Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]([O:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:9]=[CH:8][N:7]=1)=O)C.[O-]CC.[Na+]>C1(C)C=CC=CC=1>[OH:3][C:4]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:11]2[O:12][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)COc1cccnc1C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1oc2cccnc2c1O
Yield: 62.6 %

Procedure:
Ethyl 2-(2-ethoxycarbonyl-3-pyridyloxy)acetate (13.6 g, 54.0 mmol) and sodium ethoxide (8.08 g, 118.8 mmol) in toluene (200 mL) were heated under reflux for 18 h. After cooling, a precipitate was collected by filtration, dissolved in the minimum amount of hot water (about 300 mL), and acidified with acetic acid (6 mL). The resulting precipitate was filtered, and dried in vacuo to give ethyl 3-hydroxyfuro[3,2-b]pyridine-2-carboxylate as a solid (7.0 g).
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12](Br)=[N:11][C:10]=1[C:15]([NH:17][C:18]1[CH:19]=[N:20][N:21]([CH3:41])[C:22]=1[N:23]1[CH2:29][C:28]([O:31][CH3:32])([CH3:30])[CH2:27][CH:26]([NH:33]C(=O)OC(C)(C)C)[CH2:25][CH2:24]1)=[O:16])=O)(C)(C)C.[F:42][C:43]1[CH:44]=[N:45][CH:46]=[C:47]([F:62])[C:48]=1[Sn](CCCC)(CCCC)CCCC>>[NH2:8][C:9]1[S:13][C:12]([C:48]2[C:47]([F:62])=[CH:46][N:45]=[CH:44][C:43]=2[F:42])=[N:11][C:10]=1[C:15]([NH:17][C:18]1[CH:19]=[N:20][N:21]([CH3:41])[C:22]=1[N:23]1[CH2:24][CH2:25][CH:26]([NH2:33])[CH2:27][C:28]([O:31][CH3:32])([CH3:30])[CH2:29]1)=[O:16]
Reactant: CCCC[Sn](CCCC)(CCCC)c1c(F)cncc1F
Reactant: COC1(C)CC(NC(=O)OC(C)(C)C)CCN(c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)C1
Product: COC1(C)CC(N)CCN(c2c(NC(=O)c3nc(-c4c(F)cncc4F)sc3N)cnn2C)C1

Procedure:
Following the procedure for Example 422 starting from tert-butyl 1-(4-(5-(tert-butoxy-carbonyl-amino)-2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-6-methoxy-6-methylazepan-4-ylcarbamate and 3,5-difluoro-4-(tributylstannyl)pyridine gave 440 as the monoformate salt as a white solid (67 mg, 43% over two steps). 1H NMR (400 MHz, d6-DMSO) δ 8.84 (s, 1H), 8.70 (s, 2H), 8.45 (s, 1H), 7.82 (s, 2H), 7.70 (s, 1H), 3.68 (s, 3H), 3.52 (t, J=11.2 Hz, 2H), 3.36-3.19 (m, 3H), 3.13-3.04 (m, 1H), 3.04 (s, 3H), 2.98 (d, J=14.4 Hz, 1H), 2.18 (d, J=14.2 Hz, 1H), 2.12-1.98 (m, 1H), 1.85-1.75 (m, 1H), 1.68-1.57 (m, 1H), 1.03 (s, 3H). LCMS (ES+) m/z 493 (M+1)
Reaction SMILES: [Si]([O:8][CH:9]1[C:16](=[O:17])[N:15]2[CH:11]([CH2:12][CH2:13][C:14]2=[O:18])[CH2:10]1)(C(C)(C)C)(C)C.O>C(O)(=O)C>[OH:8][CH:9]1[C:16](=[O:17])[N:15]2[CH:11]([CH2:12][CH2:13][C:14]2=[O:18])[CH2:10]1
Reactant: CC(C)(C)[Si](C)(C)OC1CC2CCC(=O)N2C1=O
Solvent: CC(=O)O
Solvent: O
Product: O=C1CCC2CC(O)C(=O)N12

