Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.[N+:5]([C:8]1[CH:9]=[CH:10][C:11]([O:14][CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[N:12][CH:13]=1)([O-:7])=[O:6].[CH3:21][C:22]([CH3:24])=O.C([BH3-])#N.[Na+]>CO>[CH:22]([N:18]1[CH2:19][CH2:20][CH:15]([O:14][C:11]2[CH:10]=[CH:9][C:8]([N+:5]([O-:7])=[O:6])=[CH:13][N:12]=2)[CH2:16][CH2:17]1)([CH3:24])[CH3:21]
Reactant: O=[N+]([O-])c1ccc(OC2CCNCC2)nc1
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)N1CCC(Oc2ccc([N+](=O)[O-])cn2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 10% acetic acid in methanol was added 5-nitro-2-(piperidin-4-yloxy)pyridine (1 eq) and anhydrous acetone (5 eq). The solution was stirred at room temperature for 1 hour. The reaction mixture was cooled to 0° C. on an ice bath and sodium cyanoborohydride (1.5 eq) was added. The reaction mixture was then warmed to room temperature and stirred for 5 hours. The solvent was evaporated, the residue brought to pH=10 with sodium carbonate and extracted with EtOAc. The organic layer was washed with water, brine, dried over sodium sulfate, and evaporated to give the crude material. Purification by silica gel column chromatography using 2% methanol/dichloromethane afforded the product as a yellow solid. LC/MS (m/z): 266.3 (MH+), Rt 1.85 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH:7]([C:10]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=O)[CH:8]=O)=[CH:4][CH:3]=1.Cl.[F:21][C:22]([F:33])([F:32])[O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][NH2:31])=[CH:26][CH:25]=1.C[O-].[Na+]>CO>[Br:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][C:7]2[CH:8]=[N:31][N:30]([C:27]3[CH:28]=[CH:29][C:24]([O:23][C:22]([F:21])([F:33])[F:32])=[CH:25][CH:26]=3)[C:10]=2[CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: NNc1ccc(OC(F)(F)F)cc1
Reactant: O=CC(Cc1ccc(Br)cc1)C(=O)C1CCCCC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: FC(F)(F)Oc1ccc(-n2ncc(Cc3ccc(Br)cc3)c2C2CCCCC2)cc1

