Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]([O:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:4]=1.[C:17]1([CH3:23])C=CC=CC=1.[C-:24]#[N:25].[Na+].C(Cl)C1C=CC=CC=1>CN(C=O)C.COC(C)(C)C>[C:24]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]([O:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:4]=1)#[N:25].[C:17](#[N:25])[CH3:23]
Reactant: COc1ccc(CCl)cc1OC1CCCC1
Reactant: [C-]#N
Reactant: Cc1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCc1ccccc1
Solvent: COC(C)(C)C
Product: CC#N
Product: COc1ccc(CC#N)cc1OC1CCCC1
Temperature: 55 °C
Yield: 92.2 %

Procedure:
A 12 liter round bottom flask equipped with an overhead stirrer, and a distillation apparatus was flushed with nitrogen. The flask was charged with 4-chloromethyl-2-cyclopentyloxy-1-methoxybenzene (519 g, 2.15 mol, 1.0 equivalents) in a solution of toluene and t-butyl methyl ether. The reaction was concentrated under reduce pressure to a residue. To the 12 liter flask was charged DMF (1.44 kg) and sodium cyanide (142 g, 2.9 mol, 1.35 equivalents). The reaction was heated to 55° C. for 6 hours or until deemed complete by the disappearance of the benzyl chloride. The reaction was concentrated under reduced pressure to a residue. To the flask was charged t-butyl methyl ether (2.30 kg) and deionized water (800 mL). The contents of the flask were vigorously stirred, and allowed to settle. The top organic layer was isolated, washed three times with deionized water (3×800 mL), and concentrated under atmospheric pressure to a residue. To the flask was added acetonitrile (1.26 kg) and the distillation was continued until an additional 400 mL of solvent was collected. The product, 4-cyanomethyl-2-cyclopentyloxy-1-methoxybenzene, was isolated as a solution in acetonitrile (92.2% yield). This was used directly in the next step.
Reaction SMILES: [NH2:1][C:2](=[S:13])[C@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4].Cl[CH2:15][C:16](=O)[CH3:17]>C(O)C>[CH3:17][C:16]1[N:1]=[C:2]([C@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:11])[CH3:10])[CH3:4])[S:13][CH:15]=1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(N)=S
Reactant: CC(=O)CCl
Solvent: CCO
Product: Cc1csc([C@@H](C)NC(=O)OC(C)(C)C)n1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of tert-butyl [(1R)-2-amino-1-methyl-2-thioxoethyl]carbamate (100 mg, 0.49 mmol) with 3 equivalents of chloroacetone (0.135 g) in ethanol (1 mL) was heated at 80° C. for 2 h. After cooling, the solution was concentrated. The residue was dissolved in DCM (1 ml). To the solution was added TFA (1 mL). The mixture was stirred at RT for 30 min. The volatiles were removed under reduced pressure to yield desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15].[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[N:24]=[C:25]=[S:26]>O1CCCC1>[NH2:1][C:2]1[C:3]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])=[C:4]([NH:8][C:25]([NH:24][C:18]2[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:17]=2[Cl:16])=[S:26])[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(N)c1NCCCCCO
Reactant: S=C=Nc1ccc(Cl)cc1Cl
Solvent: C1CCOC1
Product: Nc1cccc(NC(=S)Nc2ccc(Cl)cc2Cl)c1NCCCCCO
Yield: 32.1 %

