Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)C(OC1C=C(O)C=CC=1CCCC)(C)C)C.C(=O)([O-])[O-].[K+].[K+].C([O:29][C:30](=[O:66])[C:31]([O:34][C:35]1[CH:40]=[C:39]([O:41][CH2:42][CH2:43][C:44]2[N:45]=[C:46]([C:50]3[CH:51]=[C:52]([C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)[CH:53]=[CH:54][CH:55]=3)[O:47][C:48]=2[CH3:49])[CH:38]=[CH:37][C:36]=1[CH2:62][CH2:63][CH2:64][CH3:65])([CH3:33])[CH3:32])C.[OH-].[Na+]>C(O)C>[C:52]1([C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=2)[CH:53]=[CH:54][CH:55]=[C:50]([C:46]2[O:47][C:48]([CH3:49])=[C:44]([CH2:43][CH2:42][O:41][C:39]3[CH:38]=[CH:37][C:36]([CH2:62][CH2:63][CH2:64][CH3:65])=[C:35]([CH:40]=3)[O:34][C:31]([CH3:32])([CH3:33])[C:30]([OH:66])=[O:29])[N:45]=2)[CH:51]=1
Reactant: CCCCc1ccc(OCCc2nc(-c3cccc(-c4ccccc4)c3)oc2C)cc1OC(C)(C)C(=O)OCC
Agent: CCCCc1ccc(O)cc1OC(C)(C)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCCCc1ccc(OCCc2nc(-c3cccc(-c4ccccc4)c3)oc2C)cc1OC(C)(C)C(=O)O
Temperature: 55 °C

Procedure:
To a 50 mL glass tube with screw cap and nitrogen inlet were charged 2-(2-butyl-5-hydroxyphenoxy)-2-methylpropionic acid ethyl ester, (0.050 g, 0.178 mmol) (see Example 41, Part B), toluene-4-sulfonic acid 2-(5-methyl-2-bipheny-3-yl-loxazol-4-yl)ethyl ester (0.187 mmol) (see Ex. 22, part B), and powdered potassium carbonate (0.050 g, 0.36 mmol) in 1 mL of absolute ethanol. The mixture was heated to reflux for 18 h. MS analysis of the reaction indicated that 2-{5-[2-(2-biphenyl-3-yl-5-methyloxazol-4-yl)ethoxy]-2-butylphenoxy}-2-methylpropionic acid ethyl ester, MS (ES) m/e 542 (M+1) had formed. Next 0.4 mL of 5N sodium hydoxide was added and the reaction was heated for 3 h at 55° C. The ethanol was removed in vacuo and the residue was treated with 1 mL of 5N hydrochloric acid and 1 mL of dichloromethane and poured into a 3 mL ChemElute column to remove the aqueous layer. The column was eluted with additional dichloromethane until nothing UV active remained on the column. The solvent was removed in vacuo. The crude residue was purified by mass-directed reverse phase HPLC to provide 2-{5-[2-(2-biphenyl-3-yl-5-methyloxazol-4-yl)ethoxy]-2-butylphenoxy}-2-methylpropionic acid. 1H NMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 7.95 (d, J=7.8 Hz, 1H), 7.70-7.68 (m, 3H), 7.53 (t, J=7.8 Hz, 1H), 7.46 (t, J=7.6 Hz, 2H), 7.38 (t, J=7.3 Hz, 1H), 7.04 (d, J=8.3 Hz, 1H), 6.72 (d, J=2.0 Hz, 1H), 6.53 (dd, J=8.3, 2.4 Hz, 1H), 4.20 (t, J=7.8 Hz, 2H), 2.94 (t, J=7.8 Hz, 2H), 2.56 (t, J=7.8 Hz, 2H), 2.38 (s, 3H), 1.64 (s, 6H), 1.54 (quintet, J=7.5 Hz, 2H), 1.35 (sextet, J=7.3 Hz, 2H), 0.93 (t, J=7.3 Hz, 3H), MS (ES) m/e 514 (M+1).
Reaction SMILES: CC(C)=O.[Cl:5][C:6]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=[CH:8][N:7]=1.C(N(CC)CC)C.Br[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:25](=[O:26])[O:24]1>O>[Cl:5][C:6]1[C:11]([C:12]([O:14][CH:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:25](=[O:26])[O:24]2)=[O:13])=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: O=C1OC(Br)c2ccccc21
Reactant: O=C(O)c1cccnc1Cl
Solvent: CC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C1OC(OC(=O)c2cccnc2Cl)c2ccccc21
Yield: 66.8 %

