Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:12]([O-])=[O:13].[Na+].C(OCC)=O>C(O)C.C(O)=O>[CH:12]([NH:11][NH:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)=[O:13]
Reactant: O=C[O-]
Reactant: NNc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Solvent: CCOC=O
Solvent: CCO
Solvent: O=CO
Product: O=CNNc1ccc([N+](=O)[O-])cc1

Procedure:
4-Nitrophenylhydrazine (9.2 g, 0.06 mole), sodium formate (4.08 g, 0.06 mole), and ethyl formate (148 g, 2.00 moles) were mixed in ethanol (40 ml) and formic acid (30 ml). The mixture was heated on a steam bath; the volume of the mixture was reduced to approximately 100 ml by continued boiling. The hydrazide product crystallized out of the concentrated reaction mixture upon cooling. The product was filtered off, washed with ethanol, and dried. Yield 10.2 g (94%), m.p. 183°-185° C.
Reaction SMILES: [CH2:1]([OH:23])[C@H:2]1[O:7][C@H:6]([O:8][C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22]>O>[O:8]=[CH:6][C@@H:5]([C@H:4]([C@@H:3]([C@@H:2]([CH2:1][OH:23])[OH:7])[OH:22])[OH:21])[OH:20]
Reactant: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Solvent: O
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 0.08 h

Procedure:
200 mg of the compressed yeast obtained in step (2) above is added to 2 ml of 50 mM sucrose solution (0.1M acetic acid-sodium acetate buffer, pH 4.7), and the mixture is incubated at 25° C. for 5 minutes. The resultant reaction mixture is put in boiling water at 100° C. for 1 minute to thereby terminate the reaction, following by cooling. The concentration of glucose produced in the reaction mixture is measured using Biosensor BF-2 (manufactured by KS. SYSTEMS Co., Ltd., Japan) with glucose selective electrodes and a 50 mM phosphate buffer (pH 7.0). The obtained glucose concentration is intrapolated against a calibration curve prepared using a standard invertase (invertase Grade VII from Baker's Yeast, manufactured by SIGMA Chemical Company, U.S.A.), to thereby determine the invertase activity per g of the compressed yeast. When the compressed yeast has a water content which is slightly higher than or lower than 67% (e.g., 60%, 70% or the like), the obtained invertase activity value is corrected so as to comply with that of compressed yeast having a water content of 67% by weight and a solids content of 33% by weight by the following formula: ##EQU2##
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([O:12][CH3:13])[CH:8]=[CH:7][CH:6]=2)[CH3:2].[H-].[Na+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C.O>[CH2:1]([C:3]1[N:4]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]2[C:10]([CH:11]=1)=[C:9]([O:12][CH3:13])[CH:8]=[CH:7][CH:6]=2)[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCc1cc2c(OC)cccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cc2c(OC)cccc2n1Cc1ccccc1
Reaction time: 1.5 h
Yield: 48.7 %

Procedure:
2-Ethyl-4-methoxy-1H-indole (4.2 g, 24 mmol) was dissolved in 30 mL of DMF and 960 mg (24 mmol) of 60% NaH/mineral oil was added. After 1.5 hours, 2.9 mL (24 mmol) of benzyl bromide was added. After 4 hours, the mixture was diluted with water and extracted twice with ethyl acetate. The combined ethyl acetate was washed with brine, dried (MgSO4) and concentrated at reduced pressure. The residue was chromatographed on silica gel and eluted with 20% EtOAc/hexane to give 3.1 g (49% yield) of 2-ethyl-4-methoxy-1-(phenylmethyl)-1H-indole.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[NH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1>C(O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[N:13]/[C:14]2[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=2)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CCO
Product: COC(=O)c1ccc(/N=C/c2ccc(Cl)c([N+](=O)[O-])c2)cc1
Yield: 98.4 %

