Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([I:8])=[CH:6][N:5]=[CH:4][N:3]=1.N1C=CC(=O)NC=1.CCN(CC)CC.[C:23]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>CN1C(=O)CCC1>[C:26]([O:25][C:23]([N:30]1[CH2:35][CH2:34][N:33]([C:2]2[C:7]([I:8])=[CH:6][N:5]=[CH:4][N:3]=2)[CH2:32][CH2:31]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1ncncc1I
Agent: O=c1ccnc[nH]1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCN(c2ncncc2I)CC1
Yield: 98.6 %

Procedure:
A mixture of 4-chloro-5-iodopyrimidine (3.00 g, 12.5 mmol) (prepared from 4(3H)-pyrimidinone according to the literature: Takao Sakamoto, et al. (1986) Chem. Pharm. Bull., 2719-2724), Et3N (5.22 mL, 37.4 mmol), 1-Boc piperazine (2.79 g, 15.0 mmol) and NMP (30 mL) was heated at 75° C. for 6 hours. After cooling, the reaction mixture was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography (2:1 hexanes/EtOAc) to give 4-(5-Iodo-pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (4.81 g, 99%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 8.70 (s, 1H), 8.62 (s, 1H), 3.57 (s, 8H), 1.49 (s, 9H). LCMS (APCI+) m/z 391 [M+H]+; Rt=2.96 minutes.
Reaction SMILES: [I-].[CH3:2][N:3]1[CH:33]=[CH:32][CH:31]=[C:5]([C:6]([O:8][C@@H:9]2[CH2:28][CH2:27][C@@:26]3([CH3:29])[C@@H:11]([CH2:12][CH2:13][C@@H:14]4[C@@H:25]3[CH2:24][CH2:23][C@@:22]3([CH3:30])[C@H:15]4[CH2:16][CH2:17][C@@H:18]3[C:19](=[O:21])[CH3:20])[CH2:10]2)=[O:7])[CH2:4]1.C(=O)(O)[O-].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+].O>CO>[CH3:2][N:3]1[CH2:33][CH:32]=[CH:31][CH:5]([C:6]([O:8][C@@H:9]2[CH2:28][CH2:27][C@@:26]3([CH3:29])[C@@H:11]([CH2:12][CH2:13][C@@H:14]4[C@@H:25]3[CH2:24][CH2:23][C@@:22]3([CH3:30])[C@H:15]4[CH2:16][CH2:17][C@@H:18]3[C:19](=[O:21])[CH3:20])[CH2:10]2)=[O:7])[CH2:4]1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](OC(=O)C5=CC=CN(C)C5)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [I-]
Solvent: CO
Solvent: O
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](OC(=O)C5C=CCN(C)C5)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice cold solution of the 3α-N-methyl-nicotinoyloxy-5α-pregnan-20-one iodide salt (1.01 g, 562 g/m, 1.8 mmol) in 150 mL of aqueous methanol (100 ml methanol and 50 ml water, deaerated) was added sodium bicarbonate (620 mg, 84 g/m, 7.4 mmol) and sodium dithionite (1.3 g, 174 g/m, 7.4 mmol). This mixture was stirred at 0° C. for 1 h. The reaction mixture was poured into 500 mL of water and extracted several times with chloroform. The combined organic layers were washed with potassium carbonate and concentrated. The crude product was filtered through a bed of silica gel using hexane/ethyl acetate (5:1) elution. The product was recovered in the initial fractions to give 180 mg (439 g/m, 0.4 mmol, 22%).
Reaction SMILES: FC(F)(F)C([N:5]1[CH:10]2[CH2:11][CH2:12][CH:6]1[CH2:7][C:8](=[C:13]1[C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([NH:27][CH:28]=[O:29])[C:21]=3[O:20][C:19]3[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:9]2)=O.C([O-])([O-])=O.[K+].[K+]>CO>[CH:10]12[NH:5][CH:6]([CH2:12][CH2:11]1)[CH2:7][C:8](=[C:13]1[C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([NH:27][CH:28]=[O:29])[C:21]=3[O:20][C:19]3[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:9]2
Reactant: O=CNc1cccc2c1Oc1ccccc1C2=C1CC2CCC(C1)N2C(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=CNc1cccc2c1Oc1ccccc1C2=C1CC2CCC(C1)N2
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.8 %

