Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[C:2]1([N:8]([CH2:32][C:33]([O:35]CC)=[O:34])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>>[ClH:1].[C:2]1([N:8]([CH2:32][C:33]([OH:35])=[O:34])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH2:28])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(CCc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CC(=O)O)c3ccccc3)ccc21

Procedure:
Prepared analogously to Example 26 from 1-methyl-2-[2-(4-amidinophenyl)ethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(ethoxycarbonylmethyl)amide hydrochloride and sodium hydroxide solution.
Reaction SMILES: [H-].[Na+].I[CH3:4].[Cl:5][C:6]1[N:11]=[C:10]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[C:9]([Cl:21])=[CH:8][N:7]=1>C1COCC1>[Cl:5][C:6]1[N:11]=[C:10]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH3:4])[CH:13]=2)[C:9]([Cl:21])=[CH:8][N:7]=1
Reactant: Clc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1cc(-c2nc(Cl)ncc2Cl)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.4 %

Procedure:
Sodium hydride (0.136 g, 3.41 mmol) and iodomethane (0.533 ml, 8.52 mmol) were added to a flask charged with 3-(2,5-dichloropyrimidin-4-yl)-1H-indole (INTERMEDIATE 2) (0.750 g, 2.84 mmol) and THF (18.40 ml). The reaction was stirred at RT for 2 h. The reaction was concentrated under reduced pressure and the crude solid obtained was washed with water and 3 mL of THF. The solid was dried under high vacuum to give the title product (0.564 g, 71.4%). m/z 278.
Reaction SMILES: C([N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:15]#N)(=O)C1C=CC=CC=1.[Cl-:25].[Al+3].[Cl-].[Cl-].[OH-:29].[Na+]>ClCCCl.C(Cl)Cl.O>[ClH:25].[NH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]21[CH2:17][CH2:18][C:19]1[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:15]2=[O:29]
Reactant: [Cl-]
Reactant: N#CC1(CCc2ccccc2)CCCCN1C(=O)c1ccccc1
Reactant: [OH-]
Agent: [Al+3]
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: ClCCl
Product: Cl
Product: O=C1c2ccccc2CCC12CCCCN2

Procedure:
In 250 ml of 1,2-dichloroethane was dissolved 7.64 g of 1-benzoyl-2-(2-phenylethyl)-2-piperidinecarbonitrile. Then, 8.0 g of aluminum chloride was added and the mixture was refluxed for 6 hours. The reaction mixture was cooled and poured cautiously into 10% aqueous sodium hydroxide solution. Then, methylene chloride and water were added for extraction. The methylene chloride layer was dried over anhydrous sodium sulfate and filtered and the solvent was distilled off. To the residue were added 100 ml of methanol and 100 ml of 20% aqueous sodium hydroxide solution and the mixture was refluxed for 12 hours. After the reaction mixture was allowed to cool, the methanol was distilled off and methylene chloride and water were added for extraction. The methylene chloride layer was dried over annydrous sodium sulfate and filtered and the solvent was then distilled off. The residue was purified by alumina column chromatography using an ethyl acetate-hexane solvent system and the eluate containing the desired compound was distilled under reduced pressure. The residue was treated with 6.0 ml of 4N-methanolic HCl to provide a solid. This solid was recrytallized from methylene chloride to provide 3.0 g of colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH:12]([OH:15])[CH2:13][OH:14])=[N:9][C:8]([O:16][CH3:17])=[CH:7][CH:6]=2.C(N(CC)CC)C.[S:25](Cl)([C:28]1[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=1)(=[O:27])=[O:26]>ClCCl.O.C(=O)(O)[O-].[Na+].C([Sn](=O)CCCC)CCC>[CH3:32][C:31]1[CH:33]=[CH:34][C:28]([S:25]([O:14][CH2:13][CH:12]([C:11]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([O:16][CH3:17])[N:9]=3)[N:4]=[CH:3][C:2]=2[F:1])[OH:15])(=[O:27])=[O:26])=[CH:29][CH:30]=1
Reactant: COc1ccc2ncc(F)c(C(O)CO)c2n1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CCCC[Sn](=O)CCCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc2ncc(F)c(C(O)COS(=O)(=O)c3ccc(C)cc3)c2n1
Reaction time: 3 h
Yield: 74.7 %

