Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20][C:21]1[C:22](=O)[C:23]2[C:31](=[CH:32][CH:33]=1)[C:30]1[C:25](=[CH:26][C:27]([Br:34])=[CH:28][CH:29]=1)[CH:24]=2.[C:36](Br)(Br)([Br:38])[Br:37]>O1CCCC1>[Br:20][C:21]1[CH:33]=[CH:32][C:31]2[C:30]3[C:25](=[CH:26][C:27]([Br:34])=[CH:28][CH:29]=3)[C:24](=[C:36]([Br:38])[Br:37])[C:23]=2[CH:22]=1
Reactant: BrC(Br)(Br)Br
Reactant: O=C1C(Br)=CC=C2C1=Cc1cc(Br)ccc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: BrC(Br)=C1c2cc(Br)ccc2-c2ccc(Br)cc21
Temperature: 25 °C
Yield: 58.4 %

Procedure:
Triphenylphosphine (34.89 g, 133.0 mmol) was added to a solution of 2,7-dibromofluorenone (17.94 g, 53.08 mmol) in anhydrous tetrahydrofuran (550 mL) under nitrogen and the reaction mixture was heated at just below reflux with stirring. A solution of carbon tetrabromide (35.16 g, 106.0 mmol) in anhydrous tetrahydrofuran (150 mL) was added dropwise over 1.5 h, and the reaction mixture was heated at reflux for 17 h with stirring. After cooling to room temperature, the solvent was removed under reduced pressure and dichloromethane was added forming a slurry. The solid was filtered off and washed with dichloromethane. Recrystallisation of the solid from dichloromethane afforded 2,7-dibromo-9-dibromomethylene-fluorene (2) (15.30 g, 58%) as a bright orange powder, purity 100% (GC): υmax (KBr, cm−1) 3115, 3066, 1605, 1566, 1547, 1450, 1399, 1264, 1073; 1H and 13C NMR spectra as expected; M+=494 (pent).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)[N:6]=[CH:5][C:4]=2[C:3]=1[NH2:22].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:33][N:34]1[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][O:42][C:43]2[CH:48]=[CH:47][N:46]3[C:49]([C:52](OCC)=[O:53])=[CH:50][N:51]=[C:45]3[CH:44]=2)[CH2:36][CH2:35]1>C1COCC1>[Cl:1][C:2]1[C:3]([NH:22][C:52]([C:49]2[N:46]3[CH:47]=[CH:48][C:43]([O:42][CH2:41][CH2:40][N:37]4[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]4)=[CH:44][C:45]3=[N:51][CH:50]=2)=[O:53])=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=1)[N:6]=[CH:5]2
Reactant: Nc1c(Cl)ccc2c1cnn2Cc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)c1cnc2cc(OCCN3CCN(C)CC3)ccn12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCN(CCOc2ccn3c(C(=O)Nc4c(Cl)ccc5c4cnn5Cc4cccc(C(F)(F)F)c4)cnc3c2)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 4 %

