Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[C@@:41]2([OH:43])[O:42][C@H:5]([CH2:6][C@H:7]([O:64]C)[C:8]([CH3:63])=[CH:9][CH:10]=[CH:11][CH:12]=[CH:13][C@@H:14]([CH3:62])[CH2:15][C@@H:16]([CH3:61])[C:17]([C@H:19]([O:59][CH3:60])[C@H:20]([OH:58])[C:21]([CH3:57])=[CH:22][C@@H:23]([CH3:56])[C:24]([CH2:26][C@@H:27]([C@@H:44]([CH2:46][C@H:47]3[CH2:52][C@@H:51]([O:53][CH3:54])[C@H:50]([OH:55])[CH2:49][CH2:48]3)[CH3:45])[O:28][C:29]([C@H:31]3[N:36]([C:37]([C:39]2=[O:40])=[O:38])[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])=[O:25])=[O:18])[CH2:4][CH2:3]1.O.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>ClCCl>[CH3:1][C@H:2]1[C@@:41]2([OH:43])[O:42][C@H:5]([CH2:6][C:7]([C:8]([CH3:63])=[CH:9][CH:10]=[CH:11][CH:12]=[CH:13][C@@H:14]([CH3:62])[CH2:15][C@@H:16]([CH3:61])[C:17]([C@H:19]([O:59][CH3:60])[C@H:20]([OH:58])[C:21]([CH3:57])=[CH:22][C@@H:23]([CH3:56])[C:24]([CH2:26][C@@H:27]([C@@H:44]([CH2:46][C@H:47]3[CH2:52][C@@H:51]([O:53][CH3:54])[C@H:50]([OH:55])[CH2:49][CH2:48]3)[CH3:45])[O:28][C:29]([C@H:31]3[N:36]([C:37]([C:39]2=[O:40])=[O:38])[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])=[O:25])=[O:18])=[O:64])[CH2:4][CH2:3]1
Reactant: CO[C@H]1C[C@@H]2CC[C@@H](C)[C@@](O)(O2)C(=O)C(=O)N2CCCC[C@H]2C(=O)O[C@H]([C@H](C)C[C@@H]2CC[C@@H](O)[C@H](OC)C2)CC(=O)[C@H](C)C=C(C)[C@@H](O)[C@@H](OC)C(=O)[C@H](C)C[C@H](C)C=CC=CC=C1C
Agent: CO[C@@H]1C[C@H](C[C@@H](C)[C@@H]2CC(=O)[C@H](C)/C=C(\C)[C@@H](O)[C@@H](OC)C(=O)[C@H](C)C[C@H](C)/C=C\C=CC=C(C)C(=O)C[C@@H]3CC[C@@H](C)[C@@](O)(O3)C(=O)C(=O)N3CCCC[C@H]3C(=O)O2)CC[C@H]1O
Agent: CO[C@H]1C[C@@H]2CC[C@@H](C)[C@@](O)(O2)C(=O)C(=O)N2CCCC[C@H]2C(=O)O[C@H]([C@H](C)C[C@@H]2CC[C@@H](O)[C@H](OC)C2)CC(=O)[C@H](C)/C=C(\C)[C@@H](O)[C@@H](OC)C(=O)[C@H](C)C[C@H](C)/C=C/C=C/C=C/1C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: ClCCl
Product: CO[C@@H]1C[C@H](C[C@@H](C)[C@@H]2CC(=O)[C@H](C)C=C(C)[C@@H](O)[C@@H](OC)C(=O)[C@H](C)C[C@H](C)C=CC=CC=C(C)C(=O)C[C@@H]3CC[C@@H](C)[C@@](O)(O3)C(=O)C(=O)N3CCCC[C@H]3C(=O)O2)CC[C@H]1O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of rapamycin (5 mg, 0.055 mmol) in dichloromethane (0.1 mL) was added water (0.02 mL) followed by DDQ (2.4 mg, 0.011 mmol), and the resulting dark brown suspension was stirred at room temperature for 45 min. The mixture was filtered through celite and then partitioned between dichloromethane and brine; the organic extracts were dried over anhydrous magnesium sulfate and the resulting crude material was purified by prep TLC. The desired product was isolated as a colorless oil (1.2 mg). 1 H NMR (CDCl3, 400 MHz, 3:1 mixture of trans:cis amide rotamers; data for the trans-rotamer): -- 7.145 (d, J=10.4 Hz, 1H), 6.635 (dd, J=14.9, 10.6 Hz, 1H), 6.57-6.48 (m, 2H), 6.224 (dd, J=15.1, 10.6 Hz, 1H), 5.662 (dd, J=15.1, 8.6 Hz, 1H), 5.447 (d, J=11.2 Hz, 1H), 4.305 (br d, J=5.4 Hz, 1H), 3.983 (d, J=5.4 Hz, 1H), 3.385 (s, 3H), 3.346 (s, 3H),; MS (ESl+/NH4OAc) m/z 920 (M+Na+), 915 (M+NH4+), 898, 880; UV (MeOH) max 318 nm.
Reaction SMILES: [O:1]([C:13]1[CH:18]=[C:17]([CH2:19][OH:20])[CH:16]=[CH:15][C:14]=1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH3:29])=[CH:24][CH:23]=1)[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32].Cl>CC1C=C(C)C=C(C)N=1>[CH2:34]([O:33][C:31]([O:12][CH2:11][C@H:9]1[O:10][C@@H:2]([O:1][C:13]2[CH:18]=[C:17]([CH2:19][OH:20])[CH:16]=[CH:15][C:14]=2[CH2:21][C:22]2[CH:23]=[CH:24][C:25]([CH2:28][CH3:29])=[CH:26][CH:27]=2)[C@H:3]([OH:4])[C@@H:5]([OH:6])[C@@H:7]1[OH:8])=[O:32])[CH3:35]
Reactant: CCOC(=O)Cl
Reactant: CCc1ccc(Cc2ccc(CO)cc2O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Agent: Cl
Solvent: Cc1cc(C)nc(C)c1
Product: CCOC(=O)OC[C@H]1O[C@@H](Oc2cc(CO)ccc2Cc2ccc(CC)cc2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 17 h
Yield: 22.6 %

