Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:34])[CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([S:14]([C@H:17]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]3)(=[O:16])=[O:15])=[CH:13][C:8]=2[N:7]=[C:6]1[CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31].Cl[Si](C)(C)C>CO>[CH3:1][N:2]([CH3:34])[CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([S:14]([C@H:17]3[CH2:21][CH2:20][NH:19][CH2:18]3)(=[O:15])=[O:16])=[CH:13][C:8]=2[N:7]=[C:6]1[CH2:29][C:30]([CH3:32])([CH3:31])[CH3:33]
Reactant: CN(C)CCn1c(CC(C)(C)C)nc2cc(S(=O)(=O)[C@H]3CCN(C(=O)OC(C)(C)C)C3)ccc21
Agent: C[Si](C)(C)Cl
Solvent: CO
Product: CN(C)CCn1c(CC(C)(C)C)nc2cc(S(=O)(=O)[C@H]3CCNC3)ccc21
Temperature: 50 °C
Reaction time: 16 h
Yield: 99.3 %

Procedure:
To a solution of (S)-tert-butyl 3-(1-(2-(dimethylamino)ethyl)-2-neopentyl-1H-benzo[d]imidazol-5-ylsulfonyl)pyrrolidine-1-carboxylate (STEP E, 980 mg, 1.99 mmol) in methanol (6 mL) was added chlorotrimethylsilane (1.27 mL, 9.95 mmol). The mixture was stirred at 50° C. for 16 h. The resulting mixture was concentrated. The residue was added 2 mol/L sodium hydroxide aqueous solution to pH>7 and the mixture was extracted with ethyl acetate (150 mL). The organic layer was washed with brine and dried over sodium sulfate. The resulting solution was concentrated to give the title compound (776 mg, 99%) as an oil.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[NH:25][CH:24]=[CH:23]4)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:29][CH3:30])C1C=CC=CC=1.[H][H]>CN(C=O)C.C(Cl)Cl.[Pd]>[OH:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[NH:25][CH:24]=[CH:23]4)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:29][CH3:30]
Reactant: [H][H]
Reactant: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OCc1ccccc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1O
Yield: 43.9 %

Procedure:
A solution of 7-benzyloxy-4-(indol-5-yloxy)-6-methoxyquinazoline (8 g, 20 mmol) in DMF (50 ml) and methylene chloride (100 ml) containing 10% palladium on charcoal (2g) was hydrogenated at 1.8 atmospheres pressure until uptake of hydrogen had ceased. The solution was filtered, the catalyst was washed with DMF and the filtrate was evaporated. The residue was purified by column chromatography eluting with methylene chloride, followed by methylene chloride/methanol (95/5 and 90/10). After evaporation of the solvent, the residue was triturated with ether, filtered and dried under vacuum to give 7-hydroxy-4-(indol-5-yloxy)-6-methoxyquinazoline (2.7 g; 44%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:18][CH:10]3[CH2:11][N:12]([C:15](=[O:17])[CH3:16])[CH2:13][CH2:14][CH:9]3[C:8]=2[CH:19]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[O:18][CH:10]3[CH2:11][N:12]([C:15](=[O:17])[CH3:16])[CH2:13][CH2:14][CH:9]3[C:8]=2[CH:19]=1
Reactant: CC(=O)N1CCC2c3cc([N+](=O)[O-])ccc3OC2C1
Agent: [Pd]
Solvent: CO
Product: CC(=O)N1CCC2c3cc(N)ccc3OC2C1
Reaction time: 16 h

