Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:8]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>CCOC(C)=O>[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[C:8]([B:9]3[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]3)[C:2]=2[CH3:1])=[O:24])=[CH:21][CH:20]=1
Reactant: Cc1c(N)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: CCOC(C)=O
Product: Cc1c(NC(=O)c2ccc(F)cc2)cccc1B1OC(C)(C)C(C)(C)O1
Reaction time: 22 h

Procedure:
A solution of 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (Intermediate 50-1, 1.10 g, 4.72 mmol) in EtOAc (25 mL) was treated with TEA (0.789 mL, 5.66 mmol), then with 4-fluorobenzoyl chloride (0.577 mL, 4.81 mmol) and the mixture was stirred at rt. After 22 h, the mixture was diluted with EtOAc, washed twice with water, then with brine, and dried and concentrated to provide 4-fluoro-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzamide as a glassy foam (1.705 g, ca. 90% purity, 92%). 1H NMR (400 MHz, chloroform-d) δ 7.96 (d, J=7.5 Hz, 1H) 7.90 (dd, J=8.6, 5.3 Hz, 2H) 7.66 (dd, J=7.4, 1.2 Hz, 1H) 7.63 (br. s., 1H) 7.22-7.29 (m, 1H) 7.18 (t, J=8.6 Hz, 2H) 2.53 (s, 3H) 1.36 (s, 12H). Mass spectrum m/z 356.1 (M+H)+.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[Mg+2].[Cl-].[Cl-].P([O-])([O-])([O-])=O.[O:19]=[CH:20][C@@H:21]([C@H:23]([C@@H:25]([C@@H:27](CO)[OH:28])[OH:26])[OH:24])[OH:22]>O>[O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[OH:19][CH2:20][C:21]([C@H:23]([C@@H:25]([CH2:27][OH:28])[OH:26])[OH:24])=[O:22]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)CO
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Solvent: O
Product: O=C(CO)[C@@H](O)[C@H](O)CO
Temperature: 60 °C

Procedure:
Xylose (100 gm) was dissolved in distilled water to provide a concentration of 60% w/v. The solution was placed in a reaction vessel to which was added CoCl2 and MgCl2 to provide a concentration of Co++ =10-4M and Mg++ =10-3M. The pH of the solution was adjusted to 7.5 by the addition of a phosphate buffer. To the resulting solution was then added 5 gm of glucose isomerase extracted from Streptomyces and the temperature was maintained at 60° C. overnight (18 hours). The solution was then added to a fermentation medium (DIFCO 8.5 gm/l yeast extract, NH4Cl1.3 gm/l, MgSO4 ·7 H2O·11 gm/l, and CaCl2 .06 gm/l) to yield an initial fermentation substrate concentration of 78 gm/l xylose and 20 gm/l xylulose. The resulting pH was 5.5.
Reaction SMILES: [C:1]([Cl:6])(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH:7](=[O:11])[CH:8]([CH3:10])[CH3:9]>[Cl-].[Zn+2].[Cl-]>[C:7]([O:5][CH:1]([Cl:6])[CH:2]([CH3:4])[CH3:3])(=[O:11])[CH:8]([CH3:10])[CH3:9]
Reactant: CC(C)C(=O)Cl
Reactant: CC(C)C=O
Agent: [Cl-]
Agent: [Zn+2]
Product: CC(C)C(=O)OC(Cl)C(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
To a mixture of isobutyryl chloride (10 mL, 94.7 mmol) and zinc (II) chloride (25 mg, 186 mmol) was added isobutyraldehyde (10.4 mL, 113.6 mmol) at −20° C. The reaction was stirred at 0° C. for 1 h, then at rt for another 2 h. The mixture was filtered through a short silica gel column (100% PE). The solution was concentrated in vacuo at 40° C. and the resulted oil was distilled at 75° C. under reduced pressure to give the title compound as colorless oil (13.48 g, 79.3%). The title compound was characterized by 1H NMR as shown below:
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[Cl:15][C:16]1[N:21]=[C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][CH2:30][CH2:31][O:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([N+:39]([O-])=O)[CH:34]=3)[CH:24]=2)[C:19]([Cl:42])=[CH:18][N:17]=1.C(O)(=O)C.O>CO.[Fe]>[NH2:39][C:35]1[CH:34]=[C:33]([CH:38]=[CH:37][CH:36]=1)[O:32][CH2:31][CH2:30][NH:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([NH:22][C:20]2[C:19]([Cl:42])=[CH:18][N:17]=[C:16]([Cl:15])[N:21]=2)[CH:24]=1
Reactant: O=[N+]([O-])c1cccc(OCCNc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Nc1cccc(OCCNc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Temperature: 20 °C
Reaction time: 16 h
Yield: 107.6 %

