Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][CH2:16][CH:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.[CH2:18]([NH:20][C:21](=[O:34])[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1)[CH3:19].[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC>[CH2:18]([NH:20][C:21](=[O:34])[C:22]1[CH:23]=[CH:24][C:25]([N:28]2[CH2:29][CH2:30][N:31]([CH2:2][C:3]3[CH:12]=[N:11][C:10]4[N:9]5[CH2:13][CH2:14][CH2:15][CH2:16][CH:8]5[C:7](=[O:17])[NH:6][C:5]=4[CH:4]=3)[CH2:32][CH2:33]2)=[CH:26][CH:27]=1)[CH3:19]
Reactant: CCNC(=O)c1ccc(N2CCNCC2)cc1
Reactant: O=C1Nc2cc(CO)cnc2N2CCCCC12
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CCNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)C3CCCCN43)CC2)cc1
Temperature: 90 °C
Yield: 58.4 %

Procedure:
3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one (50 mg, 0.214 mmol), N-ethyl-4-(piperazin-1-yl)benzamide (55.0 mg, 0.236 mmol), (cyanomethyl)trimethylphosphonium iodide (67.7 mg, 0.279 mmol) and N,N-diisopropylethylamine (187 μl, 1.072 mmol) were suspended in Propiononitrile (Volume: 644 μl) and heated in a closed vial at 90° C. for 1 h. It was cooled to ambient temperature, the resulting precipitate was filtered, washed with MeCN (5 mL) and dried in vacuum to afford N-ethyl-4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide (56 mg, 0.125 mmol, 58.2% yield) as a white solid. 1H NMR (DMSO-d6) δ 10.43 (s, 1H), 8.12 (t, J=5.6 Hz, 1H), 7.70 (d, J=9.1 Hz, 2H), 7.66 (d, J=2.0 Hz, 1H), 6.98 (d, J=2.0 Hz, 1H), 6.92 (d, J=9.1 Hz, 2H), 4.47-4.55 (m, 1H), 3.83 (dd, J=11.4, 2.8 Hz, 1H), 3.32-3.40 (m, 2H), 3.18-3.28 (m, 6H), 2.61 (td, J=12.6, 2.5 Hz, 1H), 2.43-2.49 (m, 4H), 2.04 (d, J=13.1 Hz, 1H), 1.80-1.91 (m, 2H), 1.64 (d, J=12.6 Hz, 2H), 1.33-1.58 (m, 3H), 1.09 (d, J=14.4 Hz, 3H); [M+H] calc'd for C25H32N6O2, 449; found, 449.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:13][C:12](=O)[CH:11]=[C:10]([C:15]([F:18])([F:17])[F:16])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.O=P(Cl)(Cl)[Cl:21]>>[Cl:21][C:12]1[CH:11]=[C:10]([C:15]([F:18])([F:17])[F:16])[N:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1
Reactant: O=c1cc(C(F)(F)F)nc(-c2cccc(Cl)c2)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1cc(Cl)nc(-c2cccc(Cl)c2)n1
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 87.5 %

Procedure:
A 250-mL round bottom flask was charged with 2-(3-chlorophenyl)-6-(trifluoromethyl)pyrimidin-4(3H)-one (3.60 g, 13.1 mmol). POCl3 (14.4 mL, 157 mmol) was cautiously added at 0° C. The resulting mixture was stirred at 100° C. for 3.5 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane (50 mL) and treated with aqueous sodium, bicarbonate until the pH˜8. The aqueous layer was extracted with dichloromethane (4×25 mL). The combined organic extract was washed the saturated sodium chloride (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica chromatography using hexanes/dichloromethane (3:1) as eluent to afford the title compound (3.36 g, 87%) as a white solid. MW=293.07. 1H NMR (CDCl3, 500 MHz) δ 8.49 (t, J=1.5 Hz, 1H), 8.39 (dt, J=8.0, 1.5 Hz, 1H), 7.57 (s, 1H), 7.53 (ddd, J=8.0, 2.0, 1.0 Hz, 1H), 7.45 (t, J=8.0 Hz, 1H).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[N:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:5]2[C@@H:4]2[CH2:21][CH2:22][CH2:23][N:3]12.O[CH2:25][CH:26]1CC1>CCO.CCO.CCO.CCO.[Ti]>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[N:14][C:15]([C:16]([O:18][CH2:19][CH:20]3[CH2:26][CH2:25]3)=[O:17])=[C:5]2[C@@H:4]2[CH2:21][CH2:22][CH2:23][N:3]12
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1ccccc1-2
Reactant: OCC1CC1
Agent: [Ti]
Solvent: CCO
Product: O=C(OCC1CC1)c1ncn2c1[C@@H]1CCCN1C(=O)c1ccccc1-2
Reaction time: 8 h

