Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:16]=[C:15]([CH2:17][C:18]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[O:19])[CH:14]=[CH:13][N:12]=1.O>CN(C)C1C=CN=CC=1.CN(C)C(=O)C>[C:1]([NH:10][C:11]1[CH:16]=[C:15]([CH2:17][C:18]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[O:19])[CH:14]=[CH:13][N:12]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc(C(=O)Cc2ccnc(N)c2)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1ccc(C(=O)Cc2ccnc(NC(=O)c3ccccc3)c2)cc1
Temperature: 70 °C
Reaction time: 12 h
Yield: 55.6 %

Procedure:
Benzoyl chloride (4.4 g, 31 mmol) and 4-dimethylaminopyridine (0.57 g, 4.7 mmol) were added to a solution of 2-(2-amino-4-pyridyl)-1-(4-methoxyphenyl)ethanone (3.8 g, 16 mmol) in N,N-dimethylacetamide (80 mL) and the mixture was stirred at 70° C. for 12 hours. After the reaction mixture was cooled to room temperature, water (50 mL) was added. The mixture was extracted with ethyl acetate and the organic layer was washed with a saturated aqueous solution of sodium chloride. The layer was dried over magnesium sulfate, filtered and concentrated. The residue was dissolved in tetrahydrofuran (80 mL) and methanol (20 mL) and 1N-aqueous solution of sodium hydroxide (50 mL) was added. The mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated and water (100 mL) was added. The mixture was extracted with ethyl acetate and the organic layer was washed with a saturated aqueous solution of sodium chloride. The layer was dried over magnesium sulfate, filtered and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain 3.1 g of the title compound (8.9 mmol, yield 57%).
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:15]([NH:17][C@H:18]([C:31]([OH:33])=[O:32])[CH2:19][CH2:20][C:21](=[O:30])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]>N1CCCCC1.O1CCOCC1>[NH2:1][C@H:2]([C:15]([NH:17][C@H:18]([C:31]([OH:33])=[O:32])[CH2:19][CH2:20][C:21](=[O:30])[O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9]
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)O
Solvent: C1CCNCC1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCCCC[C@H](N)C(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Fmoc-L-Lys(Boc)-L-Glu(OBzl)-OH (69.0 g, 0.1 mol) was dissolved in 300 ml of 20% piperidine in dioxane and stirred for 1 hour at room temperature. The solvent was evaporated in vacuum and residual oil was dissolved in 0.1% AcOH. The precipitate was filtered off and washed with 0.1% AcOH and water to neutral pH. The yield was 43.7 (94%). Rf=0.5 (CHCl3:MeOH: 32% AcOH=5:3:1).
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([O:32][CH3:33])[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([O:17][CH2:18][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:23][C:24]=2[CH3:25])=[CH:9][CH:8]=1)C.[OH-].[Na+]>C1COCC1.CCO>[CH3:33][O:32][CH:5]([CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([O:17][CH2:18][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:23][C:24]=2[CH3:25])=[CH:9][CH:8]=1)[C:4]([OH:34])=[O:3]
Reactant: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccccc12)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COC(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccccc12)C(=O)O
Reaction time: 24 h
Yield: 59.1 %

Procedure:
0.137 g of 2-Methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-naphthalen-1-yl}-propionic acid ethyl ester (0.298 mmol) was dissolved in 2 ml of THF/EtOH=1/1 and treated with 0.745 ml of 2N NaOH. The reaction mixture was kept for 24 h at ambient temperature and then quenched by pouring onto crashed ice/HCl. Twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents left a crude product, which was purified by twofold crystallisation from AcOEt/hexane to yield 0.076 g of the title compound as a white solid, mp.128-130°.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH:17]=[CH:18][C:19](=[O:21])[CH3:20])[CH:15]=2)[NH:10][CH:9]=1.CO>[Pd].C(Cl)Cl>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][CH2:18][C:19](=[O:21])[CH3:20])[CH:15]=2)[NH:10][CH:9]=1
Reactant: CC(=O)C=Cc1ccc2[nH]cc(C[C@H]3CCCN3C)c2c1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CC(=O)CCc1ccc2[nH]cc(C[C@H]3CCCN3C)c2c1

