Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:25][C:26]1[N:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[CH3:24][C:10]1[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:29]3[CH:28]=[N:27][C:26]([NH2:25])=[N:31][CH:30]=3)[CH:7]=2)[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:11]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(Cl)c2)n1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cnc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 2′-chloro-6-methyl-4-(4-trifluoromethylphenyl)-[2,4′]bipyridinyl (example E.28) (0.300 g, 0.86 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.247 g, 1.26 mmol) according to the general procedure VI. Obtained as a white solid (0.110 g, 31%). MS (ISP) 408.3 [(M+H)+]; mp>245° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:25])([CH3:4])([CH3:3])[CH3:2].C([O:29][C:30](=O)[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]#[N:41])[CH:35]=1)=[O:33])C>>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH:25][C:30](=[O:29])[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]#[N:41])[CH:35]=1)=[O:33])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1N
Reactant: CCOC(=O)CC(=O)c1cccc(C#N)c1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1NC(=O)CC(=O)c1cccc(C#N)c1

Procedure:
Prepared from (3-amino-4′-trifluoromethoxy-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G27) and 3-(3-cyano-phenyl)-3-oxo-propionic acid ethyl ester (Pol. J. Chem. 1978, 25) according to the general procedure K. Obtained as a brown semisolid (94 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]([O:8][C:9]1[CH:14]=[C:13]([C:15](=[O:23])NC2CCNCC2)[CH:12]=[C:11]([O:24][CH3:25])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].C([O:29]C(=O)C(OC1C=C(OC)C=C(C=O)C=1)(C)C)C.Cl([O-])=O.[Na+]>>[CH2:1]([O:3][C:4]([C:5]([CH3:6])([O:8][C:9]1[CH:14]=[C:13]([CH:12]=[C:11]([O:24][CH3:25])[CH:10]=1)[C:15]([OH:23])=[O:29])[CH3:7])=[O:26])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1cc(C=O)cc(OC)c1
Reactant: CCOC(=O)C(C)(C)Oc1cc(OC)cc(C(=O)NC2CCNCC2)c1
Agent: [Na+]
Agent: [O-][Cl+][O-]
Product: CCOC(=O)C(C)(C)Oc1cc(OC)cc(C(=O)O)c1

Procedure:
In analogy to the procedure described in example 50k), 2-[3-methoxy-5-(piperidin-4-ylcarbamoyl)-phenoxy]-2-methyl-propionic acid ethyl ester [prepared by i) oxidation of 2-(3-formyl-5-methoxy-phenoxy)-2-methyl-propionic acid ethyl ester with sodium chlorite in analogy to example 60c) to give 3-(1-ethoxycarbonyl-1-methyl-ethoxy)-5-methoxy-benzoic acid; ii) subsequent condensation with 4-amino-piperidine-carboxylic acid tert-butyl ester, using acid activation with 2-chloro-4,6-dimethoxy-1,3,5-triazine in analogy to the procedure described in example 50 h) followed by Boc cleavage with TFA in analogy to the procedure described in example 50i)] was reacted with 3,5-diethoxy-4-fluoro-benzaldehyde (example 50 g), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as colorless foam. MS: 561.6 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:12][C@H:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[NH:18][C:19]([C:21]2[C:26](N3N=CC=N3)=[CH:25][CH:24]=[CH:23]N=2)=[O:20])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1.Cl.C[N:34]([C:41]1[CH:46]=N[C:44]([C:47](F)(F)F)=[CH:43][N:42]=1)[C@H]1CCC[C@@H]1N.N1C=CC=NC=1C1C=CC=CC=1C(O)=O>>[CH3:1][C:2]1[C:3]([NH:12][C@H:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[NH:18][C:19](=[O:20])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:46]=2[C:41]2[N:34]=[CH:47][CH:44]=[CH:43][N:42]=2)=[N:4][CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[N:7]=1
Reactant: CN(c1cnc(C(F)(F)F)cn1)[C@H]1CCC[C@@H]1N
Reactant: Cc1nc(C(F)(F)F)cnc1N[C@H]1CCC[C@@H]1NC(=O)c1ncccc1-n1nccn1
Agent: Cl
Agent: O=C(O)c1ccccc1-c1ncccn1
Product: Cc1nc(C(F)(F)F)cnc1N[C@H]1CCC[C@@H]1NC(=O)c1ccccc1-c1ncccn1

