Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:9][CH:10]([CH3:16])[CH:11]([CH3:15])[C:12]([OH:14])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C@@:24]2([OH:32])[CH2:29][CH2:28][NH:27][CH2:26][C:25]2([CH3:31])[CH3:30])=[CH:20][CH:19]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C1COCC1>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C@@:24]2([OH:32])[CH2:29][CH2:28][N:27]([C:12](=[O:14])[CH:11]([CH3:15])[CH:10]([NH:9][C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH3:16])[CH2:26][C:25]2([CH3:30])[CH3:31])=[CH:20][CH:19]=1
Reactant: CC(NC(=O)c1ccccc1)C(C)C(=O)O
Reactant: CC1(C)CNCC[C@]1(O)c1ccc(Cl)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)c1ccccc1)C(C)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Temperature: 25 °C
Reaction time: 70 h
Yield: 35.9 %

Procedure:
To 3-benzamido-2-methylbutanoic acid (0.055 g, 0.249 mmol) in THF (2 mL) are sequentially added (S)-4-(4-chlorophenyl)-3,3-dimethylpiperidin-4-ol (WO 04/043965, 0.060 g, 0.249 mmol), N,N-diisopropylethylamine (0.087 mL, 0.497 mmol) and BOP (0.110 g, 0.249 mmol) at RT. The reaction mixture was stirred at RT for 70 h, and concentrated. The oily residue was dissolved in MeOH (2.0 mL) and subjected to preparative HPLC (Phenomex S10 30×100 mm; 10 min. gradient; solvent A=10% MeOH, 90% H2O, 0.1% TFA, solvent B=90% MeOH, 10% H2O, 0.1% TFA). Two fractions (diastereomer A and B) are collected and individually processed by concentrating and partitioning between dichloromethane (10 mL) and sat. aq. NaHCO3 (10 mL). The dichloromethane layer was dried over sodium sulfate and concentrated to yield: Diastereomer A: (0.042 g, 0.089 mmol, 35.9% yield) as a foamy solid. Retention time=3.23 min (YMC S5 Combi ODS 4.6×50 mm; 4 min. gradient; solvent A=10% MeOH, 90% H2O, 0.2% H3PO4, solvent B=90% MeOH, 10% H2O, 0.2% H3PO4. MS (ESI) m/z 443.11 (M+H)+; and Diastereomer B: (0.03 g, 0.064 mmol, 25.9% yield) as a foamy solid. Retention time=3.42 min (YMC S5 Combi ODS 4.6×50 mm; 4 min. gradient; solvent A=10% MeOH, 90% H2O, 0.2% H3PO4, solvent B=90% MeOH, 10% H2O, 0.2% H3PO4. MS (ESI) m/z 443.12 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7](N)=[CH:6][C:5]=1[NH:11][C:12](=[O:27])[C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:14]=1.N([O-])=[O:30].[Na+].S(=O)(=O)(O)O.O>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([OH:30])=[CH:6][C:5]=1[NH:11][C:12](=[O:27])[C:13]1[CH:14]=[C:15]([C:23]([F:24])([F:26])[F:25])[CH:16]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:18]=1
Reactant: O=N[O-]
Reactant: COC(=O)c1ccc(N)cc1NC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(O)cc1NC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 76.4 %

Procedure:
To a solution of 4-amino-2-(3,5-bis-trifluoromethyl-benzoylamino)-benzoic acid methyl ester (1.70 g, 4.18 mmol) in trifluoroacetic acid (25 mL) which has been cooled to 0° C. was slowly added a solution of sodium nitrite (0.35 g, 5.06 mmol in 9 mL of water). In a separate flask, concentrated sulfuric acid (21 m]L) was added to water (50 mL) to make a 30% sulfuric acid solution. After 5 minutes, the trifluoroacetic acid mixture was slowly added to the sulfuric acid solution. After complete addition, the reaction mixture was allowed to stir at ambient temperature for 15 minutes. The reaction mixture was extracted with three portions of ethyl acetate. The organics were combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography through silica gel using ethyl acetate/hexanes (20/80) to give 2-(3,5-bis-trifluoromethyl-benzoylamino)-4-hydroxy-benzoic acid methyl ester (1.30 g, 76%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6); δ 11.92 (s, 1H), 10.68 (s, 1H), 8.50 (s, 2H), 8.44 (s, 1H), 8.03 (d, 1H), 7.88 (d, 1H), 6.64 (dd, 1H), 3.84 (s, 3H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[OH:19]>>[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[O:19][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1F
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: O=[N+]([O-])c1ccc(Oc2ccc(F)cc2F)cc1

