Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([Br:7])[S:4][C:3]=1[CH:8]([OH:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10].Cl(O)(=O)(=O)=O.C(=O)([O-])[O-].[K+].[K+].C(O[C:30]([CH3:33])([CH3:32])[CH3:31])(=O)C>>[C:30]([O:14][CH:8]([C:3]1[S:4][C:5]([Br:7])=[CH:6][C:2]=1[Br:1])[C:9]([O:11][CH2:12][CH3:13])=[O:10])([CH3:33])([CH3:32])[CH3:31]
Reactant: CCOC(=O)C(O)c1sc(Br)cc1Br
Reactant: CC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [O-][Cl+3]([O-])([O-])O
Product: CCOC(=O)C(OC(C)(C)C)c1sc(Br)cc1Br
Temperature: 0 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
Ethyl 2-(3,5-dibromothiophen-2-yl)-2-hydroxyacetate (10b) (160 mg, 0.47 mmol) was dissolved in tert-butyl acetate (8.7 mL) at −20° C. and 70% perchloric acid (1.1 mL) was rapidly added. The mixture was stirred at 0° C. for 3 hours then poured in a saturated solution of potassium carbonate. Layers were separated. The aqueous layer was extracted with ethyl acetate (2×20 mL). The organic layers were washed with brine (10 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 90/10) to provide the desired product (10c) (160 mg, 0.40 mmol, 86%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([CH:15]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1C=CC(S(O[CH2:34][CH2:35][O:36][CH:37]2[CH2:39][CH2:38]2)(=O)=O)=CC=1>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:34][CH2:35][O:36][CH:37]3[CH2:39][CH2:38]3)=[CH:10][CH:9]=2)[CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOC2CC2)cc1
Reactant: Oc1ccc(Cc2cc(Br)ccc2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc(Br)cc1Cc1ccc(OCCOC2CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
A mixture of 4-(5-bromo-2-chlorobenzyl)phenol (56.7 g, 210 mmol) and Cs2CO3 (135 g, 420 mmol) in DMF (350 mL) was stirred at room temperature for 30 min, and then 2-cyclopropoxyethyl 4-methylbenzenesulfonate (crude intermediate BP from the second preceeding step above) (53.3 g, 210 mmol) was added. The reaction mixture was stirred at room temperature overnight, and then diluted with water (3 L) and extracted with EtOAc. The organic layer was washed with water, then with brine, and dried over Na2SO4. The residue was concentrated and then purified by flash column chromatography on silica gel (eluent PE:EA=10:1) to give intermediate DK as a liquid (51 g, yield 64%). 1H NMR (CDCl3, 400 MHz): δ 7.22˜7.29 (m, 3H), 7.08 (d, J=8.8 Hz, 2H), 6.88 (d, J=8.8 Hz, 2H), 4.10 (t, J=4.8 Hz, 2H), 3.86 (t, J=4.8 Hz, 2H), 3.38˜3.32 (m, 1H), 0.62˜0.66 (m, 2H), 0.49-0.52 (m, 2H).
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[C:5]([CH:18]([CH3:20])[CH3:19])[C:6]([O:16][CH3:17])=[C:7]([CH:9]([O:13]CC)OCC)[CH:8]=1.C[Mg]Br.[O:24]1[CH2:28]CCC1.Cl.[O:30]1CCCC1>>[CH:9]([C:7]1[CH:8]=[C:3]([CH:4]=[C:5]([CH:18]([CH3:19])[CH3:20])[C:6]=1[O:16][CH3:17])[C:28]([OH:24])=[O:30])=[O:13]
Reactant: C1CCOC1
Reactant: CCOC(OCC)c1cc(Br)cc(C(C)C)c1OC
Agent: C[Mg]Br
Agent: Cl
Agent: [Mg]
Product: COc1c(C=O)cc(C(=O)O)cc1C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To magnesium (2.43 g), tetrahydrofuran (100 mL), 5-bromo-1-diethoxymethyl-3-isopropyl-2-methoxybenzene (31.55 g) and a 0.97M methylmagnesium bromide-tetrahydrofuran solution (15 mL) were added, and then the mixture was stirred at room temperature for 2 hours. The reaction solution was cooled to 0° C. and stirred under a carbon dioxide atmosphere for 30 minutes, and then 2N hydrochloric acid (100 mL) was added and the reaction mixture was stirred at room temperature for 16 hours. The organic solvent was distilled off under reduced pressure, and then the mixture was extracted with diisopropylether. The organic layer was extracted with 1N sodium hydroxide (100 mL) added thereto, and then the aqueous layer was washed twice with diisopropylether. The aqueous layer was acidified with 4N hydrochloric acid added thereto, and then extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (15.85 g) as a brown solid.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:9]([C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:26])=[C:8]1[CH:34]([CH3:36])[CH3:35])C.Cl>CC(C)=O>[F:18][C:15]1[CH:14]=[CH:13][C:12]([C:11]2[N:7]([CH2:6][CH2:5][CH:4]=[O:3])[C:8]([CH:34]([CH3:36])[CH3:35])=[C:9]([C:25]([NH:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:26])[C:10]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:17][CH:16]=1
Reactant: CCOC(CCn1c(-c2ccc(F)cc2)c(-c2ccccc2)c(C(=O)Nc2ccccc2)c1C(C)C)OCC
Agent: Cl
Solvent: CC(C)=O
Product: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CCC=O
Yield: 94.3 %

