Azzindani/Open_Reaction_Data huggingface dataset:
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.[CH2:16]([O:18][C:19]([C:21]1[NH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][C:26]([OH:30])=[CH:25][CH:24]=2)=[O:20])[CH3:17]>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1.CCOC(C)=O>[CH2:16]([O:18][C:19]([C:21]1[NH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][C:26]([O:30][C:2]1[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=1)=[CH:25][CH:24]=2)=[O:20])[CH3:17]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: CCOC(=O)c1cc2cc(O)ccc2[nH]1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2cc(Oc3ccnc4cc(OC)c(OC)cc34)ccc2[nH]1
Temperature: 180 °C

Procedure:
A mixture of 4-chloro-6,7-dimethoxy-quinoline (0.4 g, 1.8 mmol), 5-hydroxy-1H-indole-2-carboxylic acid ethyl ester (0.37 g, 1.8 mmol, Biosynth AG) and DMAP (0.22 g, 1.8 mmol, Aldrich) in toluene (in a microwave tube) was heated in a microwave (Personal Chemistry, Emrys Optimizer) at 180° C. for 2 h. The mixture was cooled to RT and diluted with 30 mL of EtOAc. The solution was washed with 10 mL of brine twice, dried over Na2SO4 and concentrated in vacuo. The residue was further purified with silica gel column chromatography (50% to 100% EtOAc in hexanes) to provide a white foam as the desired compound. MS (ESI pos. ion) m/z: 393 (M+H). Calc'd Exact Mass for C22H20N2O5: 392.40.
Reaction SMILES: C[Si](C)(C)[O:3][C:4]([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)=[CH2:5].[F-].[Cs+].[OH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](=[O:34])[CH:23]=[CH:24][C:25]1[CH:30]=[CH:29][C:28]2[O:31][CH2:32][O:33][C:27]=2[CH:26]=1>CS(C)=O>[OH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](=[O:34])[CH2:23][CH:24]([C:25]1[CH:30]=[CH:29][C:28]2[O:31][CH2:32][O:33][C:27]=2[CH:26]=1)[CH2:3][C:4]([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)=[O:5]
Reactant: O=C(C=Cc1ccc2c(c1)OCO2)c1ccccc1O
Reactant: C=C(O[Si](C)(C)C)c1ccsc1
Agent: [Cs+]
Agent: [F-]
Solvent: CS(C)=O
Product: O=C(CC(CC(=O)c1ccccc1O)c1ccc2c(c1)OCO2)c1ccsc1
Temperature: 70 °C

Procedure:
1-Trimethylsilyloxy-1-(thiophen-3-yl)ethylene (7.0 mmol; prepared according to J. Chem. Soc.,Perkin Trans. I 1989, 1585) and CsF (0.27 g, 1.76 mmol) were added to a suspension 1-(2-hydroxyphenyl)-3-(3,4-methylenedioxyphenyl)-2-propen-1-one on Wang resin (2.0 g, 1.76 mmol) in dimethyl sulfoxide (30 mL). The reaction mixture was heated to 70° C. for 3 h and the reaction was quenched with 10% AcOH/CH2Cl2. The resin was filtered, washed with DMF (×2) and alternating MeOH and CH2Cl2 (×5), and dried under high vacuum overnight to give 1-(2-hydroxyphenyl)-3-(3,4-methylenedioxyphenyl)-5-(thiophen-3-yl)-1,5-pentanedione on Wang resin.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.F[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][N:14]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][N:14]=2)[N:3]=1
Reactant: Nc1ncnc2[nH]nc(I)c12
Reactant: O=[N+]([O-])c1ccc(F)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncnc2c1c(I)nn2-c1ccc([N+](=O)[O-])cn1
Temperature: 80 °C
Reaction time: 8 h
Yield: 68.1 %

Procedure:
To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1) (3 g, 11.5 mmol) and 2-fluoro-5-nitropyridine (1.96 g, 13.8 mmol) in DMF (50 mL) was added K2CO3 (4.77 g, 43.5 mmol). After the mixture was stirred at 80° C. under N2 overnight, it was slowly poured into stirred water (200 mL). The resulting precipitate was collected by filtration, washed with methanol (50 mL×3) and dried in vacuo to afford 3-iodo-1-(5-nitropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (61) (3 g, 68%) as a brown solid. LC-MS (ESI): m/z (M+1) 384.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][CH:8]=[C:7]([C:15]#[N:16])[C:6]2=O.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][C:7]=1[C:15]#[N:16]
Reactant: COc1cc2[nH]cc(C#N)c(=O)c2cc1OC
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Temperature: 0 °C

