Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:19])[C@@H:4]([NH2:18])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[Br:20][C:21]1[CH:30]=[C:29]2[C:24]([CH:25]=[C:26]([C:31](O)=[O:32])[N:27]=[CH:28]2)=[CH:23][CH:22]=1>>[C:9]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=[CH:11][C:6]([CH2:5][C@H:4]([NH:18][C:31]([C:26]2[N:27]=[CH:28][C:29]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[C:21]([Br:20])[CH:30]=3)=[O:32])[C:3]([OH:2])=[O:19])=[CH:7][CH:8]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1cc2ccc(Br)cc2cn1
Product: O=C(N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O)c1cc2ccc(Br)cc2cn1
Yield: 2 %

Procedure:
(2S)-amino-3-biphenyl-4yl-propionic acid methyl ester (340 mg, 13.9 mmol) was reacted with 7-bromo-isoquinoline-3-carboxylic acid (350 mg, 13.9 mmol) as described in general procedure A. The resulting compound was hydrolyzed by following general procedure C yielding the title compound (132 mg, 81%) as a white solid.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:25]([CH:28]([CH2:34][CH:35]=O)[C:29]([O:31][CH2:32][CH3:33])=[O:30])([CH3:27])[CH3:26]>C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:35][CH2:34][CH:28]([CH:25]([CH3:27])[CH3:26])[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: CCOC(=O)C(CC=O)C(C)C
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)C(CC=C(Br)Br)C(C)C
Yield: 48.3 %

Procedure:
In 240 g of methylene chloride were dissolved 12.5 g of carbon tetrabromide, followed by the addition of 19.8 g of triphenylphosphine. The mixture was thoroughly stirred. To this mixed solution were added 5.0 g of the ethyl 2-isopropyl-3-formyl-propionate prepared above and the mixture was stirred at room temperature overnight. Thereafter, the low-boiling fraction was distilled off under reduced pressure and the residue was stirred well with diethyl ether and water. The diethyl ether layer was taken and distilled under reduced pressure to remove the low-boiling fraction. To the residue was added petroleum ether and, after thorough stirring, the petroleum ether solution was taken and further distilled under reduced pressure to remove the low-boiling fraction. The resultant oily residue was purified by distillation under reduced pressure. By the above procedure there were obtained 4.6 g of ethyl α-(3,3-dibromoallyl)isovalerate [yield: 48% based on ethyl 2-isopropyl-3-formyl-propionate].
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.Br[C:11]1[N:16]=[C:15]([CH3:17])[N:14]=[C:13]([NH:18][C:19]2[S:20][C:21]([C:24]([NH:26][C:27]3[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:34])=[O:25])=[CH:22][N:23]=2)[CH:12]=1.CCN(C(C)C)C(C)C>C(O)CCC>[CH3:33][C:32]1[C:27]([NH:26][C:24]([C:21]2[S:20][C:19]([NH:18][C:13]3[CH:12]=[C:11]([N:7]4[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]4)[N:16]=[C:15]([CH3:17])[N:14]=3)=[N:23][CH:22]=2)=[O:25])=[C:28]([Cl:34])[CH:29]=[CH:30][CH:31]=1
Reactant: Cc1nc(Br)cc(Nc2ncc(C(=O)Nc3c(C)cccc3Cl)s2)n1
Reactant: OCCN1CCNCC1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(Nc2ncc(C(=O)Nc3c(C)cccc3Cl)s2)cc(N2CCN(CCO)CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.9 %

