Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[CH:31][C:32]([F:41])=[C:33]([NH:35][C:36](=[O:40])[CH2:37][CH2:38][CH3:39])[CH:34]=2)[CH2:25][CH2:24]1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:24][CH2:25][CH:26]([C:29]3[CH:30]=[CH:31][C:32]([F:41])=[C:33]([NH:35][C:36](=[O:40])[CH2:37][CH2:38][CH3:39])[CH:34]=3)[CH2:27][CH2:28]2)=[O:11])=[CH:13][CH:14]=1
Reactant: CCCC(=O)Nc1cc(C2CCN(CCCN)CC2)ccc1F
Reactant: O=C(O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Product: CCCC(=O)Nc1cc(C2CCN(CCCNC(=O)C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)CC2)ccc1F

Procedure:
Example 108 was prepared from bis(4-chlorophenyl)acetic acid and N-{5-[1-(3-aminopropyl)-4-piperidinyl]-2-fluorophenyl}butanamide according to the procedures described in Scheme 10: ESMS m/e: 584.2 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:15]=[CH:14][C:8]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[C:7]([CH3:16])[CH:6]=1)=O.[NH2:17][C:18](=[N:20][C:21]([NH2:23])=[S:22])[NH2:19]>C(O)C>[NH2:17][C:18](=[N:20][C:21]1[S:22][CH:2]=[C:3]([C:5]2[CH:15]=[CH:14][C:8]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[C:7]([CH3:16])[CH:6]=2)[N:23]=1)[NH2:19]
Reactant: CC(=O)NCc1ccc(C(=O)CCl)cc1C
Reactant: NC(=S)N=C(N)N
Solvent: CCO
Product: CC(=O)NCc1ccc(-c2csc(N=C(N)N)n2)cc1C
Yield: 69.1 %

Procedure:
A mixture of N-(4-chloroacetyl-2-methylbenzyl)acetamide (3.6 g) and (diaminomethylene)thiourea (2.3 g) in ethanol (100 ml) was refluxed for 2 hours under stirring. The reaction mixture was evaporated in vacuo and the residue was suspended in water and resultant mixture was adjusted to pH 8.0 with 20% potassium carbonate aqueous solution and the precipitate was collected by filtration. The precipitate was dissolved in a mixture of ethyl acetate and tetrahydrofuran, washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was recrystallized from ethanol to give 2-(diaminomethyleneamino)-4-(4-acetylaminomethyl-3-methylphenyl)thiazole (3.15 g).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][C:10]=2[C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)=[O:12])[CH2:4][CH2:3]1.[C:32]([O:36][C:37]([NH:39][C:40](=[N:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])SC)=[O:38])([CH3:35])([CH3:34])[CH3:33]>C(O)C.[Hg]=O>[C:47]([O:46][C:44]([N:43]=[C:40]([NH:39][C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:38])[NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][C:10]=2[C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)=[O:12])[CH2:4][CH2:3]1)=[O:45])([CH3:50])([CH3:49])[CH3:48]
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reactant: COc1ccc(CNC(=O)c2cc([N+](=O)[O-])ccc2N[C@H]2CC[C@H](N)CC2)cc1OC
Agent: O=[Hg]
Solvent: CCO
Product: COc1ccc(CNC(=O)c2cc([N+](=O)[O-])ccc2N[C@H]2CC[C@H](NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)CC2)cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 2-(trans-4-aminocyclohexylamino)-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide (300 mg) and 1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea (203 mg) in ethanol (20 mL) was added mercury(II) oxide (152 mg). The mixture was stirred for 2 hours at ambient temperature. The resultant precipitates were removed by filtration and the filtrate was evaporated in vacuo. The residue was purified by a silica gel column chromatography eluting with 2% methanol in chloroform. The obtained product was triturated with diisopropyl ether to give 2-{trans-4-[2,3-bis(tert-butoxycarbonyl)guanidino]cyclohexylamino}-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide as yellow powders (432 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11](=[O:24])[CH2:12][CH:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][C:15](O)=[O:16])[CH3:9])=[CH:4][CH:3]=1.B>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([NH:10][C:11](=[O:24])[CH2:12][CH:13]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:14][CH2:15][OH:16])[CH3:9])=[CH:6][CH:7]=1
Reactant: C[C@H](NC(=O)CC(CC(=O)O)c1ccccc1)c1ccc(Br)cc1
Agent: B
Solvent: C1CCOC1
Product: C[C@H](NC(=O)CC(CCO)c1ccccc1)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 102.6 %

