Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH:13]([S:17][CH3:18])[C:14]([OH:16])=O)=[CH:7][C:6]=2[CH3:19].[C:20]([NH2:24])([CH3:23])([CH3:22])[CH3:21]>>[C:20]([NH:24][C:14](=[O:16])[CH:13]([O:12][C:8]1[CH:9]=[C:10]2[C:5](=[C:6]([CH3:19])[CH:7]=1)[N:4]=[CH:3][C:2]([I:1])=[CH:11]2)[S:17][CH3:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CSC(Oc1cc(C)c2ncc(I)cc2c1)C(=O)O
Reactant: CC(C)(C)N
Product: CSC(Oc1cc(C)c2ncc(I)cc2c1)C(=O)NC(C)(C)C

Procedure:
In a similar procedure to Stage 2 of Example 1, (3-iodo-8-methyl-quinolin-6-yloxy)-methylsulfanyl-acetic acid was condensed with t-butylamine to give N-tert-Butyl-2-(3-iodo-8-methyl-quinolin-6-yloxy)-2-methylsulfanyl-acetamide as a white solid ([M+1]+ 445).
Reaction SMILES: [CH3:1][CH:2]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([NH2:19])[CH:15]=[CH:14]2)[CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5].CCN(CC)CC.[C:27]([O:35][CH2:36][C:37]1[CH:45]=[CH:44][CH:43]=[CH:42][C:38]=1[C:39](Cl)=[O:40])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C1C=CN=CC=1)C.C1COCC1>[C:27]([O:35][CH2:36][C:37]1[CH:45]=[CH:44][CH:43]=[CH:42][C:38]=1[C:39]([NH:19][C:16]1[CH:15]=[CH:14][C:13]2[C:18](=[C:9]([O:8][CH:2]([CH3:1])[CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH:10]=[CH:11][CH:12]=2)[N:17]=1)=[O:40])(=[O:34])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(OCc1ccccc1C(=O)Cl)c1ccccc1
Reactant: CC(CC(C)(C)C)Oc1cccc2ccc(N)nc12
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(CC(C)(C)C)Oc1cccc2ccc(NC(=O)c3ccccc3COC(=O)c3ccccc3)nc12
Reaction time: 8 h

Procedure:
To a 20 mL scintillation vial was added a stir bar, the title compound from Example 16 (100 mg, 0.388 mmol) and anhydr. THF (1.3 mL). To the resultant solution was added of Et3N (0.12 mL, 2.2 equiv), DMAP (5.0 mg, 1.06 equiv) and of 2-(benzoyloxymethyl)benzoyl chloride (116 mg, 1.1 equiv). The solution was stirred overnight, after which time the mixture was placed directly on a silica gel column and eluted with EtOAc/hexanes to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.23 (m, 1H), 8.16 (m, 1H), 7.92 (m, 2H), 7.72 (m, 1H), 7.55 (m, 4H), 7.38 (m, 4H), 7.24 (m, 1H), 5.51 (s, 2H), 4.82 (m, 1H), 1.88 (dd, 1H), 1.49 (dd, 1H), 1.34 (d, 3H), 0.92 (s, 9H); MS (DCI/NH3) m/z 497 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Cl[C:12]1[CH:17]=[C:16](Cl)[N:15]=[CH:14][N:13]=1.[IH:19]>>[I:19][C:12]1[CH:17]=[C:16]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[N:15]=[CH:14][N:13]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: Clc1cc(Cl)ncn1
Reactant: I
Product: Fc1cccc(-c2cc(I)ncn2)c1