Procedure:
1-(2-hydroxyethyl)piperazine (Compound 3) (65 g, 0.5 mol), 2-(6-bromo-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-formamide (Compound 14) (43.9 g, 0.1 mol), n-butanol (670 mL) and DIPEA (28.3 g, 0.2 mol) were mixed in reaction flask and reacted by refluxing for 7 h. After the reactant was cooled down to room temperature, crystals precipitated overnight. After air pump filtration, the cake was rinsed with n-butanol (500 mL) by stirring for 30 min. Then filtrated and the cake was dried to give white solid target Compound 1 (42.9 g, yield: 87.9%).
Reaction SMILES: [F:1][C:2]1[S:6][C:5]([NH:7][C:8]([C@@H:10]2[CH2:14][C@H:13]([OH:15])[CH2:12][N:11]2C(OC(C)(C)C)=O)=[O:9])=[N:4][CH:3]=1.Cl.O1CCOCC1>CO>[F:1][C:2]1[S:6][C:5]([NH:7][C:8]([C@@H:10]2[CH2:14][C@H:13]([OH:15])[CH2:12][NH:11]2)=[O:9])=[N:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@H]1C(=O)Nc1ncc(F)s1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C(Nc1ncc(F)s1)[C@@H]1C[C@H](O)CN1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2S,4S)-tert-butyl 2-(5-fluorothiazol-2-ylcarbamoyl)-4-hydroxypyrrolidine-1-carboxylate (1.42 g, 4.29 mmol) in MeOH (40 mL) was added 4N HCl in dioxane (10.71 mL, 42.9 mmol). The reaction mixture was stirred at RT for 2 h and concentrated. The residue was used for the next step without purification. LC/MS [M+H]+: 232; Ret time (Method F): 0.51 min.
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:9]([NH:11][C:12](=[O:15])[CH:13]=[CH2:14])O.Cl.CC(C)=O>O>[CH3:8][C:1]1[CH:2]=[C:3]([CH:4]=[CH:5][C:6]=1[OH:7])[CH2:9][NH:11][C:12](=[O:15])[CH:13]=[CH2:14]
Reactant: C=CC(=O)NCO
Reactant: Cc1ccccc1O
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: C=CC(=O)NCc1ccc(O)c(C)c1
Yield: 66.5 %

Procedure:
A flask was charged with 108 g of o-cresol, 101 g of N-methylolacrylamide, 5 g of 37% aqueous hydrochloric acid solution and 100 ml of acetone, and the mixture was subjected to the condensation reaction at 60° C. for 60 minutes with stirring. The obtained reaction mixture was poured into excess water to separate an organic layer. The organic layer was dissolved in 200 ml of methylene chloride, which was washed with three 100 ml portions of water to give 127 g of N-(3-methyl-4-hydroxybenzyl)acrylamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH:14]([CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21]C)=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH:14]([CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)CCCCC(CCNS(=O)(=O)c1ccc(Cl)cc1)Cc1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCCCC(CCNS(=O)(=O)c1ccc(Cl)cc1)Cc1cccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 8-(p-chlorophenylsulfonamido)-6-(3-pyridylmethyl)-octanoate (0.3 g) is dissolved in 10 mL of methanol, 20 mL of 1N aqueous NaOH added and the reaction is stirred at room temperature overnight. The methanol is evaporated off, water added and the mixture extracted with ethyl acetate. The aqueous layer is acidified to pH 6.1 and extracted with ethyl acetate. The ethyl acetate extract is dried over magnesium sulfate, filtered and concentrated to give 8-(p-chlorophenylsulfonamido)-6-(3-pyridylmethyl)-octanoic acid, NMR (CDCl3): delta 7.7 (d,2H), 7.4 (d,2H), 2.9 (m,2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([F:9])[CH:3]=1.[CH:10]#[C:11][CH2:12][CH2:13][CH3:14].O.CCOCC>C1COCC1.C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:10]#[C:11][CH2:12][CH2:13][CH3:14])=[C:4]([F:9])[CH:3]=1
Reactant: Fc1cc(Br)ccc1I
Reactant: C#CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CCCC#Cc1ccc(Br)cc1F
Temperature: 10 °C
Reaction time: 8 h

