Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH2:12][CH2:13][CH2:14][CH2:15][N:9]3[C:10]=2[C:5]([C:6](=O)[CH2:7][CH2:8]3)=[CH:4][CH:3]=1.[Cl:17][C:18]1[C:19]([Cl:31])=[C:20]([Cl:30])[C:21]([Cl:29])=[C:22]2[C:27](=[O:28])[O:26][C:24](=[O:25])[C:23]=12>C1C(Cl)=CC=C(Cl)C=1>[Cl:17][C:18]1[C:19]([Cl:31])=[C:20]([Cl:30])[C:21]([Cl:29])=[C:22]([C:27]([C:3]2[CH:4]=[C:5]3[C:10]4=[C:11]([CH2:12][CH2:13][CH2:14][CH2:15][N:9]4[CH2:8][CH2:7][CH2:6]3)[C:2]=2[OH:1])=[O:28])[C:23]=1[C:24]([OH:26])=[O:25]
Reactant: O=C1CCN2CCCCc3c(O)ccc1c32
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Solvent: Clc1ccc(Cl)cc1
Product: O=C(O)c1c(Cl)c(Cl)c(Cl)c(Cl)c1C(=O)c1cc2c3c(c1O)CCCCN3CCC2

Procedure:
To a solution of 9-hydroxy-2,3,5,6,7,8-hexahydro-1H-azepino[3,2,1-ij]quinolone (30 mg) in dichlorobenzene (1 mL), tetrachlorophthalic anhydride (0.13 mL) was added. After stirring at reflux for 2 hours, the solvent was removed, and the resulting crude product purified by preparative HPLC (gradient of ACN in 0.1% TFA in H2O) to provide the title compound (20 mg) as a green solid: MS expected 490 (C21H18Cl4NO4+, M+), found 490.
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:6](=[O:12])[NH:7][C:8](=[O:11])[NH:9][CH:10]=1)=[N+]=[N-].O.[H][H]>C(O)C.[Pd]>[NH2:1][CH2:4][C:5]1[C:6](=[O:12])[NH:7][C:8](=[O:11])[NH:9][CH:10]=1
Reactant: [N-]=[N+]=NCc1c[nH]c(=O)[nH]c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: NCc1c[nH]c(=O)[nH]c1=O
Reaction time: 2 h
Yield: 86.4 %

Procedure:
The solution of 5-(azidomethyl)-2,4(1H,3H)-pyrimidinedione (0.275 g, 1.64 mmol) in ethanol: water (25:5 ml) was degassed with nitrogen, palladium on carbon (5%) was added, reaction was charged with hydrogen (55 PSI) and shaken for 2 h. The reaction was filtered and concentrated to give the 5-(aminomethyl)-2,4(1H,3H)-pyrimidinedione (0.20 g, 85%) as a solid. MS found: (M+H)+=142.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]([C:14]1[N:15]=[N:16][N:17]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][C:28]4[CH:37]=[CH:36][C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]=4)[CH:21]=3)[N:18]=1)=[CH:6]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:45][CH2:46][CH2:47][Cl:48]>CN(C=O)C>[Cl:48][CH2:47][CH2:46][CH2:45][N:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH:6]=[C:7]([C:14]2[N:15]=[N:16][N:17]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][C:28]4[CH:37]=[CH:36][C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]=4)[CH:21]=3)[N:18]=2)[C:8]1=[O:13]
Reactant: COc1ccc2[nH]c(=O)c(-c3nnn(Cc4cccc(OCc5ccc6ccccc6n5)c4)n3)cc2c1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)cc(-c1nnn(Cc3cccc(OCc4ccc5ccccc5n4)c3)n1)c(=O)n2CCCCl
Temperature: 60 °C
Reaction time: 4 h
Yield: 47.2 %

