Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]12[CH2:22][CH:6]([N:7]([C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][CH2:18][C:19](O)=O)=[CH:13][CH:12]=3)=[O:10])[CH2:8]1)[CH2:5][C:4]([CH3:24])([CH3:23])[CH2:3]2.[C:25]([O:29][CH3:30])(=[O:28])[CH:26]=[CH2:27].C=O.O>C1(C)C=CC=CC=1>[CH3:30][O:29][C:25]([CH:26]1[CH2:19][CH2:18][N:17]([C:14]2[CH:13]=[CH:12][C:11]([C:9]([N:7]3[CH2:8][C:2]4([CH3:1])[CH2:22][CH:6]3[CH2:5][C:4]([CH3:23])([CH3:24])[CH2:3]4)=[O:10])=[CH:16][CH:15]=2)[CH2:27]1)=[O:28]
Reactant: C=CC(=O)OC
Reactant: CC1(C)CC2CC(C)(CN2C(=O)c2ccc(NCC(=O)O)cc2)C1
Agent: C=O
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)C1CCN(c2ccc(C(=O)N3CC4(C)CC3CC(C)(C)C4)cc2)C1
Reaction time: 16 h
Yield: 51.8 %

Procedure:
[4-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenylamino]-acetic acid (1.3 g, 3.93 mmol), methyl acrylate (275 μl, 3.03 mmol) and paraformaldehyde (636 mg, 21.18 mmol) were dissolved in toluene (180 ml) in a three necked reaction flask equipped with a water separator. The mixture was stirred at reflux temp. for 3 hrs at which time a small portion of methyl acrylate (40 μl) was added. The resulting mixture was stirred at reflux temp. for an additional 16 hrs. and evaporated. The residue was dissolved in EtOAc (50 ml) and washed with water (2×25 ml), dried (Na2SO4), filtered and evaporated in vacuo. The resulting residue was purified by column chromatography (silica gel) using first pure heptane (300 ml) followed by a mixture of EtOAc-Heptane (1:1) as eluents. Pure fractions were collected and evaporated to dryness affording 603 mg (52%) of 1-[4-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenyl]-pyrrolidine-3-carboxylic acid methyl ester as an oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[N:13]=[CH:12][CH:11]=[CH:10][N:9]=1.[OH-].[Na+]>C(O)C>[N:9]1[CH:10]=[CH:11][CH:12]=[N:13][C:8]=1[N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: Clc1ncccn1
Reactant: C1CNCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: c1cnc(N2CCNCC2)nc1

Procedure:
To a solution of anhydrous piperazine (95 g; 1 mol) in ethanol (475 ml), there was added 2-chloropyrimidine (22.9 g; 0.2 mol), and the resultant mixture was stirred at room temperature for 3 hours. After completion of the reaction, a 5% aqueous sodium hydroxide solution was added, followed by extraction with chloroform. The chloroform layer was washed thrice with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was distilled to give 1-(2-pyrimidinyl)piperazine. B.P., 131°-132° C./1.5 mmHg.
Reaction SMILES: C(OC([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11]([OH:22])([C:16]1[CH:17]=[N:18][CH:19]=[N:20][CH:21]=1)[CH2:12]2)=O)(C)(C)C.C(Cl)[Cl:24]>Cl.O1CCOCC1>[ClH:24].[N:18]1[CH:17]=[C:16]([C:11]2([OH:22])[CH2:12][CH:13]3[NH:8][CH:9]([CH2:15][CH2:14]3)[CH2:10]2)[CH:21]=[N:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(O)(c1cncnc1)C2
Reactant: ClCCl
Agent: Cl
Solvent: C1COCCO1
Product: OC1(c2cncnc2)CC2CCC(C1)N2
Temperature: 45 °C
Reaction time: 1 h

