Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[NH:30]1[CH2:33][CH:32]([N:34]2[CH2:39][CH2:38][C:37]([CH3:41])([OH:40])[CH2:36][CH2:35]2)[CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:30]4[CH2:33][CH:32]([N:34]5[CH2:39][CH2:38][C:37]([CH3:41])([OH:40])[CH2:36][CH2:35]5)[CH2:31]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: CC1(O)CCN(C2CNC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CCC(C)(O)CC4)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.4 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (0.207 g, 0.53 mmol), 1-azetidin-3-yl-4-methylpiperidin-4-ol (0.108 g, 0.63 mmol) and 4 Å molecular sieves (0.5 g) in DCE (5 mL)was stirred for 3 h at room temperature. Sodium triacetoxyborohydride (0.224 g, 1.06 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, MeOH:EtOAc, gradient 0:100 to 30:70) to give 551 as a white solid (0.247 g, 86%). LCMS (Method I): RT=2.35 min, [M+H]+ 546.3. 1H NMR (400 MHz, DMSO-d6): δ 8.04-7.98 (m, 1 H); 7.65-7.60 (m, 1 H); 7.27-7.20 (m, 2 H); 4.34-3.83 (m, 4 H); 3.85 (s, 2 H); 3.79-3.75 (m, 7 H); 3.43 (t, J=7.4 Hz, 2 H); 3.31-3.20 (q, J=7.4 Hz, 2 H); 2.96-2.93 (m, 2 H); 2.92-2.83 (m, 1 H); 2.27-2.23 (m, 2 H); 2.18-2.14 (m, 2 H); 1.48-1.36 (m, 4 H); 1.33 (t, J=7.4 Hz, 3 H); 1.12-1.06 (s, 3 H)
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]3[CH2:22][CH2:23][CH2:24][C:18]=3[N:17]([CH3:25])[C:16]2=[O:26])=[CH:10][C:3]=1[C:4]([O:6]C(C)C)=[O:5].[OH-].[Na+].Cl>CO.O>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]3[CH2:22][CH2:23][CH2:24][C:18]=3[N:17]([CH3:25])[C:16]2=[O:26])=[CH:10][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CC(C)OC(=O)c1cc(-n2c(=O)c3c(n(C)c2=O)CCC3)c(F)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1c2c(c(=O)n(-c3cc(C(=O)O)c(Cl)cc3F)c1=O)CCC2
Reaction time: 15 h

Procedure:
A solution of 26.6 g of isopropyl 2-chloro-4-fluoro-5-(1,2,4,5,6,7-hexahydro-1-methyl-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate in 1.7 l of methanol is treated with a solution of 3.08 g of sodium hydroxide in 700 ml of water. The reaction mixture is stirred at room temperature for 15 hours, during which 2.1 l of water are continuously added dropwise. Stirring is continued for a further 15 hours during which the pH value of the mixture reaches 9-10. The mixture is acidified with concentrated hydrochloric acid and concentrated under reduced pressure at approx. 20° C. to a volume of approx. 300 ml. The crystals are filtered off by suction, rinsed with a little water and dried at 40°-50° C. under reduced pressure. 2-Chloro-4-fluoro-5-(1,2,4,5,6,7-hexahydro-1-methyl-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoic acid, m.p. 270°-273° C., is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13](S(CC3C=CC=CC=3)(=O)=O)=[N:14][CH:15]=2)[NH:10][C:9]1=[O:28].[NH2:29][CH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>CN1CCCC1=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13]([NH:29][CH:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[N:14][CH:15]=2)[NH:10][C:9]1=[O:28]
Reactant: NC1CCOCC1
Reactant: O=C1Nc2nc(S(=O)(=O)Cc3ccccc3)ncc2CN1c1ccccc1Cl
Solvent: CN1CCCC1=O
Product: O=C1Nc2nc(NC3CCOCC3)ncc2CN1c1ccccc1Cl
Temperature: 100 °C
Reaction time: 24 h