Procedure:
Prepared according to the procedure for N-[(1S,2S)-2-{ [3-methyl-5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxamide (Example 76) from (1S,2S)-1-N-methyl-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 23; 60 mg, 0.20 mmol) and 2-(pyrimidin-2-yl)benzoic acid (CAS number 400892-62-8; 41 mg, 0.20 mmol) except this was purified only by column chromatography (silica, 0 to 100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([NH:18][C:19]4[S:20][C:21]5[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:22]=5[N:23]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH2:4]1.Br[CH2:33][CH2:34][OH:35].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[OH:35][CH2:34][CH2:33][N:3]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([NH:18][C:19]4[S:20][C:21]5[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:22]=5[N:23]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH2:4]1
Reactant: OCCBr
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)N[C@@H]3CCNC3)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)N[C@@H]3CCN(CCO)C3)ccc21
Temperature: 50 °C

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid [(R)-1-(2-hydroxy-ethyl)-pyrrolidin-3-yl]amide (25 mg) was prepared starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (R)-pyrrolidin-3-ylamide dihydrochloride (200 mg), 2-bromo-ethanol (50 uL) and Cs2CO3 (300 mg) in DMF (1 mL). The reaction was heated to 50° C. for 8 h. The reaction was filtered and purified with silica gel chromatography using DCM:10% methanol in DCM (100:0 to 0:100) as an eluent system to give pure product. LC/MS: m/z 470.6.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23](O)=[O:24])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].O[N:27]=[C:28]([NH2:36])[CH2:29][S:30]([CH:33]([CH3:35])[CH3:34])(=[O:32])=[O:31]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:10][CH:11]([C:23]3[O:24][N:36]=[C:28]([CH2:29][S:30]([CH:33]([CH3:35])[CH3:34])(=[O:32])=[O:31])[N:27]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[O:16])[CH2:14]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1C
Reactant: CC(C)S(=O)(=O)CC(N)=NO
Product: Cc1ccc(C2CC(c3nc(CS(=O)(=O)C(C)C)no3)CN(C(=O)N3CCOCC3)C2)cc1C

Procedure:
100 mg (0.289 mmol) of the compound from Example 130A and 78 mg (0.433 mmol) of N′-hydroxy-2-(propan-2-ylsulphonyl)ethanimidamide were reacted according to the General Method 2. Yield: 108 mg (75% of theory)
Reaction SMILES: [C:1]1([C:7](=[N:14][CH2:15][C:16]#[N:17])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.I[CH2:24][CH2:25][F:26]>C1COCC1>[C:1]1([C:7](=[N:14][CH:15]([CH2:24][CH2:25][F:26])[C:16]#[N:17])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CCN=C(c1ccccc1)c1ccccc1
Reactant: FCCI
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#CC(CCF)N=C(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 93.7 %

Procedure:
16.5 g (74.91 mmol) of [(diphenylmethylene)amino]acetonitrile were initially charged in 495 ml of abs. THF, and 35.96 ml (89.89 mmol) of n-butyllithium (2.5 N in hexane) were added at −78° C. under argon, and the mixture was stirred at −78° C. for 15 min. Subsequently, the reaction solution was warmed up to 0° C. 13.03 g (74.91 mmol) of 1-iodo-2-fluoroethane were added dropwise to the reaction solution, which was stirred at 0° C. for a further 15 min. The reaction solution was quenched with water at 0° C., ethyl acetate was added and the mixture was washed with saturated aqueous sodium chloride solution. The aqueous phase was reextracted twice with ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and concentrated by rotary evaporation. The residue was purified by means of silica gel chromatography (eluent:dichloromethane/cyclohexane=1/1 to 2/1). 18.7 g of the target compound were obtained (80% of theory, 85% purity).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][CH:11]1[CH2:16][NH:15][CH2:14][CH:13]([CH3:17])[N:12]1[C:18](=[O:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:18]([N:12]1[CH:11]([CH3:10])[CH2:16][N:15]([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:14][CH:13]1[CH3:17])(=[O:20])[CH3:19]
Reactant: CC(=O)N1C(C)CNCC1C
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N1C(C)CN(c2ccc(C=O)cc2)CC1C
Temperature: 130 °C
Yield: 46.7 %

