Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:15])[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=1)C.[OH-].[Na+]>O>[F:14][C:10]1[CH:9]=[C:8]([CH2:7][CH2:6][CH2:5][C:4]([OH:15])=[O:3])[CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)CCCc1cccc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCCc1cccc(F)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Crude 4-(3-fluorophenyl)butyric acid ethyl ester (10.5-kg), water (15.8 L) and 50% NaOH (12.0 kg) were charged to a reactor and stirred at 50° C. for 2 hours. The hydrolysis generated a mild exotherm to 55° C. The biphasic mixture became monophasic. Completion of the hydrolysis was confirmed by LC. The reaction mixture was cooled to 20° C. and washed with hexanes 15 kg (containing antistatic agent “ASA 3”) to remove 3′3-difluorobiphenyl impurity generated in the previous step. After phase separation the aqueous layer was acidified with 37% concentrated HCl (16.7 kg), keeping the exotherm below 40° C. Upon cooling the aqueous layer was extracted with MTBE (15 kg in three 5 kg extractions). The solvent was removed by vacuum distillation and excess MTBE removed with a hexane strip. The resulting 4-(3-fluoro-phenyl)-butyric acid (8.83 kg) was removed from the reactor as an oil and used without further purification: MS (M+1)=182; H1 NMR (300 MHz): δ ppm (CDCl3): 1.965 (2H, p, J=4.9, 2.47 hz), 2.37 (2H, t, J=2.47 Hz), 2.66 (2H, t, J=2.45), 6.87 (2H, m), 6.95 (1H, d, J=2.63), 7.22 (1H, m) 11.2(0.2H, bs).
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[N:4]=1.C([N:21]1[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]1)(=O)C>C(#N)C.[OH-].[Na+]>[CH3:26][C:24]1[N:23]([CH2:2][C:3]2[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:6]3[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=3[N:4]=2)[CH:22]=[N:21][CH:25]=1
Reactant: CC(=O)n1cnc(C)c1
Reactant: ClCc1nc2ccccc2n1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: Cc1cncn1Cc1nc2ccccc2n1-c1ccccc1
Yield: 11.7 %

Procedure:
A mixture of 2-chloromethyl-1-phenyl-1H-benzimidazole (4.8 g) and 1-acetyl-4-methylimidazole (2.4 g) in acetonitrile (25 ml) was refluxed for 48 hours. After removal of the solvent, the residue was pulverized in diethyl ether to give powder, which was taken up in 2.5 N sodium hydroxide (20 ml) and refluxed for 15 minutes. The resultant mixture was extracted twice with chloroform. The combined organic layer was extracted twice with 1 N hydrochloric acid. The combined aqueous layer was adjusted to pH 8.0 with aqueous sodium bicarbonate and extracted twice with chloroform. The combined extract was washed with water, dried over magnesium sulfate and evaporated under reduced pressure. The resultant residue was subjected to column chromatogeaphy on silica gel (60 g) eluting with a mixture of chloroform and methanol (50:1) to give an oily product. The oily product was triturated twice in diethyl ether and then in the mixture of diethyl ether and isopropyl alcohol (2:1) to give powder of 2-(5-methylimidazol-1-yl)methyl-1-phenyl- 1H-benzimidazole (0.65 g).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:6][CH:5]=2.[CH3:16][N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1>>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:20]1[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH:19]=1)=[CH:8][C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:6][CH:5]=2
Reactant: Cc1cc2cc(NS(C)(=O)=O)ccc2[nH]1
Reactant: CN1CCC(=O)CC1
Product: Cc1[nH]c2ccc(NS(C)(=O)=O)cc2c1C1=CCN(C)CC1
Yield: 33.4 %