Procedure:
Obtained from the title compound of Example 49 by a procedure similar to that described in Example 2, but using 10% palladium on charcoal as catalyst, as a foam. [α]D25 +83° (c=0.1, CH3OH). Found: C,71.61; H,8.36; N,9.02. C18H24N2O; 0.20 CH2Cl2 requires C,71.84; H,8.16; N,9.30%. LRMS: m/z 285.3 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1([C:5]([OH:20])([CH2:14][N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[CH2:4][CH2:3]1.C([Li])CCC.[S].[S:27](=O)(=O)(O)O>CCCCCC.O1CCCC1>[Cl:1][C:2]1([C:5]([OH:20])([CH2:14][N:15]2[C:19]([SH:27])=[N:18][CH:17]=[N:16]2)[CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[CH2:3][CH2:4]1
Reactant: O=S(=O)(O)O
Reactant: OC(Cc1ccccc1Cl)(Cn1cncn1)C1(Cl)CC1
Agent: [Li]CCCC
Agent: [S]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC(Cc1ccccc1Cl)(Cn1ncnc1S)C1(Cl)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
At −20° C., a mixture of 3.12 g (10 mmol) of 2-(1-chloro-cyclopropyl)-1-(2-chlorophenyl)-3-(1,2,4-triazol-1-yl)-propan-2-ol and 45 ml of absolute tetrahydrofuran is admixed with 8.4 ml (21 mmol) of n-butyl-lithium in hexane and stirred at 0° C. for 30 minutes. The reaction mixture is subsequently cooled to −70° C., admixed with 0.32 g (10 mmol) of sulphur powder and stirred at −70° C. for 30 minutes. The mixture is warmed to −10° C., admixed with ice-water and adjusted to pH 5 by addition of dilute sulphuric acid. The mixture is extracted repeatedly with ethyl acetate and the combined organic phases are dried over sodium sulphate and concentrated under reduced pressure. In this manner, 3.2 g (93% of theory) of 2-(1-chloro-cyclopropyl)-1-(2-chlorophenyl)-3-(5-mercapto-1,2,4-triazol-1-yl)-propan-2-ol are obtained in the form of a solid substance which, after recrystallization, melts at 138-139° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]([O:14][CH3:15])=[CH:12][C:6]2[CH2:7][CH2:8][NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=1.C(N(CC)CC)C.Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25]>C1(C)C=CC=CC=1>[C:24]([N:9]1[CH2:10][CH2:11][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:13]([O:14][CH3:15])=[CH:12][C:6]=2[CH2:7][CH2:8]1)([O:26][CH2:27][CH3:28])=[O:25]
Reactant: COc1cc2c(cc1OC)CCNCC2
Reactant: CCOC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCc2cc(OC)c(OC)cc2CC1

Procedure:
To a stirred solution of 42.6 g. (0.206 mole) of 7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine in 1 l. of toluene were added 35.7 ml. of triethylamine (0.256 mole) and 24.5 ml. of ethyl chloroformate (0.256 mole), at room temperature, and the mixture was refluxed for 12 hours. The reaction mixture was filtered to remove triethylamine hydrochloride and the filtrate was concentrated. The solid residue (57 g.) was recrystallized from ethyl acetate to give 3-carboethoxy-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine, m.p. 91°-93° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:13](Br)[CH:14]=[CH2:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[OH:1][C:2]1[CH:11]=[C:10]([O:12][CH2:15][CH:14]=[CH2:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(O)cc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(C(=O)OC)c(O)c1
Reaction time: 8 h

Procedure:
Methyl 2,4-dihydroxybenzoate (25 g, 148.7 mmol), allyl bromide (18.2 g, 150 mmol), and potassium carbonate (30.8 g, 22.3 mmol) were added to about 250 ml of acetone and the reaction mixture was refluxed with stirring overnight. The reaction mixture was filtered and concentrated. Separation of the pure compound was achieved by chromatography on silica gel using a Waters Prep 500™ and a 20% ethyl acetate/80% hexane solvent system.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:3]=1.[C:18]1([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(C(C)C)C(C)C)C>CN(C)C=O>[OH:17][CH2:16][CH2:15][NH:14][C:4]1[N:5]=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[C:7]([C:8]#[N:9])=[C:2]([N:27]2[CH2:28][CH2:29][N:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:25][CH2:26]2)[N:3]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1NCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1c(NCCO)nc(NCCO)nc1N1CCN(c2ccccc2)CC1

