Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[N:9]2[CH2:12][CH:11]([CH:13]([C:16]3[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=3)[CH:14]=[O:15])[CH2:10]2)=[CH:4][CH:3]=1.[CH3:31][Mg]Cl.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]2[CH2:12][CH:11]([CH:13]([C:16]3[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=3)[CH:14]([OH:15])[CH3:31])[CH2:10]2)=[CH:29][CH:28]=1
Reactant: O=CC(c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Reactant: C[Mg]Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(O)C(c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 790 mg (1.77 mmol) of {1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}(3,5-difluorophenyl)acetaldehyde in 20 mL of THF was added slowly a solution of 1.18 mL (3.54 mmol) of methylmagnesium chloride (3.0M solution in THF) at −78° C. and stirred for 1 h. The reaction mixture was warmed to 0° C. for 1 h and 3 g of sodium sulfate decahydrate was added to quench the reaction, followed by stirring for 1 h at rt. The reaction mixture was filtered and the organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography with hexanes/acetone=8:1 to afford the title compound. 1NMR (CDCl3) δ 0.94 (d, J=6.7 Hz, 3H), 3.44 (d, J=6.5 Hz, 1H), 3.77 (m, 1H), 3.97 (s, 21), 4.02 (s, 2H), 4.34 (m, 1H), 4.53 (s, 1H), 6.69 (m, 1H), 6.78 (m, 2H), 7.28 (d, J=8.5 Hz, 4H), 7.38 (d, J=8.5 Hz, 4H); Mass Spectrum: m/e=462 (M+1 35Cl, 35Cl) and 464 (M+1 35Cl, 37Cl).
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[CH:13]=[CH:12][C:7]([C:8](OC)=[O:9])=[CH:6][N:5]=1.CC(C[AlH]CC(C)C)C.[OH-].[Na+].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.O>[F:14][CH:2]([F:1])[O:3][C:4]1[N:5]=[CH:6][C:7]([CH2:8][OH:9])=[CH:12][CH:13]=1
Reactant: COC(=O)c1ccc(OC(F)F)nc1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: OCc1ccc(OC(F)F)nc1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
A cooled (−78° C.) solution of methyl 6-(difluoromethoxy)nicotinate (4.700 g; 23.13 mmol) in anh. toluene (130 ml) was treated dropwise with a solution of 1 M DIBAH in toluene (69.40 ml; 69.40 mmol), and the resulting mixture was further stirred at −78° C., under nitrogen, for 5 min., and then at 0° C. for 1.5 h. The obtained mixture was then treated successively with water (55 ml), 1 M aq. NaOH (12 ml), and aq. sat. NaHCO3 (100 ml). The separated aq. layer was further extracted with Et2O (2×100 ml). The mixed organic layers were then dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording (6-(difluoromethoxy)pyridin-3-yl)methanol as a yellow oil (3.758 g; 93%). LC-MS (conditions D): tR=0.71 min.; no ionisation.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][NH:14][C:15]([C:17]1[CH:41]=[CH:40][C:20]([CH2:21][N:22]2[CH:26]=[C:25]([CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])[C:24]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[N:23]2)=[CH:19][CH:18]=1)=[O:16].[OH-].[Na+].C(O)C.Cl>O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][NH:14][C:15]([C:17]1[CH:41]=[CH:40][C:20]([CH2:21][N:22]2[CH:26]=[C:25]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])[C:24]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[N:23]2)=[CH:19][CH:18]=1)=[O:16]
Reactant: CCOC(=O)CCc1cn(Cc2ccc(C(=O)NCc3nc(-c4ccccc4)oc3C)cc2)nc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1CNC(=O)c1ccc(Cn2cc(CCC(=O)O)c(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
A mixture of ethyl 3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethylaminocarbonyl)benzyl]-3-phenyl-1H-pyrazol-4-yl]propionate (550 mg), 1 N aqueous sodium hydroxide solution (1.3 ml), ethanol (2 ml), and tetrahydrofuran (2 ml) was stirred at room temperature for two hours. The reaction mixture was acidified with dilute hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The obtained crystals were collected by filtration, and 3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethylaminocarbonyl)benzyl]-3-phenyl-1H-pyrazol-4-yl]propionic acid (500 mg, yield: 96%) was obtained. This was recrystallized from acetone-methanol. Melting point: 177–178° C.