Procedure:
A solution of 5-chloro-1-(3-(trifluoromethyl)benzyl)-1H-indazol-4-amine (0.024 g, 0.074 mmol) in THF (0.750 mL) was cooled to −10° C. and LHMDS (0.096 mL, 0.096 mmol) was added. The mixture was stirred for 15 minutes, and ethyl 7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate (Preparation A; 0.049 g, 0.15 mmol) was added as a THF solution (0.750 mL). The mixture was slowly warmed to 0° C. where it stirred for 3 hours. The reaction was quenched with saturated aqueous NaHCO3 and extracted with CH2Cl2. The combined organic extracts were washed with brine and dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative TLC (1 mm, 10% MeOH/CH2Cl2 with 1% NH3 (7N MeOH)). The resulting solid was slurried in Et2O and filtered and the solid washed with Et2O and then finally with hexanes to provide the title compound (0.002 g, 4%) as a tan powder. MS (ES+APCI) m/z=612 (M).
Reaction SMILES: [ClH:1].[NH:2]1[CH2:5][CH2:4][CH2:3]1.[Cl:6][C:7]1[N:12]=[CH:11][C:10]([C:13]2[CH:14]=[C:15]([CH:30]=[CH:31][CH:32]=2)[CH2:16][N:17]([CH3:29])[C:18](=[O:28])[CH2:19][NH:20]C(=O)OC(C)(C)C)=[CH:9][N:8]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[ClH:6].[ClH:1].[N:2]1([C:7]2[N:8]=[CH:9][C:10]([C:13]3[CH:14]=[C:15]([CH:30]=[CH:31][CH:32]=3)[CH2:16][N:17]([CH3:29])[C:18](=[O:28])[CH2:19][NH2:20])=[CH:11][N:12]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: C1CNC1
Reactant: CN(Cc1cccc(-c2cnc(Cl)nc2)c1)C(=O)CNC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(Cc1cccc(-c2cnc(N3CCC3)nc2)c1)C(=O)CN
Temperature: 80 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Azetidine hydrochloride (287 mg) was suspended in DMF (5 ml), and tert-butyl (2-{[3-(2-chloropyrimidin-5-yl)benzyl](methyl)amino}-2-oxoethyl)carbamate (300 mg) and K2CO3 (849 mg) were added thereto, followed by stirring at 80° C. overnight. The reaction mixture was concentrated under reduced pressure, and then a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with CHCl3. The organic layer was dried over Na2SO4 and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc). The product was dissolved in EtOH (4 ml), and 4 M hydrogen chloride/EtOAc (2 ml) was added thereto, followed by stirring at room temperature overnight. The precipitated solid was collected by filtration to obtain N-[3-(2-azetidin-1-ylpyrimidin-5-yl)benzyl]-N-methylglycinamide dihydrochloride (295 mg).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([C:21]1[C:26](=[O:27])[CH:25]=[C:24]([CH3:28])[NH:23][C:22]=1[CH3:29])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(=O)([O-])[O-].[Na+].[Na+]>S(=O)(=O)(O)O>[CH2:5]([C:21]1[C:26](=[O:27])[C:25]([N+:1]([O-:4])=[O:2])=[C:24]([CH3:28])[NH:23][C:22]=1[CH3:29])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: O=[N+]([O-])O
Reactant: CCCCCCCCCCCCCCCCc1c(C)[nH]c(C)cc1=O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCCCCCCCCCCCCCCCc1c(C)[nH]c(C)c([N+](=O)[O-])c1=O
Temperature: 80 °C

Procedure:
Premixed nitric acid (d 1.5, 0.15 g) and sulfuric acid (0.05 g) was added dropwise at 5-10° C. to 4 (58 mg) in sulphuric acid (d 1.64, 0.5 g). The reaction mixture was heated at 80° C. for 1 hr then cooled and added to ice. Saturated aqueous sodium carbonate was added until effervescence ceased. The reaction mixture was extracted with portions of ethyl ether. The combined organic phase was dried over anhydrous MgSO4 and concentrated under diminished pressure to afford a crude residue Elution with hexane/ethyl acetate gave 3-hexadecyl-2,6-dimethyl-5-nitropyridin-4(1H)-one (14) as a yellow oil: yield 41 mg (62%); silica gel TLC Rf 0.60 (1:1 hexane/ethyl acetate); 1H NMR (400 MHz, CDCl3) δ 0.82-0.85 (m, 3H), 1.21-1.29 (m, 28H), 2.33 (s, 3H), 2.39 (s, 3H) and 2.46-2.52 (m, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:23]2[CH2:28][CH2:27][CH:26]([CH2:29]OS(C3C=CC(F)=CC=3)(=O)=O)[CH2:25][CH2:24]2)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[F:13][C:14]1[CH:15]=[CH:16][C:17]([S:20]([N:23]2[CH2:28][CH2:27][CH:26]([CH2:29][N:10]3[CH2:9][CH2:8][N:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[CH2:12][CH2:11]3)[CH2:25][CH2:24]2)(=[O:21])=[O:22])=[CH:18][CH:19]=1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: O=S(=O)(OCC1CCN(S(=O)(=O)c2ccc(F)cc2)CC1)c1ccc(F)cc1
Product: O=S(=O)(c1ccc(F)cc1)N1CCC(CN2CCN(c3ccccn3)CC2)CC1