Procedure:
In analogy to the procedure described in example 20b, 4-chloro-2,6-bis-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile was treated with 4-phenyl-piperazine in N,N-dimethylformamide in the presence of N-ethyl-diisopropylamine at 40° C. to yield 2,4-bis-(2-hydroxy-ethylamino)-6-(4-phenyl-piperazin-1-yl)-pyrimidine-5-carbonitrile as an amorphous, colorless solid; MS: [M+H]+=384.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([CH3:3])[CH3:2].CI.[C:13](=O)([O-])[O-].[K+].[K+]>>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH3:13])([CH3:3])[CH3:2]
Reactant: CC(C)c1ccccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: COc1ccccc1C(C)C

Procedure:
2-Isopropylphenol was reacted with methyl iodide in the presence of potassium carbonate to yield 1-isopropyl-2-methoxybenzene, which in turn was reacted with the solution of unisolated intermediate (CF3CO2)3I described above to form the bis-[3-isopropyl-4-methoxyphenyl]iodonium salt in 40-70% yield. The bis-[3-isopropyl-4-methoxyphenyl]iodonium salt precipitated as a gummy solid, making purification impracticable and contributing to the unpredictability of the yield.
Reaction SMILES: [NH2:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([N:8]([CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([C:23](=[O:31])[C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:19][CH2:18]2)[C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[F:40][C:41]([F:46])([F:45])[C:42](O)=[O:43].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:40][C:41]([F:46])([F:45])[C:42]([NH:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([N:8]([CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([C:23](=[O:31])[C:24]3[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=3)[CH2:19][CH2:18]2)[C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[O:7])=[CH:4][CH:3]=1)=[O:43]
Reactant: O=C(O)C(F)(F)F
Reactant: Nc1ccc(C(=O)N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c2cccnc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc(F)cc1)C1CCN(CCN(C(=O)c2ccc(NC(=O)C(F)(F)F)cc2)c2cccnc2)CC1
Reaction time: 3 h
Yield: 81.2 %

Procedure:
4-Amino-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(3-pyridyl)benzamide (229.3 mg, 0.51 mmol) was dissolved in methylene chloride (2.0 ml) to which were subsequently added pyridine (0.05 ml, 0.62 mmol) and anhydrous trifluoroacetic acid (0.09 ml, 0.64 mmol) at 0° C. After 3 hours of stirring at 0° C. to room temperature, the reaction solution was mixed with saturated sodium bicarbonate aqueous solution and extracted with chloroform. The resulting organic layer was washed with saturated sodium chloride aqueous solution and water in that order, and dried on anhydrous sodium sulfate. Thereafter, the solvent was removed by evaporation, and the resulting residue was purified by silica gel column chromatography (chloroform:methanol=20:1) to obtain 224.8 mg (81.2%) of the title compound in a light yellow powder form.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5]([O:7][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:6]
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1cc(O)cc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OCc1ccccc1)c1cc(O)cc(Br)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 100.6 %

