Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([CH2:14][O:15][C:16]([C:18]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=2)=[CH2:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-:38].[Na+].OO>O1CCCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)([CH2:14][O:15][CH:16]([C:18]2[CH:19]=[C:20]([C:28]([F:31])([F:29])[F:30])[CH:21]=[C:22]([C:24]([F:26])([F:25])[F:27])[CH:23]=2)[CH2:17][OH:38])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=C(OCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(COC(CO)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)CC1
Reaction time: 3 h

Procedure:
The compound of step (c) above was treated with BH3.tetrahydrofuran (5 ml of a 1M solution in tetrahydrofuran) under an atmosphere of nitrogen for 2 hours. A mixture of 4N NaOH (10 ml) and H2O2 (5 ml of a 29% solution in water) was added and the reaction stirred for 3 hours, then extracted with diethyl ether. The ethereal extracts were washed with sodium bisulphite solution then dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel eluting with ethyl acetate-petroleum ether (3:7) to give the title compound as a colourless oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.Cl.Cl[CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[O:19]1[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)[CH2:17][CH2:18]1
Reactant: ClCCN1CCOCC1
Reactant: COC(=O)c1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(OCCN2CCOCC2)cc1
Temperature: 50 °C
Yield: 141.7 %

Procedure:
To a stirring solution of methyl 4-hydroxybenzoate 191 (1.08 g, 7.10 mmol) and 4-(2-chloroethyl)morpholine hydrochloride 192 (1.45 g, 7.82 mmol) in acetonitrile was added potassium carbonate (2.95 g, 21.3 mmol). The reaction mixture was heated to 50° C. overnight then cooled to rt and the resulting precipitate was filtered and washed with methanol to provide methyl 4-(2-morpholinoethoxy)benzoate 193 (2.67 g, 142%). 1H NMR: (DMSO) δ (ppm): 400 MHz, (DMSO) d (ppm): 7.87 (s, J=9.0 Hz, 2 h), 7.03 (d, J=9.0 Hz, 2H), 4.15 (t, J=5.7 Hz, 2H), 3.80 (s, 3H), 3.56 (t, J=4.5 Hz, 4H), 2.69 (t, J=5.7 Hz, 4H), 2.47 (m, 4H). MS: 265.13 (calc), 266.1 (obs).
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].[N:7]1([CH2:13][C:14]2[CH:28]=[CH:27][C:17]3[NH:18][C:19]([C:21]4[C:25]([NH2:26])=[CH:24][NH:23][N:22]=4)=[N:20][C:16]=3[CH:15]=2)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[C:1]([CH2:3][C:4]([NH:26][C:25]1[C:21]([C:19]2[NH:18][C:17]3[CH:27]=[CH:28][C:14]([CH2:13][N:7]4[CH2:8][CH2:9][O:10][CH2:11][CH2:12]4)=[CH:15][C:16]=3[N:20]=2)=[N:22][NH:23][CH:24]=1)=[O:6])#[N:2]
Reactant: N#CCC(=O)O
Reactant: Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: N#CCC(=O)Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.3 %

Procedure:
A mixture of cyano-acetic acid (23 mg, 0.28 mmol), 3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-ylamine (70%, 100 mg, 0.23 mmol), TBTU (89 mg, 0.28 mmol) and DMF (2 ml) was stirred at 25° C. overnight. The mixture was then evaporated in vacuo. Flash chromatography, eluting with DCM—6% MeOH/DCM afforded 2-cyano-N-[3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-acetamide as a yellow solid (65 mg, 77%). (LC/MS (acidic method/final compound): Rt 4.61, [M+H]+ 366).
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[Na+].[Na+].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26](Cl)=[O:27])[CH:15]=[CH:16][CH:17]=1.O>C(Cl)Cl>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([NH:2][OH:3])=[O:27])[CH:15]=[CH:16][CH:17]=1
Reactant: COc1cccc(CCCCCCCCC(=O)Cl)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1cccc(CCCCCCCCC(=O)NO)c1
Yield: 33.7 %