Procedure:
To 600 ml of acetone, 31.5 g of 2-chloro-3-pyridinecarboxylic acid is added and suspended by stirring. Triethylamine (40 ml) is added and after 30 minutes 42.6 g of 3-bromophthalide is poured with stirring into the resulting reaction mixture. The mixture is refluxed for 4 hours and then poured into 2000 ml of water at 50° C. To obtain a precipitated compound, the reaction mixture is cooled with continuous stirring. The solid precipitate is collected by filtration, washed with cooled water and then dried under vacuum at a temperature of 40° C. A yield of 38.7 g (67% of theory) of phthalidyl 2-chloro-3-pyridinecarboxylate is obtained (m.p. 137°-8° C.).
Reaction SMILES: C(N(CC)CC)C.[N:8]([C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([C:19]([F:22])([F:21])[F:20])[CH:12]=1)=[C:9]=[S:10].[NH2:23][C:24]1([C:29]#[N:30])[CH2:28][CH2:27][CH2:26][CH2:25]1.ClCCl.CC(C)=O>C1COCC1>[NH:30]=[C:29]1[C:24]2([CH2:28][CH2:27][CH2:26][CH2:25]2)[NH:23][C:9](=[S:10])[N:8]1[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([C:19]([F:20])([F:22])[F:21])[CH:12]=1
Reactant: N#Cc1ccc(N=C=S)cc1C(F)(F)F
Reactant: N#CC1(N)CCCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc(N2C(=N)C3(CCCC3)NC2=S)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h
Yield: 73 %

Procedure:
Triethylamine (0.101 g, 0.1 mmol) was added to a solution of 1a (0.684 g, 3 mmol) and 24a (0.33 g, 3 mmol) in dry THF (5 ml). The reaction mixture was stirred at room temperature for 5 h and then concentrated to yield a brown residue which was subjected to flash chromatography (dichloromethane/acetone, 93:7) to afford 24b (0.741 g, 2.19 mmol, 73%).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]([NH:5][CH:6]1[C:14]2[C:9](=[CH:10][C:11]([CH2:15][N:16]3[CH:20]=[C:19]([CH2:21][OH:22])[C:18]([C:23]([F:26])([F:25])[F:24])=[N:17]3)=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)=O.B#B.Cl>C1COCC1>[F:28][C:2]([F:1])([F:27])[CH2:3][NH:5][CH:6]1[C:14]2[C:9](=[CH:10][C:11]([CH2:15][N:16]3[CH:20]=[C:19]([CH2:21][OH:22])[C:18]([C:23]([F:24])([F:25])[F:26])=[N:17]3)=[CH:12][CH:13]=2)[CH2:8][CH2:7]1
Reactant: O=C(NC1CCc2cc(Cn3cc(CO)c(C(F)(F)F)n3)ccc21)C(F)(F)F
Agent: B#B
Agent: Cl
Solvent: C1CCOC1
Product: OCc1cn(Cc2ccc3c(c2)CCC3NCC(F)(F)F)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,2,2-trifluoro-N-(5-((4-(hydroxymethyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2,3-dihydro-1H-inden-1-yl)acetamide (0.172 mmol, 70 mg) in THF (2 mL) was added diborane (1.719 mmol, 1.719 mL) and the whole heated to reflux for 6 h. The reaction mixture was allowed to cool to room temperature before being treated with 2N HCl (3 mL) and left to stand overnight. After this time the crude mixture was applied to an SCX column & eluted with 2N NH3/MeOH. After evaporation, the residue was further purified by prep LCMS to give a clear film (11 mg, 0.028 mmol, 16.3%). MS (ESI): m/z [M+H]+ 394.1.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O)#[N:2].[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C1COCC1>[N:11]1([CH2:6][C:5]2[CH:4]=[C:3]([CH:10]=[CH:9][CH:8]=2)[C:1]#[N:2])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C1CCNC1
Reactant: N#Cc1cccc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: N#Cc1cccc(CN2CCCC2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.2 %

