Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:5]([CH3:7])[N:6]=1.Br[CH2:14][C:15]1[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=1[C:17]([O:19][CH3:20])=[O:18]>CN(C=O)C.C(=O)([O-])[O-].[K+].[K+]>[CH3:20][O:19][C:17]([C:16]1[CH:21]=[CH:22][CH:23]=[CH:24][C:15]=1[CH2:14][S:1][C:2]1[S:3][C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:5]([CH3:7])[N:6]=1)=[O:18]
Reactant: COC(=O)c1ccccc1CBr
Reactant: COC(=O)Cc1sc(S)nc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1sc(SCc2ccccc2C(=O)OC)nc1C
Reaction time: 1 h
Yield: 79 %

Procedure:
4.1 g of methyl 2-mercapto-4-methyl-1,3-thiazol-5-yl-acetate were dissolved in 50 ml of DMF and, in the presence of 5 g of ground potassium carbonate, 5.1 g of methyl 2-bromomethylbenzoate were added dropwise. After the evolution of heat had subsided, the mixture was stirred for 1 h, filtered, and DMF was removed in a rotary evaporator. The residue was taken up in ethyl acetate and washed 2× with water. The organic phase was dried, and the solvent was removed in vacuo. 5.6 g of an oil were obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([O:11][CH2:12][C:13]([N:15]2[CH2:19][CH2:18][CH2:17][C@H:16]2[C:20](=[O:25])[NH:21][CH2:22][CH2:23][F:24])=[O:14])[N:8]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:7]=1)=[O:5])C.[OH-].[Na+]>C1COCC1.O>[F:24][CH2:23][CH2:22][NH:21][C:20]([C@@H:16]1[CH2:17][CH2:18][CH2:19][N:15]1[C:13](=[O:14])[CH2:12][O:11][C:9]1[N:8]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:10]=1)=[O:25]
Reactant: CCOC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NCCF)n(-c2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NCCF)n(-c2ccccc2)n1
Reaction time: 2 h

Procedure:
To a solution of 1.50 g 5-[2-((S)-2-(2-Fluoro-ethylcarbamoyl)-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester in 28 ml THF and 7 ml water were added 1.7 ml aqueous NaOH (2 M) portionwise at 0° C. After 2 h the solution was neutralized with Amberlite IR-120 ion exchange resin, filtered and washed with methanol. The crude product obtained after evaporation of the solvents was used in the subsequent reaction. Yield: 1.38 g.
Reaction SMILES: [O:1]1[C:5]2([CH2:9][CH2:8][N:7]([C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:25][CH2:24][C:23]5[C:18](=[CH:19][CH:20]=[C:21]([OH:26])[CH:22]=5)[C:17]4=[O:27])=[CH:12][C:11]=3[F:28])[CH2:6]2)[O:4][CH2:3][CH2:2]1.CS([CH2:33][C@@H:34]1[CH2:38][CH2:37][CH2:36][O:35]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C.O>[O:4]1[C:5]2([CH2:9][CH2:8][N:7]([C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:25][CH2:24][C:23]5[C:18](=[CH:19][CH:20]=[C:21]([O:26][CH2:33][C@@H:34]6[CH2:38][CH2:37][CH2:36][O:35]6)[CH:22]=5)[C:17]4=[O:27])=[CH:12][C:11]=3[F:28])[CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: O=C1c2ccc(O)cc2CCN1c1ccc(N2CCC3(C2)OCCO3)c(F)c1
Reactant: CS(=O)(=O)C[C@@H]1CCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1c2ccc(OC[C@@H]3CCCO3)cc2CCN1c1ccc(N2CCC3(C2)OCCO3)c(F)c1
Temperature: 75 °C

