Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[CH2:11][OH:12].O.[Sn](Cl)Cl.[OH-].[Na+]>CCOC(C)=O>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH2:11][OH:12])[CH:4]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(CO)c1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1ccc(Cl)c(CO)c1
Temperature: 25 °C
Reaction time: 21 h
Yield: 93.2 %

Procedure:
To a solution of (2-chloro-5-nitrophenyl)methanol (5.00 g, 26.7 mmol) in EtOAc (100 mL) was added water (2.41 mL, 134 mmol) followed by tin(II) chloride (12.7 g, 67.0 mmol). The solution was stirred at RT for 21 h, then additional tin(II) chloride (5.06 g, 26.7 mmol) was added, and the mixture heated at 50° C. for 2 h, and then at 70° C. for 3 h. The cooled mixture was slowly basified with 1N sodium hydroxide solution (˜300 mL). The suspension was filtered through Celite, washing with EtOAc. The aqueous layer was extracted with EtOAc (3×100 mL), then the combined organics washed with brine, dried over MgSO4, and concentrated in vacuo to give the title compound (3.92 g, 93%). LCMS (Method 3): Rt 0.98 min, m/z 158 [MH+].
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](Cl)=[O:7].[CH:9]1([NH2:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C>ClCCl>[CH:9]1([NH:15][C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: NC1CCCCC1
Reactant: O=C(Cl)CCCCCl
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCCCCl)NC1CCCCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A stirred solution of 5-chlorovaleryl chloride (50.0 g, 0.322 mol) in dichloromethane (300 ml) at 0° C. was treated dropwise with a solution containing cyclohexylamine (31.68 g, 0.320 mol), triethylamine (32.32 g, 0.320 mol) and dimethylaminopyridine (0.02 g) in dichloromethane (300 ml). The resulting solution was stirred for 2 hours at 0° C. and then for an additional 16 hours at room temperature. The solution was diluted with dichloromethane (400 ml), washed with water (3×200ml), saturated aqueous sodium hydrogen carbonate (3×100 ml), saturated aqueous ammonium chloride (3×100 ml), and brine (2×100 ml) and then dried over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure to yield a crude product. The crude product was recrystallized from ethyl acetate-hexane to yield N-cyclohexyl-5-chloropentanamide as a colorless crystalline solid, having a melting point of 70°-71° C. and the following physical characteristics:
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28](O)=[O:29])=[CH:22][CH:21]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:28](=[O:29])/[CH:27]=[CH:26]/[C:23]3[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=3)=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)/C=C/c1ccc(Cl)cc1
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)/C=C/c3ccc(Cl)cc3)n2)o1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(4-chloro-phenyl)-acrylic acid. LC-MS-conditions 05b: tR=1.03 min; [M+H]+=371.8.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]=[C:8]3[C:15]([CH3:23])([CH3:22])[C:16]4[C:21]([C:7]3=[CH:6][C:5]2=1)=[CH:20][CH:19]=[CH:18][CH:17]=4.Br[C:25]1[CH:26]=[C:27]([C:31]2[N:36]=[C:35]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:34]=[C:33]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[N:32]=2)[CH:28]=[CH:29][CH:30]=1.CC([O-])(C)C.[Na+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>CC1C=CC(C)=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:29]1[CH:30]=[CH:25][CH:26]=[C:27]([C:31]3[N:36]=[C:35]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH:34]=[C:33]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[N:32]=3)[CH:28]=1)[C:10]1[CH:9]=[C:8]3[C:15]([CH3:23])([CH3:22])[C:16]4[C:21]([C:7]3=[CH:6][C:5]2=1)=[CH:20][CH:19]=[CH:18][CH:17]=4
Reactant: Brc1cccc(-c2nc(-c3ccccc3)cc(-c3ccccc3)n2)c1
Reactant: CC1(C)c2ccccc2-c2cc3c(cc21)[nH]c1ccc(Br)cc13
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccc(C)cc1
Product: CC1(C)c2ccccc2-c2cc3c4cc(Br)ccc4n(-c4cccc(-c5nc(-c6ccccc6)cc(-c6ccccc6)n5)c4)c3cc21

