Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[N:7]([CH2:8][C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[N:12]=[N:11][N:10]=2)[CH2:6][CH2:5][NH:4][C:3]1=[O:24].[H-].[Na+].I[CH3:28]>CN(C)C=O>[CH3:28][N:4]1[CH2:5][CH2:6][N:7]([CH2:8][C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[N:12]=[N:11][N:10]=2)[CH:2]([CH3:1])[C:3]1=[O:24]
Reactant: CI
Reactant: CC1C(=O)NCCN1Cc1nnnn1-c1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1C(=O)N(C)CCN1Cc1nnnn1-c1cccc(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
To a solution of 3-methyl-4-({1-[3-(trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl)-2-piperazinone (100 mg, 0.294 mmol, Compound 32), in N,N-Dimethylformamide (DMF) (1.5 mL) was added sodium hydride (25.9 mg, 0.646 mmol). After stirring for 1 hour under argon, iodomethane (0.020 mL, 0.323 mmol) was added. The resulting reaction mixture was stirred under argon for 1 hour.
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C@@H:21]1[CH2:25][CH2:24][CH2:23][N:22]1[C:26](=[O:45])[CH2:27][C@@H:28]([O:43][CH3:44])[C@@H:29]([N:34]([CH3:42])[C:35](=[O:41])[C@H:36]([CH:38]([CH3:40])[CH3:39])[NH2:37])[C@@H:30]([CH3:33])[CH2:31][CH3:32])[C@@H:4]([CH3:20])[C:5]([NH:7][C@H:8]([C:16]([O:18][CH3:19])=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6].C1C2C(COC([NH:63][C@@:64]([C:68](O)=[O:69])([CH3:67])[CH2:65][CH3:66])=O)C3C(=CC=CC=3)C=2C=CC=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(NCC)C>ClCCl>[NH2:63][C@@:64]([C:68]([NH:37][C@H:36]([C:35]([N:34]([C@@H:29]([C@@H:30]([CH3:33])[CH2:31][CH3:32])[C@H:28]([O:43][CH3:44])[CH2:27][C:26]([N:22]1[CH2:23][CH2:24][CH2:25][C@H:21]1[C@H:3]([O:2][CH3:1])[C@@H:4]([CH3:20])[C:5]([NH:7][C@@H:8]([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:16]([O:18][CH3:19])=[O:17])=[O:6])=[O:45])[CH3:42])=[O:41])[CH:38]([CH3:39])[CH3:40])=[O:69])([CH3:67])[CH2:65][CH3:66]
Reactant: CC[C@](C)(NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC)OC)N(C)C(=O)[C@@H](N)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCNCC
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC)OC)N(C)C(=O)[C@@H](NC(=O)[C@@](C)(N)CC)C(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 29.8 %

Procedure:
A solution of #114 (447 mg, 0.707 mmol, 1.0 eq.) in 2 mL of dichloromethane was added to a solution of N-[(9H-fluoren-9-ylmethoxy)carbonyl]-D-isovaline (240 mg, 0.707 mmol, 1.0 eq.) in 4 mL of dichloromethane. Hunig's base (0.373 mL, 2.12 mmol, 3 eq.) was added followed by HATU (332 mg, 0.425 mmol, 1.2 eq.). The reaction was allowed to stir at room temperature for 12 hours. The reaction was concentrated in vacuo and then taken up in ethyl acetate before being washed two times with 1M HCl and once with brine. The organic layer was dried over sodium sulfate and decanted. The organic solvent was removed in a genevac. THF (4 mL) was added followed by diethylamine (2 mL, 19 mmol, 26.9 eq.). The reaction was allowed to stir for ˜12 hours. Reaction was concentrated using a genevac followed by silica chromatography (Gradient: 0%-30% methanol in ethyl acetate) producing #149 (154 mg, 30%) as a solid. LC-MS (Protocol Q): m/z 732.0 [M+H+] retention time=1.24 minutes. 1H NMR (400 MHz, DMSO-d6), δ 8.55 (d), 8.38-8.46 (m), 8.29 (d), 8.03-8.14 (m), 7.97 (d), 7.81 (d), 7.40-7.53 (m), 7.14-7.28 (m), 7.02 (s), 4.71-4.79 (m), 4.43-4.69 (m), 3.96-4.05 (m), 3.71-3.80 (m), 3.62-3.70 (m), 3.49-3.60 (m), 3.40-3.48 (m), 3.15-3.34 (m), 3.10-3.14 (m), 3.01-3.09 (m), 2.94-3.00 (m), 2.83-2.93 (m), 2.65-2.71 (m), 2.55-2.59 (m), 2.32-2.48 (m), 2.04-2.31 (m), 1.61-1.89 (m), 1.37-1.52 (m), 1.21-1.35 (m), 1.15-1.20 (m), 1.02-1.10 (m), 0.75-1.01 (m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([CH:16]([C:20]#[N:21])C(O)=O)[CH2:12][N+:13]([O-:15])=[O:14]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([CH2:16][C:20]#[N:21])[CH2:12][N+:13]([O-:15])=[O:14]
Reactant: N#CC(C(=O)O)C1(C[N+](=O)[O-])C(=O)Nc2ccc(Cl)cc21
Solvent: CN(C)C=O
Product: N#CCC1(C[N+](=O)[O-])C(=O)Nc2ccc(Cl)cc21

