Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:7]([O-:11])(=[O:10])(=[O:9])=[O:8].CS[C:14]1[S:18][CH:17]=[CH:16][S+:15]=1>>[Cl:7]([O-:11])(=[O:10])(=[O:9])=[O:8].[S:15]1[CH:16]=[CH:17][S:18][C:14]1=[N+:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: CSc1scc[s+]1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: c1csc(=[N+]2CCCCC2)s1

Procedure:
1.0 ml of piperidine and 2.5 g of 2-methylthio-1,3-dithiolium perchlorate were treated in the same manner as in Example 26, and the product was recrystallized from acetone-ethyl ether, whereby 2.1 g (yield: 73.6%) of 1-(1,3-dithiol-2-ylidene)piperidinium perchlorate (Compound No. 34) was obtained as crystals having a melting point of from 171° to 172° C.
Reaction SMILES: [2H][C:2]1[C:7]([2H])=[C:6]([NH2:9])[C:5]([NH2:10])=[C:4]([2H])[C:3]=1[2H].C(N(CC)CC)C.[C:20](Cl)(=O)[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C(Cl)Cl>[CH2:21]([C:20]1[NH:9][C:6]2[CH:7]=[CH:2][CH:3]=[CH:4][C:5]=2[N:10]=1)[CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCC(=O)Cl
Reactant: [2H]c1c([2H])c([2H])c(N)c(N)c1[2H]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCc1nc2ccccc2[nH]1
Yield: 46.6 %

Procedure:
To a solution of O-phenylenediamine (2.2 g) and triethylamine (2.0 g) in methylene chloride (20 ml) was added dropwise caproyl chloride (2.3 g) with stirring under ice-cooling. The mixture was stirred for 3 hours at room temperature, washed with a saturated aqueous sodium bicarbonate and water, then dried. The solvent was evaporated. To the residue was added 3N-HCl, and the mixture was heated for 1.5 hour under reflux. The reaction mixture was made basic with 6N NaOH. Then precipitating crystals were recrystallized from ethyl acetate-hexane to give colorless needles (1.5 g, 47%), m.p. 161-162° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH2:13][CH2:14][CH2:15][Cl:16])=[CH:6][C:5]=1[N+:17]([O-])=O>C(OCC)(=O)C.CO.[Pd]>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH2:13][CH2:14][CH2:15][Cl:16])=[CH:6][C:5]=1[NH2:17]
Reactant: COC(=O)c1cc(OC)c(OCCCCl)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1cc(OC)c(OCCCCl)cc1N
Reaction time: 12 h
Yield: 92.3 %

Procedure:
To a solution of the intermediate from Step 2 (29.14 g, 95.8 mmol) in ethyl acetate: methanol (3:1, 1 L) was added 10% Pd/C (3 g). The mixture was stirred under H2 for 12 hours. Completion of the reaction was monitored by LCMS. The reaction mixture was filtered using a celite pad and washed with excess ethyl acetate. The filtrate was evaporated to dryness to afford the pure 2-amino-4-(3-chloro-propoxy)-5-methoxy-benzoic acid methyl ester (24.2 g, 94%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 7.13 (s, 1H), 6.43 (s, 2H), 6.39 (s, 1H), 4.04 (t, 2H), 3.80 (t, 2H), 3.74 s, 3H), 3.65 (s, 3H), 2.19 (m, 2H), LC-MS (ESI)m/z 274 (M+H)+.
Reaction SMILES: Cl[Si:2]([Cl:5])([CH3:4])[CH3:3].[CH3:6][C:7]1[CH-:8][C:9]2[C:14]([CH:15]=1)=[C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:12]=[CH:11][CH:10]=2.[Li+]>CCOCC>[Cl:5][Si:2]([CH3:3])([CH3:4])[CH:8]1[C:9]2[C:14](=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)[CH:15]=[C:7]1[CH3:6]
Reactant: Cc1cc2c(-c3ccccc3)cccc2[cH-]1
Reactant: C[Si](C)(Cl)Cl
Agent: [Li+]
Solvent: CCOCC
Product: CC1=Cc2c(-c3ccccc3)cccc2C1[Si](C)(C)Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a colorless solution of dichlorodimethylsilane (12.90 g, 100 mmol, 3.00 eq.) in ether (30 mL) at −30° C. was added lithium (2-methyl-4-phenylindenide) (7.07 g, 33.3 mmol, 1.00 equiv.) in portions to give a cloudy yellow mixture. The reaction was allowed to warm to room temperature and stirred for 4 hours, becoming cloudy white with precipitate. The mixture was evaporated under vacuum, leaving a white solid. The solid was extracted with pentane (40 mL) and the extract was filtered to give a light yellow solution and white solid. The solution was evaporated under vacuum, leaving a white solid. Yield 9.85 g (99%). 1H NMR (C6D6): δ 7.59 (d, 2H), 7.44 (m, IH), 7.36 (m, 3H), 7.22 (m, 2H), 6.86 (d, 1H), 3.42 (d, IH), 2.11 (d, 3H), 0.27 (s, 3H), −0.03 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[C:27]([CH3:29])[C:5]2[N:6]=[C:7]([C:11]3[N:12]([C:20]4[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=4)[N:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=3)[O:8][C:9](=[O:10])[C:4]=2[CH:3]=1.[NH2:30][CH2:31][CH:32]([OH:34])[CH3:33]>C1COCC1>[Cl:1][C:2]1[CH:28]=[C:27]([CH3:29])[C:5]([NH:6][C:7]([C:11]2[N:12]([C:20]3[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=3)[N:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=2)=[O:8])=[C:4]([C:9](=[O:10])[NH:30][CH2:31][CH:32]([OH:34])[CH3:33])[CH:3]=1
Reactant: Cc1cc(Cl)cc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Reactant: CC(O)CN
Solvent: C1CCOC1
Product: Cc1cc(Cl)cc(C(=O)NCC(C)O)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Yield: 89.5 %

