Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH2:16][CH3:17])[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[C:20]2[C:28]([O:30][C:31](=O)[C:19]=12)=[O:29]>C(O)(=O)C>[CH2:16]([O:15][C:9]1[CH:8]=[C:7]([CH:2]([N:1]2[C:31](=[O:30])[C:19]3[CH:18]=[C:27]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]4=[CH:21][C:20]=3[C:28]2=[O:29])[CH2:3][C:4]([OH:6])=[O:5])[CH:12]=[CH:11][C:10]=1[O:13][CH3:14])[CH3:17]
Reactant: O=C1OC(=O)c2cc3ccccc3cc21
Reactant: CCOc1cc(C(N)CC(=O)O)ccc1OC
Solvent: CC(=O)O
Product: CCOc1cc(C(CC(=O)O)N2C(=O)c3cc4ccccc4cc3C2=O)ccc1OC
Yield: 93.5 %

Procedure:
3-(3-Ethoxy-4-methoxyphenyl)-3-(1,3-dioxo-2,3-dihydro-1H-benzo[f]isoindol-2-yl)-propanoic acid was prepared according to Example 2A from 3-amino-3-(3-ethoxy-4-methoxyphenyl)propanoic acid (3.00 g, 12.5 mmol), 2,3-napthalene dicarboxylic anhydride (2.59 g, 12.5 mmol) in acetic acid (20 mL) to afford 3-(3-ethoxy-4-methoxyphenyl)-3-(1,3-dioxo-2,3-dihydro-1H-benzo[f]isoindol-2-yl)propanoic acid as an off-white solid (4.9 g, 93% yield): mp, 193.0–194.0° C.; 1H NMR (DMSO-d6) δ 1.32 (t, J=6.9 Hz, 3H, CH3), 3.34 (dd, J=7.1, 16 Hz, 1H, CHH), 3.57 (dd, J=8.9, 16 Hz, 1H, CHH), 3.74 (s, 3H, CH3), 4.02 (q, J=6.9 Hz, 2H, CH2), 5.71 (dd, J=7, 8 Hz, 1H, NCH), 6.91–6.98 (m, 2H, Ar), 7.09 (br s, 1H, Ar), 7.74–7.78 (m, 2H, Ar), 8.23–8.27 (m, 2H, Ar), 8.50 (br s, 2H, Ar), 12.5 (br s, 1H, OH); 13C NMR (DMSO-d6) δ 14.62, 36.03, 50.28, 55.43, 63.71, 111.79, 112.28, 119.45, 124.55, 126.87, 129.27, 130.24, 131.24, 135.03, 147.74, 148.57, 167.29, 171.75; Anal Calcd for C24H21NO6: C, 68.73; H, 5.05; N, 3.34. Found: C, 68.59; H, 5.25; N, 3.17.
Reaction SMILES: [CH:1]([Mg]Cl)=[CH2:2].[N:5]1[CH:10]=[CH:9][CH:8]=[C:7](/[CH:11]=[N:12]/[CH2:13][CH:14]=[CH2:15])[CH:6]=1>>[CH2:13]([NH:12][CH:11]([C:7]1[CH:6]=[N:5][CH:10]=[CH:9][CH:8]=1)[CH:1]=[CH2:2])[CH:14]=[CH2:15]
Reactant: C=CC/N=C/c1cccnc1
Reactant: C=C[Mg]Cl
Product: C=CCNC(C=C)c1cccnc1
Reaction time: 1 h
Yield: 86.7 %

Procedure:
According to Example 2, vinyl magnesium chloride (1.00 M in THF, 1.10 mL; 1.10 mmol; 1.10 equiv) was reacted with N-[(E)-3-pyridinylmethylidene]-2-propen-1-amine (11) (146 mg; 1.00 mmol) in the presence of LaCl3.2LiCl (0.33 M; 0.30 mL, 0.10 mmol, 0.10 equiv) at room temperature for 1 h. Column chromatographical purification afforded the desired product 12 as colorless oil (151 mg, 87%). The analytical data were found to be in accordance with the literature data.
Reaction SMILES: [CH2:1]([C:3](=[CH2:6])[CH:4]=O)[CH3:2].[NH2:7][C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]>Cl.CNC.O>[CH2:1]([C:3]1[CH:4]=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)C=C(N)C(=O)OCC
Reactant: C=C(C=O)CC
Agent: CNC
Agent: Cl
Solvent: O
Product: CCOC(=O)c1cc(CC)cnc1C(=O)OCC
Temperature: 50 °C
Reaction time: 4 h
Yield: 45.7 %

