Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([OH:29])[CH2:16][NH:17][C@H:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][C:22]([OH:28])=[CH:23][CH:24]=3)[CH2:19]2)=[CH:11][C:10]=1[CH2:30][CH2:31][O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Br[CH2:43][C:44]([N:46]([CH3:48])[CH3:47])=[O:45].C(NCC)C>C(Cl)Cl.[Cl-].[Na+].O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([OH:29])[CH2:16][NH:17][C@H:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][C:22]([O:28][CH2:43][C:44]([N:46]([CH3:48])[CH3:47])=[O:45])=[CH:23][CH:24]=3)[CH2:19]2)=[CH:11][C:10]=1[CH2:30][CH2:31][O:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc2c(c1)C[C@@H](NC[C@H](O)c1ccc(OCc3ccccc3)c(CCOCc3ccccc3)c1)CC2
Reactant: CN(C)C(=O)CBr
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CCNCC
Product: CN(C)C(=O)COc1ccc2c(c1)C[C@@H](NC[C@H](O)c1ccc(OCc3ccccc3)c(CCOCc3ccccc3)c1)CC2
Temperature: 25 °C
Yield: 78.4 %

Procedure:
(-)-(1R)-1-[4-Benzyloxy-3-(2-benzyloxyethyl)phenyl]-2-((2S)-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-ylamino)ethanol (450 mg) was dissolved in 4 ml of methylene chloride, 860 μl of 5 N aqueous sodium hydroxide solution and 143 mg of 2-bromo-N,N-dimethylacetamide were added to the solution with stirring at room temperature in that order, and the mixture was subjected to 3 hours of reaction at room temperature. Then, 143 mg of 2-brorno-N,N-dimethylacetamide was additionally added to the reaction solution, and the mixture was subjected to 1 hour of reaction at room temperature. Then, 267 μl of diethylamine was added and the mixture was stirred for 30 minutes. Brine was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was purified by aminopropylated silica gel medium pressure liquid column chromatography (eluent: ethyl acetate) to give 410 mg of (-)-2-[(2S)-2-[[(2R)-2-[4-benzyloxy-3-(2-benzyloxyethyl)phenyl]-2-hydroxyethyl]amino]-1,2,3,4-tetrahydronaphthalen-7-yloxy)-N,N-dimethylacetamide in an oily form.
Reaction SMILES: [O-]CC.[Na+].[OH:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:9]=[CH:10][CH:11]=1.Br[CH2:19][C:20]1[CH:21]=[CH:22][C:23]2[O:27][C:26]([N+:28]([O-:30])=[O:29])=[C:25]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:24]=2[CH:37]=1>C(O)C>[N+:28]([C:26]1[O:27][C:23]2[CH:22]=[CH:21][C:20]([CH2:19][O:5][C:6]3[CH:7]=[C:8]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:9]=[CH:10][CH:11]=3)=[CH:37][C:24]=2[C:25]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([O-:30])=[O:29]
Reactant: CCOC(=O)Cc1cccc(O)c1
Reactant: O=[N+]([O-])c1oc2ccc(CBr)cc2c1-c1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)Cc1cccc(OCc2ccc3oc([N+](=O)[O-])c(-c4ccccc4)c3c2)c1

Procedure:
To a solution of 0.0066 ml. of sodium ethoxide in 50 ml. of ethanol is added 1.2 g. (0.0066 mole) of ethyl 3-hydroxyphenylacetate. The mixture is heated at its reflux temperature for three hours, then 2 g. (0.006 mole) of 5-bromomethyl-2-nitro-3-phenylbenzofuran is added. The mixture is heated at its reflux temperature for 16 hours. On cooling of the reaction mixture a yellow precipitate is obtained which is separated by filtration. Recrystallization from a mixture of hexane and benzene provides ethyl 3[(2-nitro-3-phenylbenzofuran-5-yl)methoxy]phenylacetate, m.p. 67°-68° C.
Reaction SMILES: C(OC([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21]CC=C)=[O:20])=[C:14]([CH2:17]O)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=O)C=C.[CH:27]([NH:29][CH2:30][C:31]1[S:35][C:34]2=[CH:36][N:37]=[CH:38][N:33]2[C:32]=1[CH3:39])=[O:28]>>[OH:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O-:21])=[O:20])=[C:14]([CH2:17][N:37]3[CH:36]=[C:34]4[S:35][C:31]([CH2:30][NH:29][CH:27]=[O:28])=[C:32]([CH3:39])[N+:33]4=[CH:38]3)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9]
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)[C@H](C)[C@H]12
Reactant: Cc1c(CNC=O)sc2cncn12
Product: Cc1c(CNC=O)sc2cn(CC3=C(C(=O)[O-])N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)c[n+]12
Yield: 3.8 %