Procedure:
A solution of dihydro-2-t-butyldimethylsilyloxy-1H-pyrrolizine-3,5(2H,6H)-dione (2.1 g) in acetic acid:water, 3:1 (18 ml) is stirred at 60° C. for six hours. The solution is cooled, concentrated, toluene added and the solution reconcentrated. The oil is triturated with anhydrous ethyl ether and filtered to yield 2-hydroxy-dihydro-1H-pyrrolizine-3,5(2H,6H)-dione as a white solid. NMR (CDCl3) and 5.48 (m, 1H), 4.47 (m, 1H), 4.10 (b.s., 1H), 2.93-1.36 (m, 6H). IR 3310, 2860, 1770, 1710, 1655, 1410, 1372, 1307, 1275.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][CH:24]=1)[O:6][CH2:7][CH2:8][NH:9][C:10]([C:12]1[CH:21]=[CH:20][C:15]([C:16](OC)=[O:17])=[CH:14][CH:13]=1)=[O:11])#[N:2].[NH3:25]>>[C:1]([C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][CH:24]=1)[O:6][CH2:7][CH2:8][NH:9][C:10](=[O:11])[C:12]1[CH:21]=[CH:20][C:15]([C:16](=[O:17])[NH2:25])=[CH:14][CH:13]=1)#[N:2]
Reactant: COC(=O)c1ccc(C(=O)NCCOc2cccc(C#N)c2)cc1
Reactant: N
Product: N#Cc1cccc(OCCNC(=O)c2ccc(C(N)=O)cc2)c1

Procedure:
100 mg (0.31 mmol) of methyl 4-[N-[2-(3-cyanophenoxy)ethyl)carbamoyl]benzoate was stirred in 100 ml of 28% aqueous ammonia overnight. The reaction liquid was evaporated under reduced pressure, and 1 N hydrochloric acid was added to the residue. After the extraction with ethyl acetate, the organic layer was washed with saturated aqueous NaCl solution and then dried over anhydrous magnesium sulfate. The solvent was evaporated to obtain the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[C:10](OC)(=[O:15])[C:11]([O:13][CH3:14])=[O:12]>>[C:4]1([C:1](=[O:3])[CH2:2][C:10](=[O:15])[C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)C(=O)OC
Reactant: CC(=O)c1ccccc1
Product: COC(=O)C(=O)CC(=O)c1ccccc1

Procedure:
Methyl 4-phenyl-2,4-dioxobutanoate (10 g) obtained by acetophenone and dimethyl oxalate as starting materials and methylhydrazine were reacted in ethanol (60 ml) at a refluxing temperature for 1 h. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (mobile phase:dichloromethane) to give methyl 1-methyl-3-phenylpyrazole-5-carboxylate (3.0 g) and methyl 1-methyl-5-phenylpyrazole-3-carboxylate (3.6 g).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]2[NH:11][N:10]=[CH:9][C:5]=2[N:6]=[CH:7][N:8]=1.[C:12]([O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25]OS(C)(=O)=O)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:12]([O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][N:11]1[C:4]2[C:3]([S:2][CH3:1])=[N:8][CH:7]=[N:6][C:5]=2[CH:9]=[N:10]1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CS(=O)(=O)OCCOCCOC(=O)c1ccccc1
Reactant: CSc1ncnc2cn[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1ncnc2cnn(CCOCCOC(=O)c3ccccc3)c12
Temperature: 60 °C
Reaction time: 4 h
Yield: 33.1 %

