Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:26]2[O:25][C:9]3[C:10](=[O:24])[N:11]([C@@H:13]([CH2:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)[C:14](O)=[O:15])[CH2:12][C:8]=3[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH2:27][C:28]1[S:29][CH:30]=[CH:31][N:32]=1.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.O>[Cl:1][C:2]1[C:26]2[O:25][C:9]3[C:10](=[O:24])[N:11]([C@@H:13]([CH2:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)[C:14]([NH:27][C:28]4[S:29][CH:30]=[CH:31][N:32]=4)=[O:15])[CH2:12][C:8]=3[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1nccs1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1CC2=C(Oc3c(Cl)cccc3C2)C1=O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1nccs1)[C@H](CC1CCCCC1)N1CC2=C(Oc3c(Cl)cccc3C2)C1=O
Yield: 84.1 %

Procedure:
A solution of (S)-2-(5-chloro-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-3-cyclohexyl-propionic acid (100 mg, 0.27 mmol) (Example 20, Step 2c), commercially available 2-aminothiazole (32 mg, 0.32 mmol), N-ethyl-N-dimethyaminopropyl carbodiimide hydrochloride (EDCI. HCl) (40 mg, 0.29 mmol), and N-hydroxybenzotriazole (HOBt) (56 mg, 0.29 mmol) in methylene chloride (5 mL) was stirred for 16 hours at 25° C. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue, upon silica gel flash chromatography using hexane-ethyl acetate gradiant elution, afforded (S)-2-(5-chloro-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-3-cyclohexyl-N-thiazol-2-yl-propionamide (104 mg, 85.2%), as a white solid. 1H NMR (DMSO-d6) δ: 12.55 (s, 1H), 7.50 (d, J=2.9 Hz, 1H), 7.40 (d, J=7.8 Hz, 1H), 7.20-7.28 (m, 2H), 7.07-7.17 (m, 1H), 5.07 (dd, J=10.5, 4.2 Hz, 1H), 4.39 (d, J=19.1 Hz, 1H), 4.08 (d, J=18.6 Hz, 1H), 3.84 (br. s., 2H), 1.52-1.90 (m, 7H), 0.76-1.29 (m, 6H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([Cl:13])[CH:3]=1.[CH3:14][NH2:15]>CC#N.O>[Cl:13][C:4]1[CH:3]=[C:2]([NH:15][CH3:14])[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=1
Reactant: CN
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1cnc(Cl)cc1NC
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
To a solution of ethyl 4,6-dichloronicotinate (5 g, 22.8 mmol) in CH3CN (30 mL) was added dropwise aqueous methylamine (65%, 5.2 g, 45.6 mmol) at 0° C. The resulting mixture was stirred at RT for 8 h. The organic solution was removed under reduced pressure to give the crude product, which was suspended in H2O and extracted with EtOAc (3×20 mL). The combined extracts were washed with brine, dried (MgSO4) and concentrated to give ethyl 6-chloro-4-(methylamino)nicotinate (4 g, 82% yield), which was used in the next step without further purification. 1HNMR (300 MHz, DMSO-d6): δ 8.48 (s, 1 H), 8.04 (d, J=4.5 Hz, 1 H), 6.71 (s, 1 H), 4.27 (q, J=6.9 Hz, 2 H), 2.85 (d, J=5.1 Hz, 3 H), 1.29 (t, J=6.9 Hz, 3 H).
Reaction SMILES: [Cl:1][C:2]1[C:7](NC(=O)C)=[CH:6][CH:5]=[C:4]([Cl:12])[N:3]=1.[N:13]1C=CC=C[CH:14]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[C:7]([C:14]#[N:13])=[CH:6][CH:5]=[C:4]([Cl:12])[N:3]=1
Reactant: c1ccncc1
Reactant: CC(=O)Nc1ccc(Cl)nc1Cl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.3 %

