Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:23])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]([O:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[O:9])[CH2:3]1.C=O.[C:27]([BH3-])#N.[Na+]>CO.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[F:24][C:2]1([F:1])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:23])([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:8]([O:10][CH:11]2[CH2:12][CH2:13][N:14]([CH3:27])[CH2:15][CH2:16]2)=[O:9])[CH2:3]1
Reactant: O=C(OC1CCNCC1)[C@](O)(c1ccccc1)[C@@H]1CCC(F)(F)C1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CN1CCC(OC(=O)[C@](O)(c2ccccc2)[C@@H]2CCC(F)(F)C2)CC1
Reaction time: 0.5 h

Procedure:
To a solution of 17 mg of piperidin-4-yl(2R)-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate and 0.03 ml of formaldehyde (35% aqueous solution) in 1 ml of methanol, 0.3 ml of advancedly prepared 0.3 M methanol solution of sodium cyanoborohydride and zinc chloride (1:0.5) was added at room temperature, followed by 30 minutes' stirring at the same temperature. The reaction liquid was diluted with ethyl acetate, washed successively with a saturated sodium hydrogencarbonate solution and with saturated brine, and dried over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, 19 mg of the title compound was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[NH2:13][C:14]1[C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([NH2:24])[CH:17]=[CH:16][C:15]=1[C:25]1[CH:29]=[CH:28][O:27][C:26]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31]>C(Cl)Cl.N1C=CC=CC=1>[NH2:13][C:14]1[C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([NH:24][S:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[Br:1])(=[O:11])=[O:10])[CH:17]=[CH:16][C:15]=1[C:25]1[CH:29]=[CH:28][O:27][C:26]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Br
Reactant: CCOC(=O)c1occc1-c1ccc(N)c(C(=O)OC)c1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1occc1-c1ccc(NS(=O)(=O)c2ccc(F)cc2Br)c(C(=O)OC)c1N
Reaction time: 1 h
Yield: 83.1 %

Procedure:
2-Bromo-4-fluorobenzenesulfonyl chloride (0.584 g) was added to a solution of ethyl 3-(2,4-diamino-3-methoxycarbonylphenyl)-furan-2-carboxylate (Intermediate 89, 0.650 g) in DCM (30 mL) and pyridine (10 mL). The resultant mixture was stirred at room temperature for 45 minutes. A further amount of 2-bromo-4-fluorobenzene-sulfonyl chloride (0.584 g) was added and the mixture stirred for a further 1 hour. A further amount of 2-bromo-4-fluorobenzenesulfonyl chloride (0.300 g) was added and the mixture stirred for a further 30 minutes. The mixture was concentrated in vacuo and the residue was partitioned between water and DCM. The organic layer was dried (MgSO4), filtered and the filtrate was concentrated in vacuo. The residue was triturated with methanol and the resultant solid was collected by filtration and air dried to give ethyl 3-[2-amino-4-(2-bromo-4-fluorobenzenesulfonylamino)-3-methoxycarbonylphenyl]-furan-2-carboxylate (0.960 g) as a powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)[C:9]([O:11][CH3:12])=[O:10].C1C(=O)N([Br:28])C(=O)C1>>[Br:28][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:9]([O:11][CH3:12])=[O:10])=[CH:15][CH:16]=1
Reactant: COC(=O)C(Oc1ccc(C)cc1)c1ccccc1Cl
Reactant: O=C1CCC(=O)N1Br
Product: COC(=O)C(Oc1ccc(CBr)cc1)c1ccccc1Cl
Yield: 76.2 %

Procedure:
The product of Step B (0.200 g, 0.69 mmol) was brominated with NBS (117 mg, 0.66 mmol) and purified using the procedure described in Step C of Example 3, and afforded 0.186 g (73%) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)=[CH:6][CH:5]=1)([O-])=O.[Cl-].[Ca+2].[Cl-]>C(O)C>[N:13]1([CH2:12][CH2:11][CH2:10][C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH:17]=[N:16][CH:15]=[N:14]1
Reactant: O=[N+]([O-])c1ccc(CCCn2cncn2)cc1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Product: Nc1ccc(CCCn2cncn2)cc1
Temperature: 25 °C
Yield: 72.6 %

