Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]([OH:26])[CH2:10][O:11][C:12]2[CH:25]=[CH:24][C:15]([CH2:16][CH:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])=[CH:14][CH:13]=2)=[N:7][CH:8]=1)[CH3:2].C(O)C.C(OC(=O)C)(=O)C.CS(C)=O>O>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9](=[O:26])[CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([CH2:16][CH:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])=[CH:24][CH:25]=2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(C(O)COc2ccc(CC3SC(=O)NC3=O)cc2)nc1
Solvent: CCO
Solvent: CS(C)=O
Solvent: CC(=O)OC(C)=O
Product: CCc1ccc(C(=O)COc2ccc(CC3SC(=O)NC3=O)cc2)nc1
Yield: 20 %

Procedure:
A mixture of 5-[4-[2-(5-ethyl-2-pyridyl)-2-hydroxyethoxy]benzyl]-2,4-thiazolidinedione. 1/2 C2H5OH (396 mg), acetic anhydride (1.5 ml) and dimethylsulfoxide (4 ml) was stirred at room temperature for 5 hours and then poured into water. The mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over magnesium sulfate and the solvent was distilled off. The oily residue was subjected to silica gel chromatography. A fraction eluted with chloroform-methanol (100:1, v/v) gave 5-[4-[2-(5-ethyl-2-pyridyl)-2-oxoethoxy]benzyl]-2,4-thiazolidinedione (75 mg, yield: 20%). This was recrystallized from ethyl acetate-hexane to obtain colorless prisms, m.p. 148°-149° C.
Reaction SMILES: [H-].[Na+].C1COCC1.[O:8]=[C:9]1[CH:15]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:14][S:13][CH2:12][CH2:11][NH:10]1.[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[F:33])[CH2:28]Br>O.CCOC(C)=O>[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[F:33])[CH2:28][N:10]1[C:9](=[O:8])[CH:15]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])[CH2:14][S:13][CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)NC1CSCCNC1=O
Reactant: Fc1ccc(CBr)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC1CSCCN(Cc2ccc(F)c(F)c2)C1=O
Yield: 61 %

Procedure:
81 mg of sodium hydride as a 60% suspension in oil (2.03 mmol) are introduced at room temperature into a 50 ml round-bottomed flask, with stirring and under an argon atmosphere, containing 20 ml of THF and 500 mg of 26 (2.03 mmol). The medium is stirred for 1 hour and 420 mg (2.03 mmol) of 3,4-difluorobenzyl bromide are then added. The medium is stirred overnight, 20 ml of EtOAc and 20 ml of water are added to the reaction medium and, after separation of the phases by settling, the organic phase is washed once with 20 ml of water. The organic phase is dried, filtered and then evaporated to dryness. 1.5 g of crude product are recovered, which product is chromatographed on silica (eluent: 80/20 heptane/EtOAc). 460 mg of product 30 are recovered (yield=61%).
Reaction SMILES: [N:1]1([C:6]2[N:10]([C:11]([CH3:14])([CH3:13])[CH3:12])[N:9]=[CH:8][C:7]=2[CH2:15]O)[CH:5]=[CH:4][CH:3]=[CH:2]1.S(Cl)([Cl:19])=O>ClCCl>[Cl:19][CH2:15][C:7]1[CH:8]=[N:9][N:10]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[N:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)n1ncc(CO)c1-n1cccc1
Solvent: ClCCl
Product: CC(C)(C)n1ncc(CCl)c1-n1cccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2.20 g of [5-(1H-pyrrol-1-yl)-1-t-butyl-1H-pyrazol-4-yl]methanol was dissolved in 20 ml of dichloromethane, and 0.73 ml of thionyl chloride was added. The mixture was stirred at room temperature for 1.5 hours and then concentrated under reduced pressure. After aqueous saturated sodium hydrogen carbonate was added, the residue was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 2.35 g of 4-(chloromethyl)-5-(1H-pyrrol-1-yl)-1-t-butyl-1H-pyrazole.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[CH:27]1([CH2:33][CH2:34][OH:35])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH:27]1([CH2:33][CH2:34][O:35][C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=2[C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:10]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: OCCC1CCCCC1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3OCCC3CCCCC3)n2)c1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (75 mg; 0.197 mmol), intermediate 42.1, and 2-cyclohexylethanol (111 μl; 0.789 mmol), example 63 was prepared analogously to the procedure for the preparation of example 43.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:18])[NH:5][NH:6][C:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15])[CH3:2].C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([NH:3][C:4]1[O:18][C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])=[N:6][N:5]=1)[CH3:2]
Reactant: CCNC(=O)NNC(=O)c1ccccc1[N+](=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNc1nnc(-c2ccccc2[N+](=O)[O-])o1
Reaction time: 4 h
Yield: 61.9 %

