Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[H-].[Na+].[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1.O>C1COCC1.CN(C=O)C>[Br:1][C:2]1[C:3]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([S:27]([C:24]3[CH:25]=[CH:26][C:21]([CH3:20])=[CH:22][CH:23]=3)(=[O:29])=[O:28])[CH:10]=2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Clc1ncc(Br)c(-c2c[nH]c3ccccc23)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nc(Cl)ncc3Br)c3ccccc32)cc1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 73.5 %

Procedure:
3-(5-Bromo-2-chloropyrimidin-4-yl)-1H-indole (INTERMEDIATE 5, 1.23 g, 4 mmol) in THF (40.0 ml) and DMF (5 ml) was cooled to −10° C. Sodium hydride (0.19 g, 4.80 mmol) was added and the reaction was stirred at −10° C. for 30 min. 4-Methylbenzene-1-sulfonyl chloride (0.84 g, 4.40 mmol) was then added. The reaction mixture was allowed to warm to RT and stirred for 15 h. Water (10 mL) was added and the resultant solids were collected by vacuum filtration to give the title product (1.36 g, 73.5%).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>>[Cl:8][C:5]1[N:4]=[N:3][C:2]([O:16][C:13]2[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=2)=[CH:7][CH:6]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: Clc1ccc(Cl)nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Product: Clc1ccc(Oc2ccc(Cl)nn2)cc1
Temperature: 160 °C
Yield: 70 %

Procedure:
A mixture of 14.9 g 3,6-dichloro-pyridazine, 10.45 g 4-chlorophenol and 13.8 g potassium carbonate is maintained for half an hour at 160° C., and then poured into an aqueous dilute sodium hydroxide solution. The precipitate which appears in isolated and recrystallised from an aromatic solvent. There is thus obtained, at 70% yield, 3-chloro-6-(4-chlorophenoxy)-pyridazine which melts at 119° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[K+]>[Cu]>[C:2]1([N:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1ccccc1
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Product: c1ccc(N(c2ccccc2)c2ccccc2)cc1
Yield: 82 %

Procedure:
The same equipment and conditions as in example I were employed with the following charge: 20.4 grams (0.1 mole) iodobenzene, 27.4 grams (0.15 mole) diphenylamine, 16.8 grams (0.3 mole) potassium hydroxide flakes, 15.0 grams of copper powder and 30.0 milliliters of Soltrol® 170. The above-identified product was obtained as colorless crystals having a melting point of 125°-126° C. Yield 82%.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][CH:17]([CH:21]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=1)[C:22]([OH:24])=[O:23])[C:18]([OH:20])=[O:19]>CS(C)=O>[C:12]([C:11]1[C:2]([NH:16][CH:17]([CH:21]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=2)[C:22]([OH:24])=[O:23])[C:18]([OH:20])=[O:19])=[N:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([Cl:15])=[CH:6][CH:5]=2)([OH:14])=[O:13]
Reactant: NC(C(=O)O)C(C(=O)O)c1cccc(F)c1
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Solvent: CS(C)=O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1NC(C(=O)O)C(C(=O)O)c1cccc(F)c1

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 2-amino-3-(3-fluoro-phenyl)-succinic acid [prepared by analogy to J. Med. Chem. 1973, 16, 1277-1280.; using alkylation of diethyl acetamidomalonate by methyl bromo-(3-fluoro-phenyl)-acetate] in DMSO to provide the title compound in good yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[CH:5]=[CH:4][C:3]=1[CH2:13]O.S(Cl)([Cl:17])=O>C1COCC1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[Cl:17][CH2:13][C:3]1[CH:4]=[CH:5][C:6]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)=[CH:7][C:2]=1[F:1]
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(-n2cccn2)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Fc1cc(-n2cccn2)ccc1CCl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (2-fluoro-4-(1H-pyrazol-1-yl)phenyl)methanol (0.71 g) in THF (15.0 mL) was added thionyl chloride (0.40 mL) under ice-cooling, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, saturated aqueous sodium bicarbonate was added thereto, and the mixture was partitioned. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.50 g).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH2:12]([O:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)[CH3:13]>>[CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:19][C:18]2[CH:20]=[CH:21][C:15]([O:14][CH2:12][CH3:13])=[CH:16][CH:17]=2)=[CH:5][CH:4]=1
Reactant: CCOc1ccc(N)cc1
Reactant: CN(C)c1ccc(C=O)cc1
Product: CCOc1ccc(NCc2ccc(N(C)C)cc2)cc1
Yield: 44.1 %

