Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10](I)=[CH:9][N:8]([C@H:12]3[CH2:17][CH2:16][C@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[F:25][C:26]1[CH:27]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:29]=[CH:30][C:31]=1[O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.ClC1C2C(C3C=CC(OC4C=CC=CC=4)=C(C=3)C#N)=CN([C@H]3CC[C@H](N4CCN(C)CC4)CC3)C=2N=CN=1.CO[C@@H]1[C@@H](C(OC)=O)[C@@H]2[C@@H](CN3[C@H](C2)C2NC4C=C(OC)C=CC=4C=2CC3)C[C@H]1OC(C1C=C(OC)C(OC)=C(OC)C=1)=O>C(#N)C>[C:33]1([O:32][C:31]2[CH:30]=[CH:29][C:28]([C:10]3[C:3]4[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=4[N:8]([C@H:12]4[CH2:17][CH2:16][C@H:15]([N:18]5[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]5)[CH2:14][CH2:13]4)[CH:9]=3)=[CH:27][C:26]=2[F:25])[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CC1(C)OB(c2ccc(Oc3ccccc3)c(F)c2)OC1(C)C
Reactant: CN1CCN([C@H]2CC[C@H](n3cc(I)c4c(Cl)ncnc43)CC2)CC1
Agent: CN1CCN([C@H]2CC[C@H](n3cc(-c4ccc(Oc5ccccc5)c(C#N)c4)c4c(Cl)ncnc43)CC2)CC1
Agent: COC(=O)[C@H]1[C@H]2C[C@@H]3c4[nH]c5cc(OC)ccc5c4CCN3C[C@H]2C[C@@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)[C@@H]1OC
Solvent: CC#N
Product: CN1CCN([C@H]2CC[C@H](n3cc(-c4ccc(Oc5ccccc5)c(F)c4)c4c(Cl)ncnc43)CC2)CC1

Procedure:
The title compound was prepared in an 85% yield from trans-4-chloro-5-iodo-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidine and 2-(3-fluoro-4-phenoxyphenyl)-4,4,5,5-tetrametyl-1,3,2-dioxaborolane in a similar manner to that described for the preparation of trans-5-(4-chloro-7-(4-(4-methylpiperazino)cyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-phenoxybenzonitrile: 1H NMR (DMSO-d6, 400 MHz) δ 8.67 (s, 1H), 8.07(s, 1H), 7.58 (d, 1H), 7.41(m, 3H), 7.22(m, 1H), 7.16(m, 1H), 7.04(d, 2H), 4.70(m, 1H), 2.2-2.6 (m, 9H), 2.16(s, 3H), 1.94-2.03(m, 6H), 1.48(m, 2H); MS MH+520.3; RP-HPLC (Hypersil HS, 5 μm, 100 A 4.6×250 mm; 25%-100% acetonitrile—0.05 M ammonium acetate over 10 min, 1 ml/min) tr 9.45 min.
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](NC)=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].CN(C)C=O.IC1C=CC(C(O)=O)=CC=1OC.S(Cl)([Cl:34])(=O)=O>>[I:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([Cl:34])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: CNC(=O)c1ccc(I)c(OC)c1
Reactant: O=S(=O)(Cl)Cl
Agent: COc1cc(C(=O)O)ccc1I
Solvent: CN(C)C=O
Product: COc1cc(C(=O)Cl)ccc1I

