Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]1([O:25][N:26]2[C:31](C)([CH3:32])[CH2:30]C(O)[CH2:28][C:27]2([CH3:36])[CH3:35])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C1(C)C=CC=CC=1>[CH:1](=[C:8]([C:9]([O:11][CH:12]1[CH2:35][C:27]([CH3:36])([CH3:28])[N:26]([O:25][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:31]([CH3:32])([CH3:30])[CH2:13]1)=[O:10])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=Cc1ccccc1)C(=O)OCC
Reactant: CC1(C)CC(O)CC(C)(C)N1OC1CCCCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=Cc1ccccc1)C(=O)OC1CC(C)(C)N(OC2CCCCC2)C(C)(C)C1
Temperature: 80 °C
Yield: 99.9 %

Procedure:
A mixture of 15.0 g (60.4 mmol) of diethyl benzalmalonate, 32.4 g (127 mmol) of 1-cyclohexyloxy-4-hydroxy-2,2,6,6-tetramethylpiperidine, and 150 ml of toluene is heated at reflux. Water is removed by fractional distillation. The reaction mixture is cooled to 80° C. and treated with 1.0 g of titanium tetrabutoxide. The mixture is heated at reflux for 7 hours while ethanol is removed by fractional distillation. The reaction mixture is diluted with ethyl acetate (400 ml). The organic solution is washed with 1N hydrochloric acid (200 ml) and saturated sodium bicarbonate solution (200 ml), dried over magnesium sulfate, and concentrated to an oil. Purification by flash chromatography on silica gel (19:1 heptane: ethyl acetate) affords 27.6 g (54% yield) of the title compound, a colorless syrup, which is a mixture of geometric isomers.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH:4](Br)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.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>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:14]2[O:13][CH:17]=[CH:16][CH:15]=2)[CH:6]=1
Reactant: COC(=O)C(Br)c1ccccc1
Reactant: OB(O)c1ccco1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)Cc1cccc(-c2ccco2)c1
Temperature: 50 °C
Reaction time: 14 h
Yield: 66.3 %

Procedure:
To a solution of bromophenylacetic acid methyl ester (0.075 g, 0.328 mmol, 1.0 eq) in tetrahydrofuran (5.0 ml) was added 2-furanboronic acid (0.048 g, 0.426 mmol, 1.3 eq) and sodium carbonate (0.328 ml of a 2M soln in H2O). The solution was degassed and sonicated three times before adding tetrakis(triphenylphosphine)palladium (0.038 g, 0.033 mmol, 0.1 eq). The mixture was degassed and sonicated a further three times before stirring at 50° C. for 14 hours. After cooling to room temperature the solution was concentrated under reduced pressure. Column chromatography (silica, 20% EtOAc/hexane) yielded 3-furanylphenylacetic acid methyl ester (0.047 g, 67%) as a white solid; 1H-NMR (CDCl3, 400 MHz): δ 7.60 (1H, d, J=1.6 Hz), 7.47 (1H, t, J=1.0 Hz), 7.34 (1H, t, J=7.5 Hz), 7.19 (2H, m), 6.65 (1H, d, J=3.6 Hz), 6.48 (1H, dd, J=3.6, 1.6 Hz), 3.71 (3H, s), 3.66 (2H, s).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7]2)[CH2:3][CH2:2]1.[CH:15]12[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH:16]1[N:25]=[C:26]=[O:27])[CH2:22]2>C(Cl)Cl.C(N(CC)CC)C>[CH:17]12[CH2:23][CH:21]3[CH2:20][CH:19]([CH2:24][CH:15]([CH2:22]3)[CH:16]1[NH:25][C:26]([N:1]1[CH2:6][CH2:5][C:4]3([C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH:8]=[CH:7]3)[CH2:3][CH2:2]1)=[O:27])[CH2:18]2
Reactant: O=C=NC1C2CC3CC(C2)CC1C3
Reactant: C1=CC2(CCNCC2)c2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1C2CC3CC(C2)CC1C3)N1CCC2(C=Cc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Spiro(1H-indene-1,4'-piperidine) (20 mg, 0.108 mmol) and 2-adamantyl isocyanate (18 mg, 0.10 mmol) were combined in CH2Cl2 and stirred overnight at ambient temperature. An additional 5 mg (0.028 mmol) of 2-adamantyl isocyanate and 2 drops of triethylamine were added and the mixture again stirred overnight at ambient temperature. The mixture was chromatographed directly on a silica gel column eluted with CH2Cl2 followed by 0.5% and 1% methanol in CH2Cl2. The product fractions were combined and evaporated to dryness in vacuo, and the residue was crystallized from petroleum ether to provide the title compound as a solid: (mp 189°-191°).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[NH:9][C:8]1=[O:16].[OH-].[Na+].[CH3:19]I>CO>[CH3:19][N:9]1[C:10]2[C:11](=[N:12][CH:13]=[CH:14][CH:15]=2)[N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:8]1=[O:16]
Reactant: O=c1[nH]c2cccnc2n1-c1ccccn1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1c(=O)n(-c2ccccn2)c2ncccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.9 %

