Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:31])=[C:9]([CH2:11][O:12][C:13]2[CH:28]=[CH:27][C:16]([CH2:17][O:18][C:19]3[C:23]([CH:24]=O)=[CH:22][N:21]([CH3:26])[N:20]=3)=[CH:15][C:14]=2[O:29][CH3:30])[N:10]=1.[CH2:32](P(=O)(OCC)OCC)[P:33](=[O:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36].CN(C)C=O.[H-].[Na+]>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:31])=[C:9]([CH2:11][O:12][C:13]2[CH:28]=[CH:27][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:32]/[P:33](=[O:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36])=[CH:22][N:21]([CH3:26])[N:20]=3)=[CH:15][C:14]=2[O:29][CH3:30])[N:10]=1
Reactant: COc1cc(COc2nn(C)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(/C=C/c1cn(C)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1)OCC
Reaction time: 15 h
Yield: 54.4 %

Procedure:
To a mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-methyl-1H-pyrazole-4-carbaldehyde (0.60 g), tetraethyl methylenediphosphonate (0.43 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.070 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (4:1 to 9:1, v/v) to give diethyl (E)-2-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-methyl-1H-pyrazol-4-yl}ethenylphosphonate as colorless crystals (0.43 g, yield 55%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 72-73° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@@H:15]([OH:17])[CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[Cl:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][C:29]=1[OH:30])[C:23]([NH:25][NH2:26])=[O:24]>>[Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@@H:15]([OH:17])[CH3:16])[C:12]([NH:26][NH:25][C:23](=[O:24])[C:22]2[CH:27]=[CH:28][C:29]([OH:30])=[C:20]([Cl:19])[CH:21]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: NNC(=O)c1ccc(O)c(Cl)c1
Reactant: Cc1c(N[C@@H](C(=O)O)[C@H](C)O)ccc(C#N)c1Cl
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(O)c(Cl)c2)[C@H](C)O)ccc(C#N)c1Cl
Temperature: 0 °C
Yield: 81.8 %