Procedure:
19.55 g (53.97 mmol) of 7-bromo-12,12-dimethyl-10,12-dihydro-10-aza-indeno[2,1-b]fluorene 19, 22.99 g (59.37 mmol) of 2-(3-bromophenyl)-4,6-diphenylpyrimidine 14 and 15.84 g (164.81 mmol) of NaOtBu are suspended in 820 ml of p-xylene. 245.0 mg (1.09 mmol) of Pd(OAc)2 and 3.3 ml of a 1M tri-tert-butylphosphine solution are added to this suspension. The reaction mixture is heated under reflux for 19 h. After cooling, the organic phase is separated off, washed three times with 100 ml of water and subsequently evaporated to dryness. The residue is extracted with hot tolu-ene, recrystallised from toluene. The yield is 21.65 g (65%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH:5]([CH3:12])[CH:6]([NH:8][CH:9]1[CH2:11][CH2:10]1)[CH3:7])[CH3:2].[Cl:14][C:15]1[N:20]=[C:19](Cl)[C:18]([N+:22]([O-:24])=[O:23])=[CH:17][N:16]=1.C(=O)(O)[O-].[K+]>O.C(OCC)C>[CH2:1]([O:3][C:4](=[O:13])[CH:5]([CH3:12])[CH:6]([N:8]([C:17]1[C:18]([N+:22]([O-:24])=[O:23])=[CH:19][N:20]=[C:15]([Cl:14])[N:16]=1)[CH:9]1[CH2:11][CH2:10]1)[CH3:7])[CH3:2]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CCOC(=O)C(C)C(C)NC1CC1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)C(C)C(C)N(c1nc(Cl)ncc1[N+](=O)[O-])C1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.7 %

Procedure:
A solution of 0.93 g (0.005 mole) of (rac)-3-cyclopropylamino-2-methyl-butanoic acid ethyl ester in 20 mL of water was added dropwise to a solution of 0.97 g (0.005 mole) of 2,4-dichloro-5-nitro-pyrimidine in 20 mL of ethyl ether. At 0 degrees, 1.0 g (0.010 mole) of potassium bicarbonate was added. The mixture was stirred at ambient temperature for 3 hours. The layers were then separated, and the aqueous layer extracted twice with 30 mL of ether. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with hexanes-ethyl acetate (100:0-80:20) gave 1.4 g of (rac)-3-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopropyl-amino]-2-methyl-butanoic acid ethyl ester (IV-46).
Reaction SMILES: [CH:1]1([C:4]2[NH:5][CH:6]=[C:7]([I:9])[N:8]=2)[CH2:3][CH2:2]1.[F:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1>C1COCC1>[CH:1]1([C:4]2[N:5]([C:14]3[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=3)[CH:6]=[C:7]([I:9])[N:8]=2)[CH2:3][CH2:2]1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Ic1c[nH]c(C2CC2)n1
Solvent: C1CCOC1
Product: Fc1ccc(-n2cc(I)nc2C2CC2)cc1
Reaction time: 8 h
Yield: 45.6 %

Procedure:
2-Cyclopropyl-4-iodo-1H-imidazole (500 mg, 2.14 mmol) was dissolved in 20 ml THF. 4-Fluorobenzene boronic acid (613 mg, 4.38 mmol) and [Cu(OH)TMEDA]2Cl2 (347 mg, 0.75 mmol) were added. Oxygen was bubbled through the reaction mixture for 60 min and stirring was continued under an oxygen atmosphere at RT overnight. The reaction mixture was filtered through a dicalite speed plus pad and washed with 30 mL ethyl acetate. After drying the crude product was purified by flash chromatography on silica gel (heptane/ethyl acetate 90:10→50:50 gradient) to get the desired compound as a white solid (320 mg, 46%), MS: m/e=329.1 (M+H+). Preparation of the Compounds of Formula I
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH:7]([C@@H:8]2[CH2:12][C@H:11]([SH:13])[CH2:10][N:9]2[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[CH2:6][N:5]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=2)=[O:28])[CH2:4]1.O(P(O[C:57]1[C@H:58]([CH3:81])[C@H:59]2[C@@H:76]([C@H:77]([OH:79])[CH3:78])[C:75](=[O:80])[N:60]2[C:61]=1[C:62]([O:64][CH2:65][C:66]1[CH:71]=[CH:70][C:69]([N+:72]([O-:74])=[O:73])=[CH:68][CH:67]=1)=[O:63])(OC1C=CC=CC=1)=O)C1C=CC=CC=1>>[OH:79][C@@H:77]([C@H:76]1[C:75](=[O:80])[N:60]2[C:61]([C:62]([O:64][CH2:65][C:66]3[CH:67]=[CH:68][C:69]([N+:72]([O-:74])=[O:73])=[CH:70][CH:71]=3)=[O:63])=[C:57]([S:13][C@@H:11]3[CH2:10][N:9]([C:14]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=4)=[O:15])[C@H:8]([CH:7]4[CH2:6][N:5]([C:27]([O:29][CH2:30][C:31]5[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=5)=[O:28])[CH2:4][CH:3]4[CH2:2][OH:1])[CH2:12]3)[C@H:58]([CH3:81])[C@H:59]12)[CH3:78]
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CC(CO)C([C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(Oc3ccccc3)Oc3ccccc3)[C@H](C)[C@@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C4CN(C(=O)OCc5ccc([N+](=O)[O-])cc5)CC4CO)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Yield: 57.3 %

