Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:18]3[C:22](=[O:23])[NH:21][N:20]=[N:19]3)[CH:13]=2)[C:10](=[O:24])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:25]([C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1)#[N:26]>CC(O)=O>[O:24]=[C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2](/[CH:1]=[CH:31]/[C:30]2[CH:33]=[CH:34][C:27]([C:25]#[N:26])=[CH:28][CH:29]=2)[N:11]1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N:18]2[C:22](=[O:23])[NH:21][N:20]=[N:19]2)[CH:13]=1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: Cc1nc2ccccc2c(=O)n1-c1cccc(-n2nn[nH]c2=O)c1
Solvent: CC(=O)O
Product: N#Cc1ccc(/C=C/c2nc3ccccc3c(=O)n2-c2cccc(-n3nn[nH]c3=O)c2)cc1
Reaction time: 72 h
Yield: 70 %

Procedure:
A mixture of 2-methyl-3-(3-(5-oxo-4,5-dihydro-1H-tetrazol-1-yl)phenyl)quinazolin-4(3H)-one (32 mg, 0.1 mmol) and 4-cyanobenzaldehyde (16 mg, 0.12 mmol) in AcOH (5 mL) was heated to reflux and stirred for 3 days (continuously monitored by LC/MS, which indicated product formation after 3 hr). After cooling, the mixture was dry-loaded onto silica gel and purified by column chromatography on silica gel using CH2Cl2/MeOH (1:0 to 95:5) as eluent to give a solid (11 mg; desired product ca. 70% purity). The solid was re-purified by preparative thin-layer chromatography using CH2Cl2/MeOH (9:1) as eluent to give the product (6 mg, 14%) as a solid.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1.[NH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]=1[O:31][CH3:32].Cl>C(O)C>[CH:15]1([N:7]2[CH2:8][C:9]([F:14])([F:13])[C:10](=[O:12])[NH:11][C:5]3[CH:4]=[N:3][C:2]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:6]2=3)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C1Nc2cnc(Cl)nc2N(C2CCCC2)CC1(F)F
Reactant: COc1cc(C(=O)O)ccc1N
Agent: Cl
Solvent: CCO
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2
Yield: 67.6 %

Procedure:
A mixture of 0.30 g (0.99 mmole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-20) and 0.20 g (1.19 mmole) of 4-amino-3-methoxy-benzoic acid in a 1:4 mixture of 5 mL of ethanol and 1M hydrochloric acid was heated at 100 degrees for 18 hours. After cooling, the precipitate was collected by filtration, washed with water and dried to give 0.29 g of 4-(9-cyclopentyl-7,7-difluoro-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-151).
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[CH2:29]([C:33]1[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=1)[CH2:30][CH2:31][CH3:32]>C1COCC1>[CH2:29]([C:33]1[CH:40]=[CH:39][C:36]([CH:37]=[CH:9][CH2:8][CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3])=[CH:35][CH:34]=1)[CH2:30][CH2:31][CH3:32]
Reactant: CCCCc1ccc(C=O)cc1
Reactant: O=C(O)CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCCCc1ccc(C=CCCCCC(=O)O)cc1
Yield: 51.3 %

