Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([OH:9])[C:6]([O:10][CH2:11][CH2:12][CH3:13])=[CH:5][N:4]=1.CO[CH:16]=[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]3[O:28][CH:29]=[CH:30][CH:31]=3)[CH:25]=2)[C:20](=[O:32])[NH:19][C:18]1=[O:33]>CN(C)C=O>[O:28]1[CH:29]=[CH:30][CH:31]=[C:27]1[C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[C:20](=[O:32])[NH:19][C:18](=[O:33])[C:17]2=[CH:16][NH:1][CH2:2][C:3]1[CH:8]=[C:7]([OH:9])[C:6]([O:10][CH2:11][CH2:12][CH3:13])=[CH:5][N:4]=1
Reactant: CCCOc1cnc(CN)cc1O
Reactant: COC=C1C(=O)NC(=O)c2ccc(-c3ccco3)cc21
Solvent: CN(C)C=O
Product: CCCOc1cnc(CNC=C2C(=O)NC(=O)c3ccc(-c4ccco4)cc32)cc1O

Procedure:
A mixture of 2-aminomethyl-5-propoxy-pyridin-4-ol (73 mg, 0.40 mmole), 5 mL of N,N-dimethylformamide is stirred, then 4-methoxymethylene-6-(furan-2-yl)-4H-isoquinoline-1,3-dione (108 mg, 0.40 mmole) is added and the reaction mixture stirred for one hour. The reaction mixture is evaporated to dryness, triturated with 5% methanol in chlororform, filtered washed with fresh 5% methanol in chloroform, washed with acetonitrile and dried to give a pale yellow solid, 139 mg, (83%); m.p. 288-90° C. dec; MS (ES+): m/z 420.2 (M+H).
Reaction SMILES: B.[C:2]1([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](O)=[O:14])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCCC1>[C:2]1([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CCCCCc1ccccc1
Agent: B
Solvent: C1CCOC1
Product: OCCCCCCc1ccccc1
Reaction time: 1.5 h

Procedure:
To 100 ml. of 1 molar borane in tetrahydrofuran cooled in an ice bath is added 19.2 g. of 6-phenylhexanoic acid over a period of 30 minutes. The solution is stirred for 1.5 hours and an additional 100 ml. of 1 molar borane in tetrahydrofuran is added. After stirring overnight at room temperature the reaction mixture is poured into 500 g. of ice. The mixture is extracted with ether, the extracts washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give 6-phenylhexanol as a light yellow liquid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].[NH2:21][CH2:22][CH2:23][CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][C:26]1=[O:30]>>[N+:18]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:21][CH2:22][CH2:23][CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][C:26]1=[O:30])=[CH:10][CH:9]=[C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:7]=2)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1cnc2cc(-c3ccccc3)ccc2c1Cl
Reactant: NCCCN1CCCC1=O
Product: O=C1CCCN1CCCNc1c([N+](=O)[O-])cnc2cc(-c3ccccc3)ccc12
Yield: 88.1 %

Procedure:
4-Chloro-3-nitro-7-phenylquinoline (3.51 g, 12.3 mmol) was treated with 1-(3-aminopropyl)pyrrolidin-2-one (2.3 mL, 16 mmol) according to the method described in Part E of Example 1 to provide 4.23 g of 1-[3-(3-nitro-7-phenylquinolin-4-ylamino)propyl]pyrrolidin-2-one as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4][NH2:5].C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([N:40]2[C:45](=[O:46])N(CC3C(F)=CC(F)=CC=3F)[C:43]3[N:57]=[CH:58][CH:59]=[CH:60][C:42]=3[S:41]2(=[O:62])=[O:61])[CH:35]=[CH:36][C:37]=1[O:38][CH3:39]>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4][N:5]1[C:43]2[N:57]=[CH:58][CH:59]=[CH:60][C:42]=2[S:41](=[O:62])(=[O:61])[N:40]([C:34]2[CH:35]=[CH:36][C:37]([O:38][CH3:39])=[C:32]([O:31][CH3:30])[CH:33]=2)[C:45]1=[O:46]
Reactant: COc1ccc(N2C(=O)N(Cc3c(F)cc(F)cc3F)c3ncccc3S2(=O)=O)cc1OC
Reactant: NCc1c(F)cccc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Product: COc1ccc(N2C(=O)N(Cc3c(F)cccc3Cl)c3ncccc3S2(=O)=O)cc1OC