Procedure:
To a solution of 5-[(2,6-diaminophenyl)amino]pentan-1-ol (Reference Example 110; 873 mg, 4.17 mmol) in tetrahydrofuran (30 mL) was added a solution of 2,4-dichlorophenyl isothiocyanate (936 mg, 4.59 mmol) in tetrahydrofuran (10 mL) at 0° C. The resultant mixture was stirred at 0° C. for 2 hr and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 50-90% ethyl acetate/n-hexane gradient mixture to give the title compound as an oil (554 mg, 1.34 mmol, 32%).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[NH:30]1[CH2:33][CH:32]([N:34]2[CH2:38][CH2:37][C@H:36]([OH:39])[CH2:35]2)[CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:30]4[CH2:33][CH:32]([N:34]5[CH2:38][CH2:37][C@H:36]([OH:39])[CH2:35]5)[CH2:31]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: O[C@H]1CCN(C2CNC2)C1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CC[C@H](O)C4)C3)n(C)c2n1
Reaction time: 65 h
Yield: 52.8 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (100 mg, 0.26 mmol), (S)-1-azetidin-3-ylpyrrolidin-3-ol (41 mg, 0.28 mmol) and 4 Å powdered molecular sieves (200 mg) in DCE (6 mL) was stirred at room temperature for 2 h before the addition of sodium triacetoxyborohydride (108 mg, 0.51 mmol). The reaction mixture was stirred for 65 h then filtered through celite, washing with DCM. The organic phase was washed with brine (×1) and concentrated in vacuo. The organic phase was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-15%) affording 536 as a yellow foam (71 mg, 53%). LCMS (Method I): RT 2.31 min [M+H]+ 518.2. 1H NMR (CDCl3, 400 MHz): δ 8.02-7.97 (m, 1 H); 7.76-7.71 (m, 1 H); 7.29-7.22 (m, 2 H); 4.53 (bs, 1 H); 4.35 (m, 4 H); 3.96 (s, 2 H); 3.90-3.82 (m, 7 H); 3.67 (bs, 2 H); 3.55 (m, 3 H); 3.34 (q, J=7.5 Hz, 2 H); 3.17 (m, 1 H); 2.99 (m, 1 H); 2.30 (m, 2 H); 2.02 (m, 2 H) and 1.44 (t, J=7.5 Hz, 3 H)
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:13](=[O:17])[CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=1)(=O)=O.[CH3:20][N:21](C)C=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:17]=[C:13]1[CH2:12][CH2:11][CH2:10][C:9]2[CH:8]=[C:7]([C:20]#[N:21])[CH:16]=[CH:15][C:14]1=2
Reactant: CN(C)C=O
Reactant: O=C1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc2c(c1)CCCC2=O
Temperature: 135 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
A mixture of 5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl trifluoromethanesulfonate (11.5 g, 39.0 mmol), prepared in the previous step, and zinc cyanide (2.7 g, 23.5 mmol) in dry dimethylformamide (100 mL) was degassed and put under a nitrogen atmosphere. Tetrakis(triphenylphosphine)palladium(0) (1.7 g, 1.5 mmol) was added and the mixture again degassed and put under a nitrogen atmosphere. The mixture was stirred at 135° C. overnight. An additional 171 mg of tetrakis(triphenylphosphine)palladium(0) was added and the reaction stirred for another 4 h. The reaction mixture was filtered through the Celite™ reagent and rinsed with ethyl acetate. The filtrate was washed with water. The layers were separated and the organic layer was dried over anhydrous sodium sulfate. The organic layer was filtered and concentrated in vacuo to give 8.1 g of crude product. Purification of the crude product on silica gel using a step-wise gradient of 5% to 15% ethyl acetate:hexane as the eluent gave 5-oxo-5,6,7,8-tetrahydro-naphthalene-2-carbonitrile (2.8 g, 41%), MS (ES) m/z 172 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([N:21]2[CH:25]=[N:24][C:23]([C:26]#[N:27])=[N:22]2)=[N:10]1.C1C(=O)N([Br:35])C(=O)C1>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][Br:35])[NH:12][C:11]([N:21]2[CH:25]=[N:24][C:23]([C:26]#[N:27])=[N:22]2)=[N:10]1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C1=C(C)NC(n2cnc(C#N)n2)=NC1c1ccc(F)cc1Br
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1=C(CBr)NC(n2cnc(C#N)n2)=NC1c1ccc(F)cc1Br
Yield: 80.5 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-2-(3-cyano-1H-1,2,4-triazol-1-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate (0.35 g, 0.8 mmol) was reacted with NBS (0.14 g, 0.81 mmol) in chloroform (15 mL) according to the procedure as described in Example 1, Step B to give the title compound as pale yellow oil (0.33 g, 80%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [S:1]([C:5]1[CH:13]=[CH:12][C:8]([N+]([O-])=O)=[CH:7][CH:6]=1)(O)(=O)=O.[O:14]=[C:15]([N:18]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:19]1([CH2:25][O:26][CH3:27])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[CH2:16][CH3:17].COC(C)(C)C>C(N(CC)CC)C>[CH3:17][CH2:16][C:15]([N:18]([C:19]1([CH2:25][O:26][CH3:27])[CH2:20][CH2:21][N:22]([CH2:7][CH2:6][C:5]2[S:1][CH:8]=[CH:12][CH:13]=2)[CH2:23][CH2:24]1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:14]
Reactant: CCC(=O)N(c1ccccc1)C1(COC)CCNCC1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: CCC(=O)N(c1ccccc1)C1(COC)CCN(CCc2cccs2)CC1
Yield: 84.2 %