Procedure:
1-[3-(4-nitrophenyl)propyl]-1,2,4-triazole (0.68 g) was dissolved in 85% ethanol solution (20.4 ml), calcium chloride (0.16 g) and reduced iron (0.82 g) were added to the mixture, and the mixture was heated to reflux for 4 hours. After allowing cooling to room temperature, the mixture was filtered with Celite, and washed with ethyl acetate. The solvent was removed under reduced pressure, and the obtained residue was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 4-[3-(1,2,4-triazol-1-yl)propyl]aniline (0.43 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([F:22])([F:21])[F:20])=[O:11].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:23][C:24]([OH:26])=[O:25])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([F:22])([F:21])[F:20])=[O:11]
Reactant: COc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)Nc1ccccc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.9 %

Procedure:
To a stirred solution of tert-butyl 3-methoxy-4-[N′-(2-trifluoromethylphenyl)ureido]phenylacetate (1.11 g, 2.62 mmol) in CH2Cl2 (10 ml) was added TFA (10 ml), and the reaction mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated to a small volume and poured into ice-H2O. The resulting precipitate was collected under a reduced pressure and the crude solid was recrystallized from MeOH—CHCl3—IPE to give 3-methoxy-4-[N′-(2-trifluoromethylphenyl)ureido]phenylacetic acid (839 mg, 87%) as a white crystalline powder. mp 218-220° C.; 1H-NMR (DMSO-d6) δ3.51 (s, 2 H), 3.87 (s, 3 H), 6.76-6.79 (m, 1 H), 6.93-6.94 (m, 1 H), 7.27-7.30 (m, 1 H), 7.61-7.69 (m, 2 H), 7.82-7.84 (m, 1 H), 7.97-7.99 (m, 1 H), 8.71 (s, 1 H), 8.89 (s, 1 H), 12.30 (br s, 1 H); Anal. Calcd. for C17H15F3N2O4: C, 55.44; H, 4.11; N, 7.61; F, 15.47. Found: C, 55.30; H, 4.08; N, 7.63; F, 15.13.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+]([O-])=O)[C:4]=1[C:12]#[N:13])#[N:2].[C:14]([C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)([CH3:17])([CH3:16])[CH3:15].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:19]=2)[C:4]=1[C:12]#[N:13])#[N:2]
Reactant: CC(C)(C)c1cccc(O)c1
Reactant: N#Cc1cccc([N+](=O)[O-])c1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cccc(Oc2cccc(C#N)c2C#N)c1
Yield: 80 %

Procedure:
1,2-dicyano-3-nitrobenzene (1.73 g) and 3-tert-butyl-hydroxybenzene (4.50 g) were allowed to react with each other at 80° C. for 2 hours in dimethylformamide (DMF, 5 ml) with the addition of K2CO3 (5.0 g). After the completion of the reaction, the reaction product was extracted twice with a mixed solvent of water and ethyl acetate (at a volumetric ratio of 1/1), and the layer extracted with ethyl acetate was dried overnight with the use of MgSO4, followed by removal of ethyl acetate by distillation. The residues were isolated and purified by silica gel column chromatography using chloroform to obtain 2.21 g of 1,2-dicyano-3-(3-tert-butylphenyloxy) benzene in a 80% yield.
Reaction SMILES: [Na].[CH3:2][N:3]([CH3:6])[CH:4]=[O:5].[Br:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)C(=O)NC=[CH:11]2.CI>O>[Br:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:4](=[O:5])[N:3]([CH3:6])[CH:2]=[CH:11]2
Reactant: O=c1[nH]ccc2cc(Br)ccc12
Reactant: CN(C)C=O
Agent: [Na]
Solvent: O
Solvent: CI
Product: Cn1ccc2cc(Br)ccc2c1=O
Reaction time: 0.5 h

Procedure:
Under nitrogen atmosphere, 60% sodium hydrogenate (18 mg) was added at 0° C. to 2 ml solution of dimethylformamide with 100 mg of 6-bromo-2H-isoquinoline-1-one, and the mixture was stirred for 30 min. Then, 0.03 ml of methyl iodide was added at 0° C., stirred at room temperature for 2 hours. Cold water was added to the reaction solution, extracted with chloroform. Chloroform layer was washed with saturated saline solution, dried with anhydrous sodium sulfate. After distilling out the solvents under reduced pressure, residues were separated and purified by preparative thin-layer chromatography (hexane/ethyl acetate=3/1) to obtain 24 mg of the above compound as a white solid.
Reaction SMILES: [B-](F)(F)(F)F.[CH3:6][N:7](C(ON1C(=O)CCC1=O)=[N+](C)C)[CH3:8].[Br:21][C:22]1[CH:23]=[C:24]([C:39]([OH:41])=O)[CH:25]=[C:26]2[C:31]=1[O:30][C:29]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)=[CH:28][C:27]2=[O:38].CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:21][C:22]1[CH:23]=[C:24]([C:39]([N:7]([CH3:8])[CH3:6])=[O:41])[CH:25]=[C:26]2[C:31]=1[O:30][C:29]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)=[CH:28][C:27]2=[O:38]
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Reactant: O=C(O)c1cc(Br)c2oc(N3CCOCC3)cc(=O)c2c1
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)C(=O)c1cc(Br)c2oc(N3CCOCC3)cc(=O)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 102.2 %

