Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:16]([CH:17]=O)=[N:15][O:14][N:13]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].[NH2:19][C:20]1[NH:24][N:23]=[N:22][N:21]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].[BH4-].[Na+].[BH4-].[Li+]>C1COCC1.[OH-].[Na+].C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:16]([CH2:17][NH:19][C:20]3[NH:24][N:23]=[N:22][N:21]=3)=[N:15][O:14][N:13]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=Cc1nonc1C(=O)Nc1ccc(F)c(Cl)c1
Reactant: Nc1nnn[nH]1
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)c(Cl)c1)c1nonc1CNc1nnn[nH]1
Temperature: 40 °C
Reaction time: 36 h
Yield: 83.7 %

Procedure:
To a solution of N-(3-chloro-4-fluorophenyl)-4-formyl-1,2,5-oxadiazole-3-carboxamide (4.5 g, 17 mmol) in THF (75 mL) was added 5-aminotetrazole (4.26 g, 50.1 mmol), sodium sulfate (1.0 g, 8.0 mmol) and acetic acid (50 μL, 0.80 mmol). The resulting mixture was stirred at 40° C. for 36 h, and then an additional 20 mL THF was added followed by sodium tetrahydroborate (947 mg, 25 mmol). After stirring for 3 h, lithium tetrahydroborate (545 mg, 25.0 mol) was added to the reaction solution and stirred overnight. The reaction solution was diluted with 1 N NaOH solution. The aqueous layer was separated and acidified with 6 N HCl to pH 1. A white solid precipitated out of solution and was filtered to afford the desired product (4.82 g, 85%). LCMS for C11H9ClFN8O2(M+H)+: m/z=339.0.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:3]=1[CH:4]([O:11][C:12]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]CC)=[O:13])[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[N+]([O-])([O-])=O>>[Cl:1][C:2]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:3]=1[CH:4]([O:11][C:12]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:13])[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1
Reactant: CCCCCCCCCCCC(=O)OC(Cn1ccnc1)c1ccc(Cl)cc1Cl
Agent: O=[N+]([O-])[O-]
Product: CCCCCCCCCC(=O)OC(Cn1ccnc1)c1ccc(Cl)cc1Cl

Procedure:
1-[2,4-dichloro-β-(n-undecylcarbonyloxy)phenethyl]imidazole, as nitrate mp 84.5°-86.5° C.,
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[S:9][C:10]3[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=3[C:12](=[O:14])[N:13]=2)[N:5]=[C:4]([CH2:19][CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])[CH:3]=1>FC(F)(F)C(O)=O>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[S:9][C:10]3[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=3[C:12](=[O:14])[N:13]=2)[N:5]=[C:4]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH:3]=1
Reactant: Cc1cc(CCC(=O)OC(C)(C)C)nc(-c2nc(=O)c3ccccc3s2)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(CCC(=O)O)nc(-c2nc(=O)c3ccccc3s2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
tert-Butyl 3-[4-methyl-6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propanoate (0.44 g, 1.1 mmol) was dissolved in trifluoroacetic acid (5 ml), and the mixture was stirred at 0° C. for 2 hrs. The solvent was evaporated, and the residue was recrystallized from diisopropyl ether-methanol to give the titled compound (0.33 g, 87%) as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][C:5]1[O:9][N:8]=[C:7]([C:10]([O:12]CC)=O)[N:6]=1.Cl.[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][CH:25]=[C:24]2[CH2:30][CH2:31][NH2:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CO.[OH-].[Na+].O.CN(C=O)C>[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][CH:25]=[C:24]2[CH2:30][CH2:31][NH:32][C:10]([C:7]1[N:6]=[C:5]([CH2:4][C:3]2[CH:15]=[CH:16][CH:17]=[CH:18][C:2]=2[F:1])[O:9][N:8]=1)=[O:12]
Reactant: CCOC(=O)c1noc(Cc2ccccc2F)n1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1noc(Cc2ccccc2F)n1
Yield: 26.1 %

