Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1]CC(C1C=CC=CC=1)C(=O)C.CO[C:15](OC)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=CC=1)=[O:17].C(C1C=CC(C(=O)C(O)(C)C)=CC=1)(C)C.C(C1C=CC(C(=O)C(O)(C)C)=CC=1)CCCCCCCCCCC.C(O[C:74]([O:89]CC)([C:83]1[CH:88]=[CH:87][CH:86]=[CH:85]C=1)[C:75]([C:77]1[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=1)=O)C>>[OH:17][C:16]1[C:15]([CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)=[C:21]([C:85]([C:86]2[CH:87]=[CH:88][CH:83]=[C:74]([OH:89])[C:75]=2[CH:77]2[CH2:78][CH2:79][CH2:80][CH2:81][CH2:82]2)=[O:1])[CH:22]=[CH:23][CH:18]=1
Reactant: CCOC(OCC)(C(=O)c1ccccc1)c1ccccc1
Reactant: CC(=O)C(CO)c1ccccc1
Reactant: COC(OC)(C(=O)c1ccccc1)c1ccccc1
Agent: CC(C)c1ccc(C(=O)C(C)(C)O)cc1
Agent: CCCCCCCCCCCCc1ccc(C(=O)C(C)(C)O)cc1
Product: O=C(c1cccc(O)c1C1CCCCC1)c1cccc(O)c1C1CCCCC1

Procedure:
hydroxymethylphenylpropanone; dimethoxyphenylacetophenone; 2-methyl-1-[4-(methylthio)phenyl]-2-morpholino-propanone-1; 1-(4-isopropylphenyl)-2-hydroxy-2-methylpropan-1-one; 1- (4-dodecylphenyl) -2-hydroxy-2-methylpropan-1-one; 4-(2-hydroxyethyoxy)phenyl-2(2-hydroxy-2-propyl)ketone;diethoxyphenyl acetophenone; and mixtures of these.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][CH2:5][NH2:6].[C:7]([O:11][C:12](=O)[O:13]C(C)(C)C)([CH3:10])([CH3:9])[CH3:8].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O>[C:7]([O:11][C:12]([NH:6][CH2:5][CH2:4][CH2:3][Cl:2])=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: NCCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCCCCl
Temperature: 0 °C

Procedure:
The compound of the title, employed as the starting material in example 1, is prepared by slowly adding a solution of 3-chloro-propylamine hydrochloride (12.98 g, 0.1 mol) in dioxane/water (100 ml 2/1 v/v) to a vigorously stirred mixture of di-(tert-butyl)carbonate (24 g, 0.11 mol), 1N Na2CO3 (100 ml) and dioxane/water (200 ml, 2/1 v/v) cooled to 0° C. When the addition is over, the reaction mixture is stirred at room temperature for an additional hour, dioxane is removed under vacuum and the aqueous phase is extracted a few times with ethyl acetate.
Reaction SMILES: S(Cl)([Cl:3])=O.Cl.[NH2:6][CH2:7][C:8]([F:13])([F:12])[C:9]([OH:11])=[O:10].[CH2:14](O)[CH3:15]>>[ClH:3].[NH2:6][CH2:7][C:8]([F:13])([F:12])[C:9]([O:11][CH2:14][CH3:15])=[O:10]
Reactant: NCC(F)(F)C(=O)O
Reactant: O=S(Cl)Cl
Reactant: CCO
Agent: Cl
Product: CCOC(=O)C(F)(F)CN
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To ethanol (12.0 mL), thionyl chloride (0.587 mL) was added at 0° C. and the mixture was stirred at that temperature for 30 minutes. After adding 3-amino-2,2-difluoropropionic acid hydrochloride (950 mg) at 0° C., the mixture was refluxed for 4 hours. After being cooled to room temperature, the mixture was concentrated under reduced pressure. After adding ethyl acetate, the resulting precipitate was removed by filtration. The filtrate was concentrated under reduced pressure to give the titled compound as a pale brown oil (920 mg).
Reaction SMILES: [C:1]1([CH:7]([C:14]([OH:16])=O)[CH2:8][C@@H:9]([C:11]([OH:13])=O)[NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]1(=O)[O:22][C:20](=[O:21])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.[NH2:28]C(N)=O.C(OC(=O)C)(=O)C>N1C=CC=CC=1.C(O)C>[C:1]1([CH:7]2[C:14](=[O:16])[NH:28][C:11](=[O:13])[CH:9]([N:10]3[C:20](=[O:21])[C:19]4[C:18](=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:17]3=[O:22])[CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: N[C@@H](CC(C(=O)O)c1ccccc1)C(=O)O
Reactant: NC(N)=O
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCO
Product: O=C1NC(=O)C(N2C(=O)c3ccccc3C2=O)CC1c1ccccc1
Yield: 79.8 %