Procedure:
To a solution of 4-fluoro-benzaldehyde (3.0 g, 0.024 mol) and 1-(2,6-dimethyl-piperazin-1-yl)-ethanone (3.0 g, 0.019 mol) in anhydrous DMF (15 mL) was added potassium carbonate (6.6 g, 0.048 mol). The reaction mixture was heated to 130° C. for 32 hours. The DMF was removed and the residue was purified by column chromatography (silica gel 230-400 mesh; eluting with 2:1 ethyl acetate and dichloromethane) to give 4-(4-acetyl-3,5-dimethyl-piperazin-1-yl)-benzaldehyde as light yellow solid (2.31 g, 46.2%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]2[CH2:7][CH:8]([OH:10])[CH2:9][CH:3]1[CH2:4][CH2:5]2.C(N(C(C)C)CC)(C)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22].C(=O)([O-])[O-].[K+].[K+]>ClCCl.O.CCCCCCC>[CH3:1][N:2]1[CH:6]2[CH2:7][CH:8]([O:10][S:21]([CH3:20])(=[O:23])=[O:22])[CH2:9][CH:3]1[CH2:4][CH2:5]2
Reactant: CN1C2CCC1CC(O)C2
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCCC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1C2CCC1CC(OS(C)(=O)=O)C2
Temperature: 20 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
Tropine (50 g) and diisopropylethylamine (48.05 g) in dichloromethane (0.5 L) were cooled to −10° C. Methane sulphonyl chloride (44.7 g) in dichloromethane (0.125 L) was added over 0.75 h at <−5° C. After 0.5 h a solution of potassium carbonate (75 g) in water (0.2 L) was added and the mixture warmed to 20° C. The phases were separated and the dichloromethane solution concentrated by distillation under reduced pressure at <20° C. to leave a residue whereby the dichloromethane content was 51% w/w. Heptane (0.05 L) was added and the solution cooled to 0° C. to crystallize the title compound. Further heptane (0.45 L) was added and the mixture kept under vacuum (350 mbar) at 20-25° C. until the dichloromethane content was 8% w/w. The mixture was cooled to 0° C. and stirred for 1 h. The product was isolated by filtration, washed and dried at <30° C. to give the title compound (68.5 g, 88.1%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C([O-])([O-])=O.[Na+].[Na+].O.[C:15](Cl)([O:17][CH2:18][CH:19]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16]>O1CCOCC1.[Na+].[Cl-]>[O:7]=[C:2]1[NH:1][CH2:6][CH2:5][N:4]([C:15]([O:17][CH2:18][CH:19]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[C:26]3[C:31]2=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:16])[CH2:3]1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: O=C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C1CN(C(=O)OCC2c3ccccc3-c3ccccc32)CCN1
Temperature: 25 °C
Reaction time: 4 h
Yield: 103.9 %

Procedure:
To a solution of piperazin-2-one (2 g, 20 mmol, 1 equiv), Na2CO3 (4.2 g, 40 mmol, 2 equiv) and water (20 mL) in 1,4-dioxane (60 mL) was added Fmoc-Cl (5.7 g, 22 mmol, 1.1 equiv) at 0° C. After the reaction mixture was stirred at room temperature for 4 h, it was diluted with saturated NaCl (200 mL). The solution was extracted with ethyl acetate (3×50 mL) and dried over Na2SO4. The combined organic layers were concentrated to give 6.7 g of the desired product, which was directly used for the next step without further purification. MS (ESI): 323 (MH+).
Reaction SMILES: [CH2:1]([C:4]1[N:5]=[C:6]([NH:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[S:7][C:8]=1[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1)[CH2:2][CH3:3]>CO.[Ni]>[CH2:1]([C:4]1[N:5]=[C:6]([NH:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[S:7][C:8]=1[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc(NCC(=O)OC)sc1Cc1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Solvent: CO
Product: CCCc1nc(NCC(=O)OC)sc1Cc1ccc(N)cc1
Yield: 75.7 %

