Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1([NH2:21])[CH2:20][CH2:19]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl.O>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([NH:21][C:18]1([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=2)[CH2:20][CH2:19]1)=[O:7]
Reactant: NC1(c2ccccn2)CC1
Reactant: Cc1ccc(C(=O)O)cc1I
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC2(c3ccccn3)CC2)cc1I
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-Iodo-4-methylbenzoic acid (2.5 g, 9.5 mmol, 1 eq), 1-(pyridin-2-yl)cyclopropanamine (1.41 g, 10.4 mmol, 1.1 eq), EDCI.HCl (2.1 g, 11.4 mmol, 1.2 eq), HOBT (1.5 g, 11.4 mmol, 1.2 eq) and DIPEA (4.9 ml, 28.62 mmol, 3 eq) were dissolved in DCM and the above solution was stirred at room temperature for 18 h. Water was added and product was extracted with DCM. The organic layer was concentrated and the crude product crystallized using dichloromethane and hexane. Yield: 2.3 g (55%). 1HNMR (400 MHz, DMSO-d6): δ 1.26 (m, 2H), 1.53 (m, 2H), 2.43 (s, 3H), 7.13 (m, 1H), 7.29 (d, J=8.00 Hz, 1H), 7.44 (d, 1H), 7.67 (t, J=3.46 Hz, 1H), 7.87 (d, J=3.24 Hz, 1H), 8.38 (s, 1H), 8.44 (d, J=1.10 Hz, 1H), 9.29 (s, 1H).
Reaction SMILES: C(N(CC)[CH:4]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH:7]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:5])C.[C:20]([O:23][C:24]1[C:25](=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:26](Cl)=[O:27])(=[O:22])[CH3:21]>C(C(C)=O)C>[NH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[CH2:4]([N:6]([CH2:5][CH2:4][N:6]1[CH2:11][CH2:10][N:9]([C:26](=[O:27])[C:25]2[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=2[O:23][C:20](=[O:22])[CH3:21])[CH2:8][CH:7]1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:7][CH3:8])[CH3:5]
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Reactant: CCN(CC)C(C)N1CCNCC1c1ccccc1
Solvent: CCC(C)=O
Product: C1CNCCN1
Product: CCN(CC)CCN1CCN(C(=O)c2ccccc2OC(C)=O)CC1c1ccccc1

Procedure:
4-Diethylaminoethyl-3-phenyl-1-(o-acetoxy benzoyl)piperazine piperazine is prepared by boiling under reflux 15 g. of 1-diethylaminoethyl-2-phenyl-piperazine dissolved in 100 ml. of methyl ethyl ketone with 11 g. of acetyl salicylic acid chloride dissolved in 50 ml. methyl ethyl ketone, for 6 hours. The solvent is removed by distillation. The residue is dissolved in water. The aqueous solution is extracted with benzene. Ammonia is added to the aqueous layer until its reaction is alkaline and the thus precipitated oil is extracted with benzene. The benzene extract is dried by means of potassium carbonate and the benzene is distilled off. The residue is distilled in a vacuum. Boiling point: 190° C./0.01 mm. (bath temperature). Light yellow, viscous oil.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]=[C:11]([Cl:22])[N:12]=[C:13]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[C:14]=2[N:15]=1)(=O)C.[OH-].[Li+]>C1COCC1.O>[Cl:22][C:11]1[N:12]=[C:13]([N:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)[C:14]2[N:15]=[C:6]([CH2:5][OH:4])[CH:7]=[CH:8][C:9]=2[N:10]=1
Reactant: CC(=O)OCc1ccc2nc(Cl)nc(N3CCOCC3)c2n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc2nc(Cl)nc(N3CCOCC3)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl acetate 5 (2.3 g, 7.1 mmol) in THF (50 mL) was added a 1M solution of lithium hydroxide in water (26 mL). The resulting solution was stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted three times with dichloromethane. The combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated to give (2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methanol 6. LCMS (MH)+=281.1. 1H-NMR (400 MHz, CDCl3, ppm): 8.09 (1H, d, J=8.8 Hz), 7.66 (1H, d, J=8.8 Hz), 4.91 (2H, s), 4.56 (4H, br), 3.91 (4H, t), 2.86 (1H, s)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[C:14]([C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1)(=[O:16])[CH3:15]>O>[C:14]([C:17]1[CH:18]=[CH:19][C:20]([S:23]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)(=[O:25])=[O:24])=[CH:21][CH:22]=1)(=[O:16])[CH3:15]
Reactant: Nc1cccnc1
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)c1ccc(S(=O)(=O)Nc2cccnc2)cc1