Procedure:
To a mixture of 2,6-dichloro-3-acetamidopyridine (6.3 g, 55% pure) and pyridine (4.93 ml, 61 mmole) in dichloromethane (100 ml), trifluoroacetic anhydride (4.23 ml, 30 mmole) was added. The reaction mixture was stirred at room temperature overnight and concentrated under reduced pressure. The crude product was purified by flash chromatography, eluting with 85% hexane:15% ethyl acetate to give a pale yellow product (1.77 g, 90%).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:24]([C:29]3[CH:30]=[CH:31][C:32]([N+:39]([O-])=O)=[C:33]([CH:38]=3)[C:34]([O:36][CH3:37])=[O:35])[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19](=[O:22])[NH:20][CH3:21])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1.[H][H]>C1COCC1.CCO>[NH2:39][C:32]1[CH:31]=[CH:30][C:29]([N:24]([C:5]2[C:4]([CH:1]3[CH2:3][CH2:2]3)=[CH:23][C:8]3[C:9]([C:19](=[O:22])[NH:20][CH3:21])=[C:10]([C:12]4[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=4)[O:11][C:7]=3[CH:6]=2)[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:38][C:33]=1[C:34]([O:36][CH3:37])=[O:35]
Reactant: [H][H]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc([N+](=O)[O-])c(C(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Solvent: C1CCOC1
Solvent: CCO
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(N)c(C(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Yield: 75 %

Procedure:
A stirred suspension of 59.5 g (102 mmol) of methyl 5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2-nitrobenzoate and 6.0 g of 10% Pd(C) in 1.2 L of 2:1 THF/EtOH was saturated with hydrogen by bubbling hydrogen gas through for 10 minutes and then subjected to balloon hydrogenation at RT. After 6 hours LCMS indicated complete reaction. After 24 hours the mixture was purged with nitrogen, catalyst removed by filtration through celite, and the filtrate concentrated to dryness at reduced pressure to give a light yellow solid. This material was recrystallized from hot EtOAc to afford 42.2 g of methyl 2-amino-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)benzoate as a white solid. The filtrate was concentrated to dryness at reduced pressure to give an additional 13.0 g of methyl 2-amino-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)benzoate as a light yellow foam determined to be 95% pure by LCMS. The two batches were combined for a total yield of 55.2 g (98%) of methyl 2-amino-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)benzoate. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.46 (q, J=4.42 Hz, 1H) 8.16 (s, 1H) 7.91-8.00 (m, 3H) 7.61 (dd, J=8.98, 2.73 Hz, 1H) 7.41 (t, J=8.88 Hz, 2H) 7.15 (s, 1H) 6.76-6.86 (m, 3H) 3.79 (s, 3H) 3.28 (s, 3H) 2.83 (d, J=4.68 Hz, 3H) 2.25-2.38 (m, 1H) 0.82-1.10 (m, 3H) 0.42 (m, 1H). LCMS(ESI): 552 (M+H+).
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.O>C1C=CC=CC=1>[Br:17][CH2:16][C:7]1[CH:6]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[CH:15]=[CH:14][C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ccc(C(C)(C)C)cc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)c1ccc(C(C)(C)C)cc1CBr

Procedure:
To 100 mL round bottom flask charged with ester 101b (230 mg, 1.04 mmol), N-bromosuccinimide (214 mg, 1.2 mmol), benzoyl peroxide (25 mg, 0.1 mmol) in benzene (5 mL). After the mixture was stirred at reflux for 4 h, H2O (10 mL) was added. The aqueous phase was extracted with CH2Cl2 (2×10 mL), and the combined organic extracts were washed with brine (10 mL), dried with Na2SO4 and concentrated. The crude 101c (287 mg, 92%) was used without further purification.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([OH:8])[CH:2]=1.[C:9]1(=O)[O:14][C:12](=[O:13])[CH:11]=[CH:10]1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.CN(C)C=O>O>[OH:8][C:3]1[CH:4]=[CH:5][C:6]([N:7]2[C:12](=[O:13])[CH:11]=[CH:10][C:9]2=[O:14])=[CH:1][CH:2]=1
Reactant: O=C1C=CC(=O)O1
Reactant: Nc1ccc(O)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Solvent: CN(C)C=O
Product: O=C1C=CC(=O)N1c1ccc(O)cc1
Temperature: 15 °C
Reaction time: 2 h
Yield: 48.4 %

