Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([C:8](O)=O)[CH2:3][CH2:4][C:5]([OH:7])=O.N[C@@H:12]([C:17]([OH:19])=[O:18])CC(=O)N.N[C@@H:21](C(O)=O)CC(O)=O.N[C@@H](C(O)=O)CS.N[C@@H](C(O)=O)CCC(=O)N.N[C@H](C(O)=O)[C@@H](C)O>O>[OH:7][C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH2:12][C:17]([OH:19])=[O:18])=[CH:8][CH:21]=1
Reactant: N[C@H](CCC(=O)O)C(=O)O
Reactant: NC(=O)C[C@@H](N)C(=O)O
Reactant: N[C@H](CC(=O)O)C(=O)O
Agent: C[C@@H](O)[C@H](N)C(=O)O
Agent: NC(=O)CC[C@@H](N)C(=O)O
Agent: N[C@H](CS)C(=O)O
Solvent: O
Product: O=C(O)CNc1ccc(O)cc1

Procedure:
We have found that addition of D-glutamic acid (D-GLU), D-asparagine (D-ASN), D-aspartic acid (D-ASP), or D-cysteine (D-CYS), or D-glutamine (D-GLN) in small amounts to a supersaturated solution of threonine in water brings about a preferred crystallization of the threonine in its L-form. Similarly, inclusion of the L-forms of the above additives leads to preferred crystallization of D-threonine. Further, we have found that from a supersaturated aqueous solution of D,L-asparagine, on addition of D-aspartic acid, D-glutamic acid of D-glutamine, there results a preferred crystallization of L-asparagine monohydrate; inclusion of the L-additives leads to preferred crystallization of D-asparagine monohydrate. Further, we have found that addition of L-tyrosine (TYR), L-tyrosine-p-toluene sulfonate (TpTS), L-dopa, L-dopa-p-toluene sulfonate (DpTS), L-α-methyl dopa, L-α-methyl dopa-p-toluene sulfonate (MDpTS), L-phenylalanine (PHE), L-phenylalanine-p-toluene sulfonate (PpTS), L-phenyl glycine (PG), L-phenyl glycine p-toluene sulfonate (PGpTS), L-p-methoxy phenyl glycine (pMPG) or L-p-methoxy phenyl glycine p-toluene sulfonate (pMPGpTS) to a supersaturated solution of pHPGpTS in an 0.5N aqueous solution of p-toluene sulfonic acid causes preferred precipitation of the D-form of pHPGpTS. On acidification the corresponding enantiomer of p-hydroxyphenylglycine can be obtained. Inclusion of the D-additives causes preferred precipitation of the L-form of pHPGpTS.
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[N:13]=[C:12]([NH:14][CH3:15])[N:11]=[C:10]([C:16]2[CH:23]=[C:22]([O:24][CH3:25])[C:19]([C:20]#[N:21])=[C:18](F)[CH:17]=2)[CH:9]=1)[CH3:2].CCN(C(C)C)C(C)C.[NH2:36][NH2:37]>CCO>[CH2:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[N:13]=[C:12]([NH:14][CH3:15])[N:11]=[C:10]([C:16]2[CH:17]=[C:18]3[C:19]([C:20]([NH2:21])=[N:36][NH:37]3)=[C:22]([O:24][CH3:25])[CH:23]=2)[CH:9]=1)[CH3:2]
Reactant: CC[C@@H]1CCCN1c1cc(-c2cc(F)c(C#N)c(OC)c2)nc(NC)n1
Reactant: NN
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@@H]1CCCN1c1cc(-c2cc(OC)c3c(N)n[nH]c3c2)nc(NC)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 52.5 %