Procedure:
(2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (1.02 g, 3.8 mmol) and 3-chloro-4-hydroxybenzohydrazide (711 mg, 3.8 mmol) were coupled in an analogous fashion as the procedure used for the preparation of intermediate 3b. The crude product was purified by boiling in chloroform (50 mL) followed by cooling to 0° C. and filtration to yield product as a white solid (1.36 g, 82%). 1H NMR (400 MHz, acetone-d6, δ in ppm) 7.93 (d, J=2.2 Hz, 1H), 7.75 (dd, J=2.2, 8.4 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 7.08 (d, J=8.6 Hz, 1H), 6.67 (m, 1H), 5.55 (d, J=6.8 Hz, 1H), 4.38 (m, 1H), 4.10 (dd, J=3.1, 7.0 Hz, 1H), 2.36 (s, 3H), 1.34 (d, J=6.5 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][CH2:26][NH:27][C:28]1[C:29]([C:77]([NH:79][C@H:80]([CH2:91][OH:92])[C:81]([O:83]CC2C=CC=CC=2)=[O:82])=[O:78])=[N:30][C:31]([NH:50][CH2:51][CH2:52][CH2:53][O:54][CH2:55][CH2:56][O:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][O:66][CH2:67][CH2:68][O:69][CH2:70][CH2:71][O:72][CH2:73][CH2:74][O:75][CH3:76])=[C:32]([C:34]([NH:36][C@H:37]([CH2:48][OH:49])[C:38](=[O:47])[O:39]CC2C=CC=CC=2)=[O:35])[N:33]=1.C([O-])=O.[NH4+]>CO.O.[Pd]>[CH3:76][O:75][CH2:74][CH2:73][O:72][CH2:71][CH2:70][O:69][CH2:68][CH2:67][O:66][CH2:65][CH2:64][O:63][CH2:62][CH2:61][O:60][CH2:59][CH2:58][O:57][CH2:56][CH2:55][O:54][CH2:53][CH2:52][CH2:51][NH:50][C:31]1[C:32]([C:34]([NH:36][C@@H:37]([C:38]([OH:47])=[O:39])[CH2:48][OH:49])=[O:35])=[N:33][C:28]([NH:27][CH2:26][CH2:25][CH2:24][O:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])=[C:29]([C:77]([NH:79][C@@H:80]([C:81]([OH:83])=[O:82])[CH2:91][OH:92])=[O:78])[N:30]=1
Reactant: COCCOCCOCCOCCOCCOCCOCCOCCCNc1nc(C(=O)N[C@H](CO)C(=O)OCc2ccccc2)c(NCCCOCCOCCOCCOCCOCCOCCOCCOC)nc1C(=O)N[C@H](CO)C(=O)OCc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: COCCOCCOCCOCCOCCOCCOCCOCCCNc1nc(C(=O)N[C@H](CO)C(=O)O)c(NCCCOCCOCCOCCOCCOCCOCCOCCOC)nc1C(=O)N[C@H](CO)C(=O)O
Temperature: 60 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
A 250 mL round-bottom flask equipped with magnetic stir bar was charged with the above bis-benzyl ester 10 (0.390 g, 0.297 mmol) and ammonium formate (0.112 g, 1.78 mmol) in MeOH (10 mL) and water (10 mL). To this was added slurry of 10% Pd/C (0.095 g) in water (10 mL) and reaction mixture was stirred at 60° C. RP-LC/MS analysis after 1 h showed ˜60% mono-ester and the rest starting material. At this stage, additional ammonium formate (0.112 g, 1.78 mmol) and 10% Pd/C (0.095 g) were added and the reaction was completed in an hour. The catalyst was removed by filtration through Celite, washed with deionized water (˜100 mL), and the combined filtrates were concentrated in vacuo. The crude product was purified by preparative HPLC and the product was concentrated in vacuo and transferred into a 4 dram vial with acetonitrile, concentrated and vacuum dried to afford 8 (0.300 g, 76%) as red oil: HRMS (ESI) m/z calculated for C48H89N6O24 (M+H)+ 1133.5923, found 1133.5958.
Reaction SMILES: [C:1]([O:14][C@H:15]([CH2:61][O:62][C:63](=[O:75])[CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH3:74])[CH2:16][S:17][CH2:18][C@H:19]([NH:43][C:44]([O:46][CH2:47][CH:48]1[C:60]2[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=2[C:54]2[C:49]1=[CH:50][CH:51]=[CH:52][CH:53]=2)=[O:45])[C:20](=[O:42])[NH:21][CH2:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][CH2:33][NH:34]C(=O)OC(C)(C)C)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>C(O)(C(F)(F)F)=O.C(Cl)Cl.C(Cl)Cl>[C:63]([O:62][CH2:61][C@@H:15]([O:14][C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:16][S:17][CH2:18][C@H:19]([NH:43][C:44]([O:46][CH2:47][CH:48]1[C:60]2[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=2[C:54]2[C:49]1=[CH:50][CH:51]=[CH:52][CH:53]=2)=[O:45])[C:20](=[O:42])[NH:21][CH2:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][CH2:33][NH2:34])(=[O:75])[CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH3:74]
Reactant: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCCOCCCCOCCCNC(=O)OC(C)(C)C)OC(=O)CCCCCCCCCCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCCOCCCCOCCCN)OC(=O)CCCCCCCCCCC

