Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:20])=[C:10]([N:14]3[CH2:18][CH2:17][CH:16]([NH2:19])[CH2:15]3)[C:11]=2[F:13])[C:6](=[O:21])[C:5]([C:22]([OH:24])=[O:23])=[CH:4]1)[CH3:2].[C:25]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1)(=[O:27])[CH3:26].C>N1C=CC=CC=1.C1C=CC=CC=1.CN(C)C=O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:20])=[C:10]([N:14]3[CH2:18][CH2:17][CH:16]([NH:19][S:35]([C:32]4[CH:31]=[CH:30][C:29]([NH:28][C:25](=[O:27])[CH3:26])=[CH:34][CH:33]=4)(=[O:37])=[O:36])[CH2:15]3)[C:11]=2[F:13])[C:6](=[O:21])[C:5]([C:22]([OH:24])=[O:23])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC(N)C3)c(F)c21
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC(NS(=O)(=O)c4ccc(NC(C)=O)cc4)C3)c(F)c21
Reaction time: 1 h
Yield: 32.7 %

Procedure:
2.80 g of 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(3-amino-1-pyrrolidinyl)-3-quinolinecarboxylic acid (see REFERENCE SYNTHESIS EXAMPLE hereinafter) is suspended in 100 ml of pyridine. To this is slowly added 3.88 g of 4-acetamidobenzenesulfonyl chloride in 20 ml of benzene. The mixture is stirred for 1 hour under ice-cooling and then overnight at room temperature. After evaporating off the solvent from the reaction mixture, the residue is added water and then adjusted to pH 12 with 2N sodium hydroxide solution. Any undissolved matter, if present, is filtered off. The filtrate is adjusted to pH 7 with acetic acid. The precipitated crystals are collected by filtration and washed. The crystals are then suspended in 100 ml of water. The suspension is adjusted to pH 4 with acetic acid, stirred and then filtered to recover the crystals, which are then thoroughly washed with water. The crude crystals thus obtained are dissolved in dimethylformamide (DMF), treated with activated charcoal, and recrystallized from DMF-methanol to give 1.45 g of the titled compound.
Reaction SMILES: C([Si]([O:8]/[C:9](/[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)=[CH:10]\[CH3:11])(C)C)(C)(C)C.CC[C@H]1[C@H]2C[C@H]([C@H](OC3C4C(=CC=CC=4)C(O[C@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:40]C)C=C4)N(CC2)C1.CS(N)(=O)=O>C(O)(C)(C)C.O>[Cl:18][C:14]1[CH:13]=[C:12]([C:9](=[O:8])[C@@H:10]([OH:40])[CH3:11])[CH:17]=[CH:16][CH:15]=1
Reactant: CC[C@@H]1CN2CC[C@@H]1C[C@@H]2[C@H](Oc1nnc(O[C@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Reactant: C/C=C(\O[Si](C)(C)C(C)(C)C)c1cccc(Cl)c1
Agent: CS(N)(=O)=O
Solvent: O
Solvent: CC(C)(C)O
Product: C[C@H](O)C(=O)c1cccc(Cl)c1

