Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:11][CH3:12])[O:9][CH3:10])=[CH:4][CH:3]=1.[C:13]1([CH2:19][CH:20]=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH4+].[Cl-].C(OCC)(=O)C>C1COCC1>[CH3:10][O:9][CH:8]([O:11][CH3:12])[C:5]1[CH:6]=[CH:7][C:2]([CH:20]([OH:21])[CH2:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:3][CH:4]=1
Reactant: COC(OC)c1ccc(Br)cc1
Reactant: O=CCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(OC)c1ccc(C(O)Cc2ccccc2)cc1

Procedure:
A mixture of Mg turnings 2.4 g (0.1 mol) and 2 mL 1-bromo-4-(dimethoxymethyl)benzene (0.012 mol) in THF (100 mL) was heated under nitrogen atmosphere until the reaction starts. Subsequently additional 1-bromo-4-(dimethoxymethyl)benzene 14.71 mL (0.088 mol) dissolved in 30 mL THF was added slowly and the reaction refluxed for 1 h mixture to complete formation of the Gringnard reagent. A solution of 11.70 mL phenylacetaldehyde (0.1 mol) in 100 mL THF was added at to 0° C. and the reaction refluxed for 2 h upon completion of the addition. The mixture was worked up by pouring into saturated aqueous NH4Cl and extraction with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4 and the solvents were evaporated under reduced pressure. The brown-black oily product was used for the next step without purification.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:18]=[C:17]([CH3:19])[C:16]([OH:20])=[C:15]([CH3:21])[CH:14]=3)[N:9]=2)=[CH:5][CH:4]=1)[CH3:2].[CH2:22]([CH:24]1[O:26][CH2:25]1)Cl>C(O)(C)C.[OH-].[Na+].C(OCC)C>[CH3:21][C:15]1[CH:14]=[C:13]([C:10]2[N:9]=[C:8]([C:6]3[S:7][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=3)[O:12][N:11]=2)[CH:18]=[C:17]([CH3:19])[C:16]=1[O:20][CH2:22][CH:24]1[CH2:25][O:26]1
Reactant: ClCC1CO1
Reactant: CCc1ccc(-c2nc(-c3cc(C)c(O)c(C)c3)no2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCOCC
Product: CCc1ccc(-c2nc(-c3cc(C)c(OCC4CO4)c(C)c3)no2)s1
Temperature: 40 °C
Reaction time: 15 h
Yield: 28.3 %

Procedure:
A mixture of 4-[5-(5-ethyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenol (367 mg, 1.22 mmol) and epichlorohydrine (565 mg, 6.10 mmol) in isopropanol (20 mL) and 3 N aq. NaOH (6 mL) is stirred at 40° C. for 15 h. The mixture is diluted with diethyl ether, washed with sat. aq. NaHCO3 and water, dried over MgSO4, filtered and evaporated. The crude product is purified by CC on silica gel eluting with heptane:EA 9:1 to give 3-(3,5-dimethyl-4-oxiranylmethoxy-phenyl)-5-(5-ethyl-thiophen-2-yl)-[1,2,4]oxadiazole (123 mg) as a pale yellow oil; LC-MS: tR=1.15 min, [M+1]+=357.11.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)=[O:21])[C:5](=[O:19])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7]=1[CH3:8].C([Sn](CCCC)(CCCC)[C:39]1[CH:44]=[N:43][CH:42]=[CH:41][N:40]=1)CCC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:8][C:7]1[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:17])([F:18])[F:16])[CH:10]=2)[C:5](=[O:19])[C:4]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:26][CH:25]=2)=[O:21])=[CH:3][C:2]=1[C:39]1[CH:44]=[N:43][CH:42]=[CH:41][N:40]=1
Reactant: Cc1c(I)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1c(-c2cnccn2)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Tris(dibenzylidene-acetone)dipalladium(0) (1 mg) was added to 5-iodo-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoro-methyl)phenyl]-1,2-dihydropyridine-3-carboxamide (Example 1 (d), 20 mg, 0.034 mmol), 2-(tributylstannyl)pyrazine (25 mg, 0.068 mmol) and triphenylphosphine (1.6 mg, 0.006 mmol) in toluene (1.5 ml) under argon and the mixture was stirred in a sealed vial at 100° C. overnight. After cooling, the mixture was filtered through celite and evaporated. The residue was dissolved in toluene and ether was added. The precipitate was filtered off and dried in vacuo (5 mg, 27%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([Br:23])[CH:17]=1)[C:10]([CH3:25])([CH3:24])[CH:9]2O)=[O:5])[CH3:2].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([Br:23])[CH:17]=1)[C:10]([CH3:24])([CH3:25])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1ccc(F)c(Br)c1)N2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(F)c(Br)c1)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.9 %