Procedure:
A mixture of 4-ethyl-1-(2-nitrobenzoyl)semicarbazide (4 g) in DCM (30 mL) was treated with triethyl amine (12 mL), PTS-Cl (4.8 g) and DMAP (100 mg). The reaction mixture was stirred for 4 hours, concentrated, and purified by silica gel chromatography to afford 2.3 g of ethyl-(5-(2-nitro-phenyl)-(1,3,4)oxadiazol-2-yl)-amine: 1H NMR (300 MHz, CDCl3) δ 8.1 (dd, 1H), 8.0 (d, 1H), 7.8 (m, 2H), 4.9 (bs, 1H), 3.6 (q, 2H), 1.4 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[I:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1>>[I:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:24])=[CH:21][CH:20]=1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: O=C(O)c1ccc(I)cc1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc(I)cc4)cc23)CC1
Yield: 59.4 %

Procedure:
Beginning with 10.0 mg (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 32.0 mg (0.131 mMol) 4-iodobenzoic acid, 12.0 mg (60%) of the title compound were recovered.
Reaction SMILES: [CH3:1][C:2]([CH3:39])([CH3:38])[CH2:3][O:4][C:5]([C:7]1([C:30]([O:32]CC(C)(C)C)=[O:31])[O:11][C:10]2[CH:12]=[CH:13][C:14]([CH2:16][C@H:17]([NH:19][CH2:20][C@@H:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=3)[OH:22])[CH3:18])=[CH:15][C:9]=2[O:8]1)=[O:6].[K+].[Br-]>C(Cl)(Cl)Cl>[CH3:38][C:2]([CH3:1])([CH3:39])[CH2:3][O:4][C:5]([C:7]1([C:30]([OH:32])=[O:31])[O:11][C:10]2[CH:12]=[CH:13][C:14]([CH2:16][C@H:17]([NH:19][CH2:20][C@@H:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=3)[OH:22])[CH3:18])=[CH:15][C:9]=2[O:8]1)=[O:6]
Reactant: C[C@H](Cc1ccc2c(c1)OC(C(=O)OCC(C)(C)C)(C(=O)OCC(C)(C)C)O2)NC[C@H](O)c1cccc(Cl)c1
Agent: [Br-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: C[C@H](Cc1ccc2c(c1)OC(C(=O)O)(C(=O)OCC(C)(C)C)O2)NC[C@H](O)c1cccc(Cl)c1

