Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:6]2([CH2:26][CH2:27][CH2:28][CH2:29][CH:30]3[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]3)[CH2:11][C:10]([OH:12])=[C:9]([CH2:13][C:14]3[N:24]=[C:17]4[N:18]=[C:19]([CH3:23])[CH:20]=[C:21]([CH3:22])[N:16]4[N:15]=3)[C:8](=[O:25])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>O1CCOCC1>[CH:1]1([C:6]2([CH2:26][CH2:27][CH2:28][CH2:29][CH:30]3[CH2:31][CH2:32][NH:33][CH2:34][CH2:35]3)[O:7][C:8](=[O:25])[C:9]([CH2:13][C:14]3[N:24]=[C:17]4[N:18]=[C:19]([CH3:23])[CH:20]=[C:21]([CH3:22])[N:16]4[N:15]=3)=[C:10]([OH:12])[CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(C)n2nc(CC3=C(O)CC(CCCCC4CCN(C(=O)OC(C)(C)C)CC4)(C4CCCC4)OC3=O)nc2n1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(C)n2nc(CC3=C(O)CC(CCCCC4CCNCC4)(C4CCCC4)OC3=O)nc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 4-(4-{2-cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}butyl)piperidine-1-carboxylate (example B(41)) (0.47 g, 0.8 mmol) was dissolved in dioxane (1 mL) and 4N HCl in dioxane (1 mL). The reaction was stirred overnight at room temperature. Solvents were removed and the residue was purified using a Dionex system (30–70% CH3CN/H2O (0.1% AcOH). H NMR (400 MHz, DMSO-d6): δ 1.37–1.70 (m, 20 H), 2.63–2.85 (m, 12 H), 3.69–3.95 (m, 4H), 7.98 (s, 1H), 11.12 (s, 1H). Anal. Calcd. For C27H39N5O3.1.0 HCl.1.5 H2O: C, 59.49; H, 7.95; N, 12.85, Found: C, 59.60; H, 8.04; N, 12.95. ESIMS (MH+): 482.
Reaction SMILES: Cl.Cl.Cl.[CH3:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[NH:11][CH2:12][CH2:13][C:14]1([C:20]([O:22]CC)=O)[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]1.Cl[C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1.C(N(CC)C(C)C)(C)C.CN1CCCC1=O.[H-].[Na+]>>[CH3:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][C:14]2([CH2:19][CH2:18][CH2:17][N:16]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=3)[CH2:15]2)[C:20]1=[O:22]
Reactant: CCOC(=O)C1(CCNc2cnccc2C)CCCNC1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccncc1N1CCC2(CCCN(c3ccc(C(F)(F)F)cn3)C2)C1=O
Reaction time: 8 h

Procedure:
A mixture of ethyl 3-{2-[(4-methylpyridin-3-yl)amino]ethyl}piperidine-3-carboxylate trihydrochloride (42.8 mg, 0.000107 mol), 2-chloro-5-(trifluoromethyl)pyridine (23 mg, 0.00013 mol) and N,N-diisopropylethylamine (0.056 mL, 0.00032 mol) in N-methylpyrrolidinone (0.8 mL, 0.008 mol) was irradiated with microwaves to 180° C. for 20 min. Sodium hydride (30.0 mg) was then added to the above solution and the mixture was stirred overnight. The product was purified by prep-HPLC. LC-MS: 391.2 (M+H)+.
Reaction SMILES: Br[C:2]1[C:7]2[NH:8][C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][N:18]=4)[CH2:13][C@H:12]3[CH3:24])=[N:10][C:6]=2[CH:5]=[C:4]([C:25]([F:28])([F:27])[F:26])[CH:3]=1.[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[C:34]([F:36])[CH:35]=1>>[Cl:23][C:22]1[C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:9]3[NH:8][C:7]4[C:2]([C:32]5[CH:31]=[C:30]([F:29])[CH:35]=[C:34]([F:36])[CH:33]=5)=[CH:3][C:4]([C:25]([F:27])([F:26])[F:28])=[CH:5][C:6]=4[N:10]=3)[C@H:12]([CH3:24])[CH2:13]2)=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: C[C@@H]1CN(c2ncccc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(Br)c2[nH]1
Reactant: OB(O)c1cc(F)cc(F)c1
Product: C[C@@H]1CN(c2ncccc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(-c3cc(F)cc(F)c3)c2[nH]1

