Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC=CC=1.[NH2:8][C:9]1[N:10]=[C:11]([O:21][CH2:22][CH3:23])[C:12]([C:16]([O:18]CC)=O)=[N:13][C:14]=1[Cl:15].[CH2:24]([N:26]([CH2:30][CH3:31])[CH2:27][CH2:28][NH2:29])[CH3:25]>CCCCCC>[CH2:24]([N:26]([CH2:30][CH3:31])[CH2:27][CH2:28][NH:29][C:16]([C:12]1[C:11]([O:21][CH2:22][CH3:23])=[N:10][C:9]([NH2:8])=[C:14]([Cl:15])[N:13]=1)=[O:18])[CH3:25]
Reactant: CCN(CC)CCN
Reactant: CCOC(=O)c1nc(Cl)c(N)nc1OCC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCOc1nc(N)c(Cl)nc1C(=O)NCCN(CC)CC
Temperature: 25 °C

Procedure:
To 8 ml. of toluene were added 0.8 g. of ethyl 5-amino-6-chloro-3-ethoxypyrazine-2-carboxylate and 0.8 g. of N,N-diethylethylenediamine and the mixture was refluxed for 20 hours. After the reaction was over, the reaction mixture was cooled to room temperature and then extracted with 20 ml. of a 1 N aqueous hydrochloric acid solution. The extract was neutralized with dilute aqueous ammonia under ice-cooling and then extracted three times each time with 30 ml. of chloroform. The extracts were combined, washed with water dried, and then the solvent was distilled off under reduced pressure. By washing the residue obtained with 30 ml. of n-hexane, 0.53 g. of colorless crystals of N-(2-diethylaminoethyl)-5-amino-6-chloro-3-ethoxypyrazine-2-carboxamide was obtained. The colorless acicular crystals obtained by recrystallizing the product from a mixture of benzene and n-hexane melted at 147°-148° C.
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][CH2:7][CH2:8][C:9]1[C:10]([Cl:19])=[N:11][C:12]2[N:13]([N:16]=[CH:17][CH:18]=2)[C:14]=1[Cl:15].[N+:20]([O-])([OH:22])=[O:21]>>[Cl:6][CH2:7][CH2:8][C:9]1[C:10]([Cl:19])=[N:11][C:12]2[N:13]([N:16]=[CH:17][C:18]=2[N+:20]([O-:22])=[O:21])[C:14]=1[Cl:15]
Reactant: ClCCc1c(Cl)nc2ccnn2c1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cnn2c(Cl)c(CCCl)c(Cl)nc12
Temperature: 0 °C
Yield: 95.5 %

Procedure:
To 100 ml of concentrated sulfuric acid cooled to 0° C with ice water, were added 50 ml of 90% nitric acid gradually so as not to raise the temperature. After the resultant mixed acid was stirred for a while, 13.80 g of the compound prepared in Example 49 as remained crystals were added gradually so as not to raise the temperature also. The resultant mixture was stirred for 4 hours while maintaining the temperature at 0° C. Since spots attributable to the raw materials on TLC disappeared, the stirring was stopped, and the reaction mixture was poured into ice water. Crystals deposited were collected by filtration and air-dried to obtain 15.61 g (yield: 95.5%) of the intended product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:13]([NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:12][N:11]([C:19]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]([C:29]4([CH3:32])[CH2:31][CH2:30]4)=[O:28])[CH2:23][CH2:22]3)=[O:20])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:34]([O:36][C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=1)=[O:35]>>[F:43][C:40]1[CH:41]=[CH:42][C:37]([O:36][C:34](=[O:35])[N:14]([C@H:13]2[C@H:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH2:10][N:11]([C:19]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]([C:29]4([CH3:32])[CH2:30][CH2:31]4)=[O:28])[CH2:23][CH2:22]3)=[O:20])[CH2:12]2)[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:38][CH:39]=1
Reactant: O=C(Cl)Oc1ccc(F)cc1
Reactant: CC(C)CN[C@@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Product: CC(C)CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 1 (step h), the title compound rac-{(3S,4R)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-isobutyl-carbamic acid 4-fluoro-phenyl ester was prepared from rac-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-isobutylamino-pyrrolidin-1-yl]-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone instead of rac-{4-[(3S,4R)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using 4-fluorophenyl chloroformate and was obtained as a colorless foam. MS m/e: 618.5 [M]+.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=2)[NH:8][CH2:7][C:6]1=O)[CH2:2][CH2:3][CH3:4].CSC.B>O1CCCC1>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=2)[NH:8][CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)CNc2ccc(C(=O)OC)cc21
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: CCCCN1CCNc2ccc(C(=O)OC)cc21
Temperature: 25 °C
Yield: 45.8 %