Procedure:
To a solution of 1-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]-1,2-ethanediol (16.5 g, 71 mmol)) in dichloromethane (200 mL), triethylamine (10 mL) and dibutyltin oxide (350 mg) was added tosyl chloride (13.2 g). After 3 hours, the mixture was diluted with water/sodium bicarbonate and extracted several times with chloroform. The combined organic extracts were dried over magnesium sulfate and evaporated under vacuum. The residue was chromatographed on silica gel eluting with 20-30% ethyl acetate in chloroform to afford the desired product (20.3 g, 75%). MS (+ve ion electrospray) m/z 393 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[S:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH:12]=[C:11]1[S:19](Cl)(=[O:21])=[O:20]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:19]([C:11]2[S:10][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH:12]=2)(=[O:21])=[O:20])=[C:4]([NH:9][S:19]([C:11]2[S:10][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH:12]=2)(=[O:20])=[O:21])[CH:3]=1
Reactant: Nc1ccc(Br)cc1N
Reactant: O=S(=O)(Cl)c1cc2ccccc2s1
Product: O=S(=O)(Nc1ccc(Br)cc1NS(=O)(=O)c1cc2ccccc2s1)c1cc2ccccc2s1

Procedure:
N,N′-(4-bromo-1,2-phenylene)bis(1-benzothiophene-2-sulfonamide) (255 mg) was prepared as in Example 31 using 4-bromobenzene-1,2-diamine and benzothiophene-2-sulfonyl chloride as requisite starting materials.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:37]=[CH:36][C:17]([O:18][CH2:19][C:20]3[N:24]([CH2:25][CH2:26][O:27][CH3:28])[C:23]4[CH:29]=[CH:30][C:31]([C:33]([NH2:35])=[NH:34])=[CH:32][C:22]=4[N:21]=3)=[CH:16][CH:15]=2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(Cl)(Cl)[Cl:46]>>[ClH:46].[ClH:46].[NH:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:15]=[CH:16][C:17]([O:18][CH2:19][C:20]3[N:24]([CH2:25][CH2:26][O:27][CH3:28])[C:23]4[CH:29]=[CH:30][C:31]([C:33]([NH2:35])=[NH:34])=[CH:32][C:22]=4[N:21]=3)=[CH:36][CH:37]=2)[CH2:9]1
Reactant: COCCn1c(COc2ccc(OC3CCN(C(=O)OC(C)(C)C)C3)cc2)nc2cc(C(=N)N)ccc21
Reactant: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COCCn1c(COc2ccc(OC3CCNC3)cc2)nc2cc(C(=N)N)ccc21
Product: Cl
Reaction time: 0.08 h

Procedure:
To a solution of 2-[4-(1-tert-butoxycarbonylpyrrolidin-3-yloxy)-phenoxymethyl]-1-(2-methoxyethyl)benzimidazole-5-carboxamidine (115 mg) in chloroform (3 ml) was added trifluoroacetic acid (3 ml), and the mixture was stirred at 5 min. The solvent was evaporated and to the obtained residue was added 1N hydrogen chloride-diethyl ether (2 ml). The solvent was evaporated and the obtained residue was washed with tetrahydrofuran and dried under reduced pressure to give the title compound (97 mg).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33](OCC)=[O:34])[C:15]1=[O:38].[N:39]1([CH2:44][CH2:45][CH2:46][NH2:47])[CH:43]=[CH:42][N:41]=[CH:40]1>CCO>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33]([NH:47][CH2:46][CH2:45][CH2:44][N:39]2[CH:43]=[CH:42][N:41]=[CH:40]2)=[O:34])[C:15]1=[O:38]
Reactant: NCCCn1ccnc1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2C(=O)c3ccccc3C2=O)c1=O
Solvent: CCO
Product: O=C(NCCCn1ccnc1)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2C(=O)c3ccccc3C2=O)c1=O
Temperature: 25 °C