Procedure:
7-Bromo-2-[(2R)-4-(3-chloropyridin-2-yl)-2-methylpiperazin-1-yl]-5-(trifluoromethyl)-1H-benzoimidazole (95 mg, 0.2 mmol, Example 77) and 3,5-difluoro-phenylboronic acid (39 mg, 0.25 mmol, Aldrich) reacted under the conditions of Example 51 a to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 508 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[CH:6]=[C:5]([OH:17])[N:4]=1)[CH3:2].Cl.Cl[CH2:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]=[C:26]([CH3:31])[CH:25]=[CH:24]2.[Li+].[OH-]>C1COCC1>[CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6]([CH2:20][C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[N:27]=[C:26]([CH3:31])[CH:25]=[CH:24]3)=[C:5]([OH:17])[N:4]=1)[CH3:2]
Reactant: Cc1ccc2cc(CCl)ccc2n1
Reactant: CCc1nc(O)cc2cc(OC)c(OC)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1nc(O)c(Cc2ccc3nc(C)ccc3c2)c2cc(OC)c(OC)cc12
Temperature: 25 °C

Procedure:
To a solution of 1-ethyl-6,7-dimethoxyisoquinolin-3-ol SLA 47022 (409 mg, 1.7 mmol) in THF (13 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added a 6-(chloromethyl)-2-methylquinolinehydrochloride SLA 47080B (400 mg, 1.7 mmol) and a 2 N aq. LiOH solution (1.75 mL, 3.5 mmol) and the mixture was stirred at 160° C. for 1.5 h under microwave irradiation. After cooling to RT, THF was removed at 40° C. under vacuum and the residue was taken up in CH2Cl2 (50 mL), washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum. Purification by column chromatography (SiO2, eluent EtOAc:MeOH=100:0 to 93:7) followed by a new purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 93:7) provided 1-ethyl-6,7-dimethoxy-4-((2-methylquinolin-6-yl)methyl)isoquinolin-3-ol. This free base was dissolved in MeOH (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.149 M HCl solution in MeOH (2.0 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford 1-ethyl-6,7-dimethoxy-4-((2-methylquinolin-6-yl)methyl)isoquinolin-3-ol dihydrochloride 81 as a yellow solid (66 mg, 8% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[C@H:11]([C:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH:28]4[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]4)[C:26]=3[CH3:27])[CH:20]=2)[NH:15][CH:14]=1)[CH3:12].[C:35]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)(=[O:37])[CH3:36].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].ClCCCl>>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[C@H:11]([C:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22]3[CH:23]=[N:24][N:25]([C@@H:28]4[CH2:33][CH2:32][C@H:31]([N:41]5[CH2:42][CH2:43][N:38]([C:35](=[O:37])[CH3:36])[CH2:39][CH2:40]5)[CH2:30][CH2:29]4)[C:26]=3[CH3:27])[CH:20]=2)[NH:15][CH:14]=1)[CH3:12]
Reactant: CC(=O)N1CCNCC1
Reactant: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(-c3cnn(C4CCC(=O)CC4)c3C)cc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(-c3cnn([C@H]4CC[C@@H](N5CCN(C(C)=O)CC5)CC4)c3C)cc12
Temperature: 60 °C

Procedure:
A mixture of 4-(4-{3-[(1S)-1-(2-chloro-3-fluoro-6-methoxyphenyl)ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5-methyl-1H-pyrazol-1-yl)cyclohexanone (12.0 mg, 0.0250 mmol), 1-acetylpiperazine (31.98 mg, 0.2495 mmol), sodium triacetoxyborohydride (10.58 mg, 0.04990 mmol) and 1,2-dichloroethane (3 mL, 40 mmol) was heated to 60° C. in a sealed tube for 6 h. The solution was extracted with DCM and sat. NaHCO3, and the organic layer was loaded onto silica gel for column chromatography, eluting with 3-7% (7N NH3 in MeOH)/DCM. The fractions containing the product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.63-1.73 (m, 3H), 1.81 (d, J=7.1 Hz, 3H), 2.00 (s, 3H), 2.10-2.14 (m, 4H), 2.25-2.43 (m, 4H), 2.58-2.66 (m, 4H), 3.59-3.70 (m, 8H), 4.34 (tdd, J=9.3, 9.3, 4.7, 4.3 Hz, 1H), 5.12 (q, J=6.8 Hz, 1H), 6.90 (dd, J=9.1, 4.3 Hz, 1H), 7.09 (t, J=8.8 Hz, 1H), 7.36 (d, J=1.0 Hz, 1H), 7.42 (s, 1H), 7.47 (s, 1H), 8.12 (s, 1H). MS (ES+): m/z=593.27/595.27 (100/50) [MH+]. HPLC: tR=1.19 min (polar—3 min, UPLC-ACQUITY).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].I[CH:20]([CH3:22])[CH3:21]>CN(C=O)C.CCOCC>[F:1][C:2]1[CH:11]=[C:10]([O:12][CH:20]([CH3:22])[CH3:21])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(O)cc1F
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)c1ccc(OC(C)C)cc1F
Temperature: 60 °C
Yield: 83.6 %