Procedure:
To a mixture of 2-(3-bromo-4-fluoro-phenyl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (1.93 g, 4.57 mmol) and triethylsilane (5 mL) at 25° C. was added trifluoroacetic acid (1 mL) dropwise. The resulting mixture was stirred at 25° C. for 1 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×50 mL), washed with saturated aqueous sodium bicarbonate solution (2×20 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company)(10% ethyl acetate/hexanes) to afford 2-(3-bromo-4-fluoro-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.63 g, 34%) as a white solid: LC/MS m/e calcd for C20H21BrFNO2 M+: 406.3, observed: 406.2, 408.2.
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[F:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13]2.O>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:22]([O:21][C:19]([C:14]1[NH:15][C:16]2[C:12]([C:13]=1[C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:11][C:10]([F:9])=[CH:18][CH:17]=2)=[O:20])[CH3:23]
Reactant: CCOC(=O)c1cc2cc(F)ccc2[nH]1
Reactant: CCOC(=O)C(=O)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(=O)c1c(C(=O)OCC)[nH]c2ccc(F)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.3 %

Procedure:
A solution of 40 ml (313 mmol) of ethyl chloroglyoxylate and of 36 ml (313 mmol) of titanium tetrachloride in 1 l of dichloromethane is stirred for 15 min at room temperature. A solution of 50 g (241 mmol) of ethyl 5-fluoro-1H-indole-2-carboxylate in dichloromethane is added and the mixture is stirred for 2 h at room temperature. The mixture is poured into water and the organic phase is separated by settling, washed with dilute sodium hydroxide solution and dried over sodium sulphate. 31.5 g (102 mmol) of product are obtained, which product is used as is in the following stage.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[C:5]([CH3:19])[CH:4]=1)=O.[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][NH2:29])=[CH:23][CH:22]=1.[BH4-].[Na+]>CO>[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][NH:29][CH2:1][C:3]2[CH:18]=[CH:17][C:6]([O:7][C:8]3[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=3)=[C:5]([CH3:19])[CH:4]=2)=[CH:23][CH:22]=1
Reactant: Cc1cc(C=O)ccc1Oc1cnc(C(N)=O)cn1
Reactant: NCCc1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(CNCCc2ccc(F)cc2)ccc1Oc1cnc(C(N)=O)cn1
Reaction time: 8 h
Yield: 53.9 %

Procedure:
Place 5-(4-formyl-2-methylphenoxy)pyrazine-2-carboxamide (Example 404, part D) (0.600 g, 2.33 mmol), 2-(4-fluorophenyl)ethylamine (0.325 g, 2.33 mmol) and 3 {acute over (Å)} molecular sieves in a vial. Add methanol (11.7 mL), cap and stir overnight. Add NaBH4 (0.088 g, 2.33 mmol) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 5% to 20% (2.0 M NH3 in methanol) in ethyl acetate. Concentrate the fraction containing the product, then take it up in EtOAc (100 mL). Wash the organic solution with 1.0 N NaOH (2×25 mL), dry it over Na2SO4 and concentrate it to give the title compound (0.478 g, 54.0%): TOF MS ES+ 381.2 (M+H)+, HRMS calcd for C21H22N4O2F 381.1727 (M+H)+, found 381.1729, time 0.39 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=11.3 min, 97.8% purity.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[S:15][CH:16]=2)=[CH:8][CH:7]=1.[F:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][NH2:25].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[S:15]1[CH:16]=[C:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][NH:25][CH2:24][C:23]3[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=3[F:21])=[CH:7][CH:8]=2)[C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]1=2
Reactant: BrCCCOc1ccc(-c2csc3ccccc23)cc1
Reactant: NCc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccccc1CNCCCOc1ccc(-c2csc3ccccc23)cc1