Procedure:
A suspension of 10.6 g of the product of Step C and 5 g of sodium hydroxide pastilles in 800 ml of methanol was refluxed for 30 minutes and the mixture was then stirred at room temperature until complete dissolution occured (about 2 hours). 45.6 g of methyl iodide were then added dropwise and the mixture was stirred for another 4 hours at room temperature and then allowed to stand overnight. The mixture was evaporated to dryness and the residue was dissolved in 700 ml of water. The aqueous phase was made alkaline with 30% sodium hydroxide solution and was extracted with chloroform. The organic phase was dried over anhydrous sodium sulfate and was filtered and the filtrate was evaporated to dryness. The residue was taken up in petroleum ether and the mixture was filtered. The product was crystallized from an xylene-petroleum ether mixture to obtain 7 g (62% yield) of 1-methyl-3-(2-pyridyl)-1,3-dihydro-imidazo-(4,5-b)-pyridin-2-one in the form of lightly colored pale yellow crystals melting at 128° -130° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=O.[N+:15]([CH3:18])([O-:17])=[O:16].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])/[CH:6]=[CH:18]/[N+:15]([O-:17])=[O:16]
Reactant: C[N+](=O)[O-]
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: COc1cc(/C=C/[N+](=O)[O-])cc(OC)c1OC
Yield: 41 %

Procedure:
A mixture of 3,4,5-trimethoxybenzaldehyde (9.80 g, 50 mmol), nitromethane (18 ml), ammonium acetate (4.11 g) and acetic acid (38 ml) was heated and refluxed for 2 hours. After the reaction mixture was concentrated under reduced pressure, 10% aqueous sodium hydroxide solution was added to the residue and the reaction mixture was extracted with dichloromethane, washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled out under reduced pressure and the residue was purified by silica gel chromatography (dichloromethane) and recrystallized to yield trans-3,4,5-trimethoxy-β-nitrostyrene (4.96 g, 41%). Properties: mp 116-118° C. (ethanol)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[F:27])([OH:19])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[NH:6][CH2:5]2.C(N(CC)C(C)C)(C)C.[CH2:37](Cl)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(#N)C>[CH2:37]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[F:27])([OH:19])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[NH:6][CH2:5]2)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: Nc1ccc2c(c1)CNN2CC(O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: ClCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: OC(CN1NCc2cc(NCc3ccccc3)ccc21)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 0.5 h
Yield: 84 %

Procedure:
To a solution of (5-Amino-2H-indazol-1-yl)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (0.065 g, 0.17 mmol) in acetonitrile (1 ml) was slowly added N,N-Diisopropylethylamine (0.033 ml, 0.19 mmol) at 0° C. and the solution was stirred for 30 min in the same condition. Benzylchloride (0.024 g, 0.19 mmol) was added to the solution, which was then stirred at room temperature for 2 hours and concentrated using vacuum evaporation. The crude product was purified by chromatography on silica gel to give the title compound. (Yield 84%).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[N:19]=2)[CH:7]=1)=[O:5].[CH3:26][C:27]1[CH:28]=[CH:29][C:30]([Mg]Br)=[N:31][CH:32]=1>O1CCCC1>[CH3:26][C:27]1[CH:28]=[CH:29][C:30]([C:4]([C:6]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[N:19]=3)[CH:7]=2)=[O:5])=[N:31][CH:32]=1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(C)n2)c2ccccc2c1=O
Reactant: Cc1ccc([Mg]Br)nc1
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)c2cn(Cc3cccc(C)n3)c3ccccc3c2=O)nc1
Yield: 35.4 %