Procedure:
This compound was prepared according to method F with ethyl 5-(2-fluorobenzyl)-1,2,4-oxadiazole-3-carboxylate (0.108 g; 0.432 mmol) in methanol (6 mL) and sodium hydroxide in water (2M, 6 mL); and 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.432 mmol), HATU (0.164 g; 0.432 mmol), N,N diisopropylethylamine (0.075 mL; 0.432 mmol), in DMF (6 mL). The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.045 g (26%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(2-fluorobenzyl)-1,2,4-oxadiazole-3-carboxamide as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][N:3]=1.[CH3:8][CH2:9][O:10][C:11]([CH:13]([C:17](OCC)=[O:18])[C:14]([CH3:16])=O)=[O:12]>C(O)(=O)C>[OH:18][C:17]1[N:3]2[N:4]=[C:5]([CH3:7])[CH:6]=[C:2]2[N:1]=[C:14]([CH3:16])[C:13]=1[C:11]([O:10][CH2:9][CH3:8])=[O:12]
Reactant: CCOC(=O)C(C(C)=O)C(=O)OCC
Reactant: Cc1cc(N)n[nH]1
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C)nc2cc(C)nn2c1O
Temperature: 120 °C
Reaction time: 3 h
Yield: 94.6 %

Procedure:
3-Amino-5-methylpyrazole (970 mg) and diethyl acetomalonate (2.0 g) were dissolved in acetic acid (5 ml) and stirred for 3 hours at 120° C. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and ethanol was added to the residue which were then cooled to 0° C. Precipitated crystals were collected by filtration and washed with cold ethanol. The crystals were dried under reduced pressure to give ethyl 7-hydroxy-2,5-dimethylpyrazolo[1,5-a]pyrimidine-6-carboxylate (2.2 g, Y.:95%) as white crystals.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([CH3:7])[CH2:3]1.CCN(CC)CC.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(Cl)Cl.CN(C1C=CN=CC=1)C.C(Cl)(Cl)Cl>[CH3:15][S:16]([O:1][CH:2]1[CH2:6][CH2:5][N:4]([CH3:7])[CH2:3]1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: CN1CCC(O)C1
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCC(OS(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
3-Hydroxy-1-methylpyrroldine (0.543 mL, 4.94 mmol) was dissolved in DCM (10 mL) and cooled to 0° C. Et3N (0.827 mL, 5.93 mmol), methanesulfonyl chloride (0.421 mL, 5.44 mmol) and DMAP (0.006 g, 0.05 mmol) were added and the mixture was stirred for 16 hours at room temperature. The mixture was diluted with CHCl3 (5 mL) and washed with sat. NaHCO3 (5 mL) and water (2×5 mL). The organic layer was concentrated in vacuo to give the title compound A22 as a yellow oil (0.717 g, 81% yield). 1H NMR (300 MHz, CDCl3) δ 1.85-2.24 (m, 6H), 2.38-2.74 (m, 3H), 2.76-2.91 (m, 3H), 4.95 (m, 1H).
Reaction SMILES: C[C:2]1([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1>CCO.[Pd]>[CH:2]1([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CCOC(=O)CC1(C)CCc2ccccc21
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC1CCc2ccccc21
Yield: 100 %

