Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(C)C=CC(S(O)(=O)=O)=C[CH:2]=1.[NH2:12][C:13]1[C:18]([NH2:19])=[C:17]([CH3:20])[N:16]=[C:15]([Cl:21])[N:14]=1>C(Cl)(Cl)Cl>[Cl:21][C:15]1[N:14]=[C:13]2[C:18]([NH:19][C:1]([CH3:2])=[N:12]2)=[C:17]([CH3:20])[N:16]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1nc(Cl)nc(N)c1N
Solvent: ClC(Cl)Cl
Product: Cc1nc2nc(Cl)nc(C)c2[nH]1
Temperature: 100 °C
Yield: 635.5 %

Procedure:
After adding 10.1 ml of ortho-triethyl acetate, 0.23 g of para-toluenesulfonic acid and 73 ml of 2-methylpyrrolidone to 7.6 g of 4,5-diamino-2-chloro-6-methylpyrimidine, the mixture was heated at 100° C. and then heated and stirred while removing out of the system the ethanol produced during the reaction. After disappearance of the 4,5-diamino-2-chloro-6-methylpyrimidine, the reaction solution was further heated and stirred at 180° C. for 2 hours. After cooling to room temperature, chloroform was added thereto for dilution. The mixture solution was washed with water and then washed with saturated brine, after which the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=95.5) to obtain 1.55 g of the title compound.
Reaction SMILES: [C:1]([Cu])#[N:2].Br[C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2>CN1CCCC1=O>[NH:10]1[C:11]2[C:7](=[CH:6][C:5]([C:1]#[N:2])=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Product: N#Cc1ccc2[nH]ccc2c1
Temperature: 0 °C
Yield: 103 %

Procedure:
CuCN (3.7 g, 40.70 mmol) was added to a solution of 5-bromo-1H-indole (5 g, 25.26 mmol) in 1-methylpyrrolidin-2-one (25 mL), and the resulting solution was stirred at reflux for 18 hours. The reaction mixture was then added to 200 g of ice and the mixture was filtered. The filter cake was washed with ammonium hydroxide (3×50 mL). The residue was dissolved in chloroform (600 mL) and then filtered. The organic layer was washed with water (200 mL), and dried (MgSO4). After a further filtration, the filtrate was concentrated to yield 3.7 g (82%) of 1H-indole-5-carbonitrile as brown oil.
Reaction SMILES: CN(CN(C)C)C.C(Cl)(=O)C.[Cl:12][C:13]1[C:21]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[CH:16][NH:17]2.C[N:30]([CH2:32][C:33]1C2C(=CC=C(OC3C=CC=CC=3)C=2Cl)NC=1)C.[C-]#N.[K+].CI>C(Cl)Cl.CN(C=O)C.CCCCCC.CCOCC>[C:32]([CH2:33][C:15]1[C:14]2[C:18](=[CH:19][CH:20]=[C:21]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:13]=2[Cl:12])[NH:17][CH:16]=1)#[N:30]
Reactant: CN(C)Cc1c[nH]c2ccc(Oc3ccccc3)c(Cl)c12
Reactant: Clc1c(Oc2ccccc2)ccc2[nH]ccc12
Agent: CN(C)CN(C)C
Agent: [C-]#N
Agent: [K+]
Solvent: CC(=O)Cl
Solvent: ClCCl
Solvent: CCCCCC
Product: N#CCc1c[nH]c2ccc(Oc3ccccc3)c(Cl)c12

