Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][C:9]([CH3:15])([CH3:14])[C:8](=O)[CH2:7]2)([OH:3])=[O:2].Cl.[NH2:18][OH:19]>C(O)C.N1C=CC=CC=1>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][C:9]([CH3:15])([CH3:14])[CH2:8][C:7]2=[N:18][OH:19])([OH:3])=[O:2]
Reactant: NO
Reactant: CC1(C)Oc2ccc(C(=O)O)cc2CC1=O
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CC1(C)CC(=NO)c2cc(C(=O)O)ccc2O1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
14.9 g of 6-carboxy-2,2-dimethyl-3-chromanone are dissolved in 100 ml of ethanol and 100 ml of pyridine, and after addition of 5.16 g of hydroxylamine hydrochloride the mixture is heated at 80° C. with stirring for 6 hours. The solvent is distilled off on a rotary evaporator. The residue is treated with water and adjusted to pH<1 using conc. hydrochloric acid, and the colorless crystals are filtered off.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][CH2:9][OH:10].C[N+]1([O-])CCOCC1>C(Cl)Cl.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][CH:9]=[O:10]
Reactant: OCCCc1ccccn1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: O=CCCc1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.3 %

Procedure:
To a stirred suspension of 2-pyridinepropanol (1.00 g, 7.29 mmol), NMO (1.281 g, 10.94 mmol) and 3 Å molecular sieves (3.645 g) in CH2Cl2 (37 mL) was added TPAP (256 mg, 0.73 mmol). The resulting black mixture was stirred at room temperature overnight. The mixture was concentrated and filtered through a silica gel plug. Purification by column chromatography on silica gel (EtOAc, 100%) afforded the desired aldehyde (111 mg, 11%) as a yellow syrup. 1H NMR (CDCl3) δ 2.90-2.95 (m, 2H), 3.11 (t, 2H, J=7.0 Hz), 7.09 (dd, 1H, J=7.0, 4.8 Hz), 7.17 (d, 1H, J=7.8 Hz), 7.54-7.63 (m, 1H), 8.48 (d, 1H, J=4.2 Hz), 9.86 (s, 1H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[C:9]2[CH:21]=[CH:20][C:19]([CH2:22][O:23]C(C)=O)=[CH:18][C:10]=2[S:11][C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(O)C>[Cl:7][C:8]1[C:9]2[CH:21]=[CH:20][C:19]([CH2:22][OH:23])=[CH:18][C:10]=2[S:11][C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1sc2cc(COC(C)=O)ccc2c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1sc2cc(CO)ccc2c1Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Potassium carbonate (2 g) was added to a stirred solution of ethyl 3-chloro-6-[(methylcarbonyloxy)methyl]benzo[b]thiophene-2-carboxylate (Preparation 14, 2.65 g, 8.5 mmol) in ethanol (40 ml). The mixture was stirred at ambient temperature for 20 hours, then the solvent was removed under reduced pressure. The residue was partitioned between dichloromethane and water. The organic layer was separated and washed with more water, dried (magnesium sulfate), and evaporated under reduced pressure. The residue was flash chromatographed on silica gel using a gradient of 0-2% methanol in dichloromethane as eluant to give the title compound, which was crystallised from diethyl ether to give a colourless solid (1.66 g).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:8][C:9]1[CH:19]=[CH:18][C:12]([C:13](OCC)=[O:14])=[CH:11][N:10]=1.C([Li])CCCCC.CC([O-])=O.[Na+].CC(O)=O.C([O-])(=O)C.[Na+]>C1COCC1.O.C(O)(=O)C>[Cl:8][C:9]1[N:10]=[CH:11][C:12]([C:13]([N:1]2[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[O:14])=[CH:18][CH:19]=1
Reactant: C1CNCCNC1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Agent: CC(=O)[O-]
Agent: [Li]CCCCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: O=C(c1ccc(Cl)nc1)N1CCCNCC1
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
A solution of homopiperazine (385.62 g, 3.85 mol) in THF (3.9 L) was cooled to an internal temperature of 0° C. and ethyl 6-chloronicotinate (285.82 g, 1.54 mol) was added in THF (0.57 L) over 5 min. After stirring for 10 minutes, n-hexyl lithium (2.3 M in hexane, 335 mL, 0.77 mol) was added to the resulting mixture, over 40 min. The resulting mixture was stirred for 2 h at 0° C., then warmed to 20° C. over 1 h. After an additional 15 h at 20° C., the resulting mixture was treated with 1M NaOAc/HOAc buffer (5 L) (prepared by diluting 47.35 g of sodium acetate and 253.2 mL of acetic acid with water to a total volume of 5 L).
