Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH:15]([OH:19])[CH2:14]1.F[C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[N+:28]([O-:30])=[O:29]>C1COCC1>[F:27][C:25]1[CH:24]=[CH:23][C:22]([N+:28]([O-:30])=[O:29])=[C:21]([O:19][C@H:15]2[CH2:16][CH2:17][CH2:18][C@@H:13]([O:12][CH3:11])[CH2:14]2)[CH:26]=1
Reactant: COC1CCCC(O)C1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CO[C@@H]1CCC[C@H](Oc2cc(F)ccc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
LiHMDS (1 M solution in THF; 5.0 ml) was added slowly to an ice/ethanol-cooled solution of 3-methoxy-cyclohexanol (7:3 mixture of cis- and trans-isomers; 601 mg) in THF (8 ml). Cooling was suspended after 5 minutes and the mixture was stirred for 15 minutes at room temperature before addition of 2,4-difluoro-1-nitro-benzene (482 μl). After 4 h another 1.5 ml of LiHMDS (1 M solution in THF) was added and the reaction mixture was stirred over night at room temperature. The reaction mixture was quenched by addition of hydrochloric acid (0.1 M), diluted with ethyl acetate, and filtered through celite. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was submitted to column chromatography (silica gel, cyclohexane/ethyl acetate 85:15) to give the cis-isomer (650 mg) and the trans-isomer (230 mg).
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH:12](O)([CH3:14])[CH3:13]>C[Si](Cl)(C)C.C(OCC)C>[CH:12]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([CH3:11])[C:2]([Cl:1])=[N:3][CH:4]=1)([CH3:14])[CH3:13]
Reactant: Cc1cc(C(=O)O)cnc1Cl
Reactant: CC(C)O
Agent: C[Si](C)(C)Cl
Solvent: CCOCC
Product: Cc1cc(C(=O)OC(C)C)cnc1Cl
Temperature: 70 °C
Reaction time: 18 h

Procedure:
To a solution of 6-chloro-5-methyl-nicotinic acid (21.64 g, 126 mmol) in isopropanol (450 mL), trimethylsilyl chloride (160 mL) is added dropwise. Upon completion of the addition, the mixture is heated to 70° C. and stirring is continued for 18 h. The mixture is diluted with diethyl ether (500 mL) and washed with sat. aq. NaHCO3 solution (5×50 mL). The washings are extracted back with diethyl ether (100 mL). The combined org. extracts are dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 6:1 to give 6-chloro-5-methyl-nicotinic acid isopropyl ester (6.09 g) as a colourless oil; LC-MS: tR=0.97 min, [M+1]+=214.03. 1H NMR (D6-DMSO): δ 1.34 (d, J=6.3 Hz, 6H), 2.41 (s, 3H), 5.11-5.22 (m, 1H), 8.27 (s, 1H), 8.73 (s, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][O:20][CH2:21][C:22]#[CH:23])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1.I[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][O:20][CH2:21][C:22]#[C:23][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1
Reactant: C#CCOCCn1c(CCOC)nc2cnc3ccccc3c21
Reactant: Ic1ccccc1
Product: COCCc1nc2cnc3ccccc3c2n1CCOCC#Cc1ccccc1
Reaction time: 0.75 h
Yield: 346.4 %

Procedure:
Using the general method of Example 12 Part A, 2-(methoxyethyl)-1-[2-(prop-2-ynyloxy)ethyl]-1H-imidazo[4,5-c]quinoline (2.72 g, 1.79 mmol) was reacted with iodobenzene (1.1 mL, 9.67 mmol) at ambient temperature. After 45 minutes the reaction was judged complete. The volatiles were removed under reduced pressure and the resulting oil partitioned between dichloromethane and 5% aqueous sodium bicarbonate. The aqueous layer was extracted with dichloromethane. The organic fractions were combined, washed with brine, dried with anhydrous sodium sulfate, and then concentrated under reduced pressure to leave a brown solid. The solid was purified by chromatography over silica gel (95/5 (dichloromethane/methanol) and trituration with hexane to provide 2.39 g of 2-(methoxyethyl)-1-{2-[(3-phenylprop-2-ynyl)oxy]ethyl}-1H-imidazo[4,5-c]quinoline as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH2:14][CH2:15][OH:16])=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6].