Procedure:
To a solution of 4-chloro-3-nitrobenzaldehyde (5.0 g, 27 mmol) in 42 mL of ethanol was added methyl 4-aminobenzoate (4.07 g, 27 mmol), and the reaction mixture was stirred over weekend. The yellow precipitates were filtered, and 8.47 g of (E)-methyl 4-(4-chloro-3-nitrobenzylidenamino)benzoate a yellow solid was obtained. (Yield=98%). (E)-methyl 4-(4-chloro-3-nitrobenzylideneamino)benzoate (8.47 g, 26.6 mmol) and yttrium(III) trifluoromethanesulfonate (800 mg, 1.33 mmol) was dissolved in dry tetrahydrofuran (100 mL), and then cooled below 0° C. Isobutyl aldehyde (2.30 g, 31.9 mmol) was added below 0° C. The reaction mixture was stirred at room temperature overnight. Thin layer chromatography showed most of starting material was consumed. 50 mL of ethyl acetate and 50 mL of water were added to the mixture, and the separated organic layer was washed with brine again. The organic layer was dried over sodium sulfate and purified on silica gel to afford 4.9 g of methyl 2-(4-chloro-3-nitrophenyl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate. (Yield=47%). MS (ESI+APCI) M+1=373.
Reaction SMILES: Cl.CN([CH2:5][CH:6]1[C:18](=[O:19])[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH3:20])[C:9]=2[CH2:8][CH2:7]1)C.[CH3:21][C:22]1[NH:23][CH:24]=[CH:25][N:26]=1>O>[CH3:20][N:10]1[C:9]2[CH2:8][CH2:7][CH:6]([CH2:5][N:23]3[CH:24]=[CH:25][N:26]=[C:22]3[CH3:21])[C:18](=[O:19])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2
Reactant: Cc1ncc[nH]1
Reactant: CN(C)CC1CCc2c(c3ccccc3n2C)C1=O
Agent: Cl
Solvent: O
Product: Cc1nccn1CC1CCc2c(c3ccccc3n2C)C1=O
Yield: 99.8 %

Procedure:
A solution of 3-[(dimethylamino)methyl]-1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one hydrochloride (1.7 g) in water (17 ml) was treated with 2-methylimidazole (1.4 g) and then heated under reflux for 20 h. The cooled mixture was filtered and the residue washed with water (3×15 ml ) to give a product (1.7 g) m.p. 221-221.50. This material was recrystallised from methanol to give the title compound (1.4 g) m.p. 231-2320.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[F:11][C:12]([F:23])([F:22])[C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:11][C:12]([F:23])([F:22])[C:13]1[CH:18]=[CH:17][C:16]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8](=[O:10])[CH3:9])[CH:3]=2)=[CH:15][CH:14]=1
Reactant: CC(=O)c1cccc(Br)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CC(=O)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 88.3 %

Procedure:
A mixture of 1-(3-bromo-phenyl)-ethanone (4.9 g, 24 mmol), 4-trifluoromethyl phenyl boronic acid (4.6 g, 24 mmol), tetrakis(triphenylphosphine)palladium(0) (1.4 g, 1.2 mmol), potassium phosphate (10 g, 49 mmol), 1,2-dimethoxyethane (50 mL) and water (10 mL) was heated to 80° C. under a blanket of nitrogen in a sealed tube. After 5 h, the mixture was partitioned between water (50 mL) and ethyl acetate (50 mL). The aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated. The residue was purified directly by FCC to afford a clear oil (5.6 g, 87%). MS (ESI): mass calcd. for C15H11F3O, 264.0; m/z found, 265.1 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.21 (t, J=1.6, 1H), 8.04-7.98 (m, 1H), 7.85-7.78 (m, 1H), 7.76-7.69 (m, 4H), 7.60 (t, J=7.7, 1H), 2.68 (s, 3H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)O1.[CH3:20][CH:21]([O:23][C:24](=[O:41])[NH:25][C@H:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33](Br)[CH:34]=2)[N:29]([C:37](=[O:39])[CH3:38])[C@@H:28]([CH3:40])[CH2:27]1)[CH3:22].C([O-])(O)=O.[Na+]>C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl.C(Cl)Cl.O1CCOCC1>[C:37]([N:29]1[C:30]2[C:35](=[CH:34][C:33]([C:9]3[CH:10]=[CH:11][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:17][CH:18]=3)=[CH:32][CH:31]=2)[C@H:26]([NH:25][C:24]([O:23][CH:21]([CH3:22])[CH3:20])=[O:41])[CH2:27][C@@H:28]1[CH3:40])(=[O:39])[CH3:38]
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2ccc3c(c2)[C@H](NC(=O)OC(C)C)C[C@H](C)N3C(C)=O)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
A flask was charged with methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.355 g, 1.354 mmol), 1-methylethyl[(2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Example 4) (0.5 g, 1.354 mmol), a saturated NaHCO3 aqueous solution (1.5 mL, 1.354 mmol) and bis(diphenylphosphino)ferrocene]dichloropalladium(II)-DCM adduct (0.111 g, 0.135 mmol) then filled with 1,4-dioxane (7 mL). The resulting mixture was degassed by bubbling nitrogen in to it, stirred at 100° C. for 1 hr under microwave irradiation then cooled to room temperature. The reaction mixture was filtered through celite and concentrated in vacuo. The residue was partitioned between EtOAC (30 mL) and water (30 mL) and the layers were separated. The organic phase was washed with brine (25 mL) dried over MgSO4 and concentrated in vacuo to give methyl 4-[(2S,4R)-1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]benzoate (0.47 g, 1.11 mmol, 82%) which was used in the next step without further purification
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:6]([C:19]([OH:21])=O)=[CH:5]2.[C:22]([NH:25][C:26]1[N:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1)(=[O:24])[CH3:23]>>[C:22]([NH:25][C:26]1[N:31]=[CH:30][C:29]([NH:32][C:19]([C:6]2[N:7]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)[C:8]3[C:4]([CH:5]=2)=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)=[O:21])=[CH:28][CH:27]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)Nc1ccc(N)cn1
Reactant: O=C(O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Product: CC(=O)Nc1ccc(NC(=O)c2cc3cc(F)ccc3n2Cc2cccc(F)c2)cn1