Procedure:
A mixture of 1-(6-nitro-3,4,4a,9a-tetrahydro-1H-benzo[4,5]furo[2,3-c]pyridin-2-yl)-ethanone (600 mg) in MeOH (60 mL) was hydrogenated for 16 h at 10 bar using a H-Cube® instrument with a 70 mm cartridge of 10% Pd—C. The solvent was evaporated to yield 1-(6-amino-3,4,4a,9a-tetrahydro-1H-benzo[4,5]furo[2,3-c]pyridin-2-yl)-ethanone. MS m/z 233 [M+H]+
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]3[CH2:26][CH2:25][CH2:24][CH:23]([NH:27]C(=O)OC(C)(C)C)[CH2:22]3)=[N:19][CH:20]=1)=[CH:11][C:10]([C:35]1[CH:40]=[C:39]([Cl:41])[C:38]([OH:42])=[C:37]([Cl:43])[CH:36]=1)=[CH:9][CH:8]=2)(=[O:3])[CH3:2].Cl>ClCCl.C(OCC)C>[NH2:27][CH:23]1[CH2:24][CH2:25][CH2:26][N:21]([C:18]2[N:19]=[CH:20][C:15]([NH:14][C:13]3[C:12]4[C:7](=[CH:8][CH:9]=[C:10]([C:35]5[CH:36]=[C:37]([Cl:43])[C:38]([OH:42])=[C:39]([Cl:41])[CH:40]=5)[CH:11]=4)[N:6]=[CH:5][C:4]=3[C:1](=[O:3])[CH3:2])=[CH:16][CH:17]=2)[CH2:22]1
Reactant: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1Nc1ccc(N2CCCC(NC(=O)OC(C)(C)C)C2)nc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1Nc1ccc(N2CCCC(N)C2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.7 %

Procedure:
tert-butyl 1-(5-(3-acetyl-6-(3,5-dichloro-4-hydroxyphenyl)quinolin-4-ylamino)pyridin-2-yl)piperidin-3-ylcarbamate (52 mg, 0.080 mmol) was dissolved in dichloromethane (5 mL). To this solution was added a 2.0 M HCl solution in diethyl ether (2 mL) the mixture was stirred for 16 h at room temperature where a precipitate formed. The precipitate was filtered off, washed with dichloromethane (10 mL), dried under vacuum to obtain the desired product as the HCl salt (40 mg, 79%) as a yellow-brown solid: 1H NMR (500 MHz, DMSO-d6) δ 10.56 (s, 1H), 8.94 (s, 1H), 8.28 (s, 1H), 8.05 (s, 1H), 7.87 (s, 1H), 7.29 (s, 2H), 4.17 (s, 1H), 3.95 (s, 3H), 2.66 (s, 3H), 2.38 (s, 4H), 2.23 (s, 2H), 2.03 (s, 2H), 1.67 (s, 1H), 1.51 (s, 2H), 1.30 (s, 3H); ESI MS m/z 454, [C25H28ClN3O3+H]+; HPLC 99.5% (AUC), tR=9.99 min.
Reaction SMILES: Br[C:2]1[S:3][C:4]([S:17](=[O:23])(=[O:22])[NH:18][CH2:19][CH2:20][OH:21])=[CH:5][C:6]=1[C:7]1[S:11][C:10]([NH:12][C:13](=[O:15])[CH3:14])=[N:9][C:8]=1[CH3:16].C([Li])CCC>C1COCC1>[OH:21][CH2:20][CH2:19][NH:18][S:17]([C:4]1[S:3][CH:2]=[C:6]([C:7]2[S:11][C:10]([NH:12][C:13](=[O:15])[CH3:14])=[N:9][C:8]=2[CH3:16])[CH:5]=1)(=[O:23])=[O:22]
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)NCCO)sc2Br)s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(C)c(-c2csc(S(=O)(=O)NCCO)c2)s1
Temperature: -70 °C
Reaction time: 2 h
Yield: 9 %

Procedure:
N-{5-[2-Bromo-5-(2-hydroxy-ethylsulfamoyl)-thiophen-3-yl]-4-methyl-thiazol-2-yl}-acetamide obtained in Step I as described above (1760 mg; 4 mmol; 1 eq), is dissolved in anhydrous THF (100 ml). The reaction mixture is then cooled down to −70° C. and put under nitrogen. n-Butyllithium (48 ml; 1.6 M; 95.9 mmol; 24 eq) is added dropwise. The reaction is stirred 2 hours at −70° C. and quenched with water. Solvents are evaporated and the resulting residue is purified by preparative HPLC, affording Compound (38) as a white solid (135 mg; 9%).
Reaction SMILES: [CH:1]1[N:2]=[CH:3][N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[N:7]3[CH2:16][CH2:17][C@H:6]3[C:5]=12.[Cl:18]N1C(=O)CCC1=O.CN(C)C=O>O>[Cl:18][C:1]1[N:2]=[CH:3][N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[N:7]3[CH2:16][CH2:17][C@H:6]3[C:5]=12
Reactant: O=C1c2ccccc2-n2cncc2[C@@H]2CCN12
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2-n2cnc(Cl)c2[C@@H]2CCN12
Reaction time: 0.67 h

