Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([CH2:19]Cl)=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[N:11]=2)[CH:8]=1.[NH:21]1[CH2:24][CH2:23][C:22]1=[O:25]>>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([CH2:19][N:21]3[CH2:24][CH2:23][C:22]3=[O:25])=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=3)[N:11]=2)[CH:8]=1
Reactant: ClCc1c(-c2ccc(Cl)cc2)nc2ccc(Cl)cn12
Reactant: O=C1CCN1
Agent: Cl
Product: O=C1CCN1Cc1c(-c2ccc(Cl)cc2)nc2ccc(Cl)cn12

Procedure:
The title compound was prepared according to Method B and the experimentals described for compound 91 from 6-chloro-3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochloride and azetidin-2-one. m/e+ 346 for C17H14Cl2N3O4 [M+H]+; 1H-NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 7.65 (d, J=8.4 Hz, 2H), 7.59 (d, J=9.5 Hz, 1H), 7.46 (d, J=8.4 Hz, 2H), 7.25 (m, 1H), 4.79 (s, 2H), 3.18 (t, J=4.0 Hz, 2H), 3.00 (t, J=4.0 Hz, 2H) ppm; 13C-NMR (100 MHz, CDCl3, δ) 168.269, 145.293, 143.807, 134.791, 132.129, 129.877, 129.324, 127.269, 122.325, 121.771, 118.185, 115.333, 39.400, 37.512, 35.449 ppm.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4]1.N1C=CC=CC=1.[C:22](OC(=O)C)(=[O:24])[CH3:23].C(=O)([O-])O.[Na+].[OH-].[Na+]>C1(C)C=CC=CC=1>[C:22]([NH:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4]1)(=[O:24])[CH3:23]
Reactant: NCC1CN(Cc2ccccc2)CCO1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(=O)NCC1CN(Cc2ccccc2)CCO1
Reaction time: 1 h
Yield: 44.9 %

Procedure:
To a solution of crude 2-aminomethyl-4-benzylmorpholine (48 g) in toluene (400 ml) was added pyridine (24.5 ml, 0.303 mol) and then acetic anhydride (26.4 ml, 0.280 mol) was added dropwise under ice-cooling over 10 minutes and then allowed to rise to room temperature and the mixture was stirred for one hour. To the reaction mixture was added aqueous saturated sodium hydrogen carbonate (200 ml) under ice-cooling and then 10% aqueous sodium hydroxide was added until the mixture became strongly basic. The reaction mixture was extracted with ethyl acetate (200 ml×3) and the combined organic layer was washed with aqueous saturated sodium chloride (200 ml). The organic layer was dried over potassium carbonate and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate-hexane (1/1) to give 2-(N-acetylaminomethyl)-4-benzylmorpholine (25.93 g). A total yield of 3 steps=56%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:39]=[CH:38][C:20]([C:21]([N:23]([CH3:37])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][NH2:36])=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:47]([O:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:48]>ClCCl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([N:23]([CH3:37])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][NH:36][C:47]([O:49][C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)=[O:48])=[O:22])=[CH:38][CH:39]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3OCCCCCN)cc2)cc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3OCCCCCNC(=O)Oc3ccccc3)cc2)cc1
Reaction time: 18 h
Yield: 63.9 %

Procedure:
A solution of 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-[2-(5-aminopentyloxy)phenyl]benzamide (750 mg) in dichloromethane (30 ml) was treated with pyridine (681 mg) and phenyl chloroformate (675 mg). After 18 hours, the solvent was removed and the residue was dissolved in ethyl acetate, washed with 1N hydrochloric acid, water, saturated sodium hydrogen carbonate solution and brine, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (SiO2; 50 g, 1% methanol in dichloromethane) to give 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-[2-(5-phenoxycarbonylaminopentyloxy)phenyl]benzamide (590 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH3:15])([CH3:14])[C:12](=[O:16])[N:11]([C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:28])([F:27])[F:26])[CH:18]=3)[C:10]2=[S:29])=[CH:5][C:4]=1[F:30].[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>C1(C)C=CC=CC=1>[F:30][C:4]1[CH:5]=[C:6]([N:9]2[C:13]([CH3:15])([CH3:14])[C:12](=[O:16])[N:11]([C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:27])([F:26])[F:28])[CH:18]=3)[C:10]2=[S:29])[CH:7]=[CH:8][C:3]=1[CH2:2][N:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: C1CCNCC1
Reactant: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=S)N1c1ccc(CCl)c(F)c1
Solvent: Cc1ccccc1
Product: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=S)N1c1ccc(CN2CCCCC2)c(F)c1
Yield: 12.3 %

