Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Cl-].C([Al+2])C.[C:6]([O:10][CH3:11])(=[O:9])[CH:7]=[CH2:8].[C:12]([O:15][C@@H:16]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@H:18]([CH2:19][CH2:20][C@@H:21]3[C:31]2=[CH:30][CH2:29][C@@:28]2([CH3:36])[C@H:22]3[CH2:23][CH2:24]/[C:25]/2=[CH:26]/[CH3:27])[CH2:17]1)(=[O:14])[CH3:13].O>C(Cl)Cl>[C:12]([O:15][C@@H:16]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@H:18]([CH2:19][CH2:20][C@@H:21]3[C:31]2=[CH:30][CH2:29][C@@:28]2([CH3:36])[C@H:22]3[CH2:23][CH:24]=[C:25]2[C@H:26]([CH3:27])[CH2:8][CH2:7][C:6]([O:10][CH3:11])=[O:9])[CH2:17]1)(=[O:14])[CH3:13]
Reactant: C=CC(=O)OC
Reactant: C/C=C1/CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](OC(C)=O)CC[C@]4(C)C3=CC[C@]12C
Agent: CC[Al+2]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COC(=O)CC[C@@H](C)C1=CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](OC(C)=O)CC[C@]4(C)C3=CC[C@]12C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 69.7 %

Procedure:
Ethyl aluminum dichloride (14.2 mL, 25 mmol, 1.8M in toluene) was added to a solution of methyl acrylate (1.89 mL, 20 mmol) in DCM (60 mL) at 0° C. under inert atmosphere. The resulting solution was stirred for 15 min and then compound 1.6a (3 g, 8.7 mmol) was added. After stifling for an additional 20 min at 0° C., the temperature was raised to 25° C. and held there for a further 18 h. At this point the reaction was determined to be complete by TLC, then the mixture was poured into cold (0° C.) water (60 mL). The phases were separated and the aqueous layer was extracted with DCM (60 mL). The organic layers were combined and washed sequentially with water (50 mL) and saturated brine solution (100 mL). It was then dried over anhydrous Na2SO4 (5 g) and filtered. The filtrate was concentrated under vacuum, providing compound 1.7b (2.6 g, 70%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:21][C@@H:22]1[C@@H:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][N:24]([C:33]2[C:42]([F:43])=[CH:41][C:36]([C:37]([O:39]C)=[O:38])=[CH:35][C:34]=2[F:44])[CH2:23]1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.C1COCC1>[C:1]([O:5][C:6]([N:8]([CH2:21][C@@H:22]1[C@@H:26]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:25][N:24]([C:33]2[C:42]([F:43])=[CH:41][C:36]([C:37]([OH:39])=[O:38])=[CH:35][C:34]=2[F:44])[CH2:23]1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1cc(F)c(N2C[C@H](CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)[C@@H](c3ccccc3)C2)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](c1cccc2ccccc12)N(C[C@H]1CN(c2c(F)cc(C(=O)O)cc2F)C[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
A 60 ml portion of a methanol-THF (1:1) mixed solution of 2.09 g of methyl 4-[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]-3,5-difluorobenzoate was mixed with 7.5 ml of 1 M sodium hydroxide aqueous solution at room temperature and stirred overnight at 80° C. The reaction solution was concentrated under a reduced pressure, 1 M hydrochloric acid was added to the thus obtained residue, and the precipitated solid was collected by filtration to obtain 2.02 g of 4-[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]-3,5-difluorobenzoic acid.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[CH3:16][C:17]1[S:21][C:20]([S:22](Cl)(=[O:24])=[O:23])=[CH:19][CH:18]=1.[CH:26]([C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=1)([CH2:28][CH3:29])[CH3:27]>>[CH:26]([C:30]1[CH:31]=[CH:32][C:33]([N:36]2[CH2:13][CH2:12][C:6]3([CH2:7][CH2:8][N:9]([S:22]([C:20]4[S:21][C:17]([CH3:16])=[CH:18][CH:19]=4)(=[O:24])=[O:23])[CH2:10][CH2:11]3)[C:4]2=[O:5])=[CH:34][CH:35]=1)([CH2:28][CH3:29])[CH3:27]