Procedure:
A solution of ethyl 1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (0.025 g, 0.049 mmol) in EtOH (1 mL) under nitrogen was treated with 3-(1H-imidazol-1-yl)-1-propanamine (0.0072 mL, 0.061 mmol) for 30 min.@150° C. The reaction was further microwaved for 30 min.@150° C. after the addition of an additional equivalent (0.0072 mL) of the amine, cooled to ambient temperature, and the resulting suspension was filtered, washed with EtOH and then thoroughly dried under high vacuum to provide the title compound as a white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.74-1.84 (m, 2 H), 3.18 (q, J=6.60 Hz, 2 H), 3.83 (t, J=6.95 Hz, 2 H), 3.91 (t, J=5.48 Hz, 2 H), 4.14 (s, 2 H), 4.57 (t, J=5.55 Hz, 2 H), 6.90 (t, J=1.05 Hz, 1 H) 7.09-7.18 (m, 3 H), 7.37 (td, J=6.00, 2.32 Hz, 2 H), 7.57 (t, J=1.12 Hz, 1 H), 7.70-7.75 (m, 2 H), 7.78-7.83 (m, 2 H), 8.19 (s, 1 H), 8.54 (s, 1 H), 9.93 (t, J=6.04 Hz, 1 H), 17.12 (bs, 1 H); ES+ MS: 595 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:37]=[CH:36][C:12]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:31][CH2:32][CH3:33])=[C:21]([NH:24][C:25](=[O:30])/[CH:26]=[CH:27]/[CH2:28]Cl)[CH:22]=3)[N:17]=[CH:16][C:15]=2[C:34]#[N:35])=[CH:11][C:10]=1[Cl:38])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C=CC(NC2C3C(=CC(OCC)=C([NH:62][C:63](=O)/[CH:64]=[CH:65]/[CH2:66]Br)C=3)N=CC=2C#N)=CC=1Cl)C1C=CC=CC=1.[NH:77]1[CH2:81][CH2:80][CH2:79][CH2:78]1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:37]=[CH:36][C:12]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:31][CH2:32][CH3:33])=[C:21]([NH:24][C:25](=[O:30])[CH2:26][CH:27]([N:62]4[CH2:63][CH2:64][CH2:65][CH2:66]4)[CH2:28][N:77]4[CH2:81][CH2:80][CH2:79][CH2:78]4)[CH:22]=3)[N:17]=[CH:16][C:15]=2[C:34]#[N:35])=[CH:11][C:10]=1[Cl:38])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: CCOc1cc2ncc(C#N)c(Nc3ccc(OCc4ccccc4)c(Cl)c3)c2cc1NC(=O)/C=C/CBr
Reactant: CCOc1cc2ncc(C#N)c(Nc3ccc(OCc4ccccc4)c(Cl)c3)c2cc1NC(=O)/C=C/CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cc2ncc(C#N)c(Nc3ccc(OCc4ccccc4)c(Cl)c3)c2cc1NC(=O)CC(CN1CCCC1)N1CCCC1
Temperature: -50 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
An amount of 612 mg (1.1 mmol) of (E)-N-{4-[4-(benzyloxy)-3-chloroanilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-chloro-2-butenamide, and (E)-N-{4-[4-(benzyloxy)-3-chloroanilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-bromo-2-butenamide, were stirred in 6 mL of N,N-dimethylformamide and cooled to −50° C. Pyrrolidine (55 μL, 0.66 mmol), was added dropwise over a period of 30 min. After stirring for 2 hrs at −50° C., another 0.250 mL (3.0 mmol) of pyrrolidine was added dropwise over a period of 1.5 hrs, and the reaction mixture was warmed to room temperature for 16 hrs. A solution of saturated sodium bicarbonate was added, and the product was extracted with ethyl acetate and methylene chloride. Both organic layers were combined, dried over sodium sulfate, poured over a hydrous magnesium silicate plug, and evaporated to an oil. Purification was carried out by flash chromatography (40:4:2=ethyl acetate: methanol:ammonium hydroxide), and preparative thin layer chromatography (40:4:1=ethyl acetate:methanol:triethylamine), to give the title compound as an orange solid (284 mg, 40%), mp 85-87° C.; 1H NMR (DMSO-d6) δ10.59 (bs, 1H), 9.57 (s, 1H), 9.01 (s, 1H), 8.46 (s, 1H), 7.51-7.33 (m, 7H), 7.26-7.16 (m, 2H), 5.21 (s, 2H), 4.23 (q, 2H), 2.98 (bs, 1H), 2.71-2.60 (m, 8H), 2.49 (m, 2H) 1.74 (m, 5H), 1.64 (m, 5H), 1.43 (t, 3H); HRMS (ESI-FTMS) 653.29959 (M+1).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:8]([CH3:27])=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[NH3:28]>CC(O)C.C(Cl)Cl>[CH3:27][C:8]1[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([NH2:28])[C:3]2=[C:10]([C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[N:18]3)=[CH:13][CH:12]=2)[N:9]=1
Reactant: N
Reactant: Cc1nc(-c2ccc3ccc(-c4ccccc4)nc3c2)c2c(Cl)nccn12
Solvent: CC(C)O
Solvent: ClCCl
Product: Cc1nc(-c2ccc3ccc(-c4ccccc4)nc3c2)c2c(N)nccn12
Temperature: 110 °C

