Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8]([OH:11])(=O)=[O:9])[CH:5]=[N:6][CH:7]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:13].P(Cl)(Cl)(Cl)=O.C([O-])(O)=O.[Na+].[Na+].[Cl-]>C(OC)(C)(C)C>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([Cl:13])(=[O:11])=[O:9])[CH:5]=[N:6][CH:7]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=S(=O)(O)c1cncc(Br)c1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O=P(Cl)(Cl)Cl
Product: O=S(=O)(Cl)c1cncc(Br)c1
Temperature: 0 °C
Yield: 98.4 %

Procedure:
A mixture of 5-bromo-pyridine-3-sulfonic acid (Example B.2 step 1) (7.14 g, 30 mmol), phosphorus pentachloride (9.68 g, 47 mmol) and phosphorus oxychloride (20 mL) was heated to reflux for 4 h (according to J. Org. Chem. 1989, 54(2), 389. ). The reaction mixture was concentrated to dryness to give a yellow semisolid, dissolved in ice water and tert-butyl-methyl-ether, and cautiously added sat. NaHCO3-sol. until neutralized, saturated with solid NaCl, separated phases, dried organic layer over Na2SO4. Removal of the solvent in vacuum gave the title compound as a yellow solid (7.57 g, 98%). MS (EI) 254.9 [(M)+], 256.9 [(M+2)+] and 258.9 [(M+4)+]; mp 64° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([S:11][C:12]3[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][C:15]4[NH:16][C:17](=[O:19])[O:18][C:14]=4[CH:13]=3)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[OH-:25].[Na+].S(=O)(=O)(O)[OH:28]>>[CH:1]1[C:10]2[C:5](=[C:6]([S:11]([C:12]3[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][C:15]4[NH:16][C:17](=[O:19])[O:18][C:14]=4[CH:13]=3)(=[O:28])=[O:25])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: [OH-]
Reactant: O=c1[nH]c2cc([N+](=O)[O-])c(Sc3cccc4cnccc34)cc2o1
Reactant: O=S(=O)(O)O
Agent: [Na+]
Product: O=c1[nH]c2cc([N+](=O)[O-])c(S(=O)(=O)c3cccc4cnccc34)cc2o1
Temperature: 25 °C
Reaction time: 6 h
Yield: 39.1 %

Procedure:
6-(5-Isoquinolylsulfanyl)-5-nitro-2,3-dihydro-benzo[d][1,3]oxazole-2-one 250 mg (0.7 mmol) was dissolved in concentrated sulfuric acid 2.5 ml, Beckmann's reagent 5.0 ml (K2Cr2O7 1 g, H2SO4 1 ml, H2O 9 ml) was added dropwise, and the mixture was stirred for 6 hours at room temperature. The reaction solution was neutralized with 4N sodium hydroxide, and the resulting precipitates were collected and washed with water, and 6-(5-isoquinolylsulfonyl)-5-nitro-2,3-dihydro-benzo[d][1,3]oxazol-2-one 110 mg (39.1%) was obtained.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][N+:21]=1[O-:29].C(N(CC)CC)C>C(O)C>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:20]2[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][N+:21]=2[O-:29])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: O=[N+]([O-])c1cc[n+]([O-])c(Cl)c1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cc[n+]([O-])c(NCCCOc2cccc(CN3CCCCC3)c2)c1
Temperature: 0 °C
Yield: 43.8 %

