Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([F:15])=[C:10]([Cl:16])[CH:9]=2)=[O:5])[CH3:2].[C:17]([O:21][C:22]([N:24]1[CH2:28][C@H:27]([CH3:29])OS1(=O)=O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C@H:27]([CH3:29])[CH2:28][NH:24][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([F:15])=[C:10]([Cl:16])[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(F)c(Cl)cc2[nH]1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Product: CCOC(=O)c1cc2cc(F)c(Cl)cc2n1[C@H](C)CNC(=O)OC(C)(C)C

Procedure:
The title compound, ISP-MS: m/e=399.4 (M+H+), was prepared in accordance with the general method of example 12b) from 6-chloro-5-fluoro-1H-indole-2-carboxylic acid ethyl ester and (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester.
Reaction SMILES: [NH:1]1[C:60](=[O:61])[C@H:49]([CH2:50][C:51]2[C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[NH:53][CH:52]=2)[NH:48][C:46](=[O:47])[C@@H:44]([CH3:45])[NH:43][C:41](=[O:42])[C@H:33]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[NH:32][C:30](=[O:31])[C@@H:12]([CH2:13][CH2:14][CH2:15][NH:16][C:17](=[NH:29])[NH:18]S(C2C=CC(C)=CC=2)(=O)=O)[NH:11][C:9](=[O:10])[C@@H:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1C(O)=CC=C(C)C=1>C(S)(S)C>[NH:1]1[C:60](=[O:61])[C@H:49]([CH2:50][C:51]2[C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[NH:53][CH:52]=2)[NH:48][C:46](=[O:47])[C@@H:44]([CH3:45])[NH:43][C:41](=[O:42])[C@H:33]([CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[NH:32][C:30](=[O:31])[C@@H:12]([CH2:13][CH2:14][CH2:15][NH:16][C:17](=[NH:18])[NH2:29])[NH:11][C:9](=[O:10])[C@@H:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H]2NC(=O)[C@H](c3ccccc3)NC(=O)[C@H](Cc3c[nH]c4ccccc34)NC(=O)[C@@H](C)NC(=O)[C@H](Cc3ccccc3)NC2=O)cc1
Agent: CC(S)S
Agent: Cc1ccc(O)cc1
Product: C[C@H]1NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@@H](CCCNC(=N)N)NC(=O)[C@H](c2ccccc2)NC(=O)[C@H](Cc2c[nH]c3ccccc23)NC1=O

Procedure:
The crude cyclo(-Phg-D-Arg(Tos)-Phe-D-Ala-Trp-) (100 mg) as obtained in Example 48 was treated with HF in the presence of p-cresol (75 mg) and ethanedithiol (50 ml) for 2 hours while cooling with ice. After HF was removed by distillation, ether was added to the residue and the precipitate formed was collected by filtration. This was purified by gel chromatography (G-25; 2 cm×80 cm). Finally, 20 g of the product was further purified by HPLC using a column for partitioning purification of D-ODS-5-ST (2 cm×15 cm; produced by YMC Co.) to obtain cyclo(-Phg-D-Arg-Phe-D-Ala-Trp-).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([CH3:18])[S:9][C:8]1=S)(=[O:3])[CH3:2].C1(C)C=CC(S(OC)(=O)=O)=CC=1.[C:32]([C:35]1[CH:36]=[CH:37][C:38]([NH:55][CH2:56][CH3:57])=[C:39]([N:41]=[C:42]2[N:46]([CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C:45](=[O:54])[CH2:44][S:43]2)[CH:40]=1)(=[O:34])[CH3:33]>>[C:1]([O:4][CH2:5][CH2:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([CH3:18])[S:9][C:8]1=[C:44]1[S:43][C:42](=[N:41][C:39]2[CH:40]=[C:35]([C:32](=[O:34])[CH3:33])[CH:36]=[CH:37][C:38]=2[NH:55][CH2:56][CH3:57])[N:46]([CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:45]1=[O:54])(=[O:3])[CH3:2]
Reactant: CCNc1ccc(C(C)=O)cc1N=C1SCC(=O)N1Cc1ccccc1
Reactant: CC(=O)OCCn1c(-c2ccccc2)c(C)sc1=S
Agent: COS(=O)(=O)c1ccc(C)cc1
Product: CCNc1ccc(C(C)=O)cc1N=C1SC(=C2SC(C)=C(c3ccccc3)N2CCOC(C)=O)C(=O)N1Cc1ccccc1

