Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[CH:8](O)[CH:7]([CH2:14][CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[CH2:6][CH2:5]2>Cl.C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[CH:8]=[C:7]([CH2:14][CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[CH2:6][CH2:5]2
Reactant: Cc1cc2c(cc1C)C(O)C(CCN1CCCC1)CC2
Agent: Cl
Solvent: CCO
Product: Cc1cc2c(cc1C)CCC(CCN1CCCC1)=C2
Yield: 64.7 %

Procedure:
1,2,3,4-Tetrahydro-6,7-dimethyl-2-[2-(1-pyrrolidinyl)ethyl]-1-naphthalenol (24.0 g) was dissolved in a 30% solution of hydrogen chloride in ethanol (240 ml), and the mixture was refluxed for one hour. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in water. The mixture was basified with potassium carbonate, and extracted with ethyl acetate. The extract was washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (eluent; chloroform:methanol=10:1), and the fractions containing the desired compound were combined, and concentrated under reduced pressure to give the desired compound (14.5 g) as an oily product.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([S:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[C:8]2[CH2:23][C:24]([CH3:30])([CH3:29])[C:25]([O:27]C)=[O:26])=[CH:4][CH:3]=1.C1COCC1.[Li+].[OH-].Cl>CO>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([S:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[C:8]2[CH2:23][C:24]([CH3:30])([CH3:29])[C:25]([OH:27])=[O:26])=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(OC)ccc2n1Cc1ccc(Cl)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2c(c1)c(SC(C)(C)C)c(CC(C)(C)C(=O)O)n2Cc1ccc(Cl)cc1
Temperature: 80 °C

Procedure:
The ester from Step 1 (51.3 g) was hydrolysed using 325 mL THF, 600 mL MeOH and 325 mL of 1N LiOH solution. The mixture was heated to 80° C. for 3 hours, then cooled, acidified with 1N HCl and extracted with 3×200 mL EtOAc. The organic phase was washed with H2O (2×150 mL) and dried (MgSO4). After removal of the solvent the title compound was obtained as a white solid, m.p. 190°-191° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([O:12][CH3:13])=[O:11])=[C:4]([NH:14][C:15]([NH:17][C:18](=[O:28])[C:19]2[CH:24]=[C:23]([F:25])[C:22]([F:26])=[CH:21][C:20]=2[Cl:27])=[O:16])[CH:3]=1.[F:29][C:30]([F:41])([F:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[N:37]=[C:38]=[O:39]>C(#N)C>[Cl:27][C:20]1[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:19]=1[C:18]([NH:17][C:15](=[O:16])[NH:14][C:4]1[CH:3]=[C:2]([NH:1][C:38]([NH:37][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[C:30]([F:29])([F:40])[F:41])=[O:39])[CH:7]=[CH:6][C:5]=1[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[O:11])=[O:28]
Reactant: COC(=O)C=Cc1ccc(N)cc1NC(=O)NC(=O)c1cc(F)c(F)cc1Cl
Reactant: O=C=Nc1ccccc1C(F)(F)F
Solvent: CC#N
Product: COC(=O)C=Cc1ccc(NC(=O)Nc2ccccc2C(F)(F)F)cc1NC(=O)NC(=O)c1cc(F)c(F)cc1Cl
Temperature: 60 °C
Reaction time: 14 h
Yield: 11 %

