Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(Cl)=O.C(=O)([O-])[O-].[K+].[K+].C1(C(C2C=CC=CC=2)[N:18]2CC(OC3C=CC=C(C(F)(F)F)C=3)C2)C=CC=CC=1.[F:39][C:40]([F:56])([F:55])[C:41]1[CH:42]=[C:43]([CH:52]=[CH:53][CH:54]=1)[O:44][CH:45]1[CH2:48][N:47]([C:49](Cl)=[O:50])[CH2:46]1.C1(C(C2C=CC=CC=2)Cl)C=CC=CC=1.N>C1(C)C=CC=CC=1>[F:39][C:40]([F:56])([F:55])[C:41]1[CH:42]=[C:43]([CH:52]=[CH:53][CH:54]=1)[O:44][CH:45]1[CH2:48][N:47]([C:49]([NH2:18])=[O:50])[CH2:46]1
Reactant: FC(F)(F)c1cccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)c1
Reactant: O=C(Cl)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Agent: ClC(c1ccccc1)c1ccccc1
Agent: N
Agent: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: NC(=O)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Reaction time: 0.5 h

Procedure:
A 16 ml solution containing 5.94 g of phosgene was prepared by dissolving phosgene gas in cold toluene. This solution was stirred with 7 g potassium carbonate in an acetone-ice bath for about 10 minutes. To this solution in the bath was added dropwise over a 13 minute period at -9° C. to +4° C. a solution of 19.2 g (0.050 mole) of 1-(diphenylmethyl)-3-[3-(trifluoromethyl)phenoxy]azetidine in 38.4 ml of toluene. The cold bath was removed and the temperature of the reaction mixture rose to 18° C. after 1/2 hr. TLC (silica gel eluted with methylene chloride) of a sample indicated all the 1-(diphenylmethyl)-3-[3(trifluoromethyl)phenoxy]azetidine had disappeared (reacted). After 1 hr, the mixture was filtered to remove solid, leaving a filtrate containing 3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarbonyl chloride and diphenylchloromethane. The filtrate was added (over a 7 min period) to about 30 ml of liquid ammonia at -60°to -30° C. Some white solid formed in the mixture. The ammonia was refluxed under a dry ice-acetone condenser for 1/2 hr and then allowed to evaporate using nitrogen gas to facilitate the removal of ammonia. Petroleum ether (60 ml) was added to the mixture and the resulting white solid was collected by filtration and rinsed twice with petroleum ether to give 18.1 g of solid. The solid was stirred in 90 ml of water at room temperature for one hr, filtered off, rinsed twice with water and dried under vacuum at about 60° C. for 2 hr to give 13 g (100%) of title compound.
Reaction SMILES: C[O:2][C:3]1[CH:30]=[CH:29][C:6]([C:7]([C:9]23[CH2:18][CH:13]4[CH2:14][CH:15]([CH2:17][C:11]([C:19](=[O:28])[C:20]5[CH:25]=[CH:24][C:23]([O:26]C)=[CH:22][CH:21]=5)([CH2:12]4)[CH2:10]2)[CH2:16]3)=[O:8])=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1>>[OH:2][C:3]1[CH:30]=[CH:29][C:6]([C:7]([C:9]23[CH2:16][CH:15]4[CH2:14][CH:13]([CH2:12][C:11]([C:19](=[O:28])[C:20]5[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=5)([CH2:17]4)[CH2:10]2)[CH2:18]3)=[O:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)C23CC4CC(C2)CC(C(=O)c2ccc(OC)cc2)(C4)C3)cc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(c1ccc(O)cc1)C12CC3CC(C1)CC(C(=O)c1ccc(O)cc1)(C3)C2
Temperature: 225 °C

Procedure:
11.0 g (0.0272 mole) of 1,3-bis(4-methoxybenzoyl)adamantane was placed in a 250 ml round-bottomed flask fitted with a reflux condenser, along with 31.5 g (0.272 mole) of pyridine hydrochloride. The slurry was heated to 225° C. for three hours and the product was precipitated in 40 ml concentrated HCl diluted with 200 ml water. The solid was filtered and dried. The solid was recrystallized from ethyl acetate. The isolated yield of the purified compound was 6.6 g (64%, melting point 208–209° C.).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.Cl[CH:15]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23][NH:24][C:25](=[O:27])[CH3:26])=[CH:19][CH:18]=1)[CH3:16]>>[F:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH:15]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][NH:24][C:25](=[O:27])[CH3:26])=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)NCc1ccc(C(C)Cl)cc1
Reactant: Fc1cccc(N2CCNCC2)n1
Product: CC(=O)NCc1ccc(C(C)N2CCN(c3cccc(F)n3)CC2)cc1