Procedure:
The same procedure as in Example 1 was repeated except that 91.3 mg of allyl (1S,5R,6S)-6-[(1R)-1-allyloxycarbonyloxyethyl]-2-hydroxymethyl-1-methyl-1-carbapen-2-em-3-carboxylate and 100 mg of 2-(formylamino)methyl-3-methylimidazo[5,1-b]thiazole were used, thereby obtaining 4 mg of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[C:5](=[O:14])[N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1.BrC1C=C(I)C(=O)N([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)C=1.ClC1C=CC=CC=1B(O)O.C1([Mg]Cl)CCCCC1.[Cl-].[NH4+]>O1CCCC1.[Ni](Cl)Cl.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:4]1[C:5](=[O:14])[N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=[C:2]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH:3]=1
Reactant: O=c1c(I)cc(Br)cn1-c1ccccc1
Reactant: O=c1c(-c2ccccc2Cl)cc(Br)cn1-c1ccccc1
Agent: Cl[Ni]Cl
Agent: Cl[Mg]C1CCCCC1
Agent: OB(O)c1ccccc1Cl
Solvent: C1CCOC1
Product: O=c1c(-c2ccccc2Cl)cc(C2CCCCC2)cn1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
30 mg of 5-bromo-3-(2-chlorophenyl)-1-phenyl-1,2-dihydropyridin-2-one synthesized from 5-bromo-1-phenyl-3-iodo-1,2-dihydropyridin-2-one and 2-chlorophenyl boronic acid in accordance with the method of Referential Example 3 was dissolved in 20 ml of tetrahydrofuran, followed by adding 1 mg of [1,3-bis(diphenylphosphino)propane] nickel (II) chloride. Under stirring in nitrogen atmosphere, 0.1 ml of cyclohexyl magnesium chloride (2.0M ether solution) was added dropwise thereinto. After stirring at room temperature in nitrogen atmosphere overnight, the mixture was heated under reflux for 1 hour. After cooling to room temperature, a saturated aqueous solution of ammonium chloride was added thereto, followed by extracting with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (chloroform/methanol system), to give 6 mg of the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[O:15][CH3:16])[CH:5]=[CH:4][N:3]=1.[CH:17]1([OH:21])[CH2:20][CH2:19][CH2:18]1.CC(C)([O-])C.[K+]>O1CCOCC1>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([O:15][CH3:16])=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([O:21][CH:17]3[CH2:20][CH2:19][CH2:18]3)[CH:7]=2)[CH:13]=1
Reactant: COc1ccc(Cl)cc1-c1ccnc(Cl)c1
Reactant: OC1CCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ccc(Cl)cc1-c1ccnc(OC2CCC2)c1
Temperature: 101 °C
Reaction time: 15 h
Yield: 114.1 %

Procedure:
2-Chloro-4-(5-chloro-2-methoxyphenyl)pyridine (Preparation 864, 150 mg, 0.00059 mol) and cyclobutanol (76.6 mg, 0.00106 mol) were dissolved in 1,4-dioxane (2 mL). Potassium tert-butoxide (132 mg, 0.00118 mol) was added and the solution stirred at 101° C. for 15 hours. The reaction was partitioned between ethyl acetate (15 mL) and a 10% aqueous solution of citric acid (10 mL). The organic layer was washed with water (10 mL) followed by a saturated aqueous sodium chloride solution (10 mL). The organics were dried over anhydrous magnesium sulphate, filtered and the solvents removed in vacuo to give a yellow oil (195 mg). The material was purified using an ISCO™ companion (12 g column, eluting with 100% heptane to 7:3 heptane/ethyl acetate). Fractions containing product were combined and concentrated in vacuo to obtain the title compound as a colourless oil (84 mg).
Reaction SMILES: S([O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH3:13])=[CH:8][CH:7]=1)(O)(=O)=O.[CH:14]1[C:19]([O:20][C:21](Cl)=[O:22])=[CH:18][CH:17]=[C:16]([Cl:24])[CH:15]=1>>[Cl:24][C:16]1[CH:17]=[CH:18][C:19]([O:20][C:21](=[O:22])[N:12]([C:9]2[CH:10]=[CH:11][C:6]([OH:5])=[CH:7][CH:8]=2)[CH3:13])=[CH:14][CH:15]=1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Reactant: CNc1ccc(OS(=O)(=O)O)cc1
Product: CN(C(=O)Oc1ccc(Cl)cc1)c1ccc(O)cc1