Procedure:
To a stirred solution of 3-bromo-5-hydroxybenzoic acid (2 g, 9.22 mmol) in dimethyl formamide (50 mL), was added potassium carbonate (1.27 g, 9.21 mmol), and the mixture was stirred at 0° C. for 20 minutes. Benzyl bromide (1.1 mL, 9.25 mmol) was added, and the reaction mixture allowed to warm to room temperature over 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The combined organic extracts were washed with brine, dried (magnesium sulphate), filtered, and concentrated under reduced pressure to afford the title compound (2.85 g, quantitative yield).
Reaction SMILES: Cl.Cl.[CH2:3]([C:5]1[N:9]([C:10]2[N:18]=[C:17]3[C:13]([N:14]=[C:15]([C:20]4([O:26][CH3:27])[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]4)[N:16]3[CH3:19])=[C:12]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[N:11]=2)[C:8]2[CH:34]=[CH:35][CH:36]=[CH:37][C:7]=2[N:6]=1)[CH3:4].CCN(C(C)C)C(C)C.[CH3:47][S:48](Cl)(=[O:50])=[O:49]>C1COCC1>[CH2:3]([C:5]1[N:9]([C:10]2[N:18]=[C:17]3[C:13]([N:14]=[C:15]([C:20]4([O:26][CH3:27])[CH2:25][CH2:24][CH2:23][N:22]([S:48]([CH3:47])(=[O:50])=[O:49])[CH2:21]4)[N:16]3[CH3:19])=[C:12]([N:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)[N:11]=2)[C:8]2[CH:34]=[CH:35][CH:36]=[CH:37][C:7]=2[N:6]=1)[CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CCCNC3)n(C)c2n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CCCN(S(C)(=O)=O)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 26 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-8-(3-methoxypiperidin-3-yl)-9-methyl-6-morpholin-4-yl-9H-purine dihydrochloride (150 mg, 0.27 mmol) and DIPEA (190 μL, 1.09 mmol) in THF (3 mL) was stirred for 5 min before the addition of methanesulfonyl chloride (21 μL, 0.27 mmol). The resulting mixture was stirred at r.t. for 4 h then partitioned between H2O and DCM. The organic phase was washed with brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, EtOAc:TBME, 0-100%) affording 766 (39 mg, 26%). LCMS (method I): RT 3.74 min, [M+H]+ 555.2. 1H NMR (DMSO, 400 MHz): δ 8.05-8.04 (1 H, m), 7.64-7.63 (1 H, m), 7.28-7.24 (2 H, m), 4.27 (4 H, brd s), 3.97 (1 H, d, J=13.24 Hz), 3.92 (3 H, s), 3.79 (4 H, t, J=4.61 Hz), 3.50-3.47 (2 H, m), 3.28-3.26 (2 H, m), 3.08 (3 H, s), 3.05-2.95 (4 H, m), 2.35-2.25 (1 H, m), 1.98-1.95 (2 H, m), 1.76-1.72 (1 H, m), 1.35 (3 H, t, J=7.43 Hz)
Reaction SMILES: [CH3:1]/[C:2](/[CH2:8][CH2:9]/[CH:10]=[C:11](\[CH3:18])/[CH2:12][CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])=[CH:3]\[CH2:4][C:5]([OH:7])=[O:6].[CH3:19][O:20][C:21](=[O:30])[C@@H:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)O.CO.C1(N=C=NC2CCCCC2)CCCCC1>C(OC)(C)(C)C.CN(C)C1C=CN=CC=1>[CH3:19][O:20][C:21]([C@H:22]([O:6][C:5](=[O:7])[CH2:4]/[CH:3]=[C:2](\[CH3:1])/[CH2:8][CH2:9]/[CH:10]=[C:11](\[CH3:18])/[CH2:12][CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:30]
Reactant: COC(=O)[C@H](O)c1ccccc1
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: COC(C)(C)C
Product: COC(=O)[C@H](OC(=O)C/C=C(\C)CC/C=C(\C)CCC=C(C)C)c1ccccc1
Temperature: 28 °C
Reaction time: 0.25 h
Yield: 97.9 %

Procedure:
To a solution of 12.5 g (50 mmol) (E,E)-4,8,12-trimethyl-trideca-3,7,11-trienoic acid (isomeric purity of 95%) [K. Ishihara et al., J. Am. Chem. Soc. 2002, 124, 3647-3655] in 100 ml methyl tert-butyl ether (MTBE) were added at r.t. 8.35 g (50 mmol) (R)-(−)-mandelic acid methyl ester, [α]D=−147.3 (c=1.0, MeOH), and 1.5 g 4-dimethylaminopyridine (DMAP). After stirring for 15 min at 28° C., 10.5 g (51 mmol) N,N′-dicyclohexylcarbodiimide (DCC) were added, during which the temperature raised to 35° C. The reaction mixture was stirred for 1.5 h at 38-40° C., cooled to r.t. and filtered. The resulting solution was concentrated in vacuo. The residue (23.1 g) was purified over 100 g silicagel, elution of the product with hexane/MTBE 1:1. Concentration of the combined fractions in vacuo and drying of the product in high vacuo (50° C./0.08 Torr) afforded 19.5 g (97%) of (E,E)-4,8,12-trimethyl-trideca-3,7,11-trienoic acid (R)-methoxycarbonyl-phenyl-methyl ester (1) in form of a colorless oil.
Reaction SMILES: C[O:2][C:3]1[C:11]2[CH:10]=[C:9]([C:12]3[N:13]([CH3:17])[CH:14]=[CH:15][N:16]=3)[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.B(Br)(Br)Br>>[OH:2][C:3]1[C:11]2[CH:10]=[C:9]([C:12]3[N:13]([CH3:17])[CH:14]=[CH:15][N:16]=3)[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2oc(-c3nccn3C)cc12
Agent: BrB(Br)Br
Product: Cn1ccnc1-c1cc2c(O)cccc2o1
Yield: 64.5 %