Procedure:
0.54 g (2.4 mmol) of (S)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one and 0.32 g (2.4 mmol) of N-chlorosuccinimide are treated with 10 ml of dimethylformamide and the mixture is stirred at 90° for 40 minutes. The mixture is poured into 50 ml of water and extracted four times with chloroform. The combined chloroform extracts are washed three times with water, dried over magnesium suphate and evaporated. The crude product is chromatographed on silica gel using chloroform/methanol (19:1) for the elution and subsequently recrystallized from ethyl acetate. There is obtained (S)-1-chloro-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one of melting point 210°-214°.
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH3:14])=[CH:10][C:9]([CH2:15][CH2:16][CH:17]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][C:20]1[CH:21]=[C:22]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:23]=[CH:24][C:25]=1[CH3:26].CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:19][C:20]1[CH:21]=[C:22]([N:27]2[CH2:28][CH2:29][N:30]([CH2:17][CH2:16][CH2:15][C:9]3[CH:10]=[C:11]([CH2:12][CH2:13][CH3:14])[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=3)[CH2:31][CH2:32]2)[CH:23]=[CH:24][C:25]=1[CH3:26]
Reactant: CCCc1cc(CCC=O)nn1-c1ccccc1
Reactant: Cc1ccc(N2CCNCC2)cc1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(c3ccc(C)c(C)c3)CC2)nn1-c1ccccc1

Procedure:
159 mg (85%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-5-propyl-1H-pyrazol-3-yl)propanal (100 mg, 0.413 mmol), 1-(3,4-dimethylphenyl)piperazine (79 mg, 0.413 mmol), DIPEA (0.110 mL, 0.620 mmol) and NaBH(OAc)3 (263 mg, 1.239 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:21]3[N:29](S(C4C=CC(C)=CC=4)(=O)=O)[C:24]4=[N:25][CH:26]=[CH:27][CH:28]=[C:23]4[CH:22]=3)=[CH:10][N:11]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)[C:6]2=[CH:5][C:4]=1[O:40][CH3:41].CO>[OH-].[K+]>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:21]3[NH:29][C:24]4=[N:25][CH:26]=[CH:27][CH:28]=[C:23]4[CH:22]=3)=[CH:10][N:11]([CH2:12][CH2:13][N:14]3[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]3)[C:6]2=[CH:5][C:4]=1[O:40][CH3:41]
Reactant: COc1cc2c(nc1OC)c(-c1cc3cccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2CCN1CCN(C)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cc2c(nc1OC)c(-c1cc3cccnc3[nH]1)cn2CCN1CCN(C)CC1