Procedure:
To a mixture of methyl 2-fluoro-4-hydroxy-benzoate (2.1 g, 12.4 mmol), potassium carbonate (6.8 g, 49.5 mmol) in dry DMF (13 mL) was added 2-iodopropane (2.5 mL, 24.8 mmol) and the reaction mixture was heated at 60° C. for 2 hours. The reaction was cooled and diluted with ether (50 mL) and filtered over Celite®. The filtrate was washed sequentially with water (3×25 mL) and brine solution (25 mL). The organic layer was separated and dried over MgSO4 and solvent was concentrated in vacuo to give a residue which was purified by silica gel column chromatography using 5-45% EtOAc/hexanes to give methyl 2-fluoro-4-isopropoxybenzoate as a colorless oil (2.2 g, 83%). To a solution of methyl 2-fluoro-4-isopropoxybenzoate (2.2 g, 10.3 mmol) in THF (5.5 mL) was added a suspension of lithium hydroxide (0.9 g, 37.1 mmol) in water (5.5 mL). The reaction mixture was stirred at 70° C. for 2 hours. The reaction mixture was cooled to room temperature and the excess LiOH was removed by filtration. The filtrate was diluted with water (9 ml), and washed with ether (2×5 mL). The aqueous layer was separated and cooled to 0° C. and the pH was adjusted to pH 2 by addition of 6 M HCl solution. The aqueous layer was extracted with EtOAc (3×30 mL). The organics were separated and washed sequentially with water and brine. The organic layer was separated, dried and concentrated in vacuo to give 2-fluoro-4-isopropoxy-benzoic acid (2.45 g, 67%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.98 (t, J=8.8 Hz, 1H), 6.69 (ddd, J=15.1, 10.9, 2.0 Hz, 2H), 4.63 (dt, J=12.1, 6.0 Hz, 1H), 1.39 (d, J=6.1 Hz, 6H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)#[N:2].[C:12]1(=[O:17])[CH2:16][CH2:15][CH:14]=[CH:13]1>>[O:17]=[C:12]1[CH2:16][CH2:15][CH:14]([C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([C:1]#[N:2])[CH:4]=3)[NH:8][CH:7]=2)[CH2:13]1
Reactant: O=C1C=CCC1
Reactant: N#Cc1ccc2[nH]ccc2c1
Product: N#Cc1ccc2[nH]cc(C3CCC(=O)C3)c2c1
Yield: 81.8 %

Procedure:
This compound was prepared in the same manner as for Intermediate 2, using 5-cyanoindole (4.26 g, 30 mmol) and 2-cyclopenten-1-one (2.95 g, 36 mmol) to give 5.5 g (82%) of the desired product: mp 136-138° C.; MS (ESI) m/z 224 [M]+.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(O)(C)C.[CH3:15][CH:16]([NH2:18])[CH3:17]>O>[CH:16]([NH:18][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1)([CH3:17])[CH3:15]
Reactant: CC(C)N
Reactant: Clc1ncnc2[nH]ccc12
Solvent: O
Solvent: CC(C)O
Product: CC(C)Nc1ncnc2[nH]ccc12
Temperature: 120 °C
Yield: 89.5 %

