Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[NH:7][C:6]1=[O:16].[C:17]1([CH:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:30]1([CH:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:24]2[CH2:25][CH2:26][N:27]([CH2:2][CH2:3][CH2:4][N:5]3[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[C:8](=[O:15])[NH:7][C:6]3=[O:16])[CH2:28][CH2:29]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=c1[nH]c(=O)n(CCCBr)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]c(=O)n(CCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)c2ccccc12
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 47 %

Procedure:
A mixture of 1-(3-bromopropyl)-2,4(1H,3H)-quinazolinedione (2.12 g), 1-diphenylmethylpiperazine (2.07 g), anhydrous potassium carbonate (3.1 g) and N,N-dimethylformamide (14 ml) was stirred for 2.5 hours at 100° C. After the reaction mixture was cooled to ambient temperature, to the mixture was added water and then stirred to give precipitates. The precipitates were collected by filtration and they were dissolved in hot chloroform containing a little quantity of methanol. The resultant solution was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate and concentrated in vacuo to give a crystal, which was washed enough with methanol and dried to give 1-[3-{4-(diphenylmethyl)piperazin-1-yl}propyl]-2,4(1H,3H)-quinazolinedione (1.6 g). This crystal was dissolved in 2N hydrochloric acid solution and then the solution was concentrated in vacuo to give a white crystal, which was washed with methanol, dissolved in water with warming and the solution was evaporated in vacuo. The resultant crystal was washed enough with methanol, to give 1-[3-{4-(diphenylmethyl)piperazin-1-yl}propyl]-2,4(1H,3H)-quinazolinedione.2HCl.0.7H2O (1.6 g).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1.Br[CH2:14][CH2:15][CH2:16][Cl:17]>CN(C=O)C.O>[Cl:17][CH2:16][CH2:15][CH2:14][O:3][C:4]1[CH:5]=[C:6]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1
Reactant: ClCCCBr
Reactant: CC(=O)c1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1cccc(OCCCCl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 110.5 %

Procedure:
To a suspension of NaH (50.5 mg, 2.00 mmol) in DMF (1.00 mL) was added 1-(3-hydroxyphenyl)ethanone (136 mg, 1.00 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h. To this mixture was added a solution of 1-bromo-3-chloropropane (188 mg, 1.20 mmol) in DMF (0.500 mL). The reaction mixture was stirred at room temperature for 5 h. The resulting crude mixture was diluted with water (20 mL), the aqueous layer was extracted with CH2Cl2 (3×20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative TLC using hexane:EtOAc (4:1) to afford the desired product 1-[3-(3-chloropropoxy)phenyl]ethanone (235 mg, 55.2%): 1H NMR (400 MHz, CDCl3) δ 7.7 (d, 1H, J=6.6 Hz), 7.52 (s, 1H), 7.25 (t, 1H, J=6.6 Hz), 7.01 (m, 1H), 4.11 (t, 2H, J=7.9 Hz), 3.69 (t, 2H, J=7.9 Hz), 2.61 (s, 3H), 1.95–1.92 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]2=[N:6][S:7][N:8]=[C:4]2[CH:3]=1.[Br:11]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)Cl>[Br:11][CH2:1][C:2]1[CH:10]=[CH:9][C:5]2=[N:6][S:7][N:8]=[C:4]2[CH:3]=1
Reactant: Cc1ccc2nsnc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)Cl
Product: BrCc1ccc2nsnc2c1
Temperature: 25 °C
Yield: 62.9 %

Procedure:
5-Methylbenzo-2,1,3-thiadiazole (5 g, 33.3 mmol) in CHCl3 (75 mL) was treated with N-bromosuccinimide (5.32 g, 33.3 mmol) and a catalytic amount of AIBN and heated at reflux for 16 hours. After cooling to ambient temperature, the resulting precipitate was fitered off and the filtrate was concentrated under reduced pressure. The residue was recrystallized from ethanol to provide 4.8 g of the title compound. 1H NMR (300 MHz, CDCl3) δ 4.62 (s, 2H), 7.65 (dd, 1H), 8.0 (m, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)([CH3:24])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:32][CH2:33][CH3:34])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:35](Cl)([Cl:37])=[O:36]>C(N(CC)CC)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([C:35]([Cl:37])=[O:36])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)([CH3:16])[C:13]([C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)([CH3:24])[N:12]=2)=[C:7]([O:32][CH2:33][CH3:34])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(F)cc2)C(C)(c2ccc(F)cc2)N1
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(F)cc2)C(C)(c2ccc(F)cc2)N1C(=O)Cl