Procedure:
By the reaction and treatment in the same manner as in Preparation Example 1 using 4-dimethylaminobenzaldehyde (11 g) and 4-ethoxyaniline (10 g) as starting materials, [(4-dimethylaminophenyl)methyl](4-ethoxyphenyl)amine (8.7 g) was obtained. melting point: 98–99° C.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:12]3[CH:19]=[CH:20][CH:21]=[C:11]3[CH2:10][CH2:9]2)=[O:7])=[C:4]([Cl:24])[CH:3]=1.C(N(CC)CC)C.[F:32][C:33]1[C:34]([CH3:42])=[C:35]([CH:39]=[CH:40][CH:41]=1)[C:36](Cl)=[O:37].[OH-].[Na+]>ClCCl>[CH:18]1[C:13]2[N:12]3[CH:19]=[CH:20][CH:21]=[C:11]3[CH2:10][CH2:9][N:8]([C:6]([C:5]3[CH:22]=[CH:23][C:2]([NH:1][C:36](=[O:37])[C:35]4[CH:39]=[CH:40][CH:41]=[C:33]([F:32])[C:34]=4[CH3:42])=[CH:3][C:4]=3[Cl:24])=[O:7])[C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: Cc1c(F)cccc1C(=O)Cl
Reactant: Nc1ccc(C(=O)N2CCc3cccn3-c3ccccc32)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(F)cccc1C(=O)Nc1ccc(C(=O)N2CCc3cccn3-c3ccccc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.9 %

Procedure:
To a mixture of 0.10 g of 6,7-dihydro-5-(4-amino-2-chlorobenzoyl)-5H-pyrrolo-[1,2-a][1,5]benzodiazepine and 0.06 g of triethylamine in 6 ml of dichloromethane is added 0.08 g of 3-fluoro-2-methylbenzoyl chloride in 0.5 ml of dichloromethane. The mixture is stirred for 2 hours at room temperature and then 2 ml of 1N NaOH added. The volatiles are evaporated under vacuum and the residue dissolved in 2 ml of tetrahydrofuran and 1 ml of methanol. The mixture is stirred for 2 hours and evaporated and the residue diluted with 2 ml of 1N NaOH and 5 ml of water. The mixture is extracted with ethyl acetate (15 ml) and the extract washed with brine and dried (Na2SO4). The solvent is removed and the residue triturated with diethyl ether-hexane to give 0.15 g of white solid:
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH:7]([N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[C:8](=[O:14])[C:9]([CH3:13])([CH3:12])[CH2:10][OH:11])=[CH:4][CH:3]=1.[BH4-].[Na+].O.C(Cl)Cl>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[CH:8]([OH:14])[C:9]([CH3:12])([CH3:13])[CH2:10][OH:11])=[CH:20][CH:21]=1
Reactant: CC(C)(CO)C(=O)C(Oc1ccc(Cl)cc1)n1cncn1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC(C)O
Product: CC(C)(CO)C(O)C(Oc1ccc(Cl)cc1)n1cncn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 68.2 %

