Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:13][NH:14][C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:16]=2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].C(=O)(O)[O-].[Na+]>CN(C=O)C>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][N:14]([CH2:13][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1)[C:15]1[O:19][N:18]=[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=1)[CH3:32]
Reactant: CCOC(=O)CBr
Reactant: c1ccc(-c2cc(NCc3cccc4ccccc34)on2)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(Cc1cccc2ccccc12)c1cc(-c2ccccc2)no1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
Charged flask with a 60% sodium hydride in oil dispersion (64.0 mg, 1.6 mmol) and suspended in DMF (1 ml). A DMF (1 ml) solution of naphthalen-1-ylmethyl-(3-phenylisoxazol-5-yl)-amine (300 mg, 1.0 mmol ) was added and the mixture stirred under argon at rt for 30 min resulting in a light yellow solution. After adding ethyl bromoacetate (333 μl, 3.0 mmol), the reaction was stirred at rt for 1 hr, poured into 10% sodium bicarbonate (aq) and extracted with ethyl acetate (3×). The extracts were combined, washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give a crude oil (370 mg). Flash chromatography on silica gel (15% ethyl acetate in hexane) gave the title compound as a colorless oil (306 mg, 73.9%).
Reaction SMILES: [OH:1]O.[CH3:3][N:4]1[C@@H:20]2[CH2:21][C:9]3[CH:10]=[CH:11][C:12]([O:24][CH3:25])=[C:13]4[O:14][C@H:15]5[C:16]([O:22]C)=[CH:17][CH:18]=[C:19]2[C@:7]5([C:8]=34)[CH2:6][CH2:5]1.[NH4+].[OH-]>C(O)=O.OS(O)(=O)=O.O>[CH3:3][N:4]1[C@@H:20]2[CH2:21][C:9]3[CH:10]=[CH:11][C:12]([O:24][CH3:25])=[C:13]4[O:14][CH:15]5[C:16]([CH:17]=[CH:18][C@:19]2([OH:1])[C@:7]5([C:8]=34)[CH2:6][CH2:5]1)=[O:22]
Reactant: COC1=CC=C2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Reactant: OO
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O=CO
Solvent: O
Product: COc1ccc2c3c1OC1C(=O)C=C[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Temperature: 40 °C
Yield: 86 %