Procedure:
By similar reaction and treatment to that in Example 1(5) using 1-(6-fluoropyridin-2-yl)piperazine instead of phenylpiperazine and N-((4-(1-chloroethyl)phenyl)methyl)acetamide instead of N-(4-chloromethylphenylmethyl)acetamide, the title compound can be obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:15][C:16]2[CH:23]=[CH:22][C:19]([CH:20]=O)=[C:18]([Cl:24])[CH:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OP([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])(OCC)=O)C.C(=O)(O)[O-].[K+].C(=O)(O)[O-].[Na+].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Na+].[Na+]>O.CS(C)=O.CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:15][C:16]2[CH:23]=[CH:22][C:19]([CH:20]=[CH:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:18]([Cl:24])[CH:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=Cc1ccc(Sc2cccc(OCc3ccccc3)c2)cc1Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1ccc(Sc2cccc(OCc3ccccc3)c2)cc1Cl

Procedure:
A mixture of 4-(3-benzyloxyphenylthio)-2-chlorobenzaldehyde (1) and ethyl diethylphosphonoacetate (2) is stirred for 3 to 8 hours at 50 to 80° C. in an organic solvent, such as dimethylformamide or dimethylsulfoxide, in the presence of a base, such as potassium bicarbonate, sodium bicarbonate, potassium carbonate or sodium carbonate. Subsequently, the reaction mixture is chilled in an ice water bath while being stirred and water is added. The resulting crystals are collected by filtration and washed with aqueous 2-propanol to give ethyl 3-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]acrylate (3) as crude crystals. This product is dissolved in ethylacetate and the mixture was washed with water. The organic layer is concentrated under reduced pressure to obtain a pale yellow oil. To this product, acetone is added and the mixture is stirred while being chilled to form crystals (Crystal seeds are added when necessary). Water is then added and the mixture is stirred while being chilled. The resulting crystals are collected by filtration and washed with acetone-water. The crystals are then dried at 40° C. or below to give ethyl 3-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]acrylate (3) or a hydrate thereof.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:17])C1=S)[CH:2]=[CH2:3].[CH:19]1(N)CCC1>O>[Cl:16][C:15]1[C:10]([NH:6][CH2:7][CH2:8][CH2:9][NH:4][CH:1]2[CH2:2][CH2:3][CH2:19]2)=[C:11]([CH3:17])[CH:12]=[CH:13][CH:14]=1
Reactant: NC1CCC1
Reactant: C=CCN1CCCN(c2c(C)cccc2Cl)C1=S
Solvent: O
Product: Cc1cccc(Cl)c1NCCCNC1CCC1
Temperature: 90 °C
Yield: 51.5 %

Procedure:
A mixture of the hydrobromide salt of Example 12, Step B (6.64 g) and cyclobutylamine (4.15 g) was heated at 90° C. for 1.5 hours. The cooled mixture was diluted with water and extracted with dichloromethane. The extracts were washed with 20% aqueous sodium chloride, dried over anhydrous potassium carbonate and evaporated to a brown oil, which was flash chromatographed on Merck-60 flash silica gel (eluant: hexane-EtOAc 1:1 to remove less polar impurities, followed by dichloromethane-methanol-ammonium hydroxide 95:5:0.1) to provide the title compound (3.08 g, 63.5%), which was used as such in the next step.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([NH:11][C:12](=[O:15])[O:13][CH3:14])[CH:7]=[CH:8][C:9]=1[OH:10].Br[CH2:17][C:18]1[S:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1.[Cl-].[NH4+]>CN(C)C=O>[S:19]1[C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=[C:18]1[CH2:17][O:10][C:9]1[CH:8]=[CH:7][C:6]([NH:11][C:12](=[O:15])[O:13][CH3:14])=[CH:5][C:4]=1[Cl:3]
Reactant: BrCc1nc2ccccc2s1
Reactant: COC(=O)Nc1ccc(O)c(Cl)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)Nc1ccc(OCc2nc3ccccc3s2)c(Cl)c1
Reaction time: 0.05 h
Yield: 81.4 %