Procedure:
In a reactor, 30.0 g (0.275 moles of p-aminophenol, 29.7 g (0.303 moles) of maleic anhydride, 39.0 g (0.275 moles) of phosphorus pentoxide and 100 g of dimethylformamide were charged and stirred at 15° C. for 2 hours. The reaction mixture was then gradually heated to 60° C., at which temperature the reaction was further continued for 2.5 hours. After cooling to room temperature, the resulting reaction mixture was admixed with water to precipitate N-(p-hydroxyphenyl)maleimide in the form of crystals. The crystals were separated by filtration, washed with water and then dried to obtain 25.1 g (0.133 moles) of N-(p-hydroxyphenyl)maleimide (yield 48.2%).
Reaction SMILES: [OH:1][NH2:2].C([O:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)C>CN(C=O)C.CO>[F:32][C:29]1[CH:28]=[CH:27][C:26]([C:23]2[CH:24]=[CH:25][C:20]([N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]([NH:2][OH:1])=[O:5])=[N:21][CH:22]=2)=[CH:31][CH:30]=1
Reactant: NO
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1ccc(-c2ccc(F)cc2)cn1
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(CCCCCCN(c1ccccn1)c1ccc(-c2ccc(F)cc2)cn1)NO
Reaction time: 72 h
Yield: 70 %

Procedure:
HONH2 (50% aqueous, 0.5 mL) was added to II (2.5 mg, 0.006 mmol) in DMF (0.2 mL) and MeOH (0.5 mL) at rt. The reaction mixture was stirred for 72 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (2×2 mL) then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:6) to furnish III as a colourless oil (1.63 mg, 70%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)(=O)=O)[N:3]=1.[C:19]1([OH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:3]=1
Reactant: Oc1ccccc1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(Oc2ccccc2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile, phenol and DBU in DME. EI-MS m/e (%): 278 (M+, 100), 277 ([M—H]+, 22), 250 (68), 249 (89).
Reaction SMILES: N1CCCC1.ClCC1C=CC([C@H](C2C=CC(Cl)=CC=2)[N:15]2[CH2:18][C:17](=[C:19]([C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=3)[S:20]([CH3:23])(=[O:22])=[O:21])[CH2:16]2)=CC=1.[I-].[Na+]>ClCCl>[F:31][C:26]1[CH:25]=[C:24]([C:19](=[C:17]2[CH2:18][NH:15][CH2:16]2)[S:20]([CH3:23])(=[O:22])=[O:21])[CH:29]=[C:28]([F:30])[CH:27]=1
Reactant: CS(=O)(=O)C(=C1CN([C@@H](c2ccc(Cl)cc2)c2ccc(CCl)cc2)C1)c1cc(F)cc(F)c1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCNC1
Solvent: ClCCl
Product: CS(=O)(=O)C(=C1CNC1)c1cc(F)cc(F)c1
Temperature: 20 °C
Reaction time: 20 h

Procedure:
50 mm3 of pyrrolidine are added to a solution of 0.32 g of 1-{(R*)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form A isomer, and 5 mg of sodium iodide in 10 cm3 of dichloromethane. After stirring for 20 hours at 20° C., 50 mm3 of pyrrolidine are added to the mixture, stirred for 8 hours and then 50 mm3 of pyrrolidine are again added and the mixture is stirred for 20 hours at 20° C. The reaction mixture is washed with water and then the organic phase is dried over magnesium sulfate and concentrated to dryness under vacuum (2.7 kPa). The residue obtained is chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 1.2 cm, height 30 cm), at an argon pressure of 0.1 bar, eluting with dichloromethane and then with a dichloromethane and methanol mixture (97.5/2.5 by volume) and collecting 3 cm3 fractions. Fractions 12 to 40 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.18 g of 1-{(R*)-(4-chlorophenyl)[4-pyrrolidinylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form A isomer, is obtained in the form of a white foam [a]20365 nm=−22.5°+/−0.7 (c=0.5%; dichloromethane) [1H NMR spectrum (300 MHz, CDCl3, δ in ppm): 1.78 (mt, 4H), 2.51 (mt, 4H), 2.81 (s, 3H), 3.58 (s, 2H), 3.84 (mt, 2H), 4.33 (mt, 2H), 4.50 (s, 1H), 6.84 (tt, J=9 and 2.5 Hz, 1H), 6.98 (mt, 2H), from 7.20 to 7.40 (mt, 8H)].
Reaction SMILES: Br[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][CH3:15])=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]1=2.[CH2:20]([S:22]([NH:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)(=[O:24])=[O:23])[CH3:21]>>[CH3:15][O:14][C:12]1[CH:11]=[CH:10][C:9]2[C:3](=[CH:2][C:28]3[CH:27]=[C:26]([NH:25][S:22]([CH2:20][CH3:21])(=[O:24])=[O:23])[CH:31]=[CH:30][CH:29]=3)[C:4]3[CH:19]=[CH:18][CH:17]=[CH:16][C:5]=3[CH2:6][CH2:7][C:8]=2[CH:13]=1
Reactant: CCS(=O)(=O)Nc1cccc(B(O)O)c1
Reactant: COc1ccc2c(c1)CCc1ccccc1C2=CBr
Product: CCS(=O)(=O)Nc1cccc(C=C2c3ccccc3CCc3cc(OC)ccc32)c1