Procedure:
To a suitably sized reaction flask (e.g., a jacketed glass reactor with stirring, nitrogen blanket, internal temperature recorder, and reflux capabilities) is charged 4-[(1-oxopropyl)phenylamino]-4-methoxymethyl piperidine nosylate (100.0 g), 2-(2-thiophenylethyl) 4-nitro-benzene sulfonate (79.2 g), tert-butyl methyl ether (MTBE, 333 mL), and triethylamine (TEA, 666 mL). The reaction mixture is warmed to 55°±5° C. and allowed to react at that temperature for not less than 24 hours. As the reaction progresses, a slurry is formed. The extent of the reaction can be followed by HPLC until most of the initial reactants are consumed. At that point, the reaction mixture is cooled to 20°±5° C. and charged with MTBE (400 mL) and water (400 mL). The diluted slurry is mixed for at least 10 minutes and then aqueous and organic phases are allowed to separate in a separatory funnel. The aqueous phase is discarded and then the organic phase is washed with water two additional times. Carbon (20 g) is then added to the resultant organic phase, mixed for at least 10 minutes and the carbon is filtered from the organic phase through a CELITE® diatomaceous earth bed. The CELITE® diatomaceous earth bed is washed with 200 ml of MTBE, the organic phases are combined and then solvent exchanged with ethanol under vacuum distillation conditions (by concentrating the organic phase to minimum stir volume three times and thereafter adding 400 mL of ethanol following each step of concentrating). The final volume should be about 600 mL. The solution is warmed to 45°±5° C. and then water (834 mL) is added slowly to give a turbid system. The hazy slurry is cooled slowly to 5°±5° C., and held at that temperature for at least 16 hours. The resultant slurry is filtered, washed with 30% aqueous ethanol and then dried in a vacuum oven at 50° C. to yield 67.9 g of the desired sufentanil product (expected yield 84%; expected purity 99.7%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([SH:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[Cl:9][CH2:10][C:11](OCC)(OCC)OCC>C(O)C>[Cl:9][CH2:10][C:11]1[S:8][C:3]2[C:2]([N:1]=1)=[CH:7][CH:6]=[CH:5][N:4]=2
Reactant: CCOC(CCl)(OCC)OCC
Reactant: Nc1cccnc1S
Solvent: CCO
Product: ClCc1nc2cccnc2s1

Procedure:
A mixture of 3-amino-2-mercaptopyridine (3.6 g) prepared by the method of J. Org. Chem., 29, 2652 (1963), 2-chloro-1,1,1-triethoxyethane (6.5 g) and ethanol (60 ml) was heated at 60° C. for 4 hours. The crude solid resulting from evaporation of ethanol was chromatographed over silica gel to obtain the product (2.94 g; m.p. 71°-73° C.).
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[C:10]3=[O:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:18](O)[CH2:19][OH:20].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[C:10]23[O:20][CH2:19][CH2:18][O:17]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1Nc2ccc(C3CCCCC3)cc2C1=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1Nc2ccc(C3CCCCC3)cc2C12OCCO2

Procedure:
5-Cyclohexyl-1H-indole-2,3-dione (1 equivalent), ethane-1,2-diol (5 equivalents) and p-toluenesulphonic acid (0.02 equivalents) in dry toluene were heated under reflux overnight with azeotropic removal of water. The reaction mixture was cooled, washed with saturated sodium bicarbonate solution, and then worked up in the usual manner to afford the title compound.
Reaction SMILES: [N:1]1([C:5]2[N:10]=[CH:9][C:8]([NH:11][C:12]([C:14]3[N:15]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=4)[C:16]4[C:21]([CH:22]=3)=[CH:20][C:19](Br)=[CH:18][CH:17]=4)=[O:13])=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:32]([SiH:34]([CH2:37][CH3:38])[CH2:35][CH3:36])[CH3:33].[O-]P(OP(OP([O-])([O-])=O)([O-])=O)(=O)[O-].[K+].[K+].[K+].[K+].[K+]>CN1CCCC1=O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[N:1]1([C:5]2[N:10]=[CH:9][C:8]([NH:11][C:12]([C:14]3[N:15]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=4)[C:16]4[C:21]([CH:22]=3)=[CH:20][C:19]([Si:34]([CH2:37][CH3:38])([CH2:35][CH3:36])[CH2:32][CH3:33])=[CH:18][CH:17]=4)=[O:13])=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Nc1ccc(N2CCC2)nc1)c1cc2cc(Br)ccc2n1Cc1cccc(F)c1
Reactant: CC[SiH](CC)CC
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=P([O-])([O-])OP(=O)([O-])OP(=O)([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CC[Si](CC)(CC)c1ccc2c(c1)cc(C(=O)Nc1ccc(N3CCC3)nc1)n2Cc1cccc(F)c1
Yield: 16.3 %

