Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]([C:11](=[O:44])[NH:12][C@H:13]([CH2:34][O:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=1)[C:14]([N:16]1[CH2:33][CH2:32][CH2:31][C:18]2([C:22](=[O:23])[N:21]([CH3:24])[CH2:20][CH:19]2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:17]1)=[O:15])([CH3:10])[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]([CH3:10])([CH3:9])[C:11]([NH:12][C@H:13]([CH2:34][O:35][CH2:36][C:37]1[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=1)[C:14]([N:16]1[CH2:33][CH2:32][CH2:31][C:18]2([C:22](=[O:23])[N:21]([CH3:24])[CH2:20][CH:19]2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:17]1)=[O:15])=[O:44]
Reactant: CN1CC(c2ccccc2)C2(CCCN(C(=O)[C@@H](COCc3ccc(F)cc3)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CC(c2ccccc2)C2(CCCN(C(=O)[C@@H](COCc3ccc(F)cc3)NC(=O)C(C)(C)N)C2)C1=O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of {1-[(R)-1-(4-Fluoro-benzyloxymethyl)-2-(2-methyl-1-oxo-4-phenyl-2,7-diaza-spiro[4.5]dec-7-yl)-2-oxo-ethylcarbamoyl]-1-methyl-ethyl}-carbamic acid tert-butyl ester (Intermediate from step 3) (154 mg, 0.24 mmol) in DCM (2.5 ml) was cooled with an ice bath and TFA (0.57 ml, 7.4 mmol) was added. The resulting solution was stirred for 3 h at 0° C. The reaction mixture was diluted with DCM (20 ml) and quenched at 0° C. with 2M NaOH aqueous solution (10 ml). The organic phase was separated, washed with brine (5 ml), dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography on silica eluting with 0-2.5% MeOH in DCM to afford the title compound.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:35]([NH2:37])=[O:36])[CH:17]=[C:18]([C:21]4[CH:25]=[C:24]([CH2:26][N:27]5[CH2:31][CH2:30][CH2:29][CH:28]5CCC)[S:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH2:38]([CH:41]1CCCN1)[CH2:39]C>>[CH2:1]([S:3]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:35]([NH2:37])=[O:36])[CH:17]=[C:18]([C:21]4[CH:25]=[C:24]([CH2:26][N:27]5[CH2:31][CH2:30][CH2:29][CH:28]5[CH:38]([CH3:41])[CH3:39])[S:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:11]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCCC1CCCN1
Reactant: CCCC1CCCN1Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cs1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN5CCCC5C(C)C)c4)cc23)CC1
Yield: 29.5 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-propyl-1-pyrrolidinyl)methyl]-3-thienyl}-1H-indole-7-carboxamide, substituting 2-(1-methylethyl)pyrrolidine (113 mg, 1.0 mmol) for 2-propylpyrrolidine to afford 16.0 mg of the title compound (29.5%).
Reaction SMILES: [OH-].[Li+].[Cl:3][C:4]1[CH:5]=[C:6]([S:11]([N:14]2[CH2:18][CH2:17][CH2:16][CH:15]2[CH2:19][C:20]([O:22]C)=[O:21])(=[O:13])=[O:12])[CH:7]=[CH:8][C:9]=1[Cl:10]>CO.O>[Cl:3][C:4]1[CH:5]=[C:6]([S:11]([N:14]2[CH2:18][CH2:17][CH2:16][CH:15]2[CH2:19][C:20]([OH:22])=[O:21])(=[O:12])=[O:13])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: COC(=O)CC1CCCN1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CC1CCCN1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Reaction time: 16 h