Procedure:
To 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 168 mg, 1.09 mmol), 2.00 mL of isopropyl alcohol is added, followed by 2-propanamine (11, 0.280 mL, 3.28 mmol). The reaction is heated by microwave at 120° C. for 20 minutes, then an additional 40 minutes. Another 0.250 mL of 2-propanamine is added and heated at 120° C. for 60 minutes. The reaction is poured into water and extracted with ethyl acetate. The organic layer is concentrated under vacuum and purified by silica gel column chromatography, eluting with a gradient of 1-5% methanol in dichloromethane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (12, 172 mg). MS (ESI) [M+H+]+=176.85.
Reaction SMILES: C([O:8][C:9]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[C:31]([CH3:32])=[CH:30][C:29]([N+:33]([O-])=O)=[C:28]3[C:24]=2[CH2:25][CH2:26][CH2:27]3)=[CH:18][C:10]=1[CH:11]=[C:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)C1C=CC=CC=1.[H][H]>C(O)C.C(OCC)(=O)C.[Pd]>[NH2:33][C:29]1[CH:30]=[C:31]([CH3:32])[C:23]([O:22][C:19]2[CH:20]=[CH:21][C:9]([OH:8])=[C:10]([CH2:11][CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:18]=2)=[C:24]2[C:28]=1[CH2:27][CH2:26][CH2:25]2
Reactant: Cc1cc([N+](=O)[O-])c2c(c1Oc1ccc(OCc3ccccc3)c(C=C3CCOCC3)c1)CCC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc(N)c2c(c1Oc1ccc(O)c(CC3CCOCC3)c1)CCC2
Yield: 80 %

Procedure:
4-[2-Benzyloxy-5-(5-methyl-7-nitroindan-4-yloxy) benzylidene]tetrahydropyran (230 mg) was dissolved in ethanol (10 mL) and ethyl acetate (2 mL). After adding 10% Pd/C (50 mg) under ice-cooling, the mixture was stirred at room temperature under an atmospheric pressure of hydrogen for 24 hours. The insoluble material was removed by filtration. The filtrate was evaporated under reduced pressure to dryness. The residue was purified by column chromatography on silica gel (eluent: exane/ethyl acetate) to give the title compound (138 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[NH:11][N:10]=[N:9]1.[CH3:14]N(C)C=O.[H-].[Na+].CI>O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[N:11]([CH3:14])[N:10]=[N:9]1
Reactant: Cc1ccccc1-n1nn[nH]c1=O
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: Cc1ccccc1-n1nnn(C)c1=O
Temperature: 25 °C

Procedure:
To a mixture of the above-mentioned 1-(2-methylphenyl)-1,4-dihydrotetrazole-5-one 69.8 g and N,N-dimethylformamide 380 mL was added 55% sodium hydride 18.2 g under ice-cooling. After stirring the resulting mixture for twenty minutes, thereto was added methyl iodide 59.4 g. The mixtures were raised to room temperature and were stirred for two and a half hours. To the reaction mixtures was added water and the mixtures were extracted with methyl tert-butyl ether. The organic layers were washed with 10% hydrochloric acid, water and saturated saline, and were dried over anhydrous magnesium sulfate and were then concentrated under reduced pressure. The resulting residues were subjected to a silica gel column chromatography to give 1-(2-methylphenyl)-4-methyl-1,4-dihydrotetrazole-5-one 52.5 g.
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]([C:32]([OH:34])=O)[CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[C:23]([NH2:30])=[C:22]([Cl:31])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:35]=[CH:36][CH:37]=[CH:38][C:4]=2[NH:3]1.[NH:39]1[CH2:44][CH2:43][CH:42]([N:45]2[CH2:49][CH2:48][CH2:47][C@H:46]2[C:50]([O:52][CH3:53])=[O:51])[CH2:41][CH2:40]1>>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:27])([F:29])[F:28])[C:23]([NH2:30])=[C:22]([Cl:31])[CH:21]=3)[C:32]([N:39]3[CH2:40][CH2:41][CH:42]([N:45]4[CH2:49][CH2:48][CH2:47][C@H:46]4[C:50]([O:52][CH3:53])=[O:51])[CH2:43][CH2:44]3)=[O:34])=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:35]=[CH:36][CH:37]=[CH:38][C:4]=2[NH:3]1
Reactant: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1C(F)(F)F
Reactant: COC(=O)[C@@H]1CCCN1C1CCNCC1
Product: COC(=O)[C@@H]1CCCN1C1CCN(C(=O)[C@@H](Cc2cc(Cl)c(N)c(C(F)(F)F)c2)OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)CC1

Procedure:
Prepared analogously to Example 9 from 100 mg (0.18 mmol) (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 42 mg (0.20 mmol) methyl(S)-1-piperidin-4-yl-pyrrolidine-2-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][CH:13]([CH2:17][CH3:18])[C:14]([OH:16])=[O:15].C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[Cl:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([NH:12][CH:13]([CH2:17][CH3:18])[C:14]([OH:16])=[O:15])[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1c(F)cccc1Cl
Reactant: CCC(N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCC(Nc1cccc(Cl)c1[N+](=O)[O-])C(=O)O
Temperature: 80 °C
Yield: 96.7 %

