Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][N:6]=1)=[O:4].[F:12][C:13]1[CH:14]=[C:15]([C:19]#[CH:20])[CH:16]=[CH:17][CH:18]=1.C(N(CC)CC)C>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:20]#[C:19][C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([F:12])[CH:14]=2)=[CH:7][N:6]=1)=[O:4]
Reactant: C#Cc1cccc(F)c1
Reactant: COC(=O)c1ccc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C#Cc2cccc(F)c2)cn1
Temperature: 80 °C
Reaction time: 20 h
Yield: 65.9 %

Procedure:
Bis-(triphenylphosphine)-palladium(II)dichloride (406 mg, 580 μmol, 0.05 equiv.) was dissolved in 25 ml DMF. (2.5 g, 11.6 mmol) 5-Bromo-pyridine-2-carboxylic acid methyl ester and 3-fluorophenylacetylene (2.22 g, 18.5 mmol, 1.6 equiv.) were added at room temperature. Triethylamine (3.5 g, 4.84 ml, 34.7 mmol, 3 equiv.), triphenylphosphine (91 mg, 347 μmol equiv.) and copper(I)iodide (66 mg, 347 μmol, 0.03 equiv.) were added and the mixture was stirred for 20 hours at 80° C. The reaction mixture was cooled and evaporated to dryness with Isolute® sorbent. The crude product was purified by flash chromatography on silica gel (70 g) eluting with an ethyl acetate:heptane gradient 0:100 to 80:20. The desired 5-(3-fluoro-phenylethynyl)-pyridine-2-carboxylic acid methyl ester (1.95 g, 66% yield) was obtained as a light yellow solid, MS: m/e=256.3 (M+H+).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:20]([C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1)[CH3:21]>>[CH2:20]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:24][CH:23]=1)[CH3:21]
Reactant: CCc1ccc(C=O)cc1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: CCc1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-ethylbenzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(4-ethylphenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [F:1][S:2]([C:5]([F:10])([F:9])[C:6](F)=[O:7])(=[O:4])=[O:3].[CH:11]([C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1)=[CH2:12].N1C=CC=CC=1.Cl>C(Cl)Cl>[F:9][C:5]([F:10])([S:2]([F:1])(=[O:4])=[O:3])[C:6](=[O:7])[NH:17][C:16]1[CH:18]=[CH:19][C:13]([CH:11]=[CH2:12])=[CH:14][CH:15]=1
Reactant: C=Cc1ccc(N)cc1
Reactant: O=C(F)C(F)(F)S(=O)(=O)F
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=Cc1ccc(NC(=O)C(F)(F)S(=O)(=O)F)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 96.4 %

Procedure:
A 100 ml flask was charged with CH2Cl2 (24 ml) under nitrogen stream and stirred for 10 min at 0° C. and then 2-(fluorosulfonyl)difluoroacetyl fluoride (6.60 g, 37.6 mmol, 1.5 eq.) was added. After 20 minutes, the CH2Cl2 (12 ml) solution of 4-vinyl aniline (2.86 g, 24.4 mmol, 1.0 eq.) and pyridine (1.93 g, 24.4 mmol, 1.0 eq.) was added dropwise to the mixture over 10 minutes. The mixture was allowed to warm to RT and was stirred for 4 hours at RT. 1N HCl was added to the final reaction mixture and the lower layer was separated and washed with 1N HCl and brine. The solution was dried over MgSO4, filtrated and then CH2Cl2 was removed by an evaporator. The target compound was obtained as a white solid (6.57 g) in 96% yield. 1H NMR (400 MHz, CDCl3); delta=5.28 (d, J=10.9 Hz, 1H), 5.74 (d, J=17.6 Hz, 1H), 6.68 (dd, J=10.9, 17.6 Hz, 1H), 7.43 (d, J=8.6 Hz, 2H), 7.53 (d, J=8.7 Hz, 2H), 8.04 (brs, 1H). 19F-NMR (376 MHz, CDCl3, C6F6 as standard) delta=41.27 (t, J=4.6 Hz, 1F), −105.26 (d, J=4.2 Hz, 2F).
Reaction SMILES: F[C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([C:9]3[C:10]([NH2:26])=[N:11][CH:12]=[C:13]([C:15]4[CH:16]=[N:17][N:18]([CH:20]5[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH:19]=4)[CH:14]=3)[S:8][C:4]=2[CH:3]=1.ClC1SC2[C:38]([O:39]C)=CC=CC=2N=1>>[CH3:38][O:39][C:3]1[C:4]2[S:8][C:7]([C:9]3[C:10]([NH2:26])=[N:11][CH:12]=[C:13]([C:15]4[CH:16]=[N:17][N:18]([CH:20]5[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH:19]=4)[CH:14]=3)=[N:6][C:5]=2[CH:27]=[CH:28][CH:2]=1
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2ccc(F)cc2s1
Reactant: COc1cccc2nc(Cl)sc12
Product: COc1cccc2nc(-c3cc(-c4cnn(C5CCNCC5)c4)cnc3N)sc12