Procedure:
190 g (0.600 mol) of 4-bromo-2-fluoro-1-iodobenzene and 65.3 ml of 1-pentyne were dissolved in a mixture of 900 ml of THF and 1.2 l of triethylamine and cooled to 10° C., and 1.14 g (6 mmol) of copper(I) iodide and 8.42 g (12 mmol) of bis(triphenylphosphine)palladium(II) chloride were added. The batch was stirred overnight at room temperature, water and MTB ether were subsequently added, and the mixture was stirred for a further 5 minutes. The reaction mixture was filtered through Celite® with suction, and the phases were separated. The aqueous phase was extracted twice with MTB ether, and the combined organic phases were washed three times with water, dried over sodium sulfate and evaporated under reduced pressure. The crude product was filtered through silica gel with n-heptane, giving 129 g of 4-bromo-2-fluoro-1-pent-1-ynylbenzene as a yellow liquid. Hydrogenation on palladium/activated carbon (10%) in THF gave 131 g (100%) of 4-bromo-2-fluoro-1-pentylbenzene as a yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[NH:10][C:9]3[CH:13]=[C:14]([CH2:17][CH2:18][OH:19])[CH:15]=[CH:16][C:8]=3[NH:7][C:6]=2[CH:20]=1.[NH:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]1=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[NH:10][C:9]3[CH:13]=[C:14]([CH2:17][CH2:18][O:19][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=4)[CH:15]=[CH:16][C:8]=3[NH:7][C:6]=2[CH:20]=1
Reactant: O=c1cccc[nH]1
Reactant: O=C1Nc2cc(CCO)ccc2Nc2cc(Cl)ccc21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1Nc2cc(CCOc3ccccn3)ccc2Nc2cc(Cl)ccc21
Yield: 37.9 %

Procedure:
A mixture of Example 204A (150 mg, 0.52 mmol), pyridin-2 (1H)-one (96 mg, 1.0 mmol), PPh3 (180 mg, 0.68 mmol) and di-tert-butyl azodicarboxylate (160 mg, 0.68 mmol) in 10 mL of THF was stirred overnight. The reaction mixture was purified by flash column chromatography on silica gel with 7:3 hexanes/ethyl acetate to provide 72 mg of the desired product. The column was then washed with 100:3:1 EtOAc/MeOH/NH4OH to give 79 mg of 3-chloro-8-[2-(2-oxo-2H-pyridin-1-yl)-ethyl]-5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-one. MS (DCI) m/e 366 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 9.83 (s, 1H), 8.13-8.14 (m, 1H), 7.97 (s, 1H), 7.65-7.68 (m, 2H), 7.05 (d, J=1.84 Hz, 1H), 6.89-6.95 (m, 5H), 6.76 (d, J=8.42 Hz, 1H), 4.38 (t, J=6.86 Hz, 2H), 2.99 (t, J=6.86 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[CH:17][C:16](=[O:19])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:27][CH2:28][CH2:29][CH2:30][OH:31].[I-].[K+]>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[CH:17][C:16](=[O:19])[C:8]4[CH:9]=[C:10]([O:15][CH2:27][CH2:28][CH2:29][CH2:30][OH:31])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: O=c1ccn2c3ccc(Br)cc3c3cc(O)cc1c32
Reactant: OCCCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=c1ccn2c3ccc(Br)cc3c3cc(OCCCCO)cc1c32
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
10-bromo-2-hydroxy-4H-pyrido[3,2,1-jk]carbazole-4-one (250 mg) obtained in Example 59 was suspended in dimethyl sulfoxide (12 ml), and potassium carbonate (220 mg) was added to the suspension. The mixture was stirred at room temperature for 30 minutes and 4-chloro-1-butanol (0.095 ml) and potassium iodide (1 grain) were added to the mixture. The mixture was stirred at 80° C. in a hot water bath for 24 hours, and the reaction mixture was poured into ice water (100 ml), and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: methylene chloride/methanol=20:1) to obtain the title compound (160 mg, 52%).
Reaction SMILES: Cl[CH2:2][C:3](=[O:5])[CH3:4].CC(C)=O.[OH:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([CH3:22])=[CH:16][C:17](=[O:21])[O:18]2)=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)(Cl)Cl.[I-].[K+]>[CH2:2]([O:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([CH3:22])=[CH:16][C:17](=[O:21])[O:18]2)=[CH:13][CH:12]=1)[C:3]([CH3:4])=[O:5]
Reactant: Cc1cc(=O)oc2cc(O)ccc12
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)COc1ccc2c(C)cc(=O)oc2c1
Yield: 97.5 %