Procedure:
Bring bisazaindole 21 (10 mg, 0.017 mmol) to reflux in KOH at 3%/MeOH (10 mL) for 5 h. Concentrate the reaction mixture, dilute the residue with H2O, add 2N HCl to adjust the pH to 8, extract with CH2Cl2, dry (MgSO4) and concentrate. Purification by flash chromatography leads to 22 (3.4 mg, 46.6%) as an ivory-colored solid: 1H NMR (CDCl3) δ 10.77 (s broad, 1H), 8.22 (d, 1H, J=4.5 Hz), 7.84 (d, 1H, J=7.4 Hz), 7.59 (s, 1H), 7.15 (s, 1H), 7.03 (m, 1H), 6.58 (d, 1H, J=1.2 Hz), 4.73 (s, 3H), 4.25 (s, 3H) overlapping with (t, 2H), 3.99 (s, 3H), 2.80 (t, 2H), 2.51 (m broad, 8H). TLC (MeOH at 10%/CH2Cl2, 0.25% of NH3) Rf=0.40, m/z obs.=421.14 (M+1).
Reaction SMILES: [CH:1]1([C:5]2[N:9]3[CH:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]3=[C:7]([C:15]3[N:23](COCC[Si](C)(C)C)[C:18]4=[N:19][CH:20]=[CH:21][CH:22]=[C:17]4[CH:16]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.Cl>>[CH:1]1([C:5]2[N:9]3[CH:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]3=[C:7]([C:15]3[NH:23][C:18]4=[N:19][CH:20]=[CH:21][CH:22]=[C:17]4[CH:16]=3)[N:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: C[Si](C)(C)CCOCn1c(-c2nc(C3CCC3)n3ccnc(N)c23)cc2cccnc21
Agent: Cl
Product: Nc1nccn2c(C3CCC3)nc(-c3cc4cccnc4[nH]3)c12

Procedure:
3-Cyclobutyl-1-[1-(2-trimethylsilylethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]imidazo[1,5-a]pyrazin-8-amine (35 mg, 0.08 mmol) was stirred with concentrated HCl for 15 min. The mixture was then concentrated in vacuo and purified via mass directed preparative HPLC to afford the title compound. 1H NMR (400 MHz DMSO-d6) δ 1.92-2.00 (m, 1H), 2.07-2.14 (m, 1H), 2.43-2.47 (m, 4H), 3.93-4.01 (m, 1H), 6.35-6.49 (bs, 2H), 6.64-6.70 (m, 1H), 7.03-7.10 (m, 2H), 7.39-7.49 (m, 1H), 7.95-8.00 (m, 1H), 8.18-8.23 (m, 1H), 11.91 (bs, 1H). MS (ES+): m/z: 305.17 [MH+].
Reaction SMILES: CC1C=CC=C2C=1C=C(C(OCC)=O)N2.[CH3:16][C:17]1[CH:25]=[CH:24][C:23]2[C:26](=[O:31])[CH2:27][CH2:28][CH2:29][CH2:30][N:21]3[C:22]=2[C:18]=1[CH:19]=[C:20]3[C:32]([O:34][CH2:35][CH3:36])=[O:33].[Br:37]N1C(=O)CCC1=O.O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:37][CH2:16][C:17]1[CH:25]=[CH:24][C:23]2[C:26](=[O:31])[CH2:27][CH2:28][CH2:29][CH2:30][N:21]3[C:22]=2[C:18]=1[CH:19]=[C:20]3[C:32]([O:34][CH2:35][CH3:36])=[O:33]
Reactant: CCOC(=O)c1cc2c(C)ccc3c2n1CCCCC3=O
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCOC(=O)c1cc2c(C)cccc2[nH]1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cc2c(CBr)ccc3c2n1CCCCC3=O

Procedure:
In accordance with the process described in Example 22(a)-(c) except for using ethyl 4-methyl-1H-indole-2-carboxylate as a starting material, ethyl 5,6,7, 8-tetrahydro-11-methyl-8-oxo-4H-azocino[3.2.1-hi]indole-2-carboxylate (m.p. 98° C., recrystallized from isopropyl alcohol) was synthesized. Ethyl 5,6,7,8-tetrahydro-11-methyl-8-oxo-4H-azocino[3.2.1-hi]indole-2-carboxylate (2.50 g, 8.76 mmol) was then dissolved in carbon tetrachloride (80 ml) and N-bromosuccinimide (1.72 g, 9.64 mmol) and 2,2'-azobisisobutyronitrile (43 mg) were added therein under refluxing condition to heat at reflux for 2 hours. The reaction mixture was poured into water and extracted with chloroform. The extract was washed with saturated sodium chloride solution and dried over magnesium sulfate. The solvent was distilled off and the obtained residue was purified with silica gel column chromatography (eluated with ethyl acetate/n-hexane=1/10) to give ethyl 5,6,7,8-tetrahydro-11-bromomethyl-8-oxo-4H-azocino[3.2.1-hi]indole-2-carboxylate (3.12 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:10]=2[CH:11]=1.O[CH2:14][C:15]1[N:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([NH2:19])=[O:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OC(C)(C)C)=O)=O)(C)(C)C>C(Cl)Cl.C1COCC1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[C:4]([O:12][CH2:14][C:15]2[N:23]=[CH:22][CH:21]=[CH:20][C:16]=2[C:17]([NH2:19])=[O:18])[CH:3]=1
Reactant: NC(=O)c1cccnc1CO
Reactant: Oc1cc(Br)cc2ncccc12
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: NC(=O)c1cccnc1COc1cc(Br)cc2ncccc12
Yield: 45 %

