Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([N:7]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:8][C@@H:9]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[S:5][CH:6]=1.[CH3:36][C:37]([OH:41])([C:39]#[CH:40])[CH3:38]>CCN(CC)CC.Cl[Pd-2](Cl)(P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[OH:41][C:37]([CH3:38])([CH3:36])[C:39]#[C:40][C:2]1[N:3]=[C:4]([N:7]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:8][C@@H:9]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[S:5][CH:6]=1
Reactant: C#CC(C)(C)O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(F)(F)F)cc1)CN(C(=O)OC(C)(C)C)c1nc(Br)cs1
Agent: Cl[Pd-2](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC(C)(O)C#Cc1csc(N(C[C@H](Cc2ccc(C(F)(F)F)cc2)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 91.6 %

Procedure:
(S)-tert-butyl 1-(N-(4-bromothiazol-2-yl)-tert-butoxylcarbonylamino)-3-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamate (0.25 g, 0.43 mmol) was taken up in 4 mL of Et3N. 2-Methylbut-3-yn-2-ol (0.21 mL, 2.2 mmol), dichlorobis(triphenylphosphino)-palladium(II) (0.030 g, 0.043 mmol), and copper(I) iodide (0.025 g, 0.13 mmol) were added. The mixture was stirred for 20 minutes. No reaction was observed, and the mixture was heated to 60° C. for 1 hour. The reaction was judged to be complete by LC/MS, the solvent was removed under reduced pressure, and the residue was purified by flash chromatography on silica gel (5% to 30% EtOAc/hexanes), to provide (S)-tert-butyl 1-(N-(4-(3-hydroxy-3-methylbut-1-ynyl)thiazol-2-yl)-tert-butoxylcarbonylamino)-3-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamate (0.23 g, 91% yield): LCMS (M+H) 584 calc. for C28H37F3N3O5S 583.6.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:10]([OH:12])=O)[N:8]=1)=[O:2].CN(C)C=O.P(Cl)(Cl)(Cl)=O.[NH2:31][CH:32]1[C:52](=[O:53])[N:34]2[C:35]([C:39]([O:41][CH2:42][C:43]3[CH:48]=[CH:47][C:46]([N+:49]([O-:51])=[O:50])=[CH:45][CH:44]=3)=[O:40])=[CH:36][CH2:37][S:38][C@H:33]12>O.CC(C)=O.O1CCCC1>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:10]([NH:31][CH:32]2[C:52](=[O:53])[N:34]3[C:35]([C:39]([O:41][CH2:42][C:43]4[CH:44]=[CH:45][C:46]([N+:49]([O-:51])=[O:50])=[CH:47][CH:48]=4)=[O:40])=[CH:36][CH2:37][S:38][C@H:33]23)=[O:12])[N:8]=1)=[O:2]
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12
Reactant: O=CNc1nc(C(=NOC2CCCCC2)C(=O)O)cs1
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=CNc1nc(C(=NOC2CCCCC2)C(=O)NC2C(=O)N3C(C(=O)OCc4ccc([N+](=O)[O-])cc4)=CCS[C@H]23)cs1
Yield: 90.8 %

Procedure:
2-(2-Formamidothiazol-4-yl)-2-cyclohexyloxyiminoacetic acid (syn isomer, 0.9 g.), N,N-dimethylformamide (266 mg.), phosphoryl chloride (557 mg.), tetrahydrofuran (20 ml.), 4-nitrobenzyl 7-amino-3-cephem-4-carboxylate (1.05 g.), acetone (3 ml.) and water (3 ml.) were treated in a similar manner to that of Example 15-(1) to give 4-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-cyclohexyloxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 1.69 g.).
Reaction SMILES: NC(N)=[S:3].[ClH:5].Cl.[CH2:7]([N:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][Cl:23])[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[OH-].[Na+]>O.C(O)C>[ClH:23].[ClH:5].[CH2:7]([N:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][SH:3])[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NC(N)=S
Reactant: ClCCCN1CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: SCCCN1CCN(Cc2ccccc2)CC1
Yield: 78 %