Procedure:
4-Iodo-3-methoxy-N-methylbenzamide. N,N-Dimethylformamide (0.1 mL) was added to a solution of 4-iodo-3-methoxybenzoic acid (2.0 g, 7.2 mmol) in sulfuryl dichloride (20 mL), and the mixture was heated to reflux for 2 h. The excess sulfuryl dichloride was removed under reduced pressure to give the crude product 4-iodo-3-methoxy-benzoyl chloride. To a solution of methyl amine (0.72 g, 10.8 mmol) and triethylamine (2.18 g, 21.6 mmol) in dichloromethane (20 mL) was added dropwise a solution of the above 4-iodo-3-methoxy-benzoyl chloride in dichloromethane (15 mL) at 0° C. After the reaction was completed, water was added, the organic layer was separated, dried over sodium sulfate evaporated to give the crude product, which was purified on silica gel column (eluting with 10-17% ethyl acetate in petroleum ether) to give 4-iodo-3-methoxy-N-methylbenzamide (0.92 g, 46% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm) 7.92 (d, J=8.0 Hz, 1H), 7.42 (d, J=5.6 Hz, 1H), 7.31 (dd, J1=8.0 Hz, J2=2.0 Hz, 1H), 3.88 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[C:17]([CH3:19])[C:16]([CH3:20])=[CH:15][C:14]=1[Cl:21])[O:8][CH:7]([C:22]([F:25])([F:24])[F:23])[C:6]([C:26]([O:28]CC)=[O:27])=[CH:5]2.O.[OH-].[Li+].[Al].Cl>C(OCC)C.C1COCC1.CO.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[C:17]([CH3:19])[C:16]([CH3:20])=[CH:15][C:14]=1[Cl:21])[O:8][CH:7]([C:22]([F:24])([F:25])[F:23])[C:6]([C:26]([OH:28])=[O:27])=[CH:5]2
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(Oc3cc(C)c(C)cc3Cl)cc2OC1C(F)(F)F
Agent: Cl
Agent: [Al]
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Cl)c(Oc2cc3c(cc2Cl)C=C(C(=O)O)C(C(F)(F)F)O3)cc1C
Temperature: 100 °C
Yield: 34.6 %

Procedure:
To the concd product of step 1 in a suitable vial was added 400 mg (mmole) of lithium hydroxide monohydrate, 1 mL of water, 2 mL of methanol and 7 mL of THF. The vial was capped, in an aluminum heating block and the block heated to 100° C. for 30 min. After allowing the vial to cool to rt, the mixture was treated with 5 mL of 1N HCl and 2 mL of diethyl ether. The organic layer was removed and the aqueous layer extracted two times with diethyl ether. Combined organic extracts were concd by evaporation of solvent under a stream of N2 followed by conc in vacuo to afford 150 mg (34.6%) of a yellow solid: 1H NMR (CDCl3/300 MHz) 2.26 (s, 3H), 5.64 (q, 1H, J=6.8 Hz), 6.27 (s, 1H), 6.94 (s, 1H), 7.26 (s, 1H), 7.3H (s, 1H), 11.28 (hs, 1H); MS (ES−) 431 (M−1, 100); HRMS (ES−) m/z calcd for (M−H; C19H12Cl2F3O4) 431.0059, found 431.0048.
Reaction SMILES: [H-].[Na+].Cl.[CH2:4]([N:6]([CH2:9][CH2:10]Cl)[CH2:7][CH3:8])[CH3:5].[CH3:12][N:13]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[NH:17][C:16](=[O:24])[C:15]2=[CH:25][S:26][CH:27]=[C:14]12>CN(C)C=O>[CH2:4]([N:6]([CH2:7][CH3:8])[CH2:9][CH2:10][N:17]1[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:13]([CH3:12])[C:14]2=[CH:27][S:26][CH:25]=[C:15]2[C:16]1=[O:24])[CH3:5]
Reactant: CCN(CC)CCCl
Reactant: CN1c2ccccc2NC(=O)c2cscc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)CCN1C(=O)c2cscc2N(C)c2ccccc21
Reaction time: 18 h