Procedure:
This compound was synthesized from 5-carboxypentyltriphenylphosphonium bromide (9.50 g, 20 mmol) and p-butylbenzaldehyde (3.24 g, 20 mmol) in THF (100 mL) by a Wittig reaction. Kugelrohr distillation yielded the product (2.67 g, 51%) as a colorless oil (bp 154°-157° C./0.05 torr). IR: 3400-2500, 1720 cm-1, 1H-NMR: 0.92 (t, 3H), 1.50 (m, 8H), 2.30 (m, 4H), 2.58 (m, 2H), 5.58+6.15 (m, 1H), 6.38 (t, 1H), 7.18 (m, 4H), 0.30 (bs, 1H). Anal. Calcd. for C17H24O2 : C, 78.42, H, 9.29%; Found: C, 78.38, H, 9.29%. Z:E=62:38.
Reaction SMILES: Br[C:2]1[C:19]2[C:20]3[C:5]([C:6]4[C:21]5[C:10]6=[C:11]([C:22]([N:24]([C:27]7[C:32]([CH:33]([CH3:35])[CH3:34])=[CH:31][CH:30]=[CH:29][C:28]=7[CH:36]([CH3:38])[CH3:37])[C:25](=[O:26])[C:9]6=[CH:8][CH:7]=4)=[O:23])[CH:12]=[CH:13][C:14]=5[C:15]=3[CH:16]=[CH:17][CH:18]=2)=[CH:4][CH:3]=1.[C:39]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]#[CH:48])(=[O:41])[CH3:40].Cl>O1CCCC1.N1CCCCC1.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.[Cu]I>[CH:36]([C:28]1[CH:29]=[CH:30][CH:31]=[C:32]([CH:33]([CH3:35])[CH3:34])[C:27]=1[N:24]1[C:25](=[O:26])[C:9]2[C:10]3[C:21]4[C:6](=[CH:7][CH:8]=2)[C:5]2[C:20]5[C:19]([C:2]([C:48]#[C:47][CH2:46][CH2:45][CH2:44][CH2:43][O:42][C:39](=[O:41])[CH3:40])=[CH:3][CH:4]=2)=[CH:18][CH:17]=[CH:16][C:15]=5[C:14]=4[CH:13]=[CH:12][C:11]=3[C:22]1=[O:23])([CH3:38])[CH3:37]
Reactant: CC(C)c1cccc(C(C)C)c1N1C(=O)c2ccc3c4cccc5c(Br)ccc(c6ccc(c2c36)C1=O)c54
Reactant: C#CCCCCOC(C)=O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1CCNCC1
Product: CC(=O)OCCCCC#Cc1ccc2c3ccc4c5c(ccc(c6cccc1c62)c53)C(=O)N(c1c(C(C)C)cccc1C(C)C)C4=O
Temperature: 70 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
2.0 g (3.56 mmol) of 9-bromo—N-(2,6-diisopropylphenyl)perylene-3,4-dicarboximide (prepared in analogy to Example 6a of WO 96/22 332 using N-(2,6-diisopropylphenyl)perylene-3,4-dicarboximide from Example 28 of WO 97/22 607 as starting material) was dissolved in 500 ml of a mixture of one part by volume of absolute tetrahydrofuran (THF) and one part by volume of dry piperidine under inert gas, admixed in succession with 4 mol % of Pd(PPh3)4 (164 mg, 0.14 mmol), 5 mol % of CuI (32 mg, 0.18 mmol) and 1.14 g (7.12 mmol) of 6-acetoxy-1-hexyne; this mixture was slowly heated to 70° C. and held at this temperature for 1 h. After cooling to room temperature, the reaction mixture was added to three times the volume of a mixture of ice and concentrated hydrochloric acid in a volume ratio of 3:1, the organic phase was separated off, the aqueous phase was extracted with 3 times 200 ml of methylene chloride, the combined organic extracts were dried over magnesium sulfate and the solvent was removed under reduced pressure. Chromatography on silica gel using methylene chloride as eluent gave 1.98 g (90%) of N-(2,6-diisopropylphenyl)-9-(6-acetoxy-1-hexynyl)perylene-3,4-dicarboximide as a red powder having a melting point >300° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=O)[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[CH:19]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:21]>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[S:21])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[CH:19]=1
Reactant: O=C1CN=C(c2ccccn2)c2cc(Br)ccc2N1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: S=C1CN=C(c2ccccn2)c2cc(Br)ccc2N1

Procedure:
A stirred solution of 6.53 g. of 7-bromo-1,3-dihydro-5-(2-pyridyl)-2H-1,4-benzodiazepin-2-one (prepared as in J. Pharm. Sci. 53, 264) in 400 ml. of dry pyridine is heated in an oil bath, under nitrogen, with 5.05 g. of phosphorus pentasulfide at between about 110° to 120° C. for about 1 hour, cooled and concentrated under vacuum. Pyridine remaining in the residue is removed by the successive addition of xylene and toluene with vacuum concentration after each addition of solvent. The dark brown solid residue is triturated with a mixture of aqueous sodium carbonate solution and chloroform and the resulting finely divided tan solid is collected by filtration, washed with water, dissolved in a mixture of chloroform and ethanol, decolorized with activated carbon and crystallized to yield 3.39 g. of product melting at 249° C. (with decomposition) and 0.559 g. melting at 243° C. (with decomposition). The analytical sample is crystallized from ethanol to give pure 7-bromo-1,3-dihydro-5-(2-pyridyl)-2H-1,4-benzodiazepine-2-thione, with a melting point of 245° to 246° C. (with decomposition) and ultraviolet (ethanol) end absorption, μmax 219 mu (ε=24,100).
Reaction SMILES: Cl.[CH:2]1([NH:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:10][S:11][C:12]1[CH:13]=[C:14]([N:18]=[C:19]=[O:20])[CH:15]=[CH:16][CH:17]=1>>[CH:2]1([N:8]([OH:9])[C:19]([NH:18][C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([S:11][CH3:10])[CH:13]=2)=[O:20])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CSc1cccc(N=C=O)c1
Reactant: ONC1CCCCC1
Agent: Cl
Product: CSc1cccc(NC(=O)N(O)C2CCCCC2)c1
Yield: 27.1 %

