Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:10])(OC1C=CC=CC=1)[NH2:2].[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>CC#N.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:1]([NH2:2])=[O:10])[CH2:14][CH2:13]1
Reactant: NC(=O)Oc1ccccc1
Reactant: CN1CCNCC1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Product: CN1CCN(C(N)=O)CC1
Temperature: 80 °C
Yield: 67.9 %

Procedure:
To a solution of phenyl carbamate (20.0 g, 146 mmol) in MeCN (200 mL) was added N-methylpiperazine (20.00 g, 200 mmol) followed by catalytic amount of ytterbium triflate (0.500 g, 1.061 mmol) and the resulting mixture was heated at 80° C. for 1 h. The solvent from the reaction mixture was completely evaporated and the residue was crystallized from MTBE to provide 4-methylpiperazine-1-carboxamide (14.2 g, 68% yield) as white solid 1H NMR (400 MHz, DMSO-d6): δ 5.92 (s, 2H), 3.42 (t, J=4.9 Hz, 4H), 2.19 (t, J=4.9 Hz, 4H), 2.14 (s, 3H).
Reaction SMILES: C1O[CH:4]([C:5]2[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([N:12]([CH3:14])[CH3:13])[CH:6]=2)[O:3]C1.Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:13][N:12]([CH3:14])[C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[OH:11])[CH:4]=[O:3]
Reactant: CN(C)c1cc(C2OCCO2)ccc1O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)c1cc(C=O)ccc1O
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A solution of the compound (2) (1.20 g, 5.74 mmol) obtained above in tetrahydrofuran (25 ml) and 1N hydrochloric acid (15 ml) was stirred at 80° C. for 2 hours. After being cooled, the mixture was slowly poured into a saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solution was concentrated and used for the next reaction without purification.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([C:19]([O:21]C)=[O:20])=[C:12]3[CH2:17][CH2:16][CH:15]([CH3:18])[N:13]3[N:14]=2)=[CH:6][CH:5]=1>CO>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:11]([C:19]([OH:21])=[O:20])=[C:12]3[CH2:17][CH2:16][CH:15]([CH3:18])[N:13]3[N:14]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1c(-c2ccc(F)cc2)nn2c1CCC2C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1CCc2c(C(=O)O)c(-c3ccc(F)cc3)nn21
Reaction time: 3 h

Procedure:
36.8 ml (73.6 mmol) of a 2 M aqueous NaOH solution are added to a solution of 7.0 g (25.5 mmol) of methyl 2-(4-fluorophenyl)-6-methyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylate in 50 ml of methanol, and the mixture is stirred for 3 h. The reaction mixture is concentrated under reduced pressure, ethyl acetate/1 M hydrochloric acid is added, the organic phase is separated off and the aqueous phase is extracted with 3×100 ml of ethyl acetate. The combined organic phases are dried over Na2SO4 and freed from the solvent under reduced pressure. The 2-(4-fluorophenyl)-6-methyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylic acid obtained (5.9 g) is reacted further without further purification.
Reaction SMILES: CC[O-].[Na+].Cl.[C:6]([NH2:9])(=[NH:8])[CH3:7].[F:10][C:11]([F:27])([F:26])[C:12]([CH:14]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:15](OCC)=[O:16])=O.CCOCC.CCCCCC>CCO>[CH3:7][C:6]1[NH:9][C:15](=[O:16])[C:14]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:12]([C:11]([F:10])([F:27])[F:26])[N:8]=1
Reactant: CCOC(=O)CC(C(=O)OCC)C(=O)C(F)(F)F
Reactant: CC(=N)N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: CCO
Product: CCOC(=O)Cc1c(C(F)(F)F)nc(C)[nH]c1=O
Yield: 26.9 %

