Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=[N:13][OH:14])=[C:10]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl[O-].[Na+].[C:22]([O-])(=[O:24])[CH3:23].[Na+].C(=O)C>C(Cl)Cl>[Cl:1][C:2]1[C:11]([C:12]2[O:24][CH:22]([CH3:23])[O:14][N:13]=2)=[C:10]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C=NO)c1Cl
Reactant: CC(=O)[O-]
Agent: CC=O
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(S(C)(=O)=O)c(C2=NOC(C)O2)c1Cl
Temperature: 55 °C
Reaction time: 1 h

Procedure:
8.0 g (27.4 mmol) of methyl 2-chloro-3-(hydroxyiminomethyl)-4-methylsulfonylbenzoate in 150 ml of methylene chloride were admixed dropwise with 16.0 g (27.4 mmol) of a 12.5% strength sodium hypochlorite solution, and a spatula-tip of sodium acetate was added. After 1 hour, 34.4 g (0.74 mol) of acetaldehyde were added a little at a time within a period of 36 hours, and the mixture was slowly heated to 55° C. The mixture was subsequently stirred at room temperature for 48 hours, washed with water, dried and concentrated. The residue was then taken up in methylene chloride, 10.0 g (0.23 mol) of acetaldehyde and a spatula-tip of sodium acetate were added and the mixture was heated under reflux for 8 hours. After 72 hours, a further 10.0 g 5 (0.23 mol) of acetaldehyde were added and the mixture was stirred at room temperature. The mixture was subsequently washed with water, dried and concentrated. The residue was passed through silica gel (eluent: isopropanol:cyclohexane=1:9). This gave 5.0 g (55% of theory) of methyl 2-chloro-3-(2-methyl-2H-1,3,4-dioxazol-5-yl)-4-methylsulfonylbenzoate.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]=[N:14][N:15]2[CH:19]=[N:18][NH:17][C:16]2=[O:20])[CH:8]=1>N1C=CC=CC=1>[CH3:1][N:2]([CH3:6])[C:3]([N:17]1[C:16](=[O:20])[N:15]([N:14]=[CH:13][C:9]2[CH:8]=[N:7][CH:12]=[CH:11][CH:10]=2)[CH:19]=[N:18]1)=[O:4]
Reactant: O=c1[nH]ncn1N=Cc1cccnc1
Reactant: CN(C)C(=O)Cl
Solvent: c1ccncc1
Product: CN(C)C(=O)n1ncn(N=Cc2cccnc2)c1=O
Reaction time: 14 h

Procedure:
3.2 g of dimethylcarbamoyl chloride are added to a suspension of 3.8 g of 4-(pyridin-3-ylmethyleneamino)-1,2,4-triazol-3-one in 50 ml of pyridine. The resulting solution is stirred for 14 hours at 20° and then concentrated by evaporation. Water is added to the residue. The crystals that have precipitated are filtered off with suction and dried under a high vacuum. 3.6 g of crystals of the title compound having a melting point of 181°-182° are obtained.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C@@H:7]2[C@H:11]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][N:9]([C@H:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH3:22])[CH2:8]2)=O)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[Si:14]([O:13][CH2:12][C@@H:11]1[CH2:10][N:9]([C@H:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH3:22])[CH2:8][C@@H:7]1[CH2:5][NH:4][CH:1]1[CH2:2][CH2:3]1)([C:17]([CH3:20])([CH3:18])[CH3:19])([CH3:16])[CH3:15]
Reactant: C[C@@H](c1ccccc1)N1C[C@@H](CO[Si](C)(C)C(C)(C)C)[C@@H](C(=O)NC2CC2)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C[C@@H](c1ccccc1)N1C[C@@H](CO[Si](C)(C)C(C)(C)C)[C@@H](CNC2CC2)C1
Temperature: 25 °C
Yield: 70.7 %