Procedure:
A mixture of 2-[4-(1,4-dioxa-7-aza-spiro[4.4]non-7-yl)-3-fluorophenyl]-6-hydroxy-3,4-dihydro-2H-isoquinolin-1-one (6.9 g), (S)-2-methanesulfonylmethyl-tetrahydrofuran (3.9 g) and cesium carbonate (17.6 g) in DMF (81.6 mL) was heated overnight at 75° C. Then the reaction mixture was diluted with ethyl acetate and water. The organic phase was washed several times with water, dried over sodium sulfate and the solvent was removed in vacuum. In this way the product was obtained with molecular weight 468.53 (C26H29FN2O5); MS (ESI): 469 (M+H+).
Reaction SMILES: O[C@H]1CCCC[C@@H]1[N:8]1[CH2:16][C:15]2[C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[C:12]([CH2:21][C:22]3[CH:23]=[N:24][C:25](SC)=[CH:26][CH:27]=3)=[CH:11][C:10]=2[C:9]1=[O:30].N[C@H]1CCCC[C@@H:33]1[OH:38].ClCC1C=CC(SC)=NC=1>>[CH3:33][O:38][C:25]1[N:24]=[CH:23][C:22]([CH2:21][C:12]2[C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[C:15]3[CH2:16][NH:8][C:9](=[O:30])[C:10]=3[CH:11]=2)=[CH:27][CH:26]=1
Reactant: CSc1ccc(Cc2cc3c(c4ccccc24)CN([C@H]2CCCC[C@@H]2O)C3=O)cn1
Reactant: N[C@H]1CCCC[C@@H]1O
Agent: CSc1ccc(CCl)cn1
Product: COc1ccc(Cc2cc3c(c4ccccc24)CNC3=O)cn1

Procedure:
5-[(6-Methoxypyridin-3-yl)methyl]-1,2-dihydro-3H-benzo[e]isoindol-3-one was prepared employing the procedures described for the construction of 2-[(1S,2S)-2-hydroxycyclohexyl]-5-{[6-(methylthio)pyridine-3-yl]methyl}-1,2-dihydro-3H-benzo[e]isoindol-3-one in Example 10, substituting ammonium hydroxide for (1S,2S)-2-aminocyclohexanol, and substituting 5-(chloromethyl)-2-methoxypyridine for 5-(chloromethyl)-2-(methylthio)pyridine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]([CH3:23])([CH3:22])[CH2:5][N:6]([C:12]1[C:17]([N+:18]([O-])=O)=[CH:16][N:15]=[C:14]([Cl:21])[N:13]=1)[CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1>[Pd].C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:24])[C:4]([CH3:22])([CH3:23])[CH2:5][N:6]([C:12]1[C:17]([NH2:18])=[CH:16][N:15]=[C:14]([Cl:21])[N:13]=1)[CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: COC(=O)C(C)(C)CN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)C(C)(C)CN(c1nc(Cl)ncc1N)C1CCCC1
Yield: 101 %

Procedure:
A mixture of 27.32 g (0.0767 mole) of 3-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]-2,2-dimethyl-propanoic acid methyl ester (IV-38), 8.21 g of 5% palladium on carbon catalyst and 700 mL of ethyl acetate was stirred under an atmosphere of hydrogen until the reaction was complete. The resulting mixture was filtered through Celite, washing the filter pad with ethyl acetate, and the filtrate was concentrated under reduced pressure to give 25.33 g of 3-[(5-amino-2-chloro-pyrimidin-4-yl)-cyclopentyl-amino]-2,2-dimethyl-propanoic acid methyl ester (V-38) as a light brown oil.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][C:11]1[CH:25]=[CH:24][C:14]([C:15]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([NH2:23])[CH2:18]2)=[O:16])=[CH:13][CH:12]=1.[OH-].[Na+].[Cl-].[Na+]>ClC1C=CC=CC=1>[CH3:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:18]2)=[O:16])=[CH:24][CH:25]=1
Reactant: Cc1ccc(C(=O)N2CCC[C@@H](N)C2)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: Clc1ccccc1
Product: Cc1ccc(C(=O)N2CCC[C@@H](NC(=O)c3ccccc3)C2)cc1
Temperature: 15 °C
Reaction time: 3 h
Yield: 95.9 %