Procedure:
A solution of [5-chloro-3-(nitromethyl)-2-oxo-2,3-dihydro-1H-indol-3-yl](cyano)acetic acid, intermediate 28 (2.00 g; 6.46 mmol) in anhydrous DMF (15 ml) was heated at 160° C. for 1 hour. After evaporation of the solvent, the residue was taken up in ethyl acetate, extracted with brine, dried (MgSO4) and the solvent removed in vacuo to give the crude [5-chloro-3-(nitromethyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]acetonitrile (1.74 g, quant, HPLC purity 93%). MS (ESI−): 264.1
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]=[S:11].[CH2:12]([NH:14][CH2:15][C:16](O)=[O:17])[CH3:13].C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:16](=[O:17])[CH2:15][N:14]([CH2:12][CH3:13])[C:10]1=[S:11]
Reactant: S=C=Nc1c(Cl)cccc1Cl
Reactant: CCNCC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCN1CC(=O)N(c2c(Cl)cccc2Cl)C1=S
Yield: 45 %

Procedure:
The title compound was prepared by the procedure described in Example 16 using 10.2 g of 2,6-dichlorophenyl-isothiocyanate, 7.4 g of N-ethyl glycine, 10 g of triethyl amine, and 250 mL of chloroform. Purification was achieved through crystallization from ethanol. The title compound (6.5 g) was obtained as a tan solid, m.p. 170°-172° C. Anal. Calcd. for. C11H10C12N2O S: C, 45.69; H, 3.48; N, 9.69. Found: C, 45.53; H, 3.19; N, 9.62. Mass spectrum (El, M.+) m/z 288/290/292.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:16][CH:15]([N:17]4[CH2:22][CH2:21][S:20](=[O:24])(=[O:23])[CH2:19][CH2:18]4)[CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:3]=1.[CH:31]([C:34]1[NH:38][C:37]2[CH:39]=[CH:40][CH:41]=[CH:42][C:36]=2[N:35]=1)([CH3:33])[CH3:32].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:31]([C:34]1[N:35]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH2:12][N:13]4[CH2:14][CH:15]([N:17]5[CH2:18][CH2:19][S:20](=[O:23])(=[O:24])[CH2:21][CH2:22]5)[CH2:16]4)[N:8]3[CH3:11])=[C:4]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[N:3]=2)[C:36]2[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=2[N:38]=1)([CH3:33])[CH3:32]
Reactant: CC(C)c1nc2ccccc2[nH]1
Reactant: Cn1c(CN2CC(N3CCS(=O)(=O)CC3)C2)nc2c(N3CCOCC3)nc(Cl)nc21
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CCS(=O)(=O)CC4)C3)n(C)c2n1
Yield: 47.9 %

