Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:20]=[CH:21][C:22]=1[OH:23])[CH2:8][C@@H:9]([C:11]([N-:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)=[O:12])[NH2:10])([CH3:4])([CH3:3])[CH3:2].[C:24]([N:34]([CH3:42])[C@H:35]([C:39](O)=[O:40])[CH:36]([CH3:38])[CH3:37])([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25].O>C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]([CH2:8][CH:9]([NH:10][C:39](=[O:40])[CH:35]([N:34]([C:24]([O:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:25])[CH3:42])[CH:36]([CH3:38])[CH3:37])[C:11](=[O:12])[NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:20]=[CH:21][C:22]=1[OH:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)[C@@H](C(=O)O)N(C)C(=O)OCc1ccccc1
Reactant: CC(C)(C)c1cc(C[C@H](N)C(=O)[N-]c2ccccn2)ccc1O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C(C(=O)NC(Cc1ccc(O)c(C(C)(C)C)c1)C(=O)Nc1ccccn1)N(C)C(=O)OCc1ccccc1
Reaction time: 3 h
Yield: 65.6 %

Procedure:
To a solution of 3-tert-butyl-4-hydroxyphenylalanyl (2-pyridyl)amide (1.48 g, 4.73 mmol), Z-N-Me-Val-OH (1.63 g, 6.15 mmol) and CMPI (1.57 g, 6.15 mmol) in THF 30 ml, TEA (1.5 ml, 10.88 mmol) was added under cooling with ice and stirred for 3 hours under cooling with ice. The mixture was mixed with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:2), giving the titled compound (1.74 g, 65%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH:12](OC)(OC)OC>>[O:11]1[C:3]2[C:4]([C:5]([OH:7])=[O:6])=[CH:8][CH:9]=[CH:10][C:2]=2[N:1]=[CH:12]1
Reactant: Nc1cccc(C(=O)O)c1O
Reactant: COC(OC)OC
Product: O=C(O)c1cccc2ncoc12

Procedure:
A solution of 3-amino-2-hydroxy-benzoic acid (12.5 mmol) in trimethyl orthoformate (19.2 mL) is heated to reflux for 20 h and concentrated in vacuo. The residue is washed three times with hot MeOH, the filtrates are combined and the solvent is removed in vacuo to give the desired product which is used without further purification. 1H-NMR (DMSO-d6): δ=13.4 (bs, 1H); 8.87 (s, 1H); 8.08 (d, J=8.0 Hz, 1H); 7.96 (d, J=7.5 Hz, 1H); 7.52 (t, J=7.9 Hz, 1H).
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]([C:14](Cl)=[O:15])[C:5]1=[O:17])([CH3:3])[CH3:2].[CH:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[C:20]([OH:27])[CH:19]=1>C1(C)C=CC=CC=1>[CH:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]([C:14]([O:27][C:20]2[CH:19]=[CH:18][C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=2)=[O:15])[C:5]1=[O:17])([CH3:3])[CH3:2]
Reactant: CC(C)n1c(=O)c(C(=O)Cl)cc2ccccc21
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: Cc1ccccc1
Product: CC(C)n1c(=O)c(C(=O)Oc2ccc([N+](=O)[O-])cc2)cc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.2 %