Procedure:
A mixture of 0.31 g. of 55% sodium hydride-mineral oil dispersion and 0.60 g. of diethylaminoethylchloride hydrochloride in 25 ml. of dry dimethylformamide is stirred at room temperature for 0.5 hours. To the mixture is added 0.4 g. of 4,9-dihydro-4-methyl-10H-thieno[3,4-b] [1,5]benzodiazepin-10-one and stirring is continued for 18 hours. The reaction mixture is cooled, quenched with water and extracted with chloroform. The chloroform extracts are concentrated under reduced pressure to an oil, which is chromatographed on silica gel preparative thin layer chromatographic (tlc) plates using 10:1 benzene:methanol as eluent. The oily product is crystallized from hexane to give white crystals, m.p. 92°-93°C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[C:9](=[N:10][C:11]=1[N:12]([CH3:14])[CH3:13])[N:8]=[C:7]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[N:6]=[C:5]2[N:21]([CH3:23])[CH3:22].[CH2:24]([OH:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([O:31][C:2]1[N:3]=[C:4]2[C:9](=[N:10][C:11]=1[N:12]([CH3:14])[CH3:13])[N:8]=[C:7]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[N:6]=[C:5]2[N:21]([CH3:23])[CH3:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: OCc1ccccc1
Reactant: CN(C)c1nc2nc(N3CCNCC3)nc(N(C)C)c2nc1Cl
Product: CN(C)c1nc2nc(N3CCNCC3)nc(N(C)C)c2nc1OCc1ccccc1

Procedure:
This compound was prepared analogous to Example 3 from 6-chloro-4,7-bis-(dimethylamino)-2-piperazino-pteridine and benzyl alcohol.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:27]#[N:28])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([NH:17][C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19])[CH:10]=2)=[O:5])C.[CH2:29]([O:31][C:32](=[O:38])[C:33]([CH3:37])([CH3:36])[CH2:34][NH2:35])[CH3:30]>C(O)C>[CH2:29]([O:31][C:32](=[O:38])[C:33]([CH3:37])([CH3:36])[CH2:34][NH:35][C:4]([C:6]1[N:7]=[C:8]([C:27]#[N:28])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([NH:17][C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19])[CH:10]=2)=[O:5])[CH3:30]
Reactant: CCOC(=O)C(C)(C)CN
Reactant: CCOC(=O)c1nc(C#N)c2cc(NC(=O)Nc3ccccc3)ccc2c1O
Solvent: CCO
Product: CCOC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2cc(NC(=O)Nc3ccccc3)ccc2c1O

Procedure:
1-Cyano-4-hydroxy-7-(3-phenyl-ureido)-isoquinoline-3-carboxylic acid ethyl ester (40 mg, 0.106 mmol) was dissolved/suspended in ethanol (3 mL) and 3-Amino-2,2-dimethyl-propionic acid ethyl ester (46 mg, 0.318 mmol) was added via syringe. The reaction was brought to reflux and maintained for 50 h. The reaction was cooled, concentrated and purified by medium pressure liquid chromatography (15 to 60% ethyl acetate in hexanes) to give the product as a white solid which was used immediately in the following reaction.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=1)[C:7]([CH3:23])=[CH:6]2.B(Br)(Br)Br.O>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]1[CH:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:21][CH:22]=1)[C:7]([CH3:23])=[CH:6]2
Reactant: COC(=O)c1ccc(-c2nc3ccc(OC)cc3cc2C)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Cc1cc2cc(O)ccc2nc1-c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 28.1 %

Procedure:
Methyl 4-(6-methoxy-3-methylquinolin-2-yl)benzoate (37 mg, 0.121 mmol) was dissolved in 2 mL of DCM and BBr3 (150 μL) was added. The mixture was stirred at room temperature for 1 day followed by addition of 10 mL of H2O. The solution was stirred vigorously for 1 h followed by filtration of the solids. The solids were washed with H2O and dried in vacuo to yield 9.5 mg (28% yield) of Compound 1. 1H NMR (DMSO-d6, 400 MHz): δ 8.37 (s, 1H), 8.10 (d, 2H), 7.94 (d, 1H), 7.78 (d, 2H), 7.42-7.39 (dd, 1H), 7.24-7.23 (d, 1H), 2.43 (s, 3H). MS (ESI): m/z 280.10 [M+H]+.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:52])[CH2:7][N:8]([CH2:46][C:47]([O:49]CC)=[O:48])[C:9](=[O:45])[C:10]1[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:13]=[CH:12][C:11]=1[O:35][CH2:36][CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)C>>[C:47]([CH2:46][N:8]([C:9](=[O:45])[C:10]1[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:13]=[CH:12][C:11]=1[O:35][CH2:36][CH2:37][CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[CH2:7][C:6]([OH:52])=[O:5])([OH:49])=[O:48]
Reactant: CCCCCCCCCCCCCCCCCCOc1ccc(OCCCc2ccccc2)c(C(=O)N(CC(=O)OCC)CC(=O)OCC)c1
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCCCCCOc1ccc(OCCCc2ccccc2)c(C(=O)N(CC(=O)O)CC(=O)O)c1
Yield: 82 %