Reaction SMILES: C(OC(Cl)=O)C(C)C.C(N(CC)CC)C.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25](O)=[O:26])=[CH:19][C:18]=1[C:28]([NH:30][CH2:31][C:32]12[CH2:41][CH:36]3[CH2:37][CH:38]([CH2:40][CH:34]([CH2:35]3)[CH2:33]1)[CH2:39]2)=[O:29]>O1CCCC1>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][OH:26])=[CH:19][C:18]=1[C:28]([NH:30][CH2:31][C:32]12[CH2:41][CH:36]3[CH2:35][CH:34]([CH2:40][CH:38]([CH2:37]3)[CH2:39]1)[CH2:33]2)=[O:29]
Reactant: O=C(O)CCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CCCO)ccc1Cl
Yield: 82.3 %

Procedure:
Isobutylchloroformate (0.575 ml) and triethylamine (0.63 ml) were added to a solution of 4-chloro-3-[[(tricyclo[3.3.1.13,7]dec-1-ylmethyl)amino]carbonyl]-benzenepropanoic acid (Example 6c, 1.64 g) in tetrahydrofuran (30 ml) at 0° C. After 1 h the precipitates were removed by filtration and the filtrate added portionwise to a solution of sodium borohydride (0.18 g) in water (10 ml) at 0° C. After a further 1 h the reaction mixture was poured onto dilute hydrochloric acid and extracted with ethyl acetate. The organic phase was extracted twice with dilute hydrochloric acid, twice with saturated sodium hydrogencarbonate solution and once with brine, dried over magnesium sulfate and concentrated under reduced pressure to give a residue. Purification by silica gel chromatography (eluting with dichloromethane/methanol 96:4); yielded the subtitled compound as a solid (1.3 g).
Reaction SMILES: C([N:8]1[CH2:19][CH2:18][C:11]2[N:12]=[C:13](Cl)[N:14]=[C:15](Cl)[C:10]=2[CH2:9]1)C1C=CC=CC=1.Cl.Cl.C[C@H]1CN[C@H](C)CN1.CCN(C(C)C)C(C)C.CC(O)C>C(OCC)C>[N:12]1[C:11]2[CH2:18][CH2:19][NH:8][CH2:9][C:10]=2[CH:15]=[N:14][CH:13]=1
Reactant: Clc1nc(Cl)c2c(n1)CCN(Cc1ccccc1)C2
Agent: C[C@@H]1CN[C@@H](C)CN1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: CC(C)O
Product: c1ncc2c(n1)CCNC2
Temperature: 80 °C

Procedure:
A mixture of 6-benzyl-2,4-dichloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (2.0 g, 6.80 mmol), (trans)-2,5-dimethylpiperazine dihydrochloride (7.63 g, 40.8 mmol), DIEA (15.4 mL, 88 mmol) and iPrOH (180 mL) was heated at 80° C. for 3.5 days. At that time the reaction was diluted with diethyl ether and the solid was removed by filtration. The filtrate was then washed with brine and the organic layer was dried (Na2SO4), filtered and concentrated to provide crude racemic 6-benzyl-2-chloro-4-(trans)-2,5-dimethylpiperazin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine, which was then carried to the next step without further purification. MS (ESI+) m/z 372.2 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:8]([C:12]2[CH:13]=[C:14]3[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH3:28])=[CH:19][N:18](S(C4C=CC(C)=CC=4)(=O)=O)[C:15]3=[N:16][CH:17]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1.[OH-].[K+].C(O)(=O)C>CN(C)C=O.CO>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:8]([C:12]2[CH:13]=[C:14]3[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH3:28])=[CH:19][NH:18][C:15]3=[N:16][CH:17]=2)=[CH:7][C:3]=1[C:4]([N:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1)=[O:6]
Reactant: C1COCCN1
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cc(Cl)c(N)c(C(=O)O)c3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccccc1-c1c[nH]c2ncc(-c3cc(Cl)c(N)c(C(=O)N4CCOCC4)c3)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.6 %

Procedure:
25.0 mg (0.046 mmol) of 2-amino-3-chloro-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzoic acid was combined with 18.5 mg (0.114 mmol) of N,N′-carbonyldiimidazole in 1.0 mL dimethylformamide. The solution was stirred at room temperature for 2 hours whereupon 9.9 μL (0.114 mmol) of morpholine was added and the solution was stirred at room temperature for 16 hours. The crude reaction mixture was then diluted with 1.0 mL methanol and 100 μL of 50% w/v potassium hydroxide aqueous solution was added. The mixture was stirred at room temperature for 2 hours and then neutralized with acetic acid. The material was filtered through a 0.45 μm syringe filter and purified by mass-triggered reverse phase HPLC in a gradient of acetonitrile and water (containing 0.1% formic acid). The clean fractions were lyophilized to afford 6.9 mg (0.015 mmol, 32% yield) of {2-amino-3-chloro-5-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-morpholin-4-yl-methanone as a fluffy white powder. 1H NMR (500 MHz, MeOD) δ 8.39 (d, 1H), 8.15 (d, 1H), 7.65 (s, 1H), 7.64 (d, 1H), 7.58 (dd, 1H), 7.36 (d, 1H), 7.31 (t, 1H), 7.13 (d, 1H), 7.06 (t, 1H), 3.86 (s, 3H), 3.72 (s, br., 8H); MS: m/z 463.0 (M+H+).
Reaction SMILES: [C:1]([NH:4][C@@H:5]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:6]([NH:8][C@H:9]([C:34](=[O:41])[NH:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:21][C:20](=[O:22])[N:19](CC3C=CC(OC)=CC=3)[S:18]2(=[O:33])=[O:32])=[CH:13][CH:12]=1)=[O:7])(=[O:3])[CH3:2].C([SiH](C)C)(C)(C)C>C(O)(C(F)(F)F)=O.CC#N.O>[C:1]([NH:4][C@@H:5]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:6]([NH:8][C@H:9]([C:34](=[O:41])[NH:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([N:17]2[CH2:21][C:20](=[O:22])[NH:19][S:18]2(=[O:33])=[O:32])=[CH:15][CH:16]=1)=[O:7])(=[O:3])[CH3:2]
Reactant: CCCCCNC(=O)[C@H](Cc1ccc(N2CC(=O)N(Cc3ccc(OC)cc3)S2(=O)=O)cc1)NC(=O)[C@H](Cc1ccccc1)NC(C)=O
Agent: C[SiH](C)C(C)(C)C
Solvent: CC#N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCCCCNC(=O)[C@H](Cc1ccc(N2CC(=O)NS2(=O)=O)cc1)NC(=O)[C@H](Cc1ccccc1)NC(C)=O
Temperature: 80 °C
Reaction time: 0.12 h

Procedure:
A solution of the title C compound, (S)-2-acetylamino-N-((S)-2-{4-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-1-pentylcarbamoyl-ethyl)-3-phenyl-propionamide (49 mg, 0.07 mmol) in TFA (1.4 mL) containing t-butyldimethylsilane (0.035 mL, 0.21 mmol) is heated at 80° C. for 1 h. The reaction is concentrated under nitrogen stream to give an oil which is taken up in 60% MeCN in water. Water (1 mL) is added, and the mixture filtered through a 0.1 micron Acrodisc filter. The resulting mixture is loaded onto a preparative reverse phase HPLC column (YMC CombiPrep Pro C18, 50×20 mm I.D., particle size S-5 micron, 12 nM) in three aliquots and eluted at 30 mL/min with a gradient of 90:10 (0.1% TFA in water:MeCN) to 10:90 over 5 min. Then held at 10:90 until 7 min. Fractions containing product are combined and concentrated on a Savant Speedvac to yield (S)-2-acetylamino-N-((S)-1-pentylcarbamoyl-2-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-ethyl)-3-phenyl-propionamide as a white solid: [M−1]−=556.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[O:42]1[CH:46]=[CH:45][C:44]([CH:47]=O)=[CH:43]1.C(O)(=O)C.C(=O)(O)[O-].[Na+]>CN1CCCC1=O.C(Cl)Cl>[O:42]1[CH:46]=[CH:45][C:44]([CH2:47][N:25]2[CH2:24][CH2:23][N:22]([C:19]3[CH:18]=[CH:17][C:16]([NH:15]/[CH:14]=[C:5]4\[C:6](=[O:13])[NH:7][C:8](=[O:12])[C:9]5[C:4]\4=[CH:3][C:2]([I:1])=[CH:11][CH:10]=5)=[CH:21][CH:20]=3)[CH2:27][CH2:26]2)=[CH:43]1