Procedure:
Benzoyl chloride (0.15 g) was added to the aqueous solution of (R)-1-(p-methylbenzoyl)-3-aminopiperidine obtained in Example 13 (amount: 3 g), and the pH of the mixture was kept from 8.0 to 9.0 using sodium hydroxide. The mixture was stirred at 15° C. for 3 hours. Chlorobenzene (3 ml) and sodium chloride (0.5 g) were added thereto, and then the mixture was stirred at 90° C. for 10 minutes. The water layer was removed, and the solvent was evaporated under reduced pressure to obtain the title compound as yellow crystal (0.33 g, yield: 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]=[C:9]2S(C)(=O)=O)=[CH:4][C:3]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24].[NH3:28]>C1COCC1>[NH2:28][C:9]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:4]=2)[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]=1
Reactant: CCOC(=O)c1cc(-n2c(S(C)(=O)=O)nc(C(F)(F)F)cc2=O)ccc1Cl
Reactant: N
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(-n2c(N)nc(C(F)(F)F)cc2=O)ccc1Cl

Procedure:
To a mixture of 3-(4-chloro-3-ethoxycarbonylphenyl)-3,4-dihydro-2-methanesulfonyl-6-trifluoromethylpyrimidin-4-one (1.0 g) and dry THF (50 ml) was blown an ammonia gas until the starting material was not found when detected with TLC. The mixture was dried on anhydrous magnesium sulfate and then the solvent was distilled off under reduced pressure. The thus obtained white solid (0.7 g) was used in the next reaction without purifying it.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:9][CH2:10][N:11]([CH3:17])[CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])=[CH:4][CH:3]=1.[C:24]([NH:26][C:27](=[N:35][CH2:36][CH2:37][CH2:38][O:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][N:47]2[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]2)[CH:41]=1)OC1C=CC=CC=1)#[N:25]>>[C:24]([NH:26][C:27]([NH:16][CH2:15][CH2:14][CH2:13][CH2:12][N:11]([CH2:10][CH2:9][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[CH3:17])=[N:35][CH2:36][CH2:37][CH2:38][O:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][N:47]2[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52]2)[CH:41]=1)#[N:25]
Reactant: CN(CCCCN)CCC(c1ccc(F)cc1)c1ccccn1
Reactant: N#CNC(=NCCCOc1cccc(CN2CCCCC2)c1)Oc1ccccc1
Product: CN(CCCCNC(=NCCCOc1cccc(CN2CCCCC2)c1)NC#N)CCC(c1ccc(F)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 1, using 0.8 g (2.5 mmol) of N-[3-(4-fluorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,4-butanediamine and 0.99 g (2.5 mmol) of N-cyano-O-phenyl-N'-[3-[3-(piperidinomethyl)phenoxy]propyl]isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int.[%])=614 ([M+H]+, 3), 214 (50.2), 154 ([m-NO2 -benzylOH], 100); IR (KBr): 2163 cm-1 (C≡N). For analytical purposes a sample is converted into the O,O'-ditoluoyltartaric acid salt and recrystallised from ether/isopropanol; m.p.: 105°-110° C. with decomposition.
Reaction SMILES: [S:1]1[C:5]([C:6]2[N:10]3[N:11]=[C:12](Cl)[C:13]([CH3:16])=[C:14]([CH3:15])[C:9]3=[N:8][CH:7]=2)=[CH:4][C:3]2[CH:18]=[CH:19][CH:20]=[CH:21][C:2]1=2.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[K+].[K+].[CH3:70][O:71][C:72]1[CH:73]=[C:74]([CH:76]=[CH:77][C:78]=1[O:79][CH3:80])[NH2:75]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[S:1]1[C:5]([C:6]2[N:10]3[N:11]=[C:12]([NH:75][C:74]4[CH:76]=[CH:77][C:78]([O:79][CH3:80])=[C:72]([O:71][CH3:70])[CH:73]=4)[C:13]([CH3:16])=[C:14]([CH3:15])[C:9]3=[N:8][CH:7]=2)=[CH:4][C:3]2[CH:18]=[CH:19][CH:20]=[CH:21][C:2]1=2
Reactant: Cc1c(Cl)nn2c(-c3cc4ccccc4s3)cnc2c1C
Reactant: COc1ccc(N)cc1OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: COc1ccc(Nc2nn3c(-c4cc5ccccc5s4)cnc3c(C)c2C)cc1OC
Temperature: 100 °C
Yield: 49.1 %