Procedure:
44.4 mg of sodium hydride (as a 60% w/w dispersion in mineral oil) were added to a solution of 203.6 mg of methyl N-(3-chloro-4-hydroxyphenyl)carbamate [prepared as described in step (a) above] in 4 ml of dimethylformamide cooled in an ice-water bath. The resulting mixture was stirred at the same temperature for 3 minutes, and then 241.9 mg of 2-bromomethylbenzothiazole were added. The temperature of the reaction mixture was then elevated to room temperature and the mixture was stirred for 1.5 hours. At the end of this time, a saturated aqueous ammonium chloride solution was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The resulting extract was washed consecutively with water and a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure to give a crude crystalline solid which was purified by column chromatography through silica gel using a 2:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 286.9 mg (yield 81%) of the title compound as a solid having a melting point of 133°-135° C.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[S:4][CH2:3]1.[CH2:14]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([CH2:30][CH2:31][CH2:32][CH2:33][C:34](=O)[C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:26][CH2:25]1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[CH2:14]([O:21][C:22]([N:24]1[CH2:25][CH2:26][CH:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH:34]([NH:1][C@@H:2]2[C:8](=[O:9])[NH:7][C:6]3[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=3[S:4][CH2:3]2)[C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:28][CH2:29]1)=[O:23])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: N[C@H]1CSc2ccccc2NC1=O
Reactant: CCOC(=O)C(=O)CCCCC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C(CCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@H]1CSc2ccccc2NC1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 38.6 %

Procedure:
A mixture of 3(R)-amino-2,3-dihydro-1,5-(5H)-benzothiazepin-4-one (1.0 g), ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-oxohexanoate (6.0 g), acetic acid (0.37 g), molecular sieves 3A (3.0 g) and ethanol (25 ml) is stirred at room temperature for 20 minutes. To the stirred mixture is added dropwise a solution of sodium cyanoborohydride (0.66 g) in ethanol (20 ml) over a period of 5 hours. After the reaction mixture is concentrated under reduced pressure, the residue is diluted with a mixture of ethyl acetate (80 ml) and water (100 ml). After the insoluble substance is removed by filtration, the ethyl acetate layer is washed with diluted hydrochloric acid, water and sodium bicarbonate solution successively, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to yield 3(R)-[5-(1-benzyloxycarbonyl-4-piperidyl)-1-ethoxycarbonylpentyl]amino-2,3-dihydro-1,5(5H)-benzothiazepin-4-one (1.1 g) as a colorless oil.
Reaction SMILES: [CH2:1]([C:3]1([CH2:13][C:14]([OH:21])([C:17]([F:20])([F:19])[F:18])[CH2:15][OH:16])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1)[CH3:2].C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl.CS(C)=O>[CH2:1]([C:3]1([CH2:13][C:14]([OH:21])([C:17]([F:19])([F:18])[F:20])[CH:15]=[O:16])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1)[CH3:2]
Reactant: CCC1(CC(O)(CO)C(F)(F)F)CCCc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCC1(CC(O)(C=O)C(F)(F)F)CCCc2ccccc21
Temperature: 25 °C
Reaction time: 65 h

Procedure:
To a solution of 2-[(1-ethyl-1,2,3,4-tetrahydro-1-naphthalenyl)methyl]-3,3,3-trifluoro-1,2-propanediol (Intermediate 16) (2.03 g, 6.71 mmol) in anhydrous dichloromethane (50 ml), anhydrous dimethylsulphoxide (50 ml) and triethylamine (5.9 ml, 42 mmol) stirred under nitrogen in an ice-water bath at 9° C., was added pyridine-sulphur trioxide complex (5.37 g, 33 mmol) portionwise over 20 min. The solution was then allowed to warm to room temperature and stirred for 65 h. The reaction mixture was added to aqueous ammonium chloride solution (350 ml) and extracted into dichloromethane (×2). The combined organic layers were washed successively with water (2×200 ml) and saturated brine (2×200 ml), dried over anhydrous magnesium sulphate and evaporated in vacuo. The brown oil obtained was applied to a 50 g silica SPE cartridge eluting with 0 to 100% dichloromethane in heptane gradient to give the title compound as a mixture of diastereomers (380 mg, 19%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH:47]1([CH2:50][NH:51][C:52]([C:54]2[N:55]=[C:56]([C:63]([F:66])([F:65])[F:64])[N:57]3[CH2:62][CH2:61][NH:60][CH2:59][C:58]=23)=[O:53])[CH2:49][CH2:48]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:47]1([CH2:50][NH:51][C:52]([C:54]2[N:55]=[C:56]([C:63]([F:64])([F:65])[F:66])[N:57]3[CH2:62][CH2:61][N:60]([C:4](=[O:5])[C:3]4[CH:7]=[C:8]([CH2:11][C:12]5[C:21]6[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=6)[C:15](=[O:22])[NH:14][N:13]=5)[CH:9]=[CH:10][C:2]=4[F:1])[CH2:59][C:58]=23)=[O:53])[CH2:49][CH2:48]1
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: O=C(NCC1CC1)c1nc(C(F)(F)F)n2c1CNCC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC1CC1)c1nc(C(F)(F)F)n2c1CN(C(=O)c1cc(Cc3n[nH]c(=O)c4ccccc34)ccc1F)CC2
Reaction time: 12 h
Yield: 30.3 %

