Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.[CH2:16]1COC[CH2:17]1.C([Li])C>O>[CH2:16]([C:2]1([OH:1])[CH2:3][CH2:4][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:6][CH2:7]1)[CH3:17]
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Reactant: C1CCOC1
Agent: [Li]CC
Solvent: O
Product: CCC1(O)CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of tert-butyl (4-oxocyclohexyl)carbamate (3.04 g) and THF (100 mL), ethyllithium (0.5 M benzene-cyclohexane solution) (56.8 mL) was added at −78° C. and stirred over 4 hours until it reached −50° C. After addition of water (150 mL), the reaction liquid was heated to room temperature and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and then dried over sodium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (eluent; chloroform:methanol=30:1) and further purified (eluent; n-hexane:ethyl acetate=2:1 to 1:1) to give tert-butyl (4-ethyl-4-hydroxycyclohexyl)carbamate (Preparation Example 246) (0.202 g), which was a low-polarity product, as a white solid and tert-butyl (4-ethyl-4-hydroxycyclohexyl)carbamate (Preparation Example 248), which was a high-polarity product, as a colorless syrup.
Reaction SMILES: C([Li])CCC.CCCCCC.C(NC(C)C)(C)C.[C:19]([O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])(=[O:23])[CH:20]([CH3:22])[CH3:21].[N:31]1[CH:36]=[CH:35][C:34]([CH:37]=[O:38])=[CH:33][CH:32]=1.[Cl-].[NH4+]>O1CCCC1>[CH3:21][C:20]([CH3:22])([CH:37]([OH:38])[C:34]1[CH:35]=[CH:36][N:31]=[CH:32][CH:33]=1)[C:19]([O:24][CH2:25][CH2:26][Si:27]([CH3:29])([CH3:28])[CH3:30])=[O:23]
Reactant: CC(C)C(=O)OCC[Si](C)(C)C
Reactant: O=Cc1ccncc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C(=O)OCC[Si](C)(C)C)C(O)c1ccncc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 51.1 %

Procedure:
1.6 M n-butyl lithium in hexane (14.0 ml, 22.4 mmol) was added to a solution of diisopropylamine (2.3 g, 22.4 mmol) in tetrahydrofuran (15 ml) under ice cooling condition, and the mixture was stirred for 30 minutes. The reaction mixture was cooled to −78° C., and a solution of 2-(trimethylsilyl)ethyl isobutyrate (4.0 g, 21.2 mmol) in tetrahydrofuran (5 ml) was added dropwise to the mixture. The reaction mixture was stirred for 45 minutes. Successively, a solution of 4-pyridinecarbaldehyde (2.5 g, 23.3 mmol) in tetrahydrofuran (10 ml) was added to the mixture, and the mixture was stirred with warming from −78° C. to room temperature for 2.5 hrs. The reaction mixture was combined with saturated aqueous ammonium chloride solution and extracted with ethylacetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel (100 g) column chromatography. The fraction eluted with hexane-ethyl acetate (3:1, v/v) were collected and concentrated to give the titled compound (3.2 g, 51%) as a colorless oil.
Reaction SMILES: [C:1]([C:6](=[CH:12]OCC)[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][OH:20]>>[C:1]([C:6](=[CH:12][NH:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][OH:20])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)C(=COCC)C(=O)OCC
Reactant: Nc1ccccc1CO
Product: CCCC(=O)C(=CNc1ccccc1CO)C(=O)OCC

