Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.[NH:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[C:8]1[O:16][C:11]2=[CH:12][N:13]=[CH:14][CH:15]=[C:10]2[CH:9]=1.[C:17]([O-])([O-])=O.[K+].[K+]>C(O)=O.C=O>[ClH:1].[ClH:1].[CH3:17][N:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[C:8]1[O:16][C:11]2=[CH:12][N:13]=[CH:14][CH:15]=[C:10]2[CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: c1cc2cc([C@@H]3CCCN3)oc2cn1
Agent: C=O
Agent: Cl
Agent: [K+]
Solvent: O=CO
Product: CN1CCC[C@H]1c1cc2ccncc2o1
Temperature: 25 °C

Procedure:
A 120 mg sample of the compound from Example 9 above was dissolved in 4 mL of formic acid and 2 mL of formalin, and the reaction mixture was heated at reflux for 30 minutes. The reaction mixture was cooled to ambient temperature and poured into saturated K2CO3 solution. The resulting mixture was extracted with CH2Cl2, the extract was dried, and the solvent was removed. The residue was chromatographed on silica gel, and the compound was converted to the salt by treatment with HCl/ether: 1H NMR (D2O, 300 MHz) δ 2.30-2.40 (m, 3H), 2.50-2.74 (m, 1H), 2.98 (s, 3H), 3.45 (br d, 1H), 3.85 (br s, 1H), 4.97 (t, 1H), 7.47 (s, 1H), 8.08 (d, 1H), 8.51 (d, 1H), 9.10 (s, 1H); MS m/z: 203 (M+H)+ ; Anal. Calcd for C12H14N2O·2 HCl.0.5H2O: C, 50.70; H, 6.03; N, 9.86. Found: C, 50.69; H, 6.09; N, 9.61.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[NH:12][C:11](=[O:13])[O:10][C:8](=O)[C:7]=12.[NH:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1C(O)=O>CS(C)=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:10])[N:14]3[CH2:21][CH2:20][CH2:19][C@H:15]3[C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2cccc(Cl)c2c(=O)o1
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: CS(C)=O
Product: O=C1Nc2cccc(Cl)c2C(=O)N2CCC[C@@H]12

Procedure:
10 g (50.6 mmol) of 6-chloroisatoic acid anhydride are stirred at 110° C. for 2 hours with 5.82 g (50.6 mmol) of L-proline in 80 ml of dimethyl sulphoxide. The solution is evaporated and the residue is crystallised from ethyl acetate. There is obtained (S)-6-chloro-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11(10H)-dione of melting point 264°-266° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[CH:33]=[C:32]([S:37]([N:40]1[CH2:45][CH2:44][N:43]3[CH:46]=[CH:47][CH:48]=[C:42]3[CH:41]1[CH2:49][C:50]([OH:52])=O)(=[O:39])=[O:38])[CH:31]=[CH:30]2.[NH:53]1[CH2:57][CH2:56][N:55]=[C:54]1[C:58]1[CH:63]=[CH:62][C:61]([CH2:64][CH2:65][NH2:66])=[CH:60][CH:59]=1.CCN(C(C)C)C(C)C>C1COCC1>[NH:55]1[CH2:56][CH2:57][N:53]=[C:54]1[C:58]1[CH:59]=[CH:60][C:61]([CH2:64][CH2:65][NH:66][C:50](=[O:52])[CH2:49][CH:41]2[N:40]([S:37]([C:32]3[CH:31]=[CH:30][C:29]4[C:34](=[CH:35][CH:36]=[C:27]([O:26][CH3:25])[CH:28]=4)[CH:33]=3)(=[O:38])=[O:39])[CH2:45][CH2:44][N:43]3[CH:46]=[CH:47][CH:48]=[C:42]23)=[CH:62][CH:63]=1
Reactant: NCCc1ccc(C2=NCCN2)cc1
Reactant: COc1ccc2cc(S(=O)(=O)N3CCn4cccc4C3CC(=O)O)ccc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc2cc(S(=O)(=O)N3CCn4cccc4C3CC(=O)NCCc3ccc(C4=NCCN4)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 35 %