Procedure:
TSTU (6.55 g, 21.74 mmol) was added to a stirred solution of 8-bromo-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (7 g, 19.77 mmol) and DIPEA (3.79 mL, 21.74 mmol) dissolved in DCM (100 mL) under nitrogen. The resulting suspension was stirred at room temperature for 4 h. More TSTU (6.55 g, 21.74 mmol) and DIPEA (3.79 mL, 21.74 mmol) were added and stirring was pursued for a further 16 h. The reaction mixture was quenched with a saturated aqueous solution of sodium hydrogencarbonate and extracted with DCM and a little MeOH. The combined organic phases were dried over MgSO4, concentrated and purified by flash chromatography on silica gel eluting with 3 to 5% MeOH in DCM. The solvent was evaporated to dryness to afford 8-bromo-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (7.70 g, 102%) as a beige solid. Mass Spectrum: m/z [M+H]+=381.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[CH2:6][C:5]1=[O:14])(=[O:3])[CH3:2].[N+:15]([O-])([O-:17])=[O:16].[NH4+].N>S(=O)(=O)(O)O>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:15]([O-:17])=[O:16])=[C:10]([Cl:13])[CH:11]=2)[CH2:6][C:5]1=[O:14])(=[O:3])[CH3:2]
Reactant: CC(=O)N1C(=O)Cc2ccc(Cl)cc21
Reactant: O=[N+]([O-])[O-]
Agent: N
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: CC(=O)N1C(=O)Cc2cc([N+](=O)[O-])c(Cl)cc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2.75 g 1-acetyl-6-chloro-2-indolinone (educt V.1) are placed in 40 ml concentrated sulphuric acid and at −10° C. 1.05 g of ammonium nitrate are added. The mixture is stirred for 1.5 hours at ambient temperature. After this time the mixture is poured onto ice water and stirred for a further 20 minutes. The solution is neutralised with concentrated ammonia, the precipitate formed is suction filtered and washed with a little ethanol and ether.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[CH:11][C:12]([NH:22][C:23]2[CH:28]=[C:27]([F:29])[C:26]([Br:30])=[CH:25][C:24]=2[O:31][CH3:32])=[C:13](/[CH:15]=[CH:16]/[C:17](OCC)=[O:18])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(P(CCCC)CCCC)CCC>CO>[CH2:1]([S:8][C:9]1[CH:14]=[C:13]2[C:12](=[CH:11][CH:10]=1)[N:22]([C:23]1[CH:28]=[C:27]([F:29])[C:26]([Br:30])=[CH:25][C:24]=1[O:31][CH3:32])[C:17](=[O:18])[CH:16]=[CH:15]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C=C/c1cc(SCc2ccccc2)ccc1Nc1cc(F)c(Br)cc1OC
Agent: CCCCP(CCCC)CCCC
Solvent: CO
Product: COc1cc(Br)c(F)cc1-n1c(=O)ccc2cc(SCc3ccccc3)ccc21
Temperature: 70 °C
Yield: 88.3 %

