Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH:13]([C:15]([OH:17])=O)[CH2:12][CH2:11][N:10]1[C:18]([O:20][CH3:21])=[O:19].N1(C(N2C=CN=C2)=O)C=CN=C1.[CH2:34]([O:36][C:37](=[O:42])[CH2:38]C([O-])=O)[CH3:35].[K+].[Cl-].[Mg+2].[Cl-].Cl>CN1C2C(N=C(N)NC=2NCC1CNC1C=CC(C(NC(C(O)=O)CCC(O)=O)=O)=CC=1)=O.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH:13]([C:15](=[O:17])[CH2:38][C:37]([O:36][CH2:34][CH3:35])=[O:42])[CH2:12][CH2:11][N:10]1[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)N1CCC(C(=O)O)CC1c1ccc(Cl)cc1Cl
Reactant: CCOC(=O)CC(=O)[O-]
Agent: CN1c2c([nH]c(N)nc2=O)NCC1CNc1ccc(C(=O)NC(CCC(=O)O)C(=O)O)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Product: CCOC(=O)CC(=O)C1CCN(C(=O)OC)C(c2ccc(Cl)cc2Cl)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 52.4 %

Procedure:
2-(2,4-Dichlorophenyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (2.44 g, 7.35 mmol) (reference compound 23) was dissolved in methyl THF (36.7 mL) and di(1H-imidazol-1-yl)methanone (1.787 g, 11.02 mmol) added. The suspension was stirred at room temperature under nitrogen for 6 h (flask 1). In a separate flask potassium 3-ethoxy-3-oxopropanoate (2.250 g, 13.22 mmol) was suspended in methyl THF (36.7 mL) and magnesium chloride (1.259 g, 13.22 mmol) added. The suspension was stirred under nitrogen for 6 h (flask 2). The white suspension in flask 2 was then added to the brown suspension in flask 1. The resulting suspension was stirred at room temperature for 40 h. The mixture was acidified to pH 1 with 3 M HCl. Water and methyl THF were added, the phases separated. The organic layer was washed with water, satd NaHCO3, brine, dried over MgSO4, filtered and evaporated. Purified by flash chromatography using 20% EtOAc in heptane ->50% EtOAc over 10 CV, 3CV at 50%. Repurified by flash chromatography using 20% EtOAc in EtOAc ->30% EtOAc over 12 CV. Methyl 2-(2,4-dichlorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.55 g, 52%) was isolated.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[C:12]1[O:11][N:10]=[C:9]([C:16]([O:18][CH3:19])=[O:17])[C:8]=1[CH2:7][CH2:6]2)=O.C(O)(=O)C.[NH:24]1[CH2:27][CH:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>CO.ClCCCl.C(O)(=O)C>[C:31]([O:30][C:28]([CH:26]1[CH2:25][N:24]([CH2:1][C:3]2[CH:4]=[C:5]3[C:13](=[CH:14][CH:15]=2)[C:12]2[O:11][N:10]=[C:9]([C:16]([O:18][CH3:19])=[O:17])[C:8]=2[CH2:7][CH2:6]3)[CH2:27]1)=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: COC(=O)c1noc2c1CCc1cc(C=O)ccc1-2
Reactant: CC(C)(C)OC(=O)C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: CO
Product: COC(=O)c1noc2c1CCc1cc(CN3CC(C(=O)OC(C)(C)C)C3)ccc1-2
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 85.2 %

