Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[C:2](OC(=O)C)(=[O:4])[CH3:3].[NH2:9][C@H:10]([C:18]([OH:20])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:2]([NH:9][C@H:10]([C:18]([OH:20])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:4])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Solvent: O
Product: CC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 0.5 h
Yield: 71 %

Procedure:
In 15 ml of water 8.26 g (50 mmol) of phenylalanine were dissolved. While vigorously stirring this aqueous solution, 10.2 g (100 mmol) of acetic anhydride were added thereto. After the exothermic reaction had been completed, the reaction mixture was further stirred for about 30 minutes and allowed to stand in a refrigerator for about 24 hours. The precipitates thus formed were filtered, washed with water and dried to obtain 7.4 g (yield: 71 %) of N-acetyl-phenylalanine. Then, 1.18 g (5.7 mmol) of this N-acetylphenyl-alanine were dissolved in a solution of 580 mg (5.7 mmol) of triethylamine dissolved in 30 ml of anhydrous tetrahydrofuran. While cooling the resulting solution in an ice bath, 690 mg (5.7 mmol) of pivalyl chloride were added thereto and the mixture was stirred for about 2 hours. To the resulting mixture was added a solution of 820 mg (5.7 mmol) of 8-aminoquinoline dissolved in 10 ml of tetrahydrofuran and the mixture was stirred for about 24 hours. After being added with chloroform, the resulting mixture was washed with a saturated sodium bisulfate solution and then with water, and dried over anhydrous sodium sulfate, followed by distillation in vacuo for the removal of the solvent. The residue was then subjected to column chromatography to obtain 890 mg of a product with a yield of 47%. The NMR, IR and MS spectra reveal that this product is 8-(N-acetylphenylalanylamino)quinoline of the formula (I) in which R1 is metyl and R2 is benzyl. The mass analysis shows:
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:20]1[S:24][N:23]=[CH:22][N:21]=1)[S:7]([C:10]1[CH:19]=[CH:18][C:13]2[NH:14][C:15](=[O:17])[O:16][C:12]=2[CH:11]=1)(=[O:9])=[O:8].[CH:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][C:39]=2[C@@H:41](O)[CH3:42])[CH:34]=[CH:33][N:32]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OC(C)(C)C)=O)=N\C(OC(C)(C)C)=O>C1COCC1>[CH:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][C:39]=2[C@H:41]([N:14]2[C:13]3[CH:18]=[CH:19][C:10]([S:7]([NH:6][C:20]4[S:24][N:23]=[CH:22][N:21]=4)(=[O:8])=[O:9])=[CH:11][C:12]=3[O:16][C:15]2=[O:17])[CH3:42])[CH:34]=[CH:33][N:32]=1
Reactant: C[C@H](O)c1cccc2ccncc12
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3[nH]c(=O)oc3c2)c(OC)c1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](c1cccc2ccncc12)n1c(=O)oc2cc(S(=O)(=O)Nc3ncns3)ccc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of N-(2,4-dimethoxybenzyl)-2-oxo-N-(1,2,4-thiadiazol-5-yl)-2,3-dihydrobenzo[d]oxazole-6-sulfonamide (100 mg, 0.214 mmol) and (S)-1-(isoquinolin-8-yl)ethanol (74.3 mg, 0.429 mmol) in THF (1072 μl) at 0° C. was treated with PS-triphenylphosphine (112 mg, 0.429 mmol) (0.233 g resin-bound PPh3, 1.84 mmol PPh3/g of resin), and (E)-di-tert-butyl diazene-1,2-dicarboxylate (99 mg, 0.429 mmol). Reaction mixtured was monitored at 0° C. After stirring at 0° C. for 2 h, the reaction was filtered and concentrated in vacuo. Residue was dissolved in 1 mL of DCM and treated with 0.25 mL of TFA. After stirring at RT for 30 minutes, the solvent and TFA were removed in vacuo. Purified by reverse phase chromatography (10-95% MeCN in water w/0.1% TFA, C18 column) to yield 14-7. 1H NMR δ (ppm)(CH3OH-d4): 9.86 (1H, s), 8.61 (1H, d, J=6.42 Hz), 8.47 (2H, dd, J=14.05, 6.52 Hz), 8.32-8.24 (2H, m), 8.14 (1H, s), 7.64-7.57 (2H, m), 7.29 (1H, d, J=8.39 Hz), 6.64-6.55 (1H, m), 2.15 (3H, d, J=7.05 Hz). HRMS [M+H]C20H15N5O4S2 calc'd 454.0638. Found 454.0633.
Reaction SMILES: C[N:2]([C:8]1[S:9][CH:10]=[CH:11][N:12]=1)[CH2:3][CH2:4][CH2:5][NH:6]C.[C:13]1([C:19]#[C:20][C:21]([OH:23])=O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C1COCC1>[S:9]1[CH:10]=[CH:11][N:12]=[C:8]1[NH:2][CH2:3][CH2:4][CH2:5][NH:6][C:21](=[O:23])[C:20]#[C:19][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)C#Cc1ccccc1
Reactant: CNCCCN(C)c1nccs1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(C#Cc1ccccc1)NCCCNc1nccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.2 %

