Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][N:11]([CH3:14])[C:10](=[O:15])[CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[C:17]1[C:25]([C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1)=[O:26]>>[NH:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[C:17]1[C:25]([C:27]1[CH:32]=[CH:31][C:30]([O:33][C:2]2[C:7]([CH:8]3[CH2:13][CH2:12][N:11]([CH3:14])[C:10](=[O:15])[CH2:9]3)=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:29][CH:28]=1)=[O:26]
Reactant: O=C(c1ccc(O)cc1)c1nc2ccccc2[nH]1
Reactant: CN1CCC(c2cccnc2F)CC1=O
Product: CN1CCC(c2cccnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)CC1=O

Procedure:
The title compound was prepared from 4-(2-fluoropyridin-3-yl)-1-methylpiperidin-2-one (Step 3, Example 1) and (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone by following the procedure described in Step 4 of Example 1. MS (ESI, pos. ion) m/z: 427.1 (M+1). IC50 (uM) +++++.
Reaction SMILES: CO[CH:3](OC)[CH2:4][CH2:5][C:6]1(N)[CH2:10][CH2:9][CH2:8][CH2:7]1.[C:14]1(C)C=CC=CC=1>[Ni].CC(C)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:14][CH2:7][CH2:8][CH2:9][CH2:10][CH2:6][CH2:5][CH2:4][CH3:3]
Reactant: Cc1ccccc1
Reactant: COC(CCC1(N)CCCC1)OC
Agent: [Ni]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CCCCCCCCC

Procedure:
Condense nitrocyclopentane (prepared from bromocyclopentane and sodium nitrite) and acrolein in tetrahydrofuran in the presence of sodium hydride to obtain 3-(1-nitrocyclopentyl)propionaldehyde. Treat this aldehyde with p-toluenesulfonic acid in methanol and isolate 3-(1-nitrocylopentyl) propionaldehyde dimethyl acetal. Hydrogenate this compound with Raney nickel. Isolate 3-(1-aminocyclopentyl)propionaldehyde dimethylacetal and dissolve in aqueous acetone in the presence of p-toluenesulfonic acid and heat under reflux, followed by addition of toluene and azeotrope the mixture to give 1-azaspiro[4.4]-Δ1 -nonane.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[O:12][C:3]=12.[NH2:17][C:18]1[CH:23]=[C:22]([OH:24])[C:21]([CH3:25])=[CH:20][CH:19]=1>C(OCCO)C>[OH:24][C:22]1[CH:23]=[C:18]([NH:17][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]3[C:10]4[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=4[O:12][C:3]=23)[CH:19]=[CH:20][C:21]=1[CH3:25]
Reactant: Cc1ccc(N)cc1O
Reactant: N#Cc1cnc2c(oc3ccccc32)c1Cl
Solvent: CCOCCO
Product: Cc1ccc(Nc2c(C#N)cnc3c2oc2ccccc23)cc1O
Temperature: 80 °C
Yield: 72.1 %

Procedure:
A mixture of 200 mg (0.88 mmol) of 4-chlorobenzo[4,5]furo[3,2-b]pyridine-3-carbonitrile and 120 mg (0.97 mmol) of 5-amino-o-cresol in 6 mL of 2-ethoxyethanol is heated at 80° C. for 15 hours and then at reflux temperature for 10 hours. The reaction mixture is cooled to room temperature and partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer is washed with saturated sodium bicarbonate, dried over sodium sulfate and filtered through a pad of diatomaceous earth. Concentration in vacuo yields 200 mg (72%) of a beige solid, mp 240° C. dec. 1HNMR (DMSO-d6): δ 2.13 (s, 3H), 6.61 (dd, 1H), 6.68 (d, 1H), 7.03 (d, 1H), 7.51 (t, 1H), 7.63–7.74 (m, 2H), 8.15 (d, 1H), 8.62 (s, 1H), 9.40 (s, 1H), 9.66 (s, 1H). MS (ES, positive ion mode): m/z calcd for C19H13N3O2: 315.3, found: 315.9 (M+H)+. Analysis for C19H13N3O2.0.2H2O Calcd: C:71.54; H:4.22; N:13.17 Found: C:71.39; H:4.31; N: 12.99.
Reaction SMILES: O.[CH:2](=[O:6])/[CH:3]=[CH:4]/[CH3:5].[CH2:7]([OH:11])[CH:8]=[CH:9][CH3:10]>CCCCCC>[CH2:2]([O:6][CH:7]([O:11][CH2:2][CH:3]=[CH:4][CH3:5])/[CH:8]=[CH:9]/[CH3:10])[CH:3]=[CH:4][CH3:5]
Reactant: C/C=C/C=O
Reactant: CC=CCO
Solvent: O
Solvent: CCCCCC
Product: CC=CCOC(/C=C/C)OCC=CC
Temperature: 70 °C
Yield: 185.6 %

