Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C@@H:9]([C:14]([OH:16])=O)[C:10]([CH3:13])([CH3:12])[CH3:11])=O)(C)(C)C.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([N:33]2[CH:37]=[N:36][CH:35]=[N:34]2)=[C:22]([CH:32]=1)[CH2:23][NH:24][C:25](=[O:31])[C@@H:26]1[CH2:30][CH2:29][CH2:28][NH:27]1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:13][C:10]([CH3:11])([CH3:12])[C@H:9]([C:14]([N:27]1[CH2:28][CH2:29][CH2:30][C@H:26]1[C:25]([NH:24][CH2:23][C:22]1[CH:32]=[C:18]([Cl:17])[CH:19]=[CH:20][C:21]=1[N:33]1[CH:37]=[N:36][CH:35]=[N:34]1)=[O:31])=[O:16])[NH2:8]
Reactant: O=C(NCc1cc(Cl)ccc1-n1cncn1)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C(C)(C)C
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)[C@@H](N)C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1-n1cncn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of N-(tert-butoxycarbonyl)-3-methyl-D-valine (53 mg, 0.23 mmol), N-[5-chloro-2-(1H-1,2,4-triazol-1-yl)benzyl]-L-prolinamide (87 mg, 0.23 mmol, 1.0 equiv), EDC (66 mg, 0.34 mmol, 1.5 equiv), HOAt (16 mg, 0.11 mmol, 0.5 equiv) in DMF (1 mL) was brought to pH 6 by addition of Hünig's base and stirred at room temperature for 18 h. The solvent was removed in vacuo, and the resulting residue was dissolved in 2:1 CH2Cl2/TFA (3 mL) and stirred for 1 h. Solvent was again removed in vacuo, and purification by reverse phase chromatography [95:5 water (+0.1% TFA)/CH3CN (+0.1% TFA) to 50:50 water (+0.1% TFA)/CH3CN (+0.1% TFA)] afforded the title compound as a clear oil. 1H NMR (400 MHz, CDCl3): δ 8.93 (s, 1 H), 8.29 (s, 1 H), 8.00 (br s, 1 H), 7.55 (d, J=2.0 Hz, 1 H), 7.39 (dd, J=2.0, 8.4 Hz, 1 H), 7.25 (d, J=8.4 Hz, 1 H), 7.01 (br s, 2 H), 4.47–4.45 (m, 1 H), 4.35–4.30 (m, 2 H), 4.15 (dd, J=5.2, 15.2 Hz, 1 H), 3.80–3.71 (m, 1 H), 3.58–3.52 (m, 1 H), 2.15–2.12 (m, 2 H), 2.01–1.98 (m, 2 H), 1.10 (s, 9 H). HRMS (APCI) M+H: calculated for (C20H27N6O2Cl)+ 419.1957, found 419.1935.
Reaction SMILES: [Cl-].[CH2:2]([O:9][C:10]1[CH:35]=[CH:34][C:33]([O:36][C:37]2[C:45]([CH3:46])=[CH:44][C:43]([N+:47]([O-:49])=[O:48])=[C:42]3[C:38]=2[CH2:39][CH2:40][CH2:41]3)=[CH:32][C:11]=1[CH2:12][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H-].[Na+].[O:52]1[CH2:57][CH2:56][C:55](=O)[CH2:54][CH2:53]1.Cl>CS(C)=O>[CH2:2]([O:9][C:10]1[CH:35]=[CH:34][C:33]([O:36][C:37]2[C:45]([CH3:46])=[CH:44][C:43]([N+:47]([O-:49])=[O:48])=[C:42]3[C:38]=2[CH2:39][CH2:40][CH2:41]3)=[CH:32][C:11]=1[CH:12]=[C:55]1[CH2:56][CH2:57][O:52][CH2:53][CH2:54]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cc1cc([N+](=O)[O-])c2c(c1Oc1ccc(OCc3ccccc3)c(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)c1)CCC2
Reactant: O=C1CCOCC1
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: CS(C)=O
Product: Cc1cc([N+](=O)[O-])c2c(c1Oc1ccc(OCc3ccccc3)c(C=C3CCOCC3)c1)CCC2
Reaction time: 0.25 h

Procedure:
