Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5](=[O:14])[C@H:6]([CH2:8][C:9]1[N:13]=[CH:12][NH:11][CH:10]=1)[NH2:7].C(N(CC)CC)C.[O:22]1[CH2:27][CH2:26][N:25]([C:28]([C:30]([S:33]([CH2:36][C@@H:37]([CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:38](O)=[O:39])(=[O:35])=[O:34])([CH3:32])[CH3:31])=[O:29])[CH2:24][CH2:23]1.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C.ON1C=CC=CC1=O.C(#N)C>[CH3:3][O:4][C:5](=[O:14])[C@H:6]([CH2:8][C:9]1[N:13]=[CH:12][NH:11][CH:10]=1)[NH:7][C:38](=[O:39])[C@@H:37]([CH2:36][S:33]([C:30]([CH3:31])([C:28]([N:25]1[CH2:26][CH2:27][O:22][CH2:23][CH2:24]1)=[O:29])[CH3:32])(=[O:34])=[O:35])[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]cn1
Reactant: CC(C)(C(=O)N1CCOCC1)S(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=c1ccccn1O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)CS(=O)(=O)C(C)(C)C(=O)N1CCOCC1
Reaction time: 18 h
Yield: 101 %

Procedure:
2.5 g (10.5 mmol) of histidine methyl ester dihydrochloride, 10 ml of acetonitrile and 2.9 ml (148 mmol) of triethylamine were stirred at 20° for 20 hours. 3.8 g (10 mmol) of (S)-α[[[1-(morpholinocarbonyl)-1-methylethyl]sulphonyl]methyl]hydrocinnamic acid, 0.11 g (1 mmol) of 1-hydroxy-2(1H)-pyridone and 20 ml of ethyl acetate were subsequently added. After 15 minutes a solution of 2.2 g (10.5 mmol) of dicyclohexylcarbodiimide in 15 ml of ethyl acetate was added within 30 minutes. The reaction had finished after stirring at 20° for 18 hours. The solid (dicyclohexylurea) was filtered off under suction and the filtrate was washed with aqueous sodium bicarbonate solution and water. 5.4 g of N-[(S)-α-[[[1-methyl-1-(morpholinocarbonyl)ethyl]sulphonyl]methyl]hydrocinnamoyl]-L-histidine methyl ester were obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.O.[NH2:10][NH2:11]>C(O)C>[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:10][NH2:11])=[CH:6][CH:7]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNc1ccc(Cl)nn1

Procedure:
As shown in FIG. 5, a mixture of 40 g (0.27 mole) of 3,6-dichloropyridazine and 40 mL of 80% hydrazine hydrate in 80 mL of ethanol was refluxed for one hour. The reaction mixture was evaporated to dryness and the residue was recrystallized from benzene to give 39 g of 1-(6-chloropyridazin-3-yl)hydrazine (compound 1003) (see Takahayashi, J. Pharm. Soc. Japan 75:778-781, 1955).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C@H:4]([NH:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[CH2:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:8][C:7]=1[CH2:21]O.C(N(CC)CC)C.CS([Cl:46])(=O)=O>ClCCl>[CH3:1][O:2][C:3](=[O:34])[C@H:4]([NH:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[CH2:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:8][C:7]=1[CH2:21][Cl:46]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@@H](Cc1cc(C)c(NC(=O)OC(C)(C)C)cc1CO)NC(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H](Cc1cc(C)c(NC(=O)OC(C)(C)C)cc1CCl)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91 %