Procedure:
To a solution of 23.7 g. of 3-aminopyridine in 400 ml. of pyridine is added 55 g. of 4-acetylbenzenesulfonyl chloride and the resulting solution is stirred at room temperature for 24 hours. The solution is poured into 1 l. of water and the mixture is cooled to 0°-5° C. The precipitate of 4-acetyl-N-(3-pyridyl)benzenesulfonamide is collected by filtration, washed with water and dried; m.p. 182°-183° after crystallization from ethanol.
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1.CO.[C:13](=O)([O-])[O-].[Na+].[Na+]>>[OH:1][CH2:2][C:3]1[S:7][C:6]([C:8]([O:10][CH3:13])=[O:9])=[CH:5][CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc(CO)s1
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(CO)s1
Temperature: 0 °C
Yield: 296.3 %

Procedure:
To a solution of 5-(hydroxymethyl)thiophene-2-carboxylic acid (1.430 g, 9.040 mmol) in anhydrous methanol (140 ml) concentrated sulfuric acid (88.7 mg, 0.904 mmol) was added, and the mixture was heated under reflux for 40 hrs. After cooling to 0° C., sodium carbonate (300 mg) was added, and the mixture was concentrated to about 50 ml under reduced pressure. Saturated brine was added, and the mixture was extracted 3 times with ethyl acetate. The combined organic layer was washed with saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give methyl 5-(hydroxymethyl)thiophene-2-carboxylate (1.444 g, yield 92.7%) as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH2:31][O:30][CH2:29][CH2:28][NH:27]2)=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C.C([O-])([O-])=O.[Na+].[Na+]>CN1C(=O)CCC1>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([CH:26]2[N:27]([C:2]3[C:11]4[C:6](=[CH:7][C:8]([C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=5[CH3:18])=[CH:9][CH:10]=4)[CH:5]=[N:4][N:3]=3)[CH2:28][CH2:29][O:30][CH2:31]2)=[CH:24][CH:25]=1
Reactant: Cc1ccccc1-c1ccc2c(Cl)nncc2c1
Reactant: Clc1ccc(C2COCCN2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1ccccc1-c1ccc2c(N3CCOCC3c3ccc(Cl)cc3)nncc2c1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
A solution of 1-chloro-6-o-tolylphthalazine (0.100 g, 0.393 mmol) in NMP (2 mL) was treated with 3-(4-chlorophenyl)morpholine (0.155 g, 0.785 mmol) and diisopropylethylamine (0.219 mL, 1.26 mmol). The reaction solution was stirred at 120° C. in a sealed tube for 16 hours. After cooling to RT, the reaction solution was treated with saturated aqueous Na2CO3 (50 mL). The mixture was extracted with ethyl acetate (3×60 mL) and the combined organic phases were washed with brine. The organic solution was dried over magnesium sulfate and concentrated under reduced pressure. Flash chromatography on silica gel (ethyl acetate) gave 1-(3-(4-chlorophenyl)morpholino)-6-o-tolylphthalazine as a yellow solid. MS (ESI, pos.ion) m/z: 416.1 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[S:18][CH:19]=[C:20]([C:22]([N:24]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:23])[CH:21]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:31]N1C(=O)CCC1=O>C(O)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[S:18][C:19]([Cl:31])=[C:20]([C:22]([N:24]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:23])[CH:21]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CCC(c2cc(C(=O)N3CCCCCC3)cs2)CC1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: O=C(OCc1ccccc1)N1CCC(c2cc(C(=O)N3CCCCCC3)c(Cl)s2)CC1
Temperature: 100 °C
Yield: 67.3 %

Procedure:
4-[4-(Azepane-1-carbonyl)-thiophen-2-yl]-piperidine-1-carboxylic acid benzyl ester (0.037 g, 0.087 mmol) was dissolved in acetic acid. N-chlorosuccinimide (0.09 mmol) was added and the reaction heated to 100° C. for 2.5 minutes using microwave irradiation. The product was purified by HPLC, eluting with 20%-98% acetonitrile in water (0.1% formic acid). The fractions containing the desired product were concentrated under vacuum to give the title compound (0.027 g). LCMS m/z 461.24 [M+H]+ RT=13.23 min (Analytical Method 1). 1H NMR (400 MHz, CHCl3-d): δ 7.4-7.25 (m, 5H), 6.6 (m, 1H), 5.1 (s, 2H), 4.3 (m, 2H), 3.65 (m, 2H), 3.35 (t, 2H), 2.9-2.8 (m, 3H), 2.0-1.9 (m, 2H), 1.85-1.75 (m, 2H), 1.7-1.6 (m, 8H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:27])[C:6]=1[C:7]1[CH:8]=[C:9]([NH:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[CH:10]=[CH:11][C:12]=1[OH:13].C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:27])[C:6]=1[C:7]1[CH:8]=[C:9]([NH:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[CH:17]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37]
Reactant: Cn1ncc(Cl)c1-c1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1O
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1ncc(Cl)c1-c1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1OCC(=O)OC(C)(C)C
Temperature: 65 °C
Reaction time: 1 h

