Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C(OC(=O)[NH:8][CH2:9][CH2:10][O:11][N:12]=[CH:13][C:14]1[CH:19]=[C:18]([C:20](=[O:26])[NH:21][O:22][CH2:23][CH2:24][OH:25])[C:17]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([I:34])=[CH:30][C:29]=2[F:35])=[C:16]([F:36])[C:15]=1[F:37])(C)(C)C.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[NH2:8][CH2:9][CH2:10][O:11][N:12]=[CH:13][C:14]1[C:15]([F:37])=[C:16]([F:36])[C:17]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([I:34])=[CH:30][C:29]=2[F:35])=[C:18]([CH:19]=1)[C:20]([NH:21][O:22][CH2:23][CH2:24][OH:25])=[O:26]
Reactant: CC(C)(C)OC(=O)NCCON=Cc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: NCCON=Cc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 10.4 %

Procedure:
1 N HCl solution in ethyl acetate (1 ml) was added to a solution of {2-[2,3-difluoro-4-(2-fluoro-4-iodo-phenylamino)-5-(2-hydroxy-ethoxycarbamoyl)-benzylideneaminooxy]-ethyl}-carbamic acid tert-butyl ester (55 mg, 0.31 mmol) prepared in Process A in ethyl acetate (5 ml). This mixture was then stirred at room temperature for 1.5 hours. After the completion of the reaction, the reaction solution was neutralized with saturated sodium bicarbonate solution (50 ml) and extracted with ethyl acetate (100 ml×3). The extract was washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated off under reduced pressure, and the resulting residue was washed with diethyl ether (10 ml) and then recrystallized from methanol to give 5-[(2-amino-ethoxyimino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide (17.31 mg, 37% yield) as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[O:12][CH2:11][CH2:10][O:9]1.[Cl-].[CH3:14][O:15][C:16](=[O:20])[C:17](O)=[O:18]>[Zn]>[O:9]1[CH2:10][CH2:11][O:12][CH:8]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:17](=[O:18])[C:16]([O:15][CH3:14])=[O:20]
Reactant: Brc1ccccc1C1OCCO1
Reactant: COC(=O)C(=O)O
Agent: [Cl-]
Agent: [Zn]
Product: COC(=O)C(=O)c1ccccc1C1OCCO1

Procedure:
174.5 g of 1-bromo-2-(1,3-dioxolan-2-yl)-benzene was reacted via the zinc-organic compound with 102 g of oxalic acid monomethyl ester chloride, analogously to Example 2. Yield: 41.6 g.
Reaction SMILES: C([Sn](CCCC)(CCCC)[CH:6]=[CH:7][O:8]CC)CCC.Br[C:20]1[CH:25]=[CH:24][C:23]([C:26]([N:28]2[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[CH2:32][N:31]3[CH:39]=[CH:40][CH:41]=[C:30]3[CH2:29]2)=[O:27])=[C:22]([Cl:42])[CH:21]=1>C1(C)C=CC=CC=1>[CH:41]1[CH:40]=[CH:39][N:31]2[CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[N:28]([C:26]([C:23]3[CH:24]=[CH:25][C:20]([C:7](=[O:8])[CH3:6])=[CH:21][C:22]=3[Cl:42])=[O:27])[CH2:29][C:30]=12
Reactant: CCCC[Sn](C=COCC)(CCCC)CCCC
Reactant: O=C(c1ccc(Br)cc1Cl)N1Cc2cccn2Cc2ccccc21
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.6 %

Procedure:
Tributyl(ethoxyvinyl)tin (1.17 g) was added to a solution of (4-bromo-2-chlorophenyl)-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (1.24 g) in toluene (10 ml). The resultant solution was purged with nitrogen for 10 minutes, then bis(triphenylphosphine)palladium (II) chloride (0.11 g) was added. The reaction mixture was heated to reflux for 24 hours. The solution was cooled to room temperature and 5% aqueous hydrochloric acid (10 ml) was added. After stirring for one hour, the mixture was filtered through a pad of diatomaceous. Diethyl ether (5 ml) was added to the filtrate, and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo to yield a brown glass. Purification by flash chromatography on silica gel eluting with hexane-ethyl acetate (1:1) resulted in a white solid (0.30 g), MS, m/z: 364 (M)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.CC1(C)C(C)(C)OB([C:18]2[CH:19]=[CH:20][C:21]3[S:25][CH:24]=[N:23][C:22]=3[CH:26]=2)O1>>[S:25]1[C:21]2[CH:20]=[CH:19][C:18]([C:2]3[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=3)=[CH:26][C:22]=2[N:23]=[CH:24]1
Reactant: Oc1ccc(Br)cc1F
Reactant: CC1(C)OB(c2ccc3scnc3c2)OC1(C)C
Product: Oc1ccc(-c2ccc3scnc3c2)cc1F