Procedure:
To a cold stirred suspension of 0.7 gms hydroxylamine hydrochloride and 1 gm sodium carbonate in 10 ml CH2Cl2 was added a solution of 2.1 gms 9(3-methoxyphenyl)nonanoyl chloride in 10 ml CH2Cl2. After stirring this mixture for 1/2 hr, 1.1 ml H2O was added, and the reaction was stirred overnight at room temperature. 30 ml water was added, the layers were separated, and the aqueous layer 3×50 ml extracted with CH2Cl2. The organic phases were combined, washed 2×20 ml water, 2×20 ml NaCl solution, dried over MgSO4, filtered, and evaporated in vacuo to give an oil which solidified on standing. The solid was crystallized from CH2Cl2 :hexanes but was still impure by thin layer chromatography. It was dissolved in 100 ml CHCl3, stirred with 20 gm silica gel, and filtered. The silica gel was suspended in 75 ml CHCl3, stirred, and filtered (process repeated three times). All filtrates were combined, evaporated in vacuo, and the residue recrystallized from CH2Cl2 :hexanes to give 0.7 gms product of m.p. 66°-8°. Elemental analysis: calculated C 68.79, H 9.02, N 5.01% found C 68.61, H 9.18, N 5.09%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[C:33]([O:34][CH3:35])=[CH:32][C:24]2[CH2:25][CH2:26][O:27][C:28](=[O:31])[N:29]([CH3:30])[C:23]=2[CH:22]=1>>[Cl:19][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:20][C:21]2[C:33]([O:34][CH3:35])=[CH:32][C:24]3[CH2:25][CH2:26][O:27][C:28](=[O:31])[N:29]([CH3:30])[C:23]=3[CH:22]=2)=[N:3][CH:4]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc2c(cc1N)N(C)C(=O)OCC2
Product: CNC(=O)c1ccccc1Nc1nc(Nc2cc3c(cc2OC)CCOC(=O)N3C)ncc1Cl
Yield: 20 %

Procedure:
In an analogous manner to Example 1503, the product was prepared from 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide and 3-Amino-2-methoxy-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one. Product isolated as a white solid (20 mg, 20%). mp: 256-258° C., MS (ESI+): 483 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 11.02 (s, 1H), 8.53 (s, J=8 Hz, 1H), 8.34 (s, 1H), 8.15 (s, 1H), 7.51 (d, J=7 Hz, 1H), 7.42 (t, J=7 Hz, 1H), 7.15 (t, J=7 Hz, 1H), 6.73 (s, 1H), 6.26 (br s, 1H), 4.53 (t, 7 Hz, 2H), 3.94 (s, 1H), 3.06 (d, J=5 Hz, 3H), 3.02 (s, 3H), 2.94 (t, J=7, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]3[CH:17]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[CH:20][CH:19]=4)[N:15]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:4][C:3]=1[NH2:41].[CH:42]1([NH:45][C:46](=O)[O:47]C2C=CC=CC=2)[CH2:44][CH2:43]1.O>CS(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]3[CH:17]=[C:16]([C:18]4[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH2:26][CH2:27][N:28]([CH2:29][CH3:30])[CH2:31][CH3:32])=[CH:22][CH:23]=4)[N:15]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:38])([CH3:39])[CH3:40])[C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:4][C:3]=1[NH:41][C:46]([NH:45][CH:42]1[CH2:44][CH2:43]1)=[O:47]
Reactant: CCN(CC)CCCOc1ccc(-c2cc3c(Oc4ccc(N)c(Cl)c4)ncnc3n2COCC[Si](C)(C)C)cc1
Reactant: O=C(NC1CC1)Oc1ccccc1
Solvent: CS(C)=O
Solvent: O
Product: CCN(CC)CCCOc1ccc(-c2cc3c(Oc4ccc(NC(=O)NC5CC5)c(Cl)c4)ncnc3n2COCC[Si](C)(C)C)cc1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
After dissolving the 2-chloro-4-[6-[4-(3-diethylaminopropoxy)phenyl]-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]phenylamine synthesized in Production Example 160-2 in 0.6 ml of dimethylsulfoxide, 23 mg of phenyl cyclopropylcarbamate was added and the mixture was stirred at 80° C. for 1.5 hours. After further adding 75 mg of phenyl cyclopropylcarbamate and stirring at 100° C. for 5 hours, 70 mg of the same reagent was added prior to stirring overnight. The mixture was then returned to room temperature, water was added, and liquid separation and extraction were performed with an ethyl acetate:tetrahydrofuran (5:1) mixed solvent. The organic layer was dried over sodium sulfate, concentrated and subjected to NH silica gel column chromatography (hexane-ethyl acetate) to obtain 18 mg of the title compound.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N:6]2[C:7]3[C:3](=[CH:2][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:5]2)=[CH:15][CH:14]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Brc1cccc2[nH]ccc12
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(-n2ccc3ccccc32)cc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 82.9 %