Procedure:
The compound was prepared according to Example 1 using 3-fluorophenylboronic acid and 4,6-dichloropyrimidine. The resultant chloro compound was converted to iodo with hydroiodic acid as described in the general procedure.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:8]([C:12]([NH:14][CH2:15][CH2:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:13])=[C:7]([Cl:23])[CH:6]=[CH:5][C:4]=2[N:3]=1.Cl.[C:25]([CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)#[N:26]>>[Cl:23][C:7]1[CH:6]=[CH:5][C:4]2[N:3]=[C:2]([N:30]3[CH2:31][CH2:32][CH:27]([C:25]#[N:26])[CH2:28][CH2:29]3)[CH:11]=[CH:10][C:9]=2[C:8]=1[C:12]([NH:14][CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:13]
Reactant: N#CC1CCNCC1
Reactant: O=C(NCCC1CCCCC1)c1c(Cl)ccc2nc(Cl)ccc12
Agent: Cl
Product: N#CC1CCN(c2ccc3c(C(=O)NCCC4CCCCC4)c(Cl)ccc3n2)CC1
Yield: 28.3 %

Procedure:
Prepared according to the method of example 51, using 2,6-dichloro-N-(cyclohexylethyl)-5-quinolinecarboxamide (Example 94 (d)) (0.35 g), and 4-cyanopiperidine hydrochloride (0.25 g) to afford the title compound (0.12 g).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][N:9]=1)=[O:7].O1CCCC1>O>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]([OH:7])=[O:5])=[N:9][CH:10]=1
Reactant: COC(=O)c1ccc(Br)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(Br)cn1

Procedure:
Lithium hydroxide, monohydrate (0.39 g, 0.0092 mol) was added to a mixture of 5-bromopyridine-2-carboxylic acid methyl ester (0.25 g, 0.0012 mol) in tetrahydrofuran (4.8 mL, 0.059 mol) and water (2.0 mL) and the reaction mixture was refluxed for 30 minutes. The reaction mixture was concentrated and was adjusted to be acidic (pH=˜4) by adding 1 N HCl. The product was extracted with ethyl acetate and the combined extract was concentrated to give the desired product. LC-MS: 202.0/204.0 (M+H+)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[CH:23][CH:22]=[CH:21][C:10]=1[O:11][CH2:12][CH2:13][O:14]C1CCCCO1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O>O1CCCC1.CO>[CH2:1]([O:8][C:9]1[CH:24]=[CH:23][CH:22]=[CH:21][C:10]=1[O:11][CH2:12][CH2:13][OH:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2ccccc2OCCOC2CCCCO2)cc1
Agent: Cl
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: OCCOc1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
To a solution of 2-[2-(2-benzyloxyphenoxy)ethoxy]tetrahydropyran (4.90 g) in tetrahydrofuran (25 ml) and methanol (25 ml) was added 6N hydrochloric acid (15 ml), and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane:ethyl acetate=1:1) to give 2-(2-benzyloxyphenoxy)ethanol (3.07 g, yield 84%).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:24][CH3:25])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[C:26]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)#[N:27]>C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+].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>[NH2:1][C:2]1[N:3]([CH2:24][CH3:25])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:30]4[CH:29]=[C:28]([CH:33]=[CH:32][CH:31]=4)[C:26]#[N:27])[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: CCN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCN1C(=O)C2(CC(c3ccccc3)Oc3ccc(-c4cccc(C#N)c4)cc32)N=C1N
Yield: 4.2 %

Procedure:
Pd(PPh3)4 (40 mg, 0.10 mmol) in a 10 mL flask under Ar was treated sequentially with 2′-amino-6-bromo-1′-ethyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (42 mg, 0.10 mmol) in toluene (5 mL), Na2CO3 (2 N, 2 mL), and 4-cyanophenylboronic acid (31 mg, 0.21 mmol). The mixture refluxed under Ar overnight. The reaction mixture was concentrated in vacuo to give a residue, which was purified by preparative TLC followed by preparative HPLC to give pure 3-(2′-amino-1′-ethyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile (1.76 mg, 3%). 1H-NMR (MeOD): 1.31 (m, 3H), 2.55 (m, 2H), 3.84 (m, 2H), 5.26 (m, 1H), 5.86 (m, 1H), 7.14 (m, 1H), 7.47 (m, 6H), 7.59 (m, 1H), 7.28 (m, 2H), 7.90 (m, 2H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][CH2:8]1.[OH-].[Na+].CN(C)[CH:22]=[O:23]>>[CH3:6][N:7]1[C:13]2[CH:14]=[CH:15][C:16]([CH:22]=[O:23])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CN1CCCCc2ccccc21
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CCCCc2cc(C=O)ccc21
Temperature: 70 °C
Reaction time: 5 h

