Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([N:23]=[N+:24]=[N-:25])=[CH:11][C:10]=1[CH:26]([CH3:28])[CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]([N:31]([CH2:39][C:40]1[CH:45]=[CH:44][C:43]([N:46]2[CH2:51][CH2:50][O:49][CH2:48][CH2:47]2)=[CH:42][CH:41]=1)[C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])#[CH:30].CCOC(C)=O.O>CN(C=O)C>[C:34]([O:33][C:32](=[O:38])[N:31]([C:29]1[N:23]([C:12]2[CH:11]=[C:10]([CH:26]([CH3:28])[CH3:27])[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:14][C:13]=2[O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:24]=[N:25][CH:30]=1)[CH2:39][C:40]1[CH:45]=[CH:44][C:43]([N:46]2[CH2:47][CH2:48][O:49][CH2:50][CH2:51]2)=[CH:42][CH:41]=1)([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)c1cc(N=[N+]=[N-])c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: C#CN(Cc1ccc(N2CCOCC2)cc1)C(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1cc(-n2nncc2N(Cc2ccc(N3CCOCC3)cc2)C(=O)OC(C)(C)C)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Yield: 56 %

Procedure:
A solution of 1,5-bis-benzyloxy-2-isopropyl-4-azido-benzene (240 mg, 0.64 mmol) and t-butyl ethynyl(4-morpholinobenzyl)carbamate (185 mg, 0.58 mmol) in DMF (2.5 ml) was degassed at RT by means of three vacuum-nitrogen cycles before adding [Cp*RuCl]4 (32 mg, 0.029 mmol). The reaction mixture was stirred at RT until completion (i.e., monitored by TLC). AcOEt and H2O were then added. The organic phase was extracted four times with AcOEt, washed with water (three times) and brine (once) and dried over Na2SO4. The solvent was removed under reduced pressure and the reaction mixture was purified by column chromatography (PE/AcOEt:60/40). The title compound was obtained as an oil.
Reaction SMILES: [CH3:1][C:2]1[C@@H:19](OC([C@H](O)[C@@H](NC(C2C=CC=CC=2)=O)C2C=CC=CC=2)=O)[CH2:18][C@:14]2(O)[C:15]([CH3:17])([CH3:16])[C:3]=1[C@@H:4](OC(C)=O)[C:5]([C@@:7]1([CH3:58])[C@H:12]([C@@H:13]2OC(C2C=CC=CC=2)=O)[C@:11]2(OC(C)=O)[CH2:51]O[C@@H:10]2[CH2:9][C@@H:8]1O)=O.CC1[C@@H](OC([C@H](O)[C@@H](NC(OC(C)(C)C)=O)C2C=CC=CC=2)=O)C[C@]2(O)C(C)(C)C=1[C@@H](O)C([C@@]1(C)[C@H]([C@@H]2OC(C2C=CC=CC=2)=O)[C@]2(OC(C)=O)CO[C@@H]2C[C@@H]1O)=O>>[CH3:51][C@H:11]1[C@H:12]2[CH2:13][C@H:14]3[C:15]([CH3:16])([CH3:17])[C@@H:3]([CH2:4][CH2:5][C@:7]2([CH3:58])[CH2:8][CH2:9][CH2:10]1)[C@H:2]([CH3:1])[CH2:19][CH2:18]3
Reactant: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](OC(=O)[C@H](O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Agent: CC(=O)O[C@@]12CO[C@@H]1C[C@H](O)[C@@]1(C)C(=O)[C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)c4ccccc4)C[C@@](O)([C@@H](OC(=O)c4ccccc4)[C@H]21)C3(C)C
Product: C[C@@H]1CCC[C@@]2(C)CC[C@H]3[C@H](C)CC[C@@H](C[C@H]12)C3(C)C