Procedure:
To a solution of 1.0 g of l-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarbonyl chloride in 30 ml of toluene was added 0.55 g of p-nitrophenol. The mixture was stirred overnight at room temperature. After solvent was distilled off, the residue was extracted with ether. The solvent was again distilled off. The resulting solid was washed with a small quantity of cold ether to give 0.56 g of 4-nitrophenyl 1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate.
Reaction SMILES: [CH2:1]([Li])CCC.[C:6]([Si:10]([CH3:22])([CH3:21])[O:11][CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O)([CH3:9])([CH3:8])[CH3:7]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[C:6]([Si:10]([CH3:22])([CH3:21])[O:11][CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH2:1])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)OCC(=O)c1ccccc1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C(CO[Si](C)(C)C(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a well stirred solution of methyl-triphenyl-phosphonium bromide (3.08 g, 8.61 mmol) in tetrahydrofuran (10 mL) at 0° C. is added n-butyllithium (4.89 mL, 7.83 mmol of a 1.6 M solution). The reaction mixture is allowed to warm to room temperature, stirred for 1 h, then cooled to 0° C. 2-(tert-butyl-dimethyl-silanyloxy)-1-phenyl-ethanone (980 mg, 3.91 mmol) in tetrahydrofuran (30 mL) is then slowly added. The mixture is stirred at room temperature for 30 min then quenched by the addition of a saturated aqueous solution of ammonium chloride and extracted several times with ethyl acetate. The organic layers are combined, washed with water, brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified via silica gel chromatography (20% ethyl acetate in hexanes) to yield 1.3 g of the title compound as a clear oil containing ethyl acetate and was used directly in the next step.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:14][CH:13]=1.[CH3:24][S:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>C1COCC1>[F:11][C:12]1[CH:13]=[CH:14][C:15]([CH:18]([C:30]([C:29]2[CH:33]=[CH:34][C:26]([S:25][CH3:24])=[CH:27][CH:28]=2)=[O:31])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:16][CH:17]=1
Reactant: CSc1ccc(C(=O)Cl)cc1
Reactant: CCOC(=O)Cc1ccc(F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)c1ccc(SC)cc1)c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
1 N Lithium bis(trimethylsilyl)amide (20 mL, 20 mmol) was added dropwise to a solution of ethyl (4-fluorophenyl)acetate prepared according to the method of Example 1A, (3.84 g, 20 mmol) in THF (20 mL) at −78° C. After 15 minutes the mixture was treated dropwise with a suspension of crude 4-(methylthio)benzoyl chloride (3.7 g, 20 mmol) in THF (50 mL), and the resulting mixture was stirred at −78° C. for 60 minutes. The reaction was quenched with saturated NH4Cl and extracted with ethyl acetate. The acetate layer was washed with water, brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was chromatographed (silica gel, 19:1 CH2Cl2-ethyl acetate) to provide the desired product (yield: 4.55 g; 69%). MS (DCI-NH3) m/z 333 (M+H)+, 350 (M+NH4)+; 1H NMR (300 MHz, CDCl3) δ1.25 (m, 3H), 2.50 (s, 3H), 4.20 (m, 2H), 5.53 (s, 1H), 7.03 (t, J=9 Hz, 2H), 7.22 (d, J=9 Hz, 2H), 7.38 (m, 2H), 7.85 (d, J=9 Hz, 2H).
Reaction SMILES: [Na].[CH3:2][C:3]([CH3:16])([CH:10](Cl)[CH:11]=[C:12]([Cl:14])[Cl:13])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]>C(O)C.C(OCC)C.Cl>[CH3:2][C:3]1([CH3:16])[CH:10]([CH:11]=[C:12]([Cl:14])[Cl:13])[CH:4]1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(C)(C)C(Cl)C=C(Cl)Cl
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)C1C(C=C(Cl)Cl)C1(C)C
Reaction time: 2 h
Yield: 87 %

Procedure:
0.4 Part of metallic sodium was dissolved in 20 parts of anhydrous ethanol, and 2.7 parts of ethyl 3,3-dimethyl-4,6,6-trichloro-5-hexenoate was added to the solution. The mixture was agitated for 2 hours under reflux of ethanol. The liquid reaction mixture was diluted with about 50 parts of diethyl ether and neutralized with dried hydrogen chloride gas. The precipitated crystal of sodium chloride was removed by filtration and low-boiling-point substances were removed from the filtrate by distillation. The residue was then subjected to distillation under reduced pressure to obtain 2.1 parts of ethyl 2,2-dimethyl-3-(2',2'-dichlorovinyl)-cyclopropane-carboxylate having a boiling point of 72° - 73° C. under 0.3 mm Hg. The yield was 87%. The properties of the product were in agreement with those of ethyl 2,2-dimethyl-3-(2',2'-dichlorovinyl)-cyclopropane-carboxylate described in Example 1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C@@:5]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[O:10][C:9](=[O:11])[N:8]([C@H:12]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH3:13])[CH2:7][CH2:6]1.CCN(CC)CC.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>>[CH:14]1([C@@H:12]([N:8]2[CH2:7][CH2:6][C@:5]([CH2:4][CH2:3][CH2:2][NH:1][S:35]([CH3:34])(=[O:37])=[O:36])([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[O:10][C:9]2=[O:11])[CH3:13])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](C1CCCCC1)N1CC[C@](CCCN)(c2ccc(F)cc2)OC1=O
Solvent: CCN(CC)CC
Product: C[C@@H](C1CCCCC1)N1CC[C@](CCCNS(C)(=O)=O)(c2ccc(F)cc2)OC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.1 %