Procedure:
Lithium hydroxide (0.75 mg, 18 mmol) was added to a cooled solution of methyl 2-(1-(3,4-dichlorophenylsulfonyl)pyrrolidin-2-yl)acetate (2.1 g, 6 mmol) in methanol (20 ml) and water (20 ml), and stirring was carried out for 16 h at room temperature (TLC monitoring). The solvent was removed using a rotary evaporator and the residue was taken up in water. The aqueous phase was washed with ethyl acetate and acidified with 1 M HCl, and then the product was extracted with ethyl acetate and the organic phase was washed with saturated NaCl solution. The organic phase was dried over sodium sulfate and concentrated to dryness. Yield: 2.0 g (99%)
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.C([O-])(O)=O.[Na+]>C(O)C.O>[C:5]1([C:3]2[N:11]=[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]3[CH:2]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Nc1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: c1ccc(-c2cn3ccccc3n2)cc1
Yield: 79 %

Procedure:
Stir a solution of 2-bromoacetophenone (1 g, 5.024 mmol) and 2-aminopyridine (591 mg, 6.280 mmol) in ethanol (4 mL) containing NaHCO3 (658 mg, 7.837 mmol) at room temperature for 6 hours. Dilute the mixture with water (15 mL) and extract with ether (3×20 mL). Wash the combined organic layers with saturated aqueous sodium chloride (25 mL), dry (MgSO4) and concentrate in vacuo. Purify the residue by flash chromatography (SiO2; eluent:hexane/EtOAc 4:1) to give a white solid, 79% yield. MS(ES+): m/z=195.1 (M+H)+
Reaction SMILES: [CH:1]1([N:4]2[C:8](=[O:9])[C:7]3=[CH:10][C:11]([N+:14]([O-])=O)=[CH:12][CH:13]=[C:6]3[C:5]2=[O:17])[CH2:3][CH2:2]1.O.O.[Sn](Cl)Cl.[OH-].[Na+]>C(O)C>[CH:1]1([N:4]2[C:8](=[O:9])[C:7]3=[CH:10][C:11]([NH2:14])=[CH:12][CH:13]=[C:6]3[C:5]2=[O:17])[CH2:3][CH2:2]1
Reactant: O=C1c2ccc([N+](=O)[O-])cc2C(=O)N1C1CC1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1ccc2c(c1)C(=O)N(C1CC1)C2=O
Temperature: 0 °C

Procedure:
N-Cyclopropyl-4-nitrophthalimide (10.0 g, 43.0 mmol) was dissolved in ethanol (200 mL). Tin (II) chloride dihydrate (49.0 g, 215 mmol) was added, and the mixture was heated to reflux overnight. After cooling, the mixture was poured over crushed ice (1.0 L), and pH adjusted to 6.5 using 1 N NaOH. The mixture was passed through a small bed of celite, and the filtrate was subsequently extracted with ethyl acetate (1.2 L). The organic phase was dried using anhydrous MgSO4, and solvent was removed by rotary evaporation in vacuo, to afford crystalline N-cyclopropyl-4-aminophthalimide. Yield: 6.0 g (69%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[Li+].CC([N-]C(C)C)C.[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=[O:23]>C1COCC1>[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]([C:7]1[C:2]([Cl:1])=[N:3][C:4]([S:9][CH3:10])=[N:5][C:6]=1[Cl:8])[OH:23]
Reactant: O=Cc1ccccc1Cl
Reactant: CSc1nc(Cl)cc(Cl)n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1nc(Cl)c(C(O)c2ccccc2Cl)c(Cl)n1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4,6-dichloro-2-(methylthio)pyrimidine (Aldrich) (5.0 g, 25.64 mmol) in dry THF (130 mL) at −78° C. under nitrogen was slowly added a solution of 2.0 M LDA (23.0 mL, 1.8 eq) in THF via a syringe. The resulting mixture was stirred at −78° C. for an additional 20 minutes, after which 2-chlorobenzaldehyde (Aldrich) (7.2 mL, 2 eq) was added dropwise via a syringe. The reaction mixture was stirred for an additional 30 minutes at −78° C. and then quenched with saturated ammonium chloride solution. Ethyl acetate was added, and the mixture was allowed to warm to room temperature. The aqueous layer was separated and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated to give the crude product (14.2 g) as an oil. Purification using Flash Column Chromatography on Silica Gel, eluting with 5% ethyl acetate in hexanes gave the title compound (8.60 g, (M+H)+=336, M.P.=109.5-112.5° C.) which crystallized upon standing to give a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([O:29]C)=[O:28])([CH3:26])[CH3:25])[CH2:14][C:13](=[O:31])[NH:12][CH:11]3[C:32]3[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=3[CH3:39])[C:5]2=[CH:4][CH:3]=1.[OH-].[Na+].O>CO>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([OH:29])=[O:28])([CH3:25])[CH3:26])[CH2:14][C:13](=[O:31])[NH:12][CH:11]3[C:32]3[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=3[CH3:39])[C:5]2=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(Cl)ccc2C)C12C(=O)Nc1cc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(Cl)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC(C)(C)C(=O)O)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 70 °C
Yield: 8.5 %