Procedure:
In a microwave tube, 4-[6-[(2R)-2-ethyl-1-pyrrolidinyl]-2-(methylamino)-4-pyrimidinyl]-2-fluoro-6-(methyloxy)benzonitrile (129 mg, 0.363 mmol), 5 mL of EtOH, Hunig's base (0.063 mL, 0.363 mmol), and hydrazine anhydrous (0.068 mL, 2.178 mmol) were added. The yellow suspension mixture was heated to 100° C. in an oil bath overnight. When the temperature of the reaction reached 100° C., the solid in the mixture was all dissolved. After overnight, there was a white colored solid formed. LCMS showed no more starting material. The reaction was cooled to room temperature, then the white solid was filtered from the yellow solution, washed by CH3CN (2 mL), and dried under reduced pressure to afford the title compound (70 mg) as a white solid. LC-MS (ES) m/z=368 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.90 (t, J=7.3 Hz, 3H), 1.37 (m, 1H), 1.80 (m, 2H), 1.93 (m, 3H), 2.82 (d, J=4.6 Hz, 3H), 3.39 (m, H), 3.47-3.63 (m, 1H), 3.93 (s, 3H), 4.05 (m, 1H), 5.02 (s, 2H), 6.19 (s, 1H), 6.41 (s, 1H), 6.92 (s, 1H), 7.46 (s, 1H), 11.51 (s, 1H).
Reaction SMILES: [C:1]([CH:6]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=O)([O:3]CC)=O.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][NH2:22])=[C:17]([F:23])[CH:16]=1.C1(C)C=CC=CC=1.C(O)(=O)C>O>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:1](=[O:3])[C:6]3[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]=3[NH:22]2)=[C:17]([F:23])[CH:16]=1
Reactant: NNc1ccc(Cl)cc1F
Reactant: CCOC(=O)C1CCCCCC1=O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: O=c1c2c([nH]n1-c1ccc(Cl)cc1F)CCCCC2

Procedure:
A mixture of 9.3 parts of 2-carbethoxycycloheptanone [prepared by the method of G. Stork, et al., J. Am. Chem. Soc., 85, 207 (1963)], 8.1 parts of 4-chloro-2-fluorophenyl hydrazine, 100 parts of toluene and 0.5 parts of acetic acid was refluxed for 4 hours until all water was evolved. The resulting solution was cooled to -50° and filtered to yield 12 parts of 2-(4-chloro-2-fluorophenyl)-1,4,5,6,7,8-hexahydrocycloheptapyrazol-3(2H)-one melting at 197°-201°. Four parts of the pyrazolone was mixed with 4.4 parts of phosphorous oxybromide and 2.2 parts of N,N-diethylaniline in 200 parts of xylene and the mixture refluxed for 3 hours. 0.5 Part of N,N-dimethyl formamide was added and the mixture refluxed for 1 hour. The mixture was poured over 100 parts of ice and the phases separated. The organic phase was evaporated under reduced pressure of 50 mm. Hg at 70° to a crude product. The product was dissolved in 100 parts of chloroform, washed with 100 parts of 10% aqueous sodium carbonate, dried with anhydrous magnesium sulfate and evaporated to an oil under reduced pressure of 500 mm. Hg at 40°. Purification by chromatography on alumina using 3% ether in hexane as the eluent gave 0.8 parts of 3-bromo-2-(4-chloro-2-fluorophenyl)-2,4,5,6,7,8-hexahydrocycloheptapyrazole melting at 59°-60°.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.S(Cl)([Cl:13])=O>ClCCl.CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:13])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(Br)cc1

