Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([N:21]1[CH2:30][C@@H:29]([OH:31])[CH2:28][C@@H:22]1[C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20].[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[C:36]([O:44][C:45]([F:48])([F:47])[F:46])[CH:35]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:40]([C:37]1[CH:38]=[CH:39][C:34]([O:33][CH3:32])=[CH:35][C:36]=1[O:44][C:45]([F:46])([F:47])[F:48])(=[O:42])=[O:41])[C:6](=[O:11])[C:5]2([N:21]1[CH2:30][C@@H:29]([OH:31])[CH2:28][C@@H:22]1[C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20]
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC(F)(F)F)c1
Reactant: COc1ccc(C)cc1C1(N2C[C@@H](O)C[C@@H]2C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(C)ccc3OC)(N3C[C@@H](O)C[C@@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Yield: 72.1 %

Procedure:
With 300 mg of the compound obtained in Step 134-1 (Isomer B) and 220 mg of 4-methoxy-2-(trifluoromethoxy)benzene sulfonyl chloride as starting materials, 340 mg of the title compound (colorless amorphous) was obtained by a similar method to Example 2.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:16]2[N:20]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)[N:19]=[C:18]([CH3:27])[C:17]=2[CH2:28][OH:29])[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1>ClCCl.O=[Mn]=O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:16]2[N:20]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)[N:19]=[C:18]([CH3:27])[C:17]=2[CH:28]=[O:29])[CH:9]=[C:10]([C:12]([F:13])([F:15])[F:14])[CH:11]=1
Reactant: COCCOc1cc(-c2c(CO)c(C)nn2C2CCCCO2)cc(C(F)(F)F)c1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: COCCOc1cc(-c2c(C=O)c(C)nn2C2CCCCO2)cc(C(F)(F)F)c1
Temperature: 40 °C
Reaction time: 3 h
Yield: 94.5 %

Procedure:
A mixture of (R/S) (5-(3-(2-methoxyethoxy)-5-(trifluoromethyl)phenyl)-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)methanol (320 mg, 0.77 mmol, 1.00 equiv) and MnO2 (672 mg, 7.73 mmol, 10.01 equiv) in dichloromethane (40 mL) was stirred at 40° C. for 3 h. The reaction mixture of cooled to room temperature and the solid material was removed by filtration. The filtrate was concentrated under vacuum to give 300 mg (94%) of (R/S) 5-(3-(2-methoxyethoxy)-5-(trifluoromethyl)phenyl)-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carbaldehyde as a yellow oil. LCMS (method D, ESI): RT=1.61 min, m/z=413.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([F:9])[C:3]=1[CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12].C1C(=O)N([Br:23])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:23][CH2:8][C:6]1[CH:7]=[C:2]([F:1])[C:3]([CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12])=[C:4]([F:9])[CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C(C)c1c(F)cc(C)cc1F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(C)c1c(F)cc(CBr)cc1F
Yield: 86.1 %

Procedure:
A solution of compound (31b) (2.3 g, 10.7 mmol) in carbon tetrachloride (70 mL) was treated with NBS (2.3 g, 12.9 mmol) in the presence of a catalytic amount of AIBN (0.04 g, 0.02 mmol). The obtained crude product was subjected to silica gel column chromatography and elution with an n-hexane/ethyl acetate (4:1) solution to give 2.7 g (86%) of compound (32b) as clear red oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:37])[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]([C:14]3[N:15]=[C:16]4[C:22]([C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:21][N:20]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:17]4=[N:18][CH:19]=3)[CH:10]=[C:11]([OH:13])[CH:12]=2)[CH2:3]1.[CH3:38][C:39]1([CH3:46])[O:43][CH:42]([CH2:44]O)[CH2:41][O:40]1.CSCCO>>[CH3:38][C:39]1([CH3:46])[O:43][CH:42]([CH2:44][O:13][C:11]2[CH:10]=[C:9]([C:14]3[N:15]=[C:16]4[C:22]([C:23](=[O:28])[C:24]([CH3:25])([CH3:26])[CH3:27])=[CH:21][N:20]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:17]4=[N:18][CH:19]=3)[CH:8]=[C:7]([N:4]3[CH2:5][CH2:6][C:2]([CH3:37])([CH3:1])[CH2:3]3)[CH:12]=2)[CH2:41][O:40]1
Reactant: CC1(C)CCN(c2cc(O)cc(-c3cnc4c(n3)c(C(=O)C(C)(C)C)cn4COCC[Si](C)(C)C)c2)C1
Reactant: CC1(C)OCC(CO)O1
Agent: CSCCO
Product: CC1(C)CCN(c2cc(OCC3COC(C)(C)O3)cc(-c3cnc4c(n3)c(C(=O)C(C)(C)C)cn4COCC[Si](C)(C)C)c2)C1

