Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[BrH:12]>>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Br:12])=[CH:4][N:3]=1
Reactant: Brc1nccc2ccccc12
Reactant: Br
Product: Brc1cnc(Br)c2ccccc12

Procedure:
The starting material was prepared by reaction of 1-bromoisoquinoline with HBr to give 1,4-dibromoisoquinoline, m.p. 95°-96°, followed by reaction of this compound with trimethyloxonium tetrafluoroborate in CH2Cl2 to give 1,4-dibromo-2-methylisoquinolinium tetrafluoroborate; n.m.r. in solvent A: 3.5(s, 3H); 7.2-8.4(m, 5H).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10](F)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].[S:19]1[CH2:23][CH2:22][NH:21][CH2:20]1.C(#N)C>CN(C)C=O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10]([N:21]3[CH2:22][CH2:23][S:19][CH2:20]3)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Reactant: C1CSCN1
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCSC3)cc21
Temperature: 25 °C
Yield: 10.1 %

Procedure:
A solution of 1.01 g (4.0 mmol) of 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.79 ml (10 mmol) of thiazolidine, 20 ml of acetonitrile and 20 ml of N,N-dimethylformamide was heated at reflux for 16 hours. The reaction was cooled to room temperature and the solid which formed was removed by filtration. After triturating with hot methanol, the residue was recrystallized from N,N-dimethylformamide to give 0.13 g of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(3-thiazolidinyl)-3-quinolinecarboxylic acid; mp 270°-273° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH:21]3[CH2:23][CH2:22]3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:24].C(OCC)(=O)C.C(OCC)(=O)C>C(Cl)(Cl)Cl>[ClH:24].[CH:21]1([C:17]2[CH:18]=[C:19]([CH3:20])[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[N:15][CH:16]=2)[CH2:23][CH2:22]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: Cc1cc(C2CC2)cnc1N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-(5-bromo-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (3.6 g), bis(tricyclohexylphosphine)palladium (II) dichloride (396 mg), tripotassium phosphate (12 g) and cyclopropylboronic acid (2.1 g) were added toluene (30 mL) and water (1.5 mL), and the mixture was refluxed for 8 hr. After cooling, the mixture was extracted with ethyl acetate, washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform) to give 4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (2.2 g). 4-(5-Cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (2.2 g) was dissolved in chloroform (5 mL), 4N hydrogen chloride/ethyl acetate (5 mL) was added, and the mixture was stirred at room temperature overnight. Ethyl acetate (20 mL) was added, and the mixture was filtered to give the title compound (1.3 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH:9][C:10]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[O:11])=[CH:4][CH:3]=1.[O:17]1CCC[CH2:18]1.C(Cl)(Cl)=O.C(OCC)(=O)C>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[N:9]=[C:10]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)[O:11][C:18]2=[O:17])=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: O=C(NNc1ccc(F)cc1)c1cccs1
Agent: O=C(Cl)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=c1oc(-c2cccs2)nn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
N′-(4-fluorophenyl)thiophene-2-carbohydrazide (575 mg, 2.43 mmol) was dissolved in dichloromethane (14 mL) and tetrahydrofuran (10 mL) in a glass flask. The flask was cooled in ice. Phosgene (20% in toluene, 3.42 mL, 6.49 mmol, 2.67 eq.) was added, and the solution was stirred overnight under a nitrogen atmosphere, allowing it to warm to room temperature. Ethyl acetate (40 mL) was added, and the solution was then washed with water (2×25 mL) and brine (25 mL). The solution was dried over magnesium sulfate, filtered and concentrated in vacuo to give 0.59 grams of crude product as a light brown solid. Purification using ISCO flash chromatography (silica, gradient heptanes/ethyl acetate) gave 3-(4-fluorophenyl)-5-(thiophen-2-yl)-1,3,4-oxadiazol-2(3H)-one (210 mg, 0.800 mmol, yield 33.0%) as an off-white solid with an HPLC purity of 99.7%. LC-MS [M+H] 263.02 (C12H7FN2O2S+H, expected 263.02). The 1H-NMR spectrum was in accordance with the chemical structure.
Reaction SMILES: [OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH:19]1([C:25]2[C:26]3[CH:27]=[CH:28][C:29]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])=[CH:30][C:31]=3[N:32]3[CH2:38][C:37]([C:39]([O:41]C)=[O:40])=[CH:36][C:35]4[CH:43]=[C:44]([O:47][CH3:48])[CH:45]=[CH:46][C:34]=4[C:33]=23)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.Cl>CO.C1COCC1>[C:52]([O:51][C:49]([C:29]1[CH:28]=[CH:27][C:26]2[C:25]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[C:33]3[C:34]4[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][C:35]=4[CH:36]=[C:37]([C:39]([OH:41])=[O:40])[CH2:38][N:32]3[C:31]=2[CH:30]=1)=[O:50])([CH3:55])([CH3:53])[CH3:54]
Reactant: COC(=O)C1=Cc2cc(OC)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC(C)(C)C)cc3n2C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C=C(C(=O)O)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)OC(C)(C)C)cc21
Temperature: 25 °C
Yield: 118 %