Procedure:
The same procedure as in Example 1-1) was carried out by using (2S, 4S)-2-[3-hydroxymethyl-N-(p-nitrobenzyloxycarbonyl)pyrrolidin-4-yl]-4-mercapto-N-(p-nitrobenzyloxycarbonyl)pyrrolidine diastereomer A (3.34 g, 5.42 mmol, compound of Reference Example 5) and p-nitrobenzyl (1R, 5S, 6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (3.22 g, 5.42 mmol) to obtain p-nitrobenzyl (1R, 5S, 6S)- 6-[(R)-1-hydroxyethyl]-2-[(2S,4S)-2-[3-hydroxymethyl-N-(p-nitrobenzyloxycarbonyl)pyrrolidin-4-yl]-N-(p-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-1-methyl-1-carbapen-2-em-3-carboxylate diastereomer A (2.81 g, yield: 57.3%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[Br:23]Br>CO>[NH2:1][C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[Br:23]
Reactant: BrBr
Reactant: COC(=O)c1cccc(-c2ccc(N)nn2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cccc(-c2cc(Br)c(N)nn2)c1
Reaction time: 16 h
Yield: 38.9 %

Procedure:
In a 150 mL round bottom flask was placed methyl 3-(6-aminopyridazin-3-yl)benzoate (2.29 g, 10 mmol), NaHCO3 (1.68 g, 20 mmol) and methanol (40 mL). To this suspension was added Br2 (1.6 g, 10 mmol) drop wise over about 30 minutes at room temperature. The mixture was stirred for 16 h, then filtered and concentrated in vacuo. The residue was purified by chromatography (silica gel, 200-300 mesh, petroleum ether:ethyl acetate=2:1) to give methyl 3-(6-amino-5-bromopyridazin-3-yl)benzoate (1.2 g, 39%) as a light orange solid. LC-MS: [M+H]+, 308.0, tR=1.377 min.
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:25])=[C:5]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH:20](O)[CH2:21][CH2:22][CH3:23])=[CH:12][N:11]=2)[C:6]([CH3:9])=[CH:7][CH:8]=1.[H-].[Na+].C(I)C.B(Br)(Br)[Br:32].Cl.[OH-].[Na+]>CN(C=O)C.C(Cl)Cl.CO.O>[Br:32][CH:20]([C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([C:5]2[C:4]([CH3:25])=[C:3]([OH:2])[CH:8]=[CH:7][C:6]=2[CH3:9])=[N:11][CH:12]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCC(O)c1cnc(-c2c(C)ccc(OC)c2C)c2ccccc12
Reactant: BrB(Br)Br
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCI
Product: CCCC(Br)c1cnc(-c2c(C)ccc(O)c2C)c2ccccc12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 94.6 %