Procedure:
100 mg (0.24 mmol) of methyl 3-{4-amino-2-[3-(2-chloro-4,5-difluorobenzoyl)-ureido]phenyl}acrylate were dissolved in 1 ml of acetonitrile and mixed with 2-trifluoromethylphenyl isocyanate and shaken at 60° C. for 14 hours. The resulting precipitate was filtered off with suction, and 16 mg (11%) of the desired product were obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([NH2:11])=[CH:4][CH:3]=1.[C:12]([O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=O)=[CH:18][CH:17]=1)(=[O:14])[CH3:13]>N1C=CC=CC=1>[C:12]([O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]2[O:8][C:7](=[O:9])[C:6]3[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=3[N:11]=2)=[CH:18][CH:17]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1
Reactant: Cc1ccc(N)c(C(=O)O)c1
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(-c2nc3ccc(C)cc3c(=O)o2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
10 gm (0.066 mol) of 5-methyl-anthranilic acid were dissolved in 65 ml of pyridine, and the solution was mixed, while cooling and stirring, with 15.7 gm (0.066 mol+20%) of 4-acetoxy-benzoyl chloride. After 2 hours the reaction was finished, and the reaction mixture was poured into ice water. The crystalline precipitate thus formed was suction-filtered off, washed well with water and dried.
Reaction SMILES: ClCCN1CCCC1.Cl.[CH3:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[C:21][Si](C)(C)C)[CH:18]=2)[N:13]([CH2:26][CH2:27][N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[C:12]=1[C:33]([O:35][CH2:36][CH3:37])=[O:34].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[C:20]([C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:26][CH2:27][N:28]1[CH2:29][CH2:30][CH2:31][CH2:32]1)[C:12]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:11]2[CH3:10])#[CH:21]
Reactant: CCOC(=O)c1c(C)c2cc(C#C[Si](C)(C)C)ccc2n1CCN1CCCC1
Agent: Cl
Agent: ClCCN1CCCC1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: C#Cc1ccc2c(c1)c(C)c(C(=O)OCC)n2CCN1CCCC1
Temperature: 60 °C
Reaction time: 42 h

Procedure:
Under an argon atmosphere 562 mg (3.3 mmol) 1-(2-chloro-ethyl)-pyrrolidine (used as the hydrochloride) are added to a suspension of 900 mg (3.0 mmol) ethyl 3-methyl-1-(2-pyrrolidin-1-yl-ethyl)-5-trimethylsilanylethynyl-1H-indole-2-carboxylate and 457 mg (3.3 mmol) K2CO3 in 10 mL DMF and the reaction mixture is stirred for 42 h at 60° C. It is diluted with water, extracted exhaustively with EtOAc, the combined organic phases are washed with water and dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified by chromatography (silica gel, EtOAc/MeOH/NH3 90:10:1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[N:16]([CH:25]=[C:26]([C:28]([O:30]CC)=[O:29])[N:27]=3)[C:17]([C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)=[CH:18][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[N:16]([CH:25]=[C:26]([C:28]([OH:30])=[O:29])[N:27]=3)[C:17]([C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)=[CH:18][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cn2c(-c3cccs3)cnc(N3CCN(C(=O)OC(C)(C)C)CC3)c2n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(-c3cccs3)n3cc(C(=O)O)nc23)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.8 %

Procedure:
A 100 mL round bottom flask was charged with ethyl 8-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-(thiophen-2-yl)imidazo[1,2-a]pyrazine-2-carboxylate (prepared as described in Example 61 steps 1-5, 0.80 g, 1.75 mmol), LiOH (0.22 g, 5.25 mmol), water (2 mL) and THF (30 mL). The mixture was stirred at 25° C. for 16 h. Reaction progress was monitored by LC-MS. Work-up: the solvent was evaporated. The residue was acidified with 2 N HCl. The precipitate was collected by filtration and dried, to afford 0.57 g (76%) of the product. MS m/z: 428 (M−H+).
Reaction SMILES: [F:1][C:2]([F:54])([F:53])[C:3]1[C:4]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([N:38]3[CH2:43][CH2:42][N:41](C(OC(C)(C)C)=O)[CH2:40][CH2:39]3)=[CH:34][C:33]=2[O:51][CH3:52])=[N:5][C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)=[CH:12][C:11]=2[O:29][CH3:30])=[N:7][CH:8]=1.Cl>C(Cl)Cl>[CH3:30][O:29][C:11]1[CH:12]=[C:13]([N:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]2)[CH:14]=[CH:15][C:10]=1[NH:9][C:6]1[N:5]=[C:4]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([N:38]3[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]3)=[CH:34][C:33]=2[O:51][CH3:52])[C:3]([C:2]([F:54])([F:53])[F:1])=[CH:8][N:7]=1
Reactant: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc(C(F)(F)F)c(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2OC)n1
Agent: Cl
Solvent: ClCCl
Product: COc1cc(N2CCNCC2)ccc1Nc1ncc(C(F)(F)F)c(Nc2ccc(N3CCNCC3)cc2OC)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.9 %

