Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21](I)[S:22][C:13]=12.C([Sn](CCCC)(CCCC)[C:29]1[CH:33]=[C:32]([CH:34]2[O:38][CH2:37][CH2:36][O:35]2)[S:31][CH:30]=1)CCC>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21]([C:29]3[CH:33]=[C:32]([CH:34]4[O:38][CH2:37][CH2:36][O:35]4)[S:31][CH:30]=3)[S:22][C:13]=12
Reactant: COc1cc(Nc2c(C#N)cnc3cc(I)sc23)c(Cl)cc1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1csc(C2OCCO2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: COc1cc(Nc2c(C#N)cnc3cc(-c4csc(C5OCCO5)c4)sc23)c(Cl)cc1Cl
Yield: 75.1 %

Procedure:
A mixture of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-iodothieno[3,2-b]pyridine-6-carbonitrile (564 mg, 1.18 mmol), tributyl-(5-[1,3]dioxolan-2-yl-thiophen-3-yl)-stannane (680 mg, 1.52 mmol) and a pinch of bis(triphenylphosphine)palladium(II) chloride in 15 mL of dioxane is heated at reflux for 5 hours. Additional bis(triphenylphosphine)palladium(II) chloride is added and the reaction is heated at reflux overnight. Additional bis(triphenylphosphine)palladium(II) chloride and 10 mL of dioxane are added and the reaction is heated at reflux for 5 hours. The reaction mixture is concentrated in vacuo and partitioned between water and chloroform. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with 1:1 hexane:ethyl acetate. The fractions containing product are combined and concentrated in vacuo to provide 447 mg of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[5-(1,3-dioxolan-2-yl)thien-3-yl]thieno[3,2-b]pyridine-6-carbonitrile as white crystals, mp 219–221° C.; 1H NMR (DMSO-d6) δ 3.85 (s, 3H), 3.92–4.10 (m, 4H), 6.08 (s, 1H), 7.36 (s, 1H), 7.63 (s, 1H), 7.75 (s, 1H), 7.80 (s, 1H), 7.97 (s, 1H), 8.60 (s, 1H), 9.69 (s, 1H); MS 502.1 (M−H)−.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:25]=[C:24]([CH3:26])[CH:23]=[C:22]([C:27]4[CH:28]=[N:29][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:32]=4)[N:21]=3)[CH:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:26][C:24]1[CH:23]=[C:22]([C:27]2[CH:28]=[N:29][C:30]([C:33]([F:35])([F:36])[F:34])=[CH:31][CH:32]=2)[N:21]=[C:20]([C:16]2[CH:15]=[C:14]([C:11]3[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=3)[CH:19]=[CH:18][CH:17]=2)[N:25]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)nc2)nc(-c2cccc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2ccc(C(F)(F)F)nc2)nc(-c2cccc(-c3ccc(S(N)(=O)=O)s3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 6.7 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-5-{3-[4-methyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide (0.1 g) in dichloromethane (4 ml) was added TFA (4 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N Na2CO3 solution (25 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by column chromatography on silica gel (dichloromethane/MeOH/NH4OH 16:1:0.1) and crystallization (diethyl ether/MeOH) yielded the title compound as a white solid (6 mg, 3%). MS (ISP) 477.1 [(M+H)+]; mp 237.5° C.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]([S:9](=[O:12])(=[O:11])[NH2:10])=[CH:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:24])[CH3:23]>CC(C)=O>[C:22]([O:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]([S:9](=[O:11])(=[O:12])[NH2:10])=[CH:8][C:4]=2[CH:3]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)Cl
Reactant: NS(=O)(=O)c1cc2cc(O)ccc2s1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc2sc(S(N)(=O)=O)cc2c1
Temperature: -5 °C
Reaction time: 4 h
Yield: 84.7 %

