Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C(C1C=CC(C(N)=N)=CC=1)CCCC.C(OC(=O)C(=COCC)C(OCC)=O)C.CC[O-].[Na+].[CH2:35]([O:37][C:38]([C:40]1[C:41](O)=[N:42][C:43]([C:46]2[CH:51]=[CH:50][C:49]([CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])=[CH:48][CH:47]=2)=[N:44][CH:45]=1)=[O:39])[CH3:36].P(Cl)(Cl)(Cl)=O>C(O)C>[CH2:35]([O:37][C:38]([C:40]1[CH:45]=[N:44][C:43]([C:46]2[CH:47]=[CH:48][C:49]([CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])=[CH:50][CH:51]=2)=[N:42][CH:41]=1)=[O:39])[CH3:36]
Reactant: CCCCCc1ccc(-c2ncc(C(=O)OCC)c(O)n2)cc1
Agent: CCCCCc1ccc(C(=N)N)cc1
Agent: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: CC[O-]
Solvent: CCO
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCc1ccc(-c2ncc(C(=O)OCC)cn2)cc1

Procedure:
The starting material can be obtained according to the data by A. R. Todd and F. Bergel, J. Chem. Soc, 1937, 366 from p-n-pentylbenzamidine hydrochloride and ethoxymethylenemalonic acid diethyl ester with sodium ethylate in ethanol and subsequent treatment of the resulting 2-(p-n-pentylphenyl)-4-hydroxy-5-pyrimidinecarboxylic acid ethyl ester (melting point 193.9°-194.4°) with phosphorus oxychloride, m.p. 58.5°-59.2°.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:17][NH:18][S:19]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)(=[O:21])=[O:20]>>[CH3:13][C:12]([CH3:15])([CH3:14])[C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:25]3[CH:24]=[CH:23][C:22]([S:19]([NH:18][CH3:17])(=[O:20])=[O:21])=[CH:27][CH:26]=3)[N:3]=2)[NH:8][CH:9]=1)=[O:16]
Reactant: CNS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(Br)nc12
Product: CNS(=O)(=O)c1ccc(-c2cnc3[nH]cc(C(=O)C(C)(C)C)c3n2)cc1

Procedure:
4-[7-(2,2-Dimethyl-propionyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-N-methyl-benzenesulfonamide was prepared starting from 1-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethyl-propan-1-one and 4-methylsulfamoylphenylboronic acid following general procedures as described in these Examples. MP 278-280° C., M+H=373.
Reaction SMILES: Cl[CH2:2][CH:3]=O.[NH2:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][N:13]=1)[C:9]#[N:10].C([O-])(O)=O.[Na+]>C(O)C>[N:5]1[CH:2]=[CH:3][N:13]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=12
Reactant: N#Cc1ccnc(N)c1
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: N#Cc1ccn2ccnc2c1
Temperature: 80 °C