Procedure:
440 mg (2.37 mmol) N1,N3-dimethyl-N1-(thiazol-2-yl)propane-1,3-diamine was dissolved, together with 347 mg (2.37 mmol) 3-phenyl propiolic acid, 412 μl (2.37 mmol) DIPEA and 761 mg (2.37 mmol) TBTU, in THF (30 ml), and stirred for 2 h at RT. The reaction solution was concentrated in vacuo and the residue was taken up by chloroform, washed with water and brine, dried over MgSO4 and concentrated in vacuo. CC (DCE/EtOH 10:1) was carried out on the residue, yielding 314 mg (1.00 mmol, 42%) N-(3-((thiazol-2-yl)amino)propyl)-3-phenylpropiolamide. MS [MH+] 314.1
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:28]=[CH:27][C:8]([O:9][C:10]2[C:11]([CH:24]=CC)=[C:12]([C:20]([O:22][CH3:23])=[O:21])[CH:13]=[C:14]([CH:19]=2)[C:15]([O:17][CH3:18])=[O:16])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[O:29]=[O+][O-]>C(Cl)Cl.CO>[CH:24]([C:11]1[C:10]([O:9][C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:28][CH:27]=2)=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:12]=1[C:20]([O:22][CH3:23])=[O:21])=[O:29]
Reactant: O=[O+][O-]
Reactant: CC=Cc1c(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)OC)cc1C(=O)OC
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c(C=O)c(C(=O)OC)c1
Temperature: 25 °C
Yield: 98 %

Procedure:
A solution of dimethyl 5-(4-(methylsulfonyl)phenoxy)-4-(prop-1-enyl)isophthalate (2.6 g, 7.8 mmol) in CH2Cl2 and methanol was cooled to −78° C. and treated with ozone until the solution appeared blue (20 min). Nitrogen was bubbled through the solution until the blue color dissipated. Dimethylsulfide (1.0 mL) was added and the cold-bath was removed allowing the reaction mixture to warm to room temperature overnight. Concentration of the solution under vacuum provided an oil, which was introduced into a silica gel column and eluted with 10-30% EtOAc in hexanes to afford the title compound (2.5 g, 98%) as a white solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.08 (q, 3 H) 3.95 (dd, 6 H) 7.08-7.16 (m, 2 H) 7.98 (q, J=2.07 Hz, 2 H) 7.99-8.03 (m, 1 H) 8.33-8.39 (m, 1 H) 10.46 (s, 1 H); LC-MS (ERS)+m/z=393.00 (M+H)+.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1(N[S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])C=CC=CC=1.[CH3:24][O:25][C:26](=[O:41])[C:27]([NH:30][C:31]([C:33]1[C:38]([OH:39])=[CH:37][C:36]([OH:40])=[CH:35][N:34]=1)=[O:32])([CH3:29])[CH3:28]>CO>[CH3:24][O:25][C:26](=[O:41])[C:27]([NH:30][C:31]([C:33]1[C:38]([OH:39])=[CH:37][C:36]([O:40][S:17]([C:20]([F:21])([F:22])[F:23])(=[O:18])=[O:19])=[CH:35][N:34]=1)=[O:32])([CH3:29])[CH3:28]
Reactant: COC(=O)C(C)(C)NC(=O)c1ncc(O)cc1O
Reactant: O=S(=O)(Nc1ccccc1)C(F)(F)F
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(C)(C)NC(=O)c1ncc(OS(=O)(=O)C(F)(F)F)cc1O
Temperature: 25 °C
Reaction time: 40 h
Yield: 36 %