Procedure:
To a solution of N-(3-(4-chloro-1-methyl-1H-pyrazol-5-yl)-4-hydroxyphenyl)-3-(trifluoromethyl)benzamide (0.396 g, 1.00 mmol) and potassium carbonate (0.207 g, 1.50 mmol) in acetone (10 mL) was added tert-butyl bromoacetate (0.215 g, 1.10 mmol). The reaction was stirred at 65° C. for 1 hour and then cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was washed with water (×2) and brine, dried over magnesium sulfate and concentrated to a white solid (0.464 g, 91.0%). LCMS m/z (%)=510 (M+H, 35Cl, 30), 512 (M+H, 37Cl, 10), 454 (M-tBu+H, 35Cl, 100). 1H NMR (400 MHz, CDCl3) δ 1.47 (s, 9H) 3.80 (s, 3H) 4.52 (s, 2H) 6.87 (d, J=9.09 Hz, 1H) 7.45 (d, J=2.78 Hz, 1H) 7.50 (s, 1H) 7.64 (t, J=7.71 Hz, 1H) 7.78-7.89 (m, 2H) 7.94 (s, 1H) 8.07 (d, J=7.83 Hz, 1H) 8.14 (s, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].Cl[C:8]1[N:9]=[N+:10]([O-:22])[C:11]2[C:21]3[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=3[CH:15]=[CH:14][C:12]=2[N:13]=1>COCCOC>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH:5][C:8]1[N:9]=[N+:10]([O-:22])[C:11]2[C:21]3[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=3[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: [O-][n+]1nc(Cl)nc2ccc3c(c21)CCCC3
Reactant: CN(C)CCN
Solvent: COCCOC
Product: CN(C)CCNc1nc2ccc3c(c2[n+]([O-])n1)CCCC3
Yield: 73.1 %

Procedure:
N,N-Dimethyl-1,2-ethanediamine (0.12 mL, 1.0 mmol) was added to a stirred solution of chloride 171 (83 mg, 0.4 mmol) in DME (20 mL) and the solution stirred at reflux temperature for 3 h. The solvent was evaporated and the residue partitioned between DCM (50 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 172 (84 mg, 84%) as a yellow solid: mp (MeOH) 151-153° C.; 1H NMR δ 7.31-7.36 (m, 2H, H-5, H-6), 5.75 (br s, 1H, NH), 3.51-3.55 (m, 2H, CH2N), 3.45-3.49 (m, 2H, CH2), 2.72-2.83 (m, 2H, CH2), 2.57 (br dd, J=6.0, 5.8 Hz, 2H, CH2N), 2.29 [s, 6H, N(CH3)2], 1.75-1.82 (m, 4H, 2×CH2); 13C NMR δ 158.4, 149.8, 137.4, 134.7, 132.4, 129.1, 123.5, 57.7, 45.0 (2), 38.6, 30.7, 29.3, 23.1, 21.6. Anal. calcd for C15H21N5O.½CH3OH: C, 61.4; H, 7.6; N, 23.1. Found: C, 61.2; H, 7.4; N, 23.4%.
Reaction SMILES: [C:1]([N:4]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Br:16])[CH:14]=2)[C:6]2([CH2:9]S[CH2:7]2)[CH2:5]1)(=[O:3])[CH3:2].CO.CC(C)=O.O[O:24][S:25]([O-:27])=O.[K+]>O>[C:1]([N:4]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Br:16])[CH:14]=2)[C:6]2([CH2:9][S:25](=[O:27])(=[O:24])[CH2:7]2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=S([O-])OO
Reactant: CC(=O)N1CC2(CSC2)c2ccc(Br)cc21
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: CO
Product: CC(=O)N1CC2(CS(=O)(=O)C2)c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred ice-cooled solution of 1-acetyl-6-bromo-1,2-dihydrospiro[indole-3,3′-thietane] (0.288 g, 0.97 mmol) in a mixture water (2.4 mL), MeOH (18.9 mL), and acetone (4.7 mL) was added a solution of oxone (1.19 g, 1.93 mmol) in water (1.8 mL). The ice bath was removed and the solution was stirred at rt for 4 h. The mixture was poured into saturated aqueous ammonium chloride and extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered and evaporated in vacuo to give 1-acetyl-6-bromo-1,2-dihydrospiro[indole-3,3′thietane]1′,1′-dioxide as a tan solid. Mass Spectrum (ESI) m/e=330.0 [(M+1) (79Br)] and 332.0 [(M+1) (81Br)].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=O)[NH:8][N:7]=[CH:6]2.P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:12]([O:13][CH3:14])[CH:11]=2)[CH:6]=[N:7][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2cn[nH]c(=O)c2cc1OC
Product: COc1cc2cnnc(Cl)c2cc1OC
Temperature: 25 °C