Procedure:
3.00 g (12 mmoles) 4-phenylglutamic acid and 2.12 g (14 mmoles) phthalic anhydride were heated for 6 hours under reflux in 40 ml of dry pyridine. After removing the solvent by distillation, the residue was taken up in 50 ml of 5% HCl and extracted with ethyl acetate. The organic phase was washed with water, decolourised with activated carbon and dried over sodium sulphate. After removing the solvent by distillation, the residue was heated under reflux for 1 hour in 40 ml acetic anhydride. The solution was subsequently concentrated and treated with ether. The precipitate formed was filtered off under suction and was recrystallised from dry toluene. 2.00 g (6 mmoles) of the crystalline material and 0.19 g (3 mmoles) urea were fused on an oil bath at about 200° C. for 30 minutes. The solidified melt was heated briefly to boiling, with 4 ml acetic anhydride and 8 ml ethanol in succession. The precipitated solid was recrystallised from DMF/water. 0.80 g (40% theoretical) 2-(5-phenyl-2,6-dioxo-piperidin-3-yl)-1,3-dihydro-2H-isoindole-1,3-dione (2) were obtained, with a melting point of 228 to 231° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([CH2:18][N:19]3C(=O)C4C(=CC=CC=4)C3=O)[C:12]=2[F:30])[CH:9]=1)[C:5]#[N:6].O.NN>CO>[NH2:19][CH2:18][C:13]1[C:12]([F:30])=[C:11]([O:10][C:8]2[CH:7]=[C:4]([CH:3]=[C:2]([Cl:1])[CH:9]=2)[C:5]#[N:6])[C:16]([Cl:17])=[CH:15][CH:14]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN3C(=O)c4ccccc4C3=O)c2F)c1
Agent: NN
Solvent: CO
Solvent: O
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reaction time: 2 h
Yield: 822.2 %

Procedure:
3-Chloro-5-({6-chloro-3-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-2-fluorophenyl}oxy)benzonitrile (1.9 g, 4.3 mmol) was dissolved in MeOH (50 mL) and hydrazine monohydrate (0.63 mL, 12.9 mmol) was added. The reaction mixture was placed in an oil bath at 60° C. and stirred for 2 h. Another portion of hydrazine monohydrate (0.63 mL, 12.9 mmol) was added and the reaction was stirred for 1 h. Purification was accomplished by column chromatography (CH2Cl2/MeOH) to afford the title compound (11 g, 82%).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH:22]=[O:23]>S(=O)(=O)(O)O>[CH2:28]([O:27][C:26]1[CH:25]=[CH:24][C:21]([CH:22]([OH:23])[C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)=[CH:20][C:19]=1[O:18][CH3:17])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: COc1cc(C=O)ccc1OCc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Product: COc1cc(C(O)c2ccc(C(F)(F)F)cc2)ccc1OCc1ccccc1
Reaction time: 0.75 h

Procedure:
92 ml of n-butyl lithium solution (1.6M in hexane) are added dropwise at -70° within 20 minutes to 33.0 g of 4-bromobenzotrifluoride (dissolved in 150 ml of tetrahydrofuran). After stirring at -70° for 45 minutes, 36 g of 3-methoxy-4-benzyloxybenzaldehyde (dissolved in 100 ml of tetrahydrofuran) are added dropwise thereto at between -70° and -60°. The reaction mixture is stirred at -70° for 2 hours and at 0° for 1 hour, poured into a mixture of ice and 100 ml of 2N sulfuric acid and extracted twice with 500 ml of ether. The combined ether phases are washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated. There is obtained 4-(benzyloxy)-3-methoxy-4'-(trifluoromethyl)benzhydrol which can be used directly in the subsequent reaction step.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[CH:4]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[CH2:26]([Br:36])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>>[Br-:36].[CH2:26]([N+:8]1[CH:9]=[CH:10][N:6]([CH2:5][CH:4]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[C:3]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:2]=2[Cl:1])[CH:7]=1)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: Clc1ccc(COC(Cn2ccnc2)c2ccc(Cl)cc2Cl)c(Cl)c1
Reactant: CCCCCCCCCCBr
Product: CCCCCCCCCC[n+]1ccn(CC(OCc2ccc(Cl)cc2Cl)c2ccc(Cl)cc2Cl)c1
Product: [Br-]

