Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[F:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31].Cl.Cl.[CH3:34][NH:35][CH:36]1[CH2:39][NH:38][CH2:37]1.CN1CCCC1>C(O)C>[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20]([N:38]4[CH2:39][CH:36]([NH:35][CH3:34])[CH2:37]4)[C:21]=3[F:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31]
Reactant: CNC1CNC1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(F)c32)c(F)cc1F
Agent: CN1CCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCO
Product: CNC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4nc(N)c(F)cc4F)c3c2F)C1
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 67.9 %

Procedure:
To 200 mg of N,N-dimethylformamide were added 65 mg 1-(6-amino-3,5-difluoropyridine-2-yl)-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 45 mg of 3-methylaminoazetidine dihydrochloride, and 100 mg of N-methylpyrrolidine together with 3 drops of ethanol, and the mixture was stirred at 85° C. for 30 minutes. After adding 0.2 ml of ethanol, the solution was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 52 mg of the title compound as a colorless powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([CH:13]=O)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[O:17]([NH2:19])[CH3:18]>>[C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[N:19][O:17][CH3:18])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CON
Reactant: CC(C)(C)OC(=O)c1ccc(C=O)cc1
Agent: Cl
Product: CON=Cc1ccc(C(=O)OC(C)(C)C)cc1

Procedure:
Reaction of 4-formyl-benzoic acid tert-butyl ester with methoxylamine hydrochloride as described in the preparation of compound 3-A gave the title oxime ether as a clear oil after chromatography on silica gel ( elution hexane-ethyl acetate, 96:4) (79% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.60 (9H, s, t-Bu), 4.00 (3H, s, OCH3), 7.62 (2H, d, J=8.0 Hz, aromatics), 7.97 (2H, d, J=8.0 Hz, aromatics), 8.08 (1H, s, CH).
Reaction SMILES: C[O:2][C:3]([C@H:5]1[NH:23][C:22](=[O:24])[C@H:21]([CH:25]([CH3:27])[CH3:26])[NH:20][C:19](=[O:28])[C@@H:18]([NH:29][S:30]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH2:17][C:16]2=[CH:40][CH:41]=[C:13]([CH:14]=[CH:15]2)[O:12][CH2:11][CH2:10][CH2:9][CH2:8][S:7][CH2:6]1)=O.CC(C[AlH]CC(C)C)C.CCOC(C)=O>C(Cl)Cl>[F:39][C:36]1[CH:35]=[CH:34][C:33]([S:30]([NH:29][C@H:18]2[CH2:17][C:16]3=[CH:40][CH:41]=[C:13]([CH:14]=[CH:15]3)[O:12][CH2:11][CH2:10][CH2:9][CH2:8][S:7][CH2:6][C@@H:5]([CH:3]=[O:2])[NH:23][C:22](=[O:24])[C@H:21]([CH:25]([CH3:26])[CH3:27])[NH:20][C:19]2=[O:28])(=[O:31])=[O:32])=[CH:38][CH:37]=1
Reactant: COC(=O)[C@@H]1CSCCCCOc2ccc(cc2)C[C@H](NS(=O)(=O)c2ccc(F)cc2)C(=O)N[C@@H](C(C)C)C(=O)N1
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)[C@@H]1NC(=O)[C@@H](NS(=O)(=O)c2ccc(F)cc2)Cc2ccc(cc2)OCCCCSC[C@@H](C=O)NC1=O
Temperature: -78 °C
Reaction time: 2 h