Procedure:
To a solution of methyl 7-formyl-4,5-dihydronaphtho[2,1-d]isoxazole-3-carboxylate (Preparation 45C, 72 mg, 0.280 mmol) in methanol (5 mL) and 1,2-dichloroethane (1 mL) was added acetic acid (0.1 mL) and tert-butyl azetidine-3-carboxylate acetic acid salt (73.0 mg, 0.336 mmol). The contents were allowed to stir at room temperature for 40 min. and then sodium triacetoxyborohydride (178 mg, 0.840 mmol) was added. The reaction mixture was allowed to stir at room temperature overnight. Additional sodium triacetoxyborohydride (2 eq) was added and the reaction mixture was allowed to stir at room temperature for 2 hours. Additional sodium triacetoxyborohydride (4 eq) was added and the reaction mixture was allowed to stir at room temperature for 3 days. Additional amine (0.5 eq.), followed by additional triacetoxyborohydride (3 eq.) was added and the reaction mixtures was stirred at room temperature for 6 more hours to drive the reaction to about 90% conversion. The solvents were evaporated and the residue was re-dissolved into 80 ml ethyl acetate, washed twice with sat. sodium bicarbonate, dried over sodium sulfate, and concentrated to give 95 mg of product. The compound had an HPLC ret. time=0.75/2.0 min. (condition E); MS:(M+H)=399.3.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([CH:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[N:6][C:7]=1[Br:8].C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>C(Cl)Cl>[Br:8][C:7]1[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([CH:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)[N:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cnc(N)c(Br)n2)CC1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncc(C2CCNCC2)nc1Br
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of tert-butyl 4-(5-amino-6-bromopyrazin-2-yl)piperidine-1-carboxylate (70 mg, 0.196 mmol) in DCM (4 mL) was added TFA (1 mL, 12.98 mmol). The reaction mixture was stirred at room temperature for 45 min. After toluene was added, the volatile materials were evaporated yielding 3-bromo-5-(piperidin-4-yl)pyrazin-2-amine. The crude product was used directly for the next reaction (99%). LCMS (m/z): 257.0/259.0 (MH+), 0.329 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH:9]=O)=[C:7]([O:11][CH3:12])[N:6]=[CH:5][N:4]=1.[CH2:13]([O:15][C:16](=[O:21])[CH2:17][C:18](=[NH:20])[NH2:19])[CH3:14]>C(O)C>[CH2:13]([O:15][C:16]([C:17]1[CH:9]([C:8]2[C:7]([O:11][CH3:12])=[N:6][CH:5]=[N:4][C:3]=2[O:2][CH3:1])[C:17]([C:16]([O:15][CH2:13][CH3:14])=[O:21])=[C:18]([NH2:19])[NH:20][C:18]=1[NH2:19])=[O:21])[CH3:14]
Reactant: COc1ncnc(OC)c1C=O
Reactant: CCOC(=O)CC(=N)N
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(N)=C(C(=O)OCC)C1c1c(OC)ncnc1OC
Yield: 56 %

Procedure:
Upon heating a solution of 8.4 g. 4,6-dimethoxypyrimidine-5-aldehyde and 13.0 g amidinoacetic acid ethyl ester in 150 ml ethanol for two hours, 2,6-diamino-4-(4,6-dimethoxypyrimid-5-yl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of m.p. 219°C (ethanol) is obtained.
Reaction SMILES: [CH3:1][O:2][CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][C:6]=1[F:12].C([Li])CCC.[CH3:18][C:19]([CH3:21])=[O:20].O>O1CCCC1>[F:12][C:6]1[CH:7]=[C:8]([C:19]([OH:20])([CH3:21])[CH3:18])[CH:9]=[CH:10][C:5]=1[CH:4]=[CH:3][O:2][CH3:1]
Reactant: CC(C)=O
Reactant: COC=Cc1ccc(Br)cc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COC=Cc1ccc(C(C)(C)O)cc1F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of compound 2-(4-bromo-2-fluorophenyl)vinyl methyl ether (115.5 g, 0.5 mol) in tetrahydrofuran (666 mL) at −78° C. was added n-butyllithium (240 mL of 2.5M in hexanes, 0.6 mol), and the resulting mixture was stirred at −78° C. for 1 hour. A solution of acetone (37.7 g, 0.65 mol) in tetrahydrofuran (283 mL) was added dropwise to the reaction mixture. Then the reaction solution was slowly warmed to 0° C., stirred for 30 minutes, and then at room temperature for 30 minutes. Water (300 mL) was added to quench the reaction. The biphasic mixture was extracted with ethyl acetate (2×). The combined organics were dried and concentrated in vacuo. Purification via flash chromatography afforded the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](Cl)[N:9]=[C:10]=[O:11])=[CH:4][CH:3]=1.[F:13][C:14]([F:29])([F:28])[C:15]1[CH:16]=[C:17]([NH:21][C:22]2[CH2:26][CH2:25][C:24](=[O:27])[CH:23]=2)[CH:18]=[CH:19][CH:20]=1.O>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:9][C:10](=[O:11])[N:21]([C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([C:14]([F:13])([F:28])[F:29])[CH:16]=3)[C:22]3[CH2:26][CH2:25][C:24](=[O:27])[C:23]2=3)=[CH:4][CH:3]=1
Reactant: O=C=NC(Cl)c1ccc(Br)cc1
Reactant: O=C1C=C(Nc2cccc(C(F)(F)F)c2)CC1
Solvent: ClCCl
Solvent: O
Product: O=C1CCC2=C1C(c1ccc(Br)cc1)NC(=O)N2c1cccc(C(F)(F)F)c1