Procedure:
Hydrogen peroxide (30%, 1.3 mL, 13 mmol) is added to a solution of thebaine O-1 (3.11 g, 10 mmol) in a mixture of formic acid (88%, 1.3 mL) and H2SO4 (0.7%, 4.1 mL). The mixture is heated at 40° C. (bath temperature) for 6.5 h, cooled, diluted with water (10 mL), and made basic with concentrated NH4OH. The precipitate is filtered, washed with H2O and dried (MgSO4). The product is recrystallized from EtOH—CHCl3 to yield O-5 (2.70 g, expected yield 86%). See Iijima, I.; Minamikawa, J.; Jacobson, A. E.; Brossi, A.; Rice, K. C.; J. Med. Chem. (1978) 21, 398.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.CCN(CC)CC.[O:16]=[C:17]([C:24]1[O:25][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[CH:27][N:28]=1)[CH2:18][CH2:19][CH2:20][CH2:21][C:22]#[CH:23]>C1COCC1.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.[Cu]I>[O:16]=[C:17]([C:24]1[O:25][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[CH:27][N:28]=1)[CH2:18][CH2:19][CH2:20][CH2:21][C:22]#[C:23][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: C#CCCCCC(=O)c1ncc(-c2ccccn2)o1
Reactant: Clc1cccc(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CCCCC#Cc1cccc(Cl)c1)c1ncc(-c2ccccn2)o1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 1-chloro-3-iodobenzene (49 mg, 0.205 mmol) in anhydrous THF (0.5 mL) was treated with PdCl2(PPh3)2 (7 mg, 0.01 mmol). After stirring for 5 min at 25° C., Et3N (0.2 mL, 0.603 mmol) and CuI (10 mg, 0.053 mmol) were added. The suspension was stirred for 35 min and 1-oxo-1-[5-(2-pyridyl)oxazol-2-yl]-hept-6-yne (3b, 30 mg, 0.067 mmol) was added. After stirring for 14 h at 25° C., the reaction mixture was filtered through Celite and concentrated. PTLC (SiO2, 50% EtOAc-hexanes) afforded 1-oxo-1-[5-(2-pyridyl)oxazol-2-yl]-7-(3-chlorophenyl)hept-6-yne (4hh, 24 mg, 0.066 mmol, 56%) as a yellow solid: mp 50-51° C.; 1H NMR (CDCl3, 500 MHz) δ 8.68-8.66 (m, 1H), 7.89-7.86 (m, 2H), 7.82 (td, 1H, J=7.7, 1.8 Hz), 7.38 (m, 1H), 7.34-7.31 (m, 1H), 7.27-7.18 (m, 3H), 3.20 (t, 2H, J=7.4 Hz), 2.49 (t 2H, J=7.0 Hz), 2.00-1.95 (m, 2H), 1.77-1.71 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 187.9, 157.2, 153.3, 150.1, 146.2, 137.1, 133.9, 131.4, 129.6, 129.3, 127.8, 126.8, 125.5, 124.1, 120.3, 90.9, 79.8, 38.5, 27.8, 23.1, 19.1; IR (film) νmax 3061, 2932, 2865, 2230, 1703, 1592, 1575, 1558, 1505, 1471, 1426, 1385, 1283, 1243, 1152, 1081, 1065, 1023, 990, 962, 930, 880, 784, 740, 683 cm−1; ESI-TOF m/z 365.1058 (C21H17ClN2O4+H+ requires 365.1051).
Reaction SMILES: [NH3:1].[CH3:2][C:3]([CH3:5])=[O:4]>>[OH:4][CH:3]([CH2:5][NH2:1])[CH2:2][O:4][C:3]1[CH:5]=[CH:5][C:3]([O:4][CH2:2][CH:3]([OH:4])[CH2:5][NH2:1])=[CH:2][CH:2]=1
Reactant: N
Reactant: CC(C)=O
Product: NCC(O)COc1ccc(OCC(O)CN)cc1

Procedure:
Japanese Pat. No. 026,341 concerns the reaction of epoxides with aqueous ammonia in acetone solution, to give 1,4-bis-(2-hydroxy-3-aminopropoxy)-benzene, of melting point 128°-132° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Br[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:25]>C(OCC)(=O)C>[CH2:23]([O:12][C:11](=[O:13])[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH3:14])[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:25]
Reactant: O=C(CBr)c1ccccc1
Reactant: CN(CCC(=O)O)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CN(CCC(=O)OCC(=O)c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 88.6 %

Procedure:
To a mixture of N-t-butoxycarbonyl-N-methyl-β-alanine (6.097 g) and triethylamine (4.18 ml) in ethyl acetate (60 ml) was added 2-bromoacetophenone (5.972 g) portionwise at 0°-5° C. After being stirred over night at ambient temperature, the solvent was evaporated and the resulting residue was dissolved in ethyl acetate (200 ml). The solution was washed with 0.5N hydrochloric acid (200 ml), water (200 ml) aqueous sodium bicarbonate (200 ml), water (200 ml) and brine (200 ml) successively, and dried over magnesium sulfate. Evaporation of the solvent gave N-t-butoxycarbonyl-N-methyl-β-alanine phenacyl ester (8.54 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:11]CC(OC)=O)=[N:9][CH:10]=1.Br.C(=O)(O)[O-].[Na+]>>[Cl:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8](=[O:11])[NH:9][CH:10]=1
Reactant: COC(=O)COc1ccc(Oc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2Cl)cn1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccc(=O)[nH]c3)c(Cl)cc2F)c1=O
Yield: 87.5 %

Procedure:
A mixture of 0.08 g of 5-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(methoxycarbonyl)methoxypyridine [present compound 7-17] and 1 ml of 48% hydrobromic acid was stirred at reflux temperature for 3 hours. The mixture was neutralized with saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated to obtain 0.06 g of 5-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-pyridone.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)[CH:5]=[C:4]([C:23]2[C:28]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)=[CH:27][CH:26]=[CH:25][C:24]=2[NH2:39])[N:3]=1.C(N(CC)CC)C.[C:47](OC(=O)C)(=[O:49])[CH3:48]>ClCCl>[C:47]([NH:39][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)[C:23]=1[C:4]1[N:3]=[C:2]([NH2:1])[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)[CH:5]=1)(=[O:49])[CH3:48]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(COc2cccc(N)c2-c2cc(C3CCCN(C(=O)OC(C)(C)C)C3)c(C#N)c(N)n2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(COc2cccc(NC(C)=O)c2-c2cc(C3CCCN(C(=O)OC(C)(C)C)C3)c(C#N)c(N)n2)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 94.4 %