[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[N:25]=[C:26]=[S:27]>O1CCCC1>[Cl:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([NH:13][CH2:14][CH2:15][OH:16])[C:2]=1[NH:1][C:26](=[S:27])[NH:25][C:19]1[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:18]=1[Cl:17]
Reactant: COC(=O)c1ccc(Cl)c(N)c1NCCO
Reactant: S=C=Nc1ccc(Cl)cc1Cl
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)c(NC(=S)Nc2ccc(Cl)cc2Cl)c1NCCO
Yield: 48.4 %

Procedure:
A solution of methyl 3-amino-4-chloro-2-[(2-hydroxyethyl)amino]benzoate (1.068 g, 3.16 mmol) and 2,4-dichlorophenylisothiocyanate (0.86 g, 4.21 mmol) in tetrahydrofuran (40 mL) was stirred at 50° C. for 14 hr. The reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 25-70% ethyl acetate/n-hexane gradient mixture and flash chromatography on NH-silica gel eluting with a 50-100% ethyl acetate/n-hexane gradient mixture to give the title compound (686.9 mg, 1.53 mmol, 48%) as a pale orange amorphous.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)=[O:4].[Cl:14][C:15]1[N:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[CH:28]=[C:29](I)[S:30][C:23]=23)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC=CC=1>C(Cl)Cl.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCO>[Cl:14][C:15]1[N:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[CH:28]=[C:29]([C:8]4[CH:9]=[CH:10][C:5]([C:3]([NH:2][CH3:1])=[O:4])=[CH:6][CH:7]=4)[S:30][C:23]=23)=[CH:17][CH:16]=1
Reactant: CNC(=O)c1ccc(B(O)O)cc1
Reactant: Clc1ccc(Oc2ccnc3cc(I)sc23)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CNC(=O)c1ccc(-c2cc3nccc(Oc4ccc(Cl)nc4)c3s2)cc1
Temperature: 85 °C
Yield: 65.2 %

Procedure:
A stirred mixture of 4-(methylcarbamoyl)phenylboronic acid (0.112 g, 0.625 mmol), 7-(6-chloropyridin-3-yloxy)-2-iodothieno[3,2-b]pyridine (0.194 g, 0.50 mmol), cesium carbonate (0.244 g, 0.750 mmol), toluene (4 mL) and EtOH (1 mL) was sparged with nitrogen for 5 minutes and then Pd(PPh3)4 (0.0347 g, 0.0300 mmol) was added. The reaction was heated to 85° C. for 5 hours in a sealed vessel. The mixture was diluted with DCM (20 mL) and water (20 mL). The phases were separated, and the organic was dried (Na2SO4), filtered, and concentrated in vacuo. The crude was purified by preparative TLC (2 mm thickness, Rf=0.36) eluting with 10% MeOH/CHCl3. The product was obtained as a solid (129 mg, 59%). HPLC: 98% purity (220 nm); LRMS (ESI+): 97% purity, 220 nm, m/z 396 (M+1) detected; 1H NMR (400 MHz, CDCl3) δ 8.55 (d, J=6 Hz, 1H), 8.36 (d, J=3 Hz, 1H), 7.85 (m, 2H), 7.79 (m, 3H), 7.53 (d, J=9 Hz, 1H), 7.44 (d, J=9 Hz, 1H), 6.59 (d, J=6 Hz, 1H), 6.41 (br d, J=5 Hz, 1H), 3.05 (d, J=5 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C@:10]2([CH2:27][N:28]3[CH:32]=[CH:31][N:30]=[CH:29]3)[O:14][C@H:13]([CH2:15]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:12][O:11]2)=[CH:4][CH:3]=1.[N-:33]=[N+:34]=[N-:35].[Na+]>CN(C)C=O.O>[N:33]([CH2:15][CH:13]1[CH2:12][O:11][C:10]([CH2:27][N:28]2[CH:32]=[CH:31][N:30]=[CH:29]2)([CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[O:14]1)=[N+:34]=[N-:35]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CO[C@@](CCc3ccc(Cl)cc3)(Cn3ccnc3)O2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC1COC(CCc2ccc(Cl)cc2)(Cn2ccnc2)O1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