Procedure:
3-[3-(Piperidinomethyl)phenoxy]propylamine (6.21 g), 2-chloro-4-nitropyridine-N-oxide (4.36 g) and triethylamine (6.32 g) were stirred, in ethanol (30 ml), under reflux for 31/2 hours. The reaction mixture was cooled gradually to 0° C. to yield 2-[3-[3-(piperidinomethyl)phenoxy]propylamino]-4-nitropyridine-N-oxide (4.23 g), m.p. 90°-90.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[S:21]([C:18]2[CH:17]=[CH:16][C:15]([O:14][CH3:13])=[CH:20][CH:19]=2)(=[O:23])=[O:22])=[CH:6][CH:7]=1
Reactant: Fc1ccc(C2CCCN2)cc1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc(S(=O)(=O)N2CCCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, white solid, m.p. 134° C. and MS: m/e=335 (M+) was prepared in accordance with the general method of example I e from (RS)-2-(4-fluoro-phenyl)-pyrrolidine and 4-methoxy-benzenesulfonyl chloride.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7](=[N:9][OH:10])[NH2:8])([O-:3])=[O:2].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](=[O:29])[CH2:24]C(OC)=O)=[CH:18][CH:17]=1.C1(C)C=CC=CC=1>CCCCCCC>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([C:24]2[O:10][N:9]=[C:7]([C:6]3[CH:11]=[CH:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[N:8]=2)=[O:29])=[CH:18][CH:17]=1
Reactant: COC(=O)CC(=O)Cc1ccc(OC)cc1
Reactant: NC(=NO)c1cccc([N+](=O)[O-])c1
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: COc1ccc(CC(=O)c2nc(-c3cccc([N+](=O)[O-])c3)no2)cc1
Temperature: 25 °C
Yield: 89.7 %

Procedure:
In a 100 ml flask, place 5 g (0.0276 m) of 3-nitrobenzamidoxime (9a), 8.6 g (0.0414 m) of methyl p-methoxyphenyacetoacetate (10c; R1=p-methoxyphenyl), and 50 ml of toluene. Heat and stir the reaction mixture under reflux with a Dean-Stark trap for 14 hrs. Cool the reaction mixture to room temperature, add 40 ml of heptane and stir for 30 min. Collect solid, wash with heptane, and dry in air to give 8.4 g (85%) of 5-(p-methoxyphenyl)acetyl-3-(3-nitrophenyl)-1,2,4-oxadiazole [Formula II: R1=p-methoxyphenyl and R2=3-nitrophenyl].
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH:7]1[CH2:16][C:15]2[N:14]=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]=2[C:9](=O)[CH2:8]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:30][NH:31][C:32]([NH:34][OH:35])=[NH:33].Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH:7]1[CH2:16][C:15]2[N:14]=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]=2[C:9](=[N:30][NH:31][C:32](=[NH:33])[NH:34][OH:35])[CH2:8]1
Reactant: Cc1ccnc2c1C(=O)CC(c1ccsc1Cl)C2
Reactant: N=C(NN)NO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCO
Product: Cc1ccnc2c1C(=NNC(=N)NO)CC(c1ccsc1Cl)C2
Temperature: 90 °C
Reaction time: 2 h
Yield: 118.5 %

Procedure:
A mixture of 7-(2-chlorothiophen-3-yl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (222 mg), 1-amino-3-hydroxyguanidine p-toluenesulfonate (314 mg) and concentrated hydrochloric acid (0.1 ml) in ethanol (4 ml) was stirred at 90° C. (bath temperature) for 2 hours. The reaction solution was concentrated under reduced pressure, and to the residue were added ethyl acetate (30 ml), tetrahydrofuran (20 ml) and 0.2 N sodium hydroxide (20 ml). The mixture was shaken, and the separated upper layer was washed with 0.2 N sodium hydroxide (15 ml) and water (10 ml, thrice). To the upper layer was added 2 N hydrochloric acid (0.8 ml), and the mixture was concentrated under reduced pressure. To the residue was added ether (3 ml), and the mixture was stirred at 90° C. (bath temperature) for 3 hours and cooled to give crystals, which were filtered, washed with ethanol and dried to give 7-(2-chlorothiophen-3-yl)-5-(1-hydroxyguanidin-3-yl)imino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 104) (183 mg) as pale yellow crystals.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:10])[CH2:4][CH:5]=[CH:6][C:7](O)=[O:8].CCN(CC)CC.C(OC(Cl)=O)C(C)C.[I:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[C:33](=[O:37])[NH:32][C:31](=[O:38])[C:30]2=[CH:39][NH:40][C:41]1[CH:46]=[CH:45][C:44]([CH:47]2[CH2:51][CH2:50][CH2:49][NH:48]2)=[CH:43][CH:42]=1>CN(C)C=O>[CH3:2][N:3]([CH3:10])[CH2:4][CH:5]=[CH:6][C:7]([N:48]1[CH2:49][CH2:50][CH2:51][CH:47]1[C:44]1[CH:45]=[CH:46][C:41]([NH:40][CH:39]=[C:30]2[C:29]3[C:34](=[CH:35][CH:36]=[C:27]([I:26])[CH:28]=3)[C:33](=[O:37])[NH:32][C:31]2=[O:38])=[CH:42][CH:43]=1)=[O:8]
Reactant: O=C1NC(=O)c2ccc(I)cc2C1=CNc1ccc(C2CCCN2)cc1
Reactant: CN(C)CC=CC(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)CC=CC(=O)N1CCCC1c1ccc(NC=C2C(=O)NC(=O)c3ccc(I)cc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.6 %