Procedure:
100 mg 7-Bromo-quinolin-5-ol, 77.5 mg of 2-(hydroxymethyl)nicotinamide 3.7, 233.5 mg of triphenylphosphine and 205 mg of Di-tertbutyl-azodicarboxylate (DBAD) were dissolved in 2.5 mL of DCM and 7.5 mL of THF under Argon at room temperature. After 14 h the precipitate was collected and dried. The mother liquor was concentrated and the formed precipitate again collected to yield 72 mg Example 22.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:16]([OH:26])[CH2:17][C:18]3[C:23]([Cl:24])=[CH:22][N:21]=[CH:20][C:19]=3[Cl:25])[CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:15])[F:14])[CH2:3][CH2:2]1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[CH:35]=[C:34]([C@H:39]([CH3:43])[C:40](O)=[O:41])[CH:33]=[CH:32]2.Cl.C(N=C=NCCCN(C)C)C.O>CN(C=O)C.CN(C)C1C=CN=CC=1>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:16]([O:26][C:40](=[O:41])[CH:39]([C:34]3[CH:33]=[CH:32][C:31]4[C:36](=[CH:37][CH:38]=[C:29]([O:28][CH3:27])[CH:30]=4)[CH:35]=3)[CH3:43])[CH2:17][C:18]3[C:19]([Cl:25])=[CH:20][N:21]=[CH:22][C:23]=3[Cl:24])[CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:14])[F:15])[CH2:3][CH2:2]1
Reactant: OC(Cc1c(Cl)cncc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2cc(C(C)C(=O)OC(Cc3c(Cl)cncc3Cl)c3ccc(OC(F)F)c(OCC4CC4)c3)ccc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.9 %

Procedure:
Compound (3) (12.0 g) was dissolved in DMF (100 ml) then (S)-2-(6-methoxy-naphthalen-2-yl)-propionic acid (7.5 g), 4-dimethylaminopyridine (3.6 g), and 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride (5.7 g) was added. After stirring at rt for 4 hours, water (1000 ml) is added. The mixture was extracted with EtOAc (500 ml×2), the combined organic layers are dried over sodium sulphate, and the solvent was removed by evaporation under reduced pressure to afford 17.0 g of an oil which is crystallized from EtOH thus obtaining 11.5 g of the title compound as mixture of diastereomers (11) and (13).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4]>OC1O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1O>[CH2:11]([OH:12])[C@H:9]1[O:10][C@@H:2]([O:1][C@@H:7]([C@@H:5]([OH:6])[C@H:3]([OH:4])[CH:2]=[O:1])[C@H:9]([OH:10])[CH2:11][OH:12])[C@H:3]([OH:4])[C@@H:5]([OH:6])[C@H:7]1[OH:8]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O
Product: O=C[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O)[C@H](O)CO