Procedure:
The title compound was prepared from 5-{(2R)-2-[(2R)-2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(2,2-dimethyl-propyl) ester according to the procedure of Example 22 as a white solid; 1H NMR (DMSO) δ 0.868 (s, 9H), 1.02-1.06 (m, 3H),3.00-3.02 (m, 1H), 3.24-3.30 (m, 1H), 3.35 (s, 5H), 3.80 (t, 2H), 4.55 (s, 1H), 5.03 (m, 1H), 6.52 (m, 1H), 6.61 (m, 1H), 6.79 (m, 1H), 7.34 (m, 3H), 7.48 (s, 1H); IR (KBr) 3398 cm-1 (--OH), 1748 cm-1 (C=O), 1654 cm-1 (C=O); MS (ES) m/z 492.3 (MH+); [α]D25 -93° (c, 1.0, CHCl3). Anal. Calcd. for C25H30ClNO7 : C, 61.04; H, 6.15; N, 2.85; Cl, 7.21. Found: C, 56.96; H,5.65; N, 2.63; Cl, 7.05.
Reaction SMILES: O[Li].O.O.[Br:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12]([CH2:16][N:17]1[C:23](=[O:24])[C@@H:22]([NH:25][C:26](=[O:38])[C@@H:27]([N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH3:30])[CH3:28])[CH2:21][O:20][C:19]3[C:39]([C:43]([O:45]C)=[O:44])=[CH:40][CH:41]=[CH:42][C:18]1=3)=[C:11]([O:47][CH3:48])[CH:10]=[CH:9]2>CO>[Br:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12]([CH2:16][N:17]1[C:23](=[O:24])[C@@H:22]([NH:25][C:26](=[O:38])[C@@H:27]([N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:35])[CH3:36])=[O:32])[CH3:30])[CH3:28])[CH2:21][O:20][C:19]3[C:39]([C:43]([OH:45])=[O:44])=[CH:40][CH:41]=[CH:42][C:18]1=3)=[C:11]([O:47][CH3:48])[CH:10]=[CH:9]2
Reactant: COC(=O)c1cccc2c1OC[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N2Cc1c(OC)ccc2cc(Br)ccc12
Agent: [Li]O
Solvent: CO
Solvent: O
Product: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)COc2c(C(=O)O)cccc21
Temperature: 50 °C
Yield: 92 %

Procedure:
LiOH.H2O (31.3 mg, 746 μmol, Eq: 2.5) and H2O (1.00 mL) was added to a solution of (S)-methyl 5-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-3-((S)-2-(tert-butoxycarbonyl (methyl)amino)propanamido)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-9-carboxylate (200 mg, 298 μmol, Eq: 1.00) in MeOH (6.0 mL) and the mixture heated to 50° C. After 90 min. the mixture was concentrated, diluted with H2O and extracted with Et2O. The combined Et2O extracts were extracted with 5% NaHCO3. The combined aqueous mixture was acidified to pH 2.0 with 1 N HCl, extracted with EtOAc and the combined organic extracts washed with brine, dried over Na2SO4 and concentrated to afford the title compound (180 mg, 91%) as an off white foam which was used without purification.
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([NH:9][C:10]2[C:15]([C:16]3[N:24]=[CH:23][N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][N:20]4C3CCCCO3)=[CH:14][CH:13]=[CH:12][N:11]=2)=[C:7]([F:31])[CH:6]=[CH:5][C:4]=1[NH:32][S:33]([C:36]1[CH:37]=[CH:38][CH:39]=[C:40]2[C:45]=1[O:44][CH2:43][CH2:42][CH2:41]2)(=[O:35])=[O:34]>>[N:24]1[C:16]([C:15]2[C:10]([NH:9][C:8]3[C:3]([F:2])=[C:4]([NH:32][S:33]([C:36]4[CH:37]=[CH:38][CH:39]=[C:40]5[C:45]=4[O:44][CH2:43][CH2:42][CH2:41]5)(=[O:34])=[O:35])[CH:5]=[CH:6][C:7]=3[F:31])=[N:11][CH:12]=[CH:13][CH:14]=2)=[C:17]2[C:21]([NH:20][CH:19]=[N:18]2)=[N:22][CH:23]=1
Reactant: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1cccc2c1OCCC2
Agent: Cl
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3[nH]cnc23)c1F)c1cccc2c1OCCC2
Reaction time: 2 h