Procedure:
Reaction of 1-pyridin-2-yl-piperazine and 4-fluoro-benzenesulfonic acid 1-(4-fluoro-benzenesulfonyl)-piperidin-4-ylmethyl ester as described in Example 1 gave the desired product, 1-[1-(4-Fluoro-benzenesulfonyl)-piperidin-4-ylmethyl]-4-pyridin-2-yl-piperazine.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:10][S:9][C@@H:8]([CH2:11][SH:12])[CH2:7]1)=[O:5])C.[OH-].[Li+].O>C1COCC1>[C:4]([C@@H:6]1[CH2:10][S:9][C@@H:8]([CH2:11][SH:12])[CH2:7]1)([OH:5])=[O:3]
Reactant: CCOC(=O)[C@@H]1CS[C@@H](CS)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@@H]1CS[C@@H](CS)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 70 %

Procedure:
To a stirred solution of trans-4-ethoxycarbonyl-2-mercaptomethyltetrahydrothiophene (compound No. 15-1, 420 mg) in THF (28 ml), 1N lithium hydroxide solution (4.1 ml) was added and the mixture was stirred for 1.5 hours at room temperature. Water was added to the mixture and washed with ethyl acetate. The aqueous layer was acidified with dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated in vacuo. The oily residue was purified by a silica gel column chromatography to give 254 mg (70%) of the titled compound (compound No. 7-1). The physical data was identified with the product obtained in Example 7.
Reaction SMILES: [ClH:1].[NH:2]1[CH2:8][CH:7]=[CH:6][CH2:5][C@:4]2([C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:17])[CH2:3]1.Cl>CO.CCOCC>[ClH:1].[NH:2]1[CH2:8][CH:7]=[CH:6][CH2:5][C:4]2([C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:17])[CH2:3]1
Reactant: O=C1Nc2ccccc2[C@]12CC=CCNC2
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: O=C1Nc2ccccc2C12CC=CCNC2

Procedure:
(S)-Spiro[indoline-3,3′-(1,3,4,7-tetrahydro-2H-azepin)]-2-one Hydrochloride The material from the second peak from STEP C (47 mg) was dissolved in methanol (5 ml) and treated with HCl in ether (1.5 ml) at room temperature overnight. The title compound was obtained upon removal of solvents. MS (TSP+) m/z [M+H]+: 215. 13C NMR: (CD3OD): 181.0, 142.1, 132.7, 132.2, 130.4, 125.7, 124.8, 123.8, 111.6, 53.8, 47.6, 47.5, 35.4 ppm.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4]([NH:11][CH2:12][CH2:13][OH:14])[N:3]=1.[C:15]1([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[Cl:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([N:24]2[CH2:25][CH2:26][CH:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:22][CH2:23]2)[N:3]=[C:4]([NH:11][CH2:12][CH2:13][OH:14])[N:5]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1c(Cl)nc(NCCO)nc1N1CCC(c2ccccc2)CC1

Procedure:
In analogy to the procedure described in example 20b, 4,6-dichloro-2-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile (example 41a) was treated with 4-phenyl-piperidine in dioxane in the presence of N-ethyl-diisopropylamine at room temperature to yield 4-chloro-2-(2-hydroxy-ethylamino)-6-(4-phenyl-piperidin-1-yl)-pyrimidine-5-carbonitrile as an amorphous, white solid; MS: [M+H]+=358.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:17][N:18]([CH3:26])[C:19]([C@H:21]1[CH2:25][CH2:24][CH2:23][NH:22]1)=[O:20]>C(#N)C>[CH3:17][N:18]([CH3:26])[C:19]([C@H:21]1[CH2:25][CH2:24][CH2:23][N:22]1[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)=[O:20]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CN(C)C(=O)[C@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(C)C(=O)[C@H]1CCCN1c1ccc([N+](=O)[O-])cc1

Procedure:
4-Fluoronitrobenzene (0.47 g, 3.34 mmol), potassium carbonate (1.39, 10 mmol) and (R)-pyrrolidine-2-carboxylic acid dimethylamide (0.50, 3.52 mmol) were pre-mixed in acetonitrile (40 ml) and heated at reflux for 36 hours. The reaction was quenched with saturated ammonium chloride (40 ml), extracted with DCM (2×100 ml), dried and solvent removed in vacuo to yield the title compound as a yellow solid. Ether was added and the solid was stirred, filtered and dried (0.85 g, 96%). M/z 264.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[C:13]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>CN1C(=O)CCC1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([N:23]2[CH2:22][CH2:21][N:20]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:25][CH2:24]2)=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CN1CCCC1=O
Product: COc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])c1
Yield: 50 %