Procedure:
rac-(4S*,5R*)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-fluoro-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was then reacted with phosgene in the presence of triethylamine to give rac-(4S*,5R*)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-fluoro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=4)=[O:22])[CH2:17]3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)#[N:2].[N-:37]=[N+:38]=[N-:39].[Na+].N(CC)(CC)CC.Cl>O1CCOCC1>[N:2]1[NH:37][N:38]=[N:39][C:1]=1[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:34])([F:35])[F:33])[CH:27]=4)=[O:22])[CH2:17]3)[CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCc1ccc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cc1
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(c3ccc(Cc4nn[nH]n4)cc3)CC2)C1

Procedure:
A solution of N-({1-[4-(4-cyanomethyl-phenyl)-cyclohexyl]-azetidin-3-ylcarbamoyl}-methyl)-3-trifluoromethyl-benzamide (as prepared in Example 21, 250 mg, 0.50 mmol), sodium azide (Aldrich, 160 mg, 2.50 mmol), and Et3N HCl salt (350 mg, 2.50 mmol) in dioxane (5 mL) was heated in a sealed tube to 120° C. overnight. The solvent was removed in vacuo and the residue was purified on a silica gel column using a CombiFlash® system using ethyl acetate and 7N NH3 in MeOH as eluent (from pure ethyl acetate to 5% 7N NH3 in MeOH in ethyl acetate) to afford the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[CH2:21][C@@H:20]2[C@@H:16]([CH2:17][C:18]3(OCC[O:22]3)[CH2:19]2)[CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(=O)(O)[O-].[Na+]>CC(C)=O.O>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[CH2:21][C@@H:20]2[C@@H:16]([CH2:17][C:18](=[O:22])[CH2:19]2)[CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1=C(CCCCCOCc2ccccc2)C[C@H]2CC3(C[C@@H]12)OCCO3
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C1C[C@@H]2CC(CCCCCOCc3ccccc3)=C[C@@H]2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.5 %

Procedure:
6.65 g of 3-(5-benzyloxypentyl)-7,7-ethylenedioxy-cis-bicyclo[3,3,0]oct-2-ene (prepared as described in Preparation 4 or 10) were added to a mixture of 120 ml of acetone, 45 ml of water and 1.0 ml of concentrated hydrochloric acid, and the mixture was stirred for 2 hours at room temperature. After completion of the reaction, sodium bicarbonate was added to the reaction mixture for neutralization, and acetone was distilled off under reduced pressure. A saturated aqueous solution of sodium chloride was added to the residue, and then the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The solvent was distilled off from the extract under reduced pressure, giving 6.00 g of residue. On purifying this residues by silica gel column chromatography, 5.33 g of the title compound were obtained from the fractions eluted with hexane containing 7-10% by volume of ethyl acetate.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:16])([F:15])[F:14])=[N:5][N:4]=[C:3]1[C:17]12[CH2:24][CH2:23][C:20]([C:25]([NH:27][NH2:28])=[O:26])([CH2:21][CH2:22]1)[CH2:19][CH2:18]2.[F:29][C:30]([F:35])([CH3:34])[C:31](O)=O>C(Cl)Cl>[F:29][C:30]([C:34]1[O:26][C:25]([C:20]23[CH2:23][CH2:24][C:17]([C:3]4[N:2]([CH3:1])[C:6]([C:7]5[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=5[C:13]([F:15])([F:14])[F:16])=[N:5][N:4]=4)([CH2:18][CH2:19]2)[CH2:22][CH2:21]3)=[N:27][N:28]=1)([F:35])[CH3:31]
Reactant: Cn1c(-c2ccccc2C(F)(F)F)nnc1C12CCC(C(=O)NN)(CC1)CC2
Reactant: CC(F)(F)C(=O)O
Solvent: ClCCl
Product: Cn1c(-c2ccccc2C(F)(F)F)nnc1C12CCC(c3nnc(C(C)(F)F)o3)(CC1)CC2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]octane-1-carbohydrazide (4-A) (334 mg, 0.850 mmol) and 2,2-difluoropropionic acid (78 mg, 0.708 mmol) was suspended in methylene chloride, and DMC (1.2 g, 7.08 mmol) was added as solid. The mixture was stirred at room temperature under nitrogen for 48 hours before it was diluted with methylene chloride, washed with water, saturated sodium bicarbonate and brine. The crude product was purified by column chromatography to give 4-B as a white solid. MS (ESI+)=468.3 (M+1); 1H NMR (500 MHz, CDCl3): δ 2.15-2.33 (15H, m), 3.52 (3H, s), 7.61 (1H, m), 7.72 (2H, m), 7.85 (1H, m) ppm.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:15])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8](I)[CH:7]=2)[CH2:3][CH2:2]1.[H-].[Na+].C([Li])CCC.[B:23](OC(C)C)([O:28]C(C)C)[O:24]C(C)C>O1CCCC1.O>[CH:1]1([NH:4][C:5]([C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([B:23]([OH:28])[OH:24])[CH:7]=2)=[O:15])[CH2:3][CH2:2]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1I
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1B(O)O
Temperature: -75 °C
Reaction time: 4 h