Procedure:
1M aqueous hydrochloric acid solution was added into the N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)chromane-8-sulfonamide (20 mg, 0.033 mmol) prepared at Step 10 and stirred for 2 hours. After the reaction, the reactant was washed with an aqueous solution of sodium hydrogen carbonate and salt water. After extraction with ethylacetate, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that the target compound was obtained.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Cl:10][C:11]1[CH:12]=[C:13]([S:18](Cl)(=[O:20])=[O:19])[CH:14]=[C:15]([Cl:17])[CH:16]=1.[CH3:22][N:23]([C:44](=[O:49])[CH2:45][CH2:46][NH:47][CH3:48])[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:33](C(OC(C)(C)C)=O)[CH2:34][CH2:35][N:36]=2)=[CH:28][CH:27]=1.[F:50][C:51]([F:56])([F:55])[C:52]([OH:54])=[O:53]>C(#N)C.O>[F:50][C:51]([F:56])([F:55])[C:52]([OH:54])=[O:53].[Cl:10][C:11]1[CH:12]=[C:13]([S:18]([CH2:48][NH:47][CH2:46][CH2:45][C:44]([N:23]([CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]([C:32]3[NH:36][CH2:35][CH2:34][N:33]=3)=[CH:30][CH:31]=2)[CH3:22])=[O:49])(=[O:20])=[O:19])[CH:14]=[C:15]([Cl:17])[CH:16]=1
Reactant: CNCCC(=O)N(C)CCc1ccc(C2=NCCN2C(=O)OC(C)(C)C)cc1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CN(CCc1ccc(C2=NCCN2)cc1)C(=O)CCNCS(=O)(=O)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
6.88 μl (65.77 μmol) of diisopropylethylamine and a solution of 3.26 mg (13.15 μmol) of 3,5-dichlorobenzenesulphonyl chloride in 150 μl of acetonitrile were added to a solution of 7.3 mg (13.15 μmol) of tert.-butyl 2-(4-{2-[methyl-(3-methylaminopropionyl)amino]ethyl}phenyl)-4,5-dihydroimidazole-1-carboxylate in 100 μl of acetonitrile. The reaction mixture was stirred at room temperature for 1.5 hours. 500 μl of a solution of trifluoroacetic acid and water (95/5) were then added, and the mixture was stirred at room temperature for a further 30 min. The reaction mixture was then evaporated to dryness in a Christ-Speedvac. The crude product obtained in this manner was purified by HPLC.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]#[N:21])[CH:15]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:21]=2)[CH:15]=1
Reactant: COC(=O)c1ccccc1S
Reactant: COc1ccnc(C#N)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1ccnc(-c2nc(=O)c3ccccc3s2)c1
Yield: 80 %

Procedure:
A mixture of methyl thiosalicylate (2.0 g, 11.7 mmol), 4-methoxy-2-cyanopyridine (1.5 g, 11.1 mmol), triethylamine (2.5 ml, 17.9 mmol) and toluene (5 ml) was refluxed for 12 hrs as described in Example 1. The precipitated crystals were collected by filtration and recrystallized from hexane-chlorobenzene to give the titled compound (2.4 g, 81%)
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]3[C:10](=[C:11]([CH2:16][CH3:17])[N:12]=2)[CH:9]=[C:8]([F:18])[CH:7]=[CH:6]3)[CH:3]=1.[BH4-].[Na+].FC(F)(F)C(O)=O.C1C=CC2C3C=CC=CC=3NCC=2C=1.C(N(CC)CC)C.[CH3:49][O:50][C:51]1[CH:56]=[CH:55][C:54]([S:57](Cl)(=[O:59])=[O:58])=[CH:53][CH:52]=1>O1CCCC1.ClCCl>[CH:8]1[CH:7]=[CH:6][C:5]2[C:4]3[CH:3]=[CH:2][CH:15]=[CH:14][C:13]=3[NH:12][CH2:11][C:10]=2[CH:9]=1.[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[N:12]([S:57]([C:54]3[CH:53]=[CH:52][C:51]([O:50][CH3:49])=[CH:56][CH:55]=3)(=[O:59])=[O:58])[CH:11]([CH2:16][CH3:17])[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([F:18])[CH:9]=3)[C:4]=2[CH:3]=1
Reactant: CCc1nc2ccc(Br)cc2c2ccc(F)cc12
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Agent: c1ccc2c(c1)CNc1ccccc1-2
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CCC1c2cc(F)ccc2-c2cc(Br)ccc2N1S(=O)(=O)c1ccc(OC)cc1