Procedure:
A mixture of 6.22 g (20 mmol) of ethyl (S)-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate, 1.52 g (6.7 mmol) of tetraethyl orthotitanate and 10 g (194 mmol) of hydroxymethyl-cyclopropane is stirred at 115° overnight, evaporated to dryness, the residue is taken up in methylene chloride and stirred for 0.5 hour with about 50 ml of water. The emulsion obtained is filtered through siliceous earth, the organic phase is washed with saturated sodium bicarbonate solution, dried over magnesium sulphate and evaporated. By recrystallization of the residue from ethyl acetate there is obtained cyclopropylmethyl (S)-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 189-190°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8](O)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(O)=O.[BH4-].[Na+]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(-c2ccccc2C(O)c2cccc(F)c2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc(-c2ccccc2Cc2cccc(F)c2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 82.2 %

Procedure:
The product of the Example 25b (140 mg, 0.393 mmol) was dissolved in anhydrous dichloromethane (10 mL) and under nitrogen atmosphere was added trifluoroacetic acid (5 mL) at 0° C. The reaction mixture was stirred at 0° C. for 10 minutes and to the resulting dark orange solution was then added, in small portions sodium borohydride (290 mg, 7.86 mmol). The reaction mixture was stirred at 0° C. for 15 minutes and then at room temperature for 5 minutes. The solvent and trifluoroacetic acid were evaporated under reduced pressure and the residue was extracted with dichloromethane. The combined organic extracts were washed with water, brine, dried over sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to give the crude which upon trituration with hexane yielded the title compound as a white solid, (110 mg, 83%), mp 97-98° C. 1H NMR (CDCl3) δ7.97 (d, J=8.3 Hz, 2H), 7.45 (d, J=8.3 Hz, 2H), 7.45-7.15 (m, 5H), 6.98 (dt, J=8.4 and 2.2 Hz, 1H), 6.75 (d, J=7.6 Hz, 1 H), 6.63 (d, J=10 Hz, 1H); 13C NMR (CDCl3) δ164.4, 161.2, 147.2, 143.3 (d, J=7 Hz), 140.3, 139.2, 137.2, 130.7, 130.1 (2×C), 129.9, 129.7 (d, J=2.5 Hz), 128.6, 127.1 (2×C), 126.9, 124.3 (d, J=2.5 Hz), 115.4 (d, J=21 Hz), 112.9 (d, J=21 Hz), 44.5, 38.9; LRMS (APIMS) m/z 358 (M+NH4)+.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[F:35][C:36]1[CH:37]=[C:38]([OH:50])[CH:39]=[C:40]([C:42]2([O:48][CH3:49])[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)[CH:41]=1>O>[F:35][C:36]1[CH:37]=[C:38]([CH:39]=[C:40]([C:42]2([O:48][CH3:49])[CH2:43][CH2:44][O:45][CH2:46][CH2:47]2)[CH:41]=1)[O:50][CH2:2][C:3]1[O:4][C:5]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1
Reactant: COC1(c2cc(O)cc(F)c2)CCOCC1
Reactant: NS(=O)(=O)c1ccc(-c2oc(CCl)nc2-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC1(c2cc(F)cc(OCc3nc(-c4ccccc4)c(-c4ccc(S(N)(=O)=O)cc4)o3)c2)CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.8 %