Procedure:
A mixture of 1-chloro-3-fluoro-2-nitrobenzene (2.00 Kg, 11.4 mol), 2-aminobutyric acid (1.22 kg, 11.8 mol) and K2CO3 (1.58 Kg, 11.4 mol) in anhydrous DMSO (4.2 L) was heated at 80° C. for 16 h (after the reaction initiated, the internal temperature went up to 110° C.). At this time LC-MS analysis showed that the reaction was complete. After cooling to rt, the reaction mixture was carefully poured into water (10 L) with vigorous stirring. The aq. layer was washed with methyl tert-butyl ether (2×5 L) to remove organic impurities. The aq. layer was then acidified to pH ˜1.5 with cond HCl to give an orange solid. The orange solid was collected by filtration, washed with water (2×4 L) and air-dried to give 2-((3-chloro-2-nitrophenyl)amino)butanoic acid (2.85 Kg), which was used as such in the next step. 1H NMR (DMSO-d6) δ ppm 7.35 (t, J=8.3 Hz, 1H), 6.82-6.91 (m, 2H), 6.25 (d, J=7.6 Hz, 1H), 4.14 (td, J=7.4, 5.4 Hz, 1H), 3.4 (br. s., 1H), 1.74-1.92 (m, 2H), 0.88 (t, J=7.4 Hz, 3H). Mass Spectrum (ESI) m/z=259.2 (M+1).
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:32][CH:33]([CH3:35])[CH3:34])[C@@H:20]([OH:31])[CH2:21][C@@H:22]([C:27]([OH:30])([CH3:29])[CH3:28])[C:23]([NH:25][CH3:26])=[O:24])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=[O:7])(C)(C)C.[O:36]1[CH2:41][CH2:40][N:39]([CH2:42][C:43]([NH:45][C@H:46](C(O)=O)[CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[O:44])[CH2:38][CH2:37]1.P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C>>[O:36]1[CH2:37][CH2:38][N:39]([CH2:42][C:43]([NH:45][C@H:46]([C:6]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:32][CH:33]([CH3:34])[CH3:35])[C@@H:20]([OH:31])[CH2:21][C@@H:22]([C:27]([OH:30])([CH3:28])[CH3:29])[C:23]([NH:25][CH3:26])=[O:24])=[O:17])[CH2:10][C:11]2[N:12]=[CH:13][S:14][CH:15]=2)=[O:7])[CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[O:44])[CH2:40][CH2:41]1
Reactant: CNC(=O)[C@@H](C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C)C(C)(C)O
Reactant: O=C(CN1CCOCC1)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Product: CNC(=O)[C@@H](C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](Cc1cscn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)CN1CCOCC1)C(C)(C)O
Yield: 79.5 %

Procedure:
A procedure similar to that described in Example 2 was repeated, except that 100 mg (0.19 mmoles) of (2S, 4S, 5S)-5-[N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanyl]amino-4-hydroxy-2-(1-hydroxy-1-methylethyl)-7-methyl-N-methyloctanamide [prepared as described in Example 16(a)], 62 mg (0.21 mmoles) of N-morpholinoacetyl-L-phenylalanine, 0.03 ml (0.20 mmoles) of diethyl cyanophosphate, and 0.08 ml (0.57 mmoles) of triethylamine were used, to obtain 104 mg (yield 78%) of the title compound as a white amorphous substance.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:17][CH2:16][C:9]2[N:10]=[N:11][C:12]([NH:14][NH2:15])=[CH:13][C:8]=2[CH2:7]1)=[O:5])[CH3:2].[CH3:18][C:19]([CH3:21])=O>>[CH2:1]([O:3][C:4]([N:6]1[CH2:17][CH2:16][C:9]2[N:10]=[N:11][C:12]([NH:14][N:15]=[C:19]([CH3:21])[CH3:18])=[CH:13][C:8]=2[CH2:7]1)=[O:5])[CH3:2]
Reactant: CC(C)=O
Reactant: CCOC(=O)N1CCc2nnc(NN)cc2C1
Product: CCOC(=O)N1CCc2nnc(NN=C(C)C)cc2C1