Procedure:
A solution of 5-hydroxy-2-sulfamoylbenzo[b]thiophene (4.00 g, 0.017 m) in acetone (70 ml) was cooled to -5° C., triethylamine (1.92 g, 0.019 m) was added, followed by the dropwise addition of a solution of acetyl chloride (1.49 g, 0.019 m) in acetone (10 ml) over 15 minutes, maintaining the temperature at -5° to -3° C. After stirring at -5° C. for 21/4 hours, the mixture was filtered and the solid was washed with acetone. The combined filtrate and washings were concentrated under reduced pressure, the residue was dissolved in ethyl acetate (7.5 ml) washed with water (2×20 ml), dried and evaporated under reduced pressure. The residue was crystallized from 1,2-dichloroethane to yield 4.01 g (87%) of product melting at 129°-132° C. An analytical sample melted at 131.5°-133° C. after recrystallization from 1,2-dichloroethane.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:32])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([OH:31])[CH2:20][O:21][CH:22]2[CH2:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23]2)[CH2:14][CH2:13]1.[CH3:33][CH:34](O)C>>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10](=[O:32])[CH2:11][N:12]1[CH2:13][CH2:14][N:15]([CH2:18][CH:19]([OH:31])[CH2:20][O:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([CH2:27][CH2:28][CH2:29][CH3:30])=[CH:34][CH:33]=2)[CH2:16][CH2:17]1
Reactant: Cc1cccc(C)c1NC(=O)CN1CCN(CC(O)COC2Cc3ccccc3C2)CC1
Reactant: CC(C)O
Product: CCCCc1ccc(COCC(O)CN2CCN(CC(=O)Nc3c(C)cccc3C)CC2)cc1

Procedure:
Compound 24 was prepared in a similar manner to compound 7, substituting the commercially available 4-n-bu-benzylalcohol for 2-propanol in part C. MS (M+1)=468.45
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10](=[O:22])[NH:11][C:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=1)([CH3:14])[CH3:13])[CH2:2]2.[CH3:23][CH:24]([CH3:29])[CH2:25]B(O)O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:23][CH:24]([CH3:29])[CH2:25][C:17]1[CH:16]=[C:15]([C:12]([NH:11][C:10](=[O:22])[O:9][CH:3]2[CH:4]3[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]3)[CH2:2]2)([CH3:14])[CH3:13])[CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)CB(O)O
Reactant: CC(C)(NC(=O)OC1CN2CCC1CC2)c1cccc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: CC(C)Cc1cccc(C(C)(C)NC(=O)OC2CN3CCC2CC3)c1
Yield: 72.6 %

Procedure:
Using general procedure E, 1-azabicyclo[2.2.2]oct-3-yl[2-(3-bromophenyl)propan-2-yl]carbamate (75 mg, 0.20 mmol), 2-methylpropyl boronic acid (28.1 mg, 0.276 mmol) and palladium (II) acetate gave the title compound as a white solid (50 mg, 71%). 1H NMR (400 MHz, CDCl3) 7.21 (d, J=4.9 Hz, 2H), 7.16 (s, 1H), 7.00 (s, 1H), 5.17 (s, 1H), 4.60 (s, 1H), 3.35-2.10 (m, 6H), 2.45 (d, J=7.1 Hz, 2H), 1.82 (dt, J=6.8, 13.5 Hz, 1H), 2.03-0.94 (m, 5H), 1.65 (s, 6H), 0.89 (d, J=6.6 Hz, 6H) ppm. 13C NMR (100 MHz, CDCl3) δ 172.6, 172.1, 170.8, 170.2, 160.1, 160.0, 157.8, 157.7, 140.4, 139.8, 130.5, 130.4, 130.0, 129.8, 129.5, 129.3, 127.9, 127.7, 120.8, 120.7, 120.3, 113.9, 113.6, 113.2, 113.0, 110.5, 110.4, 66.6, 66.5, 56.8, 56.3, 55.4, 55.4, 54.0, 53.7, 51.1, 46.6, 43.8, 43.7, 42.0, 38.4, 37.8, 37.7, 33.8, 33.2, 27.4, 27.0, 25.7, 25.5, 20.9, 20.9 ppm. Purity: 90% UPLCMS (210 nm): retention time 0.89 min: (M+1) 345.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[K+].[K+].[CH2:17]([O:19][CH:20]([O:23][CH2:24][CH3:25])[CH2:21]Br)[CH3:18]>CN(C=O)C>[CH2:17]([O:19][CH:20]([O:23][CH2:24][CH3:25])[CH2:21][O:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]=[O:5])[CH3:18]
Reactant: O=Cc1cc(F)ccc1O
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(COc1ccc(F)cc1C=O)OCC
Yield: 32.8 %