Procedure:
Ester 57 (47 mg) was dissolved in DCM (6 mL) under an atmosphere of argon. The reaction was cooled to −78° C. To the resultant solution DIBAL (0.42 mL) was added dropwise. This was stirred for 2 h before being allowed to warm to rt overnight. The reaction mixture was partitioned between EtOAc and 1M hydrochloric acid. The aqueous phase was extracted again with EtOAc and the combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. Purification was achieved using flash chromatography, eluting with a gradient of 1/1 EtOAc/(50/70) petroleum ether to EtOAc to yield a light brown solid, 9 mg, 20%. Rf=0.45 (1/1 EtOAc/(50/70) petroleum ether).
Reaction SMILES: C(OC([NH:11][C@@H:12]1[C@@H:18]2[CH:19]=[CH:20][C@@H:14]([C@@H:15]3[C@H:17]2[CH2:16]3)[C@@H:13]1[C:21]([O:23][CH3:24])=[O:22])=O)C1C=CC=CC=1.[ClH:25]>C(OCC)(=O)C.[Pd].C(OCC)C.O1CCOCC1>[ClH:25].[NH2:11][C@@H:12]1[C@@H:18]2[CH2:19][CH2:20][C@@H:14]([C@@H:15]3[C@H:17]2[CH2:16]3)[C@@H:13]1[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)[C@H]1[C@H]2C=C[C@H]([C@@H]3C[C@H]23)[C@H]1NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: C1COCCO1
Product: COC(=O)[C@@H]1[C@H](N)[C@@H]2CC[C@H]1[C@H]1C[C@H]12
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
rac-Methyl (1R,2R,4S,5S,6S,7R)-7-{[(benzyloxy)carbonyl]amino}tricyclo[3.2.2.02,4]non-8-ene-6-carboxylate (0.61 g, 1.85 mmol) was dissolved in ethyl acetate (10 mL). 5% Palladium on carbon (0.10 g) was added. The flask was degassed and backfilled with hydrogen gas via balloon. The mixture was stirred at 25° C. for 16 h. The mixture was passed through a plug of Celite and the filtrate was concentrated in vacuo to afford a thick clear oil. The oil was dissolved in diethyl ether (6 mL) and added dropwise, with vigorous stirring, to a mixture of a 4.0 M solution of hydrochloric acid in 1,4-dioxane (0.93 mL) in diethyl ether (11 mL). The mixture was concentrated and dried in vacuo to afford the desired product, rac-Methyl (1R,2R,4S,5S,6S,7R)-7-aminotricyclo[3.2.2.02,4]nonane-6-carboxylate hydrochloride (0.43 g, 1.85 mmol, 100%), as a sticky gum. LC-MS (ESI) calcd for C11H17NO2 (free amine) 195.26, found 196.5 [M+H+].
Reaction SMILES: [I-].[Na+].Cl[Si](C)(C)C.[CH:8]1([CH2:11][N:12]2[CH:17]=[C:16]([O:18]C)[C:15](=[O:20])[C:14]([C:21]3[N:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:24]=[CH:23][CH:22]=3)=[N:13]2)[CH2:10][CH2:9]1.O>C(#N)C>[CH:8]1([CH2:11][N:12]2[CH:17]=[C:16]([OH:18])[C:15](=[O:20])[C:14]([C:21]3[N:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:24]=[CH:23][CH:22]=3)=[N:13]2)[CH2:9][CH2:10]1
Reactant: COc1cn(CC2CC2)nc(-c2ccnn2-c2ccccc2)c1=O
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=c1c(O)cn(CC2CC2)nc1-c1ccnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
To a solution of sodium iodide (3.75 g) in acetonitrile (150 mL) was added chlorotrimethylsilane (3.17 mL) with stirring at room temperature for 30 min. Then, 1-(cyclopropylmethyl)-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (1.613 g) was added, and the mixture was stirred for 30 min at the same temperature and further refluxed for 4 hr. The reaction mixture was allowed to cool to room temperature, poured into water and the mixture was stirred for 30 min. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was triturated with diisopropyl ether, collected by filtration, washed successively with ethyl acetate and diisopropyl ether, and dried to give the title compound (1.23 g) as a pale-brown solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]([N:8]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH2:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=1[N+:17]([O-])=O)[C:4]([O:6][CH3:7])=[O:5].[H][H]>C(O)C.C(OCC)(=O)C.[Pd]>[OH:1][CH2:2][CH:3]([N:8]([S:20]([C:23]1[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)(=[O:22])=[O:21])[CH2:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=1[NH2:17])[C:4]([O:6][CH3:7])=[O:5]
Reactant: [H][H]
Reactant: COC(=O)C(CO)N(Cc1cc(C)ccc1[N+](=O)[O-])S(=O)(=O)c1ccc(OC)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)C(CO)N(Cc1cc(C)ccc1N)S(=O)(=O)c1ccc(OC)cc1