Procedure:
A mixture of NaOEt (0.074 mol) in EtOH (prepared from 1.7 g of Na and 75 mL of EtOH), acetamidine hydrochloride (3.5 g, 0.037 mol), and diethyl 2-trifluoroacetylsuccinate (10.0 g, 0.037 mol) was heated under reflux for 20 h. The mixture was concentrated, taken up in water, acidified to pH 4 with conc. HCl, and extracted with EtOAc. The extracts were washed with brine, dried (MgSO4), and concentrated to give an oily solid. Trituration with ether/hexane gave 2.63 g (27%) of product as a white solid. An analytical sample was recrystallized from ether/hexane, mp 108°-110° C.
Reaction SMILES: [C:1]1([CH:7]([CH3:11])[CH2:8][CH:9]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]([NH:16][OH:17])([CH3:15])([CH3:14])[CH3:13]>C1C=CC=CC=1>[C:12]([N+:16]([O-:17])=[CH:9][CH2:8][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:11])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(CC=O)c1ccccc1
Reactant: CC(C)(C)NO
Solvent: c1ccccc1
Product: CC(CC=[N+]([O-])C(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.8 %

Procedure:
To a mixture of 3-phenylbutyraldehyde (10.0 g, 67.5 mmol, 1.0 equiv) and benzene (150 ml) and silica gel (5 g) was added N-tert-butylhydroxylamine (7.22 g, 81.0 mmol, 1.2 equiv) and the mixture stirred at rt for 18 h. The mixture was filtered and the filtrate was concentrated under vacuum to give N-tert-butyl-C-(2-phenylpropyl)nitrone (13.74 g, 92.80%) as a light yellow oil. 1H NMR (CDCl3) δ 7.33–7.19 (m, 5H), 6.65 (t, 1H), 3.18–3.04 (m, 1H), 2.90–2.65 (m, 2H), 1.40 (s, 9H), 1.34–1.32 (d, 3H).
Reaction SMILES: [H-].[Li+].C(S)CC.[CH3:7][O:8][C:9]1[CH:26]=[C:25]([C:27]([O-:29])=[O:28])[CH:24]=[C:23]2[C:10]=1[C@H:11]1[C@H:20]([CH2:21][S:22]2(=[O:31])=[O:30])[C@:19]2([CH3:32])[C@H:14]([C:15]([CH3:34])([CH3:33])[CH2:16][CH2:17][CH2:18]2)[CH2:13][CH2:12]1>CN(P(N(C)C)(N(C)C)=O)C>[CH3:7][O:8][C:9]1[CH:26]=[C:25]([C:27]([OH:29])=[O:28])[CH:24]=[C:23]2[C:10]=1[C@H:11]1[C@H:20]([CH2:21][S:22]2(=[O:31])=[O:30])[C@:19]2([CH3:32])[C@H:14]([C:15]([CH3:34])([CH3:33])[CH2:16][CH2:17][CH2:18]2)[CH2:13][CH2:12]1
Reactant: COc1cc(C(=O)[O-])cc2c1[C@@H]1CC[C@H]3C(C)(C)CCC[C@]3(C)[C@H]1CS2(=O)=O
Agent: CCCS
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COc1cc(C(=O)O)cc2c1[C@@H]1CC[C@H]3C(C)(C)CCC[C@]3(C)[C@H]1CS2(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
A mixture of lithium hydride (0.66 g, 83 mmol) and n-propanethiol (8.7 mL, 99 mmol) in HMPA (20 mL) was stirred at room temperature for 30 min under N2. To the mixture (1R,10S,11S,16S)-3-methoxy-11,15,15-trimethyl-8,8-dioxo-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-5-carboxylate (59) (3.6 g, 8.3 mmol) in HMPA (10 mL) was added. The mixture was heated at 130° C. for 1 h. The mixture was cooled to room temperature and quenched with 1 M HCl, then extracted with EtOAc. The organic layer was concentrated to dryness. The residue was purified by flash chromatography on silica gel (CH2Cl2/MeOH, 10:1) to yield (1R,10S,11S,16S)-3-methoxy-11,15,15-trimethyl-8,8-dioxo-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-5-carboxylic acid (61) (3.2 g, 95% yield) as a white solid. 1H NMR (CD3OD): δ 7.91 (d, 1H), 7.54 (d, 1H), 3.59 (m, 1H), 3.38 (m, 2H), 2.24 (m, 1H), 1.86 (m, 8H), 1.36-1.16 (m, 3H), 1.09-1.03 (m, 2H), 1.02 (s, 3H), 0.89 (s, 3H), 0.87 (s, 3H). MS m/z 405 (C22H30NO5S−H+).
Reaction SMILES: [CH3:1][C:2]1[C:20]([N+:21]([O-])=O)=[CH:19][CH:18]=[C:17]([CH3:24])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2.O.NN.C(Cl)(Cl)Cl>CO>[NH2:21][C:20]1[C:2]([CH3:1])=[C:3]([C:17]([CH3:24])=[CH:18][CH:19]=1)[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2
Reactant: Cc1ccc2cccc(OCc3c(C)ccc([N+](=O)[O-])c3C)c2n1
Agent: NN
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1ccc2cccc(OCc3c(C)ccc(N)c3C)c2n1
Yield: 78.7 %

