Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([OH:31])=[C:6]([C:8]2[N:17]=[C:16]([NH:18][C@H:19]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:7]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>CC(N(C)C)=O>[F:32][C:33]1[CH:38]=[CH:37][C:36]([C:2]2[CH:3]=[CH:4][C:5]([OH:31])=[C:6]([C:8]3[N:17]=[C:16]([NH:18][C@H:19]4[CH2:23][CH2:22][NH:21][CH2:20]4)[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:9]=3)[CH:7]=2)=[CH:35][CH:34]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(-c3cc(Br)ccc3O)nc3ccccc23)C1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Oc1ccc(-c2ccc(F)cc2)cc1-c1nc(N[C@H]2CCNC2)c2ccccc2n1
Reaction time: 16 h
Yield: 27 %

Procedure:
(S)-tert-Butyl 3-(2-(5-bromo-2-hydroxyphenyl)quinazolin-4-ylamino)pyrrolidine-1-carboxylate (0.051 g, 0.105 mmol, prepared in a method analogous to that described in Synthesis 2-A), 4-fluorobenzene boronic acid (0.016 g, 0.114 mmol), palladium tetrakistriphenyl phosphine (0.028 g, 0.024 mmol) and potassium phosphate (0.051 g, 0.243 mmol) were dissolved in dimethyl acetamide (0.7 mL) and water (0.3 mL) and the mixture was heated in a microwave for 10 mins at 150° C. The mixture was filtered through a short plug of silica using ethyl acetate as eluent and the filtrate concentrated in vacuo. The residue was dissolved in methanol (1.2 mL) and 4M HCl in dioxane (1.2 mL) was added and the mixture stirred for 16 h. The mixture was concentrated and purified by ion exchange chromatography on SCX-2 Isolute acidic resin (2 g), eluting with methanol and then 1 M ammonia in methanol. The basic fractions were combined and purified by silica column chromatography, eluting with dichloromethane then 10% methanol in dichloromethane, to give the title compound as a yellow solid (0.013 g, 27%).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].C(N(CC)CC)C.[NH2:14][CH2:15][CH2:16][CH2:17][Si:18]([O:23][CH3:24])([O:21][CH3:22])[O:19][CH3:20]>O1CCOCC1>[CH3:1][N:2]([CH3:6])[C:3]([NH:14][CH2:15][CH2:16][CH2:17][Si:18]([O:23][CH3:24])([O:19][CH3:20])[O:21][CH3:22])=[O:4]
Reactant: CN(C)C(=O)Cl
Reactant: CO[Si](CCCN)(OC)OC
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CO[Si](CCCNC(=O)N(C)C)(OC)OC
Temperature: 50 °C
Yield: 82.5 %

Procedure:
5.0 g (46.5 mmol) N,N-dimethylcarbamoyl chloride (Sigma-Aldrich, Switzerland) and 40 ml, dried dioxane (Sigma-Aldrich, Switzerland) were added to a 250-mL round-bottom two-neck flask equipped with a reflux cooler. 4.71 g (46.5 mmol) triethylamine (Sigma-Aldrich, Switzerland) and 8.34 g (46.5 mmol) 3-aminopropyltrimethoxysilane (Silquest A-1110, Momentive Performance Materials Inc., USA) were added dropwise under nitrogen, with stirring. After the exothermic reaction subsided, the resulting whitish suspension was stirred at 90° C. for 3 hours. A gradual color change to orange was observed. After cooling to 50° C., the solid was separated by double filtration, and the solvent was removed at 60° C. for 1 hour on a rotary evaporator. 9.6 g of the desired silane was obtained as a brown liquid. The silane was designated as DMA1100 and used without further purification.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:31]=[CH:30][C:16]([CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=3)[C:24]([O:26][CH3:27])=[O:25])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH:32](=O)[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][N:18]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:19]3[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=3)[C:24]([O:26][CH3:27])=[O:25])=[CH:30][CH:31]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCC=O
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc(F)c(C(=O)OC)c3)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CCCCCCN(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)c1ccc(F)c(C(=O)OC)c1
Temperature: 70 °C
Reaction time: 3.5 h
Yield: 76.7 %