Reactant: Cc1ccc(S(=O)(=O)Cl)s1
Reactant: CCC(C)c1ccc(N)cc1
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Product: CCC(C)c1ccc(N2CCC3(CCN(S(=O)(=O)c4ccc(C)s4)CC3)C2=O)cc1

Procedure:
Off-white solid. MS (ESI): 447.17 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 5-methylthiophene-2-sulphonyl chloride and 4-sec-butyl-phenylamine.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[C:5]([O:9][C:10](=[O:18])[NH:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)([CH3:8])([CH3:7])[CH3:6]>C(N(CC)CC)C.C(O)C>[C:5]([O:9][C:10](=[O:18])[NH:11][CH:12]1[CH2:17][CH2:16][N:15]([CH2:3][CH2:2][C:1]#[N:4])[CH2:14][CH2:13]1)([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: C=CC#N
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCN(CCC#N)CC1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Acrylonitrile (3.6 ml, 55.0 mmol) and triethylamine (2 drops) were added sequentially to a solution of piperidin-4-yl-carbamic acid tert-butyl ester (10 g, 50.0 mmol) in ethanol (100 ml) at 25° C. The reaction mixture was stirred at 25° C. for 3.5 h, then was concentrated under reduced pressure to afford crude [1-(2-cyano-ethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester as a white solid. TLC: 5% CH3OH in CH2Cl2, Rf=0.56; 1H NMR (400 MHz, CDCl3) δ 4.42 (s, 1H), 3.45 (s, 1H), 2.82 (d, J=11.8 Hz, 2H), 2.67 (t, J=7.0 Hz, 2H), 2.49 (t, J=7.0 Hz, 2H), 2.18 (td, J=11.5, 2.3 Hz, 2H), 1.94 (d, J=12.1 Hz, 3H), 1.51-1.36 (m, 1H), 1.44 (s, 9H). This material was used in the next step below without additional purification or characterization.
Reaction SMILES: C(=O)([O-])[O-].[Li+].[Li+].Br[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[OH:17][C:18]1[C:23]([OH:24])=[C:22]([OH:25])[CH:21]=[CH:20][C:19]=1[C:26]([C:28]1[CH:33]=[C:32]([OH:34])[C:31]([OH:35])=[C:30]([OH:36])[CH:29]=1)=[O:27]>CN(C)C=O>[OH:17][C:18]1[C:23]([OH:24])=[C:22]([OH:25])[CH:21]=[CH:20][C:19]=1[C:26]([C:28]1[CH:33]=[C:32]([OH:34])[C:31]([O:35][CH2:8][C:9](=[O:10])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:30]([OH:36])[CH:29]=1)=[O:27]
Reactant: O=C(CBr)c1ccccc1
Reactant: O=C(c1cc(O)c(O)c(O)c1)c1ccc(O)c(O)c1O
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=C(COc1c(O)cc(C(=O)c2ccc(O)c(O)c2O)cc1O)c1ccccc1
Temperature: 50 °C
Reaction time: 6 h
Yield: 37.3 %

Procedure:
3.0 g of lithium carbonate then 3.5 g of ω-bromoacetophenone are added to a solution of 5.0 g of [2,3,4-trihydroxyphenyl] [3',4',5'-trihydroxyphenyl] methanone in 20 cm3 of dimethyl-formamide maintained at 50° C., under a nitrogen atmosphere. The reaction mixture is then agitated for 6 hours at 50° C. Then 400 cm3 of a molar aceto-acetic buffer solution, the pH of which is about 4.50, are added. The resultant solution is extracted with 800 cm3 of ethyl acetate. The combined organic phases are washed with 300 cm3 of distilled water, then dried over anhydrous sodium sulphate. After filtration then evaporation to dryness under reduced pressure (2.7 kPa) at 40° C. of the ethyl acetate, 9 g of a residue are obtained and purified by chromatography on a fritted disc which contains 50 g of silica gel [eluant: dichloromethane/acetone (90/10 by volume)], collecting 30 cm3 fractions. The fractions containing the mixture of monoacetylated derivatives in position -4 and -4' are concentrated to dryness under reduced pressure (2.7 kPa), at a temperature close to 40° C. After crystallization from a dichloromethane/acetone mixture (98/2 by volume), 2.6 g of [2,3,4-trihydroxyphenyl] [3',5'-dihydroxy-4'-(2-oxo-2-phenyl-ethoxy)-phenyl] methanone is obtained in the form of a yellow powder melting at around 180° C. (with decomposition).