Procedure:
In analogy to example 15.1, reaction of 4-methylaminophenol hemisulfate with 4-chlorophenylchloroformate yielded (4-Hydroxy-phenyl)-methyl-carbamic acid 4-chloro-phenyl ester, mp: 143-145° C., dec.; MS: 278 (MH+, 1Cl).
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([C:7]1[CH:12]=[C:11]([C:13]([OH:15])=O)[CH:10]=[CH:9][C:8]=1[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[S:23][CH:24]=[CH:25][C:26]=2[NH:27][S:28]([CH:31]([CH3:33])[CH3:32])(=[O:30])=[O:29])=[CH:18][CH:17]=1)#[N:6].[CH3:34][NH2:35]>ClCCl>[CH3:34][NH:35][C:13]([C:11]1[CH:10]=[CH:9][C:8]([C:16]2[CH:17]=[CH:18][C:19]([C:22]3[S:23][CH:24]=[CH:25][C:26]=3[NH:27][S:28]([CH:31]([CH3:33])[CH3:32])(=[O:30])=[O:29])=[CH:20][CH:21]=2)=[C:7]([C:5]#[N:6])[CH:12]=1)=[O:15]
Reactant: CC(C)S(=O)(=O)Nc1ccsc1-c1ccc(-c2ccc(C(=O)O)cc2C#N)cc1
Reactant: CN
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CNC(=O)c1ccc(-c2ccc(-c3sccc3NS(=O)(=O)C(C)C)cc2)c(C#N)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Add thionyl chloride (0.2 mmol) to a suspension of 2-Cyano-4′-[3-(propane-2-sulfonylamino)-thiophen-2-yl]-biphenyl-4-carboxylic acid (0.1 mmol) in dichloromethane at RT. Stir mixture for 1 h at 50° C. and concentrate to dryness under reduced pressure. Add to the resultant residue 0.5 mmol MeNH2 (2M in THF). Concentrate the reaction to dryness and purify with flash chromatography (Silica gel-5%MeOH/CH2Cl2). Concentrate the desired fractions to provide the title compound. MS (ES−):438 (M−1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[C:27]([C:31]([O:33]CC)=[O:32])=[CH:28][CH:29]=[CH:30][C:6]=2[N:5]=1)[CH3:2].[OH-].[Na+]>C(O)C>[CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:14][CH:15]=2)[C:7]2[C:27]([C:31]([OH:33])=[O:32])=[CH:28][CH:29]=[CH:30][C:6]=2[N:5]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc2nc(OCC)n(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1nc2cccc(C(=O)O)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
A solution of ethyl 2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (0.24 g) and 1N NaOH (1.5 ml) in ethanol (4 ml) was stirred at 80° C. for one hour. The reaction mixture was concentrated, and the concentrate was extracted with water and ethyl acetate. The aqueous layer was adjusted to pH 3–4 with 1N-HCl to give crystals. Recrystallization of the crystals from ethyl acetate-methanol afforded colorless crystals (0.15 g, 67%), m.p. 183–185° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([F:18])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([F:18])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)cc1F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(OCc2ccccc2)cc1F
Temperature: 25 °C
Yield: 81.35 %