Procedure:
Beginning with 1.37 gm (6.1 mMol) 2-methyl-5-methanesulfonylamino-1H-indole and 0.98 mL (7.9 mMol) 1-methyl-4-piperidone, 0.65 gm (33.3%) of the title compound were recovered as a yellow solid.
Reaction SMILES: [CH2:1]([NH2:7])[C:2]1[O:6]C=C[CH:3]=1.[O:8]=[C:9]1[NH:17][CH:16]=[N:15][C:14]2[N:13]([CH2:18][CH2:19][C:20](OCC)=[O:21])[CH:12]=[N:11][C:10]1=2>C(#N)C>[O:8]=[C:9]1[NH:17][CH:16]=[N:15][C:14]2[N:13]([CH2:18][CH2:19][C:20]([NH:7][CH2:1][CH:2]([OH:6])[CH3:3])=[O:21])[CH:12]=[N:11][C:10]1=2
Reactant: CCOC(=O)CCn1cnc2c(=O)[nH]cnc21
Reactant: NCc1ccco1
Solvent: CC#N
Product: CC(O)CNC(=O)CCn1cnc2c(=O)[nH]cnc21
Temperature: 25 °C
Yield: 60.5 %

Procedure:
0.500 g (5.15 mmol) of furfurylamine and 0.250 g (1.06 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propionic acid, ethyl ester (AIT-0027) were heated at 120° C. for two hours with stirring. The solution was allowed to cool to room temperature and 10 ml acetonitrile was added and the solution was stirred. The precipitate was collected by filtration and the white solid was washed with acetonitrile and then with ether. Upon drying, 170 mg of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-N-(2-hydroxypropyl)propanamide (AIT-0060) as a white solid was obtained.
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9]([O:12][NH2:13])(=[O:11])=[O:10].O.[NH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1>C(Cl)Cl>[C:1]1([CH3:14])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9]([O-:12])(=[O:11])=[O:10].[NH2:13][N+:19]1[CH:20]=[CH:21][CH:22]=[C:17]([NH2:16])[CH:18]=1
Reactant: Nc1cccnc1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Product: Nc1ccc[n+](N)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of O-mesitylenesulfonylhydroxylamine, ˜30-35% water, (14.5 g, 52 mmol) and CH2Cl2 (100 mL) is added to a solution of 3-aminopyridine (4.9 g, 52 mmol) and CH2Cl2 (100 mL) at 0° C. dropwise over 30 min. After 30 min at 0° C., the ice bath is removed and the solution is stirred at rt for 30 min. The volatiles are removed under reduced pressure to afford a yellow oil, N-amino-3-aminopyridinium mesityl sulfonate. DMF (100 mL) and K2CO3 (15 g, 110 mmol) are added. The dark brown mixture is cooled in a water bath. Dimethyl acetylenedicarboxylate (6.9 mL, 56 mmol) are added dropwise over 10 min. After 15 min, the water bath is removed and the mixture is left to vigorously stir under air for 66 h. The volatiles are removed under reduced pressure. The residue is slurried in MeOH and the mixture is filtered through Celite (MeOH rinse). The volatiles are removed under reduced pressure to afford a dark brown oil. 33% Sat. aq. NaHCO3 (150 mL) is added and the solution is extracted with EtOAc (6×200 mL). The combined organics are dried over Na2SO4, filtered, and concentrated. Purification by flash column chromatography (CH2Cl2) affords the title compound as an orange-red oil. LC-MS m/z (M+Na+): 272.01.
Reaction SMILES: [CH:1]1([CH:7]2[CH2:12][CH2:11][CH:10]=[CH:9][C:8]2=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC[O:16]CC>>[CH:1]1([C@@H:7]2[CH2:12][CH2:11][CH2:10][C:9](=[O:16])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1C=CCCC1C1CCCCC1
Reactant: CCOCC
Product: O=C1CCC[C@@H](C2CCCCC2)C1
Yield: 80 %