Procedure:
This material was prepared starting from 1-[2-[3-(3,3-dimethyl-pyrrolidin-1-yl)-5-hydroxy-phenyl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one via Mitsunobu type alkylation similar to that which was described above, but using “(2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol” in place of “2-methylsulfanyl-ethanol”.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([NH:7][C:8]2[N:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]=[CH:3][CH:2]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[N:13]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:7]([C:5]1[CH:6]=[CH:1][CH:2]=[CH:3][N:4]=1)[C:14](=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc(Nc2ccccn2)nc1
Product: CC(=O)N(c1ccccn1)c1ccccn1

Procedure:
To a flask were added 2,2′-dipyridylamine and 12 ml acetic anhydride. The mixture was heated to 110 C under nitrogen for 5 hours and cooled to 22 C. After quenching with a slow addition of aqueous sodium bicarbonate, the mixture was made basic with the addition of small portions of sodium carbonate. The product was extracted with ethyl acetate and after removal of solvent, it was purified by silica gel chromatography using 65% ethyl acetate in hexane to give 0.8 g of an oil.
Reaction SMILES: [N:1]1([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:25][CH2:24][CH2:23][C@H:2]1[C:3]([NH:5][C@H:6]([C:8]([NH:10][CH2:11][C:12]([N:14]1[CH2:22][CH2:21][CH2:20][C@H:15]1[C:16]([O:18]C)=[O:17])=[O:13])=[O:9])[CH3:7])=[O:4].[OH-].[Na+].Cl>CO>[N:1]1([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:25][CH2:24][CH2:23][C@H:2]1[C:3]([NH:5][C@H:6]([C:8]([NH:10][CH2:11][C:12]([N:14]1[CH2:22][CH2:21][CH2:20][C@H:15]1[C:16]([OH:18])=[O:17])=[O:13])=[O:9])[CH3:7])=[O:4]
Reactant: COC(=O)[C@@H]1CCCN1C(=O)CNC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@H](NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)C(=O)NCC(=O)N1CCC[C@H]1C(=O)O

Procedure:
The crude oil of the N-Cbz-Pro-Ala-Gly-Pro-OCH3 (5g, 12 mmol) was dissolved in methanol (20 ml) in a round bottom flask. The flask was placed in an ambient temperature water bath. 1 N Sodium hydroxide solution (12 ml) was added cautiously. The solution was stirred for 3.5 hours after which time 1 N HCl solution (12 ml) was added. The solution was concentrated on the roto-evaporator and a few more drops of 1 N HCl was added until the pH is approximately 1.5 with pH paper. The water was removed with the vacuum pump to give an oil, which was recrystalized slowly from ethanol.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[O:11][CH3:12])=O.[O:13]=[C:14]([CH3:23])[CH2:15][C:16]([O:18][CH2:19][CH2:20][C:21]#[N:22])=[O:17].C(O)(=O)C.N1CCCCC1>ClCCl>[C:7]([C:6]1[CH:9]=[CH:10][C:3]([CH:1]=[C:15]([C:14](=[O:13])[CH3:23])[C:16]([O:18][CH2:19][CH2:20][C:21]#[N:22])=[O:17])=[C:4]([O:11][CH3:12])[CH:5]=1)#[N:8]
Reactant: CC(=O)CC(=O)OCCC#N
Reactant: COc1cc(C#N)ccc1C=O
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc(C#N)ccc1C=C(C(C)=O)C(=O)OCCC#N