Procedure:
Tetrabutylammonium hydroxide (40% in water, 14.4 mL, 22 mmol) was added to a slurry of 10-tert-butyl 6-methyl 13-cyclohexyl-3-methoxy-7H-indolo[2,1-a][2]benzazepine-6,10-dicarboxylate (5.0 g, 10 mmol) in MeOH (40 mL) and THF (40 mL) and the reaction was stirred at rt ON (complete by LCMS). The reaction mixture was neutralized with 1N HCl (aq) (24 mL) and concentrated to remove the organic solvents. The sludge was diluted with water, stirred and the solids were collected by filtration. The wet solids were dissolved into EtOAc (˜250 mL), washed with brine (100 mL), dried (MgSO4), filtered and concentrated to yield 10-(tert-butoxycarbonyl)-13-cyclohexyl-3-methoxy-7H-indolo[2,1-a][2]benzazepine-6-carboxylic acid (5.73 g, 11.8 mmol, 118% yield) as a bright yellow solid. The product appears to be mixed with a tetrabutylammonium by-product. The material was used without further purification. 1HNMR (300 MHz, CDCl3) δ ppm 1.14-2.13 (m, 10H), 1.60 (s, 9H), 2.73-2.86 (m, 1H), 3.89 (s, 3H), 4.03-4.26 (m, 1H), 5.49-5.80 (m, 1H), 6.98 (d, J=2.6 Hz, 1H), 7.07 (dd, J=8.4, 2.6 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.64 (dd, J=8.4, 1.1 Hz, 1H), 7.79 (d, J=8.4 Hz, 1H), 7.89 (br s, 1H), 8.19 (s, 1H. LC-MS retention time: 4.32 min; 488 m/z (MH +). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: Cl.[CH2:2]([NH:4][C:5]1[CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[N:8]=[CH:7][C:6]=1[NH2:14])[CH3:3].C[Al](C)C.C1(C)C=CC=CC=1.CO[C:28](=O)[CH2:29][N:30]1[CH:34]=[CH:33][N:32]=[C:31]1[C:35]1[S:36][CH:37]=[CH:38][N:39]=1>C(Cl)Cl>[CH2:2]([N:4]1[C:5]2[CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[N:8]=[CH:7][C:6]=2[N:14]=[C:28]1[CH2:29][N:30]1[CH:34]=[CH:33][N:32]=[C:31]1[C:35]1[S:36][CH:37]=[CH:38][N:39]=1)[CH3:3]
Reactant: COC(=O)Cn1ccnc1-c1nccs1
Reactant: CCNc1cc(C(C)C)ncc1N
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCn1c(Cn2ccnc2-c2nccs2)nc2cnc(C(C)C)cc21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a suspension of N4-ethyl-6-isopropyl-pyridine-3,4-diamine hydrochloride (126 mg, 0.582 mmol) in CH2Cl2 (5 mL) at room temperature under N2 is added 2.0 M AlMe3 in toluene (0.35 mL, 0.728 mmol). The dark solution is then stirred at room temperature for 45 min. Next, a solution of (2-Thiazol-2-yl-imidazol-1-yl)-acetic acid methyl ester (65 mg, 0.291 mmol) in CH2Cl2 (2 mL) is added via cannula followed by a 1 mL rinse. The reaction mixture is stirred at reflux overnight. After cooling, it is treated with MeOH (˜0.5 mL) and then diluted with 0.5 N NaOH and additional CH2Cl2. The mixture is stirred vigorously for 15 min and then extracted thrice with CH2Cl2 containing some (˜5%) MeOH. The combined extracts are dried over K2CO3 and concentrated to 156 mg of a crude mixture of the desired 1-ethyl-6-isopropyl-2-{[2-(1,3-thiazol-2-yl)-1H-imidazol-1-yl]methyl}-1H-imidazo[4,5-c]pyridine and N-(4-amino-6-isopropyl-pyridin-3-yl)-2-(2-thiazol-2-yl-imidazol-1-yl)-acetamide. This material is then dissolved in AcOH (6 mL), and the resulting solution is stirred at reflux for 5 h. After cooling, the reaction mixture is concentrated in vacuo. The residue is dissolved in CH2Cl2 and washed with 0.5 N NaOH. The aqueous layer is reextracted twice with CH2Cl2, and the combined extracts are dried over K2CO3 and concentrated. The crude material is purified by preparative TLC. Developing with 15:1 CHCl3 yields 1-ethyl-6-isopropyl-2-{[2-(1,3-thiazol-2-yl)-1H-imidazol-1-yl]methyl}-1H-imidazo[4,5-c]pyridine. 1H NMR (CDCl3, 400 MHz) δ 9.01 (s, 1H), 7.83 (d, J=3.2 Hz, 1H), 7.38 (d, J=3.2 Hz, 1H), 7.15 (s, 1H), 7.12 (s, 1H), 7.09 (s, 1H), 6.32 (s, 2H), 4.21 (q, J=7.2 Hz, 2H), 3.17 (sept, J=6.8 Hz, 1H), 1.34 (d, J=6.8 Hz, 6H), 1.10 (t, J=7.2 Hz, 3H) ppm.
Reaction SMILES: [BrH:1].Cl.[NH:3]1[CH2:9][CH2:8][CH2:7][C:6](=[O:10])[CH2:5][CH2:4]1.BrBr>C(O)(=O)C>[BrH:1].[Br:1][CH:7]1[CH2:8][CH2:9][NH:3][CH2:4][CH2:5][C:6]1=[O:10]
Reactant: O=C1CCCNCC1
Agent: Br
Agent: BrBr
Agent: Cl
Solvent: CC(=O)O
Product: O=C1CCNCCC1Br