Procedure:
To a solution of 3.17 g 2-(4-bromobenzyl)-3-cyclohexyl-3-oxopropanal from Step C above and 2.47 g 4-trifluoromethoxyphenylhydrazine hydrochloride in 100 mL methanol was added 21.6 mL 0.5 M sodium methoxide in methanol. The resulting mixture was refluxed under nitrogen for two days. The solvent was removed under reduced pressure. The resulting crude product was subjected to repeated chromatography on silica gel using 0˜10% MeCN in methylene chloride, 0˜2% MeCN in methylene chloride, or 7˜10% EtOAc in hexanes. Pure 4-(4-bromobenzyl)-5-cyclohexyl-1-[4-(trifluoromethoxy)phenyl]-1H-pyrazole was obtained as the major product by recrystallization of chromatographic fractions from methanol. 1H NMR (CDCl3, 500 MHz) δ 7.64˜7.67 (m, 2H), 7.43˜7.46 (m, 2H), 7.44 (s, 1H), 7.23˜7.27 (m, 2H), 7.10˜7.13 (m, 2H), 3.82 (s, 2H), 2.63 (tt, J=3.3 & 11.8 Hz, 1H), 1.83˜1.89 (m, 4H), 1.72˜1.76 (m, 1H), 1.60˜1.69 (m, 2H), 1.27˜1.40 (m, 3H). LC-MS: 2.91 min. (M+H=479). Pure 4-(4-bromobenzyl)-3-cyclohexyl-1-[4-(trifluoromethoxy)phenyl]-1H-pyrazole was obtained as the minor product following preparative HPLC of the silica gel chromatography fractions. 1H NMR (CDCl3, 500 MHz) δ 7.59˜7.63 (m, 2H), 7.44˜7.47 (m, 2H), 7.41 (s, 1H), 7.25˜7.28 (m, 2H), 7.10˜7.13 (m, 2H), 3.82 (s, 2H), 2.64 (tt, J=3.2 & 12.1 Hz, 1H), 1.83˜1.89 (m, 4H), 1.72˜1.76 (m, 1H), 1.57˜1.66 (m, 2H), 1.27˜1.39 (m, 3H). LC-MS: 2.70 min. (M+H=479.1/481). The identity of the isomers were confirmed by NOE difference spectra.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][S:15]([C:18]2[C:27]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[C:21](F)=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C-:29]#[N:30].[Na+]>CS(C)=O.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][S:15]([C:18]2[C:27]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[C:21]([C:29]#[N:30])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2ccc(F)c3c2CCCC3)CC1
Reactant: [C-]#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2ccc(C#N)c3c2CCCC3)CC1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
4-(4-Fluoro-5,6,7,8-tetrahydro-naphthalene-1-sulfonylamino)-piperidine-1-carboxylic acid tert-butyl ester (970 mg, 2.35 mmol) was dissolved in DMSO (10 mL) and sodium cyanide (577 mg, 11.77 mmol) was added. The mixture was heated overnight at 100° C. An additional 5 equivalents of sodium cyanide (577 mg, 11.77 mmol) were added and the reaction was stirred overnight at 100° C. The reaction was cooled to room temperature and diluted with dichloromethane (100 mL). The mixture was charged to a separatory funnel and extracted three times with water, brine and then dried over MgSO4. Filtration and concentration in vacuo afforded a brown color foam that was triturated with EtOAc to afford a tan solid. Wt.: 550 mg (56%) 1H NMR (300 MHz, CDCl3) δ 7.87 (d, 1H), 7.48 (d, 1H), 4.52 (d, 1H), 3.93 (m, 2H), 3.30 (m, 1H), 3.07 (m, 4H), 2.73 (m, 2H), 1.80 (m, 6H), 1.37 (s, 9H), 1.30 (m, 2H); LC/MS m/z 418 (M−H)−.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[NH:7][C:6](=[O:8])[C:5]2([CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[N:4]=1.C(Cl)Cl.[C:24]([OH:30])([C:26]([F:29])([F:28])[F:27])=[O:25]>C(Cl)Cl>[NH2:1][CH2:2][C:3]1[NH:7][C:6](=[O:8])[C:5]2([CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[N:4]=1.[C:24]([OH:30])([C:26]([F:29])([F:28])[F:27])=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)N=C(CN)NC2=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCC1=NC2(CCNCC2)C(=O)N1
Reaction time: 0.5 h

Procedure:
For deprotection, 1E (1.0 equivalent) was dissolved in CH2Cl2 at 0° C., and slowly treated with a 1.6:1 solution of CH2Cl2/TFA (2:1 final ratio, 0.15 M). The reaction was completed in 30 minutes at 0° C. as determined by LCMS analysis. The volatiles were removed under reduced pressure to yield the respective 2-(aminomethyl)-1,3,8-triazaspiro[4.5]dec-1-en-4-one (1G) as TFA salts which were used without further purification. ESI-MS: m/z 183.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:8]=[C:9]([NH:13][C:14]([C:16]3([CH3:22])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[O:15])[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1.Cl[C:26]1[C:27]2[C:34]([Cl:35])=[CH:33][NH:32][C:28]=2[N:29]=[CH:30][N:31]=1.C(N(CC)CC)C>C(O)(C)C>[Cl:35][C:34]1[C:27]2[C:26]([N:19]3[CH2:18][CH2:17][C:16]([CH3:22])([C:14]([NH:13][C:9]4[CH:10]=[CH:11][CH:12]=[C:7]([O:6][C:5]5[CH:23]=[CH:24][C:2]([F:1])=[CH:3][CH:4]=5)[CH:8]=4)=[O:15])[CH2:21][CH2:20]3)=[N:31][CH:30]=[N:29][C:28]=2[NH:32][CH:33]=1
Reactant: CC1(C(=O)Nc2cccc(Oc3ccc(F)cc3)c2)CCNCC1
Reactant: Clc1c[nH]c2ncnc(Cl)c12
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC1(C(=O)Nc2cccc(Oc3ccc(F)cc3)c2)CCN(c2ncnc3[nH]cc(Cl)c23)CC1
Temperature: 130 °C