Procedure:
In a 500 ml four neck distillation flask with a reflux condenser were placed 2-ethyl-2-propenal 100 g (1.19 mol) and dimethylamine hydrochloride 2.0 g, and heated on an oil bath. When the inside temperature reached 90° C., ethyl β-amino-β-ethoxycarbonylacrylate 200 g (1.07 mol) was added dropwise thereto at 90° to 95° C. over a period of 4 hours. After completion of the dropping, the mixture was heated at 90° to 95° C. for 10 hours. Then, the reaction mixture was cooled to 50° C., and 30 ml of water was added thereto. The mixture was then allowed to stand still to separate into a water layer and an oil layer. The oil layer was distilled to give 123.0 g of 5-ethyl-2,3-diethoxycarbonylpyridine.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]=2[O:31][C:32]2[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=2[CH3:39])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41]>C(Cl)Cl>[F:38][C:36]1[CH:35]=[CH:34][C:33]([CH3:39])=[C:32]([CH:37]=1)[O:31][C:17]1[N:18]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:19]2[C:24]([C:16]=1[C:14]([N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:15])=[CH:23][CH:22]=[CH:21][CH:20]=2.[F:43][C:42]([F:45])([F:44])[C:40]([OH:46])=[O:41].[F:38][C:36]1[CH:35]=[CH:34][C:33]([CH3:39])=[C:32]([CH:37]=1)[O:31][C:17]1[N:18]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:19]2[C:24]([C:16]=1[C:14]([N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:15])=[CH:23][CH:22]=[CH:21][CH:20]=2
Reactant: Cc1ccc(F)cc1Oc1c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc2n1-c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(F)cc1Oc1c(C(=O)N2CCNCC2)c2ccccc2n1-c1ccccc1
Reaction time: 8 h

Procedure:
A solution of the compound of step 2 (23 mg, 43.4 μmol) in DCM (8 ml) and TFA (2 ml) was stirred at room temperature for 1 h. The solvents were evaporated and the resulting solid dissolved in MOH and water and lyophilized overnight. The title compound was obtained in the form of the [2-(5-fluoro-2-methyl-phenoxy)-1-phenyl-1H-indol-3-yl]-piperazin-1-yl-methanone trifluoroacetic acid salt as a white solid. Yield: 21.0 mg.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[C:7]2[C:3]=1[C:4](=N)[NH:5][C:6]2=[NH:13].Cl.[Cl:16][C:17]1[CH:29]=[CH:28][C:20]([NH:21][C:22]2[S:23][CH2:24][C:25](=[NH:27])[N:26]=2)=[CH:19][CH:18]=1.N=C1C2C(=CC=CC=2)C(=N)N1.Cl.N1(C2SCC(=N)N=2)CCCCC1>>[ClH:16].[NH:13]=[C:6]1[C:7]2[C:3](=[C:2]([CH3:1])[C:10]([CH3:11])=[CH:9][C:8]=2[CH3:12])[C:4](=[C:24]2[S:23][C:22]([NH:21][C:20]3[CH:19]=[CH:18][C:17]([Cl:16])=[CH:29][CH:28]=3)=[N:26][C:25]2=[NH:27])[NH:5]1
Reactant: N=C1CSC(Nc2ccc(Cl)cc2)=N1
Reactant: Cc1cc(C)c2c(c1C)C(=N)NC2=N
Agent: Cl
Agent: N=C1CSC(N2CCCCC2)=N1
Agent: N=C1NC(=N)c2ccccc21
Product: Cc1cc(C)c2c(c1C)C(=C1SC(Nc3ccc(Cl)cc3)=NC1=N)NC2=N