Procedure:
To an ice-cold, stirred solution of methyl 4-butyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (840 mg) in tetrahydrofuran (32 mL) was added borane dimethylsulfide complex (3.2 mL, 2.0 M tetrahydrofuran) and the resulting mixture was refluxed for 24 h. The mixture was cooled to room temperature, quenched with methanol, and the solvent was removed under reduced pressure. Purification by flash column chromatography (silica, 1:1 ethyl acetate/hexanes) provided 364 mg of the title compound: 1H NMR (300 MHz, CDCl3) δ 7.27, 7.22, 6.41, 3.84, 3.47–3.45, 3.32–3.23, 1.60–1.58, 1.42–1.37, 0.99–0.94.
Reaction SMILES: [O:1]=[S:2]1(=[O:33])[C:8]2[CH:9]=[C:10]([O:14][CH2:15][C:16]([OH:18])=[O:17])[C:11](Br)=[CH:12][C:7]=2[N:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:5][C:4]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:3]1.[CH3:34][S-:35].[Na+].C(O)(=O)C>CN(C=O)C>[O:1]=[S:2]1(=[O:33])[C:8]2[CH:9]=[C:10]([O:14][CH2:15][C:16]([OH:18])=[O:17])[C:11]([S:35][CH3:34])=[CH:12][C:7]=2[N:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:5][C:4]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:3]1
Reactant: C[S-]
Reactant: CCCCC1(CCCC)CN(c2ccccc2)c2cc(Br)c(OCC(=O)O)cc2S(=O)(=O)C1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCCCC1(CCCC)CN(c2ccccc2)c2cc(SC)c(OCC(=O)O)cc2S(=O)(=O)C1
Temperature: 50 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
1,1-Dioxo-3,3-dibutyl-5-phenyl-7-bromo-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 11; 500 mg, 0.93 mmol) was dissolved in DMF (10 ml). Sodium methanethiolate (200 mg, 2.85 mmol) was added and the mixture was stirred for 2 hours at 50° C. Acetic acid (0.4 ml) was added and the solvent was evaporated under reduced pressure. The residue was extracted with EtOAc/water. The EtOAc layer was separated, dried and evaporated under reduced pressure to give the title compound 450 mg (96%). NMR (300 MHz) 0.7–0.8 (m, 6H), 1.0–1.6 (m, 12H), 2.2 (s, 2H), 3.2 (brs, 2H), 3.7 (brs, 2H), 4.8 (s, 2H), 6.6 (s, 1H), 6.9–7.1 (m, 3H), 7.2–7.4 (m, 3H).
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]([S:15]([C:18]2[CH:31]=[CH:30][C:21]3[O:22][C:23]([CH3:29])([CH3:28])[C@@:24]4([CH3:27])[O:26][C@H:25]4[C:20]=3[CH:19]=2)(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=1)(C(C)(C)C)(C)C.[NH3:32]>C(O)C>[NH2:32][C@H:25]1[C@@:24]([OH:26])([CH3:27])[C:23]([CH3:29])([CH3:28])[O:22][C:21]2[CH:30]=[CH:31][C:18]([S:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([OH:8])[CH:10]=3)(=[O:17])=[O:16])=[CH:19][C:20]1=2
Reactant: N
Reactant: CC1(C)Oc2ccc(S(=O)(=O)c3cccc(O[Si](C)(C)C(C)(C)C)c3)cc2[C@@H]2O[C@@]21C
Solvent: CCO
Product: CC1(C)Oc2ccc(S(=O)(=O)c3cccc(O)c3)cc2[C@@H](N)[C@]1(C)O
Temperature: 45 °C