Procedure:
A mixture of 4-[2-chloromethyl-4-phenyloxazol-5-yl]benzenesulfonamide (Step 3) (0.5 g, 1.4 mmol), potassium carbonate (0.4 g, 2.8 mmol), dimethylformamide (20 mL), and 3-fluoro-5-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenol [prepared as described in J. Med Chem., 35, 2600-2609 (1992)] (0.3 g, 1.4 mmol) was stirred at room temperature for 16 h. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (4×30 mL). The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated. The resulting crude product was purified by flash column chromatography on silica gel eluting with 50% ethyl acetate in hexanes to give 0.3 g (40%) of 4-[2-[[3-fluoro-5-(3,4,5,6-tetrahydro-4-methoxy-pyran-4-yl)phenoxy]methyl]-4-phenyl-oxazol-5-yl]benzenesulfonamide as a sticky white solid: m.p. 70-80° C. 1H NMR (CDCl3/300 MHz) δ 7.92 (d, 2H, J=8.9 Hz), 7.77 (d, 2H, J=8.9 Hz) , 7.62 (m, 2H) , 7.43 (m, 3H) , 6.94 (s, 1H), 6.78 (m, 2H) 5.24 (s, 2H) , 4.82 (bs, 2H), 3.82 (m, 4H), 3.00 (s, 3H), 1.95 (m, 4H). Anal. calcd for C28H27FN2O6S: C, 62.44; H, 5.05; N, 5.20. Found: C, 62.50; H, 5.11; N, 5.24.
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[F:17])[C:3]=1[CH:4]=[O:5].[BH4-].[Na+]>CO.C1COCC1>[NH2:1][C:2]1[C:3]([CH2:4][OH:5])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[F:17])[CH:7]=[CH:8][N:9]=1
Reactant: Nc1nccc(-c2ccc(Cl)cc2F)c1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1nccc(-c2ccc(Cl)cc2F)c1CO
Reaction time: 1 h
Yield: 99.5 %

Procedure:
To a stirred solution of 2-amino-4-(4-chloro-2-fluorophenyl)nicotinaldehyde (50 mg, 0.199 mmol) in MeOH (2 mL) and THF (5 mL) was added sodium borohydride (9.06 mg, 0.239 mmol) then the solution was stirred for 1 h. The volatile organics were removed under reduced pressure and the residue was quenched by addition of saturated aqueous ammonium chloride solution (10 mL). The reaction mixture was extracted with CH2Cl2 (2×10 mL). The combined organic extracts were washed with brine (1×10 mL), dried over sodium sulfate and concentrated under reduced pressure to yield (2-amino-4-(4-chloro-2-fluorophenyl)pyridin-3-yl)methanol (50 mg, 0.198 mmol, 21% yield for two steps). LCMS (ESI) m/e 253 [(M+H)+, calcd for C12H11ClFN2O 253.0]; LC/MS retention time (Method C): tR=1.48 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(N1CCC(N(C2C=CC(OCC3C=CC=CC=3)=CC=2)[CH2:41][CH:42]=[C:43]([CH3:45])[CH3:44])CC1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[CH:16]2[CH2:21][CH2:20][N:19]([CH2:41][CH2:42][CH:43]([CH3:45])[CH3:44])[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)=CCN(c1ccc(OCc2ccccc2)cc1)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)=CCN(c1ccc(OCc2ccccc2)cc1)C1CCNCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)=CCN(c1ccc(OCc2ccccc2)cc1)C1CCN(CCC(C)C)CC1
Yield: 99 %

Procedure:
The preparation of (4-Benzyloxy-phenyl)-(3-methvl-but-2-enyl)-piperidin-4-yl-amine, (Ic): 4-[(4-Benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (5.0 g, 11.1 mmol) was dissolved in CH2Cl2 (20 mL) and treated with TFA (20 mL). The reaction was stirred for ten minutes, then concentrated in vacuo. The residue was redissolved in EtOAc (400 mL), then washed with saturated bicarbonate solution (2×400 mL) and brine (1×400 mL), dried over Na2SO4, and concentrated in vacuo to give 3.9 g (99%) of the desired product as a pale oil.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[CH3:7][O:8][C:9]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]([O:22][CH3:23])[C:10]=1[C:11](Cl)=[O:12].O>ClCCl>[OH:4][CH2:3][C:2]([NH:1][C:11](=[O:12])[C:10]1[C:14]([O:22][CH3:23])=[CH:15][C:16]([C:18]([F:19])([F:20])[F:21])=[CH:17][C:9]=1[O:8][CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(N)CO
Reactant: COc1cc(C(F)(F)F)cc(OC)c1C(=O)Cl
Solvent: O
Solvent: ClCCl
Product: COc1cc(C(F)(F)F)cc(OC)c1C(=O)NC(C)(C)CO
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.7 %