Procedure:
To a stirred suspension containing 2-hydroxy-5-fluorobenzaldehyde (500 mg, 3.57 mmol) and K2CO3 (524 mg, 13.79 mmol) in DMF (10 mL), bromoacetaldehyde diethyl acetal (0.6 mL, 3.93 mmol) was added dropwise. The mixture was refluxed for 4 h. After cooling, the precipitate was filtered off and the solvent was evaporated in vacuo. The crude residue was adsorbed on silica gel and purified by flash chromatography, eluting with hexane/EtOAc (4:1) to give 12 (300 mg, 33%) as an oil. 1H NMR (500 MHz, CDCl3): δ: 10.30 (1H, s, CHO), 7.31 (1H, d, J=7.85 Hz), 7.10 (1H, t, J=7.80 Hz), 6.87 (1H, d, J=8.86 Hz), 4.75 (1H, s, CH), 3.97 (2H, d, J=2.35 Hz, CH2), 3.67-3.64 (2H, m, CH2CH3), 3.53-3.50 (2H, m, CH2CH3), 1.11 (6H, t, J=6.00 Hz, 2×CH3).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[CH3:12][O:13][C:14]1[CH:21]=[C:20]([O:22][CH3:23])[C:17]([CH:18]=O)=[CH:16][CH:15]=1.Cl.O>CO>[CH3:12][O:13][C:14]1[CH:21]=[C:20]([O:22][CH3:23])[C:17]([CH:18]=[C:7]2[C:6](=[O:9])[C:5]3[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][C:4]=3[O:8]2)=[CH:16][CH:15]=1
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: O=C1COc2cc(O)ccc21
Agent: Cl
Solvent: O
Solvent: CO
Product: COc1ccc(C=C2Oc3cc(O)ccc3C2=O)c(OC)c1
Temperature: 25 °C
Yield: 47.8 %

Procedure:
After 6-hydroxy-2H-benzofuran-3-one 1 g and 4,6-dimethoxybenzaldehyde 1.23 g were dissolved in methanol 75 ml, concentrated hydrochloric acid 50 ml was added, and the mixture was refluxed for 1.5 hours. The solution was cooled to room temperature, water 400 ml was added, and precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 0.95 g.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[Na].[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]Br>CO>[CH2:8]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][Br:13])=[CH:7][CH:6]=1)[C:9]([CH3:10])=[O:11]
Reactant: CC(=O)Cc1ccc(O)cc1
Reactant: BrCCCCCCCCCCBr
Agent: [Na]
Solvent: CO
Product: CC(=O)Cc1ccc(OCCCCCCCCCCBr)cc1
Reaction time: 0.17 h

Procedure:
A solution of 4-hydroxyphenyl propan-2-one, ethylene ketal (5.26 g) in methanol at room temperature, was treated with sodium (0.66 g) and allowed to stir for 10 minutes. The resulting solution was then added dropwise over 15 minutes to a solution of 1,10-dibromodecane (9.0 g) in methanol under reflux and the reaction mixture heated for 3 h. The mixture was allowed to cool and the solvent was removed in vacuo. The residue was partitioned between diethylether and water, the organic layer separated, dried (magnesium sulphate), and the solvent removed in vacuo to give an oil which was chromatographed on silica. Elution with chloroform gave 10-(4-acetonylphenoxy)decyl bromide, ethylene ketal (3.0 g) as an oil.
Reaction SMILES: [NH2:1][C@@H:2]([CH:8]([CH3:10])[CH3:9])[CH:3]([OH:7])[C:4]([OH:6])=[O:5].Cl[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]>[OH-].[Na+].O1CCOCC1.O>[CH2:15]([O:14][C:12]([NH:1][C@@H:2]([CH:8]([CH3:10])[CH3:9])[CH:3]([OH:7])[C:4]([OH:6])=[O:5])=[O:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)[C@H](N)C(O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(O)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a solution under an atmosphere of nitrogen containing 1.0 g (6.8 mmol) of 3-(S)-amino-2-(R,S)-hydroxy-4-methylpentanoic acid in 9.5 mL of 1 N NaOH and 10 mL of dioxane was added 1.43 g (8.4 mmol) of benzyl chloroformate. The pH was maintained above pH 8 with 1 N NaOH as needed. The reaction mixture was allowed to stir at room temperature overnight. The reaction was diluted with water and washed with ether. The aqueous layer was acidified with 1 N HCl to pH=2 and extracted with ether (2X). The combined organic layers were dried over magnesium sulfate, filtered and evaporated in vacuo to afford 1.75 g (92%) of 3-(S)-[(benzyloxycarbonyl)amino]-2-(R,S)-hydroxy-4-methylpentanoic acid as a light yellow viscous oil. FAB MS [M+H] m/z; Calcd: 282, Found: 282.
Reaction SMILES: [I-].[CH2:2]([N+:4]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:7]([CH3:8])=[CH:6][CH:5]=1)[CH3:3].Cl[C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][C:17]=1[N+:27]([O-:29])=[O:28].C(N(C(C)C)CC)(C)C>C(#N)C>[CH2:23]([O:22][C:20]([C:19]1[CH:25]=[CH:26][C:16]([CH:8]=[C:7]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:4]([CH2:2][CH3:3])[CH:5]=[CH:6]2)=[C:17]([N+:27]([O-:29])=[O:28])[CH:18]=1)=[O:21])[CH3:24]
Reactant: CCOC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC[n+]1ccc(C)c2ccccc21
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)c1ccc(C=C2C=CN(CC)c3ccccc32)c([N+](=O)[O-])c1