Procedure:
To a mixture of 4-bromoindole (1.96 g, 10 mmol), and 4-methoxyphenylboronic acid (1.52 g, 10 mmol) in THF (34 mL)) were added Palladium catalyst Pd(PPh3)4 (347 mg, 0.3 mmol) and the freshly prepared sodium hydroxide solution (1.20 g, 30 mmol in 14 mL water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 70° C. oil bath for 16 hours. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed by brine, dried over Na2SO4, and concentrated. The crude product was purified by a silica gel column eluting with hexanes-EtOAc (9:1) to provide 1.85 g (83%) of the product 44-Methoxy-phenyl)-1H-indole as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[CH2:23]([N:29]=[C:30]=[O:31])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].O>CN(C)C=O>[CH2:23]([NH:29][C:30]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:21][CH:20]=1)=[O:31])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: CCCCCCN=C=O
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Temperature: 60 °C
Reaction time: 15 h
Yield: 84 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (52 mg) was dissolved in N,N-dimethylformamide (3 ml), hexyl isocyanate (0.2 ml) was added, and the admixture was stirred at 60° C. for 15 hours. After the addition of water, the reaction mixture was extracted 2 times with ethyl acetate, and the organic layer was then washed with brine and dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation, and the resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 63 mg of the title compound (yield: 84%).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.[S:14](=[O:18])(=[O:17])([OH:16])[OH:15].[CH3:19]O>>[S:14]([OH:18])([OH:17])(=[O:16])=[O:15].[CH3:19][O:11][C:10](=[O:12])[C@H:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[NH2:1]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CO
Agent: Cl
Agent: O=S(=O)(O)O
Product: COC(=O)[C@@H](N)Cc1ccccc1
Reaction time: 8 h
Yield: 66.7 %

Procedure:
The same esterification procedure as in Example 1 was followed with the exception that 165.2 g of L-phenylalanine and 165.2 g of methanol were used and that the hydrochloric acid was replaced with 120.1 g of 98% sulfuric acid. The reaction was conducted at 60° C. for 8 hours, followed by cooling in order to deposit the crystals, which were collected by filtration and then dried to obtain 184.9 g (63.8% yield) of L-phenylalanine methyl ester sulfate having a purity of 95.7% and containing 0.3% of water and 2.4% of L-phenylalanine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(OC(=O)C)(=O)C>[C:9]1(/[CH:8]=[CH:7]/[C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1ccccc1
Reactant: Cc1ccncc1
Solvent: CC(=O)OC(C)=O
Product: C(=C/c1ccncc1)\c1ccccc1
Yield: 32.9 %

Procedure:
A solution of 4-picoline (18.6 g, 0.2 mol) and benzaldehyde (21.2 g, 0.2mol) in acetic anhydride (125 ml) was stirred under reflux for 24 h. The resulting black solution was evaporated, the residue partitioned between ethyl acetate (100 ml) and aqueous sodium carbonate (100 ml) and the liquid phases decanted from the solid residue. The organic layer was washed with sodium carbonate (100 ml), dried (MgSO4), and evaporated to leave a black solid. The solid remaining from the earlier extraction was dissolved in dichloromethane (100 ml), the solution washed with sodium carbonate (75 ml), dried (MgSO4) and evaporated. The combined solid residues were dissolved in methanol (200ml), treated with charcoal, filtered and the filtrate evaporated to leave a brown solid which was triturated with cyclohexane, the suspension filtered and the solid recrystallised from cyclohexane to leave the product as a brown crystalline powder (11.94 g). The combined organic supernatants were chromatographed on silica gel eluting with ethyl acetate/hexanes (7:3) to give a further crop as a yellow solid (6.2 g).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:11][C:12]1[N:19]=[CH:18][CH:17]=[C:16](Br)[C:13]=1[C:14]#[N:15]>CN(C=O)C>[CH2:3]([O:10][C:16]1[C:13]([C:14]#[N:15])=[C:12]([Br:11])[N:19]=[CH:18][CH:17]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: N#Cc1c(Br)ccnc1Br
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(OCc2ccccc2)ccnc1Br
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 83.3 %