Procedure:
To a solution of (R)-6-(3-aminopropyl)-3-((S)-1-cyclohexylethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (30 mg, 0.10 mmol) was added Et3N (40 mg, 0.4 mmol) and MsCl (30 mg, 0.24 mmol) at 0° C. The reaction solution was stirred at rt for 2 h. The reaction was quenched by H2O and the mixture was extracted with CH2Cl2. The organic phase was concentrated to give the crude product, which was purified by preparative TLC to give N-(3-((R)-3-((S)-1-cyclohexylethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)propyl)methanesulfonamide (11.5 mg, 33%). LC-MS Method 2 tR=1.397 min, m/z=440.9; 1H NMR (CDCl3) 1.04 (d, 6H), 1.13-1.34 (m, 2H), 1.43-1.68 (m, 6H), 1.73-1.98 (m, 3H), 2.03-2.14 (m, 1H), 2.29 (d, 1H), 2.52 (tt, 1H), 2.85 (s, 3H), 2.92-3.08 (m, 3H), 3.68 (m, 1H), 3.88-3.98 (m, 1H), 4.33 (t, 1H), 7.01 (t, 2H), 7.22 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)(=[O:20])=[O:19])[N:11]([CH3:28])[C:10]=1[C:29]([OH:31])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:32]([NH:35]C(C1N(C)C(CNS(C2C=CC=CC=2)(=O)=O)=CC(=O)C=1OCC1C=CC=CC=1)=O)([CH3:34])[CH3:33]>>[CH:32]([NH:35][C:29]([C:10]1[N:11]([CH3:28])[C:12]([CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)(=[O:20])=[O:19])=[CH:13][C:14](=[O:15])[C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:31])([CH3:34])[CH3:33]
Reactant: CC(C)NC(=O)c1c(OCc2ccccc2)c(=O)cc(CNS(=O)(=O)c2ccccc2)n1C
Reactant: Cn1c(CNS(=O)(=O)c2cccc(Cl)c2)cc(=O)c(OCc2ccccc2)c1C(=O)O
Product: CC(C)NC(=O)c1c(OCc2ccccc2)c(=O)cc(CNS(=O)(=O)c2cccc(Cl)c2)n1C
Yield: 55.46 %

Procedure:
3-Benzyloxy-6-[(3-chloro-benzenesulfonylamino)-methyl]-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid isopropylamide (17-05) (363.0 mg, 55.46%) was synthesized as a gummy liquid from 3-benzyloxy-6-[(3-chloro-benzenesulfonylamino)-methyl]-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (13-05) (600.0 mg, 1.29 mmol) following the procedure described for 6-(benzenesulfonylamino-methyl)-3-benzyloxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid isopropylamide (17-01).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([N:14]=[C:15]=[S:16])=[CH:4][CH:3]=1.[NH3:17]>C(O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14][C:15]([NH2:17])=[S:16])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1
Reactant: N
Reactant: Cc1ccc(N=C=S)c(-c2ccccc2)c1
Solvent: CCO
Product: Cc1ccc(NC(N)=S)c(-c2ccccc2)c1