Procedure:
To a solution in 2-[(3,5-dihydroxy-pyridine-2-carbonyl)-amino]-2-methyl-propionic acid methyl ester, 18, (0.312 g, 1.23 mmol) in MeOH (10 mL) containing diisopropylethylamine (0.214 mL, 1.23 mmol) at 0° C. under N2 is added N-phenyltrifluoromethanesulfonamide (0.439 g, 1.23 mmol). The reaction is warmed slowly to room temperature and stirred for 40 hours. The solvent is removed under reduced pressure and the crude oil which remains is purified over silica (EtOAc:heptane 1:9) to afford 0.170 g (36% yield) of the desired compound as a yellow oil. 1H NMR (250 MHz, MeOD) δ ppm 8.85 (1H, br s), 8.19 (1H, d, J=2.4 Hz), 7.46 (1H, d, J=2.3 Hz), 3.74 (3H, s), 1.63 (6H, s). HPLC-MS: m/z 387 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:6]=[C:5]2[CH3:18].O1CCCC1.[CH3:24][S:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34](Cl)(=[O:36])=[O:35])(=[O:27])=[O:26]>C(N(CC)CC)C>[C:14]([O:13][C:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][S:34]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[S:25]([CH3:24])(=[O:27])=[O:26])(=[O:36])=[O:35])=[CH:10][CH:9]=2)[C:5]([CH3:18])=[N:6]1)=[O:12])([CH3:15])([CH3:17])[CH3:16]
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Reactant: Cc1nn(C(=O)OC(C)(C)C)c2ccc(N)cc12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nn(C(=O)OC(C)(C)C)c2ccc(NS(=O)(=O)c3ccccc3S(C)(=O)=O)cc12
Yield: 88.5 %

Procedure:
N-(N-tert-Butoxycarbonyl-3-methyl-1H-indazol-5-yl)-2-methylsulfonylbenzenesulfonamide can be obtained as described in Example 1 from 0.9 g of 5-amino-N-tert-butoxycarbonyl-3-methyl-1H-indazole, 55 ml of tetrahydrofuran, 1 ml of triethylamine and 1.02 g of 2-methylsulfonylbenzenesulfonyl chloride. 1.5 g of N-(N-tert-butoxycarbonyl-3-methyl-1H-indazol-5-yl)-2-methylsulfonylbenzenesulfonamide are thus obtained in the form of a pink solid melting at 228° C.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([C:7]#[N:8])[C:4]([C:9]#[N:10])=[CH:3][CH:2]=1>[Ti](Cl)(Cl)(Cl)Cl.ClC1C2C(=CC=CC=2)C=CC=1>[CH:1]1[CH:2]=[CH:3][C:4]2[C:5](=[C:7]3[N:8]=[C:7]4[N:10]=[C:9]([C:4]5[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=54)[N:10]=[C:9]4[NH:8][C:7]([C:5]5[CH:6]=[CH:1][CH:2]=[CH:3][C:4]=54)=[N:10][C:9]4=[N:8][C:7]([C:5]5[CH:6]=[CH:1][CH:2]=[CH:3][C:4]=54)=[N:10][C:9]=2[NH:8]3)[CH:6]=1
Reactant: N#Cc1ccccc1C#N
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Clc1cccc2ccccc12
Product: c1ccc2c(c1)-c1nc-2nc2[nH]c(nc3nc(nc4[nH]c(n1)c1ccccc41)-c1ccccc1-3)c1ccccc21