Procedure:
Prepare the title compound in the manner analogous to the procedure set fourth in example E-227 using 4-fluoro-nitrobenzene and 2,4-difluorophenol (heat 2 hours at 50° C.). Purify the material by silica gel chromatography (Prep.2000) eluting with methylene chloride/hexane 1:1 to provide the title compound as a slowly crystallizing oil. Mass spectrum (m/e): 251.1 (M*). (Bruker 300) 1H NMR (CDCl3) δ 8.17-8.22 (2H, d), 7.14-7.21 (1H, m), 6.90-703 (4H, m).
Reaction SMILES: [K:1].[NH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH2:12][CH2:13][CH:14]2[C:19](=[O:20])[O:18][C:17]([CH3:22])([CH3:21])[O:16][C:15]2=[O:23])=[C:5](Cl)[N:4]=1.C([O-])=O.[NH4+].C(Cl)(Cl)Cl.CO>CO>[K:1].[NH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH2:12][CH2:13][CH:14]2[C:19](=[O:20])[O:18][C:17]([CH3:21])([CH3:22])[O:16][C:15]2=[O:23])=[CH:5][N:4]=1
Reactant: CC1(C)OC(=O)C(CCn2cnc3c(Cl)nc(N)nc32)C(=O)O1
Agent: O=C[O-]
Agent: [K]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC1(C)OC(=O)C(CCn2cnc3cnc(N)nc32)C(=O)O1

Procedure:
A mixture of 2-amino-6-Chloro-9-[1-(2,2-dimethyl-1,3-dioxane-4,6-dione-5-yl)eth-2-yl]purine potassium salt (200 mg, 0.53 mmol), ammonium formate (148 mg, 2.34 mmol) and 10% palladuim on charcoal (80 mg) in methanol (15 ml) was heated under reflux under dry nitrogen for 3 h. T.1.c. [chloroform/methanol (2:1)] showed one spot, rf=0.15. The mixture was filtered and the filtrate evaporated to leave a gum. The material was not purified further.
Reaction SMILES: [F:1][C:2]([F:22])([C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13]Br)=[CH:8][CH:7]=1)=[O:4].[C-:23]#[N:24].[Na+].O>CS(C)=O>[F:1][C:2]([F:22])([C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:23]#[N:24])=[CH:8][CH:7]=1)=[O:4]
Reactant: O=C(Nc1ccc(CCBr)cc1)C(F)(F)C(F)(F)C(F)(F)F
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCCc1ccc(NC(=O)C(F)(F)C(F)(F)C(F)(F)F)cc1
Reaction time: 18 h
Yield: 49.1 %

Procedure:
A solution of 2,2,3,3,4,4,4-heptafluoro-N-[4-(2-bromoethyl)phenyl]butanamide (9.9 g), and sodium cyanide (1.72 g) in dimethylsulfoxide (50 mL) was stirred at room temperature under a nitrogen atmosphere for 24 hours. The mixture was treated with additional sodium cyanide (0.8 g) and the reaction was stirred for another 18 hours. The reaction mixture was poured into water (1 L) and extracted with diethyl ether. The extracts were washed with water and with saturated brine solution, dried over sodium sulfate, filtered and concentrated with a rotary evaporator. The crude orange residue was chromatographed on silica gel, eluted with a hexane-ethylacetate (7:3) mixture to give 4.2 g of 2,2,3,3,4,4,4-heptafluoro-N-[4-(2-cyanoethyl)phenyl]butanamide as a yellow solid.
Reaction SMILES: O.[OH-].[Li+].O.[F:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:15]1[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=1)[CH:10]=[C:9]2[C:25]([O:27]C)=[O:26].Cl>O1CCCC1>[C:25]([C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[C:6]([F:5])[CH:7]=2)[N:11]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)[CH:10]=1)([OH:27])=[O:26]
Reactant: COC(=O)c1cn(-c2ccnc3ccccc23)c2ccc(F)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cn(-c2ccnc3ccccc23)c2ccc(F)cc12
Reaction time: 16 h