Procedure:
In a 300-ml three-necked flask equipped with a water separator, 70 g (1 mole) of crotonaldehyde, 144 g (2 mole) of crotyl alcohol, 3 mg of stannous chloride dihydrate and 40 g of hexane were charged. The resulting mixture was heated at 70° C. under atmospheric pressure and for 4 hours in a nitrogen atmosphere while removing the water formed from the reaction mixture by azeotropic distillation. When water was no longer distilled, the solvent (hexane) and unreacted starting materials were distilled off under reduced pressure. Distillation of the residue under reduced pressure gave 182.2 g of crotonaldehyde dicrotyl acetal [R1 =a 1-propenyl group, R2 =a hydrogen atom and R3 =a crotyl group) (boiling point: 120° C./25 mmHg) (yield: 91.9%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[C:11]3[S:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:4][C:3]=1[NH2:23].[N:24](OCCC(C)C)=O>C(Cl)(Cl)Cl.C(O)(=O)C>[NH:23]1[C:3]2[C:2](=[CH:7][CH:6]=[C:5]([C:8]3[N:9]=[C:10]([N:17]4[CH2:18][CH2:19][O:20][CH2:21][CH2:22]4)[C:11]4[S:16][CH:15]=[CH:14][C:12]=4[N:13]=3)[CH:4]=2)[CH:1]=[N:24]1
Reactant: CC(C)CCON=O
Reactant: Cc1ccc(-c2nc(N3CCOCC3)c3sccc3n2)cc1N
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: c1cc2nc(-c3ccc4cn[nH]c4c3)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 2-methyl-5-(4-morpholin-4-yl-thieno[3,2-d]pyrimidin-2-yl)-phenylamine (99 mg) in chloroform (10 mL) and acetic acid (2 mL) was added isoamyl nitrite (44 μL). The reaction mixture was stirred for 2 days at room temperature. The mixture was then quenched with sodium bicarbonate solution and extracted in to chloroform and reduced in vacuo. The residue was purified using flash chromatography to yield 229. MS: ESI MH+ 338
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].[BrH:15]>C1(C)C=CC=CC=1>[Br:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13]
Reactant: Br
Reactant: OCCCCCCCCCCCCO
Solvent: Cc1ccccc1
Product: OCCCCCCCCCCCCBr

Procedure:
To 30.25 g of 1,12-dodecanediol were added 350 ml of toluene and 52 ml of 48% hydrobromic acid and the mixture was heated under reflux under azeotropic condition for 2 hours. The reaction solution was cooled and the starting material precipitated out was filtered off. The filtrate was distilled and recrystallized from hexane to afford 30.2 g of the title compound as a crystal.
Reaction SMILES: N[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.N([O-])=[O:11].[Na+]>OS(O)(=O)=O.O>[Br:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([OH:11])=[N:3][CH:4]=1
Reactant: O=N[O-]
Reactant: Cc1cc(Br)cnc1N
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1cc(Br)cnc1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 83.7 %

Procedure:
2-Amino-5-bromo-3-methylpyridine (5.0 g, 26.7 mmol) in 2.6M H2SO4 (70 mL) was treated with sodium nitrite (5.0 g, 72.5 mmol) in water (10 mL) dropwise at 0° C. The mixture was allowed to warm to ambient temperature and stir for 1.5 hours. The mixture was filtered and the filtercake washed with cold water. The filtercake was dissolved in dichloromethane (100 mL), dried (MgSO4), and concentrated to provide the title compound (4.2 g, 84% yield). MS (DCI/NH3) M/z 188/190 (M+H)+.
Reaction SMILES: [BH4-].[Na+].[OH:3][C@H:4]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5](OCC)=[O:6].O>CO>[C:12]1([CH2:11][CH2:10][C@@H:4]([OH:3])[CH2:5][OH:6])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)[C@H](O)CCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OC[C@H](O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 102.1 %