Procedure:
25 g (0.08 mol) of 1-(4-chlorophenoxy)-1-(1,2,4-triazol-1-yl)-3,3-dimethyl-4-hydroxy-butan-2-one were dissolved in 350 ml of isopropanol, and 3.5 g of sodium borohydride were added in portions at room temperature. The mixture was stirred at room temperature for 15 hours, 500 ml of water were added, the mixture was stirred at room temperature for a further 15 hours, 300 ml of methylene chloride were added and the organic phase was washed three times with 100 ml of water each time. The organic phase was dried over sodium sulphate, the solvent was distilled off under a waterpump vacuum and 100 ml of ether were added to the residue. 17 g (67.6% of theory) of 1-(4-chlorophenoxy)-1-(1,2,4-triazol-1-yl)-3,3-dimethyl-butane-2,4-diol were obtained as colorless crystals of melting point 110°-112° C. ##STR19##
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][C:9]=2[F:15])[N:3]=1.[C:16](N1C=CC=CC1=O)([N:18]1C=CC=CC1=O)=[S:17].N>ClCCl>[CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:14]=[CH:13][C:11]([NH:12][C:16]([NH2:18])=[S:17])=[CH:10][C:9]=2[F:15])[N:3]=1
Reactant: Cc1nc(C)n(-c2ccc(N)cc2F)n1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Agent: N
Solvent: ClCCl
Product: Cc1nc(C)n(-c2ccc(NC(N)=S)cc2F)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 50 %

Procedure:
Step T (3): Dichloromethane (100 mL) was added to a flask charged with 4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-3-fluoroaniline (1.67 g, 8.10 mmol and 1,1′-thiocarbonyldipyridin-2(1H)-one (1.88 g, 8.10 mmol). The resulting mixture was stirred for 24 h at rt and concentrated in vacuo. A solution of ammonia (2.0 M in methanol, 50 mL, 100 mmol) was added to the crude solid. The heterogeneous mixture was stirred at rt for 2 h, then evaporated to dryness under reduced pressure using a rotory evaporator. The solid residue was triturated with anhydrous ethanol and chilled to 0° C. for 1 h. The solid was collected by vacuum filtration and dried under high vacuum to afford 1-(4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-3-fluorophenyl)thiourea (1.10 g, 4.06 mmol, 50% yield) as a white powdery solid. LC-MS (M+H)+ 266.3. 1H NMR (500 MHz, DMSO-d6) δ ppm 10.06 (s, 1 H), 7.91 (d, J=12.5 Hz, 1 H), 7.50 (t, J=8.5 Hz, 1 H), 7.35 (d, J=8.9 Hz, 1 H), 2.26 (s, 6 H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=O.Cl.[NH2:12][OH:13].[OH-].[Na+].C(O)C>O>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=[N:12][OH:13]
Reactant: NO
Reactant: O=Cc1c(F)cccc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: ON=Cc1c(F)cccc1F
Temperature: 0 °C
Yield: 110.3 %

Procedure:
In a fashion similar to that for preparation 13, 2,6-difluorobenzaldehyde (5.00 g, 35.2 mmol), hydroxylamine hydrochloride (2.93 g, 29.6 mmol), NaOH (7.04 g in 7.0 ml of water), ethanol (15 ml), water (15 ml), and ice (30 g) afforded 2,6-difluorobenzaldehyde oxime (5.13 g, 93%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[C:23]([O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=1)(=[O:25])[CH3:24].Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:31]([C:30]2[CH:29]=[CH:28][C:27]([O:26][C:23](=[O:25])[CH3:24])=[CH:35][CH:34]=2)=[O:32])=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)c4ccc(OC(C)=O)cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 7 h
Yield: 72.3 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (110 mg) and commercially available 4-acetoxybenzoic acid (207 mg) were dissolved in N,N-dimethylformamide (6 ml), 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (223 mg) was added, and the admixture was stirred at room temperature for 7 hours. The reaction mixture was then purified in the same manner as described in Example 51 to obtain 123 mg of the title compound (yield: 72%).
Reaction SMILES: F.F.F.C(N(CC)CC)C.[B-](F)(F)(F)F.CCN([S+](F)[F:22])CC.[Cl:24][C:25]1[CH:26]=[C:27]([CH2:33]O)[C:28]([CH:31]=[CH2:32])=[N:29][CH:30]=1>C(Cl)Cl>[Cl:24][C:25]1[CH:26]=[C:27]([CH2:33][F:22])[C:28]([CH:31]=[CH2:32])=[N:29][CH:30]=1
Reactant: C=Cc1ncc(Cl)cc1CO
Reactant: CCN(CC)[S+](F)F
Agent: F
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=Cc1ncc(Cl)cc1CF
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.2 %

