Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[CH2:14]([O:18][C:19]1[CH:24]=[CH:23][C:22](O)=[CH:21][CH:20]=1)[CH2:15][CH2:16][CH3:17].O>C(Cl)(Cl)Cl>[CH2:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][C:22]2[CH:23]=[CH:24][C:19]([O:18][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:20][CH:21]=2)=[O:10])=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(C(=O)O)cc1
Reactant: CCCCOc1ccc(O)cc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: C=CCOc1ccc(C(=O)Oc2ccc(OCCCC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
30.0 g of PPE, 5.00 g (28.1 mmol) of the compound (12) and 4.40 g (28.9 mmol) of p-butoxyphenol were dissolved in 100 ml of chloroform under an argon gas atmosphere and the whole was stirred at room temperature overnight. After addition of water to the reaction mixture, the whole was extracted with methylene chloride. After removal of the solvent by distillation, the residue was purified by silica gel column chromatography to obtain 8.30 g of p-butoxyphenyl p-allyloxybenzoate (13) (yield: 94.6%).
Reaction SMILES: [O:1]=[C:2]1[CH:6]([N:7]2[CH2:11][CH2:10][CH2:9][C:8]2=[O:12])[CH2:5][CH2:4][O:3]1.[OH-:13].[Na+].Cl.C(Cl)(Cl)Cl>O.C(O)C>[OH:3][CH2:4][CH2:5][CH:6]([N:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:12])[C:2]([OH:13])=[O:1]
Reactant: [OH-]
Reactant: O=C1OCCC1N1CCCC1=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: O=C(O)C(CCO)N1CCCC1=O
Yield: 30.3 %

Procedure:
67.6 g (0.4 mol) of 1-(tetrahydro-2-oxo-3-furyl)-2-pyrrolidinone and 32 g (0.8 mol) of sodium hydroxide in 210 ml of water are heated for 2 hours under reflux, cooled and then acidified with hydrochloric acid to a pH value of 1. The reaction mixture is evaporated to dryness under reduced pressure and the residue taken up three times in benzene and evaporated in vacuo. The residue obtained is finally treated with a mixture of chloroform and ethanol (4:1 v/v) and the insoluble material filtered off. The filtrate is evaporated and the residue is recrystallized from ethanol. 22.7 g (yield: 30% of theory) of alpha-(2-hydroxyethyl)-2-oxo-1-pyrrolidineacetic acid are obtained. M.P.: 123°-124° C.
Reaction SMILES: [O:1]1[CH2:3][CH2:2]1.C([O:7][CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=O)C.C([OH:18])C>[Cr].[Co].[Pd]>[C:3]([O:1][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][CH2:8][OH:7])=[CH:15][CH:14]=1)(=[O:18])[CH3:2]
Reactant: CC(=O)OC=Cc1ccccc1
Reactant: C1CO1
Reactant: CCO
Agent: [Co]
Agent: [Cr]
Agent: [Pd]
Product: CC(=O)Oc1ccc(CCO)cc1

Procedure:
A 300 ml Fluitron autoclave (Hastelloy C) is charged with 69.5 g crude acetoxystyrene oxirane (86%; 0.335 mol), 200 ml ethanol and 1.6 g Pd/C (5% Pd on carbon; 47.8% H2O). After sealing, the stirrer is started, and the autoclave purged with nitrogen and hydrogen and then pressurized to 400 psig with hydrogen. The H2 pressure is kept constant during the one hour reaction period. The autoclave is vented and purged with N2. The reaction mixture is sucked out of the reactor (63.2 g ethanol rinse) and filtered (23.7 g ethanol rinse).
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][OH:18].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(OC(C)C)(C)C.[OH-].[Na+]>O.O1CCCC1>[C:21]1([CH2:20][O:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][OH:19])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: OCCOCCOCCOCCOCCOCCO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)OC(C)C
Product: OCCOCCOCCOCCOCCOCCOCc1ccccc1
Temperature: 20 °C
Reaction time: 17 h