Procedure:
(20R,24R)-20-(((9H-fluoren-9-yl)methoxy)carbonylamino)-2,2-dimethyl-4,19-dioxo-3,9,14-trioxa-22-thia-5,18-diazapentacosane-24,25-diyl didodecanoate was stirred in 30% TFA/DCM for 4 hours at room temperature. The reaction was then diluted with DCM and washed with 1M citric acid (pH3). The organics were then dried over anhydrous Na2SO4, filtered and concentrated to afford (2R,6R)-6-(((9H-fluoren-9-yl)methoxy)carbonylamino)-20-amino-7-oxo-12,17-dioxa-4-thia-8-azaicosane-1,2-diyl didodecanoate.
Reaction SMILES: [CH3:1][C:2]([C:6]1[C:11]([CH3:12])=[CH:10][C:9]([OH:13])=[C:8]([CH:14]([CH3:16])[CH3:15])[CH:7]=1)([CH3:5])[CH2:3][CH3:4].C=O.S(=O)(=O)(O)O.[O:24]1[CH2:29]COC[CH2:25]1>>[CH3:5][C:2]([C:6]1[CH:7]=[C:8]([CH:14]([CH3:15])[CH3:16])[C:9]2[O:13][CH2:25][O:24][CH2:29][C:10]=2[C:11]=1[CH3:12])([CH3:1])[CH2:3][CH3:4]
Reactant: C1COCCO1
Reactant: CCC(C)(C)c1cc(C(C)C)c(O)cc1C
Agent: C=O
Agent: O=S(=O)(O)O
Product: CCC(C)(C)c1cc(C(C)C)c2c(c1C)COCO2
Yield: 35 %

Procedure:
Reaction of 4-(1,1-dimethylpropyl)-2-(1-methylethyl)-5-methylphenol (22.02 g, 0.1 mol), which may be prepared as described by W. Koenigs and R. W. Carl, Chem. Ber., (1981) 25, 3892-3903, 40% formaldehyde solution (70 mL, 0.93 mol), p-dioxane (150 mL) and sulfuric acid (10 mL) according to the procedure described in Example 2, provided after chromatography and short-path distillation, 9.18 g (35% yield) of 6-(1,1-dimethylpropyl)-5-methyl-8-(1-methylethyl)-4H-1,3-benzodioxin (GLC purity 98%); 1H-NMR (CDCl3)δ 0.70 (3H, t, J=7 HZ), 1.20 (6H, d, J=7 Hz), 1.35 (6H, s), 1.78 (2H, q, J=7 Hz), 2.15(3H, s), 3.0-3.5 (1H, m), 4.80 (2H, s), 5.17(2H, s), 7.03 (1H, s); IR (film) νmax 2950, 1575, 1470 cm-1 ; MS m/e 262, 233, 217, 203, 175, 161; UVλmax (ethanol) 226 nm (ε=5530), 283 nm (ε=1520).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][CH2:24]O)[CH:18]=4)=[CH:16][C:9]=23)[C:5]([C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:37])[N:34]([CH3:36])[CH3:35])=[CH:28][CH:27]=2)=[N:4]1)[CH3:2].[CH3:38][CH2:39][N:40](CC)[CH2:41][CH3:42].N1CCCC1>C(Cl)Cl>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][CH2:24][N:40]5[CH2:41][CH2:42][CH2:38][CH2:39]5)[CH:18]=4)=[CH:16][C:9]=23)[C:5]([C:26]2[CH:27]=[CH:28][C:29]([NH:32][C:33](=[O:37])[N:34]([CH3:36])[CH3:35])=[CH:30][CH:31]=2)=[N:4]1)[CH3:2]
Reactant: CCn1cc(-c2ccnc3[nH]c(-c4cccc(CCO)c4)cc23)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Reactant: CCN(CC)CC
Solvent: C1CCNC1
Solvent: ClCCl
Product: CCn1cc(-c2ccnc3[nH]c(-c4cccc(CCN5CCCC5)c4)cc23)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 25 %

