Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([F:15])([F:14])[F:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:16][CH3:17])[CH:8]=2)[N:3]=1.[C:18]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[C:23]([F:30])[CH:22]=1)([OH:20])=[O:19]>O>[F:30][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=1[C:2]1[C:11]([C:12]([F:15])([F:14])[F:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:16][CH3:17])[CH:8]=2)[N:3]=1)[C:18]([OH:20])=[O:19]
Reactant: O=C(O)c1ccc(B(O)O)c(F)c1
Reactant: COc1ccc2nc(Cl)c(C(F)(F)F)nc2c1
Solvent: O
Product: COc1ccc2nc(-c3ccc(C(=O)O)cc3F)c(C(F)(F)F)nc2c1
Yield: 19 %

Procedure:
Followed the coupling procedure described in Step 1 of Compound VIII-2 (Example 65), where the starting materials were 2-chloro-6-methoxy-3-(trifluoromethyl)quinoxaline (Intermediate 11) and 4-carboxy-2-fluorobezeneboronic acid After H2O quench, the aqueous layer was acidified with 0.1M HCl to pH=1, followed by EtOAc/aqueous workup and column purification to give 3-fluoro-4-(6-methoxy-3-(trifluoromethyl)quinoxalin-2-yl)benzoic acid (50 mg, yield 19%).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:13]([CH:15]1[O:17][CH2:16]1)Cl>>[O:17]1[CH2:16][CH:15]1[CH2:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:7][CH:8]=1
Reactant: ClCC1CO1
Reactant: Oc1ccc(-n2ccnc2)cc1
Product: c1cn(-c2ccc(OCC3CO3)cc2)cn1

Procedure:
The title compound was prepared from 4-imidazol-1-yl-phenol and epichlorohydrin employing the procedures as set forth in Step 1 of Example 2.
Reaction SMILES: [C:1]1([C@@H:7]([CH3:20])[CH2:8][N:9]2C(=O)C3C(=CC=CC=3)C2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NN>C1(C)C=CC=CC=1>[C:1]1([C@@H:7]([CH3:20])[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H](CN1C(=O)c2ccccc2C1=O)c1ccccc1
Agent: NN
Solvent: Cc1ccccc1
Product: C[C@@H](CN)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.9 %

Procedure:
A 500 mL three necked round bottom flask equipped with a mechanical stirrer, thermometer and addition funnel is charged with 2-((2R)-2-phenylpropyl)isoindoline-1,3-dione (11.54 g, 43.49 mmol), toluene (200.0 mL) and anhydrous hydrazine (2.73 mL, 86.99 mmol). Reaction is then stirred at room temperature for 3.0 hours and then heated at 90° C.-95° C. for 2.0 hours. Cooled the slurry to room temperature, filtered precipitates, then concentrated filtrate to provide the intermediate title compound, (2R)-2-phenylpropylamine, (5.58 g, 94.9%) an oil; 1H nmr (CDCl3, 300 MHz) δ 1.21 (d, 3H), 1.40-1.60 (b, 2H), 2.68-2.80 (m, 1H), 2.81-2.87 (m, 2H) 7.20 (m, 2H), 7.32 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8](O)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.P(=O)(O)(O)O>O>[C:10]1(/[CH:9]=[CH:8]/[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Br:1])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: OC(Cc1ccccc1)c1ccccc1Br
Agent: O=P(O)(O)O
Solvent: O
Product: Brc1ccccc1/C=C/c1ccccc1
Temperature: 170 °C
Yield: 86.5 %

Procedure:
A stirred mixture of 1-(2-bromophenyl)-2-phenylethan-1-ol (15.50 g) and orthophosphoric acid (150 ml) was heated at 170° C. for 1 hour and then poured into iced water and extracted with ether. The extracts were washed with water, dried and concentrated to give the crude product as an orange oil (14.29 g). Evaporative distillation (0.3 torr; oven temperature 140° C.) gave E-1-phenyl-2-(2-bromophenyl)ethylene (12.53 g, 86% yield) as a pale yellow oil with a purity of 97% by GC.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C([O-])(O)=O.[Na+].[NH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21]>C(O)C>[OH:21][CH2:20][CH2:19][CH2:18][CH2:17][NH:16][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: NCCCCO
Reactant: O=[N+]([O-])c1cnccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1cnccc1NCCCCO
Temperature: 25 °C
Reaction time: 4 h
Yield: 61 %