Procedure:
Sodium hydroxide hydrolysis of N-(2-ethoxy-2-oxoethyl)-N-[5-(octadecyloxy)-2-(3-phenylpropoxy)benzoyl]glycine ethyl ester under conditions described in Example 81 gave N-(carboxymethyl)-N-[5-(octadecyloxy)-2-(3-phenylpropoxy)benzoyl]glycine 82% yield, mp 101°-102°).
Reaction SMILES: [CH:1]1([CH2:9][CH2:10][C:11](O)=O)[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH2:2]1.[O:14]1[C:20]2[CH:21]=[CH:22][C:23]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[CH:24][C:19]=2[O:18][CH:17]=[CH:16][CH2:15]1.C([O-])(=O)/C=C/C([O-])=O>>[CH:1]1([CH2:9][CH2:10][CH2:11][N:28]2[CH2:29][CH2:30][N:25]([C:23]3[CH:22]=[CH:21][C:20]4[O:14][CH2:15][CH:16]=[CH:17][O:18][C:19]=4[CH:24]=3)[CH2:26][CH2:27]2)[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH2:2]1
Reactant: C1=COc2cc(N3CCNCC3)ccc2OC1
Reactant: O=C(O)CCC1Cc2ccccc21
Agent: O=C([O-])/C=C/C(=O)[O-]
Product: C1=COc2cc(N3CCN(CCCC4Cc5ccccc54)CC3)ccc2OC1

Procedure:
Prepared as described in Example 9, starting from 3-(benzocyclobutan-1-yl)propionic acid and 4-(benzo-1,5-dioxepin-7-yl)piperazine. The fumarate of the title compound melts at 168°-170° C. (ethanol).
Reaction SMILES: [CH:1]12[O:6][CH:5]1[CH2:4][N:3]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2]2.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[CH2:14]([NH:21][C@@H:5]1[C@@H:1]([OH:6])[CH2:2][N:3]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC2OC2C1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1C[C@H](NCc2ccccc2)[C@@H](O)C1
Yield: 85.2 %

Procedure:
A solution of the epoxide (4.6 g, 24.9 mmol) of step A and benzylamine (5.2 g, 48.6 mmol) in ethanol was stirred at 85° C. overnight. The solvent was removed by concentration under reduced pressure to give a solid. The solid was washed with a mixed solvent of 50% EtOAc/hexanes to provide 6.2 g of the desired compound. MS calculated (M+H)+ 293, found 293.
Reaction SMILES: [CH2:1]([NH:11][C:12](=[O:25])[C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1C(OC(C)(C)C)=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([NH:11][C:12](=[O:25])[C@@H:13]1[CH2:17][CH2:16][CH2:15][NH:14]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCNC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCCCCNC(=O)[C@@H]1CCCN1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 92.8 %