Procedure:
Titanium tetrachloride (6.5 ml) is added dropwise to a mixture of phthalodinitrile (25.6 g) and α-chloronaphthalene (150 ml) in a nitrogen stream and the mixture is subjected to reaction at 200°-220° C. for 5 h. The resulting precipitate is recovered by filtration and washed successively with α-chloronaphthalene, chloroform and methanol in the order written. Thereafter, the precipitate is refluxed in aqueous ammonia to complete its hydrolysis, followed by successive washing with water and methanol and drying to obtain titanyl phthalocyanine in an amount of 21.8 g (75.6%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH3:12])[N:9]=[CH:10][CH2:11][C:3]=12.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O>[CH3:12][N:8]1[C:4]2[N:5]=[CH:6][N:7]=[C:2]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:3]=2[CH2:11][CH:10]=[N:9]1
Reactant: OB(O)c1ccccc1
Reactant: CN1N=CCc2c(Cl)ncnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CN1N=CCc2c(-c3ccccc3)ncnc21
Temperature: 100 °C
Yield: 91.9 %

Procedure:
The 5-chloro-1-methyl-1,4-dihydropyridazino[3,4-d]pyrimidine (310 mg), phenyl boronic acid (208 mg) and potassium carbonate (235 mg) were dissolved in toluene (10 mL) and water (1.0 mL). The reaction mixture was degassed with nitrogen for 30 minutes and Pd(PPh3)4 (98 mg) was added. The reaction mixture was again degassed with nitrogen for 20 minutes and then heated to 100° C. for 1 hour in a sealed tube. The reaction mixture was filtered through a celite pad and washed with ethyl acetate (2×20 mL). The combined filtrate was washed with water (10 mL) and brine (10 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated. The resulting crude product was purified by column chromatography using MeOH/CHCl3 (1.0:9.0) as eluent to afford 1-methyl-5-phenyl-1,4-dihydropyrimido[4,5-c]pyridazine (350 mg) as off white solid. 1H NMR (DMSO-d6): δ 3.41 (s, 3H), 3.52-3.53 (d, 2H), 6.86 (t, 1H), 7.47-7.49 (m, 3H), 7.56-7.60 (m, 2H), 8.66 (s, 1H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[NH:13]1[CH:17]=[N:16][CH:15]=[N:14]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[N+:10]([C:7]1[CH:8]=[CH:9][C:2]([N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)=[C:3]([CH:6]=1)[C:4]#[N:5])([O-:12])=[O:11]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc([N+](=O)[O-])ccc1-n1cncn1
Temperature: 50 °C

Procedure:
2-Fluoro-5-nitro-benzonitrile (1.0 g, 6.0 mmol) was dissolved in anhydrous DMF (6 mL), then treated with [1,2,4]-triazole (0.46 g, 6.7 mmol), cesium carbonate (2.9 g, 8.9 mmol), and heated (50° C.) overnight. After cooling to RT, the mixture was treated with water and the solid title compound collected by filtration (1.14 g). MS (ESI+) for m/z 216 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1Cl.[NH:12]1[CH:16]=[CH:15][N:14]=[CH:13]1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Reactant: c1c[nH]cn1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(-n2ccnc2)c(Cl)c1

Procedure:
1.0 g (5.21 mmol) of 3,4-dichloronitrobenzene (Fluka, Buchs, Switzerland), 532 mg (7.81 mmol) imidazole (Aldrich, Buchs, Switzerland) and 1.35 g (10.4 mmol) Hünig's base in 4 ml of DMA are heated in a microwave oven at 180° C. for 1 h 40 min. The reaction mixture is quenched with sat. aqueous NaHCO3 and extracted with EtOAc (2×). The organic layers is washed with sat. aqueous NaHCO3 (3×), with brine, dried over MgSO4, filtered and evaporated. The residue is purified by flash chromatography on silica gel (CH2Cl2-MeOH 1:0 to 93:7) to provide the title compound as an oil. ES-MS: 224 (M+H)+; analytical HPLC: tret=2.11 minutes (Grad 1).
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([C:9]([OH:11])=O)[NH:6][N:5]=1)(=[O:3])[CH3:2].[NH2:12][CH2:13][CH:14]([N:17]1[CH:21]=[CH:20][C:19]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([Cl:30])[CH:23]=2)=[N:18]1)[CH2:15][OH:16]>>[C:1]([C:4]1[CH:8]=[C:7]([C:9]([NH:12][CH2:13][CH:14]([N:17]2[CH:21]=[CH:20][C:19]([C:22]3[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([Cl:30])[CH:23]=3)=[N:18]2)[CH2:15][OH:16])=[O:11])[NH:6][N:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Reactant: N#Cc1ccc(-c2ccn(C(CN)CO)n2)cc1Cl
Product: CC(=O)c1cc(C(=O)NCC(CO)n2ccc(-c3ccc(C#N)c(Cl)c3)n2)[nH]n1
Yield: 6.49 %