Procedure:
5-((S)-1-(4-bromophenyl)ethylamino)-5-oxo-3-phenylpentanoic acid (1.92 g, 4.92 mmol, 1.0 equiv) was dissolved in THF (30 mL) and the resulting solution cooled to 0° C. Borane (1.0 M in THF, 10.5 mL, 10.5 mmol, 2.1 equiv) was added via syringe. After 0.5 h LC-MS showed formation of the alcohol. The excess borane was quenched by the drop-wise addition of 1.0 M aq HCl and the mixture was transferred to a separatory funnel. The layers were separated and the organic layer washed with brine, dried over Na2SO4, filtered and evaporated. The resulting N—((S)-1-(4-bromophenyl)ethyl)-5-hydroxy-3-phenylpentanamide (˜1.9 g, >95% yield) was of sufficient purity to use in the next step.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[O:12])=[CH:6][CH:5]=1.Cl.[CH3:21][N:22]([CH2:24][CH2:25]Cl)[CH3:23]>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].C1(C)C=CC=CC=1>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:25][CH2:24][N:22]([CH3:23])[CH3:21])=[CH:17][CH:18]=2)=[O:12])=[CH:6][CH:5]=1
Reactant: CN(C)CCCl
Reactant: O=C(Cc1ccc(Cl)cc1)c1ccc(O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: Cc1ccccc1
Product: CN(C)CCOc1ccc(C(=O)Cc2ccc(Cl)cc2)cc1
Reaction time: 0.5 h
Yield: 24.3 %

Procedure:
10% Aqueous sodium hydroxide is added to the mixture containing 2-(4-chlorophenyl)-1-(4-hydroxyphenyl)ethanone (6.0 g, 0.024 mol), TBABr (0.9 g) in toluene (60 ml) at 60° C. The mixture is stirred for 30 min. N,N-Dimethylaminoethyl chloride hydrochloride (3.6 g, 0.025 mol) is added and stirring is continued at 70-75° C. for 3 h. The layers are separated and the aqueous phase is extracted with toluene. The combined toluene phases are evaporated to give the product (1.85 g, 24%).
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH:11]=[O:12])#[N:2].[CH2:13]([O:15][CH:16]([O:19][CH2:20][CH3:21])[CH2:17][SH:18])[CH3:14].C(N(CC)CC)C>C(OCC)C>[C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([S:18][CH2:17][CH:16]([O:19][CH2:20][CH3:21])[O:15][CH2:13][CH3:14])=[CH:10][CH:11]=[O:12])#[N:2]
Reactant: CCOC(CS)OCC
Reactant: N#CCCCCCCC=CC=O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(CSC(=CC=O)CCCCCCC#N)OCC
Reaction time: 48 h

Procedure:
The starting material is prepared as follows: The mixture of 1.8 g of 9-cyano-2-nonenal, 1.4 g of 2,2-diethoxy-ethane-thiol and 50 μl of triethylamine is allowed to stand at room temperature for 48 hours. It is taken up in 100 ml of diethyl ether, the solution washed with water, dried and evaporated, to yield the 9-cyano-3-(2,2-diethoxy-ethylmercapto)-nonenal, showing in NMR spectrum peaks at 9.78, 4.55, 3.57 and 2.61 ppm.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]1[N:18]=[CH:17][C:16]([CH:19]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH2:20][NH2:21])=[CH:15][N:14]=1>>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:17]=[N:18][C:13]([CH3:12])=[N:14][CH:15]=1)[C:22]1[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=1)=[O:6]
Reactant: Cc1ncc(C(CN)c2ccncc2)cn1
Reactant: O=C(O)c1cccc(F)c1Cl
Product: Cc1ncc(C(CNC(=O)c2cccc(F)c2Cl)c2ccncc2)cn1