Reaction SMILES: CN(C)C=O.Cl.[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([NH:16][C:17]2[CH2:22][CH2:21][CH2:20][C:19](=[O:23])[CH:18]=2)=[C:12]([CH:15]=1)[C:13]#[N:14].O=C1CCCC(NC2C=CC=CC=2C#N)=C1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[NH2:14][C:13]1[C:12]2[C:11]([N:16]=[C:17]3[C:18]=1[C:19](=[O:23])[CH2:20][CH2:21][CH2:22]3)=[CH:10][CH:9]=[C:8]([Cl:7])[CH:15]=2
Reactant: N#Cc1cc(Cl)ccc1NC1=CC(=O)CCC1
Agent: Cl
Agent: N#Cc1ccccc1NC1=CC(=O)CCC1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Nc1c2c(nc3ccc(Cl)cc13)CCCC2=O
Yield: 4.3 %

Procedure:
In 5 liters of toluene were combined 200 ml of dimethylformamide, 180.71 g of 5-chloro-2-(3-oxocyclohexen-1-yl)aminobenzonitrile hydrochloride prepared in the same manner as the compounds of EXAMPLES 1 and 2, 176 g (2 eq) of milled K2CO3 and 3 g of cuprous chloride (CuCl). After 6 hours of reflux a little reaction occurred, so 3 g more of CuCl was added. After 12 hours of reflux more product had slowly formed. In order to hasten the reaction, 3 g more of CuCl was added. After overnight reflux the reaction mixture was evaporated and the residue extracted with dichloromethane via a Soxhlet extraction apparatus for 12 hours. The dichloromethane solution was evaporated to a solid. The solid was suspended in water and H2SO4 was added. The resultant salt which precipitated out, was filtered and made basic with 10% NaOH. The solid was filtered and recrystallized twice from isopropanol/toluene to yield 6.84 g (4%) of a solid, melting point over 260° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[N:10]=[C:11]([N+:14]([O-])=O)[NH:12][CH:13]=2)[CH2:4][CH2:3]1.[CH3:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=1[C:25]1[C:34]2[N:33]=[CH:32][CH:31]=[N:30][C:29]=2[C:28]([C:35](O)=[O:36])=[CH:27][CH:26]=1.CO.C1COCC1.CO>[Ni].C(Cl)Cl.CO>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[N:10]=[C:11]([NH:14][C:35]([C:28]3[C:29]4[N:30]=[CH:31][CH:32]=[N:33][C:34]=4[C:25]([C:19]4[C:20]([CH3:24])=[CH:21][CH:22]=[CH:23][C:18]=4[CH3:17])=[CH:26][CH:27]=3)=[O:36])[NH:12][CH:13]=2)[CH2:4][CH2:3]1
Reactant: Cc1cccc(C)c1-c1ccc(C(=O)O)c2nccnc12
Reactant: CN1CCN(Cc2c[nH]c([N+](=O)[O-])n2)CC1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: Cc1cccc(C)c1-c1ccc(C(=O)Nc2nc(CN3CCN(C)CC3)c[nH]2)c2nccnc12
Temperature: 60 °C
Reaction time: 8 h

Procedure:
The title compound was prepared in analogy to the procedures described in Example 14 but stirring the reaction mixture for at 60° C. overnight, using 1-methyl-4-(2-nitro-1H-imidazol-4-ylmethyl)-piperazine (Step 20.1) instead of 2-nitroimidazole in Step 14.3 and 8-(2,6-dimethyl-phenyl)-quinoxaline-5-carboxylic acid (Example 71), and using Raney nickel and MeOH/THF (1:1) instead of palladium on carbon and MeOH in Step 14.2. Title compound: ESI-MS: 456.1 [M+H]+; tR=3.18 min (System 1); TLC: Rf=0.15 (DCM/MeOH, 9:1).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[C:9](=N)([C:16]1C=CC=CC=1)[C:10]1C=CC=C[CH:11]=1>>[CH2:16]1[C@@H:2]([C:3]2[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=2)[NH:1][CH2:11][CH:10]=[CH:9]1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: NCc1cccnc1
Product: C1=CC[C@@H](c2cccnc2)NC1

Procedure:
Anatabine was prepared synthetically using 3-aminomethylpyridine and benzophenoneimine as starting materials, according to the procedures described below.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]([O:14][CH3:15])=[CH:12][C:6]2[CH2:7][CH2:8][NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=1.C([Li])CCC.[C:21]1(=[O:26])[O:25][CH2:24][CH2:23][CH2:22]1.[Cl-].[NH4+]>C1COCC1.CCCCCC>[CH3:1][O:2][C:3]1[C:13]([O:14][CH3:15])=[CH:12][C:6]2[CH2:7][CH2:8][N:9]([C:24](=[O:25])[CH2:23][CH2:22][CH2:21][OH:26])[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CCNCC2