Procedure:
To a suspension of methyl 5-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-2-fluorobenzoate (500 mg, 1.20 mmol) in anhydrous DCE (8 mL) were added hexanal (0.25 mL, 2.07 mmol) and sodium triacetoxyborohydride (825 mg, 3.89 mmol). The reaction mixture was stirred at 70° C. for 3.5 hrs. Then the reaction mixture was diluted with water (10 mL) and extracted with DCM (2×10 mL). The combined organic layers were dried over MgSO4 and the solvents were removed under reduced pressure. Purification by flash chromatography on silicagel (cHex/EtOAc) gave 460 mg (77%) of the title compound as a pale yellow oil. HPLC, Rt: 6.3 min (purity: 99.9%). 1H NMR (CDCl3) δ: 7.47 (d, J=8.3 Hz, 2H), 7.44 (d, J=8.3 Hz, 2H), 7.18 (m, 5H), 6.95 (dd, J=10.1, 9.0 Hz, 1H), 6.74 (m, 1H), 4.52 (s, 2H), 3.91 (s, 3H), 3.38 (t, J=7.7 Hz, 2H), 2.63 (t, J=7.7 Hz, 2H), 1.60 (m, 4H), 1.42-1.25 (m, 8H), 0.92 (m, 6H).
Reaction SMILES: [C:1]1([C:7]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]3[CH2:12][NH:13][CH2:14][CH2:15][N:10]3[C:9](=[O:16])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N12CCCN=C1CCCCC2.ClC(Cl)(Cl)[C:36]([NH:38][C:39]1[CH:48]=[CH:47][CH:46]=[C:45]2[C:40]=1[CH:41]=[CH:42][CH:43]=[N:44]2)=[O:37]>C(#N)C.O>[O:16]=[C:9]1[N:10]2[CH2:15][CH2:14][N:13]([C:36]([NH:38][C:39]3[CH:48]=[CH:47][CH:46]=[C:45]4[C:40]=3[CH:41]=[CH:42][CH:43]=[N:44]4)=[O:37])[CH2:12][CH:11]2[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[O:8]1
Reactant: O=C(Nc1cccc2ncccc12)C(Cl)(Cl)Cl
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)C2CNCCN12
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: O=C(Nc1cccc2ncccc12)N1CCN2C(=O)OC(c3ccccc3)(c3ccccc3)C2C1
Yield: 32.9 %

Procedure:
To a solution of hexahydro-1,1-diphenyl-3H-oxazolo[3,4-a]pyrazin-3-one (0.15 g, 0.51 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.19 g, 1.3 mmol) in acetonitrile (6 mL) was added 2,2,2-trichloro-N-(5-quinolinyl)acetamide (0.16 g, 0.55 mmol), and the mixture was heated under reflux for 6 hours. The reaction solution was diluted with water and then extracted with ethyl acetate. The organic layer was washed twice with water, once with saturated brine, and dried over magnesium sulfate. The solid was filtered off, and the filtrate was concentrated. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:1 to ethyl acetate), and then recrystallized from hexane-ethyl acetate to obtain the title compound (78 mg, yield 33%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.Cl.[CH3:22][O:23]C(=O)[C@H](CO)N.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH:16]([CH2:22][OH:23])[NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: COC(=O)[C@@H](N)CO
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1noc(C)c1Cn1cc(N2C(=O)NC(CO)C2=O)cn1
Temperature: 25 °C
Yield: 5.5 %

Procedure:
4-((4-isocyanato-1H-pyrazol-1-yl)methyl)-3,5-dimethylisoxazole (example 10-1) (784 mg, 3.6 mmol), serine methyl ester hydrochloride (672 mg, 4.32 mmol) and triethylamine (1 mL, 7.2 mmol) were refluxed in toluene (16 mL) for 8 hours. The reaction was allowed to cool to room temperature and then the solution was concentrated on the rotovap. The product was purified by reverse phase HPLC (5 to 95% acetonitrile in H2O:16 minute gradient) to afford 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-5-(hydroxymethyl)imidazolidine-2,4-dione as a white solid (60 mg, 25%). 1H NMR (CDCl3, 400 MHz): δ (s, 3H), 2.40 (s, 3H), 3.13-3.07 (m, 1H), 3.94-3.93 (d, J=4 Hz, 2H), 4.21-4.19 (t, J=4 Hz, 1H), 5.03 (s, 2H), 6.68 (bs, 1H), 7.87 (s, 1H), 7.99 (s, 1H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 3 μM.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][O:7][CH:8]1[C:12]2[N:13]=[CH:14][NH:15][C:16](=O)[C:11]=2[CH2:10][CH2:9]1.N>C(Cl)(Cl)Cl>[Cl:3][C:16]1[C:11]2[CH2:10][CH2:9][CH:8]([O:7][CH3:6])[C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: COC1CCc2c1nc[nH]c2=O
Reactant: O=P(Cl)(Cl)Cl
Agent: N
Solvent: ClC(Cl)Cl
Product: COC1CCc2c(Cl)ncnc21
Temperature: 25 °C