Procedure:
A mixture of ethyl 2-butyryl-3-ethoxyacrylate (23.5 g, 0.11 mol) and 2-aminobenzyl alcohol (12.3 g, 0.1 mol) was heated to 100° for 10 minutes, then diluted with petroleum ether. On cooling, ethyl 2-butyryl-3-(2-(hydroxymethyl)phenylamino)acrylate (24.9 g, 85%) crystallized as a mixture of E/Z isomers, and was filtered off and washed with petroleum ether.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]#[C:5][C:6]1[S:10][C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:8][CH:7]=1.[C:16](Cl)(=[O:21])[CH2:17][CH:18]([CH3:20])[CH3:19]>N1C=CC=CC=1>[C:16]([O:1][CH2:2][CH2:3][C:4]#[C:5][C:6]1[S:10][C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:8][CH:7]=1)(=[O:21])[CH2:17][CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)CC(=O)Cl
Reactant: OCCC#Cc1ccc(-c2cccs2)s1
Solvent: c1ccncc1
Product: CC(C)CC(=O)OCCC#Cc1ccc(-c2cccs2)s1
Reaction time: 8 h

Procedure:
5-(4-Hydroxy-1-butynyl)-2,2'-bithiophene (1 g) was dissolved in pyridine (10 ml). Isovaleroyl chloride (1 ml) was added at room temperature, stirred for few minutes and kept overnight. The reaction mixture was treated as in example 21. Light yellowish oily product (1.06 g) was then obtained.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:8]([C:17]([CH3:23])([CH3:22])[C:18]([O:20]C)=O)=[N:9][C:10]([CH3:16])([CH3:15])[C:11]([O:13]C)=O.C[O-].[Na+].O>CO>[N:9]([C:10]([CH3:15])([CH3:16])[C:11]([NH:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:13])=[N:8][C:17]([CH3:23])([CH3:22])[C:18]([NH:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:20]
Reactant: COC(=O)C(C)(C)N=NC(C)(C)C(=O)OC
Reactant: NC1CCCCC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(N=NC(C)(C)C(=O)NC1CCCCC1)C(=O)NC1CCCCC1
Temperature: 10 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
47.3 Grams of cyclohexylamine is mixed with 50 g of dimethyl 2,2'-azobis (2-methylpropionate) and 20 g of 28% sodium methoxide solution in methanol is dropwise added thereto under stirring, following by conducting a reaction at room temperature with stirring for 6 hours and keeping standing overnight. 100 Milliliter of water is added to the reaction solution and cooled to 10° C. to precipitate crystals. The crystals are recovered by filtration and dried to give 59.4 g (yield 81 %) of 2,2'-azobis (N-cyclohexyl-2-methylpropionamide) as yellow crystals. The solubility is shown in Table 1.
Reaction SMILES: [CH3:1][NH2:2].[C:3]1([C:9]2[N:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18]([O:20][CH2:21][C:22]([O:24]CC)=O)=[O:19])=[CH:11][CH:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>O1CCCC1.CO>[C:3]1([C:9]2[N:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18](=[O:19])[O:20][CH2:21][C:22]([NH:2][CH3:1])=[O:24])=[CH:11][CH:10]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)COC(=O)NCCc1ccc(-c2ccccc2)nc1
Reactant: CN
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=O)COC(=O)NCCc1ccc(-c2ccccc2)nc1
Reaction time: 4 h

Procedure:
4.6 ml (9.17 mmol) of a solution of methylamine (2M) in tetrahydrofuran are added to a solution of 1.0 g (3.06 mmol) of ethyl ({[2-(6-phenylpyrid-3-yl)ethyl]amino}carbonyl)-oxyacetate, obtained in stage 1.3., in 6 ml of methanol. Stirring is continued at ambient temperature for 4 hours.
Reaction SMILES: [C:1]([N:5]1[C:10]2([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[O:9][C:8]2[CH:16]=[CH:17][CH:18]=[CH:19][C:7]=2[C:6]1=[O:20])(=[O:4])[CH2:2][CH3:3].C([Mg]Cl)CCC.C(O[C@H:31]1[NH:34][C:33](=[O:35])[C@@H:32]1[C@H:36]([O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])[CH3:37])(=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.C(OCC)(=O)C>[Si:39]([O:38][C@@H:36]([C@@H:32]1[C@@H:31]([C@@H:2]([CH3:3])[C:1]([N:5]2[C:10]3([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[O:9][C:8]3[CH:16]=[CH:17][CH:18]=[CH:19][C:7]=3[C:6]2=[O:20])=[O:4])[NH:34][C:33]1=[O:35])[CH3:37])([C:42]([CH3:43])([CH3:44])[CH3:45])([CH3:40])[CH3:41]
Reactant: CCC(=O)N1C(=O)c2ccccc2OC12CCCCC2
Reactant: CC(=O)O[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Agent: CCCC[Mg]Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)N1C(=O)c2ccccc2OC12CCCCC2
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 53 %

