Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:14][N+:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=1[O:22][CH2:23][C:24]1[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=1[F:31].[C:32]([O:37][CH2:38][CH3:39])(=[O:36])[C:33]#[C:34][CH3:35].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:30][C:29]1[CH:28]=[CH:27][CH:26]=[C:25]([F:31])[C:24]=1[CH2:23][O:22][C:16]1[N:15]2[N:14]=[C:34]([CH3:35])[C:33]([C:32]([O:37][CH2:38][CH3:39])=[O:36])=[C:20]2[CH:19]=[C:18]([CH3:21])[CH:17]=1
Reactant: Cc1cc[n+](N)c(OCc2c(F)cccc2F)c1
Reactant: CC#CC(=O)OCC
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)nn2c(OCc3c(F)cccc3F)cc(C)cc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 33.9 %

Procedure:
1.62 g (3.60 mmol, 1.0 eq.) of 1-amino-2-[(2,6-difluorobenzyl)oxy]-4-methylpyridinium 2,4,6-trimethylbenzenesulphonate from Example 2A were dissolved in 36 ml of DMF, and 0.84 ml (7.19 mmol, 2.0 eq.) of ethyl but-2-ynoate [CAS No: 4341-76-8] were added. 0.994 g (7.19 mmol, 2.0 eq.) of potassium carbonate was added and the mixture was stirred at RT for 1.5 h. Subsequently, the mixture was poured onto 150 ml of water and stirred briefly, and the precipitated solids were filtered off, washed with water and dried. 440 mg of the title compound were obtained (45% of theory, 87%).
Reaction SMILES: Cl.[CH3:2][O:3][CH:4]1[CH2:7][NH:6][CH2:5]1.[F:8][C:9]([F:53])([F:52])[C:10]1[CH:11]=[C:12]([C@H:20]2[O:24][C:23](=[O:25])[N:22]([CH2:26][C:27]3[C:32]([C:33]4[CH:34]=[C:35]([CH2:41][CH2:42][C:43]([O:45][CH3:46])=[O:44])[CH:36]=[CH:37][C:38]=4[O:39][CH3:40])=[CH:31][N:30]=[C:29](S(C)(=O)=O)[N:28]=3)[C@H:21]2[CH3:51])[CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1.C(N(CC)CC)C>C1COCC1>[F:53][C:9]([F:8])([F:52])[C:10]1[CH:11]=[C:12]([C@H:20]2[O:24][C:23](=[O:25])[N:22]([CH2:26][C:27]3[C:32]([C:33]4[CH:34]=[C:35]([CH2:41][CH2:42][C:43]([O:45][CH3:46])=[O:44])[CH:36]=[CH:37][C:38]=4[O:39][CH3:40])=[CH:31][N:30]=[C:29]([N:6]4[CH2:7][CH:4]([O:3][CH3:2])[CH2:5]4)[N:28]=3)[C@H:21]2[CH3:51])[CH:13]=[C:14]([C:16]([F:18])([F:17])[F:19])[CH:15]=1
Reactant: COC(=O)CCc1ccc(OC)c(-c2cnc(S(C)(=O)=O)nc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1
Reactant: COC1CNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)CCc1ccc(OC)c(-c2cnc(N3CC(OC)C3)nc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Methoxy-azetidine hydrochloride (60.4 mg, 0.488 mmol) was added into a stirred mixture of methyl 3-{3-[4-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(methylsulfonyl)pyrimidin-5-yl]-4-methoxyphenyl}propanoate (66 mg, 0.098 mmol) and triethylamine (0.068 mL, 0.488 mmol) in THF (1 mL) at room temperature. The reaction mixture was stirred at room temperature overnight. The yellow reaction crude was concentrated in vacuo. The resulting pot residue was purified by preparative HPLC (reverse phase, SunFire Prep C18 OBD 5 um 19×150 mm) eluting with acetonitrile/water+0.05% HCOOH (20% to 100% organic in 10 min, hold 100% for 2 min, 20 mL/min) to give a colorless glass as the titled compound. LCMS calc.=682.22. found=683.27 (M+H)+. 1H-NMR (CDCl3, 500 MHz) δ 8.12 (s, 1H), 7.86 (s, 1H), 7.73 (s, 2H), 7.20 (dd, J=8.5, 2.0 Hz, 1H), 6.97 (d, J=1.5 Hz, 1H), 6.88 (d, J=8.5 Hz, 1H), 5.59 (br d, J=8.0 Hz, 1H), 4.73 (br d, J=17 Hz, 1H), 4.41-4.32 (m, 3H), 4.28 (br s, 1H), 4.11-4.03 (m, 2H), 3.91 (br s, 1H), 3.77 (s, 3H), 3.64 (s, 3H), 3.37 (s, 3H), 2.92 (t, J=7.5 Hz, 2H), 2.62 (t, J=7.5 Hz, 2H), 0.66 (br s, 3H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1.[NH2:15][N:16]1[CH:20]=[CH:19][CH:18]=[CH:17]1.[BH4-].[Na+]>C1C=CC=CC=1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH:15][N:16]2[CH:20]=[CH:19][CH:18]=[CH:17]2)[CH2:10][CH2:9]1
Reactant: Nn1cccc1
Reactant: O=C1CCN(CCc2cccs2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccccc1
Product: c1csc(CCN2CCC(Nn3cccc3)CC2)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A solution of 1-(2-thienylethyl)-4-piperidone (24.6 g, 0.12 mole) and 1-aminopyrrole (12 g, 0.15 mole) in 200 ml of benzene was stirred at reflux for 4 hours. The resultant mixture was cooled and evaporated to an oil which in turn was dissolved in 200 ml of isopropanol and 50 ml of methanol. To the resultant solution was added NaBH4 (9.1 g, 0.24 mole). The mixture was stirred at 80° C. for 2 hours, cooled, evaporated, stirred with water and then extracted with ethyl acetate-ether. The organic extract was washed twice with water and saturated NaCl solution and was dried (anhydrous MgSO4), filtered and evaporated to 33 g of an oil of 1-[2-(2-thienyl)ethyl]-4-(1H-pyrrol-1-yl)aminopiperidine.
Reaction SMILES: [K].[SH:2][C:3]1[S:7][C:6](=[S:8])[N:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]=1.[C:15]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:20]=1[OH:29])([CH3:18])([CH3:17])[CH3:16].[CH2:30]=O.S(=O)(=O)(O)O>C(O)C>[C:25]([C:21]1[CH:22]=[C:23]([CH:24]=[C:19]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:20]=1[OH:29])[CH2:30][SH:7]1[C:3]([SH:2])=[N:4][N:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]1=[S:8])([CH3:28])([CH3:27])[CH3:26]
Reactant: S=c1sc(S)nn1-c1ccccc1
Reactant: C=O
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: O=S(=O)(O)O
Agent: [K]
Solvent: CCO
Product: CC(C)(C)c1cc(C[SH]2C(=S)N(c3ccccc3)N=C2S)cc(C(C)(C)C)c1O