Procedure:
To a mixture of products from Example 131A (0.47 g, 2.3 mmol) in EtOH (20 mL) was added Pd/C (49.5 mg, 0.046 mmol). The reaction mixture was stirred under H2 atmosphere using a balloon until the starting material completely consumed. The mixture was filtered and concentrated under reduced pressure to obtain 0.47 g of the title compound. MS (DCI/NH3) m/z 222 (M+NH4)+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[CH:4]=[O:5].[BH4-].[Na+]>CO>[F:1][C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: O=Cc1cc(I)ccc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cc(I)ccc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
To an ice cooled solution of 2-Fluoro-5-iodo-benzaldehyde (1.0 g, 4.0 mmol) in CH3OH (10 mL) was added NaBH4 (0.182 g, 4.8 mmol) in two portions over 10 min. The reaction mixture was stirred for 1 h and concentrated in vacuo. The residue was dissolved in EtOAc (50 mL) and washed sequentially with 2×H2O (20 mL) and brine (20 mL). The organic layer was dried (MgSO4), and concentrated. The crude material was purified by flash chromatography (30% Ethyl acetate/Petroleum Ether) to afford the titled compound (1.0 g, 99%) as a white solid, identified by NMR and mass spectral analyses. Mp: 42° C. MS (EI+): 252 (M+).
Reaction SMILES: C[Si](C)(C(C)(C)C(C)C)[O:3][C:4]1[C:9]2[CH2:10][O:11][CH2:12][C@H:13]([C:21]3[O:25][N:24]=[C:23]([CH3:26])[N:22]=3)[NH:14][C:15](=[O:20])[CH2:16][S:17][C:18](=[O:19])[C:8]=2[C:7]([CH3:27])=[C:6]([O:28][CH3:29])[CH:5]=1.[F-].[NH4+]>CO.C(OCC)(=O)C>[OH:3][C:4]1[C:9]2[CH2:10][O:11][CH2:12][C@H:13]([C:21]3[O:25][N:24]=[C:23]([CH3:26])[N:22]=3)[NH:14][C:15](=[O:20])[CH2:16][S:17][C:18](=[O:19])[C:8]=2[C:7]([CH3:27])=[C:6]([O:28][CH3:29])[CH:5]=1
Reactant: COc1cc(O[Si](C)(C)C(C)(C)C(C)C)c2c(c1C)C(=O)SCC(=O)N[C@@H](c1nc(C)no1)COC2
Agent: [F-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(O)c2c(c1C)C(=O)SCC(=O)N[C@@H](c1nc(C)no1)COC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.4 %

Procedure:
To a solution of 268 mg of (4R)-13-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-11-methoxy-10-methyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)-3,4,5,6,7,9-hexahydro-1H-8,2,5-benzoxathiaazacycloundecine-6,9-dione in 10 ml of methanol were added 100 mg of ammonium fluoride, and the mixture was stirred for 30 min at room temperature. The mixture was diluted with 50 ml of ethyl acetate and washed with 30 ml of water and with 30 ml of brine. The organic layer was dried over sodium sulfate and the solvent was evaporated in vacuo. The residue was dissolved in ethyl acetate, then hexane was added, and the white solid was isolated by filtration to give 178 mg of (4R)-13-hydroxy-11-methoxy-10-methyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)-3,4,5,6,7,9-hexahydro-1H-8,2,5-benzoxathiaazacycloundecine-6,9-dione as a white powder, m.p. 194°-196° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:20][C:21]([NH:23][C@@H:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C@H:27]([O:34][C:35]3[CH:36]=[CH:37][C:38]4[N:39]([C:41]([N:44]([CH:48]([CH3:50])[CH3:49])[CH:45]([CH3:47])[CH3:46])=[N:42][N:43]=4)[CH:40]=3)[CH2:26][CH2:25]2)=[O:22])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][OH:19])[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:60][S:61](Cl)(=[O:63])=[O:62]>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:20][C:21]([NH:23][C@@H:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C@H:27]([O:34][C:35]3[CH:36]=[CH:37][C:38]4[N:39]([C:41]([N:44]([CH:45]([CH3:46])[CH3:47])[CH:48]([CH3:50])[CH3:49])=[N:42][N:43]=4)[CH:40]=3)[CH2:26][CH2:25]2)=[O:22])[N:8]([C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[O:16][CH2:17][CH2:18][O:19][S:61]([CH3:60])(=[O:63])=[O:62])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)N(c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCO)c4)c4ccccc43)cn12)C(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCOS(C)(=O)=O)c4)c4ccccc43)cn12)C(C)C
Reaction time: 2 h
Yield: 131.8 %

Procedure:
To an ice-bath cooled solution of Intermediate 103e (97 mg, 0.13 mmol) in DCM (2 mL) was added DIPEA (58 μL, 0.32 mmol) followed by methanesulfonyl chloride (22 μL, 0.27 mmol). The reaction mixture was stirred for 2 h then partitioned between DCM and water. The aqueous phase was extracted with DCM (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo to afford the title compound (130 mg, quantitative). LCMS (Method 1): Rt 3.69 min, m/z 759 [MH+].
Reaction SMILES: [C:1]([O:4][CH2:5][CH3:6])(=[O:3])[CH3:2].[CH:7]1[C:12](O)=[CH:11][CH:10]=[C:9]([Br:14])[CH:8]=1.Cl.C(OC=C)C>CCOCC>[CH2:5]([O:4][CH:1]([O:3][C:12]1[CH:11]=[CH:10][C:9]([Br:14])=[CH:8][CH:7]=1)[CH3:2])[CH3:6]
Reactant: Oc1ccc(Br)cc1
Reactant: CCOC(C)=O
Agent: C=COCC
Agent: Cl
Solvent: CCOCC
Product: CCOC(C)Oc1ccc(Br)cc1