Procedure:
A solution of N-(2,5-dichloropyrimidin-4-yl)-N′-[2-(3-nitrophenoxy)ethyl]benzene-1,3-diamine bis(trifluoroacetate) (100 mg, 0.15 mmol) in methanol (0.63 mL) was treated with acetic acid (0.25 mL, 4.4 mmol), water (0.13 mL, 7.0 mmol), and iron (43 mg, 0.77 mmol) and stirred at 20° C. for 16 h. The reaction mixture was diluted with methanol and treated with celite. The suspension was filtered over a pad of celite and washed with methanol. The filtrate was concentrated to give the desired product (63 mg, 94%) as a crude residue that was used without further purification.
Reaction SMILES: [OH:1][C:2]1[C:3](C(OCC)=O)=[CH:4][C:5]2[CH2:11][CH2:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8][CH2:7][C:6]=2[N:19]=1.[ClH:25]>>[ClH:25].[ClH:25].[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][N:9]([CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:8][CH2:7][C:6]=2[N:19]=1
Reactant: CCOC(=O)c1cc2c(nc1O)CCN(Cc1ccccc1)CC2
Agent: Cl
Product: Oc1ccc2c(n1)CCN(Cc1ccccc1)CC2

Procedure:
Prepared from 2-hydroxy-3-ethoxycarbonyl-7-benzyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine by treatment with hydrochloric acid at 180° C.
Reaction SMILES: C([O:8][CH2:9][CH2:10][C:11]1[NH:15][N:14]=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:12]=1)C1C=CC=CC=1>ClCCl.[Fe](Cl)(Cl)Cl>[F:22][C:19]1[CH:18]=[CH:17][C:16]([C:13]2[CH:12]=[C:11]([CH2:10][CH2:9][OH:8])[NH:15][N:14]=2)=[CH:21][CH:20]=1
Reactant: Fc1ccc(-c2cc(CCOCc3ccccc3)[nH]n2)cc1
Agent: Cl[Fe](Cl)Cl
Solvent: ClCCl
Product: OCCc1cc(-c2ccc(F)cc2)n[nH]1
Reaction time: 0.33 h
Yield: 68.1 %

Procedure:
39.4 g (242 mmol) of iron(III) chloride are initially charged in 200 ml of dichloromethane. At room temperature, a solution of 7.20 g (24.2 mmol) of 5-[2-(benzyloxy)ethyl]-3-(4-fluorophenyl)-1H-pyrazole in 90 ml of dichloromethane is added dropwise. After 20 min, the reaction mixture is washed with 2×100 ml of water. The combined aqueous phases are adjusted to pH 5-6 using sodium bicarbonate and extracted with 2×100 ml of ethyl acetate. The combined organic phases are washed with water, dried over MgSO4 and freed from the solvent under reduced pressure. Purification by column chromatography on silica gel (cyclohexane/ethyl acetate) gives 3.40 g (67%) of the desired product; log P(HCOOH): 1.39; 1H-NMR (DMSO-d6): 7.79 (dd, 2H), 7.19 (dd, 2H), 6.47 (s, 1H), 4.79 (t, 1H), 3.65 (m, 2H), 2.76 (t,
Reaction SMILES: [CH3:1][N:2](C=O)C.Br[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]([O:18][CH3:19])=[CH:16][C:15]([CH:20]([NH:22][C@@H:23]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=3)[CH3:24])[CH3:21])=[N:14]2)=[CH:9][CH:8]=1>CCOC(C)=O.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.[C-]#N.[Zn+2].[C-]#N>[Cl:31][C:27]1[CH:26]=[C:25]([C@H:23]([NH:22][CH:20]([C:15]2[CH:16]=[C:17]([O:18][CH3:19])[N:13]([C:10]3[CH:11]=[CH:12][C:7]([C:1]#[N:2])=[CH:8][CH:9]=3)[N:14]=2)[CH3:21])[CH3:24])[CH:30]=[CH:29][CH:28]=1
Reactant: CN(C)C=O
Reactant: COc1cc(C(C)N[C@H](C)c2cccc(Cl)c2)nn1-c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: COc1cc(C(C)N[C@H](C)c2cccc(Cl)c2)nn1-c1ccc(C#N)cc1
Temperature: 100 °C
Reaction time: 72 h