Procedure:
Employing a procedure similar to that described in Example 9, part B above, but substituting equivalent amounts of 4,5,7-trimethyl-1,3-diiminoisoindoline and 2-(p-chloroanilino)-4-imino-2-thiazoline hydrochloride for 1,3-diiminoisoindoline and 2-piperidino-4-imino-2-thiazoline hydrochloride respectively, there is obtained as the product 1-imino-4,5,7-trimethyl-3-[2-(p-chloroanilino)-4-imino-2-thiazolin-5-ylidene]isoindoline hydrochloride.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4]#[C:5][CH3:6].Cl[C:9]1[N:14]=[CH:13][N:12]=[C:11]([N:15]2[CH2:21][C@H:20]([CH3:22])[CH2:19][CH2:18][CH2:17][C@@H:16]2[CH3:23])[C:10]=1[F:24].[Cl-].[NH4+]>O1CCCC1>[CH2:3]([O:7][C:9]1[N:14]=[CH:13][N:12]=[C:11]([N:15]2[CH2:21][C@H:20]([CH3:22])[CH2:19][CH2:18][CH2:17][C@@H:16]2[CH3:23])[C:10]=1[F:24])[C:4]#[C:5][CH3:6]
Reactant: C[C@@H]1CCC[C@H](C)N(c2ncnc(Cl)c2F)C1
Reactant: CC#CCO
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1ncnc(N2C[C@H](C)CCC[C@@H]2C)c1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 106.1 %

Procedure:
0.10 g of sodium hydride (60% oil suspension) was suspended in 3 ml of tetrahydrofuran. 0.5 ml of tetrahydrofuran solution of 0.15 g of 2-butyn-1-ol was added dropwise at room temperature therein, and the mixture was stirred for 10 minutes. Into the mixture was added dropwise 0.5 ml of tetrahydrofuran solution of 0.30 g of 1-(6-chloro-5-fluoropyrimidin-4-yl)-cis-2,6-dimethyl-hexahydro-1H-azepine at room temperature, and stirred for 8 hours at 70° C. After the reaction mixture was cooled to near room temperature, the reaction mixture was poured into a saturated ammonium chloride aqueous solution, and the mixture was extracted with tert-butyl methyl ether three times. The organic layers were washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.36 g of 1-(6-(2-butynyloxy)-5-fluoropyrimidin-4-yl)-cis-2,6-dimethyl-hexahydro-1H-azepine (hereinafter, referred to as Compound (41)).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[CH2:10][C:11]1[N:15]([CH2:16][CH2:17][O:18][CH2:19][CH3:20])[C:14]2[CH:21]=[CH:22][CH:23]=[CH:24][C:13]=2[N:12]=1>>[CH2:19]([O:18][CH2:17][CH2:16][N:15]1[C:14]2[CH:21]=[CH:22][CH:23]=[CH:24][C:13]=2[N:12]=[C:11]1[CH2:10][N:5]1[CH2:6][CH2:7][CH2:8][N:2]([CH3:1])[CH2:3][CH2:4]1)[CH3:20]
Reactant: CN1CCCNCC1
Reactant: CCOCCn1c(CCl)nc2ccccc21
Product: CCOCCn1c(CN2CCCN(C)CC2)nc2ccccc21
Yield: 69.7 %