Procedure:
(3S,4S)-6-(3-tert-Butyldimethylsilyloxyphenyl)sulphonyl-3,4-dihydro-3,4-epoxy-2,2,3-trimethyl-2H-benzo[b]pyran (2.2 g) (see Preparation 15) was dissolved in ethanol (25 ml) and 35% aqueous ammonia solution (25ml) was added. The mixture was heated at 40-50° C. for 24 hours. The solvent was removed under reduced pressure and the residue was chromatographed on silica using 7.5:92.5 methanol: dichloromethane as the eluent to yield (3S,4R)-4-amino-3,4-dihydro-3-hydroxy-6-(3-hydroxyphenyl)sulphonyl-2,2,3-trimethyl-2H-benzo[b]pyran (1.42 g) as a foam. Found: C,54.39; H,5.22; N,3.19. C18H21NO5S, 0.50 CH2Cl2 requires C,54.75; H,5.46; N,3.45%.
Reaction SMILES: C([O:3][C:4](=[O:32])[C:5]([O:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)([CH3:23])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][NH:19][C:18](=[O:21])[N:17]2[CH3:22])=[CH:9][CH:8]=1)C.[H-].[Na+].Br[CH2:36][C:37]1[CH:46]=[CH:45][C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=1>CN(C=O)C.CCOCC.Cl>[F:31][C:28]1[CH:29]=[CH:30][C:25]([O:24][C:5]([CH3:23])([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH:16]3[CH2:20][N:19]([CH2:36][C:37]4[CH:46]=[CH:45][C:44]5[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=5)[CH:38]=4)[C:18](=[O:21])[N:17]3[CH3:22])=[CH:11][CH:12]=2)[C:4]([OH:3])=[O:32])=[CH:26][CH:27]=1
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CNC(=O)N2C)cc1)Oc1ccc(F)cc1
Reactant: BrCc1ccc2ccccc2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CN1C(=O)N(Cc2ccc3ccccc3c2)CC1CCOc1ccc(CC(C)(Oc2ccc(F)cc2)C(=O)O)cc1
Reaction time: 0.33 h
Yield: 50.9 %

Procedure:
To a mixture of 80 mg of 2-(4-Fluoro-phenoxy)-2-methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-propionic acid ethyl ester in 5 mL of dry DMF at 0° C. under an atmosphere of nitrogen, 18 mg of NaH (0.45 mmol) is added. The resulting solution is allowed to stand at r.t. for 20 min. Then 99 mg of 2-bromomethyl naphthalene is added and resulting mixture is allowed to stand at r.t. for overnight. Reaction mixture is diluted with Et2O and 1N HCl. Organic layer is then washed with 1N HCl (2×10 mL), brine (2×10 mL), dried over Na2SO4, filtered and concentrated under vacuum. The crude material is in 5 mL of EtOH and 0.4 mL of 5N NaOH. The mixture is heated to reflux for 1 h. The organic solvent is then removed under vacuum and residue is dissolved in CH2Cl2 and 1N HCl. Aqueous layer is washed with CH2Cl2 (2×10 mL). Combined organic layer is dried over Na2SO4, filtered and concentrated under vacuum. The crude material is purified by MS/LC to give 51 mg (51%) of the title product. 1H NMR (400 MHz, CDCl3): δ 7.82-7.79 (m, 3H), 7.67 (s, 1H), 7.50-7.44 (m, 2H), 7.35 (d, 1H, J=8.4 Hz), 7.14 (d, 2H, J=8.6 Hz), 6.93 (t, 2H, J=8.4 Hz), 6.87-6.83 (m, 2H), 6.71 (d, 2H, J=8.6 Hz), 5.11 (bs, 1H), 4.53 (s, 2H), 3.95-3.90 (m, 2H), 3.85-3.70 (m, 1H), 3.46 (t, 1H, L=8.7 Hz), 3.23, 3.09 (ABq, 2H, J=14.0 Hz), 3.07 (t, 1H, J=8.7 Hz), 2.89 (s, 3H), 2.26-2.18 (m, 1H), 1.96-1.87 (m, 1H), 1.36 (s, 3H). HRMS (ES+) m/z exact mass calcd for C33H34N2O5F (m+1) 557.2452, found 557.2439.
Reaction SMILES: [CH2:1]([NH2:11])[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[N:34]=[CH:33][CH:32]=[C:31]2[CH2:38][CH2:39][CH:40]1[CH2:45][CH2:44][C:43](=O)[CH2:42][CH2:41]1>ClCCl>[O:7]1[C:8]2[CH:9]=[CH:10][C:2]([CH2:1][NH:11][CH:43]3[CH2:42][CH2:41][CH:40]([CH2:39][CH2:38][C:31]4[C:30]5[C:35](=[CH:36][CH:37]=[C:28]([O:27][CH3:26])[CH:29]=5)[N:34]=[CH:33][CH:32]=4)[CH2:45][CH2:44]3)=[CH:3][C:4]=2[O:5][CH2:6]1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: COc1ccc2nccc(CCC3CCC(=O)CC3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc2nccc(CCC3CCC(NCc4ccc5c(c4)OCO5)CC3)c2c1
Reaction time: 8 h

