Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5].Br[C:13]1([CH3:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>O1CCOCC1.FC(F)(F)S([O-])(=O)=O.[Ag+]>[CH3:20][C:13]1([O:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CCOC(=O)/C(=N\O)C(C)=O
Reactant: CC1(Br)CCCCCC1
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: C1COCCO1
Product: CCOC(=O)/C(=N\OC1(C)CCCCCC1)C(C)=O
Reaction time: 5 h
Yield: 65.2 %

Procedure:
Ethyl (Z)-2-hydroxyimino-3-oxobutyrate (795 mg, 5 mmol) and 1-bromo-1-methylcycloheptane (1.lg, 5.76 mmol) in dry 1,4-dioxan (5 ml) under an atmosphere of argon in the dark were treated portionwise with silver trifluoromethanesulphonate (1.48 g, 5.76 mmol), with stirring, over 5 h. The mixture was stirred for a further 18 h in the dark and then worked up using a similar procedure to that described in Example 7a to give the title compound as an oil (878 mg; 65%); νmax (CH2Cl2) 3430, 3350, 1740, 1685, 1595, 1370, 1320, 1230, 1070, and 1,000cm-1 ; δH (250 MHz, CDCl3) 1.33 (3H, t, J 7.1Hz), 1.33 (3H, s), 1.4-1.8 (1OH, m), 1.99 (2H, dd, J ca 13.5 and 7.5 Hz), 2.40 (3H, s), and 4.35 (2H, q, J 7.1 Hz); [Found: M30 -OEt 224.1273. C12H18NO3 requires M-OEt 224.1287. Ammonia CI mass spectrum MH+ (270)].
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.C(O)C.[Cl:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[Cl:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Reactant: OB(O)c1ccc(F)cc1Cl
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: CCO
Solvent: COCCOC
Solvent: O
Product: Cc1cc([N+](=O)[O-])cnc1-c1ccc(F)cc1Cl
Temperature: 90 °C
Reaction time: 4.5 h

Procedure:
To a stirred solution of 2-chloro-3-methyl-5-nitropyridine (prepared according to the procedure of Hawkins and Roe, J. Am. Chem. Soc., page 330, 1948) (5.3 g, 30.7 mmol, 1 eq.) in 1,2-dimethoxyethane (50 mL) and ethanol (25 mL) was added 2-chloro-4-fluorobenzeneboronic acid (5.9 g, 33.8 mmol, 1.1 eq.). The resulting mixture was degassed with argon. To the mixture was added a solution of Na2CO3 (11.4 g, 107.45 mmol, 3.5 eq) in water (50 mL). The mixture was degassed with argon, and tetrakis(triphenylphosphine)palladium(0) (1.1 g, 0.95 mmol, 0.03 eq) was added. The mixture was degassed with argon and heated to 90° C. under argon. After 4.5 h, the mixture was cooled. The solvent was removed under reduced pressure. The residue was diluted with water and extracted 3× with ethyl acetate. The aqueous layer was extracted several times with ethyl acetate. The organic extracts were combined, dried over anhydrous Na2SO4, filtered and concentrated. The product was purified by flash column chromatography on silica gel eluting with 5% Et2O in hexanes giving 2-(2-chloro-4-fluorophenyl)-3-methyl-5-nitropyridine. Mass spectrum (EST) 267 (M+1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=[CH:7][C:8]([O:10][CH3:11])=[O:9])=[CH:2]1.C(O[CH2:16][C:17]([CH2:19][Si](C)(C)C)=[CH2:18])(=O)C>C1COCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:16]=[C:17]1[CH2:19][C@@H:7]([C:8]([O:10][CH3:11])=[O:9])[C@H:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[CH2:18]1
Reactant: COC(=O)C=Cc1ccsc1
Reactant: C=C(COC(C)=O)C[Si](C)(C)C
Agent: [Pd]
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=C1C[C@@H](C(=O)OC)[C@H](c2ccsc2)C1
Yield: 86.2 %

