Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1([C:12]2[C:21]([OH:22])=[CH:20][C:15]3[O:16][CH2:17][CH2:18][O:19][C:14]=3[CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[OH:22][C:21]1[C:12]([CH:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[NH:4][C:3]2=[O:11])=[CH:13][C:14]2[O:19][CH2:18][CH2:17][O:16][C:15]=2[CH:20]=1
Reactant: O=C1Nc2ccccc2C1(O)c1cc2c(cc1O)OCCO2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1Nc2ccccc2C1c1cc2c(cc1O)OCCO2
Temperature: -5 °C
Reaction time: 2.5 h
Yield: 78.2 %

Procedure:
A 2000 L reactor was charged with dichloromethane (489.4 kg), followed by 3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one (92.0 kg, 307 mol) in four 23 kg portions over 1 h. The resultant solution was stirred at ambient temperature for 1 h and triethylsilane (107.2 kg, 921 mol) was added. The mixture was cooled to −5° C. and trifluoroacetic acid (105.1 kg, 921 mol) was added at a rate of 25-30 kg/h such that the temperature of the reaction mixture remained below 0° C. The mixture was stirred at −5-0° C. for 2.5 h, warmed to 18-20° C., stirred for a further 6.5 h and concentrated to dryness under reduced pressure at a temperature <30° C. Methyl tert-butyl ether (139.8 kg) was added to the residue at 15-20° C. and the mixture concentrated to near-dryness under reduced pressure at a temperature <35° C. The mixture was filtered in a centrifugal filter and a 2000 L reactor was charged with the filter cake, followed by methanol (72.7 kg). The mixture was stirred at 10-15° C. for 0.5 h and filtered in a centrifugal filter. The filter cake was dried under reduced pressure at 40-50° C. to afford 3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one (68.0 kg, 78%) as a colorless solid: purity (HPLC-UV at 254 nm) 99.3%.
Reaction SMILES: [CH:1]1([C:5]2[C:17]3[C:16]4[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=4[C:10](=[O:18])[NH:9][C:8]=3[N:7]([CH2:19][C:20]3[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=3)[C:23]#[N:24])[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[N-:28]=[N+:29]=[N-:30].C([Sn](=O)CCCC)CCC.N>C1(C)C=CC=CC=1>[CH:1]1([C:5]2[C:17]3[C:16]4[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=4[C:10](=[O:18])[NH:9][C:8]=3[N:7]([CH2:19][C:20]3[CH:27]=[CH:26][CH:25]=[C:22]([C:23]4[NH:30][N:29]=[N:28][N:24]=4)[CH:21]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1cccc(Cn2nc(C3CCC3)c3c4c(c(=O)[nH]c32)CCCC4)c1
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Agent: N
Solvent: Cc1ccccc1
Product: O=c1[nH]c2c(c(C3CCC3)nn2Cc2cccc(-c3nnn[nH]3)c2)c2c1CCCC2
Temperature: 100 °C

Procedure:
To a suspension of Example 95A (150 mg) and trimethylsily azide (582 mg) in toluene (20 ml) was added dibutyltin oxide (28 mg). The mixture was heated at 100° C. for 3 days. Solid material was collected by filtration, washed with methanol and dried to give Example 95. Yield: 100 mg. MS (DCI/NH3) m/z 402 (M+H)+; 1H NMR (500 MHz, CD3OD): δ 1.81 (s, 2H), 1.92 (m, 1H), 2.02-2.11 (m, 1H), 2.35-2.44 (m, 4H), 2.51 (m, 2H), 2.91 (br s, 2H), 3.84-3.90 (m, 1H), 5.37 (br s, 1H), 5.51 (s, 2H), 5.51 (s, 2H), 7.30 (m, 2H), 7.97 (m, 2H),
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]1[CH2:12][CH2:11][NH:10][S:9]1(=[O:14])=[O:13].[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1)([O-:17])=[O:16].O>CN(C)C=O>[CH3:7][N:8]1[S:9](=[O:14])(=[O:13])[N:10]([CH2:22][C:21]2[CH:24]=[CH:25][C:18]([N+:15]([O-:17])=[O:16])=[CH:19][CH:20]=2)[CH2:11][CH2:12]1
Reactant: CN1CCNS1(=O)=O
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCN(Cc2ccc([N+](=O)[O-])cc2)S1(=O)=O
Reaction time: 0.08 h
Yield: 65.7 %