Procedure:
The title compound (48 mg, 0.10 mmol) was prepared in two steps from (IntC1) (82 mg, 0.25 mmol) and 2-chloro-6-fluorobenzyl amine (0.1 mL, 0.75 mmol); followed by 1,1′-carbonyldiimidazole (191 mg, 1.18 mmol) and triethylamine (0.08 mL, 0.59 mmol) using the methods of (93).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9]C(OC)=O)=[CH:4][C:3]=1[N:14]1[C:22](=[O:23])[C:17]2=[CH:18][CH2:19][CH2:20][CH2:21][N:16]2[C:15]1=[O:24].C(=O)([O-])[O-].[K+].[K+].Cl>CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:14]1[C:22](=[O:23])[C:17]2=[CH:18][CH2:19][CH2:20][CH2:21][N:16]2[C:15]1=[O:24]
Reactant: COC(=O)Oc1cc(N2C(=O)C3=CCCCN3C2=O)c(Cl)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C1C2=CCCCN2C(=O)N1c1cc(O)c(Cl)cc1Cl
Yield: 80.4 %

Procedure:
A methanol (10 mL) solution of 2-(2,4-dichloro-5-methoxycarbonyloxyphenyl)-5,6-dihydroimidazo [1,5-a] pyridine-1,3[2H, 7H]-dione (0.50 g, 1.35 mmol) and potassium carbonate (0.19 g, 1.35 mmol) was stirred at 50°-60° C. for 2 hours. 1N Hydrochloric acid (20 mL) was added to the resulting mixture, and the organic layer was separated and then the aqueous layer was extracted with ethyl acetate (10 mL×2 times). The organic layer combined was washed with a saturated sodium chloride solution (30 mL) and dried over anhydrous magnesium sulfate. After removal of magnesium sulfate by filtration, the filtrate was evaporated to give a white solid of 2-(2,4-dichloro-5-hydroxyphenyl)-5,6-dihydroimidazo [1,5-a] pyridine-1,3[2H, 7H]-dione (0.34 g, yield:81.0%).
Reaction SMILES: Br[C:2]1[CH:16]=[C:15]([CH2:17][NH:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:14]=[CH:13][C:3]=1[O:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[C:29]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)#[N:30].C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1.O>[C:29]([C:31]1[CH:36]=[C:35]([C:2]2[CH:16]=[C:15]([CH2:17][NH:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:14]=[CH:13][C:3]=2[O:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH:34]=[CH:33][CH:32]=1)#[N:30]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CC(C)(C)OC(=O)COc1ccc(CNS(=O)(=O)c2ccc(F)cc2)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)COc1ccc(CNS(=O)(=O)c2ccc(F)cc2)cc1-c1cccc(C#N)c1
Temperature: 25 °C
Yield: 76.1 %

Procedure:
t-butyl 2-(2-bromo-4-((4-fluorophenylsulfonamido)methyl)phenoxy)acetate (7) (64 mg, 0.135 mm ol, 1 eq), 3-cyanophenylboronic acid (30 mg, 0.20 mmol, 1.5 eq), K2CO3 (75 mg, 0.54 mmol, 4 eq), Pd(PPh3)4 (2.3 mg, 0.001 mmol, 0.01 eq) and 4 mL of dioxane/H2O (4:1) were heated to 140° C. for 1 h in a microwave. The mixture was then cooled to room temperature, filtered, concentrated in vacuo, and purified by preparative TLC to give 51 mg (76%) of t-butyl 2-(2-(3-cyanophenyl)-4-((4-fluorophenylsulfonamido)methyl)phenoxy)acetate (8).
Reaction SMILES: Br[CH2:2][C:3]([CH:5]1[O:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[O:7][CH2:6]1)=[O:4].[BH4-].[Na+].[OH-].[Na+]>CO>[O:10]1[C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[O:7][CH2:6][CH:5]1[CH:3]1[O:4][CH2:2]1
Reactant: O=C(CBr)C1COc2ccccc2O1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: c1ccc2c(c1)OCC(C1CO1)O2
Reaction time: 5 h

Procedure:
The starting material is prepared as follows: To the solution of 42 g of 2-(2-bromoacetyl)-1,4-benzodioxan in 360 ml of methanol, 12 g of sodium borohydride are added while stirring and keeping the temperature below 10°. After five hours, the mixture is cooled to 0° and 13.2 g of sodium hydroxide in 150 ml of methanol are added and the mixture kept at -15° overnight. It is poured onto ice, extracted with diethyl ether, the extract washed with saturated aqueous sodium chloride, dried and evaporated, to yield the 1,4-benzodioxan-2-yl-ethyleneoxide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[CH2:30][C:31]1[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][N:32]=1>C1COCC1.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:30][C:31]2[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][N:32]=2)([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccnc(CCl)c1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)C1(Cc2cc(C)ccn2)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 8 h