Procedure:
Compound (S)-10a was synthesized by a procedure similar to that described for (R)-10a using (Z)-tert-butyl(1-(3-chlorophenyl)prop-1-enyloxy)dimethylsilane (9a, 8.8 g, 0.031 mol), AD-mix-α (43.5 g), and CH3SO2NH2 (3a, 3 g, 0.032 mol) in tert-butyl alcohol-water (120 mL:120 mL). The reaction mixture was quenched with sodium sulfite (31.1 g). After purification, 4.51 g (78%) of the (S)-10a was isolated. Characterization data is similar with data reported in Fang, Q. K.; Han, Z.; Grover, P.; Kessler, D.; Senanayake, C. H.; Wald, S. A., Tetrahedron: Asymmetry 2000, 11, 3659-3663.
Reaction SMILES: [C:1]1([Si:7]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:8]2[CH:39]=[CH:38][C:11]3[O:12][C:13]4[CH:18]=[CH:17][C:16]([Si:19]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)=[CH:15][C:14]=4[C:10]=3[CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN([CH:55]=[O:56])C.Cl>C1COCC1.C1CCCCC1>[C:32]1([Si:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:16]2[CH:17]=[C:18]([CH:55]=[O:56])[C:13]3[O:12][C:11]4[CH:38]=[CH:39][C:8]([Si:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)([C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=5)[C:46]5[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=5)=[CH:9][C:10]=4[C:14]=3[CH:15]=2)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CN(C)C=O
Reactant: c1ccc([Si](c2ccccc2)(c2ccccc2)c2ccc3oc4ccc([Si](c5ccccc5)(c5ccccc5)c5ccccc5)cc4c3c2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: O=Cc1cc([Si](c2ccccc2)(c2ccccc2)c2ccccc2)cc2c1oc1ccc([Si](c3ccccc3)(c3ccccc3)c3ccccc3)cc12
Temperature: 45 °C
Reaction time: 0.25 h
Yield: 30.2 %

Procedure:
1 g (1.46 mmol) 2,8-di-(triphenylsilyl)-dibenzofuran are dissolved in 100 ml dry THF at 45° C. and 10 ml of 1.4 M sec-Buthyllithium solution in cyclohexane is added. After stirring for 15 min. at 45° C., 2 ml of dry DMF is added; the reaction mixture is stirred for 1 h. 100 ml of 0.5 M HCl is added to quench the reaction. The product is extracted with ethylacetate and purified by column chromatography on silica gel with heptane:ethylacetate (3:1) as an eluent. 2,8-di-(triphenylsilyl)-dibenzofuran-4-carboxaldehyde (5.3) is obtained in 30.2% yield.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:15][C@H:16]1[CH2:21][CH2:20][CH2:19][C@H:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:17]1.[Br:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33](O)[N:32]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Br:30][C:31]1[N:32]=[C:33]([O:15][C@@H:16]2[CH2:21][CH2:20][CH2:19][C@H:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:28])[CH3:27])[CH2:17]2)[CH:34]=[CH:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@H](O)C1
Reactant: Oc1cccc(Br)n1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H](Oc2cccc(Br)n2)C1
Reaction time: 18 h
Yield: 29.9 %

Procedure:
A solution of 0.473 mL (2.4 mmol) of diisopropylazodicarboxylate in 2 ml of tetrahydrofuran was added dropwise to a mixture of 454 mg (2.0 mmol) of tert-butyl (1S,3S)-3-hydroxycyclohexylcarbamate, 418 mg (2.40 mmol) of 2-bromo-6-hydroxypyridine and 629.5 mg (2.4 mmol) of triphenylphosphine in 5 ml of tetrahydrofuran at 0-5° C. The mixture was stirred for 18 hours. The mixture was concentrated, the residue purified via silica gel chromatography using a gradient of ethyl acetate in heptane to afford 222 mg (30%) of tert-Butyl (1S,3R)-3-(6-bromopyridin-2-yloxy)cyclohexylcarbamate. ESI MS m/z 370.9 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7](OC)=[O:8])([O-:3])=[O:2].O.[NH2:15][NH2:16]>CCO>[N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([NH:15][NH2:16])=[O:8])([O-:3])=[O:2]
Reactant: NN
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1
Solvent: CCO
Solvent: O
Product: NNC(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl 3-nitrobenzoate (940.70 mg; 5.19 mmol; 1.00 eq.) is dissolved in EtOH (24.00 ml). Hydrazine hydrate (4.04 ml; 83.09 mmol; 16.00 eq.) is added and the mixture is stirred 1 hour at RT. It is stirred at 60° C. for 6 hours and RT overnight. The precipitate formed is filtrated and dried under vacuo, affording 3-nitrobenzohydrazide as white-off solid (815.90 mg; 86.73%). 1H NMR (DMSO-d6) δ: 4.62 (s, 2H), 7.76 (m, 1H), 8.24 (m, 1H), 8.36 (m, 1H), 8.63 (s, 1H), 10.15 (s, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9](Br)[N:8]=1)=[O:6].[CH3:14][O:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23].C(O)C.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[OH:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:19]2[CH:18]=[CH:17][C:16]([O:15][CH3:14])=[C:21]([O:22][CH3:23])[CH:20]=2)[N:8]=1)=[O:6]
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: O=C(NCCO)c1cccc(Br)n1
Agent: [Pd]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: COCCOC
Product: COc1ccc(-c2cccc(C(=O)NCCO)n2)cc1OC
Temperature: 80 °C
Yield: 69.5 %