Reactant: O=C1NC(=O)c2ccc(I)cc2/C1=C/Nc1ccc(N2CCNCC2)cc1
Reactant: O=Cc1ccoc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C1NC(=O)c2ccc(I)cc2/C1=C/Nc1ccc(N2CCN(Cc3ccoc3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 81.2 %

Procedure:
(4Z)-6-Iodo-4-{[(4-piperazin-1-ylphenyl)amino]methylene}isoquinoline-1,3(2H,4H)-dione (47.4 mg, 0.1 mmol) is dissolved in N-methylpyrrolidinone (1 mL) and methylene chloride (0.3 mL), followed by addition of sodium triacetoxyborohydride (244 mg, 1.15 mmol), furan-3-carbaldehyde (0.214 mL, 2.58 mmol) and acetic acid (0.15 mL, 2.6 mmol). After stirring at room temperature for 40 min, methylene chloride and saturated sodium bicarbonate solution were added. The organic layer is separated and dried to give 45 mg (81%) of the title compound as an orange solid. MS (ESI) m/z 555.4 (M+H)+1.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[N:8]=[C:7](O)[C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][N:4]=1.P(Cl)(Cl)([Cl:18])=O>>[CH3:1][N:2]([CH3:15])[C:3]1[N:8]=[C:7]([Cl:18])[C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][N:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc(N(C)C)nc1O
Product: CCOC(=O)c1cnc(N(C)C)nc1Cl

Procedure:
A suspension of 16 g of 2-dimethylamino-4-hydroxy-5-carboethoxy-pyrimidine in 100 ml of phosphorous oxychloride is heated to the boil for half an hour whilst stirring and is then filtered hot, and the filtrate is evaporated under reduced pressure. 200 g of ice are added to the oily residue. 200 ml of methylene chloride are added and 30% strength sodium hydroxide solution is then added, whilst cooling with ice, until the pH reaches 8. Inorganic salts which have precipitated are then filtered off and rinsed with methylene chloride. The organic phase is washed with water, dried over sodium sulphate and evaporated. 2-Dimethylamino-4-chloro-5-carboethoxypyrimidine is obtained as a yellowish oil which can be used further without purification.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[CH:19]1[CH2:21][CH:20]1[CH2:22][OH:23].C(N(CC)CC)C>ClCCl>[F:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[CH:19]1[CH2:21][CH:20]1[CH:22]=[O:23]
Reactant: OCC1CC1c1cc(F)ccc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=CC1CC1c1cc(F)ccc1F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of oxalyl chloride (1.2 mL, 13.5 mmol) in dichloromethane at −78° C. was added dimethyl sulfoxide (1.9 mL, 27 mmol) dropwise and it was stirred at −78° C. for 30 minutes. A solution of [2-(2,5-difluorophenyl)cyclopropyl]methanol (Intermediate 69) (830 mg, 4.5 mmol) in dichloromethane was added dropwise. The reaction mixture was stirred at −78° C. for 30 minutes. Triethylamine (6.3 mL, 45 mmol) was added and the reaction mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. Silica gel chromatography with hexanes/ethyl acetate (9:1) afforded the desired product, 546 mg (66%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:49])[CH2:7][NH:8][C:9]([C@@H:11]1[CH2:15][C@@H:14]([S:16][C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][N:12]1[S:36]([C:39]1[CH:48]=[CH:47][C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=1)(=[O:38])=[O:37])=[O:10])([CH3:4])([CH3:3])[CH3:2].[CH2:50](Br)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.[H-].[Na+].[NH4+].[Cl-].CCOC(C)=O>CN(C=O)C>[C:1]([O:5][C:6](=[O:49])[CH2:7][N:8]([CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:9]([C@@H:11]1[CH2:15][C@@H:14]([S:16][C:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:13][N:12]1[S:36]([C:39]1[CH:48]=[CH:47][C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=1)(=[O:38])=[O:37])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CNC(=O)[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1S(=O)(=O)c1ccc2ccccc2c1