Procedure:
Chloroacetaldehyde (˜50% in H2O, 3.24 ml, 26 mmol) was added to a stirred mixture of 2-amino-isonicotinonitrile (1.6 g, 3.4 mmol) and NaHCO3 (2.23 g, 26.5 mmol) in ethanol (20 ml) at RT under N2. The reaction was stirred and heated at 80° C. for 18 hours. After cooling to RT the volatiles were removed in vacuo and the residue was partitioned between EtOAc/H2O. This mixture was filtered to remove some dark insoluble residue. The solid was washed with MeOH. The aqueous layer was extracted with EtOAc (×2). The combined EtOAc extracts were dried (Na2SO4) and filtered. The MeOH washings were added and the volatiles were removed in vacuo. The residue was purified by chromatography on silica: 100% DCM→1% 2M NH3-MeOH/DCM to give the title product. 1H NMR (400 MHz, DMSO-d6): 8.74 (1H, dd), 8.35 (1H, s), 8.19 (1H, s), 7.86 (1H, s), 7.21 (1H, dd).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:12]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17](O)=[O:18])=[N:11][CH:10]=[N:9][C:8]=2[N:23]=1)([CH3:3])[CH3:2].[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([S:31][C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[CH:34][CH:33]=2)=[C:27]([NH:46][C:47]2[C:48]3[CH:56]=[CH:55][C:54]([CH:57]([CH3:59])[CH3:58])=[N:53][C:49]=3[N:50]=[CH:51][N:52]=2)[CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CS(C)=O.O>[CH:57]([C:54]1[CH:55]=[CH:56][C:48]2[C:47]([NH:46][C:27]3[CH:26]=[C:25]([NH:24][C:17](=[O:18])[C:16]4[CH:20]=[CH:21][CH:22]=[C:14]([NH:13][C:12]5[C:7]6[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[N:23][C:8]=6[N:9]=[CH:10][N:11]=5)[CH:15]=4)[CH:30]=[CH:29][C:28]=3[S:31][C:32]3[CH:37]=[CH:36][C:35]([NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[CH:34][CH:33]=3)=[N:52][CH:51]=[N:50][C:49]=2[N:53]=1)([CH3:59])[CH3:58]
Reactant: CC(C)c1ccc2c(Nc3cccc(C(=O)O)c3)ncnc2n1
Reactant: CC(C)c1ccc2c(Nc3cc(N)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)c1ccc2c(Nc3cccc(C(=O)Nc4ccc(Sc5ccc(NC(=O)OC(C)(C)C)cc5)c(Nc5ncnc6nc(C(C)C)ccc56)c4)c3)ncnc2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.1 %

Procedure:
To a solution of the product from Example 7B (25.8 mg, 0.084 mmol) in DMSO (2.0 mL) were added the product from Example 2A (40 mg, 0.084 mmol), HATU (31.8 mg, 0.084 mmol), and Hunigs base (56 μL, 0.318 mmol), and the mixture was stirred at room temperature for 24 hours. Additional HATU (39.5 mg, 0.104 mmol), and Hunigs base (50 μL, 0.282 mmol) were added and the reaction was stirred for 48 hours. Added more HATU (39.5 mg, 0.104 mmol) and heated at 45° C. for 8 hours. Added more HATU (39.5 mg, 0.104 mmol) and stirred overnight at room temperature. Water was added and the product was collected by filtration. Purification by chromatography on silica gel eluting with (0% to 5% methanol in dichloromethane) gave the title compound (40 mg, 63% yield).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[CH:10][C:9]=2[O:17][CH:18]2[CH2:23][CH2:22][CH2:21][O:20][CH2:19]2)[C:5]2[CH:24]=[CH:25][NH:26][C:4]=2[C:3]1=[O:27].CN1C=C(C2C=C([N+]([O-])=O)C=CC=2OC2CCOCC2)C2C=CNC=2C1=O>>[NH2:14][C:12]1[CH:11]=[CH:10][C:9]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][O:20][CH2:19]2)=[C:8]([C:6]2[C:5]3[CH:24]=[CH:25][NH:26][C:4]=3[C:3](=[O:27])[N:2]([CH3:1])[CH:7]=2)[CH:13]=1
Reactant: Cn1cc(-c2cc([N+](=O)[O-])ccc2OC2CCCOC2)c2cc[nH]c2c1=O
Agent: Cn1cc(-c2cc([N+](=O)[O-])ccc2OC2CCOCC2)c2cc[nH]c2c1=O
Product: Cn1cc(-c2cc(N)ccc2OC2CCCOC2)c2cc[nH]c2c1=O

Procedure:
Example 60b was prepared according to the procedure used for the preparation of Example 29b, substituting the product of Example 60a for the product of Example 29a, to provide the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([CH3:25])[CH:3]=1.[S:26]1(=[O:32])(=[O:31])[CH2:30][CH2:29][CH2:28][NH:27]1>>[O:31]=[S:26]1(=[O:32])[CH2:30][CH2:29][CH2:28][N:27]1[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([CH3:25])[CH:3]=1
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3C)CC2)c(C)c1
Reactant: O=S1(=O)CCCN1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3C)CC2)c(C)c1
Yield: 68.7 %