Procedure:
(3R,4S)-N-Cyclopropyl-4-(tert-butyldimethylsilyl)oxymethyl-1-[(1S)-1-phenylethyl]pyrrolidine-3-carboxamide (7.00 g) was dissolved in toluene (70 mL). A borane/dimethyl sulfide complex (2.20 mL) was added and the mixture was refluxed for 5 hours while being stirred. Subsequently, the reaction was allowed to cool to room temperature, followed by addition of a 10% aqueous solution of sodium carbonate (42 mL) and stirring at 100° C. for 1 hour. The toluene layer was separated, washed with water (2×30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: hexane: ethyl acetate=4:1) to give (3S,4S)-4-(tert-butyldimethylsilyl)oxymethyl-3-cyclopropylaminomethyl-1-[(1S)-1-phenylethyl]pyrrolidine as a colorless oil (4.78 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:25].[CH3:26][O:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([CH3:43])[N:29]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:21][C:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:32]5[CH:31]=[C:30]([CH3:43])[N:29]=[C:28]([O:27][CH3:26])[CH:33]=5)[C:3]([CH3:25])=[CH:4][CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1cc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2C)cc(C)n1
Temperature: 80 °C
Yield: 87.4 %

Procedure:
To N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (200 mg, 0.54 mmol), 2-methoxy-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (408 mg, 1.64 mmol) and tetrakis(triphenylphosphine)palladium (0) (64 mg, 0.055 mmol) in 1,2-dimethoxyethane (3.3 mL), 2 M Na2CO3 (818.0 μL, 1.636 mmol) was added. The reaction mixture was stirred and heated at 80° C. for 68 hours under N2 atmosphere. The reaction mixture was diluted with ethyl acetate (5 mL), dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-15% ethyl acetate in hexane) to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(2′-methoxy-3,6′-dimethyl-2,4′-bipyridin-6-yl)cyclopropanecarboxamide (0.214 g, 86.5%). ESI-MS m/z calc. 453.4. found 454.5 (M+1)+. Retention time 1.81 minutes.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:13])[CH3:12])(=[O:3])[CH3:2].[BrH:14].BrBr>C(O)(=O)C>[Br:14][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:13])[CH3:12])=[O:3]
Reactant: Br
Reactant: CC(=O)Nc1ccccc1C(C)=O
Agent: BrBr
Solvent: CC(=O)O
Product: CC(=O)Nc1ccccc1C(=O)CBr
Temperature: 25 °C
Reaction time: 8 h

Procedure:
31 g (0.175 mol) of N-(2-Acetylphenyl)-acetamide (prepared by acylation of 2-aminoacetophenone with acetyl chloride as described by Fuerstner, Alois; Jumbam, Denis N.; Tetrahedron; 48; 29; 5991-6010, (1992)) was dissolved in 200 ml of glacial acetic acid. 127 ml of 33% strength HBr in glacial acetic acid was added and then, at room temperature, 8.75 ml (0.175 mol) of bromine was slowly run in. The mixture was stirred at room temperature overnight. The mixture was stirred into 1.5 l of ice-water, and the precipitated product was filtered off with suction, thoroughly washed with ice-water and dried in vacuo. The crude product contained, according to HPLC and NMR, some precursor and dibrominated product, but was pure enough (about 85% strength) for further reaction.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:63][O:64][C:65](=[O:78])[C:66]1[CH:71]=[CH:70][C:69]([NH2:72])=[C:68]([O:73][CH2:74][CH2:75][CH2:76][CH3:77])[CH:67]=1>>[CH3:63][O:64][C:65](=[O:78])[C:66]1[CH:71]=[CH:70][C:69]([NH:72][C:30]([C@@H:20]2[NH:19][C@@H:18]([CH2:33][C:34]([CH3:37])([CH3:35])[CH3:36])[C@:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[C@H:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[C:68]([O:73][CH2:74][CH2:75][CH2:76][CH3:77])[CH:67]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: CCCCOc1cc(C(=O)OC)ccc1N
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCCCOc1cc(C(=O)OC)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1cccc(Cl)c1F