Procedure:
A mixture of 7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidine (747 mg), 2-{2-[(methylsulfonyl)oxy]ethoxy}ethyl benzoate (1.43 g), potassium carbonate (931 mg) and N,N-dimethylformamide (12 mL) was stirred at 60° C. for 4 hrs. The reaction mixture was poured into water (30 mL), and the mixture was extracted with ethyl acetate (50 mL×2). The organic layers were combined, washed with saturated brine and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20→20:80), and further purified by basic silica gel column chromatography (eluent, hexane:ethyl acetate=90:10→40:60) to give the title compound (533 mg).
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])=[N:9][C@@H:10]([CH3:15])[C:11](=[O:14])[N:12]([CH3:13])[C:6]=2[CH:5]=[CH:4][C:3]=1[NH:23][C:24]([NH:26][CH2:27][CH:28]1[CH2:32][O:31]C(C)(C)[O:29]1)=[O:25].Cl>C(O)C>[Br:1][C:2]1[C:7]2[C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])=[N:9][C@@H:10]([CH3:15])[C:11](=[O:14])[N:12]([CH3:13])[C:6]=2[CH:5]=[CH:4][C:3]=1[NH:23][C:24]([NH:26][CH2:27][CH:28]([OH:29])[CH2:32][OH:31])=[O:25]
Reactant: C[C@@H]1N=C(c2ccccc2Cl)c2c(ccc(NC(=O)NCC3COC(C)(C)O3)c2Br)N(C)C1=O
Agent: Cl
Solvent: CCO
Product: C[C@@H]1N=C(c2ccccc2Cl)c2c(ccc(NC(=O)NCC(O)CO)c2Br)N(C)C1=O

Procedure:
A solution of 1-[(S)-6-bromo-5-(o-chlorophenyl)-2,3-dihydro-1,3-dimethyl-2-oxo-1H-1,4-benzodiazepin-7-yl]-3-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]urea in ethanol is stirred at room temperature for 5 hours with 1N hydrochloric acid. The mixture is extracted with ethyl acetate, washed with water, dried over sodium sulphate and evaporated. The residue is chromatographed on silica gel while eluting with ethyl acetate/methanol (95:5). After recrystallization from methanol/ether, there is obtained 1-[(S)-6-bromo-5-(o-chlorophenyl)-2,3-dihydro-1,3-dimethyl-2-oxo-1H-1,4-benzodiazepin-7-yl]-3-(2,3-dihydroxypropyl)urea of melting point 175° (decomposition).
Reaction SMILES: CN1CCOCC1.ClC(OCC(C)C)=O.N[C:17]1[C:25]2[C:20](=[N:21][CH:22]=[N:23][C:24]=2NC2C=CC=C(Cl)C=2)[NH:19][N:18]=1.C(O)C>C1COCC1.CS(C)=O>[NH:19]1[C:20]2=[N:21][CH:22]=[N:23][CH:24]=[C:25]2[CH:17]=[N:18]1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: CCO
Product: c1ncc2cn[nH]c2n1

Procedure:
Analogously to Example 5, 436 mg (2.3 mmol) of N-ethoxycarbonyl-(D/L)-valine [prepared from (D/L)-valine as described in J. Org. Chem. 60, 7256 (1995)] in 4.8 ml of THF and 506 μl (4.6 mmol) of NMM are activated with 349 μl (2.6 mmol) of isobutyl chloroformate and then reacted with 600 mg (2.3 mmol) of 3-amino-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine (see Step 1.6). Dissolution in DMSO (2 ml) at 100° C., addition of 25 ml of ethanol and cooling yield rac.-4-(3-chloro-phenylamino)-3{N-ethoxycarbonyl-valyl)-amino}-1H-pyrazolo[3,4-d]pyrimidine; HPLC: tRet(grad20-100/20)=13.2; FAB-MS: (M+H)+=432.
Reaction SMILES: [Si:1]([O:18][C:19]1[CH:20]=[C:21]([C:25]([C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[NH:29][N:28]=2)=[O:26])[CH:22]=[CH:23][CH:24]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:39][CH:40]([CH3:42])[CH3:41].CCCCCC.C(OCC)(=O)C>CN(C=O)C>[C:14]([Si:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[O:18][C:19]1[CH:20]=[C:21]([C:25]([C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]([CH2:39][CH:40]([CH3:42])[CH3:41])[N:28]=2)=[O:26])[CH:22]=[CH:23][CH:24]=1)([CH3:16])([CH3:17])[CH3:15]
Reactant: CC(C)(C)[Si](Oc1cccc(C(=O)c2n[nH]c3ccccc23)c1)(c1ccccc1)c1ccccc1
Reactant: CC(C)CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC(C)Cn1nc(C(=O)c2cccc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2)c2ccccc21
Yield: 85.7 %

