Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([CH:17]3[CH2:22][O:21][CH2:20][CH2:19][O:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].C(C1C(O)=C(C(C)(C)C)C=C(C)C=1)(C)(C)C.[NH:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1>>[O:18]1[CH2:19][CH2:20][O:21][CH2:22][CH:17]1[C:16]1[C:10]2[S:9][C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:25]=[CH:26][N:27]=[C:2]([N:50]4[CH2:55][CH2:54][O:53][CH2:52][CH2:51]4)[CH:3]=3)=[N:12][C:11]=2[C:13]([O:23][CH3:24])=[CH:14][CH:15]=1
Reactant: C1COCCN1
Reactant: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(N4CCOCC4)c3)nc12
Temperature: 140 °C
Yield: 43.1 %

Procedure:
A stirred suspension of 150 mg (0.33 mmol) (±)-2-bromo-N-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-isonicotinamide, 217 mg (0.67 mmol) cesium carbonate and a few crystals of 2,6-di-tert-butyl-p-cresol in 2.90 ml (3.33 mmol) morpholine in a thick-walled glass pressure tube fitted with a teflon cap was heated at 140° C. for 24 h. The reaction mixture was then cooled to room temperature and poured onto water. The mixture was extracted three times with ethyl acetate, and the combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (ethyl acetate) followed by trituration in ether afforded 65 mg (43%) (±)-N-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-2-morpholin-4-yl-isonicotinamide as a light yellow solid. ES-MS m/e (%): 457 (M+H+, 100).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Cl:14][CH2:15][Si:16](Cl)([Cl:18])[CH3:17].C([Li])CCC>>[C:5]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:7][C:2]([Si:16]([Cl:18])([CH2:15][Cl:14])[CH3:17])=[CH:3][CH:4]=1
Reactant: Brc1ccc(-c2ccccc2)cc1
Reactant: C[Si](Cl)(Cl)CCl
Agent: [Li]CCCC
Product: C[Si](Cl)(CCl)c1ccc(-c2ccccc2)cc1

Procedure:
The title compound can be prepared by reaction of equimolar quantities of 4-bromobiphenyl, chloromethyldichloro(methyl)silane, and n-butyllithium according to the procedure of Example 3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:9]2[CH2:10][CH2:11][CH2:12][CH:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Clc1cccc(C2CCCN2)c1
Product: O=S(=O)(c1ccc(Cl)cc1)N1CCCC1c1cccc(Cl)c1

Procedure:
The title compound, light brown solid, m.p. 99° C. and MS: m/e=355 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-(3-chloro-phenyl)-pyrrolidine and 4-chloro-benzenesulfonyl chloride.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[CH3:15][O:16][C:17]1[C:27]([O:28][CH3:29])=[CH:26][C:20]2[CH2:21][CH2:22][NH:23][CH2:24][CH2:25][C:19]=2[CH:18]=1.[C:30]([OH:35])(=[O:34])[C:31]([OH:33])=[O:32].CO>C(OCC)(=O)C>[C:30]([OH:35])(=[O:34])[C:31]([OH:33])=[O:32].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:23]3[CH2:24][CH2:25][C:19]4[CH:18]=[C:17]([O:16][CH3:15])[C:27]([O:28][CH3:29])=[CH:26][C:20]=4[CH2:21][CH2:22]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: COc1cc2c(cc1OC)CCNCC2
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1OC)CCN(C[C@H](O)COc1cccc3[nH]ccc13)CC2

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 48% overall yield. FDMS m/e=396 (M+ of free base). α[D]589 =-9.34 (c=0.47, methanol).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([NH:12][S:13]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[CH:17]=2)(=[O:15])=[O:14])[C:8]1=[O:28])#[N:2].C([O-])([O-])=O.[K+].[K+].[CH3:38][O:39][C:40]1[CH:47]=[CH:46][CH:45]=[CH:44][C:41]=1[CH2:42]Cl>CC(C)=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([N:12]([CH2:42][C:41]2[CH:44]=[CH:45][CH:46]=[CH:47][C:40]=2[O:39][CH3:38])[S:13]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[CH:17]=2)(=[O:15])=[O:14])[C:8]1=[O:28])#[N:2]
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4cccc(C#N)c4)C3=O)cc2c1
Reactant: COc1ccccc1CCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)=O
Solvent: ClCCl
Product: COc1ccc2ccc(S(=O)(=O)N(Cc3ccccc3OC)[C@H]3CCN(Cc4cccc(C#N)c4)C3=O)cc2c1
Reaction time: 48 h