Procedure:
Compound 4-(benzo[d]thiazol-5-yl)-2-fluorophenol (W121) was prepared using the general procedure for Suzuki coupling reaction between 4-bromo-2-fluorophenol (57 mg, 0.3 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole (78 mg, 0.3 mmol), as a white solid (45 mg, 61%). 1H NMR (400 MHz, acetone-d6) δ 9.27 (s, 1 H), 8.85 (s, 1 H), 8.28 (d, J=1.6 Hz, 1 H), 8.15 (d, J=8.4 Hz, 1 H), 7.75 (dd, J=8.4, 1.6 Hz 1 H), 7.55 (dd, J=12.4, 2.4 Hz, 1 H), 7.45 (m, 1 H), 7.12 (t, 9.2 Hz, 1 H); MS (ESI) m/z 246 (M+H+).
Reaction SMILES: [Mg:1].II.[Br:4]C1CC1.[O:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1>>[CH:10]1([Mg:1][Br:4])[CH2:11][CH2:12]1.[O:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: BrC1CC1
Reactant: [Mg]
Agent: II
Solvent: C1CCOC1
Product: Br[Mg]C1CC1
Reaction time: 1.5 h

Procedure:
Magnesium (10.7 g) was suspended in tetrahydrofuran (80 ml), and to the suspension was added iodine (5 mg). Bromocyclopropane (32.0 ml) was added dropwise thereto over 1.5 hr and the mixture was heated under reflux for 1.5 hr. Thereto was added tetrahydrofuran to give a 1M cyclopropylmagnesium bromide-tetrahydrofuran solution. Subsequently, o-anisaldehyde (8.17 g) was dissolved in tetrahydrofuran (150 ml), the 1M cyclopropylmagnesium bromide-tetrahydrofuran solution (90 ml) was added dropwise thereto over 50 min under ice-cooling, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was ice-cooled, a saturated aqueous ammonium chloride solution (9 ml) was added, and the reaction mixture was stirred at room temperature for 30 min. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=9:1) to give the title compound (6.13 g).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[C:10]([S:14](Cl)(=[O:16])=[O:15])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH2:21]>CN(C)C(=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[C:10]([S:14]([NH:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[F:18])(=[O:16])=[O:15])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1cc(S(=O)(=O)Cl)c(Cl)cc1Cl
Reactant: Nc1ccccc1F
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cc(S(=O)(=O)Nc2ccccc2F)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To ethyl 2,4-dichloro-5-(chlorosulfonyl)benzoate (1 g, 3.15 mmol) in N,N-dimethylacetamide (10.5 mL) was added 2-fluoroaniline (1.215 mL, 12.60 mmol) dropwise over 1 minute at room temperature. The mixture was stirred at room temperature for 1 hour, and then it was diluted with ethyl acetate (35 mL). The organic solution was washed with 1 N HCl (2×13 mL) and saturated NaCl (13 mL). The organic layer was concentrated, ethanol (38 mL) was added, and the mixture concentrated to give ethyl 2,4-dichloro-5-{[(2-fluorophenyl)amino]sulfonyl}benzoate.
Reaction SMILES: CS(C)=O.C(N(CC)CC)C.Cl.Cl.[NH2:14][CH2:15][CH2:16][C:17]1[N:21]=[CH:20][NH:19][CH:18]=1.F[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1>O>[N+:29]([C:26]1[CH:27]=[CH:28][C:23]([NH:14][CH2:15][CH2:16][C:17]2[NH:21][CH:20]=[N:19][CH:18]=2)=[CH:24][CH:25]=1)([O-:31])=[O:30]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: NCCc1c[nH]cn1
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(NCCc2cnc[nH]2)cc1
Temperature: 80 °C
Reaction time: 10 h
Yield: 89.6 %

