The powder is free-based by stirring in MeOH with washed (3×H2O, 5×MeOH) basic ion exchange resin. The mixture is stirred 30 minutes, filtered, concentrated, and recrystallized from EtOAc/hexanes to provide, in two crops, the product (m.p. 173-175° C.). Anal. Calcd. for C18H17N3O2: C, 70.35; H, 5.57; N, 13.67; Found: C, 70.19; H, 5.60; N, 13.66.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:34]=[CH:33][C:11]([NH:12]/[C:13](=[C:20]3\[C:21](=[O:32])[NH:22][C:23]4[C:28]\3=[CH:27][CH:26]=[C:25]([C:29]([OH:31])=O)[CH:24]=4)/[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:35]([NH:37][CH3:38])[CH3:36]>>[N:1]1([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([NH:12]/[C:13](=[C:20]3\[C:21](=[O:32])[NH:22][C:23]4[C:28]\3=[CH:27][CH:26]=[C:25]([C:29](=[O:31])[N:37]([CH2:35][CH3:36])[CH3:38])[CH:24]=4)/[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:33][CH:34]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1Nc2cc(C(=O)O)ccc2/C1=C(/Nc1ccc(CN2CCCCC2)cc1)c1ccccc1
Reactant: CCNC
Product: CCN(C)C(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCCCC2)cc1)c1ccccc1

Procedure:
Prepared from 3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-carboxy-2-indolinone and N-ethyl-N-methyl-amine Rf value: 0.5 (aluminium oxide, methylene chloride/ethanol=20:1) C31H34N4O2