Procedure:
To a cold (−78° C.) solution of ethyl N-tert-butoxycarbonyl-piperidine-4-carboxylate (5.1 g, 19.8 mmol; Example 30, Step A) in anhydrous THF (50 mL), a solution of solution of sodium bis(trimethyl-silyl)amide (20 mL, 1M, 20 mmol) was added over a period of 15 min. The resultant mixture was stirred at −78° C. for 1 h., and 2-chloromethyl-4-methylpyridine (3.5 g, 24.7 mmol) was added. The reacting mixture was allowed to warm to room temp. and stirred overnight. The product mixture was diluted with dichloromethane was washed with brine. The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 25-40% ethyl acetate in hexane gradient. Collection and concentration of appropriate fractions provided the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][NH2:13])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[C:14]1([N:20]=[C:21]=[N:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1>[C:23]1([NH:22][C:21]([NH:13][NH:12][C:9]2[CH:10]=[CH:11][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=2)=[N:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: C(=Nc1ccccc1)=Nc1ccccc1
Reactant: CCOC(=O)c1ccc(NN)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(NNC(=Nc2ccccc2)Nc2ccccc2)cc1
Reaction time: 1 h
Yield: 82.4 %

Procedure:
In 70 ml of tetrahydrofuran were dissolved 9.0 g of 4-ethoxycarbonylphenylhydrazine and 9.7 g of 1,3-diphenylcarbodiimide and after stirring the solution for one hour under ice-cooling, tetrahydrofuran was distilled off under reduced pressure. Then, when 70 ml of benzene and 70 ml of n-hexane were added to the residue thus formed, crystals deposited. By collecting the crystals thus deposited by filtration, 15.4 g of 1,2-diphenyl-3-(4-ethoxycarbonylphenylamino)guanidine was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]#[N:10])=[C:4]([Cl:11])[N:3]=1.C(N(C(C)C)C(C)C)C.[CH2:21]([CH2:23][NH2:24])[OH:22]>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]([C:9]#[N:10])=[C:6]([NH:24][CH2:23][CH2:21][OH:22])[N:7]=1
Reactant: N#Cc1c(Cl)nc(Cl)nc1Cl
Reactant: NCCO
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1c(Cl)nc(Cl)nc1NCCO
Reaction time: 18 h
Yield: 25 %

Procedure:
A solution of 3.0 g (14.4 mmol) of 2,4,6-trichloro-5-cyano-pyrimidine (example 38a) and 2.51 ml (14.4 mmol) of N-ethyl-diisopropylamine in 90 ml of dioxane was treated at room temperature with 0.88 ml (14.4 mmol) of ethanolamine and stirred during 18 hours. For the working-up, the yellow solution was evaporated and the residue dissolved in 300 ml dichloromethane. The organic phase was washed twice with 50 ml of water, and the two aqueous phases were re-extracted with 50 ml of dichloromethane. The combined organic phases were dried over sodium sulfate and evaporated under reduced pressure. For purification and separation of the two isomers, the crude material (3.2 g) was chromatographed (2×) on silica gel using a 2:1 mixture of hexane and ethyl acetate as the eluent giving 0.85 g (3.6 mmol, 25% of theory) of the 2,4-dichloro-6-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile (less polar isomer); MS: [M]+=232; 1.51 g (6.5 mmol, 45% of theory) of the 4,6-dichloro-2-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile (more polar isomer); MS: [M]+=232; and 0.26 g (1.1 mmol, 8% of theory) of a mixture of the two isomers.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[CH2:11][NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:5]=[C:6]([Cl:8])[CH:7]=1.Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[N:25]>>[C:24]([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][N:12]([CH2:11]/[CH:10]=[CH:9]/[C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=1)[S:13]([CH3:16])(=[O:15])=[O:14])#[N:25]
Reactant: CS(=O)(=O)NC/C=C/c1cc(Cl)cc(Cl)c1
Reactant: N#CCCCCCCBr
Product: CS(=O)(=O)N(C/C=C/c1cc(Cl)cc(Cl)c1)CCCCCCC#N
Yield: 79.7 %