Procedure:
To a stirred solution of N′-[4-(1-ethyl-4-{2-[3-(2-hydroxyethyl)phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)phenyl]-N,N-dimethylurea (210 mg, 0.42 mMol) in CH2Cl2 (15 mL) was added at 0° C. Et3N (120 uL, 0.86 mmol) and methanesulfonyl lchloride (40 uL, 0.52 mmol). After stirring for 3 h, pyrrolidine (2 mL, 24 mmol) was added. The reaction was allowed to warm to RT, stirred for 18 h, and evaporated to dryness under vacuum. Purification by Gilson HPLC provided the title compound (25%) as a pale yellow solid. ESMS [M+H]+: 548.4.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14]([C@H:17]4[CH2:25][C:24]5[C:19](=[CH:20][C:21]([O:26][CH3:27])=[CH:22][CH:23]=5)[C@H:18]4O)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3][CH2:2]1.C[O:30]C1C=C2C(=CC=1)C(=O)CC2>>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:12][CH2:13][N:14]([C@H:17]4[CH2:18][C:19]5[C:24](=[CH:23][CH:22]=[C:21]([O:26][CH3:27])[CH:20]=5)[C@H:25]4[OH:30])[CH2:15][CH2:16]3)[C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: COc1ccc2c(c1)CCC2=O
Reactant: COc1ccc2c(c1)[C@@H](O)[C@@H](N1CCN(c3cccc4c3OCCO4)CC1)C2
Product: COc1ccc2c(c1)C[C@H](N1CCN(c3cccc4c3OCCO4)CC1)[C@@H]2O

Procedure:
Prepared in the same manner as the compound of Example 1, but using 5-methoxyindan-1-one instead of 6-methoxyindan-1-one in Step 1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:11]([N:14]=[CH:15][N:16]([CH3:18])[CH3:17])(=[O:13])=[O:12])[CH:5]=[C:6]([F:10])[C:7]=1[CH2:8][OH:9].CCN(CC)CC.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[CH3:26][S:27]([O:9][CH2:8][C:7]1[C:2]([F:1])=[CH:3][C:4]([S:11](=[O:12])(=[O:13])[N:14]=[CH:15][N:16]([CH3:18])[CH3:17])=[CH:5][C:6]=1[F:10])(=[O:29])=[O:28]
Reactant: CN(C)C=NS(=O)(=O)c1cc(F)c(CO)c(F)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C=NS(=O)(=O)c1cc(F)c(COS(C)(=O)=O)c(F)c1
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
To a solution of N′-(3,5-difluoro-4-(hydroxymethyl)phenylsulfonyl)-N,N-dimethyl-formimidamide (80 g, 287 mmol) in DCM (500 mL) was added Et3N (121 mL, 862 mmol, 3 eq) and methanesulfonylchloride (27 mL, 245 mmol, 1.2 eq) successively at 0° C. After 30 min, the reaction mixture was extracted with DCM (300 mL×3). The combined extracts were washed with water (1 L), dried over MgSO4, concentrated and then purified by chromatography (silica, DCM/EtOAc, 1:1) to give 4-(N-((dimethylamino)methylene)sulfamoyl)-2,6-difluorobenzyl methanesulfonate (77.5 g, 28% over 4 steps) as a ivory solid. 1H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 7.59-7.39 (m, 2H), 5.32 (s, 2H), 3.18 (s, 3H), 3.09 (s, 3H), 3.08 (s, 3H).
Reaction SMILES: O[C@H]([C@H]([C:10](=[O:26])[CH:11]([C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:24][CH3:25])[C:19]=2[Br:23])[CH:14]=1)[CH3:12])C(O)=O)C(O)=O.Cl.[O:28]1CCOCC1>>[Br:23][C:19]1[C:18]([O:24][CH3:25])=[CH:17][CH:16]=[C:15]2[C:20]=1[CH:21]=[CH:22][C:13]([C@H:11]([CH3:12])[C:10]([OH:26])=[O:28])=[CH:14]2
Reactant: C1COCCO1
Reactant: COc1ccc2cc(C(C)C(=O)[C@H](C(=O)O)[C@@H](O)C(=O)O)ccc2c1Br
Agent: Cl
Product: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1Br
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of pure 2(R)-hydroxy-3(R)-[2-(5-bromo-6-methoxy-2-naphthyl)propanoyl]-butanedioic acid (0.441 g, 1 mmol), 1,4-dioxane (8 ml), and of conc. HCl (8 ml) was heated, under stirring, at 90° C. for 2 hours. The reaction mixture was worked up as described in example 52, to give pure 2(S)-(5-bromo-6-methoxy-2-naphthyl)-propionic acid in 98% enantiomeric excess, determined by HPLC and by 1H-NMR carried out as described in example 57.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH2:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16](N1C=CN=C1)(N1C=CN=C1)=[S:17]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]=[C:16]=[S:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CN=C=S)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.1 %