Procedure:
To a solution of 7-methoxynaphtalene-2-sulfonic acid [1-(3-cyanobenzyl)-2-oxopyrrolidin-3-(S)-yl]amide (0.12 g, 0.26 mmol), prepared as described in EXAMPLE 43, part A, in 20 mL of acetone is added K2CO3 (0.07 g, 0.53 mmol), 2-methoxybenzyl chloride (0.09 g, 0.28 mmol) and tetrabutylammonium iodide (0.02 g, 0.05 mmol). The resulting mixture is stirred for 48 hours, then diluted with CH2Cl2 and washed with saturated NaHCO3, H2O and saturated NaCl. The organic layer is dried over MgSO4, filtered, and concentrated. The crude product is purified by column chromatography eluting with 3% MeOH/CH2Cl2 to afford the title compound as a white foam.
Reaction SMILES: [C:1]1([CH:9]=[C:7]([OH:8])[CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].CC[O:12][C:13]([CH2:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=O)=O.OS(C(F)(F)F)(=O)=O>>[OH:2][C:1]1[C:9]2[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][C:13](=[O:12])[O:8][C:7]=2[CH:6]=[C:4]([OH:5])[CH:3]=1
Reactant: Oc1cc(O)cc(O)c1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Product: O=c1cc(-c2ccccc2)c2c(O)cc(O)cc2o1
Reaction time: 16 h
Yield: 74.1 %

Procedure:
A suspension of phloroglucinol (2.10 g, 12.9 mmol) in ethyl benzoyl acetate (2.41 mL, 13.8 mmol) was added over 0.5 hours to triflic acid (4 mL). The reaction was mechanically stirred in an ice bath for 16 h. The reaction was quenched by carefully pouring into an ice bath. The solid was filtered and dried yielding a yellow solid (2.43 g, 74.8%): mp. 179-182° C.; 1H NMR (DMSO-D6) δ 5.75 (s, 1H), 6.15 (s, 1H), 6.25 (s, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].[CH3:8][O:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[CH:17]([NH:19][C:20]1[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[C:25]([NH2:30])[CH:26]=3)[N:21]=1)[CH2:16][CH2:15]2>>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[CH:17]([NH:19][C:20]1[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[C:25]([NH:30][S:3]([N:2]([CH3:7])[CH3:1])(=[O:5])=[O:4])[CH:26]=3)[N:21]=1)[CH2:16][CH2:15]2
Reactant: COc1cccc2c1C(Nc1ccc3cc(N)ccc3n1)CC2
Reactant: CN(C)S(=O)(=O)Cl
Product: COc1cccc2c1C(Nc1ccc3cc(NS(=O)(=O)N(C)C)ccc3n1)CC2

Procedure:
The title compound was prepared in accordance with the general method described in example 66 from dimethylsulfamoyl chloride and rac-N2-(7-methoxy-indan-1-yl)-quinoline-2,6-diamine (Example 172); MS: m/e=412.6 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[NH2:14].[I:16]I>CO.S([O-])([O-])(=O)=O.[Ag+2]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([I:16])[C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[NH2:14]
Reactant: COC(=O)c1ccc(C(F)(F)F)cc1N
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: COC(=O)c1cc(I)c(C(F)(F)F)cc1N
Temperature: 80 °C
Reaction time: 1 h