Procedure:
A mixture of chloroacetone (26.23 mL, 30.48 g, 0.329 mol), potassium iodide (1.0 g, 6 mmol), and reagent grade acetone (dried over K2CO3, ca. 400 mL) was allowed to stand for 151/2 hours. 7-Hydroxy-4-methylcoumarin (50.0 g, 0.284 mol), anhyd. K2CO3 (45.50 g, 0.321 mol), and dry reagent grade acetone (1 L) were added and the mixture was refluxed for 24 hours with overhead stirring. The hot mixture was filtered and the precipitate was washed with acetone. The washes and the filtrate were combined and evaporated in vacuo to obtain a yellow solid, which dissolved in CHCl3 (1.3 L). The CHCl3 solution was extracted once with 5% aq. NaOH (500 mL), washed with two portions (500 mL) of water, dried (MgSO4), and evaporated in vacuo to obtain 7-acetonyloxy-4-methylcoumarin (64.30 g, 97.5%), mp 146.0°-148.0° C. Recrystallization of 61.82 g from 95% ethanol gave a purer product (53.91 g, 87% recovery, 85% yield), mp 150.1°-151.2° C.
Reaction SMILES: [C:1]([CH:4]([C:9](=[O:31])[CH:10]([O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[C:25]([F:30])[CH:26]=3)[N:21]=2)=[CH:15][CH:14]=1)[CH3:11])C(OC)=O)(=[O:3])[CH3:2].[H][H].FC1C=C2C(=CC=1)N=C(OC1C=CC(OC(C)C(Cl)=O)=CC=1)C=C2.[Na].COC(=O)CC(C)=O.C([O-])(=O)CCCC.[Cl-].[Na+]>CS(C)=O>[F:30][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[N:21]=[C:20]([O:19][C:16]1[CH:15]=[CH:14][C:13]([O:12][CH:10]([CH3:11])[C:9](=[O:31])[CH2:4][C:1](=[O:3])[CH3:2])=[CH:18][CH:17]=1)[CH:29]=[CH:28]2
Reactant: COC(=O)C(C(C)=O)C(=O)C(C)Oc1ccc(Oc2ccc3cc(F)ccc3n2)cc1
Reactant: [H][H]
Agent: CC(Oc1ccc(Oc2ccc3cc(F)ccc3n2)cc1)C(=O)Cl
Agent: CCCCC(=O)[O-]
Agent: COC(=O)CC(C)=O
Solvent: CS(C)=O
Product: CC(=O)CC(=O)C(C)Oc1ccc(Oc2ccc3cc(F)ccc3n2)cc1