Procedure:
A solution of 3.5 g (7.9 mmol) 6-chloro-2-[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-8-methylbenzo[d][1,3]oxazin-4-one and 2.5 g 1-amino-2-propanol in 50 ml THF is heated to a temperature of 60° C. for 2 hours. The solvent is then evaporated and the residue is treated with 50 ml hexane. After decantation of the hexane phase, the residue is crystallised in 10 ml isopropanol to give 3.65 g (89%) white crystals (m.p. 193-197° C.).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([N:18]([CH2:40][CH:41]([CH3:43])[CH3:42])[C@H:19]1[CH2:24][C@@H:23]([C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:26])[CH2:22][N:21]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:20]1)=[O:17])C.O.[NH2:46][NH2:47].[CH2:48]([OH:50])[CH3:49]>>[C:48]([NH:46][NH:47][C:4](=[O:3])[CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([N:18]([CH2:40][CH:41]([CH3:43])[CH3:42])[C@H:19]1[CH2:24][C@@H:23]([C:25]([N:27]2[CH2:28][CH2:29][O:30][CH2:31][CH2:32]2)=[O:26])[CH2:22][N:21]([C:33]([O:35][C:36]([CH3:39])([CH3:37])[CH3:38])=[O:34])[CH2:20]1)=[O:17])(=[O:50])[CH3:49]
Reactant: NN
Reactant: CCOC(=O)CCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Reactant: CCO
Solvent: O
Product: CC(=O)NNC(=O)CCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Temperature: 0 °C

Procedure:
tert-Butyl(3S, 5R)-3-[{[1-(3-ethoxy-3-oxopropyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (307 mg) was dissolved in ethanol (10 ml), hydrazine monohydrate (243 μl) was added and the mixture was heated under reflux for 6 hr with stirring. The reaction mixture was concentrated, ethyl acetate was added to the residue, and the mixture was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in THF (5 ml), and triethylamine (209 μl) was added. The reaction mixture was cooled to 0° C., acetic anhydride (71 μl) was added dropwise and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with aqueous sodium bicarbonate, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the object product (292 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:4][C:3]=1[C:15](=[O:17])[CH3:16].[C:18]([Mg]Br)#[CH:19].C1N=CN([C:27](N2C=NC=C2)=[O:28])C=1>>[Cl:14][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]3[NH:1][C:27](=[O:28])[O:17][C:15]([C:18]#[CH:19])([CH3:16])[C:3]=3[CH:4]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(=O)c1cc(-c2cccc(Cl)c2)ccc1N
Reactant: C#C[Mg]Br
Product: C#CC1(C)OC(=O)Nc2ccc(-c3cccc(Cl)c3)cc21