Procedure:
To a solution of 2-(4-ethylbenzyl)-5-hydroxymethylphenyl β-D-glucopyranoside (0.075 g) in 2,4,6-trimethypyridine (2 mL) was added ethyl chloroformate (0.037 mL, 2 mol equivalent), and the mixture was stirred at room temperature for 17 hours. To the reaction mixture was added 1 mol/L hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with 1 mol/L hydrochloric acid and water, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel (eluent: dichloromethane/-methanol=10/1) and recrystallized (recrystallization solvent: acetone/hexane=1/1) to give 2-(4-ethylbenzyl)-5-hydroxymethylphenyl 6-O-ethoxycarbonyl-β-D-glucopyranoside (0.020 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([S:19](=[O:22])(=[O:21])[NH2:20])=[CH:15][CH:14]=2)[C:10]#N)=[CH:5][CH:4]=1.O=[CH:24][C:25](=C)[CH3:26]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19](=[O:22])(=[O:21])[NH2:20])=[CH:15][CH:14]=3)[CH:24]=[C:25]([CH3:26])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(C#N)Nc2ccc(S(N)(=O)=O)cc2)cc1
Reactant: C=C(C)C=O
Product: COc1ccc(-c2cc(C)cn2-c2ccc(S(N)(=O)=O)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(iii), but using α-(4-methoxyphenyl)-α-(4-sulfamoylanilino)acetonitrile [prepared as described in step (ii) above] and methacrolein as starting materials, the title compound was obtained as a pale brown powder (yield 6%), melting at 163-166° C.
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH3:23])[CH2:18]1)[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:7])(C)(C)C.Cl.[C:25]([O:29][C:30]([NH:32][C@H:33](C(O)=O)[CH2:34][C:35]1[N:36]=[CH:37][S:38][CH:39]=1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCOCC1>[C:25]([O:29][C:30]([NH:32][C@H:33]([C:6]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH3:23])[CH2:18]1)[CH2:10][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)=[O:7])[CH2:34][C:35]1[N:36]=[CH:37][S:38][CH:39]=1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cscn1)C(=O)O
Reactant: C[C@@H]1C[C@@H]([C@H](CC2CCCCC2)NC(=O)OC(C)(C)C)OC1=O
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: C[C@@H]1C[C@@H]([C@H](CC2CCCCC2)NC(=O)[C@H](Cc2cscn2)NC(=O)OC(C)(C)C)OC1=O
Temperature: 25 °C
Reaction time: 1.08 h
Yield: 70.2 %