Procedure:
Compound 7 was prepared according to General Method 2. A solution of 4-(3-(4-(chloromethyl)-3-fluorophenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (100 mg, 0.21 mmol) and piperidine (93 mg, 1.05 mmol) in toluene (10 mL) was refluxed for 12 h. The solvent was removed and residue was purified by silica gel chromatography (eluant: 60% ethyl acetate in hexane) to obtain 13 mg of 4-(3-(3-fluoro-4-((piperidin-1-yl)methyl)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile, HPLC, Column: SUNFIRE C18, 4.6×250 mm, 5 μm, Mobile Phase A: 0.05% TFA, Mobile Phase B: ACN, Gradient: 10% to 90% B in 10 min, hold for 10 min. 90% to 10% B in 1 min, Flow Rate: 1 mL/min, Retention time: 7.635 min, M+1, 505.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[C:5](OCC)=[NH:6])[CH3:2].[C:11]1([CH2:17][C:18]([NH:20][NH2:21])=O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:22](O)[CH3:23]>>[CH2:1]([O:3][C:4]([C:5]1[N:6]=[C:18]([CH2:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:20][N:21]=1)=[O:10])[CH2:2][CH2:22][CH3:23]
Reactant: CCOC(=N)C(=O)OCC
Reactant: NNC(=O)Cc1ccccc1
Reactant: CCO
Product: CCCCOC(=O)c1n[nH]c(Cc2ccccc2)n1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Ethyl-2-ethoxy-2-iminoacetate (1.318 g, 9.08 mmol) and phenyl acetic acid hydrazide (1.364 g, 9.08 mmol) were mixed together in ethanol (20 ml) and stirred at 80° C. for 1 h. Ethanol was evaporated. The residue was dissolved in n-butanol (20 ml). The reaction mixture was stirred at 150° C. for 20 h, then solvents were evaporated.
Reaction SMILES: Br.Br[CH:3]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[C:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=O.C[C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=[S:25])=[CH:22][CH:21]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[F:12][C:9]1[CH:10]=[CH:11][C:6]([C:4]2[N:26]=[C:24]([C:23]3[CH:27]=[CH:28][CH:20]=[CH:21][CH:22]=3)[S:25][C:3]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:7][CH:8]=1
Reactant: Cc1ccc(C(N)=S)cc1
Reactant: O=C(c1ccc(F)cc1)C(Br)c1ccncc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc(-c2nc(-c3ccccc3)sc2-c2ccncc2)cc1
Yield: 19.8 %

Procedure:
A solution of 2-bromo-1-(4-fluorophenyl)-2-(4-pyridyl)ethanone hydrobromide (1.6 g, 4.1 mmol) and thiobenzamide (0.57 g, 4.2 mmol) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 14 h. To the reaction mixture was poured aqueous sodium hydrogencarbonate solution and the precipitated solid was collected by filtration. The obtained solid was washed with water and dried. The crude crystals were recrystallized from ethyl acetate to give the title compound (0.27 g, yield 19%).
Reaction SMILES: Br[C:2](P(=O)(OCC)OCC)([F:4])[F:3].[OH:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[N:18]=[C:17]2[I:30].[OH-].[K+]>CC#N.O.CCOC(C)=O>[F:3][CH:2]([F:4])[O:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[N:18]=[C:17]2[I:30]
Reactant: CC(C)(C)OC(=O)n1nc(I)c2cc(O)ccc21
Reactant: CCOP(=O)(OCC)C(F)(F)Br
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)n1nc(I)c2cc(OC(F)F)ccc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 47 %

