Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][C:15](=[O:18])[CH2:16][NH2:17])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[Br:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[CH3:31])[C:25](O)=[O:26].C(N=C=NC(C)C)(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)(Cl)Cl.C(O)(C)(C)C>[Br:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[CH3:31])[C:25]([NH:17][CH2:16][C:15]([NH:14][CH2:13][CH:10]1[CH2:9][CH2:8][N:7]([CH2:6][C:5]2[CH:19]=[CH:20][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:12][CH2:11]1)=[O:18])=[O:26]
Reactant: NCC(=O)NCC1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: Cc1ccc(C(=O)O)cc1Br
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CC(C)(C)O
Product: Cc1ccc(C(=O)NCC(=O)NCC2CCN(Cc3ccc(Cl)cc3)CC2)cc1Br
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 1-(4-chlorobenzyl)-4-{(glycylamino)methyl}piperidine (0.050 mmol) in CHCl3 (1.35 mL) and tert-butanol (0.15 mL) was treated with 3-bromo-4-methylbenzoic acid (0.060 mmol), diisopropylcarbodiimide (0.060 mmol), and HOBt (0.060 mmol). The reaction mixture was stirred at room temperature for 15 h. The mixture was loaded onto Varian™ SCX column, and washed with CH3OH/CHCl3 1:1 (12 mL) and CH3OH (12 mL). Product was eluted off using 2 N NH3 in CH3OH (5 mL) and concentrated to afford 4-[{N-(3-bromo-4-methylbenzoyl)glycyl}aminomethyl]-1-(4-chlorobenzyl)piperidine (Compound No. 1113) (16.1 mg, 65%): The purity was determined by RPLC/MS (95%); ESI/MS m/e 494.0 (C23H27BrClN3O2).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:21]([C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH:25]=[O:26])#[CH:22].C(OCC)(=O)C>C(#N)C.[Cu]I>[CH:25]([C:24]1[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=1[C:21]#[C:22][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1)=[O:26]
Reactant: CN(C)S(=O)(=O)c1ccc(Br)cc1
Reactant: C#Cc1ccccc1C=O
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CN(C)S(=O)(=O)c1ccc(C#Cc2ccccc2C=O)cc1
Temperature: 80 °C
Yield: 62.7 %

Procedure:
A mixture of 4-bromo-N,N-dimethylbenzenesulfonamide (610 mg, 2.31 mmol) bis(triphenylphosphine)palladium(II) chloride (Pd(PPh3)2Cl2) (33 mg, 0.05 mmol), copper (I) iodide (5 mg, 0.03 mmol) and triethylamine (3 mL) was degassed with argon. To the above mixture was added a degassed solution of 2-ethynyl-benzaldehyde (300 mg, 2.31 mmol) in acetonitrile (3 mL). The resulting mixture was heated at 80° C. for 3 hours under argon, and then cooled to room temperature, treated with ethyl acetate, and then washed with water. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (RediSep® Flash column, 230-400 mesh, 5-40% ethyl acetate in hexane) gave 4-(2-formyl-phenylethynyl)-N,N-dimethyl-benzenesulfonamide (454 mg, 63%) as a brown oil. MS (ESI+) cald. for C17H15NO3S [(M+H)+] 313, obsd. 314.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([O:8]C)[N:5]=[CH:4][C:3]=1[C:10]#[N:11].[BrH:12].[NH+]1C=CC=CC=1>>[Br:12][C:2]1[C:3]([C:10]#[N:11])=[CH:4][NH:5][C:6](=[O:8])[CH:7]=1
Reactant: Br
Reactant: COc1cc(I)c(C#N)cn1
Agent: c1cc[nH+]cc1
Product: N#Cc1c[nH]c(=O)cc1Br

Procedure:
4.5 g (purity 90%, 15.6 mmol) of 4-iodo-6-methoxypyridin-3-carbonitrile and 20 eq. of pyridinium hydrobromide were reacted according to General Method 3A. After aqueous work-up, the crude product was reacted further without further purification. Yield: 1.99 g (purity 77%, 49% of theory) of the title compound as a mixture with 11% of the analogous iodine compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:20]O)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=2)=[CH:4][CH:3]=1.CS(Cl)(=O)=O.C(N(CC)CC)C.O>C(OCC)(=O)C.[Fe](Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]3[N:20]=2)=[CH:4][CH:3]=1
Reactant: ON=C(Cc1ccc(C(F)(F)F)cn1)c1ccc(F)cc1
Agent: Cl[Fe]Cl
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: Fc1ccc(-c2cc3ccc(C(F)(F)F)cn3n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.5 %