To a mixture of QC-16 (201 mg, 0.42 mmol) in N,N-dimethylformamide (3 mL) was added sodium azide (546 mg, 8.40 mmol, 20 equiv). The mixture was heated at 110° C. with stirring for 2 h. The reaction mixture was cooled to room temperature, diluted with H2O, extracted with EtOAc (3×), and the combined organic extracts were washed sequentially with a saturated aqueous solution of Na2CO3, and 1120, and then dried (Na2SO4). The solution was concentrated and the golden oily residue purified by flash column chromatography on silica gel (EtOAc) to give the free base as an oil (Rf=0.29, EtOAc). High-vacuum drying left 121 mg (0.35 mmol, 83%) of QC-112 as a colorless oil: [α]D24=+6.6° (c=0.7, CDCl3); 1H NMR (400 MHz, CDCl3): δ 1.90-2.05 (m, 2H), 2.66-2.81 (m, 2), 3.20 (dd, J=13.2, 5.2 Hz, 1H), 3.39 (dd, J=13.2, 4.0 Hz, 1H), 3.44-3.51 (m, 1H), 3.64 (t, J=8.0 Hz, 1H), 3.78 (dd, J=8.0, 6.4 Hz, 1H), 4.02 (s, 2H), 6.98 (br s, 1H), 7.05 (br s, 1H), 7.12 (d, J=8.4 Hz, 2H), 7.25 (d, J=8.4 Hz, 2H), 7.49 (br s, 1H); 13C NMR (100 MHz, CDCl3): δ 29.0, 38.7, 51.8, 53.0, 67.9, 76.1, 109.9, 120.9, 128.8, 129.3, 129.8, 132.1, 138.7, 139.6; HRMS (EI) [M+H]+ Calcd. for C16H19ClN5O2: 348.1227. Found: 348.1234.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21](=[N:23][NH2:24])[NH2:22])=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>CS(C)=O.C(Cl)Cl>[C:31]([NH:24]/[N:23]=[C:21](\[C:18]1[N:17]=[C:16]2[N:12]([CH2:11][C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)[N:13]=[N:14][C:15]2=[N:20][CH:19]=1)/[NH2:22])(=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: NN=C(N)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Solvent: c1ccncc1
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(=O)N/N=C(/N)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Reaction time: 8 h
Yield: 70.6 %

Procedure:
To a solution of 1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazine-6-carbohydrazonamide (25 mg, 0.078 mmol) in DMSO (1 mL) and DCM (2.0 mL), was added pyridine (6.19 mg, 0.078 mmol) and acetic anhydride (10.39 mg, 0.102 mmol). After stirring overnight, the reaction mixture was filtered. The solid was washed with EtOH, H2O and EtOH to give 19.9 mg of title compound in 67% yield. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.48 (d, 1H), 8.88 (d, 1H), 8.34 (d, 1H), 8.05 (s, 1H), 8.01 (d, 1H), 7.86 (d, 1H), 7.53 (dd, 1H), 6.20 (s, 2H), 2.24 (s, 1H), 2.00 (s, 1H). LCMS (method B): [MH]+=362, tR=1.60 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:20]=2[CH:19]=[C:18]2[C@@:13]([CH3:32])([C@@H:14]([C:21]([C:23]4[S:27][C:26]([C:28]([O:30]C)=[O:29])=[CH:25][CH:24]=4)=[O:22])[CH2:15][CH2:16][CH2:17]2)[CH2:12]3)=[CH:4][CH:3]=1.[OH-].[Na+].Cl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:20]=2[CH:19]=[C:18]2[C@@:13]([CH3:32])([C@@H:14]([C:21]([C:23]4[S:27][C:26]([C:28]([OH:30])=[O:29])=[CH:25][CH:24]=4)=[O:22])[CH2:15][CH2:16][CH2:17]2)[CH2:12]3)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(C(=O)[C@H]2CCCC3=Cc4c(-c5ccc(F)cc5)ncn4C[C@@]32C)s1