Procedure:
4-Dimethylamino-but-2-enoic acid hydrochloride salt (66 mg, 0.40 mmol) in N,N-dimethylformamide (1 mL) is treated with Et3N (0.06 mL) at 0° C. To the mixture is then added isobutylchloroformate (0.05 mL). The mixture is then stirred at this temperature for 30 min before addition of 6-Iodo-4-[(4-pyrrolidin-2-yl-phenylamino)-methylene]-4H-isoquinoline-1,3-dione (80 mg, 0.17 mmol) in N,N-dimethylformamide (3 mL) dropwisely and the reaction is allowed to stir at room temperature overnight. After an aqueous workup, the final residue is purified with prep-TLC to afford the title compound (20 mg, 21%). 1H NMR (400 MHz, DMSO) δ12.52 (1H, d, J=12.4 Hz), 11.39-11.41 (1H, m), 8.90-8.94 (1H, m), 8.59 (1H, m), 7.21-7.75 (6H, m), 6.48-6.59 (1.4H, m), 6.01-6.05 (0.6H, m), 5.1-5.24 (1H, m), 3.57-3.91 (2H, m), 3.06-3.07 (1H, m), 2.82-2.84 (1H, m), 2.1-2.39 (2H, m), 2.18 (3H, s), 1.96 (3H, s), 1.77-1.95 (2H, m). MS (ESI): 571.0 (M+1)+1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[C:14](F)[C:13]([F:17])=[CH:12][C:11]=2[N+:18]([O-:20])=[O:19])=[N:6][CH:7]=1.[SH:22][C:23]1[N:24]([CH3:28])[CH:25]=[CH:26][N:27]=1.C(N(CC)CC)C>CC#N>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[C:14]([S:22][C:23]3[N:24]([CH3:28])[CH:25]=[CH:26][N:27]=3)[C:13]([F:17])=[CH:12][C:11]=2[N+:18]([O-:20])=[O:19])=[N:6][CH:7]=1
Reactant: Cn1ccnc1S
Reactant: O=C(Nc1ccc(Br)cn1)c1cc(F)c(F)cc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cn1ccnc1Sc1cc(C(=O)Nc2ccc(Br)cn2)c([N+](=O)[O-])cc1F
Temperature: 130 °C
Yield: 71.7 %

Procedure:
A mixture of N-(5-bromo-pyridin-2-yl)-4,5-difluoro-2-nitro-benzamide (236 mg, 0.66 mmol), 2-mercapto-1-methylimidazole (83 mg, 0.73 mmol) and triethylamine (0.18 mL, 1.32 mmol) in 2 mL CH3CN was microwave heated to 130° C. for 10 min and the resulting solid was collected by filtration, rinsed with CH3CN, and dried under high vacuum to provide 214 mg (72%) of the title compound as a yellow solid. 1H NMR (500 MHz, DMSO-d6): δ 3.70 (s, 3H), 6.91 (d, 1H, J=7 Hz), 7.20 (d, 1H, J=1 Hz), 7.58 (d, 1H, J=1 Hz), 8.07 (br s, 2H), 8.24 (d, 1H, J=10 Hz), 8.47 (br s, 1H), 11.39 (s, 1H); LCMS (m/z): 452/454 [C16H11BrFN5O3S+H]+.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].C([O-])([O-])=O.[Na+].[Na+].[F:21][C:22]1[CH:23]=[C:24]([C@H:28]2[NH:33][C:32](=O)[CH2:31][O:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>C1COCC1>[F:21][C:22]1[CH:23]=[C:24]([C@H:28]2[NH:33][C:32](=[S:2])[CH2:31][O:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C1COC[C@@H](c2cccc(F)c2)N1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1cccc([C@@H]2COCC(=S)N2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.5 %