Procedure:
0.63 g (15 mmol) of lithium hydroxide monohydrate and 75 cm3 of water are added at a temperature in the region of 20° C. to 1.6 g (5 mmol) of 5-fluoro-3-methoxycarbonyl-1-(quinol-4-yl)-1H-indole dissolved in 75 cm3 of tetrahydrofuran. After stirring at the reflux point of the solvent for 16 hours, the reaction mixture is concentrated under reduced pressure (2.7 kPa) to give a residue which is taken up with 15 cm3 of N hydrochloric acid. After filtering off and drying the solid residue at atmospheric pressure at a temperature in the region of 60° C., 1.44 g of 3-carboxy-5-fluoro-1-(quinol-4-yl)-1H-indole are obtained in the form of a yellow solid melting at approximately 148° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[C:28]([Cl:30])[CH:29]=1)[CH2:5][N:6]([CH3:26])[C:7]([C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][N:12]=[C:11](S(C)(=O)=O)[N:10]=1)=[O:8].O1[CH2:36][CH2:35]OCC1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[C:28]([Cl:30])[CH:29]=1)[CH2:5][N:6]([CH3:26])[C:7]([C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][N:12]=[C:11]([N:10]2[CH2:36][CH2:35][N:6]([CH3:5])[CH2:7][CH2:9]2)[N:10]=1)=[O:8]
Reactant: C1COCCO1
Reactant: Cc1ccccc1-c1cnc(S(C)(=O)=O)nc1C(=O)N(C)Cc1cc(Cl)cc(Cl)c1
Product: Cc1ccccc1-c1cnc(N2CCN(C)CC2)nc1C(=O)N(C)Cc1cc(Cl)cc(Cl)c1
Reaction time: 16 h
Yield: 89 %

Procedure:
To a solution of 0.25 g (0.538 mmol) 2-methylsulfonyl-5-o-tolyl-pyrimidine-4-carboxylic acid (3,5-dichloro-benzyl)-methyl-amide in 5 ml dioxane 0.15 ml (1.34 mmol) 1-methylpiperazine was added. The reaction mixture was stirred for 16 hrs. After evaporation of the solvent, the residue was distributed between 25 ml CH2Cl2 and 25 ml H2O. The aqueous layer was extracted with 20 ml CH2Cl2, the combined organic layers dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/MeOH/NH4OH) 9:1) to give 0.116 g (44%) 2-(4-methyl-piperazin-1-yl)-5-o-tolyl-pyrimidine-4-carboxylic acid (3,5-dichloro-benzyl)-methyl-amide as a colorless oil, MS (ISP): 484.3, 486.3 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:27][CH:26]=3)=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[C:9](=[O:13])[O:10]2)=[CH:5][CH:4]=1.[Br:38]Br.O>CC(O)=O>[Br:38][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:3]=1[O:2][CH3:1])[O:10][C:9](=[O:13])[C:8]([C:14]1[CH:15]=[CH:16][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:18][CH:19]=1)=[C:7]2[CH2:24][C:25]1[CH:26]=[CH:27][C:28]([O:31][C:32](=[O:37])[C:33]([CH3:34])([CH3:36])[CH3:35])=[CH:29][CH:30]=1
Reactant: BrBr
Reactant: COc1ccc2c(Cc3ccc(OC(=O)C(C)(C)C)cc3)c(-c3ccc(C(F)(F)F)cc3)c(=O)oc2c1
Solvent: CC(=O)O
Solvent: O
Product: COc1cc2oc(=O)c(-c3ccc(C(F)(F)F)cc3)c(Cc3ccc(OC(=O)C(C)(C)C)cc3)c2cc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.8 %

Procedure:
A mixture of 2,2-dimethyl-propionic acid 4-(7-methoxy-2-oxo-3-(4-trifluoromethyl-phenyl)-2H-chromen-4-ylmethyl)-phenyl ester from step C (820 mg, 1.61 mmol) and Br2 (83 μL, 1.61 mmol) in AcOH (15 mL) was stirred at room temperature for 16 h. Another portion of Br2 (80 μL, 1.55 mmol) was added, and stirring was continued for 6 h. The mixture was poured into H2O, and the aqueous layer was extracted with CH2Cl2 (2×). The combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The residual orange solid was crystallized from CH2Cl2/hexane to afford the desired compound as a white solid (710 mg, 75%). 1H NMR (300 MHz, CDCl3) δ 7.67 (s, 1H), 7.65 (d, J=8.5 Hz, 2H), 7.38 (d, J=8.5 Hz, 2H), 7.07–6.94 (m, 4H), 6.89 (s, 1H), 4.01 (s, 2H), 3.98 (s, 3H), 1.35 (s, 9H); MS (ESI) m/z 588.8 (M+H)+; HPLC tR 7.78 min.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][CH2:9][O:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:3]1.F[C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[N+:25]([O-:27])=[O:26].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:24][C:22]1[CH:21]=[CH:20][C:19]([N+:25]([O-:27])=[O:26])=[C:18]([NH:1][C@@H:2]2[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][CH2:9][O:10][C:11](=[O:16])[C:12]([CH3:13])([CH3:15])[CH3:14])[CH2:3]2)[CH:23]=1
Reactant: CC(C)(C)C(=O)OCCN1CCC[C@@H](N)C1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCCN1CCC[C@@H](Nc2cc(F)ccc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.1 %