Procedure:
3-acetyl-N-(2-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-3-hydroxypropyl)-1H-pyrazole-5-carboxamide was prepared using the method of Example 34(d) starting from 3-acetyl-1H-pyrazole-5-carboxylic acid (84 mg, 0.542 mmol) and 4-(1-(1-amino-3-hydroxypropan-2-yl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (125 mg, 0.452 mmol). The product was triturated using diethyl ether and acetonitrile, respectively. Yield 6.49%. 1H-NMR (400 MHz; MeOD): δ 2.51 (s, 3H), 3.88 (m, 2H), 3.97 (dd, 1H), 4.03 (dd, 1H), 4.65 (m, 1H), 6.77 (d, 1H), 7.21 (s, 1H), 7.75 (d, 1H), 7.79 (d, 1H), 7.91 (dd, 1H), 8.05 (d, 1H).
Reaction SMILES: [N+](C1C=C(S([O:13][CH2:14][C@:15]2([CH3:18])[CH2:17][O:16]2)(=O)=O)C=CC=1)([O-])=O.C([O-])([O-])=O.[K+].[K+].[C:25]([C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=1)#[N:26]>CC#N>[CH3:18][C@@:15]1([CH2:14][O:13][C:30]2[CH:31]=[CH:32][C:27]([C:25]#[N:26])=[CH:28][CH:29]=2)[CH2:17][O:16]1
Reactant: C[C@@]1(COS(=O)(=O)c2cccc([N+](=O)[O-])c2)CO1
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@]1(COc2ccc(C#N)cc2)CO1

Procedure:
A suspension of [(2S)-2-methyloxiran-2-yl]methyl 3-nitro-1-benzenesulfonate (37.7 g; 138 mmol; from step (a) above), K2CO3 (28 g) and p-cyanophenol (23.8 g; 200 mmol) in MeCN (300 mL) was refluxed for 20 h. The reaction mixture was ffiltered and the filtrate concentrated under reduced pressure, dissolved in ether and washed with 2M NaOH and then brine. The organic layer was concentrated and subjected to column chromatography (petroleum ether:EtOAc; 3:1) to give the sub-title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.N1C=CC=CC=1.[N+:20]([C:23]1[CH:32]=[C:31]2[C:26]([CH2:27][CH2:28][CH2:29][NH:30]2)=[CH:25][CH:24]=1)([O-:22])=[O:21]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([S:8]([N:30]2[C:31]3[C:26](=[CH:25][CH:24]=[C:23]([N+:20]([O-:22])=[O:21])[CH:32]=3)[CH2:27][CH2:28][CH2:29]2)(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Reactant: O=[N+]([O-])c1ccc2c(c1)NCCC2
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(Cl)cc1S(=O)(=O)N1CCCc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A solution of 5-chloro-2-methoxybenzenesulfonyl chloride (2.75 g, 11.20 mmol) in dichloromethane (0.15 L) was treated with pyridine (14.59 mL, 181.26 mmol) and a solution of 7-nitro-1,2,3,4-tetrahydro-quinoline (1.90 g, 10.66 mmol) in dichloromethane (6.00 mL). The mixture was stirred at room temperature for 120 hours, then the volatiles were evaporated. The residue was redissolved in dichloromethane and washed with water. The organic phase was dried over magnesium sulphate and evaporated. The residue was purified by flash chromatography (dichloromethane/methanol gradient) to yield 1-(5-chloro-2-methoxy-benzenesulfonyl)-7-nitro-1,2,3,4-tetrahydro-quinoline as an orange solid, 3.46 g (85%), MS (ISP): m/e=383.1 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][CH3:33])=[C:6]([C:8]([CH3:31])([CH3:30])[CH2:9][C:10]([OH:29])([C:25]([F:28])([F:27])[F:26])[CH2:11][N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[C:14]([CH2:23][OH:24])=[CH:13]2)[CH:7]=1.[CH3:34]I>C(#N)C.[Ag-]=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][CH3:33])=[C:6]([C:8]([CH3:30])([CH3:31])[CH2:9][C:10]([OH:29])([C:25]([F:27])([F:28])[F:26])[CH2:11][N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[C:14]([CH2:23][O:24][CH3:34])=[CH:13]2)[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(Cn1cc(CO)c(=O)c2ccccc21)C(F)(F)F
Reactant: CI
Agent: O=[Ag-]
Solvent: CC#N
Product: COCc1cn(CC(O)(CC(C)(C)c2cc(F)ccc2OC)C(F)(F)F)c2ccccc2c1=O
Temperature: 50 °C