Procedure:
2.5 ml of phosphorus oxychloride were added to 1.0 g of 6,7-dihydro-7-methoxy-3H,5H-cyclopenta[d]pyrimidin-4-one [prepared as described in step (d) above], and the mixture was heated under reflux for 5 minutes. The mixture was then cooled to room temperature, 20 ml of chloroform were added, and the mixture was then poured into ice-water. The cold mixture was made alkaline by the addition of concentrated aqueous ammonia, and then the chloroform layer was separated. This chloroform layer was washed with water, dried over anhydrous sodium sulfate and treated with active carbon. The chloroform was then evaporated off under reduced pressure, to give 1.01 g of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:8]=[C:7]([CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[S:18][C:14]=3[C:13](=[O:25])[N:12]([CH:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]3)[C:11]2=[O:39])[O:6][N:5]=1.[ClH:40]>C(Cl)Cl.O1CCOCC1>[ClH:40].[CH3:1][O:2][CH2:3][C:4]1[N:8]=[C:7]([CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[S:18][C:14]=3[C:13](=[O:25])[N:12]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:11]2=[O:39])[O:6][N:5]=1
Reactant: COCc1noc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COCc1noc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)n1

Procedure:
A solution of tert-butyl 4-[1-{[3-(methoxymethyl)-1,2,4-oxadiazol-5-yl]methyl}-2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl]piperidine-1-carboxylate (6.61 g; compound B16) in DCM (50 ml) is reacted with a solution of hydrogen chloride in 1,4-dioxane (7.5 ml, 4.0 M) according to the procedure described in example B28 to afford the title compound as a solid.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:12]([C:30]2[CH:31]=[CH:32][C:33]3[O:37][CH2:36][CH2:35][C:34]=3[CH:38]=2)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=3)[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>CO.C1COCC1.O>[C:1]([O:5][C@@H:6]([C:11]1[C:12]([C:30]2[CH:31]=[CH:32][C:33]3[O:37][CH2:36][CH2:35][C:34]=3[CH:38]=2)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=3)[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2c(ccn2Cc2ccc(F)c(F)c2)c1-c1ccc2c(c1)CCO2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc2c(ccn2Cc2ccc(F)c(F)c2)c(-c2ccc3c(c2)CCO3)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 70 °C
Yield: 85.5 %

Procedure:
A solution of (S)-methyl 2-(tert-butoxy)-2-(1-(3,4-difluorobenzyl)-4-(2,3-dihydrobenzofuran-5-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate (126 mg, 0.242 mmol) in MeOH/THF/water=2/2/1 (10 mL) was treated with LiOH (110 mg, 4.59 mmol) and the mixture was heated at 70° C. until the reaction was judged complete. The mixture was concentrated, water was added and then adjusted to pH 2 with 1N HCl. The mixture was extracted with ethyl acetate. The extracts were washed with brine, dried over Na2SO4, filtered and concentrated to afford (S)-2-(tert-butoxy)-2-(1-(3,4-difluorobenzyl)-4-(2,3-dihydrobenzofuran-5-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetic acid (105 mg, 0.207 mmol, 86% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.62-7.47 (m, 1 H), 7.39-7.27 (m, 1 H), 7.16-7.05 (m, 2 H), 7.05-6.96 (m, 2 H), 6.92 (dd, J=4.7, 8.2 Hz, 1 H), 6.30-6.16 (m, 1 H), 5.64-5.54 (m, 1 H), 5.51-5.43 (m, 1 H), 5.43-5.33 (m, 1 H), 4.67 (td, J=4.2, 8.7 Hz, 2 H), 3.41-3.20 (m, 2 H), 2.70 (s, 3H), 0.99-0.89 (s, 9 H); LC/MS ES+=507.35 (M+1).
Reaction SMILES: [N+]([C:4]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])([O-])=O.[N:16]1([CH2:22][CH2:23][OH:24])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.[OH-].[K+]>CN(C=O)C.O>[N:16]1([CH2:22][CH2:23][O:24][C:4]2[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:5]=2[C:6]#[N:7])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: OCCN1CCOCC1
Reactant: N#Cc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(C(F)(F)F)cc1OCCN1CCOCC1
Temperature: 0 °C