Procedure:
100 ml of DMSO were introduced into a 500 ml three-necked flask and treated with 30.9 g of triethylamine, 18.4 g of histamine dihydrochloride and 14.4 g of 1-fluoro-4-nitrobenzene. The mixture was stirred at 80° C. for 10 h, treated with 20 ml of water and stirred at 80° C. for a further 3 h. Following this, the mixture was allowed to cool to room temperature and poured onto 1 l of ice. The resulting precipitate was filtered off with suction and dried in vacuo at 50° C., 20.8 g of crude product being obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.[C:10]([C:14]1[O:18][N:17]=[C:16]([NH:19][C:20]([CH:22]2[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]2)=[O:21])[CH:15]=1)([CH3:13])([CH3:12])[CH3:11].Cl.C(N(CC)C(C)C)(C)C>CN(C=O)C.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:10]([C:14]1[O:18][N:17]=[C:16]([NH:19][C:20]([CH:22]2[CH2:27][CH2:26][CH2:25][N:24]([CH2:6][C:5]3[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH2:23]2)=[O:21])[CH:15]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: ClCc1ccc(Cl)cc1
Reactant: CC(C)(C)c1cc(NC(=O)C2CCCNC2)no1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(NC(=O)C2CCCN(Cc3ccc(Cl)cc3)C2)no1

Procedure:
To a solution of 4-chlorobenzyl chloride (134 mg; 0.832 mmol) in DMF (3 mL) is added piperidine-3-carboxylic acid (5-tert-butyl-isoxazol-3-yl)-amide; hydrochloride (238.86 mg; 0.83 mmol) and N,N-diisopropylethylamine (0.331 mL; 1.9 mmol). The reaction mixture is left stirring at room temperature for 18 hours in the presence of catalytic amount of 4-dimethylaminopyridine (1 mg). The mixture is diluted with ethyl acetate and washed with water 3 times then brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography on silica using methanol/methylene chloride provides the title compound, m/z 376/378 [M+H+].
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:13]([C:14]([O:16]C)=O)=[N:12][CH:11]=[CH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18](OCC)(=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].CC(C)([O-])C.[K+]>>[CH2:20]([C:19]1[C:18](=[O:24])[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2=[N:9][CH:10]=[CH:11][N:12]=[C:13]2[C:14]=1[OH:16])[CH2:21][CH2:22][CH3:23]
Reactant: COC(=O)c1nccnc1Nc1ccccc1
Reactant: CCCCCC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCCCc1c(O)c2nccnc2n(-c2ccccc2)c1=O

Procedure:
A mixture of 3.5 g. of methyl 2-phenylamino-3-pyrazine carboxylate, 30 ml. of ethyl caproate and 4 g. of potassium tertiary butoxide is stirred and heated under nitrogen at 150°-160° for one and a half hours. The reaction mixture is poured on ice, extracted with ethyl acetate and the ethyl acetate extracts washed with water. The combined aqueous layers are acidified to pH 5.5 with dilute hydrochloric acid and the solid filtered. Recrystallization from ethyl acetate-hexane yields the product of this example as a colorless solid; m.p. 183°-185° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[C:13]([Cl:33])=[CH:14][C:15]([F:32])=[C:16]([NH:18][C:19](=[O:31])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=3)[CH:17]=1)[N:5]=2.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:33][C:13]1[C:12]([O:11][C:6]2[N:5]=[C:4]3[S:3][C:2]([NH:1][C:34](=[O:37])[CH2:35][CH3:36])=[N:10][C:9]3=[CH:8][CH:7]=2)=[CH:17][C:16]([NH:18][C:19](=[O:31])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=2)=[C:15]([F:32])[CH:14]=1
Reactant: CCC(=O)Cl
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(N)sc4n3)c(Cl)cc2F)c1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCC(=O)Nc1nc2ccc(Oc3cc(NC(=O)c4cccc(C(C)(C)C#N)c4)c(F)cc3Cl)nc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
To a solution of N-{5-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-chloro-2-fluorophenyl}-3-(1-cyano-1-methylethyl)benzamide produced in Example C52(v) in pyridine (1.0 mL) was added propionyl chloride (29 μL, 0.332 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate (10 mL), washed with 5% aqueous sodium hydrogen carbonate solution (10 mL) and saturated brine (10 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=70/30→0/100), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from ethyl acetate/hexane to give the title compound (46.7 mg, 52%) as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][N:6]1[CH2:10][CH2:9][C@@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:7]1.N1C=CC=CC=1.[C:28](OC(=O)C)(=[O:30])[CH3:29].O>C(Cl)Cl>[C:28]([NH:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][N:6]1[CH2:10][CH2:9][C@@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:16])[CH3:17])[CH2:7]1)(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(Cc2cccc(N)c2)C1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(=O)Nc1cccc(CN2CC[C@@H](NC(=O)OC(C)(C)C)C2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl [(3R)-1-(3-aminobenzyl)-3-pyrrolidinyl]carbamate (681 mg) in CH2Cl2 (6.8 mL) was added pyridine (28:4 uL), acetic anhydride (265 uL), and N,N-dimethylaminopyridine (14 mg), which was stirred at room temperature for 1.5 hours. To the resultant was added H2O. The mixture was extracted with CH2Cl2. The organic phase was washed by brine, dried over Na2SO4, filtered, and evaporated in vacuo to give tert-butyl {(3R)-1-[3-(acetylamino)benzyl]-3-pyrrolidinyl}carbamate (944 mg) as a off-white amorphous.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([CH3:18])=[CH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>[Ir].C(Cl)Cl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([CH3:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)C=C(C)c1ccc2ccccc2c1
Agent: [Ir]
Solvent: ClCCl
Product: CCOC(=O)CC(C)c1ccc2ccccc2c1
Yield: 99 %

