Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[Li+].C([N:6]1[C:14]2[C:9](=[CH:10][C:11](CC([O-])=O)=[CH:12][C:13]=2[CH3:15])[CH:8]=[N:7]1)(=O)C.[Cl-].[NH4+]>CO.O1CCCC1>[CH3:15][C:13]1[CH:12]=[C:11]([OH:1])[CH:10]=[C:9]2[C:14]=1[NH:6][N:7]=[CH:8]2
Reactant: CC(=O)n1ncc2cc(CC(=O)[O-])cc(C)c21
Reactant: [OH-]
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(O)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
A 2N-aqueous lithium hydroxide solution (3.7 ml, 7.4 mmol) was added to a solution of (1-acetyl-7-methyl-1H-indazol-5-yl)acetate (850 mg, 3.66 mmol) in methanol-tetrahydrofuran (1:1, 7.4 ml), and the resulting mixture was stirred at room temperature for 30 minutes. A saturated aqueous ammonium chloride solution was poured into the reaction solution, followed by extraction with ethyl acetate, and the extract solution was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and then distilled under reduced pressure to remove the solvent. The residue was purified by a silica gel column chromatography (eluent: chloroform/methanol=100:3) to obtain 7-methyl-1H-indazol-5-ol (505 mg, 93%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].Br[C:12](Br)([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:5]([C:4]1[CH:7]=[CH:8][C:9]2[O:10][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])([C:18]([O:20][CH2:21][CH3:22])=[O:19])[O:1][C:2]=2[CH:3]=1)=[O:6]
Reactant: CCOC(=O)C(Br)(Br)C(=O)OCC
Reactant: O=Cc1ccc(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C1(C(=O)OCC)Oc2ccc(C=O)cc2O1

Procedure:
One equivalent of 3,4-dihydroxybenzaldehyde, 1.1 equivalents of diethyl dibromomalonate and powdered potassium carbonate is stirred in acetonitrile at room temperature for 18 hours. The reaction mixture is filtered, evaporated in vacuo, and distilled to give diethyl 5-formyl-1,3-benzodioxole-2,2-dicarboxylate.
Reaction SMILES: [OH:1][N:2]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[Cl:23][C:24]1[CH:50]=[CH:49][CH:48]=[CH:47][C:25]=1[CH2:26][N:27]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([C:36](O)=[O:37])[CH:34]=2)[C:29]([C:39](=[O:43])[CH:40]([CH3:42])[CH3:41])=[C:28]1[CH2:44][CH2:45][CH3:46].Cl.NO.C(N(C(C)C)CC)(C)C>CN(C)C=O>[Cl:23][C:24]1[CH:50]=[CH:49][CH:48]=[CH:47][C:25]=1[CH2:26][N:27]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([C:36]([NH:2][OH:1])=[O:37])[CH:34]=2)[C:29]([C:39](=[O:43])[CH:40]([CH3:42])[CH3:41])=[C:28]1[CH2:44][CH2:45][CH3:46]
Reactant: On1nnc2ccccc21
Reactant: CCCc1c(C(=O)C(C)C)c2ccc(C(=O)O)cc2n1Cc1ccccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1c(C(=O)C(C)C)c2ccc(C(=O)NO)cc2n1Cc1ccccc1Cl
Temperature: 20 °C
Reaction time: 8 h
Yield: 64.6 %

