Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[NH2:7][C:8]1[N:13]=[C:12]([OH:14])[C:11]([N+:15]([O-:17])=[O:16])=[C:10](Cl)[N:9]=1.[CH3:19][C:20]1[O:24][C:23](B(O)O)=[CH:22][CH:21]=1.CC1OC=CC=1>C1COCC1.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.C(OCC)(=O)C>[NH2:7][C:8]1[N:13]=[C:12]([OH:14])[C:11]([N+:15]([O-:17])=[O:16])=[C:10]([C:23]2[O:24][C:20]([CH3:19])=[CH:21][CH:22]=2)[N:9]=1
Reactant: Nc1nc(O)c([N+](=O)[O-])c(Cl)n1
Reactant: Cc1ccc(B(O)O)o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1ccco1
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2nc(N)nc(O)c2[N+](=O)[O-])o1
Temperature: 22 °C
Yield: 67 %

Procedure:
A biphasic solvent mixture of 1100 mL (22 volumes) tetrahydrofuran and 550 mL (11 volumes) of aqueous sodium carbonate solution was stirred at 22° C. in a 3000 mL three-necked round-bottomed flask. To this, 2-amino-6-chloro-5-nitro-4-pyrimidinol (11) was added portionwise. The resulting yellow solution was treated with a solution of 5-methylfuran-2-boronic acid in ca. 30 mL THF (0.43 mol, 2 eq 2-methylfuran initially). Tetrakis(triphenylphosphine)palladium (0) (5%, 0.0072 moles, 8.32 g) was added and the reaction mixture heated to a temperature of 70° C. for 3 hr. The reaction mixture was cooled to 22° C. A small amount of turbidity was apparent at this point. The entire mixture was filtered and the filtrate reduced in vacuo to remove the tetrahydrofuran phase, leaving behind the alkaline aqueous phase. 1000 mL (20 volumes) ethyl acetate was added and the mixture stirred vigorously for 15 min (this step serves to wash out neutral contaminants, particularly triphenylphosphine oxide). The aqueous and organic phases were separated and the organic phase back-extracted with aqueous sodium carbonate (800 mL). The combined aqueous phase was cooled using an ice-bath and acidified (through drop-wise addition of HCl) to pH 7. The resulting bright yellow precipitate was filtered under vacuum, washed with water and dried at 40° C. This method gave 37.8 g (67%) of the required product.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([CH:28]([CH3:30])[CH3:29])[C:24](=[NH:27])OC)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([CH:23]([CH:28]([CH3:30])[CH3:29])[C:24](=[NH:27])[O:12][CH2:11][C:10]2[CH:13]=[CH:14][CH:15]=[C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:9]=2)=[CH:21][CH:22]=1
Reactant: OCc1cccc(Oc2ccccc2)c1
Reactant: COC(=N)C(c1ccc(Cl)cc1)C(C)C
Product: CC(C)C(C(=N)OCc1cccc(Oc2ccccc2)c1)c1ccc(Cl)cc1

Procedure:
Following the procedure of Example 6B, 3-phenoxybenzyl alcohol and methyl 2-(4-chlorophenyl)-3-methylbutanimidate are reacted to yield 3-phenoxybenzyl 2-(4-chlorophenyl)-3-methylbutanimidate.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Si:23]([O:30][CH2:31][CH2:32][C:33]1[S:37][C:36]([CH2:38][CH2:39][OH:40])=[CH:35][CH:34]=1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24].S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>ClCCl.C(OCC)(=O)C>[Si:23]([O:30][CH2:31][CH2:32][C:33]1[S:37][C:36]([CH2:38][CH:39]=[O:40])=[CH:35][CH:34]=1)([C:26]([CH3:28])([CH3:27])[CH3:29])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccc(CCO)s1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCc1ccc(CC=O)s1
Reaction time: 0.5 h