Procedure:
To a suspension of NaH (1.756 g, 45.818 mmol, mineral oil 60%) in DMF (200 ml) cooled at 0° C., was added benzyl alcohol (4.542 g, 42 mmol). The resulting mixture was stirred for 5 min. Then, intermediate compound D1 (10 g, 38.18 mmol) was added. The resulting reaction mixture was gradually warmed to r.t. and stirred for 1 h, then quenched with NH4Cl (aqueous sat. solution) and diluted with H2O. The resulting mixture was extracted with Et2O. The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel; DCM/7M solution of NH3 in MeOH up to 1% as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D2 (9.2 g, 83%).
Reaction SMILES: [C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:19])=[O:18])[N:7]([C:21](OC2C=CC([N+]([O-])=O)=CC=2)=[O:22])[C:6](=[O:33])[N:5]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=2)[C:4]=1[CH3:44])#[N:2].[CH:45]1([NH2:48])[CH2:47][CH2:46]1>C(#N)C>[C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:19])=[O:18])[N:7]([C:21]([NH:48][CH:45]2[CH2:47][CH2:46]2)=[O:22])[C:6](=[O:33])[N:5]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:42])([F:43])[F:41])[CH:35]=2)[C:4]=1[CH3:44])#[N:2]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)N1c1cccc(C(F)(F)F)c1
Reactant: NC1CC1
Solvent: CC#N
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(C(=O)NC2CC2)C(=O)N1c1cccc(C(F)(F)F)c1

Procedure:
According to the General Procedure 1, 4-nitrophenyl (6S)-5-cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidine-1(2H)-carboxylate (80.0 mg, 0.128 mmol; Example 6A) was reacted with cyclopropylamine (21.9 mg, 0.384 mmol) in acetonitrile (1 ml) to give the target compound (45 mg, 65% of theory).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4](/[CH:6]=[CH:7]/[CH2:8]P(OCC)(OCC)=O)=[O:5].[H-].[Na+].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=O.CN(C)C=O>O1CCCC1>[CH3:19][O:20][C:21]1[CH:22]=[C:23](/[CH:24]=[CH:8]/[CH:7]=[CH:6]/[C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)/C=C/CP(=O)(OCC)OCC
Reactant: COc1cccc(C=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/C=C/c1cccc(OC)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36.8 %

Procedure:
To an ice-cooled solution of triethyl 4-phosphonocrotonate (24.0 g, 95.9 mmol) in tetrahydrofuran (100 mL) was added by small portions sodium hydride (60% in oil, 3.84 g, 96.0 mmol), and the mixture was stirred under nitrogen atmosphere for 30 min. A solution of 3-methoxybenzaldehyde (12.3 g, 90.0 mmol) in tetrahydrofuran (100 mL) was added dropwise to the reaction mixture and the mixture was stirred at room temperature for 2 hr. N,N-Dimethylformamide (50 mL) was added and the mixture was further stirred for 18 hr. The reaction mixture was concentrated under reduced pressure, and 1 M hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10%-30% ethyl acetate/hexane) to give the title compound (7.70 g, yield 37%) as a yellow oil.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:17][S:18](O)(=[O:20])=[O:19].ClCCl.P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>C(Cl)(Cl)Cl>[N:11]1([CH2:10][CH2:9][CH2:8][O:1][C:2]2[CH:7]=[CH:6][C:5]([S:18]([Cl:17])(=[O:20])=[O:19])=[CH:4][CH:3]=2)[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1
Reactant: c1ccc(OCCCN2CCOCC2)cc1
Reactant: O=S(=O)(O)Cl
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=S(=O)(Cl)c1ccc(OCCCN2CCOCC2)cc1
Reaction time: 0.5 h

Procedure:
[3-(Morpholin-4-yl) propoxy] benzene-4-sulfonyl chloride was prepared by chlorosulfonylation of 4-(3-phenoxypropyl)morpholine using chlorosulfonic acid in the presence of dichloromethane or chloroform. For example, to a solution of 2.2 g (10 mmole) of N-(3-phenoxypropyl) morpholine in 20 ml of chloroform, 2 ml of chlorosulfonic acid (30 mmole) was slowly added at −10° C. and stirred for 30 min. The reaction mixture was stirred at room temperature for 5 hr. Chloroform was removed from lower layer. Lower layer was treated with chopped-ice to give solids. To a mixture of ice and solid product, 10 g of sodium phosphate (tribasic) was added and stirred with cooling. Chlorosulfonyl compound was extracted with dichloromethane (300 ml). Dichloromethane extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. 1.6 g of [3-(morpholin-4-yl) propoxy]benzene-4-sulfonyl chloride was obtained.
Reaction SMILES: CC(C1C=CC=C(OC2C=CC=CC=2)N=1)O.[CH3:17][CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[N:21]=1)[OH:19].[CH:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][C:35]=1[CH:44]([CH:48]([CH3:50])[CH3:49])[C:45](O)=[O:46]>>[CH:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][C:35]=1[CH:44]([CH:48]([CH3:50])[CH3:49])[C:45]([O:19][CH:18]([CH3:17])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[N:21]=1)=[O:46]
Reactant: CC(O)c1cccc(Oc2ccc(F)cc2)n1
Reactant: CC(C)C(C(=O)O)c1ccc2ccccc2c1
Agent: CC(O)c1cccc(Oc2ccccc2)n1
Product: CC(OC(=O)C(c1ccc2ccccc2c1)C(C)C)c1cccc(Oc2ccc(F)cc2)n1