Procedure:
Sulfone 9.1 (0.205 g, 0.494 mmol) in 5 mL 1-methyl-2-pyrrolidinone was combined with 4-aminotetrahydropyran (0.100 g, 0.988 mmol). The reaction was stirred at 100° C. for 24 hours and purified by column chromatography on silica gel using 3-7% methanol/dichloromethane as eluant. The column fractions containing product were combined and concentrated in vacuo to a give the title compound as a brown gum which was redissolved in methanol. Addition of hydrochloric acid (1.0M/Et2O, 1.0 equivalent) gave 0.026 g of the hydrochloride salt 3-(2-chlorophenyl)-7-(tetrahydropyran-4-ylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[C:4](=[C:5]([O:13][CH3:14])[C:6]([CH3:12])=[CH:7][CH:8]=2)[N:3]=1.[NH2:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([OH:22])[CH2:18][CH2:17]1.C1CCN2C(=NCCC2)CC1>CC#N>[CH3:14][O:13][C:5]1[C:6]([CH3:12])=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([OH:22])[CH2:18][CH2:17]1)[N:11]=[CH:10]2
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: COc1c(C)ccc2cnc(Cl)nc12
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COc1c(C)ccc2cnc(N[C@H]3CC[C@H](O)CC3)nc12
Reaction time: 8 h

Procedure:
To a solution of 2-chloro-8-methoxy-7-methylquinazoline (20.4 g, 0.098 mol) in CH3CN (800 mL) were added trans-4-amino-cyclohexanol (22.5 g, 0.195 mol) and DBU (29.7 g, 0.195 mol) in one portion. The reaction mixture was refluxed with stirring overnight. TLC (ethyl acetate/petroleum ether=1:1) indicated the reaction was complete. The solvent was removed in vacuo. The residue was taken up with CHCl3 (550 mL), the solution was washed with water (150 mL×2). The aqueous layer was re-extracted with CHCl3 (150 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo to give the crude product. The crude product was re-crystallized from EtOH (130 mL)/water (200 mL) to give the title compound (17 g, 60.5%) as an off-white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]CC2C=CC=CC=2)=[CH:11][C:10]=1[CH:23]=O)([CH3:7])[CH3:6])[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:25])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH3:23])([CH3:6])[CH3:7])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCc2ccccc2)cc1C=O
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Reaction time: 6 h

Procedure:
2-(4-Benzyloxy-2-formyl-phenoxy)-2-methyl-propionic acid ethyl ester (9.00 g, 26.3 mmol) in ethanol (250 mL) is treated with 5% Pd/C (1.25 g) and hydrogen (60 psi, rt, overnight). Additional 5% Pd/C (1.25 g) is added, and the reaction is continued for 6 h at 40° C. The mixture is filtered and concentrated to a tan oil (6.25 g). This oil contained 9 mol % of 2-(4-Hydroxy-2-hydroxymethyl-phenoxy)-2-methyl-propionic acid ethyl ester. 1H NMR (400 MHz, CDCl3) δ 1.26 (t, 3H, J=7.3 Hz), 1.51 (s, 6H), 2.14 (s, 3H), 4.24 (q, 2H, J=7.3 Hz), 5.68 (brs, 1H), 6.47 (dd, 1H, J=3.4, 8.8 Hz), 6.59 (d, 1H, J=8.3 Hz), 6.60 (brs, 1H).
Reaction SMILES: C(=O)(O)[O-].[Na+].[CH2:6]([S:9][C:10](=[N:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[NH:11]C(OC(C)(C)C)=O)[CH:7]=[CH2:8].[I:27]I.O>ClCCl>[I:27][CH2:8][CH:7]1[CH2:6][S:9][C:10]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[N:11]1
Reactant: II
Reactant: C=CCSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)NC1=NC(CI)CS1
Yield: 74.6 %

Procedure:
17 g of sodium bicarbonate are added, at a temperature in the region of 20° C., to a suspension of 25.4 g of tert-butyl allylsulfanyl-[(tert-butoxycarbonyl)amino]methylidene-carbamate in 650 cm3 of dichloromethane, followed by addition of a solution of 24.4 g of iodine predissolved in 850 cm3 of dichloromethane. After 72 hours at a temperature in the region of 20° C., 500 cm3 of water and 500 cm3 of saturated sodium bicarbonate solution are added to the reaction medium and the resulting mixture is then extracted with twice 1 dm3 of ethyl acetate. The organic phases are washed with saturated sodium sulfite solution and then with saturated sodium chloride solution, dried over magnesium sulfate, filtered and then concentrated under reduced pressure (1 kPa) at a temperature in the region of 50° C. The residue obtained is crystallized from ethyl acetate. 20.5 g of tert-butyl N-[(4RS)-4-(iodomethyl)-4,5-dihydro-2-thiazolyl]carbamate are obtained in the form of a yellow solid [1H NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 1.41 (s: 9H); 2.97 (dd, J=11.5 and 7 Hz: 1H); from 3.30 to 3.50 (mt: 3H); 4.12 (mt: 1H); 9.89 (unresolved complex: 1H)].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:21](N1C=CN=C1)([N:23]1C=CN=C1)=O.CN>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]([CH2:17][C:18]([NH:23][CH3:21])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2cccc(Br)c2)nc2cccnc21
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Solvent: C1CCOC1
Product: CNC(=O)Cn1c(-c2cccc(Br)c2)nc2cccnc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 70.8 %