Procedure:
To a suspension of 8-(2,6-dimethyl-3-nitrobenzyloxy)-2-methylquinoline (2.34 g), ferric chloride (70.6 mg) and carbon (70.6 mg) in methanol (35 ml) was added hydrazine monohydrate (1.09 g) at 65° C., and the mixture was refluxed for 2 hours. Methanol (20 ml) was added thereto, and the mixture was refluxed for 1 hour. After cooling chloroform was added thereto, and the resulting precipitates were filtered off. The filtrate was concentrated and the residue was dissolved in chloroform. The solution was washed with saturated sodium bicarbonate solution, water and brine, dried over magnesium sulfate and concentrated. The residue was crystallized with ethyl acetate to give 8-(3-amino-2,6-dimethylbenzyloxy)-2-methylquinoline (1.67 g) as a pale brown crystal.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([O:15][CH2:16][C:17]([OH:19])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:22](CC)CC)C.ClC(OCC)=O.[OH-].[NH4+]>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([O:15][CH2:16][C:17](=[O:19])[NH2:22])[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](OCC(=O)O)CC1
Agent: CCOC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](OCC(N)=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of trans (4-tert-butoxycarbonylamino-cyclohexyloxy)-acetic acid (600 mg, 2.20 mmol) and triethylamine (400 μL, 2.90 mmol) in THF (22 mL) at 0° C. was treated dropwise with ethyl chloroformate (250 μL, 2.60 mmol). After 30 minutes ammonium hydroxide (2.20 mL, 170 mmol) was added dropwise. The golden solution was stirred at ambient temperature for 30 minutes and then concentrated under vacuum. The residue was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (2×). The combined organic extracts were washed with 1M HCl, a saturated sodium bicarbonate solution and brine, dried over sodium sulfate and concentrated under vacuum to afford 550 mg (92%) of trans (4-carbamoylmethoxy-cyclohexyl)-carbamic acid tert-butyl ester as a white solid. LCMS (Method Q, ESI): RT=2.82 min, m+H=295.0; 1H NMR (400 MHz, CDCl3) δ: 6.52 (s, 1H), 5.55 (s, 1H), 4.38 (s, 1H), 3.96 (s, 2H), 3.44 (s, 1H), 3.30 (m, 1H), 2.03 (d, 4H), 1.44 (s, 9H), 1.38 (m, 2H), 1.16 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12]Cl)[N:6]=[CH:5]2.[I-].[K+].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[N:6]=[CH:5]2
Reactant: ClCCn1ncc2cc(Br)ccc21
Reactant: C1COCCN1
Agent: [I-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Brc1ccc2c(cnn2CCN2CCOCC2)c1
Temperature: 70 °C
Yield: 91.7 %