Procedure:
7-(8-Chloro-3-methyl-imidazo[1,5-a]pyrazin-1-yl)-2-phenyl-quinoline was dissolved in 10.0 mL of 2.0M NH3 in IPA and 5.0 mL of CH2Cl2. The reaction was heated to 110° C. for 64 h. The salts were filtered off and washed with CH2Cl2. Purified with silica gel column chromatography [Jones Flashmaster, 10 g cartridge, eluting with 1% MeOH:EtOAc] to yield a dark yellow solid; 1H NMR (400 MHz, CDCl3) δ 2.71 (s, 3H), 5.61 (brs, 2H), 7.13 (d, 1H, J=5.1 Hz), 7.2 (d, 1H, J=5.1 Hz), 7.48-7.56 (m, 3H), 7.89-7.97 (m, 3H), 8.18-8.21 (m, 2H), 8.27 (d, 1H, J=8.6 Hz), 8.39 (s, 1H); MS (ES+): 352.06 (M+1), 353.07 (M+2), 354.09 (M+3).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=2)[CH2:3][CH2:2]1.O=[CH:16][CH2:17][C:18]1([C:24]([O:26][CH3:27])=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1.C(O)(=O)C>[CH3:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][CH:4]2[CH2:5][CH2:6][N:1]([CH2:16][CH2:17][C:18]3([C:24]([O:26][CH3:27])=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:2][CH2:3]2)=[N:9][CH:10]=1
Reactant: Cc1ccc(NC2CCNCC2)nc1
Reactant: COC(=O)C1(CC=O)CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)C1(CCN2CCC(Nc3ccc(C)cn3)CC2)CCCCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 8.4 %

Procedure:
To a solution of 2-(piperidin-4-ylamino)-5-methylpyridine (191 mg) and methyl 1-(2-oxoethyl)cyclohexanecarboxylate (250 mg) in tetrahydrofuran (10 mL) were added acetic acid (150 mg) and sodium triacetoxy borohydride (424 mg) at room temperature. The solution was stirred at room temperature for 20 hours. Saturated aqueous sodium bicarbonate solution was added to the solution, and it was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and then, concentrated under reduced pressure. The resulting residue was purified by chromatography [silica gel, ethyl acetate-methanol-aqueous ammonia (90:10:0.1)] to give the title compound (30 mg).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.CN(C)[CH:8]=[O:9].[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21][C:20](=O)[NH:19]2)[CH:15]=[CH:16][CH:17]=1.[OH-].[Na+]>O1CCCC1.C1(C)C=CC=CC=1>[Cl:3][C:20]1[N:19]=[C:18]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([Cl:11])[CH:13]=2)[C:27]2[C:22]([C:21]=1[CH:8]=[O:9])=[CH:23][CH:24]=[CH:25][CH:26]=2
Reactant: CN(C)C=O
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1Cc2ccccc2C(c2cccc(Cl)c2)N1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=Cc1c(Cl)nc(-c2cccc(Cl)c2)c2ccccc12
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
199 g of phosphorus oxichloride are added dropwise to a solution of 99 g of N,N-dimethyl formamide in 400 ml of tetrahydrofuran at a rate such that the temperature does not exceed 5° C. Stirring is continued for 20 minutes at room temperature. Next, 87.7 g of 1-(3-chlorophenyl)-1,4-dihydro-3-(2H)-isoquinolinone are added in portions at 0° C. After a 2 hour stirring at 0° to 5° C., the reaction solution is poured into a mixture of 1.95 l of 2N NaOH, 6 kg of ice and 1 l of toluene. The toluene phase is separated, washed twice with water and added to 1.3 l of acetone and 1.3 l of 2N H2SO4. 38.8 g of carefully pulverized potassium permanganate are added in portions and at 20° C. to the heterogeneous mixture obtained and the mixture is stirred for 6 hours. The toluene phase is separated, washed successively with water, 2N NaOH and again with water, dried, filtered and the solvent is removed under reduced pressure.
Reaction SMILES: [Li].[Cl:2][C:3]1[CH:8]=[C:7]([C:9]([O-])=[CH:10][C:11](=O)[C:12]([O:14]CC)=[O:13])[CH:6]=[CH:5][N:4]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(O)=O)C=2)C=C(F)C=1.Cl.[Cl:42][C:43]1[CH:44]=[C:45]([NH:49][NH2:50])[CH:46]=[CH:47][CH:48]=1>>[Cl:42][C:43]1[CH:44]=[C:45]([N:49]2[C:9]([C:7]3[CH:6]=[CH:5][N:4]=[C:3]([Cl:2])[CH:8]=3)=[CH:10][C:11]([C:12]([OH:14])=[O:13])=[N:50]2)[CH:46]=[CH:47][CH:48]=1
Reactant: NNc1cccc(Cl)c1
Reactant: CCOC(=O)C(=O)C=C([O-])c1ccnc(Cl)c1
Agent: Cl
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: [Li]
Product: O=C(O)c1cc(-c2ccnc(Cl)c2)n(-c2cccc(Cl)c2)n1