Procedure:
The title compound is prepared from 3-[4-(3-bromo-propoxy)-phenyl]-benzo[b]thiophene, 2-fluorobenzylamine, potassium carbonate and acetonitrile essentially as described above in Example 118. Purity by LC/MS=100%, [M+H]+=392.
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[Br:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[N:16]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:17]=[CH:18][C:11]=12.CI>C1COCC1>[Br:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[N:16]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C:17]([CH3:1])=[CH:18][C:11]=12
Reactant: CC(C)[N-]C(C)C
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Br)ccnc21
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cc2c(Br)ccnc2n1S(=O)(=O)c1ccccc1
Temperature: -45 °C
Reaction time: 0.5 h

Procedure:
1.8M Lithium diisopropylamide (270 ml) was added dropwise over 20 min to a solution of 4-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (82 g) in dry THF (820 ml) and the reaction was stirred at −45° C. for 30 min. Methyl iodide (90 ml) was added drop wise to the solution and the mixture was stirred at −45° C. for 45 min, then allowed to warm to RT. The reaction was quenched with water. The organic layer was collected and the aqueous layer extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulphate and concentrated in vacuo. The residue was triturated with ethyl acetate:cyclohexane (3:1). The solid material was collected and washed with ethyl acetate:cyclohexane (3:1) and dried in vacuo at 35° C. This residue was dissolved in DCM, washed with water, dried over magnesium sulphate and the solvent removed in vacuo to give the title compound (37.6 g) as a cream solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][S:8][C:9]2[C:14]([Br:15])=[CH:13][N:12]=[C:11]([NH:16][C:17]([NH2:19])=[S:18])[CH:10]=2)=[CH:5][CH:4]=1.Br[CH2:23][C:24](=O)[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C>CCO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8][C:9]2[C:14]([Br:15])=[CH:13][N:12]=[C:11]([NH:16][C:17]3[S:18][CH:23]=[C:24]([CH2:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:19]=3)[CH:10]=2)=[CH:20][CH:21]=1
Reactant: COc1ccc(CSc2cc(NC(N)=S)ncc2Br)cc1
Reactant: O=C(CBr)CCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(CSc2cc(Nc3nc(CCc4ccccc4)cs3)ncc2Br)cc1
Temperature: 75 °C
Yield: 61 %

Procedure:
1-(4-(4-methoxybenzylthio)-5-bromopyridin-2-yl)thiourea (3.0 g, 7.8 mmol) and 1-bromo-4-phenylbutan-2-one (1.77 g, 7.8 mmol) were diluted in EtOH (120 mL). Triethylamine (2.2 ml, 15.6 mmol) was added, and the solution was heated at 75° C. for 3 hours. The solution was cooled and concentrated to half the amount of solvent. The solid was filtered and rinsed with cold EtOH to provide the desired product (2.44 g, 61% yield) as a tan solid.
Reaction SMILES: Cl[C:2](OC(Cl)(Cl)Cl)=[O:3].[F:9][C:10]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:11]=1[C:12]([NH:14][NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Br:22])=[O:13].C(N(CC)CC)C>O1CCOCC1>[Br:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[N:15]1[N:14]=[C:12]([C:11]2[C:10]([F:9])=[CH:26][CH:25]=[CH:24][C:23]=2[F:27])[O:13][C:2]1=[O:3]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: O=C(NNc1ccccc1Br)c1c(F)cccc1F
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=c1oc(-c2c(F)cccc2F)nn1-c1ccccc1Br