To a suspension of [2-benzyloxy-5-(5-methyl-7-nitroindan-4-yloxy)benzyl]triphenylphosphonium chloride (559 mg) in dimethylsulfoxide (20 mL) was added sodium hydride (60%, 49 mg) at room temperature, the mixture was stirred for 15 min. After adding tetrahydro-4H-pyran-4-one (0.15 mL), the reaction mixture was stirred at room temperature for 6 hours. After adding dropwise diluted hydrochloric acid to make the mixture acidify fully, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed-under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate) to give the title compound (230 mg).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][Br:7].[CH2:8]([O:10][P:11]([O:15]CC)[O:12][CH2:13][CH3:14])[CH3:9]>>[Br:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][P:11](=[O:15])([O:12][CH2:13][CH3:14])[O:10][CH2:8][CH3:9]
Reactant: CCOP(OCC)OCC
Reactant: BrCCCCCBr
Product: CCOP(=O)(CCCCCBr)OCC
Temperature: 160 °C
Reaction time: 0.67 h
Yield: 104.2 %

Procedure:
A mixture of 1,5-dibromopentane (500 g.) and triethylphosphite (72.0 g.) was stirred at 160° C. for 40 minutes and then excess 1,5-dibromopentane was distilled off under reduced pressure to give oily diethyl 5-bromopentylphosphonate (129.6 g.).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:22][C:8]2[CH:9]3[CH:13]([CH2:14][C:7]=2[CH:6]=1)[CH2:12][N:11](CC1C=CC=CC=1)[CH2:10]3)=[O:4].C([O-])([O-])=O.[K+].[K+].CC(Cl)OC(Cl)=O>ClCCCl>[CH3:1][O:2][C:3]([C:5]1[S:22][C:8]2[CH:9]3[CH:13]([CH2:14][C:7]=2[CH:6]=1)[CH2:12][NH:11][CH2:10]3)=[O:4]
Reactant: COC(=O)c1cc2c(s1)C1CN(Cc3ccccc3)CC1C2
Agent: CC(Cl)OC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Product: COC(=O)c1cc2c(s1)C1CNCC1C2
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of the product from step b) (100 mg, 0.32 mmol) in DCE (1.6 ml) was added powdered K2CO3 (176 mg, 1.28 mmol) and ACE-Cl (183 mg, 1.28 mmol). The reaction mixture was heated to 80° C. and stirred for 18 hours. The reaction was cooled to room temperature, filtered, and concentrated in vacuo. The crude oil was dissolved in anhydrous MeOH (2.5 ml) and stirred at room temperature for 3 hours. The solvent was evaporated and the product triturated with anhydrous ether to give a white solid, which was filtered to give the titled compound as its hydrochloride salt: (42.3 mg, 51%), 1H NMR (300 MHz, DMSO, ppm) 2.68 (br d, J=16 Hz, 1H), 2.98-3.06 (m, 2H), 3.19-3.28 (m, 1H), 3.35-3.50 (m, 2H), 3.52-3.62 (m, 1H), 3.80 (s, 3H), 4.00-4.11 (m, 1H), 7.56 (s, 1H), 9.05 (br s, 1H), 9.31 (br s, 1H). MS calculated for C11H13NO2S+H 224, observed 224.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:11][C@H:12]([CH3:17])[CH2:13][CH2:14][CH2:15][CH3:16])[CH2:3][C:4]([O:6]C(C)(C)C)=[O:5].[ClH:18]>>[ClH:18].[NH2:1][C@@H:2]([CH2:11][C@H:12]([CH3:17])[CH2:13][CH2:14][CH2:15][CH3:16])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CCCC[C@@H](C)C[C@H](N)CC(=O)OC(C)(C)C
Agent: Cl
Product: CCCC[C@@H](C)C[C@H](N)CC(=O)O

Procedure:
A mixture of (3S,5R)-3-amino-5-methyl-nonanoic acid, tert-butyl ester (1.50 g, 6.16 mmol) in 3N HCl (100 mL) was heated at reflux for 3 hours, filtered hot over Celite, and concentrated to 30 mL in vacuo. The resulting crystals were collected, washed with additional 3N HCl, and dried to provide the title compound, mp 142.5–143.3° C. Additional crops were obtained from the filtrate to provide 1.03 g (70.4%). 1HNMR (400 MHz; CD3OD) δ=0.91(t, 3H, J=6.84 Hz), 0.92(d, 3H, J=6.35 Hz), 1.16–1.26(m, 1H), 1.27–1.35(m, 4H), 1.38–1.45(m, 1H), 1.61 (br s, 1H), 1.63–1.68(m, 1H), 2.58 (dd, 1H, J=7.32 and 17.34 Hz), 2.69(dd, 1H, J=5.13 and 17.59 Hz), and 3.59(m, 1H). Anal. Calc'd for C10H21NO2HCl: C, 53.68; H, 9.91; N, 6.26; Cl, 15.85. Found: C, 53.89; H, 10.11; N, 6.13. MS: M+1: 188.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[CH2:14][N:15]1[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[C@@H:17]([CH3:28])[CH2:16]1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[CH2:14][N:15]1[CH2:20][CH2:19][NH:18][C@@H:17]([CH3:28])[CH2:16]1
Reactant: C[C@H]1CN(Cc2ccc(N3CCOCC3)cc2Cl)CCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1CN(Cc2ccc(N3CCOCC3)cc2Cl)CCN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
A 100 mL round-bottom flask was charged with tert-butyl (2S)-4-[[2-chloro-4-(morpholin-4-yl)phenyl]methyl]-2-methylpiperazine-1-carboxylate (1.20 g, 2.93 mmol, 1.00 equiv), trifluoroacetic acid (4 mL), dichloromethane (20 mL). The resulting solution was stirred for 1 h at room temperature and concentrated under reduced pressure to yield 0.910 g (crude) of 4-(3-chloro-4-[[(3S)-3-methylpiperazin-1-yl]methyl]phenyl)morpholine as light yellow oil. LCMS (ESI, m/z): 310 [M+H]+.
Reaction SMILES: C(OC([N:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[C:11](=[O:22])[N:10]2[CH2:23][C:24](=[CH2:26])[CH2:25][C@H:9]2[C@@H:8]1O)=O)C=C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1CCCC1.C(Cl)(Cl)Cl.CO>C(Cl)Cl.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>[CH3:19][O:18][C:16]1[C:15]([O:20][CH3:21])=[CH:14][C:13]2[N:7]=[CH:8][C@@H:9]3[CH2:25][C:24](=[CH2:26])[CH2:23][N:10]3[C:11](=[O:22])[C:12]=2[CH:17]=1
Reactant: C=CCOC(=O)N1c2cc(OC)c(OC)cc2C(=O)N2CC(=C)C[C@H]2[C@@H]1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNC1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: C=C1C[C@H]2C=Nc3cc(OC)c(OC)cc3C(=O)N2C1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A catalytic amount of tetrakis(triphenylphosphine)palladium (32.4 mg, 28.1 μmol) was added to a stirred solution of the Alloc-protected carbinolamine 73 (0.42 g, 1.12 mmol), triphenylphosphine (14.7 mg, 56.2 μmol) and pyrrolidine (83.9 mg, 1.18 mmol) in CH2Cl2 (55 mL). After 2.5 hours stirring at room temperature under a nitrogen atmosphere, TLC (95% CHCl3/MeOH) revealed the complete consumption of starting material. The solvent was evaporated in vacuo and the crude residue was purified by flash chromatography (CHCl3) to afford the novel PBD (74, MMY-SJG, UP2064) as a yellow oil which was repeatedly evaporated in vacuo with CHCl3 in order to provide the N10-C11 imine form (259 mg, 85%): [α]22D=+583.14° (c=1.42, CHCl3); 1H NMR (270 MHz, CDCl3) δ7.69 (d, 1H, J=4.39 Hz), 7.51 (s, 1H), 6.82 (s, 1H), 5.21-5.17 (m, 2H), 4.44-4.23 (m, 2H), 3.96-3.81 (m, 7H), 3.17-3.08 (m, 1H), 2.95 (d, 