Procedure:
45 ml of dimethylformamide were treated under an argon atmosphere with 16.2 ml of phosphorus oxychloride. After the reaction had faded away, 7.30 g of 2,3,4,5-tetrahydro-1-methyl-1H-1-benzazepine were added and the reaction mixture was stirred at 70° C. for 5 hours. Thereafter, the mixture was poured on to ice, made alkaline with sodium hydroxide solution, extracted with ether, washed with water, dried and evaporated. Chromatography on silica gel (petroleum ether/ethyl acetate (87:13)) yielded 4.38 g of 2,3,4,5-tetrahydro-1-methyl-1H-1-benzazepine-7-carboxaldehyde.
Reaction SMILES: [NH2:1][C:2]([N:4]([CH2:17][C:18]([O:20]CC)=O)[C@@H:5]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[O:3].C(N(CC)CC)C>CO>[O:3]=[C:2]1[NH:1][C:18](=[O:20])[CH2:17][N:4]1[C@@H:5]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: CCOC(=O)CN(C(N)=O)[C@H](C(=O)OC(C)(C)C)C(C)(C)C
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)[C@@H](N1CC(=O)NC1=O)C(C)(C)C
Temperature: 50 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
A solution containing the product from Example 46B (20.0 mmol) in methanol (30 mL) was treated with triethylamine (5.6 mL, 40.2 mmol), stirred at 50° C. for 2 hours, and concentrated. The residue was chromatographed on silica gel eluting with 0-30% ethyl acetate/dichloromethane to give the title compound (4.57 g, 85% yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]=2[NH:11][C:10]1=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].O>CN(C)C=O>[CH2:35]([O:34][C:32]([CH2:31][N:11]1[C:12]2[CH:26]=[CH:25][CH:24]=[CH:23][C:13]=2[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])=[N:15][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:10]1=[O:27])=[O:33])[CH3:36]
Reactant: CC(C)(C)OC(=O)NC1N=C(c2ccccc2F)c2ccccc2NC1=O
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CN1C(=O)C(NC(=O)OC(C)(C)C)N=C(c2ccccc2F)c2ccccc21
Temperature: 5 °C
Yield: 100 %

Procedure:
To a solution of (3RS)-3-tert-butoxycarbonylamino-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one (5.88 g) in N,N-(1imethylformamide (100 ml) was added portionwise sodium hydride (60% dispersion in mineral oil, 0.76 g) under stirring and cooling at 5° C. The mixture was stirred under the same condition for 0.5 hour and at ambient temperature for 1 hour. To the mixture was added dropwise a solution of ethyl bromoacetate (3.19 g) in N,N-dimethylformamide (10 ml) under cooling in an ice-bath. After the addition was completed, the mixture was stirred at ambient temperature for 3 hours. The reaction mixture was poured into water (300 ml) under vigorous stirring. The resultant precipitates were collected by filtration, washed with water and dried under reduced pressure over phosphorus pentoxide to afford (3RS)-1-ethoxycarbonylmethyl-3-tert-butoxycarbonylamino-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one (7.25 g) as a crystalline powder, which was used in a following reaction step without further purification.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:26]C)=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([O:17]CC3C=CC=CC=3)=[C:13]([F:25])[CH:12]=1)[N:6]=[CH:5]2.B(Br)(Br)Br.O.C(OCC)(=O)C>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([F:25])[CH:12]=3)[N:6]=[CH:5][C:4]=2[C:3]=1[OH:26]
Reactant: COc1c(Br)ccc2c1cnn2-c1ccc(OCc2ccccc2)c(F)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: Oc1ccc(-n2ncc3c(O)c(Br)ccc32)cc1F
Reaction time: 8 h
Yield: 74.5 %