Procedure:
A mixture of 2-chloro-8-[3-(1,1-dioxo-1-thiomorpholin-4-yl)azetidin-1-ylmethyl]-9-methyl-6-morpholin-4-yl-9H-purine (0.162 g, 0.36 mmol), 2-isopropyl-1H-benzoimidazole (0.068 g, 0.43 mmol), Xphos (0.034 g, 0.071 mmol), Pd2(dba)3 (0.017 g, 0.018 mmol) and Cs2CO3 (0.231 g, 0.71 mmol) in dioxane (2 mL) was subjected to microwave irradiation at 145° C. for 45 min. The suspension was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, MeOH:DCM gradient 0:100 to 7.5:92.5) to give 449 as a yellow solid (0.1 g, 49%). LCMS (Method I): RT=2.56 min, [M+H]+ 580.2. 1H NMR (400 MHz, DMSO-d6): δ 7.91-7.86 (m, 1 H); 7.66-7.61 (m, 1 H); 7.26-7.21 (m, 2 H); 4.30-4.23 (m, 4 H); 3.97-3.86 (m, 1 H); 3.87 (s, 2 H); 3.82-3.71 (m, 7 H); 3.46 (t, J=6.6 Hz, 2 H); 3.26-3.18 (m, 1 H); 3.12-3.08 (m, 4 H); 3.00 (t, J=6.8 Hz, 2 H); 2.74 (m, 4 H); 1.35 (d, J=6.8 Hz, 6 H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][C:6](/[CH:12]=[CH:13]/[C:14](OCC)=[O:15])=[CH:5]2.CC(C[AlH]CC(C)C)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][C:6](/[CH:12]=[CH:13]/[CH2:14][OH:15])=[CH:5]2
Reactant: CCOC(=O)/C=C/c1cc2cc(Cl)c(Cl)cc2[nH]1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: OC/C=C/c1cc2cc(Cl)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of ethyl (E)-3-(5,6-dichloroindol-2-yl)-2-propenoate (28 g, 98.5 mmol) in dry THF (500 ml) stirred under argon at −20° DIBAL (1M solution in hexane, 200 mmol) was added dropwise while keeping the temperature below −20°. The stirring was continued for one hour, then the reaction was quenched with water (70 m). After warming to RT diethyl ether (350 m) was added and the suspension was filtered on a Celite pad. The pad was washed with diethyl ether (3×100 ml), then the pooled organic phase was dried (MgSO4) and evaporated to give 23.85 g of the title compound (98.5 mmol, yield 100%) that was used as such in the next step.
Reaction SMILES: [CH:1]1([C:6]2[C:7]3[C:14]([I:15])=[CH:13][NH:12][C:8]=3[N:9]=[CH:10][N:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1>[C:18]1([S:24]([N:12]2[C:8]3[N:9]=[CH:10][N:11]=[C:6]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[C:7]=3[C:14]([I:15])=[CH:13]2)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Ic1c[nH]c2ncnc(C3CCCC3)c12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1cc(I)c2c(C3CCCC3)ncnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.9 %

Procedure:
To 4-cyclopentyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (49, 0.161 g, 0.514 mmol) in tetrahydrofuran, sodium hydride (0.0308 g, 0.771 mmol) was added under an atmosphere of nitrogen. Benzenesulfonyl chloride (40, 0.0984 mL, 0.771 mmol) in 1 mL of tetrahydrofuran was added dropwise at room temperature under nitrogen. The reaction was stirred overnight at room temperature. The aqueous layer was separated and washed with ethyl acetate. The organic layers were combined and washed with 1 M aqueous sodium bicarbonate, water, then brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with ethyl acetate and hexane. Appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound (50, 0.121 g). MS (ESI) [M+H+]+=454.3.
Reaction SMILES: [CH2:1]([N:3]([CH2:31][CH3:32])[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:30])[CH2:9][N:10]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:13]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=2)[CH:12]=[N:11]1)[CH3:2].C([O-])=O.[NH4+]>CO.[Pd]>[NH2:27][C:24]1[CH:25]=[CH:26][C:21]([C:13]2[CH:12]=[N:11][N:10]([CH2:9][C:8]([NH:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:31][CH3:32])=[O:30])[C:14]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:22][CH:23]=1
Reactant: CCN(CC)CCCNC(=O)Cn1ncc(-c2ccc([N+](=O)[O-])cc2)c1-c1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCN(CC)CCCNC(=O)Cn1ncc(-c2ccc(N)cc2)c1-c1ccccc1
Yield: 95.9 %

Procedure:
A solution of 43.7 g (0.1 mol) of N-[3-(diethylamino)propyl]-4-(4-nitrophenyl)-5-phenyl-1H-pyrazole-1-acetamide of example 45 in 200 mL of methanol was refluxed for 2 hr with 4 g of 10% palladium on charcoal and 30 g of ammonium formate. The catalyst was filtered off and the filtrate was stripped. The residue was distributed between aqueous NaOH and 1:1 THF-ether. The ether layer was dried over magnesium sulfate, stripped and recrystallized from methyl t-butyl ether to yield 38.9 g of product, mp 75°-76° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][NH:5][CH:6]=1.Cl[C:14]1[N:24]=[CH:23][CH:22]=[CH:21][C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]>>[Cl:1][C:2]1[C:3]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][N:5]([C:14]2[N:24]=[CH:23][CH:22]=[CH:21][C:15]=2[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:6]=1
Reactant: Clc1c[nH]nc1-c1ccccc1
Reactant: CCOC(=O)c1cccnc1Cl
Product: CCOC(=O)c1cccnc1-n1cc(Cl)c(-c2ccccc2)n1