Procedure:
Prepared according to the general procedure from 3-cyclohexylcyclohexen-2-one (178 mg, 1.09 mmol) in 0.2 M Et2O for 43 h at room temperature to provide the title compound as a colorless oil (157 mg, 80% yield, 90% ee) after purification by flash chromatography on silica gel (5% Et2O/pentane). The enantiomeric ratio was determined by GLC using a Hydrodex-B-TBDAc (50 m×0.25 mm) column (110° C. isotherm, 1 mL/min.); (S) isomer tr=73.5 min. and (R) isomer tr=65.2 min. IR (film) 2924, 2853, 1715, 1449, 14223, 1346, 1317, 1263, 1225, 1101, 1056, 982, 892, 866 cm−1; 1H NMR (300 MHz, CDCl3) δ 2.44-2.21 (m, 3H), 2.16-2.04 (m, 2H), 1.93-1.85 (m, 1H), 1.80-1.54 ((m, 8H), 1.47-1.33 (m, 1H), 1.32-1.11 (m, 3H), 1.08-0.92 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 212.9, 45.6, 44.7, 42.7, 41.6, 30.0, 29.9, 28.4, 26.6, 26.59, 25.54, 25.6; HRMS (EI+) exact mass calculated for [M]+ (C12H20O) requires m/z 180.1514, found m/z 180.1508; [α]D22+11.9° (c=1.05, CHCl3).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][O:4][N:3]=1.[NH2:10][C:11]1[N:16]=[CH:15][C:14]2[C:17]([CH3:25])([CH3:24])[C:18](=[O:23])[N:19]([CH:20]3[CH2:22][CH2:21]3)[C:13]=2[CH:12]=1>>[CH:20]1([N:19]2[C:13]3[CH:12]=[C:11]([NH:10][C:7]([C:6]4[C:2]([CH3:1])=[N:3][O:4][CH:5]=4)=[O:9])[N:16]=[CH:15][C:14]=3[C:17]([CH3:24])([CH3:25])[C:18]2=[O:23])[CH2:22][CH2:21]1
Reactant: CC1(C)C(=O)N(C2CC2)c2cc(N)ncc21
Reactant: Cc1nocc1C(=O)O
Product: Cc1nocc1C(=O)Nc1cc2c(cn1)C(C)(C)C(=O)N2C1CC1

Procedure:
Prepared in analogy to example 26 from 3-methylisoxazole-4-carboxylic acid and 6-amino-1-cyclopropyl-3,3-dimethyl-1H-pyrrolo[3,2-c]pyridin-2(3H)-one (example 79c). The title compound was obtained as light brown viscous oil.
Reaction SMILES: [K].[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1.Br[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1>CN(C)C=O.CO.[Cu]>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]([O:2][C:3]2[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=2)=[CH:12][CH:13]=1
Reactant: Cc1ccc(O)cn1
Reactant: Cc1ccc(Br)cc1
Agent: [Cu]
Agent: [K]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1ccc(Oc2ccc(C)nc2)cc1

Procedure:
7.4 g of a potassium salt of 5-hydroxy-2-methylpyridine, 8.5 g of p-bromotoluene and 500 mg of a copper powder were suspended in 25 ml of dimethylformamide, and the mixture was allowed to react in a nitrogen gas stream at 130° C. for 14 hours under stirring. The reaction mixture was diluted with 70 ml of methanol and filtered. The filtrate was immediately concentrated, and to the residue was added 150 ml of chloroform. The mixture was washed with 100 ml of a 0.01 N aqueous sodium hydroxide solution, whereby the unreacted 5-hydroxy-2-methylpyridine shifted to the aqueous layer. The chloroform layer was washed with water, dried with anhydrous sodium sulfate and immediately dried to obtain 8.9 g of oily 5-(p-methylphenoxy)-2-methylpyridine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[O:15][C:16]3[C:17](=[C:19]([C:23](O)=[O:24])[CH:20]=[CH:21][CH:22]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[NH2:28][C@H:29]1[CH:34]2[CH2:35][CH2:36][N:31]([CH2:32][CH2:33]2)[CH2:30]1>>[N:31]12[CH2:30][CH:29]([NH:28][C:23]([C:19]3[C:17]4[N:18]=[C:14]([N:11]5[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:13][CH2:12]5)[O:15][C:16]=4[CH:22]=[CH:21][CH:20]=3)=[O:24])[CH:34]([CH2:35][CH2:36]1)[CH2:33][CH2:32]2
Reactant: N[C@@H]1CN2CCC1CC2
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc3c(C(=O)O)cccc3o2)CC1
Agent: Cl
Product: CC(C)(C)OC(=O)N1CCN(c2nc3c(C(=O)NC4CN5CCC4CC5)cccc3o2)CC1