Procedure:
Following the procedure of Example 3, each of methyl (6-phenoxy-2-pyridyl)methanol and methyl[6-(4-fluorophenoxy)-2-pyridyl]methanol is reacted with 2-(2-naphthyl)-3-methyl-butanoic acid to yield methyl (6-phenoxy-2-pyridyl) methyl 2-(2-naphthyl)-3-methylbutanoate and methyl[6-(4-fluorophenoxy)-2-pyridyl]methyl 2-(2-naphthyl)-3-methylbutanoate, respectively.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.C(=O)(O)[O-].[Na+].C(OC([N:21]1[C:29]2[C:24](=[CH:25][C:26]([P:30]([O:34][CH3:35])([O:32][CH3:33])=[O:31])=[CH:27][CH:28]=2)[C:23](I)=[N:22]1)=O)(C)(C)C>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.CN(C)C=O>[CH3:35][O:34][P:30]([C:26]1[CH:25]=[C:24]2[C:29](=[CH:28][CH:27]=1)[NH:21][N:22]=[C:23]2[C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:31])[O:32][CH3:33]
Reactant: OB(O)c1cccs1
Reactant: COP(=O)(OC)c1ccc2c(c1)c(I)nn2C(=O)OC(C)(C)C
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: CN(C)C=O
Product: COP(=O)(OC)c1ccc2[nH]nc(-c3cccs3)c2c1
Temperature: 130 °C
Reaction time: 5 h
Yield: 2.1 %

Procedure:
44.8 mg (0.25 eq; 0.039 mmol) of tetrakis(triphenylphosphine)palladium(0), 39.6 mg (2 eq; 0.310 mmol) of 2-thiopheneboronic acid, 3 ml of dimethylformamide and 150 μl of saturated sodium bicarbonate solution are added to 70 mg (1 eq; 0.155 mol) of 5-(dimethoxyphosphoryl)-3-iodoindazole-1-carboxylic acid tert-butyl ester. The medium is stirred at 130° C. for 5 hours. The reaction medium is filtered through paper and the solvent is evaporated off under reduced pressure in a rotary evaporator. The reaction crude is purified by LC/MS to obtain 2 mg of (3-thiophen-2-yl-1H-indazol-5-yl)phosphonic acid dimethyl ester (40% purity by NMR), along with 12.9 mg of (3-thiophen-2-yl-1H-indazol-5-yl)phosphonic acid monomethyl ester.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].C(=O)C.C(N(CC)CC)C.[CH3:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][C:20]=1[CH:25]=[C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][C:27]1=[O:35]>CN(C=O)C>[C:5]([O:4][CH:1]([N:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)/[C:26](=[CH:25]/[C:20]2[NH:21][C:22]([CH3:24])=[CH:23][C:19]=2[CH3:18])/[C:27]1=[O:35])[CH3:2])(=[O:7])[CH3:6]
Reactant: Cc1cc(C)c(C=C2C(=O)Nc3ccccc32)[nH]1
Reactant: CC(=O)OC(C)=O
Agent: CC=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)OC(C)N1C(=O)/C(=C\c2[nH]c(C)cc2C)c2ccccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 64.7 %

Procedure:
A mixture of acetic anhydride (2.1 g, 20 mmol), acetaldehyde (4.4 g, 100 mmol), triethylamine (2.0 g, 20 mmol) and 3-(3,5-dimethyl-1H-pyrrol-2-ylmethylidene)-1,3-dihydro-indol-2-one (2.38 g, 10 mmol) in DMF (30 mL) was stirred at room temperature for 3 days. The solvents were removed and the residual oil was chromatographed on silica gel to give, as the first product eluted from the column, 2.5 g of product, which was crystallized from ether to give 2.1 g of the title compound, mp 107–110° C. HPLC Rt 6.78 min. 1H NMR (CDCl3) δ 1.81 (d, 3H), 2.09 (s, 3H), 2.33 (s, 3H), 2.38 (s, 3H), 5.98 (s, 2H), 7.00–7.20 (m, 3H), 7.25 (dd, 1H), 7.39 (s, 1H), 7.51 (dd, 1H) and 13.0 (br s, 1H). Anal. Calcd for C19H20N2O3: C, 70.35; H, 6.21; N, 8.64. Found: C, 70.33; H, 6.18; N, 8.60.