Procedure:
A mixture of 5-bromo-1-(2-chloroethyl)-1H-indazole (500 mg, 1.93 mmol), potassium iodide (1.28 mg, 7.71 mmol) and morpholine (1.0 mL, 12 mmol) in NMP (3 mL) in a sealed vial was heated at 70° C. overnight. Preparative HPLC (100×30 mm Luna C18 column, Solvent A=10% Methanol, 90% H2O, 0.1% TFA; Solvent B=90% Methanol, 10% H2O, 0.1% TFA, elution gradient of 0 to 60% B over 20 min at 42 mL/min) afforded 4-(2-(5-bromo-1H-indazol-1-yl)ethyl)morpholine (549 mg, 1.77 mmol, 92% yield) as a solid. MS (ESI) m/z 311.98 (M+H). 1H NMR (500 MHz, chloroform-d) δ ppm 7.89 (1H, s), 7.81 (1H, s), 7.38-7.42 (1H, m), 7.29 (1H, d, J=8.85 Hz), 4.44 (2H, t, J=6.87 Hz), 3.58-3.63 (4H, m), 2.82 (2H, t, J=6.87 Hz), 2.41-2.48 (4H, m).
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4]1.[NH2:9][C:10]1[C:15](Br)=[N:14][C:13]([Br:17])=[CH:12][N:11]=1.O>O1CCCC1>[Br:17][C:13]1[N:14]=[C:15]([O:8][CH2:7][CH:3]2[CH2:6][CH2:5][CH2:4]2)[C:10]([NH2:9])=[N:11][CH:12]=1
Reactant: OCC1CCC1
Reactant: Nc1ncc(Br)nc1Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1ncc(Br)nc1OCC1CCC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 100 %

Procedure:
Sodium hydride (0.96 g, 23.7 mmol) was added in portions to a solution of cyclobutanemethanol (2.2 mL, 23.7 mmol) in tetrahydrofuran (30 mL) at 0° C., the reaction mixture was stirred at room temperature for 45 minutes. A solution of 2-amino-3,5-dibromopyrazine (3.0 g, 11.9 mmol) in tetrahydrofuran (10 mL) was added and the reaction mixture was heated at 50° C. for 16 hours. The reaction mixture was cooled to room temperature and water (2 mL) was added, the whole was then concentrated in vacuo to give a brown oil. The crude product was purified by flash column chromatography (100% dichloromethane) to give 5-bromo-3-cyclobutylmethoxy-pyrazin-2-ylamine as a pale yellow solid, 3.19 g (100% yield). LC@215 nm; Rt 2.11: 93%, m/z (ES+): 259 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[NH2:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][C:46]=1[NH:47][CH2:48][CH2:49][CH3:50])[C:42]#[N:43]>C(Cl)(Cl)Cl>[C:42]([C:41]1[CH:44]=[CH:45][C:46]([NH:47][CH2:48][CH2:49][CH3:50])=[C:39]([NH:38][C:13]([CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:15])[CH:40]=1)#[N:43]
Reactant: CCCNc1ccc(C#N)cc1N
Reactant: CC(C)(C)OC(=O)NCCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Product: CCCNc1ccc(C#N)cc1NC(=O)CCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In chloroform (5.0 ml), 5-t-butoxycarbonylaminovaleric acid (387 mg), WSCI hydrochloride (466 mg), and HOBt (328.3 mg) were dissolved. Then, the solution was stirred at room temperature for 1 hour. A solution (3.0 ml) of 3-amino-4-propylaminobenzonitrile (283 mg) in chloroform was dropped in this solution. Then, the solution was stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was dissolved in chloroform and then washed with a saturated aqueous sodium bicarbonate solution, a saturated aqueous ammonium chloride solution, and saturated saline solution, followed by drying with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue was then purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound as a colorless viscous substance.
Reaction SMILES: [F:1][C:2]([F:40])([CH2:36][CH2:37][CH2:38][CH3:39])[C:3](=[O:35])[CH2:4][CH2:5][C@H:6]1[C@H:10]([O:11]C2CCCCO2)[CH2:9][C:8](=[O:18])[C@@H:7]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].[Cl-].[Na+]>C(#N)C.O.P(=O)(O)(O)O>[F:1][C:2]([C@:3]1([OH:35])[O:11][C@@H:10]2[CH2:9][C:8](=[O:18])[C@H:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[C@H:6]2[CH2:5][CH2:4]1)([F:40])[CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCC(F)(F)C(=O)CC[C@H]1[C@H](OC2CCCCO2)CC(=O)[C@@H]1CCCCCCC(=O)OCc1ccccc1
Agent: O=P(O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCCCC(F)(F)[C@@]1(O)CC[C@H]2[C@@H](CC(=O)[C@@H]2CCCCCCC(=O)OCc2ccccc2)O1
Temperature: 20 °C
Reaction time: 3 h
Yield: 87.7 %