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 with 200 mg (0.593 mmol) of 1-(6-Methyl-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl amide, 5.2 mL (1.30 mmol, 0.25 M in tetrahydrofuran) of 5-methyl-2-pyridylmagnesium bromide, and 2.6 mL of tetrahydrofuran. The crude product was purified by flash column chromatography using a gradient of 20-100% ethyl acetate in hexane and further purified on the reverse phase HPLC with a C18 column, gradient of 20-70% acetonitrile—0.1% TFA to yield 77.6 mg of 3-(5-Methyl-pyridine-2-carbonyl)-1-(6-methyl-pyridin-2-ylmethyl)-1H-quinolin-4-one. LC-MSD, m/z for C23H19N3O2 [M+H]: 370.15 LC retention time on HPLC, C18 column gradient 20-95% acetonitrile with 0.1% TFA in 4 minutes: 0.91 min.
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][C:9]2[O:13][C:12]([C:14]([OH:16])=O)=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.[NH:23]1[CH2:33][CH2:32][CH2:31][CH2:30][CH:24]1[C:25]([O:27][CH2:28][CH3:29])=[O:26].Cl.C(N=C=NCCCN(C)C)C>O1CCCC1>[CH2:28]([O:27][C:25]([CH:24]1[CH2:30][CH2:31][CH2:32][CH2:33][N:23]1[C:14]([C:12]1[O:13][C:9]([CH2:8][O:7][C:4]2[CH:3]=[CH:2][C:1]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:6][CH:5]=2)=[CH:10][CH:11]=1)=[O:16])=[O:26])[CH3:29]
Reactant: CCOC(=O)C1CCCCN1
Reactant: O=C(O)c1ccc(COc2ccc(-c3ccccc3)cc2)o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)C1CCCCN1C(=O)c1ccc(COc2ccc(-c3ccccc3)cc2)o1
Yield: 59.4 %

Procedure:
A solution of 5-(biphenyl-4-yloxymethyl)-furan-2-carboxylic acid (of Intermediate 8; 0.098 g, 0.33 mmol), ethyl pipecolinate (Aldrich; 0.139 g, 0.88 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (Avocado; 0.13 g, 0.68 mmol), and N,N-dimethylaminopyridine (0.083 g, 0.68 mmol) in tetrahydrofuran (10 mL) was stirred at room temperature for 16 h. The solvents were evaporated under reduced pressure, and water and ethyl acetate were added. The aqueous phase was extracted three times with ethyl acetate, and the combined organic layers were dried (sodium sulfate), filtered, evaporated, and purified using a Biotage Flash 40 purification system, eluting with methylene chloride/acetone 9:1, to give (rac)-1-[5-(biphenyl-4-yloxymethyl)-furan-2-carbonyl]-piperidine-2-carboxylic acid ethyl ester as a colorless oil (0.085 g, 59%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2Br)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.[CH:24](N1CCOCC1)=[O:25].[Cl-].[NH4+]>C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[CH:24]=[O:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=CN1CCOCC1
Reactant: CC(C)(C)OC(=O)N1CCc2c(Br)cccc2C1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCc2c(C=O)cccc2C1
Yield: 13.6 %

Procedure:
A solution of 5-bromo-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester 19a (3.87 g, 12.39 mmol) in diethyl ether (60 mL) was cooled to −100° C. A solution of 1.7 M tert-butyllithium in hexanes (16.04 mL, 27.27 mmol) was added dropwise. After the addition, stirring was continued for 30 min to −100° C. 4-Formylmorpholine (1.87 mL, 18.59 mmol) in diethyl ether (10 mL) was added all at once and the reaction was stirred for an additional 1 h. The mixture was then allowed to reach room temperature. Ammonium chloride saturated solution was added and the product was extracted with dichloromethane (3×70 mL). The combined organics were dried with magnesium sulfate, the solvent was evaporated and the residue was purified by flash chromatography eluting with 20% ethyl acetate in hexanes, to yield 0.44 g of 5-formyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester 20a.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:16]2[C:7](=[CH:8][C:9]3[CH2:10][CH2:11][N:12]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:13](=[O:17])[C:14]=3[CH:15]=2)[NH:6][CH:5]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>ClC1C=CC=CC=1>[NH2:1][CH2:2][CH2:3][C:4]1[CH:5]=[N:6][C:7]2[C:16]=1[CH:15]=[C:14]1[C:9](=[CH:10][CH2:11][N:12]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]1=[O:17])[CH:8]=2
Reactant: NCCc1c[nH]c2cc3c(cc12)C(=O)N(Cc1ccccc1)CC3
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Clc1ccccc1
Product: NCCC1=c2cc3c(cc2N=C1)=CCN(Cc1ccccc1)C3=O