Procedure:
The intermediate dihydrophenanthridine was prepared from 2-bromo-6-ethyl-8-fluorophenanthridine (3.27 g, 10.8 mmol) by treatment with sodium borohydride (2.03 g, 53.8 mmol) and trifluoroacetic acid (3.31 mL, 43.0 mmol) in tetrahydrofuran (43 mL). In a separate, second step, the dihydrophenanthridine was treated with triethylamine (9.0 mL, 65 mmol) and 4-methoxybenzenesulfonyl chloride (2.44 g, 11.8 mmol) in dichloromethane (11 mL) according to the procedure and in the same manner as described in Example 32, Method A, Step d. The crude product was purified by flash column chromatography on silica gel, eluting with a mixture of ethyl acetate-hexane (1:9 to 1:4 gradient), to afford 2-bromo-6-ethyl-8-fluoro-5-[(4-methoxyphenyl)sulfonyl]-5,6-dihydrophenanthridine as a homogeneous, yellow, crystalline, solid, m.p. 133-136° C.;
Reaction SMILES: [C:1]([O-])(=O)CC.[CH2:6]([NH+:13]1[CH2:18][CH2:17][C:16]([C:30]2[NH:34][N:33]=[N:32][N:31]=2)([N:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:20](=[O:23])[CH2:21][CH3:22])[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[H-].[Na+].IC>CN(C=O)C>[CH2:6]([N:13]1[CH2:18][CH2:17][C:16]([C:30]2[N:34]([CH3:1])[N:33]=[N:32][N:31]=2)([N:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:20](=[O:23])[CH2:21][CH3:22])[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCC(=O)[O-]
Reactant: CCC(=O)N(c1ccccc1)C1(c2nnn[nH]2)CC[NH+](Cc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCC(=O)N(c1ccccc1)C1(c2nnnn2C)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.8 %