Procedure:
To a solution of 3.7 ml (37.22 mmol) 2-amino-2-methyl-1-propanol in 42 ml dichloromethane under nitrogen at 0° C., was added dropwise a solution of 5 g (18.61 mmol) 2,6-dimethoxy-4-trifluoromethyl-benzoyl chloride in 12 ml dichloromethane. The temperature rose to 7° C. The mixture was stirred at room temperature for 4 hours. The mixture was poured onto 75 ml water. The organic layer was separated and the aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to provide 5.66 g (yield: 94.6%) of the title compound as a yellow solid. MS (m/e): 322.2 (M+H').
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]2[CH2:17][O:16]2)=[CH:9][CH:8]=1)(C)(C)C.[CH3:20][C:21]1[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([N:28]2[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30][CH2:29]2)[N:22]=1>CC(O)C.CS(C)=O>[CH3:20][C:21]1[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([N:28]2[CH2:29][CH2:30][CH:31]([NH:34][CH2:17][CH:15]([OH:16])[CH2:14][O:13][C:10]3[CH:9]=[CH:8][C:7]([OH:6])=[CH:12][CH:11]=3)[CH2:32][CH2:33]2)[N:22]=1
Reactant: Cc1cc(C)nc(N2CCC(N)CC2)n1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(OCC2CO2)cc1
Solvent: CS(C)=O
Solvent: CC(C)O
Product: Cc1cc(C)nc(N2CCC(NCC(O)COc3ccc(O)cc3)CC2)n1
Yield: 64 %

Procedure:
Synthesis followed SP6 (iPrOH:DMSO 1:1, 120° C., 35 h), using 200 μmol tert-butyldimethyl(4-(oxiran-2-ylmethoxy)phenoxy)silane and 1-(4,6-dimethylpyrimidin-2-yl)piperidin-4-amine to give O-silylated intermediate upon purification by prep. HPLC (reversed phase) and prep. TLC (1 mm silica gel, PE/CH2Cl2/MeOH 6:4:1) with 64% yield. Product was obtained by deprotection according to SP7 and purification by prep. HPLC (reversed phase) and prep. TLC (1 mm silica gel, PE/CH2Cl2/MeOH 3:7:1.5) with 10% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][N:8]2[C:13]3[S:14][C:15]([CH:17]=C)=[CH:16][C:12]=3[C:11]3=[N:19][CH:20]=[N:21][N:10]3[C:9]2=[O:22])=[CH:5][CH:4]=1.I([O-])(=O)(=O)=[O:26].[Na+]>O1CCCC1.O.[Os](=O)(=O)(=O)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:13]3[S:14][C:15]([CH:17]=[O:26])=[CH:16][C:12]=3[C:11]3=[N:19][CH:20]=[N:21][N:10]3[C:9]2=[O:22])=[CH:23][CH:24]=1
Reactant: C=Cc1cc2c(s1)n(Cc1ccc(OC)cc1)c(=O)n1ncnc21
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Cn2c(=O)n3ncnc3c3cc(C=O)sc32)cc1
Reaction time: 4 h
Yield: 63.5 %

Procedure:
6-(4-Methoxybenzyl)-8-vinylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one (2.85 g; 8.42 mmol) was suspended in tetrahydrofuran (40 ml) and heated with a heat gun to effect dissolution. Similarly sodium periodate (4.14 g; 19.4 mmol) was heated in water (20 ml) to effect dissolution. The above solutions were combined with vigorous stifling. While the stirred mixture was still about 40° C., osmium(VIII) oxide (2.06 ml, 2.50% w/w, 0.21 mmol) was added and the mixture was stirred vigorously for 4 hours. The crude mixture was diluted with water (300 mL) and extracted with DCM (4×100). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The crude material was purified over silica gel (120 g) eluting with 0-30% IPA in ethyl acetate over 25 minutes. Product fractions were combined and concentrated to yield the aldehyde as a brown solid (1.82 g, 63%). 1H NMR (400 MHz, DMSO-d6) δ 3.75 (s, 3H), 5.40 (s, 2H), 6.94 (d, J=8.66 Hz, 2H), 7.45 (d, J=8.53 Hz, 2H), 8.58 (d, J=4.77 Hz, 2H), 9.95 (s, 1H). LCMS (MH+, 341.2).
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][CH2:6][CH2:7][CH2:8][S:9][C:10]1[O:11][CH:12]=[C:13]([CH3:15])[N:14]=1)=S.[N:16]#[C:17][NH2:18].[Pb]>>[C:17]([NH:18][C:3]([NH:2][CH3:1])=[N:5][CH2:6][CH2:7][CH2:8][S:9][C:10]1[O:11][CH:12]=[C:13]([CH3:15])[N:14]=1)#[N:16]
Reactant: N#CN
Reactant: CNC(=S)NCCCSc1nc(C)co1
Agent: [Pb]
Product: CNC(=NCCCSc1nc(C)co1)NC#N