Procedure:
Compound No. 11 is prepared from 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid (WO 2006/072736) and 6-acetylamino-3-aminopyridine according to a process similar to that described in example No. 3.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)=[O:7].[CH3:18][CH:19]([CH3:35])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:24]=1)=[O:21]>>[CH3:18][CH:19]([CH3:35])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]2[CH2:34][CH2:33][N:32]([CH2:2][CH2:3][CH2:4][CH2:5][C:6](=[O:7])[C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[CH2:31][CH2:30]2)[CH:24]=1)=[O:21]
Reactant: O=C(CCCCCl)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(C(F)(F)F)cc3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme E using 5-chloro-1-[4-(trifluoromethyl)phenyl]-1-pentanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 475.1 (M+H)+.
Reaction SMILES: [CH:1]1(B(O)O)[CH2:3][CH2:2]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([CH3:26])[CH:17]=1.C1(C)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.O>[CH:1]1([C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([CH3:26])[CH:17]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(Br)cc1C
Reactant: OB(O)C1CC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C2CC2)cc1C
Temperature: 25 °C
Yield: 69.7 %

Procedure:
Cyclopropylboronic acid (25.08 g, 292 mmol), anhydrous tribasic potassium phosphate (178.12 g, 839 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (6.925 g, 14.5 mmol), methyl 4-bromo-2-methylbenzoate (55.93 g, 244 mmol), and 600 mL of toluene were charged into a 1000 mL round bottom flask fitted with a stir bar, septum, and nitrogen inlet. Stirred the mixture rapidly and added 65 mL of water. Sparged the mixture with nitrogen for 30 min. Added tris(dibenzylideneacetone)dipalladium(0) (3.321 g, 3.63 mmol). The reaction mixture was sparged with nitrogen for 15 min. Sealed the flask with a cap and stirred at 90° overnight. Added 150 mL water and allowed to cool to room temperature. Filtered the two phase system through diatomaceous earth to remove the solids and washed the filter cake with EtOAc. Separated the filtrate phases and washed the organic phase with 2×200 mL 5% NaHCO3, 2×200 mL 10% Na2S2O3, and 200 mL brine. Dried the solution over MgSO4 and concentrated in vacuo. Vacuum distilled the residual liquid. Collected the fraction distilling at 108-111°/3 ton to obtain methyl 4-cyclopropyl-2-methylbenzoate as a clear colorless liquid (32.30 g, 170 mmol). 1H NMR (300 MHz, chloroform-d) ppm 0.71-0.80 (m, 2 H) 0.98-1.07 (m, 2 H) 1.83-1.95 (m, 1 H) 2.58 (s, 3 H) 3.87 (s, 3 H) 6.87-6.96 (m, 2 H) 7.83 (d, J=7.91 Hz, 1 H).
Reaction SMILES: S(O)(O)(=O)=O.N[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[CH2:12][CH2:11][CH2:10]2.C(O)(=O)C.N([O-])=O.[Na+].[I-:26].[K+]>O>[I:26][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[CH2:12][CH2:11][CH2:10]2
Reactant: [I-]
Reactant: Nc1ccc2c(c1)CCCC2=O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: O=C1CCCc2cc(I)ccc21