Procedure:
Following the procedures essentially as described in Example 219, below, and using 5-bromomethylene-2-methoxy-10,11dihydro-5H-dibenzo[a,d]cycloheptene (E/Z mixture, 97 mg, 0.31 mmol) with 3-ethanesulfonylaminophenylboronic acid (78 mg, 0.34 mmol) to give 57 mg (44%) of an E/Z mixture of the title compound. MS (ES) 420 (M+1) weak, 418 (M−1). HPLC shows 45% of the E isomer and 53% of the Z isomer.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[NH:12][C:11]2=[O:24])=[CH:6][CH:5]=1.[Br:27]Br>C(O)(=O)C>[F:26][C:2]([F:1])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:15](=[O:16])[C:14]([Br:27])=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[NH:12][C:11]2=[O:24])=[CH:6][CH:5]=1
Reactant: O=c1cc(-c2ccccc2Cl)[nH]c(=O)n1-c1ccc(OC(F)(F)F)cc1
Reactant: BrBr
Solvent: CC(=O)O
Product: O=c1[nH]c(-c2ccccc2Cl)c(Br)c(=O)n1-c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Yield: 89.5 %

Procedure:
3.8 g of 3-(4-trifluoromethoxyphenyl)-6-(2-chlorophenyl)-2,4(1H,3H)-pyrimidinedione was added to 75 ml of acetic acid, followed by dropwise addition of 1.7 g of bromine to the solution with stirring at room temperature. The reaction mixture was further stirred for 2 hours and then the solvent was distilled away under reduced pressure. The residue was dissolved in 200 ml of ethyl acetate, washed with an aqueous solution of sodium hydrogencarbonate and water, and dried over anhydrous sodium sulfate. Then the solvent was distilled away to obtain 4.5 g of a crude product. This crude crystal product was washed with heated diisopropyl ether and dried to obtain 4.1 g of the objective compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][NH2:14])=[O:12])=[C:5]2[CH3:15].[C:16]1([CH3:24])[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18][CH:17]=1>C(O)C>[CH3:24][C:16]1[CH:21]=[CH:20][C:19]([CH:22]=[N:14][NH:13][C:11]([C:6]2[NH:7][C:8]3[C:4]([C:5]=2[CH3:15])=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=3)=[O:12])=[CH:18][CH:17]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: Cc1c(C(=O)NN)[nH]c2ccc(Cl)cc12
Solvent: CCO
Product: Cc1ccc(C=NNC(=O)c2[nH]c3ccc(Cl)cc3c2C)cc1
Yield: 44.3 %