Procedure:
A 20 mL vial was charged with Pd(PPh3)4 (0.159 g, 0.138 mmol), zinc cyanide (0.243 g, 2.07 mmol), 3 mL of DMF, and 1-[1-(4-bromophenyl)-5-methoxy-1H-pyrazol-3-yl]-N—[(1R)-1-(3-chlorophenyl)ethyl]ethanamine 85 (0.600 g, 1.38 mmol) as a >20:1 mixture of diastereomers. The reaction mixture was heated to 100° C. After 3 d, an additional 10 mol % of Pd(PPh3)4 and 2 equivalents of ZnCN2 were added. The reaction mixture was heated in a microwave to 180° C. for 15 min. The reaction mixture was cooled to room temperature, dissolved in EtOAc, washed with water and brine, dried, and concentrated. Purification by flash column chromatography on silica gel (2% MeOH in DCM) gave 443-(1-{[(1R)-1-(3-chlorophenyl)ethyl]amino}ethyl)-5-methoxy-1H-pyrazol-1-yl]benzonitrile 96 as a >20:1 mixture of diastereomers. Mass spectrum: calculated for C2H21ClN4O 380.1; found 381.2 (M++1).
Reaction SMILES: [OH-].[Na+].[OH:3][CH2:4][CH2:5][NH:6][CH3:7].O.Cl[CH2:10][C:11]([CH3:13])=[CH2:12]>C(Cl)(Cl)Cl>[OH:3][CH2:4][CH2:5][N:6]([CH3:7])[CH2:10][C:11]([CH3:13])=[CH2:12]
Reactant: C=C(C)CCl
Reactant: CNCCO
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: C=C(C)CN(C)CCO

Procedure:
20.0 g of sodium hydroxide was added to 56.33 g (0.75 mol) of 2-hydroxy-N-methylethylamine and 101.61 g water, after which 45.28 g (0.50 mol) of 1-chloro-2-methyl-2-propene was slowly added dropwise at room temperature. Upon completion of the dropping, the system was allowed to react for 15 hours at 80° C. Upon completion of the reaction, the 150 g of chloroform added and the system was washed with a sodium carbonate aqueous solution to remove the unreacted 2-hydroxy-N-methylethylamine, 2-hydroxy-N-methylethylamine hydrochloride, and sodium hydroxide, which yielded a chloroform solution of N-hydroxyethyl-N,2-dimethyl-2-propene-1-amine. 150 g of a 4 N hydrochloric acid aqueous solution was added to the chloroform solution, the N-hydroxyethyl-N,2-dimethyl-2-propene-1-amine was converted into a hydrochloride and extracted into the aqueous phase, and the water was removed by freeze drying, which yielded 55.50 g (0.34 mol; 67% yield) of 2-propene-1-aminium, N-hydroxyethyl-N,2-dimethyl, hydrochloride in the form of a white powder. The structure of the 2-propene-1-aminium, N-hydroxyethyl-N,2-dimethyl, hydrochloride thus obtained was confirmed by 1H-NMR (400 MHz).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[Br:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([NH2:16])=[C:11]([CH3:17])[CH:10]=1>>[Br:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([NH:16][C:5](=[O:7])[CH3:6])=[C:11]([CH3:17])[CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(Br)c(F)cc1N
Product: CC(=O)Nc1cc(F)c(Br)cc1C
Reaction time: 0.17 h