Procedure:
Under a nitrogen atmosphere, 273 mg (1.0 mmol) of 3-propionyl-spiro[2,3-dihydro-4H-1,3-benzoxazine-2,1′-cyclohexan]-4-one was charged in a 30-ml three-necked flask to dissolve it in 2 ml of tetrahydrofuran. To the resulting solution, 2.44 ml (2.2 mmol) of a tetrahydrofuran solution (0.9M) of n-butylmagnesium chloride was slowly added dropwise at room temperature. The resulting mixture was reacted for 25 minutes under the same conditions. After cooling to 5° C., 2 ml of a tetrahydrofuran solution of 287 mg (1.0 mmol) of (3R,4R)-4-acetoxy-3-[(R)-1-tert-butyldimethylsilyloxyethyl]azetidin-2-one was added at the same temperature. The resulting mixture was stirred for 15 minutes, added with 10 ml of ethyl acetate and then added dropwise with 2 ml of a 10% aqueous solution of citric acid. After separation, the organic layer was washed with 2 ml of a saturated aqueous solution of sodium bicarbonate and 2 ml of a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was purified by column chromatography, whereby 263 mg (0.53 mmol) of a condensation product was obtained (yield: 53%, β:α=92:8).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH2:15][C:16]([CH3:28])([CH3:27])[CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23]>>[CH3:28][C:16]([NH:15][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])([CH3:27])[CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25]
Reactant: CC(C)(N)CCNC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Product: CC(C)(CCNC(=O)OC(C)(C)C)Nc1ccc(C(F)(F)F)cc1[N+](=O)[O-]

Procedure:
This is prepared analogously to method 2a) from a total of 3.25 g (15.5 mmol) 1-fluoro-2-nitro-4-trifluoromethyl-benzene and 2.74 g (13.5 mmol) tert-butyl (3-amino-3-methyl-butyl)-carbamate. 6.1 g yellow oil. Mass spectroscopy: [M+H]+=392.
Reaction SMILES: CS([O-])(=O)=O.[O:6]([CH:13]1[CH2:16][NH:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:17][N:18]=[C:19]=[O:20]>>[CH3:17][NH:18][C:19]([N:15]1[CH2:16][CH:13]([O:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:14]1)=[O:20]
Reactant: c1ccc(OC2CNC2)cc1
Reactant: CN=C=O
Agent: CS(=O)(=O)[O-]
Product: CNC(=O)N1CC(Oc2ccccc2)C1

Procedure:
The compound was prepared from the methane sulfonate of 3-phenoxyazetidine and methylisocyanate as described in Example 1 of U.S. Pat. No. 4,226,861, m.p. 139°-141° C.
Reaction SMILES: C(CC(Cl)=O)(C)(C)C.[CH:9]([C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[C:22]3[C:23]([CH3:37])=[C:24]([NH:29][C:30](=[O:36])[CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:25]([CH3:28])=[C:26]([CH3:27])[C:21]=3[O:20][CH:19]2[CH3:38])=[CH:14][CH:13]=1)([CH3:11])[CH3:10]>CCCCCC>[CH:9]([C:12]1[CH:17]=[CH:16][C:15]([C@@H:18]2[C:22]3[C:23]([CH3:37])=[C:24]([NH:29][C:30](=[O:36])[CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:25]([CH3:28])=[C:26]([CH3:27])[C:21]=3[O:20][C@H:19]2[CH3:38])=[CH:14][CH:13]=1)([CH3:10])[CH3:11]
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)C(C)O2
Agent: CC(C)(C)CC(=O)Cl
Solvent: CCCCCC
Product: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)[C@@H](c1ccc(C(C)C)cc1)[C@H](C)O2

