Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH3:23])[C:9]1[C:10]([NH2:22])=[CH:11][CH:12]=[C:13]([CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[CH:27]=[C:28]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:29]([O:31][CH2:32][CH3:33])=[O:30])C>C(OCC)(=O)C.CCCCCC>[CH2:1]([N:8]([CH3:23])[C:9]1[CH:14]=[C:13]([CH2:15][N:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)[CH:12]=[CH:11][C:10]=1[NH:22][CH:27]=[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(Cc1ccccc1)c1cc(CN2CCOCC2)ccc1N
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)C(=CNc1ccc(CN2CCOCC2)cc1N(C)Cc1ccccc1)C(=O)OCC
Temperature: 120 °C

Procedure:
A mixture of N2-benzyl-N2-methyl-4-(4-morpholinylmethyl)-1,2-benzenediamine (3.1 g, 10 mmol) and diethyl ethoxymethylenemalonate (4.2 g, 20 mmol) is heated at 120° C. until HPLC shows that the reaction is complete (20 min). The product is applied in 10% ethyl acetate/hexane to a silica gel column which is eluted with 20% ethyl acetate/hexane to remove excess diethyl ethoxymethylenemalonate and then with 50% ethyl acetate/hexane to elute 3.7 g of the title compound as an oil.
Reaction SMILES: [C:1]1([CH2:7][O:8][N:9]2[C:15](=[O:16])[N:14]3[CH2:17][C@H:10]2[CH2:11][CH2:12][C@H:13]3[C:18]([OH:20])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C.[NH2:37][CH:38]1[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]1>ClCCl>[CH2:7]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:37][CH:38]1[CH2:39][CH2:40][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:42][CH2:43]1)=[O:20])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CC1
Temperature: 50 °C

Procedure:
To a solution of (2S,5R)-6-(phenylmethoxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (1.484 g, 5.37 mmol) in dry dichloromethane (60 ml) was added triethylamine (1.88 ml, 13.49 mmol), 2-chloro-1-methylpridinium iodide (1.60 g, 6.26 mmol), and 4-amino-1-BOC-piperidine (1.30 g, 6.49 mmol) sequentially at room temperature under nitrogen. The reaction was then heated to 50° C. for 1 hour. The reaction mixture was concentrated under vacuum and purified by silica gel chromatography on an Isco Combiflash (40 g silica gel, 40 mL/min, 254 nM, 15% to 100% EtOAc/hexane over 14 column volumes then 100% EtOAc for 4 column volumes; title compound eluted at 65% ethyl acetate/hexane) to afford the title compound as a pale orange solid.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[CH2:5][S:6][C:7]1[NH:11][C:10]2[CH2:12][CH2:13][CH2:14][CH2:15][C:9]=2[N:8]=1.ClC1C=CC=C(C(OO)=[O:29])C=1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[CH3:1][N:2]([CH3:20])[C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[CH2:5][S:6]([C:7]1[NH:8][C:9]2[CH2:15][CH2:14][CH2:13][CH2:12][C:10]=2[N:11]=1)=[O:29]
Reactant: CN(C)c1ccccc1CSc1nc2c([nH]1)CCCC2
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CN(C)c1ccccc1CS(=O)c1nc2c([nH]1)CCCC2
Temperature: 0 °C
Yield: 35 %