Procedure:
A mixture of 6-methoxy-3-{2-[3-(2-quinolylmethoxy)benzyl]tetrazolyl}quinolin-2-one (1.00 g, 2.04 mmol), potassium carbonate (564 mg, 4.08 mmol), 1-bromo-3-chloropropane (962 mg, 6.12 mmol), and DMF (100 ml) was stirred for four hours at a bath temperature of 60° C. The solvent of the reaction mixture was removed under reduced pressure. Water was then added to the mixture, and the mixture was extracted with chloroform-methanol (10:1). The thus-obtained organic phase was dried over magnesium sulfate anhydrate, and the solvent was removed under reduced pressure. The organic phase was then subjected to silica gel column chromatography (developer: chloroform-methanol (100:1)), purified, and crystallized from a chloroform-diethylether mixture, to thereby obtain the title compound (546 mg, 0.963 mmol, 47.2%) as pale yellow powder.
Reaction SMILES: [CH3:1][N:2]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:14][C:15]3[C:20]([N:21]=2)=[CH:19][C:18]([C:22]([O:24]C)=[O:23])=[CH:17][CH:16]=3)[CH2:8][CH2:7]1)[C:3](=[O:5])[CH3:4].ClCCl.[OH-].[Na+]>CO.O>[CH3:1][N:2]([CH:6]1[CH2:7][CH2:8][N:9]([C:12]2[C:13]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[N:14][C:15]3[C:20]([N:21]=2)=[CH:19][C:18]([C:22]([OH:24])=[O:23])=[CH:17][CH:16]=3)[CH2:10][CH2:11]1)[C:3](=[O:5])[CH3:4]
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCC(N(C)C(C)=O)CC3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CC(=O)N(C)C1CCN(c2nc3cc(C(=O)O)ccc3nc2-c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of methyl 3-(4-(N-methylacetamido)piperidin-1-yl)-2-phenylquinoxaline-6-carboxylate (77 mg, 0.18 mmol, 1.00 equiv) in MeOH (15 mL). Then dichloromethane (5 mL) was added. Finally to the above was added a solution of sodium hydroxide (700 mg, 17.50 mmol, 95.00 equiv) in water (3 mL). The resulting solution was stirred for 3 hr at room temperature. The resulting mixture was concentrated under vacuum, diluted with 10 ml of H2O. The pH value of the aqueous solution was adjusted to 3 with aq. 3N hydrochloric acid. The resulting solids were collected by filtration. This resulted in 52 mg (70%) of 3-(4-(N-methylacetamido)piperidin-1-yl)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([NH2:14])=[N:11][N:10]=2)=[CH:5][CH:4]=1.[OH-].[K+].[CH2:19](O)[CH3:20].[K+].[Br-]>C(O)(=O)C>[CH2:19]([O:13][C:12]1[NH:14][C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:16])([F:15])[F:1])=[CH:4][CH:5]=2)=[N:10][N:11]=1)[CH3:20]
Reactant: Nc1nnc(-c2ccc(C(F)(F)F)cc2)o1
Reactant: CCO
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCOc1nnc(-c2ccc(C(F)(F)F)cc2)[nH]1
Temperature: 24 °C

Procedure:
5-[4-(Trifluoromethyl)phenyl]1,3,4-oxadiazol-2-amine (10 g, 44 mmol) and potassium hydroxide (7.4 g, 0.132 mol) dissolved in abs. ethanol (300 ml) were heated at reflux for 3 h. After being cooled to 24° C., the solution was neutralized with acetic acid and concentrated by rotary evaporation. The residue was taken up in ethyl acetate and washed with water and brine. Recrystallization from acetonitrile/ether (2:1) gave 9 g (82%); mp 151°-152° C.; IR(KBr, ν=cm-1) 2996, 1534, 1460, 1330, 1162, 1130, 1070; 1H NMR (300 MHz, DMSO-d6) δ1.35 (3H, t, J=7.1 Hz), 4.38 (2H, q, J=7.0 Hz), 7.82 (2H, d, J=8.3 Hz), 8.10 (2H, d, J=8.1 Hz), 13.64 (1H, br. s); MS(DCl)m/z: 258 (MH+)
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13](/[CH:14]=[C:15]2/[C:16](=[O:22])[N:17]([CH3:21])[C:18](=[O:20])[S:19]/2)=[CH:12][N:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].O1CCCC1>[CH2:1]([O:8][C:9]1[C:13]([CH2:14][CH:15]2[S:19][C:18](=[O:20])[N:17]([CH3:21])[C:16]2=[O:22])=[CH:12][N:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1C(=O)S/C(=C\c2cn(-c3ccccc3)nc2OCc2ccccc2)C1=O
Agent: [Pd]
Solvent: C1CCOC1
Product: CN1C(=O)SC(Cc2cn(-c3ccccc3)nc2OCc2ccccc2)C1=O
Yield: 55.7 %