Procedure:
A mixture of methyl 3-(3-thienyl)acrylate (10.0 g, 59.5 mmol), tetrakis(triphenylphosphine) palladium(0) (5.15 g, 5.6 mmol), 1,2-bis(diphenylphosphino)ethane (1.35 g, 3.4 mmol) and 2-((trimethylsilyl)methyl)-2-propen-1-yl acetate (20 g, 107 mmol) in THF (125 mL) under argon was heated to reflux for 24 h. The volatiles were then removed in vacuo and the residue was purified by FC (5% ethyl acetate in hexanes) to afford the title compound (11.4 g).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2OC)[N:3]=1.[NH2:30][C:31]1[CH:32]=[CH:33][C:34]([C@H:42]2[CH2:47][CH2:46][C@@H:45]([OH:48])[CH2:44][CH2:43]2)=[C:35]2[C:39]=1[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]2>>[OH:48][C@H:45]1[CH2:46][CH2:47][C@H:42]([C:34]2[CH:33]=[CH:32][C:31]([NH:30][C:2]3[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]4[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][CH:14]=4)[N:3]=3)=[C:39]3[C:35]=2[CH2:36][N:37]([CH3:41])[C:38]3=[O:40])[CH2:43][CH2:44]1
Reactant: CN1Cc2c(c(N)ccc2[C@H]2CC[C@@H](O)CC2)C1=O
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@H](O)CC4)c4c3C(=O)N(C)C4)n2)cc1)OCC

Procedure:
This compound was prepared in a manner analogous to Example 87 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and 7-amino-4-(cis-4-hydroxycyclohexyl)-2-methyl-2,3-dihydro-1H-isoindol-1-one. Purification: ISCO Combi-flash Rf system, eluting with 0 to 5% MeOH in EtOAc. 1H NMR (400 MHz, DMSO-d6) δ 10.58 (br. s., 1H), 9.87 (s, 1H), 8.46 (s, 1H), 7.37 (d, J=8.34 Hz, 1H), 7.25 (dd, J=2.53, 8.59 Hz, 3H), 4.52 (s, 3H), 4.40 (d, J=4.04 Hz, 2H), 3.89-4.02 (m, 5H), 3.17-3.26 (m, 2H), 3.08 (s, 3H), 1.91 (q, J=12.80 Hz, 1H), 1.78 (d, J=13.64 Hz, 2H), 1.48-1.62 (m, 4H), 1.18 (t, J=7.07 Hz, 6H). MS (ES+): m/z: 648.22 [MH+]. HPLC: tR=3.46 min (Micromass ZQ3: polar—5 min).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]([CH:15]2[CH2:17][O:16]2)[CH:12]=[CH:13][CH:14]=1.[CH3:18][NH2:19]>CO>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]([CH:15]([OH:16])[CH2:17][NH:19][CH3:18])[CH:12]=[CH:13][CH:14]=1
Reactant: COCCOCCOc1cccc(C2CO2)c1
Reactant: CN
Solvent: CO
Product: CNCC(O)c1cccc(OCCOCCOC)c1

Procedure:
A solution of 1.78 g of 2-{3-[2-(2-methoxyethoxy)ethoxy]phenyl}oxirane in 30 ml of 2.0 M methylamine in methanol is stirred at room temperature overnight, then concentrated under reduced pressure. Flash chromatography of the residue on silica using 5-7% methanolic ammonia in CH2Cl2 affords 809 mg of the title compound as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([NH:18][CH3:19])=[CH:16][CH:15]=1>>[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([N:18]([CH3:19])[C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:16][CH:15]=1
Reactant: Clc1ncnc2ccccc12
Reactant: CNc1ccc(OC)cc1
Product: COc1ccc(N(C)c2ncnc3ccccc23)cc1

Procedure:
The title compound was prepared from 4-chloroquinazoline and 4-methoxy-N-methylaniline by a procedure similar to example 28 (79% yield). 1H NMR (CDCl3): 8.81 (s, 1H), 7.81 (d, J=8.1 Hz, 1H), 7.57 (ddd, J=8.1, 5.4 and 2.7 Hz, 1H), 7.09-7.14 (m, 2H), 7.03-7.06 (m, 2H), 6.9-6.93 (m, 2H).
Reaction SMILES: C([O:5][CH:6]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:7][CH2:8][C@@H:9]1[C@@H:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:12](=[O:25])[CH2:11][CH2:10]1)(C)(C)C.FC(F)(F)C(O)=O>>[OH:5][CH:6]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:7][CH2:8][C@@H:9]1[C@@H:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:12](=[O:25])[CH2:11][CH2:10]1
Reactant: CCCCCC(CC[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)OCC)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCCCCC(O)CC[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)OCC
Reaction time: 0.25 h