Procedure:
To a stirred solution of of 3-cyanobenzaldehyde (15 g, 114.4 mmol) in THF (150 ml) was added pyrrolidine (9.76 g, 137.2 mmol, 1.2 eq.), acetic acid (8,24 g, 137.2 mmol, 1.2 eq.) and sodium triacetoxyborohydride (36.3 g, 171.6 mmol, 1.5 eq.). The resulting suspension was vigorously stirred at r.t. for 24 hrs. under Ar. 5% NaHCO3 was then added and the mixture stirred for a further 10-15 min. The mixture was then extracted with ethylacetate. The organic phase was washed with brine, then dried with Na2SO4. After removal of the solvent the yellow liquid was distilled over a Vigreux column to afford the title compound as a colorless liquid (19 g, 102 mmol, 89% yield). MS: m/e=186 (M+)
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][NH2:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15](O)=O.N>>[CH:1]1([CH2:7][CH2:8][NH:9][CH2:15][C:11]2[O:10][CH:14]=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCC1CCCCC1
Reactant: O=C(O)c1ccco1
Agent: N
Product: c1coc(CNCCC2CCCCC2)c1

Procedure:
The desired amine was prepared using the method described in Example 1171A starting with cyclohexylethylamine and 2-furoic acid. m/e (DCI/NH3) 208 (MH+)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[NH2:16]>>[Cl:12][C:13]1[CH:14]=[C:15]([NH:16][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])[CH:17]=[C:18]([Cl:20])[CH:19]=1
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: O=C(O)Cc1ccccc1Br
Product: O=C(O)Cc1ccccc1Nc1cc(Cl)cc(Cl)c1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid was condensed with 3,5-dichloroaniline to yield 2-[(3,5-dichlorophenyl)amino]phenylacetic acid.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[C:10]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C)P(N(C)C)(N(C)C)=O.[OH-].[Na+]>[CH2:17]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])=[CH:11][C:2]1=[O:1])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: CC(C(=O)O)c1cc(=O)[nH]c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CC(C(=O)O)c1cc(=O)n(Cc2ccccc2)c2ccccc12
Yield: 39 %

Procedure:
α-(1,2-Dihydro-2-oxoquinol-4-yl)propionic acid (217 mg.) was dissolved in a mixture of hexamethylphosphoramide (2 ml.) and 2 N-sodium hydroxide (2 ml.). A solution of benzyl bromide (0.528 ml.) in hexamethylphosphoramide (2 ml.) was added dropwise to the stirred solution during 2 hours. The mixture was then poured into water (10 ml.), and the resulting mixture washed with chloroform (3×5 ml.). The aqueous solution was acidified to pH 1 with concentrated hydrochloric acid, and the resulting mixture was filtered and the white solid residue washed with water and dried in vacuo over phosphorus pentoxide. The solid was crystallised from ethanol to give α-(1-benzyl-1,2-dihydro-2-oxoquinol-4-yl)propionic acid, m.p. 178°-180° C. (decomposition), in 39% yield.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)(=O)[CH3:2].NC1NN=C(C2C=CC(OC3C=CC=CC=3)=CC=2)C=1C#N.NC1C=C(C2N3N=C(C4C=CC(OC5C=CC=CC=5)=CC=4)C(C#N)=C3N=CC=2)C=CC=1.ClCCC(NC1C=C(C2[N:86]3[N:87]=[C:88]([C:93]4[CH:98]=[CH:97][C:96]([O:99][C:100]5[CH:105]=[CH:104][CH:103]=[CH:102][CH:101]=5)=[CH:95][CH:94]=4)[C:89]([C:90]([NH2:92])=[O:91])=[C:85]3[NH:84][CH2:83]C2)C=CC=1)=O>>[C:13]([O:12][C:10]([N:7]1[CH2:8][CH2:9][CH:4]([CH:1]2[N:86]3[N:87]=[C:88]([C:93]4[CH:98]=[CH:97][C:96]([O:99][C:100]5[CH:105]=[CH:104][CH:103]=[CH:102][CH:101]=5)=[CH:95][CH:94]=4)[C:89]([C:90]([NH2:92])=[O:91])=[C:85]3[NH:84][CH2:83][CH2:2]2)[CH2:5][CH2:6]1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCCC2c1cccc(NC(=O)CCCl)c1
Agent: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)n[nH]c1N
Agent: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2c(-c3cccc(N)c3)ccnc12
Product: CC(C)(C)OC(=O)N1CCC(C2CCNc3c(C(N)=O)c(-c4ccc(Oc5ccccc5)cc4)nn32)CC1