Procedure:
In a manner similar to that described in Example 52, intermediate 2-(5-methyl-4-phenyl-2-thioxothiazol-3-yl)ethyl acetate was alkylated with methyl p-toluenesulfonate and condensed with 2-(5-acetyl-2-ethylaminophenylimino)-3-benzylthiazolidin-4-one to yield the title compound. 1H-NMR (CDCl3): δ 7.63–7.67 (2H, m), 7.44–7.51 (5H, m), 7.28–7.37 (5H, m), 6.50 (1H, d), 5.19 (2H, s), 4.30 (1H, br t), 4.03 (4H, m), 3.06 (2H, m), 2.48 (3H, s), 2.05 (3H, s), 1.89 (3H, s), 1.05 (3H, t); MS(ESI): 627 (MH+).
Reaction SMILES: CC1N=C2NC(=O)NC2=CC=1.Cl.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[C:22]3[NH:29][C:28](=[O:30])[NH:27][C:23]3=[N:24][C:25]=2[CH3:26])=[CH:16][CH:15]=1.[CH2:31]([S:35](Cl)(=[O:37])=[O:36])CCC>>[CH3:31][S:35]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[C:22]3[NH:29][C:28](=[O:30])[NH:27][C:23]3=[N:24][C:25]=2[CH3:26])=[CH:16][CH:15]=1)(=[O:37])=[O:36]
Reactant: Cc1nc2[nH]c(=O)[nH]c2cc1-c1ccc(N)cc1
Reactant: CCCCS(=O)(=O)Cl
Agent: Cc1ccc2[nH]c(=O)[nH]c2n1
Agent: Cl
Product: Cc1nc2[nH]c(=O)[nH]c2cc1-c1ccc(NS(C)(=O)=O)cc1

Procedure:
Example 10 6-4-(Butanesulfonylamino)phenyl]-1,3-dihydro-5-methyl2H-imidazo[4,5-b]pyridin-2-one [I; Ar =4-CH3 (CH2)3SO2NHC6H4, R1 and R3 =H, R5 =CH3 ]was prepared from 1.5 g 6-(4-aminophenyl)-1,3-dihydro-5-methyl-2H-imidazo[4,5-b]pyridin-2-one hydrochloride and 0.91 ml butanesulfonyl chloride according to the procedure of Example 7, and was obtained (0.92 g) as a colorless solid, m.p. above 300° C. when recrystallized from ethanol.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[N:9]([C:17]3[CH:22]=[CH:21][C:20]([S:23](C)(=[O:25])=[O:24])=[CH:19][CH:18]=3)[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)[N:3]=1.C(B(CC)CC)C.C([O-])(=O)C.[Na+].[NH2:39]OS(O)(=O)=O>O1CCCC1.O>[CH3:1][C:2]1[N:3]=[C:4]([C:8]2[N:9]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([NH2:39])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(-c2nc(C(F)(F)F)cn2-c2ccc(S(C)(=O)=O)cc2)n1
Reactant: NOS(=O)(=O)O
Agent: CC(=O)[O-]
Agent: CCB(CC)CC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(-c2nc(C(F)(F)F)cn2-c2ccc(S(N)(=O)=O)cc2)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a clear solution of Example 34 (10 mmol) in tetrahydrofuran (60 ml) at 0° C., n-BuMgcl (2M solution in THF, 25 ml, 50 mmol) is added over 10 minutes. After stirring for an additional 20 minutes, the ice bath is removed and the solution is stirred for 2 hours. The reaction mixture is recooled to 0° C. and triethylborane (1M solution in THF, 60 ml, 60 mmol) is added. After stirring for 1 hour, the reaction is heated to reflux for 72 hours. The reaction mixture is cooled to room temperature and treated with aqueous sodium acetate (5.5 g in 22 ml water). After stirring for 5 minutes, solid hydroxylamine-O-sulfonic acid (5.5 g) is added and the mixture stirred for 24 hours. The reaction mixture is diluted with water and extracted with ether. The ethereal layer is dried over sodium sulfate, filtered and concentrated. The crude solid is chromatographed on silica gel using mixtures of hexane and isopropanol to give the desired product.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][OH:22])[CH:17]=2)[CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl.O=[Mn]=O>[CH2:1]([O:8][C:9]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH:21]=[O:22])[CH:17]=2)[CH:12]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)c1ccc2cc(CO)ccc2c1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: O=Cc1ccc2cc(C(=O)OCc3ccccc3)ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.3 %