Procedure:
To a solution of benzyl 7-[(1R,2R,3R)-2-(4,4-difluoro-3-oxooctyl)-5-oxo-3-(2-tetrahydropyranyloxy) cyclopentyl]heptanate (19) (70.49 g, 124.8 mmol) in acetonitrile (705 ml), water (70.5 ml) and 85% phosphoric acid (70.5 ml) were added and the mixture was stirred for 3 hours at approximately 20° C. The solution was supplemented with 10% aqueous sodium chloride (705 ml), and extracted three times with ethyl acetate (276 ml). The organic layers were combined and sequentially washed with 10% aqueous sodium chloride (360 ml), saturated sodium bicarbonate water (360 ml) and saturated aqueous sodium chloride (360 ml). The solution was dried with anhydrous magnesium sulfate (51 g) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji Silysia BW-300: 2100 g; ethyl acetate:hexane=1:4). The fractions containing impurities were re-purified by silica gel column chromatography (Fuji Silysia BW-300 1000 g, ethyl acetate:hexane=1:4) to give benzyl 7-[(2R,4aR,5R,7aR)-2-(1,1-difluoropentyl)-2-hydroxy-6-oxooctahydro cyclopenta[b]pyran-5-yl]heptanate (20) (52.64 g; 109.5 mmol; yield: 87.8%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([S:11]([CH2:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25]C)[C:17]([CH3:28])([CH3:27])[CH:16]=2)(=[O:13])=[O:12])[CH2:7][CH2:6]1)=[O:4].CN1C2C(=CC=[C:37]([O:40]C)C=2)C(CS(Cl)(=O)=O)CC1(C)C.COC(C1CCNCC1)=O.C(Cl)(Cl)Cl>C(#N)C.C(O)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([S:11]([CH2:14][CH:15]2[C:24]3[C:19](=[CH:20][C:21]([O:40][CH3:37])=[CH:22][CH:23]=3)[N:18]([CH3:25])[C:17]([CH3:27])([CH3:28])[CH2:16]2)(=[O:12])=[O:13])[CH2:7][CH2:6]1)=[O:4]
Reactant: CCN1c2ccccc2C(CS(=O)(=O)N2CCC(C(=O)OC)CC2)=CC1(C)C
Reactant: COc1ccc2c(c1)N(C)C(C)(C)CC2CS(=O)(=O)Cl
Agent: COC(=O)C1CCNCC1
Solvent: ClC(Cl)Cl
Solvent: CC#N
Solvent: CCO
Product: COC(=O)C1CCN(S(=O)(=O)CC2CC(C)(C)N(C)c3cc(OC)ccc32)CC1
Yield: 69 %