Procedure:
To a solution of 1-(t-butyloxycarbonyl)-4-(aminomethyl)piperidine (2.14 g) in N,N-dimethylformamide (20 ml) was added 1,1′-thiocarbonyldiimidazole (1.87 g), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was poured into ice water (100 ml), and extracted with ethyl acetate (100 ml). The extract was washed successively with 0.5M hydrochloric acid, 1M aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=4/1) to give [1-(t-butyloxycarbonyl)piperidin-4-yl]methyl isothiocyanate (1.64 g).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([NH:18][C:19]2[N:23]([CH3:24])[N:22]=[C:21]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:20]=2[C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)=[O:17])=[CH:11][CH:10]=1)C1C=CC=CC=1.C1CCCCC=1>[OH-].[Pd+2].[OH-].[C].C(O)C>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([NH:18][C:19]2[N:23]([CH3:24])[N:22]=[C:21]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:20]=2[C:32]2[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=2)=[O:17])=[CH:11][CH:10]=1
Reactant: Cn1nc(-c2ccc(F)cc2)c(-c2ccncc2)c1NC(=O)Cc1ccc(OCc2ccccc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1=CCCCC1
Product: Cn1nc(-c2ccc(F)cc2)c(-c2ccncc2)c1NC(=O)Cc1ccc(O)cc1
Temperature: 25 °C
Yield: 68.2 %

Procedure:
Under a stream of argon gas, 0.11 g of 5-(4-benzyloxyphenylacetylamino)-3-(4-fluorophenyl)-1-methyl-4-(4-pyridyl)pyrazole, 22.9 mg of palladium hydroxide-carbon, and 8 ml of cyclohexene were added to 15 ml of ethanol followed by heating under reflux for 23 hours. After the reaction mixture was cooled to room temperature, the catalyst was filtered off and the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography using 30 g of silica gel [with an elution solvent comprising chloroform-methanol (100:0-40:1)]. Thus, 61.3 mg (69% yield) of the title compound was obtained as white crystals.
Reaction SMILES: [H-].[Na+].Cl.Cl[CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[CH3:13][N:14]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[NH:18][C:17](=[O:25])[C:16]2=[CH:26][S:27][CH:28]=[C:15]12>CN(C)C=O>[CH3:13][N:14]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]([CH2:5][CH2:6][N:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[C:17](=[O:25])[C:16]2=[CH:26][S:27][CH:28]=[C:15]12
Reactant: CN1c2ccccc2NC(=O)c2cscc21
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1c2cscc2C(=O)N(CCN2CCCCC2)c2ccccc21
Reaction time: 18 h