Procedure:
(5Z)-5-[(3-Benzyloxy-1-phenyl-1H-pyrazol-4-yl)methylene]-3-methyl-1,3-thiazolidine-2,4-dione (1.0 g), 5% palladium on carbon (1.0 g) and tetrahydrofuran (150 mL) were subjected to catalytic reduction under a hydrogen atmosphere and 4.8 kgf/cm2 pressure. The catalyst was filtered off and the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (1:6, v/v) to give 5-[(3-benzyloxy-1-phenyl-1H-pyrazol-4-yl)methyl]-3-methyl-1,3-thiazolidine-2,4-dione as colorless crystals (0.56 g, yield 55%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 115-116° C.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]2[N:13](S(C3C=CC=CC=3)(=O)=O)[CH:12]=[C:11]([CH2:23][N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:10]=2[F:33])=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].O1CCCC1.[OH-].[Na+]>CO>[C:1]([C:3]1[C:8]([C:9]2[NH:13][CH:12]=[C:11]([CH2:23][N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:30])[CH3:28])[C:10]=2[F:33])=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2]
Reactant: CN(Cc1cn(S(=O)(=O)c2ccccc2)c(-c2cccnc2C#N)c1F)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(Cc1c[nH]c(-c2cccnc2C#N)c1F)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 57.2 %

Procedure:
To a mixture of tert-butyl {[5-(2-cyanopyridin-3-yl)-4-fluoro-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (5.43 g), tetrahydrofuran (50 mL), and methanol (13 mL) was added a 8 mol/L aqueous sodium hydroxide solution (2 mL) at 0° C., and the mixture was stirred at the same temperature for 30 min. The reaction mixture was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane:ethyl acetate=1:1), and further by silica gel column chromatography (eluent: hexane:ethyl acetate=1:1) to give the title compound as a yellow oil (yield 2.18 g, 57%).
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH2:25])=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH:25][C:2]2[CH:16]=[CH:15][C:5]3[C:6](=[O:14])[NH:7][C:8]4[C:13]([C:4]=3[CH:3]=2)=[CH:12][CH:11]=[CH:10][N:9]=4)=[CH:20][CH:19]=1
Reactant: O=c1[nH]c2ncccc2c2cc(Cl)ccc12
Reactant: NCc1ccc(Cl)cc1
Product: O=c1[nH]c2ncccc2c2cc(NCc3ccc(Cl)cc3)ccc12
Yield: 13.9 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 448 using 6 (100 mg, 0.43 mmol) and (4-chloro-phenyl)methanamine (245 mg, 1.73 mmol) to provide 452 (20 mg, 14% yield) as a white powder. LC-MS (M+H=337, obsd.=337). 1H NMR (400 MHz, DMSO-D6) δ 11.49 (s, 1H), 8.56 (d, J=8.3, 1H), 8.41 (s, 1H), 7.99 (d, J=8.8, 1H), 7.44 (dd, J=8.5, 22.3, 2H), 7.37 (s, 2H), 7.25 (d, J=12.5, 2H), 6.95 (s, 1H), 4.51 (s, 2H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[C:17](=[O:18])[C:16]3=CC=C[CH:22]=[C:15]3[C:14]2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN.[OH-].[Na+].O1C=CC(C=O)=C1.[BH4-].[Na+]>C(O)C>[O:18]1[CH:17]=[CH:16][C:15]([CH2:14][NH:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:22]1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCc1ccccc1
Agent: NN
Agent: O=Cc1ccoc1
Agent: [BH4-]
Solvent: CCO
Solvent: O
Product: c1ccc(CCCCCCNCc2ccoc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 9.138 g (29.73 mmol) of N-(6-phenylhexyl)phthalimide and 2.16 ml (44.6 mmol) of hydrazine monohydrate in 100 ml of ethanol was refluxed for 1 hour. After cooling to room temperature, the reaction mixture was poured into aqueous sodium hydroxide and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude 6-phenylhexylamine was dissolved in 100 ml of methanol; 2.86 g (29.7 mmol) of 3-furaldehyde was added, followed by stirring at room temperature for 0.5 hours, after which 2.25 g (59.5 mmol) of sodium borohydride was added under ice-cooling, followed by stirring at room temperature for 1 hour. The reaction mixture was poured into aqueous sodium hydroxide and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The crude product was purified by silica gel column chromatography (hexane/ethyl acetate=1/1 to ethyl acetate) to yield the desired product.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14]3[C:18]([NH:19][C:20](=[O:29])[C:21]4[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=4[F:28])=[CH:17][NH:16][N:15]=3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].O.[OH-].[Li+]>C1COCC1.O>[F:28][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([F:27])[C:21]=1[C:20]([NH:19][C:18]1[C:14]([C:11]2[NH:10][C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[C:13]=3[N:12]=2)=[N:15][NH:16][CH:17]=1)=[O:29]
Reactant: COC(=O)c1cccc2[nH]c(-c3n[nH]cc3NC(=O)c3c(F)cccc3F)nc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1c[nH]nc1-c1nc2c(C(=O)O)cccc2[nH]1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.3 %