Procedure:
32 mL 62% HBr solution in 50 mL conc. acetic acid was added to 50 g hexahydro-azepin-4-on hydrochloride in 600 mL conc. acetic acid. Then 17.2 mL bromine in 50 mL conc. acetic acid was dropped to the reaction. The solvent was removed and the residue was crystallized from a mixture of DCM/MeOH (8/2) to give 79 g of the desired compound.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:10]=[CH:9][C:6]([O:7][CH3:8])=[CH:5][CH:4]=1.Cl[C:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][N:23]=2)=[CH:17][CH:16]=1)=[O:13]>>[F:29][C:28]([F:31])([F:30])[C:25]1[CH:26]=[CH:27][C:22]([O:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][C:12](=[O:13])[N:2]([C:3]3[CH:10]=[CH:9][C:6]([O:7][CH3:8])=[CH:5][CH:4]=3)[CH3:1])=[CH:16][CH:17]=2)=[N:23][CH:24]=1
Reactant: CNc1ccc(OC)cc1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Product: COc1ccc(N(C)C(=O)Oc2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)cc1

Procedure:
The title product was prepared from N-methyl-p-anisidine and 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate, preparative HPLC (method C) (61%, off-white crystals). HPLC-MS m/z=419.2 (M+1), Rt: 4.67 min.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7](=[O:15])[CH2:8][C:9]2=[O:14])([CH3:3])[CH3:2].[N+:16]([O-])([OH:18])=[O:17].Cl>CCOCC>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7](=[O:15])[CH:8]([N+:16]([O-:18])=[O:17])[C:9]2=[O:14])([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cccc2c1C(=O)CC2=O
Reactant: O=[N+]([O-])O
Agent: Cl
Solvent: CCOCC
Product: CC(C)Oc1cccc2c1C(=O)C([N+](=O)[O-])C2=O