Procedure:
(3-{[tert-butyl(diphenyl)silyl]oxy}phenyl)(1H-indazol-3-yl)methanone (0.67 g, 0.0014 mol) was dissolved in DMF (10 mL). Sodium hydride (66%, 0.042 g, 0.0017 mol) was added, and the reaction was stirred until gas evolution stops. 1-iodo-2-methylpropane (0.242 mL, 0.0021 mol) was added. The reaction was stirred at room temperature overnight. The reaction is quenched with water and extracted with ethyl acetate. The desired product (0.650 g, 0.0012 mol, 87%) is isolated by chromatography with hexane/ethyl acetate (10:1).
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[C:6]([C:10]1[N:15]=[C:14](O)[C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][N:11]=1)([CH3:9])([CH3:8])[CH3:7]>C(N(CC)CC)C>[C:6]([C:10]1[N:15]=[C:14]([Cl:3])[C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][N:11]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: CCOC(=O)c1cnc(C(C)(C)C)nc1O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc(C(C)(C)C)nc1Cl
Temperature: 40 °C
Yield: 85 %

Procedure:
In cold (˜0° C.) POCl3 (20 mL) was dropped triethylamine (0.55 mL) with stirring. To this was added in parts of ethyl 2-tert-butyl-4-hydroxypyrimidine-5-carboxylate (2.18 g, 9.72 mmol). The mixture then warmed to 40° C. and stirred under Argon for 1 hour. The mixture was evaporated until free of POCl3, diluted with CHCl3 (100 mL) and poured carefully into ice (300 mL). The solution was stirred at RT to melt. The organic phase was separated, washed with sodium bicarbonate (100 mL), water (100 mL) and dried (Na2SO4). The solvents evaporated to give ethyl 2-tert-butyl-4-chloropyrimidine-5-carboxylate (2.0 g, 85% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.12 (s, 1H), 4.34 (q, J=6.8 Hz, 2H), 1.33 (s, 9H), 1.27 (t, J=6.8 Hz, 3H); MS (ESI) m/z: 243.0 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[C:14]([NH:16][CH2:17][CH2:18][CH3:19])[C:13]([C:20]([NH:22][CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:21])=[CH:12][N:11]=2)=[CH:5][CH:4]=1)#[N:2].[OH2:34]>C(O)C.CS(C)=O.[OH-].[Na+].OO>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[C:14]([NH:16][CH2:17][CH2:18][CH3:19])[C:13]([C:20]([NH:22][CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:21])=[CH:12][N:11]=2)=[CH:5][CH:4]=1)(=[O:34])[NH2:2]
Reactant: O
Reactant: CCCNc1nc(Nc2ccc(C#N)cc2)ncc1C(=O)NCCCNC(=O)OC(C)(C)C
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: CCCNc1nc(Nc2ccc(C(N)=O)cc2)ncc1C(=O)NCCCNC(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl (3-(2-((4-cyanophenyl)amino)-4-(propylamino)pyrimidine-5-carboxamido)propyl)carbamate (D1, 220 mg) in ethanol (4 mL) and dimethyl sulfoxide (4 mL), 1.0 mol/L aqueous sodium hydroxide (2.4 mL) and 35% aqueous hydrogen peroxide (750 μL) were added at room temperature, and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture, water was added. The solid matter was taken by filtration, washed with water, and then dried under reduced pressure to obtain tert-butyl (3-(2-((4-carbamoylphenyl)amino)-4-(propylamino)pyrimidine-5-carboxamido)propyl)carbamate (D2, 195 mg) as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11](=[O:28])[NH:12][CH:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:14]([F:17])([F:16])[F:15])[NH:8]2)=[CH:4][C:3]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30].[C:34](=O)([O-])[O-].[K+].[K+].IC>C(#N)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11](=[O:28])[NH:12][CH:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:27])[F:26])[CH:19]=3)[C:14]([F:15])([F:17])[F:16])[N:8]2[CH3:34])=[CH:4][C:3]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cc2cc(C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)[nH]c2cc1Cl
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: CCOC(=O)c1cc2cc(C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)n(C)c2cc1Cl
Temperature: 25 °C