Procedure:
A solution of 25 g. of 15-(tert-butoxy)-9-oxoprostanoic acid, ethyl ester in 100 ml. of trifluoroacetic acid is stirred in an ice bath for 1 hour and is then poured into 500 ml. of ice water and extracted several times with chloroform. The combined chloroform extracts are washed with saturated sodium bicarbonate solution, saturated sodium chloride solution, dried with anhydrousmagnesium sulfate, and taken to dryness. The resulting oil is dissolved in 200 ml. of 1N ammonium hydroxide in ethanol, kept at ambient temperature for 15 minutes, then taken to dryness. The residual oil is dissolved in chloroform and washed with 1N hydrochloric acid, saturated sodium chloride solution, dried and taken to dryness to give 21.7 g. (100%) of product as a yellow syrup. There is essentially no uv absorption; λmaxKBr 2.90, 5.75, 8.45 μ; nmr 2H quartet δ4.13 (OCH2 of ester), 1H broad singlet 3.63 (carbinolic proton), 3H triplet (CH3 of ester), and 3H distorted triplet 0.92 (terminal methyl); mass spectrum: m/e 368.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([C:14](=[O:18])[N:15]([CH3:17])[CH3:16])[CH2:9]1)(C)(C)C.C([Cl:23])(=O)C>CO>[ClH:23].[CH3:16][N:15]([CH3:17])[C:14]([C@H:10]1[CH2:11][CH2:12][CH2:13][C@H:8]([NH2:7])[CH2:9]1)=[O:18]
Reactant: CC(=O)Cl
Reactant: CN(C)C(=O)[C@H]1CCC[C@H](NC(=O)OC(C)(C)C)C1
Solvent: CO
Product: CN(C)C(=O)[C@H]1CCC[C@H](N)C1
Product: Cl
Temperature: 20 °C
Reaction time: 16 h

Procedure:
Racemic trans 3-Dimethylcarbamoyl-cyclohexyl carbamic acid tert-butyl ester (0.437 g, 1.62 mmol) was dissolved in 50 mL of MeOH and cooled to 20° C. Acetyl chloride (1.2 mL, 16.9 mmol) was added dropwise and when the addition was complete the reaction mixture was allowed to warm up to RT and stirred for 16 h. The solvent was removed under vacuum concentrated to dryness to give racemic trans 3-amino-cyclohexanecarboxylic acid dimethylamide hydrochloride which was used as is in the following step.
Reaction SMILES: CN(C=O)C.[N:6]1([CH2:10][C@@H:11]2[CH2:14][C@H:13]([N:15]3[C:19]4[N:20]=[CH:21][N:22]=[C:23]([NH2:24])[C:18]=4[C:17](I)=[CH:16]3)[CH2:12]2)[CH2:9][CH2:8][CH2:7]1.[C:26]1([C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][C:36](B4OC(C)(C)C(C)(C)C4)=[CH:37][CH:38]=3)[N:33]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([O-])([O-])=O.[Na+].[Na+]>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.O>[N:6]1([CH2:10][C@@H:11]2[CH2:14][C@H:13]([N:15]3[C:19]4[N:20]=[CH:21][N:22]=[C:23]([NH2:24])[C:18]=4[C:17]([C:36]4[CH:35]=[C:34]5[C:39]([CH:40]=[CH:41][C:32]([C:26]6[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=6)=[N:33]5)=[CH:38][CH:37]=4)=[CH:16]3)[CH2:12]2)[CH2:9][CH2:8][CH2:7]1
Reactant: CC1(C)CB(c2ccc3ccc(-c4ccccc4)nc3c2)OC1(C)C
Reactant: Nc1ncnc2c1c(I)cn2[C@H]1C[C@@H](CN2CCC2)C1
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: CN(C)C=O
Solvent: O
Product: Nc1ncnc2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)cn2[C@H]1C[C@@H](CN2CCC2)C1
Temperature: 80 °C