Procedure:
To a mixture of 4-chloro-3-nitropyridine (8 g) and NaHCO3 (4.2 g) in ethanol (200 cm3) at room temperature was added over 3 minutes 4-aminobutanol (4.5 g). The mixture was stirred at room temperature for 11/4 hours and the solvent was then removed under vacuum. The residue was suspended in saturated aqueous NaHCO3 solution (50 ml) and extracted with ethyl acetate (3×250 ml). The combined organic extracts were dried over Na2SO4, filtered and evaporated. The residue was then recrystallised from ethyl acetate to afford the title compound, (6.5 g, 62%), as yellow crystals, m.p. 80-82°.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28].C[O-].[Na+]>O>[OH:15][C:14]1[C:13]2[C:8](=[CH:9][C:10]([O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:11][CH:12]=2)[CH:7]=[N:6][C:5]=1[C:3]([NH:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[O:4]
Reactant: NCCCC(=O)O
Reactant: COC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)CCCNC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (1.08 g, 3.66 mmol) in flask was added 4-Amino-butyric acid (3.77 g, 36.6 mmol) and NaOMe (58 mL, 29.28 mmol, 0.5 M solution in MeOH). The reaction mixture was allowed to reflux. After 24 h, the mixture was cooled to rt, and concentrated in vacuo to give residue as a solid. The solid was dissolved in water (50 mL), extracted with CH2Cl2 (2×20 mL). The aqueous solution was acidified by 1N HCl solution, filtered, washed with water, dried to give 1.32 g of title of the compound as a white solid: MS (m/z) 367.0 (M+1)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH3:16][O:17][CH2:18]Cl>CC(C)=O>[CH3:16][O:17][CH2:18][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(O)c1
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCOc1cccc(C=O)c1
Temperature: 50 °C
Reaction time: 6 h
Yield: 88.2 %

Procedure:
To a solution of 3-hydroxybenzaldehyde (5.0 g) in acetone (120 mL), potassium carbonate (8.5 g) and methoxymethyl chloride (4.0 g) were added, followed by stirring at 50° C. for 6 hours. The reaction mixture was concentrated and water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried and concentrated. The residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to thereby give the title compound (6.0 g) having the following physical properties.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[CH:14]([CH:15]([CH:17]=C)[CH3:16])[O:13][C:12](=[O:19])[NH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.I([O-])(=O)(=O)=[O:22].[Na+].[BH4-].[Na+]>[Os](=O)(=O)(=O)=O.CO.O>[CH2:1]([O:8][CH2:9][C@@H:10]1[CH:14]([CH:15]([CH3:16])[CH2:17][OH:22])[O:13][C:12](=[O:19])[NH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(C)C1OC(=O)N[C@@H]1COCc1ccccc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(CO)C1OC(=O)N[C@@H]1COCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of (4R)-4-(benzyloxymethyl)-5-(but-3-en-2-yl)oxazolidin-2-one (1.0 equiv.) in 2:1 MeOH/H2O (0.04 M) was added osmium tetroxide 4% in H2O (0.07 equiv) and sodium periodate (3.0 equiv.). After stirring for 3 hours, the white precipitate was filtered and rinsed with EtOAc. The combined filtrate was concentrated in vacuo and the residue was dissolved in EtOAc, washed with NaCl(sat.), dried over MgSO4, filtered and concentrated. The crude aldehyde was dissolved in EtOH (0.08 M) and upon cooling to 0° C., sodium borohydride (2.0 equiv.) was added. After stirring for 15 hours and coming to room temperature the reaction was quenched by addition of H2O. After stirring for 20 minutes, the EtOH was removed in vacuo, EtOAc was added and the solution was washed with 1N HCl, NaHCO3(sat.) and NaCl(sat.), dried over MgSO4, filtered and concentrated yielding after purification by silica gel chromatography (4R)-4-(benzyloxymethyl)-5-(1-hydroxypropan-2-yl)oxazolidin-2-one as a 3:1 mixture of isomers (60%). LCMS (m/z): 266.1 (MH+); LC Rt=2.28 min.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29]OS(C)(=O)=O)[CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[N:12]=[CH:11][C:10]=1[CH2:35][C:36]([NH2:38])=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:39]#[N:40].[Na+].[I-].[Na+]>CN(C)C=O>[CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29][C:39]#[N:40])[CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[N:12]=[CH:11][C:10]=1[CH2:35][C:36]([NH2:38])=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: CS(=O)(=O)OCCC1CCN(c2ccc(Nc3cc(NCc4ccccc4)c(CC(N)=O)cn3)cc2)CC1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCCC1CCN(c2ccc(Nc3cc(NCc4ccccc4)c(CC(N)=O)cn3)cc2)CC1
Temperature: 120 °C
Reaction time: 8 h
Yield: 34.4 %