Procedure:
To a solution of triethylamine trihydrofluoride (Aldrich, 1.9 mL, 12 mmol) in DCM (30 mL) at −78° C., was added Xtalfluor-E (4.1 g, 18 mmol, Aldrich), followed by a solution of (5-chloro-2-vinylpyridin-3-yl)methanol (2 g, 12 mmol) in DCM (40 mL). The cold bath was removed and the reaction mixture was allowed to warm from −78° C. to rt over a period of 15 min. The reaction was quenched by the addition of aqueous saturated bicarbonate solution. After 15 min stirring at rt, the reaction mixture was diluted with EtOAc and water. The organic phase was separated and dried over MgSO4. The filtrate was absorbed onto a plug of silica gel and purified by chromatography through, eluting with a gradient of 5% to 45% EtOAc in hexane, to provide the title compound as colorless oil (1.22 g). LC/MS m/z=172.1 [M+H]+.
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])[CH:11]=4)[C@@H:6]1[CH2:5][CH2:4][C@@H:3]2[C:21](O)=[O:22].C(N(CC)C(C)C)(C)C.[B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.[NH2:53][CH2:54][CH2:55][NH:56][C:57](=[O:63])[O:58][C:59]([CH3:62])([CH3:61])[CH3:60]>CN(C)C=O>[O:20]=[C:12]1[CH2:13][CH2:14][C@@:15]2([CH3:16])[C:10]([CH2:9][CH2:8][C@@H:7]3[C@@H:17]2[CH2:18][CH2:19][C@@:2]2([CH3:1])[C@H:6]3[CH2:5][CH2:4][CH:3]2[C:21]([NH:53][CH2:54][CH2:55][NH:56][C:57](=[O:63])[O:58][C:59]([CH3:60])([CH3:62])[CH3:61])=[O:22])=[CH:11]1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCNC(=O)C1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To 0.49 g of 4-androsten-3-one-17β-carboxylic acid was added N,N-dimethylformamide (3 ml), N,N-diisopropylethylamine (0.55 ml) and O—(N-Succinimidyl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.48 g). On stirring at room temperature (under an atmosphere of nitrogen) for 1.5 hours tert Butyl N-(2-aminoethyl)carbamate (0.25 g) was added. The mixture was stirred at room temperature for 3 days after which time the volatile components were removed on a rotary evaporator. Flash column chromatography was performed and the relevant fractions combined and stripped of solvent using a rotary evaporator. This gave 0.50 g of the desired material (Formula XIII).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:15](=[O:38])[NH:16][C:17]1[C:18]([C:22]2[N:26]([CH3:27])[C:25]3[CH:28]=[CH:29][C:30]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)=[CH:31][C:24]=3[N:23]=2)=[N:19][NH:20][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(C)(C)C.CO>Cl.O1CCOCC1>[NH2:7][CH:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:15]([NH:16][C:17]1[C:18]([C:22]2[N:26]([CH3:27])[C:25]3[CH:28]=[CH:29][C:30]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)=[CH:31][C:24]=3[N:23]=2)=[N:19][NH:20][CH:21]=1)=[O:38]
Reactant: Cn1c(-c2n[nH]cc2NC(=O)C(NC(=O)OC(C)(C)C)c2ccccc2)nc2cc(N3CCOCC3)ccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cn1c(-c2n[nH]cc2NC(=O)C(N)c2ccccc2)nc2cc(N3CCOCC3)ccc21
Yield: 82.1 %