Procedure:
Compound No. 17 was prepared according to a process similar to that described in stage 8.4, by reacting 0.15 g (0.31 mmol) of N-[6-(azetidin-1-yl)pyridin-3-yl]-5-bromo-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide, prepared according to the protocol described in stage 17.3, with 110 mg (0.93 mmol) of triethylsilane in the presence of 0.2 g (0.94 mmol) of potassium triphosphate and of 16 mg (0.03 mmol) of bis(tri-tert-butylphosphine)palladium in 2 ml of dry 1-methyl-2-pyrrolidinone (NMP). 26 mg of the expected product are obtained.
Reaction SMILES: Cl.[NH:2]1[C:12]2[C:13]3[C:4]([CH2:5][NH:6][CH2:7][C:8]=3[CH:9]=[CH:10][CH:11]=2)=[CH:3]1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>N1C=CC=CC=1>[C:14]([N:6]1[CH2:5][C:4]2=[CH:3][NH:2][C:12]3[C:13]2=[C:8]([CH:9]=[CH:10][CH:11]=3)[CH2:7]1)(=[O:16])[CH3:15]
Reactant: c1cc2c3c(c[nH]c3c1)CNC2
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)N1Cc2cccc3[nH]cc(c23)C1

Procedure:
A mixture of 1,3,4,5-tetrahydropyrrolo[4,3,2-de]isoquinoline hydrochoride (9.8 g), described in Example 5, in 30 ml of pyridine and 10 ml of acetic anhydride is heated at 50°C for 2 hr. The excess anhydride is destroyed by the addition of water. The mixture is poured into cold 5% HCl. The resulting precipitate is collected and recrstallized from ethanol to give 4-acetyl-1,3,4,5 -tetrahydropyrrolo[4,3,2-de]isoquinoline, mp 205°-206°C.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[Cl:20])[N:4]=1.CN(C=O)C.[C:26]1(=[O:36])[NH:30][C:29](=[O:31])[C:28]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:27]12.[K]>>[Cl:20][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:11]=[C:12]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[C:3]([CH2:2][N:30]1[C:26](=[O:36])[C:27]3[C:28](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:29]1=[O:31])=[N:4]2
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Fc1cccc(-c2nc3c(Cl)cccc3nc2CBr)c1
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1nc2cccc(Cl)c2nc1-c1cccc(F)c1
Temperature: 100 °C

Procedure:
To a heterogeneous mixture of 2-(bromomethyl)-5-chloro-3-(3-fluorophenyl)-quinoxaline (0.2401 g, 0.6829 mmol) in DMF (5.003 mL, 0.6829 mmol) was added potassium phthalimide (0.3162 g, 1.707 mmol) and the heterogeneous mixture was stirred at 100° C. After stirring at 100° C. for 1 h, the mixture was concentrated under reduced pressure and triturated with water (30 mL). The precipitate was collected by filtration. The solid was washed with water (50 mL), then MeOH (100 mL), and dried to give 2-((5-chloro-3-(3-fluorophenyl)-quinoxalin-2-yl)methyl)isoindoline-1,3-dione as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.04 (1H, dd, J=7.6, 1.4 Hz), 7.84-7.92 (5H, m), 7.60-7.81 (4H, m), 7.38-7.46 (1H, m), 5.22 (2H, s); LC-MS (ESI) m/z 418.1 [M+H]+. The crude product was carried on crude without purification for the next step.
Reaction SMILES: [C:1]1([S:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.COCOC.C(Cl)[CH2:15][Cl:16]>[Ti](Cl)(Cl)(Cl)Cl>[CH3:8][S:7][C:1]1[CH:6]=[CH:5][C:4]([CH2:15][Cl:16])=[CH:3][CH:2]=1
Reactant: ClCCCl
Reactant: CSc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: COCOC
Product: CSc1ccc(CCl)cc1
Temperature: -5 °C
Reaction time: 24 h
Yield: 64 %