Procedure:
Piperonylamine (0.038 ml, 0.3 mmol) and sodium triacetoxyborohydride (0.05 g) were added to a solution of 4-[2-(6-methoxy-quinolin-4-yl)-ethyl]-cyclohexanone (0.05 g, 0.176 mmol) in dichloromethane (0.5 ml). The reaction mixture was stirred overnight and then filtered over Hydromatrix (wetted with an NaHCO3 solution, 2 ml) and subsequently washed with dichloromethane. The filtrate was concentrated to dryness by rotary evaporation. The residue was purified by column chromatography on silica gel (EtOAc and then EtOAc:MeOH 9/1).
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=[O:5])C.[C:24]1([N:30]=[C:31]=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:5])[N:30]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:31]2=[O:32])[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: O=C=Nc1ccccc1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Product: COc1cccc2c1ncc1c(=O)n(-c3ccccc3)c(=O)n(C3CCCC3)c12
Yield: 74.9 %

Procedure:
1-Cyclopentyl-7-methoxy-3-phenyl-1H-pyrimido[5,4-c]quinoline-2,4-dione (29 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.10 mmol) and phenyl isocyanate (0.4 mmol) following general procedure C. LCMS: m/z 388 [M+1]+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][CH:12]([C:19]([O:21]CC)=O)[CH2:13][C:14]([O:16]CC)=O.[CH2:24]([NH2:28])[CH2:25][CH2:26][CH3:27]>>[CH2:24]([NH:28][C:14]([CH2:13][CH:12]([C:19]([NH:3][CH2:4][CH2:5][CH2:6][CH3:7])=[O:21])[CH2:11][S:10][C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)=[O:16])[CH2:25][CH2:26][CH3:27]
Reactant: CCCCN
Reactant: CCOC(=O)CC(CSc1nc2ccccc2s1)C(=O)OCC
Product: CCCCNC(=O)CC(CSc1nc2ccccc2s1)C(=O)NCCCC
Temperature: 90 °C

Procedure:
18.0 parts of diethyl 3-(benzothiazol-2-ylthio)-propane-1,2-dicarboxylate and 30.0 parts of n-butylamine are stirred for 3 hours at 90° C. Volatile material are removed by heating at 90° C. under a vacuum of 0.1 mm to give N,N'-dibutyl 3-(benzothiazol-2-ylthio)-1,2-propane dicarboxylic acid diamide as a viscous liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=O.[S:11]1[CH2:17][C:15](=[O:16])[NH:14][C:12]1=[S:13].C([O-])(=O)C.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=[C:17]1[S:11][C:12](=[S:13])[NH:14][C:15]1=[O:16]
Reactant: O=C1CSC(=S)N1
Reactant: O=Cc1c(F)cccc1Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1NC(=S)SC1=Cc1c(F)cccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Chloro-6-fluorobenzaldehyde (9.50 g), rhodanine (7.98 g), and acetic acid (57 ml) were stirred at room temperature. Anhydrous sodium acetate (14.0 g) was added to the obtained suspension, and the mixture was heated with stirring for 2 hours. The reaction mixture was allowed to cool to room temperature, and ice water (190 ml) was added thereto. The precipitated crystals were collected by filtration, washed with water, and then dried to obtain 2-chloro-6-fluorobenzylidenerhodanine.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:24]=[CH:23][C:8]([O:9][C:10]2[S:11][C:12]([C:15]3[N:19]=[C:18]([CH:20]([OH:22])[CH3:21])[S:17][N:16]=3)=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:32][S:33]([O:22][CH:20]([C:18]1[S:17][N:16]=[C:15]([C:12]2[S:11][C:10]([O:9][C:8]3[CH:23]=[CH:24][C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[CH:6][CH:7]=3)=[N:14][CH:13]=2)[N:19]=1)[CH3:21])(=[O:35])=[O:34]
Reactant: CC(C)Oc1ccc(Oc2ncc(-c3nsc(C(C)O)n3)s2)cc1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)Oc1ccc(Oc2ncc(-c3nsc(C(C)OS(C)(=O)=O)n3)s2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
To a solution of Example 100D (136 g, 0.0037 mol), triethylamine (0.95 g, 0.0094 mol) and 4-(dimethylamino)pyridine in dichloromethane at 0° C. was added methanesulfonyl chloride (0.52 g, 0.0045 mol) drop wise and the mixture was stirred for 2 hours at room temperature. More dichloromethane was added and the organic layer was washed with water, then brine and dried over magnesium sulfate and filtered. The filtrate was concentrated to give 1.5 g of product as a clear oil. 1H NMR (300 MHz, CDCl3) δ ppm 1.36 (d, J=6.25 Hz, 6H) 1.90 (d, J=6.62 Hz, 3H) 3.15 (s, 3H) 4.45-4.61 (m, 1H) 6.10 (q, J=6.86 Hz, 1H) 6.87-6.99 (m, 2H) 7.17-7.25 (m, 2H) 7.96 (s, 1H). MS (ESI) m/z 442.0 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]([O:17][CH3:18])=[O:16])([O-])=O.CO>[Fe].C(O)(=O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)Cc1ccccc1Oc1cccc([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)Cc1ccccc1Oc1cccc(N)c1
Yield: 96.8 %