Procedure:
Dess-Martin periodinane (0.38 g) was added to a solution of 2-(5-(2-(tert-butyldimethylsilyloxy)ethyl)thiophen-2-yl)ethanol (example 4, step f) (0.22 g) in dichloromethane (5 mL) and the resulting mixture stirred for 30 min. A mixture of saturated sodium thiosulphate solution (5 mL), saturated sodium bicarbonate solution (5 mL) and ethyl acetate (25 mL) were added and the resulting mixture stirred for 10 min. The organic layer was separated and washed with a solution of saturated sodium bicarbonate solution (10 mL), and brine (10 mL), then dried over sodium sulphate, filtered and evaporated in vacuo to give the subtitled compound as a clear oil which was used immediately. Yield 0.21 g.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[O:10]=[C:11]1[NH:19][CH:18]=[N:17][C:16]2[N:15]([CH2:20][CH2:21][C:22](OCC)=[O:23])[CH:14]=[N:13][C:12]1=2>C(#N)C>[O:10]=[C:11]1[NH:19][CH:18]=[N:17][C:16]2[N:15]([CH2:20][CH2:21][C:22]([NH:1][CH2:2][CH2:3][N:4]3[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]3)=[O:23])[CH:14]=[N:13][C:12]1=2
Reactant: CCOC(=O)CCn1cnc2c(=O)[nH]cnc21
Reactant: NCCN1CCCCC1
Solvent: CC#N
Product: O=C(CCn1cnc2c(=O)[nH]cnc21)NCCN1CCCCC1
Temperature: 25 °C
Yield: 86 %

Procedure:
0.500 g (3.90 mmol) of 1-(2-aminoethyl)piperidine was added to a 10 ml round bottom flask equipped with a magnetic stirring bar. The amine was heated to 100°-110° C. and 0.250 g (1.06 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propionic acid, ethyl ester (AIT-0027) was added to the stirring solution. The solution was heated for one hour at which time it had solidified. The solution was allowed to cool to room temperature and 10 ml of acetonitrile was added to the solid. This mixture was stirred and the solid was collected by Buchner vacuum filtration. The white crystalline solid was washed with acetonitrile and then with ether to yield 290 mg of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-N-[[2-(1-piperidinyl)]ethyl]propanaide (AIT-0070). Yield: 86%.
Reaction SMILES: ClC1C=C(C=C(C)[C:8]=1[O:9]C1C=C2C(=CC=1)NC=C2C(C)C)N.[Cl:23][C:24]1[CH:25]=[C:26]([NH:44][C:45](=[O:51])[CH2:46][C:47]([O:49][CH3:50])=[O:48])[CH:27]=[C:28]([CH3:43])[C:29]=1[O:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[NH:36][CH:35]=[C:34]2[CH:40]([CH3:42])[CH3:41]>>[Cl:23][C:24]1[CH:25]=[C:26]([NH:44][C:45](=[O:51])[CH2:46][C:47]([O:49][CH2:50][CH2:8][OH:9])=[O:48])[CH:27]=[C:28]([CH3:43])[C:29]=1[O:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[NH:36][CH:35]=[C:34]2[CH:40]([CH3:41])[CH3:42]
Reactant: Cc1cc(N)cc(Cl)c1Oc1ccc2[nH]cc(C(C)C)c2c1
Reactant: COC(=O)CC(=O)Nc1cc(C)c(Oc2ccc3[nH]cc(C(C)C)c3c2)c(Cl)c1
Product: Cc1cc(NC(=O)CC(=O)OCCO)cc(Cl)c1Oc1ccc2[nH]cc(C(C)C)c2c1

Procedure:
This compound can be prepared starting from 3-chloro-4-[(3-isopropyl-1H-indol-5-yl)oxy]-5-methylaniline (Example III) or methyl 3-({3-chloro-4-[(3-isopropyl-1H-indol-5-yl)oxy]-5-methylphenyl}amino)-3-oxo-propanoate (Example 4a) according to methods known from the literature.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([OH:14])=O)[C:6]3[CH2:15][CH2:16][N:17]([CH3:19])[CH2:18][C:5]=3[C:4]=2[CH:3]=1.CCN=C=NCCCN(C)C.Cl.[C:32]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33]>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([N:42]3[CH2:41][CH2:40][N:39]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:44][CH2:43]3)=[O:14])[C:6]3[CH2:15][CH2:16][N:17]([CH3:19])[CH2:18][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2c(c3cc(Cl)ccc3n2CC(=O)O)C1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CN1CCc2c(c3cc(Cl)ccc3n2CC(=O)N2CCN(C(=O)OC(C)(C)C)CC2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 28 %