Procedure:
A solution of 24.8 g. (0.20 mole) of thioanisole in 180 ml. of ethylene dichloride was cooled to -5°C in an ice-methanol bath. 48 Ml. (83.6 g., 0.44 mole) of titanium tetrachloride was added dropwise over 15 minutes while maintaining the temperature at 0°-5°C. Another 10 ml. of ethylene dichloride was employed to wash forward the last quantities of titanium tetrachloride. The solution was cooled to -5°C again and 16.8 g. (0.22 mole) of methylal was added over 15 minutes while holding the temperature at 0-5°C. The reaction was stirred for 24 hours at 0-5°C and was quenched in 250 g. of ice. The organic layer was separated and the aqueous layer was extracted with 2 × 100 ml. of ethylene dichloride. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated in vacuo at 50°-60°C to give 31.6 g. of crude product. Quantitative vpc analysis showed the product to contain a 64% yield of p-methylthiobenzyl chloride and a 5% yield of the ortho isomer.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:3]=1[CH2:21][C:22]([O:24][CH3:25])=[O:23].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1[CH2:40][O:39][CH2:38]C1.BrCOC>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:3]=1[CH:21]([CH2:38][O:39][CH3:40])[C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCC3
Reactant: C1CCOC1
Agent: COCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: COCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCC3
Yield: 77.6 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3yl]acetate (0.351 g; 1 mmol), LHMDS 1N in THF (1.1 mL; 1.1 mmol), 1 bromomethylmethylether (0.122 mL; 1.5 mmol) in DMF (4 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (3-30%) in heptane furnished 0.307 g (77%) of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][CH:8]=[N:9][CH:10]=1)=[O:4].[BrH:11]>>[BrH:11].[CH3:1][O:2][C:3]([CH:5]1[CH2:10][NH:9][CH:8]=[N:7][CH2:6]1)=[O:4]
Reactant: COC(=O)c1cncnc1
Agent: Br
Product: COC(=O)C1CN=CNC1
Yield: 83 %

Procedure:
5-Methoxycarbonylpyrimidine (1.381 g, 10 mmol) in 143 ml 0.07158M HBr was hydrogenated at 26 psig over 600 mg Pd-on-carbon 10% in a Parr hydrogenator for three hours. The suspension was filtered and the filter rinsed twice with hot water (10 ml). The filtrate was evaporated in vacuo to give 1.86 g yellow oil (83%). The oil was crystallized from anhydrous ethanol/THF, and the hygroscopic crystals collected by decanting the solvents under a stream of nitrogen. Excess solvents were removed under vacuum in a drying pistol to yield 1.01 g (45%) white crystals mp 149°-153° C. (with the evolution of gas). Microanalysis calc.: C 32.3, H 4.97, N 12.56; found: C 32.12, H 5.15, N 12.34. 400 MHz nmr indicated product.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([C:14]([CH:17]=O)=[CH:15][N:16]=2)[CH:5]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=1.[CH3:19][NH:20][NH2:21].[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[S:30](Cl)(=[O:32])=[O:31]>C(O)C>[F:29][C:26]1[CH:27]=[CH:28][C:23]([CH3:22])=[C:24]([S:30]([N:20]([CH3:19])/[N:21]=[CH:17]/[C:14]2[N:4]3[CH:5]=[C:6]([C:8]4[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=4)[CH:7]=[C:2]([CH3:1])[C:3]3=[N:16][CH:15]=2)(=[O:32])=[O:31])[CH:25]=1
Reactant: CNN
Reactant: Cc1cc(-c2cccnc2)cn2c(C=O)cnc12
Reactant: Cc1ccc(F)cc1S(=O)(=O)Cl
Solvent: CCO
Product: Cc1ccc(F)cc1S(=O)(=O)N(C)/N=C/c1cnc2c(C)cc(-c3cccnc3)cn12
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 8-methyl-6-(pyridin-3-yl)imidazo[1,2-a]pyridine-3-carbaldehyde (Intermediate 5, 80 mg, 0.337 mmol) in ethanol (10 mL) was added methyl hydrazine (0.035 mL, 0.675 mmol) at RT. The reaction mixture was heated at 80° C. for 4 hours. Ethanol was evaporated. Pyridine (5 mL) was added to this residue, followed by addition 2-methyl-5-fluoro benzene sulfonylchloride (105 mg, 0.506 mmol). The reaction mixture was stirred at RT overnight. Pyridine was evaporated. Water was added to this residue and extracted with dichloromethane. Organic layer was dried over sodium sulfate and evaporated.The crude product was purified by column chromatography (silica gel, 1.5% methanol in chloroform) to obtain the title compound. Yield: 50 mg (27%); 1H NMR (CDCl3; 300 MHz): δ 9.41(s, 1H), 8.59 (s, 1H), 8.71 (d, 1H, J=3.9 Hz), 7.99 (s, 1H), 7.97 (m, 1H), 7.94 (s, 1H), 7.66 (dd, 1H, J=8.4, 2.7 Hz), 7.47 (m, 1H), 7.43 (s, 1H), 7.21 (m, 1H), 7.07 (m, 1H), 3.47 (s, 3H), 2.73 (s, 3H), 2.53 (s, 3H); MS: m/z 438 (M+1)+.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=2[O:2]1.[Cl:15][C:16]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C(Cl)CCl>[Cl:15][C:16]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:17]=1[C:18]([C:6]1[CH:7]=[C:8]2[O:9][CH2:1][O:2][C:3]2=[CH:4][C:5]=1[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:19]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Cl
Reactant: COC(=O)Cc1ccc2c(c1)OCO2
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCCl
Product: COC(=O)Cc1cc2c(cc1C(=O)c1ccc([N+](=O)[O-])cc1Cl)OCO2