Procedure:
To a stirred suspension of anhydrous potassium carbonate (14.49 g, 104.8 mmol) in anhydrous dimethylformamide (80 ml) was added dropwise over 4 minutes a solution of 2-methyl-1,2,5-thiadiazolidine-1,1-dioxide (14 g, 102.8 mmol) in anhydrous dimethylformamide (40 ml), under nitrogen. After 5 minutes, solid 4-nitrobenzyl bromide (22.43 g, 103.8 mmol) was added in one portion and stirring was continued at room temperature for 5 hours. Water (200 ml) was added and products were extracted into ethyl acetate (3×150 ml). The combined organic phases were washed with brine (1×50 ml), dried (Na2SO4) and concentrated. The crude residue was crystallized from ethyl acetate-hexane (70:30) to give 18.31 g (67%) of the title compound as pale yellow crystals. Purification of the mother liquors by flash chromatography (silica gel, hexane-ethyl acetate, 30:70) afforded a further 5.1 g (18.2%) of required product; mp 105°-107° C.; δH (250 MHz, CDCl3) 8.22 (2H, d, J=8.7 Hz, Ar--H), 7.57 (2H, d, J=8.7 Hz, Ar--H), 4.32 (2H, s, Ar--CH2 --), 3.36--3.21 (4H, m, N--CH2CH2 --N), 2.80 (3H, s, --NMe); m/z (CI) 270 (M+ -1).
Reaction SMILES: S(C1C=CC(C)=CC=1)(O)(=O)=O.[NH:12]1[CH2:16][CH2:15][N:14]=[C:13]1[NH2:17].[Na].[NH2:19][C:20]1[C:21]([C:28](OC(C)=CC(=O)NC(C)(C)C)=[O:29])=[N:22][C:23]([Cl:27])=[C:24]([NH2:26])[N:25]=1>CC(O)C>[NH2:19][C:20]1[C:21]([C:28]([NH:17][C:13]2[NH:14][CH2:15][CH2:16][N:12]=2)=[O:29])=[N:22][C:23]([Cl:27])=[C:24]([NH2:26])[N:25]=1
Reactant: CC(=CC(=O)NC(C)(C)C)OC(=O)c1nc(Cl)c(N)nc1N
Reactant: NC1=NCCN1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na]
Solvent: CC(C)O
Product: Nc1nc(N)c(C(=O)NC2=NCCN2)nc1Cl

Procedure:
A mixture of 4,5-dihydro-1H-imidazol-2-ylamine tosylate (1.69 g; 6.57 mmol) and sodium (119 mg; 5.19 mmol) in 2-propanol (20 ml) is refluxed for 30 min. 1-(tert-Butylcarbamoyl)prop-1-en-2-yl 3,5-diamino-6-chloropyrazine-2-carboxylate (example 2) (0.900 g; 2.75 mmol) is added and the mixture is refluxed for further 60 min. The precipitate formed is filtered off with suction, suspended in water, filtered off again and dried at 50° C. to yield the title compound (C8H10ClN7O).
Reaction SMILES: O=[C:2]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=3)[CH2:19][CH2:18]2)=[CH:10][CH:9]=1)[CH2:3][CH2:4][C:5](O)=[O:6].[CH2:30]([NH2:32])[CH3:31]>>[CH2:30]([N:32]1[CH:2]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=4)[CH2:19][CH2:18]3)=[CH:12][CH:13]=2)[CH2:3][CH2:4][C:5]1=[O:6])[CH3:31]
Reactant: CCN
Reactant: Cc1cccc(N2CCN(CCCc3ccc(C(=O)CCC(=O)O)cc3)CC2)c1
Product: CCN1C(=O)CCC1c1ccc(CCCN2CCN(c3cccc(C)c3)CC2)cc1