Procedure:
2-(8-chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetic acid (0.2 g, 0.719 mmol) in 10 mL of DCM was taken, EDCI.HCl (137 mg, 0.719 mmol) was added and stirred for 10 min at RT, N-Boc piperazine (133 mg, 0.719 mmol) was added to the reaction mixture and stirred for 24 h at RT. Reaction was monitored by TLC & LCMS. After completion of the reaction, reaction mixture was concentrated and purified by column chromatography (neutral alumina; 2% Methanol-DCM) then purified by reverse phase chromatography to afford 90 mg of tert-butyl 4-(2-(8-chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetyl)piperazine-1-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:13][C:12](=[O:14])[CH:11]=[CH:10][NH:9]2)=[CH:4][CH:3]=1.C([Li])CCC.[Br:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH:30]([F:32])[F:31])=[CH:23][C:22]=1[CH2:33][C:34](Cl)=[O:35].[Cl-].[NH4+]>C1COCC1>[Br:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH:30]([F:32])[F:31])=[CH:23][C:22]=1[CH2:33][C:34]([N:9]1[CH:10]=[CH:11][C:12](=[O:14])[CH2:13][C@H:8]1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:35]
Reactant: COc1cc(Br)c(CC(=O)Cl)cc1OC(F)F
Reactant: O=C1C=CN[C@H](c2ccc(F)cc2)C1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc(Br)c(CC(=O)N2C=CC(=O)C[C@H]2c2ccc(F)cc2)cc1OC(F)F
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 17.3 %

Procedure:
To 108 mg of (S)-2-(4-fluoro-phenyl)-2,3-dihydro-1H-pyridin-4-one in 8 ml THF (anhydrous, inhibitor free) at −78° C. under argon was added 0.18 ml of 2.5 M n-butyl lithium in hexanes. The mixture was stirred at −78° C. for 10 minutes and then 118 mg of (2-bromo-5-difluoromethoxy-4-methoxy-phenyl)-acetic acid chloride dissolved in 2 ml THF was added. The solution was stirred at −78° C. for 30 minutes, then allowed to warm to room temperature for 30 minutes with stirring. To this mixture was then added 10 ml saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate, the organic layer was dried over sodium sulfate, filtered and the solvent was removed in vacuo. Chromatography (20% Ethyl acetate in hexanes) gave 30 mg (S)-1-[2-(2-bromo-5-difluoromethoxy-4-methoxy-phenyl)-acetyl]-2-(4-fluoro-phenyl)-2,3-dihydro-1H-pyridin-4-one. MS (M+1) 485.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[O:8][C:6]=2[N:7]=1.[CH3:26][C:27]1[CH:28]=[C:29]([N:33]=[C:34]=[O:35])[CH:30]=[CH:31][CH:32]=1>ClCCl>[NH2:1][C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][N:23]([C:34](=[O:35])[NH:33][C:29]3[CH:28]=[C:27]([CH3:26])[CH:32]=[CH:31][CH:30]=3)[CH2:22][CH2:21]2)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[O:8][C:6]=2[N:7]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: Nc1nc(N2CCNCC2)c2nc(CCc3ccc(F)cc3)oc2n1
Solvent: ClCCl
Product: Cc1cccc(NC(=O)N2CCN(c3nc(N)nc4oc(CCc5ccc(F)cc5)nc34)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.1 %

Procedure:
To a solution of 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-piperazin-1-yl-oxazolo[5,4-d]pyrimidine (50 mg, 0.15 mmol) in dichloromethane (4 ml) was added 3-methylphenylisocyanate (0.16 mmol). The reaction was stirred at room temperature for 2 hours after which the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH2Cl2 to 2% CH3OH in CH2Cl2), yielding the pure title compound (30 mg) which was characterized by its mass spectrum: MS m/z (%): 476 ([M+H]+, 100).
Reaction SMILES: [OH-].[Na+:2].[C:3]([OH:14])(=[O:13])[C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1>O>[C:3]([O-:14])(=[O:13])[C:4]1[CH:12]=[CH:11][C:7]([C:8]([O-:10])=[O:9])=[CH:6][CH:5]=1.[Na+:2].[Na+:2]
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])c1ccc(C(=O)[O-])cc1