Procedure:
The compound (489 mg) prepared in Step 1 was dissolved in methylenechloride (6 ml), added with 4M HCl (dioxane solution, ml), and stirred at room temperature overnight. Upon completion of the reaction, the mixture was distilled under reduced pressure to remove the solvent, and dissolved again in methylenechloride. Then, the resultant was neutralized with a saturated solution of sodium bicarbonate, washed with saturated brine, and dried with sodium sulfate. The dried organic layer was distilled under reduced pressure to remove the solvent to obtain a target compound (320 mg, 89%).
Reaction SMILES: [N+:1]([CH2:4][C:5]1([CH2:11][C:12]([O:14]CC2C=CC=CC=2)=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][CH2:4][C:5]1([CH2:11][C:12]([OH:14])=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: [H][H]
Reactant: O=C(CC1(C[N+](=O)[O-])CCCCC1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NCC1(CC(=O)O)CCCCC1

Procedure:
A solution of 5 g (0.017 mol) of benzyl 1-(nitromethyl)cyclohexyl-acetate in 50 ml of methanol is added to a mixture of 0.5 g of prehydrogenated palladium, 10% on activated carbon in 50 ml of methanol. This mixture is hydrogenated at room temperature under atmospheric pressure until the calculated hydrogen is consumed, then the catalyst is filtered off, the filtrate is concentrated to about 15 ml and 30 ml of tetrahydrofuran is added to precipitate the title compound. Yield: 1.5 g (51%). Mp: 168° C.
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([N+:25]([O-])=O)[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]2)=[O:13])[CH:6]=1.[H][H]>CO.O1CCCC1.[C].[Pd]>[NH2:25][C:23]1[CH:22]=[CH:21][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]3[CH2:15][CH2:16][CH:17]([OH:20])[CH2:18][CH2:19]3)=[O:13])[CH:6]=2)=[C:2]([F:1])[CH:24]=1
Reactant: [H][H]
Reactant: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ccn1)N1CCC(O)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(Oc2ccnc(NC(=O)N3CCC(O)CC3)c2)c(F)c1
Reaction time: 2 h

Procedure:
4-(2-Fluoro-4-nitrophenoxy)-2-[(4-hydroxypiperidin-1-yl)carbonylamino]pyridine (169 mg) was dissolved in methanol (5 ml)-tetrahydrofuran (5 ml), and then 10% palladium carbon (200 mg) was added thereto under a nitrogen atmosphere, followed by replacing with hydrogen inside the system and stirring for 2 hrs. After replacing with nitrogen inside the system, the reaction mixture was filtered to remove the catalyst, which was washed with ethyl acetate. The filtrate was concentrated under a reduced pressure to provide the titled compound (168 mg, quantitatively) as pale yellow powder.
Reaction SMILES: [H-].[Na+].[N:3]1[C:11]([NH2:12])=[C:10]2[C:6]([NH:7][CH:8]=[N:9]2)=[N:5][CH:4]=1.CS(O[CH2:18][C:19]1[S:23][C:22]2[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=2[C:20]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH3:34])(=O)=O>CN(C=O)C>[C:29]1([CH3:34])[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[C:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[S:23][C:19]=1[CH2:18][N:7]1[CH:8]=[N:9][C:10]2[C:6]1=[N:5][CH:4]=[N:3][C:11]=2[NH2:12]
Reactant: Cc1ccccc1-c1c(COS(C)(=O)=O)sc2ccccc12
Reactant: Nc1ncnc2[nH]cnc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccccc1-c1c(Cn2cnc3c(N)ncnc32)sc2ccccc12
Reaction time: 0.08 h
Yield: 67.3 %