Procedure:
To an ice-cooled solution of 2,2-dimethylpropionic acid 2-((R)-3-aminopiperidin-1-yl)ethyl ester (1.675 g, 7.33 mmol) in DMF (30 mL) was added 2,4-difluoronitrobenzene (1.517 g, 9.54 mmol) and potassium carbonate (2.03 g, 14.7 mmol). The reaction mixture was stirred at RT for 16 h, then partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc and the combined organic fractions washed with water, followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, eluant 10-40% EtOAc in cyclohexane) affording the title compound as a yellow oil (2.533 g, 94%). LCMS (Method J): RT 2.31 min [M+H]+ 368.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:8]([NH2:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>>[CH2:8]([NH:14][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: Brc1cccnc1
Reactant: CCCCCCN
Product: CCCCCCNc1cccnc1
Yield: 81.9 %

Procedure:
Using the general procedure, 3-bromopyridine (96 μL, 1.0 mmol) was coupled with n-hexylamine (198 μL, 1.5 mmol) at 90° C. for 18 h. Purification of the crude product by column chromatography on silica gel using hexane/ethyl acetate (1:1) as eluent afforded the desired product as a colorless oil (146 mg, 82% yield). Rf=0.2 (hexane/ethyl acetate=2:1).
Reaction SMILES: [CH2:1]([C:3]1([CH2:6][CH3:7])[CH2:5][O:4]1)[CH3:2].[NH2:8][C:9]1[CH:10]=[C:11]([CH:15]([OH:19])[CH2:16][C:17]#[N:18])[CH:12]=[CH:13][CH:14]=1>>[CH2:1]([C:3]([OH:4])([CH2:6][CH3:7])[CH2:5][NH:8][C:9]1[CH:10]=[C:11]([CH:15]([OH:19])[CH2:16][C:17]#[N:18])[CH:12]=[CH:13][CH:14]=1)[CH3:2]
Reactant: CCC1(CC)CO1
Reactant: N#CCC(O)c1cccc(N)c1
Product: CCC(O)(CC)CNc1cccc(C(O)CC#N)c1

Procedure:
Reaction between 2,2-diethyloxirane and aniline 12 gives 3-(3-(2-ethyl-2-hydroxybutylamino)phenyl)-3-hydroxypropanenitrile.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:26])C=1.C([O-])(O)=O.[Na+].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.O>[Cl:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][S:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:26])=[O:11])=[CH:7][CH:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S(Cc1ccc(CCl)cc1)c1ccccc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=S(=O)(Cc1ccc(CCl)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
27.61 g (0.104 mol) (1a) was dissolved in 400 ml CH2Cl2. This solution was added dropwise to an ice-cooled solution of 36.03 g (0.208 mol) 3-chloroperbenzoic acid in 600 ml CH2Cl2 and 33.61 g (0.375 mol) NaHCO3 in 200 ml H2O. After the addition of (1a) the mixture was allowed to warm up to room temperature, and this was followed by another 2 hours' stirring. The reaction mixture was then poured into 500 ml 5% Na2CO3 solution. The organic layer was washed with 500 ml 5% Na2S2O3 solution. The CH2Cl2 was dried over MgSO4 and evaporated. The precipitate was purified by recrystallization from hexane/toluene. Yield: 26.65 g (91%); m.p.=170.3-170.9° C. (dec.)
Reaction SMILES: Cl[C:2]1[N:17]=[CH:16][C:15]([I:18])=[C:14](Cl)[C:3]=1[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[Na].[CH2:21]1[CH2:25][O:24][CH2:23][CH2:22]1>>[CH2:23]([O:24][C:2]1[N:17]=[CH:16][C:15]([I:18])=[C:14]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]=1[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5])[C:22]1[CH:21]=[CH:25][CH:2]=[CH:3][CH:4]=1
Reactant: C1CCOC1
Reactant: O=C(OCc1ccccc1)c1c(Cl)ncc(I)c1Cl
Agent: [Na]
Product: O=C(OCc1ccccc1)c1c(OCc2ccccc2)ncc(I)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
Into a solution of benzyl 2,4-dichloro-5-iodonicotinate (3.7 g, 9.1 mmol) in THF (20 mL) was added a solution of sodium benzoxide in THF (1.0 M×20 mL, 20 mmol). The mixture was stirred at room temperature overnight. The reaction was quenched with saturated NH4Cl. The mixture was extracted with ethyl acetate. The organic layers were combined and washed with brine, dried over sodium sulfate, evaporated and purified by silica chromatography (0-7% ethyl acetate in hexanes) to give benzyl 2,4-bis(benzyloxy)-5-iodonicotinate (2.55 g, 51%).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH:8]1[CH:12]=[N:11][C:10]([C:13]#[N:14])=[N:9]1>>[C:13]([C:10]1[N:11]=[CH:12][N:8]([CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[N:9]=1)#[N:14]
Reactant: N#Cc1nc[nH]n1
Reactant: CCOC(=O)CBr
Product: CCOC(=O)Cn1cnc(C#N)n1
Yield: 83.5 %