Procedure:
1-Ethyllepidinium iodide (5.8 g., 19.4 mmole) and ethyl 4-chloro-3-nitrobenzoate (4.6 g., 20 mmole) are stirred together in acetonitrile (50 ml.). Diisopropylethylamine (5.2 g., 40 mmole) is added and the mixture refluxed on a steam bath for 6 hours. The mixture is dissolved in 500 ml. ether and extracted five times with 200 ml. portions of water. The ether extract is dried over anhydrous magnesium sulfate. The dried ether solution is evaporated to dryness and then taken up on 25 ml. ether and chilled overnight. The precipitated dye is filtered off, washed with ether and petroleum ether, and dried. The yield is 2.8 g. (40%) with a m.p. of about 100° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7](=[O:9])[CH3:8])=[N:2]1.C[C:11]([CH3:14])([O-:13])[CH3:12].[Na+].[Cl-].[Li+]>CN(C=O)C>[CH3:12][C:11]1([CH3:14])[O:13][C@H:11]([CH2:14][N:1]2[CH:5]=[CH:4][C:3]([NH:6][C:7](=[O:9])[CH3:8])=[N:2]2)[CH2:12][O:13]1
Reactant: CC(C)(C)[O-]
Reactant: CC(=O)Nc1cc[nH]n1
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1
Temperature: 100 °C
Reaction time: 5 h
Yield: 279.4 %

Procedure:
A 3 L flask was charged with 200.0 g (1.60 mol) of N-(1H-pyrazol-3-yl)-acetamide and 1 L of anhydrous DMF. To the agitated suspension was added 173.8 g (1.75 mol) of sodium tert-butoxide in one portion. To the mixture was added 82.0 g (1.91 mol) of lithium chloride in one portion. To the mixture was added 267 g (1.75 mol) of (S)-(−)-4-(chloromethyl)-2,2-dimethyl-1,3-dimethyl-1,3-dioxolane in one portion. The mixture was agitated at 100° C. for 5 h. To the resulted mixture was added additional 31.6 g (0.32 mol) of sodium tert-butoxide and followed by 48.5 g (0.32 mol) of (S)-(−)-4-(chloromethyl)-2,2-dimethyl-1,3-dimethyl-1,3-dioxolane. The mixture was agitated at 100° C. for additional 5 h. To the resulted mixture was added additional 31.6 g (0.32 mol) of sodium tert-butoxide and followed by 48.5 g (0.32 mol) of (S)-(−)-4-(chloromethyl)-2,2-dimethyl-1,3-dimethyl-1,3-dioxolane. The mixture was agitated at 100° C. for 16 h. Then the mixture was cooled to 60° C. and concentrated under reduced pressure (60-25 mbar, 60° C.) to remove 720 g of the solvents. To the residue was added 1.6 L of water. The resulting solution was extracted with 3.2 L of dichloromethane (DCM). The combined organic phases were washed with 1.6 L of 20 wt % sodium chloride solution, and concentrated by distillation in vacuo (30-40° C. (batch)/P<−100 mbar), giving 585 g (316 g after corrected with wt %, 82.8% yield) of N-[1-((R)-2,2-Dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-acetamide as a red-brown oil which was used in the subsequent step directly without further processing. 1H-NMR (400 MHz, d6-DMSO): δ 10.37 (s, 1H), 7.57 (s, 1H), 6.44 (s, 1H), 4.33-4.36 (m, 1H), 4.08-4.11 (m, 2H), 3.98-4.02 (m, 1H), 3.71-3.75 (m, 1H), 1.98 (s, 3H), 1.31 (s, 3H), 1.26 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH:25]1([NH2:28])[CH2:27][CH2:26]1>>[CH:25]1([NH:28][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[N:9][O:10][C:11]=3[CH3:24])=[N:16][CH:17]=2)[CH2:27][CH2:26]1
Reactant: NC1CC1
Reactant: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)NC2CC2)cn1
Yield: 43 %