Procedure:
Into 100 ml of dehydrated ethyl acetate, were fed 11.0 g (50 mmol) of p-bromophenol, and 4.8 ml of a solution composed of hydrochloric acid (1.0 mol/L) and ether, and the mixture was set at 40° C. Into the mixture, 10.8 g (150 mmol) of ethylvinylether was added dropwise, and the mixture was kept with stirring for one night. After completion of the reaction, the reaction solution was rinsed with sodium hydrogen carbonate solution and then rinsed with water to remove solvent. By purifying with silica gel column chromatography (eluate: hexane), 10.7 g (36.5 mmol) of 1-(1-ethoxy)ethoxy-4-bromobenzene was obtained.
Reaction SMILES: [CH2:1]1[CH:16]2[N:4]([CH2:5][CH2:6][C:7]3[NH:8][C:9]4[N:10]=[CH:11][CH:12]=[CH:13][C:14]=4[C:15]=32)[CH2:3][CH2:2]1.[H-].[Na+].[O:19]1[CH2:21][CH:20]1[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>CN(C=O)C>[N:25]1[CH:26]=[CH:27][C:22]([CH:20]([OH:19])[CH2:21][N:8]2[C:7]3[CH2:6][CH2:5][N:4]4[CH:16]([C:15]=3[C:14]3[CH:13]=[CH:12][CH:11]=[N:10][C:9]2=3)[CH2:1][CH2:2][CH2:3]4)=[CH:23][CH:24]=1
Reactant: c1cc(C2CO2)ccn1
Reactant: c1cnc2[nH]c3c(c2c1)C1CCCN1CC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OC(Cn1c2c(c3cccnc31)C1CCCN1CC2)c1ccncc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2,3,4,5,6,10c-hexahydro-1H-3a,6,7-triaza-cyclopenta[c]fluorene (1 g, 4.6 mmol) in DMF (20 mL) were portion wise added NaH (60%, 0.552 g, 13.8 mmol) and 4-(oxiran-2-yl)pyridine (0.709 g, 5.6 mmol). The reaction mass was stirred at RT overnight. The progress of reaction was monitored by LCMS. The reaction mixture was quenched with ice cold water (300 mL) and extracted with EtOAc (3×100 mL). The combined organic layer was washed with water (10×100 mL), followed by brine (2×100 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography followed by reverse phase HPLC to yield the title compound;
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Li+].CC([N-]C(C)C)C.[F:21][C:22]1[CH:23]=[C:24]([N:28]2[C:32]([N:33]([CH3:37])[C:34](=[O:36])[CH3:35])=[C:31]([C:38]([O:40]CC)=O)[CH:30]=[N:29]2)[CH:25]=[CH:26][CH:27]=1>C1COCC1>[F:21][C:22]1[CH:23]=[C:24]([N:28]2[C:32]3[N:33]([CH3:37])[C:34](=[O:36])[CH:35]=[C:38]([OH:40])[C:31]=3[CH:30]=[N:29]2)[CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)c1cnn(-c2cccc(F)c2)c1N(C)C(C)=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cn1c(=O)cc(O)c2cnn(-c3cccc(F)c3)c21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of diisopropylamine (3.45 mL, 24.4 mmol) in 15 mL THF under argon at 0° C. was treated with n-butyllithium (14.7 mL of 1.6 M solution in hexanes, 23.5 mmol) and stirred at this temperature for 30 min. The freshly prepared LDA was added dropwise to a solution of ethyl 1-(3-fluorophenyl)-5-(N-methylacetamido)-1H-pyrazole-4-carboxylate (2.87 g, 9.40 mmol) in 5 mL of THF at −78° C. After the reaction mixture was gradually warmed to RT in 4 h, it was partitioned between 1N NaOH and 45 mL of ether. The ether layer was separated and discarded; the aqueous layer was acidified with 2 N HCl, and extracted three times with EtOAc. The combined EtOAc layers were washed with brine, dried over MgSO4, and concentrated to yield the title compound as a tan crystalline solid. MS (ESI, pos.ion) m/z: 260.1 (M+1). The crude material was used in the next step without further purification.
Reaction SMILES: C1(OC)C=CC=CC=1.COC1C=CC(C[N:16]2[C:26]3[C:27]4[C:18]([CH2:19][CH2:20][S:21][C:22]=4[N:23]=[C:24]([N:28](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[N:25]=3)=[N:17]2)=CC=1>FC(F)(F)C(O)=O>[N:17]1[NH:16][C:26]2[C:27]3[C:18]=1[CH2:19][CH2:20][S:21][C:22]=3[N:23]=[C:24]([NH2:28])[N:25]=2
Reactant: COc1ccc(Cn2nc3c4c(nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc42)SCC3)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc2c3c(n[nH]c3n1)CCS2
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.5 %