Procedure:
Following general procedure GP-C1, A mixture of 2-[4-(tert-butoxycarbonyl)piperazin-1-yl]benzoxazole-4-carboxylic acid and (S)-(−)-3-aminoquinuclidine dihydrochloride were coupled to provide tert-butyl 4-[4-(quinuclidine-8-ylcarbamoyl]benzoxazol-2-yl)piperazine-1-carboxylate (85 mg, 0.19 mmol) to which was added TFA (0.17 mL, 2.3 mmol). The reaction mixture was stirred at room temperature for 12 h, and then concentrated under reduced pressure. The TFA salt was converted to the dihydrochloride salt following general procedure GP-D1. 1H NMR and MS consistent.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O.Cl[CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:26]=[CH:27][C:28]2[NH:33][C:32](=[O:34])[O:31][C:30]([CH3:36])([CH3:35])[C:29]=2[CH:37]=1>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]2[CH:26]=[CH:27][C:28]3[NH:33][C:32](=[O:34])[O:31][C:30]([CH3:36])([CH3:35])[C:29]=3[CH:37]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCCl)cc21
Reactant: Sc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC1(C)OC(=O)Nc2ccc(OCCCCSc3ccc(Br)cc3)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Quantities of 6.23 gm (0.033 mol) of 4-bromothiophenol and 8.28 gm (0.06 mol) of potassium carbonate are stirred into 100 ml of dimethylsulfoxide, dried over a molecular sieve in a nitrogen atmosphere at ambient temperature for 15 minutes, and then mixed with 8.51 gm (0.03 mol) of 6-(4-chlorobutoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one. After stirring for one hour at ambient temperature, water is added in batches until a thick crystal slurry is produced. This is subjected to suction filtration, dried, and recrystallized from ethyl acetate/diisopropyl ether.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][OH:10])=[CH:7][CH:8]=1.[F:11][CH:12]([CH2:14][C:15](Cl)=[S:16])[F:13]>ClCCl>[F:11][CH:12]([CH2:14][C:15]([O:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[S:16])[F:13]
Reactant: FC(F)CC(=S)Cl
Reactant: COc1ccc(CO)cc1
Solvent: ClCCl
Product: COc1ccc(COC(=S)CC(F)F)cc1
Yield: 80.4 %

Procedure:
To a stirred and ice cooled solution of p-methoxybenzyl alcohol (1.2 equivalents) in dichloromethane (5 parts by weight) is added dropwise difluoromethylthioacetyl chloride, and the mixture is stirred for 4 hours. The mixture is washed with water, dried and concentrated. The residual liquid is distilled to give oily p-methoxybenzyl difluoromethylthioacetate. Yield: 80.4%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[CH:11]/N(C)C)/[CH:9]=O)=[CH:4][CH:3]=1.Cl.[NH2:16][C:17]([NH2:19])=[NH:18].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:18][C:17]([NH2:19])=[N:16][CH:11]=2)=[CH:4][CH:3]=1
Reactant: N=C(N)N
Reactant: CN(C)/C=C(\C=O)c1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Nc1ncc(-c2ccc(Br)cc2)cn1
Temperature: 80 °C
Yield: 96 %