Procedure:
mp. 90°-94° C., by the reaction of 1-[2,4-dichloro-β-(2,4-dichlorobenzyloxy)phenethyl]imidazole and n-decyl bromide after an overnight reflux.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@H:7]([CH3:9])[OH:8])[OH:6])[OH:4].CO.[C:12]1([NH:18][NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)(=O)C>[C:12]1([NH:18][N:19]=[CH:2][C@@H:3]([C@H:5]([C@H:7]([CH3:9])[OH:8])[OH:6])[OH:4])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C[C@H](O)[C@H](O)[C@@H](O)C=O
Reactant: NNc1ccccc1
Solvent: CC(=O)O
Solvent: CO
Product: C[C@H](O)[C@H](O)[C@@H](O)C=NNc1ccccc1
Reaction time: 1 h
Yield: 95.6 %

Procedure:
There was added 5.0 g (37.3 mmoles) of 5-deoxy-L-(+)-arabinose obtained in Example to 80 ml of methanol and the mixture was stirred to give a clear solution. With stirring there was added dropwise 4.5 g (42 mmoles) of phenylhydrazine to the obtained mixture and thereto further a drop of glacial acetic acid was added. Thus obtained yellow solution was allowed to stand for 1 hour at room temperature and then the solution was evaporated under a condition close to vacuum as far as possible to give a thick viscous residue. After the residue was washed with 30 ml of ether twice, the residue was dissolved in 150 ml of ethyl acetate. The thus obtained solution was washed with about 40 ml of water twice, the organic layer was dried with sodium sulfate and the solvent was evaporated under vacuum. There remained a pale yellow skin-like solid on the bottom of the flask. The solid was washed with 30 ml of ether twice (for half an hour per each washing) and dried to give 8.0 g of 5-deoxy-L-arabinose-phenylhydrazone (yield: 96%).
Reaction SMILES: ClC1C=C(C2ON=C([C@H](O)C)N=2)C=CC=1.[Cl:16][C:17]1[CH:18]=[C:19]([C:23]2[O:27][N:26]=[C:25]([CH:28]([O:31]C3N(C)C(C4C=CN=CC=4)=NN=3)[CH2:29][CH3:30])[N:24]=2)[CH:20]=[CH:21][CH:22]=1>>[Cl:16][C:17]1[CH:18]=[C:19]([C:23]2[O:27][N:26]=[C:25]([CH:28]([OH:31])[CH2:29][CH3:30])[N:24]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: CCC(Oc1nnc(-c2ccncc2)n1C)c1noc(-c2cccc(Cl)c2)n1
Agent: C[C@@H](O)c1noc(-c2cccc(Cl)c2)n1
Product: CCC(O)c1noc(-c2cccc(Cl)c2)n1

Procedure:
The title compound was synthesized analogous to (+)-(1R)-1-[5-(3-chlorophenyl)-[1,2,4]oxadiazol-3-yl]ethanol and was used directly in the next step for (+)-4-(5-{1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]propoxy}-4-methyl-4H-1,2,4-triazol-3-yl)pyridine.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>COCCOC>[C:17]1([C:2]2[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C(O)c1cccc(Br)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C(O)c1cccc(-c2ccccc2)n1
Yield: 2.5 %