Procedure:
15 g of thiourea were added to a solution of 35 g of -benzyl-4-(3-chloropropyl)piperazine dihydrochloride, 20 g of triethylamine and 250 ml of reagent ethanol, and the mixture was refluxed for 8 hours. After the addition of a solution of 10 g of sodium hydroxide in 50 ml of water, the resulting mixture was refluxed for 4 additional hours. The ethanol was removed in vacuo, and water added to the residue which was extracted with methylene chloride, dried (sodium sulfate), and the salt was precipitated with ethereal hydrochloric acid to give 25.1 g (78% of theory) of 3-(4-benzylpiperazin-1-yl)propanethiol dihydrochloride as a white crystalline solid, M.p. 270°-273° C. (dec.).
Reaction SMILES: [N:1]([N:3]([CH2:10][CH2:11][CH3:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.C(NC1C=CC=CC=1)CC.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[C:4]1([N:3]([CH2:10][CH2:11][CH3:12])[NH2:1])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCCN(N=O)c1ccccc1
Agent: CCCNc1ccccc1
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CCCN(N)c1ccccc1
Reaction time: 3 h

Procedure:
N-nitroso-N-propylaniline, prepared from N-n-propylaniline by the same method as described in Example 1, was conveniently reduced with lithium aluminum hydride (LAH). The LAH in 450 ml dry ether was heated under reflux for 15 minutes, and a solution of 32.8 g (0.2 mol) crude 4 in 250 ml dry ether was added dropwise. The reaction mixture was allowed to stir for 3 hours before it was quenched by the dropwise addition of 12 ml water and 14 ml 20% sodium hydroxide. The resultant suspension was filtered free of inorganic salts, dried and stripped of solvents under diminished pressure. Distillation of the residue yielded the desired compound bp 55°-57°/0.12 mm.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=2[CH:17]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[C:31]([S:32]([CH:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])=[CH:30][CH:29]=[CH:28][C:27]=2[F:38])[C:22]([Cl:39])=[CH:21][N:20]=1>>[Cl:39][C:22]1[C:23]([NH:25][C:26]2[C:31]([S:32]([CH:35]([CH3:36])[CH3:37])(=[O:34])=[O:33])=[CH:30][CH:29]=[CH:28][C:27]=2[F:38])=[N:24][C:19]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:12])([CH3:13])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=3[CH:17]=2)=[N:20][CH:21]=1
Reactant: CCN1C(=O)CCC(C)(C)c2ccc(N)cc21
Reactant: CC(C)S(=O)(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: CCN1C(=O)CCC(C)(C)c2ccc(Nc3ncc(Cl)c(Nc4c(F)cccc4S(=O)(=O)C(C)C)n3)cc21