Procedure:
In the same manner as described in Example 3, N-methylhomopiperazine (2.6 g) and 2-chloromethyl-1-(2-ethoxyethyl)benzimidazole (2.38 g) obtained in the same manner as described in Reference Example 3 are reacted to give 1-(2-ethoxyethyl)-2-(4-methyl-1-homopiperazinyl)methylbenzimidazole (2.2 g) as a pale yellow liquid. This liquid is treated with fumaric acid (1.63 g), and the crude crystal thus obtained is recrystallized from a mixed solvent of ethyl acetate-ethanol to give 1-(2-ethoxyethyl)-2-(4-methyl-1-homopiperazinyl)methylbenzimidazole 3/2 fumarate semihydrate (2.2 g) as colorless prisms, m.p. 119°-121.5° C.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]4[N:25](S(C5C=CC(C)=CC=5)(=O)=O)[CH:26]=[CH:27][C:20]=34)[CH:16]=[C:15]3[C:11]=2[CH:12]=[N:13][N:14]3[CH3:38])=[O:8])[N:6]=1.C[Si](C)(C)[O-].[K+]>C1COCC1>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]4[NH:25][CH:26]=[CH:27][C:20]=34)[CH:16]=[C:15]3[C:11]=2[CH:12]=[N:13][N:14]3[CH3:38])=[O:8])[N:6]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4cc(NC(=O)c5csc(C)n5)c5cnn(C)c5c4)ccnc32)cc1
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1nc(C(=O)Nc2cc(-c3ccnc4[nH]ccc34)cc3c2cnn3C)cs1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
2-Methyl-N-(1-methyl-6-{1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-indazol-4-yl)-1,3-thiazole-4-carboxamide (44 mg) and potassium trimethyl silanolate (14 mg) were added to THF (2 ml). The reaction mixture was heated at 50° C. overnight. The reaction mixture was partitioned between water (20 ml) and DCM (20 ml). The solvent was removed. The residue was purified by FlashMaster silica cartridge (10 g) using a gradient of 0-100% ethylacetate in cyclohexane followed by 0-20% methanol in ethyl acetate over 30 min. The solvent was removed to give title compound, 31 mg.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][C:12]=3[N:24]=2)=[CH:5][CH:4]=1.[ClH:27].O1CCOCC1>>[ClH:27].[F:26][C:2]([F:1])([F:25])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]3[CH2:16][CH2:15][NH:14][CH2:13][C:12]=3[N:24]=2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C1
Agent: Cl
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc(-c2nc3c(s2)CCNC3)cc1
Reaction time: 2 h
Yield: 58 %

Procedure:
0.30 g (0.91 mmol) of t-butyl 2-[4-(trifluoromethyl)phenyl]-6,7-dihydro[1,3]thiazol o[4,5-c]pyridin-5(4H)-carboxylate (product of step 3) was dissolved in 15 mL of 4.0 M HCl/Dioxan solution, followed by stirring for 2 hours. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to give 0.15 g (0.53 mmol) of the title compound in a yield of 58%.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([OH:15])=O)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.CN(C)C=O.[C:21]([C:25]1[NH:26][C:27]2[C:32]([CH:33]=1)=[CH:31][C:30]([NH2:34])=[CH:29][CH:28]=2)([CH3:24])([CH3:23])[CH3:22].C(N(CC)CC)C>S(Cl)(Cl)=O.ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:34][C:30]4[CH:31]=[C:32]5[C:27](=[CH:28][CH:29]=4)[NH:26][C:25]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:33]5)=[O:15])[CH2:11][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C)c1cc2cc(N)ccc2[nH]1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Reaction time: 0.5 h

Procedure:
1-Benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid (1.09 g, 5.30 mmol) was dissolved in 2 mL of thionyl chloride under nitrogen. A catalytic amount (0.3 mL) of N,N-dimethylformamide (DMF) was added and the reaction mixture was stirred for 30 minutes. The excess thionyl chloride was evaporated and the resulting residue was dissolved in 15 mL of dichloromethane. This solution was slowly added to a solution of 2-tert-butyl-1H-indol-5-amine (1.0 g, 5.3 mmol) in 10 mL of dichloromethane containing triethylamine (1.69 mL, 12.1 mmol). The resulting solution was allowed to stir for 10 minutes. The solvent was evaporated to dryness and the crude reaction mixture was purified by silica gel column chromatography using a gradient of 5-50% ethyl acetate in hexanes. The pure fractions were combined and evaporated to dryness to yield a pale pink powder (1.24 g 62%). ESI-MS calc. 376.18, found 377.3 (M+1)+. Retention time of 3.47 minutes. 1H NMR (400 MHz, DMSO) δ 10.77 (s, 1H), 8.39 (s, 1H), 7.56 (d, J=1.4 Hz, 1H), 7.15 (d, J=8.6 Hz, 1H), 7.05-6.87 (m, 4H), 6.03 (s, 3H), 1.44-1.37 (m, 2H), 1.33 (s, 9H), 1.05-1.00 (m, 2H).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23](O)=[O:24])[CH:21]=3)[NH:16][CH:15]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[BH4-].[Li+].C(O)(=O)C>O1CCCC1>[OH:24][CH2:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[CH2:13][CH2:12][NH:11][C:9](=[O:10])[O:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(NCCc1c[nH]c2ccc(C(=O)O)cc12)OCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(NCCc1c[nH]c2ccc(CO)cc12)OCc1ccccc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 104.3 %