Procedure:
20 mg of 4-(benzylamino)-6-({4-[4-(2-methylsulfonyloxyethyl)piperidino]phenyl}amino)pyridine-3-carboxyamide (the compound of Example 58) was dissolved in 0.5 mL of N,N-dimethylformamide, to which 3 mg of sodium cyanide and 9 mg of sodium iodide were added, and stirred overnight at 120° C. After cooling, the solvent was evaporated, water was added to the residue, and extracted with chloroform. The extract was washed with water and dried on anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel thin layer chromatography (chloroform:methanol=8:1) to obtain 6 mg (29%) of the title compound as a light yellow crystalline powder.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[F:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.[OH-].[Na+]>O.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[F:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: NCCCCCCCC(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: O=C(O)CCCCCCCNS(=O)(=O)c1ccc(F)cc1
Reaction time: 3 h
Yield: 46.2 %

Procedure:
8-Aminooctanoic acid (1.0 g, 0.006 mol) was treated with 4-fluorobenzenesulphonyl chloride (1.22 g, 0.006 mol) in the presence of sodium hydroxide (0.8 g, 0.019 mol) in 15 ml water, tetrabutylammonium hydroxide (4 drops, 40% solution) and dichloromethane and the resulting mixture was subjected to vigorous stirring for 3 hours. The organic layer was then separated and evaporated to dryness and the residue was recrystallised from 2-propanol-water to give the title compound (0.88 g, m.p. 97°-8° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][C:12]([C:18]([OH:20])=O)=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:21])=[CH:4][CH:3]=1.[N:24]1([CH2:30][CH2:31][CH2:32][NH2:33])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[N:24]1([CH2:30][CH2:31][CH2:32][NH:33][C:18]([C:12]2[CH:11]=[C:10]3[C:15]([C:16](=[O:17])[N:7]([CH2:6][C:5]4[CH:22]=[CH:23][C:2]([Cl:1])=[CH:3][CH:4]=4)[C:8](=[O:21])[NH:9]3)=[CH:14][CH:13]=2)=[O:20])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(O)c1ccc2c(=O)n(Cc3ccc(Cl)cc3)c(=O)[nH]c2c1
Reactant: NCCCN1CCCCC1
Product: O=C(NCCCN1CCCCC1)c1ccc2c(=O)n(Cc3ccc(Cl)cc3)c(=O)[nH]c2c1

Procedure:
55 mg (45%) of the target compound was obtained in the same manner of Example 1, using 3-(4-chloro-benzyl)-2,4-dioxoquinazoline-7-carboxylic acid (90 mg, 0.272 mol) obtained in Example 1 and 3-piperidine-1-yl-propylamine (85 mL, 0.598 mmol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+]([O-])=O.[Cl:15]Cl>>[Cl:15][C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: ClCl
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Product: Fc1ccc(C(F)(F)F)cc1Cl
Temperature: 320 °C