Procedure:
NaBH4 (1.82 g) was added portionwise to an ice cooled solution of ethyl (R)-2-hydroxy-4-phenylbutyrate (2.0 g) in methanol (40 ml). After the addition was completed, the reaction mixture was stirred at room temperature for 45 minutes. Water (20 ml) was added, and the resulting mixture was stirred for several minutes and then evaporated under reduced pressure. The residue was extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. Evaporation of the solvent under reduced pressure gave (R)-4-phenylbutane-1,2-diol (1.63 g) as a colorless oil. This material was used for the next reaction without further purification.
Reaction SMILES: [OH-].[K+].C(O)CO.[CH3:7][N:8]([CH2:11][CH2:12][CH:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)C#N>O>[CH3:7][NH:8][CH2:11][CH2:12][CH:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]([F:28])([F:30])[F:29])=[CH:25][CH:26]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CN(C#N)CCC(Oc1ccc(C(F)(F)F)cc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: CNCCC(Oc1ccc(C(F)(F)F)cc1)c1ccccc1
Temperature: 130 °C

Procedure:
A solution of 100 g. potassium hydroxide, 85 ml. water, 400 ml. ethylene glycol and 9.50 g. of N-methyl-N-cyano 3-(p-trifluoromethylphenoxy)-3-phenylpropylamine was prepared in a one liter three-neck, round-bottom flask equipped with magnetic stirrer and condenser. The reaction mixture was heated to refluxing temperature (130° C.) for 20 hours, and was then cooled. 500 ml. of water were added. The reaction mixture was extracted with three 500 ml. portions of ether. The ether extracts were combined, and the combined extracts washed with water. The water wash was discarded. The ether solution was next contacted with 2 N aqueous hydrochloric acid. The acidic aqueous layer was separated. A second aqueous acidic extract with 2 N hydrochloric acid was made followed by three aqueous extracts and an extract with saturated aqueous sodium chloride. The aqueous layers were all combined and made basic with 5 N aqueous sodium hydroxide. N-methyl 3-(p-trifluoromethylphenoxy)-3-phenylpropylamine, formed in the above reaction, was insoluble in the basic solution and separated. The amine was extracted into ether. Two further ether extractions were carried out. The ether extracts were combined, and the combined extracts washed with saturated aqueous sodium chloride and then dried. Evaporation of the ether in vacuo yielded about 6.3 g. of N-methyl 3-(p-trifluoromethylphenoxy)-3-phenylpropylamine. The amine free base was converted to the corresponding oxalate salt by the method set forth above. N-methyl 3-(p-trifluoromethylphenoxy) -3-phenylpropylamine oxalate thus prepared melted at 179°-182° C. with decomposition after recrystallization from an ethyl acetate-methanol solvent mixture.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:4][C:5](I)=[CH:6][CH:7]=1.[C:14]([Cu])#[N:15].O>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:4][C:5]([C:14]#[N:15])=[CH:6][CH:7]=1
Reactant: N#C[Cu]
Reactant: CCOC(=O)c1nc(I)ccc1Cl
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)c1nc(C#N)ccc1Cl
Temperature: 80 °C
Yield: 75.3 %

Procedure:
To a solution of ethyl 3-chloro-6-iodopicolinate (1.6 g, 5.38 mmol) in pyridine (40 mL) was added CuCN (480 mg, 5.36 mmol). The reaction mass was heated at 80° C. for 6 h. Then water was added to the reaction mass and it was extracted with EtOAc. The organic layer was separated, dried, filtered and concentrated to afford 850 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 8.44 (d, J=8.1 Hz, 1H), 8.28 (d, J=8.4 Hz, 1H), 4.42 (q, J=7.2 Hz, 2H), 1.33 (t, J=7.2 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[S:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.[C:14](#[N:18])[CH2:15][C:16]#[N:17].[Cl-].[Na+]>C(O)C.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>[F:1][C:2]([F:13])([F:12])[S:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[C:15]([C:14]#[N:18])[C:16]#[N:17])=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(SC(F)(F)F)cc1
Reactant: N#CCC#N
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: N#CC(C#N)=Cc1ccc(SC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.4 %