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 5 using 4-methoxy-2-(1-methylimidazol-2-yl)benzo(b)furan (2.00 g) and boron tribromide (2.0 ml), the title compound (1.21 g) was obtained as pale-yellow crystals, melting point >265° C. (decomposition).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:9]=2)[CH:4]=1.[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl.Cl>[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([C:4]2[C:3]([OH:2])=[CH:12][CH:11]=[C:10]3[C:5]=2[CH:6]=[CH:7][C:8]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9]3)=[O:23])=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COc1ccc2cc(S(C)(=O)=O)ccc2c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CS(=O)(=O)c1ccc2c(C(=O)c3ccc(F)cc3)c(O)ccc2c1
Reaction time: 16 h
Yield: 88.7 %

Procedure:
To a solution of 2-methoxy-6-methylsulfonylnaphthalene (0.93 g, 3.93 mmol), [prepared as described in step 2 above], in 1,2-dichloroethane (40 ml) was added 4-fluorobenzoyl chloride (0.93 ml, 7.87 mmol) and aluminum chloride (1.05 g, 7.87 mmol) and the reaction mixture was heated at reflux. After 16 h, the reaction mixture was poured in 2N HCl and extracted into methylene chloride. The organic layer was separated and washed with water and dried over sodium sulfate. The solvent was removed in vacuo and the crude product was purified by flash chromatography (gradient elution 10-60% ethyl acetate/hexanes) to give 1.2 g of 5-(4-fluorobenzoyl)-6-hydroxy-2-methylsulfonyl-naphthalene as a tan solid (89% yield).
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][CH2:2]1.CN(C)C=O.[OH-].[K+].[Br:14][CH2:15][CH2:16][CH2:17][CH2:18]Br>O>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][N:3]1[C:4](=[O:6])[CH2:5][S:1][CH2:2]1
Reactant: O=C1CSCN1
Reactant: BrCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CSCN1CCCCBr
Reaction time: 44 h

Procedure:
A mixture of 4-thiazolidinone (25 g), dimethylformamide (DMF hereafter, 500 ml) and KOH (27.16 g) was stirred under N2 at room temperature for 1.5 h. To the resulting mixture was added 1,4-dibromobutane (101 ml), which rapidly caused the reaction mixture to turn milky white. Stirring was continued at room temperature for 44 h. The reaction mixture was poured into H2O (1000 ml) and the aqueous mixture was extracted with ethyl acetate (EtOAc hereafter, 3×300 ml). the combined extracts were washed successively with H2O (300 ml) and brine (300 ml), dried over Na2SO4, and concentrated in vacuo to an amber oil. HPLC (high performance liquid chromatography) of a 44.95 g aliquot yielded 7.15 g of an oil which upon distillation yielded a clear liquid, b.p. 134°-137° C./0.12 mm Hg.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=O.[C:11]([CH2:13][C:14]([NH:16][C:17]([NH2:19])=[O:18])=[O:15])#[N:12]>C(O)C.N1CCCCC1>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[N:19][C:17](=[O:18])[NH:16][C:14](=[O:15])[CH2:13][C:11]#[N:12]
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: N#CCC(=O)NC(N)=O
Solvent: C1CCNCC1
Solvent: CCO
Product: N#CCC(=O)NC(=O)N=Cc1ccc(O)c(O)c1
Yield: 60.7 %