Procedure:
N-Cyclopropyl-5-fluoro-3-iodo-4-methylbenzamide (Intermediate 63) (5 g) in tetrahydrofuran (75 ml) was cooled to 0° C. then treated with sodium hydride (60% oil dispersion, 1.23 g) portionwise over 10 minutes. Once effervescence had ceased the reaction was cooled to −75° C. and n-butyl lithium (1.6M in hexanes, 20 ml) was added over 25 min maintaining a temperature of <−70° C. Triisopropyl borate (8 ml) was added over 10 min and the mixture was stirred at −70° C. for 4 h. Water (20 ml) was added and the mixture was allowed to warm to 5° C. The solvent was removed under vacuum and the residue was partitioned between saturated aqueous ammonium chloride and ethyl acetate. The organic phase was washed with saturated aqueous ammonium chloride and brine, dried (Na2SO4) and concentrated under vacuum. The residue was dissolved in dichloromethane/ethyl acetate and purified by column chromatography on silica eluting with dichloromethane:ethyl acetate (95:5 to 0:100) then methanol to give the title compound.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[Cl:15]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)C>[Cl:15][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][C:7]=1[CH2:11][C:12]([OH:14])=[O:13]
Reactant: CC(C)Oc1cccc(CC(=O)O)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)Oc1ccc(Cl)c(CC(=O)O)c1
Reaction time: 8 h
Yield: 81.1 %

Procedure:
Dissolve 2-(3-isopropoxyphenyl)acetic acid (3.24 g, 16.6 mmol) in dimethylformamide (11.1 mL). Cool on an ice bath and add a solution N-chlorosuccinimide (2.44 g, 18.3 mmol) in dimethylformamide (12.2 mL). Stir overnight allowing the reaction to reach ambient temperature. Dilute the reaction mixture with diethyl ether. Wash with water. Extract the water wash with diethyl ether. Combine the diethyl ether extracts and wash with water and brine, dry over sodium sulfate, filter and concentrate under reduced pressure. Purify the residue by silica gel chromatography eluting with acetone: hexanes (0-25% gradient) to give the title compound (3.08 g, 13.47 mmol). MS (m/z): 245.8 (M+18).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12](CCl)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17]C(N=P(N1CCCC1)(N1CCCC1)N1CCCC1)(C)C>O1CCCC1>[CH2:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:16]1[CH:15]=[CH:12][CH:11]=[CH:10][CH:17]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)N=P(N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: C1CCOC1
Product: c1ccc(COCc2ccccc2)cc1