Procedure:
A stirred mixture of 20 g of 1,4-dihydro-6,7-dimethoxy-4-oxo-3-quinolinecarbonitrile and 87 ml of phosphorous oxychloride was refluxed for 2 h, cooled, and evaporated free of volatile matter. The residue was stirred at 0° C. with dichloromethane-water as solid sodium carbonate was added until the aqueous layer was pH 8. The organic layer was separated, washed with water, dried and concentrated. Recrystallization from dichloromethane gave a solid, mp 220-223° C.
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=2[OH:19])=[C:10]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:9]2[S:26][C:27]([C:29]([O:31][CH3:32])=[O:30])=[CH:28][C:8]1=2)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[CH:20]1([C:10]2[C:9]3[S:26][C:27]([C:29]([O:31][CH3:32])=[O:30])=[CH:28][C:8]=3[N:7]([CH2:6][CH2:5][OH:4])[C:11]=2[C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=2[OH:19])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: COC(=O)c1cc2c(s1)c(C1CCCCC1)c(-c1ccc(O)cc1O)n2CCOC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1cc2c(s1)c(C1CCCCC1)c(-c1ccc(O)cc1O)n2CCO
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a solution of methyl 4-(2-acetoxyethyl)-6-cyclohexyl-5-(2,4-dihydroxyphenyl)-4H-thieno[3,2-b]pyrrole-2-carboxylate (505 mg, 1.11 mmol) in methanol (5 ml) was added potassium carbonate (476 mg, 3.44 mmol) and the mixture was stirred at room temperature for 25 min. The reaction mixture was concentration under reduced pressure, and ethyl acetate (5 ml) was added to the residue. The organic layer was washed successively with 1N hydrochloric acid (4 ml) and saturated brine (5 ml×2), and dried over sodium sulfate. Filtration and concentration gave methyl 6-cyclohexyl-5-(2,4-dihydroxyphenyl)-4-(2-hydroxyethyl)-4H-thieno[3,2-b]pyrrole-2-carboxylate as a crude product. The obtained compound was used for Step 11 without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:4][C:3]=1[C:15](=[O:17])[CH3:16].[BH4-].[Na+].C(OCC)(=O)C>CO>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:4][C:3]=1[CH:15]([OH:17])[CH3:16]
Reactant: CC(=O)c1cc(-c2cccc(Cl)c2)ccc1N
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(O)c1cc(-c2cccc(Cl)c2)ccc1N
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 57.6 %

Procedure:
To a solution of 1-(4-amino-3′-chloro-biphenyl-3-yl)-ethanone (see example 35, 0.15 g, 0.61 mmol) in anhydrous methanol was added sodium borohydride (0.07 g, 1.03 mmol) at room temperature (rt) under nitrogen. After 15 minutes, the reaction mixture was treated with ice-water. Ethyl acetate (30 mL) was added, organic layer was separated, and aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (10 mL) and dried over MgSO4. After removal of solvent, the residue obtained was crystallized from toluene to afford 1-(4-amino-3′-chloro-biphenyl-3-yl)-ethanol as white solid (0.087 g, 58%): 1H-NMR (DMSO-d6) δ7.55 (t, 1H, J=1.4 Hz), 7.50 (d, 1H, J=7.8 Hz), 7.44 (d, 1H, J=2.1 Hz), 7.39 (t, 1H, J=8.2 Hz), 7.31-7.21 (m, 2H), 6.68 (d, 1H, J=8.1 Hz), 5.25 (s, 2H), 5.20 (m, 1H), 4.83 (m, 1H), 1.35 (d, 3H, J=8.8 Hz); MS (EI) m/z 247 (M+).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][OH:8].[H-].[Na+].[N+:11]([C:14]1[CH:15]=[N:16][CH:17]=[C:18]([N+]([O-])=O)[CH:19]=1)([O-:13])=[O:12].CCOCC>CN(C=O)C.O.[Cl-].[Na+].O>[N+:11]([C:14]1[CH:19]=[C:18]([O:8][CH2:7][C@@H:3]2[CH2:4][CH2:5][CH2:6][N:2]2[CH3:1])[CH:17]=[N:16][CH:15]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1cncc([N+](=O)[O-])c1
Reactant: CN1CCCC1CO
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCC[C@H]1COc1cncc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 7.6 %