Procedure:
In a continuous process, about 8 parts per hour of 4-fluoro-3-nitrobenzotrifluoride vapors and about 15 parts per hour of chlorine gas were passed simultaneously through a vapor phase reactor maintained at a temperature of about 320° C. and the reaction product vapors were condensed and collected. The process was continued until about 40 parts of 4-fluoro-3-nitrobenzotrifluoride had been passed through the reactor, yielding about 36.3 parts of 3-chloro-4-fluoro benzotrifluoride product. The structure of the product was confirmed by spectral analysis.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([C:9]2[C:13]([NH2:14])=[C:12]([C:15](O)=[O:16])[S:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1.C(N1C=CN=C1)([N:22]1C=CN=C1)=O>CN(C=O)C>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([C:9]2[C:13]([NH2:14])=[C:12]([C:15]([NH2:22])=[O:16])[S:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1c(-c2cccc(C(F)(F)F)c2)nsc1C(=O)O
Solvent: CN(C)C=O
Product: NC(=O)c1snc(-c2cccc(C(F)(F)F)c2)c1N
Temperature: 0 °C
Reaction time: 2.25 h

Procedure:
One gram of 3-(3-trifluoromethylphenyl)-4-amino-5-isothiazolecarboxylic acid and 0.7 g. of carbonyldiimidazole were dissolved in 25 ml. of DMF at ambient temperature. The solution was stirred for 2.25 hours; 3 ml. of 14N aqueous ammonium hydroxide were added and the resulting mixture stirred overnight at ambient temperature after which time it was poured into an ice-water mixture. 3-(3-Trifluoromethylphenyl)-4-amino-5-isothiazolecarboxamide formed in the above reaction precipitated and the precipitate was collected by filtration and was dried. 3-(3-Trifluoromethylphenyl)-4-amino-5-isothiazole carboxamide, thus prepared and purified, melted at about 124° C. after recrystallization from an ethyl acetate-hexane solvent mixture; yield 0.4 g.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)[CH:12]([CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[O:11][CH2:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.O>C1COCC1>[CH2:1]([N:8]1[CH2:14][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)[CH:12]([CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:26])[CH3:27])[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCC1OCC(=O)N(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Agent: B
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC1OCCN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a solution of (6RS,7RS)-4-benzyl-7-({[tert-butyl(dimethyl)silyl]oxy}methyl)-6-(3,4-dichlorophenyl)-1,4-oxazepan-3-one (40.5 g) in THF (150 mL) was added dropwise 1.2 M borane.THF complex/THF solution (150 mL) at room temperature, and the mixture was stirred under nitrogen purging at 60° C. for 2 hr. After cooling to room temperature, water was added carefully, and the mixture was stirred at room temperature for 1 hr, and extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate (0%-50%)) to give the title compound (30.7 g) as a pale-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.[Cl:11][CH2:12][C:13](O)=O>Cl>[Cl:11][CH2:12][C:13]1[NH:10][C:4]2[CH:3]=[C:2]([Cl:1])[C:7]([Cl:8])=[CH:6][C:5]=2[N:9]=1
Reactant: O=C(O)CCl
Reactant: Nc1cc(Cl)c(Cl)cc1N
Agent: Cl
Product: ClCc1nc2cc(Cl)c(Cl)cc2[nH]1
Temperature: 25 °C
Yield: 80.7 %

Procedure:
A solution of 1.77 g (10 m mol) of 4,5-dichloro-1,2-phenylenediamine in 15 ml of 4N aqueous hydrochloric acid was stored at room temperature overnight. To the solution was added 1.42 g (15 m mol) of monochloroacetic acid, and refluxed for 3 hours and filtered. The filterate was cooled to room temperature, stirred and rendered alkaline by addition of ammonium hydroxide. The separated precipitate was washed with water and dried to give 1.9 g (68%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([OH:12])=O.C(Cl)(=O)C([Cl:16])=O>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([Cl:16])=[O:12]
Reactant: O=C(O)CCc1ccccc1F
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)CCc1ccccc1F
Temperature: 25 °C

