Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl.Cl[CH2:15][CH2:16][N:17]([CH2:19][CH2:20]Cl)[CH3:18].C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC>[CH3:18][N:17]1[CH2:19][CH2:20][N:1]([C:2]2[C:3]([OH:12])=[CH:4][C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:15][CH2:16]1
Reactant: Nc1cc2ccccc2cc1O
Reactant: CN(CCCl)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: CN1CCN(c2cc3ccccc3cc2O)CC1
Reaction time: 48 h

Procedure:
3-Aminonaphthalen-2-ol (5 g, 31.4 mmol) is brought to the reflux point of 1-butanol (100 ml) in the presence of 2-chloro-N-(chloroethyl)-N-methylethanamine hydrochloride (6.05 g, 31.4 mmol) and sodium carbonate (1.7 g, 16 mmol). After 48 h, the reaction mixture is concentrated and impregnated onto silica and then purified by flash chromatography with a mixture (93/7/1) of dichloromethane/methanol/aqueous ammonia.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:15][C:16]([F:23])([C:19]([F:22])([F:21])[F:20])[CH2:17][OH:18]>>[CH3:14][S:11]([C:8]1[CH:9]=[CH:10][C:2]([O:18][CH2:17][C:16]([F:23])([F:15])[C:19]([F:22])([F:21])[F:20])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])(=[O:13])=[O:12]
Reactant: CS(=O)(=O)c1ccc(F)c(C(=O)O)c1
Reactant: OCC(F)(F)C(F)(F)F
Product: CS(=O)(=O)c1ccc(OCC(F)(F)C(F)(F)F)c(C(=O)O)c1

Procedure:
Prepared in analogy to Example A14(c) from 2-fluoro-5-methanesulfonyl-benzoic acid (Example A14(b)) and 2,2,3,3,3-pentafluoro-1-propanol. MS (m/e): 346.9 ([M−H]−, 100%)
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].C[O-].[Na+].O.[C:14]1([C:20]2[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=2)[CH2:23]Br)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CO>[C:14]1([C:20]2[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=2)[CH2:23][CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)CC(=O)OC
Reactant: BrCc1cccc(-c2ccccc2)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)C(Cc1cccc(-c2ccccc2)c1)C(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
Solutions of dimethyl malonate (1.32 g) in dry methanol (5 ml) and 3-phenylbenzyl bromide (2.47 ) in dry methanol (5 ml, hot solution) were added successively to a stirred solution of sodium methoxide [from sodium (0.23 g) and dry methanol (20 ml)]. The resulting mixture was stirred for 2 hours at room temperature and for 2 hours under reflux, then poured into water and extracted with ether. The extracts were washed with water, dried, concentrated and purified by column chromatography using a 1:1 mixture of dichloromethane and 40°-60° C. petrol as eluant to give dimethyl (m-phenylbenzyl)malonate (1.77 g, 59%) as a yellow oil, IR (film): 1 755 and 1 740 cm-1.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[C:6]([N+:27]([O-])=O)=[C:7]([CH2:13][S:14]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1.O.NN>C(O)C.[Pd]>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([CH2:13][S:14]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C:6]=1[NH2:27]
Reactant: COc1cc(CS(=O)(=O)c2cccc3ccccc23)c([N+](=O)[O-])c(OCCCl)c1
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: COc1cc(CS(=O)(=O)c2cccc3ccccc23)c(N)c(OCCCl)c1
Temperature: 60 °C

Procedure:
A mixture of 1-[3-(2-chloro-ethoxy)-5-methoxy-2-nitro-phenylmethanesulfonyl]-naphthalene (1.0 g, 2.5 mmoles) in ethanol (25 mL) was stirred under nitrogen in a round bottom flask at 60° C. 10% Pd/C was added, and the temperature was increased to 80° C. Hydrazine hydrate (2.0 mL) was added dropwise and the mixture was stirred at reflux for 3 hours. Reaction mixture was filtered off through Celite, and the solution was washed with H2O (3×), dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off white solid (1.0 g, 2.46 mmoles).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][CH2:11][CH2:12][OH:13])=[CH:5][CH:4]=1)#[N:2].[H][H]>C(O)C.[Pd]>[OH:13][CH2:12][CH2:11][CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=1
Reactant: [H][H]
Reactant: N#Cc1ccc(C#CCCO)cc1
Agent: [Pd]
Solvent: CCO
Product: N#Cc1ccc(CCCCO)cc1