Procedure:
2-Amino-4-trifluoromethyl-benzoic acid methyl ester, (48 g, 219 mmol) was dissolved in MeOH (750 ml). Silver sulfate (68.3 g, 219 mmol) and iodine (55.6 g, 219 mmol) was added and rinsed in with MeOH (50 ml). The reaction mixture was left for 1 hour at RT. The reaction mixture was filtered under vacuum and the filtrate concentrated in vacuo. The residue was taken up in MeOH (100 ml) and water (10 ml) and the mixture heated at 80° C. The crude solution was hot filtered to remove residual inorganics and the warm filtrate was poured slowly into water (750 ml) with vigorous stirring. The mixture was left to particulate for 10 minutes and filtered to give the title compound as an orange solid. MS m/z 345 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][C:6]1[NH:11][C:10]2[CH:12]=[CH:13][C:14]([O:16]C)=[CH:15][C:9]=2[S:8](=[O:19])(=[O:18])[N:7]=1)C.B(Br)(Br)Br>ClCCl>[OH:16][C:14]1[CH:13]=[CH:12][C:10]2[NH:11][C:6]([CH2:5][C:4]([OH:20])=[O:3])=[N:7][S:8](=[O:19])(=[O:18])[C:9]=2[CH:15]=1
Reactant: CCOC(=O)CC1=NS(=O)(=O)c2cc(OC)ccc2N1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(O)CC1=NS(=O)(=O)c2cc(O)ccc2N1
Temperature: 0 °C
Reaction time: 8 h
Yield: 87.2 %

Procedure:
To a solution of compound 4a (1 g, 3.7 mmol) in dichloromethane (23 mL), a solution of 1.0 M of BBr3 in dichloromethane was added dropwise at 0° C. over 5 minutes. The reaction mixture was stirred at 0° C. to room temperature overnight. LC-MS result confirmed the completion of the reaction. The reaction mixture was poured onto 50 mL of ice which was extracted with EtOAc (150 mL×3). The combined organic layer was dried over MgSO4, filtered, concentrated under reduced pressure and further dried under high vacuum to give 826.8 mg of desired product (10c) as brown foam in 87.2% yield. This crude product was directly used in next step without further purification. LC-MS: (ESI+) m/e=257.10 [M+1]+ (exact ms: 256.02).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.Cl.[O:12]([NH2:14])[CH3:13]>>[CH3:13][O:12][N:14]=[CH:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CON
Agent: Cl
Product: CON=Cc1ccc(OC)cc1
Yield: 100 %

Procedure:
Reaction of 4-methoxybenzaldehyde with methoxylamine hydrochloride as described in the preparation of Compound 44-A gave the title oxime ether as a clear oil (100% yield). 1HNMR indicated a 95:5 mixture of E- to Z-isomers. 1HNMR 400 MHz (CDCl3) δ (ppm): (E-isomer) 3.83 (3H, s, OCH3), 3.94 (3H, s, OCH3), 6.89 (2H, m, aromatics), 7.52 (2H, m, aromatics), 8.05 (1H, s, CH).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[C:13](N1C=CN=C1)([N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1)=[S:14]>ClCCl>[N:15]1([C:13]([N:10]2[CH2:9][CH2:8][N:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH2:12][CH2:11]2)=[S:14])[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: S=C(N1CCN(c2ccccn2)CC1)n1ccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
Imidazol-1-yl-(4-pyridin-2-yl-piperazin-1-yl)-methanethione (or intermediate 3 above) was formed as follows. N-(2-pyridyl) piperazine (MW 163.22, 0.91 ml, 6.0 mmoles, 1 eq) 2 was added to a solution of 1,1′-thiocarbonyldiimidazole (MW 178.22, 1.069 g, 6.0 mmoles, 1 eq) 1 in 50 ml of dichloromethane at room temperature. The reaction mixture was stirred overnight at room temperature. The mixture was washed with water, dried over sodium sulfate, filtered and concentrated to provide imidazol-1-yl-(4-pyridin-2-yl-piperazin-1-yl)-methanethione (MW 273.36, 1.354 g, 4.95 mmol, 83% yield)3, which was used without further purification. TLC(CH2Cl2/MeOH: 95/5): Rf=0.60, Product UV and Ninhydrin stain active. 1H-NMR (400 MHz, CDCl3), δ ppm: 3.72 (s, 4H), 4.02 (s, 4H), 6.67 (d, 1H, J=7 Hz), 6.72 (dd, 1H, J=7 and 5 Hz), 7.11 (s, 1H), 7.24 (s, 1H), 7.54 (t, 1H, J=7 Hz), 7.91 (s, 1H), 8.20 (d, 1H, J=5 Hz).
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12]CC)=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[CH3:16][NH:17][NH2:18]>O1CCOCC1>[CH3:16][N:17]1[C:10](=[O:12])[CH2:9][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:18]1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: CNN
Solvent: C1COCCO1
Solvent: O
Product: CN1N=C(c2ccccc2)CC1=O
Temperature: 500 °C
Reaction time: 8 h