Procedure:
From 2-chloro-3-fluorobenzoic acid and 2-(2-methylpyrimidin-5-yl)-2-(pyridin-4-yl)ethanamine. LCMS (MH+): m/z=371.1, tR (minutes, Method F)=1.73
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5](Br)=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[CH2:7]2.[O:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[O:20][CH2:21][CH2:22][N:23]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[N:24]1.ClCCl.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]2[CH:25]=[N:24][N:23]([CH2:22][CH2:21][O:20][CH:15]3[CH2:16][CH2:17][CH2:18][CH2:19][O:14]3)[CH:27]=2)=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[CH2:7]2
Reactant: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Reactant: CN1Cc2c(Br)ccc(N)c2C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CN1Cc2c(-c3cnn(CCOC4CCCCO4)c3)ccc(N)c2C1=O

Procedure:
A mixture of [A] 7-amino-4-bromo-2-methyl-2,3-dihydro-1H-isoindol-1-one (1.0 g, 4.1 mmol), and 1-[2-(Tetrahydro-pyran-2-yloxy)-ethyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole [US 2007265272] (1.6 g, 5.0 mmol) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (0.17 g, 0.21 mmol) in a microwave tube was taken up in 1,4-Dioxane (12 mL). The mixture was treated with a solution of Potassium carbonate (1.7 g, 12 mmol) in H2O (3.0 mL, 170 mmol), flushed with N2, sealed and irradiated in the CEM for 30 minutes at 100° C. Another 1 g of boronic ester was added as well as another 0.05 eq of catalyst. The mixture was sparged with N2, sealed and irradiated for 45 min. This was worked up and purified. 1H NMR (400 MHz, DMSO-d6) δ 1.36-1.50 (m, 4H), 1.57 (td, J=9.22, 3.03 Hz, 1H), 1.63-1.71 (m, 1H), 3.03 (s, 3H), 3.35-3.41 (m, 1H), 3.57 (ddd, J=11.31, 8.40, 3.03 Hz, 1H), 3.75 (dt, J=10.80, 5.34 Hz, 1H), 3.91-3.99 (m, 1H), 4.27-4.33 (m, 2H), 4.44 (s, 2H), 4.55 (t, J=3.28 Hz, 1H), 6.06 (s, 2H), 6.62 (d, J=8.34 Hz, 1H), 7.43 (d, J=8.34 Hz, 1H), 7.74 (d, J=0.51 Hz, 1H), 7.95 (d, J=0.51 Hz, 1H).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C@H:11]([NH:18][C:19]1[O:20][C:21]([CH3:35])([CH3:34])[CH:22]([C:27]2[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=2)[S:23](=[O:26])(=[O:25])[N:24]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(C(C)(C)C)(C)C.Cl>CO.C(OCC)(=O)C>[CH3:34][C:21]1([CH3:35])[O:20][C:19]([NH:18][C@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][CH2:9][OH:8])=[N:24][S:23](=[O:26])(=[O:25])[CH:22]1[C:27]1[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=1
Reactant: Cc1cccc(C2C(C)(C)OC(N[C@@H](CCO[Si](C)(C)C(C)(C)C)c3ccccc3)=NS2(=O)=O)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cccc(C2C(C)(C)OC(N[C@@H](CCO)c3ccccc3)=NS2(=O)=O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.9 %