Procedure:
To a solution of 1-(4-fluorophenyl)-2-(5-trifluoromethyl-2-pyridinyl)ethanone oxime (2.0 g, 6.7 mmol) in ethyl acetate (8 ml) at 7° C. was added methanesulfonyl chloride (0.52 ml, 6.7 mmol) over 3 minutes. The reaction mixture was stirred for 5 minutes before the dropwise addition of triethylamine (1.92 ml, 13.8 mmol) over 5 minutes. The reaction temperature was allowed to rise to 30° C. and the resulting suspension stirred at this temperature for two hours. Iron (II) chloride (8 mg) was then added and the mixture heated at reflux for 40 minute s before the addition of further iron (II) chloride (5 mg) and heating at reflux for 6 hours. The reaction mixture was then cooled to room temperature and water was added (5 ml). The phases were separated and the aqueous phase re-extracted with ethyl acetate. The organic extracts were combined, washed with water (5 ml) and evaporated in vacuo to give an orange-brown solid. The solid was triturated with isohexane (25 ml), the mixture filtered, the filter cake washed with isohexane (2×10 ml) and dried to give the title compound as a dull orange solid (1.06 g, 56%).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH3:23][O:24][C:25](=[O:49])[C:26]1[C:31]([NH:32][CH:33]([CH2:36][OH:37])[CH2:34][CH3:35])=[CH:30][C:29]([CH3:38])=[N:28][C:27]=1[O:39][C:40]1[C:45]([CH3:46])=[CH:44][C:43]([Cl:47])=[CH:42][C:41]=1[CH3:48]>>[CH3:23][O:24][C:25](=[O:49])[C:26]1[C:31]([NH:32][CH:33]([CH:36]=[O:37])[CH2:34][CH3:35])=[CH:30][C:29]([CH3:38])=[N:28][C:27]=1[O:39][C:40]1[C:41]([CH3:48])=[CH:42][C:43]([Cl:47])=[CH:44][C:45]=1[CH3:46]
Reactant: CCC(CO)Nc1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1C(=O)OC
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Product: CCC(C=O)Nc1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1C(=O)OC

Procedure:
The title compound was prepared by Dess-Martin oxidation of 2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-hydroxymethyl-propylamino)-6-methyl-nicotinic acid methyl ester. The title compound was obtained after column chromatography. 1H NMR (CDCl3) 9.54(d,1H), 8.56(d,1H), 7.01(s,2H), 5.93(s,1H), 3.92(m,1H), 3.89(s,3H), 2.08(s,3H), 2.05(s,6H), 1.05(t,3H) ppm.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([NH:10][C:11](=[O:19])[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].CN(C)C=O.[H-].[Na+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([N:10]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:11](=[O:19])[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(NC(=O)c2ccc(F)cc2)CC1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N1CCN(N(Cc2ccccc2)C(=O)c2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of N-(4-acetyl-1-piperazinyl)-4-fluorobenzamide (230 mg) and N,N-dimethylformamide (3 ml) was added sodium hydride (60% oil dispersion, 35 mg) in one portion at 0° C. The mixture was stirred at 0° C. for 1 hour then benzyl bromide (0.17 ml) was added to this mixture at 0° C. After stirring at 0° C. for 1.5 hours, water was added and the solvent was evaporated. The residue was taken up in ethyl acetate, washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by column chromatography eluting with a mixture of methanol and ethyl acetate (1:5) to give crystals. Crystallization from ethyl acetate and n-hexane to give N-(4-acetyl-1-piperazinyl)-N-benzyl-4-fluorobenzamide (260 mg).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([O:13][CH3:14])=[N:11][N:10]=[C:9]1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:16]1([C:19]2[C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]([CH3:38])[CH:20]=2)[CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[CH2:1]([N:8]1[C:12]([O:13][CH3:14])=[N:11][N:10]=[C:9]1[C:28]1[C:19]([CH:16]2[CH2:18][CH2:17]2)=[CH:20][C:21]([CH3:38])=[C:22]([CH:27]=1)[C:23]([O:25][CH3:26])=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C2CC2)cc1C
Reactant: COc1nnc(Br)n1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(-c2nnc(OC)n2Cc2ccccc2)c(C2CC2)cc1C
Temperature: 90 °C
Yield: 89.3 %