Procedure:
4-(4-Cyanophenyl)but-3-yn-1-ol (40 g, 1 wt eq, see step (i) above) in ethanol (200 mL, 5 vol) and palladium on charcoal (20 g, 0.5 wt eq, 10% Johnson Matthey type 487, 60% water) were stirred rapidly under five bar hydrogen pressure for five hours. The reaction was monitored by HPLC for the disappearance of the starting material, and the formation of sub-title compound. The reaction was filtered through kieselguhr and washed with ethanol (80 mL, 2 vol). The ethanol solution was concentrated in vacuo to give sub-title alcohol as a yellow-brown oil. Yield 36.2g, 88.5%.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[N:11]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)[CH:18]=2)[N:13]=[CH:12]1.Cl.[NH2:30][C:31]1[CH:32]=[N:33][O:34][C:35]=1[CH3:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.O>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:30][C:31]2[CH:32]=[N:33][O:34][C:35]=2[CH3:36])=[O:7])=[CH:4][C:3]=1[N:11]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)[CH:18]=2)[N:13]=[CH:12]1
Reactant: Cc1ccc(C(=O)O)cc1-n1cnc2ccc(N3CCN(C)CC3)cc2c1=O
Reactant: Cc1oncc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc(C(=O)Nc2cnoc2C)cc1-n1cnc2ccc(N3CCN(C)CC3)cc2c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.6 %

Procedure:
To a stirred slurry of 4-methyl-3-[6-(4-methylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]benzoic acid (0.38 g) in DMF (50 ml) was added 4-amino-5-methylisoxazole hydrochloride (0.27 g), HATU (0.68 g) and triethylamine (0.55 ml) and the reaction mixture stirred at room temperature for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with 1N NaOH and dried (magnesium sulphate). The residue was purified by column chromatography on a silica column using initially ethyl acetate and then a 4:1 mixture of ethyl acetate and methanol as eluent. There was thus obtained the title compound (150 mg); NMR Spectrum: (DMSOd6) 2.15 (s, 3H), 2.40 (s, 3H), 2.83 (m, 4H), 3.15 (s, 3H), 3.40 (m, 4H), 7.50 (d, 1H), 7.60 (d, 1H), 7.64 (m, 2H), 7.98 (s, 1H), 8.04 (d, 1H), 8.13 (s, 1H), 8.70 (s, 1H), 10.10 (s, 1H); Mass Spectrum: M+H+ 459.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([OH:11])=[CH:3][C:2]=1[OH:12].[N:13]([O-])=[O:14].[Na+].OS(O)(=O)=O>[OH-].[Na+]>[NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[C:3](=[N:13][OH:14])[C:2]1=[O:12]
Reactant: O=N[O-]
Reactant: Oc1cc(O)c2ccccc2n1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C1Nc2ccccc2C(=O)C1=NO
Temperature: 0 °C
Yield: 90.1 %

Procedure:
To a mixture of 3.21 g (19.9 mmol) of 2,4-quinolinediol (Aldrich) and 1.87 g (27.1 mmol) of NaNO2 in 60 mL of 0.2N NaOH in an ice-bath was added dropwise 40 mL of aqueous 2N H2SO4. The mixture was stirred in the ice-bath for 1 h after addition of H2SO4, filtered and dried to leave 3.41 g of orange solid which was crystallized by boiling with 150 mL of ethanol (95%) and filtered. The filtrate was cooled to and kept at room temperature for 5 h. The crystalline precipitate was filtered and dried to leave 1.88 g (50%) of 17a as a red solid, mp 206° C. (decomposed, lit 208° C., dec.). 1H NMR (CDCl3 +DMSO-d6), 6.65-6.78 (m, 2), 7.15 (m, 1), 7.556 (d, 0.30, J=8.1), 7.605 (d, 0.70, J=8.1), 10.887 (s, 0.3), 11.346 (s, 0.7). MS, 190 (100, M+), 173 (25), 146 (55). High resolution MS, Calcd for C9H6N2O3, 190.0375, found 190.0400.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[CH:5]=[CH:4][N:3]=1.[CH3:19][CH:20]([NH2:24])[CH2:21][CH2:22][CH3:23]>>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:24][CH:20]([CH3:19])[CH2:21][CH2:22][CH3:23])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CCCC(C)N
Reactant: O=[N+]([O-])c1c(-c2ccc(Cl)cc2Cl)ccnc1Cl
Product: CCCC(C)Nc1nccc(-c2ccc(Cl)cc2Cl)c1[N+](=O)[O-]
Yield: 85.5 %