Procedure:
According to the general procedure, a solution of ethyl 3-(naphthalen-2-yl)-but-2-enoate) (70 mg, 0.29 mmol) and iridium catalyst (S)-32 (9.2 mg, 0.0058 mmol, 2.0 mol %) in CH2Cl2 (3 mL) was hydrogenated. Removal of the solvent in vacuo and standard purification gave 38 (70 mg, 99%) as a colorless oil. [α]20D −25.9 (c 1.02, CHCl3); CSP HPLC analysis (Chiralcel OD-H; eluent: 99.5:0.5 hexanes/i-PrOH, 1.0 ml/min) determined a 89.5:10.5 er (79% ee) [tR(minor) 12.34 min, tR(major) 14.19 min]; 1H NMR (300 MHz, CDCl3) 7.82 (d, 3H, J=8.4 Hz), 7.69 (s, 1H), 7.51-7.39 (m, 3H), 4.11 (q, 2H, J=7.2 Hz), 3.50 (sextet, 1H, J=7.5 Hz), 2.81-2.62 (m, 2H), 1.42 (d, 3H, J=6.9 Hz), 1.19 (t, 3H, J=7.2 Hz) ppm; 13C NMR (75 MHz, CDCl3) 172.3, 143.1, 135.5, 132.3, 128.1, 127.6, 127.5, 125.9, 125.4, 125.3, 124.9, 60.2, 42.8, 42.6, 36.6, 21.7, 14.1 ppm.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH:15]3[CH2:20][CH2:19][CH:18]([N:21](C(OCC4C=CC=CC=4)=O)[C:22]([NH:24]C(OCC4C=CC=CC=4)=O)=[NH:23])[CH2:17][CH2:16]3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>CO.[Pd]>[C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH:15]3[CH2:20][CH2:19][CH:18]([NH:21][C:22]([NH2:24])=[NH:23])[CH2:17][CH2:16]3)[CH2:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N=C(NC(=O)OCc1ccccc1)N(C(=O)OCc1ccccc1)C1CCC(CCN2CCN(c3ccccc3)CC2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: N=C(N)NC1CCC(CCN2CCN(c3ccccc3)CC2)CC1
Yield: 0.1 %