Procedure:
6-Bromopicolinic acid (1.0 g) was dissolved in 1,2-dimethoxyethane (15 mL) prior to the addition of palladium tetrakistriphenylphoshine (572 mg), 2M Na2CO3 (5 mL), and phenyl boronic acid (905 mg). The resulting solution was heated at reflux for 48 h. After cooling, 1N HCL was added to adjust the pH<4. A white precipitate was formed and was removed by filtration. A small portion of the filtrate was purified by reverse phase HPLC (gradient elution, water/acetonitrile/TFA) to afford 6-phenylpicolinic acid (25 mg). MS found: (M+H)+=200.1.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30](O)=[O:31])[C:25]=1[CH3:33])(=[O:12])=[O:11].[CH3:34][C@H:35]1[CH2:40][NH:39][CH2:38][C@@H:37]([CH3:41])[NH:36]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CS(C)=O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([N:39]2[CH2:38][C@H:37]([CH3:41])[NH:36][C@H:35]([CH3:34])[CH2:40]2)=[O:31])[C:25]=1[CH3:33])(=[O:11])=[O:12]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cccc(Cl)c4Cl)cc32)c(C)c1C(=O)O
Reactant: C[C@@H]1CNC[C@H](C)N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CS(C)=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cccc(Cl)c4Cl)cc32)c(C)c1C(=O)N1C[C@@H](C)N[C@@H](C)C1

Procedure:
5-[5-(2,3-Dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (110 mg, 0.22 mmol) was coupled with (2S,6R)-2,6-dimethyl-piperazine (31 mg, 1.2 eq.) using HOBt (1.2 eq.), EDAC.HCl (1.2 eq.) and TEA (3 eq.) in DMSO. The reaction was concentrated and purified on a silica gel column to give the titled compound.
Reaction SMILES: [C:1]1([C:7]2[C:8]([S:13](S(N)(=O)=O)(=[O:15])=[O:14])=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[N:25]=[C:24]([N:30](C2C=CC=CC=2)[C:31](=[O:33])[O-])[N:23]=1.[N:40]12CCCN=C1CCCCC2.CS(O)(=O)=O>C(#N)C>[C:1]1([C:7]2[C:8]([S:13]([NH:40][C:31]([NH:30][C:24]3[N:23]=[C:22]([O:21][CH3:20])[CH:27]=[C:26]([O:28][CH3:29])[N:25]=3)=[O:33])(=[O:15])=[O:14])=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: COc1cc(OC)nc(N(C(=O)[O-])c2ccccc2)n1
Reactant: NS(=O)(=O)S(=O)(=O)c1ncccc1-c1ccccc1
Agent: CS(=O)(=O)O
Solvent: CC#N
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ncccc2-c2ccccc2)n1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
1.9 g of 3-phenyl-pyridin-2-ylsulfonylsulfonamide and 2.2 g of N-(4,6-dimethoxy-pyrimidin-2-yl)-phenylcarbamat are dispersed in 40 ml of acetonitrile. A solution of 1.2 ml 1,8-diazabicyclo[5.4.0]undec-7-ene in 5 ml of acetonitrile are added dropwise, whereby a clear solution is obtained. This reaction solution is kept at room temperature for 16 hours. Then 0.7 ml of methanesulfonic acid and subsequently 15 ml of ice-water are added. A colourless percipitate is formed, which is collected, washed with water and dried. The separated precipitate is treated with ether and dried, yielding 3.2 g of N-(3-phenyl-pyridin-2-ylsulfonyl)-N'-(4,6-dimethoxypyrimidin-2-yl) urea, having a melting point of 181° C. with decomposition.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]([F:12])([F:11])[F:10].C([Li])(CC)C.C1CCCCC1.[CH3:24][Si:25](Cl)([CH3:27])[CH3:26]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Si:25]([CH3:27])([CH3:26])[CH3:24])=[C:4]([F:8])[C:3]=1[C:9]([F:12])([F:10])[F:11]
Reactant: C[Si](C)(C)Cl
Reactant: Fc1cccc(Cl)c1C(F)(F)F
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: C[Si](C)(C)c1ccc(Cl)c(C(F)(F)F)c1F
Temperature: -70 °C
Reaction time: 2 h
Yield: 76.5 %