Procedure:
2.6 g of methyl (4-propyl-5-(4-nitrobenzyl)thiazol-2-yl)aminoacetate in 60 ml of methanol are hydrogenated at normal pressure and room temperature in the presence of Raney nickel. After filtration of the catalyst and concentration of the filtrate, the residue is taken up with acidified water. The aqueous phase is extracted with ether, rendered basic with sodium carbonate and extracted with ethyl acetate. After drying and concentration, the residue is taken up with pentane to give 1.8 g of methyl (4-propyl-5-(4-aminobenzyl)thiazol-2-yl)aminoacetate in the form of a beige solid melting at 106° C.
Reaction SMILES: C[O:2][C:3]1[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][C:6]([C:7]([N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[S:11](=[O:19])(=[O:18])[CH2:10]2)=[O:8])=[CH:5][C:4]=1[C:26]([N:28]1[CH2:32][CH2:31][S:30][CH2:29]1)=[O:27].[Cl-].[Li+].Cl>CN(C)C=O>[OH:2][C:3]1[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][C:6]([C:7]([N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[S:11](=[O:19])(=[O:18])[CH2:10]2)=[O:8])=[CH:5][C:4]=1[C:26]([N:28]1[CH2:32][CH2:31][S:30][CH2:29]1)=[O:27]
Reactant: COc1c(C(=O)N2CCSC2)cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc1C(F)(F)F
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=C(c1cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc(C(F)(F)F)c1O)N1CCSC1
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 35.1 %

Procedure:
3-[4-methoxy-3-(1,3-thiazolidine-3-carbonyl)-5-trifluoromethylbenzoyl]-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (138 mg) was dissolved in N,N-dimethylformamide (2 mL), and lithium chloride (118 mg) was added to the solution, and then the mixture was stirred at 120° C. for 1.5 hours. To the reaction solution, 1N hydrochloric acid was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was crystallized from n-hexane-chloroform to obtain the title compound (47 mg) as a pale yellow crystal.
Reaction SMILES: [CH:1]([C:3]1[N:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH2:10]2)=[CH:5][C:4]=1[C:12]([O:14]C)=O)=O.O.[NH2:17][NH2:18]>>[C:12]1(=[O:14])[C:4]2[CH:5]=[C:6]3[N:11]([C:3]=2[CH:1]=[N:18][NH:17]1)[CH2:10][CH2:9][CH2:8][CH2:7]3
Reactant: NN
Reactant: COC(=O)c1cc2n(c1C=O)CCCC2
Solvent: O
Product: O=c1[nH]ncc2c1cc1n2CCCC1
Temperature: 100 °C
Yield: 75 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a reflux condenser was charged with 193d (600 mg, 2.9 mmol) and hydrazine hydrate (20 mL). The reaction mixture was heated at 100° C. for 4 hours. After this time the reaction was cooled to room temperature and filtered to afford 193e as a yellow solid (413 mg, 75%). MS-ESI: (M+H)+ 190.1. 1H NMR (500 MHz, DMSO-d6) δ 12.17 (s, 1H), 8.24 (s, 1H), 6.33 (s, 1H), 4.16 (t, J=6.0 Hz, 2H), 2.88 (t, J=6.5 Hz, 2H), 2.00-1.96 (m, 2H), 1.84-1.79 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH4+:13].[OH-]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([S:9]([NH2:13])(=[O:11])=[O:10])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=S(=O)(Cl)c1cc(F)cc(F)c1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NS(=O)(=O)c1cc(F)cc(F)c1
Reaction time: 1 h
Yield: 88 %