Procedure:
3.00 g (18.62 mmol) of the compound from Example 10A, 3.18 g (20.48 mmol) of 2-cyanoethyl 3-oxobutanoate [Yamamoto, T., et al., Bioorg. Med. Chem. Lett. 16, 798-802 (2006)], 213 μl (3.72 mmol) of acetic acid and 368 μl (3.72 mmol) of piperidine are dissolved in 50 ml of anhydrous dichloromethane and stirred under reflux with a water trap overnight. The volatile components are then removed in a rotary evaporator, and the residue is purified by column chromatography (silica gel; mobile phase: gradient cyclohexane/ethyl acetate 7:3→1:1). 2.77 g (48% of theory) of the title compound are obtained as a mixture of the E/Z isomers.
Reaction SMILES: C([Cl:6])(=O)OCC.[CH2:7]([O:9][CH:10](OCC)[CH:11]1[CH2:15][CH2:14][O:13][CH:12]1OCC)[CH3:8]>>[Cl:6][CH2:14][CH2:15][C:11](=[CH:10][O:9][CH2:7][CH3:8])[CH:12]=[O:13]
Reactant: CCOC(=O)Cl
Reactant: CCOC(OCC)C1CCOC1OCC
Product: CCOC=C(C=O)CCCl
Yield: 90.5 %

Procedure:
The operation was conducted in the same manner as in Example 8 except that the amount of ethyl chlorocarbonate was 1.3-fold mol relative to the starting material. As a result, the conversion ratio of 3-(diethoxymethyl)-2-ethoxytetrahydrofuran was 97.1%, and 4-chloro-2-ethoxymethylidenebutanal was obtained in a yield of 90.5%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.Cl.[CH3:31][O:32][C:33](=[O:39])[C@@H:34]1[CH2:38][CH2:37][CH2:36][NH:35]1>C(Cl)Cl>[CH3:31][O:32][C:33](=[O:39])[C@@H:34]1[CH2:38][CH2:37][CH2:36][N:35]1[C:10](=[O:12])[C@@H:9]1[CH2:13][CH2:14][CH2:15][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: COC(=O)[C@@H]1CCCN1
Agent: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 17 h
Yield: 85.4 %

Procedure:
METHOD 1 N-tert-butoxycarbonyl L-proline (99.69 g, 0.4631 mol) was dissolved in CH2Cl2 (800 mL). The solution was cooled to 0° C. (icebath) and triethylamine (51.50 g, 0.5089 mol) added. Pivaloyl chloride (61.45 g, 0.5096 mol) was added dropwise, resulting in the precipitation of a white solid. The reaction mixture was stirred for 1 hour at 0° C. before triethylamine (102.99 g, 1.018 mol) was added. Next, L-proline methyl ester hydrochloride (76.87 g, 0.4641 mol) was added in small portions. The icebath was removed and the reaction mixture stirred at room temperature for 17 hours. The volume was increased by addition of CH2Cl2 (2 L) and the solution washed with 30% (w/w) aqueous citric acid (3×1400 mL), saturated NaHCO3 solution (3×1400 mL) and saturated brine (2×1400 mL). The solution was dried with anhydrous MgSO4 and the solvent evaporated affording the title compound as a clear oil (129.14 g, 85%) with spectral characteristics in accordance with literature data.1
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[C:5]#[N:6].[CH3:14][C:15]1[NH:16][CH:17]=[CH:18][N:19]=1>CN(C)C(=O)C>[CH3:14][C:15]1[N:16]([C:2]2[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=2)[C:5]#[N:6])[CH:17]=[CH:18][N:19]=1
Reactant: N#Cc1cc(F)cc(C(F)(F)F)c1
Reactant: Cc1ncc[nH]1
Solvent: CC(=O)N(C)C
Product: Cc1nccn1-c1cc(C#N)cc(C(F)(F)F)c1
Temperature: 145 °C
Reaction time: 19 h