Procedure:
First, 10.0 g of 4-(trifluoromethylthio)benzaldehyde and 2.92 g of malononitrile were dissolved in 50 ml of 70% (w/w) aqueous ethanol, to which a catalytic amount of benzyltrimethylammonium hydroxide was added, and the mixture was stirred at room temperature overnight. Then, a saturated aqueous sodium chloride solution was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was recrystallized with a solvent system consisting of t-butyl methyl ether and hexane to give 10.5 g of (4-(trifluoromethylthio)benzylidene)malononitrile.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[C:28]1([CH2:34][C:35]([N:37]=[C:38]=[S:39])=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH:24][C:38]([NH:37][C:35](=[O:36])[CH2:34][C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=5)=[S:39])=[CH:20][C:19]=4[F:25])=[C:11]3[CH:10]=[N:9]2)=[CH:26][CH:27]=1
Reactant: O=C(Cc1ccccc1)N=C=S
Reactant: COc1ccc(Cn2ncc3c(Oc4ccc(N)cc4F)ccnc32)cc1
Solvent: C1CCOC1
Product: COc1ccc(Cn2ncc3c(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4F)ccnc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
To a stirred solution of 4-(1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine (0.504 g, 1.38 mmol; obtained from Example 1, Step D in THF (5 mL) was added 2-phenylethanoyl isothiocyanate (0.294 g, 1.66 mmol; prepared according to J. Org. Chem. 1964, 29, 1115-1119). The reaction was stirred at room temperature for 30 minutes. The reaction mixture was loaded directly onto a preparative TLC plate, eluting with 5% MeOH/DCM. The product was obtained as a waxy solid (630 mg, 71%). LRMS (APCI+): 93% purity, 220 nm, m/z 542 (M+1) detected; 1H NMR (400 MHz, CDCl3) δ 12.49 (br s, 1H), 8.50 (br s, 1H), 8.38 (d, J=5.5 Hz, 1H), 7.94 (m, 1H), 7.82 (s, 1H), 7.42 (m, 4H), 7.32 (m, 4H), 7.26 (m, 1H, overlaps CHCl3), 6.83 (d, J=8.6 Hz, 2H), 6.42 (d, J=5.5 Hz, 1H), 5.63 (s, 2H), 3.76 (s, 3H), 3.75 (s, 2H); 19F NMR (376 MHz, CDCl3) δ −126.3 (m).
Reaction SMILES: N#N.C([SiH2][O:8][C:9](C)(C)[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2([CH3:21])[O:20][CH2:19][CH2:18][O:17]2)[CH:11]=1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CC(=O)OCC>[CH3:21][C:16]1([C:12]2[CH:11]=[C:10]([CH2:9][OH:8])[CH:15]=[CH:14][N:13]=2)[O:17][CH2:18][CH2:19][O:20]1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ccnc(C2(C)OCCO2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N#N
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(c2cc(CO)ccn2)OCCO1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 4-(tert-butyl-dimethyl-silanyloxymethyl)-2-(2-methyl-[1,3]dioxolan-2-yl)-pyridine (840 mg, 2.71 mmol) in dry THF (15 mL) was treated at 0° C. with TBAF (4.70 mL of a 1M solution in THF, 4.70 mmol). The reaction mixture was stirred at 0° C. for 5 min and at rt for 1.5 h. The mixture was then diluted with EA (10 mL), washed with brine (3×10 mL), dried over MgSO4, filtered and concentrated under reduced pressure. Purification of the residue by FC (5:1 to 1:3 hept-EA) gave the title compound as a yellow oil. TLC: rf (1:2 hept-EA)=0.10. LC-MS-conditions 02: tR=0.33 min; [M+H]+=196.54.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[CH:6]([CH:9]([CH:11]2[CH2:13][CH2:12]2)[CH3:10])[NH:5][NH:4][C:3]1=[S:14].[OH-].[Na+].[CH3:17]COCC.CI>O>[NH2:1][N:2]1[C:7](=[O:8])[C:6]([CH:9]([CH:11]2[CH2:12][CH2:13]2)[CH3:10])=[N:5][N:4]=[C:3]1[S:14][CH3:17]
Reactant: CC(C1CC1)C1NNC(=S)N(N)C1=O
Reactant: CCOCC
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Solvent: O
Product: CSc1nnc(C(C)C2CC2)c(=O)n1N
Temperature: 10 °C
Reaction time: 4 h