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C[C@]12Cn3cnc(-c4ccc(F)cc4)c3C=C1CCC[C@@H]2C(=O)c1ccc(C(=O)O)s1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of methyl 5-((5aR,6S)-1-(4-fluorophenyl)-5a-methyl-5,5a,6,7,8,9-hexahydroimidazo[1,5-b]isoquinoline-6-carbonyl)thiophene-2-carboxylate (110 mg, 0.24 mmol) in methanol (10 mL) was added aqueous sodium hydroxide solution (1 N, 2 mL, 2 mmol) dropwise followed by water (2 mL). The reaction mixture was stirred at RT for 15 min before neutralized with hydrochloric acid solution (6 N, 0.3 mL) and aqueous 10% citric acid solution. The mixture was concentrated under reduced pressure to remove methanol. The solid was filtered, washed with water, and dried to give 5-((5aR,6S)-1-(4-fluorophenyl)-5a-methyl-5,5a,6,7,8,9-hexahydroimidazo[1,5-b]isoquinoline-6-carbonyl)thiophene-2-carboxylic acid.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Br[C:31]1[S:40][C:39]2[C:38](=[O:41])[C:37]3[CH:42]=[CH:43][CH:44]=[CH:45][C:36]=3[CH2:35][CH2:34][C:33]=2[CH:32]=1.[Cl-].[NH4+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C.C(N(CC)CC)C>[O:41]=[C:38]1[C:37]2[CH:42]=[CH:43][CH:44]=[CH:45][C:36]=2[CH2:35][CH2:34][C:33]2[CH:32]=[C:31]([CH:3]=[CH:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])[S:40][C:39]1=2
Reactant: C=CC(=O)OCC
Reactant: O=C1c2ccccc2CCc2cc(Br)sc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1cc2c(s1)C(=O)c1ccccc1CC2
Temperature: 80 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
Triethylamine (34 mL), ethyl acrylate (27.5 mL), palladium acetate (0.4 g), and P(o-Tol)3 (1.5 g) were added to a DMF (50 mL) solution of 2-bromo-9,10-dihydro-3-thiabenzo[f]azulen-4-one (7.00 g), and the mixture was stirred overnight at 80° C. in an argon atmosphere. An aqueous saturated ammonium chloride solution was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the organic layer was then washed with an aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under a reduced pressure, and the residue obtained was purified by silica gel column chromatography (chloroform-methanol=9:1), to give 6.39 g (85%) of the captioned compound as an amorphous solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.[OH:11][C:12]1[CH:17]=[CH:16][C:15]([SH:18])=[CH:14][CH:13]=1.C(N(CC)CC)C>O1CCOCC1.O>[OH:11][C:12]1[CH:17]=[CH:16][C:15]([S:18][CH2:2][C:3]2[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=2)=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(CBr)cc1
Reactant: Oc1ccc(S)cc1
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=Cc1ccc(CSc2ccc(O)cc2)cc1
Reaction time: 24 h
Yield: 62 %

Procedure:
A solution of 4-bromomethylbenzaldehyde (0.3 g, 1.5 mmol) and 4-hydroxythiophenol (0.2 g, 1.5 mmol) in 1,4-dioxane (10 mL) was degassed and treated with triethylamine (0.44 mL, 3.11 mmol). After stirring for 1 day the mixture was diluted with water (20 mL) and extracted with ethyl acetate (2-fold 20 mL). The combined organic extracts were washed with brine and dried (sodium sulphate) and the solvent removed in vacuo. The crude material was purified by flash column chromatography on silica gel eluting with heptane:ethyl acetate (9:1 changing to 0:1, by volume) to give the title compound as a solid, 62% yield, 220 mg.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.Cl[Ti](Cl)(Cl)Cl.[Zn]>[C:5]1([CH:6]=[CH:6][C:5]2[CH:8]=[CH:9][CH:2]=[CH:3][CH:4]=2)[CH:8]=[CH:9][CH:2]=[CH:3][CH:4]=1
Reactant: O=Cc1ccc(Cl)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: C(=Cc1ccccc1)c1ccccc1

Procedure:
29 grams (0.2 mole) of 4-chlorobenzaldehyde were dissolved in 300 ml of absolute dioxane and treated at about 10° C. under nitrogen with 33 ml of TiCl4. There were added 39 grams of zinc dust to the golden suspension whereupon the suspension became a black lilac color. The mixture was heated under reflux for 4-5 hours and after cooling off hydrolyzed with 10% K2CO3 solution and extracted with ether. The organic phase was dried over MgSO4, the solvent rotated off and the stilbene recrystallized.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8](=[O:20])[CH2:9][CH2:10][N:11]([CH3:19])[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:7]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([CH:8]([OH:20])[CH2:9][CH2:10][N:11]([CH3:19])[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:15])[CH3:16])[CH:7]=1
Reactant: Cc1ccc(Cl)cc1C(=O)CCN(C)C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(Cl)cc1C(O)CCN(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 3-(5-chloro-2-methylphenyl)-3-oxopropyl(methyl)carbamate (1.3 g, 4.2 mmol) in MeOH (26 mL) was added NaBH4 (0.64 g, 16.7 mmol) in portions. After addition, the mixture was stirred at room temperature overnight. The solvent was removed in vacuo to the residue, which was portioned between water and EtOAc. The organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. 1H NMR (CDCl3, 400 MHz) δ 1.49 (s, 9H), 1.65 (s, 3H), 1.94 (m, 2H), 2.87 (s, 3H), 7.26 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:23])=[C:5]([C:10]2[C:19]3[N:18]=[CH:17][CH:16]=[N:15][C:14]=3[C:13]([C:20](O)=[O:21])=[CH:12][CH:11]=2)[CH:6]=[C:7]([CH3:9])[CH:8]=1.Cl.[CH2:25]([N:27]1[CH2:32][CH2:31][N:30]([CH2:33][C:34]2[CH:35]=[CH:36][C:37]([NH2:40])=[N:38][CH:39]=2)[CH2:29][CH2:28]1)[CH3:26]>>[CH2:25]([N:27]1[CH2:28][CH2:29][N:30]([CH2:33][C:34]2[CH:35]=[CH:36][C:37]([NH:40][C:20]([C:13]3[C:14]4[N:15]=[CH:16][CH:17]=[N:18][C:19]=4[C:10]([C:5]4[CH:6]=[C:7]([CH3:9])[CH:8]=[C:3]([O:2][CH3:1])[C:4]=4[CH3:23])=[CH:11][CH:12]=3)=[O:21])=[N:38][CH:39]=2)[CH2:31][CH2:32]1)[CH3:26]
Reactant: CCN1CCN(Cc2ccc(N)nc2)CC1
Reactant: COc1cc(C)cc(-c2ccc(C(=O)O)c3nccnc23)c1C
Agent: Cl
Product: CCN1CCN(Cc2ccc(NC(=O)c3ccc(-c4cc(C)cc(OC)c4C)c4nccnc34)nc2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 8-(3-methoxy-2,5-dimethyl-phenyl)-quinoxaline-5-carboxylic acid (Step 97.1), 5-(4-ethyl-piperazin-1-ylmethyl)-pyridin-2-ylamine hydrochloride (Step 26.1) and stirring the reaction mixture for 24 h at rt. The crude product was purified by silica gel column chromatography (DCM/MeOH/NH3aq, 94:5:1). Title compound: ESI-MS: 511.1 [M+H]+; tR=3.75 min (System 1); TLC: Rf=0.29 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: ClC1SC2C=CC=CC=2N=1.N[C@H](C(O)=O)C.[S:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[C:18]1[NH:26][C@H:27]([C:29]([OH:31])=O)[CH3:28].Cl.[CH3:33][O:34][C:35](=[O:42])[C@H:36]([CH2:38][CH2:39][CH2:40][CH3:41])[NH2:37].Cl>>[CH3:33][O:34][C:35](=[O:42])[C@@H:36]([NH:37][C:29](=[O:31])[C@H:27]([CH3:28])[NH:26][C:18]1[S:17][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=1)[CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCCC[C@H](N)C(=O)OC
Reactant: C[C@H](Nc1nc2ccccc2s1)C(=O)O
Agent: C[C@H](N)C(=O)O
Agent: Cl
Agent: Clc1nc2ccccc2s1
Product: CCCC[C@H](NC(=O)[C@H](C)Nc1nc2ccccc2s1)C(=O)OC

Procedure:
Following General Procedure B and using 2-chlorobenzothiazole (Aldrich) and L-alanine (Aldrich), N-(benzothiazol-2-yl)-L-alanine was prepared. This compound was then coupled to L-norleucine methyl ester hydrochloride (Sigma) using General Procedure D (without the 1N HCl wash) to provide for the title compound as a solid (mp=99-120° C.). The latter reaction was monitored by tlc (Rf=0.42 in 1:1 EtOAc:Hexanes) and the product was purified by preparative plate chromatography using 1:1 EtOAc:Hexanes and 5:95 MeOH:dichloromethane as the eluent.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][C:28]([CH3:37])([CH3:36])[C:29]([O:31]C(C)(C)C)=[O:30])=[CH:23][CH:22]=2)[CH2:14][C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)=[C:5]([CH3:39])[CH:4]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([CH2:27][C:28]([CH3:36])([CH3:37])[C:29]([OH:31])=[O:30])=[CH:25][CH:26]=2)[CH2:14][C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)=[C:5]([CH3:39])[CH:4]=1
Reactant: COc1cc(C)c(NC(=O)CN(Cc2ccc(CC(C)(C)C(=O)OC(C)(C)C)cc2)Cc2ccco2)cc1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C)c(NC(=O)CN(Cc2ccc(CC(C)(C)C(=O)O)cc2)Cc2ccco2)cc1C
Yield: 87.4 %

Procedure:
Similarly to the procedure of Example 1-9, 170 mg (0.318 mmol) of tert-butyl 3-(4-{[(2-(4-methoxy-2,5-dimethylphenyl)amino-2-oxoethyl)(2-furylmethyl)amino]methyl}phenyl)-2,2-dimethylpropionate (Example 1-2) are reacted with 1 ml of trifluoroacetic acid in 1 ml of dichloromethane to give 133 mg (87%) of 3-(4-{[(2-(4-methoxy-2,5-dimethylphenyl)amino-2-oxoethyl)(2-furylmethyl)amino]methyl}phenyl)-2,2-dimethylpropionic acid.
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][CH:9]2[S:13][C:12](=[O:14])[NH:11][C:10]2=[O:15])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH:18](=O)[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1>C(O)C.O>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19](/[CH:18]=[CH:2]/[C:1]([C:4]2[CH:17]=[CH:16][C:7]([CH2:8][CH:9]3[S:13][C:12](=[O:14])[NH:11][C:10]3=[O:15])=[CH:6][CH:5]=2)=[O:3])=[CH:20][CH:21]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CC(=O)c1ccc(CC2SC(=O)NC2=O)cc1
Solvent: CCO
Solvent: O
Product: COc1ccc(/C=C/C(=O)c2ccc(CC3SC(=O)NC3=O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Hydrogen chloride was bubbled into an ice-cooled solution of 5-(4-acetylbenzyl)thiazolidine-2,4-dione (1.0 g, 4.0 mmol) and p-anisaldehyde (0.55 g, 4.0 mol) in ethanol (15 ml) for 1 hour. The solution was stirred overnight at room temperature, then diluted with water and the yellow precipitate of present title product collected and dried (1.37 g, 93%); m.p. 177°-180° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:23])[C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[CH2:24]([O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:23][C:4]1[C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:10][CH:9]=2)=[N:6][CH:7]=[C:2]([C:36]2[CH:37]=[CH:38][C:33]([O:32][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:34][CH:35]=2)[CH:3]=1
Reactant: CCCCCCCCOc1ccc(B(O)O)cc1
Reactant: CCCCCCCCOc1ccc(-c2ncc(Br)cc2F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CCCCCCCCOc1ccc(-c2cnc(-c3ccc(OCCCCCCCC)cc3)c(F)c2)cc1
Yield: 70 %

Procedure:
4.00 g (10.51 mmol) of 5-bromo-3-fluoro-2-(4-octyloxyphenyl)pyridine, 2.63 g (10.51 mmol) of 4-octyloxybenzeneboronic acid, 0.12 g (0.11 mmol) of tetrakis(triphenylphosphine)palladium(0) and 2.23 g (21.02 mmol) of sodium carbonate are heated at 80° C. for 3 hours in 100 ml of toluene, 70 ml of ethanol and 40 ml of water. The mixture is subsequently partitioned between aqueous sodium chloride solution and ether, and the organic phase is washed with aqueous sodium chloride solution, dried over sodium sulfate, evaporated and purified by chromatography (silica gel/dichloromethane), giving 3.72 g of 3-fluoro-2,5-di(4-octyloxyphenyl)pyridine. ##STR26## The compound has the phase sequence: X 88 (77.9) Sc 142 SA 171 N 172 I.