Procedure:
To a stirring mixture of 1-benzyl-4-(1H-tetrazol-5-yl)-4-(N-phenylpropionamido)piperidinium propionate (18.9 g, 40.7 mmol) and DMF (120 ml), NaH (2.4 g,m 100 mmol) was added. The mixture was stirred at room temperature for 30 minutes. To the resulting brown solution, iodomethane (15 g, 106 mmol) was added slowly. It was stirred for 30 minutes and poured onto H2O (400 ml). The mixture was extracted with CH2Cl2 (2×250 ml). The CH2Cl2 solution was washed with H2O (4×400 ml), dried over Na2SO4 and concentrated in vacuo. The resulting residue was chromatographed (SiO2, 1% MeOH/CH2Cl2) to give 1-benzyl-4-(1-methyl-1H-tetrazol-5-yl)-4-(N-phenylpropionamido)piperidine (4.58 g, 11.3 mmol) as a colorless viscous oil: IR (neat) 1660 cm-1 ; NMR (270 MHZ, CDCl3) δ 0.834, (t, 3H, CH3CH2CO), 1.789 (q, 2H, CH3CH2), 3.334 (s, 2H, phCH2), 4.435 (s, 3H, tetrazolyl CH3), 7.15 to 7.47 (m's, 10H, phenyl H's), and 1-benzyl-4-(2-methyl-2H-tetrazol-5-yl)-4-(N-phenyl)propionamido)piperidine (2.75 g, 6.8 mmol) as a viscous oil: IR (neat) 1660 cm-1 ; NMR (270 MHz, CDCl3) δ 0.830 (t, 3H, CH3CH2CO), 1.810 (q, 2H, CH3CH2), 3.402 (s, 2H, phCH2), 4.369 (s, 3H, tetrazolyl CH3), 7.20 to 7.54 (3m's, 10H, phenyl H's). ##STR31##
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C(C[C@@H](N)CC([N:38]2[CH2:50][C:42]3=[N:43][N:44]=[C:45]([C:46]([F:49])([F:48])[F:47])[N:41]3[CH2:40][CH2:39]2)=O)=C(F)C=C(F)C=1F.O.OP(O)(O)=O.Cl.FC(F)(F)C1N2CCNCC2=NN=1.C1(B(O)O)C=CC=CC=1.C(OC(C)C)(C)C>O.C(N(CC)CC)C.C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH2:10][C:11](=[O:13])[N:38]1[CH2:39][CH2:40][N:41]2[C:45]([C:46]([F:49])([F:47])[F:48])=[N:44][N:43]=[C:42]2[CH2:50]1)[CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC(CC(=O)O)Cc1cc(F)c(F)cc1F
Reactant: N[C@@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Agent: Cl
Agent: FC(F)(F)c1nnc2n1CCNC2
Agent: O=P(O)(O)O
Solvent: O
Solvent: CC(C)OC(C)C
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
100 g of 3-tert-butoxycarbonylamino-4-(2,4,5-trifluorophenyl)butyric acid of formula (II) was charged with 800 ml of toluene into a 2 liter 4 necked round bottom flask attached with dean stark apparatus followed by 70 ml of triethyl amine at room temperature. Then 100 g of 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine HCl was charged and stirred for 5 minutes. 7.5 g of phenyl boronic acid was charged to the reaction mass. After 48 hours of stirring at reflux temperature, the reaction was complete. The reaction mass was cooled to room temperature and 1000 ml of water was added to it. The organic layer was separated and washed twice with 500 ml of 1N HCl. The organic layer was separated and washed with 500 ml of water followed by 6% NaHCO3 and finally by 500 ml of water. The organic layer was then separated, treated with sodium sulfate and then with charcoal and filtered. The solvent was distilled out under vacuum. The solid obtained was stirred with 500 ml of diisopropyl ether for 2 hours, filtered, washed with diisopropyl ether and then dried under vacuum at 50° C. for 12-15 hours.
Reaction SMILES: C[Si]1(C)[NH:9][Si:8]([CH3:11])([CH3:10])[NH:7][Si:6]([CH3:13])([CH3:12])[NH:5][Si:4]([CH3:15])([CH3:14])N1>C[Si]1(C)N[Si](C)(C)N[Si](C)(C)N[Si](C)(C)N1.NC1C=CC(C)=C(S(O)(=O)=O)C=1>[CH3:15][Si:4]1([CH3:14])[NH:5][Si:6]([CH3:12])([CH3:13])[NH:7][Si:8]([CH3:10])([CH3:11])[NH:9]1
Reactant: C[Si]1(C)N[Si](C)(C)N[Si](C)(C)N[Si](C)(C)N1
Agent: Cc1ccc(N)cc1S(=O)(=O)O
Product: C[Si]1(C)N[Si](C)(C)N[Si](C)(C)N1
Temperature: 97 °C

Procedure:
A 200 ml volume glass flask equipped with a stirring machine, a condenser, a distillation column and a tube for distilling off the resulting product was provided. 73 g of octamethyl cyclotetrasilazane and 3.65 g of p-toluidine-m-sulfonic acid as a catalyst were introduced into the glass flask and the content of the flask was heated to 97° C. The content of the flask was stirred after it was confirmed that the octamethyl cyclotetrasilazane was completely molten. When the internal pressure of the reaction system was reduced to 65 torr with a vacuum pump to obtain a distillate, 68 g of hexamethyl cyclotrisilazane was obtained through the distillation over one hour. The resulting hexamethyl cyclotrisilazane had a high purity in the order of 99.1 GC % and the yield thereof was 93.2%. Thus, highly pure hexamethyl cyclotrisilazane could be obtained at a high yield within a short period of time. Moreover, almost no high boiling point substance remained in the reaction system.
Reaction SMILES: [OH-:1].[Na+].Cl[C:4]1[NH:5][C:6]([Cl:13])=[CH:7][C:8]2[C:9]=1[NH:10][CH2:11][N:12]=2>O>[Cl:13][C:6]1[NH:5][C:4](=[O:1])[C:9]2[NH:10][CH:11]=[N:12][C:8]=2[CH:7]=1
Reactant: [OH-]
Reactant: ClC1=CC2=NCNC2=C(Cl)N1
Agent: [Na+]
Solvent: O
Product: O=c1[nH]c(Cl)cc2nc[nH]c12
Temperature: 90 °C