Procedure:
(according to process A): ##STR19## 789 g (3.72 mols) of 4-amino-6-(1-cyclopropylethyl)-5-oxo-3-thioxo-tetrahydro-1,2,4-(2H,4H)-triazine are dissolved in a solution of 151 g (3.77 mols) of sodium hydroxide in 4 l of water. 3 ml of alkylarylpolyglycol ether are added, the mixture is cooled to 10° C., 542 g (3.82 mols) of methyl iodide are added and the mixture is stirred for 4 hours at room temperature. The mixture is filtered off with suction and the residue is washed with water and also with petroleum ether and dried at 60° C. in vacuo, after which 748 g (89% of theory) of the above compound of melting point 111°-113° C. are obtained. The purity as determined by gas chromatography is 99%.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:20])[C:5]2[N:6]=[CH:7][N:8]([C@H]3[C@@H](O)[C@@H](O)[C@H](CO)O3)[C:9]=2[N:10]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl>CS(C)=O>[NH2:1][C:2]1[NH:3][C:4](=[O:20])[C:5]2[N:6]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:7]=[N:8][C:9]=2[N:10]=1
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@@H](CO)[C@H](O)[C@@H]2O)c(=O)[nH]1
Reactant: BrCc1ccccc1
Agent: Cl
Solvent: CS(C)=O
Product: Nc1nc2ncn(Cc3ccccc3)c2c(=O)[nH]1
Temperature: 50 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
To a solution of 2-amino-9-((2R,3S,4R,5S)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1H-purin-6(9H)-one (14 g, 49.47 mmol) in DMSO (50 mL) was added (bromomethyl)benzene (10 g, 59.36 mmol). The mixture was stirred at 50° C. overnight. Then the mixture was cooled to room temperature and HCl (50 mL, 10% w.w) was added and the mixture was stirred at 70° C. for 2 h. The reaction was cooled to room temperature, filtered and the filter cake was washed with water and ethanol and dried under vacuum to give 2-amino-7-benzyl-1H-purin-6(7H)-one (10 g, 74.2% yield) as grey solid. LCMS retention time 0.529 min; LCMS MH+ 242.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C@@:11]23[CH2:24][CH2:23][C:18]4(OCC[O:19]4)[CH2:17][C@H:16]2[CH2:15][O:14][C:13]2[C:25]([F:30])=[CH:26][CH:27]=[C:28]([F:29])[C:12]3=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C1(C)C(S(Cl)(=O)=O)=CC=CC=1>CC(C)=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C@@:11]23[CH2:24][CH2:23][C:18](=[O:19])[CH2:17][C@H:16]2[CH2:15][O:14][C:13]2[C:12]3=[C:28]([F:29])[CH:27]=[CH:26][C:25]=2[F:30])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)[C@@]12CCC3(C[C@H]1COc1c(F)ccc(F)c12)OCCO3
Agent: Cc1ccccc1S(=O)(=O)Cl
Solvent: CC(C)=O
Solvent: O
Product: O=C1CC[C@@]2(S(=O)(=O)c3ccc(Cl)cc3)c3c(F)ccc(F)c3OC[C@@H]2C1

Procedure:
Trans-10a-[(4-chlorophenyl)sulfonyl]-1,4-difluoro-6a,9,10,10a-tetrahydrospiro[6H-dibenzo[b,d]pyran-8(7H), 2′-[1,3]dioxolane] (3.1 g, 6.8 mmole) was dissolved in 200 ml acetone and 10 ml water. Toluenesulfonyl chloride (1 g) was added and the mixture was refluxed overnight. Acetone was removed. 100 water and 100 ml EtOAc were added. The organic layer washed with water (50 ml), dried over Na2SO4 and concentrated. The residue was pure enough for next step. Yield: 2.8 g, 100%. 1H NMR (CDCl3 400 MHz δ 7.63 (d, J=8.1 Hz, 2H), 7.52 (d, J=8.8 Hz, 2H), 7.14 (m, 1H), 6.64 (m, 1H), 5.27 (dd, J=11.7 and 2.9 Hz, 1H), 4.13 (d, J=11.7 Hz, 1H), 3.18 (d, J=12.4 Hz, 1H), 2.79 (dt, J=12.4 and 3.7 Hz, 1H), 2.4-2.57 (m, 4H), 2.04-2.17 (m, 1H).
Reaction SMILES: [OH-].[Na+].[C:3]([OH:7])(=[S:6])[CH2:4][CH3:5].[C:8]([NH:11][C:12](=[O:15])[CH2:13]Cl)(=[O:10])[CH3:9]>O>[C:8]([NH:11][C:12](=[O:15])[CH2:13][S:6][C:3](=[O:7])[CH2:4][CH3:5])(=[O:10])[CH3:9]
Reactant: CC(=O)NC(=O)CCl
Reactant: CCC(O)=S
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCC(=O)SCC(=O)NC(C)=O
Reaction time: 0.08 h