Procedure:
To a mixture of 17.3 ml of ethyl benzoylacetate and 10 ml of water heated to 500° C. was added dropwise 5.3 ml of methyl-hydrazine over a period of 10 minutes (temperature rose to 70° C.) and the resulting mixture was heated at 60° C. for 2 hours. After adding 10 ml of dioxane the mixture was stirred at 55°-65° C. overnight, filtered, and the white solid was washed with water and dried in vacuo (P2O5) to afford 13.23 g of 2,4-dihydro-2-methyl-5-phenyl-3H-pyrazol-3-one (Formula III: R1 =CH3 ; R2 =Ph; R3 =H) as a white solid, m.p. 207° C.(d)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O)#[N:2].[Cl:11][C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[CH:17][C:18]([CH3:22])=[N:19]2)=[CH:14][CH:13]=1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>CN(C=O)C>[Cl:11][C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[CH:17][C:18]([CH:22]=[CH:6][C:5]3[CH:4]=[C:3]([CH:10]=[CH:9][CH:8]=3)[C:1]#[N:2])=[N:19]2)=[CH:14][CH:13]=1
Reactant: Cc1ccc2ccc(Cl)cc2n1
Reactant: N#Cc1cccc(C=O)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Yield: 82.9 %

Procedure:
Under the protection by nitrogen, meta-cyanobenzaldehyde (137.6 g, 1.05 mol), 7-chloroquinaldine (177 g, 1.0 mol) and sodium acetate (82 g) are added into 200 ml of acetic anhydride and 800 ml of dimethyl fomamide (DMF), and the resulted mixture solution is stirred and heated to reflux for 24 hours. After distilling the most solvent, 300 ml of water is added into the residue, and then extracted by ethyl acetate (500 ml×3), washed with saturated saline water, dried with anhydrous sodium sulfate and condensed in the vacuum. The resulted residue is then purified through Flash Column Chromatography to obtain 241 g of the title compound, with a yield of 83%.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C@@H:17]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[C:36]([Br:39])[CH:37]=3)[CH:32]=[CH:31][N:30]=2)=[CH:24][CH:23]=1)[C:18]([OH:20])=[O:19]>CS(C)=O>[Br:39][C:36]1[CH:37]=[C:38]2[C:33]([CH:32]=[CH:31][N:30]=[C:29]2[O:28][C:25]2[CH:24]=[CH:23][C:22]([CH2:21][C@H:17]([NH:16][C:2]3[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]4[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=4)[N:3]=3)[C:18]([OH:20])=[O:19])=[CH:27][CH:26]=2)=[CH:34][CH:35]=1
Reactant: N[C@@H](Cc1ccc(Oc2nccc3ccc(Br)cc23)cc1)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Solvent: CS(C)=O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@@H](Cc1ccc(Oc2nccc3ccc(Br)cc23)cc1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 109c, 2,6-dichloroquinoline-3-carboxylic acid is reacted with (S)-2-amino-3-[4-(7-bromo-isoquinolin-1-yloxy)-phenyl]-propionic acid (prepared by analogy to Example 109a,b) in DMSO to provide the title compound in good yield.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][CH:11]=[C:12]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[N:13]=2)=[CH:5][CH:4]=1.S(Cl)([Cl:23])=O.N1C2C=CC=CC=2N=N1>C(Cl)Cl.C(Cl)(Cl)Cl>[Cl:23][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][CH:11]=[C:12]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[N:13]=2)=[CH:5][CH:4]=1
Reactant: O=C(c1coc(-c2ccc(CO)cc2)n1)N1CCCC1
Reactant: O=S(Cl)Cl
Agent: c1ccc2[nH]nnc2c1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=C(c1coc(-c2ccc(CCl)cc2)n1)N1CCCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 82 %