Procedure:
5-Mercapto-3-phenyl-1,3,4-thiadiazole-2(3H) thione potassium salt (26.4 g, 0.1 mol), 2,6-di-tertbutylphenol (20.6 g, 0.1 mol), formalin (11 ml) and concentrated sulphuric acid (10 ml) in ethanol (100 ml) are heated, under reflux, for six hours. After this time, the ethanol is removed by rotary evaporation, and partitioned between ethyl acetate and water. The organic phase is dried over magnesium sulphate, filtered and the solvent removed in vacuo. A yellow oil is left (29.5 g, 66% of theory).
Reaction SMILES: [CH2:1]([C:4]1[CH:11]=[C:10]([F:12])[C:7]([C:8]#[N:9])=[C:6]([F:13])[CH:5]=1)C=C.C[N+]1([O-])CC[O:18][CH2:17]C1.[CH3:22][OH:23]>O.O=[Os](=O)(=O)=O>[OH:23][CH:22]([CH2:17][OH:18])[CH2:1][C:4]1[CH:11]=[C:10]([F:12])[C:7]([C:8]#[N:9])=[C:6]([F:13])[CH:5]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CCc1cc(F)c(C#N)c(F)c1
Reactant: CO
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: N#Cc1c(F)cc(CC(O)CO)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-allyl-2,6-difluorobenzonitrile (1.7 g, 9.2 mmol) in 30 mL of methanol and 10 mL of water was added OsO4 (210 mg) and NMO (3.11 g, 23 mmol), and the mixture was stirred at ambient temperature overnight. Remove the methanol under reduced pressure, the residue was dissolved in EtOAc, washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by fast column chromatograph to give 4-(2,3-dihydroxypropyl)-2,6-difluorobenzonitrile. MS m/z: 214 (M+1)+.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]([C:9]1[N:17]2[C:12]([CH2:13][O:14][CH2:15][CH2:16]2)=[C:11]([C:18]([OH:20])=O)[CH:10]=1)=[O:8].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[C:43]1([C@H:49]([NH2:52])[CH2:50][CH3:51])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CN(C)C=O.O>[C:43]1([C@H:49]([NH:52][C:18]([C:11]2[CH:10]=[C:9]([C:7]([N:3]3[CH2:4][CH2:5][CH2:6][C@@H:2]3[CH3:1])=[O:8])[N:17]3[CH2:16][CH2:15][O:14][CH2:13][C:12]=23)=[O:20])[CH2:50][CH3:51])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: CC[C@@H](N)c1ccccc1
Reactant: C[C@H]1CCCN1C(=O)c1cc(C(=O)O)c2n1CCOC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC[C@@H](NC(=O)c1cc(C(=O)N2CCC[C@@H]2C)n2c1COCC2)c1ccccc1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 67 %