Procedure:
4-Isopropyloxy indane-1,3-dione (0.16 g; 0.003 mole) suspended in dry ether (5 ml) was treated dropwise and with stirring with fuming nitric acid (1.0 ml) at 10° C. The resulting dark solution was treated with 5N hydrochloric acid and evaporated to a yellow crystalline product; m.p. (water, hydrochloric acid) 80°-81° C. (Found: C, 57.94; H, 4.43; N, 5.46; C12H11NO5 requires: C, 57.83; H, 4.45; N, 5.62%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29](OCC)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][C:20](=[O:27])[N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:35][CH2:36][CH:37]([OH:39])[CH3:38]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29]([NH:35][CH2:36][CH:37]([OH:39])[CH3:38])=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][C:20](=[O:27])[N:21]3[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CC(O)CN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N2CCCCC2)c1=O
Product: CC(O)CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N2CCCCC2)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-oxo-2-(1-piperidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and (±)-1-amino-2-propanol employing methods similar to those those described in Example 9 and was purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as a white solid: 1H NMR (CDCl3) δ 10.32 (1H, m), 8.55 (1H, s), 7.16 (2H, dd, J=8.5, 5.5 Hz), 7.03 (2H, t, J=8.5 Hz), 6.97 (1H, s), 4.94 (2H, m), 4.11 (2H, s), 4.04 (1H, m), 3.62 (1H, m), 3.50 (2H, t, J=5.5 Hz), 3.44 (2H, t, J=5.5 Hz), 3.35 (1H, m), 2.21 (1H, d, J=4 Hz), 1.69 (2H, m), 1.54 (4H, m), 1.26 (3H, d, J=6 Hz); HRMS calcd for C26H29FN4O5+H+: 497.2200. Found: 497.2189.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.C1C(=O)N([Br:23])C(=O)C1>ClCCl>[Br:23][CH2:1][C:2]1[C:15]2[C:10]([N:9]=[C:8]3[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]3)=[CH:11][CH:12]=[CH:13][CH:14]=2
Reactant: Cc1c2ccccc2nc2ccccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: BrCc1c2ccccc2nc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.4 %

Procedure:
To a solution of 9-methylacridine (1.93 g, 10 mmol) in dichloromethane (100 mL) was added NBS (1.78 g, 10 mmol) portion-wise in an ice-water bath. After complete addition, the solution mixture was warmed to room temperature and stirred overnight. The resulting solution was washed with water and brine. The organic phase was dried over anhydrous sodium sulfate and the solvent was removed. The residue was purified by silica gel chromatography using ethyl acetate and petroleum ether (EA:PE=1:5) as eluent to afford 10 (2.08 g) in 77% yield. 1H NMR (400 MHz, CDCl3) δ 8.27 (d, J=8.8 Hz, 4H), 7.81 (t, J=8.0 Hz, 2H), 7.68 (t, J=8.0 Hz, 2H), 5.42 (s, 2H). 13C NMR (400 MHz, CDCl3) δ 148.9, 138.7, 130.5, 130.1, 126.8, 123.8, 123.4, 23.1. MS (FAB) m/z Calcd for C14H10BrN 272.1. Found 2722. [M]+.
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[O:3][Si:4]([CH3:7])([CH3:6])[CH3:5].F[C:11](F)(S(O)(=O)=O)[C:12](F)(F)[C:13](F)(F)C(F)(F)F.N>O>[CH3:1][Si:2]([CH3:9])([CH3:8])[O:3][Si:4]([CH3:7])([CH3:6])[CH2:5][CH2:11][CH2:12][CH3:13]
Reactant: O=S(=O)(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: C[Si](C)(C)O[Si](C)(C)C
Agent: N
Solvent: O
Product: CCCC[Si](C)(C)O[Si](C)(C)C