Procedure:
560 mg (2.14 mmol) of the compound of Example 19A is reacted analogously to the synthesis of the compound of Example 20A with 422 mg (2.36 mmol) of 3-chlorophenylhydrazine hydrochloride. After hydrolysis, 494 mg (69% of theory) of the title compound is obtained.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:25]([O:27]CC)=[O:26])[C:7](=[O:24])[N:8]3[C:13]=2[C:12]([CH3:14])=[C:11]([C:15]2[CH:20]=[C:19]([Cl:21])[C:18]([NH2:22])=[C:17]([Cl:23])[CH:16]=2)[CH:10]=[CH:9]3)[CH2:3][CH2:2]1.[Li+].[OH-].Cl.C(OCC)(=O)C>C1COCC1.O>[CH:1]1([C:4]2[CH:5]=[C:6]([C:25]([OH:27])=[O:26])[C:7](=[O:24])[N:8]3[C:13]=2[C:12]([CH3:14])=[C:11]([C:15]2[CH:16]=[C:17]([Cl:23])[C:18]([NH2:22])=[C:19]([Cl:21])[CH:20]=2)[CH:10]=[CH:9]3)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3cc(Cl)c(N)c(Cl)c3)ccn2c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c(-c2cc(Cl)c(N)c(Cl)c2)ccn2c(=O)c(C(=O)O)cc(C3CC3)c12
Temperature: 60 °C

Procedure:
A solution of ethyl 1-cyclopropyl-8-(4-amino-3,5-dichloro-phenyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (140 mg, 0.326 mmol) in THF (6 mL) and water (2 mL) was treated with LiOH (55 mg, 1.31 mmol). The reaction was heated to 60° C. overnight and acidified with 1N HCl to pH 4. The precipitate was dissolved with ethyl acetate (50 mL) and washed with brine (2×20 mL). The organic phase was separated, dried, and concentrated. The precipitate was filtered to afford the title compound EXAMPLE 29 as yellow solid (90 mg, 69%). ESI-MS m/z: 403 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ ppm: 9.30 (d, J=7.5 Hz, 1H), 8.25 (s, 1H), 7.64 (d, J=7.5 Hz, 1H), 7.57 (s, 2H), 6.12 (s, 2H), 2.92 (s, 3H), 2.54-2.51 (m, 1H), 1.13-1.10 (m, 2H), 0.84-0.83 (m, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][N:8]([CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[C:7](=[NH:17])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([O:28][CH3:29])=[C:23]([CH:27]=1)[C:24](Cl)=[O:25]>O1CCCC1>[C:1]([C:5]1[CH:10]=[CH:9][N:8]([CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][O:13]2)/[C:7](=[N:17]/[C:24](=[O:25])[C:23]2[CH:27]=[C:19]([Cl:18])[CH:20]=[CH:21][C:22]=2[O:28][CH3:29])/[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Reactant: CC(C)(C)c1ccn(C[C@H]2CCCO2)c(=N)c1
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1C(=O)/N=c1\cc(C(C)(C)C)ccn1C[C@H]1CCCO1
Temperature: 60 °C
Reaction time: 14 h
Yield: 8.8 %