Procedure:
1-Hydroxybenzotriazole (68 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (72 mg) were added to a solution of 1-(2-chlorobenzyl)-3-isobutyryl-2-propylindole-6-carboxylic acid (100 mg) in dimethylformamide (3 ml), and the mixture was stirred at 20° C. overnight, then hydroxylamine hydrochloride (35 mg) and diisopropylethylamine (0.088 ml) were added. After stirred at 20° C. for 2 hours, the reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with 1N hydrochloric acid and brine, dried over sodium sulfate, and evaporated in vacuo. The residue was purified by preparative thin layer chromatography with 10% methanol in chloroform and recrystallization from ethyl acetate to give 1-(2-chlorobenzyl)-3-isobutyryl-2-propylindole-6-carbohydroxamic acid (67 mg) as pale red crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:13][CH:12]2[CH:8]([CH2:9][C:10]3[C:16]([CH2:17][OH:18])=[CH:15][S:14][C:11]=32)[CH2:7]1)=[O:5])[CH3:2].C(Cl)(Cl)[Cl:20]>C(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]1[CH2:13][CH:12]2[CH:8]([CH2:9][C:10]3[C:16]([CH2:17][OH:18])=[C:15]([Cl:20])[S:14][C:11]=32)[CH2:7]1)=[O:5])[CH3:2]
Reactant: ClC(Cl)Cl
Reactant: CCOC(=O)N1CC2Cc3c(CO)csc3C2C1
Solvent: ClCCl
Product: CCOC(=O)N1CC2Cc3c(sc(Cl)c3CO)C2C1
Reaction time: 1 h
Yield: 45 %

Procedure:
The product of step c) (185 mg, 0.74 mmol) was dissolved in CHCl3 (2.7 ml) and a solution of SO2Cl2 (59.5 μl, 0.74 mmol) in CHCl3 (1 ml) was added dropwise over 10 minutes and the contents were stirred for 1 hour. Next, the mixture was diluted with CH2Cl2 (10 ml), washed with H2O (2×25 ml), sat. NaHCO3 (25 ml) and dried (MgSO4). The crude residue was purified by preparative TLC (hexanes/EtOAc-1:3) to give the subtitle compound (99.7 mg, 45%). 1H NMR (300 MHz, CDCl3, ppm) 1.20 (t, J=7 Hz, 3H); 2.37 (br s, 1H); 2.65-2.71 (m, 1H); 2.90-3.05 (m, 1H); 3.08-3.18 (br m, 1H); 3.28-3.42 (br m, 1H); 3.52-3.72 (br m, 2H); 3.75-3.88 (m, 2H); 4.09 (q, J=7 Hz, 2H); 4.54 (s, 2H).
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:13][CH:12]=1)#[CH:10]>C(#N)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:17]([C:14]1[CH:13]=[CH:12][C:11]([C:9]#[C:10][C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=2)=[CH:16][CH:15]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: Nc1ccc(I)cc1
Reactant: C#Cc1ccc(CCCCCC)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Product: CCCCCCc1ccc(C#Cc2ccc(N)cc2)cc1
Temperature: 85 °C
Reaction time: 22 h
Yield: 87 %

Procedure:
To a stirred solution of 4-iodoaniline (10.0 g, 45.6 mmol, Aldrich) and 1-eth-1-ynyl-4-hexylbenzene (10.0 g, 53.0 mol, Maybridge) in anhydrous acetonitrile (200 mL) under nitrogen was added CuI (0.43 g, 2.2 mmol), TEA (14.0 g, 138 mmol) followed by Pd(PPh3)2Cl2 (1.6 g, 2.2 mmol). The reaction mixture was stirred at 85° C. for 22 hours. The solvent was removed under reduced pressure. The residue was diluted with Et2O (200 mL) 20 and washed with water and brine. The organic layer was dried (MgSO4) and the solvent was removed under reduced pressure. The crude product was purified by chromatography Wet ether/EtOAc 4/1) to give 11.0 g (87%) of the title compound as a pale yellow solid. TLC-Pet ether/EtOAc (4/1): Rf=0.4. HPLC purity >98%.
Reaction SMILES: C(OP(OCC)([CH:6]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=O)C.C=O.[C:21](=O)([O-])[O-].[K+].[K+].O>C(OCC)C>[CH3:15][CH:13]([CH3:14])[CH2:12][C:6](=[CH2:21])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C(CC(C)C)P(=O)(OCC)OCC
Agent: C=O
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: C=C(CC(C)C)C(=O)OCC
Yield: 63.3 %