Procedure:
A suspension of 23.7 g of 3-hydrazino-5,6,7,8-tetrahydro-6-pyrido[4,3-c]pyridazinecarboxylic acid ethyl ester in 100 cc of acetone is heated at reflux for 4 hours while stirring. The title compound has a M.P. of 171°-174° (decomp., from methanol).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[C:12](=[O:31])[NH:13][C:14](=[O:30])[C:15]=3[C:16]3[C:26]4=[C:27]5[C:22](=[CH:23][CH:24]=[CH:25]4)[CH2:21][CH:20]([CH2:28]O)[CH2:19][N:18]5[CH:17]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:33].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O.O>[Br:33][CH2:28][CH:20]1[CH2:21][C:22]2[C:27]3=[C:26]([C:16]([C:15]4[C:14](=[O:30])[NH:13][C:12](=[O:31])[C:11]=4[C:6]4[C:5]5[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=5)[NH:8][CH:7]=4)=[CH:17][N:18]3[CH2:19]1)[CH:25]=[CH:24][CH:23]=2
Reactant: BrC(Br)(Br)Br
Reactant: O=C1NC(=O)C(c2cn3c4c(cccc24)CC(CO)C3)=C1c1c[nH]c2cc(F)ccc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C1NC(=O)C(c2cn3c4c(cccc24)CC(CBr)C3)=C1c1c[nH]c2cc(F)ccc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 61 %

Procedure:
A mixture of 3-(6-fluoro-1H-indol-3-yl)-4-(5-hydroxymethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)pyrrole-2,5-dione (500 mg, 1.2 mmol), carbon tetrabromide (796 mg, 2.4 mmol), and triphenylphosphine (314 mg, 1.2 mmol) in 15 mL of dimethylformamide was stirred at room temperature for 6 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (40 mL). The organic layer was washed with saturated aqueous sodium chloride (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to reverse phase HPLC to provide 350 mg (61%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7](Cl)=[O:8])[C:4]([C:10]([F:13])([F:12])[F:11])=[N:3]1.[CH:14]1([C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[NH2:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(N(CC)CC)C>C(Cl)Cl>[CH:14]1([C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[NH:22][C:7]([C:5]2[C:4]([C:10]([F:13])([F:12])[F:11])=[N:3][N:2]([CH3:1])[CH:6]=2)=[O:8])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: Nc1ccccc1C1CCCCC1
Reactant: Cn1cc(C(=O)Cl)c(C(F)(F)F)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1cc(C(=O)Nc2ccccc2C2CCCCC2)c(C(F)(F)F)n1
Reaction time: 8 h
Yield: 111.3 %

Procedure:
To 1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid chloride (1.6 g) in CH2Cl12 (25 mL) at 0° C. was added dropwise a solution of 2-cyclohexylaniline (1.3 g) and triethylamine (1.0 mL) in CH2Cl2 (25 mL). The contents were stirred overnight, coming to RT. The contents were washed with water, 2N HCl (2×100 mL), dried (MgSO4) and concentrated in vacuo leaving an amber foam (2.9 g). Crystallization from EtOAc/hexane gave the desired amide as white crystals (1.2 g). Most of the compounds of the present invention were made via this coupling procedure.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:26])[CH:5]=[C:6]2[C:11]=1[N:10]([C:12]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([F:20])=[CH:14][C:13]=1[F:21])[CH:9]=[C:8]([C:22]([OH:24])=[O:23])[C:7]2=[O:25].[CH3:28][NH2:29]>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([NH:29][CH3:28])=[C:4]([F:26])[CH:5]=[C:6]2[C:11]=1[N:10]([C:12]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([F:20])=[CH:14][C:13]=1[F:21])[CH:9]=[C:8]([C:22]([OH:24])=[O:23])[C:7]2=[O:25]
Reactant: CN
Reactant: COc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Solvent: c1ccncc1
Product: CNc1c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(OC)c(F)cc3F)c2c1Cl
Temperature: 25 °C
Reaction time: 66 h
Yield: 95.2 %

Procedure:
8-Chloro-6,7-difluoro-1-(2,4-difluoro-5-methoxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (90 mg) and an aqueous solution (about 40%; 200 mg) of methylamine were added to pyridine (520 mg), and the mixture was stirred at room temperature for 66 hours. The reaction mixture was concentrated under reduced pressure, and ethanol (1 ml) was added to the residue. Deposits were collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (88 mg) as a colorless powder.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])=[C:22]([CH3:24])[NH:23][C:16]=23)[CH2:4][CH2:3]1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:25]([NH:27][CH:28]4[CH2:29][CH2:30][N:31]([C:34](=[O:37])[CH2:35][CH3:36])[CH2:32][CH2:33]4)=[O:26])=[C:22]([CH3:24])[NH:23][C:16]=23)[CH2:4][CH2:3]1
Reactant: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(OC)ccc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-2-methyl-N-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f14) and commercially available propionyl chloride the title compound is obtained as colorless solid.