Procedure:
1-Methylpyrrolidinylmethanol (0.46 ml, 3.9 mmol) was added to a suspension of NaH in DMF at room temperature. After stirring at room temperature for 30 minutes, 3,5-dinitro-pyridine (0.34 g, 4 mmol) was added, and the mixture was allowed to stir at room temperature for 16 hours. The mixture was diluted with 1:1 water/brine, and the aqueous solution was extrated with ether. The combined ether layers were dried over MgSO4, filtered and concentrated. The residue was chromatographed, eluting with CH2Cl2 :methanol (10:0.5) to afford 70 mg of the title compound. MS (DCI/NH3) m/e: 238 (M+1). 1H NMR (CDCl3, 300MHz) δ: 9.06 (m, 1H), 8.62 (d, 1H), 7.97 (m, 1H), 4.07 (m, 2H), 3.50 (s, 3H), 3.13 (m, 1H), 2.73 (m, 1H), 2.35 (m, 1H), 2.05 (m, 1H), 1.82 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:17][CH:18]([CH3:20])[CH3:19])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:29][C:30](Br)=[O:31].[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH2:39][NH2:40]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:17][CH:18]([CH3:20])[CH3:19])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:29][C:30]([NH:40][CH2:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][N:33]=1)=[O:31]
Reactant: NCc1ccccn1
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC(C)C)cc32)cc1OC
Reactant: O=C(Br)CBr
Product: COc1ccc(CC2c3cc(OC(C)C)c(OC)cc3CCN2CC(=O)NCc2ccccn2)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-picolylamine
Reaction SMILES: [NH:1]([C:7]([O:9][CH2:10][CH:11]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[CH2:2][CH2:3][C:4]([OH:6])=[O:5].[NH2:24][CH:25]([CH2:28][OH:29])[CH2:26][OH:27].[C:30](Cl)([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)([C:39]1[CH:46]=[CH:45][C:42]([O:43][CH3:44])=[CH:41][CH:40]=1)[C:31]1[CH:38]=[CH:37][C:34]([O:35][CH3:36])=[CH:33][CH:32]=1.CO>N1C=CC=CC=1>[NH:1]([C:7]([O:9][CH2:10][CH:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18]2[C:23]1=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:8])[CH2:2][CH2:3][C:4]([O:6][C:30]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)([C:39]1[CH:46]=[CH:45][C:42]([O:43][CH3:44])=[CH:41][CH:40]=1)[C:31]1[CH:32]=[CH:33][C:34]([O:35][CH3:36])=[CH:37][CH:38]=1)=[O:5].[NH2:24][CH:25]([CH2:28][OH:29])[CH2:26][OH:27]
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: O=C(O)CCNC(=O)OCC1c2ccccc2-c2ccccc21
Agent: NC(CO)CO
Solvent: CO
Solvent: c1ccncc1
Product: COc1ccc(C(OC(=O)CCNC(=O)OCC2c3ccccc3-c3ccccc32)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 0.25 h

Procedure:
N-Fmoc-β-Ala-Serinol (1, 93 g, 242 mmol) is co-evaporated 2×400 mL anh. pyridine, and then dissolved in 300 mL of the same solvent with magnetic stirring. The mixture is cooled in a ice bath, and DMT-Cl (86.1 g, 254 mmol) in 465 mL pyridine is added dropwise over a period of 1.5 hours. The ice bath is removed and the mixture is allowed to react for another hour at room temperature. Methanol (100 mL) is added and stirred for 15 min. to quench the remaining DMT-Cl. After evaporation in vacuo, the residue co-evaporated 3×400 mL with toluene. Silica gel column purification using ethyl acetate/methanol/triethylamine (95:5:0.25) as mobile phase yielded 90.6 g (55%) grams of isolated product 2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][C:9]([C:13]#[N:14])=[CH:8]2.CC[N:18]([CH:22]([CH3:24])[CH3:23])C(C)C.[Br:25][CH2:26]/[CH:27]=[CH:28]/[C:29](Cl)=[O:30].[Cl-].[Na+]>C1COCC1>[Br:25][C:26]1[CH:24]=[C:22]([NH:18][C:8]2[C:7]3[C:12](=[C:3]([O:2][CH3:1])[CH:4]=[C:5]([NH:15][C:29](=[O:30])[CH:28]=[CH:27][CH2:26][Br:25])[CH:6]=3)[N:11]=[CH:10][C:9]=2[C:13]#[N:14])[CH:23]=[CH:28][CH:27]=1
Reactant: COc1cc(N)cc2cc(C#N)cnc12
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Cl)/C=C/CBr
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(NC(=O)C=CCBr)cc2c(Nc3cccc(Br)c3)c(C#N)cnc12