Procedure:
Method 1 was followed using 4-chloro-3-nitroanisole (1.0 eq), 1-Boc-piperazine (1.2 eq), and TEA (2.0 eq) in NMP at 100° C. for 16 hours yielding tert-butyl 4-(4-methoxy-2-nitro phenyl)piperazine-1-carboxylate (50%). LCMS (m/z): 338.2 (MH+); LC Rt=3.37 min.
Reaction SMILES: C(N(CC)CC)C.I[C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][CH:10]=1.[CH2:16]([O:23][C:24](=[O:30])[NH:25][CH2:26][CH2:27][C:28]#[CH:29])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1.[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>[CH2:16]([O:23][C:24](=[O:30])[NH:25][CH2:26][CH2:27][C:28]#[C:29][C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][CH:10]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Ic1ccc(I)cc1
Reactant: C#CCCNC(=O)OCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCCC#Cc1ccc(I)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.5 %

Procedure:
To a mixture of anhydrous THF and triethylamine (24 mL, 2/1, v/v) were sequentially added 1,4-diiodobenzene (2.03 g, 6.15 mmol) and copper (1) iodide (0.094 g, 0.246 mmol). The mixture was stirred at room temperature for 15 min. The flask was then evacuated and re-filled with Argon. The procedure was repeated three more times to ensure no oxygen remained. The catalyst, dichlorobis(triphenylphosphine)palladium(II) (0.173 g, 0.246 mmol) was added into the mixture under Argon protection. The other starting material, but-3-ynylcarbamic acid benzyl ester (0.50 g, 2.46 mmol), dissolved in THF (8 mL) was added dropwise over 6 hours. The newly formed reaction mixture was further stirred at room temperature overnight. The solid in the reaction mixture was vacuum filtered. The filtrate was concentrated. The residue was re-dissolved in dichloromethane and purified by column chromatography, eluting with a mixture of ethyl acetate (0-12%) and hexanes (100-88%) to afford the product 22 (0.852 g, 86%) as an off-white solid. 1H NMR (300 MHz, CDCl3): δ 2.61 (t, J=6.4 Hz, 2H), 3.44 (t, J=6.4 Hz, 2H), 5.07 (br s, 1H), 5.12 (s, 2H), 7.10 (d, J=8.3 Hz, 2H), 7.35 (m, 5H), 7.63 (d, J=8.3 Hz, 2H). m/z (APCI) 405 [C18H16NO2+H]+.
Reaction SMILES: [CH3:1][O:2][P:3]([CH:5]([NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH3:6])[OH:4].C[O-].[Na+].[C:21]([O:25][CH3:26])(=[O:24])[CH:22]=[CH2:23]>CO.Cl>[CH3:1][O:2][P:3]([CH:5]([NH:7][C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9])[CH3:6])([CH2:23][CH2:22][C:21]([O:25][CH3:26])=[O:24])=[O:4]
Reactant: C=CC(=O)OC
Reactant: COP(O)C(C)NC(=O)OCc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCP(=O)(OC)C(C)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 70.7 %

Procedure:
To a stirred solution of 0.36 gm (0.0014 mol) of 1-benzyloxycarbonylaminoethylphosphonous acid methyl ester in 3 ml of methanol at 0° C. was added a solution of sodium methoxide in methanol (0.77 ml of a 2N solution) dropwise over 10 minutes whereupon was then added methyl acrylate 0.126 ml (0.0014 mol). The reaction mixture was stirred 30 minutes at 0° C. and 4 hours at room temperature whereupon it was diluted with 1N HCl. The mixture was extracted twice with ethyl acetate. The organic fractions were dried over sodium sulfate, filtered through magnesium sulfate and evaporated in vacuo. The product mixture was purified by chromatography (silica, 9:1, ethylacetate:acetonitrile) to give 0.34 gm of methyl-1-benzyloxycarbonylaminoethyl-[2-carbomethoxy-1-ethyl]phosphinate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[C:13]([N+:18]([O-])=O)[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Sn](Cl)Cl.[OH-].[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]3[C:12](=[C:13]([NH2:18])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cccc2c(-c3ccc(Br)cc3)ccnc12
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cccc2c(-c3ccc(Br)cc3)ccnc12
Yield: 77.8 %