Procedure:
6,7-Dimethoxyphthalazin-1-one (20.6 g.) was heated under reflux with phosphoryl chloride (200 ml.) for 6 hours then cooled to room temperature and the excess phosphoryl chloride removed under reduced pressure. The resultant brown solid was suspended in acetone (150 ml.) and poured onto cold (5° C.) concentrated ammonium hydroxide (200 ml.). The crude product was filtered, washed with water (200 ml.) then petroleum ether (200 ml.). The pale yellow solid was dried (20 g.), dissolved in the minimum volume of chloroform and precipitated with excess petroleum ether, after which it was recovered by filtration, washed again with petroleum ether (100 ml.) and dried to give 1-chloro-6,7-dimethoxyphthalazine (13 g.), m.p. 195°-197° C. with decomposition.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13](Br)[CH:14]=[C:15]([O:25][CH3:26])[C:16]=3[O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(=O)=O.CC(C)=O.[Li]CCCC.[B:40](OC(C)C)([O:45]C(C)C)[O:41]C(C)C>C1COCC1.CCCCCC>[C:1]12([C:11]3[CH:12]=[C:13]([B:40]([OH:45])[OH:41])[CH:14]=[C:15]([O:25][CH3:26])[C:16]=3[O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1cc(Br)cc(C23CC4CC(CC(C4)C2)C3)c1OCc1ccccc1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: CCCCCC
Product: COc1cc(B(O)O)cc(C23CC4CC(CC(C4)C2)C3)c1OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 87.9 %

Procedure:
To a solution of 3-(1-adamantyl)-4-benzyloxy-5-methoxyphenyl bromide (2.85 g, 6.67 mmol) in THF (12 mL) at −78° C. (dry ice/acetone bath) under argon was added 1.6 M n-BuLi (10.7 mmol) in hexane (6.67 mL) in one portion. This mixture was stirred at −78° C. for 15 min. Tri(isopropyl) borate (4.60 mL, 20.0 mmol) was added next, and the resulting solution was stirred at −78° C. for 20 min before being allowed to warm to room temperature with stirring overnight. The mixture was quenched with 1 N HCl (40 mL) and then extracted with EtOAc (100 and 60 mL). The combined organic extracts were washed with brine and dried. Solvents were removed at reduced pressure, and the residue was washed with hexane and dried to give 2.3 g (88%) of 3-(1-adamantyl)-4-benzyloxy-5-methoxyphenylboronic acid as a cream solid, mp 148-151° C. IR 3219, 2903, 2848, 1410, 1340, 1201 cm−1; 1H NMR (CDCl3) δ 1.72 (bs, 6H, AdCH2), 2.03 (bs, 3H, AdCH), 2.17 (m, 6H, AdCH2), 3.99 (s, 3H, OCH3), 5.21 (s, 2H, C6H5CH2), 7.31-7.58 (m, 5H, C6H5), 7.68 (d, J=1.4 Hz, 1H, 6-ArH), 7.92 ppm (d, J=1.4 Hz, 1H, 2-ArH).
Reaction SMILES: [CH2:1]([CH:8]1[O:12][C:11](=[O:13])[N:10]([CH2:14][CH2:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.[Na].O>C(O)C>[CH2:1]([CH:8]1[O:12][C:11](=[O:13])[N:10]([CH2:14][CH2:15][CH:16]([OH:23])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCN1CC(Cc2ccccc2)OC1=O)c1ccccc1
Agent: B
Agent: [Na]
Solvent: CCO
Solvent: O
Product: O=C1OC(Cc2ccccc2)CN1CCC(O)c1ccccc1
Yield: 99.6 %