Procedure:
To a solution of 0.70 g (2.4 mmol) of 2-(2-dimethylaminobenzylthio)-4,5,6,7-tetrahydro-1H-benzimidazole in 7 ml of chloroform was added under chilling with ice 0.53 g (2.4 mmol) of 80% m-chloroperbenzoic acid for 10 min. To the resulting mixture were added chloroform and aqueous NaHCO3. The chloroform portion was taken out, and then subjected to extraction using six portions of 1N aqueous NaOH. To the aqueous NaOH portion was added an excess amount of aqueous NH4Cl to separate an oil out of the solution. The oil was then extracted with chloroform and dried over anhydrous sodium sulfate. Chloroform was distilled off, and the residue was crystallized from diethyl ether/hexane. The obtained crystalline products were collected by filtration and dried under reduced pressure to give 0.26 g of the desired compound as a white crystalline product, yield 35%.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9](=[O:20])[C:8]=1[Br:21])(=O)=O.[C:24]1([C:30]#[CH:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[CH2:13]([N:10]1[CH:11]=[CH:12][C:7]([C:31]#[C:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:8]([Br:21])[C:9]1=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=c1c(Br)c(OS(=O)(=O)C(F)(F)F)ccn1Cc1ccccc1
Reactant: C#Cc1ccccc1
Solvent: CN(C)C=O
Product: O=c1c(Br)c(C#Cc2ccccc2)ccn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1-benzyl-3-bromo-2-oxo-1,2-dihydropyridin-4-yl trifluoromethanesulfonate (1.0 g) in DMF (5.0 mL) was added phenylacetylene (0.4 mL) and degassed using house vacuum. The reaction flask was then purged with argon, added diisopropylethylamine (0.53 mL), and PdCl2(PPh3)2 (0.35 g) were added. The resulting mixture was stirred at room temperature for 15 min and heated at 65° C. under an argon atmosphere for 3 h. The dark colored reaction mixture was concentrated in vacuo, and the residue was partitioned between EtOAc (50 mL) and 5% aqueous citric acid (25 mL). The organic extracts were washed with water, dried (Na2SO4), filtered, and concentrated to dryness. The resulting material was purified by silica gel flash chromatography using 25% EtOAc in hexanes as the eluent. The appropriate fractions were combined, concentrated under reduced pressure. 1H NMR (CDCl3) δ: 7.57 (m, 2H), 7.38 (m, 8H), 7.21 (d, 1H, J=6.8 Hz), 6.25 (d, 1H, J=6.8 Hz), and 5.16 (d, 2H), ES-MS: m/z=364 (MH+); HR-MS m/z (MH+) calcd C20H15NOBr 364.0337, found 364.0337.
Reaction SMILES: [CH3:1][Li].[CH3:3][C:4]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:5]=1[CH:6]=[O:7]>C(OCC)C.[Ti](Cl)(Cl)(Cl)Cl>[CH3:3][C:4]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:5]=1[CH:6]([OH:7])[CH3:1]
Reactant: Cc1ccc([N+](=O)[O-])cc1C=O
Reactant: [Li]C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCOCC
Product: Cc1ccc([N+](=O)[O-])cc1C(C)O
Yield: 100.8 %

Procedure:
Following the General Procedure of Description 8, MeTiCl3 was freshly prepared prior to use from commercial titanium tetrachloride (TiCl4) (10.0 mL, 17.3 g, 91.0 mmol) and methyl lithium (MeLi) (1.6 M in Et2O, 57.0 mL, 91.0 mmol) in anhydrous diethyl ether (Et2O) (400 mL). A solution of 2-methyl-4-nitro-benzaldehyde (5j) (12.4 g, 75.01 mmol) in anhydrous Et2O (200 mL) was added. Aqueous work-up afforded 13.7 g (99% yield) of the target compound (5k) as a yellow solid. The material was of sufficient purity to be used directly in the next step without further isolation and purification procedures. Rf: ˜0.47 (EtOAc/Hxn=1:2 v/v). 1H NMR (300 MHz, CDCl3): δ 8.41 (d, J=2.4 Hz, 1H), 8.00 (dd, J=8.4, 2.4 Hz, 1H), 7.27 (d, J=9.0 Hz, 1H), 5.16 (q, J=6.3 Hz, 1H), 2.43 (s, 3H), 1.96 (br. s, 1H), 1.50 (d, J=6.3 Hz, 3H) ppm. The analytical data correspond to the data of compound (5b) of Method A.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:16](=[O:21])C(F)(F)F)=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[OH-:22].[Na+]>O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:16]([OH:21])=[O:22])=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]([CH3:14])[CH3:15])=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: CC(C)CCn1cc(C(=O)C(F)(F)F)c2ccc(Cl)cc21
Agent: [Na+]
Solvent: O
Product: CC(C)CCn1cc(C(=O)O)c2ccc(Cl)cc21
Temperature: 25 °C
Yield: 69.5 %