Procedure:
Treatment of a cooled solution of N,N,N',N'-tetramethyldiaminomethane (0.083 g, 0.11 mL, 0.812 mmol) in CH2Cl2 (2.4 mL) with acetyl chloride (0.064 g, 0.057 mL, 0.80 mmol) followed by a solution of 4-chloro-5-phenoxy indole (0.14 g, 0.574 mmol) in CH2Cl2 (2 mL), gave after work-up: 3-(N,N-dimethylaminomethyl)4-chloro-5-phenoxyindole, as an off-white solid. This was treated with potassium cyanide (0.143 g, 2.19 mmol) and methyl iodide (0.0.33 g, 0.143 mL, 2.29 mmol) in DMF (1 mL) for 16 hr After appropriate work-up and chromatography (silica gel; hexane/Et2O; 0-55%), 3-cyanomethyl-4-chloro-5-phenoxyindole was obtained as an off-white crystalline solid, 0.094 g (58%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:19](O)=[O:20])[CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC(C)C)=O.[BH4-].[Na+].C(O)(=O)C>C1COCC1.C1COCC1.O>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:19][OH:20])[CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@H](CO)COCc1ccccc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 82.1 %

Procedure:
N-(tert-butyloxycarbonyl)-O- benzyl-L-serine 2 (6.0 g, 20.34 mmol) was dissolved in dry THF and cooled to -20° C. under argon atmosphere. To this cold stirred solution was added TEA (2.32 g, 23 mmol) and isobutyl chloroformate (3.13 g, 23 mmol). The stirring was continued for 30 min at -20° C. under argon atmosphere. The reaction mixture was filtered immediately under a blanket of argon, the precipitate was washed with dry THF (50 ml). The combined filtrate was added slowly into a cold (0° C.) solution of NaBH4 (7.4 g, 200 mmol) in THF/water (80:20, 200 ml) during 10 min period. After the addition, the reaction mixture was stirred for 2 h at 0° C. and the pH adjusted to 7 with acetic acid. The solution was evaporated to dryness, partitioned between ethyl acetate/water (300:150 ml) and extracted in ethyl acetate. The organic extract was washed with brine (100 ml), dried over anhydrous sodium sulfate and evaporated to dryness. The crude product was purified by flash column chromatography over silica gel using CH2Cl2 →EtOAc as the eluent. The pure product was pooled together and evaporated to dryness to give 4.7 g (82%) of the pure product as an oil. 1HNMR (CDCl3): δ1.41 (s, 9H, Boc), 3.60-3.70 (m, 4H), 3.82 (d, 2H), 4.53 (s, 2H, OCH2Ph), 5.20 (bs, 1H, NH) and 7.30-7.40 (m, 5H, Ph).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:7]1[CH:11]=[N:10][S:9][N:8]=1)[C:4]([OH:6])=[O:5].[Cl:12][CH:13]([Cl:17])[C:14](Cl)=[O:15]>>[Cl:12][CH:13]([Cl:17])[C:14]([O:1][N:2]=[C:3]([C:7]1[CH:11]=[N:10][S:9][N:8]=1)[C:4]([OH:6])=[O:5])=[O:15]
Reactant: O=C(O)C(=NO)c1cnsn1
Reactant: O=C(Cl)C(Cl)Cl
Product: O=C(O)C(=NOC(=O)C(Cl)Cl)c1cnsn1
Yield: 47 %

Procedure:
2-Hydroxyimino-2-(1,2,5-thiadiazol-3-yl)acetic acid (syn isomer) (4.8 g.) and dichloroacetyl chloride (9.2 g.) were reacted according to a similar manner to that of Example 6(a)(4) to give crystals of 2-dichloroacetoxyimino-2-(1,2,5-thiadiazol-3-yl)acetic acid (syn isomer) (3.7 g.).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]#[N:11])=[CH:4][CH:3]=1.[C:16]([O:20][C:21]([NH:23][C:24]1[C:33]([N+:34]([O-:36])=[O:35])=[CH:32][CH:31]=[CH:30][C:25]=1[C:26]([O:28][CH3:29])=[O:27])=[O:22])([CH3:19])([CH3:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:16]([O:20][C:21]([N:23]([C:24]1[C:33]([N+:34]([O-:36])=[O:35])=[CH:32][CH:31]=[CH:30][C:25]=1[C:26]([O:28][CH3:29])=[O:27])[CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]#[N:11])=[CH:6][CH:7]=1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1NC(=O)OC(C)(C)C
Reactant: Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cccc([N+](=O)[O-])c1N(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OC(C)(C)C
Temperature: 82 °C
Reaction time: 5 h