Procedure:
A mixture of 513 mg (1.58 mmole) of (3R, 5S)-5-[(1S)-1-(t-butoxycarbonyl)amino-2-cyclohexylethyl]-3-methyldihydrofuran-2(3H)-one (prepared as described in Preparation 2) and 20 ml of a 4N solution of hydrogen chloride in dioxane was stirred at room temperature for 65 minutes. At the end of this time, the solvent was stripped from the mixture by distillation under reduced pressure, and diethyl ether was added to the residue. The resulting mixture was then concentrated by evaporation under reduced pressure. This operation was repeated three times, in total, after which the final residue was dried by evaporation under reduced pressure for 8 hours. At the end of this time, the dried materials were suspended in 30 ml of anhydrous tetrahydrofuran, and 460 mg (1.69 mmole) of N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanine were added to the suspension. 0.27 ml (1.69 mmole) of 95% diethyl cyanophosphonate and 0.88 ml (6.34 mmole) of triethylamine were then added to the mixture, whilst ice-cooling and under an atmosphere of nitrogen. The mixture was then stirred at room temperature for 6 hours, after which the solvent was removed by distillation under reduced pressure. The resulting residue was mixed with 50 ml of water to deposit gummy materials. These were collected by filtration and washed with water. They were then dissolved in methylene chloride. The resulting solution was dried over anhydrous magnesium sulfate, and the solvent was then removed by distillation under reduced pressure. The residue was recrystallized from diisopropyl ether to afford 532 mg of the title compound as white crystals, melting at 118°-120° C.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:26])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([C:15]3[S:16][CH:17]=[C:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[N:19]=3)[CH:6]=[CH:5][C:4]1=2.C([O:30][CH2:31][CH2:32][CH2:33][CH2:34]Br)(=O)C.[OH-].[Na+]>CO>[CH3:2][C:3]1([CH3:26])[CH2:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]2[CH:8]=[C:7]([C:15]3[S:16][CH:17]=[C:18]([CH:20]4[CH2:25][CH2:24][N:23]([CH2:34][CH2:33][CH2:32][CH2:31][OH:30])[CH2:22][CH2:21]4)[N:19]=3)[CH:6]=[CH:5][C:4]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3nc(C4CCNCC4)cs3)ccc21
Reactant: CC(=O)OCCCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc(-c3nc(C4CCN(CCCCO)CC4)cs3)ccc21

Procedure:
The preparation was carried out as already described starting from 100 mg (0.28 mmol) of 4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-4-yl]piperidine hydrochloride (preparation already described above) and 61 μl (0.42 mmol) of 4-bromobutyl acetate. The protecting group was cleaved off by means of a 1N NaOH solution in methanol. The product was purified by means of preparative HPLC and is in the form of the hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=3)[O:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.O.O.[Sn](Cl)Cl>CO.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=3)[O:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(-c2nc(-c3cccc(Cl)c3)co2)cc1
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1ccc(-c2nc(-c3cccc(Cl)c3)co2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 37.7 %

Procedure:
under an N2 atmosphere, was 4-(3-chlorophenyl)-2-(4-nitrophenyl)oxazole (2.65 g, 8.81 mmol) suspended in methanol (20.0 mL) and tin(II) chloride dihydrate (7.95 g, 35.3 mmol) was added. The reaction was stirred at room temperature for ca. 72 h. LC-MS showed the reaction was not complete. The reaction was heated to 60° C. for 5 hours. The reaction was then diluted with ethyl acetate and washed with 0.1N HCl, followed by 5% NaHCO3 and brine. The organic layer was then dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by chromatography on silica gel, eluting with 20% to 40% ethyl acetate in hexanes. The resulting solid was triturated with ethyl acetate/hexanes and the resulting solid was collected by filtration to afford 4-(4-(3-chlorophenyl)oxazol-2-yl)benzenamine (0.898 g, 37.6% yield). ESI m/z=271.0 (M+H+).
Reaction SMILES: [CH3:1][C@@H:2]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[C:3]#[CH:4].Cl/[C:14](=[N:20]\[OH:21])/[C:15]([O:17][CH2:18][CH3:19])=[O:16].CCN(CC)CC>CN(C=O)C>[C:8]([O:7][C:6]([NH:5][C@@H:2]([C:3]1[O:21][N:20]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:4]=1)[CH3:1])=[O:12])([CH3:11])([CH3:10])[CH3:9]
Reactant: CCOC(=O)/C(Cl)=N/O
Reactant: C#C[C@@H](C)NC(=O)OC(C)(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc([C@@H](C)NC(=O)OC(C)(C)C)on1
Reaction time: 5 h