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.4 g, 0.69 mmol), was reacted with diisopropylethylamine (0.46 g, 3.6 mmol), diphenylphosphinic chloride (0.34 g, 1.4 mmol), then reacted with 4-amino-3-butoxy-benzoic acid methyl ester (0.24 g, 1.1 mmol) prepared in Example 149 to give rac-3-butoxy-4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-benzoic acid methyl ester as a light brown solid (Yield, 0.14 g, 30%).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:19])[CH2:9][NH:10][C:11]2[C:12](=[O:18])[N:13]([CH3:17])[N:14]=[CH:15][CH:16]=2)[CH2:4][CH2:3]1.[F:20][C:21]1[CH:22]=[CH:23][C:24]([CH3:28])=[C:25](O)[CH:26]=1>>[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:28])=[C:23]([CH:22]=1)[O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8](=[O:19])[CH2:9][NH:10][C:11]2[C:12](=[O:18])[N:13]([CH3:17])[N:14]=[CH:15][CH:16]=2)[CH2:6][CH2:7]1
Reactant: Cc1ccc(F)cc1O
Reactant: Cn1nccc(NCC(=O)N2CCC(O)CC2)c1=O
Product: Cc1ccc(F)cc1OC1CCN(C(=O)CNc2ccnn(C)c2=O)CC1
Yield: 15 %

Procedure:
Compound 14 is prepared from intermediate 5b and from 5-fluoro-2-methyl-phenol following synthesis method 3 (yield: 15%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[NH:16][CH2:17][C:18]([F:21])([F:20])[F:19].[CH3:22][S:23]([C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[C:29](Cl)=[O:30])(=[O:25])=[O:24]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[N:16]([CH2:17][C:18]([F:19])([F:21])[F:20])[C:29](=[O:30])[C:28]1[CH:32]=[C:33]([C:35]([F:38])([F:36])[F:37])[CH:34]=[C:26]([S:23]([CH3:22])(=[O:25])=[O:24])[CH:27]=1
Reactant: CS(=O)(=O)c1cc(C(=O)Cl)cc(C(F)(F)F)c1
Reactant: COc1cccc(F)c1-c1ccncc1NCC(F)(F)F
Product: COc1cccc(F)c1-c1ccncc1N(CC(F)(F)F)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1

Procedure:
The title compound was prepared in analogy to example 72, intermediate, from [4-(2-fluoro-6-methoxy-phenyl)-pyridin-3-yl]-(2,2,2-trifluoro-ethyl)-amine and 3-methanesulfonyl-5-trifluoromethyl-benzoyl chloride after a reaction time of 12 hours. The compound was purified by preparative HPLC (ammonium acetate/acetonitril e). Off-white solid (27%). MS (ESI): m/z=551.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[C:23]([F:31])[CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:19][C:4]2[CH:5]=[N:6][C:7]([O:8][C:9]3[CH:10]=[N:11][C:12]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][CH:13]=4)=[C:2]([Cl:1])[CH:3]=2)(=[O:28])=[O:29])=[C:23]([F:31])[CH:22]=1
Reactant: Nc1cnc(Oc2cnc3ccccc3c2)c(Cl)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1F
Product: O=S(=O)(Nc1cnc(Oc2cnc3ccccc3c2)c(Cl)c1)c1ccc(Cl)cc1F

Procedure:
The title compound was prepared by reacting 5-chloro-6-(quinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 1) and 4-chloro-2-fluorobenzene-1-sulfonyl chloride.
Reaction SMILES: [CH:1]1([C:7]2[N:12]=[C:11]([C:13]([OH:15])=O)[CH:10]=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:16]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[N:16]1([NH:22][C:13]([C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[N:12]=2)=[O:15])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C(O)c1cccc(C2CCCCC2)n1
Reactant: NN1CCCCC1
Product: O=C(NN1CCCCC1)c1cccc(C2CCCCC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclohexyl-pyridine-2-carboxylic acid (Example 7 b) and 1-piperidinamine (CAN 2213-43-6) as starting materials, MS (EI): 288.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.N.[CH3:17]O>>[CH3:17][O:9][C:8]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=1)=[O:10]
Reactant: O=C(O)c1cccc(Br)n1
Reactant: CO
Agent: N
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(Br)n1
Temperature: 0 °C

Procedure:
6-Bromopyridine-2-carboxylic acid (6.000 g) was heated in refluxing methanol (180 mL) containing conc. sulphuric acid (2 mL) for 4 hrs. The reaction mixture was then cooled to ˜0° C. and conc. ammonia (4.8 mL) was added. The resulting solution was evaporated to give a white residue. This white solid was partitioned between brine and dichloromethane (100/100 mL). After thorough shaking the organic layer was dried (magnesium sulphate) and evaporated to give a white solid.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH:7]2[CH2:10][N:9]([CH2:11][CH2:12][CH2:13][NH2:14])[CH2:8]2)=[CH:4][CH:3]=1.[N:17]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=1)=[C:18]=[O:19]>O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]2[CH2:10][N:9]([CH2:11][CH2:12][CH2:13][NH:14][C:18]([NH:17][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=3)=[O:19])[CH2:8]2)=[CH:15][CH:16]=1
Reactant: COc1cccc(N=C=O)c1
Reactant: NCCCN1CC(Oc2ccc(F)cc2)C1
Solvent: C1COCCO1
Product: COc1cccc(NC(=O)NCCCN2CC(Oc3ccc(F)cc3)C2)c1