Procedure:
To a nitrogen purged flask fitted with an overhead stirrer, a thermometer, and a condenser is added 20 kg (37.8 mol) of 1-(3,3-diethoxypropyl)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl- 1H-pyrrole-3-carboxamide along with 200 L of acetone. The solution is stirred and 100 L of 2 N hydrochloric acid solution is added. The mixture is heated to reflux for four hours then cooled to 50° C.±5° C., seeded, and cooled to 0° C.±5° C. The product is collected by filtration, washed with 100 L 2-propanol-water (1:1) and dried in vacuo at 50° C. for 64 hours to yield 16.2 kg of 5-(4-fluorophenyl)-2-(1-methylethyl)-1-(3-oxopropyl)-N,4-diphenyl-1H-pyrrole-3-carboxamide as an off-white solid.
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH2:6][CH2:7][O:8][C:9](=[O:12])[CH2:10]Cl)=[O:4].[P:13]([O:20]CC)([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16].[CH2:23](Cl)[CH3:24]>>[CH2:15]([O:14][P:13]([CH2:2][C:3]([O:5][CH2:6][CH2:7][O:8][C:9](=[O:12])[CH2:10][P:13]([O:14][CH2:15][CH3:16])([O:17][CH2:18][CH3:19])=[O:20])=[O:4])([O:20][CH2:23][CH3:24])=[O:17])[CH3:16].[CH2:2]=[CH2:3]
Reactant: O=C(CCl)OCCOC(=O)CCl
Reactant: CCOP(OCC)OCC
Reactant: CCCl
Product: C=C
Product: CCOP(=O)(CC(=O)OCCOC(=O)CP(=O)(OCC)OCC)OCC
Temperature: 150 °C

Procedure:
Ethylene bis[(diethyl phosphono)acetate] was prepared by a modification of the procedure described in U.S. Pat. No. 3,943,200 employing a shorter reaction time and lower final temperature. To ethylene bis(chloroacetate) (107.5 g, 0.5 mol) under nitrogen at 150° C. triethyl phosphite (166.0 g, 1.0 mol) was slowly added over 60 minutes with stirring, and the reaction mixture was maintained at 150° C. for a further 3 hours. Continuous evolution of ethyl chloride occurred throughout the reaction. Removal of volatiles under vacuum gave ethylene bis [(diethyl phosphono) acetates as a straw-coloured liquid (197.5 g, 95%), identified by NMR.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4](Cl)=[O:5].[Br:9][C:10]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[C:13]([NH2:14])=[C:12]([Cl:21])[CH:11]=1.O>C(#N)C>[Br:9][C:10]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[C:13]([NH:14][C:4](=[O:5])[CH2:3][C:2]([CH3:8])([CH3:7])[CH3:1])=[C:12]([Cl:21])[CH:11]=1
Reactant: Nc1c(Cl)cc(Br)cc1C(F)(F)F
Reactant: CC(C)(C)CC(=O)Cl
Solvent: CC#N
Solvent: O
Product: CC(C)(C)CC(=O)Nc1c(Cl)cc(Br)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.9 %