Procedure:
N-(tert-Butoxycarbonyl)-L-proline n-decyl amide (12) (120 mg; 0.339 mmol) is dissolved in methylene chloride (4 mL) at ambient temperature. Trifluoroacetic acid (2 mL) is added and the solution is stirred for 2.5 hours at ambient temperature. The solution is concentrated in vacuo at 40° C. The residue is dissolved in methylene chloride (20 mL) and poured onto saturated sodium bicarbonate solution. The pH is adjusted to 9 with saturated potassium carbonate solution. The mixture is shaken and the layers separated. The water layer is extracted with methylene chloride (3 times, 5 mL each). The combined organic extracts are washed with water, dried over MgSO4, filtered, and concentrated in vacuo affording the desired product (80 mg) as an oil. ISMS: MH+ 254.8
Reaction SMILES: COCCOC[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]([S:22]([CH3:25])(=[O:24])=[O:23])[C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:9][CH:8]=1.Cl.C[OH:28]>>[OH:28][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]([S:22]([CH3:25])(=[O:24])=[O:23])[C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:9][CH:8]=1
Reactant: COCCOCc1ccc(-c2cc3ccccc3n2S(C)(=O)=O)cc1
Reactant: CO
Agent: Cl
Product: CS(=O)(=O)n1c(-c2ccc(O)cc2)cc2ccccc21
Reaction time: 2 h

Procedure:
A solution of the product of Step D (1.5 g, 4.0 mmol) in methanol (10 mL) was treated with HCl (10 mL, 4 N in dioxane). The reaction was allowed to stir for 2 hr, concentrated, and purified by silica gel chromatography (methanol:dichloromethane), to afford the title compound (0.93 g).
Reaction SMILES: [P:1]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][C:25]([O:31][CH2:32][C:33]4[N:34]=[C:35]([C:38]5[CH:43]=[C:42]([F:44])[CH:41]=[C:40]([C:45]([F:48])([F:47])[F:46])[CH:39]=5)[O:36][CH:37]=4)=[CH:26][CH:27]=3)[O:22][CH:21]=2)=[CH:16][CH:15]=1)([O:8]C(C)(C)C)([O:3]C(C)(C)C)=[O:2].FC(F)(F)C(O)=O>C(Cl)Cl>[P:1]([OH:3])([OH:8])([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][C:25]([O:31][CH2:32][C:33]4[N:34]=[C:35]([C:38]5[CH:43]=[C:42]([F:44])[CH:41]=[C:40]([C:45]([F:46])([F:47])[F:48])[CH:39]=5)[O:36][CH:37]=4)=[CH:26][CH:27]=3)[O:22][CH:21]=2)=[CH:16][CH:15]=1)=[O:2]
Reactant: CC(C)(C)OP(=O)(Oc1ccc(-c2coc3cc(OCc4coc(-c5cc(F)cc(C(F)(F)F)c5)n4)ccc3c2=O)cc1)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1c(-c2ccc(OP(=O)(O)O)cc2)coc2cc(OCc3coc(-c4cc(F)cc(C(F)(F)F)c4)n3)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-{4-[bis(tert-butoxy)phosphinooxy]phenyl}-7-({2-[5-fluoro-3-(trifluoromethyl)phenyl](1,3-oxazol-4-yl)}methoxy)chromen-4-one prepared in Step 2 in methylene chloride (60 ml) was added trifluoroacetic acid (0.15 ml, 1.99 mmol). The reaction mixture was stirred at room temperature overnight, the solid filtered off, and washed with methylene chloride, to afford 100% pure (by HPLC) 4-[7-({2-[5-fluoro-3-(trifluoromethyl)phenyl](1,3-oxazol-4-yl)}methoxy)-4-oxochromen-3-yl]phenyl dihydrogen phosphate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH:9]([OH:18])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][OH:17])[CH:11]=2)[N:3]=1.[C:19]1([CH3:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Pd](Cl)Cl>[OH:18][CH:9]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][OH:17])[CH:11]=1)[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2](/[CH:4]=[CH:8]/[CH:9]([OH:18])[CH2:10][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:19][CH3:25])[N:3]=1
Reactant: OCc1cccc(C(O)Cc2cccc(Br)n2)c1
Reactant: Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: CCCCCCCCC(O)/C=C/c1cccc(CC(O)c2cccc(CO)c2)n1