Procedure:
In the same manner, methyl 2-acetyl-4-[4-(6-fluoro-2-quinolyloxy)phenoxy]-3-oxopentanoate (XII; X' is fluoro and X" is hydrogen) is prepared from 2-[4-(6-fluoro-2-quinolyloxy)phenoxy]propionic acid chloride and the sodium salt of methylacetoacetate. This pentanoate is then heated with sodium chloride and DMSO to give 5-[4-(6-fluoro-2-quinolyloxy)phenoxy]2,4-hexanedione (XIII; X' is fluoro and X" is hydrogen).
Reaction SMILES: [Cl:1][C:2]([Cl:15])=[CH:3][O:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[CH:8]([OH:11])[C:9]#[N:10].[CH3:16][C:17]1([CH3:27])[CH:19]([CH:20]=[C:21]([CH3:23])[CH3:22])[CH:18]1[C:24](Cl)=[O:25].N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]([Cl:15])=[CH:3][O:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[CH:8]([O:11][C:24]([CH:18]1[CH:19]([CH:20]=[C:21]([CH3:23])[CH3:22])[C:17]1([CH3:27])[CH3:16])=[O:25])[C:9]#[N:10]
Reactant: N#CC(O)c1cccc(OC=C(Cl)Cl)c1
Reactant: CC(C)=CC1C(C(=O)Cl)C1(C)C
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C)=CC1C(C(=O)OC(C#N)c2cccc(OC=C(Cl)Cl)c2)C1(C)C

Procedure:
To a solution of 9.8 g of 3-(2,2-dichlorovinyloxy)-mandelonitrile and 7.5 g of 2,2-dimethyl-3-(1-isobutenyl)-cyclopropanecarboxylic acid chloride in 100 cc toluene is added a solution of 3.5 g of pyridine in 200 ml toluene dropwise within 10 minutes. The resultant suspension is stirred for 15 hours at 20°-25° C., washed with dilute HCl and totally concentrated.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@H:7]2[O:9][C@@H:8]2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:6]=1.[NH2:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][OH:22]>>[OH:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17][NH:16][C:7]([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)([OH:9])[CH2:8][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: NCCOCCO
Reactant: c1ccc([C@H]2O[C@@H]2c2ccccc2)cc1
Product: OCCOCCNC(O)(Cc1ccccc1)c1ccccc1
Temperature: 140 °C
Reaction time: 14 h
Yield: 91.9 %

Procedure:
A mixture of trans-stilbene oxide (1.96 g, 0.010 mol) and 2-(2-aminoethoxy)ethanol (3.05 g, 0.030 mol) was heated at 140° C. for 6 hours. After standing at room temperature for 14 hours the reaction mixture was triturated with water, the solid product collected, and dried under ambient conditions for 3 days to obtain 2.77 g (92%) of material. The solid was recrystallized from methanol-isopropyl ether to obtain 1.89 g of the product; mp 140°-142° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][C:10]1[CH:19]=[CH:18][C:13]([C:14](=[O:17])[CH2:15]Cl)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:15][C:14]([C:13]2[CH:18]=[CH:19][C:10]([CH3:9])=[CH:11][CH:12]=2)=[O:17])=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: Cc1ccc(C(=O)CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(C(=O)COc2ccc(F)cc2)cc1

Procedure:
Following the procedure outlined in Example 11(a), 4-fluorophenol was interacted with an equimolar quantity of p-methylphenacyl chloride in the presence of potassium carbonate to give ω-(4-fluorophenoxy)-p-methylacetophenone which melted at 95°-96°C after recrystallization from methanol.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[C:6]([CH:12]=[O:13])[CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[N:3]=1.[CH3:22][Mg]Br>O1CCCC1>[Br:1][C:2]1[C:10]2[C:5](=[C:6]([CH:12]([OH:13])[CH3:22])[CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[N:3]=1
Reactant: C[Si](C)(C)CCOCn1nc(Br)c2cc(Cl)cc(C=O)c21
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)c1cc(Cl)cc2c(Br)nn(COCC[Si](C)(C)C)c12
Temperature: -78 °C
Reaction time: 1 h