Procedure:
73.6 mL of acetic anhydride was added with 80.0 g of 4-bromo-5-fluoro-2-methylphenylamine at room temperature, and stirred at this temperature for 10 minutes. Excess acetic anhydride was distilled off under reduced pressure, and the precipitated crystals were washed with water, to afford 77.6 g of the title compound as colorless crystal.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[C:11]2[OH:16])(=[O:4])=[O:3].C(O)C.[N:20]([O-])=[O:21].[Na+]>O.[Cl-].[Zn+2].[Cl-]>[N:20]([C:10]1[CH:9]=[CH:8][C:7]2[C:12](=[CH:13][CH:14]=[CH:15][C:6]=2[NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[C:11]=1[OH:16])=[O:21]
Reactant: O=N[O-]
Reactant: CS(=O)(=O)Nc1cccc2c(O)cccc12
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)Nc1cccc2c(O)c(N=O)ccc12
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A mixture comprising 119 g of 5-methanesulfonylamino-1-naphthol, 100 g of zinc chloride and 500 ml of ethanol was heated at 50° C., and then a solution of 35 g of sodium nitrite as dissolved in 70 ml of water was added dropwise thereto at 50° to 65° C. After being heated and stirred at 60° to 65° C. for 2 hours, the resulting solution was cooled with water to room temperature, and reddish brown crystals formed were taken out by filtration and washed with ethanol. The crystals were added to 200 ml of concentrated hydrochloric acid and stirred for 1 hour at room temperature, and then 200 ml of water was added thereto. Yellowish brown crystals (2-nitroso-5-methanesulfonylamino-1-naphthol) formed were taken out by filtration, washed with water and dried. Yield: 90 g.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][OH:11])[C:5]=1[N:12]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[H-].[Na+].I[CH3:35]>C1COCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][CH3:35])[C:5]=1[N:12]([S:20]([C:23]1[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)(=[O:22])=[O:21])[CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: CI
Reactant: COC(=O)c1cccc(CO)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCc1cccc(C(=O)OC)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Reaction time: 18 h
Yield: 28 %

Procedure:
To a solution of 0.200 g (0.452 mmol) of the product of Example 336 in 5.0 mL of dry THF was added 0.022 g (0.543 mmol) of 60% sodium hydride followed by 0.028 mL of iodomethane. The reaction was stired at room temperature for 18 h and then diluted with ethyl acetate. The organics were washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with EtOAc to provide 0.057 g (28%) of the methyl ether as ayellow solid. Electrospray Mass Spec: 457.3 (M+H)+.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:22]([OH:24])=[O:23])[CH:16]=1)[CH3:2].[CH3:25][CH2:26]O>S(=O)(=O)(O)O>[CH2:25]([O:23][C:22](=[O:24])[CH2:21][C:17]1[CH:16]=[C:15]([C:6]2[CH:7]=[CH:8][C:9]([C:11]([F:13])([F:12])[F:14])=[CH:10][C:5]=2[CH2:4][NH:3][CH2:1][CH3:2])[CH:20]=[CH:19][CH:18]=1)[CH3:26]
Reactant: CCO
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cccc(CC(=O)O)c1
Agent: O=S(=O)(O)O
Product: CCNCc1cc(C(F)(F)F)ccc1-c1cccc(CC(=O)OCC)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of (2′-ethylaminomethyl-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid (0.34 mmol) in EtOH (7 mL) was added sulfuric acid (34 drops), and the reaction was stirred at 50° C. overnight. Once no starting material was seen by analytical LCMS, the mixture was filtered over a pad of Celite and rinsed with EtOH. The filtrate was concentrated to give the title compound.
Reaction SMILES: [O:1]([CH:8]1[CH2:17][CH2:16][CH2:15][C:14]2[CH:13]=[C:12]([C:18]([OH:20])=O)[CH:11]=[CH:10][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:50][CH2:51][C:52]1[C:53]([OH:60])=[N:54][C:55]([CH3:59])=[CH:56][C:57]=1[CH3:58]>ClCCl>[OH:60][C:53]1[C:52]([CH2:51][NH:50][C:18]([C:12]2[CH:11]=[CH:10][C:9]3[CH:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:17][CH2:16][CH2:15][C:14]=3[CH:13]=2)=[O:20])=[C:57]([CH3:58])[CH:56]=[C:55]([CH3:59])[N:54]=1
Reactant: O=C(O)c1ccc2c(c1)CCCC2Oc1ccccc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc3c(c2)CCCC3Oc2ccccc2)c(O)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 64.2 %