Procedure:
2.3 ml (19 mmol) of trichloromethyl chloroformate are added dropwise at 10°-20° C. to a mixture of 5.34 g (16 mmol) of 2,6-difluoro-N'-(o-bromophenyl)-benzhydrazide and 5.50 ml (40 mmol) of triethylamine in 35 ml of dioxan. The reaction mixture is heated at the reflux temperature for a further 3 hours and the solvent and excess reagent are subsequently distilled off under reduced pressure. The residue is taken up in diethyl ether and the solution is washed in each case once with water and sodium bicarbonate solution, dried over anhydrous sodium sulfate and evaporated under reduced pressure. After crystallization of the residue from acetone/n-hexane there is obtained pure 3-(2-bromophenyl)-5-(2,6-difluorophenyl)-1,3,4-oxadiazol-2(3H)-one, m.p. 111°-114° C.; IR spectrum: 1790 cm-1 ; mass spectrum: 354/352(15), 310/308(7), 171/169(41), 90(100).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:12](=[O:22])[NH:13][C:14]3[C:19]([C:20]=2[OH:21])=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:10])=[CH:4][CH:3]=1.[CH3:23][N:24]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:25](Cl)=[O:26]>>[OH:21][C:20]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][C:12](=[O:22])[C:11]=1[C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([O:1][C:25](=[O:26])[N:24]([CH3:23])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:3][CH:4]=1)=[O:10]
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: O=C(Nc1ccc(O)cc1)c1c(O)c2ccccc2[nH]c1=O
Product: CN(C(=O)Oc1ccc(NC(=O)c2c(O)c3ccccc3[nH]c2=O)cc1)c1ccccc1

Procedure:
The title product was prepared from 4-hydroxy-2-oxo-1,2-dihydro-quinoline-3-carboxylic acid (4-hydroxy-phenyl)-amide and N-methyl-N-phenylcarbamoyl chloride (5%,). HPLC-MS: m/z=430.1 (M+1); Rt: 4.80 min, purity: 70%.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[Cu][C:12]#[N:13].Cl.O>CN(C=O)C>[C:12]([C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=[O:8])#[N:13]
Reactant: O=Cc1cc(Br)ccc1F
Reactant: N#C[Cu]
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(F)c(C=O)c1
Temperature: 190 °C
Reaction time: 5 h

Procedure:
To a solution of 5-bromo-2-fluorobenzaldehyde (1.93 g, 9.51 mmol) in DMF (4 mL) was added copper(I) cyanide (0.98 g, 10.93 mmol). The mixture was heated to 190 ° C. and stirred for 5 h. The dark brown reaction mixture was poured into a solution containing ferric chloride (3.0 g), conc. HCl (0.93 mL) and water (6 mL) and warmed to 65 ° C. for 20 min. The mixture was partitioned between toluene (20 mL) and water (20 mL). The organic was washed with diluted HCl (25 mL), water (20 mL), 10% sodium hydroxide (25 mL), dried over magnesium sulfate, and concentrated to provide a solid product:
Reaction SMILES: ClC1C=C([B:10]([OH:12])[OH:11])C=C(F)C=1O.Br[C:14]1[CH:15]=[C:16]([F:23])[C:17]([O:21][CH3:22])=[C:18]([F:20])[CH:19]=1>>[F:20][C:18]1[CH:19]=[C:14]([B:10]([OH:12])[OH:11])[CH:15]=[C:16]([F:23])[C:17]=1[O:21][CH3:22]
Reactant: COc1c(F)cc(Br)cc1F
Reactant: OB(O)c1cc(F)c(O)c(Cl)c1
Product: COc1c(F)cc(B(O)O)cc1F