Procedure:
To a solution of 3-(benzo[b]thiophen-2-yl)-6-chloro-7,8-dimethylimidazo[1,2-b]pyridazine (89 mg, 0.284 mmol, 1.0 equiv), xantphos (33 mg, 0.0567 mmol, 0.2 equiv), palladium acetate (6 mg, 0.0284 mmol, 0.1 equiv), and potassium carbonate (784 mg, 5.67 mmol, 20 equiv) in dioxane (5.00 mL) was added 3,4-dimethoxyaniline (52 mg, 0.340 mmol, 1.0 equiv) and heated to 100° C. for 2 h. Purification by column chromatography using 2% methanol in dichloromethane elution gave the 60 mg of the brown solid, 49%.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:11]([NH2:14])(=[O:13])=[O:12])[CH:8]=2)[NH:3]1.[O:15]=[C:16]1[C:21]2=[CH:22][NH:23][C:24]([CH:25]=O)=[C:20]2[CH2:19][CH2:18][O:17]1>>[O:1]=[C:2]1[C:10](=[CH:25][C:24]2[NH:23][CH:22]=[C:21]3[C:16](=[O:15])[O:17][CH2:18][CH2:19][C:20]=23)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:11]([NH2:14])(=[O:12])=[O:13])[CH:8]=2)[NH:3]1
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Reactant: NS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Product: NS(=O)(=O)c1ccc2c(c1)C(=Cc1[nH]cc3c1CCOC3=O)C(=O)N2

Procedure:
2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid amide was condensed with 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4-c]pyrrole-1-carbaldehyde to give the title compound.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:9]2[S:10][CH:11]=[C:12]([CH2:14][OH:15])[N:13]=2)[CH:6]=[CH:7][CH:8]=1.[O:18]1[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19]1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.S(=O)(=O)(O)O>[O:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[O:15][CH2:14][C:12]1[N:13]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:16])[F:17])[CH:4]=2)[S:10][CH:11]=1
Reactant: OCc1csc(-c2cccc(C(F)(F)F)c2)n1
Reactant: C1=COCCC1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: FC(F)(F)c1cccc(-c2nc(COC3CCCCO3)cs2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.2 %

Procedure:
To a solution (50 mL) of the compound (7.0 g, 27 mmol) obtained in Example 64b in toluene were added dihydropyran (4.9 mL, 54 mmol) and conc. sulfuric acid (3 drops), and the mixture was stirred at room temperature overnight. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (hexane-hexane/ethyl acetate=80/20) to give the title compound (9.2 g, 99%) as a pale-yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]2=[CH:13][S:14][CH:15]=[C:4]2[C:3]1=[O:16].[C:17](Cl)(=[O:20])[CH2:18][CH3:19]>C1C=CC=CC=1>[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:17](=[O:20])[CH2:18][CH3:19])[C:5]2=[CH:13][S:14][CH:15]=[C:4]2[C:3]1=[O:16]
Reactant: CCC(=O)Cl
Reactant: CN1C(=O)c2cscc2Nc2ccccc21
Solvent: c1ccccc1
Product: CCC(=O)N1c2cscc2C(=O)N(C)c2ccccc21
Reaction time: 48 h