Procedure:
To a stirred room temperature suspension of P4S10 (6.0 g, 13.4 mmol) and Na2CO3 (1.42 g, 13.4 mmol) in THF (40 mL) was slowly added a solution of (R)-5-(3-fluoro-phenyl)-morpholin-3-one (2.16 g, 11.1 mmol) in THF (30 mL). The mixture was stirred at room temperature for two hours, and then quenched by addition of 10% aqueous Na3PO4 (50 mL). The mixture was stirred another five minutes and then extracted with a 1:1: mixture of ethyl acetate and diethyl ether. The organic layer was separated, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was chromatographed through silica gel using a 15-30% ethyl acetate/hexanes solvent gradient to give 1.84 g (78%) of (R)-5-(3-fluoro-phenyl)-morpholine-3-thione as a white solid, MP=124-125° C.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][N:10]=[CH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]>[Pd].C1C2C(CCCC2)CCC1>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][N:10]=[CH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2c(c1)C=NCC2
Agent: [Pd]
Solvent: C1CCC2CCCCC2C1
Product: O=[N+]([O-])c1ccc2ccncc2c1
Yield: 55.1 %

Procedure:
A solution of 7-nitro-3,4-dihydroisoquinoline (3.00 g, 17.0 mmol) and 5% palladium on carbon (3.0 g) in decalin (75 ml) was heated at reflux for 3 h. Upon cooling, the solution was filtered and the catalyst washed with chloroform (200 ml). The solvent was removed in vacuo to give 7-nitroisoquinoline (1.63 g) as a tan solid. MS 175 (M+H).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([CH:13]3[CH2:18][NH:17][S:16](=[O:20])(=[O:19])[NH:15][CH2:14]3)[CH:10]=[CH:9][C:8]=2[NH2:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[C:22]([C:24]1[N:25]=[C:26]([C:37](O)=[O:38])[N:27](COCC[Si](C)(C)C)[CH:28]=1)#[N:23].[K+].C(C1N=C(C([O-])=O)N(COCC[Si](C)(C)C)C=1)#N>>[C:1]1([C:7]2[CH:12]=[C:11]([CH:13]3[CH2:14][NH:15][S:16](=[O:20])(=[O:19])[NH:17][CH2:18]3)[CH:10]=[CH:9][C:8]=2[NH:21][C:37]([C:26]2[NH:27][CH:28]=[C:24]([C:22]#[N:23])[N:25]=2)=[O:38])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: Nc1ccc(C2CNS(=O)(=O)NC2)cc1C1=CCCCC1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)O
Agent: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: [K+]
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CNS(=O)(=O)NC3)cc2C2=CCCCC2)n1
Yield: 25 %

Procedure:
2-Cyclohex-1-enyl-4-(1,1-dioxo-1λ6-[1,2,6]thiadiazinan-4-yl)-phenylamine (as prepared in the previous step, 30.7 mg, 0.100 mmol) was coupled to 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid, potassium salt (as prepared in Example 1, step (d), 33.6 mg, 0.260 mmol) as described in Example 1, step (l) to obtain the title compound (14 mg, 25%) after purification on silica (20-50% EtOAc-hexane): Mass spectrum (ESI, m/z): Calcd. for C26H36N6O4SSi, 557.2 (M+H). found 556.8.
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:11](O)[CH:10]=[CH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS([Cl:23])(=O)=O.[I-].[Na+].[C:26]([NH2:30])([CH3:29])([CH3:28])[CH3:27]>CC(C)=O.O.C(N(CC)CC)C>[ClH:23].[C:26]([NH:30][CH:10]1[CH2:11][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:8]=[CH:9]1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)N
Reactant: OC1C=CCC1(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)NC1C=CC(c2ccccc2)(c2ccccc2)C1
Product: Cl
Reaction time: 0.17 h