Procedure:
Trans-N-{4-[2-(4-phenyl-piperazin-1-yl)-ethyl]cyclohexyl-N,N'-dicarbobenzyloxyguanidine (2.77 g, 4.63 mol) was hydrogenolyzed in MeOH (250 mL) under 48 psi hydrogen pressure in the presence of 20% palladium on carbon catalyst (0.25 g). Filtration of the reaction mixture, evaporation of the filtrate, and recrystallization of the residue from isopropanol (i-PrOH)-Et2O yielded 1.39 g (91%) of the product; mp 140-170° C.
Reaction SMILES: [CH:1]1(/[CH:7]=[C:8](\[CH2:14][P:15]([O:21][CH2:22][CH3:23])([CH2:17][CH:18]([CH3:20])[CH3:19])=[O:16])/[C:9]([O:11]CC)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C.O>[CH:1]1(/[CH:7]=[C:8](\[CH2:14][P:15]([O:21][CH2:22][CH3:23])([CH2:17][CH:18]([CH3:19])[CH3:20])=[O:16])/[C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)/C(=C/C1CCCCC1)CP(=O)(CC(C)C)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOP(=O)(C/C(=C\C1CCCCC1)C(=O)O)CC(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 176 mg (0.51 millimole) of ethyl (Z)-3-cyclohexyl-2-(ethoxyisobutylphosphinoyl)methylpropenoate in 2 ml of ethanol was added 1 N sodium hydroxide (0.51 ml) and the solution was stirred at room temperature for 3 hours, and then refluxed for 30 minutes. After cooling, the reaction mixture was diluted with 30 ml of water, and extracted with 20 ml of ether. The aqueous layer was acidified with 4 N hydrochloric acid, and extracted three times with 20 ml of ether each time. The combined organic layers were washed with 10 ml of a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 143 mg (yield of the captioned compound as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:6]([C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH2:13])[CH:8]=2)[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[N:3]=1.[NH2:18][C:19]1[CH:20]=[C:21]([CH:41]=[CH:42][C:43]=1[CH3:44])[C:22]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH:35]=[CH:34][N:33]=[C:32]2[CH3:36])=[C:27]([C:37]([F:40])([F:39])[F:38])[CH:26]=1)=[O:23].CS(O)(=O)=O>CN1CCN(C)C1=O>[NH2:13][C:9]1[N:10]=[CH:11][N:12]=[C:7]([N:6]2[C:5]3[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=3[N:3]=[C:2]2[NH:18][C:19]2[CH:20]=[C:21]([CH:41]=[CH:42][C:43]=2[CH3:44])[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH:35]=[CH:34][N:33]=[C:32]3[CH3:36])=[C:27]([C:37]([F:40])([F:39])[F:38])[CH:26]=2)=[O:23])[CH:8]=1
Reactant: Cc1ccc(C(=O)Nc2ccc(-n3ccnc3C)c(C(F)(F)F)c2)cc1N
Reactant: Nc1cc(-n2c(Cl)nc3ccccc32)ncn1
Agent: CS(=O)(=O)O
Solvent: CN1CCN(C)C1=O
Product: Cc1ccc(C(=O)Nc2ccc(-n3ccnc3C)c(C(F)(F)F)c2)cc1Nc1nc2ccccc2n1-c1cc(N)ncn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 6-(2-Chloro-benzoimidazol-1-yl)-pyrimidin-4-ylamine (15 mg, 0.056 mmol), 3-amino-4-methyl-N-[4-(2-methyl-imidazol-1-yl)-3-trifluoromethyl-phenyl]-benzamide (22 mg, 0.059 mmol), and MeSO3H (11.0 μL, 0.17 mmol) in 1,3-dimethyl-2-imidazolidinone (0.2 ml) is heated at 80° C. After stirring for overnight, the reaction mixture is cooled to room temperature. Purification by reverse-phase LC-MS afforded the title compound: 1H NMR 600 MHz (DMSO-d6) δ 11.50-11.00 (bs, 1H), 10.90 (s, 1H), 9.02 (s, 1H), 8.57 (s, 1H), 8.55 (d, J=2.0 Hz, 1H), 8.37 (dd, J=8.2, 2.0 Hz 1H), 7.92 (s, 1H), 7.87 (d, J=8.2 Hz, 1H), 7.81 (d, J=2.0 Hz, 1H), 7.70 (s, 1H), 7.69 (s, 1H), 7.55-7.46 (m, 4H), 7.87 (d, J=8.2 Hz, 1H), 7.27 (t, J=8.2 Hz, 1H), 7.22 (t, J=8.2 Hz, 1H), 2.46 (s, 3H), 2.41 (s, 3H); MS m/z 584.2 (M+1).
Reaction SMILES: C(=O)(O)[O-].[Na+].[NH2:6][C:7]1[C:12]([C:13]#[N:14])=[C:11]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[C:10]([C:21]#[N:22])=[C:9]([SH:23])[N:8]=1.[CH3:24][O:25][C:26](=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33]Br)[CH:28]=1>CN(C=O)C>[NH2:6][C:7]1[N:8]=[C:9]([S:23][CH2:33][C:29]2[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=2)[C:26]([O:25][CH3:24])=[O:35])[C:10]([C:21]#[N:22])=[C:11]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[C:12]=1[C:13]#[N:14]
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: N#Cc1c(N)nc(S)c(C#N)c1C1CCCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(CSc2nc(N)c(C#N)c(C3CCCCO3)c2C#N)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
48 mg (0.58 mmol) of sodium bicarbonate are added to a solution of 50 mg (0.19 mmol) of the compound from Example 31A and 48 mg (0.21 mmol) of 3-(bromomethyl)benzoic acid methyl ester in 2 ml of dry DMF, and the mixture is stirred at RT for 20 h. The mixture is then directly purified by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].C[O-].[Na+].[I-].[Na+].Cl[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24]>O.CC(N(C)C)=O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24]
Reactant: Oc1ccc2ccccc2c1
Reactant: OCCCCCCCl
Agent: C[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: OCCCCCCOc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.6 %