Procedure:
A mixture of 1-[6-chloro-1-(3-methyl-butyl)-1H-indol-3-yl]-2,2,2-trifluoro-ethanone (284.9 mg, 0.81 mmol) in a 20% aqueous sodium hydroxide solution (2.7 mL) was heated under reflux for 17 h. At this time, the reaction was cooled to 25° C. and was diluted with water (75 mL). This mixture was extracted with diethyl ether (1×50 mL). The aqueous layer was acidified to pH=1 with concentrated hydrochloric acid and then extracted with ethyl acetate (1×75 mL). The combined organic layers were washed with water (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford 6-chloro-1-(3-methyl-butyl)-1H-indole-3-carboxylic acid (149.3 mg, 69.5%) as a light orange solid: mp 53-55° C.; EI-HRMS m/e calcd for C14H16ClNO2 (M+) 265.0870, found 265.0860.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][NH:5][CH3:6].C(N(CC)CC)C.[C:18]([O:21][CH2:22][C:23](Cl)=[O:24])(=[O:20])[CH3:19]>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][N:5]([CH3:6])[C:23]([CH2:22][O:21][C:18](=[O:20])[CH3:19])=[O:24]
Reactant: CNCc1ccccc1Br
Reactant: CC(=O)OCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)OCC(=O)N(C)Cc1ccccc1Br
Temperature: 25 °C

Procedure:
To a solution of 2-bromo-N-methyl benzylamine (CAS#698-19-1, 0.57 mL, 3.89 mmol) in THF (10 mL) at 0° C. is added triethylamine (0.98 mL, 1.03 mmol) followed by acetoxyacetylchloride (0.63 mL, 5.86 mmol). The reaction is permitted to warm to room temperature and after two hours the reaction is quenched with saturated aqueous NaHCO3 and diluted with ethyl acetate. The layers are separated and the organic layer is dried with Na2SO4, filtered, and concentrated. The resulting residue is purified by silica gel flash chromatography (ethyl acetate-hexanes, 1:4 to 3:2) to provide acetic acid [(2-bromo-benzyl)-methyl-carbamoyl]-methyl ester; MS: (ESI) m/z 300.1, 302.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]=[C:9]2[O:12][Si](C)(C)C)=[CH:4][CH:3]=1.Cl[C:18]([CH3:21])([CH3:20])[CH3:19]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: CC(C)(C)Cl
Reactant: C[Si](C)(C)OC1=CCCc2ccc(Br)cc21
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)C1CCc2ccc(Br)cc2C1=O
Temperature: -40 °C
Yield: 100.8 %