Procedure:
To a stirred solution of (R)-tert-butyl but-3-yn-2-ylcarbamate (262.5 g, 1.56 mol) and (Z)-ethyl 2-chloro-2-(hydroxyimino)acetate (78.2 g, 0.52 mol) in DMF (1 L) was added dropwise Et3N (216 mL, 1.56 mol) at 90° C. The mixture was stirred for 5 hr, and then concentrated in vacuo. The residue was re-dissolved in ethyl acetate. The ethyl acetate solution was washed with water, dried over Na2SO4, and evaporated to provide the crude compound (R)-ethyl 5-(1-(tert-butoxycarbonylamino)ethyl)isoxazole-3-carboxylate. To a solution of (R)-ethyl 5-(1-(tert-butoxycarbonylamino)ethyl)isoxazole-3-carboxylate in THF (2 L) was added aqueous 2.5 N LiOH (1 L) at RT. The mixture was stirred for 1 hr, and then evaporated under reduced pressure to remove THF. The residue was partitioned between water (1 L) and ethyl acetate (0.5 L). The organic layer was separated and the aqueous layer was extracted with ethyl acetate twice. The aqueous layer was adjusted to pH 2 with 10% HCl and extracted with ethyl acetate (2×1 L). All the organic layers were combined, washed with water, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was dried under vacuum to give the crude product N.4, (R)-5-(1-(tert-butoxycarbonylamino)ethyl)isoxazole-3-carboxylic acid (55.2 g, 44.8%), which was used without further purification. 1H NMR (CDCl3) δ 6.57 (s, 1H), 4.12 (q, 1H), 1.56 (d, 3 H), 1.37 (s, 9H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([F:28])[C:23]([O:25]CC)=[O:24])=[CH:17][CH:16]=1)[CH3:11]>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([F:28])[C:23]([OH:25])=[O:24])=[CH:17][CH:16]=1)[CH3:11]
Reactant: CCOC(=O)C(F)Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1
Solvent: ClCCl
Product: CN(CCOc1ccc(CC(F)C(=O)O)cc1)c1nc2ccccc2o1

Procedure:
The title compound, mp 146°-8° C. (dichloromethane) was prepared from ethyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-fluoropropanoate by a procedure similar to that described for Example 6.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:35]([Cl:36])=[CH:34][C:8]([CH2:9][NH:10]/[C:11](=[N:26]\[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])/[NH:12][C:13](=[O:25])[CH2:14][CH:15]([OH:24])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[CH:7][C:6]=1[Cl:37])(=[O:3])[CH3:2]>ClCCl.O=[Mn]=O>[C:1]([NH:4][C:5]1[C:6]([Cl:37])=[CH:7][C:8]([CH2:9][NH:10]/[C:11](=[N:26]\[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:30])[CH3:31])/[NH:12][C:13](=[O:25])[CH2:14][C:15]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[O:24])=[CH:34][C:35]=1[Cl:36])(=[O:3])[CH3:2]
Reactant: COc1ccc(C(O)CC(=O)N/C(=N/C(=O)OC(C)(C)C)NCc2cc(Cl)c(NC(C)=O)c(Cl)c2)cc1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: COc1ccc(C(=O)CC(=O)N/C(=N/C(=O)OC(C)(C)C)NCc2cc(Cl)c(NC(C)=O)c(Cl)c2)cc1
Temperature: 50 °C
Reaction time: 12 h
Yield: 65.6 %

Procedure:
A mixture of (E)-tert-butyl (4-acetamido-3,5-dichlorobenzylamino)(3-hydroxy-3-(4-methoxyphenyl)propanamido)methylenecarbamate (26 mg) and MnO2 in dichloromethane (0.10 mL) was stirred at 50° C. for 12 h. The crude reaction mixture was filtered and concentrated under vacuum to give the title compound as a yellow sticky oil (17 mg, 66% yield). 1H NMR (400 MHz, CDCl3) δ 1.43-1.51 (9H, m), 1.11 (3H, s), 3.76-3.90 (5H, m), 4.35-4.69 (2H, m), 6.75-7.25 (4H, m), 7.26-7.90 (3H, m), 8.70 (1H, brd s), 11.90 (1H, brd s). HPLC retention time: 2.775 min (method A). MS (ESI) (M+H)+ 551.01.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C-]#N.[K+]>COC1C=CC=CC=1CO>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][C:20]3[CH:21]=[CH:10][CH:11]=[CH:15][C:16]=3[O:18][CH3:19])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Agent: COc1ccccc1CO
Agent: [C-]#N
Agent: [K+]
Product: COc1ccccc1COC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Reaction time: 36 h