Procedure:
4-Oxo-4-[4-(3-(4-(3-methylphenyl)piperazin-1-yl)propyl)phenyl]butyric acid and ethylamine are reacted together to give N-ethyl-5-[4-(3-(4-(3-methylphenyl)piperazin-1-yl)propyl)phenyl]pyrrolidin-2-one.
Reaction SMILES: [C:1]([C@H:5]1[C@@H:11]([OH:12])[CH2:10][C@H:9]2[N:13]([CH3:14])[C@@H:6]1[CH2:7][CH2:8]2)([O:3][CH3:4])=[O:2].N1C=CN=C1.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].O>CN(C=O)C>[Si:20]([O:12][C@H:11]1[CH2:10][C@H:9]2[N:13]([CH3:14])[C@H:6]([CH2:7][CH2:8]2)[C@H:5]1[C:1]([O:3][CH3:4])=[O:2])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: COC(=O)[C@@H]1[C@H]2CC[C@@H](C[C@@H]1O)N2C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)C[C@@H]2CC[C@H]1N2C
Reaction time: 8 h
Yield: 59.1 %

Procedure:
2β-Carbomethoxy-3β-hydroxytropane (304 mg, 1.43 mmol) was dissolved in 4 mL of dry DMF. Imidazole (208 mg, 3.01 mmol) and tert-butyldimethylsilyl chloride (345 mg, 2.29 mmol) were added, and the reaction mixture was stirred overnight. Water was then added, and the mixture was extracted with ether. The combined organic layers were washed with water and brine and dried over MgSO4. The solvent was evaporated in vacuo, and the residue was chromatographed on silica gel half-saturated with ammonia using ethyl acetate as eluent to give 265 mg of the title compound (55% yield): IR (thin film) 2951, 2897, 2857, 1790, 1716, 1497, 1271, 1144, 1107, 837 cm-1 ; 1H NMR (CDCl3, 300 MHz) δ 3.91 (dt, 1H, J=11.1, 6.1 Hz), 3.67 (s, 3H), 3.45-3.35 (m, 1H), 3.25-3.17 (m,1H), 2.75-2.68 (m,1H), 2.18 (s, 3H), 2.35- 1.42 (m, 6H), 0.84 (s, 9H), 0.02 (s, 3H), 0.01 (s, 3H); 13C NMR (CDCl3, 75.46 MHz) δ 171.4, 64.6, 64.4, 61.6, 54.0, 51.1, 41.2, 39.5, 28.2, 25.8, 25.2, 18.1, 6.6, 6.3; mass spectrum m/z 313 (M+), 256, 242, 182, 97, 82; HRMS (FAB) calcd for C16H32NO3Si (MH ) 314.2143, found 314.2145.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]([CH3:27])[C:8](=[O:26])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([C:22](=O)[CH2:23]Br)=[N:11][CH:10]=1.[NH2:37][C:38]([NH2:40])=[S:39]>C(O)C>[NH2:40][C:38]1[S:39][CH:23]=[C:22]([C:12]2[CH:13]=[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[CH3:21])[C:9]([C:8]([N:7]([CH2:6][C:5]3[CH:28]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:30]=[C:3]([C:2]([F:36])([F:35])[F:1])[CH:4]=3)[CH3:27])=[O:26])=[CH:10][N:11]=2)[N:37]=1
Reactant: Cc1ccccc1-c1cc(C(=O)CBr)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: NC(N)=S
Solvent: CCO
Product: Cc1ccccc1-c1cc(-c2csc(N)n2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 86.6 %

Procedure:
A mixture of 73 mg (0.13 mmol) N-(3,5-bis-trifluoromethyl-benzyl)-6-bromoacetyl-N-methyl-4-o-tolyl-nicotinamide and 12 mg (0.15 mmol) thiourea in 1 ml ethanol was heated at reflux for 30 min. After cooling to room temperature the solvent was evaporated in vacuo and the residue was dissolved in ethyl acetate. Washing with 1 M aqueous sodium hydroxide solution was followed by extraction of the aqueous layer with three portions of ethyl acetate. The combined organic layers were dried with sodium sulfate and concentrated. Column chromatography afforded 62 mg (88%) of the title compound as a light orange solid.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:16]2([O:21][CH3:22])[CH2:20][O:19][CH2:18][CH2:17]2)[CH:12]=[C:13]([F:15])[CH:14]=1)C1C=CC=CC=1>C(O)C.[Pd]>[F:15][C:13]1[CH:14]=[C:9]([OH:8])[CH:10]=[C:11]([C:16]2([O:21][CH3:22])[CH2:20][O:19][CH2:18][CH2:17]2)[CH:12]=1
Reactant: COC1(c2cc(F)cc(OCc3ccccc3)c2)CCOC1
Agent: [Pd]
Solvent: CCO
Product: COC1(c2cc(O)cc(F)c2)CCOC1
Yield: 108.8 %