Procedure:
A reaction mixture comprising 7 g. of 4,9-dihydro-9-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one, 3.1 g. (2.9 ml.) of propionyl chloride and 70 ml. of benzene is refluxed for 3 hours and then allowed to stand for 48 hours. The benzene is distilled off. The residue is filtered, washed with ether and dried. The solid is heated to boiling in 300 ml. of ethyl acetate, filtered and the filtrate is chilled. The crystals are collected, washed with ether and dried giving the desired product, mp. 202°-203° C.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13](CC3C=C(F)C=CC=3Br)[C:12](=[O:23])[N:11]([CH3:24])[C:10](=[O:25])[CH:9]=2)[CH2:3]1.[Cl:26][C:27]1[C:34]([F:35])=[CH:33][CH:32]=[C:31]([F:36])[C:28]=1[CH2:29]Br>>[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:29][C:28]3[C:31]([F:36])=[CH:32][CH:33]=[C:34]([F:35])[C:27]=3[Cl:26])[C:12](=[O:23])[N:11]([CH3:24])[C:10](=[O:25])[CH:9]=2)[CH2:3]1
Reactant: Fc1ccc(F)c(CBr)c1Cl
Reactant: Cn1c(=O)cc(N2CCC[C@@H](N)C2)n(Cc2cc(F)ccc2Br)c1=O
Product: Cn1c(=O)cc(N2CCC[C@@H](N)C2)n(Cc2c(F)ccc(F)c2Cl)c1=O

Procedure:
The title compound was prepared from compound 1 using the same procedures as in the preparation of compound 10, except that 2-chloro-3,6-di-fluoro-benzyl bromide was used in the place of 2-bromo-5-fluoro-benzyl bromide. 1H NMR (400 MHz, CDCl3—CD3OD 10:1) δ ppm 6.98-7.06 (m, 2H), 6.90 (m, 2H), 5.31 (s, 1H), 5.01-5.20 (ABq, J=24.2, 14.4 Hz, 2H), 3.28-3.37 (m, 2H) 3.13 (s, 3H), 3.01-2.94 (m, 1H), 2.6-2.9 (m, 2H), 2.10 (m, 1H), 1.92 (m, 2H), 1.73 (s, 1H), 1.6-1.75 (m, 2H). MS (ES) [m+H] calc'd for C17H20ClF2N4O2, 385.1; found 385.1.
Reaction SMILES: [CH2:1]([C:3]1[C:4]2[CH:5]=[CH:6][C:7]([O:26][CH3:27])=[C:8]([O:24][CH3:25])[C:9]=2[CH2:10][NH+:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][C:15]4[O:23][CH2:22][O:21][C:16]=4[CH:17]=3)[C:12]=12)[CH3:2].[I-].[C:29]([Mg]Br)#[C:30][CH3:31].O1CCCC1>C(OCC)C>[CH2:1]([C:3]1[C:4]2[CH:5]=[CH:6][C:7]([O:26][CH3:27])=[C:8]([O:24][CH3:25])[C:9]=2[CH:10]([C:29]#[C:30][CH3:31])[N:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][C:15]4[O:23][CH2:22][O:21][C:16]=4[CH:17]=3)[C:12]=12)[CH3:2]
Reactant: CCC1=C2c3cc4c(cc3CC[NH+]2Cc2c1ccc(OC)c2OC)OCO4
Reactant: CC#C[Mg]Br
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC#CC1c2c(ccc(OC)c2OC)C(CC)=C2c3cc4c(cc3CCN21)OCO4
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a suspension of 13-ethyl-9,10-dimethoxy-5,6-dihydro-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinolin-7-ylium; iodide (200 mg, 0.4 mmol) in anhydrous diethyl ether (5 mL) at 0° C. was added a solution of 1-propynylmagnesium bromide solution in tetrahydrofuran (0.5 M, 8 mL, 4 mmol) dropwise. After stirring at 0° C. for 30 min, the reaction was quenched by adding saturated aqueous ammonium chloride solution (20 mL). The mixture was extracted with diethyl ether (2×50 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was re-crystallized from diethyl ether to afford 13-ethyl-9,10-dimethoxy-8-prop-1-ynyl-5,8-dihydro-6H-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinoline (130 mg, 80%). LC/MS m/e calcd for C25H25NO4 (M+H)+: 404.48, observed: 404.2; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20 (t, J=7.33 Hz, 3 H) 1.65 (d, J=2.02 Hz, 3 H) 2.60-2.81 (m, 4 H) 3.07 (m, 1 H) 3.18-3.25 (m, 1 H) 3.81 (d, J=8.84 Hz, 6 H) 5.32 (d, J=2.02 Hz, 1 H) 6.05 (d, J=6.32 Hz, 2 H) 6.86 (s, 1 H) 6.95 (s, 1 H) 6.96-7.02 (m, 2 H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH:24]=[CH:23][CH:22]=[CH:21]1)#[N:13]>C(O)C>[NH2:13][CH2:12][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH:24]=[CH:23][CH:22]=[CH:21]1
Reactant: N#Cc1ccccc1-n1cccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCO
Product: NCc1ccccc1-n1cccc1