Procedure:
3-(2-Hydroxymethyl-4-tert-butoxycarbonylamino-5-methyl-phenyl)-2-(R)-benzyloxycarbonylamino-propionic acid methyl ester (510 mg, 1.1 mmol) was dissolved in dichoromethane (5 mL). Triethylamine (250 μL, 1.8 mmol) was added to the mixture followed by methanesulfonyl chloride (100 μL, 1.3 mmol). Mixture was stirred at room temperature for 1.5 hours. Mixture was diluted with dichloromethane then washed once with water, twice with 1N hydrochloric acid, and once with brine. Organics were dried (magnesium sulfate), filtered and concentrated in vacuo. Title compound was obtained as white solid in 91% yield. MS m/e (M+H)+=491.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH2:15][C:16]2([CH2:20][CH3:21])[CH2:19][O:18][CH2:17]2)=[CH:4][CH:3]=1.C([Li])CCC.C(O[B:31]1[O:35][C:34]([CH3:37])([CH3:36])[C:33]([CH3:39])([CH3:38])[O:32]1)(C)C>C1COCC1>[CH2:20]([C:16]1([CH2:15][O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([B:31]3[O:35][C:34]([CH3:37])([CH3:36])[C:33]([CH3:39])([CH3:38])[O:32]3)=[CH:3][CH:4]=2)[CH2:19][O:18][CH2:17]1)[CH3:21]
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: CCC1(COCCCCCCc2ccc(Br)cc2)COC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC1(COCCCCCCc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)COC1
Yield: 70.6 %

Procedure:
To a stirred solution of 3-[6-(4-bromophenyl)hexyloxymethyl]-3-ethyl-oxetane (2.0 g, 5.63 mmol) in dry THF (20 ml) is added n-butyllithium (2.5 M in hexanes, 2.25 ml, 5.63 mmol) dropwise at −78° C. under nitrogen, with stirring. After complete addition, the mixture is stirred for another 20 min, followed by the addition of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.05 g, 5.64 mmol). The resultant mixture is stirred overnight at room temperature. The reaction is quenched with water, and the reaction mixture is extracted with ethyl acetate (3×50 ml). The combined organic extracts are washed with water, brine, and dried (Na2SO4). The solvent is removed under reduced pressure and the residue is purified by column chromatography on silica, eluting with petroleum ether/ethyl acetate (9:1 to 7:3), to give a brown oil (1.60 g, 71%). 1H NMR (300 MHz, CDCl3): δ(ppm) 7.72 (d, J=8.1 Hz, 2H, Ar—H), 7.17 (d, J=8.1 Hz, 2H, Ar—H), 4.43 (d, J=5.8 Hz, 2H, OCH2), 4.35 (d, J=5.8 Hz, 2H, OCH2), 3.48 (s, 2H, OCH2), 3.41 (t, J=6.4 Hz, 2H, OCH2), 2.60 (t, J=7.9 Hz, 2H, ArCH2), 1.72 (q, J=7.5 Hz, 2H, CH2), 1.56 (m, 4H, CH2), 1.32 (m, 14H, CH2 and CH3); 0.86 (t, J=7.5 Hz 3H, CH3); 13C NMR (75 MHz, CDCl3): δ (ppm) 146.1 (quat.), 134.8 (CH), 127.8 (CH), 83.5 (quat.), 78.5 (OCH2), 73.3 (OCH2), 71.5 (OCH2), 43.4 (quat.), 36.1 (CH2), 31.3 (CH2), 29.5 (CH2), 29.0 (CH2), 26.7 (CH2), 26.0 (CH2), 24.8 (CH3), 8.2 (CH3).
Reaction SMILES: [N:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:2].[O:9]=O.N1CC[CH2:16][C@H:12]1[C:13](O)=[O:14]>CC#N>[N+:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:16][CH2:12][CH:13]=[O:14])([O-:9])=[O:2]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=Nc1ccccc1
Reactant: O=O
Solvent: CC#N
Product: O=CCCc1ccccc1[N+](=O)[O-]