Procedure:
(1-Methyl-7-methoxy-2,2-dimethyl-1,2,3,4-tetrahydroquinol-4-yl-methane-sulfonyl)-piperidine-4-carboxylic acid methyl ester (20) is prepared similarly to compound (10) from compound (19) and 4-piperidinecarboxylic acid methyl ester in dry acetonitrile. It is isolated by column chromatography on silica gel using a gradient running from chloroform to ethanol.
Reaction SMILES: [C:1]([C:4]1[C:9]2[NH:10][C:11](=[O:13])[O:12][C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CI.[K].[CH3:17]C(C)([O-])C>CN(C)C=O>[C:1]([C:4]1[C:9]2[N:10]([CH3:17])[C:11](=[O:13])[O:12][C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cccc2oc(=O)[nH]c12
Reactant: CC(C)(C)[O-]
Agent: [K]
Solvent: CI
Solvent: CN(C)C=O
Product: CC(=O)c1cccc2oc(=O)n(C)c12

Procedure:
Prepared by reacting 4-acetyl-3H-benzoxazol-2-one with methyl iodide in the presence of potassium-tert.-butoxide in N,N-dimethylformamide at ambient temperature.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH2:9])[CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:22][O:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[C:34]1[C:43]2[C:38](=[CH:39][C:40]([S:44](OC3C(F)=C(F)C(F)=C(F)C=3F)(=[O:46])=[O:45])=[CH:41][CH:42]=2)[CH:37]=[CH:36][N:35]=1>C1COCC1>[CH3:22][O:23][C:24]1[CH:29]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:27]=[CH:26][C:25]=1[C:34]1[C:43]2[C:38](=[CH:39][C:40]([S:44]([NH:9][C:5]3[CH:4]=[C:3]([C:2]([F:1])([F:10])[F:11])[N:8]=[CH:7][N:6]=3)(=[O:46])=[O:45])=[CH:41][CH:42]=2)[CH:37]=[CH:36][N:35]=1
Reactant: Nc1cc(C(F)(F)F)ncn1
Reactant: COc1cc(C(F)(F)F)ccc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(C(F)(F)F)ccc1-c1nccc2cc(S(=O)(=O)Nc3cc(C(F)(F)F)ncn3)ccc12
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 15.4 %

Procedure:
A round-bottom flask was charged with 6-(trifluoromethyl)pyrimidin-4-amine (0.030 g, 0.182 mmol)) and THF (0.910 ml), and the vessel was cooled to −78° C. for 15 minutes. Lithium bis(trimethylsilyl)amide (0.218 ml, 0.218 mmol),) was then added drop wise over 1 minute. The reaction was stirred for 10 minutes, and then a solution of perfluorophenyl 1-(2-methoxy-4-(trifluoromethyl)phenyl)isoquinoline-6-sulfonate (Intermediate LLL; 0.100 g, 0.182 mmol) in THF (1.6 mL) was added drop wise. The bath was removed, and the resulting mixture was stirred for 45 minutes. The reaction was diluted with saturated ammonium chloride (aq.) solution (30 mL), and was washed with ethyl acetate (20 mL×3). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated. The resulting material was purified via silica gel chromatography (ISCO, 40 g), eluting with 0 to 100% ethyl acetate in heptanes. The fractions were concentrated under reduced pressure to yield 1-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(6-(trifluoromethyl)pyrimidin-4-yl)isoquinoline-6-sulfonamide (0.015 g, 0.028 mmol, 15.60% yield). m/z (ESI) 528.9 (M+H)+.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[Br:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][C:36](Br)=[CH:35][CH:34]=2)=[CH:29][CH:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:17]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:19][C:14]([N:13]([C:36]2[CH:35]=[CH:34][C:33]([C:30]3[CH:29]=[CH:28][C:27]([Br:26])=[CH:32][CH:31]=3)=[CH:38][CH:37]=2)[C:10]2[CH:11]=[CH:12][C:7]([C:4]3[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=3)=[CH:8][CH:9]=2)=[CH:15][CH:16]=1
Reactant: Brc1ccc(-c2ccc(Br)cc2)cc1
Reactant: c1ccc(-c2ccc(Nc3ccc(-c4ccccc4)cc3)cc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: Brc1ccc(-c2ccc(N(c3ccc(-c4ccccc4)cc3)c3ccc(-c4ccccc4)cc3)cc2)cc1
Reaction time: 0.25 h