Procedure:
Title compound was prepared from 8-Amino-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and (2,5-Dichloro-pyrimidin-4-yl)-[2-fluoro-6-(propane-2-sulfonyl)-phenyl]-amine in an analogous manner to Example 1221d. Product was obtained as a white foam. (12 mg, 8%). LCMS 562.18 (M+H), HPLC purity 99%, 1H-NMR (CDCl3, 400 MHz) δ 8.27 (s, 1H), 8.17 (s, 1H), 7.81 (d, J=7.1 Hz), 7.49-7.42 (m, 3H), 7.20 (d, J=6.5 Hz, 1H), 7.13 (d, J=8.3 Hz, 1H), 6.99 (s, 1H), 3.75-3.65 (bs, 2H), 3.13-3.03 (m, 1H), 2.29-2.24 (m, 2H), 1.67-1.61 (m, 2H), 1.33 (s, 6H), 1.25 (d, J=6.7 Hz, 6H), 1.20 (t, J=7.0 Hz, 3H).
Reaction SMILES: S(Cl)(Cl)=O.O[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[N:8][C:7]=1[C:16]([O:18]C)=O.[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([NH:29][NH2:30])=[CH:25][CH:24]=1)([O-:22])=[O:21]>C(O)C>[N+:20]([C:23]1[CH:24]=[CH:25][C:26]([N:29]2[C:16](=[O:18])[C:7]3[N:8]=[N:9][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[C:6]=3[NH:30]2)=[CH:27][CH:28]=1)([O-:22])=[O:21]
Reactant: NNc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)c1nnc2ccccc2c1O
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: O=c1c2nnc3ccccc3c2[nH]n1-c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Thionyl chloride (326 g, 200 ml) was added dropwise under inert atmosphere to methyl 4-hydroxycinnoline-3-carboxylate (10.0 g, 49 mmol). The mixture was heated to reflux for 2.5 h, cooled to room temperature and excess thionyl chloride was removed under vacuum. Toluene (100 ml) was added to the residue and removed under vacuum. This procedure was repeated with further toluene (100 ml). A brown semi-solid material was obtained and taken up in ethanol (200 ml). 4-Nitrophenylhydrazine (5.99 g, 39.2 mmol) was added portionwise. The mixture was stirred at room temperature overnight. The mixture was heated to 40-45° C. for 1 h and cooled to room temperature. The solids were collected by filtration, triturated with ethanol (100 ml) and dried under vacuum. The title compound was isolated as a brown solid (8.42 g, 27.4 mmol, 70%). LCMS: m/z 308 [M+H]+.
Reaction SMILES: S(Cl)(Cl)=O.C([O:8][C:9]1[CH:29]=[CH:28][C:12]([CH2:13][C:14]([NH:16][C@H:17]([C:25]([OH:27])=[O:26])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[S:15])=[CH:11][CH:10]=1)(=O)C.[CH3:30]O>>[CH3:30][O:27][C:25](=[O:26])[C@H:17]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[NH:16][C:14]([CH2:13][C:12]1[CH:28]=[CH:29][C:9]([OH:8])=[CH:10][CH:11]=1)=[S:15]
Reactant: CO
Reactant: CC(=O)Oc1ccc(CC(=S)N[C@@H](Cc2ccccc2)C(=O)O)cc1
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=S)Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3 Ml of thionyl chloride was dropwise added to 100 ml of anhydrous methanol at a temperature below -10° C. To the mixture was added 6 g (0.016 mol) of N-(4-acetoxybenzylthiocarbonyl)-L-phenylalanine synthesized according to Example 3. After the mixture was stirred at room temperature overnight, the solvent was evaporated under reduced pressure to obtain crude crystal. Further, the crude crystal was recrystallized from 30 ml ethyl acetate and 100 ml of n-hexane to obtain 5.1 g of white purified crystal.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([CH:8]([CH3:10])[CH3:9])[N:4]=1.[OH:11][CH:12]1[CH2:16][CH2:15][NH:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[OH:11][CH:12]1[CH2:16][CH2:15][N:14]([CH2:2][C:3]2[O:7][N:6]=[C:5]([CH:8]([CH3:10])[CH3:9])[N:4]=2)[CH2:13]1
Reactant: OC1CCNC1
Reactant: CC(C)c1noc(CCl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)c1noc(CN2CCC(O)C2)n1
Temperature: 65 °C
Yield: 81.4 %