Procedure:
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (300 mg, 1 mmol) was dissolved in 5 mL of N,N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (756 mg, 2 mmol), crude N-(cyclopropylmethyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide 24c (250 mg, 0.87 mmol) and N, N-diisopropylethylamine (0.5 mL, 3 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain N-(cyclopropylmethyl)-7-[2-fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoyl]-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-1-carboxamide 24 (150 mg, yield 30.0%) as a light yellow solid.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][C:11](=[O:13])[CH2:10][CH:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[Si](C)(C)C.[CH2:25](O)[CH2:26][OH:27]>>[CH2:26]1[O:27][C:11]2([CH2:12][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[NH:8][CH:9]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:10]2)[O:13][CH2:25]1
Reactant: O=C1CC(c2ccccc2)NC(c2ccccc2)C1
Reactant: OCCO
Agent: C[Si](C)(C)Cl
Product: c1ccc(C2CC3(CC(c4ccccc4)N2)OCCO3)cc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 69 %

Procedure:
To a stirred suspension of 10.0 g (40 mmol) of 2,6-diphenyl-4-piperidone in 150 mL of ethylene glycol chilled to 0° C. is added 35 mL (275 mmol) of chlorotrimethylsilane over a one-hour period. The reaction mixture is warmed to room temperature and stirred for 15 hours. The reaction mixture is then quenched by carefully pouring it into 600 mL of saturated aqueous sodium bicarbonate solution. The product is extracted into ether (4×200 mL). The ether solution is dried over anhydrous sodium sulfate and the solvent is removed under reduced pressure. The residue is recrystallized from methanol to yield 8.1 g (69%) of the title compound as a white solid, melting at 125°-127° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9](Br)[C:8]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:14][C:7]=2[C:6]=1[OH:21])=[O:4].[CH2:22]([Sn](CC)(CC)CC)[CH3:23]>>[CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9]([CH2:22][CH3:23])[C:8]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:14][C:7]=2[C:6]=1[OH:21])=[O:4]
Reactant: CC[Sn](CC)(CC)CC
Reactant: COC(=O)c1nc(Br)c2nc(-c3ccccc3)oc2c1O
Product: CCc1nc(C(=O)OC)c(O)c2oc(-c3ccccc3)nc12

Procedure:
Prepared from 4-bromo-7-hydroxy-2-phenyl-oxazolo[4,5-c]pyridine-6-carboxylic acid methyl ester, example 3a, and tetraethyltin under conditions analogous to example 3b. MS: (+) m/z 299.1 (M+1).
Reaction SMILES: [H-].[Na+].[CH:3]1([O:7][CH2:8][C@H:9]([OH:20])[C:10]([NH:12][C:13]2[CH:18]=[N:17][C:16]([CH3:19])=[CH:15][N:14]=2)=[O:11])[CH2:6][CH2:5][CH2:4]1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]2[N:28]([C:31]3[C:36]([C:37]([F:40])([F:39])[F:38])=[CH:35][C:34]([Cl:41])=[CH:33][N:32]=3)[N:29]=[CH:30][C:23]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Cl:41][C:34]1[CH:35]=[C:36]([C:37]([F:40])([F:38])[F:39])[C:31]([N:28]2[C:24]3[N:25]=[CH:26][N:27]=[C:22]([O:20][C@@H:9]([CH2:8][O:7][CH:3]4[CH2:6][CH2:5][CH2:4]4)[C:10]([NH:12][C:13]4[CH:18]=[N:17][C:16]([CH3:19])=[CH:15][N:14]=4)=[O:11])[C:23]=3[CH:30]=[N:29]2)=[N:32][CH:33]=1
Reactant: FC(F)(F)c1cc(Cl)cnc1-n1ncc2c(Cl)ncnc21
Reactant: Cc1cnc(NC(=O)[C@@H](O)COC2CCC2)cn1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cnc(NC(=O)[C@H](COC2CCC2)Oc2ncnc3c2cnn3-c2ncc(Cl)cc2C(F)(F)F)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 100.2 %