Procedure:
NaH (60% in mineral oil, 16 mg, 0.39 mmol) was added in one portion to a mixture of 9H-purin-6-ylamine (49 mg, 0.36 mmol) in DMF (5 mL) at RT. After 5 min stirring, a solution of methanesulfonic acid 3-o-tolylbenzo[b]thiophen-2-ylmethyl ester from Example 27 (100 mg, 0.30 mmol) in DMF (1 mL) was added dropwise and stirring at RT was continued for 19 h. The reaction mixture was then quenched by addition of water and a solid formed. The precipitated was collected by filtration and was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in EtOAc) affording 167 as a white solid (75 mg, 67%). LCMS: RT 4.13 min [M+H]+ 372.1. 1H NMR (DMSO, 400 MHz): δ 8.11 (1H, s), 7.96-7.88 (2H, m), 7.45-7.30 (6H, m), 7.23 (2H, s), 7.12-7.07 (1H, m), 5.46 (1H, d, J=16.2 Hz), 5.38 (1H, d, J=16.2 Hz), 1.99 (3H, s)
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7]3[C:12](=[O:16])[NH:13][CH:14]=[N:15][C:6]3=[C:5]([C:17]([F:20])([F:19])[F:18])[C:4]=2[CH:3]=1.[Br:21][C:22]1[CH:30]=[CH:29][C:25]([CH2:26][Mg]Br)=[CH:24][CH:23]=1>C1COCC1>[Br:21][C:22]1[CH:30]=[CH:29][C:25]([CH2:26][C:5]2([C:17]([F:18])([F:20])[F:19])[C:4]3[CH:3]=[C:2]([Cl:1])[CH:11]=[CH:10][C:9]=3[NH:8][C:7]3[C:12](=[O:16])[NH:13][CH:14]=[N:15][C:6]2=3)=[CH:24][CH:23]=1
Reactant: O=c1[nH]cnc2c(C(F)(F)F)c3cc(Cl)ccc3nc12
Reactant: Br[Mg]Cc1ccc(Br)cc1
Solvent: C1CCOC1
Product: O=c1[nH]cnc2c1Nc1ccc(Cl)cc1C2(Cc1ccc(Br)cc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h
Yield: 42.7 %