Procedure:
A mixture of methyl 2-(3-nitrophenoxy)phenylacetate (15 g), methanol (100 ml), glacial acetic acid (100 ml), and iron powder (15.0 g) was gently heated with stirring to reflux. After 30 minutes the mixture was cooled and the excess iron powder was filtered off. This filtrate was poured into water (700 ml) and extracted with ether (2×200 ml). The ether extracts were neutralized by stirring with aqueous sodium bicarbonate then dried, filtered and concentrated to give methyl 2-(3-aminophenoxy)phenylacetate (13.0 g, 97% yield) as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][C:7]2[O:8][C:9]([CH3:27])=[C:10]([CH3:26])[C:11]=2[C:12]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:15]=2)=[O:13])=[CH:4][CH:3]=1.Cl[S:31]([C:34]1[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[C:36]([OH:43])[CH:35]=1)(=[O:33])=[O:32]>>[Br:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][C:7]2[O:8][C:9]([CH3:27])=[C:10]([CH3:26])[C:11]=2[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][S:31]([C:34]3[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[C:36]([OH:43])[CH:35]=3)(=[O:33])=[O:32])=[C:16]([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:15]=2)=[O:13])=[CH:4][CH:3]=1
Reactant: Cc1oc(Cc2ccc(Br)cc2)c(C(=O)c2ccc(O)c(C3CCCC3)c2)c1C
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Product: Cc1oc(Cc2ccc(Br)cc2)c(C(=O)c2ccc(OS(=O)(=O)c3ccc(C(=O)O)c(O)c3)c(C3CCCC3)c2)c1C
Yield: 75.5 %

Procedure:
The title compound was prepared according to the procedure in Example 4 using [2-(4-bromo-benzyl)-4,5-dimethyl-furan-3-yl]-(3-cyclopentyl4-hydroxy-phenyl)-methanone (0.203 g, 0.448 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.319 g,1.34 mmol). Purification on Dynamax C18 (85% CH3CNIH20) gave 0.221 g (49%) of the title compound as a brown solid, mp 188-192° C. 1H NMR (DMSO-d6) δ1.26-1.32 (m, 2 H), 1.49-1.57 (m, 2 H), 1.64-1.74 (m, 4 H), 1.77 (s, 3 H), 2.18 (s, 3 H), 2.96 (quintet, 1 H), 3,79 (s, 2 H), 6.96 (d, 2 H), 7.23 (d, 1 H), 7.36 -7.43 (m, 4 H), 7.53-7.56 (m, 2 H), 8.00 (d, 1 H). IR (KBr) 3400, 2950, 1690, 1390 and 1190 cm−1. mass spectrum (−ESI) m/z 651 (M−H). Anal. Calcd. for C32H29BrO8S: C, 58.81; H, 4.47; N, 0.00. Found: C, 58.45; H. 4.54; N, 0.07.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13]([CH2:15][N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])([NH:25][C:26](=[O:35])[C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=2)[C:17]1=[O:43])=[O:14])(C)(C)C>C(Cl)Cl>[Cl:34][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=1[Cl:33])[C:26]([NH:25][C:18]1([CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:16]([CH2:15][C:13]([OH:14])=[O:12])[C:17]1=[O:43])=[O:35]
Reactant: CCOC(=O)CCC1(NC(=O)c2ccc(Cl)c(Cl)c2)C(=O)N(CC(=O)OC(C)(C)C)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CCC1(NC(=O)c2ccc(Cl)c(Cl)c2)C(=O)N(CC(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 103.9 %