Procedure:
3,3-dimethylbutanoyl chloride (1.08 g, 8.0 mmol) was added to a solution of 4-bromo-2-chloro-6-(trifluoromethyl)aniline (2.0 g, 7.3 mmol) in acetonitrile (10 mL). The reaction mixture was stirred at room temperature overnight. Water was added to the mixture and then extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. Purification by column chromatography (100% DCM) afforded the title compound as a powder (1.22 g, 65%) over the two steps,
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[CH3:17])[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:18]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl>[Br:18][CH2:17][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:16]=1[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:9]=[CH:10]2
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc2ccn(C(=O)OC(C)(C)C)c12
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)n1ccc2cccc(CBr)c21

Procedure:
200 mg (865 μmol) of the compound from Example 5A were introduced into 10 ml of tetrachloromethane, 169 mg (951 μmol) of N-bromosuccinimide were added, and the mixture was heated under reflux while irradiating with a sun lamp for 4 h. The residue after concentration was purified by flash chromatography (mobile phase: cyclohexane/ethyl acetate gradient) to result in 168 mg (63% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[C:5]([C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[NH:9][CH2:10][CH2:11][N:12]2[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])=[O:6].N1C=CC=CC=1.[Br:36][CH2:37][C:38](Br)=[O:39]>C(Cl)Cl>[Br:36][CH2:37][C:38]([N:9]1[C:8]2[C:13](=[CH:14][CH:15]=[CH:16][C:7]=2[C:5](=[O:6])[C:4]2[CH:27]=[CH:28][CH:29]=[C:2]([Cl:1])[CH:3]=2)[N:12]([C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[CH2:11][CH2:10]1)=[O:39]
Reactant: O=C(Br)CBr
Reactant: O=C(c1cccc(Cl)c1)c1cccc2c1NCCN2C(=O)OCc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1cccc(Cl)c1)c1cccc2c1N(C(=O)CBr)CCN2C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
To a solution of benzyl 5-(3-chlorobenzoyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate, Intermediate E-1D (50 g, 123 mmol) in DCM (500 mL) at 0° C. was added pyridine (14.91 ml, 184 mmol). Bromoacetyl bromide (26.7 ml, 307 mmol) in DCM (1.0 mL) was added dropwise. The reaction mixture was stirred at 0° C. for 3 h. The reaction mixture was washed with H2O, saturated NaHCO3, and brine, dried over Na2SO4, filtered, concentrated to afford benzyl 4-(2-bromoacetyl)-5-(3-chlorobenzoyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate, Intermediate E-1E (55 g, 104 mmol, 85% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.0 (1H, bs), 7.85 (1H, s), 7.75 (1H, m), 7.6 (2H, m) 7.4 (7H, m), 7.10 (1H, m), 5.3 (2H, s), 4.15 (2H, m), 4.0 (2H, m), 3.8 (2H, m).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[C:9](O)(=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:3]1([CH2:2][NH:1][C:9](=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CCCCCCC(=O)O
Reactant: NCC1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCCCCCC(=O)NCC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
To a solution of aminomethylcyclohexane (0.34 g, 3.0 mmol) in methylene chloride (30 mL) was added heptanoic acid (0.39 g, 3 mmol) and DMAP(0.37 g, 3.0 mmol) followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.57 g, 3.0 mmol) and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with methylene chloride (100 mL), and the organic phase was washed with 5% HCl (3×75 mL), aqueous NaHCO3 (75 mL) and brine (75 mL), and dried over Na2SO4. Concentration in vacuo afforded 0.62 g (92%) of an oil, which then crystallised.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[CH:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:16]=[C:17]1O[C:19](=[O:20])[CH2:18]1.C(Cl)Cl>CCOCC>[CH3:1][N:2]1[C:17]([CH3:16])=[CH:18][C:19](=[O:20])[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:3]1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: C=C1CC(=O)O1
Reactant: CCOC(=O)C=C(NC)c1ccccc1
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)c1c(-c2ccccc2)n(C)c(C)cc1=O
Reaction time: 117 h