Procedure:
Anisole (2.5 ml) and trifluoroacetic acid (30 ml) were added to the above di-tert-butyl {2-(4-methoxybenzyl)-7,8-dihydro-2H-6-thia-1,2,3,5-tetraazaacenaphthylen-4-yl}imidodicarbonate (6.0 g). The mixture was stirred at room temperature for 16 hours and then stirred at 55° C. for six hours. The reaction solution was concentrated under reduced pressure. Ethyl acetate was added to the resulting residue, followed by stirring. The precipitated solid was filtered off and washed with ethyl acetate to obtain the title compound (1.75 g, 78%) as a solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=1[NH2:6].Cl[C:13]1[C:18]([C:19]#[N:20])=[CH:17][N:16]=[C:15]2[C:21]3[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:22]=3[S:23][C:14]=12>CN(C)C=O>[Cl:3][C:4]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=1[NH:6][C:13]1[C:18]([C:19]#[N:20])=[CH:17][N:16]=[C:15]2[C:21]3[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:22]=3[S:23][C:14]=12
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: N#Cc1cnc2c(sc3ccc([N+](=O)[O-])cc32)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cnc2c(sc3ccc([N+](=O)[O-])cc32)c1Nc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 29 %

Procedure:
A mixture of 160 mg (4.00 mmol) of sodium hydride (60% dispersion in oil) and 648 mg (4.00 mmol) of 2,4-dichloroaniline in 10 mL of dimethylformamide is stirred at room temperature for 1 hour. 4-Chloro-8-nitrobenzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile, 578 mg (2.00 mmol), is added and the suspension is heated at 130° C. overnight. The reaction mixture is cooled to room temperature and partitioned between ethyl acetate and water. The organic layer is washed with water then dried over magnesium sulfate, filtered and concentrated in vacuo. Diethyl ether is added to the residue and the resultant solid is collected by filtration. The solid is suspended in diethyl ether and filtered. The filtrate is concentrated to a small volume and filtered to give 80 mg (29%) of 4-(2,4-dichloroanilino)-8-nitro[1]benzothieno[3,2-b]pyridine-3-carbonitrile as an off-white solid, mp 210–213° C.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([NH2:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[CH2:22][CH2:21][NH:20]1.C(N(CC)C(C)C)(C)C.C(OCC)(=O)C>CS(C)=O.O>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[CH2:22][CH2:21][N:20]1[C:2]1[N:10]=[C:9]([NH2:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2
Reactant: COc1cc2c(cc1OC)C(c1ccccc1Cl)NCC2
Reactant: Nc1nc(Cl)c2nc[nH]c2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc2c(cc1OC)C(c1ccccc1Cl)N(c1nc(N)nc3[nH]cnc13)CC2