Procedure:
A solution was prepared containing 383 grams of 50% sodium hydroxide in seven liters of water. To this solution was added 400 grams of terephthalic acid thereby producing a solution of sodium terephthalate. A solution of stannic chloride was prepared by adding 342 grams of stannic chloride to 0.4 liter water. The stannic chloride solution was then added to the sodium terephthalate solution at about 50° C. with continuous agitation, causing the development of a white precipitate. The precipitate was filtered, washed with water and dried. The stannic terephthalate produced by the above method was analyzed at 26.8% Sn; 42.5% C; 1.65% H. This analysis is within the experimental error of stannic terephthalate, i.e., Sn(C8H4O4)2 formula which theoretically provides 26.7% Sn, 42.8% C and 1.8% H. Thermogravimetric analysis for the stannic terephthalate indicated decomposition at 360° C. to a residue of SnO2. The infrared spectrum of this salt, obtained in a KBr showed strong carbon-oxygen stretching absorption at 1685 and 1290/cm, typical of metal carboxylates having the M+(C=O)O--structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]=O)=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[Br-].[C:18]1([PH+](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:19]=1>C1OCCOC1>[C:3]1([O:2][CH3:1])[CH:4]=[CH:5][C:6]([CH:9]=[CH:18][CH3:19])=[CH:7][CH:8]=1
Reactant: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Reactant: COc1ccc(C=O)cc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC=Cc1ccc(OC)cc1

Procedure:
Anethole is synthesized starting from anisaldehyde in the presence of potassium carbonate and ethyle triphenyl phosphonium bromide in dioxane-1,4.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1[C:6]2[CH:20]=[C:19]([CH3:21])[S:18][C:7]=2[N:8](C(OC(C)(C)C)=O)[C:9]=1[CH3:10]>C(Cl)Cl>[CH3:21][C:19]1[S:18][C:7]2[NH:8][C:9]([CH3:10])=[C:5]([CH2:4][C:3]([O:2][CH3:1])=[O:22])[C:6]=2[CH:20]=1
Reactant: COC(=O)Cc1c(C)n(C(=O)OC(C)(C)C)c2sc(C)cc12
Solvent: ClCCl
Product: COC(=O)Cc1c(C)[nH]c2sc(C)cc12
Temperature: 65 °C
Yield: 64.2 %

Procedure:
To a solution of tert-butyl 4-(2-methoxy-2-oxoethyl)-2,5-dimethyl-6H-thieno[2,3-b]pyrrole-6-carboxylate (0.790 g, 2.443 mmol) in DCM (13.13 mL) was added 13 mL of silica gel. The mixture was concentrated under reduced pressure and the residue was heated to 65° C. under vacuum for 24 h. The reaction mixture was purified by flash chromatography on silica gel (EtOAc/heptane 15/85), to give the title compound (0.35 g, 64%): LC/MS (Table 1, Method a) Rt=2.06 min; MS m/z 222.1 (M−H)−.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12](=[O:14])[CH3:13])[N:10]=2)[N:7]=1.[NH2:15][C:16]1[CH:17]=[C:18]([OH:23])[CH:19]=[CH:20][C:21]=1[F:22].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[NH2:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][C:21]=1[F:22])[O:23][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12](=[O:14])[CH3:13])[N:10]=2)[N:7]=1
Reactant: Nc1cc(O)ccc1F
Reactant: CC(=O)Nc1cn2nc(I)ccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1cn2nc(Oc3ccc(F)c(N)c3)ccc2n1
Temperature: 140 °C
Reaction time: 12 h
Yield: 79.4 %

Procedure:
To a solution of N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)acetamide (12 g, 39.7 mmol) in N,N-dimethylformamide (120 mL) were added 3-amino-4-fluorophenol (7.6 g, 59.6 mmol) and potassium carbonate (11.0 g, 79.5 mmol), and the mixture was stirred at 140° C. for 12 hr. After cooling the mixture to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate/tetrahydrofuran, washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=3/1→ethyl acetate alone) to give the title compound (9.5 g, 79%) as a brown powder.
Reaction SMILES: [CH3:1][C:2]([C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1)([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N+:22]=2[O-])=[CH:12][CH:11]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Fe].C(O)(=O)C>[CH3:1][C:2]([C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1)([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:14][CH:15]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)CC(C)(Cc1ccc(OCCCNc2cccc[n+]2[O-])cc1)c1cccnc1
Agent: [Fe]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Product: CCOC(=O)CC(C)(Cc1ccc(OCCCNc2ccccn2)cc1)c1cccnc1