Procedure:
Dissolved 1.2 g (4 mmol) of 6-Hydroxymethyl-2-naphthalenecarboxylic acid benzyl ester in 100 ml of CH2Cl2, slowly added 5.2 g of MnO2 (60 mmol) and stirred at room temperature for 2 hours, then filtered through Ceilite. The Celite was washed with CH2Cl2 and combined organics taken to dryness. The oily residue was solidified with EtOAc/Hexanes (1:1) and collected by vacuum filtration, washed with small amount of methanol, dried to get 1.2 g of 6-Formyl-2-naphthalenecarboxylic acid benzyl ester. 1H NMR (400 MHz, DMSO-d6): δ 10.192 (s, 1H, —CHO), 8.754 (s, 1H, Ar—H), 8.667 (s, 1H, Ar—H), 8.327(t, J=9.4, 2H, Ar—H), 8.142(dd, J=1.6&7.0 Hz, 1H, Ar—H), 7.987-7.962 (dd, J=1.6&7.0 Hz, 1H, Ar—H), 7.544-7.526 (m, 2H, Ar—H), 7454-7.375 (m, 3H, Ar—H), 5.442 (s, 2H, —COOCH2—), MS m/e 289[M+−1].
Reaction SMILES: [C:1]1([NH2:8])[C:2]([NH2:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH3:9][O:10][C:11]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:12]=1[CH:13]=O.C(O)(=O)C>C(O)C>[CH3:9][O:10][C:11]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:12]=1[C:13]1[NH:8][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[N:7]=1
Reactant: Nc1ccccc1N
Reactant: COc1ccc(C=O)c(OC)c1
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc(-c2nc3ccccc3[nH]2)c(OC)c1
Yield: 12.4 %