Procedure:
Prepared from 1-(4-amino-3′-chloro-biphenyl-3-yl)-ethanone (0.2 g, 0.82 mmol) and ethynylmagnesium bromide followed by treatment with CDI according to procedure C. Off-white solid: mp 185-186° C.; 1H-NMR (CDCl3) δ8.18 (s, 1H, D2O exchangeable), 7.53 (t, 1H, J=1.7 Hz), 7.49 (s, 1H), 7.31-7.48 (m, 4H), 6.92 (d, 1H, J=8.1 Hz), 2.81 (s, 1H), 1.87 (s, 3H); MS (ESI) m/z 304 ([M−H]−, 100%); Anal. Calc. For C17H12ClNO2: C, 68.58; H, 4.06; N, 4.70. Found: C, 68.24; H, 3.94; N, 4.65.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C@@H:11]2[CH2:12][CH2:13][CH2:14][C@@H:10]2[C:9](=[O:15])[N:8]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24](OC3C=CC=CC=3)=[O:25])=[CH:19][CH:18]=2)[C:7]2[CH:33]=[CH:34][CH:35]=[CH:36][C:6]1=2)=[O:4].[NH2:37][CH2:38][C:39]1[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=1.[C:45]1(=[O:55])[NH:49][C:48](=[O:50])[C:47]2=[CH:51][CH:52]=[CH:53][CH:54]=[C:46]12.[K]>CN(C=O)C.C(OCC)(=O)C.O>[C:45]1(=[O:55])[N:49]([CH2:2][C:3]([N:5]2[C@@H:11]3[CH2:12][CH2:13][CH2:14][C@@H:10]3[C:9](=[O:15])[N:8]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:24]([NH:37][CH2:38][C:39]4[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=4)=[O:25])=[CH:21][CH:22]=3)[C:7]3[CH:33]=[CH:34][CH:35]=[CH:36][C:6]2=3)=[O:4])[C:48](=[O:50])[C:47]2=[CH:51][CH:52]=[CH:53][CH:54]=[C:46]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: NCc1ccncc1
Reactant: O=C(Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CCl)c3ccccc32)cc1)Oc1ccccc1
Agent: [K]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCc1ccncc1)Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CN3C(=O)c4ccccc4C3=O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 44 h
Yield: 17.5 %

Procedure:
To a solution of (3aR*,10aS*)-4-(Chloroacetyl)-9-[4-(phenoxycarbonylamino)benzyl]-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one (151 mg, 0.3 mmol) in DMF (1.5 mL) was added 4-(aminomethyl)pyridine (30 μL, 0.3 mmol) and the mixture was stirred at room temperature for 44 hours. This reaction mixture was diluted with ethyl acetate and water, and the aqueous layer was extracted with 2 portions of ethyl acetate. The pooled organic layer was washed with water and saturated aqueous NaCl solution, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was dissolved in DMF (2 mL) and after addition of potassium phthalimide (55 mg, 0.3 mmol), the mixture was stirred at room temperature for 90 hours. This reaction mixture was diluted with water and ethyl acetate and the aqueous layer was separated. The organic layer was washed with water and saturated aqueous NaCl solution, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol=20:1) to provide 33 mg (yield 17%) of the title compound. Amorphous.
Reaction SMILES: II.Br[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([F:13])([F:12])[F:11].[CH2:14]([N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C:22]1=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl-].[NH4+].C1C[O:33]CC1>>[CH2:14]([N:21]1[CH2:26][CH2:25][C:24]([OH:33])([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:10]([F:13])([F:12])[F:11])[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C1CCOC1
Reactant: O=C1CCCCN1Cc1ccccc1
Reactant: FC(F)(F)c1ccccc1Br
Agent: II
Agent: [Cl-]
Agent: [NH4+]
Product: OC1(c2ccccc2C(F)(F)F)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.25 g (0.135 mol) of Mg are mixed with a spatula tipfull of I2, and a solution of 30.4 g (0.135 mol) of 2-bromo-1-trifluoromethylbenzene in 125 ml of THF is added dropwise. The mixture is stirred for one hour at room temperature and 10.1 g (0.041 mol) of benzylpiperidone are added dropwise. The mixture is stirred for 1 hour at room temperature and a saturated ammonium chloride solution is added. After extraction with ethyl ether, the organic phase is dried and the solvent is evaporated off under reduced pressure. The product is purified by chromatography on a silica gel column using a cyclohexane/ethyl acetate mixture as the eluent to give 6.8 g of 1-benzyl-4-hydroxy-4-(2-trifluoromethylphenyl)piperidine, which is hydrogenated with the aid of 0.7 g of 10% Pd/C in 75 ml of 95% ethanol which has been brought to acid pH by the addition of hydrochloric acid, the mnixture being heated at a temperature of 60° C. for 8 hours. The catalyst is filtered off to give 2.1 g of the title product. M.p. 247-251° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[C:19]([C:21](O)=[O:22])[CH:18]=[C:17]2[C:4]=1[C@H:5]1[C@H:14]([CH2:15][S:16]2(=[O:25])=[O:24])[C@:13]2([CH3:26])[C@H:8]([C:9]([CH3:28])([CH3:27])[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1.[CH3:29][N:30](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.CN>CN(C=O)C.C1COCC1>[CH3:1][O:2][C:3]1[CH:20]=[C:19]([C:21]([NH:30][CH3:29])=[O:22])[CH:18]=[C:17]2[C:4]=1[C@H:5]1[C@H:14]([CH2:15][S:16]2(=[O:25])=[O:24])[C@:13]2([CH3:26])[C@H:8]([C:9]([CH3:28])([CH3:27])[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1
Reactant: COc1cc(C(=O)O)cc2c1[C@@H]1CC[C@H]3C(C)(C)CCC[C@]3(C)[C@H]1CS2(=O)=O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(OC)c2c(c1)S(=O)(=O)C[C@H]1[C@H]2CC[C@H]2C(C)(C)CCC[C@]12C
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.7 %