Procedure:
Ethyl 2-bromoacetate (8.88 g, 53.15 mmol) was reacted with 1H-1,2,4-triazole-3-carbonitrile (5 g, 53.15 mmol) according to the procedure as described in Example 48, Step A to give the title compound as a white solid (8 g, 84%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([C:10]#[N:11])[C:7]([N:12]2[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CO[CH:20](OC)[N:21]([CH3:23])[CH3:22]>C1(C)C=CC=CC=1>[CH3:20][N:21]([CH3:23])/[CH:22]=[CH:2]/[C:1]([C:4]1[N:9]=[C:8]([C:10]#[N:11])[C:7]([N:12]2[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13]2)=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccc(N2CC[C@H](O)C2)c(C#N)n1
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CN(C)/C=C/C(=O)c1ccc(N2CC[C@H](O)C2)c(C#N)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
6-Acetyl-3-((S)-3-hydroxy-pyrrolidin-1-yl)-pyridine-2-carbonitrile (65) (1.32 g, 5.71 mmol) was dissolved in dry toluene (30 mL). N,N-dimethylformamide dimethyl acetal (2.3 mL, 17.3 mmol) was added and the mixture was stirred at reflux for 5 hours. N,N-Dimethylformamide dimethyl acetal (5.0 mL, 37.6 mmol) was added and the mixture was stirred at reflux for 4 hours. The solution was cooled to rt and the solution left to stand at rt for 16 hours. The solvent was carefully decanted and the remaining reside triturated with Et2O (50 mL) followed by EtOAc (50 mL). The residual solvent was evaporated in vacuo. The title compound 66 was afforded as an orange solid (1.11 g, 68%); LCMS, Rt=1.98 min (MeOH-FA method), m/z 287 (MH+).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH2:4]1.[NH2:17][C:18]1[C:26]([Cl:27])=[CH:25][C:21]([C:22](O)=[O:23])=[C:20]([O:28][CH2:29][CH3:30])[CH:19]=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[NH2:17][C:18]1[C:26]([Cl:27])=[CH:25][C:21]([C:22]([NH:1][CH2:2][CH:3]2[O:8][CH2:7][CH2:6][N:5]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[CH2:4]2)=[O:23])=[C:20]([O:28][CH2:29][CH3:30])[CH:19]=1
Reactant: NCC1CN(Cc2ccc(F)cc2)CCO1
Reactant: CCOc1cc(N)c(Cl)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCOc1cc(N)c(Cl)cc1C(=O)NCC1CN(Cc2ccc(F)cc2)CCO1
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.8 %