Reactant: O=C1CCCO1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cc2c(cc1OC)CCN(C(=O)CCCO)CC2
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To 6.0 g (29 mmol) of 7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine in 30 mL of THF, at 0° C., there are added, dropwise, over 15 minutes, 11.6 mL (29 mmol/1 eq.) of 2.6M n-butyl lithium solution in hexane. The mixture is then cooled to about −78° C. and poured dropwise, over 10 minutes, into a solution of 2.7 mL (34.8 mmol/1.2 eq.) of gamma-butyrolactone in 15 mL of THF. Stirring is carried out at −78° C. for 30 minutes and the temperature is then brought to −30° C. and held there for 1 hour; the temperature is then allowed to return to ambient temperature, where stirring is carried out for 48 hours. The mixture is poured into 75 mL of saturated aqueous ammonium chloride solution and is then extracted twice with 120 mL of ethyl acetate. The combined organic phases are washed with 150 mL of saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated. The residue is taken up in 300 mL of ethyl acetate and washed twice with 75 mL 1M aqueous hydrochloric acid solution. The combined aqueous acid phases are re-extracted twice with 100 mL of dichloromethane. The organic phases are combined, dried over magnesium sulphate and concentrated to yield the desired product.
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH2:9][OH:10])[C:5]([CH2:11][Cl:12])=[CH:4][N:3]=1.C(Cl)(Cl)Cl.N1C=CC=CC=1.[C:23](Cl)(Cl)=[O:24]>C1C=CC=CC=1>[Cl:12][CH2:11][C:5]1[CH:4]=[N:3][C:2]([CH3:1])=[C:7]2[O:8][C:23](=[O:24])[O:10][CH2:9][C:6]=12
Reactant: Cc1ncc(CCl)c(CO)c1O
Reactant: O=C(Cl)Cl
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Cc1ncc(CCl)c2c1OC(=O)OC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 0.01 mole of 2-methyl-3-hydroxy-4-hydroxymethyl-5-chloromethylpyridine in 50 ml. chloroform and 50 ml. pyridine is added at 0°-5° C. a solution of 0.011 moles of phosgene in benzene. The reaction mixture is allowed to warm to room temperature and is stirred overnight. The reaction mixture is then concentrated in vacuo and excess saturated sodium bicarbonate solution is added. The resulting solid is collected by filtration. Chromatography on silica gel and elution with methanol in chloroform (1-5%) gives 5-chloromethyl-8-methyl-2-oxo-4H-m-dioxino[4,5-c]pyridine.
Reaction SMILES: [BH4-].[Li+].C[O:4][C:5](=O)[C:6]([CH3:17])([CH3:16])[CH2:7][N:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][C:9]1=[O:15].CO>O1CCCC1.[O-]S([O-])(=O)=O.[Mg+2]>[Br:14][C:11]1[CH:12]=[CH:13][N:8]([CH2:7][C:6]([CH3:16])([CH3:17])[CH2:5][OH:4])[C:9](=[O:15])[CH:10]=1
Reactant: COC(=O)C(C)(C)Cn1ccc(Br)cc1=O
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(CO)Cn1ccc(Br)cc1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Lithium borohydride (25 mg) was added to a solution of 3-(4-bromo-2-oxo-2H-pyridin -1-yl)-2,2-dimethyl-propionic acid methyl ester (0.29 g) in tetrahydrofuran (3 mL) chilled in an ice bath. Then methanol (45 μL) was added and the mixture was stirred in the cooling bath for 1 h and at room temperature overnight. The mixture was diluted with tetrahydrofuran and MgSO4 was added. The mixture was filtered and the filtrate was concentrated. The residue was purified by chromatography on silica gel (cyclohexane/ethyl acetate 1:1) to afford the title compound as a colorless oil. Yield: 0.13 g (49% of theory); Mass spectrum (ESI+): m/z=260/262 (Br) [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([O:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[CH2:10][C@H:9]1[CH2:24][O:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[CH:23][C:14]=1[O:13][C@@H:11]1[CH2:12][NH:8][C@H:9]([CH2:24][O:25][C:26]2[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=2)[CH2:10]1