Procedure:
Ex-70A: A solution of benzene-1,2-diamine (2.60 g, 24.1 mmol) and 2,4-dimethoxy-benzaldehyde (4.0 g, 24.1 mmol) in ethanol (60 mL) containing catalytic amount of acetic acid was refluxed overnight. Solvent was then evaporated under reduced pressure. The residue oil was triturated in ethyl acetate to obtain 2-(2,4-dimethoxy-phenyl)-1H-benzoimidazole (0.76 g, 12%). The crude product was used without further purification. To a solution of 2-(2,4-dimethoxy-phenyl)-1H-benzoimidazole obtained above (0.76 g, 2.99 mmol) in dichloromethane (20 mL) was added dichloromethyl methyl ether (0.41 mL, 4.48 mmol) followed by addition of titanium tetrachloride (1.0M in dichloromethane, 9.0 mL, 9.0 mmol) at 0° C. The reaction mixture was allowed to stir overnight at ambient temperature and then poured into ice. A solution of sodium hydroxide (5M) was added dropwise until the pH of the solution was about 12. The basic solution was extracted with dichloromethane. The combined solution of dichloromethane was subsequently washed with brine, dried over sodium carbonate and concentrated. The product, 5-(1H-benzoimidazol-2-yl)-2,4-dimethoxy-benzaldehyde (0.40 g, 47%), was obtain and used without further purification. 1H NMR (CDCl3) δ 10.32 (s, 1H), 10.27 (bs, 1H), 9.03 (s, 1H), 7.83 (d, J=9 Hz, 1H), 7.48–7.45 (m, 1H), 7.31–7.22 (m, 1H), 6.58 (s, 1H), 4.18 (s, 3H), 4.01 (s, 3H). MS m/z=282 (M+, 100%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[CH2:10][C:11](=[NH:15])[O:12][CH2:13][CH3:14].[N:16]#[C:17]N>C(O)C.C(OCC)C>[C:17]([N:15]=[C:11]([O:12][CH2:13][CH3:14])[CH2:10][C:4]1[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:3]=1[F:2])#[N:16]
Reactant: CCOC(=N)Cc1ccc(F)cc1F
Reactant: N#CN
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: CCOC(Cc1ccc(F)cc1F)=NC#N
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of Example 4A (7.0 g, 29.7 mmol) in ethanol (100 mL) was added a solution of cyanamide (1.25 g, 29.7 mmol) in diethyl ether (25 mL). The reaction mixture was stirred at room temperature for 3 days. The reaction mixture was then filtered and the filtrate was concentrated to obtain the titled compound. MS (ESI+) m/z 225 (M+H)+.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:5]([CH2:10][NH2:11])=[N:6][CH:7]=[CH:8][N:9]=1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH2:43]([O:50][C:51]([N:53]1[CH2:58][CH2:57][CH:56]([C:59](O)=[O:60])[CH2:55][CH2:54]1)=[O:52])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C(Cl)Cl>[Cl:3][C:4]1[C:5]([CH2:10][NH:11][C:59]([CH:56]2[CH2:57][CH2:58][N:53]([C:51]([O:50][CH2:43][C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)=[O:52])[CH2:54][CH2:55]2)=[O:60])=[N:6][CH:7]=[CH:8][N:9]=1
Reactant: NCc1nccnc1Cl
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1nccnc1Cl)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of C-(3-Chloropyrazin-2-yl)methylamine bis-hydrochloride (2.00 g, 0.0107 mol) and N,N-diisopropylethylamine (2.2 g, 0.017 mol) in DCM (27.0 mL) was treated with and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (3.2 g, 0.017 mol), 1-hydroxybenzotriazole (1.5 g, 0.011 mol) and 1-[(benzyloxy)carbonyl]-4-piperidine carboxylic acid (3.8 g, 0.014 mol). The mixture was stirred at rt overnight then diluted with DCM (30 mL), washed with sat. NaHCO3 (20 mL) and brine (20 mL), then dried over Na2SO4 and concentrated in vacuo. The crude material thus obtained was chromatographed over silica gel eluting with EtOAc:hexane 1:1 yielding 3.38 g of the title compound. 1H NMR (400 MHz, CDCl3): δ 1.68-1.78 (m, 2H), 1.91-1.94 (m, 2H), 2.44 (m, 1H), 2.89-2.92 (m, 2H), 4.24-4.26 (m, 2H), 4.70 (d, J=4.8 Hz, 2H), 5.14 (s, 2H), 6.85 (br, 1H), 7.30-7.37 (m, 5H), 8.34 (d, J=2.8 Hz, 1H), 8.45 (d, J=2.8 Hz, 1H). MS (ES+): m/z 389.17 [MH+].
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:35][C:36]3[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[C:39]([NH2:46])=[C:38]([Cl:47])[CH:37]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][C@H:28]4[C:32]([OH:34])=[O:33])[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:48]=[CH:49][CH:50]=[CH:51][C:4]=2[NH:3]1.[N:52]1([CH2:58][CH2:59]O)[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1>>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:35][C:36]3[CH:41]=[C:40]([C:42]([F:43])([F:45])[F:44])[C:39]([NH2:46])=[C:38]([Cl:47])[CH:37]=3)[C:19]([N:21]3[CH2:22][CH2:23][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][C@H:28]4[C:32]([O:34][CH2:59][CH2:58][N:52]4[CH2:57][CH2:56][O:55][CH2:54][CH2:53]4)=[O:33])[CH2:25][CH2:26]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:48]=[CH:49][CH:50]=[CH:51][C:4]=2[NH:3]1
Reactant: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCC[C@H]3C(=O)O)CC2)cc1C(F)(F)F
Reactant: OCCN1CCOCC1
Product: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCC[C@H]3C(=O)OCCN3CCOCC3)CC2)cc1C(F)(F)F