Procedure:
A solution of 1-[1-(3-methoxy-2,6-dimethyl-phenyl)-isoquinolin-4-yl]-butan-1-ol (117 mg, 0.33 mmol) in DMF (2 ml) is added to a suspension of NaH (67 mg, 60% dispersion in mineral oil, 1.7 mmol) in DMF (4 ml) at 0° C. After stirring for 45 min, EtI (0.26 ml, 3.3 mmol) is added slowly. After stirring for 10 min at 0° C., the mixture is allowed to warm to room temperature and the stirring is continued for 1 h. Water is added and the mixture is extracted with Et2O. The combined extracts are washed with saturated brine, dried over Na2SO4, and concentrated to give the desired ether that is dissolved in DCM (12 ml). After cooling to −78° C., BBr3 (3.2 ml of 1 M solution in DCM, 3.2 mmol) is added dropwise and the mixture is allowed to warm to room temperature. After stirring for 1 h, MeOH (3 ml) and 1N—HCl (50 uL) are added carefully. After heating for 10 min at 80° C., the mixture is cooled and then basified with 1N—NaOH to pH 10. The resulting mixture is extracted with DCM and the combined extracts are washed with saturated brine. Drying over Na2SO4 and concentration are followed by flash chromatography to give 120 mg of 3-[4-(1-bromo-butyl)-isoquinolin-1-yl]-2,4-dimethyl-phenol as a yellow foam.
Reaction SMILES: C(OC([N:8]1[CH2:26][CH2:25][C@@H:11]2[N:12]([CH3:24])[C:13]3[C:14]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:16](Br)=[CH:17][C:18]=3[C@@H:10]2[CH2:9]1)=O)(C)(C)C.[Br-].[CH2:28]([Zn+])[CH2:29][CH2:30][CH3:31]>>[CH2:28]([C:16]1[CH:15]=[C:14]([C:20]([F:21])([F:23])[F:22])[C:13]2[N:12]([CH3:24])[C@H:11]3[CH2:25][CH2:26][NH:8][CH2:9][C@H:10]3[C:18]=2[CH:17]=1)[CH2:29][CH2:30][CH3:31]
Reactant: CCCC[Zn+]
Reactant: CN1c2c(cc(Br)cc2C(F)(F)F)[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]21
Agent: [Br-]
Product: CCCCc1cc2c(c(C(F)(F)F)c1)N(C)[C@H]1CCNC[C@@H]21

Procedure:
The title compound was prepared by following the general coupling procedure as a colorless oil from (4aS,9bR)-8-bromo-5-methyl-6-trifluoromethyl-1,3,4,4a,5,9b-hexahydro-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester (Example 45) and n-butyl zinc bromide. MS (ES+): 313 (base, M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10](O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:22])=CC=1.C(OCC)(=O)C.O>O1CCCC1>[CH3:1][C:2]1[CH:11]=[C:10]([SH:22])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cc(O)c2ccccc2n1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(S)c2ccccc2n1
Temperature: 50 °C
Reaction time: 6 h
Yield: 60.6 %

Procedure:
A stirred suspension of 2-methylquinolin-4-ol (5.10 g, 32.0 mmol, 1.0 eq.) in tetrahydrofuran (51 mL) was heated to 50° C., and 6.5 g of Lawesson's Reagent (6.5 g, 16.0 mmol, 0.5 eq.) was added in one portion. The reaction was heated to 80° C. and stirred at that temperature for 6 hours. The reaction was poured into a hot biphasic solution of ethyl acetate (200 mL) and water (200 mL) and was vigorously stirred. A viscous orange gel precipitated from the solution. The water/ethyl acetate solution was decanted into a separating funnel and the organic layer isolated. The aqueous layer was extracted with ethyl acetate (4×200 ml), and the combined extracts were dried over magnesium sulfate. The solution was filtered and concentrated in vacuo. The resulting orange gel was purified by flash chromatography (50% EtOAc:50% petroleum ether→100% EtOAc) to yield 5a as a yellow solid (1.70 g, 30%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:25]([OH:27])=O)=[N:11][C:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[Cl:24])=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[Si:55]([O:62][CH2:63][CH2:64][NH:65][CH:66]([CH3:68])[CH3:67])([C:58]([CH3:61])([CH3:60])[CH3:59])([CH3:57])[CH3:56]>O1CCCC1.O>[Si:55]([O:62][CH2:63][CH2:64][N:65]([CH:66]([CH3:68])[CH3:67])[C:25]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:14]([OH:15])[N:13]=[C:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[Cl:24])[N:11]=1)=[O:27])([C:58]([CH3:61])([CH3:60])[CH3:59])([CH3:57])[CH3:56]
Reactant: O=C(O)c1nc(Cc2cccc(Cl)c2Cl)nc(O)c1OCc1ccccc1
Reactant: CC(C)NCCO[Si](C)(C)C(C)(C)C
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(Cc2cccc(Cl)c2Cl)nc(O)c1OCc1ccccc1
Temperature: 65 °C
Yield: 32.9 %