Procedure:
To a well stirred suspension of (0.05 mol) of lithium aluminum hydride in 100 ml of anhydrous tetrahydrofuran, (0.043 mole) of 1-(2-cyanophenyl)pyrrole were added by small portions. Then the mixture was maintained with stirring at room temperature for 18 hours. Addition of aqueous ethanol to destroy the excess lithium aluminium hydride, followed by filtration afforded a solution, which was then evaporated in vacuo. The residue was extracted with ethyl ether, the organic layer washed with water and dried over anhydrous sodium sulphate. Removal of the solvent under reduced pressure gave a crude product, which was purified by passing through an alumina column eluting with chloroform to give 1-(2-aminomethylphenyl)pyrrole.
Reaction SMILES: [CH2:1]([CH:3]1[C:8]([C:9]2[CH:24]=[CH:23][C:12]3[N:13]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=4)[O:15][C:11]=3[CH:10]=2)=[N:7][NH:6][C:5](=[O:25])[CH2:4]1)[CH3:2].Cl[CH2:27][C:28](=[O:30])[CH3:29].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH2:1]([CH:3]1[C:8]([C:9]2[CH:24]=[CH:23][C:12]3[N:13]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH2:27][C:28](=[O:30])[CH3:29])=[CH:18][CH:17]=4)[O:15][C:11]=3[CH:10]=2)=[N:7][NH:6][C:5](=[O:25])[CH2:4]1)[CH3:2]
Reactant: CCC1CC(=O)NN=C1c1ccc2nc(-c3ccc(O)cc3)oc2c1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC1CC(=O)NN=C1c1ccc2nc(-c3ccc(OCC(C)=O)cc3)oc2c1

Procedure:
100 mg (298 μmol) 5-ethyl-6-[2-(4-hydroxy-phenyl)-benzoxazol-6-yl]-4,5-dihydro-2H-pyridazin-3-one, 24 μL (301 μmol) chloroacetone, 83 mg (601 μmol) potassium carbonate, 50 mg (301 μmol) potassium iodide and 10 ml acetone are heated together at 60° C. overnight. Then the mixture is extracted with 10% sodium carbonate solution and EA. The org. phase is washed with sat. saline solution, dried on sodium sulphate and then the solv. is totally eliminated i.V. The residue is purified through silica gel (eluant: DCM/methanol)
Reaction SMILES: [C-:1]#[N:2].[K+].O1CCOCCOCCOCCOCCOCC1.Cl[CH2:23][C:24]1[CH:25]=[C:26]([CH:34]=[CH:35][CH:36]=1)[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]>C(#N)C>[C:1]([CH2:23][C:24]1[CH:25]=[C:26]([CH:34]=[CH:35][CH:36]=1)[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])#[N:2]
Reactant: CC(C)(C)OC(=O)c1cccc(CCl)c1
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)c1cccc(CC#N)c1
Reaction time: 2 h
Yield: 80.6 %