Procedure:
A quantity of 0.25 g (1.0 mmoles, 1 eq) of 6-bromo-pyridine-2-carboxylic acid (2-hydroxy-ethyl)-amide and 0.28 g (1.5 mmoles, 1.5 eq) of 3,4-dimethoxyphenyl boronic acid are added in 20 mL of ethylene glycol dimethyl ether with 2 ml of ethanol and 2 ml of 2 M Na2CO3. The mixture is purged with N2 for 20 minutes, and then 57 mg (0.05 mmoles, 0.05 eq) of Tris (dibenzylideneacetone)-dipalladium (0) is added. The reaction is heated at 80° C. for 6 hours. At that time there is no starting material shown on TLC. The reaction is filtered through Celite and the solvent is removed. The residue is taken in ethyl acetate, washed with brine, dried over Na2SO4 and concentrated to afford 6-(3,4-dimethoxy-phenyl)-pyridine-2-carboxylic acid (2-hydroxy-ethyl)-amide as a yellowish oil (0.21 g, 69%), which is used in the next step without purification. Analysis: MS (LC-MS): Calculated for C16H18N2O4 302.33, found 303.39 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:22]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:28]([OH:30])=O)=[N:17][C:18]=4[CH2:19][CH2:20]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:64][CH:65]1[CH2:70][CH2:69][NH:68][CH2:67][CH2:66]1>C(OCC)(=O)C.O.ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:22]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:28]([N:68]5[CH2:69][CH2:70][CH:65]([OH:64])[CH2:66][CH2:67]5)=[O:30])=[N:17][C:18]=4[CH2:19][CH2:20]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: OC1CCNCC1
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)nc4CCC3C2C2CCCC2)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N2N=C3c4ccc(C(=O)N5CCC(O)CC5)nc4CCC3C2C2CCCC2)cc1Cl
Temperature: 25 °C
Reaction time: 96 h
Yield: 47.8 %

Procedure:
In a dried reaction flask, the crude 2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-pyrazolo[3,4-f]quinoline-7-carboxylic acid (Compound 1) (0.4 g, about 0.9 mmol), DIEA (0.5 mL, 2.89 mmol) and HATU (1.047 g, 2.754 mmol) were added to DMF (4.5 mL). To the mixture was added dropwise a solution of dichloromethane (9 mL) dissolved in 4-hydroxylpiperidine (0.446 g, 4.409 mmol) under an ice-salt bath. After the completion of the dropwise addition, the mixture was stirred at room temperature for 4 days. Water and ethyl acetate were added. The mixture was extracted with ethyl acetate. The combined organic phase was washed with water and saturated salt water, dried over anhydrous sodium sulfate, and concentrated at reduced pressure to produce a crude yellow solid, which were washed with ethyl ether and ethyl acetate respectively to produce a purified product (0.217 g) in 47.8% yield.
Reaction SMILES: Cl[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].CO.C(Cl)Cl>O1CCOCC1.O.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>[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1Cl
Reactant: OB(O)c1ccccc1F
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: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1-c1ccccc1F
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 91.5 %