Procedure:
The desired product was prepared from tert-butyl 4-acetylpiperidine-1-carboxylate and 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile according to the procedures for 7-(3-aminophenyl)-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (step 4 to 5) and compound 2 (step 1 and 2) under appropriate conditions recognized by one of ordinary skill in the art. 1H NMR (CD3OD-d4) δ 7.40 (d, J=8.4 Hz, 2H), 7.32-7.25 (m, 2H), 7.06 (t, J=7.6 Hz, 1H), 7.01-6.94 (m, 4H), 4.10-4.00 (m, 2H), 3.98-3.91 (m, 1H), 3.35-3.30 (m, 2H), 2.70-2.58 (m, 2H), 2.18-2.02 (m, 2H), 2.02-1.84 (m, 1H), 1.65-1.45 (m, 2H), 1.39-1.12 (m, 2H), 1.35 (s, 9H). MS (ESI) m/e [M+1]+ 518.0.
Reaction SMILES: [CH2:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=O)[C:13]=2[O:20][CH3:21])[N:4]=1)[CH3:2].CN.[C:24]([BH3-])#[N:25].[Na+].[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32]>C(O)(=O)C.CO>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[CH2:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH:25][CH3:24])[C:13]=2[O:20][CH3:21])[N:4]=1)[CH3:2]
Reactant: CCc1ccc(C#N)c(Oc2cccc(C=O)c2OC)n1
Reactant: [BH3-]C#N
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCc1ccc(C#N)c(Oc2cccc(CNC)c2OC)n1
Yield: 62.7 %

Procedure:
6-Ethyl-2-(3-formyl-2-methoxy-phenoxy)-nicotinonitrile (0.28 g, 1.0 mmol), methylamine (33% in ethanol 0.8 mL, 6.4 mmol) and sodium cyanoborohydride (80 mg, 1.3 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (60 mL) for 16 h. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and fumaric acid (0.12 g, 1.0 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with ethyl acetate overnight, collected by filtration, and dried to give 6-ethyl-2-(2-methoxy-3-methylaminomethyl-phenoxy)-nicotinonitrile difumarate (166 mg, 32%) as a beige solid.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22]([N:24]4[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26][CH2:25]4)=O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][N:24]4[CH2:25][CH2:26][CH:27]([OH:30])[CH2:28][CH2:29]4)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(N1CCC(O)CC1)C1(c2ccc(OCCCN3CCCC3)cc2)CCCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OC1CCN(CC2(c3ccc(OCCCN4CCCC4)cc3)CCCCC2)CC1
Yield: 46 %

Procedure:
The title compound (90 mg, 46%) was prepared using 1-({1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]cyclohexyl}carbonyl)piperidin-4-ol and lithium aluminium hydride similarly to the procedure used for example 142. 1H NMR (400 MHz, CDCl3) δ 1.29-1.55 (m, 10H), 1.64-1.69 (m, 2H), 1.77-1.81 (m, 4H), 1.90-2.06 (m, 4H), 2.10-2.13 (m, 2H), 2.23 (s, 2H), 2.26-2.30 (m, 2H), 2.51-2.54 (m, 4H), 2.62 (t, 2H), 3.51 (m, 1H), 4.01 (t, 2H), 6.83 (d, 2H), 7.25 (d, 2H). HRMS ESI+ m/z 401.3154 [MH]+.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=1[CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12]1
Reactant: N#Cc1ccc(Br)c(CN2CCc3ccccc32)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1ccc(Br)c(CN2CCc3ccccc32)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.9 %