Procedure:
To a suspension of 1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-3-hydroxymethyl-1H-quinolin-4-one (51.5 mg) and silver(I) oxide (127 mg) in acetonitrile (3 mL) was added methyl iodide (68.5 p-L). After heating at 50° C. for 15 hours, the reaction mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography with silica gel (eluted with 50%-70% ethyl acetate-hexanes) to give the title compound as a white solid (37.5 mg).
Reaction SMILES: C1(C)C=CC=CC=1.P(Cl)(Cl)([Cl:10])=O.[NH:13]1[C:25]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N+:18]([O-])=[CH:17][C:16]=2[N:15]=[CH:14]1>CN(C)C=O>[Cl:10][C:17]1[C:16]2[N:15]=[CH:14][NH:13][C:25]=2[C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:18]=1
Reactant: [O-][n+]1cc2nc[nH]c2c2ccccc21
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Clc1nc2ccccc2c2[nH]cnc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of toluene (0.45 ml/mmol) and dimethylformamide (0.90 ml/mmol) was cooled in an ice-bath and phosphorus oxychloride (2.6 eq.) was added. After 10 minutes the appropriate 1H-imidazo[4,5-c]quinolin-5-oxide was added and the solution was stirred at room temperature for 10 minutes. Subsequently the solution was heated to 100° C. on a steam bath for 30 minutes. Upon cooling, the solvent was evaporated and the resulting syrup was poured over crushed ice while stirring. The mixture was then warmed to room temperature and carefully adjusted to pH 6-7 with solid NaHCO3. After 2 hours, the solid that was formed was filtered off, washed with water and diisopropylether and subsequently dried.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[N+:9]([O-])[CH:8]=[CH:7]2>P(Cl)(Cl)(Cl)=O>[Cl:1][C:10]1[C:11]2[C:6](=[CH:5][C:4]([O:3][CH3:2])=[CH:13][CH:12]=2)[CH:7]=[CH:8][N:9]=1
Reactant: Cl
Reactant: COc1ccc2c[n+]([O-])ccc2c1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(Cl)nccc2c1
Temperature: 90 °C
Reaction time: 6 h