Procedure:
A mixture of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-methoxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-chloro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (600 mg, 1 mmol), NaOH (80 mg, 2 mmol), H2O (3 mL) and methanol (10 mL) was heated at 70° C. for 2 h. After cooled to room temperature, the solution was concentrated and then the residue was acidified to “pH” 2-3 by addition of concentrated HCl. The white solid was collected by filtration to give the title compound as a white solid (50 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.CN(C1C=CC=CN=1)C.[Si:31](Cl)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:10][C@@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@@H]1C(=O)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccccn1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (16 g, 69 mmol) was dissolved in 100 mL DMF, added imidazole (12 g, 173 mmol), dimethylaminopyridine (0.85 g, 6.9 mmol), and tert-butyldimethylsilyl chloride (12.5 g, 83 mmol). Stirred at ambient temperature overnight, dissolved in 350 mL EtOAc, washed with 10% citric acid (3×200 mL), water (2×200 mL), brine, dried with MgSO4, filtered, and concentrated to yield title compound. (20 g, 84%) APCI (AP−): 344.2 (M−H)−.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](Br)[CH:13]=1)(=[O:3])[CH3:2].[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)([O-])[O-]>COCCOC.CO>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:32]2[CH:33]=[CH:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=2)[CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Reactant: COc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CO
Product: COc1ccc(-c2cncc(O[C@@H]3SC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)c2)cc1
Temperature: 110 °C
Yield: 80 %

Procedure:
1 g (2.23 mM) of 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside, 0.4 g (2.67 mM) of 4-methoxyphenylboronic acid, 1.6 g (4.46 mM) of carbonate resin and 0.02 g (0.004 mM) of [1,1-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) dichloromethane are mixed in 7 ml of DME and 5 ml of methanol. The reaction mixture is heated for 20 minutes at 110° C. by microwaves. It is filtered, the material on the filter is rinsed with methanol and the organic phases are concentrated. The product is purified by chromatography on a silica column (eluent: dichloromethane/ethyl acetate 98/2, then 70/30; v/v) to give the expected product in the form of a cream-colored powder with a yield of 80%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:7][C:6]=1[OH:20])[CH3:2].[H-].[Na+].Br[CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:21])[C:5]1[C:6]([O:20][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:7][C:8]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:9][C:10]=1[CH3:11])[CH3:2]
Reactant: CCOC(=O)c1c(C)cc(OCc2ccccc2)cc1O
Reactant: BrCCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)cc(OCc2ccccc2)cc1OCCCc1ccccc1
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
Ethyl-4-benzyloxy-2-hydroxy-6-methyl-benzoate (0.5 g, 1.8 mmol) is dissolved in DMF (10 mL) and 60% sodium hydride (0.07 g, 1.8 mmol) is added and stirred 20 minutes, forming a clear solution. Then 1-bromo-3-phenyl propane (0.27 mL, 1.8 mol) is added and this mixture is heated at 100° C. for 4 hours and stirred at room temperature overnight. The solvent is removed in vacuo and the residue purified by flash chromatography (silica, 5% ethyl acetate in hexanes) to give the title compound: 1H NMR (300 MHz, CDCl3) δ 7.17-7.40 (m, 10H), 6.39 (d, 1H), 6.33 (d, 1H), 5.03 (s, 2H), 4.38 (q, 2H), 3.91 (t, 2H), 2.77 (t, 2H), 2.30 (s, 3H), 2.05 (m, 2H), 1.38 (t, 3H); MS (EI) 404 (M)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)[CH3:2].S(Cl)([Cl:16])=O>C1C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([Cl:16])=[O:13])=[CH:6][CH:5]=1)[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCOc1ccc(CC(=O)O)cc1
Solvent: c1ccccc1
Product: CCOc1ccc(CC(=O)Cl)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
To a stirred solution of (4-ethoxyphenyl)acetic acid (10.0 g, 55.5 mmol) in benzene (100 mL) was added thionyl chloride (50 mL, 68.5 mmol) and the reaction mixture was stirred at 80° C. for 2 hours. The solvent was evaporated in vacuo and the crude product was purified by distillation (bp 86° C., 0.4 Torr) to provide the title compound (10.39 g, 94%) as a yellow oil. MS of methyl ester: MS (ESI) (M+H)+=194.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28]([O:30]CC)=O)[C:24]=2[CH:33]=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.[CH3:43][NH2:44]>>[Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28]([NH:44][CH3:43])=[O:30])[C:24]=2[CH:33]=1)([C:14]([CH3:16])([CH3:15])[CH3:17])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12
Reactant: CN
Product: CNC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12