Procedure:
A solution of 1-bromo-4-(chloro(isocyanato)methyl)benzene (14.7 g, 47.6 mmol) in dichloromethane (100 mL) is added to a solution of 3-(3-(trifluoromethyl)phenylamino)-cyclopent-2-enone (11.0 g, 45.6 mmol) in dichloromethane (100 mL) and the mixture is heated at reflux for 1.5 hours. Water is added, and the phases are extracted twice with dichloromethane. The combined organic layers are concentrated and the residue is purified by flash chromatography on silica (gradient cyclohexane/ethyl acetate 4:1 to ethyl acetate). Yield: 7.5 g; ESI mass spectrum: ESI mass spectrum: [(79Br)-M+H]+=451, [(81Br)-M+H]+=453; Retention time HPLC: 1.15 min (V012_S01).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH:7]1[C:16]2[N:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:10][CH2:9][CH2:8]1.[Cl-].[Na+]>O>[N:1]1([CH:7]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:10][CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: ClC1CCCc2cccnc21
Reactant: C1CCNC1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: c1cnc2c(c1)CCCC2N1CCCC1
Reaction time: 0.12 h

Procedure:
Over a period of 7 minutes with stirring and while allowing it to heat up, 50 ml of pyrrolidine were added to a solution of 20 g of 8-chloro-5,6,7,8-tetrahydroquinoline in 50 ml of water. The temperature reached 57° C. at the end of the introduction and stirring was continued for 1 hour at this temperature. The temperature was then allowed to return to 20° C. and the reaction medium was saturated with sodium chloride and then was extracted with ether. The combined organic phases were dried and the solvents were eliminated under reduced pressure to obtain 20.22 g or 8-pyrrolidinyl-5,6,7,8-tetrahydroquinoline in the form of an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:11]([C:12]3[CH:29]=[CH:28][C:15]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:14][CH:13]=3)[N:10]=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[CH3:30]OC(N(C)C)(OC)C>>[CH3:30][C:9]1[CH:8]=[C:7]([C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)[N:11]([C:12]2[CH:13]=[CH:14][C:15]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:28][CH:29]=2)[N:10]=1
Reactant: COC(C)(OC)N(C)C
Reactant: c1ccc2nc(COc3ccc(-n4nccc4-c4ccncc4)cc3)ccc2c1
Product: Cc1cc(-c2ccncc2)n(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1

Procedure:
Following the procedure for the preparation of 2-[4-(5-Pyridin-4-yl-pyrazol-1-yl)-phenoxymethyl]-quinoline but substituting (1,1-Dimethoxy-ethyl)-dimethyl-amine provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.49 (d, J=6.2 Hz, 2 H), 8.20 (d, J=8.3 Hz, 1 H), 8.06 (d, J=8.7 Hz, 1 H), 7.83 (d, J=8.3 Hz,1H), 7.74 (m,1H), 7.64 (d, J=8.3 Hz, 1 H), 7.54 (m, 1H), 7.18 (d, J=8.7 Hz, 2 H), 7.07 (d, J=6.2 Hz, 2H), 7.00 (d, J=9.1 Hz, 2H), 6.40 (s, 1H), 5.38 (s, 2H), 2,35 (s, 3H); MS: (M+H m/z=393.4).
Reaction SMILES: C(C1N([CH2:14][C:15]2[CH:32]=[CH:31][C:18]3/[C:19](=[CH:28]/[C:29]#[N:30])/[C:20]4[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=4[CH2:22][CH2:23][C:17]=3[CH:16]=2)C2=NC(C)=CC(C)=C2N=1)C.N1C(C)=CC=CC=1C.[Br-:41].[Li+].CS(OS(C)(=O)=O)(=O)=O>C1COCC1.CCCCCC.C(OCC)(=O)C>[Br:41][CH2:14][C:15]1[CH:32]=[CH:31][C:18]2/[C:19](=[CH:28]/[C:29]#[N:30])/[C:20]3[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=3[CH2:22][CH2:23][C:17]=2[CH:16]=1
Reactant: [Br-]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C\C#N
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Product: N#C/C=C1\c2ccccc2CCc2cc(CBr)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.9 %