Reaction SMILES: [C:1]1([C@H:7]([O:9][C:10](=[O:25])[NH:11][C:12]2[C:13]([CH3:24])=[N:14][O:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:26]([O:28][C:29]([C:31]1([C:36]2[CH:41]=[CH:40][C:39](B3OC(C)(C)C(C)(C)O3)=[CH:38][CH:37]=2)[CH2:35][CH2:34][CH2:33][CH2:32]1)=[O:30])[CH3:27].C(=O)([O-])[O-].[K+].[K+].COCCOC>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>[CH2:26]([O:28][C:29]([C:31]1([C:36]2[CH:41]=[CH:40][C:39]([C:20]3[CH:21]=[CH:22][C:17]([C:16]4[O:15][N:14]=[C:13]([CH3:24])[C:12]=4[NH:11][C:10]([O:9][C@@H:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH3:8])=[O:25])=[CH:18][CH:19]=3)=[CH:38][CH:37]=2)[CH2:32][CH2:33][CH2:34][CH2:35]1)=[O:30])[CH3:27]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)O[C@H](C)c1ccccc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)O[C@H](C)c4ccccc4)cc3)cc2)CCCC1
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-phenyl-ethyl ester (0.077 g, 0.19 mmol), 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopentanecarboxylic acid ethyl ester (0.079 g, 0.23 mmol), and potassium carbonate (0.066 g, 0.48 mmol) were combined in 2:1 DME:H2O (3 mL). The solution was purged with N2 for 5 minutes, and then tetrakis(triphenylphosphine)palladium(0) (0.022 g, 0.02 mmol) was added. The mixture was purged with N2 for an additional 5 minutes, and then the reaction was stirred at 90° C. in a sealed tube for 1.5 hours. Aqueous work-up, followed by silica gel chromatography, provided the title compound.
Reaction SMILES: [C@@H:1]1([C:10]2[S:11][CH:12]=[C:13]([C:15]([O:17]CC)=O)[N:14]=2)[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[NH3:20].C>C(O)C>[C@@H:1]1([C:10]2[S:11][CH:12]=[C:13]([C:15]([NH2:20])=[O:17])[N:14]=2)[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: N
Reactant: CCOC(=O)c1csc([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)n1
Agent: C
Solvent: CCO
Product: NC(=O)c1csc([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)n1
Reaction time: 2 h

Procedure:
Ethyl 2-β-D-ribofuranosylthiazole-4-carboxylate (5, 120.8 g, 0.418 mol) was mixed with cold (-20° C.) methanolic ammonia (saturated at 0° C.). The mixture was protected from moisture and at 5° C. for 2 days. The mixture was evaporated (40° C., 20 mm) to a sticky foam. The residue was dissolved in hot ethanol (500 mL) and then, with stirring, 2-propanol (500 mL) was added. The mixture was allowed to stand at ambient temperature for 2 h and then was refrigerated (5° C.) for 1 d. The yellow solid was collected by filtration, washed with 2-propanol (2×100 mL) and dried (25° C., 20 mm); 98.0 g, mp 139-142° C. The washes were combined with the filtrate and the solution was evaporated (40° C., 20 mm) to dryness. The residue was dissolved in hot ethanol (100 mL). The solution was allowed to stand at ambient temperature until crystallization began and then was stored at 5° C. for 1 d. The solid was collected by filtration, washed with ethanol (2×25 mL), and dried (25° C., 20 mm); 6.9 g, mp 138-139° C. The two crops of solid (104.9 g, 0.403 mol, 96%) were combined and dissolved in boiling ethanol (1.1 L). Norit A (10 g) was added and the mixture was stirred and boiled for 5 min. The mixture was filtered through an ertel pad and pad was washed with hot ethanol (3×100 ml). The washes were combined with the filtrate; the solution was stirred rapidly and cooled in ice bath for 1 h. The mixture was refrigerated (5° C.) for 3 d. The solid was collected by filtration, washed with ethanol (2×100 mL), and dried (50° C., 1 mm) for 1 d; 91.1 g (0.35 mol, 84%), mp 140-142° C. The combined filtrate and washes was concentrated to a volume of approx. 350 mL. The solution was heated to boiling and 2-propanol (200 mL) was added. The solution was concentrated to a volume of 300 mL and then refrigerated (5° C.) for 1 d. The solid was collected by filtration, washed with 2-propanol (3×25 mL), and dried (50° C., 1 mm); 9.4 g (0.036 mol, 8%), mp 138-139° C. The crops were not combined. 1H NMR (DMSO-d6): δ3.59 (m, 2), 3.89 (s, 2), 4.07 (t, 1), 4.85 (t, 1), 4.93 (d, 1), 5.06 (d, 1), 5.36 (d, 1), 7.55 (s, 1), 7.70 (s, 1) and 8.21 (s, 1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]2[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:16])[N:5]=[C:4]([NH:17][C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)[N:3]=1.[H-].[Na+].[N:28]([CH:31]([CH3:33])[CH3:32])=[C:29]=[O:30]>CN(C=O)C>[C:22]([C:21]1[CH:20]=[CH:19][C:18]([NH:17][C:4]2[N:5]=[C:6]([CH2:8][C:9]3[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=3[Cl:16])[N:7]=[C:2]([NH:1][C:29]([NH:28][CH:31]([CH3:33])[CH3:32])=[O:30])[N:3]=2)=[CH:25][CH:24]=1)#[N:23]
Reactant: N#Cc1ccc(Nc2nc(N)nc(Cc3c(Cl)cccc3Cl)n2)cc1
Reactant: CC(C)N=C=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)NC(=O)Nc1nc(Cc2c(Cl)cccc2Cl)nc(Nc2ccc(C#N)cc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.1 %

Procedure:
A mixture of compound (1) (1.0 g) and sodium hydride (0.11 g), in DMF (20 ml) was stirred for 20 minutes at RT under argon flow. Then, 2-isocyanato-propane (0.27 ml) was added dropwise over 30 minutes and the reaction mixture was allowed to stir at RT overnight. The solvent was evaporated and water added. The residue was filtered, washed with water and diethyl ether, and recrystallized from 1,4-dioxane. The precipitate was filtered off and dried, yielding 0.95 g (85.1 %) of N-[4-[(4-cyanophenyl)amino]-6-[(2,6-dichlorophenyl)methyl]-1,3,5-triazin-2-yl]-N′-(1-methylethyl)urea (compound 6, mp. 267-268° C.).