Procedure:
Using the general method used to prepare Compound 1, N-(cyclohexyl)hydroxylamine hydrochloride (1.5 g, 10 mmol) was reacted with 3-(methylthio)phenyl isocyanate (1.6 g, 10 mmol) to provide 0.76 g of the desired product as a white solid m.p. 147.2°-147.7° C. Analysis: Calculated for C14H20N2O2S: %C, 59.97; %H, 7.19; %N, 9.99; Found: %C, 60.16; %H, 6.95; %N, 9.96.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.Cl[CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[C:27]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=2)[CH:26]=1>>[C:19]([O:18][C:16]([N:13]1[CH2:14][CH2:15][CH:10]([N:9]([CH2:24][C:25]2[CH:30]=[CH:29][N:28]=[C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=3)[CH:26]=2)[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:11][CH2:12]1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: Fc1cccc(-c2cc(CCl)ccn2)c1
Reactant: COc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Product: COc1ccc(N(Cc2ccnc(-c3cccc(F)c3)c2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
4-(p-Anisidino)-1-(tert-butoxycarbonyl)piperidine (153 mg) and 4-chloromethyl-2-(3-fluorophenyl)pyridine (111 mg) were condensed in the same manner as described in Example 9 to give the title compound.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][OH:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[O:13]=[S:14]1(=[O:37])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:16]([NH:23][C@@H:24]([CH2:29][C:30]2[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=2)[C:25]([O:27][CH3:28])=[O:26])=[N:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[O:13]=[S:14]1(=[O:37])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:16]([NH:23][C@@H:24]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([O:12][CH2:11][C:9]3[CH:8]=[CH:7][C:6]4[O:1][CH2:2][CH2:3][O:4][C:5]=4[CH:10]=3)=[CH:32][CH:31]=2)[C:25]([O:27][CH3:28])=[O:26])=[N:15]1
Reactant: OCc1ccc2c(c1)OCCO2
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC1=NS(=O)(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccc(OCc2ccc3c(c2)OCCO3)cc1)NC1=NS(=O)(=O)c2ccccc21
Temperature: 5 °C