Procedure:
Using the compound and tert-butylacetyl chloride, a mixture of cis isomer and trans isomer of N-(3-(4-isopropylphenyl)-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide was obtained in the same manner as in Example 1. The compound was purified by silica gel column chromatography (ethyl acetate:hexane=1:4) to synthesize the title compound. Yield: 18%. Melting point: 143-144° C. (hexane).
Reaction SMILES: O.[S-2:2].[Na+].[Na+].S.Cl[CH:7]1[NH:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[O:9][C:8]1=[O:17]>O.O1CCCC1>[O:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[NH:12][C:7](=[S:2])[C:8]1=[O:17]
Reactant: [S-2]
Reactant: O=C1Oc2ccccc2NC1Cl
Agent: S
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=c1oc2ccccc2[nH]c1=S

Procedure:
A solution of 3.6 g of sodium sulfide hydrate in 15 ml of water saturated with hydrogen sulfide was added dropwise to a solution of 5.45 g of 3-chloro-4H-1,4-benzoxazin-2-one in 30 ml of tetrahydrofuran at -150° C. The mixture was stirred one hour to 0° C. The tetrahydrofuran was evaporated and the precipitated filtered and recrystallized from toluene to provide the solid product 4H-1,4-benzoxazin-2-one-3-thione, m.p. 215°-220° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:22]=[C:21]2[C:16]([CH2:17][CH2:18][CH:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[O:20]2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:29][CH3:30]>>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:22]=[C:21]2[C:16]([CH2:17][CH2:18][C:19]([CH2:29][CH3:30])([C:23]([O:25][CH2:26][CH3:27])=[O:24])[O:20]2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCI
Reactant: CCOC(=O)C1CCc2ccc(OCCCOCc3ccccc3)cc2O1
Product: CCOC(=O)C1(CC)CCc2ccc(OCCCOCc3ccccc3)cc2O1

Procedure:
The title compound was prepared from ethyl 7-(3-benzyloxypropoxy)-chromane-2-carboxylate following the procedure described in Example 2, Step A employing iodoethane instead of iodopropane.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]3[C:24]([Cl:25])=[C:23]([Cl:26])[N:22]=[C:21]([NH:27][CH3:28])[N:20]=3)[CH2:15][CH2:14]2)[CH2:7][CH2:6]1.C(N(CC)CC)C.[CH2:36]([N:38]=[C:39]=[O:40])[CH3:37]>ClCCl>[Cl:25][C:24]1[C:19]([N:16]2[CH2:15][CH2:14][N:13]([CH2:12][CH2:11][C@H:8]3[CH2:9][CH2:10][C@H:5]([NH:4][C:39]([NH:38][CH2:36][CH3:37])=[O:40])[CH2:6][CH2:7]3)[CH2:18][CH2:17]2)=[N:20][C:21]([NH:27][CH3:28])=[N:22][C:23]=1[Cl:26]
Reactant: CCN=C=O
Reactant: CNc1nc(Cl)c(Cl)c(N2CCN(CC[C@H]3CC[C@H](N)CC3)CC2)n1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nc(NC)nc(Cl)c3Cl)CC2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.25 g (0.5 mmol) trans-(4-{4-[2-(4-amino-cyclohexyl)-ethyl]-piperazin-1-yl}-5,6-dichloro-pyrimidin-2-yl)-methyl-amine trihydrochloride was dissolved in dry dichloromethane (10 ml). Triethylamine (0.28 ml, 2 mmol) was added followed by the addition of ethylisocyanate (0.06 ml, 0.753 mmol), and the reaction mixture was stirred at room temperature for 4 hours. The solvent was removed in vacuo. The residue was triturated with water, and the precipitate was filtered to give the title compound (0.17 g, 72%) MS (EI): 459.2 (MH+). 1H NMR (300 MHz, DMSO-d6 (TMS)+1 drop of cc. DCl, (ppm)): 0.96 t (3H); 0.88-1.13 m (4H); 1.13-1.31 m (1H); 1.54-1.85 m (6H); 2.74 s (3H); 2.98 q (2H); 2.89-3.16 m (4H); 3.19-3.33 m (1H); 3.34-3.58 m (4H); 4.12-4.30 m (2H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+].[CH:17]([C:20]1[C:28]2[C:23](=[N:24][CH:25]=[CH:26][C:27]=2[C:29]2[CH:30]=[N:31][C:32]3[C:37]([CH:38]=2)=[CH:36][CH:35]=[CH:34][CH:33]=3)[NH:22][N:21]=1)([CH3:19])[CH3:18].C(OCC)(=O)C>CN(C=O)C.O>[CH:17]([C:20]1[C:28]2[C:23](=[N:24][CH:25]=[CH:26][C:27]=2[C:29]2[CH:30]=[N:31][C:32]3[C:37]([CH:38]=2)=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:22]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[CH3:10])[N:21]=1)([CH3:19])[CH3:18]
Reactant: Cc1cc(C#N)ccc1F
Reactant: CC(C)c1n[nH]c2nccc(-c3cnc4ccccc4c3)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(C#N)ccc1-n1nc(C(C)C)c2c(-c3cnc4ccccc4c3)ccnc21
Temperature: 80 °C
Reaction time: 18 h
Yield: 73.4 %