Procedure:
Compound 5k (0.42g, 0.98 mmol) was added to MeOH (10 mL), and K2CO3 (1 g) was added. The mixture was stirred for 3 h at rt. After that time, the solid was collected by vacuum filtration. The resulting filtrate was concentrated in vacuo. Water was added to the resulting residue and the mixture was stirred for 30 min. The solid was collected by vacuum filtration and purified by reverse phase HPLC to yield the title compound 44 (159 mg, 37%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[Cl:21])=[CH:6][C:5]=1[N:22]([CH2:24][CH2:25][P:26]([O-:30])[O:27]CC)[CH3:23])([O-:3])=[O:2].C[Si](C)(C)Br>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:13][C:12]=2[Cl:21])=[CH:6][C:5]=1[N:22]([CH2:24][CH2:25][P:26]([OH:30])[OH:27])[CH3:23])([O-:3])=[O:2]
Reactant: CCOP([O-])CCN(C)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Agent: C[Si](C)(C)Br
Product: CN(CCP(O)O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 20 °C
Reaction time: 18 h

Procedure:
A mixture of 3.2 g of monoethyl N-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenyl]-N-methylaminoethylphosphonite and 10 g of trimethylbromosilane is stirred for 18 hours at 20° C. Excess trimethylbromosilane is removed by evaporation and the residue is then taken up in ethanol and the solution is evaporated, affording as residue a yellow oil which crystallises from ether. Yield: 2.14 g (71.3% of theory) of the title compound with a melting point of 161°-164° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.N(S([O-])(=O)=O)(S([O-])(=O)=[O:16])[O].[K+].[K+]>CO.OP([O-])(O)=O.[K+].O>[OH:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2](=[O:1])[CH:3]=[CH:4][C:5]2=[O:16]
Reactant: Oc1ccc2c(O)cccc2c1
Reactant: [O]N(S(=O)(=O)[O-])S(=O)(=O)[O-]
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C1C=CC(=O)c2cc(O)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1,6-Dihydroxynaphtalene from Aldrich (3.0 g, 18.7 mmol) was dissolved in a mixture of MeOH (150 mL), KH2PO4-solution (0.167 M, 150 mL) and water (200 mL), and Potassium nitrosodisulfonate (Fremy's salt) (12.0 g, 44.7 mmol) was added. The mixture was stirred at room temperature 2 h. The reaction mixture was put in refrigerator and then filtered. Yield 3.0 g. 1H NMR (400 MHz, CD3OD) δ 6.90 (d, 2 H), 7.12 (dd, 1 H), 7.34 (d, 1 H), 7.92 (d, 1 H).
Reaction SMILES: Br[CH2:2][CH:3]1[O:20][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH:4]1[CH3:21])[NH:11][C:10](=[O:16])[C:9]([CH:17]([CH3:19])[CH3:18])=[CH:8]3.[N-:22]=[N+:23]=[N-:24].[Na+].C(OCC)(=O)C.O>CN(C)C=O>[N:22]([CH2:2][CH:3]1[O:20][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH:4]1[CH3:21])[NH:11][C:10](=[O:16])[C:9]([CH:17]([CH3:19])[CH3:18])=[CH:8]3)=[N+:23]=[N-:24]
Reactant: Cc1cc2c(c3cc(C(C)C)c(=O)[nH]c13)OC(CBr)C2C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc2c(c3cc(C(C)C)c(=O)[nH]c13)OC(CN=[N+]=[N-])C2C
Temperature: 150 °C
Reaction time: 3 h
Yield: 74.1 %