Procedure:
As described for example 105, 6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (99 mg, 0.33 mmol) was converted, using cyclopropylamine instead of 2,2,2-trifluoroethylamine, to the title compound (47 mg, 43%) which was obtained as a white solid. MS: m/e=368.0 [M+H]+.
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH:12]=[CH:13][CH2:14][CH:15]=[CH:16][CH2:17][CH3:18].C(Cl)(=O)C([Cl:24])=O>C(Cl)(Cl)Cl>[C:1]([Cl:24])(=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH:12]=[CH:13][CH2:14][CH:15]=[CH:16][CH2:17][CH3:18]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCC=CCC=CCC=CCCCCCCCC(=O)O
Solvent: ClC(Cl)Cl
Product: CCC=CCC=CCC=CCCCCCCCC(=O)Cl

Procedure:
To a solution of 834 mg of 9,12,15-octadecatrienoic acid in 8 ml of dry chloroform was added 0.4 ml of oxalyl chloride under argon at room temperature. The mixture was reacted for 2 hours. From the reaction mixture were removed the chloroform and the remaining oxalyl chloride by distillation under reduced pressure to give 9,12,15-octadecatrienoyl chloride, which was then dissolved in 6 ml of dry chloroform.
Reaction SMILES: [C:1]([C:4]1O[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:8]=1)(=O)[CH3:2].[CH2:15]([NH2:18])[CH2:16][NH2:17].O.[C:20]([OH:27])(=[O:26])/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24]>C(O)C>[C:20]([OH:27])(=[O:26])/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24].[CH3:2][C:1]1[C:4]2[N:17]([CH:6]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:8]=2)[CH2:16][CH2:15][N:18]=1
Reactant: NCCN
Reactant: CC(=O)c1cc(-c2ccccc2)co1
Agent: O=C(O)/C=C/C(=O)O
Solvent: O
Solvent: CCO
Product: CC1=NCCn2cc(-c3ccccc3)cc21
Yield: 31 %

Procedure:
2-Acetyl-4-phenylfuran (0.7 g) was heated at 100° C. for 1 hour under argon with 0.8 ml of 1,2-ethanediamine and 0.1 ml of water. After cooling 50 ml of water were added and the mixture was extracted three times with 50 ml of methylene chloride each time. The organic phases were combined, dried with MgSO4 and freed from solvent. The residue, 0.7 g of brown oil, was chromatographed on 60 g of silica gel with methylene chloride/methanol (19:1) as the eluent. The crude product, 0.4 g of brown solid, was dissolved in a 50-fold amount of hot ethanol and treated with 1.1 equivalents of a saturated solution of fumaric acid in ethanol. There was obtained 0.4 g (31%) of 3,4-dihydro-1-methyl-7-phenylpyrrolo[1,2-a]pyrazine fumarate (1:1); m.pt.: 181° C. (dec.)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:16]Br)=[CH:11][C:10]=1[CH2:26][OH:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([O:30][C:31](=[O:42])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][CH2:40][NH2:41])[CH:34]=1)[CH3:29]>>[CH2:28]([O:30][C:31](=[O:42])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][CH2:40][NH:41][CH2:16][C@@H:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:10]([CH2:26][OH:27])[CH:11]=2)[O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH:34]=1)[CH3:29]
Reactant: CCOC(=O)Cc1cccc(CCN)c1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c(CO)c1
Product: CCOC(=O)Cc1cccc(CCNC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(OCc3ccccc3)c(CO)c2)c1