Procedure:
This compound is prepared analogously to Intermediate 8 by replacing 4-Bromo-2-chloro-6-fluoro-phenol with 5-Bromo-1,3-difluoro-2-methoxy-benzene to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][C@H:11]([C:17]([O:19][CH3:20])=[O:18])[CH2:12][C:13]([O:15][CH3:16])=[O:14])=[O:9])[N:6]=1.[CH3:21][C:22]1[CH:54]=[CH:53][C:25]2[CH:26]([C:36]3[C:37](=[S:52])[NH:38][C:39](=[O:51])[N:40]([CH2:42][C:43]4[O:47][C:46]([C:48](O)=[O:49])=[CH:45][CH:44]=4)[CH:41]=3)[C:27]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:28]=3[CH:29]=[CH:30][C:24]=2[CH:23]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH3:35][C:32]1[CH:33]=[CH:34][C:27]2[CH:26]([C:36]3[C:37](=[S:52])[NH:38][C:39](=[O:51])[N:40]([CH2:42][C:43]4[O:47][C:46]([C:48]([NH:1][C:2]5[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][C@H:11]([C:17]([O:19][CH3:20])=[O:18])[CH2:12][C:13]([O:15][CH3:16])=[O:14])=[O:9])[N:6]=5)=[O:49])=[CH:45][CH:44]=4)[CH:41]=3)[C:25]3[CH:53]=[CH:54][C:22]([CH3:21])=[CH:23][C:24]=3[CH:30]=[CH:29][C:28]=2[CH:31]=1
Reactant: Cc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1cn(Cc2ccc(C(=O)O)o2)c(=O)[nH]c1=S
Reactant: COC(=O)C[C@H](NC(=O)Cc1csc(N)n1)C(=O)OC
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C[C@H](NC(=O)Cc1csc(NC(=O)c2ccc(Cn3cc(C4c5ccc(C)cc5C=Cc5cc(C)ccc54)c(=S)[nH]c3=O)o2)n1)C(=O)OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of the product of step (ii) (0.22 g), product of example 11(0.2 g), bromo-tris(pyrrolidino)-phosphonium hexafluorophosphate (0.24 g), 4-dimethylaminopyridine (0.056 g) and N,N-diisopropylethylamine (0.2 ml) in dimethylformamide (5 ml) was stirred at room temperature for 24 hours. The mixture was partitioned between ethyl acetate and brine, washed with saturated aqueous sodium bicarbonate, dilute HCl and brine, dried (MgSO4) and evaporated. Purification was by chromatography eluting with ethyl acetate. Yield 0.24 g.
Reaction SMILES: [NH2:1][C:2]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:21][CH3:22])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[NH:4][C:3]1=[O:13].Cl[C:24]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25]>N1C=CC=CC=1>[C:27]1([O:26][C:24](=[O:25])[NH:1][C:2]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH3:22])[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=3)[NH:4][C:3]2=[O:13])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCOc1ccccc1C1(N)C(=O)Nc2ccc(OC)cc21
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Product: CCOc1ccccc1C1(NC(=O)Oc2ccccc2)C(=O)Nc2ccc(OC)cc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1.8 g (6 mmol) of the intermediate from Step C were dissolved in 20 ml pyridine. At 0° C. 0.99 g (6.3 mmol) phenyl chloroformate were added and afterwards the reaction mixture was stirred for 1 h at 0° C. This mixture was poured into an ice/water mixture. The pH of the aqueous phase was adjusted to 5 and the resulting mixture was extracted with ethyl acetate. The organic phase was separated, dried over magnesium sulfate and the solvent was removed in vacuo. The resulting solid (2 g) was used in the next step without further purification.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH3:12][N+:13]1[C:17]2[CH2:18][CH2:19][CH2:20][CH2:21][C:16]=2[S:15][C:14]=1SC.[CH3:24][O:25][C:26](=[O:53])[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][N:34]2[C:38](=[O:39])[CH2:37][S:36][C:35]2=[N:40][C:41]2[CH:46]=[C:45]([C:47](=[O:49])[CH3:48])[CH:44]=[CH:43][C:42]=2[NH:50][CH2:51][CH3:52])=[CH:29][CH:28]=1>>[C:47]([C:45]1[CH:44]=[CH:43][C:42]([NH:50][CH2:51][CH3:52])=[C:41]([N:40]=[C:35]2[N:34]([CH2:33][C:30]3[CH:31]=[CH:32][C:27]([C:26]([O:25][CH3:24])=[O:53])=[CH:28][CH:29]=3)[C:38](=[O:39])[C:37](=[C:14]3[N:13]([CH3:12])[C:17]4[CH2:18][CH2:19][CH2:20][CH2:21][C:16]=4[S:15]3)[S:36]2)[CH:46]=1)(=[O:49])[CH3:48]
Reactant: CSc1sc2c([n+]1C)CCCC2
Reactant: CCNc1ccc(C(C)=O)cc1N=C1SCC(=O)N1Cc1ccc(C(=O)OC)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCNc1ccc(C(C)=O)cc1N=C1SC(=C2SC3=C(CCCC3)N2C)C(=O)N1Cc1ccc(C(=O)OC)cc1