Procedure:
A mixture of 3.45 g (10 mmol) of ethyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate, 100 mg (1.5 mmol) of potassium cyanide and 20 ml of 2-methoxybenzyl alcohol is stirred at 110° for 36 hours, the resulting ethanol being removed in vacuo from time to time. The solvent is subsequently removed by distillation in a high vacuum and the residue is chromatographed on silica gel while eluting with ethyl acetate. By recrystallization from ethyl acetate/n-hexane there is obtained o-methoxybenzyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 178°-179°.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:21]([N:28]([CH2:30][CH:31]1[O:36][CH2:35][CH2:34][NH:33][CH2:32]1)[CH3:29])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:33]4[CH2:34][CH2:35][O:36][CH:31]([CH2:30][N:28]([CH2:21][C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH3:29])[CH2:32]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CN(Cc1ccccc1)CC1CNCCO1
Product: CN(Cc1ccccc1)CC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CCO1

Procedure:
By the use of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 2-(N-benzyl-N-methylaminomethyl)morpholine, the reaction is similarly carried out as Example 11 to give 1-cyclopropyl-7-[2-(N-benzyl-N-methylaminomethyl)morpholino]-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, melting at 155°-157° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]([O:15]CC)=O)[NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[NH3:18].CO>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]([NH2:18])=[O:15])[NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2ccc(Cl)cc2c(=O)[nH]1
Reactant: N
Solvent: CO
Product: NC(=O)c1cc2ccc(Cl)cc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
Ethyl 7-chloro-1-oxo-1,2-dihydroisoquinoline-3-carboxylate (580 mg, 2.30 mmol) was dissolved in NH3/MeOH(4.0M, 15 mL) and the reaction mixture was stirred at RT overnight. The solvent was removed in vacuo. The resulting residue was washed with petroleum ether and dried to give the title compound (200 mg, 38%). ESI-MS m/z [M+H]+223.1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([N+:20]([O-])=O)=[CH:14][C:13]=2[F:23])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8]>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([NH2:20])=[CH:14][C:13]=2[F:23])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:8])[F:9]
Reactant: COc1cc(-c2nn(C)c(C(F)(F)F)c2Cl)c(F)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: COc1cc(-c2nn(C)c(C(F)(F)F)c2Cl)c(F)cc1N
Yield: 95.5 %

Procedure:
To a solution of 4.05 g of 4-chloro-3-(2-fluoro-5-methoxy-4-nitrophenyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole in 50 ml of acetic acid was added 1.39 g (0.0249 mol) of iron powder. The reaction mixture was heated near reflux for 2 hours, treated with 1.39 g of iron powder, and heated at near reflux for another hour. After cooling, concentrating and chromatography, 3.54 g of 4-chloro-3-(4-amino-2-fluoro-5-methoxyphenyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole was isolated.
Reaction SMILES: S([O-])([O-])=S.[Na+].[Na+].[C:7](=O)(O)[O-].[Na+].[Br:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([S:23](Cl)(=[O:25])=[O:24])[C:21]=1[F:22])[C:16]([OH:18])=[O:17].ClCC(O)=O.[OH-].[Na+]>O>[Br:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([S:23]([CH3:7])(=[O:25])=[O:24])[C:21]=1[F:22])[C:16]([OH:18])=[O:17]
Reactant: O=C(O)c1cc(Br)c(F)c(S(=O)(=O)Cl)c1
Reactant: O=C([O-])O
Agent: O=C(O)CCl
Agent: [Na+]
Agent: [O-]S([O-])=S
Solvent: O
Product: CS(=O)(=O)c1cc(C(=O)O)cc(Br)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To sodium thiosulfite (2.6 g, 20.7 mmol) and sodium bicarbonate (1.74 g, 20.7 mmol) in water (20 mL) at 75° C. add 3-bromo-5-chlorosulfonyl-4-fluorobenzoic acid (6.25 g, 19.7 mmol) in portions over 5 min. After 1 h, cool to room temperature and add chloroacetic acid (5.29 g, 56 mmol) and NaOH (1.18 g, 29.5 mmol) and reflux 16 h. Cool to room temperature and collect the title compound as a solid
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][OH:24])=[CH:19][CH:18]=3)=[N:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][N:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC>CS(C)=O.C([O-])(O)=O.[Na+]>[C:1]1([C:7]2[C:8]([C:17]3[CH:18]=[CH:19][C:20]([CH:23]=[O:24])=[CH:21][CH:22]=3)=[N:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][N:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCc1ccc(-c2nc3ncccc3cc2-c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=Cc1ccc(-c2nc3ncccc3cc2-c2ccccc2)cc1