Procedure:
2,3-Dihydro-1,4-benzodioxin-6-ylmethanol (0.25 g, 1.5 mmol), methyl (2S)-2-[(1,1-dioxo-1,2-benzoisothiazol-3-yl)amino]-3-(4-hydroxyphenyl)-propionate (0.36 g, 1 mmol) and triphenylphosphine (0.79 g, 3 mmol) were dissolved in tetrahydrofuran (3 ml). After cooling to 5° C., DIAD (0.61 g, 3 mmol) was added to the reaction mixture. The reaction was then stirred at room temperature for 18–24 h. THF was evaporated to obtain crude title product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5](O)=O.[NH2:12][NH:13][C:14]([NH2:16])=[S:15].P(Cl)(Cl)(Cl)=O.C(=O)(O)[O-].[Na+]>O1CCOCC1>[CH:2]1([NH:16][C:14]2[S:15][C:5]([C:4]3[CH:3]=[C:2]([OH:1])[C:10]([OH:11])=[CH:9][CH:8]=3)=[N:12][N:13]=2)[CH2:3][CH2:4][CH2:8][CH2:9][CH2:10]1
Reactant: NNC(N)=S
Reactant: O=C(O)c1ccc(O)c(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: Oc1ccc(-c2nnc(NC3CCCCC3)s2)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To a mixture of 3,4-dihydroxybenzoic acid (2.885 mmol, 0.445 g), thiosemicarbazide (5b) (2.885 mmol, 0.500 g) in anhydrous dioxane (10 mL) was added phosphorus oxychloride (3.751 mmol, 0.350 mL) at 90° C., and the mixture of sodium bicarbonate to pH 7 then stirred at RT overnight. The precipitate was filtered, washed with hexane, then dried to give the title compound. Yield: 71%.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[N:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41](O)=[O:42].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[F:17][C:15]1[CH:16]=[C:11]([C:10]([NH:9][C@H:6]2[CH2:7][CH2:8][C@H:3]([NH:2][C:41]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][N:35]=3)=[O:42])[CH2:4][CH2:5]2)=[O:27])[C:12]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)=[N:13][CH:14]=1
Reactant: O=C(O)c1ccccn1
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@H](N)CC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@H](NC(=O)c3ccccn3)CC2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of N-(trans-4-amino-cyclohexyl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide hydrochloride (250 mg, 0.666 mmol) in dimethylformamide (5 ml) and triethylamine (278 μl, 2.0 mmol) was treated with 2-pyridine carboxylic acid (90 mg, 0.73 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (141 mg, 0.73 mmol) and 1-hydroxybenzotriazole (99 mg, 0.73 mmol). The reaction was stirred under nitrogen at room temperature for 18 h and the solvent was removed under reduced pressure. The residue was partitioned between sat. sodium hydrogen carbonate solution (10 ml) and ethyl acetate (15 ml) and the aqueous phase was extracted with ethyl acetate (3×15 ml). The combined organic extracts were washed with water (2×10 ml), brine (10 ml), dried over MgSO4 and the solvent was removed under reduced pressure to give the title compound (175 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]([NH:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](=[O:17])[CH3:16])([CH3:4])[CH3:3].[NH:18]1[C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([CH:27]=O)[C:21]=2[CH:20]=[CH:19]1.[OH-].[Na+]>C(O)C.O>[CH3:4][C:2]([NH:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](=[O:17])[CH:16]=[CH:27][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:21]=1[CH:20]=[CH:19][NH:18]2)([CH3:1])[CH3:3]
Reactant: CC(=O)c1ccccc1OCCNC(C)(C)C
Reactant: O=Cc1cccc2[nH]ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)NCCOc1ccccc1C(=O)C=Cc1cccc2[nH]ccc12
Reaction time: 4 h
Yield: 89.1 %

Procedure:
A solution of 5.4 g of 1-[2-{2-(1,1-dimethylethylamino)-ethoxy}-phenyl]-ethanone in 75 ml of ethanol was added with stirring under an inert atmosphere to a mixture of 3.339 g of indole-4-carboxaldehyde and 6 ml of 50% sodium hydroxide solution and after stirring for 4 hours, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with aqueous sodium chloride solution, dried over a deshydrant and evaporated to dryness under reduced pressure. The residue was chromatographed over silica and eluted with a 9-1 ethyl acetate-triethylamine mixture to obtain 7.41 g of 1-[2-{2-(1,1-dimethylethylamino)-ethoxy}-phenyl]-3-[1H-indol-4-yl]-2-propen-1-one (E).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](OCC)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.[CH2:24]([N:31]1[CH2:36][CH2:35][N:34]([CH2:37][C:38]([N:40]([C:42]2[CH:48]=[CH:47][C:45]([NH2:46])=[CH:44][CH:43]=2)[CH3:41])=[O:39])[CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[OH-].[Na+]>CN(C=O)C.CO>[CH2:24]([N:31]1[CH2:32][CH2:33][N:34]([CH2:37][C:38]([N:40]([C:42]2[CH:43]=[CH:44][C:45]([NH:46]/[C:13](=[C:6]3\[C:5](=[O:23])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[CH:10][CH:11]=4)/[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:47][CH:48]=2)[CH3:41])=[O:39])[CH2:35][CH2:36]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CN(C(=O)CN1CCN(Cc2ccccc2)CC1)c1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CN(C(=O)CN1CCN(Cc2ccccc2)CC1)c1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 43 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and 4-[N-(4-benzylpiperazinomethylcarbonyl)-N-methylamino]-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([C:15]([C:20]1[N:21]=[CH:22][N:23](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:24]=1)([OH:19])[CH:16]([CH3:18])[CH3:17])[CH:9]=[CH:8]2)([CH3:3])[CH3:2]>C(O)(=O)C.O>[CH:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([C:15]([C:20]1[N:21]=[CH:22][NH:23][CH:24]=1)([OH:19])[CH:16]([CH3:18])[CH3:17])[CH:9]=[CH:8]2)([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc2c1
Solvent: O
Solvent: CC(=O)O
Product: CC(C)Oc1ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc2c1
Temperature: 50 °C
Reaction time: 18 h
Yield: 67.8 %