Procedure:
The general coupling method used for compound 63a was applied using 4-benzyloxybenzyl chloride and BTPP in tetrahydrofuran to give the product benzyl ether. The benzyl ether (600 mg, 1.05 mmol) and 10% palladium hydroxide on carbon (160 mg) in 2:1 methanol/tetrahydrofuran (50 mL / 25 mL) was agitated under hydrogen at 55 psi for 48 hours. The reaction mixture was filtered through a pad of Celite and then subjected to column chromatography (2:1 EtOAc/CH2Cl2) to give compound 64 as a white solid (262 mg, 52% yield).
Reaction SMILES: C1N2CCN(CC2)C1.[CH2:9]([N:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][N:24]=2)[C:19](Cl)=[C:18]([N+:27]([O-:29])=[O:28])[C:17]1=[O:30])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[N:31]1([C:37]([C:39]2[S:40][CH:41]=[CH:42][CH:43]=2)=[O:38])[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>CN1CCCC1=O.O>[CH2:9]([N:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][N:24]=2)[C:19]([N:34]2[CH2:35][CH2:36][N:31]([C:37]([C:39]3[S:40][CH:41]=[CH:42][CH:43]=3)=[O:38])[CH2:32][CH2:33]2)=[C:18]([N+:27]([O-:29])=[O:28])[C:17]1=[O:30])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=c1c([N+](=O)[O-])c(Cl)c2cccnc2n1Cc1ccccc1
Reactant: O=C(c1cccs1)N1CCNCC1
Agent: C1CN2CCN1CC2
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(c1cccs1)N1CCN(c2c([N+](=O)[O-])c(=O)n(Cc3ccccc3)c3ncccc23)CC1
Temperature: 110 °C

Procedure:
DABCO (6.26 g, 55 mmol) was added to a solution of 1-benzyl-4-chloro-3-nitro-1,8-naphthyridin-2(1H)-one (126) (8.81 g, 28 mmol) and piperazine-1-yl-thiophene-2-yl-methanone (6.57 g, 33 mmol) in N-methylpyrrolidone at room temperature. The solution was heated at 110° C. for 2 h. The solution was cooled and poured into ice cold 10% ammonium chloride solution in water. The solids formed were filtered, washed by water, and dried to yield yellow solid. Yield 11 g (83%), mp 255° C. 1H-NMR (DMSO-d6): δ 3.26 (m, 4H), 3.90 (m, 4H), 5.61 (s, 2H), 7.15 (m, 1H), 7.25 (m, 5H), 7.47 (m, 2H), 7.80 (d, J=5.2 Hz, 1H), 8.43 (d, J=7.6 Hz, 1H), 8.76 (d, J=4.4 Hz, 1H); EIMS m/z 476 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[C:9](=[N:14]\[O:15][CH3:16])/[C:10]([NH:12][CH3:13])=[O:11].[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[OH:25].C(=O)([O-])[O-].[K+].[K+].CC(C)=O>C(OCC)(=O)C>[CH3:16][O:15]/[N:14]=[C:9](\[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][O:25][C:19]1[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:18]=1[CH3:17])/[C:10]([NH:12][CH3:13])=[O:11]
Reactant: CNC(=O)/C(=N/OC)c1ccccc1CCl
Reactant: Cc1ccc(C)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CNC(=O)/C(=N/OC)c1ccccc1COc1cc(C)ccc1C
Temperature: 60 °C
Reaction time: 45 h
Yield: 53.1 %