Procedure:
N-(3-(4-Fluorophenoxy)phenyl)-4-methylpiperidine-4-carboxamide from step B (50 mg, 0.13 mmol), 4,5-dichloro-7H-pyrrolo[2,3-d]pyrimidine from step C (19 mg, 0.1 mmol), and triethylamine (0.04 mL, 0.3 mmol) were combined in isopropanol (1 mL) and heated at 130° C. for 30 minutes under microwave conditions. The product was isolated by prep HPLC to give the title compound.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.[NH3:12]>O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2].O1CCOCC1>[NH2:12][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1
Reactant: Brc1cncc2ccccc12
Reactant: N
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Nc1cncc2ccccc12
Temperature: 165 °C
Reaction time: 21 h

Procedure:
A suspension of 4-bromoisoquinoline (25.0 g), copper(II) sulfate pentahydrate (30.4 g, Nacalai Tesque), 28% aqueous ammonia (100 ml) and 1,4-dioxane (100 ml) was stirred in a sealed tube at 165° C. for 21 hours. The reaction mixture was cooled to room temperature, the insoluble matters were removed by filtration through Celite, and the filtrate was extracted twice with ethyl acetate (150 ml for each time). The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=9:1) to obtain the title compound (13.2 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])/[CH:5]=[CH:6]/[C:7]1[C:12]([NH2:13])=[CH:11][CH:10]=[C:9](Br)[N:8]=1)[CH3:2].[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O>[CH2:1]([O:3][C:4](=[O:15])/[CH:5]=[CH:6]/[C:7]1[C:12]([NH2:13])=[CH:11][CH:10]=[C:9]([C:21]2[CH:22]=[CH:23][C:18]([C:17]([F:28])([F:27])[F:16])=[CH:19][CH:20]=2)[N:8]=1)[CH3:2]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)/C=C/c1nc(Br)ccc1N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1nc(-c2ccc(C(F)(F)F)cc2)ccc1N
Temperature: 110 °C
Reaction time: 1.5 h
Yield: 64.5 %

Procedure:
3.0 g (E)-3-(3-Amino-6-bromo-pyridin-2-yl)-acrylic acid ethyl ester, 3.05 g 4-(Trifluoromethyl)phenylboronic acid and 3.61 g cesium carbonate were dissolved in a mixture of 21 ml dimethylformamide and 7 ml water. An argon stream was bubbled through the reaction mixture for thirty minutes then 333 mg Tetrakis(tripehnylphosphine)palladium(0) were added and the reaction mixture stirred at 110° C. for 1.5 hours. The reaction mixture was diluted by addition of 50 ml water and extracted three times with portions of 80 ml dichloromethane. The combined organic layers were dried over MgSO4 then the solvent was removed in vacuo. The residue was purified by chromatography on silica gel to obtain 2.4 g (E)-3-[3-Amino-6-(4-trifluoromethyl-phenyl)-pyridin-2-yl]acrylic acid ethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C[O:10][C:11]([C:13]1[C:18]([CH2:19][CH:20]=O)=[CH:17][C:16]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:15][N:14]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[F:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[C:11](=[O:10])[C:13]3[N:14]=[CH:15][C:16]([CH2:22][O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:17][C:18]=3[CH2:19][CH2:20]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: COC(=O)c1ncc(COc2ccccc2)cc1CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C1c2ncc(COc3ccccc3)cc2CCN1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.2 %

Procedure:
4-Fluoroaniline (0.032 mL, 0.34 mmol) was added to a stirred solution of 3-(2-oxo-ethyl)-5-phenoxymethyl-pyridine-2-carboxylic acid methyl ester (80 mg, 0.28 mmol, from step 7) in DCM (4 mL). The mixture was stirred at RT for 1 h. Sodium triacetoxyborohydride (89 mg, 0.42 mmol) was added and the mixture was stirred at RT for 16 h. Acetic acid (0.040 mL) was added and the mixture was stirred at RT for additional 20 h. The mixture was diluted with DCM and washed with a saturated solution of NaHCO3 and brine. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; 7N solution of ammonia in methanol in DCM 0/100 to 4/96). The desired fractions were collected and the solvents evaporated in vacuo to yield an impure fraction which was re-purified by RP-HPLC on (C18 XBridge, 19×100, 5 μm; 80%/0.1% NH4CO3H/NH4OH pH 9 solution in water, 20% CH3CN to 0%/0.1% NH4CO3H/NH4OH pH 9 solution in water, 100% CH3CN), to yield 7-(4-fluoro-phenyl)-3-phenoxymethyl-6,7-dihydro-[1,7]-naphthyridin-8(5H)-one (14.86 mg, 15% yield) as a white solid: 1H NMR (500 MHz, CDCl3) δ 3.22 (t, J=6.4, 2 H), 4.01 (t, J=6.4, 2 H), 5.17 (s, 2 H), 6.98 (d, J=7.8, 2 H), 7.01 (t, J=7.5, 1 H), 7.07-7.16 (m, 2 H), 7.29-7.35 (m, 2 H), 7.36-7.42 (m, 2 H), 7.76 (br. s, 1 H), 8.78 (d, J=1.7, 1 H); LC-MS (M+H)=349.1.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3[N:14]=[C:15]([CH:18]4[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]4)[NH:16][CH:17]=3)=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3[NH:14][C:15]([CH:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)=[N:16][CH:17]=3)=[CH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3cnc(-c4ccccc4)nc3)c[nH]2)CC1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(-c2ncc(-c3cnc(C4CCNCC4)[nH]3)cn2)cc1
Yield: 20.7 %