Procedure:
A mixture of 50.0 g (0.348 mole) of 2-naphthol, 18.8 g (0.348 mole) of sodium methoxide, 2.0 g of sodium iodide and 800 ml of dimethylacetamide was stirred at room temperature for 1 hour, 47.5 g (0.348 mole) of 6-chlorohexanol was added. The mixture was heated to reflux with stirring for two hours, allowed to cool and poured into 3 liters of water and extracted with diethylether. The ether layer was evaporated to dryness to give a solid residue which was recrystallized from methanol to give 13.3 g of 6-(2-naphthalenyloxy)hexanol, mp=64°-65° C.
Reaction SMILES: [CH2:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([O:12][CH:13]2[CH2:15][CH2:14]2)[CH:5]=1)[CH:2]=C.N1C=CC=CC=1.[O:22]=[O+][O-]>C(Cl)Cl.CO>[CH:13]1([O:12][C:6]2[CH:5]=[C:4]([CH2:1][CH:2]=[O:22])[CH:11]=[CH:10][C:7]=2[C:8]#[N:9])[CH2:15][CH2:14]1
Reactant: C=CCc1ccc(C#N)c(OC2CC2)c1
Reactant: O=[O+][O-]
Solvent: CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1ccc(CC=O)cc1OC1CC1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
A solution of 4-allyl-2-(cyclopropyloxy)benzonitrile (100 mg, 0.5 mmol) in 1:1 CH2Cl2/MeOH (15 mL) containing pyridine (0.5 mL, 6 mmol) was cooled to −78° C., and O3 was passed through until a blue color was present. N2 was then bubbled through to discharge the blue color and Me2S (5 ml) was added. The reaction mixture was allowed to warm and left overnight. The mixture was washed with 1 N HCl and aqueous NaHCO3 and then dried and concentrated to give crude 2-(cyclopropyloxy)-4-(2-oxoethyl)benzonitrile.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6](/[CH:9]=[C:10]2/[C:11]([NH:16][CH2:17][C:18]#[CH:19])=[N:12][C:13](=[O:15])[S:14]/2)[CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([C:38]#[N:39])=[CH:30][CH:29]=1.O>CN(C=O)C>[O:15]=[C:13]1[N:12]=[C:11]([NH:16][CH2:17][C:18]#[CH:19])/[C:10](=[CH:9]/[CH:6]2[CH2:7][CH2:8][N:3]([CH2:27][C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[C:31]([C:38]#[N:39])=[CH:30][CH:29]=3)[CH2:4][CH2:5]2)/[S:14]1
Reactant: C#CCNC1=NC(=O)S/C1=C\C1CCNCC1
Reactant: N#Cc1ccc(CBr)c2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C#N)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.1 %

Procedure:
To a solution of (5Z)-5-(piperidin-4-ylmethylidene)-4-(prop-2-yn-1-ylamino)-1,3-thiazol-2(5H)-one dihydrochloride (200 mg) in DMF (3 mL) were added potassium carbonate (345 mg) and 4-(bromomethyl)naphthalene-1-carbonitrile (153 mg). The reaction mixture was stirred at room temperature overnight, water was added, and the mixture was extracted with ethyl is acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (134 mg).