Procedure:
Under the above test conditions, both paclitaxel and docetaxel were completely insoluble.
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9]([C:16]3[CH:21]=[CH:20][C:19]([CH:22]=[CH:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:18][CH:17]=3)=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[C:30]1([C:36]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[CH:37][C:38]2[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>[C:30]1([C:36]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[CH:37][C:38]2[CH:43]=[CH:42][C:41]([C:2]3[C:3]4[C:8]([C:9]([C:16]5[CH:21]=[CH:20][C:19]([CH:22]=[CH:23][C:24]6[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=6)=[CH:18][CH:17]=5)=[C:10]5[C:15]=3[CH:14]=[CH:13][CH:12]=[CH:11]5)=[CH:7][CH:6]=[CH:5][CH:4]=4)=[CH:40][CH:39]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: OB(O)c1ccc(C=C(c2ccccc2)c2ccccc2)cc1
Reactant: Brc1c2ccccc2c(-c2ccc(C=Cc3ccccc3)cc2)c2ccccc12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C(=Cc1ccc(-c2c3ccccc3c(-c3ccc(C=C(c4ccccc4)c4ccccc4)cc3)c3ccccc23)cc1)c1ccccc1
Yield: 87.6 %

Procedure:
Under an atmosphere of argon, 9-bromo-10-(4-(2-phenylvinyl)-phenyl)anthracene (3.1 g, 7.1 mmole), 4-(2,2-diphenylvinyl)phenylboronic acid (2.4 g, 8.0 mmole, 1.1 eq) and tetrakis(triphenylphosphine)-palladium(0) (0.16 g, 0.14 mmole, 2% Pd) were suspended into toluene (25 ml). To the obtained suspension, a 2 M aqueous solution of sodium carbonate (2.5 g, 24 mmole, 3 eq/12 ml) was added and the resultant mixture was heated under refluxing for 10 hours. The reaction mixture was filtered and washed with water and methanol and a yellow solid was obtained. The obtained solid was suspended in boiling toluene (50 ml), cooled while being left standing, filtered and washed with toluene and a light yellow solid (3.8 g, 88%) was obtained.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.[F:13][CH:14]([CH2:20][CH2:21][CH2:22][CH3:23])[C:15](OCC)=[O:16].S(=O)(=O)(O)O>CCCCCC.O1CCCC1>[CH3:4][O:3][P:2]([CH2:1][C:15](=[O:16])[CH:14]([F:13])[CH2:20][CH2:21][CH2:22][CH3:23])(=[O:7])[O:5][CH3:6]
Reactant: CCCCC(F)C(=O)OCC
Reactant: COP(C)(=O)OC
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCC(F)C(=O)CP(=O)(OC)OC
Reaction time: 0.08 h
Yield: 80.5 %

Procedure:
To a solution of 7.7 g. (0.06 mole) of dimethyl methyl-phosphonate in 80 ml. of tetrahydrofuran at -73° C. was added dropwise 43.4 ml. of a 1.42 molar solution of butyl lithium in hexane. After stirring for 5 minutes, a solution of 4 g. (0.03 mole) of ethyl 2-fluorohexanoate in 20 ml. of tetrahydrofuran was added dropwise. The resulting solution was then allowed to warm to 0° and then acidified (pH3) with 2 N sulfuric acid. The mixture was then extracted with hexane, the hexane solution washed with a saturated sodium chloride solution and then dried (MgSO4). The solvent was then removed under reduced pressure and the residue distilled to give 5.8 g of dimethyl(2-oxo-3-fluoroheptyl)phosphonate, b.p. 116°-118°/0.4 mm.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:12]([NH:14][CH2:15][C:16](N)=[O:17])=[O:13])[CH:5]=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32].Cl.N[CH2:35]C(N)=O>>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:12]([NH:14][CH2:15][C@H:16]([OH:17])[CH3:35])=[O:13])[CH:5]=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32]
Reactant: NCC(N)=O
Reactant: Cc1ccc(C(=O)NCC(N)=O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O
Agent: Cl
Product: Cc1ccc(C(=O)NC[C@@H](C)O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O