Procedure:
Under the conditions of example 24D, 96 mg of 2-bromo-6-[(2RS)-2-hydroxy-2-(3-hydroxymethylphenyl)-ethyl]-pyridine and 160 mg of (1E)-1-(tri-n-butylstannyl)-1-undecen-(3RS)-3-ol in 1 ml of toluene is reacted in the presence of 1,1'-bis-(diphenylphosphino)-ferrocene-palladium(II) chloride as catalyst and worked up. The crude product is chromatographed on silica gel with hexane/0-25% ethyl acetate. 20 mg of the title compound is obtained as wine-red oil.
Reaction SMILES: [N:1]([C@@H:4]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)[C@@H:5]([OH:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[N+]=[N-]>C(OCC)(=O)C.[Pd]>[NH2:1][C@@H:4]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)[C@@H:5]([OH:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)[C@H](O)[C@@H](N=[N+]=[N-])c1ccc(C)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](O)[C@@H](N)c1ccc(C)cc1
Reaction time: 8 h
Yield: 80.6 %

Procedure:
0.115 g of carbon powder carrying 10% of palladium is added to a solution of 1.15 g of ethyl (2R,3S)-3-azido-2-hydroxy-3-(4-methylphenyl)propionate in 35 cm3 of ethyl acetate. The reaction mixture is stirred under a hydrogen pressure of 120 kPa and at a temperature in the region of 22° C. for 8 hours and then filtered through sintered glass lined with Celite. The sintered glass is washed with 5 cm3 of ethyl acetate and the filtrates are combined and then concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40° C. 0.83 g of ethyl (2R,3S)-3-amino-2-hydroxy-3-(4-methylphenyl)propionate is thereby obtained in the form of a pale yellow paste.
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:5]([CH3:21])=[C:6]([C:17]([O:19][CH3:20])=[O:18])[C:7]([CH:14]([F:16])[F:15])=[N:8][C:9]=1[C:10]([F:13])([F:12])[F:11])#[N:2].Cl[CH2:23][CH2:24][CH2:25][C:26](Cl)=[O:27].[OH-].[Na+]>ClCCl.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[C:1]([C:3](=[C:26]1[CH2:25][CH2:24][CH2:23][O:27]1)[C:4]1[C:5]([CH3:21])=[C:6]([C:17]([O:19][CH3:20])=[O:18])[C:7]([CH:14]([F:16])[F:15])=[N:8][C:9]=1[C:10]([F:12])([F:13])[F:11])#[N:2]
Reactant: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(CC#N)c1C
Reactant: O=C(Cl)CCCCl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(C#N)=C2CCCO2)c1C
Reaction time: 0.5 h
Yield: 53.7 %

Procedure:
To a solution of 7.00 g (22.7 mmol) 5-(cyanomethyl)-2-(difluoromethyl)-4-methyl-6-(trifluoromethyl)-3-pyridinecarboxylic acid, methyl ester, prepared as in Example E, in 450 mL dichloromethane was added 6.41 g (45.4 mmol) 4-chlorobutyryl chloride, 0.30 g benzyltriethylammonium chloride, and 135 mL 50% sodium hydroxide. The mixture was stirred for 30 minutes, poured over ice, and extracted with diethyl ether. The organic layer was dried with magnesium sulfate, treated wit decolorizing carbon, filtered through silica gel, and evaporated in vacuo. The residue was recrystallized in ethyl acetate and hexane, yielding 4.59 g of the desired product as a white crystalline solid, a 54% yield. m.p. 160°-161° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH:15](C([O-])=O)[C:16]([O-:18])=[O:17])=[C:11]([N+:22]([O-:24])=[O:23])[CH:10]=2)=[CH:5][CH:4]=1>Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[C:11]([N+:22]([O-:24])=[O:23])[CH:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2ccc(C(C(=O)[O-])C(=O)[O-])c([N+](=O)[O-])c2)cc1
Agent: Cl
Product: COc1ccc(-c2ccc(CC(=O)O)c([N+](=O)[O-])c2)cc1