Procedure:
51.7 mg of [(S)-3-(tert-butyldimethylsilanyloxy)-1-phenylpropyl]-(6,6-dimethyl-4,4-dioxo-5-m-tolyl-5,6-dihydro-4H-4lambda6-1,4,3-oxathiazin-2-yl)amine were dissolved in 2 ml of methanol, 0.1 ml of concentrated hydrochloric acid was added and the mixture was stirred at room temperature for 16 hours. The reaction solution was diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution, dried over MgSO4 and concentrated by rotary evaporation. The residue was purified in a purification laboratory by means of preparative HPLC. The product-containing fractions were combined, the acetonitrile was removed under reduced pressure, and the aqueous residue was basified with saturated aqueous sodium hydrogencarbonate solution and extracted with dichloromethane. The organic phase was dried over MgSO4 and concentrated by rotary evaporation, and the residue was taken up again in a mixture of acetonitrile and water and lyophilized. This gave the product (22.9 mg) with a molecular weight of 402.5 g/mol (C21H26N2O4S); MS (ESI): m/e=403 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[C@H:12]1[CH2:14][O:13]1.[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>CCO>[N:15]1([CH2:14][C@H:12]([C:3]2[CH:4]=[CH:5][C:6]3[C:7](=[O:11])[O:8][CH2:9][C:10]=3[C:2]=2[CH3:1])[OH:13])[CH2:20][CH2:19][N:18]([CH2:14][C@H:12]([C:3]2[CH:4]=[CH:5][C:6]3[C:7](=[O:11])[O:8][CH2:9][C:10]=3[C:2]=2[CH3:1])[OH:13])[CH2:17][CH2:16]1
Reactant: Cc1c([C@H]2CO2)ccc2c1COC2=O
Reactant: C1CNCCN1
Solvent: CCO
Product: Cc1c([C@H](O)CN2CCN(C[C@@H](O)c3ccc4c(c3C)COC4=O)CC2)ccc2c1COC2=O
Temperature: 150 °C

Procedure:
To a 20 mL microwave tube charged with 4-methyl-5-[(2S)-oxiran-2-yl]-2-benzofuran-1(3H)-one (980 mg, 5.15 mmol) and piperazine (200 mg, 2.3 mmol) was added a stir bar and EtOH (16 mL). The tube was sealed and heated in a microwave apparatus to 150° C. for 90 minutes. The crude product was adsorbed onto silica gel, and purified by flash chromatography (MeOH-DCM 0˜7% gradient). After removal of solvents, 5,5′-{piperazine-1,4-diylbis[(1S)-1-hydroxyethane-2,1-diyl]}bis(4-methyl-2-benzofuran-1(3H)-one) was collected (560 mg).
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][C@H:15](O)[CH2:14]1>>[CH3:12][C@H:13]1[CH2:18][CH2:17][CH2:16][C@H:15]([O:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:14]1
Reactant: CCOC(=O)/C(=N\O)C(C)=O
Reactant: C[C@@H]1CCC[C@H](O)C1
Product: CCOC(=O)/C(=N\O[C@H]1CCC[C@H](C)C1)C(C)=O

Procedure:
Ethyl (Z)-2hydroxyimino-3-oxobutyrate (2.65 g, 16.7 mmol) was converted into the title compound by reaction with cis 3-methylcyclohexanol (1.9 g, 16.7 mmol) as described in Example 4a method 3. After purification the title compound was obtaind as a colourless oil (0.57 g, 11%) νmax (CHCl3) 1735, 1680, and 1590 cm-1 ; δH (CDCl3) 0.8-1.3 (1H, m,. partially obscured by d, δ 0.9); 0.90 (3H, d, J 6.5 Hz), 1.1-1.4 (1H, m, partially obscured by t, δ 1.33 ), 1.33 (3H, t, J 7.11 Hz), 1.4-1.8 (2H, m, partially obscured by s, δ 1.55 ), 1.55 (3H, s), 1.85-2.1 (2H, m), 2.4 (3H, s), 4.36 (2H, q, J 7.1 Hz), and 4.50-4.64 (1H, m), δ13C (CDCl3), 14.19, 20.32, 22.28, 25.13, 26.74, 29.55, 34.16, 38.13, 61.74, 81.96, 150.2, 161.51, and 193.01.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH2:6][C@H:5]1[CH3:15])(=[O:3])[CH3:2].[N:16]([O-:18])=[O:17].[Na+].O>C(O)(C(F)(F)F)=O>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[C:10]([N+:16]([O-:18])=[O:17])[CH:11]=2)[CH2:6][C@H:5]1[CH3:15])(=[O:3])[CH3:2]
Reactant: O=N[O-]
Reactant: COc1ccc2c(c1)C[C@@H](C)N2C(C)=O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(cc1[N+](=O)[O-])N(C(C)=O)[C@H](C)C2
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.7 %