Procedure:
A solution of 3-[3-(4-fluoro-phenoxy)-azetidin-1-yl]-propylamine (0.07 g, 0.31 mmol) and 1-isocyanato-3-methoxy-benzene (0.041 g, 0.31 mmol) in dioxane (15 ml) is heated to 100° C. for 3 hours. The reaction mixture is evaporated and the crude product purified by flash silica chromatography (elution with a 1:9 methanol/dichloromethane) to afford 1-{3-[3-(4-fluoro-phenoxy)-azetidin-1-yl]-propyl}-3-(3methoxy-phenyl)-urea. [MH]+ 374.0.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][C:2]1=[CH2:3].[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][OH:16])=[CH:13][CH:12]=1>CCCCCC>[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][O:16][C:5]([CH2:4][C:2]([C:1]([OH:8])=[O:7])=[CH2:3])=[O:6])=[CH:13][CH:12]=1
Reactant: C=C1CC(=O)OC1=O
Reactant: COc1ccc(CO)cc1
Solvent: CCCCCC
Product: C=C(CC(=O)OCc1ccc(OC)cc1)C(=O)O
Temperature: 25 °C
Yield: 60.5 %

Procedure:
A 250 ml one-necked round bottomed flask equipped with reflux condenser, nitrogen inlet, and magnetic stir bar was charged with itaconic anhydride (33.6 g, 0.3 mol) toluene (100 ml) and 4-methoxybenzyl alcohol (41.5 g, 0.3 mol). The solution was then warmed to reflux for 60 minutes and then cooled to room temperature. The solution was poured into a 500 ml Erlenmeyer flask, diluted with 100 ml of hexane and allowed to stand whereupon crystals of pure monoester formed. The product was isolated by filtration on a Buchner funnel and air dried to give 45.4 g, 61% of material with mp 83°-85° C., a second crop, 12.9 g, 17% was isolated after cooling of the filtrate in an ice bath.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[C:28]1([C:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[NH:36][C:35]=2[C:43](O)=[S:44])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl.[CH3:47][NH:48][O:49][CH3:50].C(N(CC)CC)C>CN(C)C=O>[CH3:50][O:49][N:48]([CH3:47])[C:43]([C:35]1[NH:36][C:37]2[C:42]([C:34]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[CH:41][CH:40]=[CH:39][CH:38]=2)=[S:44]
Reactant: OC(=S)c1[nH]c2ccccc2c1-c1ccccc1
Reactant: CNOC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CON(C)C(=S)c1[nH]c2ccccc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.64 g, 3.7 mmol) was added to a solution of 3-phenylthioindole-2-carboxylic acid (1.0 g, 3.7 mmol), N,O-dimethylhydroxylamine hydrochloride (0.54 g, 5.5 mmol) and triethylamine (1.5 mL, 11 mmol) in degassed dimethylformamide. The reaction was stirred at room temperature overnight. The precipitated product was filtered and the filter cake washed well with water. The solid was triturated with 30% ethyl acetate in hexane, filtered and dried at 60° C. in vacuo for 72 hours.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1([CH2:13][NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:12][O:11][CH2:10]1)C1C=CC=CC=1>CO.FC(F)(F)C(O)=O.[OH-].[OH-].[Pd+2]>[NH2:8][C:9]1([CH2:13][NH:14][C:15](=[O:20])[C:16]([F:17])([F:18])[F:19])[CH2:12][O:11][CH2:10]1
Reactant: O=C(NCC1(N(Cc2ccccc2)Cc2ccccc2)COC1)C(F)(F)F
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: NC1(CNC(=O)C(F)(F)F)COC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-{[3-(dibenzylamino)oxetan-3-yl]methyl}-2,2,2-trifluoroacetamide (4.0 g, 10.57 mmol) in methanol (80 mL) was added 20% palladium hydroxide on carbon (0.8 g) and trifluoroacetic acid (one drop). The mixture was stirred at room temperature under hydrogen overnight and then filtered. The filtrate was concentrated in vacuo to afford the crude product as a white solid.
Reaction SMILES: [CH:1]([C:3]1[C:4]([F:16])=[CH:5][N:6]=[C:7]2[C:12]=1[N:11]=[C:10]([O:13][CH3:14])[CH:9]=[C:8]2F)=[CH2:2].[NH:17]1[CH2:21][CH2:20][C@H:19]([CH2:22][NH:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]3[O:29][CH2:30][C:31](=[O:35])N[C:33]=3[N:34]=2)[CH2:18]1>>[O:35]1[C:27]2[CH:26]=[C:25]([CH2:24][NH:23][CH2:22][C@@H:19]3[CH2:20][CH2:21][N:17]([CH2:2][CH2:1][C:3]4[C:12]5[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[N:11]=5)[N:6]=[CH:5][C:4]=4[F:16])[CH2:18]3)[N:34]=[CH:33][C:28]=2[O:29][CH2:30][CH2:31]1
Reactant: O=C1COc2ccc(CNC[C@H]3CCNC3)nc2N1
Reactant: C=Cc1c(F)cnc2c(F)cc(OC)nc12
Product: COc1ccc2ncc(F)c(CCN3CC[C@@H](CNCc4cc5c(cn4)OCCO5)C3)c2n1