Procedure:
3-Bromo-5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-7-carbaldehyde (1.35 g, 3.46 mmol) was dissolved in tetrahydrofuran (10 mL), cooled to −78° C. and treated with methylmagnesium bromide (3.0 M in diethyl ether, 1.7 mL, 5.20 mmol) over several minutes. After 1 h, the ice bath was removed and stirring continued for 1 h at room temperature. The reaction was cooled to 0° C., treated with saturated ammonium chloride and diluted with ethyl acetate. The layers were separated. The organic layer was washed with water (2×), brine (2×), dried over sodium sulfate, filtered and concentrated. Flash chromatography on silica gel (30% ethyl acetate/hexanes) afforded 1.29 g (92%) as a brown oil. 1H-NMR (CDCl3, 300 MHz) δ 7.51-7.53 (m, 2H), 5.91 (qAB, JAB=11.7 Hz, 2H), 5.52-5.54 (m, 1H), 3.49-3.54 (m, 2H), 1.63 (d, J=6.6 Hz, 3H), 0.78-0.83 (m, 2H), 0.09 (s, 9H). Mass spec.: 429.18 (MNa)+.
Reaction SMILES: [C:1]1(=[O:20])[N:5]([CH2:6][CH2:7][S:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[C:4](=[O:15])[C:3]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:2]12.[BH4-].[Na+].C(O)C.C(OCC)(=O)C>C(O)C>[OH:20][CH2:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:5][CH2:6][CH2:7][S:8][C:9]1[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=1)=[O:15]
Reactant: O=C1c2ccccc2C(=O)N1CCSc1ccncc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(NCCSc1ccncc1)c1ccccc1CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.7 %

Procedure:
To a solution of 2.84 g (10.0 mmol) of 4-(2-phthalimidoethylthio)pyridine in 150 ml of ethanol, 3.78 g (100 mmol) of sodium borohydride was added, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off and saturated saline was added to the residue. The mixture was extracted with chloroform and the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by column chromatography (eluent: ethanol/ethyl acetate=1:10 to give 2.24 g of the desired compound (77.8% yield, colorless crystals), mp. 132°-133° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:13]=[C:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[S:11][C:10]=2[S:18]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])=[O:19])[CH:6]=[CH:7][CH:8]=1.[CH2:26]([C:30]1[NH:31][CH:32]=[CH:33][N:34]=1)[CH2:27][CH2:28][CH3:29]>O1CCOCC1>[CH2:26]([C:30]1[N:31]([CH2:2][C:3]2[CH:4]=[C:5]([C:9]3[CH:13]=[C:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[S:11][C:10]=3[S:18]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])=[O:19])[CH:6]=[CH:7][CH:8]=2)[CH:32]=[CH:33][N:34]=1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCCc1ncc[nH]1
Reactant: CC(C)Cc1cc(-c2cccc(CBr)c2)c(S(=O)(=O)NC(C)(C)C)s1
Solvent: C1COCCO1
Product: CCCCc1nccn1Cc1cccc(-c2cc(CC(C)C)sc2S(=O)(=O)NC(C)(C)C)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
To a solution of 3-(3-bromomethylphenyl)-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (70 mg, 0.158 mmol; see Example 1(e)) in dioxane (2.0 mL) was added 2-butylimidazole (58.7 mg, 0.473 mmol) and the reaction mixture was stirred for 1 h at 80° C. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography using MeOH:CH2Cl2 (5:95) as eluent to give the sub-title compound in 55% yield as a colourless syrup (42.1 mg, 0.087 mmol).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:31])[N:4]([C:20]2[CH:21]=[C:22]([CH:27]=[CH:28][C:29]=2[CH3:30])[C:23]([NH:25][CH3:26])=[O:24])[C:5]([CH2:18][OH:19])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].N1C=CC=CC=1.[C:38](OC(=O)C)(=[O:40])[CH3:39]>>[C:38]([O:19][CH2:18][C:5]1[N:4]([C:20]2[CH:21]=[C:22]([C:23]([NH:25][CH3:26])=[O:24])[CH:27]=[CH:28][C:29]=2[CH3:30])[C:3](=[O:31])[C:2]([Br:1])=[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])[CH:6]=1)(=[O:40])[CH3:39]
Reactant: CC(=O)OC(C)=O
Reactant: CNC(=O)c1ccc(C)c(-n2c(CO)cc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Solvent: c1ccncc1
Product: CNC(=O)c1ccc(C)c(-n2c(COC(C)=O)cc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
To a solution of 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-(hydroxymethyl)-2-oxopyridin-1(2H)-yl]-N,4-dimethylbenzamide, (225 mg, 0.50 mmol) stirred in CH12Cl2 was added pyridine (55 μL, 0.69 mmol). To the resulting homogeneous solution was then added acetic anhydride (47 μL, 0.51 mmol). The mixture was stirred at rt for 3 h. Additional pyridine (150 μL, 1.8 mmol) and acetic anhydride (100 μL, 1.05 mmol) were then added and the reaction was allowed to stir overnight at rt. The reaction was then quenched with 1N NHCl4 and diluted with CH2Cl2. The layers were separated and the organic layer was then extracted with CH2Cl2 (3×). The organics were then combined, dried, and concentrated in vacuo. The residue was then triturated with Et2O and filtered to give (150 mg, 61%) an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.48 (br s, 1H), 7.87 (app d, J=7.8 Hz, 1H), 7.74-7.69 (m, 2H), 7.52 (d, J=7.5 Hz, 1H), 7.40 (app t, J=8.1 Hz, 1H), 7.28-7.19 (m, 1H), 6.91 (s, 1H), 5.43 (s, 2H), 4.60 (s, 2H), 2.79 (s, 3H), 2.06 (s, 3H), 1.94 (s, 3H). ES-HRMS m/z 535.0676 (M+H calcd for C24H22N2F2BrO5 requires 535.0675).
Reaction SMILES: [N:1](=[C:3]1[C:7]2=[C:8]3[C:13](=[CH:14][CH:15]=[C:6]2[NH:5]C1=O)[N:12]=[CH:11][CH:10]=[CH:9]3)[NH2:2].NN.[OH2:19]>>[NH2:5][C:6]1[CH:15]=[CH:14][C:13]2[N:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:7]=1[C:3]([NH:1][NH2:2])=[O:19]
Reactant: NN=C1C(=O)Nc2ccc3ncccc3c21
Reactant: O
Agent: NN
Product: NNC(=O)c1c(N)ccc2ncccc12
Temperature: 145 °C
Reaction time: 4.5 h