Procedure:
A mixture of 0.31 g. of 55% sodium hydride-mineral oil dispersion and 0.65 g. of N-(2-chloroethyl)piperidine hydrochloride in 25 ml. of dry dimethylformamide is stirred at room temperature for 0.5 hours. To the mixture is added 0.40 g. of 4,9-dihydro-4-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and stirring is continued for 18 hours. The reaction mixture is cooled, quenched with water and extracted with chloroform. The dried chloroform extracts are concentrated to an oil which is purified by preparative thin layer chromatography (tlc) on silica gel with 10:1 benzene:methanol as eluent. The oil obtained is crystallized from hexane to give white crystals, m.p. 84°-88° C.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([C:9]1[NH:10][C:11]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:12]([C:14]([OH:17])([CH3:16])[CH3:15])[N:13]=1)[CH3:8].[C:23]([N:42]1[C:46]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=2[C:53]2[CH:60]=[CH:59][C:56]([CH2:57]Br)=[CH:55][CH:54]=2)=[N:45][N:44]=[N:43]1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C(=O)C>[CH2:7]([C:9]1[N:10]([CH2:57][C:56]2[CH:55]=[CH:54][C:53]([C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=3[C:46]3[N:42]([C:23]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:43]=[N:44][N:45]=3)=[CH:60][CH:59]=2)[C:11]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:12]([C:14]([OH:17])([CH3:16])[CH3:15])[N:13]=1)[CH3:8]
Reactant: CCOC(=O)c1[nH]c(CC)nc1C(C)(C)O
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1c(C(C)(C)O)nc(CC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.7 %

Procedure:
0.52 g of potassium t-butoxide was added to a solution of 1.00 g of ethyl 2-ethyl-4-(1-hydroxy-1-methylethyl)imidazole-5-carboxylate (prepared as described in Preparation 37) in 26 ml of N,N-dimethylacetamide, and the resulting mixture was stirred at room temperature for 10 minutes. A solution of 2.71 g of 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide in 35 ml of N,N-dimethylacetamide was then added dropwise to the resulting solution, after which the reaction mixture was stirred at 50° C. for 4 hours. At the end of this time, the reaction mixture was worked up in a similar manner to that described in Example 18(a), to give 2.01 g of the title compound as crystals, melting at 150°-152° C.
Reaction SMILES: C([O:5][C:6](=[O:55])[C:7]([C:10]1[N:15]=[CH:14][C:13]([NH:16][C:17]([C:19]2[C:23]3[CH2:24][CH2:25][CH2:26][CH2:27][C:22]=3[S:21][C:20]=2[NH:28][C:29]([C:31]2[CH:32]=[C:33]([CH:52]=[CH:53][CH:54]=2)[CH2:34][N:35]([CH:47]([CH2:50][CH3:51])[CH2:48][CH3:49])[C:36](=[O:46])[CH2:37][CH2:38][C:39]([CH3:45])([CH3:44])[C:40]([O:42][CH3:43])=[O:41])=[O:30])=[O:18])=[CH:12][CH:11]=1)([CH3:9])[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:43][O:42][C:40](=[O:41])[C:39]([CH3:44])([CH3:45])[CH2:38][CH2:37][C:36]([N:35]([CH2:34][C:33]1[CH:32]=[C:31]([CH:54]=[CH:53][CH:52]=1)[C:29]([NH:28][C:20]1[S:21][C:22]2[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=2[C:19]=1[C:17]([NH:16][C:13]1[CH:12]=[CH:11][C:10]([C:7]([CH3:9])([CH3:8])[C:6]([OH:55])=[O:5])=[N:15][CH:14]=1)=[O:18])=[O:30])[CH:47]([CH2:48][CH3:49])[CH2:50][CH3:51])=[O:46]
Reactant: CCC(CC)N(Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(C(C)(C)C(=O)OC(C)(C)C)nc2)CCCC3)c1)C(=O)CCC(C)(C)C(=O)OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(CC)N(Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(C(C)(C)C(=O)O)nc2)CCCC3)c1)C(=O)CCC(C)(C)C(=O)OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.8 %