Procedure:
Prepared essentially according to the procedure for Example 22, except substituting 8-ethenyl-7-fluoro-2-(methyloxy)-1,5-naphthyridine (143 mg, 0.70 mmole) for 8-ethenyl-4,7-difluoro-2-(methyloxy)-1,5-naphthyridine, and substituting 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (115 mg, 0.70 mmole) for 6-({[(3S)-3-pyrrolidinylmethyl]amino}methyl)-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one, the title compound was prepared as an orange hygroscopic solid: LC/MS (ES) m/e 454 (M+H)+; 1H NMR (DMSO, 400 MHz) δ 9.8 (bs, 1H), 8.85 (s, 1H), 8.4 (d, J=5.6 Hz, 1H), 8.33 (d, J=9.1 Hz, 1H), 7.51 (d, J=11.6 Hz, 1H), 7.29 (d, J=9.1 Hz, 1H), 4.5 (m, 3H), 4.25 (s, 2H), 4.1 (s, 3H), 3.8 (m, 1H), 3.7 (m, 2H), 3.6 (m, 2H), 3.5 (m, 2H), 3.25 (m, 2H), 3.1 (s, 2H), 2.85 (m, 2H), 2.25 (m, 1H), 1.8 (m, 1H), 1.3 (s, 1H), 0.8 (m, 1H).
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[CH:15]([NH:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])([CH3:17])[CH3:16]>ClCCl>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][N:18]([CH:15]([CH3:17])[CH3:16])[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1)[CH3:24]
Reactant: CCOC(=O)CNC(C)C
Reactant: COC(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Solvent: ClCCl
Product: CCOC(=O)CN(c1ncc(C(=O)OC)cc1[N+](=O)[O-])C(C)C
Temperature: 25 °C
Yield: 79.6 %

Procedure:
Methyl 6-chloro-5-nitronicotinate (2 g, 9.23 mmol) was added to ethyl 2-(isopropylamino)acetate (5.0 g, 34.5 mmol) neat while stirring at room temperature. The viscous yellow reaction was heated to 90° C. for one h and then allowed to cool back to room temperature. The reaction was diluted with dichloromethane (20 mL) and purified via column chromatography (220 g SiO2, 20-30% gradient, ethyl acetate in hexanes) to yield the title compound (2.39 g, 83%) as a yellow oil. [M+H] calc'd for C14H19N3O6, 326. found, 326.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[O:11].[Br:12]Br>C(O)(=O)C>[Br:12][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[NH:1][C:2](=[O:11])[CH2:3][CH2:4]2
Reactant: BrBr
Reactant: O=C1CCc2ccccc2N1
Solvent: CC(=O)O
Product: O=C1CCc2cccc(Br)c2N1