Procedure:
2-Chloro-4-(2,4-dichloro-phenyl)-3-nitro-pyridine (0.20 g, 0.66 mmol) and 1-methyl-butylamine (0.11 g, 1.32 mmol) were treated substantially as described in Part D of Example 9 to produce 0.20 g (87%) of crude [4-(2,4-dichloro-phenyl)-3-nitro-pyridin-2-yl]-(1-methyl-butyl)-amine: MS (AP) m/z 354.2 [(M+H)+, 100].
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH:10]([C:12]([OH:14])=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[CH3:16][NH:17][O:18][CH3:19].C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CCOCC>[CH3:19][O:18][N:17]([CH3:16])[C:12]([CH:10]1[CH2:9][N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:11]1)=[O:14]
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 980 mg (4.87 mmol) of boc-azetidine-3-carboxylic acid, 951 mg (9.75 mmol) of N,O-dimethylhydroxylamine hydrochloride, 329 mg (2.435 mmol) of HOBT and 1.87 g (9.75 mmol) of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride in 30 mL of CH2Cl2 was added 2.54 mL (44.61 mmol) of N,N-diisopropylethylamine at 0° C. and it was stirred for 6 h at rt. Then the reaction mixture was poured into 100 mL of ether and washed with 20 mL of aq NaHCO3. The organic layer was dried over Na2SO4 and concentrated to afford the title compound. 1NMR (CDCl3) δ 1.46 (s, 9H), 3.23 (s, 3H), 3.62 (m, 1H), 3.68 (s, 3H), 4.07 (m, 2H), 4.09 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:4]([CH3:17])[C:3]1=[O:18].Br[C:20]1[CH:25]=[C:24]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:23]=[CH:22][C:21]=1[F:30].[F-].[Cs+]>COCCOC.CO.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]>[F:30][C:21]1[CH:20]=[CH:25][C:24]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:23][C:22]=1[C:6]1[CH:5]=[C:4]([CH3:17])[C:3](=[O:18])[N:2]([CH3:1])[CH:7]=1
Reactant: CS(=O)(=O)c1ccc(F)c(Br)c1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cn(C)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cs+]
Solvent: CO
Solvent: COCCOC
Product: Cc1cc(-c2cc(S(C)(=O)=O)ccc2F)cn(C)c1=O
Temperature: 80 °C
Reaction time: 18 h
Yield: 60.9 %