Procedure:
To a cooled (0° C.), stirred solution of tert-butyl 3-(2-amino-6-{2-amino-6-[(4-methoxybenzyl)oxy]phenyl}-3-cyano-4-pyridinyl)-1-piperidinecarboxylate (0.10 g, 0.189 mmol) obtained in the step (1) of Example 1-11 in dichloromethane (10 mL) including triethylamine (0.02 g, 0.227 mmol) was added acetic anhydride (0.08 g, 0.889 mmol). The stirring was continued at 0° C. for 5 hrs. The mixture was allowed to warm to room temperature, and the stirring was continued for 30 min. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with brine and dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1-1/1-1/2) to give tert-butyl 3-(6-{2-(acetylamino)-6-[(4-methoxybenzyl)oxy]phenyl}-2-amino-3-cyano-4-pyridinyl)-1-piperidinecarboxylate as a pale yellow oil (0.102 g, yield; 94.5%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:38])[CH2:9][N:10]2[C:15](=[O:16])[C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[C:25]([C:30]#[N:31])=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:20][CH:19]=3)=[C:13]([CH2:32][CH2:33][CH3:34])[N:12]3[N:35]=[CH:36][N:37]=[C:11]23)=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:38])[CH2:9][N:10]2[C:15](=[O:16])[C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[C:25]([C:30]#[N:31])=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:20][CH:19]=3)=[C:13]([CH2:32][CH2:33][CH3:34])[N:12]3[N:35]=[CH:36][N:37]=[C:11]23)=[CH:4][CH:3]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(=O)c2ccc(F)cc2)c2ncnn12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(O)c2ccc(F)cc2)c2ncnn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
To a solution (15 mL) of 4′-({4-[2-(4-fluorophenyl)-2-oxoethyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.78 g) in methanol was added sodium borohydride (0.12 g), and the mixture was stirred at room temperature for 1 hr. After evaporation of the solvent under reduced pressure, the residue was extracted with water and ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.78 g, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:4]=1[CH2:5][NH:6][CH2:7][CH:8](OC)OC.[CH:19](=O)[C:20]1[CH:29]=[CH:28][C:25]([O:26][CH3:27])=[C:22]([O:23][CH3:24])[CH:21]=1.[ClH:31]>>[ClH:31].[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:3]([O:2][CH3:1])=[C:4]2[C:13]=1[C:8]1[CH2:19][C:20]3[CH:29]=[CH:28][C:25]([O:26][CH3:27])=[C:22]([O:23][CH3:24])[C:21]=3[C:7]=1[N:6]=[CH:5]2
Reactant: COc1ccc(C=O)cc1OC
Reactant: COc1ccc(OC)c(CNCC(OC)OC)c1
Agent: Cl
Product: COc1ccc2c(c1OC)-c1ncc3c(OC)ccc(OC)c3c1C2
Yield: 24 %

Procedure:
Amine 12d (2.82 g, 11.1 mmol) and veratraldehyde (10a, 4.00 g, 0.030 mol) were reacted in concentrated hydrochloric acid as described previously for compound 9aa. The product was isolated as a yellow-orange hygroscopic solid (1.01 g, 24%), mp 242-244° C. 1H NMR (300 MHz, TFA) δ 9.52 (s, 1H), 7.75 (s, 1H), 7.43 (d, J=7.8 Hz, 1H), 7.38 (s, 1H), 7.08 (d, J=8.7 Hz, 1H), 4.56 (s, 2H), 4.10 (s, 3H), 4.09 (s, 3H), 4.04 (s, 6H). Anal. (C20H20NO4Cl.1.7H2O)C, H, N, Anal. Calcd for C20H20NO4Cl(H2O)1.7: C, 59.39; H, 5.83; N, 3.46. Found: C, 59.22; H, 5.53; N, 3.72.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1.[C:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O)(=[O:21])[CH3:20]>>[N:11]12[CH2:17][CH:15]3[CH2:14][CH:13]([CH2:18][CH:9]([N:8]([C:4]4[CH:3]=[C:2]([C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[C:19](=[O:21])[CH3:20])[CH:7]=[N:6][CH:5]=4)[CH2:16]3)[CH2:10]1)[CH2:12]2
Reactant: Brc1cncc(N2CC3CC4CC2CN(C4)C3)c1
Reactant: CC(=O)c1ccccc1B(O)O
Product: CC(=O)c1ccccc1-c1cncc(N2CC3CC4CC2CN(C4)C3)c1