Procedure:
An example for a compound in accordance with Formula 2 is 4-iso-propylaniline that serves as the starting material for the presently preferred compounds of the invention. The aniline derivative of Formula 2 is reacted with an acryloyl chloride derivative of Formula 2A in a basic solvent, such as pyridine, to provide the phenyl amide derivative of the acryloic acid of Formula 3. An example of the acryloyl chloride derivative of Formula 2A that is used for the synthesis of the presently preferred compounds of the invention is commercially available 3,3-dimethylacryloyl chloride. The acryloic acid amide derivative of Formula 3 is cyclized under Friedel Crafts conditions to provide the 1,2,3,4-tetrahydro-quinolin-2-one derivative of Formula 4. The 1,2,3,4-tetrahydro-quinolin-2-one derivative of Formula 4 is reacted with bromine in acetic acid to provide the 8-bromo-1,2,3,4-tetrahydro-quinoline-2-one derivative of Formula 5. The numbering of the quinoline ring system and of the heptatrienoic acid moiety that is attached to it in the 8 position of the quinoline nucleus in the compounds of the invention, is shown in Formula 1. The endocyclic oxo function of the 8-bromo-1,2,3,4-tetrahydro-quinoline-2-one derivative of Formula 5 is reduced by treatment with borane-methyl sulfide to give the 8-bromo-1,2,3,4-tetrahydro-quinoline derivative of Formula 6. An alkyl group, designated R3, where R3 is defined as in connection with Formula 1, is introduced to the nitrogen of the quinoline nucleus by treatment of the compound of Formula 6 with an alkylating agent, such as R3-I, in the presence of base, to give the 1-alkyl-8-bromo1,2,3,4-tetrahydro-quinoline compound of Formula 7. The 1-alkyl-8-bromo1,2,3,4-tetrahydro-quinoline compound of Formula 7 is reacted with dimethylformamide (DMF) in the presence of strong base, such as n-butyl lithium to give a 1-alkyl-1,2,3,4-tetrahydro-quinoline-8-carbaldehyde of Formula 8. The carbaldehyde of Formula 8 is reacted with a Grignard reagent of the formula R5MgBr, where R5 is defined as in connection with Formula 1, to provide a (1-alkyl-1,2,3,4-tetrahydro-quinoline-8-yl)-alkan-1-ol of Formula 9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:34]=[CH:33][C:6]2[CH2:7][N:8]([C:14]3[CH:23]=[C:22]([NH:24]C(=O)OC(C)(C)C)[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([CH3:32])[CH:20]=4)[N:15]=3)[CH2:9][CH2:10][S:11](=[O:13])(=[O:12])[C:5]=2[CH:4]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:34]=[CH:33][C:6]2[CH2:7][N:8]([C:14]3[CH:23]=[C:22]([NH2:24])[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([CH3:32])[CH:20]=4)[N:15]=3)[CH2:9][CH2:10][S:11](=[O:13])(=[O:12])[C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)S(=O)(=O)CCN(c1cc(NC(=O)OC(C)(C)C)c3cc(C)ccc3n1)C2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)S(=O)(=O)CCN(c1cc(N)c3cc(C)ccc3n1)C2
Yield: 22.2 %

Procedure:
A mixture solution of tert-butyl [2-(8-methoxy-1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]carbamate (59.0 mg, 0.12 mmol) and trifluoroacetic acid (0.5 mL) in dichloromethane (2.0 mL) was stirred at room temperature for 6 hours. Then the reaction mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. The residue was purified by preparative HPLC to afford 10.2 mg of the product as a white solid (yield was 21.5%). MS obsd. (ESI+) [(M+H)+] 384, 1H NMR (400 MHz, CD3OD) δ ppm 7.72 (d, J=8.34 Hz, 1 H), 7.58 (s, 1 H), 7.50 (d, J=2.78 Hz, 1 H), 7.43 (d, J=8.34 Hz, 1 H), 7.29 (dd, J=8.46, 1.89 Hz, 1 H), 7.12 (dd, J=8.34, 2.78 Hz, 1 H), 6.27 (s, 1 H), 5.02 (s, 2 H), 4.47 (brs, 2 H), 3.82 (s, 3 H), 3.56 (t, J=4.80 Hz, 2 H), 2.42 (s, 3 H).