Procedure:
A solution of 2-(3-chloro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 425; 36.7 mg, 0.117 mmol), (2-fluorophenyl)boronic acid (CombiBlocks, Inc., San Diego, Calif.; 24.63 mg, 0.176 mmol), Na2CO3 (37.3 mg, 0.352 mmol), and Pd(PPh3)4 (Strem Chemicals, Inc.; 6.78 mg, 5.87 μmol) in a mixture of 1,4-dioxane (1.5 mL) and water (0.500 mL) was stirred under argon at 100° C. for 20 min. The reaction mixture was then concentrated onto silica gel and chromatographically purified (silica gel, 50-100% EtOAc/hexanes, then 0-10% MeOH/DCM) to provide 2-(3-(2-fluorophenyl)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (39.8 mg, 0.107 mmol, 91% yield) as a brown solid. 1H NMR (400 MHz, CDCl3) δ ppm 12.07 (1H, br. s.), 8.10 (1H, dd, J=7.4, 1.2 Hz), 7.90 (1H, dd, J=8.2, 1.2 Hz), 7.78 (1H, t, J=8.0 Hz), 7.50-7.62 (2H, m), 7.38 (1H, td, J=7.5, 1.0 Hz), 7.27-7.34 (1H, m), 7.25 (1H, br. s.), 5.39 (1H, br. s.), 3.61 (2H, td, J=6.8, 2.0 Hz), 2.89 (2H, t, J=6.9 Hz), 2.75 (3H, d, J=1.6 Hz). 19F NMR (377 MHz, CDCl3) δ ppm −114.59 (1F, br. s.). m/z (ESI, +ve) 373.0 (M+H)+.
Reaction SMILES: C1(C)C=CC=CC=1.C(=O)([O-])O.[Na+].I[C:14]1[C:19]([O:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][CH:22]=2)=[CH:18][CH:17]=[C:16]([CH3:35])[N:15]=1.[CH3:36][N:37]([CH3:47])[C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1>O.CN(C)C=O>[CH3:32][O:31][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][C:27]=1[O:33][CH3:34])[N:24]=[CH:23][CH:22]=[C:21]2[O:20][C:19]1[C:14]([C:41]2[CH:42]=[CH:43][C:38]([N:37]([CH3:47])[CH3:36])=[CH:39][CH:40]=2)=[N:15][C:16]([CH3:35])=[CH:17][CH:18]=1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Reactant: CN(C)c1ccc(B(O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3ccc(N(C)C)cc3)c2cc1OC
Temperature: 80 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
Toluene (1 ml), N,N-dimethylformamide (0.5 ml) and a saturated aqueous sodium hydrogencarbonate solution (0.5 ml) were added to 4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound 116) (50 mg), tetrakistriphenylphosphine palladium (28 mg), and 4-dimethylaminophenylboronic acid (196 mg) under an argon atmosphere, and the mixture was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added thereto, and the mixture was extracted with chloroform. The chloroform layer was then washed with water and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform-methanol to give the title compound (39 mg, yield 80%).
Reaction SMILES: N#N.[H-].[Na+].[Cl:5][C:6]1[CH:7]=[C:8]([OH:15])[CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13].[CH3:16]OS(OC)(=O)=O.[NH4+].[OH-]>>[Cl:5][C:6]1[CH:7]=[C:8]([O:15][CH3:16])[CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1ccc(O)cc1Cl
Reactant: COS(=O)(=O)OC
Agent: N#N
Agent: [H-]
Agent: [NH4+]
Product: COc1ccc([N+](=O)[O-])c(Cl)c1
Reaction time: 2 h
Yield: 72.4 %

Procedure:
In an atomosphere of N2 were added to a stirred suspension of 31 g NaH in 2.2 l anhydrous THF 199.5 g (1.15 mole) 3-chloro-4-nitrophenol (3). This was followed by the addition of dimethylsulfate (575 ml). The whole mixture was heated under reflux during 1.5 h. After cooling, it was poured into a cold (0° C.) diluted NH4OH solution, to destroy the excess of dimethylsulfate, and stirred for two hours. The product was isolated by extraction with diethylether. The ethereal extracts were dried with MgSO4 and evaporated at reduced pressure affording 156 g (72.4%) of 3-chloro-4-nitroanisole.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.CN(C=O)C.C([O-])([O-])=O.[Cs+].[Cs+]>C(OCC)(=O)C.O>[Cl:1][C:2]1[C:3]([C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([F:12])[CH:18]=2)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: OB(O)c1cccc(F)c1
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1cnc(-c2cccc(F)c2)c(Cl)c1
Temperature: 90 °C
Yield: 95.2 %

