Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([SH:12])[N:11]=[C:4]2[N:3]=1.[Br:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH3:24])=[CH:19][CH:18]=1.ClC1C=CC(OCCBr)=CC=1F.C(C1C=CC(O)=CC=1)C.BrCCBr>>[CH2:23]([C:20]1[CH:21]=[CH:22][C:17]([O:16][CH2:15][CH2:14][S:12][C:10]2[N:11]=[C:4]3[N:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]3[N:9]=2)=[CH:18][CH:19]=1)[CH3:24].[Br:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH3:24])=[CH:19][CH:18]=1
Reactant: Cc1cc(C)n2nc(S)nc2n1
Agent: CCc1ccc(O)cc1
Agent: CCc1ccc(OCCBr)cc1
Agent: Fc1cc(OCCBr)ccc1Cl
Solvent: BrCCBr
Product: CCc1ccc(OCCSc2nc3nc(C)cc(C)n3n2)cc1
Yield: 51 %

Procedure:
The title compound was prepared according to the experimentals described for Example 1 above from 5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-thiol and 1-(2-bromoethoxy)-4-ethylbenzene in 51% yield. The reagent 1-(2-bromoethoxy)-4-ethylbenzene was prepared by a similar procedure for the synthesis of 4-chloro-3-fluorophenoxy-ethylbromide in Example 4 above from 4-ethylphenol and 1,2-dibromoethane. EM (calc.): 328.1; MS (ESI) m/e: 329.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:14]([OH:16])=O)=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])=[O:4].C(N(CC)CC)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl.[NH2:39][CH2:40][C:41]1[CH:49]=[CH:48][CH:47]=[C:46]2[C:42]=1[CH2:43][C:44](=[O:50])[NH:45]2>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:14](=[O:16])[NH:39][CH2:40][C:41]2[CH:49]=[CH:48][CH:47]=[C:46]3[C:42]=2[CH2:43][C:44](=[O:50])[NH:45]3)=[CH:8][C:9]=1[C:10]([F:11])([F:12])[F:13])=[O:4]
Reactant: NCc1cccc2c1CC(=O)N2
Reactant: COC(=O)c1sc(C(=O)O)cc1C(F)(F)F
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1sc(C(=O)NCc2cccc3c2CC(=O)N3)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 29.2 %

Procedure:
To a solution of 3-Trifluoromethyl-thiophene-2,5-dicarboxylic acid 2-methyl ester (590 mg, 2.32 mmol) in anhydrous DMF (10 mL) was added triethylamine (1.62 mL, 11.6 mmol), EDC (530 mg, 2.78 mmol), HOBT (380 mg, 2.78 mmol), and 4-Aminomethyl-1,3-dihydro-indol-2-one hydrochloride (550 mg, 2.78 mmol). The mixture was stirred at room temperature 15 h, then quenched by pouring into EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography with 0-90% EtOAc in hexane to afford the desired product (0.27 g, 29% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([C:14]([O:16]CC)=O)[C:8]([C:19]([O:21]CC)=O)=[C:7]2[OH:24])([O-:3])=[O:2].[C:25]1([NH:31][NH2:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(O)C>[OH:16][C:14]1[C:9]2[NH:10][C:11]3[CH:12]=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=3[C:7](=[O:24])[C:8]=2[C:19](=[O:21])[N:31]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:32]=1
Reactant: NNc1ccccc1
Reactant: CCOC(=O)c1nc2ccc([N+](=O)[O-])cc2c(O)c1C(=O)OCC
Solvent: CCO
Product: O=c1c2cc([N+](=O)[O-])ccc2[nH]c2c(O)nn(-c3ccccc3)c(=O)c12
Temperature: 25 °C