Procedure:
A solution of 4-(3-benzyloxy-5-fluorophenyl)-4-methoxytetrahydrofuran (1.1 g) in ethanol (20 ml) was hydrogenated in the presence of 10% palladium-on-charcoal catalyst (1 00 mg) for about 3 hours. The mixture was filtered and the filtrate was evaporated to give 840 mg of the title compound. m.p. 136°-137° C.
Reaction SMILES: [C:1]([C:3]([CH3:13])([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH3:4])#[N:2].[CH2:14](N)[CH2:15][NH2:16]>C(=S)=S>[CH3:4][C:3]([C:1]1[NH:2][CH2:14][CH2:15][N:16]=1)([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH3:13]
Reactant: CCCCCCCCC(C)(C)C#N
Reactant: NCCN
Solvent: S=C=S
Product: CCCCCCCCC(C)(C)C1=NCCN1
Yield: 62 %

Procedure:
18.32 g (100 mmoles) of 2-cyano-2-methyldecane, 8.5 ml (127 mmoles) of ethylenediamine and 0.5 ml of carbon disulfide are reacted according to Example 29 and the reaction mixture is worked up as mentioned therein. Distillation of the residue gives 13.91 g (62%) of the product.
Reaction SMILES: C([N:4]1[CH2:10][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]2[CH:17]=[C:18]([S:23]([Cl:26])(=[O:25])=[O:24])[C:19]([O:21][CH3:22])=[CH:20][C:7]=2[CH2:6][CH2:5]1)(=O)C.[OH-].[NH4+:28].Cl>>[ClH:26].[CH3:22][O:21][C:19]1[C:18]([S:23](=[O:25])(=[O:24])[NH2:28])=[CH:17][C:8]2[CH:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:10][NH:4][CH2:5][CH2:6][C:7]=2[CH:20]=1
Reactant: [NH4+]
Reactant: COc1cc2c(cc1S(=O)(=O)Cl)C(c1ccccc1)CN(C(C)=O)CC2
Agent: Cl
Agent: [OH-]
Product: COc1cc2c(cc1S(N)(=O)=O)C(c1ccccc1)CNCC2

Procedure:
By the procedure of Example 2, 3-acetyl-8-chlorosulfonyl-7-methoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine is treated with ammonium hydroxide followed by hydrochloric acid to give 7-methoxy-1-phenyl-8-sulfamoyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride.
Reaction SMILES: [CH2:1]([C:5]1[S:6][C:7]2[CH2:13][CH2:12][CH:11]([C:14](OCC)=[O:15])[CH2:10][C:8]=2[N:9]=1)[CH2:2][CH2:3][CH3:4]>CCOCC>[CH2:1]([C:5]1[S:6][C:7]2[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][C:8]=2[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(s1)CCC(C(=O)OCC)C2
Solvent: CCOCC
Product: CCCCc1nc2c(s1)CCC(CO)C2
Yield: 89 %

Procedure:
The compound is prepared by reduction of the above derivative (III) with AlLiH4 in ether at room temperature. B.p.0.15 =138°-142° C. Yield: 89%.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:20])[C:7]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[CH:8][O:9]2)=[CH:4][CH:3]=1.Br[CH:22]([CH3:24])[CH3:23]>>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:7]2[C:6](=[O:20])[C:5]3[C:10](=[CH:11][C:2]([O:1][CH:22]([CH3:24])[CH3:23])=[CH:3][CH:4]=3)[O:9][CH:8]=2)=[CH:13][CH:14]=1
Reactant: COc1ccc(-c2coc3cc(O)ccc3c2=O)cc1
Reactant: CC(C)Br
Product: COc1ccc(-c2coc3cc(OC(C)C)ccc3c2=O)cc1