Procedure:
To a mixture of 1.05 g (2.8 mmol) of 4-[3-bromo-phenyl)amino]-8-methoxy-6-amino-3-quinolinecarbonitrile and 3.9 ml (22.4 mmol) of Hunig's base in 50 ml of dry THF at 0° C., with stirring, was added a THF solution containing 4.11 g (22.4 mmol) of 4-bromo crotonylchloride dropwise. The mixture was stirred for additional 1 hour at 0° C. 50 mL of saturated sodium chloride solution was added to the reaction mixture, then it was extracted with ethyl acetate. The ethyl acetate solution was dried over sodium sulfate and then the drying agent was filtered off. This solution was used without further characterization.
Reaction SMILES: [ClH:1].[N:2]([O:4]CCC(C)C)=O.[CH3:10][C:11]([CH3:24])=[CH:12][CH2:13][O:14][CH2:15][C:16]1[O:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=1>>[Cl:1][C:11]([CH3:24])([CH3:10])[CH:12]([N:2]=[O:4])[CH2:13][O:14][CH2:15][C:16]1[O:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=1
Reactant: Cl
Reactant: CC(C)=CCOCc1ccc([N+](=O)[O-])o1
Reactant: CC(C)CCON=O
Product: CC(C)(Cl)C(COCc1ccc([N+](=O)[O-])o1)N=O
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
Concentrated HCl (2.5 mL) was added to a cooled (0°-5° C.) solution of isoamyl nitrite (14.0 g, 0.12 mol) and 2-[[(3-methyl-2-butenyl)oxy]methyl]-5-nitrofuran (4.0 g, 0.06 mol). The temperature was maintained below 5° C. during the addition and the reaction mixture was stirred at 5° C. for an additional 30 min. The product was filtered and washed with a cold (-20° C.) 1:1 mixture of ethanol and ether. The solid was further washed with ether to afford a light yellow solid. Yield 2.6 g (52%). mp 134°-135° C.
Reaction SMILES: [Sn].[CH3:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]2[CH2:12][CH2:13][CH2:14][C:15](=[O:16])[C:4]=12.[Br-:17].[Br-].[Br-].C[N+](C)(C)C1C=CC=CC=1.C[N+](C1C=CC=CC=1)(C)C.C[N+](C1C=CC=CC=1)(C)C>C(Cl)Cl>[Br:17][CH:14]1[CH2:13][CH2:12][N:5]2[C:6]3[C:11]([C:3]([CH3:2])=[C:4]2[C:15]1=[O:16])=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: [Br-]
Reactant: Cc1c2n(c3ccccc13)CCCC2=O
Agent: C[N+](C)(C)c1ccccc1
Agent: [Sn]
Solvent: ClCCl
Product: Cc1c2n(c3ccccc13)CCC(Br)C2=O
Temperature: 10 °C
Reaction time: 30 h
Yield: 86.8 %