Procedure:
To a solution of 2-nitro-4-trifluoromethyl benzonitrile (0.5 g, 2.3 mmol) and 2-morpholin-4-yl-ethanol (0.37 g, 0.34 ml, 2.8 mmol) in DMF (4 ml) was added dropwise a solution of KOH (0.23 g, 4.1 mmol) in water (1.5 ml). After 10 min the reaction was poured into ice water and the white crystalline product collected by filtration, washed with water and dried (0.5 g, 72%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[CH3:17]O>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(Cl)c1Cl
Yield: 92 %

Procedure:
A solution of 2,3-dichlorobenzoic acid (100 g, 0.526 mol) in methanol (1 L), was added H2SO4 (20 mL). The solution was stirred under reflux overnight. The reaction mixture was cooled and concentrated. The resulting residue was diluted with water (100 mL) and ethyl acetate (1 L). Then the organic layer was washed with aq. NaHCO3 and brine, dried over Na2SO4, filtered and the filtrate was concentrated to provide the titled compound (99 g, 92%), as a white solid; 1H NMR (300 MHz, CDCl3) δ ppm 3.95 (s, 3H), 7.27 (t, J=7.8 Hz, 1H), 7.60 (dd, J=1.8, 7.8 Hz, 1H), 7.66 (dd, J=1.8, 7.8 Hz, 1H).
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH:7]2[C:19]([O:21]C)=[O:20])=[O:5])[CH2:3][CH2:2]1.[OH-].[Na+:24]>CO.O>[CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:8][CH:7]2[C:19]([O-:21])=[O:20])=[O:5])[CH2:3][CH2:2]1.[Na+:24]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(C(=O)C2CC2)C(C(=O)[O-])C1
Reaction time: 24 h
Yield: 106.9 %

Procedure:
To a solution of 11.5 g (36.8 mmol) of 1-tert-butyl 3-methyl 4-cyclopropanecarbonylpiperazine-1,3-dicarboxylate in 127.5 ml of methanol are added 1.77 g of sodium hydroxide dissolved in 22.5 ml of water. The mixture is stirred for 24 hours and the reaction medium is then concentrated under reduced pressure and the residue co-evaporated with toluene, to give 12.6 g of sodium 1-tert-butyl 4-cyclopropanecarbonylpiperazine-1,3-dicarboxylate in the form of a white powder after drying, and is used as obtained in the rest of the synthesis.
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][C:4]([C:7](C=CC(O)=O)=[O:8])=[CH:3][CH:2]=1.C=CC=C.C1(C=CC(O)=CC=1)[OH:20].[C:27]1([CH3:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:27]1([CH3:33])[CH:32]=[CH:31][C:30]([C@H:5]2[C@H:4]([C:7]([OH:8])=[O:20])[CH2:3][CH:2]=[CH:1][CH2:6]2)=[CH:29][CH:28]=1
Reactant: Oc1ccc(O)cc1
Reactant: Cc1ccccc1
Reactant: Cc1ccc(C(=O)C=CC(=O)O)cc1
Agent: C=CC=C
Product: Cc1ccc([C@@H]2CC=CC[C@H]2C(=O)O)cc1
Reaction time: 0.25 h

Procedure:
275 g (1.695 mol) of 3-(4-toluoyl)acrylic acid (commercially available from Aldrich) is reacted according to a known process [cf.: Eur. J. Med. Chem. 11, 493 (1976)]at about 200° C. and about 20 bar for 22 h with 580 ml of 1,3-butadiene (measured in condensed form) in 480 ml of toluene with the addition of 3 g of hydroquinone. The crude mixture is diluted with toluene and extracted with 0.5M aqueous sodium hydroxide solution. The aqueous phases are then acidified with 1M hydrochloric acid and extracted with ether. The ethereal solutions are dried with sodium sulphate, evaporated and redissolved in toluene. After boiling with 5 g of active carbon for 15 minutes, the mixture is filtered off hot with suction and the solvent is evaporated down to about 120-160 ml; at 0°-4° C. 124 g (573 mmol) of product crystallise out. The filtrate is concentrated somewhat further and cooled again for recrystallisation. On repeating this process altogether a further 42 g (194 mmol) of product are obtained.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=3)=[CH:7][CH:8]=[N:9]2)=[N:4][CH:3]=1.[H][H]>CO.[Pd].CCOC(C)=O>[N:9]1[C:10]2[CH2:11][CH2:2][CH2:3][NH:4][C:5]=2[C:6]([O:12][C:13]2[CH:14]=[CH:15][C:16]([NH2:19])=[CH:17][CH:18]=2)=[CH:7][CH:8]=1
Reactant: Nc1ccc(Oc2ccnc3cc(Br)cnc23)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccc(Oc2ccnc3c2NCCC3)cc1
Reaction time: 8 h