Procedure:
To 1.92 g (11.9 mmol) 6-amino-3,4-dihydro-2H-naphthalen-1-one sulfate was added 20 mL water and 20 mL glacial acetic acid. The resulting solution was stirred in an ice bath and a solution of 1.72 grams (25 mmoles) sodium nitrite in 15 mL water was added dropwise over 0.5 hour. The reaction mixture was slowly poured into a well stirred solution of 8 grams (48 mmoles) potassium iodide in 80 mL water. The mixture was extracted with diethyl ether, and the organic phase was washed with water, saturated aqueous sodium hydrogen sulfite, and saturated aqueous sodium chloride. The organic phase was dried (magnesium sulfate) and concentrated under reduced pressure. The residue was subjected to low pressure column chromatography over silica gel 230-400 mesh eluting with 5% ethyl acetate in hexane. 6-Iodo-3,4-dihydro-2H-naphthalen-1-one was obtained as a white solid, 3.12 grams (94%), m.p. 77-78°.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH:10]([OH:37])/[CH:11]=[CH:12]/[C:13]2[N:17]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:16]=[N:15][CH:14]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O>[Pd].C1COCC1>[F:1][C:2]1[CH:9]=[C:8]([CH:10]([OH:37])[CH2:11][CH2:12][C:13]2[N:17]([C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:16]=[N:15][CH:14]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(C(O)/C=C/c2cncn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1F
Agent: [Pd]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(C(O)CCc2cncn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1F

Procedure:
Product from Step F (8.93 g, 18.4 mmol), and 10% palladium on carbon (550 mg) were suspended in THF (200 mL)/water (20 mL) and placed under a hydrogen atmosphere (1 atm) for 7 hours. The reaction solution was filtered through a Celite pad and concentrated in vacuo to provide the title compound as a white foam which was sufficiently pure for use in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH2:13][CH:12]2[CH2:11][NH:10][CH2:9]3)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>C1C=CC=CC=1>[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([N:10]2[CH2:11][CH:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)([CH2:13]3)[CH2:9]2)=[O:26])=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: Clc1ccc(C23CNCC2C3)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: O=C(c1ccc(Cl)cc1)N1CC2CC2(c2ccc(Cl)cc2)C1

Procedure:
A 19.35 g sample of 1-p-chlorophenyl-3-azabicyclo[3.1.0]hexane, 10.59 g of sodium carbonate and 17.5 g of p-chlorobenzoyl chloride are reacted in benzene. The benzene is evaporated and the dark purple residue is dissolved in 200 ml of chloroform and washed successively with 5% sodium carbonate, 0.5 N hydrochloric acid and then with water and dried over sodium sulfate giving a dark purple oil. Addition of ether gives the product 3-p-chlorobenzoyl-1-(p-chlorophenyl)-3-azabicyclo[3.1.0]hexane as grey crystals, mp 98°-100° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[C:15]([C:16](=[O:18])[CH:17]=2)=[C:14]([O:19]C)[CH:13]=[C:12]([O:21]C)[C:11]=3[C@@H:23]2[CH2:27][CH2:26][N:25]([CH3:28])[C@H:24]2[CH2:29][OH:30])[CH:5]=[CH:6][CH:7]=1.Cl.N1C=CC=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[C:15]([C:16](=[O:18])[CH:17]=2)=[C:14]([OH:19])[CH:13]=[C:12]([OH:21])[C:11]=3[C@@H:23]2[CH2:27][CH2:26][N:25]([CH3:28])[C@H:24]2[CH2:29][OH:30])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(OC)c2c(=O)cc(-c3cccc(Cl)c3)oc2c1[C@@H]1CCN(C)[C@H]1CO
Agent: Cl
Solvent: c1ccncc1
Product: CN1CC[C@@H](c2c(O)cc(O)c3c(=O)cc(-c4cccc(Cl)c4)oc23)[C@@H]1CO

Procedure:
Compound of example 73 (0.25 g, 0.58 mmol) was subjected to demethylation using pyridine hydrochloride (2.5 g, 21.64 mmol) as described in example 17 to afford the title compounds.
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].Br[C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][N:10]=1.O>CN(C=O)C>[Br:15][C:12]1[CH:13]=[CH:14][C:9]([O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)=[N:10][CH:11]=1
Reactant: OCC1CC1
Reactant: Brc1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc(OCC2CC2)nc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of cyclopropylmethanol (0.890 mL) in DMF (30 mL) was added sodium hydride (oil, 60%, 440 mg), and the mixture was stirred at room temperature for 10 min. To this mixture was added 2,5-dibromopyridine (2.00 g), and the mixture was stirred at 70° C. for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.88 g).
Reaction SMILES: [NH2:1][CH:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:13]([NH:23][C@H:24]([C:29]([OH:31])=[O:30])[CH2:25][C:26]([OH:28])=[O:27])([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].S(=O)(=O)(O)O>O>[NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:13]([NH:23][C@H:24]([C:29]([OH:31])=[O:30])[CH2:25][C:26]([OH:28])=[O:27])([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]
Reactant: NC(Cc1ccccc1)C(=O)O
Agent: O=C(O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 60 °C