Procedure:
The title compound was prepared from the product of Example 65A and 2-acetylphenylboronic acid according to General Method B: LC-MS Method D (ESI+) m/z 348.0 (M+H)+, retention time 1.26 minutes.
Reaction SMILES: [I:1]NC(=O)CCC(N)=O.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH2:20][CH2:21][NH2:22])[CH:15]=[CH:16][C:17]=1[O:18][CH3:19].FC(F)(F)C(O)=O>C(#N)C>[I:1][C:15]1[CH:16]=[C:17]([O:18][CH3:19])[C:12]([O:11][CH3:10])=[CH:13][C:14]=1[CH2:20][CH2:21][NH2:22]
Reactant: NC(=O)CCC(=O)NI
Reactant: COc1ccc(CCN)cc1OC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COc1cc(I)c(CCN)cc1OC
Yield: 70 %

Procedure:
To a solution of N-iodosuccinamide (NIS) (4.95 g, 22 mmol) in dry acetonitrile (50 mL) was added 2-(3,4-dimethoxyphenyl)ethanamine (3.32 mL, 20 mmol) and trifluoroacetic acid (3.85 mL, 50 mmol) with stirring. The mixture was stirred at room temperature in a 250 mL round bottom flask for two hours. The acetonitrile was removed and the remaining solid was taken up in water. The water solution was treated with saturated sodium bisulfite aqueous solution until the purple color disappeared. The pH was adjusted to 8 and the aqueous solution was extracted with dichloromethane (3×50 mL) The organic layers were combined and dried over sodium sulfate. The solvent was evaporated to yield 2-(2-iodo-4,5-dimethoxyphenyl)ethanamine (4.3 g, 70%). The crude product was dried under dynamic vacuum overnight and was sufficiently pure for subsequent steps.
Reaction SMILES: [C:1]([C:3]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][O:7][CH:8]2[CH2:14][N:15]1[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]1)#[N:2].[ClH:28].O1CCOCC1>C(Cl)Cl>[ClH:28].[F:13][C:12]1[CH:11]=[CH:10][C:9]2[CH:8]([CH2:14][N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[O:7][CH2:6][CH2:5][C:4]=2[C:3]=1[C:1]#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCN(CC2OCCc3c2ccc(F)c3C#N)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: N#Cc1c(F)ccc2c1CCOC2CN1CCNCC1
Reaction time: 2 h

Procedure:
A solution of tert-butyl 4-[(5-cyano-6-fluoro-3,4-dihydro-1H-isochromen-1-yl)methyl]piperazine-1-carboxylate (110 mg, 0.29 mmol) in 10 mL of DCM was added 3 mL of 4N HCl/dioxane, then sirred at room temperature for 2 hours. The solvents was removed off under vacuum to afford 6-fluoro-1-(piperazin-1-ylmethyl)-3,4-dihydro-1H-isochromene-5-carbonitrile hydrochloride. 1H-NMR (400 MHz, MeOD) δ ppm 7.63˜7.66 (m, 1H), 7.25˜7.29 (m, 1H), 5.33˜5.30 (m, 1H), 4.25˜4.30 (in, 1H), 3.87˜3.97 (m, 2H), 3.72˜3.83 (m, 3H), 3.58˜3.68 (m, 6H), 3.07˜3.17 (m, 2H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[S:23][N:22]=[C:21]([N:24]4[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]4)[N:20]=3)[CH2:15][CH2:14]2)=[O:12])=[N:2]1.[ClH:37]>O1CCCC1.CO.C(OCC)(=O)C>[ClH:37].[ClH:37].[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][C:11]([N:13]2[CH2:14][CH2:15][N:16]([C:19]3[S:23][N:22]=[C:21]([N:24]4[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]4)[N:20]=3)[CH2:17][CH2:18]2)=[O:12])=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nsc(N3CCN(C(=O)Nc4noc5ccccc45)CC3)n2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(Nc1noc2ccccc12)N1CCN(c2nc(N3CCNCC3)ns2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 65.6 %