Procedure:
According to Table 1, the α-aminooxylation reaction of 4,5 substituted o-nitro hydrocinnamaldehyde 4a with nitrosobenzene as oxygen source was carried out in the presence of L-proline (20 mol %) in CH3CN at −20° C. for 24 h to obtain α-aminooxylate o-nitrohydrocinnamaldehyde. Since α-aminooxy aldehydes are prone to racemization, it was immediately in situ subjected to catalytic hydrogenation [10% Pd/C, (1 atm) H2] by distilling out CH3CN under reduced pressure and adding MeOH into it, which gave 3-hydroxy THQ 5a in 62% yield with moderate enantioselectivity (82% ee). The low ee could possibly be due to the racemization occurring during the removal of CH3CN at slightly elevated temperature (45° C.). To obtain high enantioselectivity, a mixed solvent system of CH3CN/MeOH (1:3) was used, 5a was obtained in higher enantioselectivity (96% ee) with low yield (52%). In order to improve the yield of THQs, the inventors were further conducted experiments in several solvent systems (CHCl3, CH2Cl2 and THF). However, there was no significant improvement in yields observed in each case. Subsequently, the best result (71% yield, 96% ee) for 5a was obtained when α-aminooxylation was carried out in DMSO and the intramolecular reductive cyclization done, in MeOH in a sequential manner at ambient temperature (entry 7; Table 1).
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:13].C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>CN(C=O)C.O.C(Cl)Cl>[CH2:20]([O:12][C:11]1[CH:10]=[C:5]([CH:4]=[C:3]([OH:13])[C:2]=1[Br:1])[C:6]([O:8][CH3:9])=[O:7])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1cc(O)c(Br)c(O)c1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1cc(O)c(Br)c(OCc2ccccc2)c1
Reaction time: 8 h
Yield: 52 %