1H, J=14.29 Hz); 13C NMR (67.8 MHz, CDCl3) δ164.7, 162.6, 151.5, 147.6, 141.6, 140.8, 119.8, 111.2, 109.4, 109.4, 56.2, 56.1, 53.8, 51.4, 35.5; MS (EI), m/z (relative intensity) 273 (M+. +1, 16), 272 (M+., 100), 271 (35), 270 (9), 255 (5), 243 (7), 241 (7), 230 (6), 228 (6), 226 (5), 212 (3), 192 (4), 191 (16), 165 (4), 164 (19), 163 (4), 136 (22), 93 (6), 82 (7), 80 (3), 53 (3); IR (NEAT) 3312 (br), 3083, 2936, 2843, 1624, 1603, 1505, 1434, 1380, 1264, 1217, 1180, 1130, 1096, 1069, 1007, 935, 895, 837, 786, 696, 666, 594, 542 cm−1; exact mass calcd for C11H16N2O3 m/e 272.1161, obsd m/e 272.1154.
Reaction SMILES: Br[CH:2]([C:5]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12])[CH:3]=O.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[C:26]([C:27](=[O:29])[CH3:28])=[C:25]([CH3:30])[NH:24][C:23](=[S:31])[NH:22]2)=[CH:17][CH:16]=1>O1CCCC1>[Cl:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([Cl:11])[C:5]=1[C:2]1[S:31][C:23]2=[N:24][C:25]([CH3:30])=[C:26]([C:27](=[O:29])[CH3:28])[CH:21]([C:18]3[CH:17]=[CH:16][C:15]([O:14][CH3:13])=[CH:20][CH:19]=3)[N:22]2[CH:3]=1
Reactant: O=CC(Br)c1c(Cl)cccc1Cl
Reactant: COc1ccc(C2NC(=S)NC(C)=C2C(C)=O)cc1
Solvent: C1CCOC1
Product: COc1ccc(C2C(C(C)=O)=C(C)N=C3SC(c4c(Cl)cccc4Cl)=CN32)cc1
Temperature: 25 °C
Reaction time: 65 h
Yield: 67.9 %

Procedure:
A mixture of 1.9 g (7.09 mmol) of α-bromo-2,6-dichlorophenyl-acetaldehyde and 1.78 g (6.45 mmol) of (RS)-1-[4-(4-methoxyphenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl]ethanone in 50 ml of tetra- hydrofuran was stirred at RT for 65 h. Subsequently, the mixture was cooled to 0° C. and the precipitated solid was filtered off, dissolved in 75 ml of conc. acetic acid and heated at reflux while stirring for 8 h. The reaction mixture was concentrated and the residue was purified by column chromatography on silica gel (dichloromethane/methanol 95:5). There were obtained 1.95 g (68%) of (RS)-1-[2-(2,6-dichlorophenyl)-5-(4-methoxyphenyl)-7-methyl-5H-thiazolo[3,2-a]pyrimidin-6-yl]ethanone as a yellow foam.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:11][N:12]2[CH:17]([C:18](O)=[O:19])[CH2:16][N:15]([CH3:21])[C:14](=[O:22])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:31])=O>C(Cl)Cl.CN(C=O)C>[CH2:1]([O:8][C:9]1[C:10]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:11][N:12]2[CH:17]([C:18]([Cl:31])=[O:19])[CH2:16][N:15]([CH3:21])[C:14](=[O:22])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(C)CC2C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(C)CC2C(=O)Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 3-benzyloxy-2-ethoxycarbonyl-5-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-7-carboxylic acid (250 mg, 0.670 mmol) in anhydrous CH2Cl2 at 0° C. were added 2M oxalyl chloride in CH2Cl2 (1.339 mL, 2.678 mmol) and DMF (1 drop). The reaction was stirred at 0° C. for 30 minutes and allowed to warm to room temperature for 1 hour. The mixture was concentrated in vacuo and azeotroped twice with anhydrous CH2Cl2 to afford the title product. ES MS (M+H)=392.