Procedure:
To a solution of tert-butyl 4-(5-{4-[(1,2-benzisoxazol-3-ylamino)carbonyl]piperazin-1-yl}-1,2,4-thiadiazol-3-yl)piperazine-1-carboxylate (87.0 mg, 0.169 mmol) in tetrahydrofuran (5 ml) and methanol (3 ml) was added a solution of 4 N hydrogen chloride in ethyl acetate (8 ml), and the mixture was stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of methanol and diethyl ether to give 50.0 mg (65.6%) of the desired product.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15](CC3C=CC(OC)=CC=3OC)[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.ClC1C=C(C(F)(F)F)C=CC=1C1C=CC=C2C=1C=CC(S(NC1C=CN=CN=1)(=O)=O)=C2.C(C1C=C(C(F)(F)F)C=C[C:66]=1[C:75]1[C:84]2[C:79](=[CH:80][C:81](S(N(CC3C=CC(OC)=CC=3OC)C3SC=CN=3)(=O)=O)=[CH:82][CH:83]=2)[CH:78]=[CH:77][N:76]=1)#N>>[C:84]1([CH:75]2[CH2:66][CH2:78][CH2:77][N:76]2[C:2]2[C:11]3[C:6](=[CH:7][C:8]([S:12]([NH:15][C:16]4[S:17][CH:18]=[CH:19][N:20]=4)(=[O:13])=[O:14])=[CH:9][CH:10]=3)[CH:5]=[CH:4][N:3]=2)[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)c(OC)c1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4C#N)nccc3c2)c(OC)c1
Agent: O=S(=O)(Nc1ccncn1)c1ccc2c(-c3ccc(C(F)(F)F)cc3Cl)cccc2c1
Product: O=S(=O)(Nc1nccs1)c1ccc2c(N3CCCC3c3ccccc3)nccc2c1

Procedure:
Example 237 was synthesized in a similar manner to Example 236, except that 1-chloro-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Intermediate OOO) was used instead of 1-chloro-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide (Intermediate X). Isolated 1-(2-cyano-4-(trifluoromethyl)phenyl)-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm=12.87 (br. s., 1H), 8.51 (br. s., 1H), 8.29 (br. s., 1H), 7.84 (br. s., 1H), 7.78 (d, J=9.1 Hz, 1H), 7.36 (d, J=7.4 Hz, 3H), 7.32-7.22 (m, 2H), 7.18 (d, J=5.9 Hz, 1H), 6.87 (d, J=4.4 Hz, 1H), 5.59 (br. s., 1H), 4.36 (br. s., 1H), 3.92 (br. s., 1H), 2.02 (br. s., 2H), 1.90 (br. s., 2H). m/z (ESI) 437.2 (M+H)+.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:27]=[CH:28][C:29]=2[O:30][CH3:31])[N:10]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([OH:26])=O)[CH:19]=2)[CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(OC1C=CC2C(=CC=CC=2)[N:36]1C(OCC)=O)C>CN(C=O)C.[OH-].[NH4+]>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:27]=[CH:28][C:29]=2[O:30][CH3:31])[N:10]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([NH2:36])=[O:26])[CH:19]=2)[CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)N1c2ccccc2C=CC1OCC
Reactant: COc1ccc(N(Cc2cccnc2)c2cccc(C(=O)O)c2)cc1OC1CCCC1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1ccc(N(Cc2cccnc2)c2cccc(C(N)=O)c2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.7 %