Procedure:
Reaction of 5-methyl-2-biphenylylisothiocyanate (7.5 g) in ethanol (20 ml) with 25% aqueous ammonia solution (60 ml) at ambient temperature for 2 hours yielded N-(5-methyl-2-biphenylyl)thiourea as a colourless solid (m.p. 175°-177° C.).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:9]([C:12]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:13])[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.BrBr.[OH2:25]>C(O)(=O)C>[C:15]1([CH:14]2[C:12](=[O:13])[C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:21])([F:22])[F:1])[CH:4]=3)=[C:10]([NH2:11])[O:25]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: N#CC(C(=O)Cc1ccccc1)c1cccc(C(F)(F)F)c1
Reactant: O
Agent: BrBr
Solvent: CC(=O)O
Product: NC1=C(c2cccc(C(F)(F)F)c2)C(=O)C(c2ccccc2)O1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In this example a solution containing 21.8 g of (3-trifluoromethylphenyl)-benzylcarbonyl-acetonitrile, dissolved in 60 ml of acetic acid was treated dropwise with a solution of 12.65 g of bromine in 20 ml of glacial acetic acid. The reaction mixture was stirred for about 16 hours at room temperature. The reaction mixture was poured into 250 ml of water and the resulting mixture was extracted three times with ethyl ether. The organic extracts were washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate and concentrated in vacuo to yield 8.4 g of white solid which was dried affording 7.0 g of the title compound.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH3:10])=[CH:5][CH:4]=1.[NH2:14][C:15]([NH2:17])=[S:16]>>[NH2:17][C:15]1[S:16][CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=2)[N:14]=1
Reactant: NC(N)=S
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Product: Nc1nc(-c2ccc(C(F)(F)F)cc2)cs1
Yield: 77.5 %

Procedure:
Using 4′-(trifluoromethyl)acetophenone and thiourea as the raw materials, the same operation as the Example 395(1) gave the title compound.
Reaction SMILES: [CH2:1]([S:17][CH2:18][CH:19]([OH:41])[CH2:20][O:21][C:22]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH3:42][N:43]=[C:44]=[O:45]>ClCCl.CN(C)C1C=CN=CC=1>[CH2:1]([S:17][CH2:18][CH:19]([O:41][C:44](=[O:45])[NH:43][CH3:42])[CH2:20][O:21][C:22]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCSCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CN=C=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCSCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OC(=O)NC
Reaction time: 72 h

Procedure:
To a solution of 1-hexadecylthio-3-trityloxy-2-propanol c1 4.6 g (8.0 mmol) in dichloromethane 100 ml are added 4-dimethylaminopyridine 1.17 g (9.6 mmol) and methyl isocyanate 4.72 ml (80 mmol). The solution is allowed to stand at room temperature for 72 hr and concentrated. The residue is chromatographed on SiO2 (46 g) and eluted with ethyl acetate:hexane (1:5) to give 1-hexadecylthio-2-methylcarbamoyloxy-3-trityloxypropane c2 as a crude oil (5.6 g). The oil is dissolved in dichloromethane 100 ml and boron trifluoride-methanol complex 1.68 ml (15.5 mmol) is added under cooling. The resulting yellow solution is stirred at 0° C. for 15 min and then at room temperature for 1 hr. Sodium carbonate aq solution is added to neutralize the reaction mixture and an organic layer is separated. The organic layer is subjected to SiO2 (80 g) column chromatography and eluted with ethyl acetate:hexane (1:1) to afford crude crystals 2.07 g. The crystals are triturated and washed with pentane to yield the titled compound V c1 1.205 g. The mother liquor is purified by Lobar column chromatography with the same solvent as described above to give additional V c1 0.321 g (49% total yield), mp. 53°-55° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].P(Cl)(Cl)(Cl)(Cl)[Cl:18]>>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([Cl:18])=[O:7])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Product: O=C(Cl)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
A mixture of 75.75 gm. (0.307 mole) of 4-chloro-3,5-dinitrobenzoic acid and 64.0 gm. (0.307 mole) of phosphorus pentachloride is heated at reflux for ninety minutes and cooled to room temperature. The phosphorus oxychloride is removed by distillation in vacuo The residue is washed with Skellysolve "B" and the solvent removed by decantation. The oily residue is recrystallized from benzene-cyclohexane. There is obtained 58.2 gm. (72%) of tan needles melting at 55°-57°.
Reaction SMILES: [F:1][C:2]1[C:42]([F:43])=[CH:41][CH:40]=[CH:39][C:3]=1[CH2:4][S:5][C:6]1[N:11]=[C:10]([NH:12][S:13]([N:16]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)(=[O:15])=[O:14])[CH:9]=[C:8]([O:29][C@@H:30]([C@@H:32]2[CH2:36][O:35]C(C)(C)[O:33]2)[CH3:31])[N:7]=1>FC(F)(F)C(O)=O.C(Cl)Cl>[F:1][C:2]1[C:42]([F:43])=[CH:41][CH:40]=[CH:39][C:3]=1[CH2:4][S:5][C:6]1[N:11]=[C:10]([NH:12][S:13]([N:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]2)(=[O:15])=[O:14])[CH:9]=[C:8]([O:29][C@H:30]([CH3:31])[C@@H:32]([OH:33])[CH2:36][OH:35])[N:7]=1
Reactant: C[C@@H](Oc1cc(NS(=O)(=O)N2CCN(C(=O)OC(C)(C)C)CC2)nc(SCc2cccc(F)c2F)n1)[C@@H]1COC(C)(C)O1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](Oc1cc(NS(=O)(=O)N2CCNCC2)nc(SCc2cccc(F)c2F)n1)[C@@H](O)CO