Reactant: BrCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CN(Cc1ccccc1)C(=O)[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1S(=O)(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Yield: 70.8 %

Procedure:
A solution of 346.5 mg (0.5 mmol) (2S,4R)-{[1-(Naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidine-2-carbonyl]-amino}-acetic acid tert-butyl ester in 3 ml DMF was treated at 0° C. with 0.24 ml (2 mmol) benzylbromide and 35 mg (0.8 mmol) 55% NaH, warmed up over night to RT. The reaction was poured into aqueous saturated NH4Cl/EtOAc (3×). The organic phase was washed with aqueous 10% NaCl solution, dried over Na2SO4 and evaporated under reduced pressure. Purification by flash-chromatography on silicagel (Hexane/EtOAc 9:1) gave 277 mg (71%) (2S,4R)-[Benzyl-[1-(naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidine-2-carbonyl]- amino}-acetic acid tert-butyl ester, MS: 781 (M-H)−.
Reaction SMILES: C([O:5][C:6](=[O:9])[CH2:7]Br)(C)(C)C.[CH2:10]([O:17][CH2:18][CH:19]([CH2:45][O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[O:20][CH2:21][CH:22](O)[CH2:23][O:24][CH:25]([CH2:35][O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:26][O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[K+].C(OCC)(=O)C>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.O>[CH2:47]([O:46][CH2:45][CH:19]([CH2:18][O:17][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[O:20][CH2:21][CH:22]([CH2:7][C:6]([OH:9])=[O:5])[CH2:23][O:24][CH:25]([CH2:26][O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:35][O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: OC(COC(COCc1ccccc1)COCc1ccccc1)COC(COCc1ccccc1)COCc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)CC(COC(COCc1ccccc1)COCc1ccccc1)COC(COCc1ccccc1)COCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
14.62 g (75 mmol) of bromoacetic acid-tert-butyl ester is added [to] 30.02 g (50 mmol) of 1,3-bis-(2-benzyloxy-1-benzyloxymethyl-ethoxy)-propan-2-ol (Cassel et al., Eur. J. Org. Chem., 2001, 5, 875-896) and 5.6 g (100 mmol) of fine-powder potassium hydroxide as well as a catalytic amount (1 g) of tetra-n-butylammonium hydrogen sulfate in 250 ml of toluene at 0° C., and it is stirred for 2 hours at this temperature as well as for 12 hours at room temperature. The reaction solution is mixed with 500 ml of ethyl acetate and 300 ml of water. The organic phase is separated and washed twice with 300 ml each of water, then dried on magnesium sulfate and evaporated to the dry state in a vacuum. The residue is suspended in a mixture consisting of 400 ml of methanol and 0.5 M sodium hydroxide solution at a 2:1 ratio and then heated for 12 hours to 60° C. The reaction mixture is neutralized for working-up by mixing with Amberlite IR 120 (H+ form)-cation exchange resin, exchanger is filtered out, evaporated to the dry state, and chromatographed on silica gel (mobile solvent: ethyl acetate/hexane 1:3).