Procedure:
A solution of 5-chloro-3-methyl-indole-2-carboxylic acid hydrazide (13 mg, 0.054 mmol),p-tolualdehyde (6.5 mg, 0.054 mmol) in ethanol (5 mL) was refluxed for 8 h. It was evaporated in vacuo and the residue was purified by column chromatography (silica gel, EtOAc/Hexane=4:1) to give 7.8 mg (42%) of the title compound. 1H NMR (CD3OD): 8.26 (s, 1H), 7.72 (d, J=8.1 Hz, 2H), 7.62 (bs, 1H), 7.39 (d, J=8.7 Hz, 1H), 7.28−7.21 (m, 3H), 2.58 (s, 3H), 2.39 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15](F)[C:14]=2[N+:20]([O-:22])=[O:21])[CH:3]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)[NH2:32])=[CH:27][CH:26]=1.C(N(C(C)C)C(C)C)C>CN1CCCC1=O>[CH3:40][O:39][C:36]1[CH:35]=[CH:34][C:33]([CH:31]([NH:32][C:15]2[C:14]([N+:20]([O-:22])=[O:21])=[C:13]([CH:18]=[CH:17][CH:16]=2)[O:12][C:4]2[CH:3]=[C:2]([F:1])[CH:11]=[CH:10][C:5]=2[C:6]([O:8][CH3:9])=[O:7])[C:28]2[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)=[CH:38][CH:37]=1
Reactant: COC(=O)c1ccc(F)cc1Oc1cccc(F)c1[N+](=O)[O-]
Reactant: COc1ccc(C(N)c2ccc(OC)cc2)cc1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(F)cc1Oc1cccc(NC(c2ccc(OC)cc2)c2ccc(OC)cc2)c1[N+](=O)[O-]

Procedure:
A solution of EXAMPLE 368A (1.33 g), bis(4-methoxyphenyl)methanamine (1.046 g) and N-ethyl-N-isopropylpropan-2-amine (1.127 ml) in anhydrous 1-methyl-2-pyrrolidinone (20 mL) was stirred at 120° C. overnight. The mixture was concentrated and the residue was taken up in water (100 mL) and extracted with dichloromethane. The residue was absorbed on silica and purified by chromatography on a silica gel column, eluting with 25% ethyl acetate in hexane to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:9])=[CH:4][CH:5]=[CH:6][C:7]=1[CH3:8].C(=O)([O-])[O-].[Na+].[Na+].[Cl:16][CH2:17][C:18](Cl)=[O:19]>C1(C)C=CC=CC=1.O>[Cl:16][CH2:17][C:18]([NH:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9])=[O:19]
Reactant: Cc1cccc(C)c1N
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cccc(C)c1NC(=O)CCl
Reaction time: 1.5 h
Yield: 95 %

Procedure:
In 3 l of toluene was dissolved 182 g of 2,6-xylidine, and in 1.5 l of water was dissolved 159 g of sodium carbonate. The two solutions were combined, and 203 g of chloroacetyl chloride was added thereto dropwise over 1.5 hours at an inner temperature of from 20° to 35° C., followed by stirring at that temperature for 1.5 hours. The reaction mixture was cooled with ice, and the precipitated crystals were collected by filtration and dried under reduced pressure to obtain 282 g (95%) of the titled compound.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].[H-].[Na+].Cl>C(Cl)(Cl)Cl.CN(C=O)C>[CH2:11]([O:1][CH2:2][C:3]([CH2:8][O:9][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11])([CH2:6][O:7][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11])[CH2:4][OH:5])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: OCC(CO)(CO)CO
Reactant: CCCCCCCCCCCCCCCCCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCOCC(CO)(COCCCCCCCCCCCCCCCCCC)COCCCCCCCCCCCCCCCCCC
Temperature: 100 °C
Reaction time: 22 h
Yield: 22.5 %

Procedure:
To pentaerythritol (1.5 g, 11.0 mmol) were added DMF (100 ml), 1-bromooctadecane (11.4 g, 34.2 mmol) and sodium hydride (60 wt %, 1.54 g, 38.5 mmol), and the mixture was stirred at 100° C. for 22 hr. The reaction mixture was cooled to room temperature, chloroform (150 ml) was added, and 1N hydrochloric acid (150 ml) was added further dropwise. After stirring, the aqueous layer was removed, and the organic layer was further washed with 1N hydrochloric acid (100 ml) and water (100 ml). The organic layer was evaporated under reduced pressure, and the residue was precipitated with methanol (150 ml), and the obtained precipitate was washed with methanol (150 ml). The crude crystals were dried and purified by silica gel column chromatography (hexane:chloroform=1:1→hexane:ethyl acetate=10:1) to give 2,2,2-tris(octadecyloxymethyl)ethanol (2.21 g, 2.47 mmol, yield 23%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[N-:11]=[N+:12]=[N-:13].[Na+]>CN(C=O)C.CCOCC>[N:11]([CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[N+:12]=[N-:13]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(CCl)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1ccc(CN=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 4-methoxybenzyl chloride (8.52 mL, 62.8 mmol) in DMF (40 ml) was added sodium azide (4.08 g, 62.8 mmol). The suspension formed was stirred at RT for 24 hrs. The reaction mixture was diluted with ether (400 ml) and washed with water (2×200 mL) and brine (20 ml). The organic layers were dried (MgSO4) and concentrated (water bath temp 20° C.) under reduced pressure to afford the title compound;
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:14])[CH:8]=2)[N:3]=1.Br[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:1][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:8]=2)[N:3]=1
Reactant: O=Cc1cc2cc(O)ccc2nc1Cl
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)COc1ccc2nc(Cl)c(C=O)cc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.6 %