Procedure:
A mixture of 5-chloromethyl-3-isopropyl-[1,2,4]oxadiazole (1.6 g, 10 mmol) and (RS)-3-hydroxypyrrolidine (960 mg, 11 mmol) were combined neat, diluted with MeCN (10 mL), and K2CO3 (2.75 g, 20 mmol) was added. The mixture was heated at 65° C. for 1 h, and was filtered upon cooling. The solvent was removed and the residue was taken up in CH2Cl2 and rinsed with water. The organic extract was dried over MgSO4, the solvent was removed, and the residue was taken up in ether and filtered in order to remove a small amount of quaternary ammonium byproduct. Solvent removal from the filtrate gave (RS)-3-hydroxy-1-[(3-isopropyl-1,2,4-oxadiazol-5-yl)methyl]pyrrolidine as an amber oil (1.72 g, 82% yield): 1H NMR (DMSO-d6) δ 4.76 (d, 1H, J=4.5 Hz), 4.19 (m, 1H), 3.90 (s, 2H), 3.05 (m, 1H), 2.79 (m, 1H), 2.69 (m, 1H), 2.53 (m, 1H), 2.43 (m, 1H), 1.98 (m, 1H), 1.54 (m, 1H), 1.25 (d, 6H, J=6.8 Hz); MS m/z 212.1 (M+).
Reaction SMILES: C([Li])CCC.CCCCCC.C(NC(C)C)(C)C.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28].[CH3:34][O:35][C:36]1[CH:37]=[C:38]([C:44]([CH:51]([CH3:53])[CH3:52])([CH2:47][CH2:48][CH2:49]Cl)[C:45]#[N:46])[CH:39]=[CH:40][C:41]=1[O:42][CH3:43].Cl>C1COCC1.O.CN(C)P(N(C)C)(N(C)C)=O>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH2:29][CH:30]([C:31]([OH:33])=[O:32])[CH2:49][CH2:48][CH2:47][C:44]([C:45]#[N:46])([CH:51]([CH3:52])[CH3:53])[C:38]2[CH:39]=[CH:40][C:41]([O:42][CH3:43])=[C:36]([O:35][CH3:34])[CH:37]=2)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: COc1ccc(C(C#N)(CCCCl)C(C)C)cc1OC
Reactant: COc1ccc(CCC(=O)O)cc1OC
Agent: Cl
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Solvent: CC(C)NC(C)C
Product: COc1ccc(CC(CCCC(C#N)(c2ccc(OC)c(OC)c2)C(C)C)C(=O)O)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
A 1.6M solution of n-butyllithium in hexane (91.8 mL, 147 mmol) was added to a -20° C. solution of diisopropylamine (21 mL, 150 mmol) in THF (480 mL). Hexamethylphosphoramide (56 mL) was added and the mixture maintained at -20° C. while a solution of 3-(3,4-dimethoxyphenyl)propionic acid (15.1 g, 72 mmol) in THF (75 mL) was added. The resulting solution was stirred at room temperature for one hour, and then cooled to -50° C. A solution of 2-(3,4-dimethoxyphenyl)-2-isopropyl-2-(3-iodopropyl)acetonitrile (22, 27.9 g, 72 mmol) was added, and the mixture allowed to warm to room temperature while stirring for 12 hours. The resulting mixture was added to water, acidified with HCl, and extracted three times with ether. The organic layer was washed with aqueous Na2SO3 and brine, dried over Na2SO4, and evaporated to yield 1-(3,4-dimethoxyphenyl)-2-carboxy-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)hexane (23, 31 g) as a thick oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:26]=[C:25]([CH2:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[CH2:35][C:36]([O-])=[O:37])[C:24]([C:39]([F:42])([F:41])[F:40])=[CH:23][N:22]=3)=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].O[N:45]1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.C(N(CC)C(C)C)(C)C.C(=O)([O-])[O-].[NH4+].[NH4+]>C1COCC1.CN(C=O)C>[NH2:45][C:36](=[O:37])[CH2:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH2:28][CH2:27][C:25]1[C:24]([C:39]([F:40])([F:41])[F:42])=[CH:23][N:22]=[C:21]([NH:20][C:17]2[CH:18]=[CH:19][C:14]([CH:10]3[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]3)=[CH:15][CH:16]=2)[N:26]=1
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(=O)[O-])n3)cc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)cc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77 %

Procedure:
Lithium 2-(2-(2-(2-((4-(1-(tert-butoxycarbonyl)piperidin-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetate (I27) (0.246 g, 0.416 mmol) was dissolved in dry THF (10 mL) and dry DMF (2 mL) under an atmosphere of nitrogen. To the solution were added 1-hydroxybenzotriazole (0.067 g, 0.50 mmol) and EDCl (0.096 g, 0.50 mmol) and N,N-diisopropylethylamine (0.290 mL, 1.66 mmol) and the reaction mixture was stirred at room temperature for 10 minutes. Ammonium carbonate (0.160 g, 1.66 mmol) was added in one portion, and the reaction was stirred at room temperature for 45 hours. The volatiles were removed in vacuo and the residual solution was diluted with EtOAc (70 mL) and sat. aq. NaHCO3 (70 mL). The layers were separated and the aqueous layer was extracted with EtOAc (70 mL), the combined organic layers were washed with water (70 mL), brine (70 mL), dried (MgSO4), filtered and concentrated in vacuo to give an off-white solid. The crude product was purified by silica gel chromatography (Biotage Isolera, 40 g Si Cartridge, 0-100% EtOAc in petroleum benzine 40-60° C., then 0-10% methanol in EtOAc) to give the title compound (I28) (0.186 g, 77% yield) as a white solid; 1H NMR (400 MHz, d6-DMSO) δ 10.17 (s, 1H), 8.67 (s, 1H), 7.69 (d, J=8.6 Hz, 2H), 7.44 (brs, 1H), 7.28-7.11 (m, 6H), 6.93 (br s, 1H), 4.02-3.89 (m, 2H), 3.50 (s, 2H), 3.15-3.07 (m, 2H), 3.06-2.98 (m, 2H), 2.89-2.67 (m, 2H), 2.61-2.51 (m, 1H), 1.88 (d, J=11.1 Hz, 1H), 1.74-1.55 (m, 2H), 1.50-1.35 (m, 10H). LCMS Method C: rt 6.57 min; m/z 584.3 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH:27]2[CH2:29][CH2:28]2)[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[O:30]1[C:34]2[CH:35]=[CH:36][C:37](B(O)O)=[CH:38][C:33]=2[CH2:32][CH2:31]1.N1C=CC=CC=1.C(N(CC)CC)C>C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[CH2:1]([C:5]1[N:6]=[C:7]([CH:27]2[CH2:28][CH2:29]2)[N:8]([C:37]2[CH:36]=[CH:35][C:34]3[O:30][CH2:31][CH2:32][C:33]=3[CH:38]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: OB(O)c1ccc2c(c1)CCO2
Reactant: CCCCc1nc(C2CC2)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCCc1nc(C2CC2)n(-c2ccc3c(c2)CCO3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 48 h
Yield: 98.9 %