Procedure:
984 g of adduct (8 mol of Mbutyl (=butyl-Me2SiO0.5) and 1312 (8 mol) of hexamethyldisiloxane are initially introduced into a flask equipped with stirrer, thermometer, water separator, reflux condenser and nitrogen blanketing, admixed with 0.1% sulphuric acids and 0.05% perfluorobutanesulphonic acid, neutralized for 4 h at a bottom temperature of 70° C. with 20 g of calcined soda, 3 g of water and 0.5 g of 25% strength NH3 solution, distilled to 110° C., cooled and filtered. This gives 1950 g of a crude product consisting of 36% hexamethyldisiloxane, 47% 1,1,1,3,3-pentamethyl-3-butyldisiloxane and 17% 1,1,3,3-tetramethyl-1,3-dibutyldisiloxane, which, as result of fractional distillation, produces 810 g of 97%-pure 1,1,1,3,3-pentamethyl-3-butyldisiloxane with a boiling temperature of 166-169° C. Bottoms and separated-off hexamethyldisiloxane can be passed to further equilibrations.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CCN(CC)CC.[NH:20]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C@H:21]([C:26](OC1C(F)=C(F)C(F)=C(F)C=1F)=[O:27])[CH2:22][CH:23]([CH3:25])[CH3:24]>CN(C=O)C>[NH:20]([C:40]([O:42][C:43]([CH3:45])([CH3:44])[CH3:46])=[O:41])[C@H:21]([C:26]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:27])[CH2:22][CH:23]([CH3:25])[CH3:24]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)Oc1c(F)c(F)c(F)c(F)c1F
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
H-Phe-OH (1.49 g, 9 mmol) fine powder was suspended in DMF (20 ml). After cooling at 0°, Et3N (1.26 ml, 9 mmol) was added, followed by Boc-Leu-pentafluorophenylester, i.e., Boc-Leu-OPfp (3.93 g, 9.9 mmol). It was stirred for 1 hr at 0° C and for 2.5 hr at room temperature. After filtration the solvent was evaporated and the residue was treated with H2O. The separated oil was extracted with EtOAc. The organic phase was washed with 10% citric acid, H2O, dried (Na2SO4) and evaporated to a smaller volume. Addition of petroleum ether and standing overnight in the refrigerator provided the product (XVI) which was recrystallized from EtOAc-petroleum ether to fine crystals, yield 2.3 g (67.6%); mp 104°-106° C; [α]D25 -3.40° (c 1, EtOH). Anal. Calcd for C20H30N2O5 (378.476): C, 63.47; H, 7.99; N, 7.40. Found: C, 63.46; H, 8.18; N, 7.49.
Reaction SMILES: [C:1]([C:3]1[C:4]([S:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[N:5][S:6][C:7]=1[NH:8][C:9](=[O:13])[N:10]([CH3:12])[CH3:11])#[N:2].S(=O)(=O)(O)[OH:22]>>[CH3:11][N:10]([CH3:12])[C:9](=[O:13])[NH:8][C:7]1[S:6][N:5]=[C:4]([S:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:3]=1[C:1]([NH2:2])=[O:22]
Reactant: CCCCCCSc1nsc(NC(=O)N(C)C)c1C#N
Reactant: O=S(=O)(O)O
Product: CCCCCCSc1nsc(NC(=O)N(C)C)c1C(N)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78 %

Procedure:
A mixture of 3-(4-cyano-3-hexylsulfanyl-isothiazol-5-yl)-1,1-dimethyl-urea (0.09 g, 0.29 mmol) and concentrated sulfuric acid (0.18 mL) was stirred at ambient temperature for 1.5 hours. The mixture was diluted with ice water, extracted three times into ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo affording 0.076 g (78%) of 5-(3,3-dimethyl-ureido)-3-hexylsulfanyl-isothiazole-4-carboxylic acid amide as a colorless solid: 1H NMR (300 MHz, acetone-d6) δ 7.08 (bs, 2H), 3.20 (t, 2H, J=7.2 Hz), 3.02 (s, 6H), 1.63 (p, 2H, J=7.2 Hz), 1.35 (m, 2H), 1.23 (m, 4H), 0.78 (t, 3H, J=6.9 Hz) ppm; MS (APCl, m/z): 331 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:15]C(=O)OC(C)(C)C)[CH2:9][CH2:10][NH:11][C:12]([NH2:14])=[O:13])=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O>[NH2:15][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH2:9][CH2:10][NH:11][C:12]([NH2:14])=[O:13]
Reactant: CC(C)(C)OC(=O)NC(CCNC(N)=O)c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)NCCC(N)c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 62.6 %