Procedure:
The compound obtained in Example 327 (1.97 g, 5.62 mmol) was dissolved in dimethylformamide (25 ml). To the resultant solution, sodium azide (2.2 g, 33.84 mmol) was added, and the mixture was stirred at 150° C. for 3 hours. After the mixture was cooled, ethyl acetate-water was added for phase separation. The organic phase was washed with water, and saturated aqueous sodium chloride solution in this order, and dried. The solvent was distilled off under reduced pressure, and the residue was washed with hexane. 1.3 g of the title compound was obtained (78%).
Reaction SMILES: CC[N:3](C(C)C)C(C)C.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[C:13](F)[CH:12]=1>CS(C)=O>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[C:13]([CH:12]=1)[NH2:3]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Reactant: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Nc1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 19 h

Procedure:
Amino-(4-methoxyphenyl)-methylpolystyrene (loading 1.69 mmol/g, 7.00 g, 11.8 mmol) was soaked in DMSO in a peptide vessel for 30 min. The solvent was then drained. DIEA (11.3 mL, 65.1 mmol) in DMSO (88 mL) was added to the resin, followed by 4-chloro-2-fluoronitrobenzene (10.4 g, 59.2 mmol). The mixture was shaken at room temperature for 19 h, at which point it was drained. The resin was washed with DMSO (3×), EtOH (3×), DMF (3×), MeOH (3×) and DCM (3×). It was then dried under vacuum overnight. A small sample (approx. 10 mg) was treated with 23:2:75 (v/v/v) TFA/H2O/DCM (0.5 mL) for ca. 1 h. The solution containing the released material was concentrated and analyzed with LC/MS. UV (254 nm): 97% @ 5.65 min. MS: m/e 171 (M−1).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][C@H:6]([OH:8])[C@@H:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O/[N:32]=[C:33](/[C:39](=[O:41])[CH3:40])\[C:34]([O:36][CH2:37][CH3:38])=[O:35].N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[CH3:1][C@@H:2]1[CH2:7][C@@H:6]([O:8]/[N:32]=[C:33](/[C:39](=[O:41])[CH3:40])\[C:34]([O:36][CH2:37][CH3:38])=[O:35])[C@@H:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1
Reactant: CCOC(=O)/C(=N\O)C(C)=O
Reactant: CC(C)[C@H]1CC[C@H](C)C[C@@H]1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)/C(=N\O[C@@H]1C[C@@H](C)CC[C@@H]1C(C)C)C(C)=O
Yield: 14 %