Procedure:
A solution of 5-bromo-1-{3-fluoro-4-[(phenylmethyl)oxy]phenyl}-4-(methyloxy)-1H-indazole (D20) (71 mg) in dry dichloromethane (2 mL) was cooled to −78° C. under argon and treated dropwise with boron tribromide solution (0.75 mL of 1M solution in dichloromethane, 0.75 mmol). The mixture was allowed to reach room temperature and was stirred overnight. Water and ethyl acetate were added and the pH of the aqueous layer was adjusted to 7 and the product was extracted into ethyl acetate. The extracts were dried (Na2SO4), concentrated and chromatographed (silica gel, 0-100% ethyl acetate in hexane) to give the title compound (E11) as a beige solid (40 mg)
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([C:10]#[N:11])[C:7]([CH2:12]Br)=[CH:6][C:5]=1[O:14][CH2:15][CH3:16].[N-:18]=[N+:19]=[N-:20].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][NH:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([C:10]#[N:11])[C:7]([CH2:12][N:18]=[N+:19]=[N-:20])=[CH:6][C:5]=1[O:14][CH2:15][CH3:16]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOc1cc(CBr)c(C#N)cc1C(=O)NC
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1cc(CN=[N+]=[N-])c(C#N)cc1C(=O)NC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After next dissolving N1-methyl-4-(bromomethyl)-5-cyano-2-ethoxybenzamide in dimethylformamide (100 ml), sodium azide (6 g) was added and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with water and brine, and then the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to yield the title compound (15.5 g).
Reaction SMILES: FC(F)(F)C(O)=O.[BH4-].[Na+].[N+:10]([C:13]1[CH:30]=[CH:29][C:16]([C:17]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][C:23](=[O:28])[CH2:22]3)=O)=[CH:15][CH:14]=1)([O-:12])=[O:11]>>[N+:10]([C:13]1[CH:14]=[CH:15][C:16]([CH2:17][C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][C:23](=[O:28])[CH2:22]3)=[CH:29][CH:30]=1)([O-:12])=[O:11]
Reactant: O=C1Cc2cc(C(=O)c3ccc([N+](=O)[O-])cc3)ccc2N1
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: O=C1Cc2cc(Cc3ccc([N+](=O)[O-])cc3)ccc2N1
Temperature: 25 °C
Reaction time: 36 h
Yield: 61 %

Procedure:
In a dried 250 mL round bottom flask, 20.73 mL of trifluoroacetic acid was added and then cooled to 0° C. under Ar(g). NaBH4 in pellet form (1.35 g, 35.71 mmol, ˜1.5 pellets) was added to the flask. 5-(4-Nitro-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 7, 1.0 g, 3.55 mmol) was then added in slowly over 15 min. After the addition was completed, the reaction was allowed to warm to room temperature and was stirred for 36 hours forming a yellow foamy mixture. The mixture was poured over ice-water and allowed to warm to room temperature, during which a tan solid precipitated out of solution. The tan solid was collected by filtration and washed with water affording 5-(4-Nitro-benzyl)-1,3-dihydro-indol-2-one in 61% yield (0.589 g, 2.165 mmol).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.Br.[Br:13][C:14]1[S:18][C:17]([NH2:19])=[N:16][CH:15]=1.C(N(C(C)C)C(C)C)C>C(O)C>[Br:13][C:14]1[S:18][C:17]2=[N:19][C:3]([C:5]3[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=3)=[CH:2][N:16]2[CH:15]=1
Reactant: Nc1ncc(Br)s1
Reactant: O=C(CBr)c1ccc(F)cc1
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Fc1ccc(-c2cn3cc(Br)sc3n2)cc1
Yield: 19.4 %

Procedure:
To a solution of 2-bromo-1-(4-fluoro-phenyl)-ethanone (2 g, 9.215 mmol) in 100 ml ethanol were added 5-bromo-thiazol-2-ylamine hydrobromide (2.396 g, 9.215 mmol) and ethyl-diisopropyl-amine (1.19 g, 9.215 mmol). The mixture was stirred under reflux for 8 h and evaporated. Water was added to the residue and extracted with ethyl acetate. The organic layer was separated, washed with water, dried and evaporated. The crude product was purified by preparative HPLC (RP18, acetonitrile/water 0.1% TFA) to yield 532 mg (20%) of the desired product. MS: M+H+=296.96.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13].[C:14]1(=O)[O:19][C:17](=[O:18])[CH2:16][CH2:15]1.Cl>C1COCC1.O>[Cl:6][C:7]1[C:8]([Cl:13])=[CH:9][CH:10]=[CH:11][C:12]=1[CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: O=C1CCC(=O)O1
Reactant: Clc1ccccc1Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCCc1cccc(Cl)c1Cl
Reaction time: 0.5 h