Procedure:
60% Sodium hydride in mineral oil (60 mg, 1.50 mmol) was added in one portion to (S)-3-cyclobutoxy-2-hydroxy-N-(5-methylpyrazin-2-yl)propanamide (Intermediate R1) (251 mg, 1.00 mmol) in anhydrous THF (5 mL) at 0° C. under nitrogen. The resulting suspension was stirred at 0° C. for 10 minutes and then 4-chloro-1-(5-chloro-3-(trifluoromethyl)pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate K3) (334 mg, 1.00 mmol) as suspension in dry THF (2.5 mL) added dropwise over 1 minute. The mixture was stirred at 0° C. for 15 mins, allowed to warm to ambient temperature and stirred for 6 hours. 1M Citric acid (10 mL) was added and the mixture extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with water (25 mL) and brine (25 mL), dried (MgSO4) and evaporated. The residue was purified by flash silica chromatography, eluting with 50 to 100% ethyl acetate in isohexane to give the product (550 mg, 100%). 1H NMR (400 MHz, CDCl3) δ 1.46-1.54 (1H, m), 1.66-1.74 (1H, m), 1.89-2.01 (2H, m), 2.18-2.25 (2H, m), 2.54 (3H, s), 3.98-4.08 (3H, m), 6.04 (1H, t), 8.12 (1H, d), 8.25 (1H, d), 8.43 (1H, s), 8.62 (1H, s), 8.63-8.65 (1H, m), 8.82 (1H, d), 9.44 (1H, d); m/z (ESI+) (M+H)+=549; HPLC tR=2.56 min.
Reaction SMILES: [O:1]=[C:2]([N:40]1[C@@H:44]([CH:45]([CH3:47])[CH3:46])[CH2:43][O:42][C:41]1=[O:48])[C@H:3]([CH2:15][C:16]1[N:17]=[CH:18][N:19]([C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=1)[CH2:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].BrCC(OCC1C=CC=CC=1)=O>C1COCC1>[O:1]=[C:2]([N:40]1[C@@H:44]([CH:45]([CH3:46])[CH3:47])[CH2:43][O:42][C:41]1=[O:48])[CH:3]([CH2:15][C:16]1[N:17]=[CH:18][N:19]([C:21]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:20]=1)[CH2:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)[C@H]1COC(=O)N1C(=O)[C@@H](CC(=O)OCc1ccccc1)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C(CBr)OCc1ccccc1
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)[C@H]1COC(=O)N1C(=O)C(CC(=O)OCc1ccccc1)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
3{1,4-Dioxo-4-(phenylmethoxy)-2(R) -{[1-(triphenylmethyl)-1H-imidazol-4-yl]methyl}butyl}-4(S)-(1-methylethyl)-2-oxazolidinone: A 1.0M solution of sodium bis(trimethylsilyl)amide (18.0 mL, 18.0 mmol, Aldrich Chemical Co., Inc., Milwaukee, Wis., USA) was added dropwise (18 min) to a cold (-78°) solution of the product of the preceding section (8.06 g, 16.3 mmol) in THF (65 mL). After 40 min at -78°, to a solution of benzyl 2-bromoacetate (7.48 g, 32.7 mmol) in THF (2 mL) was added dropwise to the solution. The reaction mixture was stirred at -78°for 1.5 h, quenched with an aqueous saturated solution of NH4Cl, allowed to warm to room temperature and then poured into a mixture of H2O (500 mL) and aqueous saturated solution of NH4Cl (100 mL). The resulting mixture was extracted with EtOAc. The EtOAc extract was washed with a saturated aqueous solution of NaHCO3 and then brine, dried (MgSO4) and concentrated under reduced pressure to give 3-{1,4-dioxo-4-(phenylmethoxy)-2-{[1-(triphenylmethyl)-1H-imidazol-4-yl]methyl}butyl}-4(S)-(1-methylethyl)-2-oxazolidinone as a mixture of 2(R)- and 2(S)-epimers in a 8 to 1 ratio by weight. Separation of the epimers by flash chromatography (SiO2, eluent: hexane-EtOAc, 1:2) yielded the desired 2(R)-epimer (Rf=0.25, eluent: hexane-EtOAc,1:2). The 1H NMR (CDCl3) of the 2(R)-epimer showed δ7.34-7.28 (m, 15H), 7.13-7.08 (m, 6H), 6.59 (d, J=1.3 Hz, 1H), 5.06 (s,2H), 4.55-4.45 (m, 1H), 4.38 (td, J=3.9 Hz,5.4 Hz, 1H), 4.15-4.10 (m,2H), 2.97 (dd, J=10.3 Hz,16.9 Hz, 1H), 2.88 (dd, J=6.3 Hz,14.3 Hz, 1H), 2.73 (dd, J=7.0 Hz,14.3 Hz, 1H), 2.59 (dd, J=4.4 Hz,16.9 Hz, 1H), 2.32 (hept d, J=3.9 Hz,7.0 Hz, 1H), 0.87 (d, J=7.1 Hz, 3H), 0.85 (d, J=6.8 Hz, 3H).
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[NH:8][C:7]1=[S:16])[CH2:2][CH2:3][CH2:4][CH3:5].S(OC)(O[CH3:21])(=O)=O.C(O)(=O)C>[OH-].[Na+].O>[CH3:21][S:16][C:7]1[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[N:8]=1
Reactant: CCCCCn1c(=S)[nH]c(=O)c2[nH]cnc21
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CCCCCn1c(SC)nc(=O)c2[nH]cnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.9 %