Procedure:
A solution of (2R)-1-acetyl-2-methyl-5-(methyloxy)-2,3-dihydro-1H-indole (100 mg, 0.487 mmol)—see (Arp, Forrest O.; Fu, Gregory C. Kinetic Resolutions of Indolines by a Nonenzymatic Acylation Catalyst. Journal of the American Chemical Society (2006), 128(44), 14264-14265.)—in TFA (2 mL) at 0° C. was treated with sodium nitrite (33.6 mg, 0.487 mmol). The resulting red solution was stirred at 0° C. for 1 h. H2O (20 mL) was added, the resulting slurry was filtered and the solids were washed with water to afford (2R)-1-acetyl-2-methyl-5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole as a yellow solid (85 mg, 70%). 1H NMR (400 MHz, DMSO-d8) δ ppm 1.22 (d, J=6.41 Hz, 3H), 2.22 (s, 3H), 2.76 (d, J=17.21 Hz, 1H), 3.45 (dd, J=17.12, 8.88 Hz, 1H), 3.89 (s, 3H), 4.59-4.74 (m, 1H), 7.35 (s, 1H), 8.40 (s, 1H); ESIMS (M+H)+=251.00.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]([Br:12])=[CH:10][C:9]([F:13])=[CH:8][C:7]=1Br)(=[O:3])[CH3:2].[F:15][C:16]1[C:24]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=2[N:18]2[CH2:25][CH2:26][NH:27][C:28](=[O:29])[C:17]=12.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[C:1]([O:4][CH2:5][C:6]1[C:7]([N:27]2[CH2:26][CH2:25][N:18]3[C:19]4[CH2:20][CH2:21][CH2:22][CH2:23][C:24]=4[C:16]([F:15])=[C:17]3[C:28]2=[O:29])=[CH:8][C:9]([F:13])=[CH:10][C:11]=1[Br:12])(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(Br)cc(F)cc1Br
Reactant: O=C1NCCn2c3c(c(F)c21)CCCC3
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(=O)OCc1c(Br)cc(F)cc1N1CCn2c3c(c(F)c2C1=O)CCCC3
Temperature: 100 °C
Yield: 58.1 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 1,4-dioxane (60 mL), 2,6-dibromo-4-fluorobenzyl acetate 101c (2.34 g, 7.2 mmol), 119b (500 mg, 2.4 mmol), and cesium carbonate (1.6 g, 4.8 mmol). After bubbling nitrogen through the resulting mixture for 30 minutes, Xantphos (140 mg, 0.24 mmol) and tris(dibenzylideneacetone)dipalladium(0) (220 mg, 0.24 mmol) were added and the reaction mixture was heated at 100° C. for 12 h. After this time the reaction was cooled to room temperature and filtered. The filtrate was partitioned between ethyl acetate (40 mL) and water (40 mL). The aqueous layer was separated and extracted with ethyl acetate (3×70 mL). The combined organic layer was washed with brine (30 mL) and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica-gel column eluting with 3:1 petroleum ether/ethyl acetate to afford 119c (632 mg, 58%) as a yellow solid. MS: [M+H]+ 453.2
Reaction SMILES: Cl.[OH:2][CH:3]([C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[F:16])[C:4](=[NH:8])[O:5]CC.[O:17]1CCC[CH2:18]1>>[F:15][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]([F:16])[C:9]=1[CH:3]1[O:2][C:18](=[O:17])[NH:5][C:4]1=[O:8]
Reactant: C1CCOC1
Reactant: CCOC(=N)C(O)c1c(F)cccc1F
Agent: Cl
Product: O=C1NC(=O)C(c2c(F)cccc2F)O1