Procedure:
To a mixture of 3-(2-fluorophenyl)propionic acid (18.64 g, 0.111 mol) and dimethylformamide (5 drops) at room temperature was added dropwise oxalyl chloride (60 mL). The mixture was stirred at room temperature until gas evolution had ceased. The excess oxalyl chloride was removed by distillation to give 3-(2-fluorophenyl)propionyl chloride. A solution of the 3-(2-fluorophenyl)propionyl chloride in dichloromethane (230 mL) was added dropwise to a mixture of aluminum chloride (16.25 g, 0.12 mol) in dichloromethane (230 mL), and the mixture was refluxed for 3.5 h. The reaction mixture was poured into ice water (1200 mL), and the two phases were separated. The dichloromethane phase was washed successively with 0.1N aqueous sodium hydroxide (2×100 mL), water (200 mL), and brine (200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residual oil was chromatographed on silica gel eluting with hexane:dichloromethane (9:1) to give 11.0 g of crude 4-fluoro-1-indanone as a yellow solid. Recrystallization from acetone: water mixtures gave 8.02 g (48%) of 4-fluoro-1-indanone as a pale yellow solid: m.p., 71°-72° C.; NM (DMSO-d6): d 7.51 (m, 3H, Ar), 3.13 (t, 2H, CH2), 2.74 (t, 2H, CH2).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH3:9])=[N:6][C:5]([Br:10])=[CH:4][N:3]=1.[H-].[Na+].[CH2:13]([O:20][C:21]([N:23]([C:25]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:26]=1[CH:27]=[CH:28][CH:29]=[C:30]2[S:35](Cl)(=[O:37])=[O:36])[CH3:24])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>C(COC)OC>[CH2:13]([O:20][C:21]([N:23]([C:25]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:26]=1[CH:27]=[CH:28][CH:29]=[C:30]2[S:35]([NH:1][C:2]1[C:7]([O:8][CH3:9])=[N:6][C:5]([Br:10])=[CH:4][N:3]=1)(=[O:36])=[O:37])[CH3:24])=[O:22])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CN(C(=O)OCc1ccccc1)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: COc1nc(Br)cnc1N
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1nc(Br)cnc1NS(=O)(=O)c1cccc2c(N(C)C(=O)OCc3ccccc3)cccc12
Reaction time: 0.17 h
Yield: 61 %

Procedure:
2-Amino-5-bromo-3-methoxypyrazine (0.3 g) was added to a stirred suspension of sodium hydride (60% dispersion in oil; 0.15 g) in dimethoxyethane (5 ml). After 10 minutes, 5-(N-benzyloxycarbonyl-N-methylamino)-1-naphthalenesulphonyl chloride (0.6 g) in dimethoxyethane (2 ml) was added and stirring was continued for 2 hours. The mixture was poured into water (20 ml) and washed with ethyl acetate (20 ml). The aqueous layer was acidified with concentrated hydrochloric acid to pH2 and extracted with ethyl acetate (3×50 ml). The combined organic extracts were dried (MgSO4) and evaporated. The residue was purified by flash chromatography on silica gel (25 g), eluting with a gradient of 20-50% ethyl acetate in hexane to give 5-(N-benzyloxycarbonyl-N-methylamino)-N-(5-bromo-3-methoxy-2-pyrazinyl)-1-naphthalenesulphonamide (0.50 g) as a white foam; 1H NMR (d6 -DHSO): 3.34 (s,3H), 3.90 (s,3H), 5.08 (br,2H), 6.95 (br,1H), 7.19 (br,2H), 7.22-7.56 (m,2H), 7.6-7.77 (m,3H), 7.79 (s,1H), 8.07 (d,1H), 8.37 (dd,1H), 8.80 (d,1H), 11.58 (br,1H); mass spectrum (+ve FAB, DMSO/NBA): 557(M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=[N:3]1.C1N=CN(C(N2C=NC=C2)=O)C=1.[S:22]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:23]1.[H-].[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:1][N:2]1[C:6]([C:7](=[O:9])[CH:27]([C:24]2[CH:25]=[CH:26][S:22][CH:23]=2)[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:5][CH:4]=[N:3]1
Reactant: CCOC(=O)Cc1ccsc1
Reactant: Cn1nccc1C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)c1ccnn1C)c1ccsc1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 22.7 %