Procedure:
A solution of tert-butyl 4-{[(2-[(2,3-difluorobenzyl)thio]-6-((1R)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethoxy}pyrimidin-4-yl)amino]sulfonyl)piperazine-1-carboxylate (the product of step i) (0.23 g) in 10% trifluoroacetic acid/DCM (5 mL) was stirred at room temperature for 1 h. The mixture was evaporated to dryness in vacuo. The resulting crude oil was purified by reverse phase HPLC (75% to 5% gradient of 0.1% aqueous ammonium acetate in acetonitrile as eluent) to give the title compound as a white solid, Yield: 40 mg.
Reaction SMILES: [C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([O:20]C3C(F)=C(F)C(F)=C(F)C=3F)=O)=[C:14]([F:32])[CH:13]=2)[CH2:7]1)(=[S:3])[CH3:2].[CH3:33][NH2:34]>C1COCC1>[C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([NH:34][CH3:33])=[O:20])=[C:14]([F:32])[CH:13]=2)[CH2:7]1)(=[S:3])[CH3:2]
Reactant: CN
Reactant: CC(=S)NC[C@H]1CN(c2ccc(C(=O)Oc3c(F)c(F)c(F)c(F)c3F)c(F)c2)C(=O)O1
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(N2C[C@H](CNC(C)=S)OC2=O)cc1F
Yield: 80 %