Procedure:
To a stirred mixture of hexaethylene glycol (10 g), benzyl bromide (4.53 mL) and diisopropyl ether (25 mL) was added tetrahydrofuran (10 mL). The mixture was cooled to 15–20° C. and aqueous sodium hydroxide (10.8M, 4.92 mL) was added slowly maintaining the temperature at 15–20° C. during addition. The resulting mixture was allowed to warm to 20° C. and stirred for a further 17 hours. Water (50 mL) was then added to the reaction mixture, which was then washed with diisopropyl ether (25 mL). Sodium chloride (10 g) was added to the aqueous phase which was extracted with ethyl acetate (3×25 mL). The combined ethyl acetate extracts were dried (Na2SO4) and concentrated in vacuo to give the title compound as a mobile oil (6.29 g). GC retention time 14.2 mins
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C(N(CC)CC)C.[C:18](Cl)(=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].O>CC(C)=O>[C:18]([N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH2:1])(=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: Nc1nc2ccccc2[nH]1
Reactant: CCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(C)=O
Product: CCCCCC(=O)n1c(N)nc2ccccc21
Reaction time: 1 h
Yield: 50.5 %

Procedure:
A solution of 2-amino benzimidazole (8 g, or 0.060 mole) and triethylamine (10 g, or 0,099 mole) in 150 ml of anhydrous acetone, is chilled to a temperature of -65° C. under nitrogen. To this solution is added 12.1 g (0.09 mole) hexanoyl chloride in solution in 150 ml of anhydrous acetone at a temperature of -60° C. After the mixture has been agitated at this temperature for around 1 hour, 100 ml of water is added to it, at a temperature of between -30° and -20° C., after which it is all poured into 500 ml of water. The precipitate is filtered, and dried in a dessicator. After purification, 7 g (50.5% yield) is obtained of a crystallized compound having a melting point of 200° C. and the following structure (90% purity): ##STR5##
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:9]2[CH:10]=[C:11]([CH:15]=[C:16]([N:18]3[CH:22]=[N:21][N:20]=[N:19]3)[CH:17]=2)[C:12]([OH:14])=O)=[N:5][CH:6]=[CH:7][CH:8]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[F:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][NH2:44])=[CH:38][CH:37]=1.O>CN1C(=O)CCC1>[F:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][NH:44][C:12](=[O:14])[C:11]2[CH:15]=[C:16]([N:18]3[CH:22]=[N:21][N:20]=[N:19]3)[CH:17]=[C:9]([C:4]3[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][N:5]=3)[CH:10]=2)=[CH:38][CH:37]=1
Reactant: NCCc1ccc(F)cc1
Reactant: COc1cccnc1-c1cc(C(=O)O)cc(-n2cnnn2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1cccnc1-c1cc(C(=O)NCCc2ccc(F)cc2)cc(-n2cnnn2)c1
Reaction time: 0.67 h
Yield: 7.6 %

Procedure:
3-(3-Methoxy-pyridin-2-yl)-5-tetrazol-1-yl-benzoic acid (140 mg) and dissolved in dry NMP (15 mL), and CDI (80 mg, 0.49 mmol) was added. The reaction mixture was stirred for 40 minutes, and then 2-(4-fluorophenyl)-ethylamine (0.16 mL, 1.22 mmol) was added. The reaction mixture was stirred for 24 hours at room temperature, and then poured into 30 mL water. The resulting mixture was extracted with EtOAc, and the combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified via flash chromatography using EtOAc/hexanes (30%-100%) to give 15 mg of N-[2-(4-fluoro-phenyl)-ethyl]-3-(3-methoxy-pyridin-2-yl)-5-tetrazol-1-yl-benzamide, MS (M+H)=419.
Reaction SMILES: [H-].[Na+].[CH2:3]([NH:6][C:7](=[S:18])[NH:8][C:9]1[S:10][CH:11]=[CH:12][C:13]=1[C:14]([O:16]C)=O)[CH2:4][CH3:5].[CH3:19]I>O1CCCC1>[CH3:19][S:18][C:7]1[N:6]([CH2:3][CH2:4][CH3:5])[C:14](=[O:16])[C:13]2[CH:12]=[CH:11][S:10][C:9]=2[N:8]=1
Reactant: CCCNC(=S)Nc1sccc1C(=O)OC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCn1c(SC)nc2sccc2c1=O
Yield: 91.1 %