Procedure:
To a solution of 1-methyl-1H-pyrazole-5-carboxylic acid (300 mg, 2.4 mmol) in DMF (7 mL) was added CDI (372 mg, 2.6 mmol), and the reaction mixture was heated to 50° C. for two hours. Then the mixture was cooled to −5° C., a solution of ethyl 2-(thiophen-3-yl)acetate (444 mg, 2.6 mmol) in DMF (1 mL) was added to the mixture and NaH (330 mg, 8.2 mmol) was added in portions. The mixture was stirred at 0° C. for 10 minutes, then warmed to room temperature and stirred for 1 hour. Ice water was added, followed by a standard aqueous/EtOAc workup. Crude was purified by column chromatography (PE: EtOAc=5:1) (150 mg, yield: 22.7%).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]1)[CH3:4].Cl[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[C:19]1[N:27]=[CH:26][C:25]2[NH:24][C:23]3[N:28]=[CH:29][C:30]([C:32]4[CH:33]=[N:34][N:35]([CH3:37])[CH:36]=4)=[CH:31][C:22]=3[C:21]=2[CH:20]=1>CN(C=O)C>[CH2:3]([N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:19]2[N:27]=[CH:26][C:25]3[NH:24][C:23]4[N:28]=[CH:29][C:30]([C:32]5[CH:33]=[N:34][N:35]([CH3:37])[CH:36]=5)=[CH:31][C:22]=4[C:21]=3[CH:20]=2)[CH2:7][CH2:6]1)[CH3:4]
Reactant: CCN1CCC(O)CC1
Reactant: Cn1cc(-c2cnc3[nH]c4cnc(-c5cnccc5Cl)cc4c3c2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1CCC(Oc2ccncc2-c2cc3c(cn2)[nH]c2ncc(-c4cnn(C)c4)cc23)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 13 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.133 g, 3.32 mmol) was added to a solution of 1-ethyl-piperidin-4-ol (0.306 g, 2.37 mmol) in DMF (5 mL) and the reaction mixture was stirred at ambient temperature for 45 minutes. 6-(4-Chloro-pyridin-3-yl)-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (0.121 g, 0.474 mmol) was added and the reaction mixture was heated at 80° C. for 5 h. The material was partitioned between water and ethyl acetate. The solid suspended in the aqueous layer was removed by filtration then the aqueous layer was separated, adsorbed onto HM-N and purified by flash chromatography (silica, 12 g column, ISCO, 0-10% (2N ammonia in methanol) in DCM). The resultant residue was triturated with ethyl acetate and cyclohexane to afford the title compound as a yellow solid (28 mg, 13%). 1H NMR (MeOD, 400 MHz): 8.97 (d, J=1.1 Hz, 1H), 8.83-8.80 (m, 2H), 8.73 (s, 1H), 8.60 (d, J=1.1 Hz, 1H); 8.43 (d, J=5.9 Hz, 1H), 8.11 (s, 1H), 7.97 (d, J=0.8 Hz, 1H), 7.28 (d, J=6.0 Hz, 1H), 3.98 (s, 3H), 2.65-2.54 (m, 2H), 2.53-2.43 (m, 2H), 2.39 (q, J=7.3 Hz, 2H), 2.13-2.03 (m, 2H), 1.97-1.86 (m, 2H), 1.02 (t, J=7.2 Hz, 3H). LCMS (Method A): RT=4.0 min, M+H+=454.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]([OH:14])=O)[C:9]([OH:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[C:10]([C:12]([NH:22][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([Cl:16])=[CH:18][CH:19]=2)=[O:14])[C:9]([OH:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=C(O)c1cc(Cl)c2cccnc2c1O
Reactant: NCc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)cc1)c1cc(Cl)c2cccnc2c1O
Temperature: 0 °C
Reaction time: 8 h
Yield: 32.1 %

Procedure:
To a solution of 5-chloro-8-hydroxyquinoline-7-carboxylic acid (0.335 g) of Preparation 3 and 4-chlorobenzylamine (0.219 g) in 20 mL DMF is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.305 g) and 1-hydroxybenzotriazole monohydrate (0.217 g). The mixture is stirred overnight. The solution is then poured into 30 mL ice-water. The resulting solid is collected and dried to yield 0.167 g of the title product as an off-white solid.