Procedure:
A solution of 3-[2-[[(phenylmethoxy)carbonyl]amino]ethyl]-1H-indole-5-carboxylic acid (9 g) and carbonyldiimidazole (5.2 g) in dry tetrahydrofuran (THF) (150 ml) was stirred vigorously under nitrogen at room temperature for 5 h. A solution of lithium borohydride (1.6 g) in dry THF (70 ml) was added over 70 min and the mixture then stirred for 18 h. Aqueous acetic acid (30%, 25 ml) was added slowly to the ice-cooled mixture and the solution was then partitioned between brine (25%, 300 ml) and ethyl acetate (250 ml). The organic layer was washed with sulphuric acid (0.4M, saturated with sodium chloride, 3×80 ml), brine (100 ml) and potassium carbonate solution (25%, 2×100 ml). The dried (MgSO4) solution was evaporated in vacuo, the residue taken up in dichloromethane (150 ml) and insoluble material was filtered off. The filtrate was evaporated in vacuo to leave the alcohol (9 g) as a colourless oil containing some (ca. 45 mole %) ethyl acetate. T.l.c. Si02 /Et2O, Rf 0.25.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:15])[NH:10][CH2:11][CH2:12][CH:13]=[CH2:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:24])C=1>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9](=[O:15])[NH:10][CH2:11][CH2:12][CH:13]1[CH2:14][O:24]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCCNC(=O)OCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: O=C(NCCC1CO1)OCc1ccccc1
Reaction time: 20 h
Yield: 93 %

Procedure:
To a solution of but-3-enyl-carbamic acid benzyl ester (prepared according to Heterocycles (2006), 67(2), 549-554; 21.5 g, 105 mmol) in chloroform (380 mL) was added, dropwise over a period of 1 h, a solution of MCPBA (28.3 g, 1.1 eq.) in chloroform (270 mL) at 10° C. Stirring was continued for 20 h at rt. The reaction mixture was filtered and 10% sodium sulfite solution was added to the filtrate (until starch-iodide paper test was negative). The mixture was washed with 5% Na2CO3 and brine. The org. layer was dried over MgSO4 and concentrated to afford the title intermediate as a colourless liquid (21.6 g, 93% yield).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].O[CH2:10][C:11]1[C:16]([CH3:17])=[C:15]([CH3:18])[CH:14]=[C:13]([CH2:19]O)[C:12]=1[OH:21].Cl>O>[OH:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][C:8]=1[CH2:10][C:11]1[C:16]([CH3:17])=[C:15]([CH3:18])[CH:14]=[C:13]([CH2:19][C:6]2[CH:7]=[CH:8][C:1]([OH:2])=[CH:3][C:4]=2[OH:5])[C:12]=1[OH:21]
Reactant: Oc1cccc(O)c1
Reactant: Cc1cc(CO)c(O)c(CO)c1C
Agent: Cl
Solvent: O
Product: Cc1cc(Cc2ccc(O)cc2O)c(O)c(Cc2ccc(O)cc2O)c1C
Temperature: -12 °C
Yield: 55.7 %