Procedure:
A suspension of 2-(3-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (6.0 g, 0.018 mole), 1,1'-carbonyldiimidazole (2.9 g, 0.018 mole), and anhydrous tetrahydrofuran (200 ml) was stirred at room temperature with a stream of nitrogen bubbling through for 4 hours. The nitrogen flow was stopped and a solution of methylamine in tetrahydrofuran (36 ml of 1M) was added. The solution was stirred at room temperature under nitrogen for 1/2 hour. The reaction mixture was filtered and concentrated in vacuo and the residue triturated in water (100 ml) and filtered. The filter cake was recrystallized from tetrahydrofuran-isopropyl ether, giving 4.6 g (74%). Recrystallization from isopropyl alcohol-isopropyl ether gave 4.4 g of off-white needles, mp 199°-201° C.
Reaction SMILES: Cl.[F:2][C:3]([F:16])([F:15])[C:4]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.CCN(C(C)C)C(C)C.Cl[C:27]1[N:32]=[CH:31][C:30]([C:33]2[CH:34]=[C:35]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][N:49]=3)[C:36]3[S:40][C:39]([NH:41][C:42]([NH:44][CH2:45][CH3:46])=[O:43])=[N:38][C:37]=3[CH:47]=2)=[CH:29][N:28]=1>CC(N(C)C)=O>[CH2:45]([NH:44][C:42](=[O:43])[NH:41][C:39]1[S:40][C:36]2[C:35]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][N:49]=3)=[CH:34][C:33]([C:30]3[CH:31]=[N:32][C:27]([N:7]4[CH2:6][CH2:5][C:4]([C:3]([F:2])([F:15])[F:16])([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:9][CH2:8]4)=[N:28][CH:29]=3)=[CH:47][C:37]=2[N:38]=1)[CH3:46]
Reactant: CCOC(=O)C1(C(F)(F)F)CCNCC1
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(Cl)nc3)cc(-c3ccccn3)c2s1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C(=O)OCC)(C(F)(F)F)CC4)nc3)cc(-c3ccccn3)c2s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.8 %

Procedure:
To the solution of ethyl 4-(trifluoromethyl)piperidine-4-carboxylate hydrochloride (0.1 g, 0.44 mmol) in DMA (5.0 mL) was added DIPEA (0.25 mL, 1.46 mmol) at rt and the mixture stirred at rt for 10 min followed by addition of 1-(5-(2-chloropyrimidin-5-yl)-7-(pyridin-2-yl)benzothiazol-2-yl)-3-ethylurea (0.12 g, 0.29 mmol). The reaction was heated up to 80° C. for 16 h and after completion (by TLC), the mixture was poured into 50 mL of ice cold water, extracted with EtOAc (3×50 mL) and the combined organics washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude residue was purified over 100-200 M silica-gel using 1.50% MeOH: DCM to obtain an off white solid (0.09 g, 51%). 1H NMR (DMSO-d6): δ 1.15 (t, J=7.20 Hz, 3H), 1.20 (t, J=6.80 Hz, 3H), 1.45 (m, 2H), 2.06 (m, 2H), 2.54 (m, 2H), 3.21 (q, J=7.20, 2H), 4.15 (q, J=6.80 Hz, 2H), 4.32 (m, 2H), 6.86 (br s, 1H), 7.44 (m, 1H), 7.99 (m, 2H), 8.23 (s, 1H), 8.47 (m, 1H), 8.80 (m, 1H), 8.92 (s, 2H) and 10.56 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13]C)=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([O:21][C@H:22]2[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]2[OH:28])=[CH:17][CH:16]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:16]=[CH:17][C:18]([O:21][C@H:22]2[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]2[OH:28])=[CH:19][CH:20]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(O[C@H]4CCCC[C@@H]4O)cc3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccc(O[C@H]4CCCC[C@@H]4O)cc3)cc12
Temperature: 70 °C
Reaction time: 24 h
Yield: 14.8 %