Procedure:
4,4′-Iminobis(biphenyl) (2.0 g, 6.23 mmol), and 4,4′-dibromobiphenyl (3.9 g, 12.6 mmol) were mixed in 150 mL of anhydrous toluene. To the solution was bubbled nitrogen while stirring for 15 min. Pd(OAc)2 (0.02 g, 0.089 mmol), triphenylphosphine (0.09 g, 0.34 mmol) and tBuONa (1.15 g, 11.9 mmol) were added in sequence. The mixture was heated to reflux overnight under nitrogen. After cooling, the reaction mixture was filtered through Celite pad and the solvent was then evaporated. The residue (3.1 g, 90%) was recrystallized by toluene and the crystal was further purified by boiling with 15 ml degassed toluene, 2.7 g (78%) of the desired compound was collected.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.C([O:11][C:12](=O)[CH2:13][C:14]([CH3:31])([C:16]1[N:17]=[C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[S:19][CH:20]=1)[CH3:15])C>CN(C=O)C>[CH3:31][C:14]([C:16]1[N:17]=[C:18]([C:21]2[CH:22]=[CH:23][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:25][CH:26]=2)[S:19][CH:20]=1)([CH3:15])[CH2:13][C:12]([N:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)=[O:11]
Reactant: C1CCNCC1
Reactant: CCOC(=O)CC(C)(C)c1csc(-c2ccc(C(F)(F)F)cc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(CC(=O)N1CCCCC1)c1csc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
27.5 mg (0.63 mmol) of sodium hydride (55% in mineral oil) were added to 53.6 mg (0.63 mmol) of piperidine in 2 ml of DMF. After stirring at room temperature for 30 min, 150 mg (0.42 mmol) of 3-methyl-3-[2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-butyric acid ethyl ester in 2 ml of DMF were added, and the reaction mixture was stirred at room temperature for 2 h. After evaporation, water and dichloromethane were added, the organic phase was separated, washed with water, dried, and evaporated. The product was purified by RP18 chromatography. Yield: 6.3 mg.
Reaction SMILES: C(N[C:4]1[S:5][CH:6]=[C:7]([C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:8]=1)=O.C(OCC)(=O)C.[Br-:22].[K+].N([O-])=O.[Na+]>C(O)C.O1CCOCC1.S(=O)(=O)(O)O.O>[Br:22][C:4]1[S:5][CH:6]=[C:7]([C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:8]=1
Reactant: [Br-]
Reactant: CCOC(=O)C(=O)c1csc(NC=O)n1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(=O)c1csc(Br)n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 52.1 %

Procedure:
Commercially available ethyl (2-formamido-1,3-thiazol-4-yl)(oxo)acetate (5.09 g, 22.3 mmol) was dissolved in a mixed solvent of ethanol (50 mL) and 1,4-dioxane, and 30% sulfuric acid (12 mL) was added, followed by stirring at 60° C. for 1 hour. The reaction solution was cooled to room temperature, water (20 mL) and ethyl acetate (20 mL) were added, and the solution was separated. The solvent was distilled off under reduced pressure, and 30% sulfuric acid (40 mL) and potassium bromide (9.3 g, 78.2 mmol) were added, followed by cooling to 0° C. Sodium nitrite (20.0 g, 290 mmol) was dissolved in water (40 mL), followed by dropwise addition over 1 hour, and stirring was further carried out at 0° C. for 1 hour. The solution was separated with ethyl acetate (200 mL), the organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=0%-20%) to afford the desired compound (3.07 g, yield 52%) as a yellow oil.