Procedure:
The title compound was prepared using a procedure similar to that used in Step 4 of the synthesis of 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-N-[1-(aminocarbonyl)methyl]-4-methylbenzamide by substituting (R)-(−)-1-amino-2-propanol for glycineamide HCl. 1H NMR (CD3OD/400 MHz) δ8.32 (s, 1H), 7.92 (m, 1H), 7.77 (s, 1H), 7.61 (q, 1H, J=8.0 Hz), 7.53 (d, 1H, J=8.0 Hz), 7.02 (m, 2H), 5.60 (m, 2H), 3.94 (m, 1H), 3.30 (m, 2H), 2.20 (s, 3H), 1.18 (s, 3H). ESHRMS m/z 464.1167 (M+H calculated for C22H21ClF2N3O4 requires 464.1183).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11]N)([O-:4])=[O:3].[C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)(=O)[CH3:14]>>[N+:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:6]=1[NH:11][C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)=[CH:14]2)([O-:4])=[O:3]
Reactant: NNc1ccccc1[N+](=O)[O-]
Reactant: CC(=O)c1ccccn1
Agent: Cl
Product: O=[N+]([O-])c1cccc2cc(-c3ccccn3)[nH]c12
Yield: 16.1 %

Procedure:
2-Nitrophenylhydrazine hydrochloride (5 g, 26 mmol) and 2-acetylpyridine (2.5 ml, 26 mmol) were reacted according to the same procedures as Preparations 4 to 5 to give the title compound (1 g, Yield 16%).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].[NH2:8][C:9]1[C:10]([F:22])=[CH:11][C:12]([Cl:21])=[C:13]([CH:20]=1)[C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15]>C(C(C)=O)C>[Cl:21][C:12]1[CH:11]=[C:10]([F:22])[C:9]([NH:8][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])=[CH:20][C:13]=1[C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(C)OC(=O)c1cc(N)c(F)cc1Cl
Solvent: CCC(C)=O
Product: CC(C)OC(=O)c1cc(NC(=O)C(C)(C)C)c(F)cc1Cl
Yield: 79 %

Procedure:
A solution of trimethylacetyl chloride (2.53 g, 0.021 mole) and 1-methylethyl 5-amino-2-chloro-4-fluorobenzoate (4.62 g, 0.020 mole) in methyl ethyl ketone was stirred at room temperature for 16 hours and then refluxed for 2 hours. The solvent was removed and the residue triturated with diethyl ether to give a tan solid, m.p. 81°-83° C. (5.0 g, 79% yield).
Reaction SMILES: [CH3:1][CH2:2][C@:3]12[CH2:19][C@:18]([OH:24])([C:20]([O:22][CH3:23])=[O:21])[N:17]3[C:9]4=[C:10]([CH2:25][CH2:26][N:7]([C@@H:8]14)[CH2:6][CH2:5][CH2:4]2)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=13.[OH:27][C:28]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][C:29]=1[C:30]([OH:32])=[O:31]>O>[CH3:1][CH2:2][C@:3]12[CH2:19][C@:18]([OH:24])([C:20]([O:22][CH3:23])=[O:21])[N:17]3[C:9]4=[C:10]([CH2:25][CH2:26][N:7]([C@@H:8]14)[CH2:6][CH2:5][CH2:4]2)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=13.[OH:27][C:28]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][C:29]=1[C:30]([O-:32])=[O:31]
Reactant: O=C(O)c1cc(O)ccc1O
Agent: CC[C@]12CCCN3CCc4c(n(c5ccccc45)[C@@](O)(C(=O)OC)C1)[C@@H]32
Solvent: O
Product: O=C([O-])c1cc(O)ccc1O

Procedure:
By repeating the Example 5a., starting from 7.08 g (2.10-2 moles) of vincamine and 3.08 g (2.10-2 moles) of 2,5dihydroxybenzoic acid, 10 g are obtained of an amorphous product, insoluble in water and in alcohol, having a vincamine content of 69%.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[N:15]1[C:24]2[C:19](=[C:20]([N:25]3[C:29]([NH2:30])=[CH:28][C:27]([C:31]([F:34])([F:33])[F:32])=[N:26]3)[CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:30][C:29]2[N:25]([C:20]3[CH:21]=[CH:22][CH:23]=[C:24]4[C:19]=3[CH:18]=[CH:17][CH:16]=[N:15]4)[N:26]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:28]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1cc(C(F)(F)F)nn1-c1cccc2ncccc12
Solvent: c1ccncc1
Product: CC(C)Oc1ccc(S(=O)(=O)Nc2cc(C(F)(F)F)nn2-c2cccc3ncccc23)cc1
Temperature: 80 °C
Yield: 47 %