Procedure:
4-Fluoro-3-methylbenzonitrile (0.077 g) and cesium carbonate (0.203 g) were added to a solution of compound (6c) (0.150 g) in DMF (1.73 mL), followed by stirring at 80° C. for 18 hr. The reaction solution was distributed between ethyl acetate and water. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled away, and the residue was purified by neutral silica gel column chromatography (hexane/ethyl acetate) to obtain 4-{3-isopropyl-4-(quinolin-3-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}-3-methylbenzonitrile (0.154 g, 73%). This 4-{3-isopropyl-4-(quinolin-3-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}-3-methylbenzonitrile was dissolved in DMSO (5.0 mL) and ethanol (5.0 mL). A 4 N aqueous sodium hydroxide solution (0.195 mL) and a 30% hydrogen peroxide solution (0.088 mL) were added to the resulting solution, followed by stirring at room temperature for 30 min. Water was added to the reaction solution, and the precipitate was collected by filtration, washed with diethyl ether, and dried under reduced pressure to obtain compound (80) (0.135 g, 83%) as a white solid.
Reaction SMILES: [Br:1][CH2:2][C@H:3]([CH3:9])[CH2:4][CH2:5][C:6]([OH:8])=[O:7].[C:10]1([P:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(#N)C>C(OCC)C>[Br-:1].[C:6]([CH2:5][CH2:4][CH:3]([CH3:9])[CH2:2][P+:16]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)([OH:8])=[O:7]
Reactant: C[C@@H](CBr)CCC(=O)O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCOCC
Product: CC(CCC(=O)O)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]

Procedure:
A stirred solution of 61.3 g. of (R)-5-bromo-4-methylpentanoic acid [J. S. Dalby et al., J. Chem. Soc., 1962, 4387], 92.0 g. of triphenylphosphine, and 160 ml. of acetonitrile is refluxed for 96 hours. The solution is cooled until crystallization begins and then diluted with 750 ml. of diethyl ether to complete the precipitation. The salt is obtained by filtration and is dried in vacuo at 75°C., m.p. 151°-164°C.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[O:6][C:7]3[CH:18]=[CH:17][CH:16]=[CH:15][C:8]=3[CH2:9][N:10]([C:11]([NH:13][NH2:14])=[O:12])[C:4]=2[CH:3]=1.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[CH2:26][CH2:27][CH2:28][C:29](O)=[O:30].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[O:30]=[C:29]([NH:14][NH:13][C:11]([N:10]1[CH2:9][C:8]2[CH:15]=[CH:16][CH:17]=[CH:18][C:7]=2[O:6][C:5]2[CH:19]=[CH:20][C:2]([Cl:1])=[CH:3][C:4]1=2)=[O:12])[CH2:28][CH2:27][CH2:26][C:22]1[S:21][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(O)CCCc1cccs1
Reactant: NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(CCCc1cccs1)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Temperature: 5 °C
Reaction time: 18 h