Procedure:
5 ml of trifluoroacetic acid was added to a solution of 700 mg of ethyl 3-[1-(t-butoxycarbonylmethyl)-3-(3,4-dichlorobenzoylamino)-2,3-dihydro-2-oxo-1H-indol-3-yl]propionate in methylene chloride (20 ml). The mixture was stirred at room temperature for 3 hours. The reaction mixture was evaporated to dryness under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to afford 651 mg of 2-[3-(3,4-dichlorobenzoylamino)-2,3-dihydro-3-(2-ethoxycarbonylethyl)-2-oxo-1H-indol-1-yl]acetic acid as colorless prism crystals. Melting point: 219° to 220° C., IR (Nujol) (cm-1): 3280, 1735, 1720, 1705, 1670, 1610, FAB-MS (m/z): 481 & 479 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[N:10]=[C:11]3[C:16](O)=[N:15][CH:14]=[N:13][C:12]=23)=[CH:4][CH:3]=1.C(N(CC)C1C=CC=CC=1)C.O=P(Cl)(Cl)[Cl:38]>ClCCCl>[Cl:38][C:16]1[C:11]2[C:12](=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[N:10]=2)[N:13]=[CH:14][N:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncnc2c(-c3ccc(Cl)cc3)n(-c3ccccc3Cl)nc12
Solvent: ClCCCl
Solvent: CCN(CC)c1ccccc1
Product: Clc1ccc(-c2c3ncnc(Cl)c3nn2-c2ccccc2Cl)cc1
Temperature: 25 °C
Yield: 76 %

Procedure:
To a suspension of 3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-ol I-2A-1 b (17.55 g, 49.1 mmol) in 1,2-dichloroethane (109 ml) was added N,N-diethylaniline (32.8 ml, 206.22 mmol) followed by POCl3 (70 ml, 0.7 M). The reaction mixture was heated to reflux under nitrogen for 3 hours, and cooled to room temperature. The solvent was removed under reduced pressure. Excess POCl3 was removed by co-evaporation with toluene three times. The residue was dissolved in methylene chloride and slowly poured into vigorously stirred 1:1 CH2Cl2/saturated aqueous NaHCO3 (500 ml). Additional saturated aqueous NaHCO3 was added until the pH of the mixture was adjusted to neutral. The organic layer was separated and the aqueous layer was extracted with 200 ml methylene chloride three times. The organic layers were combined, dried (MgSO4), and concentrated. The residue was purified by SiO2-gel chromatography using 100% CH2Cl2 as the eluant to give 7-chloro-3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidine I-2A-1c (18.4 g, 76%): MS: 375.0 (M+1)+.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[N:13]1[CH2:22][C:21]2[C:16](=[N:17][C:18](S(C)=O)=[N:19][CH:20]=2)[N:15]([CH2:26][CH3:27])[C:14]1=[O:28].[NH2:29][CH:30]([CH2:33][OH:34])[CH2:31][OH:32]>>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[N:13]1[CH2:22][C:21]2[C:16](=[N:17][C:18]([NH:29][CH:30]([CH2:33][OH:34])[CH2:31][OH:32])=[N:19][CH:20]=2)[N:15]([CH2:26][CH3:27])[C:14]1=[O:28]
Reactant: CCN1C(=O)N(c2c(F)c(OC)cc(OC)c2F)Cc2cnc(S(C)=O)nc21
Reactant: NC(CO)CO
Product: CCN1C(=O)N(c2c(F)c(OC)cc(OC)c2F)Cc2cnc(NC(CO)CO)nc21
Yield: 95.9 %

Procedure:
3-(2,6-Difluoro-3,5-dimethoxy-phenyl)-1-ethyl-7-(2-hydroxy-1-hydroxymethyl-ethylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one was prepared as described in Example 5 using 0.5 g (1.21 mmol) of 3-(2,6-difluoro-3,5-dimethoxy-phenyl)-1-ethyl-7-methylsulfinyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one and 0.33 g (3.64 mmol) of serinol. The crude product was purified using medium-pressure chromatography eluting with 20:1 dichloromethane/methanol to give 0.51 g (96%) of the title compound: mp 168° C.–172° C. MS (APCI) (m+1)/z 440.1