Procedure:
Diethyl bromodifluoromethylphosphonate (1.13 g, 4.22 mmol) was added in one portion to a cooled (−30° C.) solution of tert-butyl 5-hydroxy-3-iodo-1H-indazole-1-carboxylate and KOH (2.36 g, 42.2 mmol) in MeCN/H2O (20 mL/20 mL). The reaction mixture was allowed to warm to room temperature. After 20 min, the reaction mixture was diluted with EtOAc (15 mL), and the organic phase was separated. The water phase was extracted with EtOAc (10 mL). The combined organic layers were dried over Na2SO4. Evaporation of the solvent gave a crude product that was purified by column chromatography on silica gel eluting with petroleum ether/EtOAc (5:1) to give tert-butyl 5-(difluoromethoxy)-3-iodo-1H-indazole-1-carboxylate (0.41 g, 47% over two steps) as a white solid. 1H NMR (300 MHz, CDCl3): δ 8.13 (d, 1H, J=9.0 Hz), 7.39 (dd, 1H, J=9, 2.4 Hz), 7.23 (d, 1H, J=2.4 Hz), 6.57 (t, 1H, J=73.2 Hz), 1.73 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:13][C:14]1[CH:15]=[C:16]([CH:28]=[CH:29][CH:30]=1)[CH2:17][N:18]1[C:26]2[C:21](=[CH:22][C:23]([NH2:27])=[CH:24][CH:25]=2)[CH:20]=[N:19]1.ClCCCl>CC(O)(C)C>[ClH:1].[F:13][C:14]1[CH:15]=[C:16]([CH:28]=[CH:29][CH:30]=1)[CH2:17][N:18]1[C:26]2[C:21](=[CH:22][C:23]([NH:27][C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=4)[N:5]=[CH:4][N:3]=3)=[CH:24][CH:25]=2)[CH:20]=[N:19]1
Reactant: Nc1ccc2c(cnn2Cc2cccc(F)c2)c1
Reactant: Clc1ncnc2ccc(I)cc12
Solvent: ClCCCl
Solvent: CC(C)(C)O
Product: Cl
Product: Fc1cccc(Cn2ncc3cc(Nc4ncnc5ccc(I)cc45)ccc32)c1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
Follow general procedure from Example 1, step E. 4-chloro-6-iodoquinazoline (1.18 g, 4.06 mmol) is mixed with 1-(3-Fluoro-benzyl)-1H-indazol-5-ylamine (1.09 g, 4.52 mmol), and a mixture of DCE (10 ml) and t-BuOH (10 ml) is added. The mixture is heated at 90° C. (oil bath temperature) for 8 hours. At 5 hours of heating LC/MS reveals substantial amount of product. Yield is 1.35 g (56%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[C:13]2[C:8](=[CH:9][C:10]([C:14]#[N:15])=[CH:11][CH:12]=2)[CH2:7][O:6]1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C(C)C>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:5]2([CH2:4][CH2:3][CH2:2][N:34]3[CH2:33][CH2:32][N:31]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[O:24][CH3:23])[CH2:36][CH2:35]3)[C:13]3[C:8](=[CH:9][C:10]([C:14]#[N:15])=[CH:11][CH:12]=3)[CH2:7][O:6]2)=[CH:17][CH:18]=1
Reactant: COc1ccccc1N1CCNCC1
Reactant: N#Cc1ccc2c(c1)COC2(CCCCl)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: COc1ccccc1N1CCN(CCCC2(c3ccc(F)cc3)OCc3cc(C#N)ccc32)CC1
Temperature: 25 °C

Procedure:
A mixture of 1-(3-chloropropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (2.5 g, 7.9 mmol), 1-(2-methoxyphenyl)piperazine (2.0 g, 10.4 mmol), potassium carbonate (3 g, 22 mmol) and methyl isobutyl ketone (200 mL) was boiled under reflux for 16 h. After cooling to room temperature the organic phase was washed with water (200 mL), the solvents were evaporated in vacuo and the remaining oil purified by column chromatography (ethyl acetate/heptane/triethylamine 75:20:5). The title compound crystallised from diethyl ether 1.5 g (40 %): mp 147-49° C.; 1H NMR (DMSO-d6) δ 1.30-1.65 (m, 2H), 2.10-2.30 (m, 2H), 2.40 (t, 2H), 2.50-2.70 (m, 4H), 2.90-3.20 (m, 4H), 3.85 (s, 3H), 5.20 (m, 2H), 6.70-7.10 (m, 6H), 7.30-7.55 (m, 4H), 7.60 (d, 1H); MS m/z, 472 (MH+, 100), 262 (14), 109 (19).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[OH:11].[C:12]([N:16]1[CH2:19][CH:18]([OH:20])[CH2:17]1)([CH3:15])([CH3:14])[CH3:13].[OH-].[K+]>Cl>[CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[O:11][CH2:17][CH:18]([OH:20])[CH2:19][NH:16][C:12]([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)(C)N1CC(O)C1
Reactant: COc1ccc(O)c(C)c1C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: COc1ccc(OCC(O)CNC(C)(C)C)c(C)c1C
Temperature: 140 °C
Yield: 72.5 %