Procedure:
A mixture of 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one (2.50 g, 10.0 mmol), 2-bromo-1-fluoro-4-methylsulfonylbenzene (2.54 g, 10.0 mmol), CsF (3.8 g, 25.0 mmol), Pd(dppf)Cl2 (0.73 g, 1.0 mmol) in DME (50 mL) and MeOH (25 ml) was stirred at 80° C. for 18 hrs under N2. The mixture was concentrated and the residue was purified by column chromatography on silica gel (PE: EA=2:1-0:1) to give the title compound (1.8 g, 61%) as a red solid. LCMS: 295.9 (M+H)+
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([C:10]2[C:18]3[C:17]4[CH:19]=[C:20]([NH2:23])[CH:21]=[CH:22][C:16]=4[O:15][C:14]=3[C:13]([O:24][CH3:25])=[CH:12][CH:11]=2)=[O:9])[CH:2]=1.[C:26](Cl)(=[O:28])[CH3:27].N1C=CC=CC=1>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([C:10]2[C:18]3[C:17]4[CH:19]=[C:20]([NH:23][C:26](=[O:28])[CH3:27])[CH:21]=[CH:22][C:16]=4[O:15][C:14]=3[C:13]([O:24][CH3:25])=[CH:12][CH:11]=2)=[O:9])[CH:2]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc(C(=O)Nc2cccnc2)c2c1oc1ccc(N)cc12
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2cccnc2)c2c1oc1ccc(NC(C)=O)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N1-(pyrid-3-yl)-4-methoxy-8-amino-dibenzo[b,d]furan-1-carboxamide (100 mg, 0.30 mmol) (step 2) was treated with acetyl chloride (1.1 eq.) in THF (10 ml) containing pyridine (1.1 eq) at 0° C. and allowed to warm to room temperature. The reaction was stirred at room temperature for 1 h. THF was evaporated and the residue was purified by silica gel column chromatography using 25% acetone-chloroform as eluent to obtain 6 mg of N1-(pyrid-3-yl)-4-methoxy-8-acetamido-dibenzo[b,d]furan-1-carboxamide as white solid;
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:25]=[CH:24][C:23]([CH2:26][O:27][CH3:28])=[CH:22][N:21]=3)[CH2:16][CH2:15]2)[CH:5]=[C:4]([F:29])[C:3]=1[CH2:30][C:31]([OH:33])=O.[NH:34]1[CH2:37][CH2:36][CH2:35]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:34]1([C:31](=[O:33])[CH2:30][C:3]2[C:2]([F:1])=[CH:7][C:6]([O:8][CH2:9][CH2:10][C@@H:11]3[CH2:13][C@@H:12]3[CH:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:25]=[CH:24][C:23]([CH2:26][O:27][CH3:28])=[CH:22][N:21]=4)[CH2:16][CH2:15]3)=[CH:5][C:4]=2[F:29])[CH2:37][CH2:36][CH2:35]1
Reactant: C1CNC1
Reactant: COCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3cc(F)c(CC(=O)O)c(F)c3)CC2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[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: COCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3cc(F)c(CC(=O)N4CCC4)c(F)c3)CC2)nc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of {2,6-difluoro-4-[2-((1S,2R)-2-{1-[5-(methoxymethyl)pyrimidin-2-yl]piperidin-4-yl}cyclopropyl)ethoxy}phenyl]acetic acid (5.00 g, 10.8 mmol) in 8 ml anhydrous DMF at RT was added azetidine (0.928 g, 16.3 mmol) and N,N-diisopropylethylamine (3.78 ml, 21.7 mmol). o-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (6.18 g, 16.3 mmol) was added to the solution and the mixture stirred at RT for 4 hrs. The residue was purified by preparative biotage reverse phase (C-18) (100 g column), eluting with Acetonitrile/Water+0.1% formic acid (35% to 90%). The solid was purified by column chromatography on silica gel (Biotage 40M), eluting with EtOAc/hexanes (30% to 90%). The product was further purified by preparative biotage Reverse phase (C-18)(100 g), eluting with Acetonitrile/Water+0.1% formic acid (35% to 90%) to give the title compound. 1H NMR (500 MHz, DMSO-d6) δ 8.28 (s, 2H), 6.67 (d, J=9.4 Hz, 2H), 4.67 (t, J=13.9 Hz, 2H), 4.18 (m, 4H), 4.06 (m, 211), 3.85 (t, J=7.8 Hz, 2H), 3.38 (s, 2H), 3.23 (s, 3H), 2.85 (m, 2H), 2.20 (m, 211), 2.03 (m, 1H), 1.75 (t, J=14.2 Hz, 2H), 1.51 (m, 114), 1.21-1.25 (m, 3H), 0.87 (m, 1H), 0.57 (m, 2H), −0.08 (m, 1H). LC/MS (m/z): 501.4 (M+H)+. GPR119 Human EC50: 0.18 nM
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]([O:12]C(C)(C)C)=[O:11])=[N:4][CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:10]([OH:12])=[O:11])=[N:4][CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ncc(C#N)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cnc(C(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
To a solution of tert-butyl 3-chloro-5-cyanopicolinate (1.4 g, 3.23 mmol) in DCM (10.75 ml) was added TFA (25 ml, 323 mmol). The orange solution was stirred at RT for 1 hr. It was concentrated. Then the residue was passed through a PEAX column and the acid was eluted with 2% conc. HCl in MeOH (0.3 mL in 15 mL MeOH) to yield 3-chloro-5-cyanopicolinic acid (0.55 g, 3.01 mmol, 93% yield) as yellow solid. MS m/z=183 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:11]3([N:15]=[C:14]([NH2:16])[C:13]([CH3:17])=[N:12]3)[CH2:10][CH:9]([CH:18]3[CH2:23][CH2:22][CH2:21][O:20][CH2:19]3)[O:8][C:5]2=[CH:6][CH:7]=1.[Cl:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>[Cl-].[Na+].O.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]>[Cl:24][C:25]1[CH:30]=[C:29]([C:2]2[CH:3]=[C:4]3[C:11]4([N:15]=[C:14]([NH2:16])[C:13]([CH3:17])=[N:12]4)[CH2:10][CH:9]([CH:18]4[CH2:23][CH2:22][CH2:21][O:20][CH2:19]4)[O:8][C:5]3=[CH:6][CH:7]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CC1=NC2(CC(C3CCCOC3)Oc3ccc(Br)cc32)N=C1N
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC1=NC2(CC(C3CCCOC3)Oc3ccc(-c4cccc(Cl)c4)cc32)N=C1N
Temperature: 130 °C