Procedure:
{[3-(5-Morpholin-4-yl-methyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl-carbamoyl]-phenyl-methyl}-carbamic acid tert-butyl ester (Example 232) (30 mg) was dissolved in 4M HCl/dioxane, and 3 ml of methanol and stirred at room temperature overnight. The solvent was removed in vacuo and residue triturated with diethylether to give 2-amino-N-[3-(5-morpholin-4-yl-methyl-1H-benzimidazol-2-yl-)-1H-pyrazol-4-yl]-2-phenyl-acetamide (AT8162) as a white solid (20 mg, 83%). (LC/MS (acidic method): Rt 2.39 min, [M+H]+ 432).
Reaction SMILES: C(O)C.[C:4]([CH2:12][C:13]#[N:14])(=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C.[C:22](=[N:25][OH:26])(Cl)[CH3:23]>[Cl-].[Na+].O.C(OCC)(=O)C>[CH3:23][C:22]1[C:12]([C:13]#[N:14])=[C:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[O:26][N:25]=1
Reactant: N#CCC(=O)c1ccccc1
Reactant: CC(Cl)=NO
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: Cc1noc(-c2ccccc2)c1C#N
Temperature: 25 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
To an ethyl alcohol solution of benzoylacetonitrile was added 1.5 eq of triethyl amine, followed by 1.5 eq of acetylchloride oxime, the reaction mixture was stirred at r.t. for 4 hours. To the reaction mixture was added ethyl acetate and brine. The organic phase was dried with magnesium sulfate and the solvent was removed under reduced pressure. After chromatographic purification the title compound was obtained in 72% yield.
Reaction SMILES: Br[CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:15][O:16][C:17](=[O:43])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][CH2:25][CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([Cl:36])[CH:34]=2)[NH:29][C:28]=1[CH2:37][CH2:38][NH:39][C:40](=[O:42])[CH3:41].CC(C)([O-])C.[K+].O>C(#N)C.C(OC(=O)C)C>[CH3:15][O:16][C:17](=[O:43])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][CH2:25][CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([Cl:36])[CH:34]=2)[N:29]([CH:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:28]=1[CH2:37][CH2:38][NH:39][C:40](=[O:42])[CH3:41]
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccccc1OCCc1c(CCNC(C)=O)[nH]c2ccc(Cl)cc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1ccccc1OCCc1c(CCNC(C)=O)n(C(c2ccccc2)c2ccccc2)c2ccc(Cl)cc12
Yield: 50.6 %

Procedure:
Bromodiphenylmethane (208.3 g 0.843 mol) and 4-{2-[2-(2-Acetylamino-ethyl)-5-chloro-1H-indol-3-yl]-ethoxy-benzoic acid methyl ester (250.0 g, 0.603 mol) were suspended in acetonitrile (10 L). The suspension was stirred and cooled to −1 C and potassium tert. butoxide (94.6 g 0.843 mol) was added in one portion. the reaction was complete by HPLC analysis after stirring for 2.5 h at −1 C. Water (125 mL) was added to the reaction mixture. The suspension was heated to 50 C and then 8.3 L solvent was removed by vacuum distillation (180 mmHg). Aqueous Potassium hydroxide (84.4 g KOH (87%) in 300 mL of water) was added and the reaction mixture was refluxed for 3 h. The solution was cooled to 35 C and acidified (pH=3) with 4N hydrochloric acid (435 mL). The suspension was stirred for 20 min. at 5 C and the precipitate was collected by filtration. The cake was washed with water (250 mL×3) and ethyl acetate (250 mL) and the wet cake was dried at 70 C/30 mmHg for 36 h to yield 253 g crude product. The solid was suspended with 1 L ethylacetate and stirred and warmed at refluxed for 4 h. This ethylacetate slurry was repeated two times. The wet product was collected by filtration and dried for 16 h at 60 C/30 mmHg to obtain 177.3 g (50%) product. The structure was determined by 1H-NMR. δ(300 MHz, DMSOd6) 1.78 (s, 3H), 2.97 (m, 2H), 3.15-3.25 (m, 4H), 4.22 (t, J=6 Hz, 2H), 6.48 (d, J=9 Hz, 1H), 6.80 (dd, J=2 Hz, J=9 Hz, 1H), 6.87 (d, J=8 Hz, 2H), 7.10-7.13 (m, 4H), 7.26 (s, 1H), 7.31-7.40 (m, 6H), 7.66 (d, J=2 Hz, 1H), 7.85 (d, J=8 Hz, 2H), 8.15 (t, J=5 Hz, 1H) ppm.
Reaction SMILES: [CH:1]1([CH3:11])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([SH:10])[CH2:2]1.CI.[O-][CH2:15]C.[Na+]>C(O)C>[CH3:15][S:10][CH:3]1[CH:4]([CH:7]([CH3:8])[CH3:9])[CH2:5][CH2:6][CH:1]([CH3:11])[CH2:2]1
Reactant: CC[O-]
Reactant: CC1CCC(C(C)C)C(S)C1
Agent: [Na+]
Solvent: CI
Solvent: CCO
Product: CSC1CC(C)CCC1C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
p-Menthane-3-thiol (3.5 g., 20 mmole), methyl iodide (3.5 g., 25 mmole) and sodium ethoxide in ethanol (25 ml. of 0.8 M solution) were mixed together and stirred at room temperature for 21/2 hours. The ethanol was then removed and water was added to the residue, which was extracted with ether. The ether extracts were dried (MgSO4) and the solvent was removed. The residue was eluted with 40/60 petroleum ether down a silica column and the product was distilled to give p-menth-3-yl methyl sulphide b.p. 83°-5°/0.05 mm.
Reaction SMILES: [C:1]([N:4]1[C:9]2[CH:10]=[C:11]([NH:17]C(=O)C(F)(F)F)[C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:8]=2[O:7][C:6]([CH3:25])([CH3:24])[CH2:5]1)(=[O:3])[CH3:2].CO.C(=O)(O)[O-].[Na+]>O>[C:1]([N:4]1[C:9]2[CH:10]=[C:11]([NH2:17])[C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:8]=2[O:7][C:6]([CH3:25])([CH3:24])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CC(C)(C)Oc2cc([N+](=O)[O-])c(NC(=O)C(F)(F)F)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(=O)N1CC(C)(C)Oc2cc([N+](=O)[O-])c(N)cc21
Temperature: 25 °C
Reaction time: 7 h
Yield: 85.1 %