Procedure:
Prepared according to the procedure used for preparation 22 using [2-(benzyloxy)-5-((1R)-2-bromo-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)phenyl]methanol (Preparation 23) and ethyl[3-(2-aminoethyl)phenyl]acetate (Preparation 58) to give the title compound as a yellow oil.
Reaction SMILES: O=[C:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4][CH2:3]1.[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][NH2:24])[N:18]=1>CCOCC>[Br:16][C:17]1[N:18]=[C:19]([NH:23][N:24]=[C:2]2[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4][CH2:3]2)[CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)CC1
Reactant: NNc1cccc(Br)n1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCCC(=NNc2cccc(Br)n2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.9 %

Procedure:
tert-Butyl 4-oxoazepane-1-carboxylate (1.7 g, 8.1 mmol) was added to a solution of 2-bromo-6-hydrazinylpyridine (1.5 g, 8.1 mmol) in Et2O (27 mL), and the resulting solution was stirred at ambient temperature for 1.5 h. The solution was concentrated under reduced pressure to provide the title compound (3.1 g, 99%) as a light orange solid: 1H NMR (300 MHz, DMSO-d6) δ 9.89-9.68 (m, 1H), 7.50-7.45 (m, 1H), 7.04-7.01 (m, 1H), 6.89-6.85 (m, 1H), 3.48-3.28 (m, 4H), 2.59-2.50 (m, 4H, overlaps with H2O), 1.69-1.53 (m, 2H), 1.38-1.36 (m, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=[C:8](/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24])[CH2:7][CH2:6]2.[N+:26]([C:29]1[CH:34]=[CH:33][C:32](O)=[CH:31][CH:30]=1)([O-:28])=[O:27].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:26]([C:29]1[CH:34]=[CH:33][C:32]([O:24][C:23](=[O:25])/[CH:22]=[CH:21]/[C:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]=2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:31][CH:30]=1)([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COc1ccc(C2=C(/C=C/C(=O)O)CCc3cc(OC)ccc32)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1ccc(C2=C(/C=C/C(=O)Oc3ccc([N+](=O)[O-])cc3)CCc3cc(OC)ccc32)cc1
Yield: 43.3 %

Procedure:
As in Example 113, (E)-3-[3,4-dihydro-6-methoxy-1-(4-methoxyphenyl)-2-naphthalenyl]-2-propenoic acid (1.7 g) was reacted with 4-nitrophenol (0.775 g) in dichloromethane (25 mL) in the presence of 1,3-dicyclohexylcarbodiimide (1.04 g) overnight at room temperature. After the normal work up, the crude ester was triturated with diethyl ether and then crystallized from 2-propanol to give 1 g of (E)-3-[3,4-dihydro-6-methoxy-1-(4-methoxyphenyl)-2-naphthalenyl]-2-propenoic acid 4-nitrophenyl ester as a yellow solid, mp 151°-152° C. Anal. Calcd for C27H23NO6 : C, 70.89; H, 5.07; N, 3.06 Found: C, 70.52; H, 5.10; N, 3.08
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.CC(C)([O-])C.[K+].[Br:12][C:13]1[CH:14]=[C:15]([CH:21]=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:16]=[CH:17][C:18]=1[CH2:19]Br.C1OCCOCCOCCOCCOCCOC1>CCOCC.O>[Br:12][C:13]1[CH:14]=[C:15]([CH:21]=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:16]=[CH:17][C:18]=1[CH2:19][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCOC(=O)C=Cc1ccc(CBr)c(Br)c1
Reactant: c1c[nH]cn1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)C=Cc1ccc(Cn2ccnc2)c(Br)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of imidazole (0.25 g, 3.67 mmol), potassium tert-butoxide (0.42 g, 3.75 mmol), ethyl 3-(3-bromo-4-bromomethylphenyl)prop-2-enoate (1.29 g, 3.7 mmol) and 18-crown-6 (0.1 g) in dry ether was stirred at room temperature for 72 h. Water (5 ml) was then added, and the aqueous layer was extracted with ether (3×50 ml). The ether solutions were combined, dried (MgSO4) and then concentrated to afford a pale yellow oil. The oil was `flash` chromatographed using chloroform/methanol 9:1 as eluant. The product fractions were combined, dried (MgSO4) and concentrated to afford ethyl 3-[3-bromo-4-(imidazol-1-ylmethyl)phenyl]prop-2-enoate as a white solid. NMR data was consistent with the assigned structure.