Procedure:
A mixture of 6-bromo-5′-methyl-2-(tetrahydro-2H-pyran-3-yl)spiro[chroman-4,2′-imidazol]-4′-amine (Isomeric mixture 1 from Example 47 Step 3, 0.181 g, 0.48 mmol), 3-chlorophenylboronic acid (0.112 g, 0.72 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride (0.035 g, 0.04 mmol), K2CO3 (2 M aq.) (0.479 mL, 0.96 mmol) and 1,4-dioxane (4 mL) were mixed in a vial and heated in a microwave reactor at 130° C. for 15 min. When cooled to r.t. the mixture was diluted with brine (3 mL) and extracted with DCM (3×3 mL). The combined organics were concentrated and the resulting residue was taken up in MeOH (1.5 mL), filtered and purified by preparative chromatography. The stereoisomers were separated using chiral SFC HPLC on a Phenomenex Lux C4; 4.6*250 mm; 5 μm column, and a mobile phase consisting of 20% MeOH (containing 0.1% diethylamine) and 80% CO2 and a flow rate of 50 mL/min to give:
Reaction SMILES: C(O[C:5]1[CH:10]=[CH:9][C:8](Cl)=[CH:7][CH:6]=1)(=O)C.[C:12]([O:15][C:16](C)=[CH2:17])(=[O:14])[CH3:13]>>[C:12]([O:15][C@@H:16]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH3:17])(=[O:14])[CH3:13]
Reactant: C=C(C)OC(C)=O
Reactant: CC(=O)Oc1ccc(Cl)cc1
Product: CC(=O)O[C@H](C)c1ccccc1
Yield: 95 %

Procedure:
The procedure of Example 1 was repeated except that 3 molar equivalents of p-chlorophenyl acetate (a conventional acylating agent) was used in place of isopropenyl acetate in the presence of three times the amount of the enzyme catalyst used in Example 1 over a reaction period of 42 hours, to obtain (R)-1-phenylethyl acetate having an optical purity of higher than 99%, at a yield of 95%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][O:13][NH:14][C:15](=[O:17])[CH3:16].[I:18]CC(Cl)=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][O:13][NH:14][C:15](=[O:17])[CH2:16][I:18]
Reactant: O=C(Cl)CI
Reactant: COc1ccc2[nH]cc(CONC(C)=O)c2c1
Product: COc1ccc2[nH]cc(CONC(=O)CI)c2c1

Procedure:
By carrying out the procedure in the same manner as for the synthesis of the compound of Example 13, but replacing the acetic acid chloride with iodoacetic acid chloride, the title compound is obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([CH2:22][O:23][CH2:24][CH3:25])[N:14]([CH2:15][CH:16]3[O:20][N:19]=[C:18]([CH3:21])[CH2:17]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:26]>CO>[CH2:24]([O:23][CH2:22][C:13]1[N:14]([CH2:15][CH:16]2[O:20][N:19]=[C:18]([CH3:21])[CH2:17]2)[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:26])[C:11]=2[N:12]=1)[CH3:25]
Reactant: N
Reactant: CCOCc1nc2c(Cl)nc3ccccc3c2n1CC1CC(C)=NO1
Solvent: CO
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CC1CC(C)=NO1
Temperature: 150 °C

Procedure:
4-Chloro-2-(ethoxymethyl)-1-[(3-methyl-4,5-dihydroisoxazol-5-yl)methyl]-1H-imidazo[4,5-c]quinoline (1.30 g, 3.62 mmol) was treated with a solution of 7 M ammonia in methanol (60 mL), and the mixture was sealed in a pressure vessel and heated at 150° C. for 24 hours. The volatiles were removed under reduced pressure, and the residue was partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The aqueous layer was extracted with two additional portions of dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography (silica gel, gradient elution using 98:2 to 96:4 dichloromethane/methanol) to afford 2-(ethoxymethyl)-1-[(3-methyl-4,5-dihydroisoxazol-5-yl)methyl]-1H-imidazo[4,5-c]quinolin-4-amine (1.10 g) as a white solid that was crystallized from acetonitrile to provide white needles, mp 204-205° C.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH:5]([CH:8]([CH3:10])[CH3:9])[CH2:4][CH:3]=1.CC(CCCCCC)CC.CC1C=CC=C(C(C)C)C=1>>[CH3:1][C:2]1[CH2:7][CH2:6][C@@H:5]([C:8]([CH3:10])=[CH2:9])[CH2:4][CH:3]=1
Reactant: CC1=CCC(C(C)C)CC1
Agent: CCCCCCC(C)CC
Agent: Cc1cccc(C(C)C)c1
Product: C=C(C)[C@H]1CC=C(C)CC1