Procedure:
3-Hydroxy-3-pyrimidin-5-yl-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.14 g, 0.46 mmol) was dissolved in a solution of hydrogen chloride in dioxane (4 N, 1.5 mL). The mixture was stirred for 1 hour at 45° C., DCM (3 mL) added and stirred for 5 minutes. The solvent was removed by evaporation under vacuum afford the title compound. LCMS m/z 206.3 [M+H]+. R.T.=2.90 min (Analytical Method 3).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][C:34]=2[CH:36]=O)[CH:29]=[CH:28]1>ClCCCl.ClCCl>[CH2:1]([NH:8][CH2:36][C:34]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:35]=1[NH:27][CH:28]=[CH:29]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: O=Cc1cccc2cc[nH]c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CC(=O)O
Product: c1ccc(CNCc2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 82 %

Procedure:
Add benzyl amine (7.5 g, 69.7 mmol), sodium triacetoxyborohydride (20.7 g, 97.5 mmol) and acetic acid (6.0 mL, 104.6 mmol) to a solution of 1H-indole-7-carboxaldehyde (10.1 g, 69.7 mmol) in 1,2-dichloroethane (100 mL). Stir at ambient temperature for 24 hours. Dilute with dichloromethane and wash the organic layer with water. Dry with magnesium sulfate and concentrate. Purify by chromatography (silica gel; ethyl acetate/methanol; 10:0.3 to 10:1) to yield a light yellow solid (13.5 g, 82%). MS (ESI) m/z 237 (M+H)+.
Reaction SMILES: [C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[C:16]([F:18])[C:15]([N:19]3[CH2:24][CH2:23][C:22]([O:28][P:29](=[O:32])([OH:31])[OH:30])([CH2:25][O:26][CH3:27])[CH2:21][CH2:20]3)=[C:14]([F:33])[CH:13]=2)[CH2:7]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+:38].[K+]>>[K+:38].[K+:38].[C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[C:16]([F:18])[C:15]([N:19]3[CH2:24][CH2:23][C:22]([O:28][P:29](=[O:30])([O-:31])[O-:32])([CH2:25][O:26][CH3:27])[CH2:21][CH2:20]3)=[C:14]([F:33])[CH:13]=2)[CH2:7]1)(=[O:3])[CH3:2]
Reactant: COCC1(OP(=O)(O)O)CCN(c2c(F)cc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COCC1(OP(=O)([O-])[O-])CCN(c2c(F)cc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)CC1
Temperature: 7.5 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
To a solution of phosphoric acid mono-(1-{4-[(S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2,6-difluoro-phenyl}-4-methoxymethyl-piperidin-4-yl) ester (5.0g, 0.010mol) anhydrous methanol (50 ml) at 0-5° C., under argon, was added anhydrous potassium carbonate (1.38 gm, 0.010 mol). The reaction mixture was stirred at 5-10° C. for 2 hours. The ice-bath was removed and the stirring continued further at 30-35° C. for 1 hour. The reaction mixture was filtered and the filtrate evaporated under reduced pressure. Acetone (25 ml) was added to the residue and triturated. The solvent was decanted. This procedure was repeated twice with acetone (50 ml). Acetone after the third trituration was decanted and the residue dried under reduced pressure to obtain the product as white solid, 5.1 g, in 89% yield, Mp>165° C. (dec); MF: C19H24F2Na2N3O8P. Aqueous solubility at pH 7 was >200 mg/ml.