Procedure:
In an analogous manner to the procedure described in Step A of Example 1, trans-N-[3-(3,5-dichloro-phenyl)-allyl]-methanesulfonamide (500 mg, 2.45 mmol) was alkylated with 7-bromoheptanenitrile (781 mg, 2.94 mmol) at room temperature over 24 h to provide the title compound of Step A (760 mg). 1H NMR (CDCl3 400 MHz) δ 7.26 (m, 3H), 6.49 (d, 1H), 6.22 (m, 1H), 3.98 (m, 2H), 3.22 (t, 2H), 2.88 (s, 3H), 2.36 (t, 2H), 1.68–1.35 (m, 8H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[C:9]1(=O)[CH2:13][CH2:12][CH2:11][CH2:10]1.[BH3-]C#N.[Na+]>C(Cl)Cl.C(OC)(C)(C)C.Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)nc1
Reactant: O=C1CCCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: Brc1ccc(NC2CCCC2)cn1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 31.5 %

Procedure:
To a solution of 6-bromopyrid-3-ylamine (2.0 g, 11.6 mmol) in CH2Cl2 (30 mL) was added cyclopentanone (1.3 mL) 15.5 mmol), followed by TiCl4 (1.4 mL, 12.7 mmol) in CH2Cl2 (20 mL) and after stirring for 3.5 h at room temperature, NaBH3CN (2.17 g, 34.5 mmol) was added portion-wise. The reaction was left to stir overnight at ambient temperature, diluted with t-BuOMe (200 mL), washed with water, brine and dried (Na2SO4). Solvent removal and purification by chromatography afforded the sub-title compound (880 mg, 40%).
Reaction SMILES: CC(C[AlH]CC(C)C)C.[C:10]1([C:16]2[CH:21]=[C:20](/[CH:22]=[CH:23]/[C:24](OCC)=[O:25])[CH:19]=[C:18]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([C:16]2[CH:21]=[C:20](/[CH:22]=[CH:23]/[CH2:24][OH:25])[CH:19]=[C:18]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:17]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCOC(=O)/C=C/c1cc(-c2ccccc2)cc(-c2ccccc2)c1
Agent: CC(C)C[AlH]CC(C)C
Product: OC/C=C/c1cc(-c2ccccc2)cc(-c2ccccc2)c1

Procedure:
The colourless solid (E)-3-[1,1′;3′,1″]terphenyl-5′-yl-prop-2-en-1-ol was prepared by DIBAL-H reduction of (E)-ethyl 3-[1,1′;3′,1″]terphenyl-5′-yl-acrylate by a procedure analogous to that described for example 52b.
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[CH:9]=[C:10]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:12].[S:25](Cl)([C:28]1[C:40]2[CH:39]=[CH:38][CH:37]=[C:33]([N:34]([CH3:36])[CH3:35])[C:32]=2[CH:31]=[CH:30][CH:29]=1)(=[O:27])=[O:26]>O>[CH3:35][N:34]([CH3:36])[C:33]1[CH:37]=[CH:38][CH:39]=[C:40]2[C:32]=1[CH:31]=[CH:30][CH:29]=[C:28]2[S:25]([NH:7][C:8]1[CH:9]=[C:10]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:12])(=[O:27])=[O:26]
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NS(=O)(=O)c1cccc2c(N(C)C)cccc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 91.1 %

Procedure:
Pyridine (5 mL) was added to a mixture of 3-amino-4-methoxy-N-phenyl-benzamide (0.73 g, 3.0 mmol) and dansyl chloride (0.81 g, 3.0 mmol) and stirred under an inert atmosphere at room temperature. After 20 hours, the mixture was diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined extracts were washed with water then saturated brine, then dried over MgSO4 and stripped of solvent under reduced pressure to afford the product (1.3 g); m.p. 231-232° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]2[C:15](=[O:16])[C:14]3[CH:17]=[CH:18][C:19]([OH:21])=[CH:20][C:13]=3[O:12]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:22](Cl)(=[O:24])[CH3:23].C(OCC)(=O)C>N1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]2[C:15](=[O:16])[C:14]3[CH:17]=[CH:18][C:19]([O:21][C:22](=[O:24])[CH3:23])=[CH:20][C:13]=3[O:12]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CC(=O)Cl
Reactant: COc1ccc(C=C2Oc3cc(O)ccc3C2=O)cc1C
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1ccc(C=C2Oc3cc(OC(C)=O)ccc3C2=O)cc1C
Temperature: 25 °C