Procedure:
An aqueous NaOH solution (2 equiv.) was added to a solution of 4,6-dichloro-3,5-dihydro-imidazo[4,5-c]pyridine in water. The reaction mixture was stirred at 90° C. until the completion of the reaction (monitored by TLC). The reaction mixture was allowed to cool down to room temperature and filtered to give light yellow residue. The residue was dissolved in water and acidified to pH 3-4 and was filtered to give 2.
Reaction SMILES: Cl[C:2]1[C:7]2=[CH:8][CH:9]=[CH:10][N:6]2[NH:5][C:4]([N:12]([CH3:14])[CH3:13])(N)[N:3]=1.[NH2:15][C:16]1[CH:21]=[C:20]([OH:22])[C:19]([CH3:23])=[CH:18][CH:17]=1>C(O)C>[CH3:14][N:12]([CH3:13])[C:4]1[N:3]=[C:2]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH3:23])=[C:20]([OH:22])[CH:21]=2)[C:7]2=[CH:8][CH:9]=[CH:10][N:6]2[N:5]=1
Reactant: Cc1ccc(N)cc1O
Reactant: CN(C)C1(N)N=C(Cl)c2cccn2N1
Solvent: CCO
Product: Cc1ccc(Nc2nc(N(C)C)nn3cccc23)cc1O
Temperature: 75 °C
Reaction time: 8 h
Yield: 70.6 %

Procedure:
To a solution of 4-chloro-2-dimethylaminopyrrolo[2,1-f][1,2,4]triazin-2-amine (50 mg, 0.26 mmol) (Tetrahedron, 3037, 52, 1996, José Ma. Quintela, Maria J. Moreira and Carlos Peinador) in ethanol (2.5 mL) under argon was added 5-amino-o-cresol (35 mg, 0.28 mmol). The reaction mixture was stirred overnight at 75° C. Upon cooling, a solid precipitated which was recrystallized from warm ethanol to provide 52 mg (72%) of the title compound as white solid. MS: [M+H]+=284.2, ESI [M−H]−=282.1; 1H NMR (CDCl3): δ 7.52 (s, 1H), 7.13-6.98 (m, 4H), 6.58 (s, 1H), 3.15 (s, 6H), 2.19 (s, 3H).
Reaction SMILES: CC(C)([O-])C.[K+].F[C:8]1[C:18]([F:19])=[C:17]([F:20])[CH:16]=[CH:15][C:9]=1[NH:10][C@@H:11]([CH3:14])[CH2:12][OH:13].C(O[CH:24]=[C:25]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27])C>CN(C=O)C>[F:20][C:17]1[CH:16]=[CH:15][C:9]2[N:10]([CH:24]=[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:31]([O:33][CH2:34][CH3:35])=[O:32])[C@@H:11]([CH3:14])[CH2:12][O:13][C:8]=2[C:18]=1[F:19]
Reactant: C[C@@H](CO)Nc1ccc(F)c(F)c1F
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(=CN1c2ccc(F)c(F)c2OC[C@@H]1C)C(=O)OCC
Yield: 65.2 %

Procedure:
To DMF (2 ml) was added potassium tertiary-butoxide (226 mg) under ice-cooling. After dropping a solution of the compound (100 mg) obtained in Example 51 and diethyl ethoxymethylenemalonate (293 mg) in DMF (0.5 ml), the resultant mixture was stirred at room temperature for 18 hours. After treating in a conventional manner, the obtained residue was subjected to silica gel column chromatography to thereby give 113 mg (65%) of the title compound. The physical constants of the obtained compounds was identical with those described in Japanese Patent No. 2,769,174.