Procedure:
A mixture of 9.1 parts of 2,3-dimethyl-4-methoxyphenol, 6.5 parts of 1-(tert.-butyl)-3-azetidinol and 0.3 part of potassium hydroxide was heated under nitrogen gas at 140° C. for 8 hours with agitation. The reaction product was dissolved in 100 parts of 2N-hydrochloric acid aqueous solution and washed twice with 100 parts of ether. The water layer was made alkaline with 4N-sodium hydroxide aqueous solution, and the resulting crystals were recovered by filtration and dried. Then the crystals were dissolved in 100 parts of ether and decolored. The decolored liquid was concentrated and allowed to cool. As a result 10.2 parts of 1-(2',3'-dimethyl-4'-methoxyphenoxy)-3-(tert.-butylamino)-2-propanol melting at 73° - 75° C were obtained. The yield was 72.5%. The results of infra-red spectrum analysis and nuclear magnetic resonance analysis of the product are as follows:
Reaction SMILES: [O:1]=[C:2]1[C:11]2[NH:12][CH:13]=[C:14]([C:15]([OH:17])=[O:16])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[NH:3]1.C(N(CC)CC)C.C(OS(OCCC)(=O)=O)CC>>[O:1]=[C:2]1[C:11]2[NH:12][CH:13]=[CH:14][C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[NH:3]1.[CH2:14]([C:15]([O-:17])=[O:16])[CH2:10][CH3:9]
Reactant: O=C(O)c1c[nH]c2c(=O)[nH]c3ccccc3c12
Agent: CCCOS(=O)(=O)OCCC
Solvent: CCN(CC)CC
Product: CCCC(=O)[O-]
Product: O=c1[nH]c2ccccc2c2cc[nH]c12

Procedure:
4-Oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-propyl carboxylate was prepared according to method of esterification C from 194 mg (0.85 mmol) of 4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid, 1.29 mL (12.75 mmol) of triethylamine and 698 μL (1.1 mmol) of di-n-propylsulfate to give, after precipitation in water, 200 mg (87%) of 4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-propyl carboxylate in the form of a beige solid.
Reaction SMILES: [C:1]([C:3]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][N:5]([C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][N:22]=2)[C:17]([NH2:19])=O)[CH:4]=1)#[N:2].[N-:23]=[N+:24]=[N-:25].[Na+].C(#N)C.Cl[Si](Cl)(Cl)Cl>O.O1CCCC1>[C:8]1([C:7]2[C:3]([C:1]#[N:2])=[CH:4][N:5]([C:14]3[CH:15]=[C:16]([C:17]4[NH:25][N:24]=[N:23][N:19]=4)[CH:20]=[CH:21][N:22]=3)[CH:6]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: N#Cc1cn(-c2cc(C(N)=O)ccn2)cc1-c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl[Si](Cl)(Cl)Cl
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: C1CCOC1
Product: N#Cc1cn(-c2cc(-c3nnn[nH]3)ccn2)cc1-c1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 80.9 %