Procedure:
To a solution of 5-phenoxy-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (0.032 g, 0.12 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.06 g, 0.3 mmol) and N-hydroxybenzotriazole (0.03 g, 0.22 mmol) in dichloromethane (10 mL) was added triethylamine (0.03 g, 0.3 mmol). The reaction mixture was stirred for 15 minutes at room temperature, then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (0.03 g, 0.2 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours. After the reaction, the mixture was washed with water (10 mL×3). The organic phase was concentrated and the residue was purified by column chromatography (silica gel, dichloromethane/methanol=15:1) to give pure product N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-5-phenoxy-5,6,7,8-tetrahydronaphthalene-2-carboxamide (Compound I-52) as a white solid (0.031 g, 63%). LRMS (M+H+) m/z: calcd 402.19. found 402. 1H NMR (300 MHz, CD3OD): δ 7.59 (s, 1H), 7.57 (d, J=7.5 Hz, 1H), 7.37 (d, J=7.8 Hz, 1H), 7.28 (t, J=7.2 Hz, 2H), 7.02-6.92 (m, 3H), 6.10 (s, 1H), 5.43 (t, J=4.5 Hz, 1H), 4.48 (s, 2H), 2.90-2.82 (m, 2H), 2.37 (s, 3H), 2.24 (s, 3H), 2.08-1.83 (m, 4H).
Reaction SMILES: [C:1]1([CH2:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:16]([Si:20](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:19])([CH3:18])[CH3:17]>C(#N)C>[Si:20]([NH:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](NCc1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of benzenemethanamine (21.8 mL, 0.20 mol) and triethylamine (41.2 mL, 0.30 mol) in acetonitrile (400 mL) was added dropwise t-butylchlorodiphenylsilane (52 mL, 0.20 mol). The mixture was stirred at room temperature for 3 hours and then filtered to remove the insoluble white precipitate (triethylamine hydrochloride). After removal of the solvent in vacuo, the crude product was taken up in a 4:1 mixture of ether/hexane and washed sequentially with H2O, saturated NaHCO3 solution and H2O. The solution was dried (Na2SO4 /K2CO3) and concentrated to leave an oil which was distilled under high vacuum. The major fraction consisting of the pure product (45.9 g, 66%) distilled from 140° to 160° C. at about 0.1-0.2 mm Hg and crystallized on standing at room temperature, m.p. 34°-36° C.
Reaction SMILES: [CH2:1]1[CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][CH:2]1[N:10]1[CH2:26][CH2:25][C:13]2([N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:16][CH2:15][CH:14]2[OH:24])[CH2:12][CH2:11]1.[C:27]([O-:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([O-:32])=[O:31].C(O)(=O)/C=C/C(O)=O>C(OCC)C>[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31].[CH2:1]1[CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][CH:2]1[N:10]1[CH2:26][CH2:25][C:13]2([N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:16][CH2:15][C:14]2=[O:24])[CH2:12][CH2:11]1
Reactant: OC1CCN(c2ccccc2)C12CCN(C1CC3CCCCC3C1)CC2
Reactant: O=C([O-])/C=C/C(=O)[O-]
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCOCC
Product: O=C1CCN(c2ccccc2)C12CCN(C1CC3CCCCC3C1)CC2