Procedure:
Same procedure as 3-(6-fluorobenzothiazol-2-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine except using 2-chloro-7-methoxy-1,3-benzothiazole in place of 2-chloro-6-fluorobenzothiazole to afford the title compound as a yellow solid. 1H NMR (400 MHz, CD3OD): δ=8.80 (d, J=2.0 Hz, 1H), 8.38 (s, 1H), 8.35 (d, J=2.0 Hz, 1H), 8.07 (s, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.59 (m, 1H), 7.13 (d, J=7.6 Hz, 1H), 4.66 (m, 1H), 4.06 (s, 3H), 3.59-3.62 (m, 2H), 2.33-2.39 (m, 4H). MS(ES+): m/z=407.13 [MH+]. HPLC: tR=1.78 min (polar—5 min, ZQ3).
Reaction SMILES: Cl[CH:2]([CH2:6][CH:7]([Cl:10])[CH2:8][CH3:9])[C:3](=[O:5])[CH3:4].[SH:11][CH2:12][CH2:13]O.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:10][CH:7]([CH2:8][CH3:9])[CH2:6][C:2]1[S:11][CH2:12][CH2:13][O:5][C:3]=1[CH3:4]
Reactant: OCCS
Reactant: CCC(Cl)CC(Cl)C(C)=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCC(Cl)CC1=C(C)OCCS1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 26 g (0.14 mole) of 3,5-dichloro-2-heptanone, 12 g (0.15 mole) of 2-mercaptoethanol, and 15 g (0.15 mole) of triethylamine in 200 ml toluene, was stirred at ambient temperature overnight. The mixture was then washed with dilute hydrochloric acid and subsequently refluxed with 0.1 g. p-toluenesulfonic acid with azeotropic removal of water for six hours. Upon cooling, it was washed with aqueous sodium bicarbonate, dried (magnesium sulfate), and the solvent was removed to leave the product.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=O.O.[NH2:18][NH2:19]>C(O)COCCO>[NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4](=[N:18][NH2:19])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12]
Reactant: Nc1ccccc1C(=O)c1ccccc1Cl
Reactant: NN
Solvent: OCCOCCO
Solvent: O
Product: NN=C(c1ccccc1N)c1ccccc1Cl

Procedure:
In the manner given in Preparation 1, 2-amino-2'-chlorobenzophenone is refluxed with hydrazine hydrate in diethylene glycol to give 2-amino-2'-chlorobenzophenone hydrazone.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH:4]([CH:7]=[CH:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:3][CH2:2]1>C(O)C.[C].[Pd]>[S:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:3][CH2:2]1
Reactant: CCOC(=O)C=CC1CCSCC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCC1CCSCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 90.1 %

Procedure:
A solution of ethyl 3-(4-thianyl)acrylate (10 g) in ethanol (150 ml) is hydrogenated over 10% palladium-carbon (9 g, 50% wet) under atmospheric pressure. After the mixture is stirred for 20 minutes at room temperature and then for 8 hours at 50° C., the catalyst is removed by filtration. To the filtrate 10% palladium carbon (9 g, 50% wet) is added and the mixture is hydrogenated at 50° C. for 1 day. After the catalyst is removed by filtration, the filtrate is evaporated in vacuo to give ethyl 3-(4-thianyl)propionate (9.1 g) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:12][CH:11]2[C:13](=O)[CH:7]([CH2:8][CH2:9][CH2:10]2)[CH2:6]1)=[O:4].C([O-])(=O)C.[NH4+].[BH3-]C#[N:22].[Na+]>CO>[CH3:1][O:2][C:3]([CH:5]1[CH2:12][CH:11]2[CH:13]([NH2:22])[CH:7]([CH2:8][CH2:9][CH2:10]2)[CH2:6]1)=[O:4]
Reactant: [BH3-]C#N
Reactant: COC(=O)C1CC2CCCC(C1)C2=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1CC2CCCC(C1)C2N