Procedure:
To a solution of 2-chloro-6-hydroxyquinoline-3-carbaldehyde (2.35 g, 11.3 mmol) in N,N-dimethylformamide (15 mL) was added tert-butyl 2-bromoacetate (2.0 mL, 13.6 mmol) and potassium carbonate (3.13 g, 22.6 mmol). The reaction was stirred at room temperature for 1.5 hours. The reaction was diluted with water (100 mL) and allowed to stir for 1 hour. The resulting solid was collected by filtration, washed with water, and dried under vacuum to give the title compound (3.62 g, 99%) as an off-white solid. +ESI (M+H) 322.1; 1H NMR (400 MHz, CDCl3, δ): 10.54 (s, 1 H), 8.60 (s, 1 H), 7.99 (d, J=9.36 Hz, 1 H), 7.59 (dd, J=9.17, 2.93 Hz, 1 H), 7.11 (d, J=2.73 Hz, 1 H), 4.65 (s, 2 H), 1.49 (s, 9 H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH:21][C:22](=[O:38])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]2[CH:36]=[CH:35][N:34]=[C:33]2[CH3:37])[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([N:32]5[CH:36]=[CH:35][N:34]=[C:33]5[CH3:37])[CH:27]=4)[CH2:23][C:22](=[O:38])[NH:21][C:9]=3[CH:10]=2)=[CH:19][CH:18]=1
Reactant: Cc1nccn1-c1cccc(C(=O)CC(=O)Nc2cc(-c3ccc(F)cc3)ccc2NC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nccn1-c1cccc(C2=Nc3ccc(-c4ccc(F)cc4)cc3NC(=O)C2)c1

Procedure:
Prepared from (4′-fluoro-3-{3-[3-(2-methyl-imidazol-1-yl)-phenyl]-3-oxo-propionylamino}-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example K53) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a yellow solid (178 mg).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[O:29]C)/[CH:6]=[CH:7]/[C:8]1[N:16]([CH3:17])[C:15]2[C:14](=[O:18])[N:13]([CH2:19][CH2:20][CH3:21])[C:12](=[O:22])[N:11]([CH2:23][CH2:24][CH3:25])[C:10]=2[N:9]=1.B(Br)(Br)Br.CO>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[OH:29])/[CH:6]=[CH:7]/[C:8]1[N:16]([CH3:17])[C:15]2[C:14](=[O:18])[N:13]([CH2:19][CH2:20][CH3:21])[C:12](=[O:22])[N:11]([CH2:23][CH2:24][CH3:25])[C:10]=2[N:9]=1
Reactant: CCCn1c(=O)c2c(nc(/C=C/c3ccc(OC)c(OC)c3)n2C)n(CCC)c1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: CCCn1c(=O)c2c(nc(/C=C/c3ccc(O)c(O)c3)n2C)n(CCC)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
Compound 1 (770 mg, 1.87 mmol) obtained in Reference Example 1 was dissolved in 15 ml of methylene chloride. To the solution was added 5.6 ml (5.6 mmol) of boron tribromide (1.0M methylene chloride solution) under ice cooling in argon atmosphere, and the mixture was stirred overnight at room temperature. Methanol was added thereto and the mixture was separated with chloroform-an aqueous solution of sodium bicarbonate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, followed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography to give 550 mg (yield 77%) of Compound 54 as a yellow solid, which was then triturated with ether to give a yellow powder.