Procedure:
As described in Scheme 1, treatment of 7-hydroxy-3-(4-methoxyphenyl)-4H-chromen-4-one (1) with 2-bromopropane gives 3-(4-methoxyphenyl)-7-isopropoxy-4H-chromen-4-one (2) which is then reacted with NH2OH to give 5-isopropoxy-2-(4-(4-methoxyphenyl)isoxazol-5-yl)phenol (3) in a good overall yield. Reaction of 3 with polyethylenedibromide affords monobromoisoxazoles 4 which are respectively treated with substituted amines to afford the respective aminoalkoxy substituted 4,5-diphenylisokazoles 5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]([C:11]1[N:15]2[CH:16]=[C:17]([C:20]3[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=3)[CH:18]=[CH:19][C:14]2=[N:13][C:12]=1[CH3:26])O.II>C(O)(=O)C.[PH2](=O)O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][C:11]1[N:15]2[CH:16]=[C:17]([C:20]3[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=3)[CH:18]=[CH:19][C:14]2=[N:13][C:12]=1[CH3:26]
Reactant: Cc1nc2ccc(-c3cnn(C)c3)cn2c1C(O)c1cc(Cl)ccc1Cl
Agent: II
Agent: O=[PH2]O
Solvent: CC(=O)O
Product: Cc1nc2ccc(-c3cnn(C)c3)cn2c1Cc1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 26.1 %

Procedure:
To a suspension of Example 8 (0.10 g) in a mixture of acetic acid (2 mL) and phosphinic acid (0.1 mL) was added iodine (0.05 g). The mixture was heated at 100° C. for 1.5 h before the addition of extra iodine (8 mg) and phosphinic acid (0.02 mL). Heating was continued for 4 h and then the mixture was cooled to room temperature overnight. The mixture was concentrated in vacuo and the residue was partitioned between DCM (20 mL) and saturated aqueous NaHCO3 solution (20 mL). The organic phase was separated, dried (Na2SO4), filtered and concentrated in vacuo. The resulting crude product was purified by preparative HPLC to give the title compound (0.025 g) as a white solid. δH (400 MHz, DMSO-d6) 7.21 (t, 1H, J 1.2 Hz), 6.95 (s, 1H), 6.78 (d, 1H, J 0.6 Hz), 6.55 (m, 2H), 6.46 (d, 1H, J 8.5 Hz), 6.27 (dd, 1H, J 8.5, 2.5 Hz), 5.93 (d, 1H, J 2.5 Hz), 3.45 (s, 2H), 2.91 (s, 3H), 1.36 (s, 3H). MH+ 372.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].Cl.[C:12]1([C:18]2[N:22]=[C:21]([CH:23]3[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]3)[O:20][N:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl.CO>[F:1][C:2]1[CH:3]=[C:4]([C:5]([N:25]2[CH2:26][CH2:27][CH2:28][CH:23]([C:21]3[O:20][N:19]=[C:18]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[N:22]=3)[CH2:24]2)=[O:6])[CH:8]=[CH:9][CH:10]=1
Reactant: c1ccc(-c2noc(C3CCCNC3)n2)cc1
Reactant: O=C(Cl)c1cccc(F)c1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: O=C(c1cccc(F)c1)N1CCCC(c2nc(-c3ccccc3)no2)C1
Yield: 53 %

Procedure:
The compound was prepared following the procedure described in the Example 3(D), using 3-Fluoro-benzoyl chloride as the acyl chloride of choice and the 3-(3-Phenyl-[1,2,4]oxadiazol-5-yl)-piperidine hydrochloride (already prepared before in the Example 7). Yield: 53% (yellow oil); Rf=0.25 (DCM/MeOH: 98/2); LCMS (Tr): 4.77 min (Method C); MS (ES+) gave m/z: 352.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][C:8]2[S:9][CH:10]=[C:11]([C:13]([OH:15])=O)[N:12]=2)=[CH:5][CH:4]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([C:28]2([CH2:33][NH2:34])[CH2:32][CH2:31][CH2:30][CH2:29]2)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(#N)C>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([C:28]2([CH2:33][NH:34][C:13]([C:11]3[N:12]=[C:8]([CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:17][CH:16]=4)[S:9][CH:10]=3)=[O:15])[CH2:29][CH2:30][CH2:31][CH2:32]2)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: COc1ccc(C2(CN)CCCC2)cc1OC
Reactant: COc1ccc(Cc2nc(C(=O)O)cs2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(Cc2nc(C(=O)NCC3(c4ccc(OC)c(OC)c4)CCCC3)cs2)cc1
Reaction time: 16 h
Yield: 44.4 %