Procedure:
The product of Example 7A (2.03 g, 10.38 mmol) was stirred at room temperature in the presence of ammonium acetate (8 g, 103.8 mmol) and NaBH3CN (3.3 g, 51.9 mmol) in methanol (30 mL) for twelve hours at 23° C. The solvent was then evaporated and the residue was dissolved in dichloromethane; washed with water, NaHCO3 solution, and brine; and dried (Na2SO4). After filtration and evaporation of the solvent, the amine was used without further purification.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].ClC1C=CC=C(C(OO)=[O:26])C=1>ClCCl>[O:26]1[CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:1]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCCCCCCCCCCCCCCC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.2 %

Procedure:
In 100 ml of dichloromethane was dissolved 26.2 g (0.11 mole) of 1-heptadecene, and a solution of 24.5 g of m-chloroperbenzoic acid in 250 ml of dichloromethane was added dropwise to the solution. The mixture was stirred at room temperature overnight. The resulting crystalline precipitate was filtered off and the filtrate was washed with water, aqueous sodium sulfite, aqueous sodium hydrogen carbonate and aqueous sodium chloride, dried and concentrated. The residue was purified by silica gel column chromatography [eluent: hexane-ethyl acetate (30:1)] to give 16 g of the desired compound as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:17][C:16]([C:22]3[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=3)([C:18]([F:21])([F:20])[F:19])[O:15][N:14]=2)=[CH:9][C:8]=1[CH3:30])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:49])C=CC=CC=1>O1CCCC1>[C:1]([O:5][C:6](=[O:31])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:17]([OH:49])[C:16]([C:22]3[CH:23]=[C:24]([Cl:29])[CH:25]=[C:26]([Cl:28])[CH:27]=3)([C:18]([F:20])([F:19])[F:21])[O:15][N:14]=2)=[CH:9][C:8]=1[CH3:30])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)OC(C)(C)C
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2O)ccc1C(=O)OC(C)(C)C
Reaction time: 3 h

Procedure:
To a solution of 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid tert-butyl ester (preparation of similar compounds described in, for example, EP 1,731,512) (2.83 g) in tetrahydrofuran (25 ml) that was stirred at −78° C. for 5 minutes under argon, was slowly added lithium bis(trimethyl-silyl)amide (“LiHMDS”) (1M in hexane) (6.9 ml). After 3 hours at −78° C., a cold (−20° C.) solution of 2-benzenesulfonyl-3-phenyl-oxaziridine (commercially available) (2.34 g) in tetrahydrofuran (10 ml) was added quickly. The temperature was kept below −65° C. for 4 hours and 30 minutes. The reaction was quenched by addition of aqueous ammonium chloride (saturated) at −78° C. tent-Butyl methyl ether (“TBME”) was added and the phases were separated. The organic layer was washed successively with ammonium chloride and brine, dried over magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: heptane/TBME 9:1) to give 4-[5-(3,5-dichloro-phenyl)-4-hydroxy-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid tert-butyl ester (738 mg) as a white solid.
Reaction SMILES: [NH2:1][C@@H:2]1[C:26](=[O:27])[N:4]2[C:5]([C:23]([OH:25])=[O:24])=[C:6]([C:9]([CH2:19][PH:20]([OH:22])=[O:21])([S:13][C:14]3[NH:18][N:17]=[N:16][N:15]=3)[O:10][CH2:11][CH3:12])[CH2:7][S:8][C@H:3]12.[C:28](OC(=N)N(C(C)C)C(C)C)([CH3:31])([CH3:30])[CH3:29]>C(Cl)Cl>[C:6]([O:24][C:23]([C:5]1[N:4]2[C:26](=[O:27])[C@@H:2]([NH2:1])[C@H:3]2[S:8][CH2:7][C:6]=1[C:9]([CH2:19][PH:20]([O:22][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:21])([S:13][C:14]1[NH:18][N:17]=[N:16][N:15]=1)[O:10][CH2:11][CH3:12])=[O:25])([CH3:9])([CH3:7])[CH3:5]
Reactant: CCOC(C[PH](=O)O)(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CC(C)N(C(=N)OC(C)(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(C[PH](=O)OC(C)(C)C)(Sc1nnn[nH]1)C1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](N)[C@H]2SC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a suspension of 21.8 g (0.05 mol) of 7β-amino-3-(1-ethoxyhydroxyphosphinylmethyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid in 500 ml of methylene chloride is added over a 30 minute interval a solution of 60.0 g (0.30 mol) of O-t-butyldiisopropylpseudourea in 100 ml of methylene chloride. The mixture is stirred at ambient temperature for 72 hours. The precipitate is removed by filtration and the filtrate is evaporated to a residue which is taken up in 200 ml of benzene and filtered again. The filtrate is extracted with three 100 ml portions of cold 1 N hydrochloric acid. The aqueous extracts are layered with ethyl acetate and the pH is adjusted to 7.5 by addition of solid sodium bicarbonate. The organic layer is separated and the aqueous phase is extracted with two 150 ml portions of ethyl acetate. The combined extracts are dried (MgSO4), filtered and evaporated to dryness to give 7β-amino-3-(1-ethoxy-t-butoxyphosphinylmethyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid t-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[C:6]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.CC#N.[OH2:25]>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[N:4][C:5]([OH:25])=[C:6]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1
Reactant: O
Reactant: Clc1ccc(-c2c(Cl)nnc(Cl)c2-c2ccncc2)cc1
Solvent: ClCCl
Solvent: CC#N
Product: Oc1nnc(Cl)c(-c2ccc(Cl)cc2)c1-c1ccncc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 48 %