Procedure:
The reaction was carried out in analogy to reaction step 3.1 by reacting 4-chloro-3-phenyl-1H-pyrazole and ethyl 2-chloronicotinate. ESI-MS [M+H]+: 328.1
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:39])=[C:6]([C@:8]([N:19]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:20](=[O:29])[CH:21](Cl)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([CH3:18])[CH2:9][O:10][Si](C(C)(C)C)(C)C)[CH:7]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:39])=[C:6]([C@@:8]2([CH3:18])[N:19]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=3)[C:20](=[O:29])[CH:21]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[O:10][CH2:9]2)[CH:7]=1
Reactant: COc1ccc(CN(C(=O)C(Cl)c2ccccc2)[C@@](C)(CO[Si](C)(C)C(C)(C)C)c2cc(Br)ccc2F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)C(c3ccccc3)OC[C@@]2(C)c2cc(Br)ccc2F)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A solution of (RS)-N-[(R)-1-(5-bromo-2-fluoro-phenyl)-2-(tert-butyl-dimethyl-silanyloxy)-1-methyl-ethyl]-2-chloro-N-(4-methoxy-benzyl)-2-phenyl-acetamide (1.068 g, 1.68 mmol) in tetrahydrofuran (30 ml) was cooled to 0° C. and treated dropwise during 10 minutes with a solution of tetrabutylammonium fluoride (1 M, 3.36 mmol) in tetrahydrofuran. The orange-colored reaction mixture was stirred at 0° C. for 5 minutes, then for 4 hours at room temperature. For the workup, the reaction mixture was evaporated at reduced pressure, the residue partitioned between water (10 ml) and ethyl acetate (25 ml) and stirred for 15 minutes. The layers were separated and the aqueous layer re-extracted with ethyl acetate (25 ml). The combined organic layers were dried over sodium sulfate and evaporated at reduced pressure. After chromatography on a Silicycle-Si-amine column using a gradient of heptane and ethyl acetate=100/0 to 50/50 as the eluent, the (2RS,5R)-5-(5-bromo-2-fluoro-phenyl)-4-(4-methoxy-benzyl)-5-methyl-2-phenyl-morpholin-3-one was obtained as a white foam (369 mg, 45% of theory). Mass (calculated) C25H23BrFNO3 [484.37]; (found) [M+H]+=484, [M+2-H]+=486.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:21])[C:6]1[C:7](=[C:12]([CH2:16][NH:17][C:18]([NH2:20])=[O:19])[CH:13]=[CH:14][CH:15]=1)[C:8]([O:10]C)=[O:9]>O.C(O)C>[NH:17]([CH2:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:6]([C:5]([OH:21])=[O:4])[C:7]=1[C:8]([OH:10])=[O:9])[C:18]([NH2:20])=[O:19]
Reactant: COC(=O)c1cccc(CNC(N)=O)c1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: NC(=O)NCc1cccc(C(=O)O)c1C(=O)O
Temperature: 25 °C
Yield: 79.2 %