Procedure:
The title compound was prepared in a manner similar to Example 168 by condensing intermediate 3-methyl-2-methylthio-4,5,6,7-tetrahydro-benzothiazol-3-ium p-toluenesulfonate with 4-[2-(5-acetyl-2-ethylaminophenylimino)-4-oxothiazolidin-3-ylmethyl]benzoic acid methyl ester. MS(ESI): 577 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:16][CH3:17])[C:10](=[N:13][C:14]#[N:15])SC)=[CH:4][CH:3]=1.[CH3:18][NH2:19]>C(#N)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:16][CH3:17])[C:10]([NH:19][CH3:18])=[N:13][C:14]#[N:15])=[CH:4][CH:3]=1
Reactant: CN
Reactant: CCN(Cc1ccc(Cl)nc1)C(=NC#N)SC
Solvent: CC#N
Product: CCN(Cc1ccc(Cl)nc1)C(=NC#N)NC
Yield: 81.4 %

Procedure:
To a mixture of 0.42 g of 1-(6-chloro-3-pyridylmethyl)-3-cyano-1-ethyl-2-methylisothiourea and 5 ml of acetonitrile was added each 0.5 g of 40% methylamine aqueous solution at an hour interval in total six time (3.0 g), while refluxing and stirring. The reaction mixture was stirred for 6 hours in total. Then, the mixture was concentrated to afford 0.32 g of 1-(6-chloro-3-pyridylmethyl)-2-cyano-1-ethyl-3-methylguanidine (Compound No. 3).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[C:12]1(C)C=CC(S(O)(=O)=O)=C[CH:13]=1>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)Cc1ccc(Br)cc1
Reaction time: 8 h
Yield: 74 %

Procedure:
4-Bromophenylacetic acid, 7-c, (30 g, 0.14 mol) was dissolved in ethanol (150 mL) at reflux along with p-toluenesulphonic acid (2.4 g, 0.014 mol). The reaction mixture was then stirred overnight. The ethanol was the removed in vacuo and the residue was taken up in EA. Combined organic layers were washed with water and the aqueous layer was re-extracted with EA. Combined organic layers were then dried over Na2SO4 and concentrated to afford the titled compound, 12-a, (25 g, 74%). 1H NMR (300 MHz, CDCl3) δ 1.23-1.29 (m, 3H), 3.56 (s, 2H), 4.11-4.18 (m, 2H), 7.16 (d, J=8.1 Hz, 2H), 7.44 (d, J=8.1 Hz, 2H). LC-MS (M+H)+ 243, 245.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:17][C:3]=1[O:4][C:5]1[C:6]([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[N:7][CH:8]=[CH:9][CH:10]=1.[C:35](=O)([O-])[O-].[Na+].[Na+]>C(O)C>[Cl:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:17][C:3]=1[O:4][C:5]1[C:6]([O:11][CH2:12][C:13]([O:15][CH2:16][CH3:35])=[O:14])=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Yield: 89.2 %

Procedure:
A mixture of 0.60 g of methyl [3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-pyridyloxy]acetate (compound a-6), 0.13 g of sodium carbonate, and 7.0 ml of ethanol was heated at reflux for 2 hours. After cooling to room temperature, the solvent was distilled out under reduced pressure, and the residue was subjected to silica gel chromatography to give 0.55 g of ethyl [3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-pyridyloxy]acetate (compound a-10).