Procedure:
A mixture of 100 g (0.497 mole) of 4-bromobenzoic acid and 100 g of thionyl chloride in 300 ml of dichloromethane containing a few drops of N,N-dimethylformamide was heated at reflux for two days. The low boiling liquid were then removed by evaporation, and the remaining liquid was distilled to provide 4-bromobenzoyl chloride.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]([C:16]([OH:18])=O)[N:7]=1.C(N(CC)CC)C.ClC(OCC)=O.[CH3:32][NH:33][CH:34]([CH2:36][CH3:37])[CH3:35]>C(Cl)(Cl)Cl>[CH3:32][N:33]([CH:34]([CH3:35])[CH2:36][CH3:37])[C:16]([C:8]1[N:7]=[C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[C:15]2[C:10]([CH:9]=1)=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:18]
Reactant: O=C(O)c1cc2ccccc2c(-c2cccs2)n1
Reactant: CCC(C)NC
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCC(C)N(C)C(=O)c1cc2ccccc2c(-c2cccs2)n1
Yield: 65.6 %

Procedure:
Operations are carried out as for Example 7, starting from 3 g of 1-(2-thienyl) isoquinoline 3-carboxylic acid, 1.73 g of triethylamine, 1.86 g of ethyl chloroformate and 1.69 g of N-methyl 2-butanamine in 150 ml of chloroform. 2.5 g of N-methyl N-(1-methyl propyl) 1-(2-thienyl) isoquinoline 3-carboxamide, melting at 146° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10](Cl)[C:9]2[C:4](=[C:5]([CH3:15])[CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.ClC1C=C([O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)C2C(=C(Cl)C(OC)=CC=2)N=1>>[Cl:1][C:2]1[CH:11]=[C:10]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[C:9]2[C:4](=[C:5]([CH3:15])[CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1
Reactant: COc1ccc(COc2cc(Cl)nc3c(Cl)c(OC)ccc23)cc1
Reactant: COc1cc(C)c2nc(Cl)cc(Cl)c2c1
Product: COc1ccc(COc2cc(Cl)nc3c(C)cc(OC)cc23)cc1
Yield: 58 %

Procedure:
Compound 221f was synthesized from compound 220f as a white solid in 58% yield, following the procedure as described for compound 221d. 1H NMR (CDCl3, 400 MHz) δ (ppm) 2.68 (s, 3H), 3.80 (s, 3H), 3.83 (s, 3H), 5.11 (s, 2H), 6.72 (s, 1H), 6.97 (d, J=9.03 Hz, 2H), 7.15 (dd, J=3.01 Hz and J=0.96 Hz, 1H), 7.20 (d, J=3.00 Hz, 1H), 7.40 (d, J=9.03 Hz, 2H).
Reaction SMILES: C[C@H]1O[C@H]([O:8][C@@H:9]2[C@@H:14]([OH:15])[C@@H:13]([OH:16])[C@H:12]([OH:17])[C@H:11]([OH:18])[C@H:10]2[OH:19])[C@@H](N)C[C@@H]1NC(C(O)=O)=N.FC(F)(F)C(O)=O>>[CH:9]1([OH:8])[CH:10]([OH:19])[CH:11]([OH:18])[CH:12]([OH:17])[CH:13]([OH:16])[CH:14]1[OH:15]
Reactant: C[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H]2O)[C@@H](N)C[C@@H]1NC(=N)C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: OC1C(O)C(O)C(O)C(O)C1O

Procedure:
The need for investigational and commercial quantifies of D-chiro-inositol has led to the development of several methods for the isolation (by extraction from plant tissues), partial synthesis or complete synthesis of that compound. Especially promising is hydrolysis of the aminoglycoside kasugamycin (produced by fermentation of Streptomyces kasugaspinus) as described in U.S. Pat. No. 5,091,596 issued to Kennington et al. According to that patent, kasugamycin is treated with trifluoroacetic acid for 3 hours at 100° C., after which the resulting D-chiro-inositol is isolated by resin and gel chromatography and purified by recrystallization from 90% ethanol. Alternatively, kasugamycin may be treated with hydrochloric acid for 8 hours at 90° C., followed by isolation of the D-chiro-inositol by resin chromatography and subsequent purification.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1.C1C(=O)N([I:19])C(=O)C1>C(#N)C.C(OCC)(=O)C>[I:19][C:6]1[N:2]([CH3:1])[C:3]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)=[N:4][CH:5]=1
Reactant: Cn1ccnc1-c1cccs1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cn1c(I)cnc1-c1cccs1
Temperature: 120 °C