Procedure:
Prepared analogously to Example 9.2 from 70 mg (0.10 mmol) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-((S)-2-carboxy-pyrrolidin-1-yl) -piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 13.2 mg (0.11 mmol) 2-morpholin-4-yl-ethanol.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7](Br)[CH:6]=1)(=[O:3])[CH3:2].[Li]CCCC.CCCCC.[C:23](OCC)(=[O:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25]>C1COCC1>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([C:23](=[O:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C)c(Br)c1
Reactant: CCOC(=O)C(=O)OCC
Agent: [Li]CCCC
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1cc(NC(C)=O)ccc1C
Temperature: -78 °C
Reaction time: 1 h
Yield: 10.5 %

Procedure:
To a solution of N-acetyl-3-bromo-4-methylaniline (1.43 g, 627 mmol) in THF (50 mL) at −78° C. is added 2M BuLi in pentane (7.83 mL, 15.66 mmol) dropwise. After a further 1 h, diethyl oxalate (4.26 mL, 31.3 mmol) is added. After stirring for 4 hours at −78° C., the reaction mixture is quenched with saturated NH4Cl solution. The mixture is partitioned between ethyl acetate and water. The layer is separated and the aqueous layer is extracted with ethyl acetate. The combined organic extracts are washed with brine, dried over Na2SO4, filtered and concentrated. The residue is purified by column chromatography (silica gel, eluting with ethyl acetate; hexanes from 1/1 to 2/1) to afford fee title compound (0.82 g, 52%).
Reaction SMILES: [N:1]1([CH2:6][C:7]([N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=3)[CH2:12][CH2:11][CH2:10]2)=O)[CH:5]=[CH:4][N:3]=[CH:2]1.Cl.[OH-].[Na+]>C1COCC1>[N:1]1([CH2:6][CH2:7][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=3)[CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(Cn1ccnc1)N1CCCc2ccc([N+](=O)[O-])cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2c(c1)N(CCn1ccnc1)CCC2
Temperature: 0 °C

Procedure:
In a 100-ml round-bottomed, three-necked flask fitted with a condenser and a thermometer, under an inert (nitrogen) atmosphere, 8.6 g (30 mmol) of 2-(1H-imidazol-1-yl)-1-(7-nitro-3,4-dihydroquinolin-1-(2H)-yl)ethanone are dissolved in 10 ml of dry THF. The solution was stirred at 0° C. and 150 ml (5 eq) of a 1.0M solution of BH3 in THF were added. The reaction medium was left to return to ambient temperature and was then stirred overnight. The reaction mixture was carefully acidified (drop by drop) with 1N HCl (considerable foaming and release of gas), before being brought to reflux for 0.5 h. The mixture was then cooled to ambient temperature and neutralized with 4.0N sodium hydroxide. The medium is extracted several times with ethyl acetate. The organic phases were combined, and dried over MgSO4. After filtration, the solvent was removed by evaporation. The residue was purified by chromatography on a column of silica (dichloromethane/methanol). After evaporation of the solvents, crystallization was initiated with diethyl ether so as to give the expected product: 1-(2-(1H-imidazol-1-yl)ethyl)-7-nitro-1,2,3,4-tetrahydroquinoline in the form of an orange solid (Mp 120-121° C.).
Reaction SMILES: [C:1]([CH2:4][C:5]1[C:6]([CH3:14])=[C:7](C(O)=O)[NH:8][C:9]=1[CH3:10])([OH:3])=[O:2].[OH-].[K+]>O>[CH3:10][C:9]1[NH:8][CH:7]=[C:6]([CH3:14])[C:5]=1[CH2:4][C:1]([OH:3])=[O:2]
Reactant: Cc1[nH]c(C(=O)O)c(C)c1CC(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1c[nH]c(C)c1CC(=O)O
Temperature: 68 °C
Yield: 39.7 %