Procedure:
1-Hydrazono-1,3-dihydro-pyrrolo[3,2-f]quinoline-2-one (1.07 g, 5.05 mmol) was combined with 6.0 mL of anhydrous hydrazine and 5.0 mL of water in a 100 mL flask (oversize to allow for foaming) and heated at reflux (145° C. oil bath) under a condenser and nitrogen atmosphere, with stirring. After 4.5 hr, analytical HPLC showed that all of the hydrazone had been consumed. The reaction was cooled, diluted with 75 mL of water, and filtered to give 0.45 g (air dried) of 6-aminoquinoline-5-carboxylic acid hydrazide as an olive brown solid. Mass spectrum (negative ion electrospray): m/z=215 (100%). NMR (DMSO-d6): δ3.64 (s, 2H), 4.22 (s, 2H), 5.66 (s, 2H), 7.25 (d, 1H, J=9.1 Hz), 7.34 (m, 1H), 7.65 (d, 1H, J=9 Hz), 8.34 (d, 1H, J=8.5 Hz), 8.50 (s, 1H), 9.27 (s, 1H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=O)=[CH:3][CH:2]=1.S(Cl)([Cl:16])=O>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([Cl:16])=[O:13])=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccnc2ccccc12
Product: O=C(Cl)c1ccnc2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-quinolinecarboxylic acid (Aldrich, 0.25 g, 1.4 mmol) in 5 mL of thionyl chloride was warmed to reflux and allowed to stir for 1 hour. The mixture was then cooled to ambient temperature and concentrated under reduced pressure. This material was dissolved in 10 mL toluene and concentrated under reduced pressure (3×) to afford the title compound.