Procedure:
A mixture of 19 g (67.9 mmol) of ethyl 2-(diethoxyphosphinyl)-4-methylpentanoate, 27 ml (360.3 mmol) of formaldehyde and 28 g (202.6 mmol) of potassium carbonate is maintained at reflux for 3 hours. A mixture of water and diethyl ether is added. The aqueous phase is extracted with diethyl ether. The combined organic phases are washed with water, dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue is distilled under reduced pressure. 6.7 g of product are recovered in the form of an oil (yield=63.3%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:14]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][N:21]=[CH:20]2)([O-:16])=[O:15].C(N(CC)CC)C>C(#N)C>[N+:14]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([S:10]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:12])=[O:11])[N:21]=[CH:20]2)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(S(=O)(=O)n2ncc3cc([N+](=O)[O-])ccc32)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
In 100 ml of acetonitrile were dissolved 10 g of 4-nitrophenylsulfonyl chloride and 8.8 g of 5-nitroindazole and the solution was cooled to 0° C. Then, 6.8 g of triethylamine was gradually added dropwise to the solution and the mixture was allowed to stand overnight to precipitate crystals. Then, 50 ml of water was added dropwise to the system and the crystals formed were collected by filtration, washed with water and then ethyl acetate, and dried to provide 12.1 g of the desired product having a melting point of from 196° C. to 197° C.
Reaction SMILES: [Cl:1][C:2](=[CH2:13])[CH2:3][N:4]([CH2:10][CH:11]=O)[C:5](=[O:9])[O:6][CH2:7][CH3:8].[CH3:14][NH:15][C@H:16](C(O)=O)[CH3:17]>C1(C)C=CC=CC=1>[Cl:1][C:2]12[CH2:3][N:4]([C:5]([O:6][CH2:7][CH3:8])=[O:9])[CH2:10][CH:11]1[N:15]([CH3:14])[CH:16]([CH3:17])[CH2:13]2
Reactant: CN[C@@H](C)C(=O)O
Reactant: C=C(Cl)CN(CC=O)C(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CC2N(C)C(C)CC2(Cl)C1

Procedure:
10.3 g (50 mmol) of ethyl N-(2-chloroallyl)-N-(2-oxoethyl)-carbamate are heated under reflux overnight with 5.2 g (50.5 mmol) of N-methylalanine in 200 ml of toluene. The mixture is concentrated and the residue is distilled.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:18][N:19]2[C:27]3[C:22](=[CH:23][C:24]([C:28]([OH:30])=O)=[CH:25][CH:26]=3)[CH:21]=[CH:20]2)[CH:9]=[CH:10][CH:11]=1)=[O:5])[CH3:2].[N+:31]([C:34]1[CH:39]=[CH:38][C:37]([C@@H:40]([NH2:42])[CH3:41])=[CH:36][CH:35]=1)([O-:33])=[O:32]>>[N+:31]([C:34]1[CH:35]=[CH:36][C:37]([C@@H:40]([NH:42][C:28]([C:24]2[CH:23]=[C:22]3[C:27](=[CH:26][CH:25]=2)[N:19]([CH2:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:7]=2)[CH:20]=[CH:21]3)=[O:30])[CH3:41])=[CH:38][CH:39]=1)([O-:33])=[O:32]
Reactant: CCOC(=O)c1cccc(-c2ccccc2Cn2ccc3cc(C(=O)O)ccc32)c1
Reactant: C[C@H](N)c1ccc([N+](=O)[O-])cc1
Product: CCOC(=O)c1cccc(-c2ccccc2Cn2ccc3cc(C(=O)N[C@@H](C)c4ccc([N+](=O)[O-])cc4)ccc32)c1