Procedure:
1-(6-Isopropoxynaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (0.438 g) was dissolved in a mixture of acetic acid (20 ml) and water (0.5 ml), and the solution was stirred at 50° C. for 18 h. The solvent was evaporated, and to the mixture was added ethyl acetate. The mixture was washed with saturated aqueous solution of sodium hydrogencarbonate and saturated sodium chloride solution. The organic layer was dried and concentrated. The obtained residue was purified by silica gel column chromatography (eluent, dichloromethane:methanol=40:1→20:1) to give the titled compound (0.170 g) as an amorphous product.
Reaction SMILES: [CH3:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH2:13][C:14]([OH:16])=O)[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.C1CCC(N=C=NC2CCCCC2)CC1.[C:32]([O:36][C:37]([NH:39][CH2:40][CH2:41][NH:42][CH2:43][C:44]([O:46][CH2:47]C)=[O:45])=[O:38])([CH3:35])([CH3:34])[CH3:33]>CN(C=O)C>[CH3:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH2:13][C:14]([N:42]([CH2:41][CH2:40][NH:39][C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:38])[CH2:43][C:44]([O:46][CH3:47])=[O:45])=[O:16])[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CNCCNC(=O)OC(C)(C)C
Reactant: Cc1ccc2cc(CC(=O)O)c(=O)[nH]c2n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: COC(=O)CN(CCNC(=O)OC(C)(C)C)C(=O)Cc1cc2ccc(C)nc2[nH]c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.7 %

Procedure:
To a precooled (0° C.) solution of (7-methyl-1,8-naphthyridin-2(1H)-on-3-yl)acetic acid (0.995 g, 4.60 mmol) and DhbtOH (0.744 g, 4.60 mmol) in DMF (25 mL)was added DCC (1.04 g, 5.00 mmol) and the mixture was stirred for 40 min at 0° before addition of ethyl N-(2-(tert-butyloxycarbonyl)aminoethyl)glycinate (1.10 g, 5.0 mmol). This mixture was stirred at rt overnight, evaporated in vacuo, redissolved in ethyl acetate (75 mL) and washed with 5% aqueous NaHCO3 (3×25 mL) and with brine (2×25 mL). The organic phase was dried over MgSO4, filtered and evaporated in vacuo. The crude product purified on silica using dichloromethane/methanol (90:10 v/v) as the eluent. Fractions containing the product were pooled and evaporated in vacuo to yield the desired product (790 mg, 41%) (mp 98-100° C.). 1H NMR (DMSO-d6; this compound exist as two rotamers; chemical shifts for the minor rotamer is given in brackets): δ 12.05 (s br, 1H), 7.91 (7.96) (d, 8.0 Hz, 1H), 7.74 (7.71) (s, 1H), 7.10 (d, 8.0 Hz, 1H), 6.90 (6.99) (m, 1H), 4.05 (4.36) (s, 2H), 4.09 (q, J=5.2 Hz, 3H), 3.63 (s, 3H), 3.47 (m, 2H), 3.17 (s, 2H), 3.16 (s, 3H), 1.36 (1.35) (s, 9H). 13C NMR (DMSO-d6): δ 170.44 (170.66), 170.11, 162.65 (162.73), 159.22, 155.83 (155.71), 148.99, 136.43 (136.77), 136.04 (136.17), 128.61 (128.29), 118.21, 112.00 (112.07), 78.04, 51.81 (52.20), 47.63 (48.20), 38.59 (38.45), 33.42 (33.75), 28.27, 24.22. FAB+ HRMS: 433.2086, calc. C21H29N4O6 433.2087.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][C:3]=1[N+:16]([O-])=O>[Ni].C1COCC1>[NH2:16][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:2]=1[Cl:1])[CH2:6][NH:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Ni]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(N)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of N-(4-chloro-3-nitrobenzyl)-2,2-dimethyl-propionamide (5.92 g, 21.9 mmol), THF (150 mL) and Ra—Ni (1.50 g) was stirred for 2 days at RT under a hydrogen atmosphere (3.0 bar). The catalyst was removed by filtration and the mixture was concentrated. The crude was purified by chromatography to give the sub-title compound.
Reaction SMILES: [ClH:1].[CH2:2]([C:6]1[N:7]=[C:8]([NH2:11])[NH:9][CH:10]=1)[CH2:3][C:4]#[CH:5].[N:12]([CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[N+:13]=[N-:14]>>[ClH:1].[C:18]1([CH2:17][CH2:16][CH2:15][N:12]2[CH:5]=[C:4]([CH2:3][CH2:2][C:6]3[N:7]=[C:8]([NH2:11])[NH:9][CH:10]=3)[N:14]=[N:13]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: [N-]=[N+]=NCCCc1ccccc1
Reactant: C#CCCc1c[nH]c(N)n1
Agent: Cl
Product: Nc1nc(CCc2cn(CCCc3ccccc3)nn2)c[nH]1
Yield: 36 %