Procedure:
To a solution of 6-((S)-2-methyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid (Comp. No. 7c) (300 mg, 0.914 mmol) in dimethylformamide (4 ml) was added 1-hydroxybenzotriazole (136 mg, 1 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (193 mg, 1 mmol). The mixture was stirred for 90 min at 50° C., then (R)-1-phenyl-propylamine (85 mg, 1 mmol) was added and the mixture was stirred at 25° C. overnight. An excess of water was added, the solid which precipitated was filtered off, washed with a small amount of water and purified by reverse phase HPLC (acetonitrile/water gradient with 0.1% trifluoroacetic acid) to give 243 mg (67%) of 6-((S)-2-methyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid ((R)-1-phenyl-propyl)-amide (Comp. No. 16a; compounds with a compound number starting with “16” are compounds of the formula I) as white solid. LC/MS (method 4): Rt=1.12 min; m/z=396.22 (M+H+). 1H-NMR: δ (ppm)=8.07 (1H, d), 7.26-7.35 (5H, m), 7.19-7.22 (1H, m), 4.98 (1H, d), 4.81-4.89 (2H, m), 4.17-4.30 (2H, m), 3.92-3.99 (2H, m), 3.80-3.85 (1H, m), 3.68 (2H, bs), 2.03-2.09 (1H, m), 1.92-1.99 (1H, m), 1.74-1.84 (3H, m), 1.53-1.59 (1H, m), 1.18 (3H, d), 0.88 (3H, t).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([CH2:6][N:7]([S:30]([C:33]1[CH:34]=[CH:35][CH:36]=[C:37]2[C:42]=1[N:41]=[CH:40][CH:39]=[CH:38]2)(=[O:32])=[O:31])[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[C:13](=[O:19])[C:12]([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[NH:26])=[CH:23][CH:22]=1)=[N:11]2)=[O:5].O.[C:44](=[O:47])([O-])[O-].[K+].[K+].ClC([O:53][CH2:54][CH3:55])=O>O1CCCC1>[CH3:2][O:3][C:4]([CH2:6][N:7]([S:30]([C:33]1[CH:34]=[CH:35][CH:36]=[C:37]2[C:42]=1[N:41]=[CH:40][CH:39]=[CH:38]2)(=[O:31])=[O:32])[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[C:13](=[O:19])[C:12]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([N:27]=[C:44]=[O:47])=[N:26][O:53][CH2:54][CH3:55])=[CH:28][CH:29]=1)=[N:11]2)=[O:5]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)CN(c1ccc2c(c1)nc(Cc1ccc(C(=N)N)cc1)c(=O)n2C)S(=O)(=O)c1cccc2cccnc12
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCON=C(N=C=O)c1ccc(Cc2nc3cc(N(CC(=O)OC)S(=O)(=O)c4cccc5cccnc45)ccc3n(C)c2=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
450 mg (0.74 mmol) of 4-{[6-(N-methoxycarbonylmethyl-quinolin-8-yl-sulphonylamino)-1-methyl-2-oxo-1,2-dihydroquinoxalin-3-yl]-methyl}benzamidine-hydrochloride are dissolved in 30 ml tetrahydrofuran and 5 ml water and after the addition of 0.3 g (2.2 mmol) of potassium carbonate, stirred for 10 minutes at ambient temperature. Then 0.07 ml (0.74 mmol) of ethyl chloroformate are added and stirred for a further 1 hour. The aqueous phase is separated off, the organic phase is dried and evaporated down.
Reaction SMILES: [N+:1]([C:4]1[C:5]([N:10]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:11][CH2:12][CH2:13][N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H]>[Pd].C(O)C.C(OCC)(=O)C>[NH2:1][C:4]1[C:5]([N:10]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:11][CH2:12][CH2:13][N:14]2[C:15](=[O:24])[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]2=[O:23])=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCN(c1ccccc1)c1ncccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1cccnc1N(CCCN1C(=O)c2ccccc2C1=O)c1ccccc1