Procedure:
Starting materials: ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6R)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 210, 5.16 g, 8.73 mmol) and methylamine (2M in THF).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].C(N(CC)CC)C.Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)=[O:15]>C1COCC1>[N+:24]([C:21]1[CH:20]=[CH:19][C:18]([CH2:17][O:16][C:14]([NH:1][CH2:2][CH2:3][CH2:4][OH:5])=[O:15])=[CH:23][CH:22]=1)([O-:26])=[O:25]
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: NCCCO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCCCO)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 314.7 %

Procedure:
To a solution stirred under argon at room temperature of 3-amino-1-propanol (0.77 g, 1.1 mmol) and triethylamine (2.85 mL, 7 mmol) in THF (5 mL) was added a suspension of 4-nitrobenzyl chloroformate (2 g, 1 mmol) in THF (20 mL). The resulting mixture was allowed to stir at room temperature over the weekend, then was concentrated. The residue was purified by chromatography on silica gel (0%-2% MeOH/CH2Cl2) to give the title compound (0.80 g, 34%) as a pale yellow oil: MS (ES) m/e 254.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([CH:18]([C:20]3[NH:29][C:28](=O)[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)[CH3:19])[CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:33])=O>>[Cl:33][C:28]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[C:20]([CH:18]([N:15]2[CH2:16][CH2:17][N:12]([S:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)(=[O:11])=[O:10])[CH2:13][CH2:14]2)[CH3:19])[N:29]=1
Reactant: COc1ccc(S(=O)(=O)N2CCN(C(C)c3nc4ccccc4c(=O)[nH]3)CC2)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc(S(=O)(=O)N2CCN(C(C)c3nc(Cl)c4ccccc4n3)CC2)cc1
Temperature: 90 °C
Yield: 100 %