Procedure:
Using (4-bromo-2-methylphenyl) [4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (402 mg) described in Preparation Example 253 and isothiazolidine 1,1-dioxide (158 mg) and by the reaction and treatment in the same manner as in Example 262, the title compound (304 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:36])=[C:5]([C:21]([O:23][CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][OH:35])=[CH:29][CH:28]=2)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].N1C=CC=CC=1.[C:43](OC(=O)C)(=[O:45])[CH3:44].O>C(Cl)Cl>[CH3:1][C:2]1[NH:3][C:4]([CH3:36])=[C:5]([C:21]([O:23][CH2:24][CH2:25][O:26][C:27]2[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][O:35][C:43](=[O:45])[CH3:44])=[CH:31][CH:32]=2)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCOc2ccc(CCO)cc2)C1c1cccc([N+](=O)[O-])c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCOc2ccc(CCOC(C)=O)cc2)C1c1cccc([N+](=O)[O-])c1
Reaction time: 24 h

Procedure:
To a solution of 2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-(2-[4-(2-hydroxyethyl)phenoxy]ethoxycarbonyl)-1,4-dihydropyridine (1.25 g, 2.52 mmoles) in CH2Cl2 (15 mL) cooled to 0° C., were added pyridine (0.25 mL, 3.10 mmoles) and acetic anhydride (0.85 mL, 9.0 mmoles). The reaction mixture was left at room temperature for 24 hours. Water (20 mL) was then added to extract the pyridine. The organic layer was dried over anhydrous Na2SO4. After evaporation of the solvent, the crude product (1.5 g) was purified by flash chromatography (solvent=93:7 CH2Cl2 :acetone) to yield 2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-5-(2-[4-(2-acetoxyethyl)phenoxy]ethoxycarbonyl)-1,4-dihydropyridine, mp=110° C. NMR (CDCl3) δppm: 8.2(m, 9H); 5.15(s, 1H); 4.5-3.9(m, 6H); 3.63(s, 3H); 2.87(t, 2H); 2.37(s, 6H); 2.07(s, 3H).
Reaction SMILES: [CH3:1][C:2]([SH:7])([CH3:6])[CH2:3][CH2:4][OH:5].N1C=CC=CC=1.[C:14](Cl)(=[O:16])[CH3:15]>C(Cl)Cl>[C:14]([O:5][CH2:4][CH2:3][C:2]([CH3:6])([SH:7])[CH3:1])(=[O:16])[CH3:15]
Reactant: CC(=O)Cl
Reactant: CC(C)(S)CCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCCC(C)(C)S
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
3-Methyl-3-sulfanylbutan-1-ol (Sweetman et al, J. Med. Chem. 14:868 (1971), the disclosure of which is incorporated by reference herein in its entirety) (5 g, 42 mmol) and pyridine (3.6 mL, 43 mmol) were dissolved in methylene chloride (50 mL) and cooled to −78° C. Acetyl chloride (3.1 mL, 43 mmol) was added dropwise. The solution was kept cold for 30 min then allowed to warm to room temperature. Stirring was continued for 1.5 hours. The reaction mixture was diluted with methylene chloride, washed with 1 N HCl and brine, and dried over sodium sulfate. Evaporation of the solvent gave 6.6 g of the title compound which was used without further purification. 1H-NMR (CDCl3): δ1.41 (s, 3H), 1.92 (t, J=7.2 Hz, 2H), 2.03 (s, 3H), 2.21 (s, 1H), 4.25 (t, J=7.1 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])[O:3]1.C(N(CC)CC)C.[C:18](Cl)(=O)[CH2:19][CH2:20][CH3:21]>ClCCl>[CH2:18]([CH:6]1[C:7](=[O:8])[O:9][C:2]([CH3:10])([CH3:1])[O:3][C:4]1=[O:5])[CH2:19][CH2:20][CH3:21]
Reactant: CCCC(=O)Cl
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC1C(=O)OC(C)(C)OC1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Meldrum's acid (2,2-dimethyl-1,3-dioxane-4,6-dione, 6.15 g, 42.7 mmol) and triethyl amine (8.63 g, 85.4 mmol) were dissolved in dichloromethane (60 mL). Butyric acid chloride (4.99 g, 46.9 mmol) was added to the solution thus obtained dropwise while cooling with ice, followed by stirring at room temperature for about 12 hours. The reaction mixture was concentrated under reduced pressure, and then the resulting residue was subjected to extraction using ethyl acetate. The thus-obtained organic layer was washed with dilute hydrochloric acid and an aqueous saturated sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified using silica gel chromatography (developing solvent: n-hexane/ethyl acetate=8/2) to obtain 5-butyl-2,2-dimethyl-1,3-dioxane-4,6-dione.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].O.Br[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[N:29]([C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=2)[N:28]=[N:27][N:26]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1.CO>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]2[N:29]([C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=3)[N:28]=[N:27][N:26]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(-n2nnnc2-c2ccccc2Br)cc1
Reactant: Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(-c2ccccc2-c2nnnn2-c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 60 °C
Yield: 95.1 %