Procedure:
2-(4-Methoxy-benzyl)-thiazole-4-carboxylic acid (101 mg, 0.405 mmol) and C-[1-(3,4-Dimethoxy-phenyl)-cyclopentyl]-methylamine (96.5 mg, 0.410 mmol) were dissolved in acetonitrile (2 mL) containing triethylamine (84.1 μL, 0.600 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (171 mg, 0.450 mmol) was added and the solution was allowed to stir for 16 hours. The reaction mixture was evaporated to dryness and purified by column chromatography on silica gel using a gradient of 5-30% ethyl acetate in hexanes. The pure fractions were combined and evaporated to dryness to yield a yellow solid (84.0 mg, 0.180 mmol, 43.9%). ESI-MS m/z calc. 466.6, found 467.2 (M+1)+. Retention time of 8.32 minutes. 1H NMR (400 MHz, CD3CN) δ1.68-2.07 (m, 8H), 3.50 (d, J=6.3 Hz, 2H), 3.82 (s, 9H), 4.20 (s, 2H), 6.83-7.29 (m, 8H), 7.87 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[C:13]2[O:12][CH2:11][C:10]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[C:7]([N+:16]([O-])=O)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CCCCCC.CCOC(C)=O>[Pd].CCO>[NH2:16][C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:13]2[O:12][CH2:11][C:10]([CH3:14])([CH3:15])[C:9]=2[CH:8]=1
Reactant: CC(C)(C)c1cc([N+](=O)[O-])cc2c1OCC2(C)C
Agent: [Pd]
Solvent: CCO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(N)cc2c1OCC2(C)C
Reaction time: 3 h
Yield: 88.1 %

Procedure:
A suspension of 7-tert-butyl-2,3-dihydro-3,3-dimethyl-5-nitro-benzofuran (2.2 g, 8.8 mmol) and 10% palladium on carbon (200 mg) in absolute EtOH (60 mL) is hydrogenated at 40 psi of H2 pressure on a Parr hydrogenation apparatus for 3 h at 22° C. The reaction is judged complete by TLC (hexane:EtOAc, 19:1; visualized with Dragendorff reagent). The reaction mixture is filtered through Celite and evaporated to yield the title compound as a purple solid (1.7 g, 88%), which is used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[OH:14][C:15]1[C:22]([CH3:23])=[CH:21][C:18]([CH:19]=O)=[CH:17][C:16]=1[CH3:24].S(=O)(O)[O-].[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O.CN(C)C(=O)C>[OH:14][C:15]1[C:22]([CH3:23])=[CH:21][C:18]([C:19]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][CH:9]=[C:8]([N+:11]([O-:13])=[O:12])[CH:7]=3)[N:1]=2)=[CH:17][C:16]=1[CH3:24]
Reactant: NC(=O)c1cc([N+](=O)[O-])ccc1N
Reactant: Cc1cc(C=O)cc(C)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cc(-c2nc3ccc([N+](=O)[O-])cc3c(=O)[nH]2)cc(C)c1O
Temperature: 155 °C
Yield: 18.8 %