Procedure:
(1S, 2R, 5S)-(+)-Menthol (7.03 g, 45 mmol), triphenylphosphine (8.65 g, 33 mmol), ethyl (Z)-2-hydroxyimino-3-oxobutyrate (4.77 g, 33 mmol) and diethyl azodicarboxylate (5.7 g, 33 mmol) were reacted by analogy with Example 4a Method 3 to give the title compound (1.37 g, 14%), νmax (CH2Cl2) 2960, 2930, 2870, 1745, 1690, 1370, 1320, 1235, 1075, and 1010cm-1 ; δH (400 MHz, CDCl3) 0.87 (3H, d, J 6.6 Hz), 0.90 (3H, d, J 6.8 Hz), 0.92 (3H, d, J 6.7 Hz), ca 0.9 (1H, m), 1.02-1.12 (2H, m), 1.1-1.3 (1H, m), 1.32 (3H, t, J 7.1 Hz), 1.50-1.65 (2H, m), 1.67-1.78 (2H, m), 2.06-2.18 (1H, m), 2.40 (1H, s), 4.34 (2H, dq, J 7.1 and 1.0 Hz), and 4.70 (1H, broad s); δ13C (100 MHz, CDCl3), 14.24 (CH3), 20.70 (CH3), 20.97 (CH3), 22.26 (CH3) 25.04 (CH2), 25.11 (CH3) 26.06 (CH), 29.10 (CH), 34.77 (CH2), 39.44 (CH2) 46.98 (CH), 61.70 (CH2), 83.43 (CH), 150.28, 161.53, 192.94 [Ammonia CI mass spectrum Found: MH+ (298); MNH+ (315)].
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[Br:6][C:7]1[CH:37]=[CH:36][C:10]([CH2:11][CH:12]([NH:25][C:26](=[O:35])[O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:13]([NH:15][CH2:16][C:17](=O)[CH2:18][C:19]([CH3:23])([CH3:22])[CH2:20][CH3:21])=O)=[CH:9][CH:8]=1>C1(C)C(C)=CC=CC=1>[Br:6][C:7]1[CH:37]=[CH:36][C:10]([CH2:11][CH:12]([NH:25][C:26](=[O:35])[O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:13]2[NH:15][CH:16]=[C:17]([CH2:18][C:19]([CH3:23])([CH3:22])[CH2:20][CH3:21])[N:5]=2)=[CH:9][CH:8]=1
Reactant: [NH4+]
Reactant: CCC(C)(C)CC(=O)CNC(=O)C(Cc1ccc(Br)cc1)NC(=O)OCc1ccccc1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1C
Product: CCC(C)(C)Cc1c[nH]c(C(Cc2ccc(Br)cc2)NC(=O)OCc2ccccc2)n1
Temperature: 150 °C
Reaction time: 2 h

Procedure:
Ammonium acetate (48 g, 620 mmol) was added to an ambient temperature solution of benzyl {1-(4-bromobenzyl)-2-[(4,4-dimethyl-2-oxohexyl)amino]-2-oxoethyl}carbamate (6.23 g, 12.4 mmol) in xylene (124 mL). After stirring at 150° C. for 2 h, the reaction mixture was quenched with saturated aqueous sodium bicarbonate and extracted with methylene chloride. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo to afford benzyl {2-(4-bromophenyl)-1-[4-(2,2-dimethylbutyl)-1H-imidazol-2-yl]ethyl}carbamate which was used in the subsequent step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1.Cl>>[ClH:1].[Cl:1][C:2]1[C:11]([C:12]([F:15])([F:13])[F:14])=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][CH2:9]2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1c(Cl)ccc2ccncc12
Agent: Cl
Product: FC(F)(F)c1c(Cl)ccc2c1CNCC2

Procedure:
7-Chloro-8-trifluoromethylisoquinoline is converted to the hydrochloride and hydrogenated by the procedure of Example 9 to give 7-chloro-8-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline hydrochloride.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:40][C:41]3[CH:46]=[C:45]([CH3:47])[CH:44]=[C:43]([CH3:48])[CH:42]=3)[C:19]([N:21]3[CH2:26][CH2:25][N:24]([CH:27]4[CH2:32][CH2:31][N:30](OC(C)(C)C)[C:29](=C=O)[CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:49]=[CH:50][CH:51]=[CH:52][C:4]=2[NH:3]1.C([O-])([O-])=O.[K+].[K+]>Cl.CN(C=O)C>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:40][C:41]3[CH:46]=[C:45]([CH3:47])[CH:44]=[C:43]([CH3:48])[CH:42]=3)[C:19](=[O:20])[N:21]3[CH2:22][CH2:23][N:24]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[CH2:25][CH2:26]3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:49]=[CH:50][CH:51]=[CH:52][C:4]=2[NH:3]1
Reactant: Cc1cc(C)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCN(OC(C)(C)C)C(=C=O)C3)CC2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCNCC3)CC2)c1