Procedure:
In a one liter reaction flask were dissolved 220.0 g of resorcinol in 300 ml of de-mineralized water. To this solution 18.22 g of 2,6-bis(hydroxymethyl)-3,4-dimethylphenol was added and stirred until it dissolved. 5 ml of concentrated hydrochloric acid was then added and the reaction mixture stirred at ambient temperature for about 15 hours. The mixture was then chilled to -12° C. and the crystalline precipitate isolated in a chilled Buchner funnel. The crude product was suspended in 300 ml of de-mineralized water and re-isolated by vacuum filtration. The wet solid was first partially air dried and then vacuum oven dried at 60° C. to yield 20.4 g product having a purity of about 95% as determined by HPLC.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]=[C:27]([CH3:35])[CH:26]=3)[CH:19]=2)=[O:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1.[CH2:54](O)[CH2:55][CH2:56][OH:57]>CCOC(C)=O>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]2([C:18]3[CH:19]=[C:20]([NH:24][C:25]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[N:28]=[C:27]([CH3:35])[CH:26]=4)[CH:21]=[CH:22][CH:23]=3)[O:57][CH2:56][CH2:55][CH2:54][O:17]2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCCO
Reactant: Cc1cc(Nc2cccc(C(=O)CCN3CCC(Cc4ccccc4)CC3)c2)c2ccccc2n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cc(Nc2cccc(C3(CCN4CCC(Cc5ccccc5)CC4)OCCCO3)c2)c2ccccc2n1

Procedure:
To the mixture of the compound of Example 209 (0.31 g, 0.67 mmol) in toluene/propane-1,3-diol (7 ml/7 ml) was added p-TsOH (0.32 g, 1.68 mmol) at room temperature. The resulting mixture was heated under reflux in a Dean-Stark setup overnight before the reaction was diluted with EtOAc (80 ml). The mixture was washed with 1 N NaOH (2×50 ml) and brine (50 ml). The organic layer was dried over Na2SO4 and concentrated on a rotavap to dryness. The residue was purified by reverse phase HPLC to afford the desired product as an off-white solid (74 mg, 42% with 50% starting material recovered). The compound of Example 348 was synthesized in the same manner as for Example 191 using 1-benzylpiperazine instead of compound 36.
Reaction SMILES: [NH2:1]N.[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]=[C:12]([NH:14]CN=O)[CH2:11][N+:10]([O-:18])=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:8]=2[CH:25]=1.O1CCCC1>CO>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]=[C:12]([NH:14][NH2:1])[CH2:11][N+:10]([O-:18])=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:8]=2[CH:25]=1
Reactant: O=NCNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=[N+]([O-])C1
Reactant: NN
Solvent: CO
Solvent: C1CCOC1
Product: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=[N+]([O-])C1
Reaction time: 1 h