Procedure:
To a solution of (E)-ethyl 3-(5-(benzylthio)-2-((4-bromo-5-fluoro-2-methoxyphenyl)amino)phenyl)acrylate (250.0 g, 484.0 mmol, 1.0 equiv) in methanol (2.5 L) was added tri(n-butyl)phosphine (50% solution in ethyl acetate, 48.9 mL, 96.8 mmol, 0.2 equiv, Spectrochem) and the reaction mixture was heated at 70° C. for 5 h. The reaction mixture was allowed to cool to rt, concentrated under reduced pressure to obtain the crude material which was purified by stirring with 5% ethyl acetate in hexanes (1.0 mL) and filtered to obtain 6-(benzylthio)-1-(4-bromo-5-fluoro-2-methoxyphenyl)quinolin-2(1H)-one (201.0 g, 88%) as off white solid. TLC solvent system: 30% ethyl acetate in hexanes. Product's Rf: 0.3. MS (ESI, positive ion) m/z; 470.0 (M+1). 1H NMR (400 MHz, DMSO) δ 7.92 (d, J=9.1 Hz, 1H), 7.79 (d, J=1.7 Hz, 1H), 7.65 (d, J=6.1 Hz, 1H), 7.57 (d, J=8.8 Hz, 1H), 7.40-7.22 (m, 6H), 6.68 (d, J=9.6 Hz, 1H), 6.56 (d, J=8.8 Hz, 1H), 4.24 (s, 2H), 3.69 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2)=[O:4].[N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[CH2:24][O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Cl>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:29][C:28]1[CH:31]=[CH:32][CH:33]=[C:26]([O:25][CH2:24][C:15]3[CH:16]=[CH:17][C:18]4[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:14]=3)[CH:27]=1)[CH:9]=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Reactant: ClCc1cccc(OCc2ccc3ccccc3n2)c1
Product: COC(=O)c1ccc2c(ccn2Cc2cccc(OCc3ccc4ccccc4n3)c2)c1

Procedure:
This compound was prepared from methyl-5-indole carboxylate and 3-(quinolin-2-ylmethoxy)benzyl chloride (Example 5a) by the method described in Example 1b, part i.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[CH:8]([C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)[O:7]C(C)C2.[CH3:23][C:24]([CH3:26])=[O:25].OS(O)(=O)=O.O=[Cr](=O)=O.Cl(O)(=O)(=O)=O>>[CH2:23]([C:9]1([CH:4]=[CH:3][C:2]([Cl:1])=[C:11]([Cl:12])[CH2:10]1)[C:8]([C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)=[O:7])[C:24]([CH3:26])=[O:25]
Reactant: CC(C)=O
Reactant: CC1Cc2cc(Cl)c(Cl)cc2C(c2ccc([N+](=O)[O-])cc2)O1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Agent: [O-][Cl+3]([O-])([O-])O
Product: CC(=O)CC1(C(=O)c2ccc([N+](=O)[O-])cc2)C=CC(Cl)=C(Cl)C1

Procedure:
4.75 g (14.0 mmoles) of the isochromane derivative prepared in Step A are oxidized according to the method of Example 1, Step B using Jones' reagent with the exception that instead of reacting the crude product with perchloric acid, the 1-acetonyl-3,4-dichloro-4'-nitrobenzophenone derivative (m.p.: 121°-122° C.) is isolated by chromatography. The solution of the above derivative in isopropanol is reacted with 98% hydrazine hydrate at 25° C. to obtain the monohydrazone derivative (m.p.: 167°-169° C.). The monohydrazone compound is reacted with methanol containing 15% hydrogen chloride, then, the hydrochloride of the title compound is treated with triethylamine to obtain the free base that is purified by recrystallization from hot dimethylformamide. M.p.: 231°-233° C.
Reaction SMILES: [Cl:1][CH:2](Cl)[C:3]1C=[CH:7][CH:6]=[C:5](CCl)[CH:4]=1.ClC(Cl)=C(Cl)Cl.[Cl:18][C:19]([Cl:25])([Cl:24])[C:20](Cl)(Cl)Cl.[OH-].[K+]>[Cl-].C([N+](C)(C)C)CCCCCCCCCCC.O>[Cl:18][C:19]([Cl:25])([Cl:24])[C:20]1[C:3]([CH2:2][Cl:1])=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCc1cccc(C(Cl)Cl)c1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: CCCCCCCCCCCC[N+](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: ClC(Cl)=C(Cl)Cl
Solvent: O
Product: ClCc1ccccc1C(Cl)(Cl)Cl
Temperature: 75 °C
Yield: 85.2 %

Procedure:
α,α,α'-Trichloro-m-xylene (22.5 grams, 93.2% a.i., 0.1 moles) was dissolved in 18 mls. of tetrachloroethylene. Hexachloroethane (59.2 grams, 0.25 moles), potassium hydroxide (12.8 grams, 87.7%, 0.2 moles), water (2.13 grams), and dodecyltrimethylammonium chloride (0.255 grams, 0.001 moles) were added. The mixture was heated at 75° C. for 2.5 hours with good stirring. The reaction was quenched with 30 mls. of water and 18 mls tetrachloroethylene. The organic phase was separated and washed with water. The excess solvent and hexachloroethane were distilled off to give an 85.2% yield of α,α,α,α'-tetrachloroxylene with a purity of 84%.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([NH2:6])=[C:4]([CH3:10])[CH:3]=1.Cl[C:12]([O:14][CH2:15][CH2:16][CH3:17])=[O:13].O1CCCC1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:15]([O:14][C:12](=[O:13])[NH:6][C:5]1[C:7]([CH3:9])=[CH:8][C:2]([Br:1])=[CH:3][C:4]=1[CH3:10])[CH2:16][CH3:17]
Reactant: CCCOC(=O)Cl
Reactant: Cc1cc(Br)cc(C)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: C1CCOC1
Product: CCCOC(=O)Nc1c(C)cc(Br)cc1C
Yield: 86 %