Procedure:
To a round-bottomed flask were added 2-amino-5-nitro-benzamide (0.681 g, 3.76 mmol), 4-hydroxy-3,5-dimethyl-benzaldehyde (0.565 g, 3.76 mmol), sodium bisulfite (0.747 g, 4.2 mmol), p-toluenesulfonic acid, monohydrate (0.072 g, 0.376 mmol) and N,N-dimethylacetamide (60 mL). The reaction mixture was refluxed at 155° C. for 16 h before being cooled to room temperature. Water was added and the precipitated solid was filtered off, washed with water and methanol to obtain a crude which was purified by column chromatography (silica gel (50 g) employing 1-20% methanol in dichloromethane as eluents, to obtain 2-(4-hydroxy-3,5-dimethyl-phenyl)-6-nitro-3H-quinazolin-4-one (0.220 g, 19%). The compound 2-(4-hydroxy-3,5-dimethyl-phenyl)-6-nitro-3H-quinazolin-4-one (0.220 g, 0.71 mmol) was hydrogenated in dimethyl formamide (20 mL) using palladium on activated carbon (0.076 g, 0.071 mmol) at room temperature for 14 h. The solvent was evaporated and the crude was purified by column chromatography (silica gel 25 g) employing 1-5% methanol in dichloromethane as eluents to obtain 6-amino-2-(4-hydroxy-3,5-dimethyl-phenyl)-3H-quinazolin-4-one (0.132 g). The compound 6-amino-2-(4-hydroxy-3,5-dimethyl-phenyl)-3H-quinazolin-4-one was dissolved in pyridine under nitrogen. Acetic anhydride was added at room temperature and stirred for 4 h. Pyridine was removed and the residue was dried. Methanol was added to the flask and a solution of potassium carbonate in water was added and stirred for 4 h. The solvent was removed, acidified with 1 N hydrochloric acid and the precipitated solid was filtered off and dried to obtain N-(2-(4-hydroxy-3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)acetamide (0.037 g, 17%). Selected data: MS (ES) m/z: 324.1; MP 336.5° C. (decomposed).
Reaction SMILES: [BH4-].[Na+].[CH3:3][CH:4]([CH3:20])[CH2:5][CH:6]([C:12](=[O:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:7]([O:9][CH2:10][CH3:11])=[O:8].Cl>C(O)C.O>[OH:19][CH:12]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]([CH2:5][CH:4]([CH3:3])[CH3:20])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)CC(=O)C(CC(C)C)C(=O)OCC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CC(O)C(CC(C)C)C(=O)OCC
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
Sodium borohydride (1.1 g, 29 mmol) was added to an ice-cold solution of diethyl 2-(2-methylpropyl)-3-oxopentanedioate (7.5 g, 29 mmol) in ethanol (75 ml). The mixture was stirred at 5°-10° C. for 2 h, then 2 N hydrochloric acid (18 ml) was added slowly at 0° C., and the mixture was stirred at room temperature for 45 min. The mixture was diluted with water (400 ml), then was extracted with ethyl acetate (4×100 ml). The extracts were washed with water (2×100 ml) and brine (100 ml), then were dried (Na2SO4) and evaporated in vacuo to leave the title compound as an oil (7.5 g, 100%).
Reaction SMILES: C(SCCC([N:9]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20](F)(F)F)=[CH:16][CH:15]=2)[S:11]C1C(OCC1C=CC=CC=1)=O)=O)(=O)C.S[CH2:35][CH2:36][C:37](N1N=C(C2C=CC(C(F)(F)F)=CC=2)SC1C(O)=O)=O>>[CH:19]1[C:18]2[C:17](=[CH:20][CH:35]=[CH:36][CH:37]=2)[CH:16]=[CH:15][C:14]=1[C:12]([NH:13][NH2:9])=[S:11]
Reactant: O=C(O)C1SC(c2ccc(C(F)(F)F)cc2)=NN1C(=O)CCS
Reactant: CC(=O)SCCC(=O)N1N=C(c2ccc(C(F)(F)F)cc2)SC1C(=O)OCc1ccccc1
Product: NNC(=S)c1ccc2ccccc2c1

Procedure:
The sub-title product was prepared from appropriate starting materials by the processes of Example 7, steps (a), (b), (c) and (d). mp 166°-167°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([N+:15]([O-])=O)=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][C:3]=1[F:18]>[Ni].C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([NH2:15])=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][C:3]=1[F:18]
Reactant: O=[N+]([O-])c1cccnc1Nc1ccc(Cl)c(F)c1
Agent: [Ni]
Solvent: CCOC(C)=O
Product: Nc1cccnc1Nc1ccc(Cl)c(F)c1
Reaction time: 20 h

Procedure:
A mixture of N-(4-chloro-3-fluorophenyl)-3-nitropyridin-2-amine (C11) (5.0 g, 19 mmol) and Raney nickel (3 g) in ethyl acetate (400 mL) was degassed three times with hydrogen. The reaction mixture was then hydrogenated at room temperature for 20 hours. After removal of the catalyst via filtration, the filtrate was concentrated in vacuo. Purification via silica gel chromatography afforded the product as a gray solid. Yield: 3.1 g, 13 mmol, 68%. 1H NMR (400 MHz, CDCl3) δ 7.87 (dd, J=4.9, 1.6 Hz, 1H), 7.38 (dd, J=11.5, 2.5 Hz, 1H), 7.24 (dd, J=8.5, 8.4 Hz, 1H), 7.06 (dd, J=7.6, 1.6 Hz, 1H), 6.92 (ddd, J=8.7, 2.5, 1.0 Hz, 1H), 6.82 (dd, J=7.6, 4.9 Hz, 1H), 6.37 (br s, 1H), 3.38 (br s, 2H).