Procedure:
5-Benzyl-3-(3-oxo-3-phenylpropyl)-1,3-oxazolidin-2-one (0.31 g, 1 mmol) prepared in the above (1) was dissolved in 3 ml of ethanol. To the solution, sodium boron hydride (80 mg, 2 mmol) was added under stirring while chilling with ice. After the resulting solution was stirred to cause reaction at room temperature for 30 minutes, water was added. The obtained solution was extracted with ethyl acetate. The organic portion was sequentially washed with water and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure to obtain 0.31 g of the titled compound as a colorless oil (yield: 100%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:26])[NH:15][C:16]2[CH:17]=[N:18][C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:10][CH:9]=1)(C)(C)C>ClCCl.FC(F)(F)C(O)=O.O>[NH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]([NH:15][C:16]2[CH:17]=[N:18][C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:26])=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)Nc2cnc3ccccc3c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: Nc1ccc(C(=O)Nc2cnc3ccccc3c2)cc1

Procedure:
A solution of [4-(quinolin-3-ylcarbamoyl)-phenyl]-carbamic acid tert-butyl ester (7.2 g, 19.8 mmol) in dichloromethane (70 mL), trifluoroacetic acid (70 mL) and water (7 mL) was stirred at ambient temperature for approximately 18 hours. The solvent was evaporated in vacuo, and the resultant residue was triturated in water (100 mL) and saturated aqueous sodium bicarbonate (100 mL). The product was collected by filtration, washed with water and dried in vacuo, to give a colorless solid, 4.36 g (84%). MS: m/z 264 (MH+). 1H NMR (DMSO-d6): δ 5.87 (br s, 2 H), 6.64 (d, 2 H), 7.55-7.67 (m, 2 H), 7.81 (d, 2 H), 7.94 (t, 2 H), 8.81 (d, J=2 Hz, 1 H), 9.14 (d, J=2 Hz, 1 H) and 10.22 (br s, 1 H).
Reaction SMILES: C(N=C=S)C1C=CC=CC=1.C(NC(=S)NN)C1C=CC=CC=1.ClC(OCC)=O.[CH2:29]([N:36]1[C:40]([SH:41])=[N:39][N:38]=[C:37]1[OH:42])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.Br[C:44]1[S:45][C:46]([N+:49]([O-:51])=[O:50])=[CH:47][N:48]=1>>[CH2:29]([N:36]1[C:40]([S:41][C:44]2[S:45][C:46]([N+:49]([O-:51])=[O:50])=[CH:47][N:48]=2)=[N:39][N:38]=[C:37]1[OH:42])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=[N+]([O-])c1cnc(Br)s1
Reactant: Oc1nnc(S)n1Cc1ccccc1
Agent: CCOC(=O)Cl
Agent: NNC(=S)NCc1ccccc1
Agent: S=C=NCc1ccccc1
Product: O=[N+]([O-])c1cnc(Sc2nnc(O)n2Cc2ccccc2)s1
Yield: 17.8 %