Procedure:
A mixture of the product of STEP 8 (150 mg, 0.33 mmol), iron powder (28 mg, 0.5 mmol), triphenylphosphine (87 mg, 0.33 mmol), and acetic acid (4.0 ml) was heated at reflux for 15 min. The cooled reaction was filtered through a short column of Celite®, and washed with ethyl acetate. The filtrate was concentrated. The residue was purified by chromatography (on silica gel, CH2Cl2/CH3OH/NH4OH-97.5/2/0.5) to afford a colorless oil in148 mg. The NMR spectra were consistent for the proposed structure.
Reaction SMILES: Br[C:2]1[C:6]2[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][N:3]=1.[NH2:12][CH2:13][CH2:14][CH2:15][NH2:16]>CO.C(OCC)(=O)C>[CH3:11][C:7]1[C:6]2[C:2]([NH:12][CH2:13][CH2:14][CH2:15][NH2:16])=[N:3][S:4][C:5]=2[CH:10]=[CH:9][CH:8]=1
Reactant: Cc1cccc2snc(Br)c12
Reactant: NCCCN
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cccc2snc(NCCCN)c12
Temperature: 25 °C

Procedure:
3-Bromo-4-methylbenzo[d]isothiazole (2.70 g, 11.84 mmol), and 1,3-diaminopropane (10.0 g, 135 mmol) in methanol (15 ml) was heated at 64° C. for 1.5 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude reaction mixture was diluted with ethyl acetate and washed successively with saturated aqueous sodium bicarbonate solution and brine. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Lyophilization of the crude sample in acetonitrile/water yielded N1-(4-methylbenzo[d]isothiazol-3-yl)propane-1,3-diamine sample. 1H NMR (300 MHz, DMSO-d6): 7.70 (d, 1H), 7.30 (t, 1H), 7.15 (dd, 1H), 6.58 (t, 1H), 3.47 (t, 2H), 2.96 (t, 2H), 2.73 (s, 3H), 1.92 (t, 2H), 1.56 ppm (m, 2H). MW=221 confirmed by LC-MS, tr=2.30 min (Method E) MH+=222.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[C:11]([C:25](=[O:27])[CH3:26])[C:12]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23]Br)=[CH:13][CH:14]=2)[CH:9]=1.[OH:29][C:30]1[C:35]([CH2:36][CH2:37][CH3:38])=[C:34]([OH:39])[CH:33]=[CH:32][C:31]=1[C:40](=[O:42])[CH3:41].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[C:11]([C:25](=[O:27])[CH3:26])[C:12]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:39][C:34]3[CH:33]=[CH:32][C:31]([C:40](=[O:42])[CH3:41])=[C:30]([OH:29])[C:35]=3[CH2:36][CH2:37][CH3:38])=[CH:13][CH:14]=2)[CH:9]=1
Reactant: COC(=O)CCCOc1ccc2ccc(OCCOCCBr)c(C(C)=O)c2c1
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(OCCOCCOc2ccc3ccc(OCCCC(=O)OC)cc3c2C(C)=O)ccc(C(C)=O)c1O
Yield: 86 %

Procedure:
A mixture of 1.6 g of 4-[[8-acetyl-7-[2-(2-bromoethoxy)ethoxy]-2-naphthalenyl]oxy]butanoic acid methyl ester, 0.82 g of 1-(2,4-dihydroxy-3-propylphenyl)-ethanone and 0.73 g of anhydrous potassium carbonate in 33 ml of anhydrous acetone and 11 ml of anhydrous dimethylformamide was stirred at reflux for 16 hours. The mixture was filtered and filtrate was concentrated to an oil. The oil was purified by high pressure liquid chromatography using 50% ethyl acetate-hexane to give 1.72 g (86%) of 4-[[8-acetyl-7-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]-2-naphthalenyl)oxy]butanoic acid methyl ester as an oil.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]([C:14]3[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=3[C:16]([OH:18])=O)=[O:13])[CH:10]=[CH:11][C:5]=2[O:4][CH2:3]1.CN1CCOCC1.C1C=NC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:64][C:65]1[CH:72]=[CH:71][C:68]([CH2:69][NH2:70])=[CH:67][CH:66]=1>CN(C)C=O>[Cl:64][C:65]1[CH:72]=[CH:71][C:68]([CH2:69][N:70]2[C:16](=[O:18])[C:15]3[C:14](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]2([C:9]2[CH:10]=[CH:11][C:5]3[O:4][CH2:3][C:2](=[O:1])[NH:7][C:6]=3[CH:8]=2)[OH:13])=[CH:67][CH:66]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: O=C1COc2ccc(C(=O)c3ccccc3C(=O)O)cc2N1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C1COc2ccc(C3(O)c4ccccc4C(=O)N3Cc3ccc(Cl)cc3)cc2N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10.2 %