Procedure:
In a flask containing of 2-{1-[4-(4-methoxy-benzenesulfonyl)-piperazin-1-yl]-ethyl}-3H-quinazolin-4-one (380.0 mg, 0.89 mmol) in phosphorus oxychloride (20 ml) was heated to 90° C. for 2 hours, then the solvent was concentrated under reduced pressure to give 4-Chloro-2-{1-[4-(4-methoxy-benzenesulfonyl)-piperazin-1-yl]-ethyl}-quinazoline (Yield 394.2 mg, 100%) that was used directly without further purification. 1H NMR (400 MHz, CDCl-3): δ 1.93 (d, 3H, J=6.82 Hz), 3.23-3.04 (m, 3H), 3.54-3.34 (m, 1H), 3.87-3.65 (m, 4H), 3.90 (s, 3H), 4.77 (q, 1H, J=14.15, 6.82 Hz), 7.05 (d, 2H, J=8.84), 7.69 (d, 2H, J=8.84), 7.87 (t, H, J=7.84), 8.10 (t, 1H, J=8.34 Hz), 8.18 (d, 1H, 8.34 Hz), 8.35 (d, 1H, 8.34 Hz). MS m/z calc. 446.12, found (ESI); 447.4 (M+1)+. Retention time 2.67 minutes.
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[CH:9]=[C:8]([Cl:12])[NH:7][C:6]1=[O:13])[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1>CN(C)C=O>[CH2:1]([N:5]1[C:10](=[O:11])[CH:9]=[C:8]([Cl:12])[N:7]([CH2:28][C:27]2[CH:30]=[CH:31][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)[C:6]1=[O:13])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)cc(Cl)[nH]c1=O
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCn1c(=O)cc(Cl)n(Cc2ccc(OC)cc2)c1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 3-butyl-6-chlorouracil (5.0 g, 24.6 mM), potassium carbonate (4.4 g, 32 mM) and potassium iodide (0.17 g, 1 mM) in dimethylformamide [DMF] (50 ml) was added 4-methoxybenzyl chloride (4.65 ml, 32 mM). The mixture was stirred at room temperature for 5 hours and was then concentrated under reduced pressure, and the resulting residue was diluted with water (50 ml) and extracted with chloroform (100 ml). The organic layer was washed with water, dried (MgSO4), and concentrated to dryness to give a brown syrup. The syrup was purified by flash chromatography on silica gel (elution with chloroform) to give 3-butyl-6-chloro-1-(4-methoxybenzyl)uracil as an oil. To a solution of the oil in ethanol (50 ml) was added hydrazine hydrate (20 ml) and the mixture was stirred at room temperature for 2 hours. The solution was concentrated under reduced pressure to give crude crystals, which were recrystallized from 70% ethanol to give pale yellow crystals (4.23 g, 54%), m.p. 167°-170° C.
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[C:16]2[O:15][CH2:14][CH2:13][O:12][C:11]=2[CH:10]=[C:9]([F:17])[CH:8]=1.O=[C:19]1[CH2:23][CH2:22][CH2:21][N:20]1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>C1COCC1>[F:17][C:9]1[CH:8]=[C:7]([C:19]2[N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21][CH2:22][CH:23]=2)[C:16]2[O:15][CH2:14][CH2:13][O:12][C:11]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1=O
Reactant: Fc1cc(Br)c2c(c1)OCCO2
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC=C1c1cc(F)cc2c1OCCO2
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A solution of isopropyl magnesium chloride in THF (2M, 5.39 mL, 10.78 mmol) was added to a solution of 5-bromo-7-fluoro-2,3-dihydrobenzo[b][1,4]dioxine (Int-53) (1 g, 4.31 mmol) in THF (10 mL) at −45° C. drop-wise and then allowed it to warm up to 5° C. over a period of 1 h. The reaction mixture was cooled again to −45° C. and a solution of tert-butyl 2-oxopyrrolidine-1-carboxylate (1.6 g, 8.62 mmol) in THF (10 mL) was added drop-wise maintaining the temperature at −45° C. The reaction mixture was warmed to 25° C. and stirred for 1 h and then quenched with saturated NH4Cl solution (100 mL). The reaction mixture was extracted with ethyl acetate (3×30 mL) and the organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure and purified by column chromatography (using silica gel and 20% ethyl acetate Hexane as eluent) to afford tert-butyl 5-(7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-2,3-dihydro-1H-pyrrole-1-carboxylate (Int-54). MS (ESI) m/z 340 (M-+1).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:19][OH:20])=[C:4]([CH2:9][NH:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)[CH:5]=[N:6][C:7]=1[CH3:8].Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=1>>[C:29]([C:26]1[CH:27]=[CH:28][C:23]([CH2:22][O:1][C:2]2[C:3]([CH2:19][OH:20])=[C:4]([CH2:9][NH:10][C:11]3[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=3)[CH:5]=[N:6][C:7]=2[CH3:8])=[CH:24][CH:25]=1)#[N:30]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: Cc1ncc(CNc2ccc(C#N)cc2)c(CO)c1O
Product: Cc1ncc(CNc2ccc(C#N)cc2)c(CO)c1OCc1ccc(C#N)cc1
Yield: 2 %