Procedure:
To a stirred solution of 5-benzyloxy-2-(2,3-dichlorobenzyl)-6-hydroxypyrimidine-4-carboxylic acid (131) (5.5 g, 13.58 mmol) in tetrahydrofuran (70 mL) were added N,N-diisopropylethylamine (9.36 mL, 54.32 mmol) and T3P (17.3 mL, 27.16 mmol) followed by [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropyl-amine (8b) (5.89 g, 27.16 mmol) at room temperature. The mixture was heated at 65° C. for 4 h. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate. The separated organic part was dried and concentrated to get a crude product which was purified by a normal silica column using 10 to 20% ethyl acetate in hexane to obtain 5-benzyloxy-2-(2,3-dichlorobenzyl)-6-hydroxypyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]isopropylamide (132) (2.7 g, 32.8%) as a light yellow solid.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:5])[CH2:3][OH:4].[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9](I)[CH:8]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(O)CO>CC(O)C.[Cu](I)I.O>[Cl:6][C:7]1[CH:8]=[C:9]([NH:1][C@@H:2]([CH3:5])[CH2:3][OH:4])[CH:10]=[CH:11][CH:12]=1
Reactant: C[C@H](N)CO
Reactant: Clc1cccc(I)c1
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: O
Solvent: CC(C)O
Product: C[C@@H](CO)Nc1cccc(Cl)c1
Yield: 95.7 %

Procedure:
A solution of (2S)-2-aminopropan-1-ol (11.7 g), 1-chloro-3-iodobenzene (36.1 g), tripotassium phosphate (66.4 g), copper iodide (1.42 g) and ethylene glycol (16.7 mL) in propane-2-ol (155 mL) was stirred at 80° C. for 24 hr under an argon atmosphere. Water (500 mL) was added to the reaction solution, and the mixture was extracted with diethyl ether. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=0→30%) to give the title compound as a colorless oil (yield: 26.9 g, 97%).
Reaction SMILES: COC1C=C(OC)C=CC=1C(Cl)=O.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[N:22]=[CH:21][CH:20]=[C:19]2[O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1.[CH3:36][O:37][C:38]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[CH:40][C:39]=1[C:46]([N:48]=[C:49]=[S:50])=[O:47]>C1(C)C=CC=CC=1.C(O)C>[CH3:36][O:37][C:38]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[CH:40][C:39]=1[C:46]([N:48]=[C:49]=[S:50])=[O:47].[CH3:36][O:37][C:38]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[CH:40][C:39]=1[C:46]([NH:48][C:49]([NH:33][C:32]1[CH:34]=[CH:35][C:29]([O:28][C:19]2[C:18]3[C:23](=[CH:24][C:25]([O:26][CH3:27])=[C:16]([O:15][CH3:14])[CH:17]=3)[N:22]=[CH:21][CH:20]=2)=[CH:30][CH:31]=1)=[S:50])=[O:47]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: COc1ccc(C(=O)Cl)c(OC)c1
Agent: COc1ccc(C(=O)N=C=S)c(OC)c1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(C(=O)NC(=S)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
2,4-Dimethoxy-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2,4-dimethoxy-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2,4-dimethoxy-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (42 mg, yield 48%).
Reaction SMILES: [Si:1]([N:8]1[C:11](=[O:12])[CH2:10][C@H:9]1[C:13]([OH:15])=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:26](Br)[CH:27]=[CH2:28]>C1COCC1>[CH2:28]([C@H:10]1[C:11](=[O:12])[N:8]([Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[C@@H:9]1[C:13]([OH:15])=[O:14])[CH:27]=[CH2:26]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)C[C@H]1C(=O)O
Reactant: C=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC[C@H]1C(=O)N([Si](C)(C)C(C)(C)C)[C@@H]1C(=O)O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-1-(tert-butyldimethylsilyl)-4-oxoazetidine-2-carboxylic acid (4) (2.00 g, 8.73 mmol.) in anhydrous THF (20 mL) at −78° C. was added 1.0 M solution of LiHMDS (20 ml, 20.1 mmol, 2.3 eq.) in THF. After the solution was stirred for 30 min. at −78° C., it was warmed to 0° C. for 10 min. The solution was recooled to −78° C. and allyl bromide (1.28 g, 10.5 mmol, 1.2 eq.) was added slowly. The reaction solution was stirred at −78° C. for 1 h, then warmed up to room temperature and stirred for another hour. The reaction mixture was quenched with aqueous 10% KHSO4 solution (30 ml) and extracted with ethyl acetate (40 mL×3). The combined organic layers were washed with brine twice and dried over Na2SO4. After removal of solvent, compound 57 was obtained as crystalline solid (2.0 g, 85%); 78% purity by LCMS, 1HNMR (300 MHz, CDCl3): 0.12 (s, 3H), 0.30 (s, 3H), 0.95 (s, 9H), 2.55 (m, 2H), 3.41 (m, 1H), 3.80 (d, J=2.61 Hz, 1H), 5.16 (m, 2H), 5.72 (m, 1H). Anal. C13H23NO3Si, Mol. Wt.: 269.41. Found: ESI-MS: 270.0 (M+H)+.
Reaction SMILES: [S:1]=[C:2]1[NH:6][C:5]([C:7]2[CH:34]=[CH:33][C:10]([O:11][CH2:12][CH2:13][CH2:14][O:15][C:16]3[CH:29]=[CH:28][C:19]4[CH2:20][CH2:21][CH:22]([C:24]([O:26]C)=[O:25])[O:23][C:18]=4[C:17]=3[CH2:30][CH2:31][CH3:32])=[C:9]([CH2:35][CH2:36][CH3:37])[C:8]=2[O:38][CH3:39])=[CH:4][S:3]1.CO.C1COCC1.[OH-].[Li+]>C(OCC)(=O)C.O>[S:1]=[C:2]1[NH:6][C:5]([C:7]2[CH:34]=[CH:33][C:10]([O:11][CH2:12][CH2:13][CH2:14][O:15][C:16]3[CH:29]=[CH:28][C:19]4[CH2:20][CH2:21][CH:22]([C:24]([OH:26])=[O:25])[O:23][C:18]=4[C:17]=3[CH2:30][CH2:31][CH3:32])=[C:9]([CH2:35][CH2:36][CH3:37])[C:8]=2[O:38][CH3:39])=[CH:4][S:3]1
Reactant: CCCc1c(OCCCOc2ccc(-c3csc(=S)[nH]3)c(OC)c2CCC)ccc2c1OC(C(=O)OC)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCCc1c(OCCCOc2ccc(-c3csc(=S)[nH]3)c(OC)c2CCC)ccc2c1OC(C(=O)O)CC2
Yield: 96 %