Procedure:
A mixture of (E)-2-(2-chloromethylphenyl)-2-methoxyimino-N-methylacetamide (500 mg), 2,5-dimethylphenol (700 mg), potassium carbonate (700 mg) and acetone (5.0 ml) was stirred in a sealed tube at 60° C. for 45 hours. After the mixture was cooled by allowing it to stand, ethyl acetate was added thereto. The mixture was washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The resulting residue was subjected to column chromatography on silica gel (ethyl acetate:hexane=1:2) to obtain the title compound (360 mg, 53%). In this chromatographic separation, some of the starting compound was recovered.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[F:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24]>>[CH2:17]1[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]3[C:5]([F:19])=[CH:4][N:3]=[C:2]([NH:24][C:23]4[CH:25]=[CH:26][CH:27]=[C:21]([F:20])[CH:22]=4)[N:7]=3)=[CH:10][C:11]=2[O:18]1
Reactant: Nc1cccc(F)c1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Product: Fc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 3-fluoroaniline were reacted to yield N4-(3,4-ethylenedioxyphenyl)-N2-(3-fluorophenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.76 (d, 1H, J=5.6 Hz), 7.39 (m, 2H), 7.14 (d, 1H, J=2.4 Hz), 6.94-6.85 (m, 3H), 6.75 (d, 1H, J=9 Hz), 4.21 (s, 4H); LCMS: ret. time: 22.60 min.; purity: 100%; MS (m/e): 357 (MH+).
Reaction SMILES: [C:1]([C:3]([CH3:15])([CH3:14])[CH:4]([OH:13])[CH2:5][C:6]([O:8]C(C)(C)C)=[O:7])#[N:2].[OH-].[Na+].CO>C1(C)C=CC=CC=1>[C:1]([C:3]([CH3:15])([CH3:14])[CH:4]([OH:13])[CH2:5][C:6]([OH:8])=[O:7])#[N:2]
Reactant: CC(C)(C)OC(=O)CC(O)C(C)(C)C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C)(C#N)C(O)CC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To the reaction mixture obtained in Example 2 were added 10% aqueous sodium hydroxide solution (113.8 g) and methanol (20 mL), and the mixture was stirred at room temperature overnight. The disappearance of tert-butyl 4-cyano-3-hydroxy-4-methylpentanoate was confirmed by gas chromatography (GC). Toluene (50 mL) was added and the mixture was stirred and then partitioned to remove the toluene layer. 20% Aqueous hydrochloric acid solution (67.5 g) was added to the aqueous layer to adjust its pH to an acidic one (ca. pH 1-2) and the mixture was extracted twice with ethyl acetate (150 mL). The ethyl acetate layer was concentrated under reduced pressure to give 4-cyano-3-hydroxy-4-methylpentanoic acid (19.9 g) as an oil. When left standing, this oil crystallized. The yield was 89% relative to tert-butyl 4-cyano-3-hydroxy-4-methylpentanoate.
Reaction SMILES: C[C@@H](PC)[C]1[C](P(C2C3C(=CC=CC=3)C=CC=2)C2C3C(=CC=CC=3)C=CC=2)[CH][CH][CH]1.[CH2:31]([C:38]1[C:47]2[C:42](=[CH:43][CH:44]=[C:45]([Br:48])[CH:46]=2)[CH2:41][CH2:40][C:39]=1[NH:49][C:50](=[O:53])[CH2:51][CH3:52])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[H][H]>[Rh+].ClC1CCCCC=CC=1.C(O)C>[CH2:31]([C@@H:38]1[C:47]2[C:42](=[CH:43][CH:44]=[C:45]([Br:48])[CH:46]=2)[CH2:41][CH2:40][C@@H:39]1[NH:49][C:50](=[O:53])[CH2:51][CH3:52])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: [H][H]
Reactant: CCC(=O)NC1=C(Cc2ccccc2)c2cc(Br)ccc2CC1
Agent: [Rh+]
Agent: CP[C@H](C)[C]1[CH][CH][CH][C]1P(c1cccc2ccccc12)c1cccc2ccccc12
Agent: ClC1=CC=CCCCC1
Solvent: CCO
Product: CCC(=O)N[C@H]1CCc2ccc(Br)cc2[C@H]1Cc1ccccc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
Chlorocyclooctadiene rhodium(I) dimer (0.217 g, 0.881 mmol of Rh), Josiphos SL-J216-2 (0.595 g, 0.926 mmol), and N-(1-benzyl-7-bromo-3,4-dihydronaphthalen-2-yl)propionamide (10.88 g, 29.4 mmol) were combined in a metal reactor, and the vessel was inerted with argon. Degassed ethanol (163 ml) was added, and the mixture was agitated under argon for 30 min at 50° C. The vessel was pressurized with 60 psig of hydrogen and agitated at 55° C. for 14.5 hrs. HPLC analysis indicated 89.4% conversion and 93.8% ee. The mixture was concentrated, and the resulting solid was crystallized from MeOH to yield 7.41 g (yield: 68%) of the title compound.
Reaction SMILES: [CH:1]1([CH:7](O)[CH:8]=[CH2:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C=CCCC=C.S(Br)([Br:19])=O>ClCCCl>[Br:19][CH2:9]/[CH:8]=[CH:7]/[CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(Br)Br
Reactant: C=CC(O)C1CCCCC1
Agent: C=CCCC=C
Solvent: ClCCCl
Product: BrC/C=C/C1CCCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 42.5 %