Procedure:
4-(4-Bromophenyl)-8-nitroquinoline (30 g, 91.1 mmol) was added to absolute ethanol (120 mL) and purged with nitrogen. To this was added tin (II) chloride (190 mmol) and the reaction mixture refluxed for 4 hours. The pH was adjusted to 12 with aqueous NaOH and the organics were extracted using methylene chloride. The organics were then purified on basic alumina (methylene chloride/methanol 99:1) to yield 21.2 g of 4-(4-bromophenyl)quinolin-8-yl amine.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]([F:34])([F:33])[O:21][C:22]1[CH:23]=[C:24](/[CH:28]=[CH:29]/[C:30](O)=[O:31])[CH:25]=[CH:26][CH:27]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:30](=[O:31])/[CH:29]=[CH:28]/[C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([O:21][C:20]([F:33])([F:34])[F:19])[CH:23]=3)[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)/C=C/c1cccc(OC(F)(F)F)c1
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)/C=C/c3cccc(OC(F)(F)F)c3)n2)o1

Procedure:
Following general procedure A followed by L, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and (E)-3-(3-trifluoromethoxy-phenyl)-acrylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]([NH:20][CH:21]2[CH2:23][CH2:22]2)=[O:19])[CH:8]=1)=[O:5].C(=O)([O-])[O-].[K+].[K+].Cl[C:44]1[N:51]=[CH:50][CH:49]=[CH:48][C:45]=1[C:46]#[N:47]>O1CCOCC1>[Cl:1][C:2]1[CH:27]=[CH:26][C:25]([C:44]2[C:45]([C:46]#[N:47])=[CH:48][CH:49]=[CH:50][N:51]=2)=[CH:24][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]([NH:20][CH:21]2[CH2:23][CH2:22]2)=[O:19])[CH:8]=1)=[O:5]
Reactant: CC1(C)OB(c2ccc(Cl)c(C(=O)Nc3cc(C(=O)NC4CC4)nn3-c3ccccc3)c2)OC1(C)C
Reactant: N#Cc1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: N#Cc1cccnc1-c1ccc(Cl)c(C(=O)Nc2cc(C(=O)NC3CC3)nn2-c2ccccc2)c1

Procedure:
The title compound was prepared according to the method described for Example 83 using 5-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamido)-N-cyclopropyl-1-phenyl-1H-pyrazole-3-carboxamide in dioxane (Preparation 10) and 2-chloronicotinonitrile with potassium carbonate as base.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1.[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][CH2:30]1>>[N:29]1([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[C:10]([NH:15][S:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=3)=[CH:5][CH:4]=2)[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][CH2:30]1
Reactant: c1ccc2c(c1)CCN2
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1C(F)(F)F
Product: O=S(=O)(Nc1nccnc1-c1ccc(CN2CCc3ccccc32)cc1)c1ccccc1C(F)(F)F
Yield: 66 %