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:14][C@H:13]([NH:15][C:16]([N:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:17])[C:12]2[C:7](=[CH:8][C:9]([Cl:32])=[CH:10][C:11]=2[Cl:31])[NH:6]1)=[O:4]>CS(C)=O>[C:3]([C@H:5]1[CH2:14][C@H:13]([NH:15][C:16]([N:18]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:17])[C:12]2[C:7](=[CH:8][C:9]([Cl:32])=[CH:10][C:11]=2[Cl:31])[NH:6]1)([OH:4])=[O:2]
Reactant: COC(=O)[C@H]1C[C@H](NC(=O)N(c2ccccc2)c2ccccc2)c2c(Cl)cc(Cl)cc2N1
Solvent: CS(C)=O
Product: O=C(O)[C@H]1C[C@H](NC(=O)N(c2ccccc2)c2ccccc2)c2c(Cl)cc(Cl)cc2N1

Procedure:
This compound was prepared by the method given in Example 37 step b) using trans-2-methoxycarbonyl-5,7-dichloro-4-(N,N-diphenylamino)carbonylamino-1,2,3,4-tetrahydroquinoline in place of trans-5,7-dichloro-2-methoxycarbonyl-4-phenylmethylcarbonylamino-1,2,3,4-tetrahydroquinoline to give the title compound as colourless crystals, m.p. 214°-216° C. δ (360 MHz, DMSO), 1.63 (1H, ddd, 13.0, 12.1 and 3.9 Hz, CHACHBHCCHD), 2.33 (1H, dm, J=13.0 Hz, CHACHBHCCHD), 3.88 (1H, dm, J=12.1 and 2.8 Hz, CHACHBHCCHD), 4.99 (1H, m, CHACHBHCCHD), 6.63 (1H, d, J=2.0 Hz, 6-H or 8-H), 6.65 (1H, d, J=7.2 Hz, NHCO), 6.80 (1H, d, J=2.0 Hz, 6-H or 8-H), 7.12 (5H, m, ArH), 7.16 (1H, s, ArNH), 7.31 (5H, m, ArH); m/e (CI+) 456 (M+1); Found C, 59.63; H, 4.36; N, 8.89. C23H19Cl2N3O3.0.5H2O requires C, 59.37; H, 4.33; N, 9.03%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[NH:9][C:10]1[C:15]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][N:17]=2)=[CH:14][CH:13]=[CH:12][N:11]=1.[C:22]1([N:28]=[C:29]=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:29]([NH:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:30])=[CH:4][C:3]=1[NH:9][C:10]1[C:15]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][N:17]=2)=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: Cc1ccc(N)cc1Nc1ncccc1-c1ccncn1
Reactant: O=C=Nc1ccccc1
Solvent: Cc1ccccc1
Product: Cc1ccc(NC(=O)Nc2ccccc2)cc1Nc1ncccc1-c1ccncn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-methyl-N3-(3-pyrimidin-4-yl-pyridin-2-yl)-benzene-1,3-diamine (30 mg, 0.11 mmol) in toluene (2.0 mL) was added phenyl isocyanate (0.012 mL, 0.11 mmol). The mixture was stirred overnight at RT. The resulting solid was filtered, washed with toluene and dried to yield N-(4-methyl-3-((3-(4-pyrimidinyl)-2-pyridinyl)amino)phenyl)-N′-phenylurea. MS m/z=397 [M+1]+. Calc'd for C23H20N6O: 396.46.
Reaction SMILES: Cl.C(O[C:5](=[NH:18])[CH2:6][N:7]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]1[C:13]([O:15][CH2:16][CH3:17])=[O:14])C.[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>C(O)C>[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][N:29]([C:5](=[NH:18])[CH2:6][N:7]2[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:28][CH2:27]1
Reactant: CCOC(=N)Cn1c(C)ccc1C(=O)OCC
Reactant: Fc1ccccc1N1CCNCC1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1ccc(C)n1CC(=N)N1CCN(c2ccccc2F)CC1
Temperature: 55 °C
Yield: 85.4 %

Procedure:
A mixture of ethyl 1-(2-ethoxy-2-iminoethyl)-5-methyl-1H-pyrrole-2-carboxylate hydrochloride (950 mg, 3.46 mmol) and 1-(2-fluorophenyl)piperazine (1.87 g, 10.4 mmol) in ethanol (5 mL) was heated at 55° C. overnight. At this time, the reaction was concentrated in vacuo. Reverse phase column chromatography (0-100% acetonitrile/water) afforded ethyl 1-(2-(4-(2-fluorophenyl)piperazin-1-yl)-2-iminoethyl)-5-methyl-1H-pyrrole-2-carboxylate (1.1 g, 85.4%) as a white solid. LC-MS calcd. for C20H26N4O2 [(M+H)+] 373, obsd. 373.0.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13]CC)=[O:12])=[C:5]2[CH2:16][CH2:17][CH2:18][O:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1.[C:30]1([CH2:36]/[CH:37]=[CH:38]/B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[Li+].[OH-]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:20]1([O:19][CH2:18][CH2:17][CH2:16][C:5]2[C:9]3[C:8](=[CH:4][CH:3]=[C:2](/[CH:38]=[CH:37]/[CH2:36][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:10]=3)[NH:7][C:6]=2[C:11]([OH:13])=[O:12])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1[nH]c2ccc(Br)cc2c1CCCOc1cccc2ccccc12
Reactant: OB(O)/C=C/Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)c1[nH]c2ccc(/C=C/Cc3ccccc3)cc2c1CCCOc1cccc2ccccc12

Procedure:
A mixture of EXAMPLE 11C (45.2 mg), (E)-3-phenylprop-1-enylboronic acid (21.1 mg), bis(triphenylphosphine)palladium(II) dichloride (catalytic), and 2M LiOH (0.3 mL) in 7/2/3dimethoxyethane/ethanol/H2O (2 mL) was heated under microwave (CEM Discover) conditions at 150° C. for 30 minutes. The mixture was quenched with 1 MHCl (0.4 mL) and extracted with ethyl acetate. The extract was dried (MgSO4), filtered, and concentrated. The cruconcentrate was purified by reverse phase HPLC (Zorbax SB-C18, 20-100% acetonitrile/water/0.1% trifluoroacetic acid). 1H NMR (500 MHz, DMSO-d6) δ 12.95 (brs, 1H), 11.44 (s, 1H), 8.34 (d, 1H), 7.88 (d, 1H), 7.54 (m, 2H), 7.44 (m, 2H), 7.31 (m, 5H), 7.18 (m, 3H), 6.83 (d, 1H), 6.00 (m, 2H), 4.08 (t, 2H), 2.21 (m, 2H).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1CCCC#N.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([CH:7]([CH2:6][CH3:5])[C:8]#[N:9])=[CH:19][CH:18]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccccc1CCCC#N
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCC(C#N)c1ccc(-c2c(O)ccc3[nH]c(=O)c4sccc4c23)cc1
Temperature: 25 °C
Yield: 11.4 %

Procedure:
Following General Procedure F, 2-(4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl phenyl)butanenitrile (80 mg, 0.21 mmol) in CH2Cl2 at 0° C. was added BBr3 (1.0 M in CH2Cl2, 3 mL, 3 mmol) and the reaction was warmed to room temperature for 4 h. The reaction was quenched by pouring onto water or ice-water and the resulting mixture was concentrated and purified by preparatory HPLC (C18 silica, acetonitrile/water (with 0.05% TFA) gradient). The desired product was dissolved in aqueous HCl, concentrated and dried under high vacuum to afford the desired product as a light yellow solid (4.3 mg, 6%): 1H NMR (500 MHz, CD3OD) δ 7.56 (dd, J=10.8, 4.6 Hz, 3H), 7.43-7.31 (m, 3H), 7.17 (d, J=8.9 Hz, 1H), 6.00 (d, J=5.4 Hz, 1H), 4.15 (t, J=7.2 Hz, 1H), 2.07 (p, J=7.3 Hz, 2H), 1.16 (t, J=7.4 Hz, 3H): ESI MS m/z 361 [C21H16N2O2S+H]+; HPLC 98.5% (AUC), tR=12.2 min.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12](=[O:26])[O:13][C:14]3[C:19]([C:20]=2[CH3:21])=[CH:18][CH:17]=[C:16]([O:22]C(=O)C)[CH:15]=3)=[CH:7][CH:6]=1)(=O)C.Cl>C1COCC1.[OH-].[Na+]>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:12](=[O:26])[O:13][C:14]3[C:19]([C:20]=2[CH3:21])=[CH:18][CH:17]=[C:16]([OH:22])[CH:15]=3)=[CH:9][CH:10]=1
Reactant: CC(=O)Oc1ccc(-c2c(C)c3ccc(OC(C)=O)cc3oc2=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(-c2ccc(O)cc2)c(=O)oc2cc(O)ccc12
Reaction time: 1 h