Procedure:
To a solution of 2-aminomethyl-4-(4-fluorobenzyl)morpholine (2.5 g) in dichloromethane (50 ml), 4-amino-5-chloro-2-ethoxybenzoic acid (2.7 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.4 g) are added, and the mixture is stirred at 25° C. for 4 hours. The reaction mixture is washed successively with water, aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and evaporated under reduced pressure. The residue is recrystallized from ethanol to give the title compound (3.0 g), mp 151°-153° C.
Reaction SMILES: Cl[CH2:2][C:3]([O:5][C:6]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])([CH:8]=[CH2:9])[CH3:7])=[O:4].[CH2:16]([NH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[C:6]([O:5][C:3](=[O:4])[CH2:2][N:28]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])([CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])([CH:8]=[CH2:9])[CH3:7]
Reactant: C=CC(C)(CCC=C(C)C)OC(=O)CCl
Reactant: CCCCCCCCCCCCNCCCCCCCCCCCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=CC(C)(CCC=C(C)C)OC(=O)CN(CCCCCCCCCCCC)CCCCCCCCCCCC
Temperature: 60 °C

Procedure:
Linalyl chloroacetate (5.77 g, 25 mmol, 1 eq), in toluene (50 ml), was slowly added to didodecylamine (10 g, 28.3 mmol, 1.13 eq) and sodium carbonate (5.3 g, 0.05 mol, 2 eq), in toluene (50 ml). The reaction mixture was stirred at 60° C. for two weeks after which the reaction seemed completed by 1H NMR. The sodium carbonate was filtered off, the filtrate was concentrated under vacuum and diethyl ether (200 ml) was added before storage of the solution at 4° C. for 12 hours. Then, the solution was filtered and removal of ether under vacuum yielded to the expected N,N-didodecylglycine linalyl ester as a yellow oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1.O=[C:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[CH:29]([C:36]([O-:38])=[O:37])[O:28]1.[Li+]>C(COC)OC>[O:10]=[C:2]1[C:3](=[C:27]2[C:31]3[C:30](=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:29]([C:36]([OH:38])=[O:37])[O:28]2)[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1]1
Reactant: O=C1OC(C(=O)[O-])c2ccccc21
Reactant: O=C1Cc2ccccc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: COCCOC
Product: O=C1Nc2ccccc2C1=C1OC(C(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 13.2 %

Procedure:
To a solution of oxindole (1.10 g, 8.27 mmol) in dimethoxyethane (30.0 ml) at room temperature was added 1.0M LiHMDS/THF (17.0 ml). The mixture was stirred for 10 minutes at room temperature, and lithium 3-oxo-1,3-dihydro-2-benzofuran-1-carboxylate (1.37 g, 7.44 mmol) was added in one portion. After the reaction was rapidly stirred at room temperature for 18 hours, it was quenched into 4% HCl aqueous solution (200 mL), and the mixture was stirred 5 minutes. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and then extracted with saturated NaHCO3 aqueous solution. The aqueous layer was acidified with 4% HCl aqueous solution, and extracted with EtOAc. The combined organic layers were washed with brine, dried with anhydrous Na2SO4, and rotary evaporated to obtain a yellow solid. The yellow solid was triturated at room temperature with CHCl3, and then triturated with hot isopropanol to give 3-(2-oxo-1,2-dihydro-indol-3-ylidene)-1,3-dihydro-isobenzofuran-1-carboxylic acid as a yellow solid (287 mg, 13%).
Reaction SMILES: [Cl:1]C1N(CC(OC(C)C)=O)C2C(C(CC)CC)=CC=C(Cl)C=2N=1.[Br:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[C:27](Cl)[CH:26]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C(C)=CC=CC=1>O>[Br:24][C:25]1([Cl:1])[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH2:26]1
Reactant: Nc1ccc(Br)cc1Cl
Reactant: CCC(CC)c1ccc(Cl)c2nc(Cl)n(CC(=O)OC(C)C)c12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: NC1=CCC(Cl)(Br)C=C1
Temperature: 150 °C
Reaction time: 2 h

Procedure:
A mixture of isopropyl [2,4-dichloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]acetate (Reference Example 10; 1.33 g, 3.72 mmol), 4-bromo-2-chloroaniline (1.92 g, 9.31 mmol), p-toluenesulfonic acid monohydrate (707.6 mg, 3.98 mmol) and xylene (10.0 mL) was stirred at 150° C. for 2 hr. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate (×3). The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-15% ethyl acetate/n-hexane gradient mixture to give isopropyl {2-[(4-bromo-2-chlorophenyl)amino-4-chloro]-7-(1-ethylpropyl)-1H-benzimidazol-1-yl}acetate and 4-bromo-4-chloroaniline. The mixture was used for the next step without further purification.