Procedure:
A solution of 6-chloro-9H-purin-2-amine (0.25 M in dimethylsulfoxide) (800+2400 DMSO or 3200 μl) was added to 1-(2-chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline followed by N,N-diisopropylethylamine (175 μl). The mixture was shaken at XX ° C. until complete then evaporated to dryness. The residue obtained was shaken at 50° C. with ethyl acetate (3 ml) and water (2 ml), for 30 minutes. The ethyl acetate layer was separated and the aqueous layer re-extracted with ethyl acetate (3 ml). The combined ethyl acetate fractions were evaporated to dryness and the residue obtained dissolved in dimethylsulfoxide (1.5 ml). 6-(1-(2-chlorophenyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-9H-purin-2-amine was purified from the dimethylsulfoxide solution by reverse phase chromatography on a preparative LC/UV/MS system using a mass triggered fractionation. Compounds were eluted from the HPLC column (Maccel 120-10-C18 SH 10 μm 20 mmID×50 mm) at 88 ml/min with 5-95 acetonitrile/water gradient using 0.1% TFA as modifier: LCMS m/e 437 (M+1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[CH2:5][CH2:6][OH:7].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[CH3:24][S:25]([O:1][CH2:2][CH2:3][N:4]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)[CH2:5][CH2:6][O:7][S:25]([CH3:24])(=[O:27])=[O:26])(=[O:27])=[O:26]
Reactant: COc1ccc(CN(CCO)CCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CN(CCOS(C)(=O)=O)CCOS(C)(=O)=O)cc1
Temperature: -7.5 °C
Reaction time: 16 h
Yield: 84.9 %

Procedure:
25 gms (0.1111 moles) of the product obtained from Example 1 and 45 gms (0.4455 moles) of triethylamine with 125 ml of dichloromethane were charged in a reaction vessel and cooled to −5 to −10° C. A solution of Methane sulphonyl chloride (45 gms, 0.3888 moles) in dichloromethane (50 ml) was added slowly at −5 to 10° C. and stirred for about 16 hours at 25-30° C. The resulting mixture was washed with water (25 ml). The collected organic layer was concentrated to obtain the title compound (36 gms).
Reaction SMILES: [C:1]([OH:11])(=[O:10])[C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].NC1CCC2C(=CC=C(OC)C=2)C1>CO>[C:1]([OH:11])(=[O:10])[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3]
Reactant: O=C(O)[C@H](O)c1ccccc1
Agent: COc1ccc2c(c1)CCC(N)C2
Solvent: CO
Product: O=C(O)C(O)c1ccccc1
Reaction time: 3 h

Procedure:
47 of D-(-)-mandelic acid, dissolved in 650 ml of methanol, are added dropwise, whilst stirring, to a solution of 55 g of 2-amino-1,2,3,4-tetrahydro-6-methoxy-naphthalene in 650 ml of methanol. The reaction solution so obtained is left to stand for 3 hours at room temperature, the precipitated crystals filtered off, washed with ether and dried. The (-)-mandelic acid salt thus obtained, is recrystallised from hot methanol and the procedure repeated until, at any given time a test showed that the optical rotation of the amine set free from the mandelic acid salt by extraction with IN sodium carbonate solution/methylene chloride is constant. The (+)-antipode of the title compound thus obtained is converted to the hydrochloride and recrystallised from methanol. M.P. 262°-264°. [α]D20 =+77.6° (C=1 in methanol). [Hydrochloride salt form].
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[N:7]1[C:17]2[N:16]3[CH2:18][CH2:19][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH:15]3[CH2:14][CH2:13][NH:12][C:11]=2[CH:10]=[CH:9][CH:8]=1>C(Cl)Cl>[CH:1]1([C:4]([N:12]2[CH2:13][CH2:14][CH:15]3[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:19][CH2:18][N:16]3[C:17]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]2=3)=[O:5])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCN2c3ncccc3NCCC2C1
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN2c3ncccc3N(C(=O)C3CC3)CCC2C1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of cyclopropylcarbonyl chloride (0.072 mL, 0.79 mmol) CH2Cl2 (1 mL) was added to an ice-cooled solution of the product of Example 72A (218 mg, 0.716 mmol) in CH2Cl2 (5 mL). The reaction was stirred with ice cooling under nitrogen for 45 minutes and then it was allowed to warm to room temperature for 4 hours. The reaction was quenched by addition of methanol (2 mL) and the solution was stirred for 10 minutes. The reaction mixture was then concentrated under vacuum. The residue was purified by HPLC (30×100 mm, C18, Waters XBridge™ column eluted with 0.1 M aqueous (NH4)2CO3-methanol, 80:20-0:100 over 15 minutes) to provide the title compound: MS (DCI) m/z 373 (M+H)+.