Procedure:
A mixture of 675 mg of methyl 5-[{3-[(3-{[6-(1-tert-butoxy-2-methyl-1-oxopropan-2-yl)pyridin-3-yl]carbamoyl}-4,5,6,7-tetrahydro-1-benzothiophen-2-yl)carbamoyl]benzyl}(pentan-3-yl)amino]-2,2-dimethyl-5-oxopentanoate, 10 mL of methylene chloride, and 1.3 mL of TFA was stirred 15 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and a saturated aqueous sodium hydrogen carbonate solution was added to the residue, followed by extraction by using ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (10% methanol/chloroform), thereby obtaining 550 mg of 2-{5-[({2-[(3-{[(5-methoxy-4,4-dimethyl-5-oxopentanoyl)(pentan-3-yl)amino]methyl}benzoyl)amino]-4,5,6,7-tetrahydro-1-benzothiophen-3-yl}carbonyl)amino]pyridin-2-yl}-2-methylpropanoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]#1.[F-].[Cs+]>CC#N>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:16])[C:10]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)Nc1ccc(Cl)cc1
Reactant: c1ccccc#1
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Product: CCOC(=O)C(C(=O)Nc1ccc(Cl)cc1)(c1ccccc1)c1ccccc1
Yield: 85 %

Procedure:
The present invention further provides one pot process for C-arylation of ethyl 3-(4-chlorophenylamino)-3-oxo-propanoate (2) using benzyne precursor (1) in presence of CsF and CH3CN to obtain ethyl 3-(4-chlorophenylamino)-3-oxo-2,2-diphenylpropanoate (4) with more than 85% yield (cf scheme 3).
Reaction SMILES: [OH-:1].[Na+].[CH:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]3[CH:15]=[C:16]([NH:20][C:21](=[O:25])[N:22]([CH3:24])[CH3:23])[CH:17]=[N:18][CH:19]=3)[CH:12]=2)[N:7]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[N:6]=1)=[O:4]>O.O1CCOCC1.[N+]([O-])([O-])=O.[Ag+]>[CH3:23][N:22]([CH3:24])[C:21](=[O:25])[NH:20][C:16]1[CH:15]=[C:14]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[N:6]=[C:5]3[C:3]([OH:1])=[O:4])[CH:19]=[N:18][CH:17]=1
Reactant: CN(C)C(=O)Nc1cncc(-c2ccc3c(c2)c(C=O)nn3C2CCCCO2)c1
Reactant: [OH-]
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CN(C)C(=O)Nc1cncc(-c2ccc3c(c2)c(C(=O)O)nn3C2CCCCO2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.8 %

Procedure:
A solution of sodium hydroxide (0.173 g, 4.33 mmol) in water (5 mL) was added to a solution of silver nitrate (0.367 g, 2.16 mmol) in water (5 mL) to give a brown precipitate. 3-(5-(3-formyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-1,1-dimethylurea (CXXIII) (0.340 g, 0.86 mmol) was dissolved in 1,4-dioxane (10 mL) and added to the reaction which was stirred overnight at room temperature. The solution was diluted with water and then extracted with diethyl ether. The aqueous layer was separated and carefully brought to pH=3 with aqueous HCl. The aqueous layer was then extracted with 10% iPrOH/chloroform. The combined organic layers were then dried (Na2SO4), filtered and concentrated to give 5-(5-(3,3-dimethylureido)pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylic acid (CXXIV) as a brownish white solid (246 mg, 0.60 mmol, 70% yield). 1H NMR (DMSO-d6) δ ppm 13.26 (br. s, 1H), 8.87 (s, 1H), 8.63 (s, 1H), 8.41 (s, 1H), 8.34 (s, 1H), 8.03 (d, J=7.1 Hz, 1H), 7.86 (dd, J=7.2, 1.3 Hz, 1H), 6.06 (dd, J=8.0, 4.0 Hz, 1H), 3.92 (m, 1H), 3.80 (m, 1H), 2.98 (s, 6H), 2.42-2.39 (m, 1H), 2.03-2.02 (m, 2H), 1.79-1.77 (m, 1H) 1.61 (m, 2H); ESIMS found for C21H23N5O4 m/z 410.0 (M+H).