Procedure:
To a solution of methyl 6-chloro-5-(4-{[(1S,2S)-2-hydroxycyclohexyl]oxy}phenyl)-1H-indole-3-carboxylate (80 mg, 0.22 mmol) in methanol (8 mL) was added aq. 1.0M NaOH (2.0 mL, 2.0 mmol). The mixture was stirred at 70° C. for 24 hours. The mixture was adjusted to pH 7 and purified by reverse phase HPLC to give the title compound (12.6 mg, 16% yield) as a white solid. MS (ES+) 408.2 (M+Na)+. 1H NMR (400 MHz, DMSO-d6): δ 12.40-11.90 (br. s, 1H), 11.85 (s, 1H), 8.10 (s, 1H), 7.90 (s, 1H), 7.61 (m, 1H), 7.32 (d, 2H), 7.00 (d, 2H), 4.93 (m, 1H), 4.10 (m, 1H), 3.57 (m, 1H), 2.05 (m, 1H), 1.88 (m, 1H), 1.53 (m, 2H), 1.40-1.10 (m, 4H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=2)=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:4]=[N:3]1.[CH:24]([NH2:27])([CH3:26])[CH3:25]>>[CH:24]([NH:27][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:9]([O:8][CH2:7][C:6]2[N:2]([CH3:1])[N:3]=[N:4][C:5]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[N:10][CH:11]=1)([CH3:26])[CH3:25]
Reactant: CC(C)N
Reactant: Cn1nnc(-c2ccccn2)c1COc1ccc(C(=O)O)cn1
Product: CC(C)NC(=O)c1ccc(OCc2c(-c3ccccn3)nnn2C)nc1
Yield: 71 %

Procedure:
As described for example 26b, 6-(3-methyl-5-pyridin-2-yl-3H-[1,2,3]triazol-4-ylmethoxy)-nicotinic acid (76 mg, 0.24 mmol) was converted, using isopropylamine instead of 4-aminotetrahydropyran, to the title compound (61 mg, 71%) which was obtained as a white solid. MS: m/e=353.2 [M+H]+.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:8]1[CH2:12][CH2:11]OC1=O>>[C:1]1([S:7][CH2:11][CH2:12][OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: O=C1OCCO1
Product: OCCSc1ccccc1

Procedure:
Benzenethiol is reacted with 1,3-dioxolan-2-one to form 2-(phenylthio)ethanol. The 2-(phenylthio)ethanol is isolated and then converted to 2-(phenylthio)ethanethiol using triphenylphosphine, diisopropyl azodicarboxylate (DIAD), and thiolacetic acid followed by hydrolysis of the resulting acetate with potassium hydoxide in methanol.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:20])[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:21].[C:22]([NH:25][CH:26]1[CH2:30][CH2:29][NH:28][CH2:27]1)(=[O:24])[CH3:23].C(=O)(O)[O-].[Na+]>C(#N)C>[C:22]([NH:25][CH:26]1[CH2:30][CH2:29][N:28]([C:2]2[N:11]=[C:10]3[C:5]([C:6](=[O:20])[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:8][N:9]3[CH:12]3[CH2:14][CH2:13]3)=[CH:4][C:3]=2[F:21])[CH2:27]1)(=[O:24])[CH3:23]
Reactant: CCOC(=O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Reactant: CC(=O)NC1CCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1cn(C2CC2)c2nc(N3CCC(NC(C)=O)C3)c(F)cc2c1=O
Yield: 93.4 %

Procedure:
A mixture of ethyl 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (1.24 g), 3-acetylaminopyrrolidine (563 mg), sodium bicarbonate (437 mg) and acetonitrile (40 ml) was refluxed for 30 minutes. After evaporation to dryness under reduced pressure, water was added to the residue. The resulting crystals were filtered and recrystallized from ethanolisopropyl ether to give ethyl 7-(3-acetylamino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (1.50 g), m.p. 246°-248° C.
Reaction SMILES: [NH2:1][CH2:2][P:3]([OH:6])(=[O:5])[OH:4].O.[F:8][C:9]([F:22])([F:21])[C:10]1[CH:11]=[C:12]([N+:18]([O-:20])=[O:19])[C:13](Cl)=[CH:14][C:15]=1[Cl:16]>C(#N)C>[N+:18]([C:12]1[CH:11]=[C:10]([C:9]([F:8])([F:21])[F:22])[C:15]([Cl:16])=[CH:14][C:13]=1[NH:1][CH2:2][P:3]([OH:6])(=[O:4])[OH:5])([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)cc1Cl
Reactant: NCP(=O)(O)O
Solvent: O
Solvent: CC#N
Product: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)cc1NCP(=O)(O)O
Temperature: 120 °C
Yield: 68.2 %