Procedure:
To a solution of 2-(3-cyano-4-phenylpyrrole-1-yl)isonicotinamide (0.058 g) and sodium azide (0.039 g) in a mixed solvent of acetonitrile (1.0 mL) and tetrahydrofuran (0.5 mL) was added tetrachlorosilane (0.068 g) at room temperature, and this mixture was stirred at 80° C. overnight. To this reaction mixture was added water, this obtained solid was collected by filtration. After washing with water, this solid was dried at 50° C. under reduced pressure to give the title compound (0.051 g).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7]O)=[CH:5][N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.S(Cl)([Cl:17])=O>C1(C)C=CC=CC=1>[Cl:17][CH2:7][C:6]1[C:2]([CH3:1])=[N:3][N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:5]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1nn(-c2ccccn2)cc1CO
Solvent: Cc1ccccc1
Product: Cc1nn(-c2ccccn2)cc1CCl
Temperature: 70 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
A mixture of 3-methyl-1-(2-pyridyl)-1H-pyrazol-4-ylmethanol (3.00 g), thionyl chloride (2.5 mL) and toluene (50 mL) was stirred at 70° C. for 2 hrs. The reaction mixture was concentrated under reduced pressure, and saturated aqueous sodium hydrogencarbonate was added to the residue. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 4-chloromethyl-3-methyl-1-(2-pyridyl)-1H-pyrazole (3.10 g, yield 94%) as a colorless oil.
Reaction SMILES: [CH3:1][O-:2].[Na+].[NH2:4][C:5]1[C:6]([F:29])=[CH:7][C:8]([F:28])=[C:9]([N:11]2[C:20]3[C:15](=[CH:16][C:17]([F:23])=[C:18](F)[C:19]=3[CH3:21])[C:14](=[O:24])[C:13]([C:25]([OH:27])=[O:26])=[CH:12]2)[CH:10]=1>C(O)(=O)C.CO>[NH2:4][C:5]1[C:6]([F:29])=[CH:7][C:8]([F:28])=[C:9]([N:11]2[C:20]3[C:15](=[CH:16][C:17]([F:23])=[C:18]([O:2][CH3:1])[C:19]=3[CH3:21])[C:14](=[O:24])[C:13]([C:25]([OH:27])=[O:26])=[CH:12]2)[CH:10]=1
Reactant: C[O-]
Reactant: Cc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c12
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c2c1C
Temperature: 40 °C
Reaction time: 48 h
Yield: 80.2 %

Procedure:
Methanol (500 mg) and sodium methoxide (28% methanol solution; 200 mg) were added to 1-(5-amino-2,4-difluorophenyl)-6,7-difluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (350 mg), and the mixture was heated and stirred at 40° C. for 2 days. Acetic acid (2 drops) was added to the reaction mixture to collect solids by filtration. The solids were washed with ethanol and dried to obtain the title compound (290 mg) as a pale yellow powder.
Reaction SMILES: [C:1]([NH:4][C:5](=[O:30])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)(=[O:16])=[O:15])=[CH:9][C:8]=1[N+:27]([O-])=O)(=[O:3])[CH3:2].[H][H]>CO.COCCO.[Ni]>[C:1]([NH:4][C:5](=[O:30])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:24])([F:26])[F:25])[CH:18]=2)(=[O:15])=[O:16])=[CH:9][C:8]=1[NH2:27])(=[O:3])[CH3:2]
Reactant: CC(=O)NC(=O)Nc1ccc(OS(=O)(=O)c2cccc(C(F)(F)F)c2)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: COCCO
Solvent: CO
Product: CC(=O)NC(=O)Nc1ccc(OS(=O)(=O)c2cccc(C(F)(F)F)c2)cc1N

Procedure:
59 g of 2-(3-acetylureido)-5-(3-trifluoromethylphenylsulfonyloxy)nitrobenzene in 200 ml of methanol and 200 ml of 2-methoxyethanol are hydrogenated under normal pressure with a catalytic amount of Raney nickel. After hydrogen uptake is complete, the catalyst is filtered off with suction, washed with warm 2-methoxyethanol and the solution is evaporated under reduced pressure. Water is added to the residue and it is then filtered off with suction, washed with water and dried over sodium hydroxide, melting point 182° C.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[C:16]([NH2:23])[C:17]3[N:22]=[N:21][NH:20][C:18]=3[N:19]=2)=[N:6]1.[CH3:28]CN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.IC>CN(C)C=O>[F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[C:16]([NH2:23])[C:17]3[N:22]=[N:21][N:20]([CH3:28])[C:18]=3[N:19]=2)=[N:6]1
Reactant: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2[nH]nnc12
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1nnc2c(N)nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc21
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
250 mg (0.692 mmol) of the compound from example 53 and 190 mg (0.692 mmol) of BEMP were initially charged in 12 ml of dimethylformamide, and a solution of 98 mg (0.692 mmol) of iodomethane in 3 ml of dimethylformamide was added dropwise at 0° C. within 10 min. The mixture was stirred at 0° C. for 20 min. Subsequently, the reaction solution was concentrated under reduced pressure and the residue was purified by means of preparative HPLC (eluent: methanol/aqueous 0.1% ammonia solution=65:35). The residue was stirred with acetonitrile and filtered with suction, and the solids were dried under high vacuum. 78 mg of the title compound (30% of theory) and 50 mg of example 55 were obtained (19% of theory).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:9]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:7]=[CH:6][N:5]=1)C.[ClH:17].C(O[CH2:26][CH3:27])(OCC)OCC>C(O)=O>[Cl:17][N+:3]1([CH2:26][CH3:27])[C:4]2=[N:5][CH:6]=[CH:7][CH:8]=[C:9]2[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH-:1]1
Reactant: CCNc1ncccc1Nc1ccccc1
Reactant: CCOC(OCC)OCC
Reactant: Cl
Solvent: O=CO
Product: CC[N+]1(Cl)[CH-]N(c2ccccc2)c2cccnc21
Temperature: 25 °C
Yield: 91 %