Procedure:
A mixture of 4-methylphenyl boronic acid (9.7 g; 71 mmol), sodium carbonate (16.7 g; 158 mmol), water (100 ml), methanol (50 ml) and toluene (50 ml) was heated to 60° C. to give a clear solution. Compound C (20.0 g; 55 mmol) was then added, followed by tetrakis(triphenylphosphine)palladium (0.3 g; 0.25 mmol) and the mixture heated at reflux for 3 hours. Toluene (30 ml) was added and the warm mixture was filtered through diatomaceous earth. The organic phase was separated and the aqueous phase extracted with toluene (40 ml). The combined organic phases were evaporated to give a solid which was recrystallised from toluene/petroleum ether (100°-120° C.) (1:1 v/v) to give 5-(4'-methylbiphenyl-2-yl)-1-(4-nitrophenyl)-1H-tetrazole (D) (18.7 g; 90% yield), m.p. 164°-166° C.; NMR (CDCl3): 2.3(3H, s), 6.45(2H, d), 6.85(4H, m), 7.38(1H, d), 7.65(2H, m), 7.85(1H, d), 8.0(2H, d).
Reaction SMILES: Cl([O-])=O.[Na+].[CH2:5]([O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[C:15]([CH:21]([CH3:23])[CH3:22])[CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.P([O-])(O)(O)=[O:25].[K+].CC(=CC)C>C(O)(C)(C)C.O>[CH2:5]([O:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]([OH:25])=[O:18])=[C:15]([CH:21]([CH3:23])[CH3:22])[CH:14]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=P([O-])(O)O
Reactant: CC(C)c1cc(OCc2ccccc2)ccc1C=O
Agent: CC=C(C)C
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)c1cc(OCc2ccccc2)ccc1C(=O)O
Temperature: 0 °C

Procedure:
A mixture of N-methylformanilide (9.92 g) and phosphoryl chloride (11.3 g) was stirred at room temperature for 30 minutes, and benzyloxy-3-isopropylbenzene (16.6 g) was added to the mixture. After being stirred at room temperature overnight, ice was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford 4-benzyloxy-2-isopropylbenzaldehyde (19.4 g) as a crude product. An aqueous solution (200 mL) of sodium chlorite (33.2 g) was added dropwise to an ice-cooled suspension of the crude 4-benzyloxy-2-isopropylbenzaldehyde and potassium dihydrogenphosphate (50.0 g) in tert-butylalcohol (200 mL)/2-methyl-2-butene (100 mL) with stirring. The mixture was stirred at room temperature for 3 hrs. To the resulting mixture was added water, and the insoluble materials were removed by filtration. The filtrate was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford 4-benzyloxy-2-isopropylbenzoic acid (23.3 g) as a crude product. A suspension of the crude 4-benzyloxy-2-isopropylbenzoic acid, ethyl iodide (13.7 g) and potassium carbonate (15.2 g) in N,N-dimethylformamide (300 mL) was stirred at room temperature for30 minutes. The reaction mixture was partitioned between diethyl ether and water. The organic layer was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5) to afford ethyl 4-benzyloxy-2-isopropylbenzoate (16.8 g). A suspension of ethyl 4-benzyloxy-2-isopropylbenzoate and 10% palladium-carbon (0.1 g) in ethanol (100 mL) was stirred at room temperature for 30 minutes under an atmosphere of hydrogen. The catalyst was removed by filtration, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5) to afford the title compound (1.1 g).
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH:8]1[CH2:12][CH2:11][NH:10][CH2:9]1.F[C:14]1[CH:15]=[CH:16][C:17]([N+:21]([O-:23])=[O:22])=[C:18]([CH3:20])[CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:2][CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH:8]1[CH2:12][CH2:11][N:10]([C:14]2[CH:15]=[CH:16][C:17]([N+:21]([O-:23])=[O:22])=[C:18]([CH3:20])[CH:19]=2)[CH2:9]1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: CC1CCCN1C1CCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1[N+](=O)[O-]
Temperature: 85 °C