Procedure:
To a solution of 3.4 g of methyl 3-hydroxy-2-[(4-methoxybenzenesulfonyl)-(5-methyl-2-nitrobenzyl)-amino]propionate in 200 ml of ethanol-ethyl acetate (1:1) was added 0.34 g of 10% palladium on carbon (wet -50% H2O). The mixture was then shaken in a Parr hydrogenator under 35 psi of hydrogen for 2.5 hours. The mixture was filtered through diatomaceous earth and the filtrate concentrated under vacuum to give 2.86 a of a brown oil. Anal. for Cl19H4N2O6S: Calc'd: C,55.9; H,5.9; N,6.9: Found: C,55.6; H,5.9; N,6.4: Mass spectrum (ES) 409 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][N:6]=1)[CH3:3].[CH3:14][I:15]>C(OCC)(=O)C>[I-:15].[NH:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([CH2:4][N+:2]([CH3:14])([CH3:1])[CH3:3])=[N:6]1
Reactant: CI
Reactant: CN(C)Cc1n[nH]c2ccccc12
Solvent: CCOC(C)=O
Product: C[N+](C)(C)Cc1n[nH]c2ccccc12
Product: [I-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
3-Dimethylaminomethyl-1H-indazole (25.6 g, 146 mmol) obtained in Step 2 was dissolved in ethyl acetate (350 mL), and the solution was added with methyl iodide (33.3 mL, 535 mmol), followed by stirring at room temperature overnight. The resulting precipitates were collected by filtration to obtain (1H-indazol-3-ylmethyl)trimethylammonium iodide (45.0 g, 97%).
Reaction SMILES: [C:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][N:10]2[CH:13]2[CH2:18][CH2:17][N:16](C(OCC3C=CC=CC=3)=O)[CH2:15][CH2:14]2)=[CH:6][CH:5]=1)(=[O:3])[NH2:2].CO.[H][H]>[C].[Pd].O1CCCC1>[NH:16]1[CH2:15][CH2:14][CH:13]([N:10]2[C:11]3[C:7](=[CH:6][CH:5]=[C:4]([C:1]([NH2:2])=[O:3])[CH:12]=3)[CH:8]=[CH:9]2)[CH2:18][CH2:17]1
Reactant: NC(=O)c1ccc2ccn(C3CCN(C(=O)OCc4ccccc4)CC3)c2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: NC(=O)c1ccc2ccn(C3CCNCC3)c2c1
Temperature: 25 °C

Procedure:
43 g of benzyl 4-(6-carbamoyl-1H-indol-1-yl)piperidin-1-carboxylate was suspended in a mixed solution consisting of 400 ml of methanol and 600 ml of tetrahydrofuran. Thereafter, 3.3 g of 10% palladium carbon was added thereto. This suspension was substituted by hydrogen, and it was then stirred at room temperature. After completion of the reaction, 10% palladium carbon was filtered off from the reaction solution, and the reaction solution was then concentrated under a reduced pressure. Tetrahydrofuran was added to the residue, and the obtained mixture was concentrated again under a reduced pressure. Tetrahydrofuran was added to the generated residue, followed by stirring, so as to solidify the subject compound. Thereafter, tetrahydrofuran and ether were added thereto, followed by cooling on ice. The solidified subject compound was collected by filtration. The generated filtrate was concentrated, and thus, the subject compound was obtained in the same above manner. The total amount of the subject compounds was 25.2 g.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([Cl:14])[CH:8]=[CH:7][C:5]=2[N:6]=1.[N:15]12[CH2:23][CH2:22][CH:19]([CH2:20][CH2:21]1)[NH:18][CH2:17][CH2:16]2.C(=O)([O-])[O-].[K+].[K+]>C(O)CCCC>[Cl:14][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([N:18]3[CH:19]4[CH2:22][CH2:23][N:15]([CH2:21][CH2:20]4)[CH2:16][CH2:17]3)[S:3][C:4]=2[C:10]=1[N+:11]([O-:13])=[O:12]
Reactant: C1CN2CCC(CC2)N1
Reactant: O=[N+]([O-])c1c(Cl)ccc2nc(Cl)sc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCO
Product: O=[N+]([O-])c1c(Cl)ccc2nc(N3CCN4CCC3CC4)sc12
Temperature: 150 °C