Procedure:
A mixture of 4′-[(4-butyl-2-cyclopropyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (0.58 g), 2,3-dihydro-1-benzofuran-5-ylboronic acid (0.49 g), copper(II) acetate (0.55 g), pyridine (0.61 mL), triethylamine (1.1 mL), molecular sieves 4 A (1.2 g) and dichloromethane (12 mL) was stirred for 2 days. The reaction mixture was diluted with ethyl acetate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (0.75 g, 100%) as a pale-yellow liquid.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13]O.S(Cl)([Cl:17])=O>ClCCl.O>[Cl:17][CH2:13][C:3]1[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][O:6][C:2]=1[CH3:1]
Reactant: O=S(Cl)Cl
Reactant: Cc1onc(-c2ccccc2)c1CO
Solvent: O
Solvent: ClCCl
Product: Cc1onc(-c2ccccc2)c1CCl
Temperature: 0 °C
Reaction time: 2 h
Yield: 9.4 %

Procedure:
To a solution of (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (4.5 g, 236 mmol) in dichloromethane (50 mL) was added at 0° C. thionyl chloride (3.6 g, 2.7 mL, 306 mmol) dropwise over 3 min and the solution stirred at 0° C. for 2 h. After this time, the mixture was diluted with water (50 mL) and the organic phase separated and washed with brine. The aqueous phase was extracted with dichloromethane and the combined extracts dried over sodium sulfate, filtered and evaporated to afford the title compound (4.6 g, 93%) which was obtained as a light brown liquid. MS: m/e=208.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([S-:5])([CH3:4])[CH3:3].[Na+].[CH3:7][S:8](Cl)(=[O:10])=[O:9]>O1CCCC1.ClCCl>[CH3:7][S:8](=[O:10])([S:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:9]
Reactant: CC(C)(C)[S-]
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)SS(C)(=O)=O
Temperature: -60 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
Tetrahydrofuran (100 ml) was added to sodium 2-methyl-2-propanethiolate (7.83 g, 69.8 mmol), and the mixture was cooled to −60° C. or lower. A solution of methanesulfonyl chloride (6.77 ml, 87.0 mmol) in tetrahydrofuran (50 ml) was added dropwise to this suspension over 25 minutes. The reaction solution was gradually warmed to room temperature over 2 hours and stirred at room temperature for additional 1 hour. The reaction solution was diluted with dichloromethane (300 ml) and washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford S-tert-butyl methanesulfonothioate (Compound SP684) (11.17 g, 76%). The obtained compound was confirmed based on the compound data described in Non patent literature (Inorganic Chemistry, 2010, 49, 8637-8644).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1>>[CH3:21][O:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][C:16]=1[O:22][CH3:23])[N:13]=[CH:12][N:11]=[C:10]2[S:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[NH2:1]
Reactant: Nc1cccc(S)c1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Product: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Yield: 103.8 %