Procedure:
4-Bromo-2,6-dimethyl-aniline (4.3 g) and propyl chloroformate (2.70 mL) were mixed in acetonitrile (50 mL) and tetrahydrofuran (20 mL) and the reaction mixture was heated to reflux for 1 hour. Potassium carbonate (4.5 g) was added and the reaction mixture was refluxed for 1 hour and then poured onto crushed ice and saturated aqueous potassium carbonate (50 mL). The product was collected by filtration and washed with water (100 mL) to furnish 5.26 g (86% yield) of the title compound as a solid. LC-MS (m/z) 287 (MH+); tR=3.18, (UV, ELSD) 99%, 95%. 1H NMR (500 MHz, CDCl3): 0.93 (t, 3H), 1.62 (m, 2H), 2.15 (s, 6H), 4.00 (t, 2H), 7.28 (s, 2H), 8.74 (b, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([O:24][CH3:25])=[C:8]2[N:13]([CH:14]=1)[N:12]=[CH:11][N:10]=[C:9]2NC1C=CC(C)=C(O)C=1)=[O:5])[CH3:2].[Br:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[C:29]([F:34])[CH:28]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:24][CH3:25])=[C:8]2[N:13]([CH:14]=1)[N:12]=[CH:11][N:10]=[C:9]2[NH:31][C:30]1[CH:32]=[CH:33][C:27]([Br:26])=[CH:28][C:29]=1[F:34])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn2ncnc(Nc3ccc(C)c(O)c3)c2c1OC
Reactant: Nc1ccc(Br)cc1F
Product: CCOC(=O)c1cn2ncnc(Nc3ccc(Br)cc3F)c2c1OC

Procedure:
The title compound was prepared from Compound G of Example 96 (0.2 mmol) and 4-bromo-2-fluoro-aniline (76 mg, 0.3 mmol) by the procedure analogous with the preparation of Compound H of Example 96. Thus, when the reaction was complete it was concentrated and washed with 1 N aqueous HCl to provide a solid which was triturated with aqueous NaHCO3 and water and then dried to provide 58 mg (70.9%) white solid. MS: [M+H]+=409, 411 (1:1); 1H NMR (d-DMSO): δ 8.83 (s, 1H), 7.97-7.93 (m, 2H), 7.90 (s, 1H), 7.66 (d, J=8.4 Hz, 1H), 7.43 (d, J=8.4 Hz, 1H), 4.24 (q, J=7.5 Hz, 2H), 3.97 (s, 3H), 1.26 (t, J=7.0 Hz, 3H).
Reaction SMILES: C([O:5][C:6](=[O:19])[CH2:7][C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([F:18])[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)(C)(C)C.[OH-].[Na+]>>[F:18][C:16]1[CH:17]=[C:8]([CH2:7][C:6]([OH:19])=[O:5])[CH:9]=[C:10]2[C:15]=1[N:14]=[CH:13][CH:12]=[CH:11]2
Reactant: CC(C)(C)OC(=O)Cc1cc(F)c2ncccc2c1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)Cc1cc(F)c2ncccc2c1