Procedure:
step a—A solution of (7-bromo-3,4-dihydronaphthalen-1-yloxy)trimethylsilane (6.85 g, 11.5 mmol, CASRN 309929-09-7) and DCM (23.0 mL) was cooled to −40° C. 2-Chloro-2-methylpropane (1.12 g, 1.32 mL, 12.1 mmol) was added and the solution stirred under nitrogen. A solution of TiCl4 (2.19 g, 1.27 mL, 11.5 mmol) in DCM (6 mL) was added dropwise while maintaining the solution at −40° C. Soon after addition was complete TLC indicated ca. 50% conversion. The reaction was stirred at RT over the weekend then poured onto ice. The mixture was partitioned between EtOAc and H2O and aqueous layer was neutralized with satd. aq. NaHCO3. The mixture was filtered through a plug of celite to a remove chunky white precipitate. The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated. The crude product was applied to a hexane equilibrated SiO2 column and eluted with an EtOAc/hexane gradient (0 to 5% EtOAc) to afford 3.26 g (quantitative) of 7-bromo-2-tert-butyl-3,4-dihydro-2H-naphthalen-1-one (109) a yellow solid.
Reaction SMILES: [F:1][C:2]1[C:3]([C:21]2[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=2)=[N:4][C:5]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[C:6]([CH:10]=1)[C:7](O)=[O:8].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[NH2:61][CH2:62][C@H:63]1[CH2:66][CH2:65][N:64]1[C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68].CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[C:3]([C:21]2[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=2)=[N:4][C:5]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[C:6]([CH:10]=1)[C:7]([NH:61][CH2:62][C@H:63]1[CH2:66][CH2:65][N:64]1[C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68])=[O:8]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]1CN
Reactant: Cn1cc(-c2nc(NCCc3cccc(F)c3)c(C(=O)O)cc2F)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(-c2nc(NCCc3cccc(F)c3)c(C(=O)NC[C@H]3CCN3C(=O)OC(C)(C)C)cc2F)cn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of 5-fluoro-2-(3-fluorophenethylamino)-6-(1-methyl-1H-pyrazol-4-yl)nicotinic acid (14.3 g, 40 mmol) and DMF (300 mL) was added of HBTU (18.2 g, 48 mmol) and HOBT (6.49 g, 48 mmol). The mixture was cooled down to 0° C., 8.93 g (48 mmol) of (R)-tert-butyl 2-(aminomethyl)azetidine-1-carboxylate was added, followed by 13.9 ml of DIEA (80 mmol). The mixture was stirred at r.t for 1 hour and extracted with 300 mL EtOAc. The organic layer was washed with 500 mL brine, dried over MgSO4 and then concentrated. The residue was purified by Biotage silica gel chromatography using EtOAc:Hex (1:1) as eluant. (R)-tert-butyl 2-((5-fluoro-2-(3-fluorophenethylamino)-6-(1-methyl-1H-pyrazol-4-yl)nicotinamido)methyl)azetidine-1-carboxylate was obtained as a yellow solid (16.5 g, yield 80%). LRMS (M+H+) m/z 527.1.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[SH:6].Cl[C:8]1[S:12][C:11]([C:13](=[O:15])[CH3:14])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17].C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O>[N+:16]([C:9]1[CH:10]=[C:11]([C:13](=[O:15])[CH3:14])[S:12][C:8]=1[S:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1)([O-:18])=[O:17]
Reactant: Sc1nccs1
Reactant: CC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)c1cc([N+](=O)[O-])c(Sc2nccs2)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.9 %

Procedure:
To a solution of thiazole-2-thiol (0.05 g, 0.5 mmol) in toluene (10ML), was added 1-(5-Chloro-4-nitro-2-thienyl)ethanone (0.102 g, 0.5 mmol) and K2CO3 (0.69 g, 5 mmol). The resulting reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was diluted with water (10 mL) and was extracted with ethyl acetate. The organic extract was dried (Na2SO4), concentrated under vacuum and the residue purified by silica gel chromatography using a mixture of 70:30 ethyl acetate and hexane as eluent to afford the title product as a solid (60 mg, 43% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.51 (2H, s), 8.26 (2H, dd), 8.23 (2H, dd), 2.54 (3H, s). MS m/z: 287.9 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[CH2:12]([O:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1>[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]([NH:24][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:25][CH:26]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1cccnc1Nc1ccc(OCc2ccccc2)cc1
Temperature: 100 °C
Yield: 75 %

Procedure:
A mixture of 2-chloro-3-nitropyridine (2.0 g), 4-(benzyloxy)aniline hydrochloride (3.6 g), and cesium carbonate (12.3 g) in NMP (50 mL) was heated at 100° C. for 5 h. After cooling to rt, the mixture was partitioned between AcOEt and H2O. The organic layer was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography (SiO2, hexane/AcOEt=1/1) to give N-[4-(benzyloxy)phenyl]-3-nitropyridin-2-amine (3.04 g) as a brown solid.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:20]([NH:22][C@H:23]([C:28]([NH:30][CH2:31][CH2:32][C:33]([CH:35]=[N+]=[N-])=[O:34])=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26])=[O:21])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCOCC.[ClH:43].C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[C:4]([O:3][C:1]([NH:8][C@H:9]([C:20]([NH:22][C@H:23]([C:28]([NH:30][CH2:31][CH2:32][C:33]([CH2:35][Cl:43])=[O:34])=[O:29])[CH2:24][CH:25]([CH3:26])[CH3:27])=[O:21])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:2])([CH3:7])([CH3:5])[CH3:6]
Reactant: Cl
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(=O)NCCC(=O)C=[N+]=[N-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(=O)NCCC(=O)CCl