Reaction SMILES: Cl.CN.C1([CH2:10][NH2:11])CCCCC1.[O:12]=[C:13]1[C:21]2([CH2:25][O:24][C:23]3[CH:26]=[C:27]4[C:31](=[CH:32][C:22]2=3)[CH2:30][CH2:29][O:28]4)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]1[CH2:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][CH:35]=1.O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[CH3:10][NH:11][C:38](=[O:39])[C:37]1[CH:36]=[CH:35][C:34]([CH2:33][N:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]3([CH2:25][O:24][C:23]4[CH:26]=[C:27]5[C:31](=[CH:32][C:22]3=4)[CH2:30][CH2:29][O:28]5)[C:13]2=[O:12])=[CH:42][CH:41]=1
Reactant: O=C(O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1
Reactant: NCC1CCCCC1
Agent: CN
Agent: Cl
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: CNC(=O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using methylamine hydrochloride to replace cyclohexanemethylamine, and 4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, N-methyl-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide was obtained (86%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ7.71 (d, J=8.0 Hz, 2H), 7.34 (d, J=8.0 Hz, 2H), 7.22-7.12 (m, 2H), 7.02 (t, J=7.6 Hz, 1H), 6.73 (d, J=7.6 Hz, 1H), 6.57-6.45 (m, 1H), 6.42 (s, 1H), 6.39 (s, 1H), 4.95 (ABq, 2H), 4.81 (ABq, 2H), 4.53-4.34 (m, 2H), 2.95 (d, J=4.0 Hz, 3H), 2.90-2.73 (m, 2H); 13C NMR (75 MHz, CDCl3) δ178.2, 167.5, 161.9, 161.4, 141.8, 139.0, 134.2, 132.5, 128.8, 127.6, 127.4, 124.0, 123.7, 120.0, 119.8, 118.7, 109.2, 93.3, 80.6, 72.4, 57.7, 43.8, 28.9, 26.8; MS (ES+) m/z 427.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[C:6]([CH3:9])[N:5]=[CH:4][N:3]=1.[Br-].[F:11][C:12]([F:23])([F:22])[C:13]1[CH:18]=[CH:17][C:16]([C:19]#[C:20][Zn+])=[CH:15][CH:14]=1.O1CCCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C)C=O>[Cl:1][C:2]1[C:7]([C:20]#[C:19][C:16]2[CH:17]=[CH:18][C:13]([C:12]([F:11])([F:22])[F:23])=[CH:14][CH:15]=2)=[C:6]([CH3:9])[N:5]=[CH:4][N:3]=1
Reactant: Cc1ncnc(Cl)c1I
Reactant: FC(F)(F)c1ccc(C#C[Zn+])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1ncnc(Cl)c1C#Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
4-Chloro-5-iodo-6-methylpyrimidine and [4-(trifluoromethyl)phenyl]ethynylzinc bromide were reacted in a solvent mixture of tetrahydrofuran and N,N-dimethylformamide (1:1) in the presence of tetrakis(triphenylphosphine)palladium while stirring under room temperature to heating to obtain a target substance. The target substance was subjected to e.g., proton nuclear magnetic resonance spectrometry (1H-NMR) and mass spectrometry (MS) and confirmed as the titled compound. Furthermore, MS measurement result is shown.
Reaction SMILES: [C:1]1([C:7]2[N:11]3[CH:12]=[CH:13][CH:14]=[N:15][C:10]3=[N:9][C:8]=2[C:16]2[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl.Cl.[S:33]1[CH:37]=[CH:36][N:35]=[C:34]1[C:38]1[NH:42][N:41]=[C:40]([CH:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[N:39]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1.C(Cl)(Cl)Cl>[C:1]1([C:7]2[N:11]3[CH:12]=[CH:13][CH:14]=[N:15][C:10]3=[N:9][C:8]=2[C:16]2[CH:23]=[CH:22][C:19]([CH2:20][N:46]3[CH2:45][CH2:44][CH:43]([C:40]4[N:39]=[C:38]([C:34]5[S:33][CH:37]=[CH:36][N:35]=5)[NH:42][N:41]=4)[CH2:48][CH2:47]3)=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1csc(-c2nc(C3CCNCC3)n[nH]2)n1
Reactant: O=Cc1ccc(-c2nc3ncccn3c2-c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: c1ccc(-c2c(-c3ccc(CN4CCC(c5n[nH]c(-c6nccs6)n5)CC4)cc3)nc3ncccn23)cc1
Reaction time: 0.08 h