Procedure:
To a solution of 3-cyclopentyloxy-4-methoxy-N-(3-carboxyphenyl)-N-(3-pyridylmethyl)aniline (50 mg, 0.125 mmol) in 1 mL of DMF at room temperature was added 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ) (50 mg, 0.20 mmol). The mixture was warmed slightly until everything was in solution, then cooled to room temperature and stirred for 1 h. 5 drops of ammonium hydroxide (28-30%) was added and the mixture was stirred for an additional hour. The mixture was partitioned between water (25 mL) and EtOAc (25 mL). The EtOAc fraction was separated, washed with brine (25 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography eluting with a linear gradient from 0% to 10% MeOH in EtOAc to give 3-cyclopentyloxy-4-methoxy-N-(3-aminocarbonylphenyl)-N-(3-pyridylmethyl)aniline (28 mg, 54% yield) as a white solid. EIMS (m/z) 418 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10]C(=O)C)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Cl>CCO>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][CH3:9])[NH2:10]
Reactant: COc1ccc(NC(C)=O)cc1Br
Agent: Cl
Solvent: CCO
Product: COc1ccc(N)cc1Br
Temperature: 80 °C
Yield: 85.9 %

Procedure:
To a solution of N-(3-bromo-4-methoxyphenyl)acetamide III (5.0 g, 20.50 mmol) in EtOH (40.0 mL) was added concentrated HCl (20.0 mL) and heated the reaction mixture to 80° C. for 4-5 h. After the completion of the reaction (TLC monitoring), EtOH was distilled off and the residue was cooled to 0° C. followed by basification with aqueous NH3 till pH 12 and extraction with EtOAc (2×250 mL). The combined organics was washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to obtain the desired product (3.56 g, 87%). 1H NMR (400 MHz, DMSO-d6): δ 3.67 (s, 3H), 4.88 (br s, 2H), 6.54 (dd, J=2.40 and 8.40 Hz, 1H) and 6.80 (m, 2H). MS: 202.17 (M+H)+.
Reaction SMILES: F[C:2]1[C:7]([I:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][NH2:10]>>[I:8][C:7]1[C:2]([NH:10][CH3:9])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN
Reactant: Fc1ncccc1I
Product: CNc1ncccc1I
Temperature: 25 °C
Yield: 95 %

Procedure:
A 1 L round bottom flask was charged with 2-fluoro-3-iodopyridine (27.0 g, 121 mmol) and 500 mL of 40% aqueous solution of methylamine. This was stirred at reflux for 4 h before being cooled to ambient temperature. The product was extracted with dichloromethane. Evaporation of the dichloromethane gave 3-iodo-N-methylpyridin-2-amine (26.8 g, 95% yield).
Reaction SMILES: [OH-].[K+].[F:3][C:4]([F:28])([C:18]([F:27])([F:26])[C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])[CH2:5][CH2:6][CH:7](C(OCC)=O)[C:8](OCC)=[O:9].Cl.B.CSC>O.C(O)C.CO>[F:3][C:4]([F:28])([C:18]([F:26])([F:27])[C:19]([F:24])([F:25])[C:20]([F:21])([F:22])[F:23])[CH2:5][CH2:6][CH2:7][CH2:8][OH:9]
Reactant: CCOC(=O)C(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)OCC
Agent: B
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: CCO
Solvent: CSC
Product: OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 60 °C
Reaction time: 6 h
Yield: 67.4 %

Procedure:
A solution of potassium hydroxide (53.59 g, 955.09 mmol) in water (200 ml) was added to a solution of diethyl 2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)malonate (19.4 g, 47.75 mmol) in ethanol (400 ml), followed by stirring for 6 hours at 60° C. After the reaction was completed, the reaction mixture was adjusted to pH 5 at room temperature by slowly adding 1N hydrochloric acid dropwise, and then extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was stirred in dimethyl sulfoxide for 18 hours at 170° C. After the reaction was completed, water was added to the reaction mixture, which was then extracted three times with ethyl acetate. The combined organic layers were washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, anhydrous tetrahydrofuran (200 ml) was added to the residue and the resulting mixture was cooled to −30° C. Borane-methyl sulfide complex (10M in THF, 8.5 ml, 85 mmol) was slowly added dropwise to this mixture, followed by stirring for 3 hours at room temperature. After treatment with methanol at 0° C., water was added to the reaction mixture, which was then extracted twice with ethyl acetate. The combined organic layers were washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/20) to give 5,5,6,6,7,7,8,8,8-nonafluorooctan-1-ol (9.4 g, Yield 60%).