Procedure:
The title compound was prepared following the same protocol as described in Step 8, Example 1, using the 1-((3′-(ethoxycarbonyl)-[1,1′-biphenyl]-2-yl)methyl)-1H-indole-5-carboxylic acid instead of the 1-((2′-(tert-Butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid and the (S)-1-(4-nitrophenyl)ethanamine instead of the (S)-1-(4-bromophenyl)ethanamine.
Reaction SMILES: [CH3:1][Si:2]([CH3:22])([CH3:21])[O:3][C:4]#[C:5][C:6]1([Si:12]([CH3:20])([CH3:19])[NH:13][Si:14]([CH3:18])([CH3:17])[CH:15]=[CH2:16])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C=C[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1(C)C=CC=CC=1>[CH3:22][Si:2]([CH3:21])([CH3:1])[O:3][C:4]#[C:5][C:6]1([Si:12]([CH3:20])([CH3:19])[NH:13][Si:14]([CH3:18])([CH3:17])/[CH:15]=[CH:16]/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: C=C[Si](C)(C)N[Si](C)(C)C1(C#CO[Si](C)(C)C)CCCCC1
Reactant: C=Cc1ccccc1
Solvent: Cc1ccccc1
Product: C[Si](C)(/C=C/c1ccccc1)N[Si](C)(C)C1(C#CO[Si](C)(C)C)CCCCC1

Procedure:
As in reaction conditions of Example XIX Step 2, to 2.87 mL of toluene, the 0.016 g carbonylchlorohydridebis(tricyclohexylphosphine)ruthenium(H) was added, and the reaction was carried out between the 1-[(1-trimethylsiloxy-1-ethynyl)cyclohexyl]-1,1,3,3-tetramethyl-3-vinyldisilazane obtained in Step 1 and 0.69 g styrene. Product was separated under the purification conditions of Example XII. The product, 1-[(1-trimethylsiloxy-1-ethynyl)cyclohexyl]-1,1,3,3-tetramethyl-3-[(E)-styryl]disilazane, was obtained with a total yield of 85% pure product in the form of an oily liquid, light yellow in color.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH:25]([C:42]([O:44][CH2:45][CH:46]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[C:52]2[C:47]1=[CH:48][CH:49]=[CH:50][CH:51]=2)=[O:43])[C@@H:26]([C:39](O)=[O:40])[CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].CCN=C=NCCCN(C)C.Cl>C(Cl)(Cl)Cl.C1C=CC2N(O)N=NC=2C=1>[NH:25]([C:42]([O:44][CH2:45][CH:46]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[C:52]2[C:47]1=[CH:48][CH:49]=[CH:50][CH:51]=2)=[O:43])[C@@H:26]([C:39]([NH:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:11][CH:12]([CH3:13])[CH3:14])=[O:8])[CH2:3][CH:4]([CH3:5])[CH3:6])=[O:40])[CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33]
Reactant: CC(C)(C)OC(=O)NCCCC[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CC(C)C[C@H](NC(=O)[C@@H](N)CC(C)C)C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Product: CC(C)C[C@H](NC(=O)[C@@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
The obtained wet crystals of Leu-Leu-OBzl (2-MeO-4-OC12OC22) were dissolved in chloroform (13 mL), Fmoc-D-Lys(Boc)-OH (481 mg, 1.03 mmol) and HOBt (13.9 mg, 103 μmol) were added at room temperature, and EDC HCl (216 mg, 1.13 mmol) was further added under ice-cooling. The mixture was warmed to room temperature, stirred overnight and concentrated under reduced pressure. The residue was precipitated with methanol (10 mL) to give Fmoc-D-Lys(Boc)-Leu-Leu-OBzl (2-MeO-4-OC12OC22) (1.14 g, 86% yield relative to Bzl (2-MeO-4-OC12OC22)OH).
Reaction SMILES: [CH3:1][C:2]([C:5]([C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1OS(C(F)(F)F)(=O)=O)[C:10]([O:12][CH3:13])=[O:11])=[CH2:6])([CH3:4])[CH3:3].CN(C=O)C.[F:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][C:32]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>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>[CH3:4][C:2]([C:5]([C:7]1[CH:8]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[CH:14]=[CH:15][C:16]=1[C:32]1[CH:33]=[C:34]([O:37][CH3:38])[CH:35]=[CH:36][C:31]=1[F:30])=[CH2:6])([CH3:1])[CH3:3]
Reactant: C=C(c1cc(C(=O)OC)ccc1OS(=O)(=O)C(F)(F)F)C(C)(C)C
Reactant: COc1ccc(F)c(B(O)O)c1
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: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(c1cc(C(=O)OC)ccc1-c1cc(OC)ccc1F)C(C)(C)C
Temperature: 90 °C
Reaction time: 17 h
Yield: 19.5 %