Procedure:
A solution of 5-(S)-thioacetamidomethyl-3-[4′-(pentafluorophenoxy)carbonyl-3′-fluorophe-nyl]oxazolidine-2-one (0.100 g, 0.209 mmol) in 2 M methylamine in THF (1.0 mL) was stirred at r.t. for 1 h. Solvent was removed under vacuum and the residue purified by PTLC (10% MeOH in DCM) to give the pure product as a white solid (0.054 g, 80%). M.p. 176-7° C. MS (m/z): [M+H]+=326.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].C(N(CC)C(C)C)(C)C.Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH:25][C:26]1[CH:38]=[CH:37][C:29]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:28][CH:27]=1)=[O:24]>CN(C)C=O>[OH:5][CH2:4][CH2:3][N:2]([CH3:1])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH:25][C:26]1[CH:38]=[CH:37][C:29]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:28][CH:27]=1)=[O:24]
Reactant: CC(C)(C)OC(=O)c1ccc(NC(=O)CCCCCCCBr)cc1
Reactant: CNCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(CCO)CCCCCCCC(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(methylamino)ethanol (10.7 g, 11.5 ml, 144 mmol, 1.5 equivalents, commercially available e.g. from Aldrich) in dry N,N-dimethylformamide (300 ml) was added N,N-diisopropylethylamine (25 ml, 18.5 g, 144 mmol, 1.5 equivalents). To this mixture was added 1,1-dimethylethyl 4-[(8-bromooctanoyl)amino]benzoate (38.1 g, 96 mmol, 1 equivalent) in dry N,N-dimethylformamide (250 ml) over 12 minutes. The mixture was then heated to and at about 60° C. for 4.25 hours. The mixture was then cooled and the solvent was removed by evaporation using high vacuum to give a golden oil. An attempt to partition this oil between water and ethyl acetate gave a cloudy organic phase and phase separation was poor; an oil separated out as a third layer, some of which was collected and evaporated to give crude product (16.69 g). The remaining emulsion was allowed to stand overnight, giving a clear organic layer which was decanted off, dried (MgSO4) and evaporated to give further crude product as a golden oil (28.11 g). Attempts to further extract the aqueous phase with ethyl acetate or dichloromethane gave an emulsion again, from which further crude product (about 10 g) was finally isolated. The combined crude product was purified by chromatography on silica gel (about 1400 ml of 7734 silica), eluting with 5% methanol in dichloromethane, then 8% methanol in dichloromethane, then 10% methanol in dichloromethane, and finally 20% and 30% methanol in dichloromethane, to afford the title compound as a white foam (28.4 g). LCMS showed MH+=393; TRET=2.52 min.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH3:34][O:35][CH2:36][C:37]([N:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3]1)=[O:38]
Reactant: COCC(=O)Cl
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CCCNC4)c[nH]c23)cc1F
Agent: Cl
Product: COCC(=O)N1CCC[C@H](NC(=O)c2c[nH]c3c(-c4cc(F)c(OC)cc4OCC4CC4)ncnc23)C1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (S)-piperidin-3-ylamide hydrochloride (example A168) and methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[CH:8][N:9]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:10](B(O)O)=[C:6]2[C:5](=[O:22])[N:4]([CH3:23])[C:3]1=[O:24].Br[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1>>[F:32][C:28]1[CH:27]=[C:26]([C:10]2[N:9]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:8]=[C:7]3[C:6]=2[C:5](=[O:22])[N:4]([CH3:23])[C:3](=[O:24])[N:2]3[CH3:1])[CH:31]=[CH:30][CH:29]=1
Reactant: Fc1cccc(Br)c1
Reactant: Cn1c(=O)c2c(B(O)O)n(COCC[Si](C)(C)C)cc2n(C)c1=O
Product: Cn1c(=O)c2c(-c3cccc(F)c3)n(COCC[Si](C)(C)C)cc2n(C)c1=O

Procedure:
The title compound was prepared from 1,3-dimethyl-2,4-dioxo-6-((2-(trimethylsilyl)ethoxy)methyl)-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-d]pyrimidin-5-ylboronic acid (Example 9, step 2) and 1-bromo-3-fluorobenzene by a similar method to Example 9 step 3;
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[NH:22][C:23](=[O:37])[C:24]4[C:29]([CH:30]=3)=[C:28]([C:31]#[C:32][Si](C)(C)C)[CH:27]=[CH:26][CH:25]=4)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[NH:22][C:23](=[O:37])[C:24]4[C:29]([CH:30]=3)=[C:28]([C:31]#[CH:32])[CH:27]=[CH:26][CH:25]=4)=[CH:17][CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(-c3cc4c(C#C[Si](C)(C)C)cccc4c(=O)[nH]3)cc2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1cccc2c(=O)[nH]c(-c3ccc(CN4CCN(C(=O)OC(C)(C)C)CC4)cc3)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a stirred solution of 4-[4-(1-oxo-5-trimethylsilanylethynyl-1,2-dihydroisoquinolin-3-yl)benzyl]piperazine-1-carboxylic acid tert-butyl ester compound (70.0 mg, 0.136 mmol) in THF (5 mL) was added TBAF (1M in THF, 272 μL, 0.272 mmol). The resulting reaction mixture was stirred at RT for 2 h and then quenched by the addition of water (20 mL). The mixture was extracted with EtOAc (3×20 mL) and the combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo to obtain 4-[4-(5-ethynyl-1-oxo-1,2-dihydroisoquinolin-3-yl)benzyl]piperazine-1-carboxylic acid tert-butyl ester (60.3 mg, 100%) as an orange solid. The crude compound was used for the next step without further purification.