Procedure:
Mixture components were 45% C10H14 and about 55% C10H20 with trace amounts of 1-methyl-4-(1-methylethyl)-cyclohexene, cis-p-menth-8(10)en-ol, 3-methyl nonane and 1-methyl-3-(1-methylethyl) benzene as determined by gas chromatography.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[C@H:5]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:29]([O:30]C)=[CH:28][CH:27]=[CH:26][C:25]=2[O:32][CH2:33]OC)=[CH:20][CH:19]=1)[NH:6][C:7](=[O:16])[C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])[CH3:2].Cl>CCO.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:36])[C@H:5]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:25]([O:32][CH3:33])=[CH:26][CH:27]=[CH:28][C:29]=2[OH:30])=[CH:20][CH:19]=1)[NH:6][C:7](=[O:16])[C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc(-c2c(OC)cccc2OCOC)cc1)NC(=O)c1c(Cl)cccc1Cl
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](Cc1ccc(-c2c(O)cccc2OC)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.4 %

Procedure:
To a solution of N-(2,6-dichlorobenzoyl)-4-(6-methoxy-2-methoxymethoxyphenyl)-L-phenylalanine ethyl ester (938 mg) in EtOH (25 mL) was added HCl (4 N in dioxane, 5 mL), and then the mixture was stirred under N2 for 4 h at room temperature. The mixture was diluted with AcOEt, washed with H2O and brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography (silica gel; eluent: AcOEt/hexane 1:2) to afford N-(2,6-dichlorobenzoyl)-4-(6-methoxy-2-hydoxyphenyl)-L-phenylalanine ethyl ester (795 mg). ESMS m/Z 488 (MH+), 486 (M−H)−.
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH:4]([CH:5]=[CH:6]1)[C:3](=[N:9][OH:10])[S:2]2.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.CC1C=CC(S(O)(=O)=O)=CC=1.O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:10][N:9]=[C:3]1[CH:4]2[CH2:7][CH2:8][CH:1]([CH:6]=[CH:5]2)[S:2]1
Reactant: C1=COCCC1
Reactant: ON=C1SC2C=CC1CC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C1=CC2CCC1SC2=NOC1CCCCO1
Yield: 93.4 %

Procedure:
A solution of 10 g (0.06 m) of 2-thiabicyclo[2.2.2]oct-5-en-3-one oxime, 9 g (0.1 m) of 98% dihydropyran, and a catalytic amount of ptoluenesulfonic acid in 30 ml of methylene chloride was heated under reflux overnight. Sodium bicarbonate was added to neutrality. The residue after removal of solvent was purified by dry column chromatography (silica gel-ethyl acetate:hexane::1:1) to give 14.4 g of yellow solid. Recrystallization from etherhexane yielded 10.1 g of the title compound as a white solid, m. 84°-5° C.
Reaction SMILES: [NH2:1][C@H:2]([C:23]([O:25]CC1C=CC=CC=1)=[O:24])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([S:13]([C:16]2[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH:5]=1>C(O)(=O)C>[NH2:1][C@H:2]([C:23]([OH:25])=[O:24])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([S:13]([C:16]2[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=2)(=[O:14])=[O:15])[CH:5]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(C[C@H](N)C(=O)OCc3ccccc3)c3ccccc32)cc1
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)n2cc(C[C@H](N)C(=O)O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 80% acetic acid (20 ml) was suspended Tr-Trp(Tos)-OBzl (1.3 g, 1.88 mM) and the mixture was stirred at room temperature for one hour, whereby the material was dissolved. The precipitated triphenylmethanol was filtered off and the filtrate was subjected to catalytic reduction for 4 hours in the presence of palladium black at room temperature. The catalyst was filtered off and the acetic acid was distilled off. The residue was recrystallized from water to give H-Trp(Tos)-OH. Yield 585 mg (86.9%); m.p. 227° C. (decomp.); [α]D21 -29.2° (c=0.5, acetic acid).