Procedure:
To the DMF solution from the preparation of cis-7-(3-azetidin-1-ylmethylcyclobutyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine were added 2-phenyl-7-(4,4,5,5-tetramethyl-[2,3,2]dioxaborolan-2-yl)-quinoline (40 mg, 0.12 mmol), Na2CO3 (27 mg, 0.25 mmol), Pd(PPh3)4 (7 mg, 0.006 mmol), and water (0.6 mL). The solution was purged with nitrogen for 10 min and heated to 80° C. for 16 h. To the cooled reaction solution was added sat. Na2CO3 solution (10 mL), the mixture was extracted with EtOAc (3×20 mL), the combined organic layers were washed with water (3×15 mL) and brine, dried over MgSO4, filtered, and concentrated to give a brown oil. Purification by HPLC gave the title compound as brown oil. 1H NMR (CDCl3, 400 MHz): δ=2.06-2.26 (m, 5H), 2.56-2.57 (d, 2H, J=6.2), 2.71-2.77 (m, 2H), 3.21-3.24 (m, 4H), 5.17 (brs, 2H), 5.19-5.26 (m, 1H), 7.31 (s, 1H), 7.46-7.56 (m, 3H), 7.69-7.71 (dd, 1H, J=1.6 & 8.4 Hz), 7.90-7.94 (m, 2H), 8.18-8.20 (m, 2H), 8.26-8.29 (m, 2H), 8.35 (s, 1H). MS (ES+): 461.2 [MH+]. HPLC: tR=2.0 min (polar—5 min).
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O.C(OCC)(=O)C>[CH2:16]([O:8][C:7]([C@@H:2]1[CH2:3][CH2:4][C:5](=[O:6])[NH:1]1)=[O:9])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CC[C@@H](C(=O)O)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1CC[C@@H](C(=O)OCc2ccccc2)N1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 387 g of L-pyro-glutamic acid in 300 mL of dimethylformamide is treated with 103.6 g of potassium carbonate at room temperature. Benzyl bromide (35.6 mL) is added and the suspension stirred room temperature for 4 hours. The suspension is filtered and the solid washed with 300 mL of acetone. The filtrate is evaporated at 50° C. to give an oil. The oil is dissolved in 300 mL of ethyl acetate and washed with 300 mL of water. The aqueous phase is re-extracted with 150 mL of ethyl acetate and the organic layers combined, dried and the solvent removed to give (S)-5-oxo-pyrrolidine-2-carboxylic acid benzyl ester as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:10][N:11]1[CH2:16][CH2:15][CH:14]([O:17][CH2:18][C:19](=O)[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:13][CH2:12]1.[NH2:27]/[C:28](/[CH3:34])=[CH:29]\[C:30]([O:32][CH3:33])=[O:31]>>[CH3:10][N:11]1[CH2:16][CH2:15][CH:14]([O:17][CH2:18][C:19]2[NH:27][C:28]([CH3:34])=[C:29]([C:30]([O:32][CH3:33])=[O:31])[CH:4]([C:3]3[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=3[Cl:1])[C:20]=2[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:13][CH2:12]1
Reactant: O=Cc1ccccc1Cl
Reactant: CCOC(=O)CC(=O)COC1CCN(C)CC1
Reactant: COC(=O)/C=C(/C)N
Product: CCOC(=O)C1=C(COC2CCN(C)CC2)NC(C)=C(C(=O)OC)C1c1ccccc1Cl

Procedure:
Reaction of 2-chlorobenzaldehyde, ethyl 4-(1-methylpiperid-4-yloxy)acetoacetate and methyl 3-aminocrotonate according to the method of Example 22(ii) gave the title compound which was used directly in the next stage.
Reaction SMILES: C(O)C.C([O-])(O)=O.[Na+].[OH:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[OH:18])[CH:13]=O.Cl.[CH3:20][O:21][C:22](=[O:27])[C@H:23]([CH2:25][SH:26])[NH2:24]>O>[OH:9][C:10]1[CH:11]=[C:12]([CH:13]2[NH:24][C@H:23]([C:22]([O:21][CH3:20])=[O:27])[CH2:25][S:26]2)[CH:15]=[CH:16][C:17]=1[OH:18]
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: COC(=O)[C@@H](N)CS
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COC(=O)[C@@H]1CSC(c2ccc(O)c(O)c2)N1
Temperature: 25 °C
Reaction time: 5 h
Yield: 83 %