Procedure:
A mixture of (Z)-2-(4-bromophenyl)-3-(dimethylamino)acrylaldehyde (1.27 g, 5 mmol), guanidine hydrochloride (0.525 g, 5.5 mmol) and potassium carbonate (1.38 g, 10 mmol) in ethanol (10 mL) was heated at 80° C. overnight. After cooling, the reaction mixture was filtered, washed with methanol and water, and dried under high vacuum to give the desired product (1.2 g, 96%). LCMS: (M+H)=249.9/251.9.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([N:12]1[CH2:22][CH2:21][C:15]2([C:19](=[O:20])[NH:18][CH2:17][CH2:16]2)[CH2:14][CH2:13]1)(=[O:11])=[O:10].FC(F)(F)C(C1C=CC(N2CCC3(CCN(S(C4C=CC=CC=4C(F)(F)F)(=O)=O)CC3)C2=O)=CC=1)O.I[C:62]1[CH:67]=[CH:66][C:65]([C:68]([OH:71])([CH3:70])[CH3:69])=[CH:64][CH:63]=1>>[OH:71][C:68]([C:65]1[CH:66]=[CH:67][C:62]([N:18]2[CH2:17][CH2:16][C:15]3([CH2:21][CH2:22][N:12]([S:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[C:2]([F:1])([F:23])[F:24])(=[O:11])=[O:10])[CH2:13][CH2:14]3)[C:19]2=[O:20])=[CH:63][CH:64]=1)([CH3:70])[CH3:69]
Reactant: O=C1NCCC12CCN(S(=O)(=O)c1ccccc1C(F)(F)F)CC2
Reactant: CC(C)(O)c1ccc(I)cc1
Agent: O=C1N(c2ccc(C(O)C(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1ccccc1C(F)(F)F)CC2
Product: CC(C)(O)c1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4C(F)(F)F)CC3)C2=O)cc1

Procedure:
This material was prepared In analogy to example 162 step B) from 8-(2-trifluoromethyl-benzenesulfonyl)-2,8-diaza-spiro[4.5]decan-1-one, product of example 166 A) and 2-(4-iodo-phenyl)-propan-2-ol (synthesis: Brown et al.; JACS; 79; 1957, p 1906). Light yellow solid. MS (ESI): 497.17 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[N:7][C:8]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[CH:10]=2)[N:5]([CH3:27])[C:4](=[O:28])[C:3]=1[CH3:29].[H-].[Na+].[C:32](Cl)(=[O:34])[CH3:33].CCN(CC)CC>C1COCC1.CN(C=O)C>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([C:9]2[CH:10]=[C:11]3[C:6](=[N:7][C:8]=2[C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])[N:5]([CH3:27])[C:4](=[O:28])[C:3]([CH3:29])=[C:2]3[NH:1][C:32](=[O:34])[CH3:33])=[CH:17][CH:16]=1
Reactant: CC(=O)Cl
Reactant: Cc1c(N)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2n(C)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1c(C)c(=O)n(C)c2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12

Procedure:
To the product of EXAMPLE 40 (72 mg) in THF (3 mL) and DMF (0.2 mL) was added NaH (10 mg, 60% dispersion in mineral oil) followed by acetyl chloride (30 μL). After stirring 30 minutes at room temperature NEt3 (45 μL) was added. After an additional hour of reaction time TLC indicated incomplete reaction. Acetyl chloride (15 μL) and NEt3 (45 μL) was added to the reaction, however this generated the imide (N-acetyl-N-(7-(2,4-dichlorophenyl)-6-(4-chlorophenyl)-1,2-dihydro-1,3 dimethyl-2-oxo-1,8-naphthyridinyl)acetamide). The reaction was quenched with methanol and NaHCO3, diluted with EtOAc and washed with 2 M aqueous HCl followed by 1 M aqueous NaOH solution. The solution was concentrated and the residue in 8 mL of 2:1 THF:methanol was treated with CS2O3 (80 mg). TLC indicated conversion of the imide to the amide after about 10 minutes at room temperature. The reaction was concentrated, dissolved in EtOAc and washed with brine. The concentrated solution was then purified by flash chromatography (silica gel) gradient eluted with 0-90% EtOAc in hexane affording the title compound. HPLC/MS: 486.0 (M+1), 488.0 (M+3); Rt=4.24 min.
Reaction SMILES: [F:1][C:2]1[C:3]([O:19][C:20]2[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=2[O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:23]#[N:24])=[N:4][C:5](F)=[C:6]([F:17])[C:7]=1[O:8][CH2:9][CH:10]1[CH2:14][O:13][C:12]([CH3:16])([CH3:15])[O:11]1.C([O-])([O-])=O.[Cs+].[Cs+].[OH:42][C:43]1[CH:44]=[C:45]([C:49]2[N:50]([CH3:54])[CH2:51][CH2:52][N:53]=2)[CH:46]=[CH:47][CH:48]=1>CS(C)=O>[F:1][C:2]1[C:3]([O:19][C:20]2[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=2[O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:23]#[N:24])=[N:4][C:5]([O:42][C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([C:49]3[N:50]([CH3:54])[CH2:51][CH2:52][N:53]=3)[CH:44]=2)=[C:6]([F:17])[C:7]=1[O:8][CH2:9][CH:10]1[CH2:14][O:13][C:12]([CH3:16])([CH3:15])[O:11]1
Reactant: CN1CCN=C1c1cccc(O)c1
Reactant: CC1(C)OCC(COc2c(F)c(F)nc(Oc3cc(C#N)ccc3OCc3ccccc3)c2F)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CN1CCN=C1c1cccc(Oc2nc(Oc3cc(C#N)ccc3OCc3ccccc3)c(F)c(OCC3COC(C)(C)O3)c2F)c1
Temperature: 55 °C
Reaction time: 24 h
Yield: 66.7 %