Procedure:
10.25 g of ethyl beta-methylaminocinnamate, 9.4 g of technical grade diketene and 25 ml dry methylene chloride are mixed in a flask fitted with a calcium chloride drying tube. The reaction mixture is stored at room temperature for 117 hours. Approximately 75 ml of dry ether is added and the resulting crystalline solid is filtered to yield 8.5 g of ethyl 1,6-dimethyl-2-phenyl-4-oxonicotinate. mp (toluene)=244°-248° C.
Reaction SMILES: [H][H].C([N:10]1[CH:15]=[CH:14][C:13](=[O:16])[C:12]2[C:17]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([O:26]CC4C=CC=CC=4)=[CH:22][CH:21]=3)[O:19][C:11]1=2)C1C=CC=CC=1.ClCCl.C(O)(=O)C>[Pd].C(OCC)(=O)C>[OH:26][C:23]1[CH:22]=[CH:21][C:20]([C:18]2[O:19][C:11]3[NH:10][CH:15]=[CH:14][C:13](=[O:16])[C:12]=3[C:17]=2[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[CH:25][CH:24]=1
Reactant: [H][H]
Reactant: O=c1ccn(Cc2ccccc2)c2oc(-c3ccc(OCc4ccccc4)cc3)c(-c3ccccc3)c12
Agent: [Pd]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=c1cc[nH]c2oc(-c3ccc(O)cc3)c(-c3ccccc3)c12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A 500-mL round bottom flask equipped with a rubber septum and hydrogen (g) balloon was charged with 7-benzyl-2-(4-benzyloxy-phenyl)-3-phenyl-7H-furo[2,3-b]pyridin-4-one (4a) (1.20 g, 2.50 mmol), dichloromethane (100 mL), acetic acid (100 mL), and ethyl acetate (20 mL). Palladium on carbon (10 wt %, 0.200 g) was added, and the system was evacuated and purged with hydrogen three times. The mixture stirred at room temperature for 24 h and was filtered through Celite. The filtrate was concentrated and the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous phase was separated and extracted with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated to afford 2-(4-hydroxy-phenyl)-3-phenyl-7H-furo[2,3-b]pyridin-4-one 5 as an off-white solid. MS (MH+) 304.1; Calculated 303 for C19H13NO3.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc3[nH]ccc3c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 125.6 %

Procedure:
5-Aminoindole (100 mg, 0.757 mmol) was dissolved in acetonitrile (2 mL), and the solution was added with 1-(tert-butoxycarbonyl)-4-piperidinone (181 mg, 0.908 mmol), acetic acid (0.870 mL, 15.2 mmol) and sodium triacetoxyborohydride (160 mg, 0.755 mmol) little by little, followed by stirring at room temperature for 1 hour. The reaction mixture was added with water and sodium carbonate to adjust the pH to 9. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain 5-[1-(tert-butoxycarbonyl)-4-piperidylamino]indole (300 mg).
Reaction SMILES: C(N(CC)CC)C.Cl[CH2:9][C:10](Cl)=[O:11].[NH2:13][C:14]1([CH2:27][OH:28])[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][CH2:15]1.CC(C)([O-])C.[K+]>C1COCC1.C(Cl)Cl>[C:21]1([CH2:20][N:17]2[CH2:18][CH2:19][C:14]3([NH:13][C:10](=[O:11])[CH2:9][O:28][CH2:27]3)[CH2:15][CH2:16]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NC1(CO)CCN(Cc2ccccc2)CC1
Reactant: O=C(Cl)CCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1COCC2(CCN(Cc3ccccc3)CC2)N1
Temperature: 23 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
Triethylamine (2 mL 14 mmol) was added to a DCM (50 mL) solution containing chloroacetyl chloride (1 mL, 14 mmol) and compound 391 (3 g, 14 mmol). The resulting mixture was stirred 2 h at 23° C. The solvent was stripped and THF was added followed by potassium tert-butoxide (5 g, 41 mmol). The resulting solution was stirred overnight at room temperature. The reaction was then concentrated to dryness and the resulting residue was washed with 200 mL of absolute ethanol. The ethanolic solution was then concentrated to give 3.16 g of 9-(phenylmethyl)-4-oxa-1,9-diazaspiro[5.5]undecan-2-one. The material was used in the next step without further purification. LCMS-ESI (POS), M/Z, M+1: Found 261, Calculated 261.
Reaction SMILES: [H-].[Na+].[OH:3][C@H:4]1[CH2:8][CH2:7][O:6][CH2:5]1.[CH:9]([CH:12]1[C:17]2[N:18]=[CH:19][NH:20][C:16]=2[CH2:15][CH2:14][N:13]1[C:21](OCC(Cl)(Cl)Cl)=[O:22])([CH3:11])[CH3:10]>C1COCC1>[CH:9]([CH:12]1[C:17]2[N:18]=[CH:19][NH:20][C:16]=2[CH2:15][CH2:14][N:13]1[C:21]([O:3][C@H:4]1[CH2:8][CH2:7][O:6][CH2:5]1)=[O:22])([CH3:11])[CH3:10]
Reactant: CC(C)C1c2nc[nH]c2CCN1C(=O)OCC(Cl)(Cl)Cl
Reactant: O[C@H]1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)C1c2nc[nH]c2CCN1C(=O)O[C@H]1CCOC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 1.2 %