Procedure:
Solid tert-butyl 4-(4-(2-phenylpyrimidin-5-yl)-1H-imidazol-2-yl)piperidine-1-carboxylate (Example 17, 122 mg, 0.30 mmol) was treated with trifluoroacetic acid 2.0 mL) at room temperature for 15 minutes. Three times the reaction mixture was diluted with toluene and concentrated under reduced pressure to provide a dark semi-solid. The crude material was chromatographed on silica (12 g) eluted with 1:5:85 v/v acetic acid-methanol-dichloromethane. Some clean fractions were collected, concentrated, and the purified material was three times diluted with toluene and concentrated then promoted to solidify under hexane with scratching to afford the title compound (19 mg) as a light-pink acetate salt. The remaining fractions were collected, concentrated, three times diluted with toluene and concentrated to afford a semi-solid; Rf 0.17 with 1/10/90 v/v acetic acid/methanol/dichloromethane; 1H-NMR (400 MHz; DMSO-d6) δ 9.20 (s, 2H), 8.6-8.8 (br d, 1H), 8.3-8.5 (m, 3H), 7.83 (s, 1H), 7.45-7.55 (m, 3H), 3.2-3.5 (m, 2H), 2.95-3.2 (m, 3H), 2.1-2.2 (m, 2H), 1.8-2.0 (m, 5H); MS (ESI+) m/z 306 (M+1); H-PGDS FPBA IC50: 1 μM.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[C-:9]#[N:10].[Na+]>C(OCC)C.CN(C)C>[CH3:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:9]#[N:10])[N:7]=1
Reactant: Cc1ccnc(Cl)n1
Reactant: [C-]#N
Agent: CN(C)C
Agent: [Na+]
Solvent: CCOCC
Product: Cc1ccnc(C#N)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.9 %

Procedure:
To a solution of 2-chloro-4-methylpyrimidine (3.00 g, 23.3 mmol; 3B Pharmachem International, China) in ethyl ether (24 mL) was added a solution of sodium cyanide (2.86 g, 58.3 mmol) in trimethylamine solution (1:3, trimethylamine:water, 24.0 mL). The reaction mixture was stirred at room temperature overnight. The aqueous layer was extracted with ethyl ether (3×20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to yield the title compound, 4-methyl-pyrimidine-2-carbonitrile (1.80 g; 64.8%), which was used in the next step without further purification. 1H NMR (400 MHz, D2O) δ8.64 (d, J=5.4 Hz, 1H), 7.59 (d, J=5.5 Hz, 1H).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][NH2:10])[CH2:2]2.C([O-])([O-])=O.[K+].[K+].Cl[C:18](=[CH2:21])[C:19]#[N:20]>O.CO>[NH2:20][C:19]1[N:9]([CH:3]2[CH:4]3[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]3)[CH2:2]2)[N:10]=[CH:21][CH:18]=1
Reactant: C=C(Cl)C#N
Reactant: NNC1CN2CCC1CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Nc1ccnn1C1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Quinuclidinyl-hydrazine (D2) (5.0 g, 35.5 mmol) was added to a solution of K2CO3 (4.90 g, 35.5 mmol) in water (13 ml) and the ice-cooled solution was stirred vigorously while 2-chloroacrylonitrile (3.10 g, 2.83 ml, 35.5 mmol) was added dropwise over 1 minute. The solution was then stirred at room temperature overnight. The mixture was diluted with MeOH, evaporated to a slurry under reduced pressure, suspended in saturated aqueous potassium carbonate and extracted with EtOAc (3×100 ml), followed by CHCl3 (4×250 ml). The organic extracts were dried (Na2SO4), filtered and evaporated to dryness under reduced pressure to yield a brown oil, which was purified by column chromatography (neutral alumina eluting with chloroform), to yield a faster running fraction (E3) (44 mg) and a slower running fraction (E4) (32 mg). Both were crystallised separately by trituration with diethyl ether, to yield white crystalline solids.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[N:7]([CH2:14][C:15]#[C:16][CH2:17][CH3:18])[C:6](=[O:19])[C:5]2([CH3:21])[CH3:20].[CH2:22]1[CH2:26][O:25][CH2:24][CH2:23]1>>[CH3:21][C:5]1([CH3:20])[C:4]2[C:8](=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:2]([NH:1][C:24](=[O:25])[CH2:23][CH2:22][C:26]3[CH:4]=[CH:3][CH:2]=[CH:10][CH:9]=3)[CH:3]=2)[N:7]([CH2:14][C:15]#[C:16][CH2:17][CH3:18])[C:6]1=[O:19]
Reactant: C1CCOC1
Reactant: CCC#CCN1C(=O)C(C)(C)c2cc(N)c([N+](=O)[O-])cc21
Product: CCC#CCN1C(=O)C(C)(C)c2cc(NC(=O)CCc3ccccc3)c([N+](=O)[O-])cc21