Procedure:
2-Methyl-[1,3′]bipyrrolidinyl hydrochloride (Intermediate (ii) obtained above, 5.3 g, 21.6 mmol, 1.12 equiv.) was dissolved in anhydrous DMSO (30 mL). To this solution was added 5-fluoro-2-nitrotoluene (3.00 g, 18.78 mmol, 1 equiv.), followed by powdered potassium carbonate (8.9 g, 65 mmol). The suspension was heated on an oil bath to 85° C. for 4 h when the starting material was consumed as determined by TLC (5% MeOH in DCM) and LC/MS. To the suspension were added 20 mL of water and 50 mL of DCM. The two layers were separated, and the aqueous layer was extracted with DCM (20 mL×2). The combined DCM extracts were washed with sodium bicarbonate (20 mL), and brine (15 mL×2), dried (anhydrous potassium carbonate), filtered, and concentrated in vacuo. The crude product was purified on a silica gel column, eluted with 5% MeOH in DCM to get the title compound as a yellow solid after drying, 5.47 g (100%). MS: 290 (M+H+).
Reaction SMILES: O=[C:2]1[C:11]2[CH2:12][CH2:13]O[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([O:15][C:16]([F:19])([F:18])[F:17])[C:4]=2[NH:3]1.[CH3:20][C:21]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:22]=1[NH2:23]>C(O)COCCO.[Cl-].[Na+].O>[CH3:20][C:21]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:22]=1[N:23]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([O:15][C:16]([F:19])([F:18])[F:17])[C:4]=3[N:3]=[C:2]([NH:3][CH2:4][CH2:5][OH:15])[C:11]=2[CH2:12][CH2:13]1
Reactant: O=c1[nH]c2c(OC(F)(F)F)cccc2c2c1CCO2
Reactant: Cc1cccc(N)c1C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: OCCOCCO
Product: Cc1cccc(N2CCc3c(NCCO)nc4c(OC(F)(F)F)cccc4c32)c1C
Temperature: 250 °C
Yield: 113.5 %

Procedure:
4-Oxo-6-trifluoromethoxy-2,3,4,5-tetrahydrofuro[3,2-c]quinoline(5.0 g, 19 mmol) was dissolved in diethylene glycol(30 ml), and 2,3-dimethylaniline(5.6 ml, 46 mmol) was added under nitrogen. The reaction mixture was refluxed at 250° C. for 15 hours. The reaction mixture was diluted in brine(20 ml), and the aqueous layer was extracted with dichloromethane(15 ml) for 3 times. The organic layer was washed with water(15 ml) for 3 times, dried with by anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate as eleunt to obtain 4.5 g of desired compound as solid in 65% of yield.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].Cl.[NH2:31][CH2:32][C:33]([NH2:35])=[O:34].C(N(CC)CC)C.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C(#N)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][NH:31][CH2:32][C:33]([NH2:35])=[O:34])=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Reactant: NCC(N)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CNCC(N)=O)ccc21
Yield: 120.6 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-chloro-7-[1-(tert.-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (30.0 mg, 0.0730 mmol) was dissolved in acetonitrile (2 mL), and the solution was treated with glycineamide hydrochloride (96 mg, 0.87 mmol), triethylamine (0.243 mL, 1.74 mmol), acetic acid (0.252 mL, 4.40 mmol) and sodium triacetoxyborohydride (231 mg, 1.09 mmol). The reaction mixture was added with 1 mol/L hydrochloric acid and ethyl acetate, followed by extracting with 1 mol/L hydrochloric acid. The aqueous layer was added with sodium carbonate to adjust the pH to 9. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 4-chloro-7-{1-(tert-butoxycarbonyl)-5-[(aminocarbonylmethyl)aminomethyl]indol-2-yl}isoindolinone (41.3 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:11](=[O:33])(=[O:32])[N:12]([CH3:31])[C:13]3[CH:20]=[CH:19][C:18]([C:21]#[C:22][CH2:23][O:24]C4CCCCO4)=[CH:17][C:14]=3[C:15]=2[OH:16])=[O:9])=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:11](=[O:33])(=[O:32])[N:12]([CH3:31])[C:13]3[CH:20]=[CH:19][C:18]([C:21]#[C:22][CH2:23][OH:24])=[CH:17][C:14]=3[C:15]=2[OH:16])=[O:9])=[CH:34][CH:35]=1
Reactant: CN1c2ccc(C#CCOC3CCCCO3)cc2C(O)=C(C(=O)NCc2ccc(Cl)cc2)S1(=O)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CN1c2ccc(C#CCO)cc2C(O)=C(C(=O)NCc2ccc(Cl)cc2)S1(=O)=O
Temperature: 55 °C
Yield: 63.7 %