Procedure:
To a stirred suspension of 7 (200 mg, 0.667 mmol) in THF (4 mL) at −40° C. was added 4-bromobenzyl magnesium bromide (0.25 M in Et2O, 13.3 mL, 3.34 mmol). The reaction was warmed slowly to 0° C. over 2 h. After stirring an additional 2 h, the reaction was quenched with H2O (20 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine, dried (MgSO4) and concentrated. Chromatography (SiO2, 40 to 50% EtOAc-hexane) afforded the desired product as a viscous orange oil (134 mg, 43%). ESI-MS m/z 470.2 (M++H, C19H12BrClF3N3O).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[Si:13]([O:20][CH2:21][CH:22]([CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH2:23][OH:24])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].[Br:34][C:35]1[N:40]=[CH:39][C:38](O)=[CH:37][CH:36]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Br:34][C:35]1[CH:36]=[CH:37][C:38]([O:24][CH2:23][CH:22]([CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:28])[CH3:29])[CH2:21][O:20][Si:13]([C:16]([CH3:17])([CH3:19])[CH3:18])([CH3:15])[CH3:14])=[CH:39][N:40]=1
Reactant: CC(C)(C)[Si](C)(C)OCC(CO)CO[Si](C)(C)C(C)(C)C
Reactant: Oc1ccc(Br)nc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC(COc1ccc(Br)nc1)CO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
Diethylazodicarboxylate (3.445 mL, 22.2 mmol) was added dropwise to a stirred mixture of 3-{[tert-butyl(dimethyl)silyl]oxy}-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1-propanol (184) (reported by Kim et al., 2001, via silylation and hydroboration of 2-methylene-1,3-propanediol) (5.706 g, 17.1 mmol), 6-bromo-3-pyridinol (3.571 g, 20.5 mmol) and triphenylphosphine (5.386 g, 20.5 mmol) in anhydrous THF (55 mL) at 0° C. under N2. After stirring at 0° C. for 1 h, and then at room temperature for 41 h, the mixture was concentrated under reduced pressure and the residue was chromatographed on silica gel. Elution with 0-5% Et2O/petroleum ether firstly gave foreruns, and then further elution with 5% Et2O/petroleum ether gave 2-bromo-5-[3-{[tert-butyl(dimethyl)silyl]oxy}-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)propoxy]pyridine (185) (8.09 g, 97%) as a colourless oil; 1H NMR (CDCl3) δ 8.06 (d, J=3.0 Hz, 1H), 7.35 (dd, J=8.7, 0.3 Hz, 1H), 7.11 (dd, J=8.7, 3.2 Hz, 1H), 4.03 (d, J=5.9 Hz, 2H), 3.73 (dd, J=10.1, 5.7 Hz, 1H), 3.69 (dd, J=10.0, 6.0 Hz, 1H), 2.16 (sept, J=5.8 Hz, 1H), 0.88 (s, 18H), 0.03 (2 s, 12H); HRESIMS calcd for C21H41BrNO3Si2 m/z [M+H]+ 492.1783, 490.1803. found 492.1786, 490.1804.
Reaction SMILES: [F:1][C:2]1([F:14])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([OH:13])=[O:12])[C:4]=2[O:3]1.C([Li])CCC.[Cl:20]C(Cl)(Cl)C(Cl)(Cl)Cl.Cl>O1CCCC1.CCCCCC>[Cl:20][C:7]1[C:5]2[O:6][C:2]([F:1])([F:14])[O:3][C:4]=2[C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: O=C(O)c1cccc2c1OC(F)(F)O2
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Cl)c2c1OC(F)(F)O2
Temperature: 0 °C
Reaction time: 1 h
Yield: 42.1 %

Procedure:
7.5 g (0.038 mol) of 2,2-difluoro-1,3-benzodioxole-4-carboxylic acid, prepared according to the process described in European Application 0,333,658, are dissolved, with stirring and under an argon atmosphere, in 75 ml of dry tetrahydrofuran (THF). ml (0.081 mol) of n-butyllithium in solution in hexane are run in dropwise at -70° C. After stirring for 1 hour, 8.9 g (0.038 mol) of hexachloroethane in solution in 50 ml of dry tetrahydrofuran (THF) are run in. After 2 hours at -70° C., the temperature is allowed to return to 10° C. The reaction mixture is hydrolysed with 150 ml of ice-cold water and brought to a pH of approximately 1 by addition of 1N hydrochloric acid. The aqueous phase is extracted with ether, dried over magnesium sulphate and concentrated under vacuum. The solid is washed with heptane to give 3.7 g (0.016 mol) of 7-chloro-2,2-difluoro-1,3-benzodioxole-4-carboxylic acid (yield: 42%; melting point: 185° C.).
Reaction SMILES: [C:1]([C:3]1[O:4][C:5]2[C:11]([C:12]3[CH:35]=[CH:34][C:15]([O:16][CH2:17][C:18]4[CH:19]=[C:20]([CH:31]=[CH:32][CH:33]=4)[C:21]([N:23]4[CH2:30][CH2:29][CH2:28][C@H:24]4[C:25]([OH:27])=[O:26])=[O:22])=[CH:14][CH:13]=3)=[CH:10][C:9]([F:36])=[C:8]([F:37])[C:6]=2[CH:7]=1)#[N:2].C([O-])(=[O:40])C.[Na+].Cl.NO.C(OC(=O)C)(=O)C>C(O)(=O)C>[F:37][C:8]1[C:6]2[CH:7]=[C:3]([CH:1]=[N:2][OH:40])[O:4][C:5]=2[C:11]([C:12]2[CH:13]=[CH:14][C:15]([O:16][CH2:17][C:18]3[CH:19]=[C:20]([CH:31]=[CH:32][CH:33]=3)[C:21]([N:23]3[CH2:30][CH2:29][CH2:28][C@H:24]3[C:25]([OH:27])=[O:26])=[O:22])=[CH:34][CH:35]=2)=[CH:10][C:9]=1[F:36]
Reactant: CC(=O)[O-]
Reactant: N#Cc1cc2c(F)c(F)cc(-c3ccc(OCc4cccc(C(=O)N5CCC[C@H]5C(=O)O)c4)cc3)c2o1
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C(O)[C@@H]1CCCN1C(=O)c1cccc(COc2ccc(-c3cc(F)c(F)c4cc(C=NO)oc34)cc2)c1
Reaction time: 2 h
Yield: 15 %