Procedure:
After dissolving the 4-benzyloxy-2-fluoronitrobenzene crude crystals (16.06 g, 63.65 mmol) in ethanol (1000 ml) and water (200 ml), electrolytic iron powder (14.0 g, 254.60 mmol) and ammonium chloride (27.2 g, 509.20 mmol) were added and the mixture was heated to reflux for 4.5 hours. The reaction solution was cooled to near room temperature, the insoluble portion was filtered off, washing was performed with ethanol and the solvent of the filtrate was distilled off under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was adsorbed onto silica gel and purified by silica gel column chromatography (hexane-ethyl acetate system) to obtain the title compound (11.25 g, 51.78 mmol, 81.35%) as a brown oil.
Reaction SMILES: N1C(C(Cl)=O)=CC=CC=1C(Cl)=O.NC[C:15]1[C:16]2[C:21]([C:22](CN)=[C:23]3[C:28]=1[CH:27]=[CH:26][CH:25]=[CH:24]3)=[CH:20][CH:19]=[CH:18][CH:17]=2.C(N(CC)CC)C.CO>C(Cl)(Cl)Cl>[CH:17]1[C:16]2[C:21](=[CH:22][C:23]3[C:28]([CH:15]=2)=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:20]=[CH:19][CH:18]=1
Reactant: NCc1c2ccccc2c(CN)c2ccccc12
Agent: O=C(Cl)c1cccc(C(=O)Cl)n1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClC(Cl)Cl
Product: c1ccc2cc3ccccc3cc2c1
Reaction time: 8 h

Procedure:
Clear solutions of 2,6-pyridinedicarbonyl dichloride (84 mg, 0.41 mmol) in 15 mL of chloroform and 9,10-bis(aminomethyl)anthracene (97 mg, 0.41 mmol) in 15 mL of chloroform were simultaneously added dropwise over 10 h to a stirred solution of squaraine 13a (32 mg, 0.05 mmol, synthesized according to E. Arunkumar et al. Chem. Eur. J. 2006, 12, 4884-4690) and triethylamine (81 mg, 0.8 mmol) in 30 mL of chloroform. After overnight stirring, the mixture containing rotaxane 13 and polymer co-products was filtered, washed with chloroform (100 mL) to extract rotaxane 13, and the filtrate was concentrated. Purification of the crude material by column chromatography using silica gel (gradient, 0-1% of MeOH in CHCl3) gave the rotaxane 13. λmax (abs): 651 m, λmax (em): 707 nm, 59% (methanol); λmax (abs): 648 nm, λmax (em): 700 nm, Q.Y.: 65% (chloroform).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][C:11]2[CH:12]=[C:13]3[C:22]4([CH2:26][O:25][C:24]([NH:27]C(=O)OC(C)(C)C)=[N:23]4)[C:19]4([CH2:21][CH2:20]4)[CH2:18][O:17][C:14]3=[CH:15][CH:16]=2)=[O:9])=[N:6][CH:7]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:27][C:24]1[O:25][CH2:26][C:22]2([C:13]3[C:14](=[CH:15][CH:16]=[C:11]([NH:10][C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=4)=[O:9])[CH:12]=3)[O:17][CH2:18][C:19]32[CH2:20][CH2:21]3)[N:23]=1
Reactant: CC(C)(C)OC(=O)NC1=NC2(CO1)c1cc(NC(=O)c3ccc(F)cn3)ccc1OCC21CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1=NC2(CO1)c1cc(NC(=O)c3ccc(F)cn3)ccc1OCC21CC1
Reaction time: 2 h
Yield: 41.1 %

Procedure:
To a mixture of tert-butyl (6′-{[(5-fluoropyridin-2-yl)carbonyl]amino}dispiro[cyclopropane-1,3′-chromene-4′,4″-[1,3]oxazol]-2″-yl)carbamate (135 mg, 0.288 mmol) and CH2Cl2 (5.4 mL) was added trifluoroacetic acid (1.30 mL, 17.0 mmol) at ambient temperature. After stirring for 2 hours at the same temperature, the mixture was concentrated at reduced pressure. The residue was partitioned between CHCl3 and saturated aqueous NaHCO3. The organic layer was washed with water, dried over Na2SO4 and filtered. The filtrate was concentrated at reduced pressure, and the residue was purified with column chromatography on silica gel (CHCl3-EtOH, a linear gradient of EtOH from 0 to 20%) to afford N-(2″-aminodispiro[cyclopropane-1,3′-chromene-4′,4″-[1,3]oxazol]-6′-yl)-5-fluoropyridine-2-carboxamide (43.6 mg).
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C.[Na]>O>[C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2ccc3ccccc3n2)cc1
Agent: [Na]
Solvent: CCO
Solvent: O
Product: c1ccc(C2CCc3ccccc3N2)cc1
Temperature: 25 °C