Procedure:
After 2-[(3-methyl-4-methoxyphenyl)methylene]-6-hydroxy-3(2H)- benzofuranone 0.5 g was dissolved in pyridine 5 ml, acetyl chloride 0.2 ml was added, and the mixture was refluxed for 1.5 hours. The solution was cooled to room temperature, ethyl acetate 50 ml was added, and the mixture was washed with 2N-hydrochloric acid 50 ml twice. After the ethyl acetate solution was dehydrated with anhydrous magnesium sulfate, it was concentrated under reduced pressure. The residue was fractionated by silica gel column chromatography (silica gel: 50 g, eluted with solvent 500 ml of hexane:ethyl acetate=1:1) and the fraction was concentrated to dryness at a temperature of 40° C. under reduced pressure to obtain crystals. The crystals were dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 436.6 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([NH:20][CH:21]([CH3:23])[CH3:22])[C:5]([C:6]([NH:8][CH:9]([C:15](=[O:17])[CH3:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=O)=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]2[O:17][C:15]([CH3:16])=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:8]=2)=[C:18]([NH:20][CH:21]([CH3:23])[CH3:22])[CH:19]=1
Reactant: CCOC(=O)C(NC(=O)c1cnc(Cl)cc1NC(C)C)C(C)=O
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1nc(-c2cnc(Cl)cc2NC(C)C)oc1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of ethyl 2-(6-chloro-4-(isopropylamino)nicotinamido)-3-oxobutanoate (27a) (200 mg, 0.58 mmol) in DCM (10 mL), triphenyl phosphine (2 equiv.), iodine (2 equiv.) and triethyl amine (3 equiv.) were added and stirred at room temperature for 4 h. The reaction mixture was diluted using DCM and washed with water. The organic layer was collected, dried over Na2SO4, filtered and concentrated. The crude material obtained was purified by column chromatography using silica gel and EtOAc: Pet. Ether as eluent to obtain the title compound, ethyl 2-(6-chloro-4-(isopropylamino)pyridin-3-yl)-5-methyloxazole-4-carboxylate. 1H NMR: 400 MHz, DMSO-d6: δ 1.25 (d, J=6.40 Hz, 6H), 1.33 (t, J=7.20 Hz, 3H), 2.67 (s, 3H), 3.90-3.95 (m, 1H), 4.31 (q, J=7.20 Hz, 2H), 6.89 (s, 1H), 8.47 (d, J=7.60 Hz, 1H), 8.54 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[C:8]([CH3:13])([CH3:12])[CH:7]2O.[NH:15]1[CH:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[N:17]=[CH:16]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.Cl.O1CCOCC1>C1COCC1>[CH3:23][O:22][C:20]([C:18]1[N:17]([CH:7]2[C:6]3[C:10](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=3)[C:9](=[O:11])[C:8]2([CH3:13])[CH3:12])[CH:16]=[N:15][CH:19]=1)=[O:21]
Reactant: COC(=O)c1c[nH]cn1
Reactant: CC1(C)C(=O)c2c(Cl)cccc2C1O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: COC(=O)c1cncn1C1c2cccc(Cl)c2C(=O)C1(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 7-chloro-3-hydroxy-2,2-dimethyl-indan-1-one (1.10 g, 5.24 mmol) in THF (50 mL) is added methyl 4-imidazolecarboxylate (CAS#17325-26-7, 1.0 g, 7.85 mmol), followed by triphenylphosphine (2.1 g, 7.85 mmol). The reaction is cooled to 0° C. and di-t-butyl azodicarboxylate (1.8 g, 7.85 mmol) is added. The reaction is permitted to warm to room temperature and stirred for 2 hours. The reaction mixture is then cooled to 0° C., quenched with 4 N HCl in dioxane (5 mL, 20 mmol) and stirred for 30 minutes. The reaction is concentrated to near dryness and diluted with ethyl acetate. The organic layer is extracted three times with 1 N aqueous HCl. The aqueous extracts are combined, neutralized with Na2CO3, and extracted three times with ethyl acetate. The organic layers are combined, dried over Na2SO4, filtered concentrated. The resulting residue is purified by silica gel flash chromatography (ethyl acetate-heptane, 0:1 to 1:1) to furnish 3-(4-chloro-2,2-dimethyl-3-oxo-indan-1-yl)-3H-imidazole-4-carboxylic acid methyl ester; MS: (ESI) m/z 319.0 (M+H)+
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([NH:15][CH3:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11].[C:17]([O:21][C:22]([CH2:24][NH:25][CH:26]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:27](O)=[O:28])=[O:23])([CH3:20])([CH3:19])[CH3:18].C(N(C(C)C)C(C)C)C.CCN=C=NCCCN(C)C>C1COCC1>[C:17]([O:21][C:22]([CH2:24][NH:25][CH:26]([CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:27]([CH2:16][NH:15][CH:9]([CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[I:1])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:28])=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)CNC(Cc1ccccc1)C(=O)O
Reactant: CCOC(=O)C(Cc1ccccc1I)NC
Agent: CCN=C=NCCCN(C)C
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(Cc1ccccc1I)NCC(=O)C(Cc1ccccc1)NCC(=O)OC(C)(C)C
Yield: 56.1 %