Procedure:
2-[3-[(3-Nitro-2-pyridinyl)phenylamino]propyl]-1H-isoindole-1,3(2H)dione is reduced with hydrogen and palladium-on-carbon catalyst in ethanol-ethyl acetate mixtures to give the title compound.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25](I)=[C:26]([C:28]([O-:30])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12].[CH2:32]([OH:35])[C:33]#[CH:34].[CH3:36]CN(C(C)C)C(C)C>C1COCC1.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.[Cu]I>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([C:34]#[C:33][CH2:32][OH:35])=[C:26]([C:28]([O:30][CH3:36])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: CCN(C(C)C)C(C)C
Reactant: C#CCO
Reactant: O=C(Nc1nc2ccccc2s1)c1cccc2c1CN(c1nc(C(=O)[O-])c(I)s1)CC2
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)sc1C#CCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.2 %

Procedure:
To a solution of methyl 2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-iodothiazole-4-carboxylate (8C) (1.2 g, 2.03 mmol) and prop-2-yn-1-ol (336 mg, 6 mmol) in THF (20 mL) was added Pd(Ph3P)4 (231 mg, 0.2 mmol), CuI (76 mg, 0.121 mmol), DIEA (520 mg, 4 mmol). The mixture was stirred under nitrogen at rt overnight. The mixture was then diluted with DCM (400 mL) and washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The crude material was purified by column chromatography on a silica gel column eluting with 5% MeOH in DCM to provide 0.76 g (73%) of the desired product methyl 2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-hydroxyprop-1-ynyl)thiazole-4-carboxylate (8D): LC/MS (APCI): m/z 505.1 (M+H)
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.Cl[C:13]1[S:17][N:16]=[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:14]=1.C(N(CC)CC)C.O>CN(C)C=O>[C:18]1([C:15]2[N:14]=[C:13]([N:1]3[CH2:2][CH2:3][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:10][CH2:11]3)[S:17][N:16]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Clc1nc(-c2ccccc2)ns1
Reactant: CCOC(=O)C1CCNCC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(c2nc(-c3ccccc3)ns2)CC1
Yield: 75.7 %

Procedure:
A mixed solution of ethyl isonipecotate (0.782 ml, 5.08 mmol), 5-chloro-3-phenyl-1,2,4-thiadiazole (1.00 g, 5.08 mmol) and triethylamine (0.708 ml, 5.08 mmol) in N,N-dimethylformamide (10 ml) was stirred at room temperature for 30 minutes. The reaction mixture was poured to water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and ethyl acetate to yield 1.22 g (75.8%) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:14][C:13]=2[CH:12]=[C:11]([O:30][CH3:31])[CH:10]=1.[CH3:32][NH2:33]>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18][NH:33][CH3:32])[CH2:14][C:13]=2[CH:12]=[C:11]([O:30][CH3:31])[CH:10]=1
Reactant: COc1cc2c(c(-c3cccc(Cl)c3Cl)c1)OC(COS(=O)(=O)c1ccc(C)cc1)C2
Reactant: CN
Product: CNCC1Cc2cc(OC)cc(-c3cccc(Cl)c3Cl)c2O1

Procedure:
The title compound was prepared (0.053 g, 68%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(2,3-dichlorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}4-methylbenzenesulfonate (0.135 g, 0.28 mmol) and methylamine (0.087 g, 2.8 mmol). mp 178-180° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=2[F:18])[CH:5]=[CH:4][N:3]=1.[H][H]>CO.O1CCCC1.[C].[Pd]>[NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=2[F:18])[CH:5]=[CH:4][N:3]=1
Reactant: [H][H]
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ccn1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ccnc(N)c2)c(F)c1
Reaction time: 144 h
Yield: 107.8 %