Procedure:
A solution of 3-(2-Amino-ethyl)-6-benzyl-1,6,7,8-tetrahydro-pyrrolo[2,3-g]isoquinolin-5-one (1 mmole) and 2,3-dichloro-5,6-dicyanobenzoquinone (2 mmole) in chlorobenzene (15 mL) at reflux under nitrogen for 24 hours provides the titled compound as a yellow colored solid.
Reaction SMILES: I[C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][C:5]([Br:11])=[CH:4][C:3]=1[CH:12]([CH3:14])[CH3:13].[Li]CCCC.CN([CH:23]=[O:24])C>C1(C)C=CC=CC=1>[CH:12]([C:3]1[CH:4]=[C:5]([Br:11])[CH:6]=[C:7]([CH:8]([CH3:10])[CH3:9])[C:2]=1[CH:23]=[O:24])([CH3:14])[CH3:13]
Reactant: CN(C)C=O
Reactant: CC(C)c1cc(Br)cc(C(C)C)c1I
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: CC(C)c1cc(Br)cc(C(C)C)c1C=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A 150 mL of dry toluene solution of 1-iodo-2,6-diisopropyl-4-bromobenzene (17.6 g, 0.048 mol) was treated with n-BuLi (1.6 M in hexane, 75 mL) at −78° C. in 30 minutes. After stirring for 15 minutes, dry DMF (20 mL) in 50 mL of toluene was added dropwise. The resulting mixture was slowly warmed up to room temperature. After regular work up, the crude product was distilled at 140° C. under vacuum to afford 2,6-diisopropyl-4-bromobenzaldehyde (11.5 g).
Reaction SMILES: [H-].[Na+].CS(C)=O.[I-].[CH3:8][S+](C)(C)=O.[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[C:28](=[O:30])[CH3:29])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1>[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[C:28]1([CH3:8])[CH2:29][O:30]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: C[S+](C)(C)=O
Reactant: CC(=O)c1cc(Cl)ccc1OCc1ccccc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC1(c2cc(Cl)ccc2OCc2ccccc2)CO1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 60% sodium hydride (1.2 g,30 mmol) in tetrahydrofuran (30 mL)-dimethyl sulfoxide (30 mL) was heated at external temperature of 60° C., and trimethylsulfoxonium iodide (6.5 g, 30 mmol) was added portionwise to the mixture. The resultant mixture was stirred for 1 hour and then cooled to room temperature. A solution of 1-(2-(benzyloxy)-5-chlorophenyl)-1-ethanone [compound (9-1)] (5.0 g, 19 mmol) in tetrahydrofuran (10 mL) was added dropwise to the mixture, and the mixture was stirred for 3 hours at external temperature of 60° C. After the mixture was cooled to room temperature, the mixture was added to ice-water, followed by extraction with diethyl ether. The extracted substance was washed with water and dried over magnesium sulfate. The solvent was removed under reduced pressure, to thereby yield 2-(2-(benzyloxy)-5-chlorophenyl)-2-methyloxirane as a colorless oily product (yield: 4.4 g). The obtained product was used in the subsequent reaction step without purification.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])#[N:2].[N:11](Cl)=[O:12].C(Cl)Cl>C(Cl)(Cl)Cl>[C:1]([C:3](=[N:11][OH:12])[C:4]([NH:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])#[N:2]
Reactant: O=NCl
Reactant: CC(C)(C)NC(=O)CC#N
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)NC(=O)C(C#N)=NO