Procedure:
To a solution of 0.340 g (1.137 mM) of 4-(3-phenylimidazo[1,2-a]pyrimidin-2-yl)benzaldehyde in 7 mL of THF is added triethylamine (2 eq). The reaction mixture is stirred for 5 minutes. To this solution is added 4-[5-(1,3-thiazol-2-yl)-1H-1,2,4-triazol-3-yl]piperidine dihydrochloride (Intermediate G) (1.5 eq) followed by acetic acid (2.5 eq). The reaction mixture is stirred for 10 minutes. To this mixture is added NaBH(OAc)3 (6 eq) over a period of 60 minutes. The reaction mixture is stirred overnight. The reaction mixture is quenched with methanol and concentrated. The residue obtained is taken up in chloroform and washed with water, dried and concentrated. The crude is purified on a flash column chromatography to obtain the desired compound.
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][C:7]([C:9]1[NH:10][CH:11]=[CH:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)=[O:8].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C.C(#N)C>[N+:20]([C:17]1[CH:18]=[CH:19][C:14]([C:13]2[CH:12]=[CH:11][NH:10][C:9]=2[C:7]([NH2:6])=[O:8])=[CH:15][CH:16]=1)([O-:22])=[O:21]
Reactant: COc1ccc(CNC(=O)c2[nH]ccc2-c2ccc([N+](=O)[O-])cc2)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: NC(=O)c1[nH]ccc1-c1ccc([N+](=O)[O-])cc1
Temperature: 65 °C
Reaction time: 4.5 h
Yield: 42.1 %

Procedure:
To 1.96 g (5.139 mmol) of 2-(2,4-dimethoxybenzylamino)carbonyl-3-(4-nitrophenyl)-1H-pyrrole dissolved in 55 cm3 of toluene are added, at a temperature in the region of 20° C. under an argon atmosphere, 2.224 g (11.69 mmol) p-toluenesulfonic acid monohydrate. After stirring for 4.5 hours at a temperature in the region of 65° C., the reaction mixture is diluted with 70 cm3 of ethyl acetate and then washed successively with three times 50 cm3 of water and 50 cm3 of saturated aqueous sodium chloride solution. The resulting organic phase is dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give a yellow solid, which is then stirred in 15 cm3 of acetonitrile for 16 hours. After filtering through a No. 3 sinter funnel, the solid is washed with twice 4 cm3 of ice-cold acetonitrile and then dried under reduced pressure (2.7 kPa) at a temperature in the region of 35° C. for 5 hours to give 0.5 g of 3-(4-nitrophenyl)-1H-pyrrole-2-carboxamide in the form of an ochre-coloured solid; EI: m/z=231: M+ base peak; m/z=214 [M−NH3]+; m/z=184 [M-HNO2]+.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]2[C:14]([F:17])([F:16])[CH2:15][CH:9]1[CH2:10][CH:11](CC([O-])=O)[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=[O:23].[K+].[K+]>CO>[CH2:1]([N:8]1[CH:13]2[C:14]([F:17])([F:16])[CH2:15][CH:9]1[CH2:10][CH:11]([OH:23])[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])CC1CC2CC(F)(F)C(C1)N2Cc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: OC1CC2CC(F)(F)C(C1)N2Cc1ccccc1

Procedure:
A solution of compound 116f (1.48 g, 4 mmol, 1.0 eq) and K2CO3 (1.1 g, 8 mmol, 2.0 eq) in MeOH (20 mL) was stirred at room temperature for 16 h. The mixture was quenched with water (100 mL), extracted with EA (100 mL) two times, the organic layer was combined, dried over Na2SO4 and concentrated to give 8-benzyl-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-ol 116g as a colorless oil, 1.02 g, crude yield: 100° A. MS: calc'd (MH+) 254, measured (MH+) 254.
Reaction SMILES: ClC1C=CC(N2[C:16]([C:17]([NH:19][CH3:20])=[O:18])=[C:15]3[C:10]([CH:11]=[C:12]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[C:13]([CH:21]4[CH2:23][CH2:22]4)=[CH:14]3)=[N:9]2)=CC=1.[F:29][C:30]1[CH:31]=[C:32]([CH:34]=[CH:35][C:36]=1[CH3:37])[NH2:33]>>[CH:21]1([C:13]2[C:12]([NH:24][S:25]([CH3:28])(=[O:26])=[O:27])=[CH:11][C:10]3[C:15](=[C:16]([C:17]([NH:19][CH3:20])=[O:18])[N:33]([C:32]4[CH:34]=[CH:35][C:36]([CH3:37])=[C:30]([F:29])[CH:31]=4)[N:9]=3)[CH:14]=2)[CH2:22][CH2:23]1
Reactant: CNC(=O)c1c2cc(C3CC3)c(NS(C)(=O)=O)cc2nn1-c1ccc(Cl)cc1
Reactant: Cc1ccc(N)cc1F
Product: CNC(=O)c1c2cc(C3CC3)c(NS(C)(=O)=O)cc2nn1-c1ccc(C)c(F)c1