Procedure:
Oxidation of 8-(octahydro-inden-2-yl)-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol (mixture of diastereoisomers) according to the general method of example 20 and formation of the fumarate with fumaric acid in diethyl ether yielded the title compound, pale brown solid, m.p. 225° C. and MS: m/e=353.4 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[C:12]([O:30][CH3:31])=[N:13][C:14]([C:26]([F:29])([F:28])[F:27])=[CH:15][C:16]=1[CH2:17][O:18][Si](C(C)(C)C)(C)C)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[C:12]([O:30][CH3:31])=[N:13][C:14]([C:26]([F:27])([F:28])[F:29])=[CH:15][C:16]=1[CH2:17][OH:18])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1nc(C(F)(F)F)cc(CO[Si](C)(C)C(C)(C)C)c1CCNC(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1nc(C(F)(F)F)cc(CO)c1CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of the compound from Step K above (1.12 g, 2.41 mmol) in tetrahydrofuran (20 mL) was added tetrabutylammonium fluoride (11.0M in tetrahydrofuran, 2.41 mL, 2.41 mmol). The reaction was then stirred at room temperature for 10 min and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel; 20% to 40% ethyl acetate/hexanes gradient elution) to afford the title compound. 1H NMR (400 MHz, CDCl3) δ 7.38 (s, 1H), 4.87 (br s, 1H), 4.76 (d, 2H, J=6 Hz), 4.02 (s, 3H), 3.54 (t, 1H), 3.35 (m, 2H), 2.88 (t, 2H, J=6 Hz), 1.38 (s, 9H).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18]([OH:20])=O.[NH2:21][C@H:22]1[CH2:27][C:26]2[C:28]([N:32]3[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]3)=[CH:29][CH:30]=[CH:31][C:25]=2[O:24][CH2:23]1>CN(C)C=O>[CH3:38][N:35]1[CH2:36][CH2:37][N:32]([C:28]2[C:26]3[CH2:27][C@H:22]([NH:21][C:18]([C:14]4[NH:13][CH:17]=[CH:16][CH:15]=4)=[O:20])[CH2:23][O:24][C:25]=3[CH:31]=[CH:30][CH:29]=2)[CH2:33][CH2:34]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CO3)CC1
Reactant: O=C(O)c1ccc[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc[nH]2)CO3)CC1
Temperature: 75 °C
Reaction time: 0.75 h

Procedure:
A mixture of 1,1′-carbonyldiimidazole (360 mg, 1.85 mmol) and pyrrole-2-carboxylic acid (225 mg, 2.03 mmol) in anhydrous N,N-dimethylformamide (8 mL) was stirred at 75° C. for 45 min. The mixture was allowed to cool, and a solution of (S)-3-amino-5-(4-methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran (457 mg, 1.85 mmol) in N,N-dimethylformamide (10 mL) was added. The reaction mixture was stirred for 7 days at room temperature under nitrogen. The solvent was removed in vacuo, and the residue was extracted with diethyl ether (50 mL) and water (20 mL). The aqueous layer was extracted with another portion of diethyl ether (50 mL). The combined ethereal layers were dried (MgSO4), and the solvent was removed in vacuo. The residue was purified by column chromatography on silica (eluent: chloroform/ethanol; 90:10+0.5% conc. NH3) yielding the title compound as an oil. Evaporation with diethyl ether afforded 300 mg (48% yield) of the title compound as a white powder: mp sinters >96° C.; [α]21D−82.8° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 340 (10, M+).
Reaction SMILES: [H-].[Na+].[C:3]([C:10]1([NH2:37])[N:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]2[CH:23]=[CH:24][CH:25]=[CH:26][C:13]=2[N:12]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]#[N:34])[C:28]=2[CH3:35])[C:11]1=[O:36])([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].CI.[CH3:40]COCC>C1COCC1.CCOC(C)=O.CCCCCC>[C:3]([C:10]1([NH:37][CH3:40])[N:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]2[CH:23]=[CH:24][CH:25]=[CH:26][C:13]=2[N:12]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]#[N:34])[C:28]=2[CH3:35])[C:11]1=[O:36])([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: CCOCC
Reactant: Cc1c(C#N)cccc1N1C(=O)C(N)(C(=O)OC(C)(C)C)N=C(c2ccccc2)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CNC1(C(=O)OC(C)(C)C)N=C(c2ccccc2)c2ccccc2N(c2cccc(C#N)c2C)C1=O
Yield: 71.5 %

Procedure:
N-methylation was accomplished via dropwise addition of NaH (0.24 g, 6 mmol, THF) to a solution of the above product, Boc-3-amino-1-(methyl-3-cyanophenyl)-1,3-dihydro-5-phenyl-1,4-benzodiazapin-2-one (1.28 g, 2.74 mmol), in THF (20 ml) containing CH3I (0.65 ml, 10.4 mmol) at 0° C. for 8 hr. After dilution with Et2O and aqueous workup, concentration of the organic phase and flash chromatography (silica gel, 35% EtOAc/hexane) yielded the product, Boc-3-methylamino-1-(methyl-3-cyanophenyl)-1,3-dihydro-5-phenyl-1,4-benzodiazapin-2-one (0.94 g, 71.5 %). 1H NMR, 13C NMR, and mass analysis were consistent with structure.