Procedure:
Ethyl 3-(2-iodophenyl)-2-methylaminopropionate (3.94 g, 12 mmol), 2-(tert-butoxycarbonylmethylamino)-3-phenylpropionic acid (3.7 g, 13 mmol), N-ethyldiisopropylamine (7.8 g, 61 mmol) and EDAC (4.6 g, 24 mmol) were stirred in THF (abs., 50 ml) for 16 h. The reaction solution was concentrated on a rotary evaporator. The residue was taken up in ethyl acetate, washed, dried and concentrated. Purification by column chromatography (SiO2, hexane/ethyl acetate) gave 4.0 g (56%) of the target compound.
Reaction SMILES: [CH3:1][C:2]([CH3:6])([OH:5])[C:3]#[N:4].C(O)(=[O:10])CC.CC(C)=O.[OH:16][C:17]([CH3:22])([CH3:21])[C:18]([OH:20])=[O:19]>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[OH:16][C:17]([CH3:22])([CH3:21])[C:18]([OH:20])=[O:19].[OH:5][C:2]([CH3:6])([CH3:1])[C:3]([NH2:4])=[O:10]
Reactant: CCC(=O)O
Reactant: CC(C)(O)C#N
Agent: CC(C)(O)C(=O)O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(O)C(N)=O
Reaction time: 4 h

Procedure:
A suspension of 0.383 g (wet cell paste) Comamonas testosteroni 5-MGAM4D cells (ATCC 55744) in 5.56 mL of 50 mM potassium phosphate buffer (pH 6.0) was placed into a 15-mL polypropylene centrifuge tube, then 51.0 mg of acetone cyanohydrin (0.10 M final concentration of acetone cyanohydrin in the suspension) was added and the resulting suspension mixed on a rotating platform at 25° C. Samples for analysis (0.180 mL) were mixed with 0.020 mL of 1.0 M propionic acid (HPLC external standard), centrifuged, and the supernatant analyzed by HPLC for acetone cyanohydrin, acetone, and 2-hydroxyisobutyric acid. After 4 h, the yields of 2-hydroxyisobutyric acid, 2-hydroxyisobutyramide, and acetone were 73.5%, 0%, and 20.4%, respectively, with no acetone cyanohydrin remaining.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:22][CH3:23])[CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([F:20])[CH:13]=1)[CH:8]=[C:7]2[OH:21].[C:24]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)#[N:25]>>[C:24]([C:26]1[CH:31]=[CH:30][C:29]([C:2]2[CH:3]=[C:4]([O:22][CH3:23])[CH:5]=[C:6]3[C:11]=2[N:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([F:20])[CH:13]=2)[CH:8]=[C:7]3[OH:21])=[CH:28][CH:27]=1)#[N:25]
Reactant: COc1cc(Br)c2nc(-c3ccc(OC)c(F)c3)cc(O)c2c1
Reactant: N#Cc1ccc(B(O)O)cc1
Product: COc1cc(-c2ccc(C#N)cc2)c2nc(-c3ccc(OC)c(F)c3)cc(O)c2c1
Yield: 56 %

Procedure:
This compound was prepared from 41b using 4-cyanophenylboronic acid according to method P. Orange solid; Yield: 56%; mp 248–250° C.; 1H NMR (300 MHz, DMSO-d6) δ 3.89 (s, 3H), 3.94 (s, 3H), 7.28 (t, J=8.8 Hz, 1H), 7.36 (s, 1H), 7.44 (d, J=2.9 Hz, 1H), 7.53 (d, J=2.9 Hz, 1H), 7.75–7.79 (m, 2H), 7.97 (br s, 4H), 11.50 (s, 1H); MS (ESI) m/z 401 ([M+H]+). Anal. Calcd for C24H17FN2O3: C: 71.99, H: 4.28, N: 7.00. Found: C: 71.55, H: 4.47, N: 6.60.