Procedure:
A solution of 2-[4-(hydroxymethyl)phenyl]-4-(pyrrolidin-1-ylcarbonyl)-1,3-oxazole (0.467 g, 1.89 mmol) in CH2Cl2 was treated with a solution of thionyl chloride (0.281 g, 2.36 mmol) and benzotriazole (0.281 g, 2.36 mmol) in CH2Cl2, stirred for 6 hours at room temperature, diluted with CHCl3, filtered over Celite and concentrated under vacuum, The resultant residue was purified by flash chromatography (silica, MeOH:CH2Cl2 5%) to give the title product in 82% yield, identified by NMR and mass spectral analyses. LCMS (ESI+) 291 (MH+) mp 126-128° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH3:11])[N:9]=[CH:10][C:3]=12.OC1N=CN=C2N(C)N=CC=12.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C(O)(C)C>[CH3:11][N:8]1[C:4]2=[N:5][CH:6]=[N:7][C:2]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[C:3]2[CH:10]=[N:9]1
Reactant: Cn1ncc2c(Cl)ncnc21
Reactant: C1CNCCN1
Agent: Cn1ncc2c(O)ncnc21
Solvent: CC(C)O
Product: Cn1ncc2c(N3CCNCC3)ncnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
According to the method described in J. Org. Chem., 21: 1240-1256 (1956), 4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine was derived from 4-hydroxy-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (1.20 g, 8.03 mmol). To this partially purified product, an isopropanol solution (50 mL) of piperazine (5.55 g, 64.4 mmol) was added, followed by stirring at room temperature for 1 hour and then heating under reflux for 1 hour. The reaction solution was concentrated, saturated brine was added thereto, the mixture was extracted with chloroform, the extract was washed with saturated brine and dried over anhydrous sodium sulfate, and then the solvent was evaporated to give the target compound (1.44 g, 6.61 mmol).
Reaction SMILES: [OH:1][N:2]1[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][C:5](=NO)[CH2:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH2:22]([OH:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].CS(O)(=O)=O>>[OH:1][N:2]1[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][C:5]([O:30][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])([O:30][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCCCCCCCO
Reactant: ON=C1CC(c2ccccc2)N(O)C(c2ccccc2)C1
Agent: CS(=O)(=O)O
Product: CCCCCCCCOC1(OCCCCCCCC)CC(c2ccccc2)N(O)C(c2ccccc2)C1
Yield: 32.5 %