Procedure:
The title compound was prepared from methyl 3,4-methylenedioxyphenylacetate (12.5 g, 64.4 mmol) in ClCH2CH2Cl (150 mL), 2-chloro-4-nitrobenzoic acid (25.0 g, 124 mmol) and P2O5 (37 g) as a yellow solid (11 g, 29 mmol, 45%). 1H NMR (CDCl3) 8.15 (s, 1H), 8.14 (d, J=8.4, 1H), 7.58 (d, J=8.4, 1H), 6.84 (s, 1H), 6.71 (s, 1H), 6.05 (s, 2H), 4.03 (s, 2H), 3.73 (s, 3H).
Reaction SMILES: [CH:1]([CH:3]([O:6][CH:7]([N:10]1[CH:18]=[N:17][C:16]2[C:15](=[O:19])[NH:14][CH:13]=[N:12][C:11]1=2)[CH:8]=[O:9])[CH2:4][OH:5])=[O:2].[N:20]1[C:28]([NH2:29])=[C:27]2[C:23]([N:24]=[CH:25][NH:26]2)=[N:22][CH:21]=1>CO.O>[OH:9][CH:8]1[C@H:7]([N:10]2[CH:18]=[N:17][C:16]3[C:15](=[O:19])[NH:14][CH:13]=[N:12][C:11]2=3)[O:6][C@H:3]([CH2:4][OH:5])[CH:1]([OH:2])[N:29]1[C:28]1[N:20]=[CH:21][N:22]=[C:23]2[C:27]=1[NH:26][CH:25]=[N:24]2
Reactant: Nc1ncnc2nc[nH]c12
Reactant: O=CC(CO)OC(C=O)n1cnc2c(=O)[nH]cnc21
Solvent: CO
Solvent: O
Product: O=c1[nH]cnc2c1ncn2[C@@H]1O[C@H](CO)C(O)N(c2ncnc3nc[nH]c23)C1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.8 %

Procedure:
[R-(R*, R*)]-α-(1-Formyl-2-hydroxyethoxy)-1,6-dihydro-6-oxo-9H-purine-9-acetaldehyde, (inosinedialdehyde), (2.66 g) was dissolved in a mixture of methanol (100 ml) and water (100 ml). To the solution was added adenine (1.35 g). The mixture was stirred at ambient temperature for one day and filtered. The filtrate was evaporated in vacuo at 35° C. The residue was triturated with acetone to give 9-[(2R, 6R)-3,5-dihydroxy-6-hydroxymethyl-4-(6-purinyl)morpholin-2-yl]hypoxanthine (3.20 g).