Procedure:
To a stirred solution of 66.18E (0.550 g, 1.5 mmol) in DMF (3.0 mL, 1.5 mmol) at 23° C. was added 2-fluoro-5-methoxyphenylboronic acid (0.38 g, 2.3 mmol) (commercially available from Aldrich), potassium carbonate (0.62 g, 4.5 mmol) and then tetrakis(triphenylphosphine)palladium (0.12 g, 0.11 mmol). The mixture was heated to 90° C. and stirred for 17 hours. The resulting mixture was then cooled to room temperature, diluted with water and extracted three times with EtOAc. After drying over anhydrous magnesium sulfate and filtering, the organic solvent was removed under reduced pressure and the product was then purified on silica gel (0-10% EtOAc in hexanes) to yield 66.18F as a colorless oil (0.100 g, 19% yield).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:31]=[CH:32][C:33]=1[F:34])[O:15][C:16]1[CH:17]=[CH:18][C:19]2[N:20]([CH:22]=[C:23]([NH:25][C:26]([CH:28]3[CH2:30][CH2:29]3)=[O:27])[N:24]=2)[N:21]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:28]1([C:26]([NH:25][C:23]2[N:24]=[C:19]3[CH:18]=[CH:17][C:16]([O:15][C:14]4[CH:31]=[CH:32][C:33]([F:34])=[C:12]([NH:11][C:8]([C:4]5[S:3][C:2]([CH3:1])=[N:6][C:5]=5[CH3:7])=[O:10])[CH:13]=4)=[N:21][N:20]3[CH:22]=2)=[O:27])[CH2:29][CH2:30]1
Reactant: Cc1nc(C)c(C(=O)O)s1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(C)c(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2F)s1
Yield: 32.2 %