Procedure:
In a sulfonation flask, 2.9 g (0.072 mol) of a ca. 60% sodium hydride dispersion is added to 50 ml of absolute tetrahydrofurane. Then 17.7 g (0.069 mol) of methyl 2-(3-propylthioureido)thiophene-3-carboxylate, dissolved in 100 ml of absolute tetrahydrofurane, are added dropwise, such that the internal temperature remains constant at about 25° C. The mixture is stirred at reflux temperature for 5 hours and after cooling to room temperature 10.9 g (0.077 mol) of methyliodide, dissolved in 10 ml of tetrahydrofurane, are added dropwise. Then the mixture is stirred another 2 hours at reflux temperature. After completion of the reaction, the tetrahydrofurane is removed in the water-jet vacuum and the residue taken up in ethyl acetate. The organic layer is washed twice with water and then dried over sodium sulfate. After removal of the solvent in the water-jet vacuum, the crude product is obtained, which is purified by digestion in n-hexane. 15.1 g of 2-methylsulfanyl-3-propyl-3H-thieno[2.3-d]pyrimidin-4-one are obtained in the form of a slightly yellowish powder having a melting point of 94-96° C.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Cl:19][C:20]1[C:25]([F:26])=[CH:24][C:23](/[CH:27]=[CH:28]/[C:29](O)=[O:30])=[CH:22][C:21]=1[F:32]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:23]3[CH:24]=[C:25]([F:26])[C:20]([Cl:19])=[C:21]([F:32])[CH:22]=3)=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Reactant: O=C(O)/C=C/c1cc(F)c(Cl)c(F)c1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)/C=C/c3cc(F)c(Cl)c(F)c3)n2)o1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(4-chloro-3,5-difluoro-phenyl)-acrylic acid. LC-MS-conditions 01b: tR=0.97 min; [M+H]+=406.11.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18]([NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]4[O:31][CH2:32][O:33][C:26]=34)=[N:19][CH:20]=[N:21]2)=[CH:16][C:15]=1[O:34][CH3:35].[CH3:36][S:37]([CH2:40][CH2:41][CH2:42]O)(=[O:39])=[O:38].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)[Cl:64]>>[ClH:64].[CH3:35][O:34][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:14]=1[O:13][CH2:42][CH2:41][CH2:40][S:37]([CH3:36])(=[O:39])=[O:38])[N:21]=[CH:20][N:19]=[C:18]2[NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]2[O:31][CH2:32][O:33][C:26]=12
Reactant: ClCCl
Reactant: CS(=O)(=O)CCCO
Reactant: COc1cc2c(Nc3cccc4c3OCO4)ncnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1cc2c(Nc3cccc4c3OCO4)ncnc2cc1OCCCS(C)(=O)=O
Product: Cl
Temperature: 25 °C

Procedure:
Diethyl azodicarboxylate (0.101 ml) was added dropwise to a stirred mixture of 7-hydroxy-6-methoxy-4-(2,3-methylenedioxyanilino)quinazoline (0.1 g), 3-methylsulphonylpropan-1-ol (0.057 g), triphenylphosphine (0.168 g) and methylene chloride (5 ml) and the reaction mixture was stirred at ambient temperature. After a few minutes further portions of triphenylphosphine (0.084 g) and 3-methylsulphonylpropan-1-ol (0.022 g) were added followed by the dropwise addition of diethyl azodicarboxylate (0.050 ml). After another few minutes third portions of the same amounts of these reagents were added. The reaction mixture was evaporated and the residue was purified by column chromatography on silica using a 10:6:1 mixture of methylene chloride, ethyl acetate and methanol as eluent. The material so obtained was triturated under a 6M solution of hydrogen chloride in diethyl ether. There was thus obtained the title compound (0.108 g) as a white solid; NMR Spectrum: (DMSOd6 and CF3CO2D) 2.3 (m, 2H), 3.05 (s, 3H), 3.35 (m, 2H), 4.0 (s, 3H), 4.35 (t, 2H), 6.1 (s, 2H), 7.0 (m, 3H), 7.3 (s, 1H), 8.1 (s, 1H), 8.15 (s, 1H); Mass Spectrum: M+H+ 432.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[N:9]=[C:8]2[C:3]=1[C:4](=[O:31])[CH:5]=[C:6]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[N:7]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[C:32](O)(=[O:35])[CH2:33][CH3:34].CCN=C=NCCCN(C)C.CN1CCOCC1>CN(C1C=CN=CC=1)C.C(Cl)Cl.O>[CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:32](=[O:35])[CH2:33][CH3:34])[CH2:14][CH2:13]2)[N:9]=[C:8]2[C:3]=1[C:4](=[O:31])[CH:5]=[C:6]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[N:7]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1cc(N2CCNCC2)nc2c1c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Reactant: CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN1CCOCC1
Solvent: O
Solvent: ClCCl
Product: CCC(=O)N1CCN(c2cc(C)c3c(=O)cc(Nc4ccccc4)n(-c4ccccc4)c3n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
A mixture of 5-methyl-1-phenyl-2-phenylamino-7-piperazin-1-yl-1H-[1,8]naphthyridin-4-one (21.0 mg, 0.052 mmol), propionic acid (0.004 mL, 0.055 mmol), EDCI (11.9 mg, 0.062 mmol), DMAP (7.6 mg, 0.062 mmol), and NMM (0.006 mL, 0.062) in CH2Cl2 (0.8 mL) was stirred at room temperature overnight. The reaction was diluted with water and extracted with CH2Cl2. The combined organic extracts were washed with 0.5 N HCl and brine and concentrated in vacuo. The residue was purified by prep-TLC eluting with 100% EtOAc to give 5-methyl-1-phenyl-2-phenylamino-7-(4-propionyl-piperazin-1-yl)-1H-[1,8]naphthyridin-4-one (9.0 mg, 37%): LCMS RT: 2.29 min, MH+: 468.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[C:25](O)(=O)[CH3:26].C(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([CH:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH3:26])[CH2:21][CH2:20]3)=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2[nH]c(C3CCNCC3)cc2-c2ccncc2)cc1
Reactant: CC(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCN1CCC(c2cc(-c3ccncc3)c(-c3ccc(F)cc3)[nH]2)CC1
Reaction time: 2 h