Procedure:
To a stirring 5 mL dichloromethane (DCM) solution of 0.29 g (one mmol) of 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, hydrazide (1), prepared as described above in Example 1, and 0.17 g (one mmol) of 4-(2-thienyl)butyric acid cooled to 5° C. was added 0.23 g (1.1 mmol) of dicyclohexylcarbodiimide. With warming to room temperature, the reaction was stirred for 18 hours. The reaction mixture was filtered through a sintered-glass funnel. The filtrate was dried under water aspirator vacuum. The resultant solid product was chromatographed as described previously. Analysis calculated for C22H20N3O3SCl (M.W. 441.94): C, 59.79; H, 4.56; N, 9.51; Cl, 8.02. Found: C, 59.77; H, 4.62; N, 9.51; Cl, 8.23.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=O)[C:2]2=O.COP([CH2:16][C:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24])(=O)OC.O.[NH2:27][NH2:28]>>[C:19]1([CH3:24])[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:17]1[CH:16]=[C:3]2[C:2]([CH:1]3[CH2:7][CH:4]2[CH2:5][CH2:6]3)=[N:28][N:27]=1
Reactant: COP(=O)(CC(=O)c1ccccc1C)OC
Reactant: O=C1C(=O)C2CCC1C2
Reactant: NN
Solvent: O
Product: Cc1ccccc1-c1cc2c(nn1)C1CCC2C1

Procedure:
light yellow gum. MS (EI): 236.3 (M+). Prepared from bicyclo[2.2.1]heptane-2,3-dione, (2-Oxo-2-o-tolyl-ethyl)-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-:18].O.[CH2:20]([O:27][C:28]1[CH:51]=[C:50]([Cl:52])[C:31]([CH2:32][C@@H:33]2[CH2:37][CH2:36][N:35]([C@H:38]3[CH2:43][CH2:42][C@H:41](OS(C)(=O)=O)[CH2:40][CH2:39]3)[C:34]2=[O:49])=[C:30]([Cl:53])[CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(#N)C>[CH2:20]([O:27][C:28]1[CH:51]=[C:50]([Cl:52])[C:31]([CH2:32][C@@H:33]2[CH2:37][CH2:36][N:35]([C@H:38]3[CH2:43][CH2:42][C@@H:41]([F:18])[CH2:40][CH2:39]3)[C:34]2=[O:49])=[C:30]([Cl:53])[CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: [F-]
Reactant: CS(=O)(=O)O[C@H]1CC[C@H](N2CC[C@@H](Cc3c(Cl)cc(OCc4ccccc4)cc3Cl)C2=O)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Solvent: O
Product: O=C1[C@H](Cc2c(Cl)cc(OCc3ccccc3)cc2Cl)CCN1[C@H]1CC[C@@H](F)CC1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
Dissolve TBAF.3H2O (1.595 g, 1.30 mmol) in 10 ml of acetonitrile. Add water (0.18 ml, 9.91 mmol) and stir for 10 minutes. Add (R)-trans-Methanesulfonic acid 4-[3-(4-benzyloxy-2,6-dichloro-benzyl)-2-oxo-pyrrolidin-1-yl]-cyclohexyl ester (Preparation 14) (1.30 g, 2.48 mmol). Stir at 80° C. for 12 hours. Quench with saturated NaHCO3 and extract with ethyl acetate. Wash the extract with brine. Dry over magnesium sulfate, filter, and concentrate. After flash column chromatography receive 0.230 g (21%) of the title compound: Mass spectrum (apci) m/z=450 (M+H).
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7](=[O:10])[CH:8]=[CH2:9].[CH3:11][CH:12]([CH3:15])[CH:13]=O>C1C=CC=CC=1>[CH3:11][C:12]1([CH3:15])[CH2:13][CH2:6][C:7](=[O:10])[CH:8]=[CH:9]1
Reactant: CC(C)C=O
Reactant: C=CC(C)=O
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: CC1(C)C=CC(=O)CC1
Temperature: 25 °C