Procedure:
A mixture of (1R,10S,11S,16S)-3-methoxy-11,15,15-trimethyl-8,8-dioxo-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-5-carboxylic acid (61) (0.35 g, 0.83 mmol), HATU (0.61 g, 1.7 mmol), N-methylmorpholine (0.18 mL, 2.5 mmol), methylamine (2 M in THF, 1.04 mL, 2.08 mmol), THF (10.0 mL) and DMF (2.0 mL) in a sealed tube was stirred at room temperature for 18 h. The THF was evaporated and the residue was quenched with water. The resulting solid was collected by filtration. The crude product was purified by flash chromatography on silica gel (Hexanes/EtOAc, 1:1) to yield (1R,10S,11S,16S)-3-methoxy-N,11,15,15-tetramethyl-8,8-dioxo-8λ6thiatetracyclo[8.8.0.02,7.011,16]-octadeca-2,4,6-triene-5-carboxamide (0.26 g, 74%) (Compound No. 62) as a white solid. 1H NMR (CDCl3): δ 8.77 (s, 1H), 8.07 (s, 1H), 7.60 (s, 1H), 6.59 (m, 1H), 3.52 (m, 1H), 3.37 (m, 1H), 3.24 (m, 1H), 3.05 (d, 3H), 2.32 (d, 1H), 1.65-1.10 (m, 13H), 0.97 (s, 3H), 0.88 (s, 3H), 0.84 (s, 3H). MS m/z 420 (C23H33NO4S+H+).
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]1=[O:17].[H-].[Na+].[F:20]N(CC(C)(C)C)S(C1C=CC(C)=CC=1)(=O)=O.Cl>C1COCC1.ClCCl>[F:20][C:2]1([CH3:1])[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]1=[O:17]
Reactant: Cc1ccc(S(=O)(=O)N(F)CC(C)(C)C)cc1
Reactant: CC1C(=O)N(c2ccccc2)c2ncccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC1(F)C(=O)N(c2ccccc2)c2ncccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Add 1,3-dihydro-3-methyl-1-phenyl-2H-pyrrolo[2,3-b]-pyridin-2-one (H) (3.0 g, 0.013 mole) portionwise to sodium hydride (0.63 g of 60% NaH in oil, 0.015 mole, washed with hexane) in dry THF (35 mL) at 10° C. under a N2 atmosphere. Stir for 30 minutes at room temperature, and then recool to 10° C. Add N-fluoro-N-neopentyl-p-toluenesulfonamide (4.1 g, 0.015 mole) in dry THF (30 mL) dropwise over 10 minutes. Warm reaction mixture up to room temperature slowly, and stir for 16 hours. Pour onto ice/water (100 mL), and neutralize to pH=4 to 5 with 15% aqueous HCl. Separate layers. Dry organic solution with MgSO4, filter, and rotoevaporate to give an oil. Dissolve the oil in dichloromethane, and chromatograph on silica gel, eluting with 30% ethyl acetate-hexane. Combine the appropriate fractions, and concentrate under reduced pressure. Triturate with isopropyl ether-petroleum ether and filter to give the title compound AA as a white solid (1.1 g, m.p. 83°-85° C.).
Reaction SMILES: C([O:4][CH:5]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][N:22]=1)[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15](Br)[C:16]([O:18]C)=O)=[CH:10][CH:9]=1)(=O)C.[NH2:29][C:30](N)=[S:31].C([O-])(=[O:35])C.[Na+]>C(O)C>[CH2:27]([C:24]1[CH:25]=[CH:26][C:21]([CH:5]([OH:4])[CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]([CH2:14][CH:15]3[S:31][C:30](=[O:35])[NH:29][C:16]3=[O:18])=[CH:12][CH:13]=2)=[N:22][CH:23]=1)[CH3:28]
Reactant: NC(N)=S
Reactant: CCc1ccc(C(COc2ccc(CC(Br)C(=O)OC)cc2)OC(C)=O)nc1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CCc1ccc(C(O)COc2ccc(CC3SC(=O)NC3=O)cc2)nc1