Procedure:
To a solution of 1-methyl-2-(2-thienyl)-1H-imidazole (116 mg, 0.706 mmol) in acetonitrile (5 ml) was added NIS (159 mg, 0.706 mmol) at room temperature. The reaction mixture was heated in the Biotage Initiator Series microwave for 1 hour at 120° C. The reaction mixture was diluted in ethyl acetate, washed with 1N aqueous sodium hydroxide and brine then dried over sodium sulfate, filtered and concentrated to give 5-iodo-1-methyl-2-(2-thienyl)-1H-imidazole. The material was taken forward without any additional purification. LRMS (ESI) calculated for C8H8N2SI [M+H]+, 290.9; found 291.0.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[N:5]=[C:4](/[CH:13]=[CH:14]/[C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[C:18]#[N:19])[N:3]=1.[N-:23]=[N+:24]=[N-:25].[Na+].[NH4+].[Cl-]>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:9][CH2:10][CH2:11][CH2:12]2)[N:5]=[C:4](/[CH:13]=[CH:14]/[C:15]2[CH:22]=[CH:21][CH:20]=[C:17]([C:18]3[N:23]=[N:24][NH:25][N:19]=3)[CH:16]=2)[N:3]=1
Reactant: Cc1cc(N2CCCC2)nc(/C=C/c2cccc(C#N)c2)n1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(N2CCCC2)nc(/C=C/c2cccc(-c3nn[nH]n3)c2)n1
Temperature: 70 °C
Yield: 17.6 %

Procedure:
A mixture of 100 mg (0.34 mmol) of (E)-3-[2-(4-methyl-6-pyrrolidin-1-yl-pyrimidin-2-yl)-vinyl]-benzonitrile, 448 mg (6.9 mmol) NaN3 and 368 mg (6.9 mmol) NH4Cl in 10 ml DMF was heated at 70° C. for 20 h until completion of the reaction according to TLC analysis. The reaction mixture was cooled to RT, concentrated in vacuo and then partitioned between 1N HCl and CH2Cl2. The organic layer was separated and the aqueous layer extracted several times with CH2Cl2. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crystalline solid which formed was filted off by suction and dried in a high vacuum to give ((E)-4-methyl-6-pyrrolidin-1-yl-2-{2-[3-(2H-tetrazol-5-yl)-phenyl]-vinyl}-pyrimidine (20 mg, 17.4%) as an off-white solid. ISP mass spectrum, m/e: 334.3 (M+1 calculated for C18H19N7: 334).
Reaction SMILES: CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:32][C:33]1[CH:34]=[C:35]2[C:39](=[C:40]([C:42]([OH:44])=O)[CH:41]=1)[NH:38][CH:37]=[CH:36]2.[C:45]([C:49]1[CH:65]=[CH:64][C:52]([CH2:53][NH:54][CH2:55][CH2:56][C:57]2[CH:62]=[CH:61][C:60]([F:63])=[CH:59][CH:58]=2)=[C:51]([Cl:66])[CH:50]=1)([CH3:48])([CH3:47])[CH3:46]>CN(C=O)C.O>[C:45]([C:49]1[CH:65]=[CH:64][C:52]([CH2:53][N:54]([CH2:55][CH2:56][C:57]2[CH:58]=[CH:59][C:60]([F:63])=[CH:61][CH:62]=2)[C:42]([C:40]2[CH:41]=[C:33]([Cl:32])[CH:34]=[C:35]3[C:39]=2[NH:38][CH:37]=[CH:36]3)=[O:44])=[C:51]([Cl:66])[CH:50]=1)([CH3:48])([CH3:46])[CH3:47]
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(F)cc2)c(Cl)c1
Reactant: O=C(O)c1cc(Cl)cc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)c1ccc(CN(CCc2ccc(F)cc2)C(=O)c2cc(Cl)cc3cc[nH]c23)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.5 %