Reactant: COC(=O)c1ccc(OC[C@@H]2C[C@H](Oc3ccc4ccccc4c3)CN2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(OC[C@@H]2C[C@H](Oc3ccc4ccccc4c3)CN2)cc1
Yield: 114.2 %

Procedure:
To a stirred solution of methyl 4-[(2S, 4S)-1-tert-butoxycarbonyl-4-(2-naphthyloxy)-2-pyrrolidinyl]methoxybenzoate (870 mg, 1.74 mmol) in CH2Cl2 (24 ml) was added TFA (6 ml) at room temperature. The mixture was stirred over night, which was concentrated in vacuo. The residue was diluted with CH2Cl2 and made basic by the addition of 1 N NaOH, which was extracted with CH2Cl2. The organic layer was washed with brine, dried over NaSO4 and concentrated. The residue was chromatographed on silica gel [100 g, n-hexane/EtOAc(211)], to give methyl 4-[(2S, 4S)-4-(2-naphthyloxy)-2-pyrrolidinyl]methoxybenzoate (750 mg, 100%) as a black oil 1H-NMR (CDCl3) δ 1.99 (dd, J=14.2, 5.6 Hz, 1H), 2.48 (m, 1H), 3.22 (dd, J=12.2, 4.6 Hz, 1H), 3.43 (d, J=12.5 Hz, 1H), 3.67 (m, 1H), 3.86 and 3.87 (s, 3H, amide isomers), 4.11 (m, 2H), 5.04 (m, 1H), 6.83 (d, J=8.5 Hz, 1H), 6.89 (d, J=8.8 Hz, 2H), 7.07 (d, J=2.0 Hz, 1H), 7.12 (d, J=9.0 Hz, 1H), 7.33 (dt, J=8.1, 1.2 Hz, 1H), 7.44 (dt, J=6.8, 1.2 Hz, 1H), 7.70 (d, J=8.1 Hz, 1H), 7.75 (dd, J=9.0, 5.1 Hz, 2H), 7.90 (d, J=8.5 Hz, 1H), 7.96 (dd, J=6.8, 2.0 Hz, 2).
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][C@@H:11]1[C@H:15]([CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:14][C@@H:13]([OH:25])[CH2:12]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].Cl[C:27]1[N:35]=[CH:34][N:33]=[C:32]2[C:28]=1[N:29]=[CH:30][N:31]2[CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][O:37]1>CN(C=O)C>[Si:3]([O:10][C@@H:11]1[C@H:15]([CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:19])[CH3:20])[CH2:14][C@@H:13]([O:25][C:27]2[N:35]=[CH:34][N:33]=[C:32]3[C:28]=2[N:29]=[CH:30][N:31]3[CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][O:37]2)[CH2:12]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](O)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Oc2ncnc3c2ncn3C2CCCCO2)C[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
In DMF (4 mL, 0.05 mol) was suspended sodium hydride (47 mg, 0.0012 mol) at 0° C., to which was added a solution of (1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentanol (0.200 g, 0.000554 mol) in 2.5 mL DMF. The mixture was stirred at 0° C. for 10 minutes and was added a solution of 6-Chloro-9-(tetrahydropyranyl)purine (0.265 g, 0.00111 mol) (Example 33, step b) in 4 mL DMF. The reaction was stirred at 0° C. for 1 h and warmed to 23° C. overnight. The reaction was quenched by addition of saturated aqueous NH4Cl, and the mixture was extracted with ethyl acetate, washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (0 to 5% acetone/toluene) to obtain 271 mg (86.8%).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:15]([CH3:21])[C:16](OCC)=[O:17])[CH:8]=[CH:9][C:10]=1[O:11]C(=O)C)(=O)C.[CH3:22][NH2:23]>>[CH3:22][NH:23][C:16](=[O:17])[CH:15]([C:7]1[CH:8]=[CH:9][C:10]([OH:11])=[C:5]([OH:4])[CH:6]=1)[CH3:21]
Reactant: CN
Reactant: CCOC(=O)C(C)c1ccc(OC(C)=O)c(OC(C)=O)c1
Product: CNC(=O)C(C)c1ccc(O)c(O)c1
Temperature: 150 °C
Reaction time: 2 h

Procedure:
A mixture of 2 g of ethyl 3,4-diacetoxyphenylpropionate and 2.1 g of a 40% aqueous methylamine solution was heated to 150° C. with stirring for 2 hours in an autoclave. After cooling, the reaction mixture was acidified, extracted three times with 25 ml of ethyl acetate and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by column chromatography using silica gel. A solvent mixture of chloroform:methanol=20:1 was used as eluent. Pure N-methyl-3,4-dihydroxyphenylpropionamide thus obtained was 0.35 g.