Procedure:
The reaction was performed in the dark (the flask wrapped in a tin-foil), and with the provision for maintaining a nitrogen atmosphere. To a solution of 10-methyl-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-one (described in Example 7, 49.75 g) in methylene chloride (250 mL) was added a solution of trimethylphenylammonium tribromide (94 g) in methylene chloride (1200 mL) as fast as possible (over 2 min); the inside temperature was maintained at 10° C. The reaction mixture was stirred at room temperature for 30 hr, evaporated in vacuo, and the solid residue was partitioned between water (600 mL) and benzene-diethyl ether 1:1 (800 mL, v/v). The separated organic layer was dried (MgSO4), filtered, and the filtrate was evaporated. The crude product was dissolved in chloroform (55 mL), and diethyl ether (600 mL) was added at once, whereby a voluminous, dark-green material precipitated. It was quickly removed by filtration (without suction), and the filtrate was chilled to 0° C. The crystals which formed were collected by filtration; 38 g, mp 126°-128° C. This material was recrystallized from chloroform-diethyl ether (1:8, v/v) to give 35 g of the title compound, mp 131°-133° C.; IR (CHCl3) 1665-1660, and 1535 cm-1 ; UV max (MeOH) 246 and 327 nm, (ε16000) and (18200) respectively; NMR (CDCl3) δ 2.67 (br s, 3H), overlapping with 2.65 (m, 2H), 4.29 (dd, J1 =7.5 Hz, J2 =4.5 Hz, 2H), 4.67 (t, J=4 Hz, 1H), 7.25-7.7 (m, 4H); Anal. Calcd for C13H12BrNO: C, 56.12% H, 4.35% N, 5.03% and Found: C, 56.20% H, 4.32% N, 5.05%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH:10]([C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([F:19])[C:13]=1[Cl:20])[CH3:11])[NH2:5].[S-:21][C:22]#[N:23].[K+].BrBr>>[Cl:1][C:2]1[C:8]([O:9][CH:10]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([F:19])[C:13]=2[Cl:20])[CH3:11])=[CH:7][C:6]2[S:21][C:22]([NH2:23])=[N:5][C:4]=2[CH:3]=1
Reactant: CC(Oc1ccc(N)cc1Cl)c1c(Cl)ccc(F)c1Cl
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Product: CC(Oc1cc2sc(N)nc2cc1Cl)c1c(Cl)ccc(F)c1Cl
Yield: 61 %

Procedure:
5-Chloro-6-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1,3-benzothiazol-2-amine was prepared according to the method described in Example 20d but from 1.19 g of 3-chloro-4-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]aniline, 1.38 g of potassium thiocyanate and 0.182 cm3 of dibromine. We obtain 0.85 g of 5-chloro-6-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1,3-benzothiazol-2-amine in the form of a yellow-coloured solid, which has the following characteristics:
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:11]([N:6]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]1[C:7]([F:9])=[CH:8][C:2]([Br:1])=[CH:3][C:4]=1[F:10])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: Nc1c(F)cc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1cc(Br)cc(F)c1N(Cc1ccccc1)Cc1ccccc1
Yield: 85.6 %

Procedure:
A suspension of 416 g of 4-bromo-2,6-difluoroaniline, 752 g of benzyl bromide and 608 g of potassium carbonate in 2 l of acetonitrile is refluxed for 48 hours. The mixture is subsequently evaporated in a rotary evaporator, the residue is dissolved in toluene and extracted with hydrochloric acid (10%), the toluene phase is evaporated in a rotary evaporator, and the product is stirred into heptane and stirred with silica gel for about 4.5 hours, filtered with suction and evaporated in a rotary evaporator, giving dibenzyl(4-bromo-2,6-difluorophenyl)amine, yield 85.6%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([O:14][CH3:15])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH2:16](N(CC)CC)[CH3:17].ICC>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([O:14][CH3:15])[CH2:13][CH2:12][N:11]([CH2:16][CH3:17])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC1(c2ccc(F)c(F)c2)CCNC1
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCI
Product: CCN1CCC(OC)(c2ccc(F)c(F)c2)C1

Procedure:
Preparation according to Example 22: (+)-3-(3,4-difluorophenyl)-3-methoxypyrrolidine (0.01 g, 0.047 mmol), triethylamine (13.1 μL, 0.093 mmol), tetrahydrofuran (2 ml) and iodoethane (5.6 μL, 0.07 mmol). The crude product analyzed by GCMS. Analysis showed 92% conversion. MS m/z (relative intensity, 70 eV) 241 (M+, 6), 226 (46), 211 (23), 141 (43), 71 (bp).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12]([OH:14])=[O:13])=[CH:9][C:8]([S:15][CH3:16])=[CH:7][CH:6]=2.[C:27](Cl)(=O)C(Cl)=O.C(N(CC)CC)C>CN(C=O)C.ClCCl>[CH3:1][C:2]1[C:3]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:24])[F:25])[CH:18]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12]([O:14][CH3:27])=[O:13])=[CH:9][C:8]([S:15][CH3:16])=[CH:7][CH:6]=2
Reactant: CSc1ccc2nc(-c3cccc(C(F)(F)F)c3)c(C)c(C(=O)O)c2c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1c(C)c(-c2cccc(C(F)(F)F)c2)nc2ccc(SC)cc12
Reaction time: 1 h
Yield: 68.9 %