Procedure:
In a co-solvent of ethanol (5 mL) and water (5 mL), a solution including NaHCO3 (486 mg, 5.79 mmol), 3,4-dihydroxybenzaldhehyde (3,4-dihydroxybenzaldehyde) (800 mg, 5.80 mmol), and L-cysteine methyl ester hydrochloride (1.0 g, 5.84 mmol) was stirred at room temperature for 5 hours. After ethanol was evaporated, the reaction mixture was distributed between ethyl acetate and water, and an organic layer was dried, filtered, and evaporated. The residual was purified by silica gel column chromatography using hexane and ethyl acetate (4:1) to obtain a solid Compound 104 (1.23 g, 83%).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)=[O:6].C(N(CC)CC)C.CS(Cl)(=O)=O.[NH:29]1[CH:33]=[CH:32][N:31]=[CH:30]1>C1COCC1.[Na+].[I-].O>[N:29]1([CH2:2][CH2:3][CH2:4][C:5]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=2)=[O:6])[CH:33]=[CH:32][N:31]=[CH:30]1
Reactant: O=C(CCCO)c1ccc2ccccc2c1
Reactant: c1c[nH]cn1
Agent: CS(=O)(=O)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: O=C(CCCn1ccnc1)c1ccc2ccccc2c1
Reaction time: 1 h
Yield: 22.7 %

Procedure:
To a cooled (0° C.) solution of 4-hydroxy-1-(2-naphthyl)-1-butanone (4.32 g) in THF (60 ml) were added triethylamine (5.6 ml) and methanesulfonyl chloride (2.4 ml) successively. The mixture was stirred at 0° for 1 hour. Imidazole (2.93 g) and NaI (0.02 g) were added to the mixture and resulting mixture was refluxed for 16 hours. Water was added and the mixture was concentrated. The residue was extracted with ethyl acetate and the extract was washed with water and brine, dried and concentrated. The residue was chromatographed on silica gel, eluting with ethyl acetate-methanol=20:1, followed by crystallization from ethyl acetate-CH2Cl2-cyclohexane to give the titled compound (1.21 g) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:20])[C:11]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[CH:14]=1)=[O:12].[F:21][C:22]([Si](C)(C)C)([F:24])[F:23].O.O.O.[F-].C[N+](C)(C)C.CCCCCCC>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:20])[C:11]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[CH:14]=1)([OH:12])[C:22]([F:24])([F:23])[F:21]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: COc1ccc(C(C)C(=O)c2ccnc(Cl)c2)c(Cl)c1
Agent: C[N+](C)(C)C
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCCCCCC
Solvent: O
Product: COc1ccc(C(C)C(O)(c2ccnc(Cl)c2)C(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.7 %

Procedure:
To a solution of 2-(2-chloro-4-methoxy-phenyl)-1-(2-chloro-pyridin-4-yl)-propan-1-on (14.75 g, 0.0475 mol) in tetrahydrofuran (900 ml) was added a solution of (trifluoromethyl)-trimethylsilane (14.89 g, 0.104 mol) in tetrahydrofuran (100 ml) at 0° C. (duration: 5 min.). Tetramethylammonium fluoride trihydrate 1M in THF (4.76 ml, 4.76 mmol) was added and the mixture was stirred at r.t. for 3 h. A second portion of Tetramethylammonium fluoride trihydrate 1M in THF (4.76 ml, 4.47 mmol) was added and the mixture was stirred at r.t. for 1 h. The mixture was poured in ice water and extracted twice with AcOEt. The organic phases were washed with saturated aqueous NaHCO3 solution and brine, dried over MgSO4, filtered and concentrated to give an oil, which solidified over night. The residue was treated with heptane, filtered off and dried to give the title compound (13.85 g) as a light yellow crystalline product. MS (m/e, ISP neg. ion)=378.4 [M−H+].
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)([OH:3])=[O:2].Br[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21]([NH2:23])=[O:22].C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>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.O.C(O)C>[NH:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:1]([OH:3])=[O:2])[CH:5]=1)[C:21]([NH2:23])=[O:22]
Reactant: NC(=O)Nc1ccccc1Br
Reactant: O=C(O)c1cccc(B(O)O)c1
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: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: NC(=O)Nc1ccccc1-c1cccc(C(=O)O)c1
Temperature: 100 °C
Yield: 96.7 %