Procedure:
Ethyl 6-chloro-2-({2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}carbamoyl)-1H-indole-5-carboxylate (1.30 g, 2.63 mmol) (Synthesis Example 8, Stage 3) and potassium carbonate were initially charged in acetonitrile (39 ml) and admixed with iodomethane (561 mg, 3.95 mmol). The reaction mixture was heated under reflux overnight. After cooling to room temperature, the mixture was concentrated to dryness under reduced pressure, and the residue taken up in ethyl acetate and washed with water. The organic phase was dried over sodium sulphate, filtered and concentrated to dryness under reduced pressure.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH2:7])=[N:3]1.[H-].[Na+].Br[C:11]1[C:12]2[N:13]([C:18]([C:21]([NH:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][C:25]=3[F:30])=[O:22])=[CH:19][N:20]=2)[N:14]=[C:15]([Cl:17])[CH:16]=1.CO>CN(C=O)C>[Cl:17][C:15]1[CH:16]=[C:11]([NH:7][C:4]2[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=2)[C:12]2[N:13]([C:18]([C:21]([NH:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][C:25]=3[F:30])=[O:22])=[CH:19][N:20]=2)[N:14]=1
Reactant: Cn1ccc(N)n1
Reactant: O=C(Nc1ccncc1F)c1cnc2c(Br)cc(Cl)nn12
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: Cn1ccc(Nc2cc(Cl)nn3c(C(=O)Nc4ccncc4F)cnc23)n1
Reaction time: 0.17 h
Yield: 43.9 %

Procedure:
To a solution of 1-methyl-1H-pyrazol-3-amine (37.2 mg, 0.383 mmol) in DMF (0.8 mL) was added 60% NaH (14.10 mg, 0.353 mmol). The mixture was stirred for 10 min. Solid 8A (50 mg, 0.153 mmol) was added in one portion. The reaction mixture was stirred at room temperature for 3 h. Methanol (5 mL) was added and a solid precipitated that was collected by filtration and dried to give 18A (26 mg, 37%) as an off white solid. [M+H]=387. HPLC Peak Rt=2.753 minutes. (Chromolith column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 mL/min, monitoring at 254 nm.)
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([S:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:21]([S:20][C:16]1[N:15]=[C:14]([C:12]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:13]=2)[CH:19]=[CH:18][CH:17]=1)[CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: COC(=O)c1ccccc1S
Reactant: CCCCCSc1cccc(C#N)n1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCSc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 44.2 %