Procedure:
To a solution of 5,5-diphenyl-2-cyclopenten-1-ol (0.30 g) in acetone were added methanesulfonyl chloride (0.12 ml) and triethylamine (0.21 ml) at 1° C. to 3° C. After being stirred for 15 minutes sodium iodide (0.23 g) was added thereto and the mixture was stirred for 10 minutes. To the mixture was added t-butylamine (2.67 ml) at -1° C. to 2° C. and the mixture was stirred at room temperature overnight. Cold water was added to the mixture and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was dissolved in ethyl acetate. To the solution was added 3N hydrochloric acid (1 ml) with cooling in an ice bath, and the mixture was stirred for 30 minutes. The resulting precipitates were collected by filtration, washed with water, ethyl acetate successively and dried to give N-t-butyl-4,4-diphenyl-2-cyclopentenylamine hydrochloride (0.31 g).
Reaction SMILES: [BH4-].[Na+].[C:3]([O:6][C@H:7]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:8][N:9]1[CH2:14][CH2:13][C:12]([CH2:15][CH2:16][O:17][CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:11][CH2:10]1)(=[O:5])[CH3:4].[OH-:37].[Na+].OO>C(O)C.O.C1COCC1>[C:3]([O:6][C@H:7]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][O:17][CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:11]([OH:37])[CH2:10]1)(=[O:5])[CH3:4]
Reactant: CC(=O)O[C@@H](CN1CC=C(CCOC(c2ccccc2)c2ccccc2)CC1)c1ccccc1
Reactant: [OH-]
Agent: OO
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CC(=O)O[C@@H](CN1CCC(CCOC(c2ccccc2)c2ccccc2)C(O)C1)c1ccccc1

Procedure:
With reference to FIG. 8, general procedure II was used. The quantities of the chemicals in order of addition are as follows: NaBH4 (0.116 g, 3.08 mmol), THF (20 ml), BF3-ether complex (0.4 ml, 3.265 mmol), (R)-2-(4-(2-(benzhydryloxy)ethyl)-5,6-dihydropyridin-1(2H)-yl)-1-phenylethyl acetate 7a (0.7 g, 1.536 mmol), water (2 ml), ethanol (2 ml), 3N NaOH (1.1 ml) and 30% H2O2 (0.8 ml, 7.68 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](OC)=[CH:5][C:4]=1[C:11](=[O:29])[CH2:12][N:13]1[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][C:15]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)=[N:14]1.N1C=CC=C(C2C=C([C:41](OCC)=[O:42])NN=2)C=1.BrCC(C1C=CC(OC)=CC=1OC)=O>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:42][CH3:41])[CH:6]=[CH:5][C:4]=1[C:11](=[O:29])[CH2:12][N:13]1[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][C:15]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)=[N:14]1
Reactant: CCOC(=O)c1cc(-c2cccnc2)n[nH]1
Reactant: CCOC(=O)c1cc(-c2cccnc2)nn1CC(=O)c1cc(OC)ccc1OC
Agent: COc1ccc(C(=O)CBr)c(OC)c1
Product: CCOC(=O)c1cc(-c2cccnc2)nn1CC(=O)c1ccc(OC)cc1OC