Procedure:
To a solution of 4-(7-bromo-1,5-naphthyridin-4-yloxy)benzenamine (0.150 g, 0.474 mmol) in MeOH (7 mL) at RT was added a suspension of 10% palladium on carbon (0.0505 g, 0.474 mmol) in EtOAc (2 mL). The mixture was subjected to an atmosphere of hydrogen (balloon) and stirred overnight. After 18 hrs, the mixture was filtered over celite and concentrated in vacuo. The resulting tan foam, crude 4-(5,6,7,8-tetrahydro-1,5-naphthyridin-4-yloxy)benzenamine, was advanced without further purification. MH+=242.2@0.49 min
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]([CH:12]=[CH:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[CH2:5][CH:6]=[CH:7][C:8]([O:10][CH3:11])=[O:9].[H][H]>C(O)C.[Pd]>[OH:1][CH2:2][CH2:3][CH:4]([CH2:12][CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: [H][H]
Reactant: COC(=O)C=CCC(C=Cc1cccnc1)CCO
Agent: [Pd]
Solvent: CCO
Product: COC(=O)CCCC(CCO)CCc1cccnc1

Procedure:
A solution of 1.75 g methyl 7-hydroxy-5-[2-(3-pyridyl)ethenyl]-hept-2-enoate in 50 ml ethanol is hydrogenated with 0.35 g 10% palladium on charcoal at 3 atmospheres (=3.04 bar) pressure of hydrogen and room temperature for 21 h. The catalyst is filtered off and washed with ethanol (4×10 ml). The filtrate is evaporated to give a yellow oil which is chromatographed to yield methyl 7-hydroxy-5-[2-(3-pyridyl)ethyl]-heptanoate.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][CH2:8][N:7]([CH:14]3[CH2:18][CH2:17][CH:16]([CH3:19])[CH2:15]3)[C:6]=2[N:20]=1.[NH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]=1[O:31][CH3:32].C(O)C>Cl.O>[CH3:32][O:31][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:22]=1[NH:21][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][CH2:8][N:7]([CH:14]3[CH2:18][CH2:17][CH:16]([CH3:19])[CH2:15]3)[C:6]=2[N:20]=1)[C:26]([OH:28])=[O:27]
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: CC1CCC(N2CCC(=O)N(C)c3cnc(Cl)nc32)C1
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCC(C)C1)CCC(=O)N2C
Yield: 74.4 %

Procedure:
A mixture of 0.09 g (0.0003 mole) of (rac)-2-chloro-5-methyl-9-(3-methyl-cyclopentyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-58), 0.06 g (0.00036 mole) of 4-amino-3-methoxy-benzoic acid, 0.5 mL of ethanol, 2 mL of water, and 2 drops of hydrochloric acid was heated at 100 degrees overnight. Upon cooling, a precipitate formed which was collected by filtration to give 0.095 g of (rac)-3-methoxy-4-[5-methyl-9-(3-methyl-cyclopentyl)-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino]-benzoic acid (I-58a) as an off-white solid.
Reaction SMILES: BrC1C=C(C#N)C=NC=1.[I-:10].[Na+].[CH3:12][NH:13][C@@H:14]1[CH2:19][CH2:18]CC[C@H:15]1[NH:20][CH3:21]>O1CCOCC1.[Cu]I>[I:10][C:18]1[CH:21]=[N:20][CH:15]=[C:14]([N+:13]#[C-:12])[CH:19]=1
Reactant: CN[C@@H]1CCCC[C@H]1NC
Reactant: [I-]
Agent: [Cu]I
Agent: N#Cc1cncc(Br)c1
Agent: [Na+]
Solvent: C1COCCO1
Product: [C-]#[N+]c1cncc(I)c1
Temperature: 120 °C