Procedure:
106 mg (1.05 mmol) of N-methyl morpholine and then 199 mg (0.53 mmol) of HBTU were added to 68 mg (0.35 mol) of 5-chloro-1H-indol-7-carboxylic acid and 136 mg (0.39 mmol) of (4-tert-butyl-2-chloro-benzyl)-[2-(4-fluoro-phenyl)-ethyl]-amine dissolved in 3.5 ml DMF at rt under nitrogen. The reaction mixture was stirred at rt for 3 h. Water was added and the reaction mixture was extracted twice with EtOAc. The combined organic layers were washed once with 1N aqueous HCl solution, once with saturated aqueous NaHCO3 solution and once with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and the solvent was evaporated. The residue was purified by column chromatography (20 g silica gel, heptane/EtOAc 7:3) to yield 160 mg (92%) product as a light yellow foam. MS (EI) 496.1 (M)+.
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[CH3:11][CH:12]([NH:14][CH:15]1[C:20]2=[C:21]([CH3:28])[C:22]3[C:27]([N:19]2[CH2:18][CH2:17][CH2:16]1)=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH3:13]>O1CCCC1>[CH3:28][C:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:19]2[CH2:18][CH2:17][CH2:16][CH:15]([N:14]([CH:12]([CH3:13])[CH3:11])[CH:1]=[O:3])[C:20]=12
Reactant: Cc1c2n(c3ccccc13)CCCC2NC(C)C
Reactant: O=CO
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: Cc1c2n(c3ccccc13)CCCC2N(C=O)C(C)C
Temperature: 60 °C
Reaction time: 12 h
Yield: 90 %

Procedure:
A mixture of formic acid (6 mL) and acetic anhydride (12 mL) was heated at 60° C. for 4 hours. A solution of 6,7,8,9-tetrahydro-N-(1-methylethyl)-10-methylpyrido[1,2-a]indol-9-amine (6 g, 24.7 mmol, described in Example 22) in tetrahydrofuran (60 mL) was added at once at 25° C. under exclusion of moisture. The reaction mixture was stirred at 25° C. for 12 hours, then poured into ice water (120 mL). The product was extracted with ether (3×80 mL), and the combined organic layer washed with 5% HCl, 10% NaHCO3, and water. The separated organic layer was dried over MgSO4, filtered, and evaporated to afford 6 g (90%) of the title compound as an amber oil.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[CH3:7][NH:8][C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=1[NH2:11]>C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:7][N:8]1[C:9]2[C:10](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:11][C:2](=[O:3])[C:1]1=[O:5]
Reactant: CNc1ccccc1N
Reactant: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cn1c(=O)c(=O)[nH]c2ccccc21