Reaction SMILES: [CH2:1]([OH:6])[CH:2]([OH:5])[CH:3]=[CH2:4].N1C=CN=C1.[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>C(Cl)Cl.[NH4+].[Cl-]>[C:15]([Si:12]([CH3:14])([CH3:13])[O:6][CH2:1][CH:2]([OH:5])[CH:3]=[CH2:4])([CH3:18])([CH3:17])[CH3:16]
Reactant: C=CC(O)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C=CC(O)CO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.1 %

Procedure:
To a solution of (+/−)-3-butene-1,2-diol (500 mg, 5.67 mmol) in CH2Cl2 (25 mL) was added imidazole (444 mg, 6.53 mmol). The solution was cooled to 0° C. and t-butyidimethylsilyl chloride (1.0 M in THF, 6.24 mL, 6.24 mmol) was added. The reaction was stirred at 0° C. for 15 minutes and at room temperature for 1 hour and 30 minutes. The mixture was diluted with aqueous NH4Cl and extracted with CH2Cl2 (3×). The organic solution was washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by medium pressure chromatography eluting with a solvent gradient (5% EtOAc in hexanes to 100% EtOAc) to provide 827.5 mg of 1-(tert-butyl-dimethyl-silanyloxy)-but-3-en-2-ol. 1H NMR (CDCl3) δ 5.81 (m, 1H), 5.34 (d, 1H), 5.19 (d, 1H), 4.17 (m, 1H), 3.66 (dd, 1H), 3.45 (dd, 1H), 0.90 (s, 9H), 0.08 (s, 6H); MS m/z 202.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[C:11]([O:14]C)[CH:10]=[CH:9][CH:8]=2)=[O:4].B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[C:11]([OH:14])[CH:10]=[CH:9][CH:8]=2)=[O:4]
Reactant: COC(=O)c1cc2c(OC)cccc2[nH]1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1cc2c(O)cccc2[nH]1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice cold solution of 4-Methyloxy-1H-indole-2-carboxylic acid methyl ester (1 g, 4.87 mmol) in DCM (10 ml) is added BBr3 (1M in DCM, 4.9 ml, 4.9 mmol). It is stirred for 1 hour and another equivalent (4.9 ml) of BBr3 is added. After another hour, the mixture is poured on ice and the pH is adjusted to 7 with sodium bicarbonate. Extraction with DCM gave a yellow powder.
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][N:17]([S:20]([C:23]5[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=5)(=[O:22])=[O:21])[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@@H:5]([NH2:30])[CH2:4]1)[CH3:2].Cl[C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33]>C1COCC1>[CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][N:17]([S:20]([C:23]5[CH:24]=[CH:25][C:26]([CH3:27])=[CH:28][CH:29]=5)(=[O:22])=[O:21])[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@@H:5]([NH:30][C:32](=[O:33])[O:34][CH:35]([CH3:37])[CH3:36])[CH2:4]1)[CH3:2]
Reactant: CC(C)OC(=O)Cl
Reactant: CC[C@@H]1C[C@H](N)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Solvent: C1CCOC1
Product: CC[C@@H]1C[C@H](NC(=O)OC(C)C)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87 %

Procedure:
To a solution of (1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine (0.080 g, 0.19 mmol, Preparation #BB.1*) in THF (2 mL) was added TEA (0.079 mL, 0.565 mmol) and the solution was stirred at ambient temperature for about 10 min. To the reaction was added isopropyl chloroformate (1 M in toluene, 0.18 mL, 0.18 mmol) and the reaction mixture was stirred for about 1 h. The solvent was removed under reduced pressure and DCM (5 mL) and saturated aqueous NaHCO3 (2 mL) were added. The layers were separated and the organic layer was washed with brine (2 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give crude isopropyl (1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylcarbamate (0.080 g, 60%) which was used without further purification: LC/MS (Table 1, Method b) Rt=2.33 min; MS m/z: 511 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C@H:14]([OH:15])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:19](Br)[CH:20]=[CH2:21]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:16][C@H:14]([O:15][CH2:21][CH:20]=[CH2:19])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCO[C@@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.1 %