Procedure:
A mixture of methyl thiosalicylate (1.21 g, 7.2 mmol), 2-cyano-6-pentylthiopyridine (1.48 g, 7.2 mmol), triethylamine (1.5 ml, 10.8 mmol) and toluene (30 ml) was refluxed for 48 hrs. The reaction mixture was concentrated under reduced pressure to give the precipitated crystals, which were recrystallized from ethyl acetate-hexane to give the titled compound (1.09 g, 44%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[N+:10]([O-])([OH:12])=[O:11]>O.CCOCC>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[OH:9]
Reactant: Oc1ccc(F)cc1Cl
Reactant: O=[N+]([O-])O
Solvent: CCOCC
Solvent: O
Product: O=[N+]([O-])c1cc(F)cc(Cl)c1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 2-Chloro-4-fluorophenol (25 g, 0.171 mol) in H2O (100 mL) and Et2O (300 mL) at 0° C. was added dropwise concentrated nitric acid (25 mL). After the addition was complete the reaction was warmed to rt and stirred for 3 hr. The layers were separated and the organic phase washed with 1:1 brine:H2O, brine, dried over MgSO4, filtered and concentrated in vacuo to a slurry. The slurry was diluted with hexane and the yellow solid collected and dried to provide 23.6 g of compound 711. ##STR90##
Reaction SMILES: [C:1](Cl)(=[O:5])[O:2][CH2:3][CH3:4].[CH2:7]([O:10][C:11]([C:13]1[O:20][C:19]2[C:18]([NH2:21])=[N:17][NH:16][C:15]=2[CH:14]=1)=[O:12])[CH2:8][CH3:9].C(N(C(C)C)CC)(C)C>O1CCCC1>[CH2:7]([O:10][C:11]([C:13]1[O:20][C:19]2[C:18]([NH2:21])=[N:17][N:16]([C:1]([O:2][CH2:3][CH3:4])=[O:5])[C:15]=2[CH:14]=1)=[O:12])[CH2:8][CH3:9]
Reactant: CCCOC(=O)c1cc2[nH]nc(N)c2o1
Reactant: CCOC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCOC(=O)c1cc2c(o1)c(N)nn2C(=O)OCC
Reaction time: 0.08 h
Yield: 97 %

Procedure:
A solution of ethyl chlorocarbonate (4.90 mL, 51.7 mmol) in tetrahydrofuran (THF, 60 mL) was slowly added to a mixture of 3-Amino-1H-furo[3,2-c]pyrazole-5-carboxylic acid propyl ester (12.0 g, 50.2 mmol) and diisopropylethylamine (DIEA, 51.5 mL, 301 mmol) in THF (300 mL), maintaining the temperature between −5 and −10° C. The reaction was kept at the same temperature for 5 minutes then allowed to reach room temperature. The obtained mixture was evaporated to dryness under vacuum and the residue extracted with ethyl acetate (AcOEt) and water. The organic layer was separated, dried over sodium sulphate and evaporated to dryness. The resulting raw material was triturated with diethyl ether to give 13.7 g of the title compound as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:9])=[N:7][CH:8]=1.[CH3:10][S-:11].[Na+]>C(O)C>[Cl:9][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][S:11][CH3:10])=[CH:8][N:7]=1
Reactant: C[S-]
Reactant: ClCc1ccc(Cl)nc1
Agent: [Na+]
Solvent: CCO
Product: CSCc1ccc(Cl)nc1
Yield: 93.7 %

Procedure:
A solution of 5-chloromethyl-2-chloropyridine (8.1 g, 50 mmol) in ethanol (50 mL) was added to a suspension of sodium thiomethoxide solid (4.2 g, 60 mmol) in 100 mL ethanol under stirring. An exothermic reaction was observed during the addition and the mixture was then stirred at room temperature overnight. The solvent ethanol was removed under reduced pressure and the residue was re-dissolved in ether-EtOAc solvent and mixed with brine. The two phases were separated and the organic layer was dried over anhydrous Na2SO4, filtered, concentrated and purified by eluting through a silica gel plug with 40% EtOAc in hexane to give 8.14 g of 2-chloro-5-[(methylthio)methyl]pyridine (A) as a colorless oil in 94% yield. The product was analytically pure and directly used for the next step reaction. 1H NMR (300 MHz, CDCl3) δ 8.28 (dd, 1H), 7.65 (dd, 1H), 7.30 (d, 1H), 3.63 (s, 2H), 2.00 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH:7]([N:10]=[N+]=[N-])[CH:6]1[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=[O:4].[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:27]([C:30]2[CH:34]=[CH:33][S:32][CH:31]=2)=[CH:26][C:23]=1[CH:24]=O>>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH:7]([NH:10][CH2:24][C:23]2[CH:26]=[C:27]([C:30]3[CH:34]=[CH:33][S:32][CH:31]=3)[CH:28]=[CH:29][C:22]=2[O:21][CH3:20])[CH:6]1[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=[O:4]
Reactant: COC(=O)C1CCC(N=[N+]=[N-])C1c1ccc(F)cc1
Reactant: COc1ccc(-c2ccsc2)cc1C=O
Product: COC(=O)C1CCC(NCc2cc(-c3ccsc3)ccc2OC)C1c1ccc(F)cc1