Procedure:
Boc-tryptophyl-leucyl-β-alanyl-diazomethane (Section 5.7.1) (0.24 g, 0.47 mmol) was dissolved in ethyl acetate (50 ml). Ether/HCl (40 ml) was added followed by 5% NaHCO3 (60 ml) 1 minute later. The mixture was agitated to neutralise the acid and the aqueous layer was removed. The organic phase was dried over magnesium sulphate and reduced to dryness. The peptide was recrystallised from ethyl acetate/petrol ether (40°/60° C.) and then diethyl ether/petrol ether (40°/60° C.). Yield 0.2 g (82%), m.p. 79°-81° C. The product was homogeneous as judged by tlc in chloroform/methanol (4:1) (Rf 0.770) or chloroform/methanol (1:1) (Rf 0.777). (Found: C, 59.83; H, 7.35; N, 10.81. C26H37O5N4Cl1 requires C, 60.00; H, 7.11; N, 10.77%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.I[C:22]1[N:27]=[CH:26][N:25]=[C:24]([C:28]([C:30]2[CH:39]=[C:38]([CH3:40])[C:33]3[O:34][CH2:35][CH2:36][O:37][C:32]=3[CH:31]=2)=[O:29])[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:22]4[CH:23]=[C:24]([C:28]([C:30]5[CH:39]=[C:38]([CH3:40])[C:33]6[O:34][CH2:35][CH2:36][O:37][C:32]=6[CH:31]=5)=[O:29])[N:25]=[CH:26][N:27]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: Cc1cc(C(=O)c2cc(I)ncn2)cc2c1OCCO2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5c(c4)OCCO5)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
61 mg (0.22 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 84 mg (0.22 mmol) (6-iodo-pyrimidin-4-yl)-(8-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-methanone and 0.08 mL (0.44 mmol) DIPEA were combined in 2.5 mL DMF and stirred overnight at RT. Then the reaction mixture was purified by preparative HPLC-MS. The fractions containing the product were combined and the organic solvent was evaporated down. The residue was combined with 1N aqueous sodium hydroxide solution, the precipitate formed was suction filtered, washed with water and dried.
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5]1[CH:6]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26](=[O:28])[NH2:27])[CH:21]=2)[N:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[CH:8]=[CH:9][CH:10]=1)C>C(O)C.[OH-].[Na+]>[C:26]([C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[O:19][CH:6]1[N:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[CH:8]=[CH:9][CH:10]=[C:5]1[C:4]([OH:29])=[O:3])(=[O:28])[NH2:27]
Reactant: CCOC(=O)C1=CC=CN(Cc2ccccc2Cl)C1Oc1cccc(C(N)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(=O)c1cccc(OC2C(C(=O)O)=CC=CN2Cc2ccccc2Cl)c1

Procedure:
A solution of 2-(3-Carbamoyl-phenoxy)-N-(2-chloro-benzyl)-nicotinic acid ethyl ester (4.31 grams, 16.08 mmole) in ethanol (100 ml) and 1 N sodium hydroxide (40.21 ml) was refluxed for 4 hours. The mixture was concentrated to 1/3 volume, diluted to 300 ml with water, acidified to pH 3 with 1 N hydrochloric acid and filtered to isolate a white solid which was recrystalized from ethyl acetate/hexane (3.8 g). M.P. 220-224° C.; Anal. calcd. for C13H10N2O4: C, 60.45; H, 3.91; N, 10.85. Found: C, 61.70; H, 3.61; N, 10.69.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH2:2][OH:3].[H-].[Na+].Cl[C:11]1[C:16]([C:17](OCC)=[O:18])=[CH:15][N:14]=[CH:13][CH:12]=1>COCCOC>[OH:18][C:17]1[C:16]2[CH:15]=[N:14][CH:13]=[CH:12][C:11]=2[O:3][C:2]=1[C:1]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)c1cnccc1Cl
Reactant: CCOC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)c1oc2ccncc2c1O
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 83.7 %