Procedure:
To a mixture of methyl 4-bromo-3,5-dihydroxybenzoate (18.8 g, 76 mmol) and potassium carbonate (5.26 g, 38.1 mmol) in DMF (190 mL) was added benzyl bromide (3.17 mL, 26.6 mmol). The mixture was stirred overnight, diluted with 200 mL water and acidified to pH 1 by slow addition of concentrated hydrochloric acid. The solution was extracted with 1:1 ethyl acetate/ether (6×) and the combined extracts were washed with water (8×), saturated sodium bicarbonate, brine, then dried over magnesium sulfate and concentrated to provide an orange solid. The solid was suspended in DCM (200 mL) and stirred overnight. The solid (primarily unreacted 4-bromo-3,5-dihydroxybenzoate) was removed by filtration and the filtrate was concentrated to provide an orange oil which was purified by column chromatography (80 g silica gel, 2:1 DCM in heptane elution, followed by DCM elution) to provide methyl 3-(benzyloxy)-4-bromo-5-hydroxybenzoate (4.66 g). MS (M+1)=337.0. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.32-7.57 (m, 6H), 7.26 (d, J=1.52 Hz, 1H), 5.77 (s, 1H), 5.22 (s, 2H), 3.93 (s, 3H) as well as the di-benzylated methyl 3,5-bis(benzyloxy)-4-bromobenzoate (1.8 g).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:12]1([Li])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2cccnc2c1
Reactant: [Li]c1ccccc1
Solvent: C1CCOC1
Product: Cc1ccc2ccc(-c3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 7-methylquinoline (1.63 g, 11.4 mmol) in dry THF (10mL), cooled by ice/water, is added phenyllithium (1.9M in cyclohexane/ether 70/30, 6.0 mL, 11.4 mmol) dropwise over 5 min. After 15 min, the cooling bath is removed, and the solution is stirred at rt for 5 h. The reaction is quenched by adding MeOH, and stirring is continued overnight. Water is added, the mixture is extracted with EtOAc (3×35 mL), and the combined extracts are dried over MgSO4. The drying agent is filtered off, and air is bubbled into the solution for 7 d. The solvent is evaporated; the residue is dissolved in warm (≈50° C.) EtOAc/hexanes and filtered warm. The filtrate is concentrated and dried in vacuo to obtain the crude title compound that is used directly for the next step. Further purification is possible by chromatography on silica gel (Jones Flashmaster, eluting with hexanes:EtOAc 3:1→2:1→1:1). 1H NMR (CDCl3, 400 MHz) δ 2.58 (s, 3H), 7.31 (d, J=3.7 Hz, 1H), 7.36-7.49 (m, 1H), 7.52 (t, J=8.0 Hz, 2H), 7.72 (d, J=8.2 Hz, 1H), 7.82 (d, J=8.2 Hz, 1H), 7.96 (s, 1H), 8.16 (t, J=8.0 Hz, 2H). MS (ES+): m/z 220.3 (100) [MH+]. HPLC: tR=2.7 min (Platform II, nonpolar—5 min).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18](/[CH:25]=[CH:26]/[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:17]3)=[CH:12][CH:11]=2)=[N:7][CH:8]=1.CC[C@H]1[C@H]2C[C@H]([C@H](OC3C4C(=CC=CC=4)C(O[C@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:55]C)C=C4)N(CC2)C1.CS(N)(=O)=O.CC(O)C.[OH2:101]>>[OH:101][C@H:26]([C@@H:25]([OH:55])[C:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:16]([C:13]2[CH:14]=[CH:15][C:10]([O:9][C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:32])[F:33])=[CH:8][N:7]=3)=[CH:11][CH:12]=2)[CH:17]=1)[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)/C=C/c1cn(-c2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)c2ccccc12
Reactant: O
Reactant: CC[C@@H]1CN2CC[C@@H]1C[C@@H]2[C@H](Oc1nnc(O[C@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Agent: CS(N)(=O)=O
Solvent: CC(C)O
Product: CCOC(=O)[C@H](O)[C@@H](O)c1cn(-c2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(2R,3S)-Ethyl 2,3-dihydroxy-3-(1-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)-phenyl)-1H-indol-3-yl)propanoate (4) was prepared as follows: A mixture of compound 3 (0.12 g, 1.0 eq), Ad-Mix-α (1.5 eq, Aldrich), and MeSO2NH2 (Aldrich, 1.2 eq) in 10 mL of i-PrOH/water (1/1) was shaken at room temperature for 4 hours. The reaction was quenched with EtOAc/water (60 mL/20 mL). The organic layer was separated, washed with brine, concentrated and purified by column (EtOAc/hexanes 5/4) to give compound 4 as a colorless oil (80 mg): 1H-NMR (400 MHz, CDCl3) δ: 8.42 (s, 1H), 8.05 (s, 1H), 7.89 (1H, dd, 2.6 & 8.7 Hz), 7.77-7.8 (m, 1H), 7.5-7.57 (m, 3H), 7.18-7.28 (m, 4H), 7.04 (d, 1H, 8.8 Hz), 6.9 (s, 1H), 6.28 (d, 1H, 1.5 Hz), 4.36 (q, 2H, 7.1 Hz), 1.37 (t, 3H, 7.2 Hz).
Reaction SMILES: N(C(OC(C)(C)C)=O)[C@H](C(O)=[O:7])C(C)C.N[C@H](C(O)=O)C.[NH2:22][C@H:23]([C:27]([NH:29][CH2:30][C:31]([O:33]CC1C=CC=CC=1)=[O:32])=[O:28])[CH:24]([CH3:26])[CH3:25].CC1C=CC(S(O)(=O)=O)=CC=1.C1C=CC(COC(CN)=O)=CC=1.[OH:64][N:65]1[C:69]2[CH:70]=[CH:71][CH:72]=[CH:73][C:68]=2N=N1>O>[NH2:22][C@H:23]([C:27]([NH:29][CH2:30][C:31]([O:33][C:72]1[CH:73]=[CH:68][C:69]([N+:65]([O-:64])=[O:7])=[CH:70][CH:71]=1)=[O:32])=[O:28])[CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)[C@H](N)C(=O)NCC(=O)OCc1ccccc1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: On1nnc2ccccc21
Agent: C[C@H](N)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: NCC(=O)OCc1ccccc1
Solvent: O
Product: CC(C)[C@H](N)C(=O)NCC(=O)Oc1ccc([N+](=O)[O-])cc1