Procedure:
A solution of 45 mg (0.06 mmol) of (R)-1-(3,5-dimethyl-benzyl)-2-[4-(1-tert-butoxy-carbonyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 42) in 10 mL 2 M HCl was stirred overnight at RT. The reaction mixture was lyophilised. The crude product was taken up in 1 mL DMF, made alkaline with 0.6 mL saturated K2CO3 solution and purified chromatographically by HPLC.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][C:15]2[C:23]3[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=3[NH:17][C:16]=2[CH:24]=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:26]([S:28]([C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[NH:36][C:35](=[O:40])[CH2:34]2)(=[O:30])=[O:29])[CH3:27]>>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([CH2:12][CH2:13][CH2:14][C:15]2[C:23]3[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=3[NH:17][C:16]=2/[CH:24]=[C:34]2\[C:35](=[O:40])[NH:36][C:37]3[C:33]\2=[CH:32][C:31]([S:28]([CH2:26][CH3:27])(=[O:30])=[O:29])=[CH:39][CH:38]=3)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: CCOC(=O)N1CCN(CCCc2c(C=O)[nH]c3c2CCCC3)CC1
Product: CCOC(=O)N1CCN(CCCc2c(/C=C3\C(=O)Nc4ccc(S(=O)(=O)CC)cc43)[nH]c3c2CCCC3)CC1

Procedure:
4-[3-(2-Formyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-propyl]-piperazine-1-carboxylic acid ethyl ester (65 mg, 0.1 87 mmol), prepared as described in Example 8, was condensed with 5-ethylsulfonyloxindole (61 mg, 1.01 eq.) give the desired product.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[Cl:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>ClCCl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:24]4[CH:23]=[CH:22][CH:21]=[C:20]([Cl:19])[CH:25]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Reactant: OB(O)c1cccc(Cl)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4cccc(Cl)c4)cc3CC[C@@H]12
Yield: 74.2 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 3-chlorophenylboronic acid (122 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution and 1.5 mL of toluene, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with dichloromethane (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 164 mg (74%) of the title compound as an amorphous foam. mp 158°-65°. FDMS: m/e=339. α[D]589 =+74.90 (c=1.00, methanol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=3[CH3:22])[NH2:18])[N:9]=2)[CH:5]=[N:6][CH:7]=1.Cl.Cl.[CH2:25]([N:27]1[CH2:32][CH2:31][N:30]([CH2:33][C:34]2[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][C:35]=2[C:43]([F:46])([F:45])[F:44])[CH2:29][CH2:28]1)[CH3:26]>>[CH2:25]([N:27]1[CH2:28][CH2:29][N:30]([CH2:33][C:34]2[CH:42]=[CH:41][C:37]([C:38]([NH:18][C:17]3[CH:19]=[CH:20][C:21]([CH3:22])=[C:15]([NH:14][C:10]4[N:9]=[C:8]([C:4]5[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=5)[CH:13]=[CH:12][N:11]=4)[CH:16]=3)=[O:39])=[CH:36][C:35]=2[C:43]([F:46])([F:44])[F:45])[CH2:31][CH2:32]1)[CH3:26]
Reactant: Cc1ccc(N)cc1Nc1nccc(-c2cncc(Br)c2)n1
Reactant: CCN1CCN(Cc2ccc(C(=O)Cl)cc2C(F)(F)F)CC1
Agent: Cl
Product: CCN1CCN(Cc2ccc(C(=O)Nc3ccc(C)c(Nc4nccc(-c5cncc(Br)c5)n4)c3)cc2C(F)(F)F)CC1
Reaction time: 24 h

Procedure:
This compound was prepared in the same manner as in Example 1, except that 3-[4-(5-bromopyridin-3-yl)pyrimidin-2-ylamino]-4-methylaniline (Reference Example 19) and 4-(4-ethylpiperazin-1-ylmethyl)-3-trifluoromethylbenzoyl chloride dihydrochloride (Reference Example 5) were used, and that the reaction was conducted at room temperature for 24 hours and the amorphous obtained by purification with silica gel column chromatography was crystallized by adding chloroform-diethyl ether (1:1).
Reaction SMILES: Cl[CH2:2][C:3]1[C:7]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=2[Cl:16])=[CH:6][S:5][CH:4]=1.[C-:17]#[N:18].[Na+]>CS(C)=O>[Cl:16][C:10]1[C:11]([CH3:15])=[CH:12][CH:13]=[CH:14][C:9]=1[NH:8][C:7]1[C:3]([CH2:2][C:17]#[N:18])=[CH:4][S:5][CH:6]=1
Reactant: Cc1cccc(Nc2cscc2CCl)c1Cl
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cccc(Nc2cscc2CC#N)c1Cl
Reaction time: 3 h