Procedure:
To 3-[[3,5,6-trifluoro-4-[(2,2-dimethyldioxolan-4-yl)methoxy]pyridin-2-yl]oxy]-4-(benzyloxy)benzonitrile (1.0 g, 2.1 mmol) in DMSO (6 mL) was added Cs2CO3 (0.7 g, 2.1 mmol) and 2-(3-hydroxyphenyl)-1-methylimidazoline (0.4 g, 2.2 mmol). After stirring in an oil bath at 55° C. for 24 hours, the reaction was partitioned with water and ethyl acetate. The layers were separated, washed with water and brine, dried (Na2SO4), and the solvent was removed in vacuo. The residue was chromatographed on silica with CH2Cl2/MeOH/NH4OH (240/10/1) to give 3-[[3,5-difluoro-6-(3-(1-methylimidazolin-2-yl)phenoxy)-4-[(2,2-dimethyldioxolan-4-yl)methoxy]pyridin-2-yl]oxy]-4-(benzyloxy)benzonitrile (0.9 g).
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([NH:21][NH2:22])[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].[Cl:23][C:24]1[C:29]([CH:30]=O)=[C:28](Cl)[N:27]=[CH:26][N:25]=1>C1(C)C=CC=CC=1>[C:8]([O:12][C:13]([N:15]1[CH2:16][CH2:17][CH:18]([N:21]2[C:28]3=[N:27][CH:26]=[N:25][C:24]([Cl:23])=[C:29]3[CH:30]=[N:22]2)[CH2:19][CH2:20]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCC(NN)CC1
Reactant: O=Cc1c(Cl)ncnc1Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Yield: 34 %

Procedure:
Triethylamine (19.5 mL, 140 mmol) was added to a stirred solution of 4-hydrazino-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 9; 15.0 g, 69.7 mmol) and 4,6-dichloro-pyrimidine-5-carbaldehyde (Intermediate 16; 12.34 g, 69.7 mmol) in toluene (100 mL) at room temperature under nitrogen and the resulting mixture was heated to reflux for 6 hours. The solvent was removed in vacuo and the crude reaction mixture was purified by column chromatography (silica gel, 100-200 mesh; 5% ethyl acetate/hexanes) to give 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (8.0 g, 34%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.43 (s, 9H), 1.97-2.00 (m, 2H), 2.19-2.29 (m, 2H), 2.90-3.00 (br s, 2H), 4.25-4.35 (m, 2H), 4.92-5.00 (m, 1H), 8.15 (s, 1H), 8.74 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 28.3, 31.1, 42.8, 55.3, 79.8, 113.8, 131.8, 152.4, 154.1, 154.4, 154.7. HRMS Calcd. for C15H21ClN5O2 (MH+): 338.1379. Found: 338.1377.
Reaction SMILES: [CH2:1]([C:3]1[CH:31]=[CH:30][C:6]([C:7]([N:9]2[CH2:29][CH2:28][C:12]3([C:17]4=[CH:18][CH:19]=[CH:20][N:16]4[C:15]4[CH:21]=[CH:22][C:23]([C:25](O)=[O:26])=[CH:24][C:14]=4[O:13]3)[CH2:11][CH2:10]2)=[O:8])=[CH:5][C:4]=1[O:32][CH3:33])[CH3:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[BH4-].[Na+]>O1CCCC1.O>[CH2:1]([C:3]1[CH:31]=[CH:30][C:6]([C:7]([N:9]2[CH2:10][CH2:11][C:12]3([O:13][C:14]4[CH:24]=[C:23]([CH2:25][OH:26])[CH:22]=[CH:21][C:15]=4[N:16]4[CH:20]=[CH:19][CH:18]=[C:17]34)[CH2:28][CH2:29]2)=[O:8])=[CH:5][C:4]=1[O:32][CH3:33])[CH3:2]
Reactant: CCc1ccc(C(=O)N2CCC3(CC2)Oc2cc(C(=O)O)ccc2-n2cccc23)cc1OC
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCc1ccc(C(=O)N2CCC3(CC2)Oc2cc(CO)ccc2-n2cccc23)cc1OC
Reaction time: 0.5 h
Yield: 63.6 %