Procedure:
To a mixed liquid of 1.51 g of potassium cyanide and 70 ml of acetonitrile, 6.12 g of 1,4,7,10,13,16-hexaoxacyclooctadecane was added, followed by stirring for 2 hours. Thereafter, a solution of 5.00 g of tert-butyl 3-(chloromethyl)benzoate in 30 ml of acetonitrile was added thereto, followed by stirring at room temperature for 18 hours. The reaction solution was concentrated, diluted with diethyl ether-hexane (1:1), and then washed with water and a saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was evaporated, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain 3.86 g of tert-butyl 3-(cyanomethyl)benzoate as a colorless oily substance.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]([CH3:18])[N:10]=1.[N+:19]([O-])([OH:21])=[O:20]>>[F:1][C:2]1[CH:7]=[C:6]([N+:19]([O-:21])=[O:20])[C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:13]=[C:12]([C:14]([F:16])([F:15])[F:17])[N:11]([CH3:18])[N:10]=1
Reactant: Cn1nc(-c2cc(F)ccc2F)cc1C(F)(F)F
Reactant: O=[N+]([O-])O
Product: Cn1nc(-c2cc(F)c([N+](=O)[O-])cc2F)cc1C(F)(F)F
Temperature: 25 °C

Procedure:
To an ice cooled solution of 50 ml of fuming nitric acid (90%) was added slowly 8.29 g of 3-(2,5-difluorophenyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole. After addition, the mixture was allowed to warm to room temperature and then gently heated to 52° C. Heated for 2.5 hours, then cooled and poured onto ice. The resulting mixture was extracted with ether and the ether then washed twice with water, dried with anhydrous magnesium sulfate, filtered and the solvent removed by concentration in vacuo. The residue was purified utilizing a combination of chromatography and crystallization to give 5.62 g of 3-(2,5-difluoro-4-nitrophenyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole, mp 80°-81° C.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:10])[CH2:8][NH2:9])([CH3:5])([CH3:4])[CH3:3].[C:11](=N)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl>[C:2]([O:6][C:7](=[O:10])[CH2:8][N:9]=[C:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CN=C(c1ccccc1)c1ccccc1
Reaction time: 16 h
Yield: 91.5 %

Procedure:
A solution of glycine t-butyl ester hydrochloride (10 g, 59.65 mmol) in 250 mL of di-chloromethane is treated with benzophenoneimine (10.8 g, 59.6 mmol) at RT. After 16 h, the mixture is washed with brine, dried over anhydrous MgSO4 and concentrated to give benzhydrylideneaminoacetic acid t-butyl ester as a white solid (16.1 g, 91%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:21])([F:20])[C:15]([O:17]CC)=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C[Li].[CH2:24](OCC)C.[Cl-].[NH4+]>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:20])([F:21])[C:15]([CH3:24])=[O:17])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CCOCC
Reactant: CCOC(=O)C(F)(F)c1ccc(-c2ccc(Br)cc2)cc1
Agent: [Cl-]
Agent: [Li]C
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)C(F)(F)c1ccc(-c2ccc(Br)cc2)cc1
Reaction time: 0.5 h

Procedure:
Ethyl (4′-bromobiphenyl-4-yl)(difluoro)acetate (1.8 g, 5.1 mmol) obtained in Example 30-(1) was dissolved in tetrahydrofuran (20 mL), and a solution of methyllithium in diethyl ether (1.1 M, 14 mL, 15 mmol) was added under a nitrogen atmosphere at −78° C., followed by stirring at the same temperature for 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate, and subsequently the extract was concentrated under reduced pressure to afford 1-(4′-bromobiphenyl-4-yl)-1,1-difluoroacetone as a pale yellow oil.