Procedure:
A mixture of 3-fluoro-5-(trifluoromethyl)-benzonitrile (Lancaster Synthesis GmbH; 17 g, 89 mmol) and 2-methylimidazole (Fluka, Buchs, Switzerland; 22.2 g, 270 mmol) in N,N-dimethylacetamide (80 mL) is stirred at 145° C. for 19 h. The solvent is evaporated off under reduced pressure and the residue is dissolved in ethyl acetate (200 mL). The solution is washed with brine (200 mL), dried (Na2SO4) and the solvent is evaporated off under reduced pressure to give the crude product which is purified by recrystallisation from ether-hexane to afford the title compound as yellow crystalline solid, m.p. 132–134° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].[CH2:34]([O:36][CH2:37][CH2:38][N:39]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=[C:40]1[N:48]1[CH2:54][CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)[CH3:35].C(N(CC)C(C)C)(C)C.C(N(CC)CC)C>C(#N)C.ClCCl>[CH3:33][O:32][C:28]1[CH:27]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:29]=1[O:30][CH3:31])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:51]2[CH2:52][CH2:53][CH2:54][N:48]([C:40]3[N:39]([CH2:38][CH2:37][O:36][CH2:34][CH3:35])[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=4[N:41]=3)[CH2:49][CH2:50]2)([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccc(F)cc3)C2)cc(OC)c1OC
Reactant: CCOCCn1c(N2CCCNCC2)nc2ccccc21
Solvent: CC#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCCn1c(N2CCCN(CCC3(c4ccc(F)cc4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21
Reaction time: 48 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-(4-fluorophenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine (0.62 g, 1.4 mmol) and 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (0.5 g, 1.7 mmol), and N,N-diisopropylethylamine (0.39 g, 3.0 mmol) in acetonitrile (10 mL). Heat to reflux. After 2 days, cool evaporate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with 2% triethylamine/20% methanol/ethyl acetate to give a residue. Dissolve the residue in dichloromethane, extract with brine, dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give the title compound: Rf=0.36 (silica gel, 2% triethylamine/30% methanol/ethyl acetate).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2OC3C=CC(OC)=CC=3N=2)=[CH:4][CH:3]=1.[CH3:19][C:20]1[CH:25]=[CH:24][C:23](C2OC3C=C(OC)C=CC=3N=2)=[CH:22][CH:21]=1>>[C:8]1([C:5]2[CH:4]=[CH:3][C:2]([CH:1]=[CH:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:7][CH:6]=2)[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: COc1ccc2nc(-c3ccc(C)cc3)oc2c1
Reactant: COc1ccc2oc(-c3ccc(C)cc3)nc2c1
Product: C(=Cc1ccc(-c2ccccc2)cc1)c1ccccc1

Procedure:
In place of the 2-(4'-methylphenyl)-5-methoxybenzoxazol of formula (17), the 2-(4'-methylphenyl)-6-methoxybenzoxazol of formula ##STR19## can be employed to yield the 4-(6"-methoxybenzoxazolyl-2")-4'-phenylstilbene of formula (11), which is obtained in comparably good yield and can be purified as given in the foregoing.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)([CH2:7][O:8][CH2:9][CH:10]=[CH2:11])[C:4](=[O:19])[N:3]1[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([C:28]([F:31])([F:30])[F:29])[CH:21]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:38](Br)[C:39]#[CH:40]>CN(C=O)C>[O:1]=[C:2]1[N:6]([CH2:40][C:39]#[CH:38])[C:5]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)([CH2:7][O:8][CH2:9][CH:10]=[CH2:11])[C:4](=[O:19])[N:3]1[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([C:28]([F:30])([F:31])[F:29])[CH:21]=1
Reactant: C=CCOCC1(c2ccc(F)cc2)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCN1C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)C1(COCC=C)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 0.42 g of 4-[2,5-dioxo-4-(4-fluorophenyl)-4-[(2-propenyloxy)methyl]imidazolidin-1-yl]-2-trifluoromethylbenzonitrile in 3 mL of DMF, 160 mg of potassium carbonate and 0.2 mL of propargylbromide (80% solution in toluene) are added. The mixture is stirred at room temperature for 4 hours under argon atmosphere. Then 0.04 mL of propargylbromide (80% solution in toluene) is added and the mixture is stirred 1 hour at room temperature, evaporated to dryness, diluted with water and brine and extracted with ethyl acetate. The organic layer is dried over sodium sulfate filtered and evaporated.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH2:18][CH3:19])[C:14]([O:16]C)=[O:15])=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:20]=[CH:21][CH:22]=[CH:23][C:3]1=2.CO.[OH-].[Na+]>O>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH2:18][CH3:19])[C:14]([OH:16])=[O:15])=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:20]=[CH:21][CH:22]=[CH:23][C:3]1=2
Reactant: CCC(C(=O)OC)c1ccc2c(=O)c3ccccc3ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC(C(=O)O)c1ccc2c(=O)c3ccccc3ccc2c1