Procedure:
N-tert-Butoxycarbonyl(4R)-hydroxyproline (9.25 g, 40 mmol) was added to a solution of 60% sodium hydride (3.36 g, 84 mmol) in 100 ml of anhydrous tetrahydrofuran and stirred for 2 hours at room temperature. Allyl bromide (6.9 ml, 80 mmol) was added to the mixture and refluxed for 6 hours. The mixture was quenched with the addition of ice chips, then additional water was added and the mixture was washed with hexane. The aqueous layer was acidified with 10% sodium hydrogen sulfate and extracted with ethyl acetate (2×150 ml). The combined extracts were dried over anhydrous sodium sulfate, filtered and evaporated to give 5 g of the title product with no further purification. 1H NMR (CDCl3; exist as rotamers) δ5.92-5.82 (1H, m), 5.3-5.14 (2H, m) 4.5-4.31 (1H, m), 4.16-4.05 (1H, m), 4.04-3.9 (1H, m), 3.79-3.5 (3H, m), 2.43-2.2 (1.5H, m), 2.15-2.10 (0.5H, m), 1.45 (4.5H, s), 1.35 (4.5H, s).
Reaction SMILES: [CH2:1]([OH:14])[CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]#[C:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].N1C=CN=C1.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].ClCCl>CN(C)C=O>[Si:20]([O:14][CH2:1][CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]#[C:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: OCCCCC#CC#CCCCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCCCC#CC#CCCCCO
Temperature: 25 °C
Reaction time: 20 h

Procedure:
5,7-Dodecadiyn-1,12-diol (1) (4 g, 20.6 mmol) and imidazole (2.8 g, 41 mmol) were dissolved in dimethylformamide (15 ml). To the solution, tert-butyldimethylsilylchloride (2.38 g, 18.8 mmol) was added at once. The solution was stirred for 20 hours at room temperature under a nitrogen atmosphere. At this point, the reaction mixture was transferred into a separatory funnel along with dichloromethane (100 ml) and washed with saturated sodium bicarbonate solution and water successively. The organic layer was died (MgSO4) and concentrated followed by purification of the residue by flash column chromatography (silica gel, 7% acetone in dichloromethane) affording 3.17 g of a pale yellow oil (55% yield) of the title compound.
Reaction SMILES: [O:1]1[C:7]2([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:2]1[CH2:3][N:4]([CH3:14])[CH2:5][CH2:6]2.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:27]([OH:31])(=[O:30])[CH2:28][CH3:29]>>[OH:1][CH:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([O:30][C:27](=[O:31])[CH2:28][CH3:29])[CH2:6][CH2:5][N:4]([CH3:14])[CH2:3]1
Reactant: CN1CCC2(c3ccccc3)OC2C1
Reactant: CCC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCC(=O)OC1(c2ccccc2)CCN(C)CC1O

Procedure:
A solution of 4.0 g of 3,4-epoxy-1-methyl-4-phenyl-piperidine and 4.5 g of p-toluenesulfonic acid monohydrate in 50 ml of propionic acid was stirred at room temperature for 10 minutes then the mixture evaporated to dryness. Water was added to the residue and the mixture made alkaline with sodium carbonate. The residual solid was filtered off and washed with water. Recrystallization of this solid from hot ethyl acetate gave 2.4 g of 3-hydroxy-1-methyl-4-phenyl-4-propionoxy-piperidine with a melting point of 142°-3° C. The corresponding hydrochloride salt had a melting point of 186°-8° C.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][CH:9]=[CH:10][C:11]([OH:13])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.C1(C)C=CC=CC=1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][C:28]=1[N:34]1[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]1>ClCCl.C(N(CC)CC)C>[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:11](=[O:13])[CH:10]=[CH:9][CH:8]=[CH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:29][C:28]=1[N:34]1[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]1