Procedure:
The title compound was prepared in a manner similar to that described in Example 5 starting with benzyl isothiocyanate. The intermediate 4-benzyl-3-thiosemicarbazide (1.81 g) was treated with ethyl chloroformate (1.09 g) as in Example 5. The reaction product 4-benzyl-3-hydroxy-5-mercapto-1,2,4-triazole (1.04 g) was reacted with 1.05 g of 2-bromo-5-nitrothiazole as in Example 5. Crystallization from ethanol and water gave 0.3 g of 4-benzyl-3-hydroxy-5-[(5-nitrothiazol-2-yl)mercapto]1,2,4-triazole, a yellow solid, MP 221°-224° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[CH:22]=[C:21]([O:23][CH2:24][C@@H:25]([NH:27]C(=O)OC(C)(C)C)[CH3:26])[N:20]=[CH:19][C:18]=3[N:35]=2)=[CH:11][C:10]=1[F:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:38](OCC)(=[O:40])[CH3:39]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[CH:22]=[C:21]([O:23][CH2:24][C@@H:25]([NH:27][C:38](=[O:40])[CH3:39])[CH3:26])[N:20]=[CH:19][C:18]=3[N:35]=2)=[CH:11][C:10]=1[F:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(C)=O
Reactant: C[C@@H](COc1cc2oc(-c3ccc(OCc4ccccc4)c(F)c3)nc2cn1)NC(=O)OC(C)(C)C
Agent: Cl
Product: CC(=O)N[C@@H](C)COc1cc2oc(-c3ccc(OCc4ccccc4)c(F)c3)nc2cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To tert-butyl ((2S)-1-((2-(4-(benzyloxy)-3-fluorophenyl)[1,3]oxazolo[4,5-c]pyridin-6-yl)oxy)propan-2-yl)carbamate (1.35 g) was added 4 M hydrogen chloride/ethyl acetate (20 mL), and the mixture was stirred at room temperature for 10 min, and then concentrated. To the residue were added pyridine (10 mL) and acetic anhydride (10 mL), and the mixture was stirred at room temperature for 15 min. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in THF and methanol, and the solution was subjected to NH silica gel column chromatography (ethyl acetate). The solvent was evaporated, and the obtained solid was washed with ethyl acetate/hexane to give the title compound (1.00 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([F:9])=[C:4](Cl)[N:3]=1.[C:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:14])[NH:12][NH2:13].C(N(C(C)C)CC)(C)C.CCOC(C)=O>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:13][NH:12][C:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:5]([F:9])=[C:6]([Cl:8])[N:7]=1
Reactant: CC(C)(C)OC(=O)NN
Reactant: Fc1c(Cl)nc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NNc1nc(Cl)nc(Cl)c1F
Reaction time: 1.5 h
Yield: 101.4 %

Procedure:
2,4,6-Trichloro-5-fluoropyrimidine (20.92 g, 104.1 mmol) was dissolved in THF (300 mL) at room temperature and stirred. To this stirring solution was added t-butyl carbazate (13.74 g, 104.1 mmol), followed by diisopropylethylamine (19.0 mL, 109.3 mmol). The reaction mixture turned light yellow, and after several minutes a precipitate formed. The reaction appeared complete after 1.5 h, as monitored by TLC (10% EtOAc/Hex). The reaction mixture was concentrated in vacuo to remove most of the THF, and the residue was dissolved in CH2Cl2 (˜400 mL). The solution was washed with ˜400 mL of sat. aq. NH4Cl. The organics were dried and concentrated to give a pale yellow solid (31.37 g). LCMS: (M+H+2Na-Boc)+: 241.
Reaction SMILES: CS(O)(=O)=O.[CH3:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(O[CH:17]([CH3:19])[CH3:18])(=O)C.[C:20]([OH:23])(=[O:22])C>O>[CH2:8]([C@H:9]([CH2:10][CH2:11][CH2:12][CH2:18][CH2:17][CH3:19])[C:20]([OH:23])=[O:22])[CH2:7][CH3:6]
Reactant: CC(=O)OC(C)C
Reactant: CCCCCCC
Reactant: CC(=O)O
Agent: CS(=O)(=O)O
Solvent: O
Product: CCCCCC[C@@H](CCC)C(=O)O
Temperature: 108.5 °C
Reaction time: 13 h

Procedure:
Under an argon atmosphere, the compound (100 g) produced in Reference Example 3 was dissolved in acetic acid (230 mL) at about 40° C. (inner temperature). A solution of methanesulfonic acid (130 g) in water (182 mL) was added to the above solution, then stirred at about 105-112° C. (inner temperature) for about 13 hours, and cooled to about 28° C. (inner temperature). Then, water (400 mL) and a mixture of n-heptane: isopropyl acetate (5:1) (500 mL) were added and the mixture was extracted. The organic layer was washed twice with water (400 mL) and concentrated to give (2R)-2-propyloctanoic acid having the following physicochemical properties (103 g, 99.3% e.e.).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[C:4]([O:10]C)[CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8].B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[CH:9]=[C:6]([CH:5]=[C:4]([OH:10])[C:3]=1[OH:12])[CH:7]=[O:8]
Reactant: COc1cc(C=O)cc(Cl)c1O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=Cc1cc(O)c(O)c(Cl)c1
Temperature: 0 °C
Yield: 77.3 %

Procedure:
37.2 g of commercial 5-chloro vanillin and 800 ml of dichloromethane were mixed together under nitrogen and cooled to 0° C. 300 ml of a molar solution of boron tribromide in dichloromethane were added and the mixture stood for one night at ambient temperature. It was concentrated, cooled again to 0° C. and acidified. The crystallized product was separated, washed with water, dried and crystallized from an isopropanol-water mixture (1-2 by volume) to obtain 26.6 g of the expected product melting at >260° C.