Procedure:
Another method is described in, for example, "N. K. Richtmyer, C. S. Hudson, J, Am. Chem. Soc., 57, 1716 (1935)". In this method, the 2- and 3-positions of the D-glucose portion included in lactose are subjected to walden inversion so as to obtain neolactose consisting of D-altrose and D-galactose, followed by hydrolyzing neolactose so as to obtain the desired D-altrose product. The D-galactose contained in the mixture obtained after the hydrolysis is consumed by allowing yeast to act thereon and, thus, is removed. The remaining D-altrose is refined as a benzyl mercaptal derivative and, then, returned to D-altrose. It should be noted that this method necessitates a step of protecting the hydroxyl group which is irrelevant to the reaction and another step of releasing the protective group after the reaction. It follows that as many as eight steps are involved in this method starting with the Walden inversion of lactose. Naturally, troublesome operations are required for synthesizing the product D-altrose. In addition, the product yield is as low as only 8%.
Reaction SMILES: [N:1]1([C:7](=[O:29])[CH2:8][CH2:9][CH:10]=[CH:11][CH2:12][CH:13]=[CH:14][CH2:15][CH:16]=[CH:17][CH2:18][CH:19]=[CH:20][CH2:21][CH:22]=[CH:23][CH2:24][CH:25]=[CH:26][CH2:27][CH3:28])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:30](O)(=[O:38])[C:31]1[C:32](=[CH:34][CH:35]=[CH:36][CH:37]=1)[OH:33].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC#N>[OH:33][C:32]1[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=1[C:30]([N:4]1[CH2:5][CH2:6][N:1]([C:7](=[O:29])[CH2:8][CH2:9][CH:10]=[CH:11][CH2:12][CH:13]=[CH:14][CH2:15][CH:16]=[CH:17][CH2:18][CH:19]=[CH:20][CH2:21][CH:22]=[CH:23][CH2:24][CH:25]=[CH:26][CH2:27][CH3:28])[CH2:2][CH2:3]1)=[O:38]
Reactant: O=C(O)c1ccccc1O
Reactant: CCC=CCC=CCC=CCC=CCC=CCC=CCCC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCC=CCC=CCC=CCC=CCC=CCC=CCCC(=O)N1CCN(C(=O)c2ccccc2O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.7 %

Procedure:
To a mixture of 1-(piperazin-1-yl)docosa-4,7,10,13,16,19-hexaen-1-one (1.17 g, 2.95 mmol), salicylic acid (0.61 g, 4.43 mmol) and Et3N (0.89 g, 8.85 mmol) in CH3CN (10 mL) was added HATU (1.68 g, 4.43 mmol). The mixture was stirred (RT, 16 h). The solvent was removed under reduced pressure and the residue was extracted with EtOAc (4×50 mL). The combined organic layers were washed successively with 1 N aqueous HCl, water, 5% NaHCO3 and water, and dried over MgSO4. The solvent was removed under reduced pressure. Purification of the crude product by prep-HPLC afforded 1-(4-(2-hydroxybenzoyl)piperazin-1-yl)docosa-4,7,10,13,16,19-hexaen-1-one (300 mg, 19.6%) as a light yellow oil. Mass calculated for C33H44N2O3=516.71. found: [M+H]+ 517.6.
Reaction SMILES: C([O:8][CH2:9][CH2:10][N:11]1[C:15]([CH3:16])=[C:14](CC2C=CC(CC)=CC=2)[C:13](O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)=[N:12]1)C1C=CC=CC=1>C(O)C.[C].[Pd]>[OH:8][CH2:9][CH2:10][N:11]1[C:15]([CH3:16])=[CH:14][CH:13]=[N:12]1
Reactant: CCc1ccc(Cc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)nn(CCOCc3ccccc3)c2C)cc1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccnn1CCO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 372.5 %