Procedure:
1-Chloro-3-fluoro-2-(trifluoromethyl)benzene (10 g, 50 mmol) was dissolved in tetrahydrofuran (100 ml), cooled to −70° C. under argon, and treated with a 1.4M solution of sec-butyl lithium in cyclohexane (37.5 ml, 52.5 mmol). Stirring was continued for 2 hrs and then trimethylsilyl chloride (6.7 ml, 52.5 mmol) was added and stirring continued, still at −70° C., for a further 1 hr. The mixture was allowed to warm to room temperature and the tetrahydrofuran was then removed in vacuo. The residue was partitioned between diethyl ether and water and then the organic layer was separated and washed with 2N aqueous hydrogen chloride. The organic phase was separated and concentrated to give the crude product which was purified by flash silica-gel column chromatography, eluting with hexane, to give pure [4-chloro-2-fluoro-3-(trifluoromethyl)phenyl](trimethyl)silane as a clear oil (10.35 g).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1.[O:26]1[CH2:30][CH2:29][NH:28][C:27]1=[O:31]>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[N:6]=[CH:7][C:2]([N:28]5[CH2:29][CH2:30][O:26][C:27]5=[O:31])=[N:3][CH:4]=4)=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2cnc(Br)cn2)CC1
Reactant: O=C1NCCO1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2cnc(N3CCOC3=O)cn2)CC1
Yield: 47.3 %

Procedure:
Using (5-bromopyrazin-2-yl) [4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (100 mg) described in Preparation Example 243 and oxazolidin-2-one (26 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (48 mg) was obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[N:7]([CH3:15])[CH2:8][C:9]1[N:13]=[C:12]([CH3:14])[NH:11][N:10]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>CC#N>[C:1]([O:5][C:6]([N:7]([CH2:8][C:9]1[N:13]=[C:12]([CH3:14])[N:11]([CH2:24][C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[N:10]=1)[CH3:15])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: Cc1nc(CN(C)C(=O)OC(C)(C)C)n[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cc1nc(CN(C)C(=O)OC(C)(C)C)nn1CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl-(5-methyl-1H-[1,2,4]triazol-3-ylmethyl)-carbamic acid tert-butyl ester (470 mg) in MeCN (20 mL) was added Cs2CO3 (677 mg) followed by benzyl bromoacetate (0.343 mL). The reaction mixture was stirred at RT overnight and evaporated to dryness. The residue was taken up in DCM and washed with water. The aq. layers were extracted with DCM, the combined org. layers were dried (Na2SO4), filtered off and evaporated in vacuo. The residue was purified by CC (silica gel, Hept/EA 1/1 then DCM/MeOH 9/1) to afford benzyl 2-(3-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-methyl-1H-1,2,4-triazol-1-yl)acetate (290 mg, yellow oil). LC-MS (B): tR=0.83 min; [M+H]+: 375.14. 1H-NMR (CD3OD): 7.39-7.35 (m, 5H); 5.24 (s, 2H); 5.09 (s, 2H); 4.43 (m, 2H); 2.89 (m, 3H); 2.41 (s, 3H); 1.44 (d, 9H). Roesy signal seen between CH2 at 5.09 ppm and CH3 at 2.41 ppm.
Reaction SMILES: C(Br)(C)(C)C.[C:6]([OH:11])(=[O:10])[CH:7]([CH3:9])[OH:8].C(=O)(O)[O-].[Na+].O.[CH3:18][S:19]([CH3:21])=O>>[CH3:18][S:19][CH2:21][O:10][C:6](=[O:11])[CH:7]([CH3:9])[OH:8]
Reactant: CS(C)=O
Reactant: CC(O)C(=O)O
Agent: CC(C)(C)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CSCOC(=O)C(C)O
Reaction time: 48 h

Procedure:
153 ml (1.1 mol) of tert.butyl bromide are slowly added dropwise to a suspension of 10 g (0.11 mol) of L (+)-lactic acid and 94.2 g (1.1 mol) of sodium bicarbonate in 200 ml of dimethyl sulphoxide. The mixture is stirred for 48 hours, then poured into 1 liter of water and extracted twice with 100 ml of ethyl acetate each time. The organic phase is back-washed three times with 200 ml of water each time and subsequently evaporated. The crude product is chromatographed on a 20-fold amount of silica gel with n-hexane/ethyl acetate (4:1) and the eluate is evaporated. There are obtained 5.7 g of L (-)-lactic acid [(methylthio)methyl] ester; [α]D20 =-39.27° (c=1.3% in chloroform).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([N:12]=[N+]=[N-])([CH3:11])[CH3:10])=[CH:5][CH:4]=1.[H][H]>CO.[Pt]=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH2:12])([CH3:10])[CH3:11])=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: COc1ccc(C(C)(C)N=[N+]=[N-])cc1
Agent: O=[Pt]
Solvent: CO
Product: COc1ccc(C(C)(C)N)cc1
Yield: 94.8 %