Procedure:
1.075 Ml. of 1.6 molar n-butyllithium in hexane is added to a solution of 0.242 ml. of diisopropylamine in 15 ml. of dry tetrahydrofuran. 0.300 Ml. of hexamethylphosphoric triamide is added and the mixture is cooled to about -60° C. 0.465 G. of methyl (5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)acetate is added, and after 15 minutes, 0.137 ml. of ethyl iodide is added. The mixture is warmed slowly to room temperature and a further 0.05 ml. of ethyl iodide is added. After 30 minutes an additional 0.05 ml. of ethyl iodide is added. After 30 minutes, a few drops of methanol are added, and then ether and water are added. The organic layer is washed with water, dilute hydrochloric acid and saturated sodium chloride solution, then dried and evaporated to yield the impure product, which, after chromatography on 40 g. silica gel, eluting with hexane:ether (5:1) affords methyl 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)butyrate. 0.326 G. of methyl 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)butyrate is refluxed for 4 hours in 10 ml. of methanol and 20 ml. of water containing 0.5 g. of sodium hydroxide. The mixture is cooled, washed with ether and acidified with dilute hydrochloric acid. The product is extracted with ether and the extract washed, dried and evaporated to yield 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)butyric acid (m.p. 147°-148° C).
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH3:16])=[C:6]2[C:11](=[C:12]([CH3:14])[CH:13]=1)[N:10]=[CH:9][CH:8]=[C:7]2[CH3:15])([O-])=O.O.O.[Sn](Cl)Cl.C(O)C.[OH-].[Na+]>O>[NH2:1][C:4]1[C:5]([CH3:16])=[C:6]2[C:11](=[C:12]([CH3:14])[CH:13]=1)[N:10]=[CH:9][CH:8]=[C:7]2[CH3:15]
Reactant: Cc1cc([N+](=O)[O-])c(C)c2c(C)ccnc12
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(N)c(C)c2c(C)ccnc12
Temperature: 25 °C

Procedure:
A mixture of 6-nitro-4,5,8-trimethylquinoline (0.60 g), tin(II)chloride dihydrate (3.13 g), and ethanol (40 mL) is heated for 3 hours at 60°-65° C. and then cooled to room temperature. 10% Aqueous sodium hydroxide (24 mL) and water (48 mL) are added, and the mixture is extracted three times with chloroform. The combined organic layers are washed with saturated sodium bicarbonate solution, dried over sodium sulfate, filtered and evaporated to afford a crude product. The crude product is purified by flash chromatography using 25% ethyl acetate in hexane as eluent, providing 6-amino-4,5,8-trimethylquinoline.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].S([O-])(OC)(=O)=O.ClCCCl.[C-:22]#[N:23].[Na+]>O>[C:22]([C:4]1[C:3]([O:2][CH3:1])=[C:8]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:6][N:5]=1)#[N:23]
Reactant: COc1cnccc1[N+](=O)[O-]
Reactant: [C-]#N
Agent: COS(=O)(=O)[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: COc1c([N+](=O)[O-])ccnc1C#N
Temperature: 70 °C
Reaction time: 4 h
Yield: 53 %

Procedure:
A mixture of 12.5 g (12.5 moles) of the N-oxide of 3-methoxy-4-nitropyridine, 7.72 mL (1.1 eq.) of methyl sulphate and 70 mL of 1,2-dichloroethane is heated at 70° C. for 2.5 hours. It is allowed to cool and 70 mL of water are added. It is cooled in a salt and ice bath and, in portions, 7.55 g (2.1 moles) of sodium cyanide are added, controlling the temperature so as not to exceed 10° C. After 4 hours stirring, the reaction mixture is extracted with ethyl ether, the organic phase is washed with water, concentrated and the residue chromatographed (ethyl acetate/dichloromethane). There is obtained 7.06 g of a yellow oil (yield 53%).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([I:28])=[C:7]([C:19]([I:27])=[C:20]([NH:23][C:24](=[O:26])[CH3:25])[C:21]=1[I:22])[C:8]([NH:10][C@H:11]([C:16]([OH:18])=[O:17])[CH2:12][CH:13]([CH3:15])[CH3:14])=[O:9])(=[O:3])[CH3:2].[N+:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1O)([O-:31])=[O:30].C1(N=C=NC2CCCCC2)CCCCC1>>[N+:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[O:17][C:16](=[O:18])[C@H:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[NH:10][C:8](=[O:9])[C:7]1[C:6]([I:28])=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[C:21]([I:22])=[C:20]([NH:23][C:24](=[O:26])[CH3:25])[C:19]=1[I:27])([O-:31])=[O:30]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: CC(=O)Nc1c(I)c(NC(C)=O)c(I)c(C(=O)N[C@@H](CC(C)C)C(=O)O)c1I
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CC(=O)Nc1c(I)c(NC(C)=O)c(I)c(C(=O)N[C@@H](CC(C)C)C(=O)Oc2ccccc2[N+](=O)[O-])c1I