Procedure:
Following the general method as outlined in Example 1 (Method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzenesulfonamide (Intermediate 9), and 2,3-dihydro-1H-indole, the title compound was isolated as a yellow solid in 66% yield (94% purity by HPLC).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][CH:8]=[C:9]([Br:11])[N:10]=1)=O)C.[CH3:12][NH2:13]>CO>[CH3:12][NH:13][C:4]([C:6]1[S:7][CH:8]=[C:9]([Br:11])[N:10]=1)=[O:3]
Reactant: CN
Reactant: CCOC(=O)c1nc(Br)cs1
Solvent: CO
Product: CNC(=O)c1nc(Br)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Bromothiazole-2-carboxylic acid ethyl ester (500 mg, 2.13 mmol) is dissolved in methanol (1 mL) and methyl amine in methanol (10 mL) is added. The mixture is stirred overnight at room temperature. Evaporation of the solvent under reduced pressure affords the title compound as yellow solid. LCMS: Rt 0.92 min (100%) m/z (ESI) 219/221 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([O:9]C)[CH:6]=[CH:5][C:4]=1[C:11](=[O:23])[CH2:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1.B(Br)(Br)Br.[CH2:28](Cl)Cl>>[OH:2][C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:4]=1[C:11](=[O:23])[CH2:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH2:20][CH3:28])=[O:18])=[CH:15][CH:14]=1
Reactant: ClCCl
Reactant: COC(=O)c1ccc(CC(=O)c2ccc(OC)cc2OC)cc1
Agent: BrB(Br)Br
Product: CCOC(=O)c1ccc(CC(=O)c2ccc(O)cc2O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
To a solution of methyl 4-(2-(2,4-dimethoxyphenyl)-2-oxoethyl)benzoate (55 g, 141.6 mmol) in DCM (600 ml) was added dropwise BBr3 (164 ml, 1.7 mol) at −10° C. When the addition was complete, the mixture was stirred at room temperature overnight and poured into crashed ice (700 g) with stirring. The volatiles were evaporated to afford a yellow solid, which was dried in high vacuo and dissolved in absolute ethanol (500 ml). To the solution was added dropwise thionyl chloride (80 ml) at 0-10° C. When the addition was complete, the resultant mixture was heated to reflux for 3 hours. The volatiles were evaporated and the residue was partitioned between EtOAc (600 ml) and saturated sodium carbonate (200 ml). The organic phase was separated, washed with brine (200 ml), dried with anhydrous sodium sulfate, filtered and concentrated to afford brown slurry, which was purified by column chromatography (PE/EtOAc=3/1) to afford product (24.5 g, 58%) as a yellow solid. 1H NMR (CDCl3 500 MHz TMS): δ 12.58 (s, 1H), 8.01 (d, J=8.5 Hz, 2H), 7.69 (d, J=9.0 Hz, 1H), 7.33 (d, J=8.0 Hz, 2H), 7.05 (brs, 1H), 6.41 (d, J=8.0 Hz, 1H), 6.37 (s, 1H), 4.38 (q, J=7.0 Hz, 2H), 4.26 (s, 2H), 1.38 (t, J=7 Hz, 3H). MS (ESI): m/z 301.1 [M+1]+.
Reaction SMILES: CC1C=CC(S(O[C:12]2[C:13]3[CH2:23][CH2:22][CH2:21][C:20]4[N:24]([CH3:27])[N:25]=[CH:26][C:19]=4[C:14]=3[N:15]=[C:16]([NH2:18])[N:17]=2)(=O)=O)=CC=1.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>C(#N)C>[CH3:27][N:24]1[C:20]2[CH2:21][CH2:22][CH2:23][C:13]3[C:12]([N:32]4[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]4)=[N:17][C:16]([NH2:18])=[N:15][C:14]=3[C:19]=2[CH:26]=[N:25]1
Reactant: Cc1ccc(S(=O)(=O)Oc2nc(N)nc3c2CCCc2c-3cnn2C)cc1
Reactant: CN1CCNCC1
Solvent: CC#N
Product: CN1CCN(c2nc(N)nc3c2CCCc2c-3cnn2C)CC1

Procedure:
A solution of the product from Example 8C (0.048 g, 0.12 mmol) and N-methylpiperazine (0.25 g, 0.25 mmol) in acetonitrile (1 mL) was heated in a microwave at 160° C. for 1 hour. The reaction mixture was partitioned in dichloromethane/water, the organic layer was separated, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel, eluting with 5% methanol/dichloromethane/1% ammonium hydroxide to yield the title compound: 1H NMR (300 MHz, DMSO-d6) δ 7.84 (m, 1 H), 5.96 (m, 2 H), 3.76 (s, 3 H), 3.07 (m, 4 H), 2.93 (t, J=6.27 Hz, 2 H), 2.59 (m, 2 H), 2.43 (m, 4 H), 2.22 (s, 3 H), 1.90 (m, 2 H); MS (ESI+) m/z 314 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9](CCCCCCCCCCCCCCC)[C:5]=1[C:6](Cl)=[O:7])[CH3:2].[NH2:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[C:31]([C:37]([F:40])([F:39])[F:38])[CH:30]=1.C(N(CC)CC)C>ClCCl>[C:33]([C:32]1[CH:35]=[CH:36][C:29]([NH:28][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[O:3][CH2:1][CH3:2])=[CH:30][C:31]=1[C:37]([F:38])([F:39])[F:40])#[N:34]
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Reactant: CCCCCCCCCCCCCCCc1cccc(OCC)c1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1ccccc1C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1

Procedure:
2-ethoxy-6-pentadecyl-benzoyl chloride was condensed with 4-Amino-2-trifluoromethyl benzonitrile in dichloromethane in presence of triethylamine as acid scavenger to yield N-(4-Cyano-3-trifluoromethyl-phenyl)-2-ethoxy-benzamide. The reaction mixture was then concentrated in vacuo and the residue was extracted into ethyl acetate. The ethyl acetate layer was washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulphate and finally concentrated in vacuo. The residue obtained was chromatographed over silica gel to afford the desired product.