Procedure:
1.29 g (5.15 mmol) of 2,6-dichloro-7-nitrobenzothiazole, 0.65 g (5.15 mmol) of 1,4-diazabicyclo[3.2.2]nonane, 0.71 g (5.15 mmol) of potassium carbonate and 60 ml of pentan-1-ol are successively introduced into a 250 ml round-bottomed flask. The mixture is heated at 150° C. for 14 h and is then cooled to ambient temperature before being filtered. The solvent is evaporated under reduced pressure and the residue is purified by chromatography on a column of silica gel, elution being carried out with a 98/2/0.2 mixture of chloroform, ethanol and aqueous ammonia. After recrystallizing from isopropyl alcohol, 0.54 g of crystals is collected by filtration.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C@@H:25]1[C@H:31]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@@H:30]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C@H:29]([CH3:48])[O:28][C@H:26]1[OH:27])(=[O:3])[CH3:2].[Cl:49][C:50]([Cl:54])([Cl:53])[C:51]#[N:52].C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[Cl:49][C:50]([Cl:54])([Cl:53])[C:51]([O:27][C@@H:26]1[O:28][C@@H:29]([CH3:48])[C@H:30]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C@@H:31]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@H:25]1[O:24][C@@H:6]1[O:7][C@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:5]1[NH:4][C:1](=[O:3])[CH3:2])=[NH:52]
Reactant: CC(=O)N[C@H]1[C@H](O[C@@H]2[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](C)O[C@H]2O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: N#CC(Cl)(Cl)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(=O)N[C@H]1[C@H](O[C@H]2[C@H](OC(=N)C(Cl)(Cl)Cl)O[C@@H](C)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
The hemiacetal 320 (541 mg, 0.80 mmol) was dissolved in CH2Cl2 (20 mL), placed under argon and cooled to 0° C. Trichloroacetonitrile (0.810 mL, 8 mmol), then DBU (10 μL, 80 μmol) were added. The mixture was stirred at 0° C. for 1 h. The mixture was concentrated and toluene was co-evaporated from the residue. The residue was eluted from a column of silica gel with 1:1 cyclohexane-EtOAc and 0.2% of Et3N to give 307 (560 mg, 86%) as a colourless foam; [α]D+20 (c 1, CHCl3). 1H NMR: δ 8.56 (s, 1H, NH), 7.50-7.20 (m, 10H, Ph), 6.29 (d, 1H, J1,2=1.3 Hz, H-1A), 5.50 (d, 1H, J2,NH=8.3 Hz, NHD), 5.17 (pt, 1H, J2,3=J3,4=9.5 Hz, H-3D), 5.09 (dd, 1H, J4,5=9.5 Hz, H-4D), 4.85-4.60 (m, 4H, CH2Ph), 4.68 (d, 1H, J1,2=8.0 Hz, H-1D), 4.22-4.10 (m, 2H, J5,6=5.0, J6a,6b=12.2 Hz, H-6aD, 6bD), 4.00 (m, 1H, H-2D), 3.99 (dd, 1H, J2,3=3.5 Hz, H-2A), 3.90 (dq, 1H, J4,5=9.6, J5,6=6.2 Hz, H-5A), 3.89 (dd, 1H, J3,4=9.5 Hz, H-3A), 3.62 (m, 1H, H-5D), 3.50 (dd, 1H, H-4A), 2.02, 2.00, 1.98 (3s, 9H, OAc), 1.65 (s, 3H, NHAc), 1.32 (d, 3H, H-6A); 13C NMR: δ 171.2, 171.0, 170.4, 169.6 (C═O), 160.5 (C═NH), 138.2-128.0 (Ph), 103.3 (C-1D), 97.3 (C-1A), 91.4 (CCl3), 80.3 (C-4A), 79.9 (C-3A), 77.5 (C-2A), 76.0, 73.8 (2C, CH2Ph), 73.1 (C-3D), 72.2 (C-5D), 71.1 (C-5A), 68.8 (C-4D), 62.5 (C-6D), 54.8 (C-2D), 23.3 (NHAc), 21.4, 21.1, 21.0 (3C, OAc), 18.4 (C-6A). Anal. Calcd for C36H43Cl3N2O13: C, 52.85; H, 5.30; N, 3.42. Found: C, 52.85; H, 5.22; N, 3.47.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([NH:19][NH:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[S:29])=[CH:23][CH:22]=1)(=[O:18])[CH3:17].C(NNC1C=CC(NC(N(CC2C=CC=CC=2)CC2C=CC=CC=2)=S)=CC=1)=O>>[C:16]([NH:19][NH:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[S:29])=[CH:23][CH:22]=1)(=[O:18])[CH3:17]
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: CC(=O)NNc1ccc(N=C=S)cc1
Agent: O=CNNc1ccc(NC(=S)N(Cc2ccccc2)Cc2ccccc2)cc1
Product: CC(=O)NNc1ccc(NC(=S)N(Cc2ccccc2)Cc2ccccc2)cc1