Procedure:
By the procedure of Example 89, ethyl 1-hydroxy-1-(2,6-difluorophenyl)methanecarboximidate hydrochloride (12 g., 0.048 mole) in 500 ml. of tetrahydrofuran was converted to crude product. The crude was recrystallized from about 60 ml. of isopropanol to yield purified 5-(2,6-difluorophenyl)oxazolidine-2,4-dione [5.8 g., 57%; m.p. 196°-198° C., m/e 213 ir (KBr) 3175, 1812, 1739, 1361, 1152 cm-1 ].
Reaction SMILES: [C:1]([C:3]([C:11]1[S:12][C:13]([C:16]#[N:17])=[CH:14][CH:15]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6]O)#[N:2].C(N(CC)CC)C.S(Cl)(C)(=O)=O.[I-:30].[Na+]>C(#N)C.[Cl-].[Na+].O.C(OCC)(=O)C>[C:1]([C:3]([C:11]1[S:12][C:13]([C:16]#[N:17])=[CH:14][CH:15]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6][I:30])#[N:2]
Reactant: CC(C)C(C#N)(CCCO)c1ccc(C#N)s1
Reactant: [I-]
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)C(C#N)(CCCI)c1ccc(C#N)s1
Reaction time: 0 h
Yield: 91.7 %

Procedure:
1.05 g (4.23 mmol) of 4-cyano-5-methyl-4-(5-cyano-2-thienyl)hexanol was dissolved in 40 ml of acetonitrile and 0.80 ml (5.71 mmol) of triethylamine. 0.39 ml (5.07 mmol) of mesyl chloride was added thereto. After about 0.10 minutes, 6.34 g (42.3 mmol) of sodium iodide was added. After completion of the reaction, brine and ethyl acetate were added. The ethyl acetate layer was washed with an aqueous sodium thiosulfate and brine, dried over magnesium sulfate and evaporated, to give a crude product. The crude product was subjected to silica gel (eluted with ethyl acetate:hexane=1:2), to give 1.39 g (3.88 mmol, 91.7%) of the title compound as a yellow oil.
Reaction SMILES: C([O-])(=O)C.[Na+].O.Br[CH:8](Br)[C:9]([C:11]([F:14])([F:13])[F:12])=[O:10].[F:16][C:17]1[CH:22]=[C:21]([Cl:23])[C:20]([O:24][CH:25]([CH3:27])[CH3:26])=[CH:19][C:18]=1[NH:28][NH2:29]>C(OCC)C>[Cl:23][C:21]1[C:20]([O:24][CH:25]([CH3:26])[CH3:27])=[CH:19][C:18]([NH:28][N:29]=[CH:8][C:9](=[O:10])[C:11]([F:14])([F:13])[F:12])=[C:17]([F:16])[CH:22]=1
Reactant: O=C(C(Br)Br)C(F)(F)F
Reactant: CC(C)Oc1cc(NN)c(F)cc1Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CC(C)Oc1cc(NN=CC(=O)C(F)(F)F)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a mixed solution of 5.3 g (53.5 mmol) of sodium acetate and about 100 ml of water was added under ice cooling 6.6 g (24.3 mmol) of 1,1-dibromo-3,3,3-trifluoroacetone, and the reaction was allowed to proceed at 70° C. for 20 minutes. Then, the reaction mixture was cooled to room temperature, to which a solution of 5.8 g (21.5 mmol) of 2-fluoro-4-chloro-5-isopropoxyphenylhydrazine dissolved in about 20 ml of diethyl ether was added, and the reaction mixture was stirred at room temperature for 1 hour. The ether layer was separated, washed once with 10 ml of saturated sodium chloride solution, and dried with magnesium sulfate. The diethyl ether was distilled out, which afforded 6.5 g (20.0 mmol) of 3,3,3-trifluoro-2-oxo-propanal 1-(4-chloro-2-fluoro-5-isopropoxyphenylhydrazone).
Reaction SMILES: C(OC([N:8]1[CH2:15][C@H:14]2[N:16](C(OC(C)(C)C)=O)[C@H:10]([CH2:11][C:12]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][O:36][C:37]4[C:42]([Cl:43])=[CH:41][C:40]([CH3:44])=[CH:39][C:38]=4[Cl:45])=[CH:29][CH:28]=3)=[C:13]2[C:24](O)=[O:25])[CH2:9]1)=O)(C)(C)C.[CH:46]1([NH:49][CH2:50][C:51]2[CH:56]=[C:55]([CH2:57][CH2:58][O:59][CH3:60])[CH:54]=[CH:53][C:52]=2[CH3:61])[CH2:48][CH2:47]1>>[CH:46]1([N:49]([CH2:50][C:51]2[CH:56]=[C:55]([CH2:57][CH2:58][O:59][CH3:60])[CH:54]=[CH:53][C:52]=2[CH3:61])[C:24]([C:13]2[C@@H:14]3[NH:16][C@H:10]([CH2:11][C:12]=2[C:27]2[CH:28]=[CH:29][C:30]([O:33][CH2:34][CH2:35][O:36][C:37]4[C:42]([Cl:43])=[CH:41][C:40]([CH3:44])=[CH:39][C:38]=4[Cl:45])=[CH:31][CH:32]=2)[CH2:9][NH:8][CH2:15]3)=[O:25])[CH2:47][CH2:48]1
Reactant: COCCc1ccc(C)c(CNC2CC2)c1
Reactant: Cc1cc(Cl)c(OCCOc2ccc(C3=C(C(=O)O)[C@H]4CN(C(=O)OC(C)(C)C)C[C@@H](C3)N4C(=O)OC(C)(C)C)cc2)c(Cl)c1
Product: COCCc1ccc(C)c(CN(C(=O)C2=C(c3ccc(OCCOc4c(Cl)cc(C)cc4Cl)cc3)C[C@@H]3CNC[C@H]2N3)C2CC2)c1