Procedure:
A mixture of 4-benzyl-3-bromo-5-methoxy-4H-1,2,4-triazole (compound 91.3, 1.2 g, 4.48 mmol), methyl 4-cyclopropyl-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 91.1, 1.56 g, 4.93 mmol), PdCl2(dppf)CH2Cl2 (0.37 g, 0.45 mmol) and potassium carbonate (3.10 g, 22.5 mmol) in dioxane (50 mL) and water (20 mL) was degassed with argon. The mixture was heated at 90° C. for 18 hours under argon, then cooled to room temperature. The mixture was diluted with ethyl acetate (300 mL) and washed with water then brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexanes:EtOAc 10:1 to 4:1) to yield 1.51 g (89%) of the title compound as thick oil. m/z (ES+) 378 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[O:28]1[CH2:32][CH2:31][CH2:30][CH:29]1[C:33]1[CH:34]=[CH:35][C:36]([NH2:39])=[N:37][CH:38]=1.NC1C=CC=CN=1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O.O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([NH:39][C:36]2[CH:35]=[CH:34][C:33]([CH:29]3[CH2:30][CH2:31][CH2:32][O:28]3)=[CH:38][N:37]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Reactant: Nc1ccc(C2CCCO2)cn1
Agent: Nc1ccccn1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccc(C3CCCO3)cn2)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 24 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 1, 250 mg, 0.76 mmol) in methylene chloride (5 mL) was cooled to 0° C. and then was treated with a 2.0M solution of oxalyl chloride in methylene chloride (435 μL, 0.87 mmol) and N,N-dimethylformamide (1 drop). The reaction mixture was stirred at 0° C. for 30 min and then concentrated in vacuo. The resulting oil was dissolved in tetrahydrofuran (2 mL) at 25° C. and then was treated dropwise with a solution of the inseparable mixture of 5-(tetrahydro-furan-2-yl)-pyridin-2-ylamine and 2-aminopyridine (224 mg, 1.36 mmol) and 2,6-lutidine (263 μL, 2.27 mmol) in tetrahydrofuran (3 mL) via an addition funnel. The resulting cloudy solution was then stirred overnight for 16 h at 25° C. After this time, the reaction was diluted with water (10 mL) and then extracted with methylene chloride (3×25 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Biotage chromatography (FLASH 12M, Silica, 65/35 to 50/50 hexanes/ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(tetrahydro-furan-2-yl)-pyridin-2-yl]-propionamide (86 mg, 24%) as a white foam: (ES)+-HRMS m/e calcd for C24H29ClN2O4S (M+H)+ 477.1610, found 477.1616.
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.C([Li])CCC.[B:27](OCC)([O:31]CC)[O:28]CC.Cl>C1COCC1.CCCCCC>[C:16]1([C:9]2[C:8]3[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:2]([B:27]([OH:31])[OH:28])=[C:15]3[C:10]=2[CH:11]=[CH:12][CH:13]=[CH:14]3)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOB(OCC)OCC
Reactant: Brc1c2ccccc2c(-c2ccccc2)c2ccccc12
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1c2ccccc2c(-c2ccccc2)c2ccccc12
Temperature: -80 °C
Reaction time: 12 h
Yield: 80 %