Procedure:
To a suspension of 2-(4-fluorophenyl)-5-(piperidin-4-yl)-3-(4-pyridyl)-pyrrole (Reference Example, 1000 mg, 3.11 mmol; hereinafter referred to as Compound A) and acetic acid (0.18 ml, 3.11 mmol) in anhydrous 1,2-dichloroethane (50 ml) under nitrogen at room temperature, acetaldehyde (0.21 ml, 3.73 mmol) and sodium triacetoxyborohydride (989 mg, 4.67 mmol) were added slowly. The resulting mixture was allowed to stir for 2 hours. The crude product was purified by flash silica gel column (MeOH—CH2Cl2, 8:92 v/v containing 1% NH4OH). After drying, 930 mg of 2-(4-fluorophenyl)-5-(N-ethylpiperidin-4-yl)-3-(4-pyridyl)pyrrole (Compound B) was obtained as the free base.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.COCN[C:15]([CH:17]1[CH2:21][C:20](=O)[N:19]([C@H:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH3:24])[CH2:18]1)=[O:16].[O:31]1CCCC1>>[O:1]1[CH:5]=[C:4]([C:15]([CH:17]2[CH2:21][CH2:20][N:19]([C@H:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH3:24])[C:18]2=[O:31])=[O:16])[N:3]=[CH:2]1
Reactant: c1cocn1
Reactant: C1CCOC1
Reactant: COCNC(=O)C1CC(=O)N([C@@H](C)c2ccccc2)C1
Agent: [Li]CCCC
Product: C[C@@H](c1ccccc1)N1CCC(C(=O)c2cocn2)C1=O
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a cooled solution (−78° C.) of oxazole (10.3 g, 149.1 mmol) in tetrahydrofuran (150 mL) was added n-butyl lithium (2.5 M in hexane, 53.7 mL, 134.2 mmol). The solution was stirred at −78° C. for three hours. To the cold solution was added a solution of 5-oxo-1-((S)-1-phenylethyl)pyrrolidine-3-carboxylic acid, methoxymethylamide (8.2 g, 29.8 mmol [WO 0031062]) in tetrahydrofuran (50 mL). The mixture was warmed to ambient temperature and allowed to stir three hours followed by treatment with water, saturated aqueous ammonium chloride, and extraction with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and the solvent removed under reduced pressure. The resulting residue was purified by silica gel column chromatography, eluting with hexane:ethyl acetate (1:4) to obtain 1.96 g of the title compound as a 1:1 mixture of isomers.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[C:19](=[O:20])[C:18]2[S:21][CH:22]=[CH:23][C:17]=2[N:16]=[C:15]1[CH:24]=CN(C)C>O1CCCC1>[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[C:19](=[O:20])[C:18]2[S:21][CH:22]=[CH:23][C:17]=2[N:16]=[C:15]1[CH:24]=[O:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CN(C)C=Cc1nc2ccsc2c(=O)n1-c1ccccc1Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1nc2ccsc2c(=O)n1-c1ccccc1Cl