Procedure:
To a solution of [4-(3-phenyl-1,8-naphthyridin-2-yl)phenyl]methanol (9-2) (289 mg, 0.925 mmole) in DMSO (2 mL) was added Et3N (1.3 mL, 9.25 mmole) then a solution of pyridine-SO3 (442 mg, 2.78 mmole) in DMSO (2 mL). After 1 hr the mixture was diluted with saturated NaHCO3 and extracted with EtOAc (3×). The combined organic layers were washed with H2O (2×), brine then dried (MgSO4), filtered, and concentrated to give the title compound as a greenish foam which was sufficiently for use in the next step: 1H-NMR (500 MHz, CDCl3) δ 10.02 (s, 1), 9.19 (dd, J=1.95, 2.20 Hz, 1 H), 8.28 (dd, J=1.95, 6.10 Hz, 1 H), 8.26 (s, 1 H), 7.79 (d, J=8.05 Hz, 2 H), 7.73 (d, J=8.30 Hz, 2 H), 7.56 (m, 1H), 7.35 (m, 3 H), 7.27 (m, 2 H).
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][C@H:16]([NH:30]C(=O)OC(C)(C)C)[CH2:17][N:18]([CH3:29])[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:11][CH2:10]1)(C(C)(C)C)(C)C>Cl.CO>[NH2:30][C@@H:16]([CH2:15][CH:12]1[CH2:13][CH2:14][CH:9]([OH:8])[CH2:10][CH2:11]1)[CH2:17][N:18]([CH3:29])[C:19](=[O:20])[O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CN(C[C@H](CC1CCC(O[Si](C)(C)C(C)(C)C)CC1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: Cl
Solvent: CO
Product: CN(C[C@@H](N)CC1CCC(O)CC1)C(=O)OCc1ccccc1
Temperature: 30 °C
Reaction time: 1 h

Procedure:
(S)-tert-butyl 1-(4-(tert-butyldimethylsilyloxy)cyclohexyl)-3-(N-methyl-N-(benzyloxycarbonyl)amino)propan-2-ylcarbamate (1.2 g, 2.25 mmol) was dissolved in 2 M HCl MeOH (10 mL) and stirred at 30° C. for 1 hr. The solvent was removed to give the crude (S)-benzyl 2-amino-3-(4-hydroxycyclohexyl)propyl(methyl)carbamate which was used for next step directly.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:27][C:28]3[CH:29]=[N:30][C:31](Br)=[CH:32][CH:33]=3)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(C)C.C1(C)C=CC=CC=1>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:27][C:28]3[CH:29]=[N:30][C:31]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=4[CH3:35])=[CH:32][CH:33]=3)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccccc1B(O)O
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(Br)nc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: Cc1ccccc1-c1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)OC(C)(C)C)cn1

Procedure:
To a stirred slurry of 1.75 g (3.35 mmol) of (S)-tert-butyl 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(6-bromo-pyridin-3-yl)propanoate and 913 mg (6.70 mmol, 2 eq.) of 2-methylphenylboronic acid in 50 mL of 1:1 isopropanol/toluene was added 25.0 mL of 2 M aqueous sodium carbonate solution. The reaction mixture was purged twice with argon and evacuated and then 124 mg (0.167 mmol, 0.05 equivalents) of bis(tricyclohexylphosphine)palladium (II) chloride was added and the mixture again purged with argon and evacuated.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:14])[C:6](=[CH:10][C:11]=1[O:12][CH3:13])[C:7](O)=[O:8].Cl.[CH:16](N)=[NH:17]>[OH-].[Na+]>[CH3:13][O:12][C:11]1[CH:10]=[C:6]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[N:14]=[CH:16][NH:17][C:7]2=[O:8]
Reactant: COc1cc(N)c(C(=O)O)cc1OC
Reactant: N=CN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1cc2nc[nH]c(=O)c2cc1OC
Temperature: 210 °C
Reaction time: 0.5 h
Yield: 63.8 %

Procedure:
36.9 g of 4,5-dimethoxyanthranilic acid was mixed with 25.0 g of formamidine hydrochloride, and the mixture was stirred at 210° C. for 30 minutes. After completion of the reaction, the solid thus obtained was cooled to room temperature, stirred with 200 ml (0.33 M) of aqueous sodium hydroxide and filtered under a reduced pressure. The solid thus obtained was washed with water and air-dried to obtain the title compound (24.6 g, 64%).