Procedure:
The compound (20 mg, 0.04 mmol) of Example 54 was dissolved in acetic acid (5 mL), and sodium acetate (45 mg, 0.56 mmol) and hydroxylamine hydrochloride (14 mg, 0.21 mmol) were added thereto, and at 60° C. for 2 hours and stirred. After that, acetic anhydride (0.026 mL, 0.28 mmol) were added to, at 100° C. for 2 hours and stirred. After cooling, the solvent was distilled away, and the resulting residue was purified by reversed-phase HPLC in the same manner as in Step 2 of Example 1 to thus obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([C:20]([OH:22])=O)[C:14]=3[CH:13]=[CH:12][N:11]=2)=[N:7][CH:8]=1.NC1C2C=CC=C(C([NH:36][C:37]3[CH:42]=[C:41]([C:43](=[O:55])[NH:44][C:45]4[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=4)[CH:40]=[CH:39][C:38]=3[CH3:56])=O)C=2C=CN=1.NC1C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([C:20]([NH:36][C:37]4[CH:42]=[C:41]([C:43](=[O:55])[NH:44][C:45]5[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:52])([F:53])[F:54])[CH:46]=5)[CH:40]=[CH:39][C:38]=4[CH3:56])=[O:22])[C:14]=3[CH:13]=[CH:12][N:11]=2)=[N:7][CH:8]=1
Reactant: COc1ccc(Nc2nccc3c(C(=O)O)cccc23)nc1
Reactant: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1NC(=O)c1cccc2c(N)nccc12
Solvent: Nc1ccccc1
Product: COc1ccc(Nc2nccc3c(C(=O)Nc4cc(C(=O)Nc5cccc(C(F)(F)F)c5)ccc4C)cccc23)nc1
Yield: 33 %

Procedure:
The procedures of Example 1 were repeated, except for using 1-((5-methoxypyridin-2-yl)amino)isoquinoline-5-carboxylic acid obtained in Step (3) of Example 19 and 3-amino-4-methyl-N-(3-(trifluoromethyl)phenyl)benzamide obtained in Example 3 instead of carboxylic acid and aniline in Step (3) of Example 1 to obtain the title compound (24 mg, 33%).
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[F:22])=O>O1CCCC1.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:22][C:15]1[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:14]=1[C:12]([CH3:1])=[CH2:11]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COc1ccc(C(C)=O)c(F)c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C(C)c1ccc(OC)cc1F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of sodium bis(trimethylsilyl)-amide, 1.0M in tetrahydrofuran (714 ml, 0.714 m) was added to a suspension of methyltriphenylphosphonium bromide (255 g, 0.714 m) in THF (2.50 L) cooled with an ice bath. The resultant yellow colored suspension was stirred for 30 minutes at ice bath temperature and then cooled to −78° C. A total of 2-fluoro-4-methoxyacetophenone (100 g, 0.595 m) in THF (200 ml) was added dropwise and stirred at −78° C. for 1.5 hours. Reaction mixture was allowed to warm to room temperature for one hour, quenched with acetic acid (˜80 ml) where color change was observed from yellow to off white and stirred for 30 minutes (pH˜7)(slight exotherm noted). The mixture was concentrated to a slush, diluted with 7:2 hexane:ethyl acetate, and was allowed to sit overnight. Solids were removed by filtration and the filtrate was concentrated to yellow oil. The title compound was obtained after flash column using 9:1 hexane:ethyl as the eluant.
Reaction SMILES: Cl.[C:2]1([N:8]([CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])[C:9]([C:11]2[CH:33]=[CH:32][C:14]3[N:15]([CH3:31])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][C:21]=4[O:29][CH3:30])=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>ClCCl.C(O)C>[C:2]1([N:8]([CH2:34][CH2:35][C:36]([OH:38])=[O:37])[C:9]([C:11]2[CH:33]=[CH:32][C:14]3[N:15]([CH3:31])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH2:28])=[CH:22][C:21]=4[O:29][CH3:30])=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1OC)n2C)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: COc1cc(C(=N)N)ccc1NCc1nc2cc(C(=O)N(CCC(=O)O)c3ccccc3)ccc2n1C
Yield: 71 %