Procedure:
HATU (563 mg, 1.48 mmol, 2.0 eq.) was added to a mixture of 2-(2-(6-methoxynaphthalen-2-ylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)acetic acid (S-2) (297 mg, 0.74 mmol, 1.0 eq.), 2-(4-(4,5-Dihydro-1H-imidazol-2-yl)phenyl)ethanamine (A49) (140 mg, 0.74 mmol, 1.0 eq.), and DIPEA (0.39 ml, 2.22 mmol, 3.0 eq.) in THF (10 ml) at 0° C. and the resulting reaction mixture was stirred at RT for 14 h. The solvent was evaporated under reduced pressure, the residue dissolved in DCM (30 ml) and washed with saturated ammonium chloride solution (15 ml), saturated sodium bicarbonate solution (15 ml), water (15 ml) and brine (15 ml). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to yield the crude product which was purified by column chromatography (neutral alumina; 1% MeOH/DCM) to afford the desired product as an off-white solid. Yield: 35% (140 mg, 0.245 mmol); MS, Rt=3.3 min; m/z=572.5 [MH]+
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[O:9])=[C:6]([OH:21])[CH:5]=1.[CH3:22][O:23][CH2:24][CH2:25][O:26][CH2:27]Cl>CN(C=O)C>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH2:12][N:13]([CH2:14][CH3:15])[CH2:16][CH3:17])=[O:9])=[C:6]([O:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])[CH:5]=1
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1O
Reactant: COCCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCOCCOC
Reaction time: 4 h
Yield: 95 %

Procedure:
To a well stirred suspension of sodium hydride (0.34 g of 60%, 0.014 mole) in 5 ml dry DMF was added a solution of 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxy benzamide (3.57 g, 0.012 mole) in 15 ml dry DMF at room temperature over 18 minutes. The mixture was then stirred an additional hour giving essentially a clear solution. To this was added dropwise a solution of 2-methoxyethoxymethyl chloride (1.74 g, 0.014 mole) in 5 ml dry DMF. After an additional four hours at ambient temperature, the mixture was concentrated in vacuo, and the residue partitioned between water (200 ml) and methylene chloride (75 ml). The aqueous phase was extracted twice with 75 ml portions of methylene chloride. After combining, the organic phase was washed three times with 50 ml of 10% aqueous sodium hydroxide and three times with brine; dried over sodium sulfate, filtered, concentrated in vacuo, to give 4.26 grams of residue. Crystallization from ether gave 2.53 grams of the title compound, mp 79°-81° C. The NMR spectrum (90 MHz) in CDCl gave the following resonances: δ 8.18 (s, 2H); 6.61 (s, 1H); 5.40 (s, 2H); 4.40 (s, 2H); 3.84 (m, 2H); 3.50 (m, 4H); 3.44 (s, 3H); 2.56 (m, 6H); 1.04 (t, 6H).
Reaction SMILES: O=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[S:12]1[CH2:18][C:16](=[O:17])[NH:15][C:13]1=[S:14].C([O-])(=O)C.[Na+].C(O)(=O)C>O>[OH:9][C:8]1[CH:10]=[CH:11][C:3]([CH:2]=[C:18]2[S:12][C:13](=[S:14])[NH:15][C:16]2=[O:17])=[CH:4][C:5]=1[O:6][CH3:7]
Reactant: COc1cc(C=O)ccc1O
Reactant: O=C1CSC(=S)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(C=C2SC(=S)NC2=O)ccc1O