Procedure:
In the same manner as in Example 261 and using 2,4-dimethyl-1,3-thiazole-5-carboxylic acid (190 mg, 1.2 mmol), N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.62 mmol), 1-hydroxybenzotriazole (170 mg, 1.2 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (240 mg, 1.2 mmol), N,N-diisopropylethylamine (240 mg, 1.9 mmol) and N,N-dimethylformamide (5 mL) as starting materials, the title compound (93 mg, 32%) was obtained as a pale-yellow solid.
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([CH:18]([CH3:20])[CH3:19])=[C:12]([O:21][CH3:22])[CH:11]=1)(=O)OCC)C.[H-].[Na+].[F:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH:28]=O.O>C1COCC1>[CH3:17][O:16][C:14]1[CH:15]=[C:10]([CH:9]=[CH:28][C:27]2[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=2[F:25])[CH:11]=[C:12]([O:21][CH3:22])[C:13]=1[CH:18]([CH3:19])[CH3:20]
Reactant: O=Cc1ccccc1F
Reactant: CCOP(=O)(Cc1cc(OC)c(C(C)C)c(OC)c1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C=Cc2ccccc2F)cc(OC)c1C(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of diethyl(3,5-dimethoxy-4-i-propylbenzyl)phosphonate (0.50 g, 1.5 mmol) in THF (10 mL) at 0° C. was added NaH (60% in mineral oil) (0.14 g, 3.5 mmol) under N2. After the addition was completed, the suspension was stirred at 0° C. for 1 h and then 2-fluorobenzaldehyde (0.2 mL, 1.9 mmol) in THF (10 mL) was added. The reaction was kept at 0° C. for 1 h and then at 50° C. for 5 h. The reaction was cooled to 0° C. Water (5 mL) was added slowly to quench the reaction followed by addition of 2N HCl (8 mL). The mixture was extracted with ether (3×20 mL). The extract was dried over anhydrous Na2SO4. Evaporation of ether followed by flash chromatography using 5% ethyl acetate in hexane as eluent afforded 2-(3,5-dimethoxy-4-i-propylphenyl)-1-(2-fluorophenyl)ethene (1). (0.31 g, 68%) as a yellow crystal. 1HNMR (CDCl3, ppm): δ 1.34 (d, J=7.1 Hz, 6H), 3.60 (qint. J=7.1 Hz, 1H), 3.89 (s, 6H), 6.74 (s, 2H), 7.0-7.2 (m, 5H), 7.4-7.6 (m, 1H).
Reaction SMILES: [I:1][C:2]1[C:7]([CH:8]([OH:13])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:14])[N:5]=[C:4]2[S:15][C:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=3[C:3]=12.C(O[C:26]([CH3:29])([CH3:28])[CH3:27])(=O)C.Cl(O)(=O)(=O)=O>>[I:1][C:2]1[C:7]([CH:8]([O:13][C:26]([CH3:29])([CH3:28])[CH3:27])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:14])[N:5]=[C:4]2[S:15][C:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=3[C:3]=12
Reactant: COC(=O)C(O)c1c(C)nc2sc3c(c2c1I)CCCC3
Reactant: CC(=O)OC(C)(C)C
Agent: [O-][Cl+3]([O-])([O-])O
Product: COC(=O)C(OC(C)(C)C)c1c(C)nc2sc3c(c2c1I)CCCC3
Temperature: 25 °C
Reaction time: 72 h
Yield: 32.6 %

Procedure:
To a solution of methyl 2-[4-iodo-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-hydroxyacetate (2.1 g; 5.03 mmol) in tert-butyl acetate (15 mL; 112 mmol) under a nitrogen atmosphere was added perchloric acid 70% (0.342 mL; 5.52 mmol). The reaction was stirred at room temperature for 3 days and quenched by adding a saturated solution of sodium bicarbonate. The mixture was diluted with dichloromethane and the phases were separated. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethylacetate (1-40%) in heptane furnished 0.776 g (32%) of the title compound as a solid.
Reaction SMILES: [C:1]([C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:13]([CH3:14])=[CH:12][C:11](=[O:15])[C:10]([C:16]([OH:18])=[O:17])=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].[Br:21]Br.O>C(O)(=O)C>[Br:21][C:12]1[C:11](=[O:15])[C:10]([C:16]([OH:18])=[O:17])=[CH:9][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:20][CH:19]=2)[C:13]=1[CH3:14]
Reactant: Cc1cc(=O)c(C(=O)O)cn1Cc1ccc(C#N)cc1
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: Cc1c(Br)c(=O)c(C(=O)O)cn1Cc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 1-(4-cyano-benzyl)-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid (preparation 1b, 12.9 g, 48.2 mmol) in glacial acetic acid (50 ml) is added at room temperature bromine (5.0 mL). The reaction mixture is stirred for 1 day at room temperature, then additional bromine (3.0 mL) is added. After stirring for an additional 4 days at room temperature, water is added to the reaction mixture and the formed precipitate is filtered off and dried. Yield: 14.0 g (84% of theory); ESI mass spectrum: [M+H]+=347 (bromine isotope pattern); Retention time HPLC: 1.07 min (Z002—005).
Reaction SMILES: [Cl:1][C:2]1[C:9]([OH:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1C=O.ClC1C=CC=C(C(OO)=[O:21])C=1>C(Cl)Cl>[Cl:1][C:2]1[C:9]([OH:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[OH:21]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(C=O)c(Cl)c1O
Solvent: ClCCl
Product: COc1ccc(O)c(Cl)c1O
Reaction time: 1 h