Procedure:
N-(3,3-Dimethyl-6-nitro-2-oxo-1-pent-2-ynyl-2,3-dihydro-1H-indol-5-yl)-3-phenyl-propionamide is prepared as described in Example 25a starting from A7 (73 mg) using THF (3 ml) as solvent. The crude material (106 mg) is used without further purification.
Reaction SMILES: C(=O)(O)[O-:2].[Na+].Cl.NO.[Cl:9][C:10]1[C:11]([C:18]([F:21])([F:20])[F:19])=[CH:12][C:13]([C:16]#[N:17])=[N:14][CH:15]=1>C(O)C>[Cl:9][C:10]1[C:11]([C:18]([F:21])([F:19])[F:20])=[CH:12][C:13]([C:16]([NH2:17])=[O:2])=[N:14][CH:15]=1
Reactant: O=C([O-])O
Reactant: N#Cc1cc(C(F)(F)F)c(Cl)cn1
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1cc(C(F)(F)F)c(Cl)cn1
Reaction time: 5 h
Yield: 74.6 %

Procedure:
To 7 ml of ethanol were added 0.61 g of sodium bicarbonate and 0.5 g of hydroxylamine hydrochloride, and the mixture was heated to reflux for 1 hour. After allowing to cool, 0.74 g of 5-chloro-4-trifluoromethylpyridine-2-carbonitrile was added at 0° C., and the mixture was stirred for 5 hours, and concentrated. To the residue was added water, the resultant solution was extracted with ethyl acetate three times, and the organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.6 g of 5-chloro-4-trifluoromethylpyridine-2-carboxamide=oxime.
Reaction SMILES: Cl[TeH:2]1[C:6]2[CH:7]=[C:8]([CH3:15])[C:9]3[C:14]([C:5]=2[NH:4]O1)=[CH:13][CH:12]=[CH:11][CH:10]=3.[BH4-].[Na+].[C:18](OC(=O)C)(=O)[CH3:19].Cl>O1CCCC1.CO>[CH3:18][C:19]1[Te:2][C:6]2[CH:7]=[C:8]([CH3:15])[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:5]=2[N:4]=1
Reactant: Cc1cc2c(c3ccccc13)NO[TeH]2Cl
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc2c(cc(C)c3ccccc32)[te]1
Temperature: 5 °C
Yield: 32.8 %