Procedure:
To the acetonitrile solution where BMB is mixing with 2-(4-methylphenyl)benzonitrile [MPB] which was not brominated and 2-(4,4-dibromomethylphenyl)benzonitrile which is a compound similar to BMB, was added a mixture of methyl 2-tert-butoxycarbonylamino-3-nitrobenzoate [BAN] 30.1 g, potassium carbonate 40.8 g and acetonitrile 160 ml and the solution was stirred at about 82° C. for about 5 hours to proceed the reaction. The solution was cooled to room temperature and precipitated crystals were filtered off. The filtrate was concentrated to give methyl 2-[N-t-butoxycarbonyl-N-[(2′-cyano-biphenyl-4-yl)methyl]amino]-3-nitrobenzoate [BBN]. The concentrate was dissolved in methanol 190 g. To the methanol solution was dropped concentrated hydrochloric acid 106 g and the solution was heated to refluxing temperature for 2 hours and thereafter stirred under reflux for 2 hours to proceed the reaction. The reaction solution was cooled and the precipitated crystals were filtered and dried to give methyl 2-[N-(2′-cyanobiphenyl-4-yl)methylamino]-3-nitrobenzoate [MBN] 35.1 g (yield based on 2-(4-methylphenyl)benzonitrile [MPB]: 76.1%).
Reaction SMILES: [C:1]([O:6][CH2:7][CH:8]1[O:12][C:10](=[O:11])[CH2:9]1)(=[O:5])[C:2]([CH3:4])=[CH2:3].B(F)(F)F>C1(C)C=CC=CC=1>[C:1]([O:6][CH:7]1[CH2:8][O:12][C:10](=[O:11])[CH2:9]1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OCC1CC(=O)O1
Agent: FB(F)F
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)OC1COC(=O)C1
Temperature: 30 °C
Yield: 55 %

Procedure:
In a 20 mL Schlenk flask, 2.0 g of crude β-methacryloyloxymethyl-β-propiolactone was put, and dissolved in 8.0 g of toluene. Further, 54 μL of diethyl ether complex of boron trifluoride was added thereto, and the resulting mixture was warmed to 30° C. and stirred. After the mixture was stirred for 2 hours, the resulting reaction mixture was washed with a 10% sodium hydrogen carbonate aqueous solution and saturated brine, and dried over magnesium sulfate. After separation by filtration, the solvent was distilled off using an evaporator to give 1.1 g of crude β-methacryloyloxy-γ-butyrolactone represented by formula (10). FIG. 3 shows an NMR measurement chart.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22]CC)=[O:21])=[CH:15][CH:14]=1.[OH-].[K+]>C(O)C.O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:17][CH:18]=1
Reactant: CCOC(=O)Cc1ccc(OCc2ccc3ccccc3n2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)Cc1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.8 %

Procedure:
To a stirred solution of ethyl 2-(4-(quinolin-2-ylmethoxy)phenyl)acetate (38.0 g, 106.741 mmol) in ethanol (200 mL) and water (100 mL) was added KOH (23.9 g, 426.964 mmol) at room temperature. The mixture was stirred at RT for 4 h and after complete consumption of starting material as monitored by TLC, the reaction mixture was diluted with water (50 mL) and acidified using 1 N HCl at 0° C. The aqueous layer was extracted with EtOAc (2×150 mL) and the combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, and evaporated in vacuo to afford 2-(4-(quinolin-2-ylmethoxy)phenyl)acetic acid (30.0 g, 95%) as a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:13][CH2:14][N:15]1[CH:19]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:17]=[N:16]1)[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[F:29][C:30]1[CH:46]=[C:45]([N+:47]([O-:49])=[O:48])[CH:44]=[CH:43][C:31]=1[O:32][C:33]1[CH:38]=[CH:37][N:36]=[C:35]2[CH:39]=[C:40](I)[S:41][C:34]=12.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C(Cl)Cl.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>[F:29][C:30]1[CH:46]=[C:45]([N+:47]([O-:49])=[O:48])[CH:44]=[CH:43][C:31]=1[O:32][C:33]1[CH:38]=[CH:37][N:36]=[C:35]2[CH:39]=[C:40]([C:18]3[CH:17]=[N:16][N:15]([CH2:14][CH2:13][N:5]([CH2:4][CH2:3][O:2][CH3:1])[C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:10])[CH3:11])[CH:19]=3)[S:41][C:34]=12
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Reactant: COCCN(CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1)C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: COCCN(CCn1cc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)cn1)C(=O)OC(C)(C)C