Procedure:
A mixture of 21.6 g 4-acetyl-3,4-dihydro-2,2-dimethyl-7-nitro-6-trifluoroacetylamino-2H-1,4-benzoxazine, 500 ml methanol, 50 ml water and 10.5 g sodium bicarbonate was stirred at room temperature for seven hours, the reaction mixture was poured into 1.5 l ice water, and the precipitate which separated out was collected by filtration and recrystallized from 450 ml ethanol, giving 13.5 g of 4-acetyl-6-amino-3,4-dihydro-2,2-dimethyl-7-nitro-2H-1,4-benzoxazine.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].O=C(O)[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>>[CH2:11]([OH:12])[C@H:9]1[O:10][C:2](=[O:1])[C@H:3]([OH:4])[C@@H:5]([OH:6])[C@@H:7]1[OH:8]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=C(O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: O=C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 21 h

Procedure:
The wet immobilized cells of Example 1 (47.3 g) were placed in 100 ml of an aqueous solution containing 10 g of glucose, and the mixture was stirred with aeration for 21 hours at room temperature. A 99% conversion to a mixture of gluconic acid and delta gluconolactone was obtained, and 75% of the original enzyme activity was recovered.
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]2[CH2:17][C:16]3[NH:15][CH:14]=[CH:13][C:12]=3[C:11](=[O:18])[CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[CH2:19]([N:15]1[C:16]2[CH2:17][CH:9]([C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH2:10][C:11](=[O:18])[C:12]=2[CH:13]=[CH:14]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CC(c2ccccc2)Cc2[nH]ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CC(c2ccccc2)Cc2c1ccn2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.4 %

Procedure:
To a suspension of 60% sodium hydride (0.18 g, washed with hexane thrice) in dimethylformamide (10 ml) was added 6-phenyl-4,5,6,7-tetrahydroindol-4-one (0.8 g), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added a solution of benzyl bromide (0.71 g) in dimethylformamide (3 ml), and the mixture was stirred at the same temperature for 2.5 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethyl acetate. The solution was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was purified with silica gel column chromatography (EtOAc/hexane) and recrystallized from ethyl acetate-isopropylether to give colorless crystals of 1-benzyl-6-phenyl-4,5,6,7-tetrahydroindol-4-one (0.86 g).