Procedure:
To a solution of Example 36A (5.62 g, 40.1 mmol) and 1,5-hexadiene (3.56 mL, 30.1 mmol) in 1,2-dichloroethane (70 mL), stirring at 0° C., was added thionyl bromide (4.66 mL, 60.12 mmol). The reaction was stirred for 2 hours at 0° C. and then quenched with water. The mixture was extracted with diethyl ether and the diethyl ether layer was washed with saturated sodium bicarbonate solution, dried with sodium sulfate, filtered, and concentrated in vacuo to give the title compound (3.46 g, 43%). 1H NMR (300 MHz, CDCl3): δ ppm 1.16 m, 6 H) 1.69 m, 4 H) 1.98 m, 1 H) 3.94 m, 2 H) 5.65 m, 2 H).
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:14]([N:26]=[C:27]=[O:28])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>CCCCCC>[CH2:1]([NH:13][C:27](=[O:28])[NH:26][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCN=C=O
Reactant: CCCCCCCCCCCCN
Solvent: CCCCCC
Product: CCCCCCCCCCCCNC(=O)NCCCCCCCCCCCC
Reaction time: 1 h

Procedure:
Didodecylurea was prepared as follows: Dodecylamine (37 mmol, 6.84 g, commercially available from Sigma Aldrich Fine Chemicals, Milwaukee, Wis.) was dissolved in hexane (100 ml) in a 250 ml single neck, round bottomed flask. A solution of dodecyl isocyanate (37 mmol, 7.8 g, commercially available from Sigma Aldrich Fine Chemicals) in hexane (100 ml) was slowly added to the amine solution through an addition funnel. The mixture was stirred for 1 hr during which a white precipitate was formed. IR was used to confirm completion of reaction. The white precipitate was filtered and dried under vacuum overnight to give 14.64 g of a white solid (99.7% yield). The product is believed to be of the formula
Reaction SMILES: C(O/[CH:4]=[CH:5]\[C:6]1[CH:7]=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[N:10]([CH:12]=[N:13][N:14]=2)[CH:11]=1)C.C1C(=O)N(Br)C(=O)C1.[CH2:29]([NH:32][C:33]([NH2:35])=[S:34])[CH2:30][CH3:31]>O1CCOCC1.O>[C:15]1([C:8]2[C:9]3[N:10]([CH:12]=[N:13][N:14]=3)[CH:11]=[C:6]([C:5]3[S:34][C:33]([NH:32][CH2:29][CH2:30][CH3:31])=[N:35][CH:4]=3)[CH:7]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCO/C=C\c1cc(-c2ccccc2)c2nncn2c1
Reactant: CCCNC(N)=S
Agent: O=C1CCC(=O)N1Br
Solvent: C1COCCO1
Solvent: O
Product: CCCNc1ncc(-c2cc(-c3ccccc3)c3nncn3c2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.4 %

Procedure:
A solution of (Z)-6-(2-ethoxyvinyl)-8-phenyl-[1,2,4]triazolo[4,3-a]pyridine (13 mg, 0.049 mmol) in 1,4-dioxane (1 mL) and water (1 mL) was added NBS (9.4 mg, 0.054 mmol) and stirred at rt for 1 h. The mixture was then added 1-propylthiourea (6.4 mg, 0.054 mmol), heated to 85-90° C. for 10 h, then cooled and concentrated. The residue was dissolved in a mixture of 20% MeOH in dichloromethane and purified by 500 μm silica gel prep plate using 75% ethyl acetate in hexanes as an eluent. The product was collected (4.5 mg, 27.4% yield). LCMS: 336.55 (M+H), Tr 2.98 min, (Conditions A).