Procedure:
A mixture of 78 (369.3 mg, 0.93 mmol), 7-(2-fluoro-4-nitrophenoxy)-2-iodothieno[3,2-b]pyridine (24) [US 2006/0287343 A1](466.6 mg, 1.12 mmol), Pd(PPh3)4 (54 mg, 0.05 mmol) and Na2CO3 (305 mg, 2.8 mmol) in DME (1.9 mL) was heated to reflux overnight under nitrogen. It was then diluted with DCM, washed with water, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by flash chromatography, eluents EOAc/Hex 1:1, EtOAc, 5% MeOH in DCM affording title compound 79 (203 mg, 39%) as brown syrup. MS (m/z): 558.2 (100%) (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.C([Li])CCC.Cl.[O:17]1CCC[CH2:18]1>>[O:9]1[C:5]2[CH:4]=[CH:3][C:2]([CH:18]=[O:17])=[CH:10][C:6]=2[CH2:7][CH2:8]1
Reactant: C1CCOC1
Reactant: Brc1ccc2c(c1)CCO2
Agent: Cl
Agent: [Li]CCCC
Product: O=Cc1ccc2c(c1)CCO2
Temperature: -78 °C
Reaction time: 1.42 h
Yield: 90 %

Procedure:
To a solution of 5-bromo-2,3-dihydro-benzofuran described in Preparation Example 173 (15.0 g, 75.4 mmol) in tetrahydrofuran (300 mL) was added n-butyl lithium (31.2 mL, 82.9 mmol) at −78° C. The reaction solution was stirred for 85 minutes at −78° C., then, N,N-dimethytformamide (6.42 mL, 82.9 mmol) was added thereto, followed by stirring at room temperature for 1 hour. 1N Hydrochloric acid was added to the reaction solution, which was then extracted with ethyl acetate, and the organic layer was washed with brine. Anhydrous magnesium sulfate was added to the organic layer for drying, which was then filtered, the filtrate was concentrated in vacuo, the residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1), and the title compound (10.1 g, 90%) was obtained as a pale yellow oil.
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([CH3:8])[N:7]=1.[CH2:10]([O:12][C:13]([N:15]=[C:16]=[S:17])=[O:14])[CH3:11].C1(C)C=CC=CC=1>CO>[CH3:8][C:6]1[N:7]=[C:2]2[S:17][C:16]([NH:15][C:13](=[O:14])[O:12][CH2:10][CH3:11])=[N:9][C:3]2=[N:4][CH:5]=1
Reactant: Cc1cnc(N)c(Br)n1
Reactant: CCOC(=O)N=C=S
Solvent: Cc1ccccc1
Solvent: CO
Product: CCOC(=O)Nc1nc2ncc(C)nc2s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63.1 %