Procedure:
N2-ethyl-N3-phenylpyridine-2,3-diamine (8.5 g, 40 mmol), concentrated HCl (6 mL), and 4 mL of formic acid were added to the triethyl orthoformate (376 mL). The reaction was refluxed overnight. After it cooled to room temperature, the beige solid was collected by filtration. The solid was further purified by recrystallizing from ethanol to give 3-chloro-3-ethyl-1-phenyl-2,3-dihydro-1H-imidazo[4,5-b]pyridin-3-ium-2-ide (9.4 g, 91% yield).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]=[C:10]=[O:11].[OH:12][C:13]1[N:17]=[C:16]([S:18][CH3:19])[S:15][N:14]=1.C(OC(C)C)(C)C>O1CCCC1>[CH3:8][NH:9][C:10]([N:14]1[C:13](=[O:12])[N:17]=[C:16]([S:18][CH3:19])[S:15]1)=[O:11]
Reactant: CSc1nc(O)ns1
Reactant: CN=C=O
Solvent: C1CCOC1
Solvent: CC(C)OC(C)C
Solvent: CCN(CC)CC
Product: CNC(=O)n1sc(SC)nc1=O
Temperature: 20 °C
Reaction time: 3 h

Procedure:
0.1 ml of triethylamine and 5 ml of methyl isocyanate were added to a solution of 7.5 g of 3-hydroxy-5-methylthio-1,2,4-thiadiazole in 50 ml of tetrahydrofuran and after stirring at 20° C for 3 hours, 25 ml of isopropyl ether were added. The mixture was vacuum filtered and the recovered crystals were washed, dried and crystallized from acetone to obtain 5.2 g of 2-(N-methylcarbamoyl)-5-methylthio-1,2,4-thiadiazole-3-one melting at 144° C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[CH3:14][C:15]1[C:20]([F:21])=[C:19](F)[N:18]=[C:17]([F:23])[C:16]=1[F:24]>CN(C=O)C.C(#N)C>[CH3:14][C:15]1[C:20]([F:21])=[C:19]([O:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=2)[N:18]=[C:17]([F:23])[C:16]=1[F:24]
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: Cc1c(F)c(F)nc(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: Cc1c(F)c(F)nc(Oc2cccc(C(F)(F)F)c2)c1F
Temperature: 75 °C
Reaction time: 16 h
Yield: 76 %

Procedure:
To a solution of 3-trifluoromethyl phenol (13.2 ml, 0.11 mol) in anhydrous DMF (200 ml) is added sodium hydride (4.8 g, 60%, 0.12 mol). After 30 min at ambient temperature the solution is added to another solution of 4-methyl-2,3,5,6-tetrafluoropyridine (16.5 g, 0.1 mol) in anhydrous acetonitrile (700 ml) at 50° C. during 3 hours. The resulting mixture is then stirred for 1 hour at 50° C. and 16 hours at 75° C. The solvents are removed in vacuo and to the residue is added ethyl acetate/pentane (1000 ml, 1/1 by volume). The mixture is washed twice with 2 M NaOH and 5 times with water. After drying and evaporation of the organic layer, the residue is purified by vacuum destillation. One obtains a colorless oil (23.3 g, 76 mmol, 76% yield, bp. 76° C. at 0.025 mbar) of 4-methyl-2,3,5-trifluoro-6-(3-trifluoromethylphenoxy)pyridine.