Procedure:
Compound (45) was prepared in a similar manner to the synthesis of Compound (44) with the following variation: 3-fluoro-4-methylaniline was used instead of 4-chloroaniline at Step d. ESI-MS m/z [M+H]+: 417.1, 1H NMR (400 MHz, Acetone) δ 7.95 (brs, 1H), 7.81 (s, 1H), 7.75 (brs, 1H), 7.64 (s, 1H), 7.47-7.36 (m, 3H), 3.18 (s, 3H), 2.98 (d, J=4.7 Hz, 3H), 2.37 (d, J=1.9 Hz, 3H), 2.26-2.16 (m, 1H), 1.13-1.06 (m, 2H), 0.81-0.74 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[N:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:20]1[CH:25]=[N:24][CH:23]=[CH:22][N:21]=1)CCC.CN(C=O)C>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:21]1[CH:22]=[CH:23][N:24]=[CH:25][C:20]=1[C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(-c2cnccn2)cn1
Temperature: 120 °C
Reaction time: 10 h

Procedure:
To a flask containing tert-butyl 5-bromopicolinate 41-1 (1.55 g, 6.0 mmol), 2-(tributylstannyl)pyrazine 41-2 (2.21 g, 6.0 mmol) and Pd(PPh3)4 (426 mg, 0.6 mmol) under argon was added DMF (15 mL). The mixture was stirred at 120° C. for 10 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed with H2O and brine, dried over Na2SO4, and concentrated to dryness by rotary evaporation. The crude product was purified by silica gel flash chromatography, eluted with 5% methanol in dichloromethane to give tert-butyl 5-(pyrazin-2-yl)picolinate 41-3 as a pale yellow solid. MS m/z 258.1 (M+1)
Reaction SMILES: [F:1][C:2]1[C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:7][C:6]=2[C:5]([Si](C)(C)C)=[C:4]([O:20][CH:21]([CH3:23])[CH3:22])[CH:3]=1.[F-].[Cs+]>CN(C=O)C.[Cl-].[Na+].O>[F:1][C:2]1[C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:7][C:6]=2[CH:5]=[C:4]([O:20][CH:21]([CH3:23])[CH3:22])[CH:3]=1
Reactant: CC(C)Oc1cc(F)c2c(c1[Si](C)(C)C)Oc1ccccc1S2
Agent: [Cl-]
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1cc(F)c2c(c1)Oc1ccccc1S2
Temperature: 25 °C
Yield: 77.9 %