Procedure:
A mixture of vanillin (30.4 g, 0.2 mol), rhodanine (26.6 g, 0.2 mol), anhydrous sodium acetate (41 g, 0.5 mol) and glacial acetic acid was stirred and heated at reflux for one and one-half hours. The cooled reaction mixture was added to water (1200 mL) and the yellow-orange solid that separated was collected, washed with water and air dried; yield 46 g.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH:12]([C:14]1[N:18]2[N:19]=[C:20]([C:23]3[CH:24]=[N:25][N:26]([CH2:28][CH2:29][O:30]C4CCCCO4)[CH:27]=3)[CH:21]=[CH:22][C:17]2=[N:16][CH:15]=1)[CH3:13].Cl>C(Cl)Cl.O1CCOCC1>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH:12]([C:14]1[N:18]2[N:19]=[C:20]([C:23]3[CH:24]=[N:25][N:26]([CH2:28][CH2:29][OH:30])[CH:27]=3)[CH:21]=[CH:22][C:17]2=[N:16][CH:15]=1)[CH3:13]
Reactant: CC(c1cc2cccnc2cc1F)c1cnc2ccc(-c3cnn(CCOC4CCCCO4)c3)nn12
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(c1cc2cccnc2cc1F)c1cnc2ccc(-c3cnn(CCO)c3)nn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (rac)-7-fluoro-6-[1-(6-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-4-yl}-imidazo[1,2-b]pyridazin-3-yl)-ethyl]-quinoline (Stage 255.1, 49 mg, 0.101 mmol) in DCM (3 mL) stirred at rt was added a solution of HCl in dioxane (4 M, 0.252 mL). The RM was stirred 1 h at rt, during this time the product precipitated as an oil. The residue was taken in DCM and water, then neutralized with a solution of 10% NaHCO3 and extracted with DCM. The combined organic phase was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (CombiFlash® Companion System®, with RediSep® silica gel column, EtOAc/MeOH (1% NH3)=100:0->80:20) to afford the title compound as a white crystalline powder (tR 3.40 min (conditions 3), MH+=403.3, 1H-NMR in DMSO-d6: 8.81 (d, 1H), 8.35-8.28 (m, 2H); 8.05 (d, 1H); 7.95-7.88 (m, 2H), 7.76 (d, 1H); 7.72 (s, 1H); 7.49 (d, 1H); 7.46-7.40 (m, 1H); 5.03 (q, 1H); 4.92 (t, 1H); 4.15 (t, 2H); 3.72 (q, 2H); 2.83 (d, 3H)).
Reaction SMILES: O[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[CH2:13][N:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:15][C:3]=12.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[CH2:13][N:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:15][C:3]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc2c(c1O)CN(C(=O)OC)C2
Product: CCOC(=O)c1cnc2c(c1Cl)CN(C(=O)OC)C2
Temperature: 25 °C

Procedure:
A mixture of 8.44 g of ethyl 4-hydroxy-5,7-dihydro-6-methoxycarbonylpyrrolo[3,4-b]pyridine-3-carboxylate and 50 ml of phosphorous oxychloride is refluxed for four hours, cooled to room temperature, and evaporated to dryness. The residue is taken up in methylene chloride, cooled by the addition of ice and basified with 10N sodium hydroxide. The layers are separated, and the aqueous phase is re-extracted with methylene chloride. The combined organic extract is dried, filtered, and evaporated to dryness to give ethyl 4-chloro-5,7-dihydro-6-methoxycarbonylpyrrolo[3,4-b]pyridine-3-carboxylate
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([N+:23]([O-])=O)[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[C:7]([O:9][CH3:10])=[O:8])([O-])=O.[H][H]>C(O)(=O)C.[Pd]>[NH2:23][C:12]1[CH:11]=[C:6]([CH:5]=[C:4]([NH2:1])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: [H][H]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Oc2ccc(OC)cc2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)c1cc(N)c(Oc2ccc(OC)cc2)c(N)c1
Yield: 31.8 %