Procedure:
In Scheme A, step 2, the 2-phenyl-1,2,3,4-tetrahydroquinoline of formula (3) is prepared by reducing 2-phenylquinoline of formula (2). For example, 2-phenylquinoline of formula (2) is dissolved in a suitable alcoholic solvent, such as absolute ethanol. Sodium metal is then added and the reaction is allowed to cool to room temperature. The reaction mixture may then be diluted with water and extracted with a suitable organic solvent, such as methylene chloride, ethyl acetate, or chloroform. The combined extracts may then be washed with water and brine, the organic layer is separated and dried and the solvent is evaporated in vacuo to provide the 2-phenyl-1,2,3,4-tetrahydroquinoline of formula (3) which may be used without further purification.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH2:18])(C)(C)C.C(O[C:25](=[O:49])[CH2:26][C:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[S:35][C:36]([CH2:39][CH2:40][O:41]C3CCCCO3)=[N:37][N:38]=2)[CH:29]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:17][C:11]1[C:12]([N:14]([CH3:16])[CH3:15])=[CH:13][C:8]2[N:7]=[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]4[S:35][C:36]([CH2:39][CH2:40][OH:41])=[N:37][N:38]=4)[CH:29]=3)[CH2:26][C:25](=[O:49])[NH:18][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2nnc(CCOC3CCCCO3)s2)c1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3nnc(CCO)s3)c1)=N2

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-dimethylamino-phenyl)-carbamic acid tert.-butyl ester (Example J1) (0.15) and crude 3-oxo-3-(3-{5-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-[1,3,4]thiadiazol-2-yl}-phenyl)-propionic acid tert-butyl ester (0.24 g) (Example K30) according to the general procedure M. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (0.10 g).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].BrC1C=CC(S([O:17][C@@H:18]2[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:20]([C:30]([O:32][CH3:33])=[O:31])[CH2:19]2)(=O)=O)=CC=1.[CH2:34]([CH:37]1[CH:46](O)[C:45]23[N:48]=[CH:49][CH:50]=[C:44]2[CH:43]=[CH:42][CH:41]=[C:40]3[N:39]([CH3:51])[CH2:38]1)[CH:35]=[CH2:36]>CN1C(=O)CCC1.CCOC(C)=O.Cl>[CH2:34]([CH:37]1[CH:46]([O:17][C@H:18]2[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[C@H:20]([C:30]([O:32][CH3:33])=[O:31])[CH2:19]2)[C:45]23[N:48]=[CH:49][CH:50]=[C:44]2[CH:43]=[CH:42][CH:41]=[C:40]3[N:39]([CH3:51])[CH2:38]1)[CH:35]=[CH2:36]
Reactant: C=CCC1CN(C)C2=CC=CC3=CC=NC32C1O
Reactant: COC(=O)[C@@H]1C[C@H](OS(=O)(=O)c2ccc(Br)cc2)CN1C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: C=CCC1CN(C)C2=CC=CC3=CC=NC32C1O[C@@H]1C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1
Temperature: 60 °C
Yield: 44 %

Procedure:
Cs2CO3 (8.20 g, 25.20 mmol) and 1-tert-butyl 2-methyl (2S,4S)-4-{[(4-bromophenyl)sulfonyl]oxy}pyrrolidine-1,2-dicarboxylate (3.80 g, 8.18 mmol) were added in sequence to a solution of 3-allyl-1-methyl-3H-pyrrolo[2,3-e]quinolin-4-ol (1.50 g, 6.29 mmol) in NMP (42 mL). The mixture was heated at 60° C. for 12 h, then cooled and diluted with EtOAc and aqueous HCl (1 N). The organic layer was separated, washed with brine and dried over Na2SO4. Filtration and removal of the volatiles gave a residue that was purified on silica gel (gradient elution, 20-100% EtOAc/petrol ether) to afford the title compound (1.30 g, 44%) as a solid. LCMS (ES+) m/z 466 (M+H)+.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9](Cl)=[C:8]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[F-:25].[K+].CS(C)=O>O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([F:25])=[C:8]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(CSc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Reactant: [F-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)c1ccc(CSc2cnn(C(C)(C)C)c(=O)c2F)cc1
Temperature: 120 °C