Procedure:
To a solution of 3,5-difluorobenzenesulfonyl chloride (25 g, 0.117 mol) in THF (150 mL) was added 35% aq. NH4OH (120 mL) over 1 h in an ice-bath. After the reaction was complete, it was evaporated in vacuo. To a solution of this residue in water (150 mL) was added 2N HCl (1 mL). After stirring 1 h, the reaction mixture was filtered and dried under high vacuum to give 3,5-difluorobenzenesulfonamide as a light brown solid (19.9 g, 88%). 1H NMR (400 MHz, CDCl3) δ 7.49-7.44 (m, 2H), 7.04-6.99 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-])=O)[N:4]=1>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])[N:4]=1
Reactant: COc1cc(OC)nc(Cc2ccccc2[N+](=O)[O-])n1
Solvent: CCO
Product: COc1cc(OC)nc(Cc2ccccc2N)n1
Temperature: 0 °C
Yield: 83.7 %

Procedure:
The product of stage (i) (32.6 g) was added to a stirred suspension of stannous chloride dihydrate (133 g) in ethanol (300 ml). After refluxing for 2 hours the solution was poured into ice-water (2500 ml) and extracted with ethyl acetate (3×500 ml). The combined extracts were washed with saturated sodium chloride solution, dried and evaporated to give 24.3 g of the desired product as a brown solid, mp 82°-84° C.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH2:14][CH2:13][CH2:12][C:9]=3[CH:10]=2)[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[C:4]([C:22]([O:24]CC)=[O:23])[C:3]1=[O:27].[OH-].[K+].C(O)C.Cl>O>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH2:14][CH2:13][CH2:12][C:9]=3[CH:10]=2)[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[C:4]([C:22]([OH:24])=[O:23])[C:3]1=[O:27]
Reactant: CCOC(=O)c1c(-c2ccccc2C)c2cc3c(cc2n(C)c1=O)CCC3
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccccc1-c1c(C(=O)O)c(=O)n(C)c2cc3c(cc12)CCC3
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 100.3 %

Procedure:
A mixture of ethyl 1-methyl-4-(2-methylphenyl)-2-oxo-1,2,7,8-tetrahydro-6H-cyclopenta[g]quinoline-3-carboxylate (2.0 g), potassium hydroxide (1.55 g) and 80% ethanol (20 ml) was stirred at 80° C. for 20 minutes. The mixture was diluted with water and acidified with 2N HCl to give crystals of 1-methyl-4-(2-methylphenyl)-2-oxo-1,2,7,8-tetrahydro-6H-cyclopenta[g]quinoline-3-carboxylic acid (1.85 g, 99.6%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=3[F:30])[C:16]=2[C:31](=[O:33])[NH2:32])[CH:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[O:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=2[F:30])[C:16]=1[C:31]([NH2:32])=[O:33]
Reactant: CC(C)(C)OC(=O)Nc1cccc(Oc2cc(F)cc(Nc3ccc(I)cc3F)c2C(N)=O)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1c(Nc2ccc(I)cc2F)cc(F)cc1Oc1cccc(N)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.4 %

Procedure:
In analogy to GP 4, 163 mg of {3-[2-Carbamoyl-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxy]-phenyl}-carbamic acid tert-butyl ester (0.28 mmol) were suspended in dichloromethane, 0.29 ml of TFA (3.78 mmol, 13 eq.) were added and the mixture was stirred at rt for 4 h. The reaction mixture was concentrated, redissolved in dichloromethane and sodium hydroxide solution (1M, aq.) was added. After phase separation the organic phase was concentrated to afford 129 mg (96%, 0.27 mmol) of the desired product, which required no further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([CH2:11][CH2:12][CH3:13])[C:5]=1[OH:14].C(Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)(O)[O-].[Na+]>CO.[OH-].[Na+].CN(C)C=O>[C:17]1([CH2:1][O:2][C:3](=[O:15])[C:4]2[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([CH2:11][CH2:12][CH3:13])[C:5]=2[OH:14])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCc1ccccc1
Reactant: CCCc1c(O)ccc(C(=O)OC)c1O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: CCCc1c(O)ccc(C(=O)OCc2ccccc2)c1O
Yield: 70 %