Procedure:
To a solution of 3-pentyl-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one (13.0 g, 54.6 mmol) in 2 M of sodium hydroxide in water (250 mL) was added dimethyl sulfate (6.2 mL, 66 mmol), and the reaction mixture was stirred at room temperature for 1 hour, then neutralized with acetic acid. The precipitate was collected by filtration and recrystallized from ethyl acetate-MeOH (1:1) to give the desired product (5.50 g, 40%). LCMS calculated for C11H17N4OS (M+H): 253.1. Found: 253.1.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4]1.Cl[C:10]1[N:15]=[CH:14][CH:13]=[CH:12][N:11]=1>>[N:11]1[CH:12]=[CH:13][CH:14]=[N:15][C:10]=1[O:1][CH2:2][C:3]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4]1
Reactant: Clc1ncccn1
Reactant: OCC1(CO)CCC1
Product: OCC1(COc2ncccn2)CCC1

Procedure:
The title compound was prepared using the same experimental procedure as in example 25a from [1-(hydroxymethyl)cyclobutyl]methanol and 2-chloropyrimidine. 1H NMR (300 MHz, CDCl3) δ 8.50-8.47 (m, 2H), 6.95-6.89 (m, 1H), 4.48 (s, 2H), 3.63 (d, J=6 Hz, 2H), 3.02 (t, J=6 Hz, 1H), 2.01-1.78 (m, 6H). GC-MS m/z 195 (M+H).
Reaction SMILES: [C:1]1([C:7]2[N:11]3[CH2:12][CH2:13][N:14](C(OC(C)(C)C)=O)[CH2:15][C:10]3=[C:9]([C:23](=[O:35])[NH:24][CH:25]3[C:30]([CH3:32])([CH3:31])[CH:29]4[CH2:33][C:26]3([CH3:34])[CH2:27][CH2:28]4)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:36]>C(Cl)Cl>[ClH:36].[C:1]1([C:7]2[N:11]3[CH2:12][CH2:13][NH:14][CH2:15][C:10]3=[C:9]([C:23]([NH:24][CH:25]3[C:30]([CH3:31])([CH3:32])[CH:29]4[CH2:33][C:26]3([CH3:34])[CH2:27][CH2:28]4)=[O:35])[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCn2c(-c3ccccc3)nc(C(=O)NC3C4(C)CCC(C4)C3(C)C)c2C1
Agent: Cl
Solvent: ClCCl
Product: CC12CCC(C1)C(C)(C)C2NC(=O)c1nc(-c2ccccc2)n2c1CNCC2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a cooled (0° C.) and stirred solution of Compound 30 (0.5 g, 1.04 mmol) in dry DCM (10 mL) was added hydrogen chloride [4M in 1,4-dioxane] (5.2 mL, 20.8 mmol). The mixture was warmed to ambient temperature and left to stir overnight (with a calcium chloride drying tube). The reaction solvents were removed under reduced pressure, and the residue was azeotroped twice with methanol and diethyl ether to give the title compound as a white solid in quantitative yield. LCMS (+ESI) m/z 379.36 [M+H]+.