Procedure:
1 ml of concentrated sulphuric acid is added at room temperature to 81 ml of but-3-en-2-one and 88 ml of 2-methylpropionaldehyde in 450 ml of benzene, and then the reaction mixture is refluxed for 13 hours to remove the water by azeotropic entrainment. After cooling to room temperature, the reaction mixture is washed with a saturated aqueous sodium bicarbonate solution and then with water. The organic phase is dried over magnesium sulphate and the solvents are evaporated off under reduced pressure. After distillation, 31.1 g of the expected compound are isolated; b.p.=78° C. (at a pressure of 22 mbar).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:15]=[C:16]([Br:20])[CH:17]=[CH:18][CH:19]=1.[C:21](O)(=[O:23])C>O1CCCC1.O>[Br:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([F:13])[C:15]=1[CH:21]=[O:23]
Reactant: CC(=O)O
Reactant: Fc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1c(F)cccc1Br
Temperature: -78 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a solution of diisopropylamine (15.7 ml 112 mmol) in anhydrous tetrahydrofuran (200 ml) cooled to 0° C. was added dropwise n-butyllithium (2.5M in hexanes, 44.8 ml, 112 mmol). After complete addition the mixture was cooled to −78° C. and 3-fluorobromobenzene (19.6 g, 112 mmol) added over 10 minutes. The mixture stirred at −78° C. for 1 hour then N,N diimethylformamide (9.72 ml, 125 mmol) was added dropwise over 5 minutes. The mixture was stirred for a further 10 minutes, then acetic acid (10 ml) and water (350 ml) were added. The mixture was allowed to warm to room temperature and was extracted with Et2O (250+150 ml). The combined extracts were washed with water (×2) 0.2N HCl, brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica eluting with 5% Et2O in iso-hexanes to give the title compound (20 g, 88%) as a white solid.
Reaction SMILES: C(OC([CH2:8][NH:9][C:10]1[CH:11]=[C:12]([C:16]2[N:21]=[CH:20][C:19]([CH2:22][CH:23]([O:29][CH2:30][CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:18][CH:17]=2)[CH:13]=[CH:14][CH:15]=1)=O)(C)(C)C.ClCCl.FC(F)(F)C(O)=O>O>[CH2:30]([O:29][CH:23]([CH2:22][C:19]1[CH:20]=[N:21][C:16]([C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([NH:9][CH3:8])[CH:11]=2)=[CH:17][CH:18]=1)[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:31]
Reactant: CCOC(=O)C(Cc1ccc(-c2cccc(NCC(=O)OC(C)(C)C)c2)nc1)OCC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C(Cc1ccc(-c2cccc(NC)c2)nc1)OCC
Yield: 81.2 %

Procedure:
0.11 g (0.3 mmol) of ethyl 3-{6-[3-(tert-butoxycarbonylmethylamino)phenyl]pyrid-3-yl}-2-ethoxypropanoate, 5 ml of dichloromethane and 0.15 ml (1.9 mmol) of trifluoroacetic acid are stirred at room temperature for 24 hours. After addition of water, the reaction medium is extracted with dichloromethane. The organic phase is dried over magnesium sulfate, filtered and evaporated. 80 mg (94%) of ethyl 2-ethoxy-3-[6-(3-methylaminophenyl)pyrid-3-yl]propanoate are obtained.