Procedure:
(E)-(2-Hydroxymethyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)acetonitrile (JP-B-2526005; 10.00 g, 38.3 mmol) was dissolved in THF (380 mL), 2,6-lutidine (26.7 mL, 230 mmol), lithium bromide (19.94 g, 230 mmol) and methanesulfonic anhydride (16.67 g, 95.7 mmol) were added, and the mixture was stirred at room temperature for 16 hr. Ethyl acetate was added to the mixture, and the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a residue. Ethyl acetate (10 mL) and hexane (5 mL) were added to the residue, and the mixture was filtered to give the title compound (9.18 g, 74%).
Reaction SMILES: [CH3:1][C:2]1[S:6][N:5]=[N:4][C:3]=1[C:7]([O:9]CC)=O.C(Cl)(=O)C([Cl:15])=O>>[CH3:1][C:2]1[S:6][N:5]=[N:4][C:3]=1[C:7]([Cl:15])=[O:9]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOC(=O)c1nnsc1C
Product: Cc1snnc1C(=O)Cl

Procedure:
Hydrolysis of ethyl 5-methyl-1,2,3-thiadiazole-4-carboxylate (D. L. Pain and R. Slack, J. Chem. Soc., 5166 (1965)) and subsequent treatment of the acid with oxalyl chloride according to the method of Example 3 provides 5-methyl-1,2,3-thiadiazole-4-carbonyl chloride.
Reaction SMILES: [Br-].[CH:2]1([Zn+])[CH2:4][CH2:3]1.[Cl:6][C:7]1[CH:12]=[C:11](I)[CH:10]=[C:9]([Cl:14])[N:8]=1>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:6][C:7]1[CH:12]=[C:11]([CH:2]2[CH2:4][CH2:3]2)[CH:10]=[C:9]([Cl:14])[N:8]=1
Reactant: [Zn+]C1CC1
Reactant: Clc1cc(I)cc(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: Clc1cc(C2CC2)cc(Cl)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Cyclopropylzinc bromide (0.5 M in tetrahydrofuran, 15 mL, 7.3 mmol) was added to a mixture of 2,6-dichloro-4-iodopyridine (1.0 g, 3.65 mmol) and tetrakis(triphenylphosphine)palladium(0) (211 mg, 0.182 mmol) in anhydrous tetrahydrofuran (10 mL) at 0° C. After being stirred at room temperature for 4 hours, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=100:1) to provide 2,6-dichloro-4-cyclopropylpyridine. MS ESI calc'd. for C8H8Cl2N [M+H]+ 188. found 188. 1H NMR: (400 MHz, CDCl3) δ 6.89 (s, 2H), 1.87-1.80 (m, 1H), 1.18-1.13 (m, 2H), 0.84-0.80 (m, 2H).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1.C(N(CC)CC)C.[N+:14]([C:17]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:28]=2[Cl:37])=[CH:22][C:18]=1[C:19](Cl)=[O:20])([O-:16])=[O:15]>C1(C)C=CC=CC=1>[N+:14]([C:17]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:29][C:28]=2[Cl:37])=[CH:22][C:18]=1[C:19]([O:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1)=[O:20])([O-:16])=[O:15]
Reactant: O=C(Cl)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: OC1CCOC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(OC1CCOC1)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
3-Hydroxytetrahydrofuran (1.76 grams; 0.02 mole), toluene (50 ml) and triethylamine (2.0 grams; 0.02 mole) were charged into a glass reaction vessel equipped with a mechanical stirrer and addition funnel. A solution of 2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)benzoyl chloride (7.60 grams; 0.02 mole) in toluene (10 ml) was slowly added with stirring. After the addition was completed, stirring was continued overnight. After this time, the reaction mixture was washed with water and dried over anhydrous sodium sulfate. The dried solution was then stripped of solvent under reduced pressure leaving a brown oil. This oil was purified by silica gel chromatography using toluene and ethyl acetate/toluene mixtures as the eluant. The purified oil was triturated in ethanol to yield the desired product 3-tetrahydrofuryl 2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)benzoate as a white solid, melting point at 55° C.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([S:14]([N:17](CC3C=CC(OC)=CC=3OC)[C:18]3[S:22][N:21]=[CH:20][N:19]=3)(=[O:16])=[O:15])[CH:12]=2)[N:7]([C:34]2[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][C:35]=2[Cl:44])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([S:14]([NH:17][C:18]3[S:22][N:21]=[CH:20][N:19]=3)(=[O:15])=[O:16])[CH:12]=2)[N:7]([C:34]2[CH:39]=[CH:38][C:37]([C:40]([F:41])([F:43])[F:42])=[CH:36][C:35]=2[Cl:44])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(c2)N(C(C)=O)CCN3c2ccc(C(F)(F)F)cc2Cl)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CCN(c2ccc(C(F)(F)F)cc2Cl)c2ccc(S(=O)(=O)Nc3ncns3)cc21
Reaction time: 0.5 h