Procedure:
To 3-bromo-5-methylpyrazin-2-amine (850 mg, 4.52 mmol) was added ethoxycarbonyl isothiocyanate (0.51 mL, 4.52 mmol) followed by toluene (1 mL). The mixture was placed in a preheated 100° C. oil bath, and within a minute, all the solids had dissolved. After 15 min, all had seized to a solid mass. After an additional 15 minutes, methanol (˜5 mL) was added and the mixture refluxed to digest the solids. The mixture was cooled to rt after 5 minutes and the solids collected by filtration, washing with methanol to give ethyl 6-methylthiazolo[5,4-b]pyrazin-2-ylcarbamate (680 mg, 2.85 mmol, 63.1% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.48 (br. s., 1H) 8.48 (s, 1H) 4.30 (q, J=7.03 Hz, 2H) 2.56-2.65 (m, 3H) 1.31 (t, J=7.15 Hz, 3H). MS (LC/MS) R.T.=2.10; [M+H]+=239.17.
Reaction SMILES: [CH3:1][O:2][NH:3][C:4](=[O:7])[O:5][CH3:6].[H-].[Na+].[Br:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14]Br.O>CN(C)C=O>[CH3:1][O:2][N:3]([CH2:14][C:13]1[CH:16]=[CH:17][CH:18]=[C:11]([Br:10])[CH:12]=1)[C:4](=[O:7])[O:5][CH3:6]
Reactant: BrCc1cccc(Br)c1
Reactant: CONC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)N(Cc1cccc(Br)c1)OC
Reaction time: 3 h
Yield: 455 %

Procedure:
2.52 g of methyl N-methoxycarbamate in N,N-dimethylformamide (30 ml) was stirred together with 1.15 g of 60% sodium hydride at room temperature for 30 minutes. 1.00 g of 3-bromobenzyl bromide was added dropwise at room temperature, and the resulting solution was stirred for 3 hours. After the reaction, the reaction solution was poured into water and extracted with ethyl acetate, and the organic layer was separated, dried over anhydrous magnesium sulfate and evaporated under reduced pressure for removal of the solvent. The residue was purified by silica gel column chromatography to give 4.99 g of methyl N-methoxy-N-(3-bromobenzyl)carbamate as a transparent viscous liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:33]=[C:34]([Cl:36])[CH:35]=1)[CH2:5][N:6]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:7](=[O:24])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH:9]=1.[Cl:37][C:38]1[C:39]([OH:49])=[C:40]([S:45](Cl)(=[O:47])=[O:46])[CH:41]=[C:42]([Cl:44])[CH:43]=1.CCN(CC)CC>C1COCC1>[Cl:37][C:38]1[C:39]([OH:49])=[C:40]([S:45]([N:15]([CH2:14][C:10]2[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=2)[C:7]([N:6]([CH2:5][C:4]2[CH:3]=[C:2]([Cl:1])[CH:35]=[C:34]([Cl:36])[CH:33]=2)[CH2:25][C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)=[O:24])[CH2:16][C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)(=[O:47])=[O:46])[CH:41]=[C:42]([Cl:44])[CH:43]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1O
Reactant: O=C(c1cccc(CNCc2ccc(F)cc2)c1)N(Cc1ccc(F)cc1)Cc1cc(Cl)cc(Cl)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(c1cccc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1)N(Cc1ccc(F)cc1)Cc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.3 %

Procedure:
To a solution of N-(3,5-dichlorobenzyl)-N-(4-fluorobenzyl)-3-((4-fluorobenzylamino)methyl)benzamide (70 mg, 0.13 mmol) in THF (3 mL) were added 3,5-dichloro-2-hydroxybenzenesulfonyl chloride (42 mg, 0.16 mmol) and Et3N (0.02 mL, 0.13 mmol). The resulting mixture was stirred at rt for 2 h, concentrated and the residue was dissolved in MeOH and purified by preparative HPLC to give the desired product as a white solid (51 mg, 51%). 1H NMR (CD3OD): δ 7.71 (s, 7.66 (d, J=4.0 Hz, 1H), 7.34-7.07 (m, 13H), 6.81 (t, J=8.0 Hz, 2H), 4.75-4.65 (m, 2H), 4.54 (s, 2H), 4.43-4.40 (m, 4H); MS (ESI): [M+H]+=751.0.
Reaction SMILES: [CH2:1]([C@@H:8]1[O:12][C:11]([CH3:14])([CH3:13])[O:10][C:9]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.[C:24]([O:28][CH3:29])(=[O:27])[CH:25]=[CH2:26]>C1COCC1>[CH3:29][O:28][C:24](=[O:27])[CH2:25][CH2:26][C:8]1([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:14])[O:12]1
Reactant: CC1(C)OC(=O)[C@H](Cc2ccccc2)O1
Reactant: C=CC(=O)OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)CCC1(Cc2ccccc2)OC(C)(C)OC1=O
Yield: 53.6 %