Procedure:
To a solution of 2-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-yl)carbonylbenzoic acid (50 mg, 0.17 mmol) in N,N-dimethylformamide (1.00 mL) was added N-methylmorpholine (74 uL, 0.67 mmol) followed by addition of HOAt (55 mg, 0.40 mmol) and HATU (130 mg, 0.34 mmol). The mixture was stirred for 30 minutes at room temperature followed by the addition of 4-chloro-benzylamine (49 uL, 0.40 mmol). The reaction mixture was then heated to 60° C. for 2 h. The mixture was cooled to room temperature and the solvent was evaporated. The residue was dissolved in ethyl acetate and the organic layer was washed with brine, 1.0 M aq. hydrochloric acid, brine, saturated aq. sodium-hydrogencarbonate and brine. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated in vacuo. The residue was recrystallized from methanol to afford the title compound (7.3 mg, 15%). MS (EI) for C22H15ClN2O4: 443 (MNa+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([N+:24]([O-])=O)=[C:13]([CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:14]=2)=[CH:4][CH:3]=1.[Cl-].[NH4+].C(O)C>[Fe].O>[NH2:24][C:12]1[CH:11]=[CH:10][C:9]([O:8][C:5]2[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:14][C:13]=1[CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22]
Reactant: CC(C)(C)OC(=O)NCc1cc(Oc2ccc(Cl)nc2)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NCc1cc(Oc2ccc(Cl)nc2)ccc1N
Yield: 100.7 %

Procedure:
The reaction and post-treatment were carried out according to Example (1b) using tert-butyl{5-[(6-chloropyridin-3-yl)oxy]-2-nitrophenyl}methylcarbamate produced in Example (18a) (8.0 g, 21 mmol), iron powder (5.6 g, 105 mmol), ammonium chloride (0.56 g, 11 mmol), ethanol (40 mL) and water (20 mL) to obtain the title compound (7.4 g, 99%) as a brown oil.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([NH:13][NH2:14])(=[O:12])[CH3:11]>C(O)C>[C:10]([NH:13][NH:14][C:8]([NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[S:9])(=[O:12])[CH3:11]
Reactant: CC(=O)NN
Reactant: S=C=Nc1ccccc1
Solvent: CCO
Product: CC(=O)NNC(=S)Nc1ccccc1

Procedure:
By reacting 27 g of phenyl isothiocyanate and 15 g of acetylhydrazine in ethanol at room temperature, 1-acetyl-4-phenylthiosemicarbazide was formed, which was collected by filtration and refluxed in ethanol in the presence of sodium ethylate to provide 3-mercapto-5-methyl-4-phenyl-1,2,4-triazole.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[C:3]=1[CH2:4][NH:5][C:6]([NH2:8])=[O:7].[C:17](OC(C)(C)C)(=[O:22])[CH2:18][C:19]([CH3:21])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CC(O)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:15])[F:16])[C:3]=1[CH2:4][N:5]1[C:19]([CH3:21])=[CH:18][C:17](=[O:22])[NH:8][C:6]1=[O:7]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: NC(=O)NCc1c(F)cccc1C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(=O)[nH]c(=O)n1Cc1c(F)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
(2-Fluoro-6-trifluoromethyl-benzyl)-urea (2.568 g, 10.9 mmol) in toluene (125 mL) was heated briefly to reflux under a Dean-Stark trap. T-butyl acetoacetate (5.0 g) was added and the mixture heated to reflux for 4 hrs. p-Toluenesulfonic acid monohydrate (2.82 g, 14.8 mmol) was added and the reflux was continued for one additional hour. Toluene was displaced with i-PrOH and the volume of the solution was reduced to approximately 30 mL. The solution was stirred overnight at room temp. The crystalline product was filtered and washed with a few mL of i-PrOH to provide 2.01 g (63% yield) of 1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione. LCMS (ESI) m/z 303.0 (MH+)