Procedure:
Synthesis: The synthesis of the peptide, Boc-Val-L. Pro-D. Ala-L. Val-Gly-OBzl (I), was carried out using classical solution methods starting from the C-terminal glycine benzyl ester p-tosylate. Each amino acid was coupled to the growing peptide chain by means of the water soluble carbodiimide 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) and 1-hydroxybenzotriazole. The tert-butyloxycarbonyl group was used for amino group protection, and its removal was achieved with trifluoroacetic acid. Peptide I was converted to the free acid by hydrogenolysis and then to the corresponding p-nitrophenyl ester using p-nitrophenyl trifluoroacetate. After deblocking the Nα -protecting group and neutralizing, H-L. Val-L. Pro-D. Ala-L. Val-Gly-ONp was polymerized in dimethyl sulfoxide for 14 days. The reaction mixture was diluted with water, dialyzed against water and lyophilized. Purity of all intermediate peptides was checked by thin layer chromatography and C-13 NMR spectra. The overall yields were 80-90% in the preparation of the intermediate products and 50% during the polymerization step.
Reaction SMILES: [C:1]1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH2:27]Cl.C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[C:16]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][N:13]([CH2:27][C:26]3[CH:29]=[C:30]([O:34][CH3:35])[C:31]([O:32][CH3:33])=[C:24]([O:23][CH3:22])[CH:25]=3)[CH2:14][CH2:15]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1ccc(C(CCN2CCNCC2)c2ccccc2)cc1
Reactant: COc1cc(CCl)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc(CN2CCN(CCC(c3ccccc3)c3ccccc3)CC2)cc(OC)c1OC
Yield: 82.5 %

Procedure:
N-3,3-Diphenylpropylpiperazine in the amount of 2.8 g (0.01 mole), 2.17 g (0.01 mole) of 3,4,5-trimethoxybenzyl chloride, 0.51 g (0.005 mole) of triethylamine, and 1.4 g (0.01 mole) of potassium carbonate were mixed with 20 ml of toluene, and the resulting mixture was heated at the refluxing temperature for 2 hours. The reaction liquid was left to cool, washed by shaking with water, and then the organic liquid layer was concentrated under reduced pressure to obtain 3.8 g (82.5% yield) of oily 1-(3,3-diphenylpropyl)-4-(3,4,5-trimethoxybenzyl)piperazine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C[O-].[Na+].Br[C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=1.[NH2:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[O-:24].[Na+]>CC(N(C)C)=O.CO.N1C=CC=CC=1>[NH2:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][C:13]1[CH:18]=[CH:17][C:16]([O:24][C:23]2[CH:25]=[CH:26][CH:27]=[C:21]([NH2:20])[CH:22]=2)=[CH:15][CH:14]=1
Reactant: Nc1cccc(O)c1
Reactant: Brc1ccc(Br)cc1
Reactant: Nc1cccc([O-])c1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CO
Solvent: c1ccncc1
Product: Nc1cccc(Oc2ccc(Oc3cccc(N)c3)cc2)c1
Temperature: 117 °C
Yield: 42 %