Procedure:
The coupling of 4-[(5-hydroxy-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl)-amino]-benzonitrile (805 mg, 3.0 mmol) (7) and α-bromo-p-tolunitrile (588 mg, 3.0 mmol), as described in Example 3, gave 4-{[5-(4-cyano-benzyloxy)-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl]-amino}-benzonitrile (8) (23 mg, 9% yield) as a colorless solid.
Reaction SMILES: [OH:1][C:2]([CH3:25])([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:3]=[CH:4][C@@H:5]1[CH2:9][CH2:8][C:7](=[O:10])[C@H:6]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].[CH3:26]O>>[OH:1][C:2]([CH3:25])([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:3]=[CH:4][C@@H:5]1[CH2:9][CH2:8][C:7](=[O:10])[C@H:6]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:26])=[O:18]
Reactant: CO
Reactant: CCCCCC(C)(O)C=C[C@@H]1CCC(=O)[C@H]1CCCCCCC(=O)O
Product: CCCCCC(C)(O)C=C[C@@H]1CCC(=O)[C@H]1CCCCCCC(=O)OC

Procedure:
In the same manner but using the appropriate choice of the compound of formula 1 and lower alkanol, other corresponding esters of formula 1 (R1 = lower alkyl) are prepared; for example, the corresponding lower alkyl esters of the products of Table IV. More specifically exemplified, the choice of trans-7-[2-(3-hydroxy-3-methyl-1-octenyl)-5-oxocyclopentyl]heptanoic acid, described in Example 68, as the compound of formula 1 and methanol as the lower alkanol in the procedure of this example give methyl trans-7-[2-(3-hydroxy-3-methyl-1-octenyl)-5-oxocyclopentyl]heptanoate, γmaxfilm 3475, 1730 cm-1, nmr (CDCl3) δ0.89 (t, 3H), 3.64 (s, 3H), 5.61 (m, 2H).
Reaction SMILES: [F:1][C:2]1[C:22]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)=[CH:21][C:5]2=[N:6][C:7]3[N:8]([CH3:20])[CH:9]=[C:10]([C:15]([O:17]CC)=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1.O>C(O)(=O)C.Cl>[F:1][C:2]1[C:22]([N:23]2[CH2:24][CH2:25][N:26]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH2:27][CH2:28]2)=[CH:21][C:5]2=[N:6][C:7]3[N:8]([CH3:20])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1
Reactant: CCOC(=O)c1cn(C)c2nc3cc(N4CCN(c5ccc(F)cc5)CC4)c(F)cc3cc2c1=O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCN(c5ccc(F)cc5)CC4)cc3nc21
Temperature: 110 °C
Reaction time: 4 h
Yield: 94.1 %

Procedure:
A suspension of 10.5 g of ethyl 7-fluoro-8-[4-(4-fluorophenyl)piperazin-1-yl]-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylate in 100 cm3 of acetic acid and 100 cm3 of 17.5% aqueous hydrochloric acid solution was heated, with stirring, at a temperature around 110° C. for approximately 4 hours. After cooling to approximately 20° C., 25 cm3 of water were added to the reaction mixture. The insoluble material was filtered off and washed 3 times with 200 cm3 of water and 2 times with 100 cm3 of ethanol. 9.3 g of 7-fluoro-8-[4-(4-fluorophenyl)piperazin-1-yl]-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid were obtained in the form of a yellow solid melting at approximately 320° C., which solid was used without additional purification in the subsequent stages.