Procedure:
4-Carboxymethyl-3,5-dimethyl-1H-pyrrole-2-carboxylic acid wet mixture (778 g, 3.95 mol), 880 mL of 9 N potassium hydroxide and 880 mL of water were heated to an internal temperature of 65° C., removed from the heat, and 800 mL of 10 N hydrochloric acid were slowly added with stirring to a pH of 2.5. The temperature increased to 68° C. and then decreased to 58° C. with the evolution of carbon dioxide. Thin layer chromatography (ethyl acetate:hexane:acetic acid 4:6:0.5) showed a major spot at Rf 0.7 and a small spot at the origin. The mixture was cooled to 4° C. The solids were collected by vacuum filtration and washed 3 times with 200 mL of water each time. The solid was air dried to give 240 g (40% yield) of (2,4-dimethyl-1H-pyrrol-3-yl)-acetic acid as a brown solid. 1H-NMR (dimethylsulfoxide-d6) δ 1.89, 2.06 (2×s, 2×3H, 2×CH3), 3.17 (s, 2H, CH2), 6.26 (s, 1H, pyrrole CH), 10.02 (s, 1H, NH), 11.74 (br s, 1H, COOH).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=2[N:16]([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)[S:17]([CH3:20])(=[O:19])=[O:18])[C:9]([O:11]C)=[O:10])[CH2:3][CH2:2]1.[Li+:30].[OH-]>C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=2[N:16]([CH2:21][CH2:22][N:23]2[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]2)[S:17]([CH3:20])(=[O:18])=[O:19])[C:9]([O-:11])=[O:10])[CH2:3][CH2:2]1.[Li+:30]
Reactant: COC(=O)c1ccc(N(CCN2CCN(C)CC2)S(C)(=O)=O)c(OCC2CC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN1CCN(CCN(c2ccc(C(=O)[O-])cc2OCC2CC2)S(C)(=O)=O)CC1

Procedure:
To a solution of methyl 3-(cyclopropylmethoxy)-4-(N-(2-(4-methylpiperazin-1-yl)ethyl)methylsulfonamido)benzoate (370 mg, 0.869 mmol) in THF (3 ml), a solution of LiOH 1M (43.8 mg, 1.043 mmol) was added. The final solution was stirred at RT for 6 hours, then the solvent was evaporated and the residue was dried under vacuum to give lithium 3-(cyclopropylmethoxy)-4-(N-(2-(4-methylpiperazin-1-yl)ethyl)methyl-sulfonamido)benzoate as a pale yellow solid (380 mg, yield considered to be quantitative, MS/ESI+ 412.0 [MH]+) that was used in the following step without further purification.
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH2:17][CH:18]=[O:19])[C:4]([NH:6][C:7]1[S:8][C:9]([CH:12]2[CH2:15][CH2:14][CH2:13]2)=[N:10][N:11]=1)=[O:5])[CH3:2].Cl>O>[CH:12]1([C:9]2[S:8][C:7]([N:6]3[CH:18]([OH:19])[CH2:17][CH2:16][N:3]([CH2:1][CH3:2])[C:4]3=[O:5])=[N:11][N:10]=2)[CH2:15][CH2:14][CH2:13]1
Reactant: CCN(CCC=O)C(=O)Nc1nnc(C2CCC2)s1
Agent: Cl
Solvent: O
Product: CCN1CCC(O)N(c2nnc(C3CCC3)s2)C1=O