Procedure:
A mixture of 12 g of 98% oxalylchloride in 19.5 ml of triethylamine and 50 ml of toluene was added dropwise to a stirred solution of 8.5 g of o-N-methylamino aniline in 80 ml of toluene. The resulting mixture was heated at reflux for one hour. The precipitate was washed wih ether. The residue was stirred with water and filtered to give 1,2,3,4-tetrahydro-1-methyl-2,3-dioxo-quinoxaline.
Reaction SMILES: P(Br)(Br)[Br:2].[CH2:5]([C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14]O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(Cl)(Cl)(Cl)Cl>[CH2:5]([C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14][Br:2])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: BrP(Br)Br
Reactant: OCc1ccccc1Cc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccccc1Cc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
A solution of phosphorus tribromide (2.1 mL, 6.0 g, 22.1 mM) in 30 mL of carbon tetrachloride was slowly added dropwise to solution of 2-benzylbenzyl alcohol (1.98 g, 10 mM) in 70 mL of carbon tetrachloride at 0° C. The mixture was stirred at 0° C. for 2 hours, then at room temperature for 2 hours. The solvent was removed in vacuo and the residue diluted with ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to afford 2.6 g (99%) of 2-benzylbenzyl bromide as a yellow solid. 1H NMR (DMSO-d6) δ7.5-7.0 (m, 9H), 4.7 (s, 2H), and 4.15 (s, 2H). IR (CDCl3, cm−1) 3065, 1601, 1495, and 1453. MS (FD) m/e 260, 262.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:11][C:10]2[NH:9][C:8](=[S:12])[C:7]([C:13]#[N:14])=[CH:6][C:5]=2[C:4](=[O:15])[CH2:3]1.Br[CH:18]([CH3:20])[CH3:19]>>[CH:18]([S:12][C:8]1[C:7]([C:13]#[N:14])=[CH:6][C:5]2[C:4](=[O:15])[CH2:3][C:2]([CH3:16])([CH3:1])[CH2:11][C:10]=2[N:9]=1)([CH3:20])[CH3:19]
Reactant: CC(C)Br
Reactant: CC1(C)CC(=O)c2cc(C#N)c(=S)[nH]c2C1
Product: CC(C)Sc1nc2c(cc1C#N)C(=O)CC(C)(C)C2
Yield: 21 %

Procedure:
In analogy to the procedure described in Example 1, 7,7-dimethyl-5-oxo-2-thioxo-1,2,5,6,7,8-hexahydroquinoline-3-carbonitrile was treated with 2-bromopropane to give the title compound in 21% yield.
Reaction SMILES: [N:1]1([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@@H:2]1[C:11]([OH:13])=O.Cl.[CH3:22][N:23](C)[OH:24].F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCC[CH2:36]1.C(NC(C)C)(C)C>ClCCl.C(OCC)(=O)C>[CH3:36][O:24][N:23]([CH3:22])[C:11]([C@H:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:10][N:1]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:13]
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@@H]1C(=O)O
Reactant: CN(C)O
Reactant: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: CON(C)C(=O)[C@H]1Cc2ccccc2CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 16 h
Yield: 92.2 %

Procedure:
6.95 g of Boc-D-Tic-OH are dissolved in 25 ml of dichloromethane. 2.69 g of dimethylhydroxylamine hydrochloride and 11.68 g of bromotrispyrrolidino-phosphonium hexafluorophosphate are added. After cooling of the solution to 0° C., 9.72 ml of diisopropylamine are slowly added. The reaction medium is then stirred at ambient temperature for 16 h. After hydrolysis, extraction is carried out with ethyl acetate until the aqueous phase is completely depleted. Drying over MgSO4 and concentration to dryness are carried out. The crude obtained is chromatographed on silica gel, elution being carried out with a 99/1 mixture of dichloromethane and methanol. 7.4 g of tert-butyl (3R)-3-{[methoxy(methyl)amino]carbonyl}-3,4-dihydroisoquinoline-2(1H)-carboxylate are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([Te:11]([Cl:14])(Cl)Cl)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[N+:15]([O-])([OH:17])=[O:16].C(O)C.[PH2](O)=O>C(O)(=O)C>[Cl:14][TeH:11]1[C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[CH:7][C:6]=2[NH+:15]([O-:17])[O:16]1
Reactant: O=[N+]([O-])O
Reactant: COc1ccc([Te](Cl)(Cl)Cl)cc1OC
Agent: O=[PH2]O
Solvent: CCO
Solvent: CC(=O)O
Product: COc1cc2c(cc1OC)[TeH](Cl)O[NH+]2[O-]
Reaction time: 1 h