Procedure:
3-Aminothiophenol (1.42 mL, 13.3 mmol) and 4-chloro-6,7-dimethoxyquinazoline (3.0 g, 13.3 mmol) were reacted using the procedure described in Example 46 to give 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (4.32 g, 13.8 mmol, 100% (wet with H2O)). 1H NMR (300 MHz, DMSO-d6) δ 8.70 (s, 1H), 7.33 (s, 1H), 7.31 (s, 1H), 7.13 (t, 1H), 6.80 (s, 1H), 6.73 (d, 1H), 6.68 (d, 1H), 5.34 (br s, 2H), 3.98 (s, 3H), 3.97 (s, 3H); LC-MS (ESI) m/z 314 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:16]=[CH:15][C:14]2[C:13](=O)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=O)[C:5]=2[CH:4]=1.[NH4+].[OH-].Cl>CC(O)C.[Zn]>[CH:4]1[C:5]2[C:14](=[CH:13][C:12]3[C:7]([CH:6]=2)=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:15]=[CH:16][C:3]=1[CH2:2][OH:1]
Reactant: O=C1c2ccccc2C(=O)c2cc(CO)ccc21
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(C)O
Product: OCc1ccc2cc3ccccc3cc2c1

Procedure:
To a 2 L 3-neck flask fitted with condenser, thermometer and overhead stirrer was added 2-(hydroxymethyl)anthraquinone (Aldrich, 20 g, 0.084 mol), Zn dust (Mallinckrodt, 50 g, 0.765 mol), CuSO4.5H2O (Mallinckrodt, 0.5 g), and 28% NH4OH (Mallinckrodt, 600 mL). The temperature was increased to 80°, and the initial dark-red color faded (about 3 h). After refluxing for an additional 30 min, the mixture was filtered. The filtrate was treated with conc. HCl until acidic, and the resulting precipitate collected. The zinc solid was extracted with EtOAc until the washings were clear, and the EtOAc removed to give an oil. The oil and the precipitate were added to a mixture of conc. HCl (12 ml) in i-PrOH (1200 mL). This solution was concentrated by rotary evaporation to near dryness and CH3OH (100 mL) was added to give after filtration and drying 13.48 g (77%) of (2-anthracenyl)methanol mp 218°-221° (lit mp 223°-224°, P. Arjunan and K. D. Berlin, Org. Prep. and Procedure., 13(5), 368 (1981)).
Reaction SMILES: CO[C:3](=[O:28])[CH:4]([N:13]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1.O.[OH-].[Li+].Cl.[NH:33]1[CH2:38][CH2:37][CH:36]([N:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)[CH2:35][CH2:34]1.C(N(CC)CC)C.[PH2](Cl)=O>CO.O>[N:39]1([CH:36]2[CH2:37][CH2:38][N:33]([C:3](=[O:28])[CH:4]([N:13]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH2:5][N:6]3[CH2:7][CH2:8][CH:9]([OH:12])[CH2:10][CH2:11]3)[CH2:34][CH2:35]2)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: COC(=O)C(CN1CCC(O)CC1)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=[PH2]Cl
Agent: [Li+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C(CN1CCC(O)CC1)C(=O)N1CCC(N2CCCCC2)CC1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
To a solution of 2-(di-tert-butoxycarbonylamino)-3-(4-hydroxy-piperidin-1-yl)-propionic acid methyl ester (1.0 g, 2.5 mmol) in methanol (6 mL) was added a solution of lithium hydroxide monohydrate (400 mg, 3.9 equiv) in water (1 mL). The reaction was stirred 6 h, cooled to 0° C., neutralized with concentrated hydrochloric acid, and concentrated. The crude acid was used without purification. The crude acid was suspended in methylene chloride (25 mL), treated with a few drops of methanol to aid in dissolving the acid, and cooled to 0° C. The resulting suspension was treated sequentially with 4-piperidyl-piperidine (0.53 g, 1.25 equiv), triethylamine (0.70 mL, 2.0 equiv), and bis-2-oxo-3-oxazolidinyl)phoshinic chloride (0.80 g, 1.25 equiv). The reaction was allowed to warm to room temperature overnight. The reaction was concentrated and then purified by Prep HPLC to afford 310 mg (23%, 2 steps). Mass spec.: 539.49 (MH)+.