Procedure:
4-But-3-ynyl-1H-imidazol-2-ylamine hydrochloride (0.0735 g, 0.428 mmol) was reacted with (3-azido-propyl) benzene, which was synthesized using previously reported methods (Suenaga et al., Tetrahedron Letters 2003, 44, 5799-5801), (0.083 g, 0.514 mmol) following the general procedure for click reactions outlined above to produce 4-{2-[1-(3-Phenyl-propyl)-1H-[1,2,3]triazol-4-yl]-ethyl}-1H-imidazol-2-ylamine hydrochloride (0.051 g, 36%) of a pale yellow oil. 1H NMR (300 MHz, CD3OD) δ 7.87 (s, 1H), δ 7.32-7.22 (m, 5H), δ 6.54 (s, 1H), δ 4.31 (t, 2H), δ 3.05 (t, 2H), δ 2.93 (t, 2H), δ 2.67 (t, 2H), δ 2.23 (m, 2H) ppm; 13C (75 MHz CD3OD) δ 153.3, 146.6, 140.4, 134.3, 128.8, 128.7, 128.6, 126.6, 121.5, 67.5, 53.9, 32.8, 32.9, 29.5 ppm; HRMS (ESI) calcd for C16H20N6 (M+) 296.1822. found 296.1828.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[CH:29]([CH3:31])[CH3:30]>C(#N)C>[CH2:28]([O:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9])[CH:29]([CH3:31])[CH3:30]
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)c(OC)c1O
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2ccc3c(c2)COC3=O)c(OC)c1OCC(C)C
Temperature: 80 °C
Yield: 31.4 %

Procedure:
To a stirring solution of 5-(3-Hydroxy-2,4-dimethoxy-phenyl)-3H-isobenzofuran-1-one (80 mg, 0.279 mmol) in acetonitrile (10 mL) was added potassium carbonate (115 mg, 0.837 mmol) and isobutyl bromide (115 mg, 0.837 mmol) and the resultant reaction mixture was heated to 80° C. for 4 h. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, 0-50% ethyl acetate in pet ether) to afford the title compound as a solid (30 mg, 31.4%).
Reaction SMILES: C([Mg]Br)C.[CH3:5][C:6]([CH3:12])([CH3:11])[C:7]#[C:8][C:9]#[CH:10].[CH2:13]([Sn:17](Cl)([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].O>CCOCC>[CH3:5][C:6]([CH3:12])([CH3:11])[C:7]#[C:8][C:9]#[C:10][Sn:17]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C#CC#CC(C)(C)C
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC[Mg]Br
Solvent: O
Solvent: CCOCC
Product: CCCC[Sn](C#CC#CC(C)(C)C)(CCCC)CCCC
Temperature: -78 °C
Reaction time: 16 h
Yield: 39.7 %

Procedure:
(5,5-dimethyl-1,3-hexadiynyl)tri-n-butylstannane was synthesized as follows a solution containing ethylmagnesium bromide (19.3 millimoles) and 5,5-dimethyl-1,3hexadiyne (19.3 millimoles) in 50 milliliters of ether was refluxed for 5 hours under nitrogen, then cooled to -78° C. To this solution, 18.6 millimoles of tri-n-butyltin chloride in 10 milliliters of ether was added slowly. The reaction mixture was allowed to warm to room temperature and stirred for 16 hours. Water was added to form a two-phase mixture, the phases were separated, and the aqueous phase was washed with ether. The ether wash was combined with the organic phase from the initial phase separation, and evaporated under reduced pressure to yield a crude oil. Distillation in vacuo produced 2.92 grams of pure (5,5-dimethyl-1,3-hexadiynyl)tri-n-butylstannane.