Procedure:
NaH (0.40 g, 10.0 mmol, 60% dispersion in mineral oil) was suspended in anhydrous THF (20 mL), cooled to 0° C. and (S)-3-hydroxytetrahydrofuran (0.88 g, 0.68 mL, 10.0 mmol) was added. The suspension was stirred at 0° C. for 30 min then added to a solution of Intermediate 2 (3.30 g, 10.0 mmol, 70% pure) in THF (60 mL) and the reaction mixture was stirred at room temperature. Two additional such portions of NaH and (S)-3-hydroxytetrahydrofuran in THF were added after 5 and 29 h, respectively. After 2 d the reaction mixture was quenched with water (10 mL) and the solvents were removed in vacuo. The residue was dissolved in EtOAc (100 mL), washed with 1 M aq Na2CO3 solution (4×100 mL), dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by column chromatography (normal phase, 20 g, Strata SI-1, silica gigatube, DCM (200 mL) followed by 2%, 4% and 5% MeOH in DCM (200 mL each)) and reverse phase HPLC (YMC ODS-A 100×20 mm, 5 μm, 25 mL/min, gradient 30% to 60% (over 7 min) then 100% (3 min) MeOH in 10% MeOH/water) to give (3S)-tetrahydro-furan-3-yl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate (34.8 mg, 1.1%) as a white solid.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([P-:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[K+].C1COCC1.F[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[NH:28][C@@H:29]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@H:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:31]=1>C1COCC1>[C:8]1([P:7]([C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]2[NH:28][C@@H:29]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C@H:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:31]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Fc1ccccc1C1=N[C@@H](c2ccccc2)[C@H](c2ccccc2)N1
Reactant: c1ccc([P-]c2ccccc2)cc1
Agent: [K+]
Solvent: C1CCOC1
Product: c1ccc([C@@H]2N=C(c3ccccc3P(c3ccccc3)c3ccccc3)N[C@H]2c2ccccc2)cc1
Temperature: 25 °C

Procedure:
13.9 ml of 0.5M potassium diphenylphosphide/THF (6.95 mmol, 1.1 eq.) was heated to 60° in a thermostated oil bath. To this warm solution was then added a solution of 2.00 g fluoride 8 (6.32 mmol, 1 eq.) in 5 ml THF via syringe over 2 minutes. The resulting solution was then heated at reflux for 1 hour, cooled to room temperature and quenched by the addition of 10 ml water. The resulting mixture was extracted with methylene chloride (2×25 ml), dried (MgSO4), and the solvents removed in vacuo to give an oil.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]3[NH:15][C:14](=O)[NH:13][C:10]3=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:14]1[NH:13][C:10]2=[N:11][CH:12]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=[C:9]2[N:15]=1
Reactant: O=c1[nH]c2ncc(-c3ccccc3)nc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1nc2nc(-c3ccccc3)cnc2[nH]1
Reaction time: 0.5 h