Procedure:
To a round bottom flask was added 3,6-dichloro-4-(4-chlorophenyl)-5-(pyridin-4-yl)pyridazine (1.5 gm, 4.464 mmol), CH3CN (5 ml), water (1 ml) and LiOH monohydrate (0.938 gm, 22.32 mmol). The reaction was heated to 80° C. and stirred at this temperature for 4 hrs. After this time, the reaction was colled to rt and concentrated under reduced pressure. The residue was diluted with water (30 ml). The pH of the aqueous solution was adjusted to 7 with 1N HCl. The resulting solution was poured into a separatory funnel and extract with EtOAc (4×20 ml). The combined organic layers were washed with saturated aqueous NaCl (30 ml). The organic layer was then slurried with MgSO4 to remove excess water, filtered and concentrated to give a white solid residue. The residue was stirred in CH2Cl2 (10 ml) for 15 min. The solution was then filter and the solid was collected to give product 6-chloro-5-(4-chlorophenyl)-4-(pyridin-4-yl)pyridazin-3-ol as white solid (0.70 gm, 48% yield). HPLC retention time (method A) 1.332 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][C:14](=[O:18])[NH:15]2)=[CH:11][CH:10]=1.[CH3:19][N:20]([CH3:35])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=O)[NH:28][C:27]=1[CH3:34])=[O:25]>>[CH3:19][N:20]([CH3:35])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=[C:13]2[C:12]3[C:16](=[CH:17][C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[CH:10][CH:11]=3)[NH:15][C:14]2=[O:18])[NH:28][C:27]=1[CH3:34])=[O:25]
Reactant: COc1ccccc1-c1ccc2c(c1)NC(=O)C2
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN(C)C
Product: COc1ccccc1-c1ccc2c(c1)NC(=O)C2=Cc1[nH]c(C)c(C(=O)NCCN(C)C)c1C
Yield: 103.5 %

Procedure:
6-(2-Methoxyphenyl)-1,3-dihydroindol-2-one (30 mg, 0.13 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-dimethylaminoethyl)amide (30 mg) to give 0.06 g (100%) of the title compound as a yellow-orange gum.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][C:7]([CH3:18])([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.Cl[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]Cl.Cl>C1(C)C(C)=CC=CC=1>[N:1]1([C:2]2[CH:3]=[CH:4][C:5]([CH2:6][C:7]([CH3:18])([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:19][CH:20]=2)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1
Reactant: ClCCNCCCl
Reactant: CCOC(=O)C(C)(Cc1ccc(N)cc1)C(=O)OCC
Agent: Cl
Solvent: Cc1ccccc1C
Product: CCOC(=O)C(C)(Cc1ccc(N2CCNCC2)cc1)C(=O)OCC
Yield: 76.3 %