Procedure:
This compound was synthesized from (1R,5S)-7-{4-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy]-phenyl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid 3,9-di-tert-butyl ester and cyclopropyl-[5-(2-methoxy-ethyl)-2-methyl-benzyl]-amine as for compound L1, and then Example 1. MS (ESI, Q+) m/z 664.1.
Reaction SMILES: C(C1N=C(N2CC[C@H](O)C2)C2C(=NN(CC3C(C)=NON=3)N=2)N=1)(C)(C)C.[C:27]([C:31]1[N:32]=[C:33]([N:40]2[CH2:44][CH2:43][C@H:42]([O:45]C(=O)C(F)(F)F)[CH2:41]2)[C:34]2[N:39]=[N:38][NH:37][C:35]=2[N:36]=1)([CH3:30])([CH3:29])[CH3:28].Br.Br[CH2:54][C:55]1[C:56]([Cl:61])=[N:57][CH:58]=[CH:59][CH:60]=1>>[C:27]([C:31]1[N:32]=[C:33]([N:40]2[CH2:44][CH2:43][C@H:42]([OH:45])[CH2:41]2)[C:34]2[C:35](=[N:37][N:38]([CH2:54][C:55]3[C:56]([Cl:61])=[N:57][CH:58]=[CH:59][CH:60]=3)[N:39]=2)[N:36]=1)([CH3:29])([CH3:28])[CH3:30]
Reactant: CC(C)(C)c1nc(N2CC[C@H](OC(=O)C(F)(F)F)C2)c2nn[nH]c2n1
Reactant: Clc1ncccc1CBr
Agent: Br
Agent: Cc1nonc1Cn1nc2nc(C(C)(C)C)nc(N3CC[C@H](O)C3)c2n1
Product: CC(C)(C)c1nc(N2CC[C@H](O)C2)c2nn(Cc3cccnc3Cl)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of (S)-1-[5-tert-Butyl-2-(4-methyl-furazan-3-ylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-ol (example 73), the title compound was prepared from Trifluoro-acetic acid (S)-1-(5-tert-butyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)-pyrrolidin-3-yl-ester and 3-(bromomethyl)-2-chloropyridine hydrobromide and isolated as light brown gum. MS (m/e): 388.3 (MH+).