Procedure:
By following the same procedure as described in Example 1, methyl 3-{4-[2-acetoxy-2-(5-ethyl-2-pyridyl) ethoxy]phenyl}-2-bromopropionate (10.0 g), thiourea (2.0 g) and sodium acetate (2.2 g) were allowed to undergo reaction in ethanol and hydrolysis was performed to give 5-{4-[2-(5-ethyl-2-pyridyl)-2-hydroxyethoxy]benzyl}-2,4-thiazolidinedione in the form of crystals. Yield of 6.2 g. Recrystallization from ethyl acetate-hexane produced colorless prisms. m.p. 129°-130° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16].[CH3:19][N:20]([CH3:22])[NH2:21]>C1CCCCC1>[CH3:19][N:20]([CH3:22])[NH:21][C:6]1[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]([C:15]([F:18])([F:17])[F:16])=[C:2]([Cl:1])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c1Cl
Reactant: CN(C)N
Solvent: C1CCCCC1
Product: CN(C)Nc1c([N+](=O)[O-])cc(C(F)(F)F)c(Cl)c1[N+](=O)[O-]
Reaction time: 0.33 h
Yield: 85 %

Procedure:
To 20.0 g. (0.065 mole) of 2,4-dichloro-3,5-dinitrobenzotrifluoride and 300 ml. of cyclohexane in a 500 ml. roundbottom flask equipped with a stirrer and dropping funnel was added 7.86 g. (0.13 mole) of 1,1-dimethylhydrazine at ambient temperature. The addition was drop-wise over a period of about 20 minutes. Stirring was continued for 22 hours at room temperature. The resultant mixture was filtered and the insoluble solid then stirred with 300 ml. of water for one hour to dissolve the hydrazine hydrochloride. The insoluble product was isolated by filtration and washed with water. Recrystallization from 95% ethanol gave 18.3 g. (85%) of the desired product as a yellow solid, m.p. 130°-131° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][C:17]1=[O:22]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:19]2[CH2:20][CH2:21][NH:16][C:17](=[O:22])[CH2:18]2)=[O:15])=[CH:6][CH:7]=1
Reactant: O=C1CNCCN1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Product: Cc1ccc(-c2oncc2C(=O)N2CCNC(=O)C2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and piperazinone (6.0 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (4.6 mg). Calcd for C15H15N3O3: 285.1113, found 285.1113.
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH2:27][OH:28])[C@@H:10]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(Cl)Cl.N1C=CC=CC=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>CCOC(C)=O>[Si:1]([O:8][C@H:9]([CH:27]=[O:28])[C@@H:10]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccc(F)c1)[C@@H](CO)O[Si](C)(C)C(C)(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cccc(F)c1)[C@@H](C=O)O[Si](C)(C)C(C)(C)C
Temperature: 23 °C
Reaction time: 0.03 h