Procedure:
A solution of 2-[4-(2,6-difluoro-benzoylamino)-1H-pyrazol-3-yl]-1H-benzimidazole-4-carboxylic acid methyl ester (220 mg, 0.55 mmol) in THF/water (1:1, 10 ml) was treated with lithium hydroxide hydrate (70 mg, 1.66 mmol) and the mixture stirred at ambient temperature for 18 h. The volatiles were removed in vacuo, the mixture acidified to pH5 by the addition of 2M aqueous hydrochloric acid and the solid formed collected by filtration, washed with water then dried under vacuum to give 2-[4-(2,6-difluoro-benzoylamino)-1H-pyrazol-3-yl]-1H-benzimidazole-4-carboxylic acid (165 mg) as a brown solid. (LC/MS: Rt 3.28, [M+H]+ 384).
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH:13](C#N)[S:14]([N:17]([CH:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:18])(=[O:16])=[O:15])=[CH:10][CH:11]=2)[C:6]([CH2:34][C@H:35]2[CH2:39][CH2:38][CH2:37][N:36]2[CH3:40])=[CH:5]1)[CH:2]=[CH2:3].[OH-].[K+]>C(O)C>[CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][S:14]([N:17]([CH:19]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:18])(=[O:15])=[O:16])=[CH:10][CH:11]=2)[C:6]([CH2:34][C@H:35]2[CH2:39][CH2:38][CH2:37][N:36]2[CH3:40])=[CH:5]1)[CH:2]=[CH2:3]
Reactant: C=CCn1cc(C[C@H]2CCCN2C)c2cc(C(C#N)S(=O)(=O)N(C)C(c3ccccc3)c3ccccc3)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C=CCn1cc(C[C@H]2CCCN2C)c2cc(CS(=O)(=O)N(C)C(c3ccccc3)c3ccccc3)ccc21
Temperature: 25 °C
Yield: 75.8 %

Procedure:
To a stirred solution of 1-[(R)-1-allyl-3-(1-methyl-2-pyrrolidinylmethyl)-1H-indol-5-yl]-1-cyano-N-diphenylmethyl-N-methylmethanesulfonamide (from step (b), 5.11 g, 9.25 mmol) in ethanol (10.22 ml) at ambient temperature was added 2N potassium hydroxide solution (20.4 ml, 41 mmmol). The dark brown solution was then brought to reflux and maintained at this temperature for 15 hr. The oily reaction mixture was then cooled to ambient temperature and extracted with ethyl acetate (3×50 ml). The organic extracts were combined and evaporated in vacuo to yield a dark brown oil. This was purified by flash column chromatography (ethyl acetate:hexane:diethylamine 1:1:0.1 as eluant) to yield the title compound (3.7 g, 76%) as a brown oil.
Reaction SMILES: C([O:3][C:4](=[O:35])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:33])[C:16]([OH:32])([C:21]2[CH:22]=[CH:23][C:24]3[O:28][C:27](=[O:29])[N:26]([CH3:30])[C:25]=3[CH:31]=2)[C:17]([F:20])([F:19])[F:18])=[C:11]([Cl:34])[CH:10]=1)([CH3:7])[CH3:6])C.[Li+].[OH-].O.Cl>C1COCC1>[Cl:34][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[CH:15]([CH3:33])[C:16]([OH:32])([C:21]1[CH:22]=[CH:23][C:24]2[O:28][C:27](=[O:29])[N:26]([CH3:30])[C:25]=2[CH:31]=1)[C:17]([F:19])([F:18])[F:20])[O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:35])=[O:3]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(C(C)C(O)(c2ccc3oc(=O)n(C)c3c2)C(F)(F)F)c(Cl)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(c1ccc(OC(C)(C)C(=O)O)cc1Cl)C(O)(c1ccc2oc(=O)n(C)c2c1)C(F)(F)F
Reaction time: 3 h
Yield: 16 %