Procedure:
An amount of 14 g (42 mmol) of 9-bromo-10-phenylanthracene was dissolved in dehydrated THF and cooled to −80° C. Then, 31.2 ml (49 mmol) of a solution of n-butyllithium in n-hexane was added dropwise. Forty minutes later, 13 g (89 mmol) of triethyl borate was added. After two-hour reaction, a diluted hydrochloric acid solution was added and allowed to stand for 12 hours. Then, the separated organic layer was recrystallized to obtain 10 g (33.6 mmol) of 10-phenylanthracene-9-boronic acid. The yield was 75.2%.
Reaction SMILES: [CH3:1][C:2]1([C:34]([O:36]CC)=[O:35])[CH2:7][CH2:6][CH:5]([CH2:8][C:9]2[C:14]3[C:15]([CH3:18])=[N:16][NH:17][C:13]=3[N:12]3[N:19]=[CH:20][C:21]([C:22]4[CH:23]=[N:24][C:25]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)=[CH:26][CH:27]=4)=[C:11]3[N:10]=2)[CH2:4][CH2:3]1.C1COCC1.O[Li].O.Cl>O>[CH3:1][C:2]1([C:34]([OH:36])=[O:35])[CH2:3][CH2:4][CH:5]([CH2:8][C:9]2[C:14]3[C:15]([CH3:18])=[N:16][NH:17][C:13]=3[N:12]3[N:19]=[CH:20][C:21]([C:22]4[CH:23]=[N:24][C:25]([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=5)=[CH:26][CH:27]=4)=[C:11]3[N:10]=2)[CH2:6][CH2:7]1
Reactant: CCOC(=O)C1(C)CCC(Cc2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c3[nH]nc(C)c23)CC1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cc1n[nH]c2c1c(CC1CCC(C)(C(=O)O)CC1)nc1c(-c3ccc(-c4ccccc4)nc3)cnn12
Temperature: 80 °C
Reaction time: 96 h

Procedure:
To a 20 mL scintillation vial was charged ethyl 1-methyl-4-((3-methyl-6-(6-phenylpyridin-3-yl)-1H-dipyrazolo[1,5-a:4′,3′-e]pyrimidin-4-yl)methyl)cyclohexanecarboxylate (Int-6c, 0.03 mmol). To this residue was added 2:1 THF:H2O (1.5 mL) and LiOH.H2O (20 mg). The resulting solution was stirred at 80° C. for 4 days. After 4 days, the reaction was brought to pH 3 with 1N HCl(aq). The reaction was reduced in vacuo and the residue was purified via reverse-phase preparatory HPLC to 1-methyl-4-((3-methyl-6-(6-phenylpyridin-3-yl)-1H-dipyrazolo[1,5-a:4′,3′-e]pyrimidin-4-yl)methyl)cyclohexanecarboxylic acid (3). (M+H=481.27, retention time=4.01 min).
Reaction SMILES: C(O[C:4]1[CH:5]=[C:6](OC(C)C)[C:7]([F:25])=[C:8]([N:10]([CH2:19][C:20]2[CH:24]=[CH:23][NH:22][N:21]=2)[C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)[CH:9]=1)C.[CH2:30](C1C=CC(F)=C(C=1)C=CC1C=CC(C#N)=CC=1)[CH3:31].C(OC(N1C=CC=N1)(OCC)C)C>>[CH2:30]([C:4]1[CH:5]=[CH:6][C:7]([F:25])=[C:8]([N:10]([CH2:19][C:20]2[CH:24]=[CH:23][NH:22][N:21]=2)[C:11]2[CH:12]=[CH:13][C:14]([C:15]#[N:16])=[CH:17][CH:18]=2)[CH:9]=1)[CH3:31]
Reactant: CCOc1cc(OC(C)C)c(F)c(N(Cc2cc[nH]n2)c2ccc(C#N)cc2)c1
Reactant: CCc1ccc(F)c(C=Cc2ccc(C#N)cc2)c1
Agent: CCOC(C)(OCC)n1cccn1
Product: CCc1ccc(F)c(N(Cc2cc[nH]n2)c2ccc(C#N)cc2)c1