Procedure:
2-Cyano-N-(1,1-dimethylethyl)acetamide 11 (Bhawal, B. M.; Khanapure, S. P.; Biehl, E. R.; Syn. Commun., 1990, 20, 3235) is allowed to react with nitrosyl chloride in an inert organic solvent such as CH2Cl2 or CHCl3 at moderate temperature (e.g., ambient temperature to −25° C., preferably about 0° C.). The resulting 2-cyano-N-(1,1-dimethylethyl)-2-(hydroxyimino)acetamide 13 is isolated and reduced, for example with sodium dithionite in an aqueous organic solvent, but preferably with aluminum amalgam in water at moderate temperature (e.g., ambient temperature to about 0° C., preferably about 0° C.).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[CH3:11][C:12]([CH3:19])([CH3:18])[C:13](=O)[CH2:14][C:15]#[N:16]>>[C:12]([C:13]1[CH:14]=[C:15]([NH2:16])[N:9]([C:6]2[CH:7]=[CH:8][C:3]([Cl:2])=[CH:4][CH:5]=2)[N:10]=1)([CH3:19])([CH3:18])[CH3:11]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NNc1ccc(Cl)cc1
Agent: Cl
Product: CC(C)(C)c1cc(N)n(-c2ccc(Cl)cc2)n1
Yield: 32.7 %

Procedure:
Following the procedure in Example 161A Step 3, 4-chlorophenylhydrazine hydrochloride (1.43 g, 8.0 mol) and 4,4-dimethyl-3-oxopentanenitrile (1.0 g, 8.0 mmol) were reacted to give 3-tert-butyl-1-(4-chlorophenyl)-1H-pyrazol-5-amine (653 mg, 2.62 mmol, 33%). 1H NMR (300 MHz, DMSO-d6) δ 7.61 (d, 1H), 7.49 (d, 2H), 5.39 (s, 1H), 5.28 (s, 1H), 1.09 (s, 9H); LC-MS (ESI) m/z 250 (M+H)+.
Reaction SMILES: C([NH:4][C:5]1[CH:17]=[C:16]2[C:8]([C:9]3[C:14]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:15]2)[CH2:13][CH2:12][C:11](=[O:22])[CH:10]=3)=[CH:7][CH:6]=1)(=O)C.C([O-])(O)=O.[Na+]>CO.Cl.CCOC(C)=O>[NH2:4][C:5]1[CH:17]=[C:16]2[C:8]([C:9]3[C:14]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:15]2)[CH2:13][CH2:12][C:11](=[O:22])[CH:10]=3)=[CH:7][CH:6]=1
Reactant: CCCCC12CCC(=O)C=C1c1ccc(NC(C)=O)cc1C2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCC12CCC(=O)C=C1c1ccc(N)cc1C2
Temperature: 80 °C

Procedure:
The crude product from step 3 (7.0 g) was dissolved in MeOH (100 mL) and the solution was diluted with 6N HCl (100 mL). The resulting brown solution was stirred and heated in an oil bath at 80° C. for one hour. After cooling, the mixture was diluted with EtOAc (300 mL), stirred, and neutralized by the careful addition of aqueous 5% NaHCO3 and solid NaHCO3. The layers were separated and the aqueous portion was extracted with EtOAc (100 mL). The combined organics were washed with water and brine, dried over MgSO4, filtered, and concentrated under vacuum to an orange-red solid. The crude product was purified by Biotage flash chromatography on a 75 L silica gel column (7.5×35 cm), eluting with 2:1 hexane-EtOAc. The product-containing fractions were evaporated under vacuum to an orange solid (4.2 g) which was shown by 1H NMR to contain 7-amino-9a-butyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one along with approximately 10% of the 9a-butyl-4-methyl-8,9,9a,10-tetrahydro-7H-indenol[1,2-g]quinolin-7-one by-product. This material was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][NH:4][CH:3]=1.[H-].[Na+].Cl[CH2:10][CH2:11][N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>CN(C=O)C>[Br:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:10][CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:3]=1
Reactant: ClCCN1CCCC1
Reactant: Brc1cc[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1ccn(CCN2CCCC2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 30.2 %