Procedure:
Following the procedure of example 33, the product is synthesized from 14.6 g (20 mMol) N-(3,5-diacetamido-2,4,6-triiodobenzoyl)-L-leucine, 3,5 g (25 mMol) o-nitrophenol and 5 g (24 mMol) N,N'-dicyclohexylcarbodiimide. Yield: 12.5 g (73%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](O)=[O:11])=[CH:5][C:4]=1[F:13])#[N:2].S(C)C>C1COCC1>[F:13][C:4]1[CH:5]=[C:6]([CH2:9][CH2:10][OH:11])[CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: N#Cc1ccc(CC(=O)O)cc1F
Solvent: CSC
Solvent: C1CCOC1
Product: N#Cc1ccc(CCO)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (4-cyano-3-fluorophenyl)acetic acid (25.6 g, 143 mmol) in 150 mL of dry THF was cooled by ice/water, and then BH3/Me2S (10 M, 15.7 mL, 157 mmol) was added slowly. The reaction was warmed to ambient temperature and stirred overnight. The mixture was quenched with MeOH and concentrated to dryness. The residue was partitioned between water and EtOAc. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated to afford 2-fluoro-4-(2-hydroxyethyl)benzonitrile. 1H-NMR (400 MHz, CDCl3) δ ppm 7.52˜7.56 (m, 1H), 7.11˜7.15 (m, 2H), 3.89 (t, J=6.3 Hz, 2H), 2.92 (t, J=6.3 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[N:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=O)=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:40]([O:44][C:45](=[O:56])[NH:46][CH2:47][C:48]1[CH:53]=[CH:52][C:51]([CH2:54][NH2:55])=[CH:50][CH:49]=1)([CH3:43])([CH3:42])[CH3:41].CN1CCOCC1>CN(C)C=O>[C:40]([O:44][C:45](=[O:56])[NH:46][CH2:47][C:48]1[CH:49]=[CH:50][C:51]([CH2:54][NH:55][C:9]([C:8]2[C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:17][CH:16]=3)=[N:15][CH:14]=[CH:13][CH:12]=2)=[O:11])=[CH:52][CH:53]=1)([CH3:43])([CH3:41])[CH3:42]
Reactant: O=C(O)c1cccnc1Oc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NCc1ccc(CN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccc(CNC(=O)c2cccnc2Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.1 %

Procedure:
2-(4-Fluoro-phenoxy)-nicotinic acid (see reference Patent application WO 98/45268) (6.20 g, 26 mmol), 1-hydroxybenzotriazole (5.39 g, 40 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (6.62 g, 34 mmol) were disolved in N,N-dimethylformamide (50 ml) at room temperature and (4-aminomethyl-benzyl)-carbamic acid tert-butyl ester (6.28 g, 26 mmol) (see Preparation 1) added followed by addition of N-methyl morpholine (4.4 ml, 40 mmol). The reaction mixture was stirred under an atmosphere of nitrogen at room temperature for 18 hours, and then partitioned between ethyl acetate (100 ml) and water (100 ml) and the organic layer separated. The organic phase was then washed with a saturated aqueous solution of sodium chloride (100 ml), dried over anhydrous magnesium sulphate and the solvent removed in vacuo. The residue was triturated with diethylether (15 ml) giving [4-({[2-(4-fluoro-phenoxy)-pyridine-3-carbonyl]-amino}-methyl)-benzyl]-carbamic acid tert-butyl ester (9.52 g) as an off-white solid.