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.CS(C)=O.[F:18][C:19]([P:37](=[O:42])([O:40][CH3:41])[O:38][CH3:39])([F:36])[CH:20]([OH:35])[CH:21]=[C:22]([CH3:34])[CH2:23][CH2:24][CH:25]=[C:26]([CH3:33])[CH2:27][CH2:28][CH:29]=[C:30]([CH3:32])[CH3:31].C(N(CC)CC)C>ClCCl.O>[F:36][C:19]([P:37](=[O:42])([O:40][CH3:41])[O:38][CH3:39])([F:18])[C:20](=[O:35])[CH:21]=[C:22]([CH3:34])[CH2:23][CH2:24][CH:25]=[C:26]([CH3:33])[CH2:27][CH2:28][CH:29]=[C:30]([CH3:32])[CH3:31]
Reactant: COP(=O)(OC)C(F)(F)C(O)C=C(C)CCC=C(C)CCC=C(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: COP(=O)(OC)C(F)(F)C(=O)C=C(C)CCC=C(C)CCC=C(C)C
Temperature: -78 °C
Reaction time: 0.03 h

Procedure:
In Scheme I, step b, the alcohol (3) is oxidized to the ketone described by structure (5). For example, an equivalent of trifluoroacetic acid anhydride is added dropwise to 2 equivalents of dimethylsulfoxide in a suitable organic solvent, such as dichloromethane at approximately -60° C. After addition is complete, the reaction is stirred for approximately 2 minutes. An equivalent of an appropriately substituted alcohol (3), such as dimethyl 1,1-difluoro-2-hydroxy-4,8,12-trimethyl-3,7,11-tridecatrienylphosphonate dissolved in a suitable organic solvent, such as dichloromethane, is added to the reaction dropwise. After addition is complete, the reaction is stirred for approximately 45 minutes. The reaction is then cooled to -78° C. and an excess of triethylamine is added dropwise. The reaction is then allowed to warm to ambient temperature and stirred for approximately 45 minutes. The reaction mixture is then poured into water and extracted with a suitable organic solvent, such as diethyl ether. The organic phase is dried over a suitable drying agent, such as anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue is then purified by techniques well known in the art. For example, the residue can be purified by flash chromatography using a suitable organic eluent, such as 20% ethyl acetate/hexane, to provide dimethyl 1,1-difluoro-2-oxo-4,8,12-trimethyl-3,7,11-tridecatrienylphosphonate.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[O:21][CH3:22])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:23]I>>[Cl:1][C:2]1[N:11]=[C:10]([N:12]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[O:21][CH3:22])[CH3:23])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1ccc(OC)c(Nc2nc(Cl)nc3ccccc23)c1
Reactant: CI
Product: COc1ccc(OC)c(N(C)c2nc(Cl)nc3ccccc23)c1

Procedure:
The title compound was prepared from (2-chloro-quinazolin-4-yl)-(2,5-dimethoxy-phenyl)-amine and methyl iodide by a procedure similar to example 36 (78% yield). 1H NMR (CDCl3): 7.72-7.75 (m, 1H), 7.56 (ddd, J=8.4, 5.7 and 2.1 Hz, 1H), 6.98-7.00 (m, 2H), 6.92-6.92 (m, 2H), 6.78-6.79 (m, 1H), 3.75 (s, 3H), 3.58 (s, 3H), 3.56 (s, 3H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)C.[NH2:12][C:13]1[CH:14]=[C:15]([CH:20]=[C:21]([S:30](=[O:33])(=[O:32])[NH2:31])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:16](OC)=[O:17].C(OCC)(=O)C>N1C=CC=CC=1.O>[NH2:12][C:13]1[CH:14]=[C:15]([CH:20]=[C:21]([S:30](=[O:33])(=[O:32])[NH2:31])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:16][OH:17]
Reactant: COC(=O)c1cc(N)c(Cc2ccccc2)c(S(N)(=O)=O)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: O
Product: Nc1cc(CO)cc(S(N)(=O)=O)c1Cc1ccccc1
Reaction time: 3 h

Procedure:
To a stirred mixture of lithium aluminium hydride (12 g) and dry diethyl ether (350 ml), a solution of methyl 3-amino-4-benzyl-5-sulfamylbenzoate (30 g) in dry pyridine (300 ml) is dropwise added during 1-1.5 hours. After additional stirring for 3 hours, the mixture is cooled and ethyl acetate (25 ml) followed by water (50 ml) are very cautiously added dropwise. After stirring for a further 30 minutes, the solids are collected by filtration and dried in air. The filter cake is treated with hot 4 N hydrochloric acid (about 500 ml) to dissolve inorganic material. After cooling 3-amino-4-benzyl-5-sulfamylbenzyl alcohol is collected by filtration and dried in air. After recrystallization from aqueous ethanol it is obtained with a melting point of 159°-161° C.