Procedure:
To a mixture of 4-isopropoxybenzenesulfonyl chloride (0.080 g, 0.35 mmol) and 1-(quinolin-5-yl)-3-(trifluoromethyl)-1H-pyrazol-5-amine (prepared from Example 21 step a, 0.032 g, 0.11 mmol) in pyridine (0.5 mL) was heated at 80° C. for 4 h with stirring. After cooling to room temperature, the reaction mixture was concentrated in vacuo and the crude residue was purified by reverse phase HPLC(C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.025 g, 0.052 mmol, 47%). 1H NMR (400 MHz, DMSO-d6) δ 8.94 (dd, J=1.6, 4.0 Hz, 1H), 8.19 (d, J=8.4 Hz, 1H), 7.82 (t, J=8.4 Hz, 1H), 7.50-7.46 (m, 2H), 7.40 (s, 1H), 7.38 (s, 1H), 7.35 (d, J=8.4 Hz, 1H), 6.83 (s, 1H), 6.81 (s, 1H), 6.64 (s, 1H), 4.63 (pent, J=6.0 Hz, 1H), 1.28 (d, J=6.0 Hz, 6H); MS: (ES) m/z calculated for C22H20F3N4O2S [M+H]+ 477.2. found 477.3.
Reaction SMILES: CCN(C(C)C)C(C)C.F[C:11]1[C:12]([CH3:31])=[N:13][C:14]2[C:19]([N:20]=1)=[C:18]([C:21]1[NH:29][C:28]3[CH2:27][CH2:26][NH:25][C:24](=[O:30])[C:23]=3[CH:22]=1)[CH:17]=[CH:16][CH:15]=2.[NH2:32][CH:33]1[CH2:37][CH2:36][S:35](=[O:39])(=[O:38])[CH2:34]1>CS(C)=O>[O:38]=[S:35]1(=[O:39])[CH2:36][CH2:37][CH:33]([NH:32][C:11]2[C:12]([CH3:31])=[N:13][C:14]3[C:19]([N:20]=2)=[C:18]([C:21]2[NH:29][C:28]4[CH2:27][CH2:26][NH:25][C:24](=[O:30])[C:23]=4[CH:22]=2)[CH:17]=[CH:16][CH:15]=3)[CH2:34]1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Reactant: NC1CCS(=O)(=O)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC1CCS(=O)(=O)C1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Prepared according to Example 127, using DIPEA (141 μl, 0.803 mmol), 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 40 mg, 0.135 mmol), (±) 3-amino-tetrahydrothiophene 1,1-dioxide (54.7 mg, 0.405 mmol, Sigma Aldrich), and DMSO (1.4 mL) and stirring at 80° C. for 2 h. Purification by high throughput parallel purification (Rilas Technologies, Woburn, Mass.) provided 2-(3-(((±)-1,1-dioxidotetrahydro-3-thiophenyl)amino)-2-methyl-5-quinoxalinyl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one. 1H NMR (DMSO-d6) δ: 11.52-11.67 (m, 1H), 7.80-7.88 (m, 1H), 7.59-7.69 (m, 1H), 7.34-7.41 (m, 1H), 7.25-7.33 (m, 1H), 6.98-7.07 (m, 1H), 6.85-6.98 (m, 1H), 4.91-5.02 (m, 1H), 3.61-3.72 (m, 2H), 3.39-3.49 (m, 3H), 3.21-3.28 (m, 1H), 2.87-2.97 (m, 2H), 2.65-2.74 (m, 1H), 2.55-2.60 (m, 3H), 2.25-2.40 (m, 1H). m/z (ESI, +ve) 412.1 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:17]=2F)=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][NH:28][NH2:29].C([O-])(O)=O.[Na+]>C(O)CCC>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:16]3[C:17](=[CH:18][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=3)[N:28]([CH3:27])[N:29]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(C(F)(F)F)cc1F)C1CCN(Cc2ccccc2)CC1
Reactant: CNN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Product: Cn1nc(C2CCN(Cc3ccccc3)CC2)c2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Yield: 82.4 %