Procedure:
A solution of diethyl 2-(4-aminobenzyl)-2-methylmalonate (2.00 g, 7.17 mmol) and Bis-(2-chloroethyl) amine.HCl (1.90 g, 10.8 mmol) in xylene (10 ml) were heated at reflux for 48 h. The reaction mixture was concentrated and the residue was partitioned between saturated sodium bicarbonate solution and ethyl acetate. The separated organic layer was washed with water, brine solution, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product. Purification by column chromatography over neutral alumina using 5% methanol in CHCl3 as eluent afforded 1.90 g (76.3%) of diethyl 2-(4-(piperazin-1-yl)benzyl)-2-methylmalonate as brown oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][C:21]=3[F:27])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:28][CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]2[C:42](=[O:43])[C:41]([C:44](O)=[O:45])=[CH:40][N:39]([CH2:47][CH3:48])[C:38]2=[O:49])=[CH:33][CH:32]=1>>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:44]([C:41]4[C:42](=[O:43])[N:37]([C:34]5[CH:35]=[CH:36][C:31]([F:30])=[CH:32][CH:33]=5)[C:38](=[O:49])[N:39]([CH2:47][CH3:48])[CH:40]=4)=[O:45])=[CH:22][C:21]=3[F:27])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:28][CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(Oc3ccc(N)cc3F)ccnc2cc1OCc1ccccc1
Reactant: CCn1cc(C(=O)O)c(=O)n(-c2ccc(F)cc2)c1=O
Product: CCn1cc(C(=O)Nc2ccc(Oc3ccnc4cc(OCc5ccccc5)c(OC)cc34)c(F)c2)c(=O)n(-c2ccc(F)cc2)c1=O

Procedure:
1-Ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid [4-(7-benzyloxy-6-methoxyquinolin-4-yloxy)-3-fluorophenyl]-amide was synthesized using 4-(7-benzyloxy-6-methoxyquinolin-4-yloxy)-3-fluorophenylamine and 3-(4-fluorophenyl)-1-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid by the method for example 1. mp=142-4° C.; LCMS m/z=651 (M+1); 1H NMR (DMSO) δ: 11.0 (s, 1H), 8.89 (s, 1H), 8.47 (d, 1H, J=5.3 Hz), 7.98, 8.02 (dd, 1H, J=2.3, 13 Hz), 7.50-7.54 (m, 5H), 7.41-7.46 (m, 5H), 7.33-7.38 (m, 3H), 6.48 (d, 1H, J=5 Hz), 5.31 (s, 2H), 4.90 (q, 2H, J=7 Hz), 3.95 (s, 3H), 1.29 (t, 3H, J=7 Hz).
Reaction SMILES: [C:1]1([CH:7]2[S:11][CH:10]([CH2:12]O)[CH2:9][S:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OCC1CSC[S:17]1>>[C:1]1([CH:7]2[S:11][CH:10]([CH2:12][SH:17])[CH2:9][S:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCC1CSC(c2ccccc2)S1
Reactant: OCC1CSCS1
Product: SCC1CSC(c2ccccc2)S1

Procedure:
The same method was followed as in Example 1 except that 2-phenyl-4-hydroxymethyl-1,3-dithiolane produced in Example 2 was used in stead of 4-hydroxymethyl-1,3-dithiolane synthesized in Manufacturing Example 1 to obtain 2-phenyl-4-mercaptomethyl-1,3-dithiolane represented by the following formula (2-6).
Reaction SMILES: COC(=O)[NH:4][C:5]1[S:6][C:7]2[C:13]([NH2:14])=[CH:12][CH:11]=[C:10]([O:15][CH3:16])[C:8]=2[N:9]=1.[OH-].[Na+]>O1CCOCC1.C(O)CO>[CH3:16][O:15][C:10]1[C:8]2[N:9]=[C:5]([NH2:4])[S:6][C:7]=2[C:13]([NH2:14])=[CH:12][CH:11]=1
Reactant: COC(=O)Nc1nc2c(OC)ccc(N)c2s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: OCCO
Product: COc1ccc(N)c2sc(N)nc12
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 82.7 %