Procedure:
3,4-Dimethoxyphenyltellurium trichloride (74 g=0.2 mole) was suspended in glacial acetic acid (200 ml) in a 1500 ml Erlenmeyer flask. Nitric acid (18 g of 70%=0.2 mole) was added gradually to the stirred mixture, which caused formation of a clear, red solution and a mildly exothermic reaction. Stirring was continued for one hour at room temperature, then ethanol (1000 ml) and hypophosphorous acid (24.0 g of 50 weight percent aqueous) were added in order. Over a period of 30 minutes there occurred crystallization of a red solid, which was collected by filtration to give 47.3 g, 68.8% of theory, m.p. 199°-200° C. The material was identical to product isolated by procedure A. Elemental analyses were in agreement with that calculated for the structural formula.
Reaction SMILES: [CH:1]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:10](Cl)(=[O:15])[O:11][CH:12]([Cl:14])[CH3:13]>C(Cl)(Cl)Cl.N1C=CC=CC=1>[C:10](=[O:15])([O:9][CH:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[O:11][CH:12]([Cl:14])[CH3:13]
Reactant: OC1CCCCCCC1
Reactant: CC(Cl)OC(=O)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(Cl)OC(=O)OC1CCCCCCC1
Temperature: -60 °C
Reaction time: 3 h

Procedure:
To a solution of cyclooctanol (1.79 g) in chloroform (40 mL), pyridine (1.13 mL) was added, and then the reaction solution was cooled to −60° C. To the reaction solution, 1-chloroethyl carbonochloridate (1.53 mL) was added at the same temperature over 10 minutes. The reaction solution was thereafter heated to room temperature and stirred at the same temperature for 3 hours. Chloroform was added to the reaction solution and the organic layer was washed three times with brine and then dried over magnesium sulfate. The insoluble was filtered and the filtrate was concentrated under reduced pressure to give 1-chloroethyl cyclooctyl carbonate (A-11-1, 3.70 g) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13](Br)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[C:26]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)#[N:27].C(=O)([O-])[O-].[Na+].[Na+]>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>[C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:31]2[CH:32]=[CH:33][C:28]([C:26]#[N:27])=[CH:29][CH:30]=2)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CN(Cc1cc(-c2ccc(C#N)cc2)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C

Procedure:
By a similar operation as in Reference Example 79 and using tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (430 mg), (4-cyanophenyl)boronic acid (176 mg), sodium carbonate (254 mg) and tetrakis(triphenylphosphine)palladium (57.8 mg), the title compound was obtained as a pale-yellow oil (yield 382 mg, 84%).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:36])[C@H:15]([CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:22][C:21]=1[Cl:35])[CH2:16][CH:17]=C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C[O:40]CC1.C(O)(C)(C)C.I([O-])(=O)(=O)=O.[Na+]>[Os](=O)(=O)(=O)=O.O>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:36])[C@H:15]([CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:22][C:21]=1[Cl:35])[CH2:16][CH:17]=[O:40])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: C=CC[C@@H](Cc1c(Cl)cc(OCc2ccccc2)cc1Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC(C)(C)O
Solvent: O
Product: O=CC[C@@H](Cc1c(Cl)cc(OCc2ccccc2)cc1Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Yield: 48 %

Procedure:
Treat a mixture of (R)-4-benzyl-3-[(S)2-(4-benzyloxy-2,6-dichloro-benzyl)-pent-4-enoyl]-oxazolidin-2-one (0.96 g, 1.8 mmol), THF (21 mL) and water (7 mL) with 2.5% osmium tetroxide in t-butanol (46 mg, 0.18 mmol). Add sodium periodate (1.17 g, 5.5 mmol) and stir the reaction 4 hr at room temperature. Quench the reaction with water and extract with ethyl acetate. Wash the organic phase with aqueous 1N sodium thiosulfate then brine. Dry the organic layer over magnesium sulfate, filter, and concentrate under vacuum. Purify the crude material by silica gel chromatography using hexanes:ethyl acetate to elute the pure product. Concentrate the fractions containing product under vacuum to afford 0.46 g (48%) of desired product. MS (m/z): 526 (M+).