Procedure:
To a solution of 4.0 g. (0.1 mole) of sodium hydroxide in 50 ml. of water, cooled in ice and having nitrogen bubbled therethrough, was added 9.5 g. (0.1 mole) of thiopropionic acid. The reaction mixture was stirred for 5 minutes, after which there was added 13.7 g. of N-acetyl-chloroacetamide in 50 ml. of water. The reaction mixture was heated on a steam bath for 10 minutes, then cooled, filtered, and air dried. The product was washed with ether/hexane (3:1) three times with 150 ml. each washing, and then air dried. The product was recrystallized from water to yield 8.0 g. of white crystals.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:32])[C:12](=[CH:15][C:16]3[N:17]=[CH:18][N:19](S(C4C=CC(C)=CC=4)(=O)=O)[C:20]=3[CH3:21])[CH2:13][CH2:14][C:3]=12.O1CCCC1.CO.[OH-].[Na+]>O.C(O)(=O)C>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:32])[C:12](=[CH:15][C:16]3[N:17]=[CH:18][NH:19][C:20]=3[CH3:21])[CH2:13][CH2:14][C:3]=12
Reactant: Cc1ccc(S(=O)(=O)n2cnc(C=C3CCc4c(C)c5ccccc5n4C3=O)c2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1[nH]cnc1C=C1CCc2c(C)c3ccccc3n2C1=O
Temperature: 80 °C
Yield: 76.5 %

Procedure:
To a solution of 8,9-dihydro-10-methyl-7-[(5-methyl-1-tosyl-1H-imidazol-4-yl)methylene]pyrido[1,2-a]indol-6(7H)-one (1.0 g) in the mixture of tetrahydrofuran (10 ml) and methanol (10 ml) was added 2N-sodium hydroxide. The mixture was heated at 80° C. for 5 hours. After being cooled, the reaction mixture was neutralized with acetic acid, and added water (40 ml). The precipitates were filtered to give 8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methylene]pyrido[1,2-a]indol-6(7H)-one (0.5 g).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[C:6]12([NH2:16])[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH2:9]3)[CH2:7]1)[CH2:13]2.N1C=CC=CC=1>C(OCC)C>[C:6]12([NH:16][C:3](=[O:4])[CH2:2][Cl:1])[CH2:13][CH:12]3[CH2:11][CH:10]([CH2:9][CH:8]([CH2:14]3)[CH2:7]1)[CH2:15]2
Reactant: O=C(Cl)CCl
Reactant: NC12CC3CC(CC(C3)C1)C2
Solvent: c1ccncc1
Solvent: CCOCC
Product: O=C(CCl)NC12CC3CC(CC(C3)C1)C2
Reaction time: 1 h
Yield: 34.1 %

Procedure:
A solution of chloroacetyl chloride (1.6 mL, 20 mmol) in anhydrous diethyl ether (10 mL) was added dropwise within 5 min to a solution of 1-adamantanamine (3.0 g, 20 mmol) and pyridine (1.63 mL, 20 mmol) in anhydrous diethyl ether (40 mL) at 0° C. The yellow suspension was stirred for 1 h at that temperature. The precipitate was removed by filtration and washed by diethyl ether (10 mL). The combined organic solution was washed with HCl (2 N, 2×15 mL), followed by sat. NaHCO3 (15 mL), sat. NaCl (15 mL) solutions and dried with Na2SO4. The solvent was removed at reduced pressure and the residue was recrystallized from diethyl ether-hexanes to afford N-(1-adamantyl)chloroacetamide (1.551 g, 34%) as a yellow solid.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([CH2:30][CH2:31][CH2:32][CH3:33])[N:7](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:8]=1[C:9]#[N:10])(=[O:3])[CH3:2]>C(O)(=O)C>[C:1]([C:4]1[N:5]=[C:6]([CH2:30][CH2:31][CH2:32][CH3:33])[NH:7][C:8]=1[C:9]#[N:10])(=[O:3])[CH3:2]
Reactant: CCCCc1nc(C(C)=O)c(C#N)n1C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC(=O)O
Product: CCCCc1nc(C(C)=O)c(C#N)[nH]1
Temperature: 60 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
A suspension of 1.78 g of 4-acetyl -2-butyl-5-cyano-1-tritylimidazole [prepared as described in step (ii) above] in 80% v/v aqueous acetic acid was stirred at 60° C. for 1 hour. The solution thus obtained was concentrated to dryness by evaporation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 3:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 0.66 g of the title compound as a colorless solid, melting at 77°-78° C.