Procedure:
To 0.69 g (5 mmol) 3,4-dihydroxybenzaldehyde and 0.6 g (5.3 mmol) cyanoacetylurea in 40 ml ethanol was added 2 drops piperidine. The reaction mixture was refluxed for 2 hours, cooled, filtered and washed with cold ethanol to yield 0.75 g (60% yield) of a yellow-orange solid, m.p. 235° C. (decomposition).
Reaction SMILES: [CH3:1][N:2]([CH3:35])[C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:13]([N+:14]([O-])=O)=[CH:12][C:11]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[CH:25]=[N:26][N:27]5[CH2:32][CH2:31][CH2:30][CH2:29][C:28]=45)[CH:21]=[CH:20][N:19]=3)=[C:10]([O:33][CH3:34])[CH:9]=2)[CH2:4]1.[NH4+].[Cl-]>C(O)C.O.[Fe]>[CH3:35][N:2]([CH3:1])[C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([O:33][CH3:34])[C:11]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[CH:25]=[N:26][N:27]5[CH2:32][CH2:31][CH2:30][CH2:29][C:28]=45)[CH:21]=[CH:20][N:19]=3)=[CH:12][C:13]=2[NH2:14])[CH2:4]1
Reactant: COc1cc(N2CC[C@@H](N(C)C)C2)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1cc(N2CC[C@@H](N(C)C)C2)c(N)cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Temperature: 25 °C
Yield: 84.4 %

Procedure:
A mixture of N-{4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-2-methoxy-5-nitrophenyl}-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-amine (Intermediate 135, 198.7 mg, 0.42 mmol), iron (139 mg, 2.49 mmol) and NH4Cl (15.6 mg, 0.29 mmol) in ethanol (15 mL) and water (5 mL) was heated at reflux for 2.5 h. The mixture was then allowed to cool to r.t., filtered and concentrated in vacuo. Part-purification by ion exchange chromatography, using an SCX column, eluting with 0.7M methanolic ammonia provided crude material as a yellow gum. Further purification by FCC, eluting with 0-5% 7N methanolic ammonia in CH2Cl2 gave the title compound (159 mg, 85%) as a brown foam; 1H NMR (CDCl3): 1.83-1.97 (3H, m), 2.05-2.17 (3H, m), 2.29 (6H, s), 2.83-2.91 (1H, m), 2.98-3.08 (2H, m), 3.15-3.20 (2H, m), 3.24 (2H, t), 3.69 (2H, s), 3.83 (3H, s), 4.20 (2H, t), 6.69 (1H, s), 6.78 (1H, d), 7.45 (1H, s), 7.97 (2H, d), 8.29 (1H, d); m/z: ES+ MH+ 449.65.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[N:3]=1.[CH3:17][CH:18]([SH:20])[CH3:19].[H-].[Na+]>>[CH:18]([S:20][C:2]1[C:7]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[N:3]=1)([CH3:19])[CH3:17]
Reactant: O=C(O)C=Cc1ccc(C(F)(F)F)nc1Cl
Reactant: CC(C)S
Agent: [H-]
Agent: [Na+]
Product: CC(C)Sc1nc(C(F)(F)F)ccc1C=CC(=O)O
Yield: 36.3 %

Procedure:
3-(2-Chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (245 mg, 0.974 mmol) was reacted with 2-propanthiol (240 mg, 3.15 mmol) and sodium hydride (143 mg, 3.56 mmol) to afford the title compound (103 mg) after purification by column chromatography (Hex/EtOAc=2.5/1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.C(O)(=O)[CH2:12][C:13]([OH:15])=[O:14].N1CCCCC1.Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=[CH:12][C:13]([OH:15])=[O:14]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccc(F)c(Cl)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1ccc(F)c(Cl)c1
Temperature: 0 °C

Procedure:
A stirred mixture of 3-chloro-4-fluorobenzaldehyde (55 g, 0.35 mole), malonic acid (47 g, 0.45 mole) and 3.5 ml of piperidine in 138 ml of pyridine was heated on a steam bath for 2 hours. The reaction solution was poured into a mixture of 200 ml of concentrated hydrochloric acid and 320 g of ice to give after filtration and water wash 44 g (63%). The crude intermediate was used without further purification in part D.