Procedure:
A stirred solution of 1-fluoro-3-isopropoxy-4-(trimethylsilyl)phenoxathiin (230 mg, 0.66 mmol) (Example 25) and CsF (200 mg, 1.32 mmol) in 5 mL 10% (v/v) aqueous DMF was heated under nitrogen at 100° C. for 0.5 h. After cooling to room temperature, the reaction was diluted with brine (30 mL), dried (Na2SO4), and concentrated in vacuo to a pale yellow oil (178 mg). Filtration of the crude product through silica gel (20 g) with 10% CH2Cl2 /hexanes yielded 142 mg (78%) of the title compound as a colorless oil: TLC (CH2Cl2 /hexanes, 10:90) Rf =0.31; 1H-NMR (CDCl3) d, J=6 Hz, 6 H), 4.43-4.47 (m, 1 H), d 6.36-6.41 (m, 2 H), C2 --H and C4 -H), d 6.95-7.14 (m, 4 H); MS m/e (relative intensity) 277 (MH+, 100).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH3:27][CH:28]([CH3:31])[CH2:29][NH2:30]>C(#N)C>[CH3:27][CH:28]([CH3:31])[CH2:29][NH:30][CH2:12][C@@H:13]1[O:18][C:17]2[CH:19]=[C:20]([S:23]([CH3:26])(=[O:24])=[O:25])[CH:21]=[CH:22][C:16]=2[O:15][CH2:14]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc(S(C)(=O)=O)cc3O2)cc1
Reactant: CC(C)CN
Solvent: CC#N
Product: CC(C)CNC[C@H]1COc2ccc(S(C)(=O)=O)cc2O1
Temperature: 120 °C

Procedure:
A mixture of [(2R)-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.19 g, 0.48 mmol), 2-methylpropane-1-amine (0.9 ml) and ACN (3 ml) was heated under microwave radiation at 120° C. for 20 min. Purification on SCX-3 column (TEA/MeOH) and flash column chromatography (DCM/MeOH). Yield: 0.11 g, 74%. The amine was converted to the hydrochloric acid salt and crystallized from MeOH/Et2O. M.p. 214° C. MS m/z (rel. intensity, 70 eV) 299 (M+, 6), 86 (100), 256 (21), 57 (8), 70 (6). [α]=−58° (MeOH).
Reaction SMILES: [CH3:1][CH:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][CH:7]=1)[CH:3]=[O:4].C(N(CC)CC)C.[C:23]([O-])(=[O:25])[CH3:24].[Na+].O>C(OC(=O)C)(=O)C>[C:12]([C:9]1[CH:8]=[CH:7][C:6]([CH2:5][C:2]([CH3:1])=[CH:3][O:4][C:23](=[O:25])[CH3:24])=[CH:11][CH:10]=1)([CH3:14])([CH3:13])[CH3:15]
Reactant: CC(C=O)Cc1ccc(C(C)(C)C)cc1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)OC=C(C)Cc1ccc(C(C)(C)C)cc1
Yield: 459.7 %

Procedure:
A solution of 200 g 2-methyl-3-(4-tert-butylphenyl)-propanal, 280 ml triethylamine and 13.4 g sodium acetate in 800 ml of acetic anhydride was stirred at 120° C. for 5.5 hours. Then the solution was cooled, water was added and the water phase was extracted with hexane. The organic phase was washed with 2N NaOH and water to neutrality, dried and evaporated to dryness. The residue was distilled to yield 185 g of a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:13][C:14]([OH:16])=[O:15])[CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[C:17](OC(=O)C)(=O)[CH3:18].C(N(CC)CC)C>>[CH2:17]([O:11][C:10](=[O:12])[CH2:9][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:13][C:14]([OH:16])=[O:15])[CH3:18]
Reactant: O=C(O)CC(CC(=O)O)c1ccc(Cl)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(CC(=O)O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 70.7 %