Procedure:
2-{3-Chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(3-methyl-2-oxo-2,3-dihydro-benzooxazol-5-yl)-propyl]-phenoxy}-2-methyl-propionic acid ethyl ester (99 mg, obtained in Example 229) was dissolved in THF (2.3 mL) under argon. LiOH solution (1M, 0.31 mL) was added and the mixture was stirred for 3 hours. Another 0.19 mL of the LiOH solution was added and stirring was continued at r.t. for 48 hours. The reaction mixture was poured into water containing ice and the aqueous solution was acidified with 1M HCl to pH 1. The aqueous mixture was extracted with ethyl acetate and the organic extracts were washed with brine, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (silica gel, ethyl acetate, then ethyl acetate containing 0.25% acetic acid) to provide the title compound 2-{3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(3-methyl-2-oxo-2,3-dihydro-benzooxazol-5-yl)-propyl]-phenoxy}-2-methyl-propionic acid as a light brown foam (15 mg). MS (m/e, ISP neg. ion)=486.5 [M−H+].
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.NC(N)=[S:14].[OH-].[K+].[OH-].[Na+]>O.C(O)C>[SH:14][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1
Reactant: NC(N)=S
Reactant: FC(F)(F)c1ccnc(Cl)c1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: FC(F)(F)c1ccnc(S)c1
Yield: 51 %

Procedure:
To 1.0 g of 2-chloro-4-trifluoromethylpyridine (Lancaster Chemical Co) is added 10 ml of absolute ethanol and 417 mg of thiourea. The reaction mixture is heated at reflux for 4 hours and 1.25 ml of a solution of 7.44 g KOH in 20 ml of water is added. The solution is heated at reflux for an additional 1 hour. The reaction solution is cooled and poured into 100 ml of a 0.1N NaOH solution. The resulting solution is extracted three times with 100 ml of methylene chloride and the resulting aqueous solution is acidified to pH 4 by addition of glacial acetic acid. The aqueous solution is extracted three times with 100 ml of methylene chloride and the organic solution is dried over anhydrous sodium sulfate. Filtration followed by evaporation to dryness gives 501 mg of a yellow crystalline solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:20]([OH:22])=O)[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(C1NC=CN=1)(C1NC=CN=1)=O.[CH3:35][O:36][C:37]1[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=1[CH2:39][NH2:40]>O1CCOCC1>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)[C:20]([NH:40][CH2:39][C:38]1[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=1[O:36][CH3:35])=[O:22])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccccc1CN
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1COCCO1
Product: COc1ccccc1CNC(=O)C(Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of N-(t-butoxycarbonyl)tryptophan (46.4 g, 152.6 mmoles) in 500 ml of dioxane was added carbonyl diimidazole (25.4 g, 156 mmoles) in a portionwise manner. The resulting mixture was stirred for about 2.5 hours at room temperature and then stirred at 45° C. for 30 minutes. Next, 2-methoxybenzylamine (20.7 ml, 158.7 mmoles) was added and the reaction mixture was then stirred for 16 hours at room temperature.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[CH:10][CH:9]=[C:8](I)[N:7]=1.[C:29]1([C:35]#[CH:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[CH:10][CH:9]=[C:8]([C:36]#[C:35][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:7]=1
Reactant: COC(=O)CCc1nc(I)ccc1OCCCC/C=C/c1ccc(OC)cc1
Reactant: C#Cc1ccccc1
Product: COC(=O)CCc1nc(C#Cc2ccccc2)ccc1OCCCC/C=C/c1ccc(OC)cc1
Yield: 56.5 %

Procedure:
Under the conditions of example 5 A, 500 mg of 3-{6-iodo-3-[6-(4-methoxyphenyl)-(5E)-5-hexenyloxy]-2-pyridyl}-propionic acid methyl ester is reacted with 102 mg of phenylacetylene, worked up, and the crude product is chromatographed on silica gel with hexane/0-7% ethyl acetate. 265 mg of 3-{3-[6-(4-methoxyphenyl)-(5E)-5-hexenyloxy]-6-(2-phenylethinyl)-2-pyridyl}-propionic acid methyl ester is obtained as oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.[C:17]([CH2:19][N:20]([C@H:25]1[CH2:30][CH2:29][C@@H:28]([NH:31][C:32]2[C:37]([Cl:38])=[CH:36][N:35]=[C:34](Cl)[N:33]=2)[CH2:27][CH2:26]1)[S:21]([CH3:24])(=[O:23])=[O:22])#[N:18]>>[Cl:38][C:37]1[C:32]([NH:31][C@@H:28]2[CH2:27][CH2:26][C@H:25]([N:20]([CH2:19][C:17]#[N:18])[S:21]([CH3:24])(=[O:23])=[O:22])[CH2:30][CH2:29]2)=[N:33][C:34]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:35][CH:36]=1
Reactant: CS(=O)(=O)N(CC#N)[C@H]1CC[C@@H](Nc2nc(Cl)ncc2Cl)CC1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(N[C@H]4CC[C@@H](N(CC#N)S(C)(=O)=O)CC4)n3)cc2CC1