Procedure:
This compound was made in an analogous fashion to ethyl 1-(2-(2,5-dimethoxyphenyl)-2-oxoethyl)-3-(pyridin-3-yl)-1H-pyrazole-5-carboxylate using ethyl 3-(pyridin-3-yl)-1H-pyrazole-5-carboxylate and 2-bromo-1-(2,4-dimethoxyphenyl)ethanone (purchased from Aldrich). 1H-NMR δ 9.08 (s, 1H), 8.58 (d, 1H), 8.14 (d, 1H), 8.00 (d, 1H), 7.33 (m, 11-1), 7.27 (s, 1H), 6.58 (dd, 1H), 6.49 (d, 1H), 5.98 (s, 2H), 4.31 (q, 2H), 4.00, (s, 3H), 3.88 (s, 3H), 1.34 (t, 3H). Calculated mass for C21H21N3O5, 395.15, observed, 396.2 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][CH:7]=[CH:6][N:5]=1)[CH3:2].C([Li])(C)(C)C.[Cl:23]C(Cl)(Cl)C(Cl)(Cl)Cl>O1CCCC1.CCCCC.CCOCC>[Cl:23][C:8]1[CH:7]=[CH:6][N:5]=[C:4]([O:3][CH2:1][CH3:2])[C:9]=1[NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: CCOc1ncccc1NC(=O)OC(C)(C)C
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCOc1nccc(Cl)c1NC(=O)OC(C)(C)C
Temperature: -60 °C

Procedure:
To a solution of 15 g (63 mmol) of t-butyl N-(2-ethoxy-3-pyridinyl)carbamate in 175 mL of dry tetrahydrofuran was added with stirring at -60° C., 78 mL (132 mmol) of 1.7M t-butyl lithium in pentane. The resulting solution was allowed to warm to -10° C. over a 30 min. period and was then cooled to -60° C. A A 22.3 g (94 mmol) amount of hexachoroethane was added all at once with stirring and the mixture are allowed to warm to ambient temperature. It was then diluted with 600 mL of ether and the resulting solution was washed with 150 mL of water, dried over magnesium sulfate, filtered, and concentrated by evaporation. The residue was purified by column chromatography to obtain 11.1 g (65 percent of theory) of the title compound as a colorless solid melting at 73°-74° C.
Reaction SMILES: C[O:2][C:3]1[CH:19]=[CH:18][C:6]2[CH2:7][C@@H:8]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:9](=[O:12])[NH:10][CH2:11][C:5]=2[CH:4]=1.B(Br)(Br)Br.CO>C(Cl)(Cl)Cl.O.CO>[OH:2][C:3]1[CH:19]=[CH:18][C:6]2[CH2:7][C@@H:8]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:9](=[O:12])[NH:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COC(=O)C[C@@H]1Cc2ccc(OC)cc2CNC1=O
Agent: BrB(Br)Br
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CO
Product: COC(=O)C[C@@H]1Cc2ccc(O)cc2CNC1=O
Temperature: -8 °C
Reaction time: 0.5 h
Yield: 68.3 %

Procedure:
A solution of methyl (S)-(−)-8-methoxy-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate (15.0 g, 0.057 mole) in CHCl3 (160 mL) was added dropwise over 30 min to a solution of boron tribromide (20.53 mL, 0.217 mole) in CHCl3 (160 mL) at −8° C. under argon, maintaining the temperature between −5° C. and 0° C. The reaction mixture was stirred at ca. −8° C. for 30 min and then MeOH (200 mL) was added, dropwise initially, maintaining the temperature at ca. 0° C. The reaction mixture was concentrated to give a viscous oil which was reconcentrated from MeOH (100 mL). The oil was dissolved in H2O/MeOH and a small amount of dark solid was removed by filtration. The filtrate was neutralized (to pH 7) with 50% sodium hydroxide, depositing a white solid. The suspension pH was adjusted to 4.5 by the addition of a small amount of acetic acid and the solid was collected and dried in vacuum to give afford the title compound (9.7 g, 68%). The product was assayed for chiral purity by HPLC: Chiralpak AS® column (4.6×50 mm), 100% EtOH mobile phase, 0.5 mL/min flow rate, uv detection at 215 nm; tR=7.5 min (S-enantiomer, 99%); tR=4.4 min (R-enantiomer, 1%).
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([CH3:10])[N:3]=1.Cl.Cl.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][C@@H:15]1[CH3:20].C(N(CC)CC)C.CO>C1COCC1>[Cl:9][C:6]1[C:7]([F:8])=[C:2]([N:17]2[CH2:18][CH2:19][N:14]([CH3:13])[C@@H:15]([CH3:20])[CH2:16]2)[N:3]=[C:4]([CH3:10])[N:5]=1
Reactant: Cc1nc(Cl)c(F)c(Cl)n1
Reactant: C[C@H]1CNCCN1C
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nc(Cl)c(F)c(N2CCN(C)[C@@H](C)C2)n1
Reaction time: 8 h
Yield: 98.2 %