Procedure:
The compound of Example 25 (47 mg, 82.2 μmol) was added to 2.5 ml of 4:1 methanol/THF, and 0.2 ml of 1N lithium hydroxide was added. The mixture was allowed to react at room temperature for 2.5 hours. The reaction mixture was poured into ethyl acetate/water and the ethyl acetate was washed with brine, dried over sodium sulfate and concentrated. Flash chromatography of the residue on silica gel using 7:1 to 5:1 hexane/ethyl acetate (1% acetic acid) as eluant gave the product, melting point 149-51° C., (44 mg, 79 μmol, 96% yield). High resolution mass spectrum, m/e 557.1895 (calculated for C29H5NO6S2, 557.1906).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:22]([NH:23][C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>C(O)C.[Pd]>[F:27][C:25]([F:26])([F:28])[C:24]([NH:23][C:22]1[C:17]([N:14]2[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]2)=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:29]
Reactant: O=C(OCc1ccccc1)N1CCN(c2ncccc2NC(=O)C(F)(F)F)CC1
Agent: [Pd]
Solvent: CCO
Product: O=C(Nc1cccnc1N1CCNCC1)C(F)(F)F
Reaction time: 20 h

Procedure:
1-[Benzyloxycarbonyl]-4-[3-(2,2,2-trifluoroacetamido)-2-pyridinyl]piperazine (PREPARATION 101), is dissolved in 70 ml of ethanol and 0.25 g of 10% palladium on carbon is added. The reaction is hydrogenated at 40 psi for 20 hr. Then it is filtered through a pad of celite and concentrated in vacuo to afford the title compound which is used without further purification, NMR (300 MHz, CDCl3) 8.51, 8.21, 7.19, and 3.45-3.47 δ.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6](/[CH:9]=[CH:10]/[C:11]([O:13]CC)=[O:12])=[N:7][CH:8]=1.[CH3:16][CH:17](CC1C=CC(CO)=CC=1)C(O)=O>>[CH2:16]([CH:10]([CH2:9][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][OH:1])=[CH:8][N:7]=1)[C:11]([OH:13])=[O:12])[CH3:17]
Reactant: CCOC(=O)/C=C/c1ccc(CO)cn1
Reactant: CC(Cc1ccc(CO)cc1)C(=O)O
Product: CCC(Cc1ccc(CO)cn1)C(=O)O

Procedure:
The title compound was prepared from Intermediate E by the same methodology used to make Intermediate B.