Procedure:
To a solution of 3-bromo-1H-pyrrole (100 mg, 0.68 mmol) in DMF at 0° C. was added NaH (60% oil dispersion, 81 mg, 2.05 mmol). The reaction mixture was stirred for 1 hour, followed by the addition of 1-(2-chloroethyl)pyrrolidine (108 mg, 0.82 mmol). The reaction mixture was for 6 hours at 100° C. After cooling, the reaction mixture was treated with 20 mL of ice cold water, extracted with EtOAc (3×20 mL), washed with brine solution (20 mL), dried (Na2SO4), filtered, and concentrated under vacuum at 48° C. to obtain crude product. Purification by silica gel chromatography yielded 3-bromo-1-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrrole (50 mg, 31% yield); 1H-NMR (400 MHz, CHCl3): 6.69 (1H, s), 6.59 (1H, s), 6.12 (1H, s), 3.95 (2H, t), 2.80 (2H, t), 2.51 (4H, m), 1.81 (4H, m).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:19])[C:8]2[CH:16]=[C:15](C=O)[S:14][C:9]=2[N:10]([CH2:12][CH3:13])[CH:11]=1)=[O:5])[CH3:2].Cl.[NH2:21][OH:22].[OH-].[Na+]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:19])[C:8]2[CH2:16][C:15](=[N:21][OH:22])[S:14][C:9]=2[N:10]([CH2:12][CH3:13])[CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(CC)c2sc(C=O)cc2c1=O
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1cn(CC)c2c(c1=O)CC(=NO)S2
Yield: 80 %

Procedure:
In 50 ml of warm ethanol was dissolved 0.5 g of 4,7-dihydro-7-ethyl-2-formyl-4-oxo-thieno[2,3-b]pyridine-5-carboxylic acid ethyl ester. The solution was cooled to room-temperature, then 0.2 g of hydroxylamine hydrochloride was added followed by 2 ml of a 5%-solution of sodium hydroxide. After filtration, 4,7-dihydro-7-ethyl-2-hydroxyimino-4-oxo-thieno[2,3-b]pyridine-5-carboxylic acid ethyl ester was obtained in a yield of 80%.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[NH:10][C:11]1[C:20]([Br:21])=[C:19]2[C:14]([C:15](=[O:32])[C:16]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)=[C:17]([CH:22]([CH3:24])[CH3:23])[O:18]2)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:40](Br)[CH:41]=[CH2:42]>CN(C)C=O.O>[CH2:1]([O:8][C:9](=[O:33])[N:10]([CH2:42][CH:41]=[CH2:40])[C:11]1[C:20]([Br:21])=[C:19]2[C:14]([C:15](=[O:32])[C:16]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)=[C:17]([CH:22]([CH3:24])[CH3:23])[O:18]2)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCBr
Reactant: CC(C)c1oc2c(Br)c(NC(=O)OCc3ccccc3)ccc2c(=O)c1-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCN(C(=O)OCc1ccccc1)c1ccc2c(=O)c(-c3ccc(Cl)cc3)c(C(C)C)oc2c1Br
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of [8-bromo-3-(4-chlorophenyl)-2-isopropyl-4-oxo-4H-chromen-7-yl]carbamic acid benzyl ester (0.231 g, 0.44 mmol) and cesium carbonate (0.228 g, 0.701 mmol, 1.6 eq.) in N,N-dimethylformamide (10 ml) is treated with allyl bromide (0.058 g, 0.042 ml, 0.48 mmol, 1.1 eq.), and the mixture is stirred at room temperature for 4 h. The mixture is diluted with water and washed twice with ethyl acetate. The aqueous phase is additionally washed with methylene chloride. The combined organic phases are dried (magnesium sulfate) and filtered and the solvent is removed by evaporation in vacuo to afford the title compound as a yellow solid. The product is used in the next step without further purification.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[C:10]1([CH2:16][CH2:17][CH2:18]O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>ClCCl>[F:7][CH2:18][CH2:17][CH2:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OCCCc1ccccc1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: FCCCc1ccccc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 60.8 %

Procedure:
15.6 g of diethylaminosulfurtrifluoride (DAST, 96.91 mmol) were dissolved in 18 ml of dichloromethane. At 0-5° C., 12 g of 3-phenyl-1-propanol (88.1 mmol) dissolved in 30 ml of dichloromethane, were added dropwise. The reaction mixture was stirred for 18 h, and, after addition of 30 ml of dichloromethane, poured onto 100 ml of ice water. The organic layer was separated, dried over magnesium sulfate, filtered, and the solvent evaporated. The crude product was purified by distillation at a bath temperature of 106° C. at 20 mm to yield 7.4 g of the title compound.