Procedure:
To a Parr shaker bottle containing a suspension of methyl 3,5-di-nitro-4-(4-methoxyphenoxy)-benzoate (20.2 g; 77.5 mmol) in glacial acetic acid (80 mL) was added 10% palladium on charcoal (0.7 g). The bottle was shaken under an atmosphere of hydrogen (3 atm) until no more hydrogen was consumed. The catalyst was filtered off and the resulting solution concentrated to approximately 10 mL. The residue was dissolved in acetone (50 mL) and heated on a steam bath while water (100 mL) was added in portions. Upon cooling, medium brown needles formed which were collected by suction filtration and dried to give 7.1 g (86%) of methyl 3,5-diamino-4-(4-methoxyphenoxy)benzoate. 300 MHz 1H NMR (CDCl3) d 3.73 (s, 3H, OCH3), 3.80 (bs, 4H, ArNH2) 3.86 (s, 3H, OCH3), 6.84 (m, 4H, ArH), 6.91 (s, 2H, ArH).
Reaction SMILES: [C:1]([C:3]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:4][OH:5])#[N:2].[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(N(CC)CC)C>C1C=CC=CC=1>[CH3:22][S:23]([O:5][CH2:4][C:3]([C:1]#[N:2])([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])(=[O:25])=[O:24]
Reactant: CCCCCCCCC(C#N)(CO)c1ccc(Cl)cc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCCCC(C#N)(COS(C)(=O)=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2-cyano-2-(2,4-dichlorophenyl)decan-1-ol (40g., 0.12 mole) and methane sulfonyl chloride (15.3g., 0.13 mole) in 2 liters of benzene is added dropwise at 10° C., 14.8g., (0.14 mole) of triethylamine. The reaction mixture is stirred at room temperature for 30 minutes and then heated on a steam bath for another 30 minutes. The precipitate formed is filtered and the filtrate is washed with dilute hydrochloric acid, water, saturated sodium bicarbonate solution, saturated sodium chloride solution and dried over magnesium sulfate. The solvent is evaporated to give 41.3g. of product, which is identified by nmr.
Reaction SMILES: [C:1]([O:10]CC)(=[O:9])[CH2:2][CH2:3][C:4]([O:6]CC)=[O:5].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[C:21]([O:25][CH3:26])[C:22]=1[O:23][CH3:24])[CH:18]=O.[H-].[Na+].[OH-].[Na+]>C(O)C>[CH3:26][O:25][C:21]1[CH:20]=[C:17]([CH:18]=[C:3]([CH2:2][C:1]([OH:10])=[O:9])[C:4]([OH:6])=[O:5])[CH:16]=[C:15]([O:14][CH3:13])[C:22]=1[O:23][CH3:24]
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: CCOC(=O)CCC(=O)OCC
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(C=C(CC(=O)O)C(=O)O)cc(OC)c1OC
Temperature: 0 °C
Yield: 83.9 %

Procedure:
To a stirred mixture of 17.4 g of diethyl succinate, 19.6 g of 3,4,5-trimethoxybenzaldehyde in 175 ml of ethanol chilled to 0° C. under argon was added 5.0 g of sodium hydride (60% in oil) in three equal portions. The solution was then refluxed for 30 minutes and 125 ml of 2N sodium hydroxide added. The solution was refluxed for 2 hours and concentrated under vacuum. The residue was diluted with water, extracted with ether and the aqueous layer acidified with concentrated hydrochloric acid. The mixture was extracted three times with 45 ml of ether and the ether extracts washed with saturated sodium chloride solution. The ether layer was dried (MgSO4) and the solvent removed under vacuum to give 24.82 g of [(3,4,5-trimethoxyphenyl)methylene]butanedioic acid as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1[CH2:16]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:18]#[N:19].[Na+]>CN(C=O)C.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1[CH2:16][C:18]#[N:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1cc(Br)ccc1OCc1ccccc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1cc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.7 %

Procedure:
A mixture of 2-bromomethyl-4-bromophenyl benzyl ether (0.28 moles) and NaCN (16 g) in DMF (200 ml) was stirred at ambient temperature for 16 hours, then heated at 100° C. for 5 hours. A further 2 g of NaCN was added and the reaction heated for 5 hours at 100° C. The mixture was diluted with water (200 ml) and stirred (1 hour). The resulting solid was filtered off and recrystallised from methanol to give 4-bromo-2-cyanomethylphenyl benzyl ether (48 g) mpt. 75°-76° C.
Reaction SMILES: C[O:2][C:3](=[O:30])[C@H:4]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1)[NH:5][C:6]([C:8]1([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].[N+:31]([C:34]1[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=1[C:36](O)=[O:37])([O-:33])=[O:32]>>[CH3:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][C:8]2([C:6]([NH:5][C@H:4]([C:3]([OH:2])=[O:30])[CH2:22][C:23]3[CH:24]=[CH:25][C:26]([NH:29][C:36]([C:35]4[CH:39]=[CH:40][CH:41]=[CH:42][C:34]=4[N+:31]([O-:33])=[O:32])=[O:37])=[CH:27][CH:28]=3)=[O:7])[CH2:9][CH2:10][CH2:11][CH2:12]2)=[CH:19][CH:18]=1
Reactant: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)C1(Cc2ccc(OC)cc2)CCCC1
Reactant: O=C(O)c1ccccc1[N+](=O)[O-]
Product: COc1ccc(CC2(C(=O)N[C@@H](Cc3ccc(NC(=O)c4ccccc4[N+](=O)[O-])cc3)C(=O)O)CCCC2)cc1
Yield: 51 %