Procedure:
To a round bottom flask was added 5,6-dichloronicotinic acid (500 mg, 2.60 mmol), 3-fluorophenylboronic acid (364 mg, 2.60 mmol), DMF (25 mL), 2 M Cs2CO3 (6 mL) and Pd(Ph3)4 (30.1 mg, 0.0026 mmol). The reaction mixture was heated to 90° C. for 3 hrs and then allowed to cool to rt. The mixture was diluted with ethyl acetate/water and the layers separated. The organic layer was washed with brine, dried (MgSO4) and the solvent removed to give a solid, which was purified by chromatography (silica, DCM/MeOH) to give the desired product, 5-chloro-6-(3-fluorophenyl)nicotinic acid (623 mg, 95%). LC/MS (M+H)=252 observed, 252.02 expected.
Reaction SMILES: [C:1]([NH:4][C:5](=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([OH:17])[CH:11]=1)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].[H][H]>>[C:1]([NH:4][C@H:5]([C:6]([OH:8])=[O:7])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([OH:17])[CH:11]=1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)NC(=Cc1ccc(O)c(O)c1)C(=O)O
Product: CC(=O)N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O

Procedure:
reacting α-acetamido-3,4-dihydroxycinnamic acid with hydrogen in the presence of a catalytic amount of a chiral hyrogenation catalyst of the formula ##STR36## to produce N-acetyl-3,4-dihydroxy-L-phenylalanine; and (b) hydrolyzing the N-acetyl-3,4-dihydroxy-L-phenylalanine to produce 3,4-dihydroxy-L-phenylalanine.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:11]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[O:12])[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.Cl.[CH3:19][N:20]([CH3:25])[CH2:21][C:22]([Cl:24])=[O:23]>N1C=CC=CC=1>[ClH:24].[CH3:19][N:20]([CH3:25])[CH2:21][C:22]([NH:1][C:2]1[N:3]=[C:4]([C:11]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[O:12])[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1)=[O:23]
Reactant: Nc1nc(C(=O)c2cccs2)c2sccc2n1
Reactant: CN(C)CC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CN(C)CC(=O)Nc1nc(C(=O)c2cccs2)c2sccc2n1
Temperature: 25 °C
Yield: 14.7 %

Procedure:
A solution of 2-aminothieno[3,2-d]pyrimidin-4-yl 2-thienylmethanone (0.15 g, 0.57 mmol) in anhydrous pyridine (6 mL) under argon at 0° C. was treated with N,N-dimethylglycinyl chloride hydrochloride (0.11 g, 0.69 mmol), warmed to room temperature, refluxed for 16 h, cooled, concentrated in vacuo and partitioned between 3-M HCl (25 mL) and EtOAc (25 mL). The aqueous phase was washed with EtOAc (25 mL), filtered through celite, basified to pH 12 with 10% aqueous sodium hydroxide and the resulting precipitate filtered and dried in vacuo to give a brown solid which was purified by chromatography [SiO2; EtOAc-MeOH (100:0 to 85:15)]. The resulting yellow solid was dissolved in CH2Cl2 (5 mL), treated with 1-M HCl in ether (0.25 mL) and the resulting precipitate filtered and dried in vacuo to give the title compound (32 mg, 11%) as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:33]=[CH:32][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:20]=[C:21]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[N:22]=2)[C:11]([NH:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[O:12])=[CH:5][CH:4]=1)#[N:2].[C:34]([O:38][C:39](=[O:45])[NH:40][CH2:41][CH2:42][CH2:43]Br)([CH3:37])([CH3:36])[CH3:35].C(=O)([O-])[O-].[K+].[K+]>>[C:34]([O:38][C:39](=[O:45])[NH:40][CH2:41][CH2:42][CH2:43][N:17]1[CH2:16][CH2:15][CH:14]([NH:13][C:11]([C:10]2[CH:20]=[C:21]([O:23][C:24]3[CH:25]=[CH:26][C:27]([C:30]#[N:31])=[CH:28][CH:29]=3)[N:22]=[C:8]([O:7][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:33][CH:32]=3)[CH:9]=2)=[O:12])[CH2:19][CH2:18]1)([CH3:37])([CH3:36])[CH3:35]
Reactant: N#Cc1ccc(Oc2cc(C(=O)NC3CCNCC3)cc(Oc3ccc(C#N)cc3)n2)cc1
Reactant: CC(C)(C)OC(=O)NCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)NCCCN1CCC(NC(=O)c2cc(Oc3ccc(C#N)cc3)nc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 80.6 %