Procedure:
A solution of (1-benzyl-piperidin-4-yl)-(2-fluoro-4-trifluoromethyl-phenyl)-methanone (2.0 g, 5.46 mmol), methylhydrazine (327 mg, 7.10 mmol), and n-butanol (22 mL) was heated at 120° C. in a seal vessel for 18 hours. The reaction was cooled to room temperature and basified with NaHCO3 and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over magnesium sulfate, filtered, and evaporated. The product was chromatographed on silica, eluting with 1:1 ethyl acetate/heptane, to afford 1.68 g (82%) of the desired product as an oil.
Reaction SMILES: Br[CH:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5].[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.N1C=CN=C1C(C(C(C1NC=CN=1)=O)=O)=O.O>C(#N)C>[CH3:5][C:4]([C:3]([CH:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[N:17]1[CH:18]=[N:19][CH:20]=[CH:21]1)=[O:8])([CH3:7])[CH3:6]
Reactant: c1c[nH]cn1
Reactant: CC(C)(C)C(=O)C(Br)Oc1ccc(Cl)cc1
Agent: O=C(C(=O)c1ncc[nH]1)C(=O)c1ncc[nH]1
Solvent: O
Solvent: CC#N
Product: CC(C)(C)C(=O)C(Oc1ccc(Cl)cc1)n1ccnc1

Procedure:
The antigingivitis agent utilized in present invention is 1-imidazoyl-(p-chlorophenoxy)3-3-dimethyl 2-butanone having the structural formula: ##STR2## which is prepared by reacting 1-bromo-1-(4-chlorophenoxy)-3,3-dimethyl-2-butanone with imidazole dissolved in acetonitrile as disclosed in U.S. Pat. Nos. 3,812,142 and 3,903,287, which is made a part of this specification. This imidazoyl ketone is a water insoluble crystalline powder having a melting point of 94.5°-97.8° C. which may be obtained from the Bayer Company as Climbazole. Due to the water insolubility of this imidazole compound, it must first be solubilized in a nonionic compound prior to the addition of ionic materials in an aqueous medium.
Reaction SMILES: [CH:1](=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:10]=O>>[CH2:3]([C:2](=[CH2:10])[CH:1]=[O:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC=O
Reactant: C=O
Product: C=C(C=O)CCCCCC
Yield: 38775.3 %

Procedure:
100 G (0.78 mmol) of n-octanal, 73 g of 36% formic aldehyde and 260 g (0.78 mol) of catalyst (aqueous diethylamine chlorhydrate; 3 mol/kg) were charged in a 3-neck flask. The mixture was heated to reflux for 1 h and distilled. The reaction product was extracted with ether, dried and concentrated to give 42.41 g of 2-hexyl-2-propenal. Extraction of the flask's residue provided yet 64 g of raw product. The aldehyde was used as such in the next step.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>O1CCCC1>[F:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([NH:19][C:18]2[CH:20]=[CH:21][C:15]([C:12]3[N:13]=[CH:14][N:10]([C:7]4[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:22])[F:23])=[CH:9][CH:8]=4)[N:11]=3)=[CH:16][CH:17]=2)=[O:33])=[CH:27][CH:26]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)cc1)Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 65 °C
Yield: 49.1 %