Procedure:
To the reaction mixture of 5-bromo-3-cyanopyridine (3 g, 15.9 mmol, 1 eq), sodium iodide (4.77 g, 2 eq), copper(I) iodide (303 mg, 0.1 eq) in anhydrous 1,4-dioxane (40 mL) under nitrogen atmosphere was added trans-N,N′-dimethylcyclohexane-1,2-diamine (0.52 mL, 0.2 eq). After the reaction mixture was heated at 120° C. for 16 hours, it was cooled to room temperature and partitioned between aqueous ammonium chloride and ethyl acetate. The organic layer was isolated, washed with saturated aqueous sodium bicarbonate, brine, and dried with anhydrous sodium chloride. The upper clear solution was decanted, concentrated, and the brown oily residue was subject to a column chromatography (EtOAc-Hex 1:15 to 1:4) yielding 3-iodo-5-isocyanopyridine as a white solid in the amount of 2.41 g.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][NH2:6])[CH3:2].[C:9](N1C=CN=C1)(N1C=CN=C1)=[O:10].[CH2:21]([N:23]([CH2:36][CH3:37])[CH2:24][CH2:25][NH:26][CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:22].[C:38]([OH:50])(=[O:49])[CH2:39][C:40]([CH2:45][C:46]([OH:48])=[O:47])([C:42]([OH:44])=[O:43])[OH:41]>O1CCCC1.CO.C(OCC)C>[C:38]([OH:50])(=[O:49])[CH2:39][C:40]([CH2:45][C:46]([OH:48])=[O:47])([C:42]([OH:44])=[O:43])[OH:41].[CH2:36]([N:23]([CH2:21][CH3:22])[CH2:24][CH2:25][N:26]([CH2:27][CH2:28][O:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:9]([NH:6][CH2:5][CH2:4][N:3]([CH2:7][CH3:8])[CH2:1][CH3:2])=[O:10])[CH3:37]
Reactant: CCN(CC)CCN
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCN(CC)CCNCCOc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CO
Product: CCN(CC)CCNC(=O)N(CCOc1ccccc1)CCN(CC)CC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2.72 g (0.0235 mole) of N,N-diethylethylenediamine and 4.37 g (0.027 mole) of 1,1'-carbonyldiimidazole in 400 ml of tetrahydrofuran was stirred at room temperature for 1 hr. A solution of 5.11 g (0.0216 mole) of N,N-diethyl-N'-(2-phenoxyethyl)-1,2-ethanediamine in 50 ml of tetrahydrofuran was added, and the solution was refluxed for 20 hr. The solvent was removed in vacuo and the residue was dissolved in a mixture of 250 ml of diethyl ether and 250 ml of methylene chloride. The solution was extracted with several portions of water and was dried over magnesium sulfate. The solvent was removed in vacuo to give an oil. A solution of the oil in methanol was treated with a two-fold excess of citric acid, diethyl ether was added, and 12.22 g (74.2%) of the title compound crystallized as a white crystalline solid, m.p. 80°-85° C.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:14]3=[CH:15][C:16]4[O:20][CH2:19][O:18][C:17]=4[CH:21]=[C:13]3[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=1.O=C1C2(C3=CC4OCOC=4C=C3OC2)C2C(=CC=CC=2)N1CC1C=CC=CC=1C(OC)=O>>[O:1]=[C:2]1[C:10]2([C:14]3=[CH:15][C:16]4[O:20][CH2:19][O:18][C:17]=4[CH:21]=[C:13]3[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:31][CH:32]=1
Reactant: COC(=O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)cc1
Agent: COC(=O)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Product: O=C(O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)cc1

Procedure:
Following the procedure described in EXAMPLE 6, and making non-critical variations using methyl 4-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]benzoate to replace methyl 2-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]benzoate, the title compound was obtained (100%): 1H NMR (300 MHz, CDCl3) δ 12.96 (s, 1H), 7.90 (d, 2H), 7.43 (d, 2H), 7.22 (t, 1H), 7.17 (d, 1H), 7.00 (t, 1H), 6.94 (d, 1H), 6.68 (s, 1H), 6.21 (s, 1H), 5.90 (s, 2H), 4.98 (s, 2H), 4.76 (ABq, 2H); 13C NMR (75 MHz, CDCl3) δ 177.4, 167.5, 156.0, 148.9, 142.6, 142.3, 141.8, 132.1, 130.5, 130.3, 129.3, 127.7, 124.2, 123.7, 120.1, 109.9, 103.5, 101.9, 93.8, 80.4, 58.0, 43.4.