Procedure:
In a 100 ml three necked RB flask equipped with a nitrogen gas inlet and an additional funnel, was taken 4 ml of n-butyl lithium (4 ml, 1.8 M in hexanes). Then 10 ml of dry THF was added and the reaction mixture was kept in −80° C. for 0.5 h. A solution of orthodichlorobenzene (0.01 mol, 1.47 g) in 10 ml THF was added in drops by the additional funnel to the n-butyl lithium solution for the period of 10 minutes with keeping the temperature below −78° C. The mixture was stirred for half an hour to form a pale yellow color. Then a solution of succinic anhydride 1 g (0.01 mol) in 10 ml THF was added slowly for the period of 15 minutes. As the addition continued the reaction mixture turned to yellow color. After one hour water 20 ml was added to quench the reaction and acidified with 5 N HCl. It was then extracted with DCM. The organic layer was dried and evaporated to give the required product as oil which was recrystallized from toluene. LCMS analysis revealed the formation of the product. m/e: 246.98
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[O:19]1[CH2:24][CH2:23][N:22]([CH:25]([CH3:29])[CH2:26][CH2:27]Cl)[CH2:21][CH2:20]1>>[O:19]1[CH2:24][CH2:23][N:22]([CH:25]([CH3:29])[CH2:26][CH2:27][O:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[O:5][C:4](=[O:12])[C:3]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:21][CH2:20]1
Reactant: CC(CCCl)N1CCOCC1
Reactant: O=c1oc2ccccc2c(O)c1-c1ccccc1
Product: CC(CCOc1c(-c2ccccc2)c(=O)oc2ccccc12)N1CCOCC1
Yield: 72.5 %

Procedure:
Prepared according to the method of Example 8 from 4-hydroxy-3-phenyl-coumarin and 3-morpholino-1-chlorobutane. An oil is obtained which cannot be crystallised. Yield 72.5%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[C:22]([OH:23])=[CH:21][CH:20]=[CH:19][N:18]=1>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:23][C:22]1[C:17]([OH:16])=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: Oc1cccnc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cccnc3O)c2cc1OC
Temperature: 160 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (252 mg), 2,3-dihydroxypyridine (396 mg), and 4-dimethylaminopyridine (400 mg) were suspended in o-dichlorobenzene (13 ml), and the suspension was stirred at 160° C. overnight. The reaction solution was cooled to room temperature, the solvent was then removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give 6,7-dimethoxy-4-(2-hydroxy-pyridin-3-yloxy)-quinoline (84 mg, yield 25%).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:50]([O:54][C:55]([N:57]1[C:65]2[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=2)[CH:59]=[C:58]1[C:66]1[CH:71]=[CH:70][CH:69]=[C:68]([NH2:72])[CH:67]=1)=[O:56])([CH3:53])([CH3:52])[CH3:51]>CN(C=O)C>[C:50]([O:54][C:55]([N:57]1[C:65]2[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=2)[CH:59]=[C:58]1[C:66]1[CH:71]=[CH:70][CH:69]=[C:68]([NH:72][C:23]([C:18]2[C:19](=[O:22])[O:20][C:21]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[O:11][CH3:10])=[O:25])[CH:67]=1)=[O:56])([CH3:53])([CH3:51])[CH3:52]
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: CC(C)(C)OC(=O)n1c(-c2cccc(N)c2)cc2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4cc5ccccc5n4C(=O)OC(C)(C)C)c3)c(=O)oc12
Temperature: 25 °C
Yield: 72.3 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.014 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 2-(3-Amino-phenyl)-indole-1-carboxylic acid tert-butyl ester (0.02 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.024 g of product in 76% yield: LCMS (ESI) m/z 511 (MH+).
Reaction SMILES: I[CH3:2].[Mg].[Cl:4][CH2:5][CH2:6][CH2:7][C:8](=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>CCOCC>[Cl:4][CH2:5][CH2:6][CH2:7][C:8]([OH:14])([CH3:2])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CI
Reactant: CCCCCC(=O)CCCCl
Agent: [Mg]
Solvent: CCOCC
Product: CCCCCC(C)(O)CCCCl
Temperature: 0 °C