Reaction SMILES: [C:1]([C:4]1[CH:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[N:8]2[CH:18]=[C:19]([S:21]([OH:24])(=[O:23])=[O:22])[N:20]=[C:7]2[NH:6][C:5]=1[CH3:25])(=[O:3])[NH2:2]>O1CCOCC1.O=[Mn]=O>[C:1]([C:4]1[C:5]([CH3:25])=[N:6][C:7]2[N:8]([CH:18]=[C:19]([S:21]([OH:24])(=[O:23])=[O:22])[N:20]=2)[C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17])(=[O:3])[NH2:2]
Reactant: CC1=C(C(N)=O)C(c2ccc(Cl)cc2Cl)n2cc(S(=O)(=O)O)nc2N1
Agent: O=[Mn]=O
Solvent: C1COCCO1
Product: Cc1nc2nc(S(=O)(=O)O)cn2c(-c2ccc(Cl)cc2Cl)c1C(N)=O
Temperature: 80 °C
Reaction time: 48 h

Procedure:
A suspension of 6-carbamoyl-5-(2,4-dichlorophenyl)-7-methyl-5,8-dihydroimidazo[1,2-a]pyrimidine-2-sulfonic acid (90 mg, 0.23 mmol) and MnO2 (110 mg, 1.27 mmol) in dioxane (2 mL) was heated to 80° C. for 24 h. HPLC analysis indicated 50% conversion, and additional MnO2 (200 mg) was added and heating was continued for additional 48 h. After removal of catalyst and solvent, 6-carbamoyl-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidine-2-sulfonic acid was obtained as a brown solid ˜90% pure (75mg, 82%). The crude product was used for the subsequent reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[C:8]1([CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[O:7][C:6]2=[O:19].C1OC(C2C=CC=CC=2)(C(F)CC)OC1.Cl[CH:36]([CH2:46][CH3:47])[C:37]([C:39]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=1)=[O:38]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[C:8]1([CH2:13][CH2:12][N:11]([CH2:47][CH2:46][CH2:36][C:37](=[O:38])[C:39]3[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=3)[CH2:10][CH2:9]1)[O:7][C:6]2=[O:19]
Reactant: CCC(Cl)C(=O)c1ccc(F)cc1
Reactant: COc1cc2c(cc1OC)C1(CCNCC1)OC2=O
Agent: CCC(F)C1(c2ccccc2)OCCO1
Product: COc1cc2c(cc1OC)C1(CCN(CCCC(=O)c3ccc(F)cc3)CC1)OC2=O

Procedure:
Reaction of 1,3-dihydro-5,6-dimethoxyspiro-[isobenzofuran-1,4'-piperidine]-3-one and αchloro-p-fluorobutyrophenone fluorobutyrophenone ethylene ketal by the method described in Example 6 provides 1,3-dihydro-5,6-dimethoxy-1'-[3-(4-fluorobenzoyl)propyl]spiro[isobenzofuran-1,4'-piperidine] -3-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]([C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[F:17])O.C(N(CC)CC)C.CS(Cl)(=O)=O.[Cl:30][C:31]1[N:36]=[CH:35][C:34]([SH:37])=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>CCCCCC.C(OCC)(=O)C.CN(C)C=O.ClCCl>[Cl:30][C:31]1[CH:32]=[CH:33][C:34]([S:37][CH:8]([C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[Cl:1])[C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[F:17])=[CH:35][N:36]=1
Reactant: OC(c1cc(F)ccc1F)c1ccncc1Cl
Reactant: Sc1ccc(Cl)nc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: Fc1ccc(F)c(C(Sc2ccc(Cl)nc2)c2ccncc2Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
To a dichloromethane (3 ml) solution of the 3-chloro-4-[(2,5-difluorophenyl)-hydroxymethyl]pyridine (153 mg, 0.60 mmol) obtained in Referential Example 23 were added triethylamine (0.167 ml, 1.20 mmol) and methanesulfonyl chloride (0.070 ml, 0.90 mmol) sequentially at 0° C. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate. The organic layer was then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. To an N,N-dimethylformamide (3 ml) solution of the residue thus obtained was added an N,N-dimethylformamide (2 ml) solution of 6-chloro-3-pyridinethiol and potassium carbonate (100 mg, 0.72 mmol) sequentially. The resulting mixture was stirred at room temperature for 18 hours. Ethyl acetate was added to the reaction mixture. The resulting mixture was washed with a saturated aqueous solution of sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel chromatography. The fraction obtained from the hexane:ethyl acetate=17:3 eluate was concentrated under reduced pressure to give the title compound (111 mg, 0.29 mmol, 48%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([CH2:11][CH:12]([OH:15])CO)[N:6]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])=[O:4]>CCOCC.[Cl-].[Na+].O>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([CH2:11][CH:12]=[O:15])[N:6]1[C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17])=[O:4]