Procedure:
) 3.3 g (30 mmol) of aminomethanephosphonic acid is introduced into 120 ml of water and 120 ml of acetonitrile together with 3.37 g (31.8 mmol) of soda and mixed with 7.8 g (97%, 30 mmol) of 3-trifluoromethyl-4,6-dichloronitrobenzene and refluxed for 4 hours at a bath temperature of 120° C. After the acetonitrile is drawn off in a rotary evaporator, it is extracted three times with 100 ml of ethyl acetate. The organic phase is washed with a little water. It contains starting material and is discarded. The collected aqueous phase is made acidic at pH 1 with 4N hydrochloric acid and extracted three times with 100 ml of ethyl acetate each. The organic phase is washed with water, dried, filtered and concentrated by evaporation. 6.85 g (68% of theory) of N-(2-nitro-4-trifluoromethyl-5-chloro-phenyl)-aminomethanephosphonic acid with a melting point of 207.3° C. is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH2:6][CH2:7][OH:8].C(O[CH:17](OCC)[CH2:18][NH2:19])C.Cl>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH:17]([CH2:18][NH2:19])[O:8][CH2:7][CH2:6]2
Reactant: CCOC(CN)OCC
Reactant: COc1ccc(CCO)cc1OC
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc2c(cc1OC)C(CN)OCC2
Reaction time: 48 h

Procedure:
A solution of the starting material of formula II, 3,4-dimethoxyphenethyl alcohol (108 g), described by E. Z. Khafagy and J. P. Lambooy, J. Med. Chem., 9, 936 (1966), and the starting material of formula III, aminoacetaldehyde diethyl acetal (78 g), in dry dioxane (250 ml) is stirred and cooled (ice bath) while being saturated with hydrogen chloride over a period of 1 hour. The mixture is kept at room temperature for 2 days. The crystalline precipitate is collected, washed with dry dioxane and then ether to yield the hydrochloric acid addition salt (hydrochloride) of the title compound, m.p. 250°-255° C. (dec.), after recrystallization from methanol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH3:12][C:13]1[N:18]=[C:17]2[CH2:19][O:20][C:21](=O)[C:16]2=[CH:15][CH:14]=1.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:21]1[C:16]2[C:17](=[N:18][C:13]([CH3:12])=[CH:14][CH:15]=2)[CH2:19][O:20]1
Reactant: Cc1ccc2c(n1)COC2=O
Reactant: O=C1Cc2cc(F)ccc2N1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1ccc2c(n1)COC2=C1C(=O)Nc2ccc(F)cc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 48 %

Procedure:
A solution of 5-fluoro-1,3-dihydro-indol-2-one (752 mg, 4.98 mmol.) in THF (5 mL) is placed under an argon atmosphere and cooled in an ice bath. A solution of Li bis(trimethylsilyl)amide (13.2 mL of a 1M in THF, 13.2 mmol) is added slowly at 0° C. and the resulting solution is stirred at 0° C. for 10 min. The ice-bath is removed and a solution of 2-methyl-7H-furo[3,4-b]pyridin-5-one (495 mg, 3.32 mmol) in THF (6 mL) is added dropwise to the reaction mixture. The resulting solution is stirred for 4.5 h and then poured into 50 mL of aqueous 10% HCl solution. After 10 min at room temperature, the reaction is heated to ˜90° C. for 45 min and is then stirred at room temperature for 36 h. The solid which precipitated from solution is collected by filtration and washed sequentially with small volumes of MeOH (3×5 mL), EtOAc (3×5 mL) and Et2O (3×5 mL) followed by drying to give the title compound as a yellow solid (450 mg, 48%).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]2[C:15]([N:16]=[C:17]3[C:22]=1[C:21](=[O:23])[CH2:20][CH2:19][CH2:18]3)=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[NH4+].[Cl-]>O1CCCC1.CCOCC>[CH2:1]([NH:8][C:9]1[C:10]2[C:15]([N:16]=[C:17]3[C:22]=1[CH:21]([OH:23])[CH2:20][CH2:19][CH2:18]3)=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCc2nc3ccccc3c(NCc3ccccc3)c21
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC1CCCc2nc3ccccc3c(NCc3ccccc3)c21
Reaction time: 0.5 h
Yield: 75.4 %