Procedure:
1.58 g of platinum oxide were added to a solution of 21.0 g of 1-(4-methoxyphenyl)-1-methylethyl azide [prepared as described in step (a) above] in 100 ml of methanol. The reaction mixture was then stirred for 5 hours under a stream of hydrogen. At the end of this time, the mixture was filtered, diluted with methylene chloride, and washed with an aqueous solution of sodium hydrogencarbonate, with water and with a saturated aqueous solution of sodium chloride, in that order. It was then dried over anhydrous magnesium sulfate, and concentrated by evaporation under reduced pressure, to give 17.2 g (yield 95%) of the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(C1NC=CN=1)(C1NC=CN=1)=O>C(Cl)Cl>[O:1]1[C:5]2[CH:6]=[C:7]([C:10]([N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)c1ccc2ncoc2c1
Reactant: C1CCNCC1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: ClCCl
Product: O=C(c1ccc2ncoc2c1)N1CCCCC1

Procedure:
The amide is prepared by coupling 1,3-benzoxazol-6-carboxylic acid with piperidine by activation of the acid with carbonyl diimidazole as described for the preparation of Invention Compound V. Dilution of the reaction solution with more CH2Cl2 causes the product to precipitate. Purification is achieved by chromatography on silica gel. EMIS m/z=230 (parent), 229, 146 (base), and 118. 1H NMR δ 1.55 (br m, 4), 1.70 (br, 2), 3.4 (br, 2), 3.75 (br, 2), 7.48 (dd, 1, J=8.29, 1.22 Hz), 7.62 (d, 1, J=8.44 Hz), 7.84 (d, 1, J=1.00 Hz), and 8.15 ppm (s, 1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12][C:11](=[O:13])[NH:10][CH:9]2[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.[H-].[Na+].[C:27]1([CH2:37]Cl)[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1>CN(C)C=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12][C:11](=[O:13])[N:10]([CH2:37][C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=[CH:29][CH:28]=3)[CH:9]2[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1
Reactant: O=C1NC(Cc2ccc(C(F)(F)F)cc2)C(c2ccc(F)cc2)O1
Reactant: ClCc1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1OC(c2ccc(F)cc2)C(Cc2ccc(C(F)(F)F)cc2)N1Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87 %

Procedure:
To a solution of (4RS,5SR)-5-(4-fluorophenyl)-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one (1 g, 2.95 mmol) in N,N-dimethylformamide (10 ml) was added 60% sodium hydride (142 mg, 3.54 mmol) and the mixture was stirred at room temperature for 15 min. To the reaction solution was added 1-naphthylmethyl chloride (480 ml, 3.25 mmol) and the mixture was stirred for 1 hr. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1). Recrystallization from diisopropyl ether-hexane gave (4RS,5SR)-5-(4-fluorophenyl)-3-(1-naphthalenylmethyl)-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one (1.23 g, 87%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:10][C@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][O:29][Si](C(C)(C)C)(C)C)=[CH:22][N:21]=1)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:10][C@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][OH:29])=[CH:22][N:21]=1)[C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(CCCO[Si](C)(C)C(C)(C)C)cn1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(CCCO)cn1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of di-tert-butyl (4R)—N-(tert-butoxycarbonyl)-4-{[5-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)pyridin-2-yl]methyl}-L-glutamate (140 mg, 0.23 mmol) in tetrahydrofuran (7 ml) was added acetic acid (80 μl, 1.40 mmol). The solution was cooled to 0° C., and tetra-n-butylammonium fluoride (1M in tetrahydrofuran, 674 μl) was added dropwise. The cooling bath was removed and the reaction was stirred overnight, then mixed with 1 N aqueous sodium hydrogen carbonate solution (20 ml), and extracted with dichloromethane (3×20 ml). The organic phases were washed with brine (10 ml), dried over sodium sulfate and concentrated in vacuo. The crude material was used without further purification.