Procedure:
To a solution of 1-(2-benzyloxyethyl)-4-[(4-ethylphenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-methyl-1H-pyrazole (0.012 g) in ethanol (2 mL) was added a catalytic amount of 10% palladium-carbon powder, and the mixture was stirred at room temperature under a hydrogen atmosphere for 30 minutes. Insoluble materials were removed by filtration, and the solvent was removed under reduced pressure to give 4-[(4-ethylphenyl)methyl]-3-(β-D-glucopyranosyloxy)-1-(2-hydroxyethyl-5-methyl-1H-pyrazole (0.011 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([CH:9]([NH:16][CH3:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:3]=1.ClC(Cl)(O[C:22](=[O:28])OC(Cl)(Cl)Cl)Cl.O.CCOC(C)=O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[NH:8][C:22](=[O:28])[N:16]([CH3:17])[CH:9]2[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CNC(c1ccccc1)c1cc(Br)ccc1N
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CN1C(=O)Nc2ccc(Br)cc2C1c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of reactant 4-Bromo-2-(methylamino-phenyl-methyl)-phenylamine (3.4 g, 12 mmol) in THF (150 mL) is added triphosgene (3.81 g, 13 mmol). After the addition the mixture is stirred at r.t. for 3 h. Then H2O is added and is extacd with EtOAc, dried over Na2SO4 and concentrated. The residue is purified by chromatography on silica gel to give product.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([CH3:8])=[N:6][CH:7]=1.[CH3:9][Si:10]([C:13]#[CH:14])([CH3:12])[CH3:11]>CCN(CC)CC.C1COCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:8][C:5]1[N:4]=[CH:3][C:2]([C:14]#[C:13][Si:10]([CH3:12])([CH3:11])[CH3:9])=[CH:7][N:6]=1
Reactant: Cc1ncc(Br)cn1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ncc(C#C[Si](C)(C)C)cn1
Yield: 72.5 %

Procedure:
5-Bromo-2-methyl-pyrimidine (prepared according to UK patent application GB 2 157 288) (0.2 g, 1.16 mmol), (trimethylsilyl)acetylene (164 μL, 1.3 mmol), CuI (0.022 g, 0.116 mmol) and PdCl2(PPh3)2 (0.082 g, 0.116 mmol) in Et3N (2 mL) and THF (2 mL) were stirred at 80° C. for 4 h. After cooling, the solvents were removed under vacuum and the residue chromatographed to give the subtitle compound (0.16 g, 50%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[Cl:23][C:24]1[CH:33]=[CH:32][C:27]([C:28](OC)=[O:29])=[CH:26][CH:25]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.CCCCCC.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([S:14]([CH2:17][C:28](=[O:29])[C:27]2[CH:32]=[CH:33][C:24]([Cl:23])=[CH:25][CH:26]=2)(=[O:15])=[O:16])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(S(C)(=O)=O)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)CC(=O)c2ccc(Cl)cc2)CC1
Temperature: -78 °C
Reaction time: 3 h
Yield: 39.3 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-4-methanesulfonylpiperazine (1.32 g) in tetrahydrofurane (10 ml) was added dropwise at 0° C. 1.6 M n-butyllithium in hexane (6.25 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was cooled to −78° C., and to the mixture was added a solution of methyl 4-chlorobenzoate (853 mg) in tetrahydrofurane (5 ml). The mixture was stirred for 3 hours at the same temperature and raised to 0° C. To the reaction solution was added water (10 ml), and the mixture was made acidic with citric acid aqueous solution and extracted with ether. The organic layer was washed with brine, dried, concentrated, and purified with silica gel column chromatography (hexane/ethyl acetate=2/1) to give a colorless solid of the title compound (790 mg).
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2].Cl[C:12]1[O:13][C:14]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:15]([C:17]([F:20])([F:19])[F:18])[N:16]=1>C(OCC)C>[CH3:2][CH:1]([N:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:12]1[O:13][C:14]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:15]([C:17]([F:19])([F:18])[F:20])[N:16]=1)[CH3:3]
Reactant: CC(C)Nc1ccccc1
Reactant: CCOC(=O)c1oc(Cl)nc1C(F)(F)F
Solvent: CCOCC
Product: CCOC(=O)c1oc(N(c2ccccc2)C(C)C)nc1C(F)(F)F
Yield: 21.5 %

Procedure:
By the procedure of Example 15, 2.59 g (0.019 mol) of N-isopropyl aniline was reacted neat with 2.32 g (0.0095 mol) of ethyl 2-chloro-4-trifluromethyl-5-oxazolecarboxylate at 140°-150° C. for 4 hours. The product mixture was slurried in ethyl ether, washed with 25% sulfuric acid and water, dried and concentrated. The residue was distilled and the distillate was recrystallized from methylcyclohexane to yield 0.7 g of a white-powder product (m.p.=66°-68° C.) identified in Table 1.