Procedure:
Into a reaction flask was introduced 2 g of 2-chloro-3-hydroxy-4-methoxybenzaldehyde in 50 ml methylene dichloride with an excess of m-chloroperbenzoic acid and the reaction refluxed for 2.5 hrs. After removal of the solvent, the solid residue was dissolved in 10 ml methanol and stirred with approximately 10 weight percent aqueous sodium hydroxide (10 ml) for 1 hr. After acidification to pH 1 with dilute HCl, the solution was filtered and the precipitate washed with 10 ml of cold water. The combined filtrate and wash was extracted with ether, the ether washed with 5% NaHCO3 (2×10 ml) and saturated NaCl solution (1×10 ml) and then evaporated to leave a solid which was crystallized from ethyl acetate-hexane mixture to provide the product as white silky needles (1.35 g). mp 69°-70°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:7]([OH:10])=[CH:8][CH:9]=1)[CH:5]=[O:6].C1(=O)O[CH2:14][CH2:13][O:12]1>[Br-].C([N+](CC)(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:7]([O:10][CH2:14][CH2:13][OH:12])=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=C1OCCO1
Reactant: O=Cc1cc(Cl)ccc1O
Agent: CC[N+](CC)(CC)CC
Agent: [Br-]
Product: O=Cc1cc(Cl)ccc1OCCO

Procedure:
Synthesized from 25 g of 3-chloro-6-hydroxybenzaldehyde, 14 g of ethylene carbonate and 45 g of tetraethylammonium bromide as described in Example XIIa.
Reaction SMILES: [CH2:1]([O:8][C:9]([O:11]N1C(=O)CCC1=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][NH:20][CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1.C(N(CC)CC)C>CN(C=O)C>[CH2:1]([O:8][C:9]([N:20]([CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)[CH3:19])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CNCc1c[nH]c2ccccc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 73.2 %

Procedure:
N-(Benzyloxycarbonyloxy)succinimide (8.9 g, 35.7 mmole) was added to a solution of 3-(methylaminomethyl)-1H-indole (5.2 g, 32.5 mmole), from Preparation 16, and triethylamine (5.0 mL, 65.7 mmole) in DMF (100 mL) at RT. The reaction was stirred overnight then was concentrated in vacuo. The residue was diluted with water and the mixture was extracted with ethyl acetate. The combined extracts were dried over Na2SO4 and concentrated. Flash chromatography on silica gel (33% ethyl acetate/hexanes) gave the title compound (7.0 g, 74%) as an off-white solid: MS (ES) m/e 295 (M+H)+.
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH:3]=[CH:2]1.[C:8]([O:12][C:13]([NH:15][CH:16]=[CH:17][CH:18]=[CH2:19])=[O:14])([CH3:11])([CH3:10])[CH3:9]>O1CCCC1>[C:8]([O:12][C:13]([NH:15][CH:16]1[CH:17]=[CH:18][CH2:19][CH:3]2[CH:2]1[C:1](=[O:7])[NH:5][C:4]2=[O:6])=[O:14])([CH3:10])([CH3:11])[CH3:9]
Reactant: O=C1C=CC(=O)N1
Reactant: C=CC=CNC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1C=CCC2C(=O)NC(=O)C12
Reaction time: 8 h
Yield: 42.8 %

Procedure:
48.0 g (0.5 mol) of maleimide dissolved in 200 ml of absolute tetrahydrofuran are introduced into a reaction vessel, and 120 g (0.5 mol) of approx. 70% 1-(tert.-butyloxycarbonylamino)-1,3-butadiene dissolved in 500 ml of absolute tetrahydrofuran are added dropwise, during which process the temperature is kept at 20° to 30° C. Stirring is continued overnight at room temperature. The mixture is then concentrated, and the product is recrystallised from ethyl acetate. 57 g of product of a melting point of 177° to 182° C. are obtained. A further 13 g of a melting point of 158° to 160° C. are obtained from the mother liquor.