Procedure:
3-Chloro-5-methylnaphth[2,1-c][1,2,5]oxatellurazole (Example 4) (16.7 g=0.05 mole) was suspended in a mixture of tetrahydrofuran (THF, 200 ml) and methanol (40 ml) in a 500 ml three necked flask fitted with a nitrogen inlet, a condenser, and a powder addition funnel. Sodium borohydride was added under a nitrogen atmosphere and in small portions until the reaction mixture was a pale orange yellow. This required about 5 to 6 g. The powder addition funnel was then removed and replaced with a stopper. The reaction mixture was then cooled to 5° C. and acetic anhydride (5.1 g=0.05 mole) added slowly through the condenser. The reaction mixture transiently turned a bright orange. Concentrated hydrochloric acid (25 ml) was then added in one portion, the ice bath removed, and the mixture stirred to room temperature. As the reaction mixture warmed up, a crystalline deposit appeared and was collected by filtration. The crystalline deposit was washed with tetrahydrofuran until the filtrate was colorless and clear. The filtrate was then heated to boiling with a mixture of isopropanol (175 ml) and concentrated ammonium hydroxide (25 ml) and filtered hot with Celite®, the cooled filtrate was diluted with water until crystallization started. A first crop of pale yellow needles (5.06 g), m.p. 110°-112° C. was obtained. A further 1.65 g of product were obtained by two further extractions with the same solvent mixture, giving a total yield of 6.71 g=43.3% of theory. For analysis, the material was recrystallized from isopropanol. This did not change the melting point. Elemental analyses were in agreement with that expected for the structural formula.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[Cl:21][CH2:22][C:23](Cl)=[O:24]>C1COCC1>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:23](=[O:24])[CH2:22][Cl:21])[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: O=C(Cl)CCl
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Solvent: C1CCOC1
Product: O=C1CCC(N2C(=O)c3cccc(NC(=O)CCl)c3C2=O)C(=O)N1
Yield: 95.5 %

Procedure:
To a stirred suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (1.37 g, 5.00 mmol) in THF (30 ml) was added chloroacetyl chloride-(0.62 g, 5.5 mmol). The mixture was heated to reflux for 30 minutes. The solvent was evaporated in vacuo and the resulting solid was slurried in diethyl ether (20 ml) and filtered to give 1.67 g (96%) of product as an off-white solid: 1H NMR (DMSO-d6) δ 11.18 (s, 1H), 10.31 (s, 1H), 8.54 (d, J=8.4 Hz, 1H), 7.88 (t, J=7.7 Hz, 1H), 7.68 (d, J=7.3 Hz, 1H), 5.17 (dd, J=5.2 and 12.7 Hz, 1H), 4.54 (s, 2H), 2.90-2.85 (m, 1H), 2.65-2.51 (m, 2H), 2.10-2.06 (m, 1H).
Reaction SMILES: O.O.[Sn](Cl)Cl.[NH2:6][C:7]1[C:16]([N+:17]([O-])=O)=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10]>CO>[NH2:6][C:7]1[C:16]([NH2:17])=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1N
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Product: COC(=O)c1cccc(N)c1N
Temperature: 65 °C
Reaction time: 16 h
Yield: 96.8 %

Procedure:
Tin(II)chloride dihydrate (17.25 g, 76.5 mmol) was added in one portion to methyl 2-amino-3-nitrobenzoate (5.0 g, 25.5 mmol) in methanol (100 mL) under nitrogen. The yellow mixture was vigorously stirred at 65° C. for 16 h, and the solvent was removed by rotory evaporation to near dryness. The residue was taken up in ethyl acetate and the solution was poured into a large beaker containing 1:1 ethyl acetate/NaHCO3 soln. (300 mL) and stirred 15 min. The precipitates were removed by filtration and the organic layer was separated. The aqueous layer was extracted twice with ethyl acetate, and the combined organic layers were washed with saturated NaHCO3 solution, brine, and dried (Na2SO4). Concentration gave methyl 2,3-diaminobenzoate as a deep red viscous oil 4.1 g (97%).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][O:14][CH:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:9]1)C1C=CC=CC=1.C(O)(=O)C>C(O)C.[Pd]>[C:16]1([CH:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:14][CH2:13][CH:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: c1ccc(CN2CCC(COC(c3ccccc3)c3ccccc3)C2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: c1ccc(C(OCC2CCNC2)c2ccccc2)cc1
Yield: 78.5 %

Procedure:
A solution of 1-benzyl-3-(diphenylmethoxymethyl)pyrrolidine (1.43 g, Preparation 8) in ethanol (50 ml) containing acetic acid (1.0 ml) was stirred at room temperature for six days under an atmosphere of hydrogen in the presence of 5% palladium on charcoal. The mixture was filtered and the filtrate was diluted with ethyl acetate, washed with 10% aqueous sodium carbonate solution and water, dried over magnesium sulphate and evaporated to give the title compound (0.84 g) as a pale yellow oil which was characterised by its 1H-NMR spectrum.