Procedure:
To a suspension of 4.28 g (16.9 mmol) (7-amino-4-methoxy-benzothiazol-2-yl)-carbamic acid methyl ester in 100 ml dioxane and 50 ml ethylene glycol was added 100 ml 5 N NaOH and the mixture was heated at 100° C. for 16 h. After cooling to room temperature, the reaction mixture was concentrated in vacuo and the residue diluted with 300 ml tetrahydrofuran and stirred for 10 minutes. The mixture was filtered and the filtrate concentrated in vactio. The residue was triturated in ether to afford 2.73 g (83%) 4-methoxy-benzothiazole-2,7-diamine as a brown solid. ES-MS m/e (%): 196 (M+H+, 100). b) 4-Methoxy-N7,N7-dimethyl-benzothiazole-2,7-diamine
Reaction SMILES: C(OC([N:8]1[C:12]2[CH2:13][C@H:14]([C:30](=[O:48])[NH:31][CH2:32][CH2:33][C:34]3[N:35]([CH2:39][C:40]4[CH:45]=[CH:44][C:43]([C:46]#[N:47])=[CH:42][CH:41]=4)[CH:36]=[N:37][CH:38]=3)[CH:15](C(OC(C)(C)C)=O)[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]=2[N:10]=[CH:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:46]([C:43]1[CH:42]=[CH:41][C:40]([CH2:39][N:35]2[C:34]([CH2:33][CH2:32][NH:31][C:30]([C@H:14]3[CH2:13][C:12]4[NH:8][CH:9]=[N:10][C:11]=4[N:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH2:15]3)=[O:48])=[CH:38][N:37]=[CH:36]2)=[CH:45][CH:44]=1)#[N:47]
Reactant: CC(C)(C)OC(=O)C1[C@@H](C(=O)NCCc2cncn2Cc2ccc(C#N)cc2)Cc2c(ncn2C(=O)OC(C)(C)C)N1c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(Cn2cncc2CCNC(=O)[C@H]2Cc3[nH]cnc3N(c3ccccc3)C2)cc1
Reaction time: 0.75 h

Procedure:
To a solution of 6(S)-{2-[3-(4-cyano-benzyl)-3H-imidazol-4yl]ethylcarbamoyl}-4-phenyl-6,7-dihydro-4H-imidazo [4,5-]pyridine-1,5-dicarboxylic acid di-tert-butyl ester (0.58 g) in CH2Cl2 (10 ml) was added TFA (5 ml) and the solution was stirred 45 min. The solvents were removed in vacuo and the crude product was purified by preparative HPLC to obtain diastereomer A and diastereomer B as the title compounds.
Reaction SMILES: [Li+].[OH-].[CH3:3][N:4]([CH3:25])[C:5]([C:7]1[CH:8]=[CH:9][C:10]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:11]([CH:16]=1)[C:12]([O:14]C)=[O:13])=[O:6].Cl>O.O1CCCC1>[CH3:3][N:4]([CH3:25])[C:5]([C:7]1[CH:8]=[CH:9][C:10]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:11]([CH:16]=1)[C:12]([OH:14])=[O:13])=[O:6]
Reactant: COC(=O)c1cc(C(=O)N(C)C)ccc1OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)c1ccc(OCc2ccccc2)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of LiOH (585 mg, 13.95 mmol) in water (8 ml) was added to a stirred solution of methyl 5-[(dimethylamino)carbonyl]-2-[(phenylmethyl)oxy]benzoate (may be prepared as described in Description 58; 437 mg, 1.40 mmol) in tetrahydrofuran (2 ml) at room temperature. The mixture was stirred at room temperature for 3 h. The mixture was acidified with HCl (6 mol/l) and extracted with ethyl acetate (3×40 ml). The organic phase was washed with saturated brine (25 ml), dried over sodium sulfate, and evaporated in vacuo to give the crude product as a white solid. 350 mg.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:18])[N:8]([CH2:11][CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:19]=O.[F:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][C:30]=1[NH:31][C:32](=[O:35])[CH2:33][OH:34])[NH:27][C:26](=[O:36])[CH2:25]2>>[F:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][C:30]=1[NH:31][C:32](=[O:35])[CH2:33][OH:34])[NH:27][C:26](=[O:36])[C:25]2=[CH:19][C:3]1[NH:4][C:5]2[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)[C:7](=[O:18])[C:6]=2[C:2]=1[CH3:1]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Reactant: O=C(CO)Nc1cc2c(cc1F)CC(=O)N2
Product: Cc1c(C=C2C(=O)Nc3cc(NC(=O)CO)c(F)cc32)[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Yield: 43 %

Procedure:
The title compound was prepared under the same conditions as described in Example 13 with 3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-hydroxy-acetamide as starting materials to give N-{5-fluoro-3-[3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-hydroxy-acetamide (40 mg, 43%) as a yellow solid.