Procedure:
4-Amino-N-[[1-[(4-methoxyphenyl)methyl]cyclopentyl]carbonyl]-L-phenylalanine methyl ester (32.3 mg, 0.079 mmol) and 2-nitrobenzoic acid (17 mg, 0.10 mmol) were reacted as described in example 40 to give 22 mg of N-[[1-[(4-methoxyphenyl)methyl]cyclopentyl]carbonyl]-4-[[(2-nitrophenyl)carbonyl]amino]-L-phenylalanine, HR-FAB-MS: obs. mass 546.2235. Calcd. mass 546.2240 (M+H).
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:25][N:26](C)[C:27](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][OH:24])[CH:18]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.Cl>C(OCC)(=O)C.CC(O)C>[F:1][C:2]1[C:3]([CH2:25][NH:26][CH3:27])=[CH:4][N:5]([S:14]([C:17]2[CH:18]=[C:19]([CH2:23][OH:24])[CH:20]=[CH:21][CH:22]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2cccc(CO)c2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CNCc1cn(S(=O)(=O)c2cccc(CO)c2)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.1 %

Procedure:
To a solution of tert-butyl [(4-fluoro-5-(2-fluoropyridin-3-yl)-1-{[3-(hydroxymethyl)phenyl]sulfonyl}-1H-pyrrol-3-yl)methyl]methylcarbamate (207 mg) in ethyl acetate (3 mL) and 2-propanol (2 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (6 mL), and the mixture was stirred at room temperature for 2 hr. The solvent was concentrated under reduced pressure, diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate solution. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→ethyl acetate:methanol=32:1) (basic TLC:Rf=0.1 (ethyl acetate)) to give a free base of the title compound as a pale-yellow oil (yield 82.6 mg). A solution of the obtained free base in ethyl acetate (1 mL) was added dropwise to a solution of fumaric acid (24 mg) in ethanol (1 mL) and the mixture was concentrated under reduced pressure. The residue was recrystallized from ethanol to give the title compound as a white solid (yield 69 mg, 36%).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]([CH:19]([CH3:21])[CH3:20])[C:16](=[O:18])[CH3:17])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)=O.[NH2:22][C:23]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[C:24]=1[C:25]([NH2:27])=[O:26].OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>CC(N(C)C)=O.O>[CH3:35][O:34][C:28]1[CH:29]=[C:30]([O:32][CH3:33])[CH:31]=[C:23]2[C:24]=1[C:25](=[O:26])[NH:27][C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]3[CH2:14][CH2:13][CH:12]([N:15]([CH:19]([CH3:21])[CH3:20])[C:16](=[O:18])[CH3:17])[CH2:11][CH2:10]3)=[CH:5][CH:4]=1)=[N:22]2
Reactant: CC(=O)N(C(C)C)C1CCN(c2ccc(C=O)cc2)CC1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCC(N(C(C)=O)C(C)C)CC4)cc3)nc2c1
Temperature: 155 °C
Yield: 20.7 %

Procedure:
To a solution of N-(1-(4-formylphenyl)piperidin-4-yl)-N-isopropylacetamide (0.300 g, 1.04 mmol) in DMA (10 mL) was added 2-amino-4,6-dimethoxybenzamide (0.204 g, 1.04 mmol), NaHSO3 (0.129 g, 1.24 mmol) and p-TsOH (0.019 g, 0.10 mmol). The resulting solution was heated to 155° C. overnight and then cooled to room temperature. The solution was diluted with water, extracted with CH2Cl2, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The material was purified by flash chromatography on silica gel eluting, with 30% to 100% of 92:7:1 CHCl3/MeOH/concentrated NH4OH in CH2Cl2, to afford the title compound (0.100 g, 20%). 1H NMR (300 MHz, DMSO-d6): mixture of rotamers δ 11.66 (s, 1H), 8.07 (d, J=8.3 Hz, 2H), 6.89-7.15 (m, 2H), 6.67 (s, 1H), 6.46 (s, 1H), 3.90-4.11 (m, 3H), 3.88 (s, 3H), 3.83 (s, 3H), 2.80-3.02 (m, 2H), 2.39-2.66 (m, 1H), 1.92-2.06 (m, 3H), 1.63-1.82 (m, 2H), 1.32-1.47 (m, 1H), 1.21-1.32 (m, 3H), 1.08-1.21 (m, 4H). ESI MS m/z 463 [M−H]−.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.CC(C)([O-])C.[K+].Cl[C:17]1[CH:22]=[CH:21][N:20]=[C:19]2[CH:23]=[C:24]([I:26])[S:25][C:18]=12.O>CS(C)=O>[F:9][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[O:8][C:17]1[CH:22]=[CH:21][N:20]=[C:19]2[CH:23]=[C:24]([I:26])[S:25][C:18]=12)[NH2:1]
Reactant: Nc1ccc(O)c(F)c1
Reactant: Clc1ccnc2cc(I)sc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 32 %