Procedure:
Dibenzylamine (0.20 g, 0.001 mole) and 4-(2-acetylhydrazino)phenyl isothiocyanate (0.21 g, 0.001 mole) were reacted according to the procedure described for NA-11 in Example 3. Yield 0.35 g (88 percent), m.p. 207°-209° C.
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][CH:7]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=2)=[CH:11][CH2:10][O:9][CH2:8]1)(=[O:4])=[O:3].[NH2:20][C:21]([NH2:23])=[S:22].C(#N)C>C(O)(C)C>[CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[C:21]([S:22][CH2:6][CH:7]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=2)=[CH:11][CH2:10][O:9][CH2:8]1)(=[NH:20])[NH2:23]
Reactant: CS(=O)(=O)OCC1COCC=C1c1cccc(Br)c1
Reactant: NC(N)=S
Solvent: CC#N
Solvent: CC(C)O
Product: CS(=O)(=O)O
Product: N=C(N)SCC1COCC=C1c1cccc(Br)c1
Temperature: 0 °C

Procedure:
A mixture of (4-(3-bromophenyl)-3,6-dihydro-2H-pyran-3-yl)methyl methanesulfonate (4.82 g, 11.7 mmol) and thiourea (1.78 g, 23.3 mmol) in isopropyl alcohol (100 mL) is heated to reflux for 24 h. The reaction is cooled and the solvent is removed under reduced vacuum to give a residue that is combined with acetonitrile (30 mL) and hexanes (10 mL). A solid crystallizes and the slurry is cooled to 0° C. The slurry is filtered using 3:1 ACN:hexanes as a rinse (25 mL) to give the title compound as the mesylate salt (3.45 g, 70%). ES/MS m/e (79Br/81Br) 327, 329 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]=[C:6]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1)[CH3:7])[CH3:2].[Br:20]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:19])[CH:5]=[C:6]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:18])[F:17])[CH:10]=1)[CH2:7][Br:20])[CH3:2]
Reactant: CCOC(=O)C=C(C)Oc1cccc(C(F)(F)F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C=C(CBr)Oc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 83.1 %

Procedure:
A solution of 3-(3-trifluoromethyl-phenoxy)-but-2-enoic acid ethyl ester (1.31 g, 4.77 mmol) in carbon tetrachloride (25 mL) was treated with N-bromosuccinimide (0.94 g, 5.28 mmol) and benzoyl peroxide (0.12 g). The reaction was then warmed to reflux for 5 h. At this time, the reaction was cooled to 25° C. and then placed in the freezer over the weekend. At this time, the reaction was removed from the freezer and allowed to thaw. The resulting precipitate was removed by filtration. The filtrate was concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 1-10% ethyl acetate/hexanes) afforded impure 4-bromo-3-(3-trifluoromethyl-phenoxy)-but-2-enoic acid ethyl ester (1.40 g, 83%) as a pale, yellow oil. The material was used without further purification.
Reaction SMILES: O1CCCC[C@@H]1O[CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=1.O.C1(C)C=CC(S(O)(=O)=[O:31])=CC=1>CO>[OH:31][C@@H:9]([CH3:8])[CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:21][CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCOC(=O)c1ccc(OCCCO[C@H]2CCCCO2)cc1
Solvent: O
Solvent: CO
Product: CCOC(=O)c1ccc(OC[C@H](C)O)cc1
Yield: 891.8 %

Procedure:
A mixture of 4.5 g (0.014 mol) of (S)-ethyl 4-(2-tetrahydropyranyloxy)propoxybenzoate, 0.2 g (0.0011 mol) of p-toluenesulfonic acid monohydrate and 45 ml of methanol were refluxed for 1 h. Then the same procedure as in Referential Example 2 was repeated to obtain 2.2 g of the crude product.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[N:8]=[CH:9][N:10](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:11]=1)=[O:6].ON>CO.C(Cl)Cl.CCOCC>[NH:10]1[CH:11]=[C:7]([C:5]2[O:6][N:2]=[CH:3][CH:4]=2)[N:8]=[CH:9]1
Reactant: CN(C)/C=C/C(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: NO
Solvent: ClCCl
Solvent: CCOCC
Solvent: CO
Product: c1cc(-c2c[nH]cn2)on1
Temperature: 25 °C
Yield: 30.3 %