Procedure:
0.5 g of (8-fluoro-quinolin-6-yl)-acetic acid tert-butyl ester with 2.0 ml of 4N aq. sodium hydroxide solution was heated at 90° C. for 3 h. After cooling the reaction mixture was extracted with ethyl acetate. The aqueous layer was made just acidic with acetic acid, filtered to afford the title compound as an off white solid (0.24 g, 61%). 1H NMR (300 MHz, DMSO-d6) δ 8.91˜8.93 (m, 1H), 8.37˜8.40 (m, 1H), 7.51˜7.69 (m, 3H), 3.80 (s, 2H); ES-MS m/z: 206.2 (M++1).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[C:6]=2[CH:5]=[CH:4]1.Br[CH2:17][CH2:18][O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1>CN(C=O)C>[CH3:15][O:14][C:12]([C:7]1[C:6]2[CH:5]=[CH:4][N:3]([CH2:17][CH2:18][O:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][O:21]3)[C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:13]
Reactant: BrCCOC1CCCCO1
Reactant: COC(=O)c1cccc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1ccn2CCOC1CCCCO1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
NaH (60% dispersion in mineral oil, 86 mg, 2.14 mmol) is added to a solution of methyl indole-4-carboxylate (250 mg, 1.427 mmol) in DMF (20 ml) and the resulting suspension is stirred at room temperature for 30 minutes. After this time (2-(2-bromoethoxy)tetrahydro-2H-pyran (388 mg, 1.86 mmol) is added and the reaction is stirred at room temperature for 22 hours. Dilution with EtOAc (50 ml), washing with water (25 ml×3), saturated NaHCO3 (25 ml×2) and brine (25 ml), drying over MgSO4, concentration in vacuo and purification by chromatography (SiO2, DCM/MeOH) affords 1-[2-(Tetrahydro-pyran-2-yloxy)-ethyl]-1H-indole-4-carboxylic acid methyl ester; [M+H]+ 304
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1)=[O:4].[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[C:20]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[N:21][CH:22]=[CH:23][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C:3](=[O:4])[CH2:2][N:28]2[CH2:29][CH2:30][N:25]([C:20]3[C:19]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=4)=[CH:24][CH:23]=[CH:22][N:21]=3)[CH2:26][CH2:27]2)[CH:10]=[CH:9][CH:8]=1
Reactant: COc1cccc(C(=O)CBr)c1
Reactant: c1ccc(-c2cccnc2N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cccc(C(=O)CN2CCN(c3ncccc3-c3ccccn3)CC2)c1

Procedure:
A stirred mixture of 2-bromo-1-(3-methoxyphenyl)ethanone (0.5 g, 2.2 mmol), 1-[3-(2-pyridyl)-2-pyridyl]piperazine (0.6 g, 2.6 mmol) and K2CO3 (3 mmol) in acetonitrile was refluxed overnight. After cooling, the mixture was evaporated to dryness and H2O (20 mL) was added to the residue. The aqueous phase was extracted with AcOEt (2×30 mL). The collected organic layers were dried over Na2SO4 and evaporated under reduced pressure. The crude residue was chromatographed (CHCl3/AcOEt, 9:1, as eluent) to afford pure compound in quantitative yield. 1H NMR (CDCl3): δ 2.52 (br s, 4H), 2.93 (app t, 4H), 3.78 (s, 2H), 3.80 (s, 3H), 6.84-6.90 (m, 3H), 7.04-7.10 (m, 2H) 7.20-7.26 (m, 1H), 7.71 (dd, 1H, J=1.6, 7.4 Hz), 7.83 (dt, 1H, J=1.9, 7.4 Hz), 7.88-7.92 (m, 1H), 8.27 (dd, 1H, J=1.9, 4.9 Hz), 8.69-8.72 (m, 1H). GC-MS m/z 387 (M+1, 2), 390 (M+, 8), 254 (100), 184 (63).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[NH:13][C:14](=[O:29])[C:15]1[C:20]([S:21][CH3:22])=[CH:19][C:18]([C:23]([F:26])([F:25])[F:24])=[CH:17][C:16]=1[O:27][CH3:28])(C)(C)C.Cl.C(=O)([O-])[O-].[Na+].[Na+]>CO>[NH2:7][CH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[NH:13][C:14](=[O:29])[C:15]1[C:20]([S:21][CH3:22])=[CH:19][C:18]([C:23]([F:25])([F:26])[F:24])=[CH:17][C:16]=1[O:27][CH3:28]
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1CCCC1NC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1CCCC1N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
[(1SR,2RS)-2-(2-Methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoylamino)-cyclopentyl]-carbamic acid tert-butyl Ester (intermediate N, 0.2 g, 0.45 mmol) was dissolved in 2 mL methanol. Hydrochloric acid (4M in dioxane, 0.56 mL, 2.2 mmol) was added and the reaction mixture was stirred at room temperature for 4 h. The mixture was poured into 2N sodium carbonate solution and was extracted three times with ethyl acetate. The combined organic phases were dried on sodium sulfate, filtered and evaporated. The crude product was used without any further purification, white solid (147 mg, 94%), MS: m/e=349.2 [(M+H)+].