Yield: 36.8 %

Procedure:
A suspension of 3-(4-acetoxyphenyl)-7-acetoxy-4-methylcoumarin (500 mg) in THF (10 mL) and 1N aqueous sodium hydroxide (10 mL) was stirred for 1 h. The mixture is acidified to pH=1 with concentrated HCl and extracted with EtOAc 1 water. The organic layer was washed with brine and dried over MgSO4. Evaporation of the solvent and trituration of the residue with ether gave the title compound (140 mg)
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[O:11][CH2:12][CH:13]1[CH2:15][CH2:14]1.[Li]CCCC.C(O[B:25]1[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]1)(C)C>C(OC)CCC>[CH:13]1([CH2:12][O:11][C:3]2[CH:4]=[CH:5][C:6]([CH:8]([F:10])[F:9])=[CH:7][C:2]=2[B:25]2[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]2)[CH2:15][CH2:14]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: FC(F)c1ccc(OCC2CC2)c(Br)c1
Agent: CCCCOC
Agent: [Li]CCCC
Product: CC1(C)OB(c2cc(C(F)F)ccc2OCC2CC2)OC1(C)C
Yield: 98.6 %

Procedure:
2-Bromo-1-cyclopropylmethoxy-4-difluoromethyl-benzene (example B.b18; 24.35 g; 87.9 mmol) is dissolved in dry tert. BuOMe (440 mL). n-BuLi (1.6M in hexane; 60.0 mL; 96.0 mmol) is slowly syringed into the well stirred reaction mixture at −40° C. After one hour commercially available 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (17.86 g; 96.0 mmol) is added at −40° C. followed by stirring at 0° C. for one additional hour. The reaction mixture is quenched by addition of 2M aqueous citric acid (90.0 mL). The organic layer is separated, washed with brine, dried over Mg2SO4 and filtered through a pad of neutral alumina (act.2-3). The solvent is removed under reduced pressure to yield 28.1 g of the title compound as pale yellow oil.
Reaction SMILES: OC(C[PH:11]([CH2:13][S:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=1)=[O:12])(CC(C)C)C(O)=O.C(N1C=CN=C1)(N1C=CN=C1)=[O:26].O=C1CCC2=CN(C3C=CC=CC=32)CCCCCCN1>C1COCC1>[N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:15]=1[S:14][CH2:13][PH:11](=[O:12])[OH:26]
Reactant: CC(C)CC(O)(C[PH](=O)CSc1ccc2ccccc2n1)C(=O)O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: O=C1CCc2cn(c3ccccc23)CCCCCCN1
Solvent: C1CCOC1
Product: O=[PH](O)CSc1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A single stereoisomer of 2-(hydroxy) (quinolin-2-ylthiomethyl)phosphinoylmethyl-4-methylpentanoic acid (300 mg, 0.81 mmol) and 1,1'-carbonyldiimidazole (174 mg, 1.0 mmol) were stirred at 0° C. in 6 mL THF for 11/2 hours. (10S)-10-Amino-(9-oxo-1,8-diazatricyclo[10.6.1.013,18 ]nonadeca-12(19),13(18),14,16-tetraene (270 mg, 0.95 mmol) was added to the solution and the resulting mixture was allowed to warm to room temperature and then stirred for 18 hours. The THF was removed by evaporation and the residue dissolved in 60 mL ethyl acetate. The ethyl acetate was washed with 10 mL H2O, 10 mL brine, dried with MgSO4 and evaporated to yield (10S)-[4-methyl-2-(9-oxo-1,8-diazatricyclo[10.6.1.013,18 ]nonadeca-12(19) 13(18)14,16-tetraen-10-ylcarbamoyl)pentyl](quinolin-2-ylthiomethyl)phosphinic acid as a yellow oil. Purification was carried out by reverse phase HPLC using a gradient of acetonitrile and 50 mm NH4OAc buffer as the eluents. The more polar stereoisomer was isolated (30 mg) at 41% acetonitrile, and the less polar stereoisomer (10 mg) at 43% acetonitrile. The fractions were lyophilized to off-white powders, MS: 635 (MH+).