Procedure:
A solution of sodium hydroxide (0.4 g, 10.5 mmol) in water (10 mL) was added to a stirred suspension of 3-ureidomethyl-phthalic acid dimethyl ester (1.4 g, 5.3 mmol) in ethanol (30 mL). The mixture was refluxed for one hour and then cooled to room temperature. The mixture was concentrated, and the residue was dissolved in water (30 mL). The mixture was acidified with 4N HCl to pH 1. The mixture was filtered to give 3-ureidomethyl-phthalic acid (1.0 g, 76%): 1H NMR (DMSO-d6) δ 4.22 (d, J=5.9 Hz, 2H, CH2), 5.68 (s, 2H, NH2), 6.40 (t, J=6.0 Hz, 1H, NH), 7.46-7.56 (m, 2H, Ar), 7.73 (d, J=6.9 Hz, 1H, Ar), 13.23 (b, 2H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:7]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[O:10][C:9]2([CH3:20])[CH3:19])[CH:6]=[N:5][CH:4]=1.[H-].[Na+].[CH3:23]I>CN(C=O)C>[CH3:23][O:1][CH2:2][C:3]1[N:7]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[O:10][C:9]2([CH3:20])[CH3:19])[CH:6]=[N:5][CH:4]=1
Reactant: CC1(C)OC(=O)c2ccccc2C1n1cncc1CO
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1cncn1C1c2ccccc2C(=O)OC1(C)C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4-(5-hydroxymethyl-imidazol-1-yl)-3,3-dimethyl-isochroman-1-one (0.125 g, 0.495 mmol) (Example 6d) in DMF (2 mL) is added sodium hydride (0.018 g, 0.495 mmol). The reaction mixture is stirred at room temperature for 5 min and then methyl iodide (0.028 mL, 0.495 mmol) is added. The reaction is stirred for 2.5 h at room temperature. It is then washed with water and extracted with ethyl acetate twice. The organic layer is dried over Na2SO4 and concentrated in vacuo. The residue is purified by silica gel chromatography (dichloromethane-methanol, 19:1) to give 4-(5-methoxymethyl-imidazol-1-yl)-3,3-dimethyl-isochroman-1-one; MS (ESI) m/z 287.2 (M+H); 1H NMR (400 MHz, MeOD) δ ppm 1.70 (s, 3H), 1.77 (s, 3 H), 3.90 (s, 3 H), 4.39 (s, 2 H), 4.88 (br. s, 1 H), 6.99 (s, 1 H), 7.44-7.53 (m, 1H), 7.56-7.64 (m, 2 H), 7.76 (s, 1 H), 7.86 (d, J=7.6 Hz, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].[NH2:14][C:15]1[C:16]([Cl:34])=[CH:17][C:18]([F:33])=[C:19]([NH:21][C:22](=[O:32])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N:29]([CH3:31])[CH3:30])[CH:24]=2)[CH:20]=1>N1C=CC=CC=1>[Cl:34][C:16]1[CH:17]=[C:18]([F:33])[C:19]([NH:21][C:22](=[O:32])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N:29]([CH3:30])[CH3:31])[CH:24]=2)=[CH:20][C:15]=1[NH:14][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: CN(C)c1cccc(C(=O)Nc2cc(N)c(Cl)cc2F)c1
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2cc(NC(=O)c3cccc(N(C)C)c3)c(F)cc2Cl)cc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 27.9 %

Procedure:
A mixture of 3,4-dimethoxybenzoyl chloride (0.5 g), N-(5-amino-4-chloro-2-fluorophenyl)-3-dimethylaminobenzamide (0.781 g) and pyridine (8 ml) was stirred at ambient temperature for 18 hours. The mixture was evaporated and the residue was partitioned between methylene chloride and a saturated aqueous copper sulphate solution. The organic phase was washed in turn with water and a saturated aqueous sodium chloride solution, dried (MgSO4) and evaporated. The residue was purified by column chromatography on silica using a 99:1 mixture of methylene chloride and methanol as eluent. There was thus obtained the title compound as a solid (0.328 g);
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.Br[C:12]1[CH:16]=[CH:15][S:14][C:13]=1[CH:17]=[O:18]>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.C(O)CCC>[F:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][C:12]2[CH:16]=[CH:15][S:14][C:13]=2[CH:17]=[O:18])=[CH:6][CH:5]=1
Reactant: Fc1ccc(S)cc1
Reactant: O=Cc1sccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCO
Product: O=Cc1sccc1Sc1ccc(F)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 65.5 %