Procedure:
cis-N-(4-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-cyclohexyl)-N-cyanomethyl-methanesulfonamide was prepared from 3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and cis-N-cyanomethyl-N-[4-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide in an analogous manner to Example 308c. Product isolated as a pale yellow foam (52 mg, 54%). LCMS (m/e) 562 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 7.94 (s, 1H), 7.33 (s, 1H), 7.28 (d, 1H, J=8.0 Hz), 7.02 (d, 1H, J=8.0 Hz), 6.95 (s, 1H), 5.25 (d, 1H, J=6.0 Hz), 4.33-4.27 (m, 1H), 4.25 (s, 2H), 3.91-3.79 (m, 1H), 3.56 (t, 2H, J=5.6 Hz), 3.39 (s, 3H), 3.09 (s, 3H), 2.95-2.86 (m, 4H), 2.80-2.67 (m, 6H), 2.29-2.20 (m, 2H), 1.97-1.73 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[O:4].C(=O)([O-])[O-].[Na+].[Na+]>O.[Pd]>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:13]=[CH:14][CH:15]=1)=[O:4]
Reactant: COC(=O)c1cccc(C=CC(=O)O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cccc(CCC(=O)O)c1

Procedure:
A solution of 3-methoxycarbonyl-cinnamic acid (15.0 g) and sodium carbonate (7.7 g) in water (200 ml) was hydrogenated at 50 psi over 10% palladium on charcoal (0.5 g) for 1.5 hours. The catalyst was filtered off and the filtrate was acidified with 2M hydrochloric acid to precipitate the product as a white solid, m.p. 81° C.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH:5]([NH:18]C=O)/[CH:6]=[C:7](\[CH:15]([CH3:17])[CH3:16])/[CH2:8][P:9]([O:13]C)([O:11]C)=[O:10])C>O>[NH2:18][CH:5](/[CH:6]=[C:7](\[CH:15]([CH3:17])[CH3:16])/[CH2:8][P:9]([OH:13])([OH:11])=[O:10])[C:4]([OH:21])=[O:3]
Reactant: CCOC(=O)C(/C=C(/CP(=O)(OC)OC)C(C)C)NC=O
Solvent: O
Product: CC(C)/C(=C\C(N)C(=O)O)CP(=O)(O)O

Procedure:
Hydrolysis of E-2-formylamino-4-isopropyl-5-dimethylphosphono-3-pentenoic acid ethyl ester analogously to Example 11 yields E-2-amino-4-isopropyl-5-phosphono-3-pentenoic acid, m.p. 201° (H2O).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>C(Cl)(Cl)Cl>[CH3:13][N:14](/[CH:16]=[C:3]1\[C:2](=[O:10])[NH:1][C:9]2[C:4]\1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:15]
Reactant: COC(OC)N(C)C
Reactant: O=C1Cc2ccccc2N1
Solvent: ClC(Cl)Cl
Product: CN(C)/C=C1\C(=O)Nc2ccccc21
Temperature: 70 °C
Reaction time: 4.5 h

Procedure:
To a solution of 1,3-dihydro-2H-indol-2-one (ii-a, 25.0 g, 189 mmol) in CHCl3 (150 mL) was added N,N-dimethylformamide dimethyl acetal (29.2 mL, 209 mmol) and the reaction was heated at 70° C. under an atmosphere of argon. After 4.5 h, the reaction was cooled to RT and was concentrated. The resulting solid was triturated with ether and filtered to give (3Z)-3-[(dimethylamino)methylene]-1,3-dihydro-2H-indol-2-one as a yellow solid (iii-a, 33.0 g, 93%). NH4OAc QC conditions. DAD Retention Time =1.19 min. M+H=189.