Procedure:
To a solution of compound 56 (3.180 g, 15.42 mmol) in THF was added 9.42 mL LDA (1.8 M in THF, 16.96 mmol) at −78° C. Methyl acrylate (1.460 g, 16.96 mmol) was added to the solution at −78° C. after 15 min. After 1 h the reaction was quenched with saturated NH4Cl aqueous solution, extracted with EtOAc 3×30 mL, dried with MgSO4 and purified on silica gel with 8-17% EtOAc-PE which gave the title compound (2.418 g, 54%) as colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][O:13][C:14]1[CH:29]=[CH:28][C:17]3[O:18][CH2:19][C:20]4[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=4[CH:22](O)[C:16]=3[CH:15]=1)[CH:6]=[CH:5]2.[SH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34]>>[C:33]([CH2:32][CH2:31][S:30][CH:22]1[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[CH2:19][O:18][C:17]2[CH:28]=[CH:29][C:14]([O:13][CH2:12][C:7]3[CH:6]=[CH:5][C:4]4[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=4)[N:8]=3)=[CH:15][C:16]1=2)([OH:35])=[O:34]
Reactant: O=C(O)CCS
Reactant: OC1c2ccccc2COc2ccc(OCc3ccc4cc(F)ccc4n3)cc21
Product: O=C(O)CCSC1c2ccccc2COc2ccc(OCc3ccc4cc(F)ccc4n3)cc21

Procedure:
2-(6-Fluoroquinolin-2-yl)methoxy-11-hydroxy-6,11-dihydrodibenz[b,e]oxepine and 3-mercaptopropionic acid were used and reacted in the same manner as in Example 1 to obtain the title compound.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:15][CH2:16][NH:17][C:18](=[O:22])[C:19](O)=[O:20])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.Cl.[NH2:30][OH:31].C(N(CC)CC)C>C(Cl)Cl.CN(C)C=O.O.O1CCCC1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:15][CH2:16][NH:17][C:18]([C:19]([NH:30][OH:31])=[O:20])=[O:22])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NO
Reactant: COc1ccc(CCNC(=O)C(=O)O)cc1OC1CCCC1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(CCNC(=O)C(=O)NO)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
To a solution of N-[2-(3-cyclopentyloxy-4-methoxyphenyl)ethyl]oxamic acid (651 mg, 2.12 mmol) in methylene chloride (5 mL) containing 2 drops of dimethylformamide at 0° C. under an argon atmosphere was added oxalyl chloride (0.39 mL, 4.45 mmol) and the resulting mixture was stirred for 1 h. This was added to a solution of hydroxylamine hydrochloride (591 mg, 8.50 mmol) and triethylamine (1.75 mL, 12.70 mmol) in 1:5 water/tetrahydrofuran (10 mL) at 0° C. under an argon atmosphere. The reaction mixture was stirred at 0° C. for 1 hour then allowed to warm to room temperature and stirred an additional 2 h. The mixture was partitioned between water and methylene chloride and the organic extract was dried (potassium carbonate). The solvent was removed in vacuo and the residue was purified by flash chromatography, eluting with 1:5:94 acetic acid/methanol/methylene chloride, to provide the hydroxy oxamide (489 mg, 72% ): m.p. 136°-137° C.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:12]([CH3:32])[C:13](=[O:31])[C:14]2[C:19]([C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=1[CH3:28])=[CH:18][CH:17]=[C:16]([C:29]#[CH:30])[CH:15]=2)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].C([O:36][CH2:37][CH2:38][N:39]=[N+:40]=[N-:41])(=O)C.O=C1O[C@H]([C@H](CO)O)C(O)=C1O.[OH-].[Li+]>C(O)C.O.C(OCC)(=O)C.CO.O1CCCC1.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH3:4][C:1]([O:5][CH:6]([C:11]1[N:12]([CH3:32])[C:13](=[O:31])[C:14]2[C:19]([C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=1[CH3:28])=[CH:18][CH:17]=[C:16]([C:29]1[N:41]=[N:40][N:39]([CH2:38][CH2:37][OH:36])[CH:30]=1)[CH:15]=2)[C:7]([OH:9])=[O:8])([CH3:2])[CH3:3]
Reactant: CC(=O)OCCN=[N+]=[N-]
Reactant: C#Cc1ccc2c(-c3ccc(C)cc3C)c(C(OC(C)(C)C)C(=O)OC)n(C)c(=O)c2c1
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCO
Product: Cc1ccc(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3cc(-c4cn(CCO)nn4)ccc23)c(C)c1
Temperature: 60 °C