Procedure:
The crude 4-bromo-3-(2,3-dihydro-indol-1-ylmethyl)-benzonitrile (3.04 g) dissolved in dry tetrahydrofuran (50 mL) was dropped to an ice-cold slurry of lithium aluminium hydride 4.16 g, 0.11 mmol) in dry tetrahydrofuran (50 mL). The mixture was stirred for 1 h at ambient temperature, and then heated at reflux for another hour. The flask was cooled on ice, and the reaction mixture quenched with water (4.2 mL) followed by 15% NaOH(aq) (4.2 mL). Additional water (12.6 mL) was added and the mixture stirred at ambient temperature for 1 h. The white precipitate was filtered and washed with tetrahydrofuran. Evaporation afforded crude 4-bromo-3-(2,3-dihydro-indol-1-ylmethyl)-benzylamine (3.20 g) as a yellow oil. This was stirred together with ethyl trifluoroacetate (2.5 ml, 20.9 mmol) in dry methylene chloride (50 mL) for 17 h at room temperature. Evaporation followed by chromatography (ethyl acetate/heptane: 25/75) gave the sub-title compound.
Reaction SMILES: [C:1]1([P:7]([O:15][C:16]2[C@H:17]([CH3:40])[C@H:18]3[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]3[C:20]=2[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)=[O:22])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Si:41](Cl)([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42].N1C=CN=C1.CO>CN(C)C=O>[Si:41]([O:38][C@@H:36]([C@H:35]1[C:34](=[O:39])[N:19]2[C:20]([C:21]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([N+:31]([O-:33])=[O:32])=[CH:29][CH:30]=3)=[O:22])=[C:16]([O:15][P:7]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:8])[C@H:17]([CH3:40])[C@@H:18]12)[CH3:37])([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@@H]12
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CO
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@@H]12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
To a solution of p-nitrobenzyl(1R,5S,6S)-2-(diphenylphosphoryloxy)-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (5.00 g, 8.41 mmol) in dimethylformamide (250 ml) were added t-butyldimethylsilyl chloride (2.54 g, 16.8 mmol) and imidazole (1.14 g, 16.8 mmol) in an ice bath, and the reaction mixture was stirred in the ice bath for 7 hours. After checking the completion of the reaction, methanol was added thereto and the resulting mixture was stirred for 30 minutes. The reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The obtained organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (3:1) as the eluant to afford p-nitrobenzyl (1R,5S,6S)-6-[(R)-1-t-butyldimethylsilyloxyethyl]-2-(diphenylphosphoryloxy)-1-methylcarbapen-2-em-3-carboxylate (5.27 g, yield 88%) as a pale yellow oil.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1.N1C=CN=C1.CN(C)C=O>C(OCC)(=O)C.CCCCCC.O>[Si:1]([O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][OH:15])=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=Cc1ccc(O)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.7 %

Procedure:
Tert-butyldimethylsilyl chloride (24.1 g) was added to a mixture of 4-hydroxybenzaldehyde (17.8 g), imidazole (19.8 g) and N,N-dimethylformamide (100 ml). After stirring at room temperature for 2 hours, water was added and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was dissolved in tetrahydrofuran (300 ml) and methanol (40 ml), and then sodium borohydride (11.1 g) was added in portions at 0° C. After stirring for 30 minutes, water was added and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain 4-(tert-butyldimethylsilyloxy)benzylalcohol (27.7 g, yield 79%) as a colorless oil from an ethyl acetate-hexane (1:4, v/v)-eluted fraction.
Reaction SMILES: [C:1]([CH2:3][C@@H:4]([OH:9])[CH2:5][C:6]([OH:8])=[O:7])#[N:2].S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+].[CH:21](O)([CH3:23])[CH3:22]>>[CH:21]([O:7][C:6](=[O:8])[CH2:5][C@H:4]([OH:9])[CH2:3][C:1]#[N:2])([CH3:23])[CH3:22]
Reactant: CC(C)O
Reactant: N#CC[C@@H](O)CC(=O)O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(C)OC(=O)C[C@H](O)CC#N
Yield: 90 %