Procedure:
Eight grams of DL-phenylalanine, 8.1 g of N-carbobenzoxy-L-aspartic acid and 1.2 g of sulfuric acid were added to 100 ml of water and the resulting solution was heated to 60° C. This solution was cooled to 40° C. at a rate of 2° C. per hour while stirring, and was stirred for another two hours. The resulting crystal was separated, washed in 20 ml of water and dried to give 8.2 g of an L-phenylalanine/N-carbobenzoxy-L-aspartic acid salt. Analysis of this salt revealed that the optical purity of the L-phenylalanine was 97%.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[CH:9][NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[I:11]N1C(=O)CCC1=O.C(Cl)(Cl)Cl.O>CN(C=O)C>[Cl:1][C:2]1[C:7]2[C:8]([I:11])=[CH:9][NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: Clc1nccc2[nH]ccc12
Reactant: O=C1CCC(=O)N1I
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Clc1nccc2[nH]cc(I)c12
Temperature: 0 °C
Reaction time: 1 h
Yield: 100.9 %

Procedure:
4-Chloro-1H-pyrrolo[3,2-c]pyridine (247 mg) synthesized by the method disclosed in WO2007/095223 was dissolved in DMF (7.0 ml). After cooling to 0° C., N-iodosuccinimide (382 mg) was added thereto. The resulting mixture was stirred at room temperature for 1 hour, and then chloroform and water were added thereto to separate the organic layer. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound as a dark-brown solid (455 mg). Physical properties: m/z [M+H]+ 279.1
Reaction SMILES: [C:1]1([C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(O)[CH2:8][CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.[Pd]>[C:13]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][CH2:10][OH:11])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: OCCCC(O)(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: OCCCC(c1ccccc1)c1ccccc1
Yield: 90.5 %

Procedure:
1,1-Diphenyl-1,4-butanediol (26.62 g, 0.110 mol) was dissolved in MeOH and shaken with 20% Pd/C (1.50 g) on a Parr apparatus under an H2 atmosphere (50 psi) for 17 hours. The MeOH was removed in vacuo, and the residue chromatographed on silica gel eluting with 35% EtOAc/Hexanes gave 22.53 g (91%) of desired product.
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][C:5]=1[CH3:20])([O-])=O.ClC1C(=O)C2C(C(=O)C=1Cl)=CC=CC=2.[OH-].[Na+].C=O>C(O)C>[NH2:1][C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][C:5]=1[CH3:20]
Reactant: Cc1ccc2c(c1[N+](=O)[O-])C(=O)c1ccccc1C2=O
Agent: C=O
Agent: O=C1C(Cl)=C(Cl)C(=O)c2ccccc21
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc2c(c1N)C(=O)c1ccccc1C2=O

Procedure:
53 parts of 1-nitro-2-methylanthraquinone and 0.6 part of 2,3-dichloro-1,4-naphthoquinone in 300 parts by volume of ethanol and 150 parts by volume of 50% aqueous sodium hydroxide solution are heated to 78°-80° C. At this temperature, 37% aqueous formaldehyde solution is added dropwise to the solution in accordance with the consumption. The consumption of formaldehyde can be checked and the addition controlled by measuring the changes in the redox potential. The time taken for the addition is 11/2 to 2 hours. The 1-amino-2-methylanthraquinone so obtained is then completely precipitated by addition of water, and the precipitate is isolated by filtration, washed with water and dried in vacuo at 80° C. Yield: about 43 g (~90% of theory) of 1-amino-2-methylanthraquinone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].N1C=CN=C1.[Cl-].[NH4+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1cc(Cl)cc(Cl)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cc(Cl)cc(Cl)c1
Temperature: 20 °C
Reaction time: 3 h
Yield: 105.4 %

Procedure:
A mixture of 5.02 g of 3,5-dichlorophenol, 5.57 g of tert-butyldimethylsilyl chloride, 5.24 g of imidazole and 50 ml of N,N-dimethylformamide was stirred at 20° C. for 3 hours and then was poured into a saturated solution of ammonium chloride and extracted with dichloromethane. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure to obtain 9 g of residue is obtained which was chromatographed on silica, eluant: essence G with 1/00 of triethylamine to obtain 7.45 g of the expected product.