Procedure:
Crude 4′-methoxy-3-nitro-biphenyl-4-malonate was heated at 100° C. in 60 mL of 6 N hydrochloric acid for 15 hours and cooled. The precipitate was collected by filtration, washed with water and hexane, and dried to give 7.2 g of crude 4′-methoxy-3-nitrobiphenyl-4-acetic acid as a light tan solid.
Reaction SMILES: C=C[C:3]1[CH:8]=[CH:7][CH:6]=CC=1.[C:9]([O:13]CCC(O)=O)(=[O:12])[CH:10]=[CH2:11]>C(OC(OC(=O)C=C)CCCCCCCCCCC)(=O)C=C.C(S)CCCCCCCCCCC>[C:9]([O:13][CH2:6][CH2:7][CH2:8][CH3:3])(=[O:12])[CH:10]=[CH2:11]
Reactant: C=CC(=O)OCCC(=O)O
Reactant: C=Cc1ccccc1
Agent: C=CC(=O)OC(CCCCCCCCCCC)OC(=O)C=C
Agent: CCCCCCCCCCCCS
Product: C=CC(=O)OCCCC
Yield: 686.3 %

Procedure:
A mixture of about 1581 grams styrene, about 58 grams beta carboxyethyl acrylate (β-CEA), about 7 grams dodecanediol diacrylate (A-DOD), about 7.25 grams dodecanethiol and about 354 grams butyl acrylate was produced by dispersing under high shear conditions in a separate mixing vessel to form a homogenous emulsion.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:8]=[CH:9][NH:10][CH:11]=2)[CH:2]=1.C(O)(=O)C.[CH3:16][C:17]([CH3:21])=[CH:18][CH:19]=[O:20]>C1COCC1>[CH3:16][C:17]([CH3:21])([N:10]1[CH:11]=[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[N:8]=[CH:9]1)[CH2:18][CH:19]=[O:20]
Reactant: c1cncc(-c2c[nH]cn2)c1
Reactant: CC(C)=CC=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(CC=O)n1cnc(-c2cccnc2)c1

Procedure:
To a solution of 4-pyridin-3-yl-imidazole (1 g) in THF (34 mL) was added acetic acid (1.6 mL) and 3-methyl-2-butenal (3.3 mL) and the resulting solution was heated under gentle reflux for 24 hours. THF was then removed in vacuo and the residue was purified on a Flash 75 (silica gel column made by Biotage Division of Dyax Corp, U.S.) long column eluting with MeOH—CH2Cl2 to give the title compound as slightly yellow oil.
Reaction SMILES: [H-].[Na+].C1COCC1.[CH3:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[CH:15][CH:16]=2)[NH:11][N:10]=1.[CH3:21][Si:22]([CH2:25][CH2:26][O:27][CH2:28]Cl)([CH3:24])[CH3:23]>CCOC(C)=O.O>[CH3:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[CH:15][CH:16]=2)[N:11]([CH2:28][O:27][CH2:26][CH2:25][Si:22]([CH3:24])([CH3:23])[CH3:21])[N:10]=1
Reactant: Cc1n[nH]c2cc([N+](=O)[O-])ccc12
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1nn(COCC[Si](C)(C)C)c2cc([N+](=O)[O-])ccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.1 %

Procedure:
A flask was charged with NaH (60% dispersion in mineral oil, 0.325 g, 13.6 mmol) and THF (40 mL). The mixture was cooled to about 0° C. followed by the addition of 3-methyl-6-nitro-1H-indazole (2.00 g, 11.3 mmol, ArkPharm). The mixture was stirred for about 30 min followed by the addition of SEMCl (2.26 g, 13.6 mmol). The mixture was warmed to rt and stirred for about 12 h. Water (5 mL) and EtOAc (70 mL) were added and the layers were separated. The organic layer was concentrated under reduced pressure to give 3-methyl-6-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (3.2 g, 91%): LC/MS (Table 2, Method f) Rt=2.18 min; MS m/z: 308 (M+H)+.