Procedure:
To a solution of the crude product of Example 61A (0.8 g, 1.7 mmol) in tetrahydrofuran (10 mL) were added 5-chloro-2-methoxybenzoyl chloride (0.4 g, 1.9 mmol) and triethylamime (0.7 mL, 5.1 mmol). After stirring at 60° C. for 14 hours, the reaction mixture was cooled and quenched with saturated NaHCO3 (10 mL). The aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-5% methanol in dichloromethane) to provide 60 mg of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.26 (s, 9H), 1.50-1.69 (m, 1H), 1.69-2.09 (m, 3H), 3.57-3.70 (m, 1 H), 3.75 (s, 3H), 3.76-3.86 (m, 1H), 4.00 (dd, J=12.9, 8.5 Hz, 1H), 4.30 (dd, 1H), 4.57 (dd, J=12.7, 3.2 Hz, 1H), 6.87 (dd, J=7.0, 2.2 Hz, 1H), 7.03 (d, J=8.8 Hz, 1H), 7.34 (dd, J=8.8, 2.7 Hz, 1H), 7.53 (d, J=2.7 Hz, 1H), 7.95 (d, J=7.1 Hz, 1H), 8.28 (d, J=2.4 Hz, 1H) MS (ESI+) m/z 403 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][CH2:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].C(=O)([O-])O.[Na+].O>CO>[N+:11]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[NH:14][CH2:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18])([O-:13])=[O:12]
Reactant: NCC(F)(F)C(=O)O
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(O)C(F)(F)CNc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 24 h
Yield: 83.1 %

Procedure:
To a solution of 2-chloro-1,3-dinitrobenzene (2.94 g, 14.54 mmol) in methanol (30.0 mL) were added 3-amino-2,2-difluoropropanoic acid (2.0 g, 15.99 mmol), sodium hydrogen carbonate (2.69 g, 31.98 mmol) and water (15 mL). The reaction mixture was stirred at 80° C. for 1 day. The starting material wasn't consumed completely. To the mixture was added sodium hydrogen carbonate (5.88 g, 63.96 mmol) and the mixture was stirred at 80° C. for 0.5 day. After cooling, the solvent was removed. The residue was neutralized with 1N hydrochloric acid (100 mL) and extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the title compound as a yellow solid (3.52 g, 12.09 mmol, 83%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.O[CH2:28][CH2:29][CH2:30][NH:31][C:32](=[O:41])[O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)Cl>[C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([O:9][CH2:28][CH2:29][CH2:30][NH:31][C:32]([O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:41])=[O:8])(=[O:3])[CH3:2]
Reactant: O=C(NCCCO)OCc1ccccc1
Reactant: CC(=O)Oc1ccccc1C(=O)O
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccccc1C(=O)OCCCNC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 53.9 %

Procedure:
To a solution of 2-acetoxybenzoic acid (2.0 g, 11.1 mmol) and triethylamine (1.8 mL, 11.1 mmol) in CH2Cl2 (40 mL) at 0° C. was slowly added ClCO2Et (1.1 mL, 167 mmol). The reaction mixture was stirred (0° C., 2 h) and filtered. The filtrate was added to a solution of benzyl 3-hydroxypropylcarbamate (2.1 g, 10.0 mmol) and triethylamine (15 mL) in CH2Cl2 (40 mL). The reaction mixture was stirred (RT, 4 h) and quenched with H2O (50 mL). The organic layer was washed with 1M aqueous HCl, saturated aqueous Na2CO3 (30 mL) and H2O (50 mL). The organic solution was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography, (PE-EtOAc, 5:1) to afford 3-(benzyloxycarbonylamino)propyl 2-acetoxybenzoate (2.0 g, 54%) as a colorless oil. Mass calculated for C20H21NO64=371.38; found: [M+H]+=372.3.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[C:9]([NH:16][CH2:17][C:18]#[CH:19])([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[CH3:20][CH2:21][O:22]CC>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:12]([O:11][C:9](=[O:10])[N:16]([CH2:17][CH2:18][CH2:19][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1)[CH2:20][CH:21]=[O:22])([CH3:13])([CH3:14])[CH3:15]
Reactant: CCOCC
Reactant: Brc1cccc(Br)n1
Reactant: C#CCNC(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(CC=O)CCCc1cccc(Br)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 2,6-dibromopyridine 20-1 (111 g, 468 mmol) and N-BOC-propargylamine (80.0 g, 515 mmol) in 500 ml of triethylamine at 0° C. was treated with copper(I) iodide (2.23 g, 11.7 mmol). The mixture was purged with argon and then dichlorobis(triphenylphosphine)-palladium(II) 8.22 g, 11.7 mmol) was added. The solution was stirred at 0° C. for one hour, then at room temperature for 16 hours. The solution was diluted with 250 mL ether and washed with H2O (4×100 mL). The organic extract was washed with brine and dried over Na2SO4. The solvents were removed in vacuo and the crude product was purified by silica gel chromatography (25% EtOAc/hexane) to afford 20-2.