Reactant: COC(=O)C1CCCC(CC(O)CO)N1C(=O)OCc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: COC(=O)C1CCCC(CC=O)N1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
6-(2,3-Dihydroxy-propyl)-piperidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester (Compound 235, 0.614 g, 1.75 mmol) was dissolved in Et2O (20 mL) and cooled to 0° C. Ten percent NaIO4 aqueous solution (4 mL) was added, and the reaction was stirred for 1 hour. The reaction mixture was poured into brine (15 mL) and extracted with Et2O (3×20 mL). The combined organic layer was further washed with aqueous NaS2O3 (10 mL), NaHCO3 saturated solution (10 mL), brine (10 mL) and finally dried over MgSO4. The solvents were removed to afford Compound 236 (0.53 g, 95%). Rf=0.67 (1:1 EtOAc/hexanes). The material was of sufficiently good quality to be used in the next reaction without purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:10]([C:11](=[O:13])[CH3:12])[C@@H:9]([CH3:14])[CH2:8][NH:7][C:6]=2[N:15]=1.[CH:16]1([N:19]2[CH:23]=[C:22](B3OC(C)(C)C(C)(C)O3)[CH:21]=[N:20]2)[CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl.O1CCOCC1>[CH:16]1([N:19]2[CH:23]=[C:22]([C:2]3[CH:3]=[CH:4][C:5]4[N:10]([C:11](=[O:13])[CH3:12])[C@@H:9]([CH3:14])[CH2:8][NH:7][C:6]=4[N:15]=3)[CH:21]=[N:20]2)[CH2:18][CH2:17]1
Reactant: CC(=O)N1c2ccc(Br)nc2NC[C@@H]1C
Reactant: CC1(C)OB(c2cnn(C3CC3)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(=O)N1c2ccc(-c3cnn(C4CC4)c3)nc2NC[C@@H]1C
Temperature: 80 °C

Procedure:
A reaction vial was charged with (S)-1-(6-bromo-2-methyl-3,4-dihydropyrido[2,3-b]pyrazine-1(2H)-yl)ethanone (0.1 M solution in 1,2-dichloroethane, 0.30 mL, 0.03 mmol), 1,4-dioxane (100 μL), 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.2 M solution in 1,4-dioxane, 0.27 mL, 0.054 mmol), potassium carbonate (1.0 M solution in water, 0.090 mL, 0.090 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (0.02 M solution in 1,2-dichloroethane, 150 μL, 0.003 mmol). The reaction was purged with nitrogen, and heated to 80° C. on a heater shaker overnight. The reaction was diluted with ethyl acetate and washed with 1 N aqueous sodium hydroxide solution and brine. The combined organic layers were concentrated under a stream of nitrogen and vacuum to yield (S)-1-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydropyrido[2,3-b]pyrazine-1(2H)-yl)ethanone. The crude product was dissolved in 1,2-dichloroethane (200 μL), and N,N-diisopropylethylamine (0.052 mL, 0.300 mmol) was added. 2-Isocyanatopropane (0.020 mL, 0.200 mmol) was then added along with a catalytic amount of DMAP (˜1 mg), and the reaction was shaken at 80° C. for 3 hours. The reaction was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution. The aqueous layer was separated and extracted with ethyl acetate and the combined organic layers were concentrated in a Genevac. The crude product was purified by mass triggered preparatory HPLC. The product-containing fractions were combined and concentrated to afford (S)-1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-N-isopropyl-2-methyl-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxamide. MS (ESI, pos. ion) m/z 383 [M+H]+.