Reactant: COc1ccc(N)cc1N1CCN(C)CC1
Reactant: O=C(O)C=CC=Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(NC(=O)C=CC=Cc2ccccc2)cc1N1CCN(C)CC1
Reaction time: 1 h
Yield: 101.7 %

Procedure:
5-Phenylpenta-2,4-dienoic acid (270 mg, 1.55 mmol) was heated at reflux with thionyl chloride (3 ml) and toluene (40 ml) for 2 h, and then evaporated to dryness under reduced pressure. 4-Methoxy-3-(4-methyl-1-piperazinyl)phenylamine (340 mg, 1.55 mmol) in dry dichloromethane (40 ml) was added with triethylamine (1 ml) and the mixture stirred for 1 h. The solution was partitioned between dichloromethane (40 ml) and saturated aqueous potassium carbonate (40 ml), the organic solution dried (sodium sulphate) and evaporated to dryness under reduced pressure to afford an oil, which was purified by column chromatography (silica, chloroform/methanol 5%) to afford the title compound (595 mg, 100%) which was crystallised from methanol/diethyl ether as the oxalate salt.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([Cl:19])=[CH:14][N:13]=2)=[N:8][O:9][C:10]=1[CH3:11])=[O:5])C.[OH-].[Na+].C(O)C.Cl>O.O1CCCC1>[Cl:18][C:17]1[C:12]([C:7]2[C:6]([C:4]([OH:5])=[O:3])=[C:10]([CH3:11])[O:9][N:8]=2)=[N:13][CH:14]=[C:15]([Cl:19])[CH:16]=1
Reactant: CCOC(=O)c1c(-c2ncc(Cl)cc2Cl)noc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Cc1onc(-c2ncc(Cl)cc2Cl)c1C(=O)O

Procedure:
Combine 3-(3,5-dichloro-pyridin-2-yl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester (0.755 g, 0.0025 mol) with aqueous sodium hydroxide (2N, 6.0 mL, 0.012 mol), ethanol (2 mL), and tetrahydrofuran (2 mL) and stir overnight at ambient temperature. Add water and adjusted to approx. pH 3.0 with aqueous hydrochloric acid. Extract with ethyl acetate and dry over sodium sulfate and concentrate in vacuo. Drying nets the desired isoxazole acid as a tan solid(0.65 g, 95%). MS (ES): (M+1)+ 273.0,275.0 m/z.
Reaction SMILES: [C:1]1([CH2:7][NH:8][CH2:9][CH:10]2[O:19][C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[O:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:20]1[CH2:22][CH:21]1[CH2:23][N:24]1[CH2:28][C:27](=[O:29])[NH:26][C:25]1=[O:30]>CO>[O:12]1[C:13]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[O:19][CH:10]([CH2:9][N:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:22][CH:21]([OH:20])[CH2:23][N:24]2[CH2:28][C:27](=[O:29])[NH:26][C:25]2=[O:30])[CH2:11]1
Reactant: O=C1CN(CC2CO2)C(=O)N1
Reactant: c1ccc(CNCC2COc3cccnc3O2)cc1
Solvent: CO
Product: O=C1CN(CC(O)CN(Cc2ccccc2)CC2COc3cccnc3O2)C(=O)N1
Yield: 62.9 %

Procedure:
A mixture of 2,3-dihydro-N-(phenylmethyl)-1,4dioxino[2,3-b]pyridine-3-methanamine (0.0059 mol) and intermediate (18) (0.00497 mol) in methanol (30 ml) was stirred and refluxed overnight. The solvent was evaporated. The residue was purified by short open column chromatography over silica gel (eluent: CH2Cl212-propanone 96/4, 90/10 and 80/20), then CH2Cl2/CH3OH 96/4 and 90/10). The product fractions were collected and the solvent was evaporated, yielding 1.29 g of (±)-1-[3-[[(2,3-dihydro-1,4-dioxino-[2,3-b]pyridin-3-yl)methyl](phenylmethyl)amino]-2-hydroxypropyl]-2,4-imidazolidine-dione (compound 12).