Procedure:
Ethyl glycolate (7.26 g, 59.7 mmol) was added slowly into a suspension of sodium hydride (2.95 g of 60% dispersion in mineral oil, 73.8 mmol) in 85 mL of 1,2-dimethoxyethane (DME) at 0° C., and the mixture was stirred for another 30 min. A solution of ethyl 4-chloronicotinate (6.20 g, 33.4 mmol) in 20 mL of DME was added slowly into the reaction mixture at room temperature. The mixture was heated to 70° C. and maintained at that temperature overnight. The solvent was evaporated and the residue was dissolved in 100 mL of water, and washed with hexane 3 times. The pH of the water solution was adjusted to about 5 using acetic acid to pH 5, and a yellow precipitate was formed. The yellow precipitate was filtered, washed with a small amount of water (20 mL×3), and dried overnight in vacuo to give ethyl 3-hydroxyfuro[3,2-c]pyridine-2-carboxylate free base as a yellow solid (5.79 g) which was used for the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[C:13]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=1)#[N:14].[Cl-].[Na+]>>[C:13]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH:20][S:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])=[CH:17][CH:16]=1)#[N:14]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: N#Cc1ccc(CN)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Product: N#Cc1ccc(CNS(=O)(=O)c2ccc(F)cc2)cc1
Yield: 89.5 %

Procedure:
Reaction was carried out in the same manner as in a Reference Example 2-(d) except for using 4-fluorobenzenesulfonyl chloride (1.18 g, 6.06 mmol) in place of 3-pyridylsulfonyl chloride, and using 4-cyanobenzylamine hydrochloride (1.00 g, 5.93 mmol) in place of (6-phenylpyridazin-3-ylmethyl)amine hydrochloride. After completion of the reaction, a saturated aqueous sodium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate. The separated organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. To the resulting residue dissolved in a small amount of methylene chloride was added hexane, and a precipitated solid was collected by filtration. The resulting solid was dried under reduced pressure at 60° C. to afford the title compound (1.54 g) as a slightly brown solid. (Yield: 89%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([NH:12][C:13](=[O:36])[O:14][CH2:15][C@@H:16]([N:22]([CH3:35])[C:23]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=1[Cl:34])=[O:24])[CH2:17][CH:18]([OH:21])[CH2:19][OH:20])=[CH:5]2.CO>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([NH:12][C:13](=[O:36])[O:14][CH2:15][C@@H:16]([N:22]([CH3:35])[C:23]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=1[Cl:34])=[O:24])[CH2:17][C@H:18]([OH:21])[CH2:19][OH:20])=[CH:5]2
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](COC(=O)Nc1cc2cc(F)ccc2cn1)CC(O)CO
Solvent: CO
Solvent: ClCCl
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](COC(=O)Nc1cc2cc(F)ccc2cn1)C[C@H](O)CO
Reaction time: 0.17 h
Yield: 14.3 %

Procedure:
A solution of crude (2S)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-4,5-dihydroxypentyl 6-fluoroisoquinolin-3-ylcarbamate (0.07 g) in DCM (1 mL) was loaded onto a TLC Silica gel 60 F254 (20×20 cm) plate and developed with a mixture of DCM and methanol (20:1). The top layer was collected and stirred in methanol (50 mL) for 10 min. After filtration, the filtrate was concentrated to give (2S,4S)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-4,5-dihydroxypentyl 6-fluoroisoquinolin-3-ylcarbamate (0.01 g, 14.3%). LRMS (M+H+) m/z 523.2. The same process was applied to the bottom layer to give (2S,4R)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-4,5-dihydroxypentyl 6-fluoroisoquinolin-3-ylcarbamate (27 mg, 38.6%). LRMS (M+H+) m/z 523.2.