Procedure:
In 75 ml of dry tetrahydrofuran was dissolved 3.81 g of 9-benzylamino-3,4-dihydroacridin-1(2H)-one with mechanical stirring. The solution was cooled in ice under N2 and 5.9 ml (0.5 eq) of 1.1M LiAl4 solution in ether was added dropwise. After 0.5 hour the reaction was complete based on thin layer chromatography analysis. The excess hydride was neutralized with 0.5 ml of saturated NH4Cl solution and the inorganic salts were extracted into 30% potassium hydroxide. The tetrahydrofuran solution was decanted and evaporated to a solid which was recrystallized from 1:10 dichloromethane/EtOAc to yield 2.89 g (75%) of a solid, melting point 159° C.
Reaction SMILES: [CH:1]([S:4][CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1)([CH3:3])[CH3:2].C([Li])CCC.[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1.CCCCCC>[C:16]1([S:22]([N:9]2[CH:5]([S:4][CH:1]([CH3:3])[CH3:2])[CH2:6][CH2:7][C:8]2=[O:10])(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)SC1CCC(=O)N1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)SC1CCC(=O)N1S(=O)(=O)c1ccccc1
Yield: 46 %

Procedure:
To 2.5 g of 5-isopropylthio-pyrrolidin-2-one in 130 cm3 of tetrahydrofuran, there is added at -70° to -65° C., 10.48 cm3 of a 1.5M solution of butyllithium in hexane. This is maintained for 20 minutes at this temperature, then 2.76 g of benzenesulphonyl chloride is added in 25 cm3 of tetrahydrofuran. After allowing to return to ambient temperature, concentrating under reduced pressure, taking up with water, filtering and drying, 2.15 g of the expected product is obtained. m.p., 91°-93° C., crystallized from ethanol.
Reaction SMILES: O.C[O-].[Na+].[SH:5][CH:6]([C:10](=[O:15])[CH2:11][CH:12]([CH3:14])[CH3:13])[CH:7]([CH3:9])[CH3:8].Cl[CH:17]([C:20](=[O:24])[CH2:21][CH2:22][CH3:23])[CH2:18][CH3:19]>CO>[CH:7]([CH:6]([S:5][CH:17]([CH2:18][CH3:19])[C:20]([CH2:21][CH2:22][CH3:23])=[O:24])[C:10]([CH2:11][CH:12]([CH3:14])[CH3:13])=[O:15])([CH3:9])[CH3:8]
Reactant: CC(C)CC(=O)C(S)C(C)C
Reactant: CCCC(=O)C(Cl)CC
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCC(=O)C(CC)SC(C(=O)CC(C)C)C(C)C
Reaction time: 0.03 h

Procedure:
Into a 50 ml, round bottom, three-necked flask equipped with magnetic stirrer, pot thermometer, "Y" tube, nitrogen inlet tube, reflux condenser with cotton plug, and water bath is placed a solution of 0.65 grams (0.012 moles) of sodium methoxide dissolved in 10 ml anhydrous methanol. While maintaining the temperature of the reaction mass at 24°-27° C, a solution of 2.1 grams of 3-mercapto-2,6-dimethyl-4-heptanone dissolved in 12 ml anhydrous methanol is added to the sodium methoxide solution. 1.78 grams of 3-chloro-4-heptanone is then added to the reaction mass with stirring over a period of 2 minutes, the reaction mass temperature rising to 38° C. Two ml anhydrous methanol used as rinse is then added to the reaction mass, and with stirring the reaction mass temperature cools to 25° C. The reaction mass is continued to be stirred at 25° C for a period of 5 hours. At this point 25 ml distilled water is added, and the resulting solid dissolves. The oil phase is extracted with three 15 ml portions of methylene chloride, and the extracts are combined and washed with one 10 ml portion of water. The extracts are then dried over anhydrous sodium sulfate and gravity filtered and concentrated on a rotary evaporator using water aspirator vacuum to a weight of 3.20 grams (yellow oil). GLC analysis (8 feet × 1/4inch SE-30 column), NMR, IR and mass spectral analyses of GLC isolated material yield the information that the resulting product is 85% pure and has the structure: ##STR57##