Procedure:
According to procedure for the preparation of Intermediate 183.1, reaction of Intermediate 262.1 with 1-(1,1-diethoxyethyl)-1H-pyrazole afforded Intermediate 264.1.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])=[CH:10][O:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][C@@H:16]([C:20]([OH:22])=[O:21])[CH2:15]2)=[C:5]([CH3:30])[CH:4]=1.[OH-].[Na+].O>C(O)C>[ClH:1].[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])=[CH:10][O:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]=[C:16]([C:20]([OH:22])=[O:21])[CH2:15]2)=[C:5]([CH3:30])[CH:4]=1
Reactant: Cc1ccccc1C(=COCCN1CCC[C@@H](C(=O)O)C1)c1ccc(F)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccccc1C(=COCCN1CCC=C(C(=O)O)C1)c1ccc(F)cc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-[2-[[2-(4-Fluoro-2-methylphenyl)-2-(2-methyl-phenyl)ethenyl]oxy]ethyl]-1,2,5,6-tetrahydro-3-pyridine carboxylic acid methyl ester (0.74 g, 0.0018 mol) (prepared as described in Method C) was dissolved in ethanol (15 ml) and 10N sodium hydroxide solution (1.8 ml) was introduced. After stirring the reaction mixture for 2 h at room temperature TLC indicated that saponification was incomplete, so further 10 N sodium hydroxide solution (1.8 ml) was added, and the reaction mixture was heated for 10 min. at 40° C. Water (400 ml) was added, and the solution was extracted with diethyl ether (100 ml). The aqueous layer was acidified to pH 5 with 2N hydrochloric acid solution and extracted with dichloromethane (4×50 ml). The combined extracts were dried (MgSO4) and evaporated to a residue (0.61 g) which was dissolved in toluene (50 ml). Methanol (0.2 ml) and chlorotrimethylsilane (0.216 ml) were added, and after mixing, a layer of cyclohexane (ca. 30 ml) was added. After storing this mixture at 4° for 18 h, the title compound was collected by filtration (0.60 g, 77%), m.p. 190°-201° (after drying in vacuo).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]1[CH:13]=[C:12]([CH3:14])[C:11]([CH3:15])=[CH:10][C:7]=1[CH:8]=[O:9].[Br:16]Br.O>C(Cl)Cl>[Br:16][C:13]1[C:6]([CH3:5])=[C:7]([CH:10]=[C:11]([CH3:15])[C:12]=1[CH3:14])[CH:8]=[O:9]
Reactant: Cc1cc(C)c(C=O)cc1C
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C=O)c(C)c(Br)c1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.4 %

Procedure:
Aluminum chloride (48.0 g, 360 mmol) was added to a solution of 2,4,5-trimethylbenzaldehyde (21.3 g, 144 mmol) in methylene chloride (200 ml) under ice cooling and the mixture was allowed to warm to room temperature. To the mixture was added dropwise bromine (7.80 ml, 151 mmol) at room temperature. The mixture was stirred for 4 hours, poured into water. Methylene chloride was removed under reduced pressure. The residue was extracted with ethyl acetate, and the organic extract was washed with water, saturated aqueous sodium bicarbonate, 5% aqueous sodium sulfite, water and saturated sodium chloride, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain 32.5 g (yield 100%) of the title compound. mp. 108–110° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[C:13]([CH3:14])=[N:12][C:11]([C:15]3[O:19][N:18]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=4)[N:16]=3)=[N:10]2)[CH:5]=[CH:4][N:3]=1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>CS(C)=O>[CH3:14][C:13]1[N:9]([CH2:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:7]=2)[N:10]=[C:11]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=3)[N:16]=2)[N:12]=1
Reactant: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1ccnc(Cl)c1
Reactant: C1COCCN1
Solvent: CS(C)=O
Product: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1ccnc(N2CCOCC2)c1
Temperature: 130 °C
Yield: 62.4 %

Procedure:
5-(1-((2-Chloropyridin-4-yl)methyl)-5-methyl-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole (50 mg, 0.115 mmol) and morpholine (100 mg, 1.15 mmol) were dissolved in DMSO (0.5 mL) in a sealed tube reaction vessel. The reaction was heated at 130° C. overnight and then cooled to RT. The reaction was then filtered and purified by prep-HPLC (MeCN/H2O 30%—MeCN 70% containing 0.1% TFA). The product was taken up in EtOAc (10 mL), washed with sat. NaHCO3 (10 mL), dried over Na2SO4, filtered, and concentrated to afford 4-(4-((5-methyl-3-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-1,2,4-triazol-1-yl)methyl)pyridin-2-yl)morpholine as a yellow solid (35 mg, 63%). MS (ES+) C22H20F3N7O3 requires: 487. found 488 [M+H]+; 1H NMR (600 MHz, CDCl3) δ 8.28 (d, J=8.8 Hz, 2H), 8.18 (d, J=5.3 Hz, 1H), 7.34 (d, J=8.8 Hz, 2H), 6.44 (d, J=5.3 Hz, 1H), 6.37 (s, 1H), 5.37 (s, 2H), 3.82-3.77 (m, 4H), 3.51-3.45 (m, 4H), 2.55 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C1C(=O)N([Br:17])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccnc1C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ncccc1CBr