Procedure:
2.72 g (10 mmoles) of 3-chloromethyl-4-(2-chloro-3-methylanilino)thiophen in 15 ml of dimethylsulfoxide are added dropwise to a solution of 650 mg of sodium cyanide in 15 ml of dimethylsulfoxide at 40°. The mixture is stirred for a further three hours, poured onto water and extracted three times with ethyl acetate. The combined extracts are washed with 50 ml each of 6 N hydrochloric acid and water, dried and concentrated. Crude 4-(2-chloro-3-methylanilino)-3-thiophenacetonitrile is obtained as an oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:15]=[C:14]2[N:5]([C:6](=[O:16])[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=32)[N:4]=1.[C:17]1([N:23]=[C:24]=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(OCC)(=O)C>N1C=CC=CC=1>[C:17]1([NH:23][C:24]([O:1][CH2:2][C:3]2[CH:15]=[C:14]3[N:5]([C:6](=[O:16])[NH:7][C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=43)[N:4]=2)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C=Nc1ccccc1
Reactant: O=c1[nH]c2ccccc2c2cc(CO)nn12
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(Nc1ccccc1)OCc1cc2c3ccccc3[nH]c(=O)n2n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2.0 g (0.0093 mole) of 2-(hydroxymethyl)pyrazolo[1,5-c]-quinazolin-5(6H)-one prepared as described in Example 6B and 1.55 ml (≅ 1.7 g or 0.014 mole) of 98% phenylisocyanate are refluxed in 20 ml of dry pyridine under N2 for 1 hour. The crude product is poured onto 200 ml of ice-water layered with ethyl acetate (50 ml) and stirred for 30 minutes. The precipitates that form are filtered off, air-dried and taken up in dioxane (150 ml). The solution is filtered while hot and the clear filtrate concentrated down to a volume of 100 ml and cooled. The precipitates are filtered off and dried in vacuo at 85°. Yield 2.45 g, 78.8% crude yield.
Reaction SMILES: C([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([C:20](=[O:24])[CH:21](O)O)=[CH:11][CH:10]=1)C1C=CC=CC=1.[F:25][C:26]1[CH:27]=[C:28]([CH:34]=[C:35]([F:37])[CH:36]=1)[CH2:29][C:30]1([NH2:33])[CH2:32][CH2:31]1.FC(F)(F)C([O-])=O>>[F:25][C:26]1[CH:27]=[C:28]([CH:34]=[C:35]([F:37])[CH:36]=1)[CH2:29][C:30]1([NH:33][CH2:21][CH:20]([C:12]2[C:13]3[O:18][CH2:17][C:16](=[O:19])[NH:15][C:14]=3[C:9]([OH:8])=[CH:10][CH:11]=2)[OH:24])[CH2:32][CH2:31]1
Reactant: NC1(Cc2cc(F)cc(F)c2)CC1
Reactant: O=C1COc2c(C(=O)C(O)O)ccc(OCc3ccccc3)c2N1
Agent: O=C([O-])C(F)(F)F
Product: O=C1COc2c(C(O)CNC3(Cc4cc(F)cc(F)c4)CC3)ccc(O)c2N1