Procedure:
2-Amino-4-(2-fluoro-4-nitrophenoxy)pyridine (1.246 g) was dissolved in methanol (20 ml)-tetrahydrofuran (10 ml), and then 10% palladium carbon (1.0 g) was added thereto under a nitrogen atmosphere, followed by replacing with hydrogen inside the system and stirring for 6 days. After replacing with nitrogen inside the system, the catalyst was filtered and washed with ethanol. The filtrate was concentrated under a reduced pressure to provide the titled compound (1.182 g, quantitative) as brown crystals.
Reaction SMILES: NC1C([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)=C(O)C=CC=1.[C:16]([O:20][C:21]([NH:23][C:24](=[N:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[NH:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([O-:32])=[O:31])=[CH:28][CH:27]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17].O1CCCC1.[N:48]1(CO)[C:52]2C=CC=CC=2N=N1>C(O)C>[C:39]([O:38][C:36]([NH:35][C:24](=[N:23][C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])[NH:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([O:32][C:13]2[CH:14]=[CH:9][C:10]([NH:48][CH3:52])=[C:11]([Cl:15])[CH:12]=2)=[O:31])=[CH:28][CH:27]=1)=[O:37])([CH3:42])([CH3:41])[CH3:40]
Reactant: OCn1nnc2ccccc21
Reactant: Nc1cccc(O)c1-c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)Nc1ccc(C(=O)[O-])cc1
Solvent: CCO
Solvent: C1CCOC1
Product: CNc1ccc(OC(=O)c2ccc(NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.5 %

Procedure:
To a solution of 4 amino-3-chlorophenylphenol 4-[N′,N″-bis(tert-butoxycarbonyl)carbamimidamido]benzoate (600 mg) in ethanol (6.00 mL)-tetrahydrofuran (6.00 mL) was added 1H-1,2,3-benzotriazole-1-ylmethanol (195 mg), followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and then to the residue were added N,N-dimethylformamide (6.00 mL) and tetrahydrofuran (6.00 mL). Sodium borohydride (89.9 mg) was added thereto under ice-cooling, followed by stirring at room temperature for 3 hours. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 3-chloro-4-(methylamino)phenyl 4-[N′,N″-bis(tert-butoxycarbonyl)carbamimidamido]benzoate (362 mg).
Reaction SMILES: [C:1]([C:5]1[CH:31]=[CH:30][CH:29]=[CH:28][C:6]=1[CH:7]=[N:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:17]=2[Cl:26])=[CH:11][C:10]=1[OH:27])([O:3][CH3:4])=[O:2].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>C(Cl)(Cl)Cl>[C:1]([C:5]1[CH:31]=[CH:30][CH:29]=[CH:28][C:6]=1[C:7]1[O:27][C:10]2[CH:11]=[C:12]([O:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:17]=3[Cl:26])[CH:13]=[CH:14][C:9]=2[N:8]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1ccccc1C=Nc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1O
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccccc1-c1nc2ccc(Oc3ccc(C(F)(F)F)cc3Cl)cc2o1
Yield: 81.9 %