Procedure:
A 250 mL, 3-necked, round bottom flask fitted with a mechanical stirrer, a still head, a condenser with a nitrogen inlet on the take-off adapter, and a thermometer was charged with 150 mL of pyridine and 21.8 g (0.20 mole) of m-aminophenol. After the m-aminophenol dissolved, 10.8 g (0.20 mole) of sodium methoxide was added. Methanol, formed in this reaction, was distilled off. When the still head temperature reached 110° C., the still head was replaced with a reflux condenser, and 23.6 g (0.10 mole) of p-dibromobenzene and 0.1 g of cuprous chloride were added. The mixture was heated at reflux at 117° C. for 3 hours; 25 mL of DMAc was added to help dissolve sodium m-aminophenoxide formed in the first step. Refluxing was continued for 19 additional hours; the reaction mixture was then cooled to room temperature, filtered to remove inorganic salts, and poured into water. The resulting aqueous solution was extracted with three 300 mL portions of methylene chloride; the extract was dried over magnesium sulfate, decolorized with active carbon, and filtered through diatomaceous earth. Methylene chloride was vacuum-evaporated, and the liquid residue was poured into stirred concentrated hydrochloric acid. The precipitated dihydrochloride of 1,4-bis(3-aminophenoxy)benzene was filtered, washed with concentrated hydrochloric acid, and dried. It then was dissolved in a minimum amount of water containing a small amout of ascorbic acid as antioxidant. The solution was decolorized with activated carbon, filtered through diatomaceous earth, and neutralized with concentrated ammonium hydroxide. The precipitated product was separated by filtration and vacuum-dried overnight at 65° C. The dry diamine weighed 12.4 g (42% yield). Recrystallization from 35 mL of butanol gave 8.6 g of product melting at 98°-99° C., which was distilled bulb-to-bulb to give 6.5 g of colorless 1,4-bis(3,5-aminophenoxy)benzene melting at 99°-100° C.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C:4]2[C:9]([C:10]=1[N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[Li:16]CCCC>CCCCCC>[CH3:1][C:2]1[C:10]([Li:16])([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: [Li]CCCC
Reactant: CC1=C(N2CCCC2)c2ccccc2C1
Solvent: CCCCCC
Product: [Li]C1(N2CCCC2)C(C)=Cc2ccccc21
Reaction time: 8 h
Yield: 87 %

Procedure:
1-(2-Methyl-1H-3-indenyl)pyrrolidine (16.276 g, 81.67 mmol) was stirred in hexane (250 mL) as n-BuLi (98.0 mmol, 49.0 mL of 2.0 M solution in cyclohexane) was added dropwise. This mixture was allowed to stir overnight during which time a precipitate formed. After the reaction period the mixture was filtered. The desired product was isolated as a pale yellow solid following washing with hexane and drying under vacuum and was used without further purification or analysis (14.51 g, 87 percent yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH3:13])[CH:11]=1)[NH:8][C:7](=O)[N:6]=[CH:5]2.O.O=P(Cl)(Cl)[Cl:18]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH3:13])[CH:11]=1)[N:8]=[C:7]([Cl:18])[N:6]=[CH:5]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc(Br)cc2cnc(=O)[nH]c12
Solvent: O
Product: COc1cc(Br)cc2cnc(Cl)nc12

Procedure:
6-bromo-8-methoxy-1H-quinazolin-2-one (2.62 g, 10.27 mmol) is suspended in 30 mL POCl3 and refluxed for 30 min. The reaction mixture is stirred into water, while the temperature never exceeds 15° C. The aqueous phase is extracted with DCM, the organic phase is dried and 6-bromo-2-chloro-8-methoxy-quinazoline (HPLC-MS: tRet.=1.88 min, MS(M+H)+=273/275/277; method FSUN) is obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].[Li]CCCC.CCCCCC.[CH2:20]([N:22]([CH2:41][CH3:42])[CH2:23][CH2:24][N:25]1[C:35]2[C:30](=[C:31]([C:37]([F:40])([F:39])[F:38])[CH:32]=[C:33]([I:36])[CH:34]=2)[C:28](=[O:29])[C:26]1=[O:27])[CH3:21]>C1COCC1>[CH2:41]([N:22]([CH2:20][CH3:21])[CH2:23][CH2:24][N:25]1[C:35]2[C:30](=[C:31]([C:37]([F:38])([F:40])[F:39])[CH:32]=[C:33]([I:36])[CH:34]=2)[C:28]([OH:29])([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[F:8])[C:26]1=[O:27])[CH3:42]
Reactant: CCN(CC)CCN1C(=O)C(=O)c2c1cc(I)cc2C(F)(F)F
Reactant: Fc1ccccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCN(CC)CCN1C(=O)C(O)(c2ccccc2F)c2c1cc(I)cc2C(F)(F)F
Reaction time: 0.17 h
Yield: 8.9 %