Procedure:
The title compound was prepared by employing the method described in Example 91, Step D with (1RS,2RS,3RS)-2-(4-fluorophenyl)-3-azidocyclopentanecarboxylic acid methyl ester (from Example 89, Step A) and the known 2-methoxy-5-(thiophen-3-yl)benzaldehyde (P. J. Ward, D. R. Armour, D. E. Bays, B. Evans, G. M. P. Giblin, N. Hernon, T. Hubbard, K. Liang, D. Middlemiss, J. Mordaunt, A. Naylor, N. A. Pegg, M. V. Vinder, S. P. Watson, C. Bountra, and D. C. Evans, J. Med. Chem. 1995, 38, 4985-92).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13]([O:17][CH3:18])(=[O:16])[C:14]#[CH:15].CN1CCOCC1>C(#N)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][CH:15]=[CH:14][C:13]([O:17][CH3:18])=[O:16])=[O:9])=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: C#CC(=O)OC
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Solvent: CN1CCOCC1
Solvent: CC#N
Product: COC(=O)C=COC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 83.9 %

Procedure:
4-Nitrobenzoic acid (10 g, 59.8 mmol) and methyl propargylate (5.5 g, 65.8 mmol) were dissolved in acetonitrile (100 ml), N-methylmorpholine (3 g, 30 mmol) was added, and the mixture was stirred overnight at 40° C. The reaction mixture was concentrated under reduced pressure, and the residue was washed with ether to give the title compound (12.6 g, 50.2 mmol, 83.9%).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([N+:25]([O-])=O)[CH:22]=[CH:21][C:3]=1[O:4][CH2:5][CH2:6][N:7]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)[CH3:8].[O-]S(S([O-])=O)=O.[Na+].[Na+].O>C(O)C>[NH2:25][C:23]1[CH:22]=[CH:21][C:3]([O:4][CH2:5][CH2:6][N:7]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)[CH3:8])=[C:2]([Cl:1])[CH:24]=1
Reactant: COc1ccc(CCN(C)CCOc2ccc([N+](=O)[O-])cc2Cl)cc1OC
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(CCN(C)CCOc2ccc(N)cc2Cl)cc1OC
Yield: 32.8 %

Procedure:
A portion (15.63 g, 0.040 mol) of the 1-(2-chloro-4-nitrophenoxy)-2-[N-(3,4-dimethoxyphenethyl)-N-methylamino]ethane produced in (2) above was dissolved in hot ethanol (500 ml) and, thereafter, a solution consisting of a mixture of Na2S2O4 (27.56 g) and water (125 ml) was added to the resulting solution, thereby forming a precipitate. The mixture was heated at the reflux temperature for 20 min. Thereafter, the solvent was evaporated and the residue was diluted with water, followed by extraction with ethyl acetate. An aqueous solution of sodium carbonate was added to the aqueous layer such that it became basic up to a pH of about 9, followed by three extractions with ethyl acetate. The organic extracts were combined, dried with magnesium sulfate, and the solvent was evaporated; thereafter, the residue was purified by being subjected to column chromatography on silica gel using, as an eluent, ethyl acetate containing methanol (10%). The fractions containing the end compound were combined and the solvent was evaporated to yield the end compound 1-(4-amino-2-chlorophenoxy)-2-[N-(3,4-dimethoxyphenethyl)-N-methylamino]ethane (4.78 g) as a yellow oil.