Procedure:
4-Acetyl-1-(2-chloro-4-(trifluoromethyl)phenyl)-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)-1,2,3,4-tetrahydroquinoxaline-6-sulfonamide (0.048 g, 0.072 mmol) was dissolved in 1 mL of DCM and TFA (0.1 mL, 1.298 mmol) was added. The reaction was stirred for 30 minutes. The material was concentrated, dissolved in acetonitrile and loaded onto an ion exchange column (pre-wetted with acetonitrile). The column was flushed several times with acetonitrile, then the product was liberated by flushing the column several times with about 1M HCl solution in MeOH/EtOAc (made by adding acetyl chloride to a MeOH/EtOAc mixture). The second filtrate was concentrated to afford 4-acetyl-1-(2-chloro-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-1,2,3,4-tetrahydroquinoxaline-6-sulfonamide as a light pink solid. 1H NMR (400 MHz, DMSO-d6) δ=8.42 (s, 1 H), 8.12 (d, J=1.7 Hz, 1 H), 7.90 (dd, J=1.6, 8.4 Hz, 1 H), 7.81 (d, J=8.5 Hz, 1 H), 7.31 (d, J=7.9 Hz, 1 H), 6.21 (d, J=8.8 Hz, 1 H), 3.96 (t, J=4.6 Hz, 2 H), 3.68 (br. s., 2 H), 2.24 (s, 3 H). m/z (ESI) 517.8 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.C(C1NC=CN=1)(C1NC=CN=1)=O.[Cl:22][C:23]1[C:24]([CH2:33][NH2:34])=[N:25][CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1>ClCCl>[Cl:22][C:23]1[C:24]([CH2:33][NH:34][C:7]([C:5]2[O:6][C:2]([Br:1])=[CH:3][CH:4]=2)=[O:9])=[N:25][CH:26]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:28]=1
Reactant: O=C(O)c1ccc(Br)o1
Reactant: NCc1ncc(C(F)(F)F)cc1Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: ClCCl
Product: O=C(NCc1ncc(C(F)(F)F)cc1Cl)c1ccc(Br)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-bromofuroic acid (0.19 g) and carbonyl diimidazole (CDI) in dichloromethane was added (3-chloro-5-trifluoromethyl-2-pyridyl)methylamine and the mixture was stirred at room temperature overnight. The mixture was washed with 2M hydrochloric acid, then saturated sodium bicarbonate, dried (MgSO4) and evaporated to give the title product, m.p. 77.8° C.
Reaction SMILES: [CH3:1][C:2]1[S:23][C:5]2[N:6]=[C:7]([CH2:11][N:12]3[CH:16]=[C:15]([CH:17]=O)[C:14]([C:19]([F:22])([F:21])[F:20])=[N:13]3)[NH:8][C:9](=[O:10])[C:4]=2[CH:3]=1.[S:24]1[CH:28]=[CH:27][N:26]=[C:25]1[CH2:29][NH2:30].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:1][C:2]1[S:23][C:5]2[N:6]=[C:7]([CH2:11][N:12]3[CH:16]=[C:15]([CH2:17][NH:30][CH2:29][C:25]4[S:24][CH:28]=[CH:27][N:26]=4)[C:14]([C:19]([F:22])([F:21])[F:20])=[N:13]3)[NH:8][C:9](=[O:10])[C:4]=2[CH:3]=1
Reactant: Cc1cc2c(=O)[nH]c(Cn3cc(C=O)c(C(F)(F)F)n3)nc2s1
Reactant: NCc1nccs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1cc2c(=O)[nH]c(Cn3cc(CNCc4nccs4)c(C(F)(F)F)n3)nc2s1
Yield: 24.1 %