Procedure:
The general procedure of Example 12 is repeated using 10.0 g (0.035 mole) 1-hydroxy-2,6-diphenyl-4-piperidone oxime, 25.0 g (0.19 moles) 1-octanol and 7.0 g (0.073 moles) methanesulfonic acid. 5.8 g (32% yield) of the title compound is isolated as a clear oil after purification by LC (silica gel, ethyl acetate:hexane).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(CC)CC)C.[N+:22]([C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1)([O-:24])=[O:23]>C(Cl)Cl.C(OCC)(=O)C>[N+:22]([C:25]1[CH:26]=[CH:27][C:28]([C:29]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:4]3[CH:3]=[CH:2][CH:1]=[C:5]3[CH2:6]2)=[O:30])=[CH:32][CH:33]=1)([O-:24])=[O:23]
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1Cc2cccn2Cc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
To a solution of 3.3 g of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 50 ml of methylene chloride under argon is added 5.0 ml of triethylamine followed by ice bath cooling. A solution of 4.0 g of 4-nitrobenzoyl chloride in 20 ml of methylene chloride is added dropwise. Following complete addition, the ice bath is removed and the reaction mixture stirred at room temperature for 2 hours. The volatiles are removed in vacuo to give a residue which is dissolved in ethyl acetate. The solution is washed with water, 1N HCl, NaHCO3, brine, dried with Na2SO4 and filtered. The filtrate is concentrated in vacuo to a solid which is dissolved in methylene chloride, passed through silica gel and the pad washed with ethyl acetate. The combined filtrate is concentrated in vacuo to give 5.3 g of the desired product as a yellow solid, m.p. 188°-190° C.
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]([Mg]Br)[CH3:11].[OH-].[Na+]>O1CCCC1>[CH2:7]([C:8]1([NH2:9])[CH2:11][CH2:10]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC[Mg]Br
Reactant: N#CCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC1(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4.5 g (38 mmol) of phenylacetonitrile was dissolved in 50 mL of tetrahydrofuran, mixed with 12.4 mL (41.9 mmol) of tetraisopropyl propylorthotitanate and 78 mL (76 mmol) of 0.98M ethylmagnesium bromide in tetrahydrofuran and stirred at room temperature for 1 hour. After the stirring, 9.6 mL (78 mmol) of boron trifluoride ethyl etherate complex was added, and the reaction solution was stirred at room temperature for another 1 hour. After completion of the reaction, 2 M aqueous sodium hydroxide was added, and the reaction solution was extracted with diethyl ether. After addition of 3 M hydrochloric acid, the organic layer was separated. The resulting aqueous layer was basified with 5 M aqueous sodium hydroxide and extracted with methylene chloride.
Reaction SMILES: [C:1]([NH:11][C@@H:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH:13]1[O:15][CH2:14]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(OCC)C>[CH2:20]([NH:27][CH2:14][CH:13]([OH:15])[C@@H:12]([NH:11][C:1]([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2])[CH2:16][CH:17]([CH3:19])[CH3:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C1CO1
Reactant: NCc1ccccc1
Solvent: CCOCC
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(O)CNCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 100 mg of (3S)-3-carbobenzoxyamino-5-methyl-1,2-epoxyhexane in 10 ml of diethyl ether were added 2 g of dry silica gel and 0.1 ml of benzylamine, and the mixture was stirred for 16 hours at room temperature, then heated under reflux for 2 hours. After filtration of the silica gel, the filtrate was evaporated under reduced pressure. The residue was purified by preparative silica gel thin layer chromatography (developing solvent: lower layer of chloroform/methanol/water=8/3/1 by volume) to obtain 56 mg of (3S)-N-benzyl-3-carbobenzoxyamino-2-hydroxy-5-methylhexylamine as a colorless viscous oil. To a solution of 54 mg of the amine compound obtained in 10 ml methanol was added 0.2 ml of a 2N-hydrochloric acid. The mixture was hydrogenated over 10 mg of palladium charcoal under hydrogen atmosphere. After filtration of the catalyst, the filtrate was evaporated under reduced pressure to obtain 43 mg of (3S) -N-benzyl-3-amino-2-hydroxy-5-methylhexylamine dihydrochloride.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:13])[C:8]([CH3:12])=[CH:9][CH:10]=2)[NH:5][C:4](=[O:14])[CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:19](Cl)(=[O:21])[CH3:20].C(O)(=O)CC>O.C(Cl)CCl>[C:19]([C:3]1[C:4](=[O:14])[NH:5][C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[C:8]([CH3:12])[C:7]=2[CH3:13])(=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: Cc1ccc2c(O)cc(=O)[nH]c2c1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CCC(=O)O
Solvent: ClCCCl
Product: CC(=O)c1c(O)c2ccc(C)c(C)c2[nH]c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
10 g of 4-hydroxy-7,8-dimethyl-2-quinolone was added to 60 cc of ethylene dichloride, and 14 g of aluminum chloride was added thereto under stirring at room temperature. The reaction solution was first slurried by the formation of a complex and then became a uniform solution. Then, a solution of a mixture of 5.3 cc of acetyl chloride and 16 cc of ethylene dichloride was dropwise added thereto at room temperature, and the acetylation reaction was conducted at 50° C. for 3 hours. The reaction solution was cooled to room temperature, and 50 cc of water was carefully added for hydrolysis. Then, 5 cc of propionic acid was added thereto, and ethylene dichloride was distilled off together with water under heating, and the mixture was aged at 100° C. for 3 hours under stirring. The slurry was cooled at room temperature and subjected to filtration. The obtained crystals were dried to obtain 11.5 g of 3-acetyl-4-hydroxy-7,8-dimethyl-2-quinolone. Yield was 94%, and the purity was 98% (as analyzed by liquid chromatography). ##STR7##