Procedure:
A solution of 3-(4-chlorophenyl)glutaric acid (1.0 g, 4.1 mmol) in acetic anhydride (20 mL, 200 mmol) was heated to reflux, stirred for 17 h, cooled at room temperature, and concentrated to dryness. The crude residue was dried under vacuum for 1 h. The crude anhydride was dissolved in ethanol (30 mL) and triethylamine (3.0 mL, 22 mmol) was added. The reaction was stirred for 17 h at room temperature and then concentrated to dryness. The crude residue was dissolved in dichloromethane (5 mL) and purified on SiO2 (40 g) using 5% MeOH/DCM to provide the title product (0.785 g, 70% yield) as a clear oil. 1H NMR (DMSO-d6, 400 mHz) δ (ppm): 12.09 (s, 1H), 7.30-7.22 (m, 4H), 3.93-3.87 (m, 2H), 3.4 (m, 1H), 2.71-2.46 (s, 4H), 1.0 (t, J=7 Hz, 3H).
Reaction SMILES: N1C2C(=O)OC(=O)C=2C=CN=1.C[O:13][C:14]([C:16]1[N:25]=[CH:24][C:23]2[CH:22]=[CH:21][N:20]=[N:19][C:18]=2[C:17]=1[OH:26])=[O:15].[OH-].[Na+]>>[OH:26][C:17]1[C:18]2[N:19]=[N:20][CH:21]=[CH:22][C:23]=2[CH:24]=[N:25][C:16]=1[C:14]([OH:15])=[O:13]
Reactant: COC(=O)c1ncc2ccnnc2c1O
Agent: O=C1OC(=O)c2nnccc21
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ncc2ccnnc2c1O

Procedure:
As shown in Example 1, furo[3,4-c]pyridazine-5,7-dione 1.4 (WO 994492) is converted, as described above, into 8-hydroxy-pyrido[4,3-c]pyridazine-7-carboxylic acid methyl ester 1.5, and the ester is hydrolyzed with sodium hydroxide to give 8-hydroxy-pyrido[4,3-c]pyridazine-7-carboxylic acid 1.6.
Reaction SMILES: [Br-:1].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[S:34]1[CH:38]=[CH:37][C:36]2[CH:39]=[CH:40][CH:41]=[C:42]([C:43](=[O:46])[CH2:44][CH3:45])[C:35]1=2>O1CCCC1>[S:34]1[CH:38]=[CH:37][C:36]2[CH:39]=[CH:40][CH:41]=[C:42]([C:43](=[O:46])[CH:44]([Br:1])[CH3:45])[C:35]1=2
Reactant: CCC(=O)c1cccc2ccsc12
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: CC(Br)C(=O)c1cccc2ccsc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 112.5 %

Procedure:
Phenyltrimethylammonium tribromide (1.52 g) was added in portions under nitrogen at 0° C. over 30 minutes to a stirred solution of 1-(benzo[b]thiophen-7-yl)propan-1-one (0.77 g) in tetrahydrofuran (110 ml), then the mixture was stirred at ambient temperature for 18 hours. Further phenyltrimethylammonium tribromide (0.76 g) was added and the mixture was heated under reflux for 4 hours. Further phenyltrimethylammonium tribromide (0.76 g) was added, then the mixture was heated under reflux for 90 minutes, cooled to ambient temperature and filtered. The solvent was removed in vacuo and the residue was purified by flash chromatography over silica using a 7:3 mixture of petroleum ether (b.p. 60-80° C.) and dichloromethane as eluant. Appropriate fractions were combined and the solvents removed in vacuo to give 1-(benzo[b]thiophen-7-yl)-2-bromopropan-1-one (0.71 g) as an oil which was used without further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=[O:28]>C1(C)C=CC=CC=1>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([O:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1)=[O:28]
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: COc1cccc(C(=O)Cl)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)OC2CCN(Cc3ccccc3)CC2)c1
Yield: 79.7 %

Procedure:
1.41 g (0.00733 mol) of 1-benzyl-4-hydroxypiperidine and 1.8 ml (0.0129 mol) of triethylamine were dissolved in 50 ml of toluene and treated with 0.79 ml (0.00586 mol) of 3-methoxy-benzoyl chloride. The mixture was boiled at reflux for 2 hrs., the precipitate was filtered off and the filtrate was concentrated. The residue was chromatographed over silica gel with ethyl acetate/hexane (1:3→1:2→1:1)). 1.52 g (80%) of 1-benzyl-piperidin-4-yl 3-methoxy-benzoate were obtained as a yellowish oil. MS: me/e (% basic peak)=325 (C20H23NO3+, 7.6), 248 (4), 173 (30.3), 135 (13), 91 (78), 82 (100).