Procedure:
Prepared according to general method 3 from 329 mg (1 mmol) 5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and 183 mg (1 mmol) 1-(3,5-difluoro-benzyl)-cyclopropylamine. Yield: 66 mg (13%, trifluoroacetate); mass spectroscopy: [M+H]+=391.
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:17]([C@@H:18]([OH:23])[C:19]([F:22])([F:21])[F:20])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:24](C)[C:25](=O)OC(C)(C)C)[S:14]2)[CH2:10]1)C1C=CC=CC=1.B(Cl)(Cl)Cl>C(Cl)Cl>[CH3:25][NH:24][C:13]1[S:14][C@H:15]2[O:16][C@H:17]([C@@H:18]([OH:23])[C:19]([F:22])([F:20])[F:21])[C@@H:9]([OH:8])[CH2:10][C@H:11]2[N:12]=1
Reactant: CN(C(=O)OC(C)(C)C)C1=N[C@@H]2C[C@H](OCc3ccccc3)[C@@H]([C@@H](O)C(F)(F)F)O[C@@H]2S1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: CNC1=N[C@@H]2C[C@H](O)[C@@H]([C@@H](O)C(F)(F)F)O[C@@H]2S1
Temperature: 0 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
To tert-butyl ((3aR,5R,6S,7aR)-6-(benzyloxy)-5-((R)-2,2,2-trifluoro-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (0.052 g, 0.11 mmol) and PMB (0.10 g, 0.67 mmol) in anhydrous DCM (5 mL) at −78° C. under N2, was added BCl3 (1.0 M in DCM, 0.60 mL, 0.60 mmol). The mixture was stirred for ˜3 h while the temperature of the cooling bath warmed to 0° C. The reaction mixture was cooled at −78° C., quenched with mixed MeOH/DCM, and then concentrated to dryness. The residue was purified on silica gel by flash column chromatography (1.0 M NH3 in MeOH/DCM, 1:12), affording (3aR,5S,6S,7aR)-2-(methylamino)-5-((R)-2,2,2-trifluoro-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol as a white solid (0.023 g, 74%). 1H NMR (400 MHz, CD3OD) δ 6.21 (d, J=6.4 Hz, 1H), 4.29-4.24 (m, 1H), 4.21-4.15 (m, 1H), 4.01-3.96 (m, 1H), 3.70 (d, J=8.8 Hz, 1H), 2.83 (s, 3H), 2.22-2.16 (m, 1H), 2.08-2.01 (m, 1H); 13C NMR (100 MHz, CD3OD) δ 163.69, 126.47 (q, J=281.2 Hz), 91.73, 73.5 (br.), 69.62 (q, J=30.1 Hz), 69.34, 64.60, 35.16, 30.60; MS, (ES, m/z) [M+H]+ 287.1.
Reaction SMILES: [Zn:1].[C:2]([O-:5])(=[O:4])[CH3:3].[Zn+2].[C:7]([O-:10])(=[O:9])[CH3:8]>OCC(CO)O>[C:2]([O-:5])(=[O:4])[CH3:3].[Zn+2:1].[C:7]([O-:10])(=[O:9])[CH3:8].[O-2:4].[Zn+2:1]
Reactant: [Zn]
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: OCC(O)CO
Product: [O-2]

Procedure:
A method according to claim 9 wherein the zinc glycerolate complex is formed by the process of reacting zinc oxide or zinc acetate with glycerol in the proportions of about 50 gms zinc oxide or zinc acetate to 500 gms glycerol, raising the temperature of the mix to about 260° C. and maintaining the temperature until reaction is completed, cooling and pouring the mixture so formed into water, filtering, washing and drying to isolate the zinc glycerolate complex.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][N:24]=2)[CH:17]=1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:22][C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][C:18]=2[C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][N:24]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Cl)cc1-c1nccc2ccccc12
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-c2nccc3ccccc23)cc1

Procedure:
The title compound was prepared according to the general procedure using 4-tert-butyl-benzenesulfonyl chloride and 4-chloro-2-isoquinolin-1-yl-phenylamine and purified by preparative HPLC. MS: (M+H)/z=451.