Procedure:
To a solution of 4-amino-2-fluorophenol (1.83 g, 14.38 mmol) in DMSO (30 mL) was added potassium tert-butoxide (1.61 g, 14.38 mmol). After 15 min, 7-chloro-2-iodothieno[3,2-b]pyridine (2.5 g, 8.46 mmol, Ragan J. A. et al, Organic Process Research and Development, 2003, 7. 676-683) was added and the reaction mixture was heated at 100° C. for 60 min. The mixture was cooled down to RT then poured into water (250 mL) at 40-45° C. and stirred for 30 min. The precipitate was collected by filtration, washed with water, dried and purified by flash column chromatography on silica gel (eluent 60% EtOAc in Hexane) to afford title compound 268 (1.06 g, 32% yield) as a brown solid. 1H NMR (300 MHz, CDCl3) δ (ppm): 8.41 (d, J=5.4 Hz, 1H), 7.75 (s, 1H), 7.03 (t, J=9.0 Hz, 1H), 6.57-6.45 (m, 3H), 3.83 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:44])[C@H:15]([NH:24][C:25]([C@@H:27]2[CH2:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29][N:28]2[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:26])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:10][CH2:9]1.N1C=CC=CC=1.[C:51]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[S:59](Cl)(=[O:61])=[O:60])#[N:52]>ClCCCl>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][C@@H:15]([NH:24][C:25]([C@@H:27]2[CH2:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29][N:28]2[C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])=[O:26])[C:14]([N:11]2[CH2:12][CH2:13][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[NH:1][S:59]([C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=3[C:51]#[N:52])(=[O:61])=[O:60])[CH2:9][CH2:10]2)=[O:44])=[CH:22][CH:21]=1
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(c2ccccc2N)CC1
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(c2ccccc2NS(=O)(=O)c2ccccc2C#N)CC1
Yield: 85.4 %

Procedure:
To a 50 mL round-bottomed flask equipped with stirring was added tert-butyl 3-(N-{(1R)-2-[4-(2-aminophenyl)piperidyl]-1-[(4-chlorophenyl)methyl]-2-oxoethyl}carbamoyl)(3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (Example 20) (154 mg, 0.25 mmol), 1,2-dichloroethane (10 mL) and pyridine (0.03 mL, 0.3/5 mmol). The reaction mixture was stirred for 5 min at RT, treated with 2-cyanobenzenesulfonyl chloride (Lancaster Synthesis) (50 mg, 0.25 mmol) and stirred at RT for 16 h. The reaction was quenched with satd NH4Cl (10 mL), the organic layer separated, and the aqueous layer extracted with CH2Cl2 (2×10 mL). The organic fractions were combined, washed with satd NaCl (10 mL), dried over Na2SO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (100% EtOAc) provided the title compound as a white foam (167 mg). MS (ESI, pos. ion) m/z: 782 (M+1); MS (ESI, neg. ion) m/z: 780 (M−1). Calc'd for C42H44ClN5O6S: 781.27.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH3:12][N:13]=[C:14]=[O:15]>O1CCCC1.C(N(CC)CC)C>[CH3:12][NH:13][C:14](=[O:15])[O:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1cc(O)ccc1[N+](=O)[O-]
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CNC(=O)Oc1ccc([N+](=O)[O-])c(C)c1

Procedure:
3-Methyl-4-nitrophenol (46.0g., 0.30 mole) was dissolved in tetrahydrofuran (200 ml.) and triethylamine (2 ml.). To this solution was added dropwise methylisocyanate (18.8g., 0.33 mole, 25 ml.) which resulted in an exotherm to about 40° C. Refluxing for one hour, followed by quenching in excess water, yieldig a light tan precipitate. After filtration and drying the material (51g.) melted at .99°-101° C.