Procedure:
To a well stirred mixture of sodium periodate (9.7 9, 45.3 mmol) in pH 7 buffer (115 mL) and tetrahydrofuran (115 mL) was added 3-(2-chloro-phenyl)-2-(dimethylamino-vinyl)-4-oxo-3,4-dihydro-thieno[3,2-d]pyrimidine (5.0 g, 15.1 mmol) all at once. The mixture warmed slightly to the touch and was stirred for 1 hour at ambient temperature. The reaction was filtered through celite and the pad was washed with ethyl acetate. The phases were separated from the filtrate and the aqueous layer was extracted with ethyl acetate. The combined organic phase was washed with brine, dried over sodium sulfate and concentrated to a yellow oil. The oil was flash chromatographed on silica gel (70 g) with elution proceeding as follows: 50% methylene chloride/hexane (500 mL), unweighed forerun; 50% ethyl acetate/hexane (1000 mL), 4.6 g (100%) of 3-(2-chloro-phenyl)-4-oxo-3,4-dihydro-thieno[3,2-d]pyrimidine-2-carbaldehyde as a foam which was a 2:1 mixture of free aldehyde and hydrate and had: 1H NMR δ 9.56 (s) [CHO], 7.94 and 7.87 (pair of d, J=5.2, 5.4 Hz, respectively, 1H), 7.60-7.30 (m, 5H), 5.30 (dd, J=7, 9.5 Hz) [hydrate methine CH], 4.76 (d, J=9.5 Hz) [hydrate OH], 3.79 (d, J=7 Hz) [hydrate OH]. Note that the doublets at 4.76 and 3.79 ppm are washed out and the dd at 5.30 ppm is converted to a singlet when deuterium oxide is added to the NMR sample.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=O.[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:12]>>[C:11]([C:13](=[C:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:12]
Reactant: CCOC(=O)CC#N
Reactant: O=C1Cc2ccccc2C1
Product: CCOC(=O)C(C#N)=C1Cc2ccccc2C1

Procedure:
Prepared from 2-indanone and ethyl cyanoacetate according to a procedure identical to that used in Stage A of Example 15.
Reaction SMILES: [NH2:1][C@@H:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[ClH:10].N1C=CC([C:16]([NH2:18])=[NH:17])=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[ClH:10].[N:4]12[CH2:9][CH2:8][CH:7]([CH2:6][CH2:5]1)[C@@H:2]([NH:1][C:16]([NH2:18])=[NH:17])[CH2:3]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: N=C(N)c1cc[nH]n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N=C(N)N[C@H]1CN2CCC1CC2
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a mixture of (R)-3-aminoquinuclidine (5.85 g, 46.4 mmol) and pyrazole carbox-amidine hydrochloride (6.80 g, 46.4 mmol) is added Hunig's base (8.07 ml, 46.4 mmol) and DMF (30 ml). The reaction is heated at 70° C. for 40 hours. The reaction is then cooled to room temperature and quenched by adding 400 ml of diethyl ether and stirring at room temperature for 2 hours. Product separates out as a white solid, which is filtered, washed and dried (8.94 g, 94%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@:15]3([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]3)[C:14]3[CH:13]=[C:12](Cl)[N:11]=[CH:10][C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[F:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[N:28][CH:29]=1.Cl.[F:34][C:35]1([F:40])[CH2:39][CH2:38][NH:37][CH2:36]1>>[F:34][C:35]1([F:40])[CH2:39][CH2:38][N:37]([C:12]2[N:11]=[CH:10][C:9]3[O:8][C:5]4[C:4]([C@:15]5([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]5)[C:14]=3[CH:13]=2)=[CH:3][C:2]([C:26]2[CH:27]=[N:28][CH:29]=[C:24]([F:23])[CH:25]=2)=[CH:7][CH:6]=4)[CH2:36]1
Reactant: FC1(F)CCNC1
Reactant: OB(O)c1cncc(F)c1
Reactant: NC1=N[C@@]2(COC1)c1cc(Br)ccc1Oc1cnc(Cl)cc12
Agent: Cl
Product: NC1=N[C@@]2(COC1)c1cc(-c3cncc(F)c3)ccc1Oc1cnc(N3CCC(F)(F)C3)cc12