Procedure:
To a stirred solution of 2.7 grams (0.006 mole) N-(o-carbomethoxybenzylidene)-2-hydroxy-4-(2-chloro-4-trifluoromethylphenoxy)aniline in 25 ml of chloroform was added portionwise 2.9 grams (0.007 mole) lead tetraacetate. The reaction mixture was stirred for an additional hour, then washed sequentially with three portions of water and an aqueous saturated sodium chloride solution. The organic layer was concentrated under reduced pressure to a residual oil. The oil was dissolved in methylene chloride and passed through a column of activated magnesium silicate. The appropriate fractions were combined and concentrated under reduced pressure to give 2.2 grams of 2-(o-carbomethoxyphenyl)-6-(2-chloro-4-trifluoromethylphenoxy)-benzoxazole as an oil. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.ClC1C=CC=C(C(OO)=[O:20])C=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N+:10]([O-:20])=[CH:9][CH:8]=[CH:7]2
Reactant: Cc1cccc2cccnc12
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1cccc2ccc[n+]([O-])c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 40 mL of a chloroform solution containing 2.0 g of 8-methylquinoline, 3.6 g of m-chloroperbenzoic acid was added, and the mixture was stirred at room temperature overnight. Thereto was added 1.0 g of m-chloroperbenzoic acid, and the mixture was stirred at room temperature overnight. An aqueous saturated sodium hydrogen carbonate solution was added to the reaction mixture, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed with an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 2.2 g of a brown oily substance, 8-methylquinoline N-oxide.
Reaction SMILES: ClCC([C:5]1[C:15]2[CH2:14][CH2:13][C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=O.[F:20][C:21]1[CH:35]=[CH:34][C:24]2[C:25]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:26][O:27][C:23]=2[CH:22]=1.C([O-])([O-])=O.[K+].[K+].[C:42]([OH:49])(=[O:48])/[CH:43]=[CH:44]/[C:45]([OH:47])=[O:46]>C(O)C>[C:42]([OH:49])(=[O:48])/[CH:43]=[CH:44]/[C:45]([OH:47])=[O:46].[F:20][C:21]1[CH:35]=[CH:34][C:24]2[C:25]([CH:28]3[CH2:29][CH2:30][N:31]([CH2:44][C:45]([N:10]4[C:11]5[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=5[CH2:13][CH2:14][C:15]5[CH:5]=[CH:6][CH:7]=[CH:8][C:9]4=5)=[O:46])[CH2:32][CH2:33]3)=[N:26][O:27][C:23]=2[CH:22]=1
Reactant: O=C(CCl)c1cccc2c1CCc1ccccc1N2
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C(CN1CCC(c2noc3cc(F)ccc23)CC1)N1c2ccccc2CCc2ccccc21

Procedure:
A stirred mixture of 2-chloroacetyl-10,11-dihydro-5H-dibenz[b,f]azepine (6.6 g, 24.3 mmol), 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (5 g, 22.7 mmol) and K2CO3 (3.5 g, 40 mmol) was heated at reflux for 4 hours. The insolubles were filtered, and the solvent was removed on a rotary evaporator. The crude product was purified by flash chromatography over a silica gel column (100 g of SiO2 ; eluted with dichloromethane (DCM) and 1-2% CH3OH in DCM). The product thus obtained weighed 8.7 g as a yellow oil. A sample (1.5 g) of this material was dissolved in ethanol and was treated with a solution of fumaric acid in ethanol (360 mg/3 ml). The solids collected were recrystallized from acetonitrile to yield 890 mg of white crystals, m.p. 182°-183° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]([C@@H:13]([CH2:21][CH3:22])[C:14]([O:16]C(C)(C)C)=[O:15])[C:9]2=[O:12])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]([C@@H:13]([CH2:21][CH3:22])[C:14]([OH:16])=[O:15])[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: CC[C@@H](C(=O)OC(C)(C)C)n1ccc2ccc(Cl)cc2c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@@H](C(=O)O)n1ccc2ccc(Cl)cc2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
A solution of (S)-2-(7-Chloro-1-oxo-1H-isoquinolin-2-yl)-butyric acid, tert butyl ester (322 mg) in dichloromethane (14 ml) was cooled to 0° C. Trifluoroacetic acid (3.5 ml) was added and the resulting mixture allowed to warm to room temperature and stir for 2 hours. The mixture was then concentrated under reduced pressure and the residue redissolved in dichloromethane. This process was repeated several times in order to remove excess trifluoroacetic acid. The resulting solid was slurried in diethyl ether, filtered and washed with more diethyl ether. The solid was then dried to constant weight under vacuum. This gave the sub-title product as a white solid (236 mg, 89%); m.p. 159.6-160.1° C.; [α]24D−47.0° (c=1.01, CHCl3); ir (solid) 1731.4, 1639.3, 1577.8, 1209.1, 1168.1 cm−1; 1H NMR (400 MHz, d6-DMSO) δ 0.82 (3H, t), 2.00-2.25 (2H, m), 5.20 (1H, m), 6.70 (1H, d), 7.49 (1H, d), 7.70-7.81 (2H, m), 8.18 (1H, s; 13C NMR (100 MHz, d6-DMSO) δ 10.8, 22.7, 60.8, 104.9, 126.5, 126.6, 128.8, 131.6, 132.5, 133.1, 135.8, 160.5, 171.7; MS ES (+) 266.27 (M+H).