Procedure:
To 4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)aniline (0.200 g, 0.624 mmol) and 1-fluoro-4-isocyanatobenzene (0.257 g, 1.87 mmol) in a 25 mL round-bottomed flask was added tetrahydrofuran (10 mL). The solution was heated to 65° C. for 2 hours before the solvent was removed under reduced pressure. Purification by flash column chromatography provided the title compound (0.140 g, 49%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH2:8][CH2:9][CH2:10][CH:11]1[CH2:13][O:12]1)([CH3:4])([CH3:3])[CH3:2].[NH2:15][C:16]1[CH:17]=[CH:18][C:19]2[S:24][CH2:23][C:22](=[O:25])[NH:21][C:20]=2[CH:26]=1>CCO.O>[C:1]([O:5][C:6](=[O:14])[NH:7][CH2:8][CH2:9][CH2:10][CH:11]([OH:12])[CH2:13][NH:15][C:16]1[CH:17]=[CH:18][C:19]2[S:24][CH2:23][C:22](=[O:25])[NH:21][C:20]=2[CH:26]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCC1CO1
Reactant: Nc1ccc2c(c1)NC(=O)CS2
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCC(O)CNc1ccc2c(c1)NC(=O)CS2
Yield: 37.7 %

Procedure:
A solution of ((rac)-3-oxiranyl-propyl)-carbamic acid tert-butyl ester (1.08 g, 5.34 mmol) and 6-amino-4H-benzo[1,4]thiazin-3-one (1.01 g, 5.61 mmol) in 9:1 EtOH/H2O (20 mL) was heated at 70° C. overnight. After cooling the mixture was concentrated in vacuo and chromatographed on SiO2 (DCM-MeOH—NH4OH: 1000:50:4) to afford the title intermediate as beige foam (767 mg, 38% yield).
Reaction SMILES: FC1C=C(C=CC=1)COC1C=CC(N)=CC=1.[F:17][C:18]1[CH:34]=[CH:33][C:21]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][CH:25]=2)=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:34]=[CH:33][C:21]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccc(F)cc2)cc1
Agent: Nc1ccc(OCc2cccc(F)c2)cc1
Product: Nc1ccc(OCc2ccc(F)cc2)cc1
Yield: 100 %

Procedure:
Prepared in analogy to 4-(3-fluoro-benzyloxy)-phenylamine, by hydrogenation of 4-(4-fluoro-benzyloxy)-nitrobenzene. Yield: 100% of a slightly red solid. MS: m/e=218.2 (M++H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[CH:11][CH:10]=1.[OH:19]O>C(O)=O>[F:1][C:2]([F:17])([F:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([OH:19])=[O:16])=[CH:11][CH:10]=1
Reactant: OO
Reactant: O=Cc1ccc(-c2ccccc2C(F)(F)F)cc1
Solvent: O=CO
Product: O=C(O)c1ccc(-c2ccccc2C(F)(F)F)cc1
Reaction time: 36 h
Yield: 69 %

Procedure:
Procedure C′: 2′-trifluoromethyl-biphenyl-4-carbaldehyde (Array 4PNL-S04-0) (0.63 g, 2.5 mmol) is suspended in formic acid (3.5 mL), and the solution is placed in an ice bath. Hydrogen peroxide is added (0.875 mL, 7.5 mmol), and the reaction vessel is placed in the refrigerator and is allowed to stand for 1-2 days. The yellow solid that precipitates out is filtered, washed with cold water and dried in a vacuum oven to give the title compound (0.45 g, 69%). MS (ES−) 265.1
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[O:7][CH2:6][CH:5]([CH2:8][O:9][C:10]2[C:15]([CH3:16])=[CH:14][N:13]=[C:12]([CH2:17][OH:18])[C:11]=2[CH3:19])[CH2:4][O:3]1.O.C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C1(C)C=CC=CC=1.O1CCCC1.C(OCC)(=O)C>[CH3:29][S:30]([O:18][CH2:17][C:12]1[C:11]([CH3:19])=[C:10]([O:9][CH2:8][CH:5]2[CH2:6][O:7][C:2]([CH3:20])([CH3:1])[O:3][CH2:4]2)[C:15]([CH3:16])=[CH:14][N:13]=1)(=[O:32])=[O:31]
Reactant: Cc1cnc(CO)c(C)c1OCC1COC(C)(C)OC1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cnc(COS(C)(=O)=O)c(C)c1OCC1COC(C)(C)OC1
Yield: 93.3 %