Procedure:
To a solution of 1-bromo-2-fluorobenzene (0.09 mL, 0.823 mmol) in THF (4 mL) was added dropwise 1.53 N BuLi in hexane (0.54 mL, 0.826 mmol) over 10 min at −78° C. and the mixture was stirred for 10 min. The resulting solution was then transferred into the cooled solution of 1-(2-diethylaminoethyl)-4-trifluoromethyl-6-iodoisatin (330 mg, 0.75 mmol) in THF (2 mL) at −78° C. via a cannula. The mixture was stirred for 30 min at the same temperature and the reaction was quenched with aqueous NaHCO3. The mixture was extracted with ethyl acetate and the extracts were dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography with 50:1 to 30:1 chloroform/methanol to give the title compound (35.9 mg, 9%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[C:20]([C:22]([N:24]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[S:28][CH2:27][CH2:26][CH2:25]2)=[O:23])[CH:19]=[CH:18][C:4]=1[C:5]([NH:7][C:8]1[C:16]2[N:15]=[C:14]([CH3:17])[NH:13][C:12]=2[CH:11]=[CH:10][CH:9]=1)=[O:6].OO.C([O-])(O)=[O:38].[Na+]>CC(O)=O>[CH3:1][O:2][C:3]1[CH:21]=[C:20]([C:22]([N:24]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[S:28](=[O:38])[CH2:27][CH2:26][CH2:25]2)=[O:23])[CH:19]=[CH:18][C:4]=1[C:5]([NH:7][C:8]1[C:16]2[N:15]=[C:14]([CH3:17])[NH:13][C:12]=2[CH:11]=[CH:10][CH:9]=1)=[O:6]
Reactant: COc1cc(C(=O)N2CCCSc3ccccc32)ccc1C(=O)Nc1cccc2[nH]c(C)nc12
Reactant: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cc(C(=O)N2CCCS(=O)c3ccccc32)ccc1C(=O)Nc1cccc2[nH]c(C)nc12
Reaction time: 4 h

Procedure:
To a solution of 2-methoxy-N-(2-methyl-1H-benzimidazol-4-yl)-4-(2,3,4,5-tetrahydro-1,5-benzothiazepin-5-yl)carbonylbenzamide (20 mg) in AcOH (1 ml), was added 30% aqueous H2O2 (1 ml), and the mixture was stirred for 4 hours. Saturated aqueous NaHCO3 was added to the reaction mixture, and the mixture was extracted with AcOEt, washed with brine and dried over Na2CO3. The solvent was removed under reduced pressure to give 2-methoxy-N-(2-methyl-1H-benzimidazol-4-yl)-4-(1-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-5-yl)carbonylbenzamide (20 mg).
Reaction SMILES: [F:1][C@@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=1[C:34]1[S:35][CH:36]=[C:37]([C:39](O)=[O:40])[N:38]=1>>[NH2:9][C@H:8]1[C@@H:2]([F:1])[CH2:3][O:4][C@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[NH:23][C:39]([C:37]2[N:38]=[C:34]([C:28]3[C:27]([F:26])=[CH:32][CH:31]=[CH:30][C:29]=3[F:33])[S:35][CH:36]=2)=[O:40])[CH2:6][CH2:7]1
Reactant: O=C(O)c1csc(-c2c(F)cccc2F)n1
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1
Product: Cn1ncc(NC(=O)c2csc(-c3c(F)cccc3F)n2)c1[C@@H]1CC[C@@H](N)[C@@H](F)CO1

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3R,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 24), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 2-(2,6-difluorophenyl)thiazole-4-carboxylic acid (see US2012/225061) gave 319. 1H NMR (400 MHz, DMSO-d6) δ 10.02 (s, 1H), 8.63 (s, 1H), 7.86 (s, 1H), 7.74-7.59 (m, 1H), 7.38 (t, J=8.9 Hz, 2H), 5.03-4.81 (m, 2H), 4.19-3.88 (m, 2H), 3.75 (s, 2H), 2.24-2.10 (m, 1H), 1.93-1.81 (m, 1H), 1.82-1.70 (m, 1H), 1.65 (d, J=14.0 Hz, 1H). LCMS (ES+) m/z 452 (M+1).