Procedure:
Reaction of N-methyl-N'-[ 3-(4-methyl-2-oxazolyl)thiopropyl]thiourea with lead cyanamide by the procedure of Example 121 gives the title compound.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:13][CH2:12][C@H:11]([OH:14])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:15][S:16](Cl)(=[O:18])=[O:17].C(N(CC)CC)C>COC(C)(C)C>[Si:1]([O:8][C@@H:9]1[CH2:13][CH2:12][C@H:11]([O:14][S:16]([CH3:15])(=[O:18])=[O:17])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@H](O)C1
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@H](OS(C)(=O)=O)C1
Temperature: -5 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
Dissolve (-)-cis-3-tert-butyldimethylsilyloxy-cyclopentanol (9.20 g, 42.5 mmol) in anhydrous tert-butyl methyl ether (50 mL) and cool to -5° C. Treat the solution with methanesulfonyl chloride (3.6 g, 46.5 mmol, mesyl chloride), followed by triethylamine (7.2 mL, 51.7 mmol), at such a rate as to keep the temperature between -5° C. and -2° C. with an ice bath. The ice bath is removed and the solution is stirred for 2 hours. The mixture is then transferred to a separatory funnel and treated with brine/water (50 mL/50 mL). The layers are separated and the aqueous layer is extracted with tert-butyl methyl ether (2×50 mL). The organic layer and extracts are combined, washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide the title compound (12.1 g, 97% yield) as a colorless oil; 1 H NMR (CDCl3) δ 5.1 (m, 1 H), 4.2 (m, 1 H), 2.99 (s, 3 H), 2.3 (m, 1 H), 2.0 (m, 3 H), 1.8 (m, 2 H), 0.88 (s, 9 H), 0.05 (s, 6 H).
Reaction SMILES: [CH2:1]([S:3]([O-])=[S:4])[CH3:2].S[CH2:7][CH2:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])=[O:10].[OH-].[Na+]>C(O)C.O>[CH2:1]([S:3][S:4][CH2:7][CH2:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])=[O:10])[CH3:2]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)CCS
Reactant: CCS([O-])=S
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCSSCCC(=O)N1CCC[C@H]1C(=O)O

Procedure:
A solution of ethylthiosulfinate (8.4 g) in ethanol (50 ml) is added to an aqueous solution of 3-mercaptopropanoyl-L-proline (10 g) maintained at pH 6-7 by careful addition of sodium hydroxide. The mixture is stirred vigorously at room temperature until negative thiol reaction. The mixture is diluted with water, adjusted to pH 8 and extracted with ethyl acetate, the aqueous phase is acidified to pH 3 and extracted again with ethyl acetate. This latter extract is washed with water, dried and concentrated to dryness to yield 1-[3-(ethyldithio)propanoyl]-L-proline.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[C:9](Cl)(=[O:21])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].Cl>[OH-].[Na+]>[C:9]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])(=[O:21])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CCCCCCCCCCCC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCCCC(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 100.9 %

Procedure:
L-proline (11.6 g, 0.1 mol) was dissolved in 150 mL of 1M NaOH solution and cooled in an ice both. To this solution dodecanoyl chloride (24.1 g or 0.11 mol) and 200 mL of 1M NaOH solution were added simultaneously over a period of 20 min. The solution was stirred at room temperature for 45 min and acidified with concentrated HCl (pH 2-3). The solution was extracted with diethyl ether and the organic phase was washed with 12% NaCl solution. The organic phase was then dried over sodium sulfate and evaporated to provide 30 g of N-dodecanoyl-L-proline as an oil (100% yield) which was carried on without purification.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:12]([CH3:13])=[N+:11]([O-:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N+:4]=1[O-:15].[Br:16]Br>CO>[OH:1][CH2:2][C:3]1[C:12]([CH2:13][Br:16])=[N+:11]([O-:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N+:4]=1[O-:15]
Reactant: Cc1c(CO)[n+]([O-])c2ccccc2[n+]1[O-]
Reactant: BrBr
Solvent: CO
Product: [O-][n+]1c(CO)c(CBr)[n+]([O-])c2ccccc21
Reaction time: 48 h
Yield: 62 %