Procedure:
10 ml. of anhydrous hydrazine was added to a solution of 10 g. of 7-chloro-2-(N-nitrosomethylamino)-5-phenyl-3H-1,4-benzodiazepine 4-oxide in 100 ml. of tetrahydrofuran and 50 ml. of methanol. After sitting at room temperature for 1 hour, the reaction mixture was evaporated under reduced pressure. The crystalline residue was partitioned between methylene chloride and water. The methylene chloride solution was dried and evaporated. Crystallization from methylene chloride/ether yielded 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine 4-oxide with a melting point of 290°-292° dec.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:42])[CH:10]([CH2:31][C:32]1[CH:40]=[C:39]([CH3:41])[CH:38]2[CH:34]([CH:35]=[N:36][NH:37]2)[CH:33]=1)[CH2:11][C:12](=[O:30])[N:13]1[CH2:18][CH2:17][CH:16]([N:19]2[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][C:20]2=[O:29])[CH2:15][CH2:14]1.[CH:43](=O)[CH3:44].[BH4-].[Na+]>CO>[CH2:43]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:42])[CH:10]([CH2:31][C:32]1[CH:40]=[C:39]([CH3:41])[CH:38]2[CH:34]([CH:35]=[N:36][NH:37]2)[CH:33]=1)[CH2:11][C:12](=[O:30])[N:13]1[CH2:14][CH2:15][CH:16]([N:19]2[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][C:20]2=[O:29])[CH2:17][CH2:18]1)[CH3:44]
Reactant: CC1=CC(CC(CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)Nc2ccccc2N)=CC2C=NNC12
Reactant: CC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCNc1ccccc1NC(=O)C(CC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1)CC1=CC2C=NNC2C(C)=C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of N-(2-aminophenyl)-2-((7-methyl-3a,7a-dihydro-1H-indazol-5-yl)methyl)-4-oxo-4-(4-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidin-1-yl)butanamide (0.24 mmol) in methanol (5 mL) was treated with acetaldehyde (1 mL) at room temperature. The mixture was stirred for 2 h at room temperature before the solvent was removed in vacuo. The residue was taken up in methanol (5 mL) and then sodium borohydride (0.48 mmol) was added. After 30 min, the methanol was removed in vacuo and the residue was taken up in methylene chloride (15 mL). The final product was obtained by filtration through a pad of celite and concentration of the filtrate. (95%) MS(ESI)[M+H]+=594.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:13][C:12]2[CH:14]=[C:15]([N:19]3[CH2:24][CH2:23][CH2:22][C:21]4([CH2:29][CH2:28][CH2:27][NH:26][CH2:25]4)[CH2:20]3)[CH:16]=[C:17]([CH3:18])[C:11]=2[N:10]=1.[NH2:30][CH2:31][C@H:32]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=1)[OH:33].CCN(CC)CC>CCO>[Cl:40][C:36]1[CH:35]=[C:34]([C@H:32]([OH:33])[CH2:31][NH:30][C:2]2[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=2[C:9]2[NH:13][C:12]3[CH:14]=[C:15]([N:19]4[CH2:24][CH2:23][CH2:22][C:21]5([CH2:29][CH2:28][CH2:27][NH:26][CH2:25]5)[CH2:20]4)[CH:16]=[C:17]([CH3:18])[C:11]=3[N:10]=2)[CH:39]=[CH:38][CH:37]=1
Reactant: NC[C@@H](O)c1cccc(Cl)c1
Reactant: Cc1cc(N2CCCC3(CCCNC3)C2)cc2[nH]c(-c3c(Cl)cc[nH]c3=O)nc12
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(N2CCCC3(CCCNC3)C2)cc2[nH]c(-c3c(NC[C@@H](O)c4cccc(Cl)c4)cc[nH]c3=O)nc12
Temperature: 25 °C
Yield: 46.9 %

Procedure:
A solution of 4-Chloro-3-[6-(2,8-diaza-spiro[5.5]undec-2-yl)-4-methyl-1H-benzoimidazol-2-yl]-1H-pyridin-2-one (16 mg, 0.039 mmol), (S)-2-amino-1-(3-chlorophenyl)-ethanol (20 mg, 0.117 mmol) and Et3N (16 mg, 0.156 mmol) in EtOH (0.5 mL) was heated at 80° C. for 16 h. After it was cooled to room temperature, the reaction mixture was filtered to furnish yellow solid that was washed with MeOH (3×3 mL). The yellow solid then was mixed with 3 mL MeOH and the mixture was heated at 100° C. for 1 h. After it was cooled to room temperature, the mixture was filtered to furnish yellow solid that was washed with MeOH (3×2 mL) to afford the title compound (10 mg, 47%). ESI-MS m/z 547 (MH+).
Reaction SMILES: [O-:1]O.[CH3:3][C:4]1[CH:8]2[CH2:9][C:7]2([CH:10]([CH3:12])[CH3:11])[CH2:6][CH:5]=1>[Ni]>[CH3:11][CH:10]([C:7]12[CH2:9][CH:8]1[C:4]([OH:1])([CH3:3])[CH2:5][CH2:6]2)[CH3:12]
Reactant: [O-]O
Reactant: CC1=CCC2(C(C)C)CC12
Agent: [Ni]
Product: CC(C)C12CCC(C)(O)C1C2

Procedure:
The hydroperoxide resulting from α-thujene can be reduced to 4-hydroxy-β-thujene and can then be hydrogenated, e.g. in the presence of Raney nickel, to give sabinene hydrate.