Procedure:
The Grignard reagent prepared from iodomethane (14.2 g., 0.1 mole) and magnesium (2.4 g., 0.1 mole in ether solution is added, dropwise to an ether solution of 1-chloro-4-nonanone (Example A, Step 1) (17.6 g., 0.1 mole). The reaction is refluxed gently for three hours then cooled and poured carefully into ice water (300 ml.). The ether layer is separated, washed with brine, and dried over sodium sulfate. Removal of the ether in vacuo gives 1-chloro-4-hydroxy-4-methylnonane as an oil. The tertiary alcohol is dissolved in pyridine and treated with one molar equivalent of acetic anhydride at 60°-80° for 8-16 hours to give 1-chloro-4-acetoxy-4-methylnonane as a colorless oil.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Cl:12][C:13]1[C:14](=[O:28])[N:15]([C:24]([CH3:27])([CH3:26])[CH3:25])[N:16]=[CH:17][C:18]=1[NH:19][CH2:20][CH2:21][CH2:22][OH:23].ClCCl>N1C=CC=CC=1>[Cl:12][C:13]1[C:14](=[O:28])[N:15]([C:24]([CH3:25])([CH3:27])[CH3:26])[N:16]=[CH:17][C:18]=1[NH:19][CH2:20][CH2:21][CH2:22][O:23][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: CC(C)(C)n1ncc(NCCCO)c(Cl)c1=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCNc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Temperature: 0 °C

Procedure:
2.55 g of p-toluenesulfonyl chloride was added to a mixture comprising 3.16 g of 4-chloro-5-(3-hydroxypropylamino)-2-t-butyl-3(2H) pyridazinone prepared in Reference Example 4, 1.44 g of pyridine and 50 ml of dichloromethane under stirring and cooling with ice, and the mixture was stirred at the same temperature for 2 hours. Then, 2.0 g of pyridine and 2.5 g of p-toluenesulfonyl chloride were added to the reaction mixture in this order. The mixture was stirred for further 2 hours under cooling with ice, and left to stand overnight in an ice chamber. The solvent was distilled off, and the pale yellow oily substance thereby obtained was extracted with benzene. The extract was washed sequentially with dilute hydrochloric acid, water (twice) and a saturated sodium chloride aqueous solution, and dried over sodium sulfate. Then, solvent was distilled off to obtain a pale yellow oily substance. The oily substance was purified by silica gel column chromatography by using benzene-ethyl acetate (1:1, v/v) as the developer, to obtain 4.67 g of the above identified compound as a pale yellow viscous oily substance.
Reaction SMILES: Cl[C:2]1([C:8]([O:10][CH3:11])=[O:9])[C:6](=[O:7])[CH:5]=[CH:4][S:3]1.[ClH:12]>C(O)(=O)C>[Cl:12][C:4]1[S:3][C:2]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([OH:7])[CH:5]=1
Reactant: Cl
Reactant: COC(=O)C1(Cl)SC=CC1=O
Solvent: CC(=O)O
Product: COC(=O)c1sc(Cl)cc1O
Reaction time: 72 h

Procedure:
A solution of 2-chloro-2-methoxycarbonylthiophene-3(2H)-one (30 mmol) in acetic acid (20 ml) was saturated with dry hydrogen chloride gas. After standing for 3 days the solvent was removed under reduced pressure and the oily residue distilled to give a yellow liquid which crystallised on addition of aqueous acetic acid (m.p. 42°-44° C.).