Procedure:
6-Methoxy-isoquinoline-N-oxide hydrochloride (1a, 85 g; 400 mmol) was carefully added in portions to phosphoryl chloride (550 mL) at a temperature of 90° C., after which the mixture was stirred for 6 h at 90° C. Excess of phosphoryl chloride was removed in vacuo. The remaining white solid was washed with water, filtered and dried in vacua. Yield: 68 g (88%); white solid; m.p. 72-74° C.; El-MS: 193 (M+).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:12]2[NH:11][N:10]=[CH:9][C:8]=2[C:7]2[CH2:13][N:14]([CH2:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[C:15](=[O:22])[C@H:16]([CH2:18][C:19](O)=[O:20])[CH2:17][C:6]=2[CH:5]=1.Cl.[F:31][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]2[C:41]=1[NH:40][C:39](=[O:42])[N:38]([CH:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)[CH2:37]2.ClC1C2NN=CC=2C2CN(CC(C)(C)C)C(=O)[C@H](CC(=O)N3CCC(N4CC5C(=CC=CC=5)NC4=O)CC3)CC=2C=1>>[Cl:3][C:4]1[C:12]2[NH:11][N:10]=[CH:9][C:8]=2[C:7]2[CH2:13][N:14]([CH2:23][C:24]3[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=3)[C:15](=[O:22])[C@H:16]([CH2:18][C:19]([N:46]3[CH2:45][CH2:44][CH:43]([N:38]4[CH2:37][C:36]5[C:41](=[C:32]([F:31])[CH:33]=[CH:34][CH:35]=5)[NH:40][C:39]4=[O:42])[CH2:48][CH2:47]3)=[O:20])[CH2:17][C:6]=2[CH:5]=1
Reactant: O=C(O)C[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(Cc2ccncc2)C1=O
Reactant: O=C1Nc2c(F)cccc2CN1C1CCNCC1
Agent: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@@H](CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C1=O
Agent: Cl
Product: O=C(C[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(Cc2ccncc2)C1=O)N1CCC(N2Cc3cccc(F)c3NC2=O)CC1
Yield: 16 %

Procedure:
(S)-2-(4-Chloro-8-oxo-9-(pyridin-4-ylmethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetic acid dihydrochloride (100 mg, 0.2 mmol) and 8-fluoro-3-(piperidin-4-yl)-3,4-dihydroquinazolin-2(1H)-one hydrochloride (61 mg, 0.2 mmol) were reacted in a manner analogous to the preparation of 4-Chloro-9-(2,2-dimethyl-propyl)-7-(S)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one. Title compound was obtained as white solid in 16% yield. MS m/e (M+H)+=616.2. 1H NMR (500 MHz, DMSO-D6): δ=13.46 (s, 1H), 9.23 (d, J=6.41, 1H), 8.31 (m, 2H), 8.24 (d, J=6.10, 1H), 7.22 (s, 1H), 7.13 (dd, J1=9.46, J2=4.88, 2H), 7.05 (m, 1H), 6.91 (m, 1H), 6.85 (s, 1H), 5.40 (d, J=17.09, 1H), 4.66 (m, 3H), 4.54 (d, J=11.90, 1H), 4.41 (m, 1H), 4.36 (s, 1H), 4.28 (d, J=4.58, 1H), 4.10 (d, J=12.51, 1H), 4.00 (m, 1H), 3.17 (m, 2H), 3.04 (m, 1H), 2.94 (m, 1H), 2.62 (d, J=11.29, 1H), 2.43 (m, 1H), 1.83 (m, 1H), 1.62 (m, 3H).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]([O:17][C:18]([NH:20][CH:21]([CH2:25][NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH2:33])[C:22](O)=[O:23])=[O:19])([CH3:16])([CH3:15])[CH3:14].C(OCC)(=O)C>CN(C)C=O>[C:13]([O:17][C:18]([NH:20][C@@H:21]1[C:22](=[O:23])[NH:33][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[NH:26][CH2:25]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)NC(CNc1ccccc1N)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CNc2ccccc2NC1=O
Reaction time: 18 h
Yield: 71.2 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (8.54 g, 44.5 mmol) was added to a cooled (0° C.) solution of 2-tert-butoxycarbonylamino-3-(2-aminophenylamino)propionic acid (11.95 g, 40.5 mmol) in 100 ml of dimethylformamide and stirred for 18 hours. The reaction was poured into 700 ml of ethyl acetate and washed four times with 100 ml of water. The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated to give a brown solid that was purified by flash chromatography eluting with 3:7 ethyl acetate/hexane to give 8 g (71%) of the title compound: 1H NMR (CDCl3) δ 7.78 (1H, s), 7.02-6.95 (1H, m), 6.88-6.82 (1H, m), 6.82-6.78 (1H, m), 6.75-6.70 (1H, m), 5.8-5.7 (1H, d), 4.55-4.45 (1H, m), 3.95 (1H, s), 3.9-3.82 (1H, m), 3.48-3.40 (1H,m), 1.45 (9H, s).