Procedure:
DMF (5 drops) was added to a suspension of 3-methyl-6-(methylthio)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (2.1 g, 5.56 mmol) in dichloromethane (100 mL). Oxalyl chloride (0.731 mL, 8.35 mmol) was added slowly and the mixture was stirred for 1 h. The solvent was removed under reduced pressure, the residue was redissolved in methanol (50 mL), and triethylamine (1.55 mL, 11.13 mmol) was added slowly. The mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure, the residue was diluted with aqueous saturated NaHCO3, and the aqueous mixture was extracted with ethyl acetate (3 times). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via column chromatography (ISCO, 0-30% ethyl acetate/hexanes) to give methyl 3-methyl-6-(methylthio)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (1.5 g, 69% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.95-8.04 (m, 3H), 7.88 (d, J=8.03 Hz, 1H), 7.69-7.81 (m, 2H), 7.41 (d, J=2.01 Hz, 1H), 4.08 (s, 3H), 2.62 (s, 3H), 2.35 (s, 3H); MS (m/z) 392.1 (M+H+).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>CC#N>[C:10]([O:9][C:7]([N:4]1[CH2:5][CH2:6][CH:2]([NH:1][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:3]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(NS(C)(=O)=O)C1
Reaction time: 2.5 h

Procedure:
To a solution of (+/−)-3-amino-1N—BOC-pyrrolidine (0.5 g) in MeCN (10 mL) was added triethylamine (0.41 mL) then methanesulfonyl chloride (0.22 mL). The mixture was stirred for 2.5 h. An aqueous work-up followed by purification on silica gave 3-methanesulfonylamino-pyrrolidine-1-carboxylic acid tert-butyl ester (0.49 g).
Reaction SMILES: [F:1][C:2]([F:14])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][C:9]([NH2:12])=[N:8]1.[CH3:15][C:16]1[O:17][C:18]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:19]([C:21](O)=[O:22])[N:20]=1>>[F:14][C:2]([F:1])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][C:9]([NH:12][C:21]([C:19]2[N:20]=[C:16]([CH3:15])[O:17][C:18]=2[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:22])=[N:8]1
Reactant: Cc1nc(C(=O)O)c(-c2ccccc2)o1
Reactant: CC(F)(F)CCCCn1ccc(N)n1
Product: Cc1nc(C(=O)Nc2ccn(CCCCC(C)(F)F)n2)c(-c2ccccc2)o1

Procedure:
Following general procedure B, starting from 1-(5,5-difluoro-hexyl)-1H-pyrazol-3-ylamine and 2-methyl-5-phenyl-oxazole-4-carboxylic acid. LC-MS-conditions 05b: tR=1.19 min; [M+H]+=389.29.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[N:13]([CH3:14])[CH2:12][CH2:11][N:10]([CH3:15])[C:9]2=[O:16])=[CH:4][CH:3]=1.Br[C:18]1[C:19](=[O:26])[N:20]([CH3:25])[CH:21]=[C:22]([Br:24])C=1.C([N:30](C(C)C)CC)(C)C>CC(O)C>[Br:24][C:22]1[N:30]=[C:18]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C@@H:8]3[C:9](=[O:16])[N:10]([CH3:15])[CH2:11][CH2:12][N:13]3[CH3:14])=[CH:6][CH:7]=2)[C:19](=[O:26])[N:20]([CH3:25])[CH:21]=1
Reactant: CN1CCN(C)[C@H](c2ccc(N)cc2)C1=O
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CN1CCN(C)[C@H](c2ccc(Nc3nc(Br)cn(C)c3=O)cc2)C1=O
Temperature: 110 °C
Yield: 88.6 %

Procedure:
A sealed tube equipped with a magnetic stirrer was charged with (R)-3-(4-aminophenyl)-1,4-dimethylpiperazin-2-one (1.08 g, 5 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (1.47 g, 5.5 mmol), diisopropylethylamine (1.94 g, 15 mmol), and iPrOH (20 mL). After three cycles of vacuum/argon flush, the mixture was heated at 110° C. overnight. After cooling down to room temperature, water (20 mL) was added to, and the mixture was extracted with ethyl acetate (50 mL×2). The organic layer was separated, combined, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography eluting with dichloromethane/methanol (10:1, V/V) to afford 114a (1.8 g, 90%) as a red solid. LCMS: [M+H]+ 406