Procedure:
A mixture of (E)-3-(dimethylamino)-1-(1-trityl-1H-imidazol-4-yl)prop-2-en-1-one (54.0 g, 133 mmol) and HONH2*HCl (10.13 g, 146 mmol) in MeOH (800 mL) was heated to reflux for 18 h. The mixture was then allowed to cool to RT and was concentrated in vacuo. The residue obtained was taken up in DCM and washed with H2O. The org. phase was then dried over Na2SO4, filtered and concentrated in vacuo. The residue obtained was stirred in Et2O, and the suspension was filtered. The filter cake was dried in vacuo at 40° C. The aqueous phase was then concentrated in vacuo and the residue obtained was placed in a Soxlet apparatus and continuously extracted with DCM for 36 h. The organic phase was then concentrated in vacuo and the residue obtained was stirred in DCM. The suspension was then filtered and the filter cake was dried in vacuo at 40° C. The two filter cakes were then crystallized in AcOEt to give the title compound (5.44 g). UPLC-MS: MS 136.1 (M+H+); UPLC rt 0.33 min.
Reaction SMILES: C(OC(=O)[N:7]([CH2:13][C:14]1[C:19]([F:20])=[CH:18][C:17]([C:21]2[CH:26]=[CH:25][C:24]([C:27](=[O:29])[NH2:28])=[CH:23][C:22]=2[CH3:30])=[CH:16][C:15]=1[F:31])[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])(C)(C)C.[ClH:33]>ClCCl.O1CCOCC1>[ClH:33].[F:20][C:19]1[CH:18]=[C:17]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([NH2:28])=[O:29])=[CH:23][C:22]=2[CH3:30])[CH:16]=[C:15]([F:31])[C:14]=1[CH2:13][NH:7][CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11]
Reactant: Cc1cc(C(N)=O)ccc1-c1cc(F)c(CN(CCC(C)C)C(=O)OC(C)(C)C)c(F)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cc(C(N)=O)ccc1-c1cc(F)c(CNCCC(C)C)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(4′-Carbamoyl-3,5-difluoro-2′-methyl-biphenyl-4-ylmethyl)-(3-methyl-butyl)-carbamic acid tert-butyl ester (I-1e: 40 g) was dissolved in 500 mL of dichloromethane and treated with 34 ml of a 4.0 M hydrogen chloride solution in dioxane. After stirring overnight at room temperature, the volatiles were removed under reduced pressure and the resulting crude material was suspended in ethanol (200 mL), heated at reflux for 20 minutes and stirred overnight at room temperature. The resulting slurry was collect via filtration, rinsing with chilled ethanol, and dried under vacuum to provide the title compound (E1-01: 25 g).
Reaction SMILES: [ClH:1].[CH2:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C:4](=[O:12])[O:3]1.[CH3:13]O>>[Cl:1][CH2:2][C:11]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:5][C:4]([O:3][CH3:13])=[O:12]
Reactant: O=C1Cc2ccccc2CO1
Reactant: CO
Reactant: Cl
Product: COC(=O)Cc1ccccc1CCl
Reaction time: 2 h
Yield: 98 %

Procedure:
Gaseous hydrogen chloride was bubbled through a solution of 3-isochromanone (2.0 g, 13.5 mmol) in methanol (30 ml) for 0.5 hour at room temperature and the reaction stirred for a further 2 hours. The methanol was removed under reduced pressure and the residue was dissolved in dichloromethane and dried. Removal of the solvent gave methyl 2-chloromethylphenylacetate (2.62 g, 98%) as an oil which was used without further purification; 1H NMR (270 MHz)δ: 3.70(3H,s), 3.81(2H,s), 4.68(2H,s), 7.22-7.40(4H,m) ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](F)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.CN(C=O)C.Cl.[CH2:33]([O:35][C:36](=[O:39])[CH2:37][NH2:38])[CH3:34]>C1COCC1>[CH2:33]([O:35][C:36](=[O:39])[CH2:37][NH:38][C:6]1[CH:7]=[C:2]([F:1])[C:3]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10])[CH3:34]
Reactant: O=[N+]([O-])c1cc(OCc2ccccc2)c(F)cc1F
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)CNc1cc(F)c(OCc2ccccc2)cc1[N+](=O)[O-]
Yield: 7.8 %

Procedure:
By using 4.41 g of benzyl 2,4-difluoro-5-nitrophenyl ether, 5.05 g of triethylamine, 30 ml of DMF, 30 ml of THF and 2.32 g of glycine ethyl ester hydrochloride, 454 mg (8%) of N-(4-benzyloxy-5-fluoro-2-nitrophenyl)glycine ethyl ester was obtained.