Procedure:
3-Carboxyphenyl boronic acid (100 mg, 0.60 mmol), 2-bromophenyl urea (130 mg, 0.60 mmol), tetrakis(triphenylphosphine)palladium(0) (35 mg, 0.030 mmol), sodium carbonate (192 mg, 1.81 mmol), toluene (5 mL), water (3 mL), and ethanol (3 mL) were mixed at 25° C. under nitrogen then heated in a microwave reactor for 30 minutes at 100° C. Water (5 mL) was added followed by removal of the EtOH in vacuo. The aqueous layer was washed with diethyl ether (2×) and the pH was adjusted to 3 with 1N HCl. The aqueous layer was extracted with ethyl acetate (2×) and the combined were dried over sodium sulfate and then concentrated in vacuo to give 2′-ureidobiphenyl-3-carboxylic acid (150 mg, 0.58 mmol, 97% yield) as a tan glass. MS found: (M+H)+=257.29
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][CH:7]=1.[C:10]1(=[O:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([OH:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc([Mg]Br)c1
Reactant: O=C1CCCCC1
Solvent: C1CCOC1
Product: OC1(c2cccc(Cl)c2)CCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.2 %

Procedure:
3-Chlorophenylmagnesium bromide (3.4 mL, 3.4 mmol) was added to a cooled (−10° C.) solution of cyclohexanone (0.3 g, 3.1 mmol) in anhydrous tetrahydrofuran slowly over 30 min. After complete addition, the reaction mixture was slowly warmed to room temperature, stirred for 18 hours. Again cooled (−5° C.), than quenched with sat. ammonium chloride solution over 30 min. The reaction mixture was extracted with ethyl acetate, dried, filtered and concentrated to afford 550 mg of 1-(3-chlorophenyl)cyclohexanol.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1)(=[O:9])=[O:8].[F:17][C:18]([F:30])([F:29])[O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:23]2[CH:22]=[CH:21][C:20]([O:19][C:18]([F:17])([F:29])[F:30])=[CH:25][CH:24]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8]
Reactant: O=S(=O)(NCCCCO)c1ccc(Br)cc1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Product: O=S(=O)(NCCCCO)c1ccc(-c2ccc(OC(F)(F)F)cc2)cc1

Procedure:
Using a method analogous to that described in Example 40, 4-bromophenyl-sulfonic acid-(4-hydroxybutyl)-amide and 4-trifluoromethoxyphenyl boronic acid were reacted to give the title compound as a white solid. δC (DMSO, 62.9 MHz): 25.9, 29.6, 42.6, 60.2, 121.7, 127.1, 127.4, 129.0, 137.9, 139.8, 142.3 and 148.5.
Reaction SMILES: [C@H:1]12[CH2:8][C@H:4]([CH2:5][CH:6]1[OH:7])[CH2:3][NH:2]2.F[C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O>[OH:7][CH:6]1[C@H:1]2[CH2:8][C@H:4]([CH2:3][N:2]2[C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[CH2:5]1
Reactant: OC1C[C@@H]2CN[C@H]1C2
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc(N2C[C@@H]3CC(O)[C@H]2C3)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 47.2 %

Procedure:
To a round bottom flask was added (1S,4R)-2-azabicyclo[2.2.1]heptan-6-ol (0.5 gm, 3.34 mmol), 4-fluorobenzonitrile (0.405 gm, 3.34 mmol), DMF (6 ml) and K2CO3 (1.386 gm, 10.03 mmol). The reaction was stirred at 80° C. for 5 hrs. After this time, the reaction was diluted with EtOAc. The resulting solution was washed with water (4×) and saturated aqueous NaCl. The organic layer was separated, dried over MgSO4, filtered and concentrated. The resulting residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-100% EtOAc/Hex to give product 4-((1R,4S)-6-hydroxy-2-azabicyclo[2.2.1]heptan-2-yl)benzonitrile (338 mg, 1.578 mmol, 47.2% yield) as a white solid. Anal. Calcd. for C13H14N2O m/z 214.2, found: 215.1 (M+H)+.