Procedure:
A round bottom flask is charged with 2-tert-butyl-4-chloro-5-(4-tert-butylbenzyl)thio 3(2H)-pyridazinone (100 mg, 0.27 mmol) and to it is added potassium fluoride (23.4 mg, 0.40 mmol) and 2 ml dimethyl sulfoxide. This is heated to 120° C. for 6 hours. The reaction mixture is then poured into water and extracted with ethyl acetate. This is washed with water and dried. Purification by flash chromatography (silica gel; ethyl acetate/hexanes) gave the above mentioned compound.
Reaction SMILES: Cl[CH2:2][N:3]1[C:7](=[O:8])[C:6]2=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=[C:5]2[C:4]1=[O:16].[SH:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>C(O)C>[N+:13]([C:10]1[CH:9]=[C:6]2[C:7](=[O:8])[N:3]([CH2:2][S:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[C:4](=[O:16])[C:5]2=[CH:12][CH:11]=1)([O-:15])=[O:14]
Reactant: O=C1c2ccc([N+](=O)[O-])cc2C(=O)N1CCl
Reactant: Sc1ccncc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C1c2ccc([N+](=O)[O-])cc2C(=O)N1CSc1ccncc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.1 %

Procedure:
N-Chloromethyl-4-nitrophthalimide [2.89 g (12 mmol)] was added under ice-cooling with stirring to a suspension of 1.11 g (10 mmol) of 4-mercaptopyridine and 1.4 ml (12 mmol) of triethylamine in 50 ml of ethanol. The mixture was stirred at room temperature for 16 hours. The solvent was distilled off and the residue was purified by column chromatography (eluent: ethyl acetate) to obtain 1.99 g of the desired compound (yield: 63.1%, yellow crystals).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]1[CH:9]=[N:10][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[N:15]=2)=[N:12][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+].I[CH:38]([CH3:40])[CH3:39].O>CC(C)=O>[F:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][N:16]1[C:17]2=[N:18][CH:19]=[CH:20][CH:21]=[C:22]2[C:14]([C:11]2[N:10]=[CH:9][C:8]([N:2]3[CH2:3][CH:4]4[CH2:7][CH:1]3[CH2:6][N:5]4[CH:38]([CH3:40])[CH3:39])=[CH:13][N:12]=2)=[N:15]1
Reactant: Fc1ccccc1Cn1nc(-c2ncc(N3CC4CC3CN4)cn2)c2cccnc21
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)N1CC2CC1CN2c1cnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50 mg (0.13 mmol) of 3-[5-(2,5-diazabicyclo[2.2.1]hept-2-yl)-2-pyrimidinyl]-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine (example 9) are dissolved in 5 ml of absolute acetone, and 92 mg (0.87 mmol) of sodium carbonate are added. 64 mg (0.37 mmol) of 2-iodopropane are added to the suspension, and the mixture is stirred at RT overnight. The reaction solution is mixed with water and extracted with DCM. The organic phases are combined, washed with saturated aqueous sodium chloride solution, dried and filtered. The solvent is removed in vacuo, and the residue is purified by preparative HPLC with addition of small portions of aqueous hydrochloric acid. 25 mg (42% of theory) of the product are obtained.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14].Br[CH2:16][C:17]([O:19][CH3:20])=[O:18].O>CN(C=O)C.CCOC(C)=O>[CH3:20][O:19][C:17](=[O:18])[CH2:16][O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[Br:7]
Reactant: COC(=O)CBr
Reactant: Oc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)COc1ccccc1Br
Reaction time: 0.05 h
Yield: 96.8 %

Procedure:
Powdered potassium carbonate (3.84 g, 27.8 mmol) is added to a stirred solution of 2-bromophenol (3.20 g, 18.5 mmol) and methyl bromoacetate (3.11 g, 20.3 mmol) in anhydrous DMF (20 mL). The resultant mixture is stirred at ambient temperature under nitrogen for 16 hours. Water (140 mL) and EtOAc (120 mL) are added to the mixture and the two-layered solution is stirred vigorously for 3 minutes. The organic layer is separated, dried over MgSO4, filtered and concentrated. The crude product is chromatographed oh silica (gradient 2-8% EtOAc in hexane) to give 4.39 g (17.9 mmol, 97% yield) of the title compound. EIMS: m/z 244 (M+, 79Br), 246 (M+, 81Br).