Procedure:
A solution of 37 g (0.18 mol) of 2,4-dihydroxy-3-propylbenzoic acid methyl ester in 750 mL of methanol and 415 mL of 3N sodium hydroxide was stirred at reflux for 3 hours. The methanol was removed under reduced pressure and the residue was treated with water and 6N hydrochloric acid to acidify. The solid product was extracted with ethyl acetate and the extract was dried and concentrated under reduced pressure to a tan solid which was used without purification. This crude acid (35 g, 0.18 mol), 23 mL (0.2 mol) of benzyl chloride and 17 g (0.2 mol) of sodium bicarbonate in 250 mL of anhydrous dimethylformamide was stirred and heated at 60° for 23 hours. The solvent was removed under reduced pressure and the residue was treated with saturated sodium bicarbonate solution and the product was extracted with ethyl acetate. The dried extract was concentrated under reduced pressure and the residual oil was purified by HPLC using 15% ethyl acetate hexane to give 36 g (70% yield), mp 86°-88° of 2,4-dihydroxy-3-propylbenzoic acid phenylmethyl ester.
Reaction SMILES: [OH:1][CH2:2][C:3]1([OH:27])[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]3=[O:25])=[CH:11][C:10]=2[F:26])[CH2:5][CH2:4]1.[CH3:28][S:29](Cl)(=[O:31])=[O:30].C(N(CC)CC)C>ClCCl>[CH3:28][S:29]([O:1][CH2:2][C:3]1([OH:27])[CH2:4][CH2:5][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]3=[O:25])=[CH:11][C:10]=2[F:26])[CH2:7][CH2:8]1)(=[O:31])=[O:30]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(O)(CO)CC3)c(F)c2)C(=O)O1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(O)(COS(C)(=O)=O)CC3)c(F)c2)C(=O)O1
Yield: 80 %

Procedure:
The title compound was prepared by reacting (S)-N-{3-[4-(4-hydroxymethyl-4-hydroxy-piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.00 mmol) with methanesulfonyl chloride (1.20 mmol) and triethylamine (1.50 mmol) in dichloromethane (15 ml) at a temperature 0-10° C. for 4 hours and by purifying the compound by silica gel column chromatography in 80% yield.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[S:18][C:19]4[C:20]([N:38]=3)=[N:21][CH:22]=[C:23]([C:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH:26]=3)[CH:24]=4)[CH2:12][CH2:11]2)=[N:8][CH:9]=1)[CH2:2][CH3:3].C(O)(C(F)(F)F)=O.C(C1C=NC(N2CCC(OC3SC4C=C(C5CCNCC=5)C=CC=4N=3)CC2)=NC=1)CC>>[CH2:1]([C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[S:18][C:19]4[C:20]([N:38]=3)=[N:21][CH:22]=[C:23]([C:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH:26]=3)[CH:24]=4)[CH2:12][CH2:11]2)=[N:8][CH:9]=1)[CH2:2][CH3:3]
Reactant: CCCc1cnc(N2CCC(Oc3nc4ncc(C5=CCN(C(=O)OC(C)(C)C)CC5)cc4s3)CC2)nc1
Agent: CCCc1cnc(N2CCC(Oc3nc4ccc(C5=CCNCC5)cc4s3)CC2)nc1
Solvent: O=C(O)C(F)(F)F
Product: CCCc1cnc(N2CCC(Oc3nc4ncc(C5=CCNCC5)cc4s3)CC2)nc1

Procedure:
Compound 21F was prepared from Compound 21E and TFA in a similar manner to the procedure described for Compound 1E in Example 1. LC/MS (m/z)=437 (M+H)+.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[OH:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32]N)=[CH:28][CH:27]=1>>[OH:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)=[CH:28][CH:27]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O
Reactant: NNc1ccc(O)cc1
Product: CS(=O)(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccc(O)cc3)n2)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-7) and 4-hydroxy-phenylhydrazine according to the method described for example 43. MS: M=409.1 (M+H)+