Procedure:
A mixture of 1-((6-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)methyl)-3-(trifluoromethyl)-1H-pyrazole-4-carbaldehyde (0.55 g, 1.62 mmol) and thiazol-2-ylmethanamine (925 mg, 8.10 mmol) in DCM (11 mL) was acidified to pH 5 with acetic acid (1 mL) before the addition of sodium triacetoxyborohydride (1.72 g, 8.10 mmol). The resultant mixture was stirred at RT overnight. The reaction mixture was quenched with MeOH, passed through an SCX column and eluted with 2M NH3 in MeOH. The sample was concentrated in vacuo. Purification by flash column chromatography-silica gel and elution with 3-5% MeOH:DCM (3 drops of DIPEA per litre), followed by a second flash column and elution with 3-4% MeOH:DCM (3 drops of DIPEA per litre) gave the title product as a white solid (172 mg, 0.391 mmol, 24%).
Reaction SMILES: [C:1]1([C:7]([OH:18])([C:9]#[C:10][CH:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)C)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=C(C2C=CC=CC=2C(OO)=[O:29])C=CC=1>ClCCl>[OH:18][C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH3:8])[C:9](=[O:29])[CH:10]=[CH:11][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CC(C#CC(C)(O)c1ccccc1)N1CCCC1
Reactant: O=C(OO)c1ccccc1-c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(O)(C(=O)C=CN1CCCC1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To an ice cold solution of 2-phenyl-5-(pyrrolidin-1-yl)-hex-3-yn-2-ol (0.49 g) in dichloromethane (5 ml) was added in small portions 3-chlorophenylperoxybenzoic acid (0.38 g) over a period of about 2 minutes. After the reaction was stirred at 0° C. for 5 minutes, the mixture was passed over 20 weight equivalents of basic alumina (Brockmann Grade I, 150 mesh) and eluted with 5% methanol in dichloromethane. All fractions containing the desired amine N-oxide were combined and evaporated to near dryness in vacuo. The resulting residue was dissolved in methanol (20 ml) and heated to reflux temperatures for 13 hours. The mixture was then cooled and the solvent removed in vacuo. The resulting residue consisted of 4-hydroxy-4-phenyl-1-pyrrolidin-1-yl-pent-1-en-3-one and 2,5-dimethyl-2-phenyl-furan-3-one, and was used directly and without further purification in the next step (Example 36).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:9]=[O:10])[CH:6]=[CH:7][CH:8]=1.BrCCCl.C(N(C(C)C)CC)(C)C.CNC.B(Br)(Br)Br>CN1CCCC1=O.CCOC(C)=O>[OH:2][C:3]1[CH:4]=[C:5]([CH:9]=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C=O)c1
Agent: BrB(Br)Br
Agent: CNC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCBr
Solvent: CCOC(C)=O
Product: O=Cc1cccc(O)c1
Reaction time: 0.5 h
Yield: 10.6 %

Procedure:
A portion of (trans,trans,trans,trans)-4-(3-fluoro-2-methylphenyl)-2,6-dimethylpiperidine-3,5-diyl)bis((3-methoxyphenyl)methanone (200 mg, 0.41 mmol), 1-bromo-2-chloroethane (0.1 mL, 0.6 mmol), and diisopropylethylamine (0.1 mL, 0.6 mmol) in N-methylpyrrolidone (1 mL) was heated to 150° C. in a microwave oven for 30 min. The mixture was diluted in EtOAc, washed with saturated NaHCO3, dried over Na2SO4, and evaporated to dryness. The residue was resuspended in dimethylamine solution (0.2 mL, 2 M in THF, 0.4 mmol) and NMP (1 mL), and heated to 120° C. for 30 min. The solution was diluted with EtOAc, washed with saturated NaHCO3, dried over Na2SO4, and concentrated under vacuum. This residue was redissolved in dichloromethane (10 mL) and treated with boron tribromide (2 mL, 1 M in dichloromethane, 2 mmol) at room temperature. After stirring 30 min, the reaction was quenched with methanol and the solvents removed under vacuum. Purification of the crude product by reverse phase chromatography (HPLC, C18) using acetonitrile and water with 0.1% TFA buffer gave pure desired (trans,trans,trans,trans)-1-(2-(dimethylamino)ethyl)-4-(3-fluoro-2-methylphenyl)-2,6-dimethylpiperidine-3,5-diyl)bis((3-hydroxyphenyl)methanone (5.3 mg, 2.4% yield) (characterized by LCMS and 1H NMR, LRMS (M+H+) m/z=533.2.