Procedure:
To a solution of N-(4-chlorobenzyl)-4-hydroxy-1-methyl-6-(3-(tetrahydro-2H-pyran-2-yloxy)-1-propynyl)-1H-2,1-benzothiazine-3-carboxamide 2,2-dioxide (Preparation 53, 0.30 g) in CH3OH (30 mL) is added p-TsOH.H2O (30 mg). The reaction mixture is heated to 55° C. for 2 h. The solvent is evaporated in vacuo and the residue is diluted with Et2O (20 mL) and sonicated. The resulting precipitate is filtered and washed with Et2O to afford 0.16 g (61%) of the title compound as a white solid. Physical characteristics: m.p. 167-168° C.; 1H NMR (300 MHz, CDCl3) δ 15.82, 8.21, 7.93, 7.69, 7.36, 7.17, 4.60, 4.53, 3.49, 2.21; IR (diffuse reflectance) 3344, 1615, 1579, 1554, 1540, 1490, 1392, 1385, 1325, 1310, 1293, 1279, 1160, 1093, 1031 cm−1; MS (ESI+) m/z 433 (MH+); HRMS (FAB) m/z 433.0614 (C20H17ClN2O5S+H). Anal. Found: C, 54.57; H, 4.16; N, 6.10.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([O:20]CC)=[O:19])=[CH:14]2)=[O:7].CO.[OH-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([OH:20])=[O:19])=[CH:14]2)=[O:7]
Reactant: CCOC(=O)c1cc2cccc(NC(=O)c3cccs3)c2[nH]1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc2cccc(NC(=O)c3cccs3)c2[nH]1
Temperature: 25 °C
Reaction time: 7 h
Yield: 87 %

Procedure:
To a mixed solution of ethyl 7-[(2-thienylcarbonyl)amino]-1H-indole-2-carboxylate (410 mg) in tetrahydrofuran (6 mL)-methanol (6 mL) was added aqueous solution (3 mL) of 85% potassium hydroxide (400 mg), and the mixture was stirred at room temperature for 7 hr. Aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were washed with ethyl acetate-hexane to give the title compound (325 mg, yield 87%) as pale-yellow crystals. melting point>268° C. (decomposition).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH2:16])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1.[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][C:32]=2[C:34](O)=[O:35])[CH:27]=[CH:26][CH:25]=1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH:16][C:34]([C:32]3[CH:31]=[CH:30][CH:29]=[C:28]4[C:33]=3[N:24]=[CH:25][CH:26]=[CH:27]4)=[O:35])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1
Reactant: NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1
Reactant: O=C(O)c1cccc2cccnc12
Product: Nc1nc(C(=O)N2[C@H](CNC(=O)c3cccc4cccnc34)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [2-amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl)-methanone with quinoline-8-carboxylic acid. LC-MS (basic): tR=0.82 min; [M+H]+=488.2.