Procedure:
(R)-4-cyano-3-hydroxybutyric acid (1.0 mol) in isopropanol (500 ml) and conc. sulfuric acid (5 g) were refluxed for 5 hours. The reaction mixture was neutralized with sodium carbonate and filtered. The filtrate was concentrated in vacuo to afford (R)-4-cyano-3-hydroxybutyric acid isopropyl ester (163 g, 90%).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[N:14]1([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C([O-])(O)=O.[Na+]>CCO>[CH2:23]([O:22][C:20]([N:14]1[CH2:19][CH2:18][N:17]([C:2]2[S:3][C:4]3[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:16][CH2:15]1)=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=[N+]([O-])c1ccc2nc(Cl)sc2c1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=C(OCc1ccccc1)N1CCN(c2nc3ccc([N+](=O)[O-])cc3s2)CC1
Yield: 60.9 %

Procedure:
A mixture of 2-chloro-6-nitrobenzothiazole (1.00 g, 4.66 mmol), benzyl 1-piperazinecarboxylate (1.03 g, 4.66 mmol), and NaHCO3 (0.783 g, 9.32 mmol) in EtOH was heated at reflux temperature for 2 h, concentrated, and extracted with EtOAc. The combined extracts were dried over Na2SO4 and concentrated in vacuo to provide the title compound (1.13 g, 61%), characterized by NMR and mass spectral analyses.
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].N1C=CC=CC=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>C(Cl)Cl>[F:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:5][CH2:1][CH:2]([CH3:4])[CH3:3])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CC(C)CN
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)CNS(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.2 %

Procedure:
A solution of isobutylamine (6.64 mL, 66.8 mmol) and pyridine (6.24 mL, 77.1 mmol) in DCM (100 mL) was treated with 4-fluorobenzene sulfonyl chloride (10.0 g, 51.4 mmol) and stirred at room temperature for 18 hours. The mixture was diluted with DCM, washed with 1 N aqueous HCl, saturated aqueous NaHCO3, water and brine, dried over Na2SO4 and concentrated under vacuum. Trituration with pentane gave 4-fluoro-N-isobutyl-benzenesulfonamide (10.48 g, 88%) as a pale yellow solid. 1H NMR (400 MHz, DMSO) δ 7.88-7.81 (m, 2H), 7.63 (t, J=6.1 Hz, 1H), 7.47-7.39 (m, 2H), 2.54 (t, J=6.5 Hz, 2H), 1.67-1.55 (m, 1H), 0.80 (d, J=6.7 Hz, 6H). LCMS (m/z, Method B) ES+ 232.0 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[NH2:25][C@@H:26]([CH2:28][OH:29])[CH3:27]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:25][C@H:26]([CH3:27])[CH2:28][OH:29])=[O:21])=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1onc(-c2ccc(Cl)cc2)c1COc1ccc(C(=O)O)cn1
Reactant: C[C@@H](N)CO
Product: Cc1onc(-c2ccc(Cl)cc2)c1COc1ccc(C(=O)N[C@H](C)CO)cn1
Yield: 94 %

Procedure:
As described for example 254, 6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (100 mg, 0.29 mmol) was converted, using D-alaninol instead of 2-amino-2-methyl-1-propanol, to the title compound (100 mg, 94%) which was obtained as a white solid. MS: m/e=402.2 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:18](=O)[CH3:19])[C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(=O)(O)[O-].[Na+].S(O)(O)(=O)=O.[CH3:31][O:32][C:33](=[NH:35])[NH2:34]>CN(C)C=O.O>[CH3:31][O:32][C:33]1[NH:35][C:18]([CH3:19])=[C:11]([C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])[CH:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:34]=1
Reactant: COC(=N)N
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)OC(C)C
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC1=NC(c2cccc([N+](=O)[O-])c2)C(C(=O)OC(C)C)=C(C)N1
Temperature: 60 °C
Yield: 67 %

Procedure:
A reaction mixture containing 2-[(3-nitrophenyl)methylene]-3-oxobutanoic acid, 1-methylethyl ester (10.0 g, 36.0 mmol), sodium bicarbonate (8.40 g, 108 mmol), and O-methylpseudourea hydrogen sulfate (8.06 g, 46.8 mmol) in dimethylformamide (54 ml) was heated at 60° C. under argon for about 21/2 days. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water (six times) and saturated sodium chloride, dried (potassium carbonate) and evaporated. The residue was passed through a short pad of silica gel and crystallized from isopropyl ether/hexanes to give the title compound as yellow crystals (8.04 g).