Procedure:
A mixture of methyl 2-(tert-butoxy)-2-(4-(2,4-dimethylphenyl)-7-ethynyl-2-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)acetate (26.0 mg, 0.060 mmol), 2-azidoethyl acetate (10.11 mg, 0.078 mmol), ascorbic acid (2.123 mg, 0.012 mmol) and copper sulfate monohydrate (1.923 mg, 0.012 mmol) in Ethanol (1.2 mL) and Water (0.2 mL) was irradiated in the microwave at 120° C. for 10 minutes. The mixture was diluted with ethyl acetate, then washed with saturated sodium bicarbonate and brine. The organic phase was dried over sodium sulfate, filtered and concentrated. The resulting crude residue in methanol (1.0 mL), tetrahydrofuran (THF) (1.0 mL) and water (0.2 mL) was treated with lithium hydroxide (28.8 mg, 1.205 mmol) and then heated to 60° C. for 90 minutes. The mixture was concentrated to dryness, water was added and the mixture was adjusted to pH 3-4 with 1N hydrochloric acid. The mixture was extracted with ethyl acetate; the extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by reverse phase chromatography to afford the desired product as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) (atropisomers) δ=8.75-8.54 (m, 1 H), 8.14 (br. s., 2 H), 7.43 (d, J=7.6 Hz, 1 H), 7.15 (d, J=14.6 Hz, 2 H), 7.04-6.85 (m, 1 H), 5.44-5.15 (m, 1 H), 4.56 (m, 2 H), 4.14 (m, 2 H), 3.83-3.64 (m, 3 H), 2.43 (s, 3 H), 2.15-1.83 (m, 3 H), 1.29-0.97 (m, 9 H); LC/MS (m/z) ES+=505 (M+1).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[C:11]([O:23][CH3:24])[CH:10]=1)=O)(C)(C)C.[ClH:25].CO>>[ClH:25].[CH3:16][O:15][C:13]1[CH:14]=[C:9]([CH:10]=[C:11]([O:23][CH3:24])[C:12]=1[O:17][CH2:18][C:19]([F:20])([F:21])[F:22])[NH2:8]
Reactant: COc1cc(NC(=O)OC(C)(C)C)cc(OC)c1OCC(F)(F)F
Agent: Cl
Solvent: CO
Product: COc1cc(N)cc(OC)c1OCC(F)(F)F
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
N-t-butoxycarbonyl-3,5-dimethoxy-4-(2,2,2-trifluoroethoxy)aniline (1.10 g, 3.13 mmol) was added to a 10% solution of hydrogen chloride in methanol (20 mL, 55 mmol), and the resulting solution was stirred at 50° C. for 30 minutes. The reaction mixture was concentrated under reduced pressure to give crude 3,5-dimethoxy-4-(2,2,2-trifluoroethoxy)aniline hydrochloride.