Procedure:
Reflux a solution of 5-phenyl-1,3-dihydro-imidazo[4,5-b]pyrazin-2-one (200 mg) in phosphorus oxychloride (10 mL) for 18 hours. After cooling, remove the excess POCl3 in vacuo, and triturate the residue in ice-water (200 mL). After stirring for 30 minutes, filter the precipitate to obtain 2-chloro-5-phenyl-1H-imidazo[4,5-b]pyrazine as a gray solid. D. 1′-(5-Phenyl-1H-imidazo[4,5-b]pyrazin-2-yl)-spiro[isobenzofuran-1,4′-piperidin]-3-one
Reaction SMILES: [F:1][CH2:2][C:3]1([CH2:23][F:24])[CH:8]=[C:7]([N:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]2=S)[C:6]2[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:5]=2[O:4]1.CI.[N:27]#[C:28][NH2:29].[H-].[Na+]>C(Cl)Cl.O1CCCC1>[C:28]([N:29]=[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][N:9]1[C:7]1[C:6]2[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:5]=2[O:4][C:3]([CH2:23][F:24])([CH2:2][F:1])[CH:8]=1)#[N:27]
Reactant: O=[N+]([O-])c1ccc2c(c1)C(n1ccccc1=S)=CC(CF)(CF)O2
Reactant: N#CN
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: ClCCl
Solvent: C1CCOC1
Product: N#CN=c1ccccn1C1=CC(CF)(CF)Oc2ccc([N+](=O)[O-])cc21
Yield: 54.3 %

Procedure:
A mixture of 0.09 g of 2,2-bisfluoromethyl-6-nitro-4-(1,2-dihydro-2-thioxo-1-pyridyl)-2H-1-benzopyran, 0.20 g of methyl iodide and 5 ml of tetrahydrofuran was refluxed for 50 minutes. To the mixture were added 57 mg of cyanamide and 13 mg of sodium hydride (60%) and the mixture was refluxed for 1.5 hours. Methylene chloride was added thereto and the mixture was filtered to remove insoluble materials. The mother liquor was distilled off and the resultant residue was purified using silica gel column chromatography (developing solution, AcOEt:hexane=1:1) to obtain 0.05 g of 4-(2-cyanoimino-1,2-dihydro-1-pyridyl)-2,2-bisfluoromethyl-6-nitro-2H-1-benzopyran represented by the following formula having a melting point of 238°-240° C.
Reaction SMILES: [CH2:1]([Cl:11])[CH2:2][CH:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])[CH3:4].CCCCC.O.[ClH:18]>C(O)(=O)C>[Cl:11][CH2:1][CH2:2][CH:3]([CH3:4])[CH2:5][CH2:6][CH2:7][C:8]([Cl:18])([CH3:10])[CH3:9]
Reactant: CC(C)=CCCC(C)CCCl
Reactant: Cl
Solvent: O
Solvent: CC(=O)O
Solvent: CCCCC
Product: CC(CCCl)CCCC(C)(C)Cl
Reaction time: 4 h

Procedure:
Into a well stirred solution of citronellyl chloride (8-chloro-2,6-dimethyl-2-octene; 26.1 g, 0.15 mol) in glacial acetic acid (600 ml), hydrochloric acid gas is passed for 4 hours at room temperature. Pentane (300 ml) and water (150 ml) are then added, the mixture stirred and transferred to a separatory funnel with additional pentane and water. The layers are separated, and the pentane layer is washed with several portions of water followed by saturated sodium bicarbonate solution. The pentane layer is then dried, and the solvent evaporated giving a quantitative yield of the product, boiling point 90° C to 93° C at 1.9 mm.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]=[O:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:14][NH:15][CH3:16]>O1CCOCC1.O>[CH3:14][N:15]([CH3:16])[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]=[O:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: CNC
Reactant: O=Cc1ccc2ncnc(Cl)c2c1
Solvent: C1COCCO1
Solvent: O
Product: CN(C)c1ncnc2ccc(C=O)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Chloro-quinazoline-6-carbaldehyde (200 mg, 1 mmol) was dissolved in 10 ml dioxane. To this solution was added a solution of dimethylamine in water (Seq.). The mixture was stirred during 2 h at r.t. Evaporation of the solvents and remaining amine under high vacuum afforded pure 4-Dimethylamino-quinazoline-6-carbaldehyde as a yellow solid, which was used for the next step without further purification (190 mg=91%).