Procedure:
To a stirred suspension of 2-hyroxymethyl-3-methylquinoxaline-1,4-dioxide (10.3 g., 0.05 mole) in 100 ml. of methanol was added 1.5 ml. (0.055 mole) of bromine over a period of ten minutes at room temperature. The reaction mixture was then stirred for two days. The resulting yellow solid was collected, washed with methanol and ether, and air dried to give 8.9 g. (62 percent yield of the title compound, mp-138°-140°.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([NH:20][CH2:21][CH2:22][CH3:23])(=[O:19])=[O:18].[H-].[Na+].O>CS(C)=O>[Br:1][C:2]1[C:3]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[S:17]([NH:20][CH2:21][CH2:22][CH3:23])(=[O:19])=[O:18])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CCCNS(=O)(=O)c1ccccc1N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCNS(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Br
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of 5-bromo-2,4-dichloropyrimidine (90 μL, 0.70 mmol) and 2-amino-N-propyl-benzenesulfonamide (100 mg, 0.47 mmol), sodium hydride (54.2 mg, 0.56 mmol) in DMSO (1.0 mL) is added and the resulting solution is stirred at 80° C. for 3.0 h. The mixture is poured into water and extracted with ethyl acetate three times. The organic layer is washed with water and then brine, dried over sodium sulfate, and evaporated in vacuo. The residue is purified with silica gel column chromatography (n-hexane:ethyl acetate=5:1) to afford the title compound as a slightly yellow solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][C:12]1[C:13]([CH3:19])=[N:14][N:15]([CH3:18])[C:16]=1[CH3:17]>C(O)C.O>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:11][C:12]1[C:13]([CH3:19])=[N:14][N:15]([CH3:18])[C:16]=1[CH3:17])([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Cc1nn(C)c(C)c1N
Solvent: O
Solvent: CCO
Product: Cc1nn(C)c(C)c1Nc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 49.3 %

Procedure:
To a solution of 1-fluoro-2-nitrobenzene (7.47 mL, 70.9 mmol) in ethanol (35 mL) and H2O (105 mL) was added 4-amino-1,3,5-trimethylpyrazole (8.8 g, 70.9 mmol). The solution was refluxed for 15 h, then cooled to room temperature. The precipate was separated by filteration and washed with 25% aqueous ethanol to yield the title compound (8.6 g): 1HNMR (CDCl3, 300 MHz) δ 8.81 (s, 1H), 8.18 (dd, 2H, J=1.6, 8.7), 6.69(m, 1H) 6.61 (dd, 1H, J=1.2, 8.7), 3.77 (s, 3H), 2.10 (s, 3H), 2.06 (s, 3H); low resolution MS(FAB) m/z 247(MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C@H:10]([C:14]([OH:16])=[O:15])[CH:11]([CH3:13])[CH3:12].[Cl:17]N1C(=O)CCC1=O.C1C=CC=CC=1>CCCCCC>[CH3:8][C:4]1[CH:5]=[C:6]([Cl:17])[CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C@H:10]([C:14]([OH:16])=[O:15])[CH:11]([CH3:12])[CH3:13]
Reactant: Cc1cccc(C)c1N[C@H](C(=O)O)C(C)C
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCCCCC
Solvent: c1ccccc1
Product: Cc1cc(Cl)cc(C)c1N[C@H](C(=O)O)C(C)C
Reaction time: 8 h

Procedure:
A mixture of 0.5 g of the m-phenoxybenzyl ester of N-(2,6-dimethylphenyl)valine, 0.21 g of N-chlorosuccinimide and 3 ml of benzene is heated at reflux for 2 hours. The reaction is diluted with hexane, washed with water (2×) and solvent stripped to give the crude product. To the crude product is added 0.1 g of N-chlorosuccinimide and 3 ml benzene. The mixture is heated at reflux for 30 min and then allowed to stand overnight at RT. The reaction is worked up by diluting with hexane, washing with water and stripping off solvent to yield the m-phenoxybenzyl ester of N-(2,6-dimethyl-4-chlorophenyl)valine, MS m/e 437.1 (M+, 15.3).