Procedure:
2,6-Bis(4-cyano phenoxy)-N-piperidin-4-yl-isonicotinamide 0.16 g (0.364 mmol), (3-bromo-propyl)-carbamic acid tert-butyl ester 0.12 g (0.50 mmol) and potassium carbonate 0.175 g (1.26 mmol) were used and the procedure of Example 11(e) was followed to afford 0.175 g of the required product. Percentage purity (LCMS): 80.4%, (M+1)=596.2+1. NMR (DMSO-d6): δ 1.40 (9H, s), 1.88 (9H, m), 2.95 (4H, m), 3.85 (2H, m), 6.86 (2H, brs), 7.26 (2H, s), 7.34 (4H, d), 7.85 (4H, d), 8.15 (2H, brs), 9.02 (1H, brs).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([NH:13][NH2:14])=[O:12])[O:8][C:7]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[CH:27]=1.[C:28](Cl)(Cl)=[O:29]>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]3[O:12][C:28](=[O:29])[NH:14][N:13]=3)[O:8][C:7]([CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]3)([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[CH:27]=1
Reactant: O=C(Cl)Cl
Reactant: NNC(=O)C1Oc2ccc(Cl)cc2C(C2CCCCC2)(C2CCCCC2)O1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=c1[nH]nc(C2Oc3ccc(Cl)cc3C(C3CCCCC3)(C3CCCCC3)O2)o1
Temperature: 25 °C

Procedure:
To a solution of 300 mg 6-chloro-4,4-dicyclohexyl-4H-benzo[1,3]dioxine-2-carboxylic acid hydrazide in 4.3 ml toluene was added 4 ml of a 1.9M solution of phosgene in toluene. The reaction mixture was heated to reflux for 4 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with water and brine and dried with MgSO4. Then the solvent was removed in vacuo and the crude product purified by preparative HPLC (C18 reverse phase column, elution with water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a solid. Yield: 180 mg.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:20])[N:10]([C@H:12]1[CH2:17][CH2:16][C@H:15]([CH:18]=O)[CH2:14][CH2:13]1)[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-].[Br:22][CH2:23][CH2:24][CH2:25][CH2:26][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>CC(O)(CC)C>[CH2:1]([O:8][C:9](=[O:20])[N:10]([CH:12]1[CH2:17][CH2:16][CH:15]([CH:18]=[CH:26][CH2:25][CH2:24][CH2:23][Br:22])[CH2:14][CH2:13]1)[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C(=O)OCc1ccccc1)[C@H]1CC[C@H](C=O)CC1
Reactant: BrCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CCC(C)(C)O
Product: CN(C(=O)OCc1ccccc1)C1CCC(C=CCCCBr)CC1
Temperature: 25 °C

Procedure:
A solution of 126.5 g (459.4 mmol) of trans-(4-Formyl-cyclohexyl)-methyl-carbamic acid benzyl ester in 1.27 l 2-methyl-2-butanol was treated with 263.6 g (551.3 mmol) (4-bromobutyl)triphenylphosphonium bromide and 254 g (1838 mmol) of K2CO3 and was heated at reflux for 3.5 h. The reaction was cooled (RT), filtered and evaporated. The residue was suspended in hexane (1.8 l, first at RT then at 0° C.) and filtered. Purification by column chromatography on silica gel (hexane/EtOAc 4:1) gave 149.9 g (83%) of trans-(1 E/Z)-[4-(5-Bromo-pent-1-enyl)-cyclohexyl]-methyl-carbamic acid benzyl ester, MS: 293 (M, 1Br).