Procedure:
A mixture of sodium hydride (0.20 g) and n-butanol (10 mL) was treated with 4-fluorothiophenol (0.64 g), and the resulting mixture was added to a mixture of 3-bromothiophene-2-carbaldehyde (0.96 g), tetrakis(triphenylphosphine)palladium (0) (0.12 g) and n-butanol (5.0 mL). The resulting mixture was stirred at 100° C. for 2 hours and then at 120° C. for 4 hours. The mixture was cooled to room temperature, concentrated under reduced pressure and the residue partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate, and the combined organic solution was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of cyclohexane and dichloromethane (2:1 to 0:1 by volume) to afford the title compound as a yellow solid (0.78 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12](I)[S:11][N:10]=2)=[CH:5][CH:4]=1)[CH3:2].[CH3:20][S:21]([O-:23])=[O:22].[Na+]>[Cu]I.CN(C)C=O>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([S:21]([CH3:20])(=[O:23])=[O:22])[S:11][N:10]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCOC(=O)c1c(-c2ccc(CC)cc2)nsc1I
Reactant: CS(=O)[O-]
Agent: [Cu]I
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(-c2ccc(CC)cc2)nsc1S(C)(=O)=O
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Into a 50-mL round-bottom flask, was placed N,N-dimethylformamide (8 mL), CuI (391 mg, 2.05 mmol, 1.99 equiv), ethyl 3-(4-ethylphenyl)-5-iodo-1,2-thiazole-4-carboxylate (400 mg, 1.03 mmol, 1.00 equiv), sodium methanesulfinate (421.7 mg, 4.13 mmol, 4.00 equiv). The resulting solution was stirred for 16 h at 80° C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:20). The collected fractions were combined and concentrated under vacuum. This resulted in 170 mg (48%) of ethyl 3-(4-ethylphenyl)-5-methanesulfonyl-1,2-thiazole-4-carboxylate as a yellow solid. Mass spectrum (ESI, m/z): Calcd. for C15H17NO4S2, 340.1 (M+H). found 340.1.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:34])[CH:21]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31](=[O:33])[CH3:32])[CH2:22][CH3:23])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:52])[C@@H:15]2[CH2:35][CH2:36][C@H:37]2[O:42][C:41](=[O:43])[CH2:40][C@H:39]([O:44][Si](C(C)(C)C)(C)C)[CH2:38]2)=[CH:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:34])[CH:21]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31](=[O:33])[CH3:32])[CH2:22][CH3:23])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:52])[C@@H:15]2[CH2:35][CH2:36][C@H:37]2[O:42][C:41](=[O:43])[CH2:40][C@H:39]([OH:44])[CH2:38]2)=[CH:10]1
Reactant: CCC(Oc1ccccc1C(C)=O)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(Oc1ccccc1C(C)=O)C(=O)O[C@H]1C[C@H](O)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Yield: 43.9 %

Procedure:
A procedure similar to that described in Example 2, above, was followed, but using 1.11 g of (4R,6R)-6-([1S,2S,6S,8S,8aR]-2-{1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-[(2RS)-2-(2-acetylphenoxy)butyryloxy]-2-methyl-1-naphthyl}ethyl)tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described inExample 97, above] and 35.3 ml of a 1.0 molar solution of tetrabutylammonium fluoride in tetrahydrofuran, to give 0.34 g of the title compound as white crystals, melting at between 148° and 150° C. Nuclear Magnetic Resonance Spectrum (270 MHz CDCl3) δ ppm: 1.10 (3H, triplet, J=7.3 Hz); 2.62 (3H, singlet); 4.32-4.52 (3H, multiplet); 4.81 (1H, triplet, J=5.9 Hz); 5.44 (1H, broad singlet); 5.52 (1H, broad singlet); 5.82 (1H, doublet of doublets, J=5.9 & 9.9 Hz); 5.93 (1H, doublet, J=9.9 Hz); 6.88 (1H, doublet, J=7.9 Hz); 7.00 (1H, triplet, J=8.6 Hz); 7.41 (1H, triplet, J=8.6 Hz); 7.72 (1H, doublet, J=7.9Hz).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[CH:11]=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:20]([PH:24](=[O:28])[O:25][CH2:26][CH3:27])[CH2:21][CH2:22][CH3:23]>C(N(CC)CC)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[CH:11]([P:24]([CH2:20][CH2:21][CH2:22][CH3:23])(=[O:28])[O:25][CH2:26][CH3:27])[OH:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC(C=O)c1ccc(Cl)cc1
Reactant: CCCC[PH](=O)OCC
Solvent: CCN(CC)CC
Product: CCCCP(=O)(OCC)C(O)C(CNC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A material of 283 mg of 3-(N-tert.-butyloxycarbonylamino)-2-(4-chlorophenyl)-propionaldehyde, 150 mg of ethyl n-butyl-phosphinate and 101 mg of triethylamine is heated to 100° C. for 21/2 hours. The mixture is cooled to room temperature and the volatile components are removed in high vacuum. Chromatography of the residue on silica-gel affords ethyl 3-(N-tert.-butyloxycarbonylamino)-2-(4-chlorophenyl)-1-hydroxy-propyl-(n-butyl)phosphinate.