Procedure:
To a solution of 4,6-dichloro-5-fluoro-2-methylpyrimidine (0.181 g, 1.0 mmol) and (2S)-1,2-dimethylpiperazine dihydrochloride (0.189 g, 1.0 mmol) in THF (10 mL) was added triethylamine (0.42 mL, 3.0 mmol) at room temperature. MeOH (1 mL) was added to improve solubility. The reaction mixture was stirred overnight, and then the solvent was removed in vacuo. Ether, THF and water were added to the resulting residue. The organics were separated, dried (Na2SO4) and evaporated to provide 4-chloro-6-[(3S)-3,4-dimethyl-1-piperazinyl]-5-fluoro-2-methylpyrimidine as a yellow solid (0.254 g, 98%). LCMS: (M+H)+=259.3.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[N:11]([CH2:12][CH2:13][OH:14])[CH2:10][CH2:9][NH:8][C:7]1=[O:15].C(N(CC)CC)C.[Cl:23][C:24]1[CH:34]=[CH:33][C:27]([O:28][CH2:29][C:30](Cl)=[O:31])=[CH:26][CH:25]=1>C(Cl)(Cl)Cl>[ClH:23].[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[N:11]([CH2:12][CH2:13][O:14][C:30]([CH2:29][O:28][C:27]2[CH:33]=[CH:34][C:24]([Cl:23])=[CH:25][CH:26]=2)=[O:31])[CH2:10][CH2:9][NH:8][C:7]1=[O:15]
Reactant: O=C(Cl)COc1ccc(Cl)cc1
Reactant: O=C1NCCN(CCO)C1c1cccs1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cl
Product: O=C(COc1ccc(Cl)cc1)OCCN1CCNC(=O)C1c1cccs1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
18.1 g (0.08 mol) of 3-(2-thienyl)-4-hydroxyethylpiperazin-2-one, prepared in accordance with Example 27, are dissolved in 160 ml of chloroform and acylated with 10.1 g (0.1 mol) of triethylamine and 20.5 g (0.1 mol) of 4-chlorophenoxyacetyl chloride. The mixture is stirred for a further 4 hours at room temperature and evaporated, and the residue is extracted by shaking with ethyl acetate. The ethyl acetate extract is dried with sodium sulphate, and the compound is precipitated as the hydrochloride by adding hydrochloric acid in ether.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)=O.[F:12][C:13]([F:25])([F:24])[O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH2:21])=[O:20])=[CH:17][CH:16]=1.O>CN(C)C=O>[F:12][C:13]([F:24])([F:25])[O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]2[O:20][CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=3)[N:21]=2)=[CH:17][CH:16]=1
Reactant: O=C(CBr)c1ccc(O)cc1
Reactant: NC(=O)c1ccc(OC(F)(F)F)cc1
Solvent: O
Solvent: CN(C)C=O
Product: Oc1ccc(-c2coc(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 140 °C
Reaction time: 2 h
Yield: 12 %

Procedure:
2-Bromo-1-(4-hydroxyphenyl)ethanone (0.39 g) and 4-trifluoromethoxybenzamide (0.39 g) were dissolved in N,N-dimethylformamide (10 ml) and stirred at 140° C. for 2 hours. After cooling the reaction mixture to room temperature, water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride aqueous solution, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=75:25). The result was concentrated to dryness under reduced pressure to afford the title compound as a pale yellow solid (70 mg).