Procedure:
Tert-butyl 1-(4-chlorophenyl)-3-ureidopropylcarbamate (Intermediate 110) (346 mg, 1.06 mmol) was dissolved in TFA (3 mL) and stirred at 20° C. for 2 hours. The reaction was vacuumed to dryness and was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 0.35M NH3/MeOH and pure fractions were evaporated to dryness to afford 1-(3-amino-3-(4-chlorophenyl)propyl)urea (151 mg, 62.8%) as a yellow gum.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[N:13]=1.[F:21][C:22]([F:36])([F:35])[CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([Sn](C)(C)C)=[CH:27][N:26]=1.[Cl-].[Li+]>O1CCOCC1.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:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([C:28]3[CH:29]=[CH:30][C:25]([O:24][CH2:23][C:22]([F:36])([F:21])[F:35])=[N:26][CH:27]=3)=[CH:16][CH:15]=2)[N:13]=1
Reactant: C[Sn](C)(C)c1ccc(OCC(F)(F)F)nc1
Reactant: Fc1cccc(F)c1C1=NC(c2ccc(Br)cc2)CO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: Fc1cccc(F)c1C1=NC(c2ccc(-c3ccc(OCC(F)(F)F)nc3)cc2)CO1

Procedure:
2-(2,6-Difluorophenyl)-4-(4-bromophenyl)oxazoline (VP4) (2.0 g, 5.9 mmol) was mixed with 2-trifluoroethoxy-5-trimethylstannylpyridine (2.61 g, 7.7 mmol), tetrakis(triphenylphosphine)palladium (0.22 g, 0.18 mmol) and lithium chloride (0.38 g, 8.9 mmol) in dioxane (30 ml) and refluxed for 9 hours. After extractive work-up and column chromatography, 2-(2,6-difluorophenyl)4-[4-(2-trifluoroethoxypyridin-5-yl)phenyl]oxazoline was obtained, 1.37 g, colorless crystals. 19F NMR (CDCl3): −75.05 (CF3), −110.45 (ArF).
Reaction SMILES: [CH2:1]([C:4]1[C:16]([OH:17])=[CH:15][C:7]2[C:8]([CH3:14])([CH3:13])[CH:9]([O:11]C)[O:10][C:6]=2[CH:5]=1)[CH:2]=[CH2:3].C(O)(=O)C>O>[CH2:1]([C:4]1[C:16]([OH:17])=[CH:15][C:7]2[C:8]([CH3:13])([CH3:14])[CH:9]([OH:11])[O:10][C:6]=2[CH:5]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1cc2c(cc1O)C(C)(C)C(OC)O2
Solvent: CC(=O)O
Solvent: O
Product: C=CCc1cc2c(cc1O)C(C)(C)C(O)O2
Yield: 94 %

Procedure:
A mixture of 6-allyl-3,3-dimethyl-5-hydroxy-2-methoxy-2,3-dihydrobenzofuran, E70a, (20 gm; 85 mmoles), acetic acid (160 mL) and water (40 mL) was refluxed for 18 hours. The mixture was concentrated in vacuo and the residue chromatographed on silica gel using 20% ethyl acetate in hexane as eluent to obtain 17.8 gm (94%) of 6-allyl-2,5-dihydroxy-3,3-dimethyl-2,3-dihydrobenzofuran, E79, m.p. 66°-67° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[CH2:24][CH3:25]>CN(C=O)C>[CH2:24]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:18]=1[CH2:17][S:8][C:6]1[N:5]=[C:4]([OH:9])[CH:3]=[C:2]([CH3:1])[N:7]=1)[CH3:25]
Reactant: CCc1cnccc1CBr
Reactant: Cc1cc(O)nc(S)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cnccc1CSc1nc(C)cc(O)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 7 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (686 mg, 4.8 mmol) was dissolved in anhydrous DMF (30 mL), and then potassium carbonate (2.0 g, 14.5 mmol) and 4-(bromomethyl)-3-ethylpyridine (5.8 mmol) in DMF (10 mL) were added. The mixture was stirred for 2.5 hours at room temperature. The solid was removed by filtration and washed with methanol, and the filtrate was evaporated. The residue was dissolved in DCM/MeOH and purified on silica gel using 3-12% DCM/MeOH to afford 2-{[(3-ethylpyridin-4-yl)methyl]sulfanyl)-6-methylpyrimidin-4-ol (88 mg, 6% yield for 3 steps).