Procedure:
Prepared analogously to Example 26 from 1-methyl-2-[N-(4-amidino-2-methoxyphenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)amide hydrochloride and sodium hydroxide solution. Yield: 71% of theory, C27H28N6O4 (500.6); Rf value: 0.15 (silica gel; dichloromethane/ethanol=4:1); EKA mass spectrum: (M+H)+=501; (M+Na)+=523; (M+2Na)++=273.
Reaction SMILES: [OH-].[Na+].CO.[CH:5]1([C:8]2[CH:13]=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([N:21]4[CH2:30][CH2:29][C:28]5[N:27]=[C:26]([CH2:31][CH2:32][CH3:33])[C:25]([C:34]([O:36]C)=[O:35])=[CH:24][C:23]=5[C:22]4=[O:38])[CH2:17][CH2:16]3)[CH:11]=[C:10]([O:39][CH2:40][CH3:41])[C:9]=2[C:42]2[CH:47]=[CH:46][C:45]([F:48])=[C:44]([F:49])[CH:43]=2)[CH2:7][CH2:6]1.Cl>C(OCC)(=O)C.C1COCC1>[CH:5]1([C:8]2[CH:13]=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([N:21]4[CH2:30][CH2:29][C:28]5[N:27]=[C:26]([CH2:31][CH2:32][CH3:33])[C:25]([C:34]([OH:36])=[O:35])=[CH:24][C:23]=5[C:22]4=[O:38])[CH2:17][CH2:16]3)[CH:11]=[C:10]([O:39][CH2:40][CH3:41])[C:9]=2[C:42]2[CH:47]=[CH:46][C:45]([F:48])=[C:44]([F:49])[CH:43]=2)[CH2:6][CH2:7]1
Reactant: CCCc1nc2c(cc1C(=O)OC)C(=O)N(C1CCN(Cc3cc(OCC)c(-c4ccc(F)c(F)c4)c(C4CC4)c3)CC1)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CCCc1nc2c(cc1C(=O)O)C(=O)N(C1CCN(Cc3cc(OCC)c(-c4ccc(F)c(F)c4)c(C4CC4)c3)CC1)CC2
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
A 2 M aqueous sodium hydroxide solution (1.50 mL) was added at room temperature to methanol (5 mL)-THF (5 mL) solution of methyl 6-(1-((2-cyclopropyl-6-ethoxy-3′,4′-difluorobiphenyl-4-yl)methyl)piperidin-4-yl)-5-oxo-2-propyl-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate (580 mg), and the mixture was stirred at 60° C. for 30 minutes. The reaction mixture was neutralized with hydrochloric acid at room temperature. Then, ethyl acetate was added thereto, and the solvent was distilled off under reduced pressure. The deposited solid was collected by filtration and washed with diethyl ether. The obtained solid was recrystallized (DMSO/ethanol/hexane) to obtain the title compound (487 mg).