Procedure:
Synthesized from 3-methylpicolinonitrile (1.00 g, 8.47 mmol), NBS (1.66 g, 9.31 mmol) and DBPO (103 mg, 0.42 mmol) in CCl4 according to Method A. Yield: 616 mg, 3.12 mmol, 37%. 1H NMR (CDCl3, 500 MHz): δH (ppm): 4.63 (s, 2H), 7.54 (dd, J=7.9, 4.9 Hz, 1H), 7.92 (dd, J=7.9, 1.5 Hz, 1H), 8.64 (dd, J=4.9, 1.5 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=26.8, 115.2, 127.1, 133.2, 138.1, 138.3, 150.5; MS (ESI): m/z=199.79 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:12]([CH3:13])[CH2:11][N:10](C(=O)C(F)(F)F)[CH2:9][CH2:8][C:7]=2[N:20]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O.C([O-])(O)=O.[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:12]([CH3:13])[CH2:11][NH:10][CH2:9][CH2:8][C:7]=2[N:20]=1
Reactant: COc1ccc2c(n1)CCN(C(=O)C(F)(F)F)CC2C
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc2c(n1)CCNCC2C

Procedure:
A mixture of 2-methoxy-5-methylene-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (495 mg, 1.73 mmol), 10% Pd/C (60 mg) and MeOH (40 ml) was stirred under a H2 atmosphere (1 atm) for 2 h at ambient temperature. Filtration and concentration of the filtrate in vacuo gave 490 mg (98%) of 2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. 1H-NMR (DMSO-d6) δ 7.52 (d, 1H), 6.65 (m, 1H), 3.94-3.73 (m, 5H), 3.65-3.44 (m, 2H), 3.24-3.05 (m, 3H), 1.20 (m, 3H) ppm. A mixture of 2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (97.0 mg, 346 μmol) and K2CO3 (100 mg) in MeOH (10 ml) was heated at reflux for 2 h. The reaction mixture was parted between EtOAc and NaHCO3.The organic phase was washed with brine, dried over Na2SO4 and concentrated in vacuo. Chromatographic purification rendered 63 mg (95%) of 2-methoxy-5-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. 1H-NMR (CDCl3) δ 7.35 (d, 1H), 6.51 (d, 1H), 3.90 (s, 3H), 3.10 (m, 2H), 3.04-2.93 (m, 4H), 2.75 (dd, 1H), 1.30 (d, 3H) ppm.
Reaction SMILES: Br[CH2:2][CH:3]([OH:19])[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.[F:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[CH:30][CH:29]=1>C1(C)C=CC=CC=1>[F:27][C:28]1[CH:29]=[CH:30][C:31]([N:34]2[CH2:39][CH2:38][N:37]([CH2:2][CH:3]([OH:19])[CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:36][CH2:35]2)=[CH:32][CH:33]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CC(O)CBr
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=S1(=O)c2cccc3cccc(c23)N1CC(O)CN1CCN(c2ccc(F)cc2)CC1
Temperature: 20 °C
Yield: 46.9 %

Procedure:
2-(3-Bromo-2-hydroxypropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (26.8 g), triethylamine (11 cc) and 4(4-fluorophenyl)piperazine (14.1 g) in toluene (280 cc) are heated at boiling point for 8 hours. The mixture is then cooled to a temperature of about 20° C. and stirring is maintained for 15 hours at this temperature. The precipitate formed is separated by filtration and washed with toluene (2 x 50 cc). The filtrate is evaporated to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). The residue obtained is purified by chromatography on a silica column, with ethyl acetate as eluant, and recrystallized from boiling acetonitrile (120 cc). 2-(3[4-(4-Fluorophenyl)-1-piperaz-invl]-2-hydroxypropyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (16.2 g) is obtained, m.p. 130° C.