Procedure:
(4-((2,2-dimethyl-1,3-dioxan-5-yl)methoxy)-3,5-dimethylpyridin-2-yl)methanol (2.5 g, 8.35 mmol as the water content was regarded as 7.28%) was dissolved in toluene and the mixture was subjected twice to azeotropic dehydration. The residue was dissolved in tetrahydrofuran (30 ml). To the solution, triethylamine (2.33 ml, 16.7=mol) was added and the mixture was stirred in nitrogen atmosphere under ice-cool. Further, methanesulfonyl chloride (0.766 ml, 10 mmol) was added dropwise at an inner temperature below 11.5° C. for 2 minutes. The reaction mixture was stirred for 13 minutes under the same conditions, diluted with ethyl acetate and washed with a saturated aqueous sodium hydrogencarbonate solution and a saturated saline solution. The organic layer was dried over magnesium sulfate and filtrated through silica gel and the filtrate was concentrated under reduced pressure to obtain the title compound (2.8 g, 93.3%) as a light orange solid.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6]([OH:8])=[O:7])=[O:2].[CH2:13]([Zn]CC)C>>[CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH2:12][CH3:13])[C:6]([OH:8])=[O:7])=[O:2]
Reactant: CC[Zn]CC
Reactant: Cc1ccc(C(=O)O)cc1C=O
Product: CCc1ccc(C(=O)O)cc1C=O

Procedure:
The title compound is prepared in analogy to 3-formyl-4-methyl-benzoic acid using diethyl zinc in step b). LC-MS*: tR=0.45 min, [M−H]−=177.30; 1H NMR (D6-DMSO): δ 1.21 (t, J=7.5 Hz, 3H), 3.10 (q, J=7.5 Hz, 2H), 7.53 (d, J=8.0 Hz, 1H), 8.11 (dd, J=7.8, 1.5 Hz, 1H), 8.39 (d, J=1.3 Hz, 1H), 10.30 (s, 1H), 13.10 (br s, 1H).
Reaction SMILES: C[O:2][C:3](=[O:18])[CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[NH:7][C:6]1=[O:17].[OH-].[Li+]>CO>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]2[NH:7][C:6](=[O:17])[N:5]([CH2:4][C:3]([OH:18])=[O:2])[CH:9]=2)=[CH:11][CH:12]=1
Reactant: COC(=O)Cn1cc(-c2ccc(Cl)cc2)[nH]c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cn1cc(-c2ccc(Cl)cc2)[nH]c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
770 mg (2.89 mmol) of methyl[4-(4-chlorophenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-acetate from Example 232A are placed in 20 ml methanol, treated with 5.8 ml of 1 M aqueous lithium hydroxide solution and stirred for 18 hrs at room temperature. The methanol is then removed on the rotary evaporator and the residue is acidified with 1 N hydrochloric acid. The resulting precipitate is filtered off at the pump, washed with water and dried under high vacuum. 690 mg (94% of theory) of the target compound are thus obtained.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]([CH:39]=[CH:40][CH:41]=1)[CH2:11][N:12]1[C:16](=[O:17])[C:15]2([CH2:22][CH2:21][N:20](C(OCC3C=CC=CC=3)=O)[CH2:19][CH2:18]2)[N:14]([CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)[CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].C(OCC)(=O)C>[CH:33]1([N:14]2[C:15]3([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:16](=[O:17])[N:12]([CH2:11][C:10]3[CH:9]=[C:8]([CH:41]=[CH:40][CH:39]=3)[C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:13]2)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]1
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(C3CCCCC3)C3(CCN(C(=O)OCc4ccccc4)CC3)C2=O)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1cccc(CN2CN(C3CCCCC3)C3(CCNCC3)C2=O)c1
Yield: 99.7 %

Procedure:
Benzyl 3-(3-(tert-butoxycarbonyl)benzyl)-1-cyclohexyl-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (1.37 g, 2.44 mmol) and palladium on carbon (10 wt. %, wet, Degussa type E101 NE/W,) (0.27 g) in ethyl acetate (20 mL) was stirred at room temperature under hydrogen (balloon) for 3 hours. The catalyst was removed by filtration and the filtrate evaporated and dried under vacuum to give product as a foam (1.04 g, quant.); MS for C25H37N3O3 m/z 428 (M+H)+.