Procedure:
The title compound was synthesized by steps analogous to those described in Method A3, but using Intermediate 10B, 5-fluoropyridin-3-ylboronic acid, and 3,3-difluoropyrrolidine hydrochloride. MS m/z=468.3 [M+H]+. Calculated for C24H20FN5O2: 467.16.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=O)[CH2:7][CH2:8][CH2:9][C:2]1=2.BrBr.[OH2:13].[CH3:14]O>>[OH:13][CH2:14][C:6]1[C:3]2[CH:4]=[CH:5][S:1][C:2]=2[CH:9]=[CH:8][CH:7]=1
Reactant: CO
Reactant: O
Reactant: O=C1CCCc2sccc21
Agent: BrBr
Product: OCc1cccc2sccc12
Temperature: 110 °C

Procedure:
To a solution (400 ml) of 4,5,6,7-tetrahydrobenzo(b)thiophen-4-one (70.0 g) in methanol was added dropwise a solution (200 ml) of bromine (75.0 g) in methanol at room temperature. After the completion of the reaction, the reaction mixture was poured into water and extracted with chloroform, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in DMF (500 ml) and lithium bromide (30.0 g) was added. The reaction mixture was stirred with heating at a reaction temperature of 110° C. for 1 hr. The reaction mixture was poured into ice water, extracted with chloroform, the extract was dried over magnesium sulfate and concentrated under reduced pressure to give 4-hydroxymethylbenzo(b)thiophene (50.5 g). This was dissolved in DMF (300 ml) and boron hydride (15.0 g) was added. The mixture was stirred at room temperature for 1 hr. To this reaction mixture was added dropwise methoxymethyl chloride (16.5 g). After the completion of the reaction, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried and concentrated under reduced pressure. The residue was dissolved in THF (400 ml) and n-BuLi (1.6M hexane solution) (250 ml) was added dropwise at −78° C. After the mixture was stirred for 30 min, and carbonic acid gas was blown in until the reaction ended. The reaction mixture was poured into water, and the aqueous layer was made acidic with hydrochloric acid, and after extraction with ethyl acetate, the solvent was evaporated under reduced pressure to give the title compound as white crystals, melting point 212–214° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[CH3:10].[CH2:11]([NH2:16])[CH2:12][CH:13]([CH3:15])[CH3:14].[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:16][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(C=O)ccc1Br
Reactant: CC(C)CCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(CNCCC(C)C)ccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
4-bromo-3-methyl-benzaldehyde (2a: 10.20 g, 51.2 mmol) was dissolved in methanol (150 ml) before adding isoamyl amine (6.75 g, 77 mmol). After stirring overnight at room temperature, sodium borohydride (5.9 g, 154 mmol) was added. After stirring for 1 hour at room temperature, the reaction was quenched using concentrated (37%) hydrochloric acid and the volatiles were removed with a rotary evaporator under reduced pressure. The resulting residue was made basic with a 2 N aqueous sodium hydroxide solution and extracted twice with ethyl acetate. The combined organics were washed with a saturated aqueous sodium bicarbonate solution and dried over sodium sulfate, filtered and concentrated under reduced pressure to provide 13.7 g of the title compound (I-2b).
Reaction SMILES: C[N:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH2:3]1.[Mn]([O-])(=O)(=O)=O.[K+].[C:14](=O)([O-:16])[O-:15].[Na+].[Na+]>O>[N:2]1[CH:7]=[CH:6][C:5]([C:14]([OH:16])=[O:15])=[N:4][CH:3]=1
Reactant: CN1C=CC=NC1
Reactant: O=C([O-])[O-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccncn1
Yield: 11 %

Procedure:
3-Methyl-pyrimidine (9.41 g, 100 mmol), potassium permanganate (26.9 g) and sodium carbonate (10.6 g) was refluxed in water (100 ml) for 72 h followed by filtration through celite. The filtrate was washed with several portions of DCM and EtOAc before acidification with conc. HCl. The formed precipitate was collected and washed with water to yield 1.37 g of the title compound as a white solid. 1H NMR (DMSO-d6) d (ppm): 13.94 (br. s, 1H), 9.37 (d, 1H), 9.07 (d, 1H), 8.01 (dd, 1H).