Procedure:
To 1-(4-ethyl-3-methoxy-benzoyl)spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-7′-carboxylic acid (550 mg, 1.2 mmol) in tetrahydrofuran (2.2 mL) at 0° C. was added triethylamine (200 μL, 1.4 mmol) then isobutyl chloroformate (180 μL, 1.4 mmol). The mixture was stirred for 30 min then filtered. The filtrate was added dropwise to a solution of sodium borohydride (70 mg, 1.8 mmol) in water (770 μL) at 0° C. The mixture was allowed to slowly reach room temperature before it was concentrated to ⅓ volume, diluted with ethyl acetate and washed with 1M HCl. The organics were dried over sodium sulfate, filtered and evaporated to yield (4-ethyl-3-methoxyphenyl)(7-(hydroxymethyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone (330 mg, 62%). ESI-MS m/z calc. 432.5, found 433.5 (M+1)+; Retention time: 1.78 minutes (3 min run).
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:14]2[N:15]=[C:16](Cl)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][O:22][CH:21]([CH3:25])[CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH2:1]([S:8][C:9]1[C:14]2[N:15]=[C:16]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][O:22][CH:21]([CH3:25])[CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CNCCN1
Reactant: CC1CN(c2nc(Cl)nc3c(SCc4ccccc4)ncnc23)CCO1
Product: CC1CN(c2nc(N3CCNCC3)nc3c(SCc4ccccc4)ncnc23)CCO1

Procedure:
This compound was prepared analogous to Example 1 from 8-benzylthio-2-chloro-4-(2-methylmorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 40°-60° C.) and piperazine.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[N:11]([CH2:15][CH2:16][NH:17][C:18](=O)[CH3:19])[CH:12]=[CH:13][CH:14]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32]>O.C(O)C>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[N:11]4[CH2:15][CH2:16][N:17]=[C:18]([CH3:19])[C:12]4=[CH:13][CH:14]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(=O)NCCn1cccc1-c1ccc2c(c1)OCO2
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: O=P(Cl)(Cl)Cl
Product: CC1=NCCn2c1ccc2-c1ccc2c(c1)OCO2
Reaction time: 0.75 h
Yield: 66 %

Procedure:
N-[2-[2-(1,3-Benzodioxol-5-yl)-pyrrol-1-yl]-ethyl]acetamide (1.7 g) was treated with 10 ml of phosphorus oxychloride under argon and boiled for 45 minutes while stirring. The reaction mixture was hydrolyzed at 0° C. with 50 ml of 2N sodium hydroxide solution and 50 ml of 28% sodium hydroxide solution, diluted with 600 ml of water and extracted with methylene chloride (1×100 ml, 2×60 ml). The organic extracts were combined, dried with MgSO4 and freed from solvent. 1.4 g of crude product was dissolved in a 20-fold amount of ethanol and treated with 1.1 equivalents of a saturated solution of fumaric acid in ethanol. There were obtained 1.5 g (66%) of 6-(1,3-benzodioxol-5-yl)-3,4-dihydro-1-methylpyrrolo[1,2-a]pyrazine fumarate (1:1); m.pt.: 191°-193° C. (dec.).