Procedure:
The dimethyl acetal of 3-[1-ethyl-3-(5-cyclobutyl-1,3,4-thiadiazol-2-yl)ureido]propionaldehyde (15 grams), water (400 ml) and hydrochloric acid (4 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. The reaction mixture is then filtered while hot and the filtrate is cooled to form a precipitate. The precipitate is recovered by filtration, is dried and is recrystallized to yield the desired product tetrahydro-1-(5-cyclobutyl-1,3,4-thiadiazol-2-yl)-3-ethyl-6-hydroxy-2(1H)-pyrimidinone.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19].[CH3:20][S:21](Cl)(=[O:23])=[O:22]>N1C=CC=CC=1>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:21]([CH3:20])(=[O:23])=[O:22])=[C:3]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])[CH:4]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(N)c(Nc2ccc(F)cc2F)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)c1ccc(NS(C)(=O)=O)c(Nc2ccc(F)cc2F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.9 %

Procedure:
A mixture of 4'-amino-3'-(2,4-difluorophenylamino)acetophenone (1.7 g) and methanesulfonyl chloride (0.9 g) in pyridine (17 ml) was stirred for 4 hours at room temperature. Pyridine was evaporated and the residue was stirred with an aqueous solution of sodium hydroxide (5%) for 30 minutes. The solution was washed with toluene, acidified to pH 3 with hydrochloric acid, and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium bicarbonate, dried, and concentrated under reduced pressure. The syrupy residue (1.8 g) was crystallized from ethanol to give pale yellow crystals of 4'-acetyl-2'-(2,4-difluorophenylamino)methanesulfonanilide (1.3 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10]Br.[CH2:13]([O:15][P:16]([O:20]CC)[O:17][CH2:18][CH3:19])[CH3:14]>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][P:16]([O:17][CH2:18][CH3:19])([O:15][CH2:13][CH3:14])=[O:20]
Reactant: CCOP(OCC)OCC
Reactant: COC(=O)c1ccccc1CBr
Product: CCOP(=O)(Cc1ccccc1C(=O)OC)OCC
Temperature: 150 °C
Reaction time: 16 h
Yield: 104.7 %

Procedure:
A mixture of 2-bromomethyl-benzoic acid methyl ester (5 g; 21.83 mmol; 1 eq.) and phosphorous acid triethyl ester (4.53 mL; 26.19 mmol; 1.2 eq.) was stirred at 150° C. for 16 hours then concentrated in vacuo to afford the title compound (6.54 g, quantitative) a yellow oil. HPLC (max plot) 88.8%; Rt 3.11 min.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([N:5]1[CH2:14][C:13]2[CH:15]=[CH:16][C:17]([S:18]([Cl:21])(=[O:20])=[O:19])=[C:11]3[C:12]=2[C:7](=[CH:8][CH:9]=[CH:10]3)[CH2:6]1)=[O:4].[N+:24]([O-])([OH:26])=[O:25]>>[N+:24]([C:10]1[C:11]2[C:12]3[C:7](=[CH:8][CH:9]=1)[CH2:6][N:5]([C:3](=[O:4])[C:2]([F:1])([F:22])[F:23])[CH2:14][C:13]=3[CH:15]=[CH:16][C:17]=2[S:18]([Cl:21])(=[O:19])=[O:20])([O-:26])=[O:25]
Reactant: O=[N+]([O-])O
Reactant: O=C(N1Cc2cccc3c(S(=O)(=O)Cl)ccc(c23)C1)C(F)(F)F
Product: O=C(N1Cc2ccc([N+](=O)[O-])c3c(S(=O)(=O)Cl)ccc(c23)C1)C(F)(F)F
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Solid 2,3-dihydro-2-trifluoroacetyl-1H-Benz[de]isoquinoline-6-sulfonyl chloride (6 mmol) is added portionwise to cold (0° C.) 90% nitric acid (5 mL). The resulting mixture is stirred at 0° C. overnight then cautiously poured into ice-water. The precipitate is collected by filtration and washed with ice-water to give the title compound. The crude product can be purified by recrystallization or chromatography.