Procedure:
To a 150 mL RBF containing tert-butyl(2S,3S)-3-(tert-butyldimethylsilyloxy)-1-(3-fluorophenyl)-4-hydroxybutan-2-ylcarbamate (170.00 mg, 411 μmol) was added DCM (10 mL) and the mixture was allowed to stir at 23° C. for 2 minutes. At this time, pyridine (299 μl, 3699 μmol) was added via syringe before the addition of Dess-MartinPeriodinane (262 mg, 617 μmol) in one portion. The reaction stayed a clear solution and was allowed to stir 1 h before loading directly to a silica gel column (20% EtOAc). The purified product was concentrated to give the title compound as a colorless oil.
Reaction SMILES: FC1C=CC(CN2C3C=CC=CC=3N=C2)=CC=1.CCCCCC.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][CH:37]([C:40](OC)=[O:41])[CH2:36][CH2:35]2)=[CH:28][CH:27]=1>C1COCC1>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][CH:37]([CH:40]=[O:41])[CH2:36][CH2:35]2)=[CH:28][CH:27]=1
Reactant: COC(=O)C1CCN(CCc2ccc(OC)cc2)CC1
Agent: Fc1ccc(Cn2cnc3ccccc32)cc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(CCN2CCC(C=O)CC2)cc1
Reaction time: 0.29 h

Procedure:
To a stirred, -78° C., solution of 1-[(4-fluorophenyl)methyl]-1H-benzimidazol (1.13 g, 5.00×10-3 mole) and dry THF (12 ml) under argon was added a 2.5 molar hexane solution of n-butyl ithium (2.1 ml, 5.25×10-3 mole). After 15-20 minutes at -78° C., a solution of 1-[2-(4-methoxyphenyl)ethyl]-4-piperidinecarboxylic acid, methyl ester (1.39 g, 5.01×10-3 mole) and dry THF (6 ml) was added dropwise via syringe. After 5-10 minutes, the cooling bath was removed and the reaction was allowed to warm. After ca. 30 minutes, the reaction was quenched by the addition of saturated aqueous NH4Cl. The reaction was transferred to a separatory funnel where the aqueous mixture was extracted two times with ethyl acetate. The ethyl acetate extracts were combined, washed with saturated aqueous NaCl, and dried over anhydrous Na2SO4. The drying agent was removed by filtration and the filtrate was evaporated at reduced pressure affording a viscous oil. This was purified by a combination of flash chromatography (ethyl acetate) and crystallization (cyclohexane) affording 1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl][1-[2-(4-methoxyphenyl)ethyl]-4-piperidinyl]methanone as off white matted needles: 0.90 g (38%), m.p. 109°-111° C.
Reaction SMILES: O[C:2]1([C:14]([O:16]CC)=O)[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH2:3]1.[H-].C([Al+]CC(C)C)C(C)C.C1C[O:32]CC1>C1(C)C=CC=CC=1>[OH:16][CH2:14][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:32])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1(O)C=CC(c2ccccc2)=CC1
Reactant: C1CCOC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: OCc1ccc(-c2ccc(O)cc2)cc1
Reaction time: 2 h

Procedure:
15.0 g (60.7 mmol) of ethyl 4-hydroxybiphenyl-4-carboxylate are dissolved in 500 ml of THF, and 200 ml of a 1 M solution of diisobutylaluminium hydride in toluene are added at −70° C. The cooling is subsequently removed, and the batch is stirred at room temp. for 2 h. After addition of 5 ml of isopropanol, the solution is added to water, extracted three times with MTB ether, and the combined org. phases are washed with water and dried over sodium sulfate. The solvent is removed in vacuo, and the residue is filtered through silica gel with toluene/ethyl acetate, giving 4′-hydroxymethyl-4-biphenylol as a colourless solid.
Reaction SMILES: [OH2:1].[NH2:2][NH2:3].CCO.Cl[C:8]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=[O:17])=[CH:12][C:9]=1[C:10]#[N:11]>O>[N+:16]([C:13]1[CH:12]=[C:9]2[C:8](=[CH:15][CH:14]=1)[NH:3][N:2]=[C:10]2[NH2:11])([O-:17])=[O:1]
Reactant: NN
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: O
Solvent: CCO
Product: Nc1n[nH]c2ccc([N+](=O)[O-])cc12
Reaction time: 0.5 h

Procedure:
Hydrazine monohydrate (4.87 ml) was added to an EtOH (19 ml) solution containing 2-chloro-5-nitrobenzonitrile (1.83 g), followed by stirring for 0.5 hour under ice cooling. Water was added to the reaction solution, and a solid precipitate was collected by filtration and washed with IPE and ethyl acetate. A red solid of 5-nitro-1H-indazol-3-amine (1.45 g) was thus obtained.