Procedure:
To a stirred suspension of diethyl 6-nitro-4-hydroxy-quinoline-2,3-dicarboxylate (1.670 g, 5.00 mM) in ethanol (30 mL) vas added phenyl hydrazine (3.44 mL, 35.00 mM) to give a deep red solution. The solution was heated to reflux for 1 hour and concentrated to about 15 mL. Continued heating gave a thick suspension which was diluted with ethanol (5 mL) and refluxed for 16 additional hours. The mixture was cooled to room temperature and filtered to give the phenyl hydrazine salt of the title compound as a tan solid. This material was refluxed in glacial acetic acid (25 mL) for 2 hours and cooled to room temperature. Filtration gave the title compound (1.01 g, 58%) as a tan powder, mp 368° C. (decomp.); MS(CI): 351 (M+H).
Reaction SMILES: [O-]S([O-])(=O)=O.[Mg+2].[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]=O.[NH2:15][C@H:16]([CH:19]([CH3:21])[CH3:20])[CH2:17][OH:18]>C(Cl)Cl>[CH3:20][CH:19]([CH3:21])[C@@H:16](/[N:15]=[CH:13]/[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][N:7]=1)[CH2:17][OH:18]
Reactant: O=Cc1ccccn1
Reactant: CC(C)[C@@H](N)CO
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CC(C)[C@H](CO)/N=C/c1ccccn1
Reaction time: 2 h
Yield: 100 %

Procedure:
Anhydrous MgSO4 (50 g, 415 mmol, 4.15 eq) and a substituted aryl or heteroaryl carboxaldehyde, e.g. 2-pyridinecarboxaldehyde (9.5 ml, 100 mmol, 1 eq), were added to a solution of (R)-(−)-2-amino-3-methyl-1-butanol (10.32 g, 100 mmol) in dry DCM (150 ml) at 0° C. The reaction was followed by LC/MS. The mixture was stirred at this temperature for 2 h 25. MgSO4 was filtered off and the DCM removed by evaporation to give the desired product (XVIII*), e.g. (2R)-3-methyl-2-{[(E)-2-pyridinylmethylidene]amino}-1-butanol as a yellowish oil (19.23 g, quantitative yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][C@H:16]([O:32][CH:33]([CH3:35])[CH3:34])[C:17](N2[C@@H](CC3C=CC=CC=3)COC2=O)=[O:18])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[OH:37]O.[OH-].[Li+].O>O1CCCC1>[C:1]([O:5][C:6]([NH:7][CH2:8][C:9]1[CH:10]=[C:11]([CH2:15][C@H:16]([O:32][CH:33]([CH3:35])[CH3:34])[C:17]([OH:18])=[O:37])[CH:12]=[CH:13][CH:14]=1)=[O:36])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)O[C@@H](Cc1cccc(CNC(=O)OC(C)(C)C)c1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: OO
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)O[C@@H](Cc1cccc(CNC(=O)OC(C)(C)C)c1)C(=O)O
Reaction time: 8 h

Procedure:
15.3 g of {3-[3-(4 (S)-Benzyl-2-oxooxazolidin-3-yl)-2(S)-isopropoxy-3-oxopropyl]benzyl}carbamic acid t-butyl ester was dissolved in 300 ml of tetrahydrofuran, and 15 ml of 30% aqueous hydrogen peroxide and 75 ml of 1N aqueous lithium hydroxide were successively added under ice-cooling, and stirring was continued overnight at room temperature. The reaction solution was treated with water, extracted with dichloromethane, and the aqueous layer was acidified with 1N hydrochloric acid. The mixture was extracted (×3) with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated, to give 16.68 g of 3-[3-(t-butoxycarbonylaminomethyl)phenyl]-2(S)-isopropoxypropionic acid. The product was then dissolved in 100 ml of N,N-dimethylformamide, and 7 g of potassium hydrogen carbonate and 3.5 ml of iodomethane were successively added, and the mixture was stirred overnight at room temperature. The reaction solution was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography, to give 8.58 g of the title compound as a white solid in the 4:1 hexane-ethyl acetate fraction.
Reaction SMILES: [CH2:1](N(CC)CC)[CH3:2].[F:8][C:9]1[CH:14]=[CH:13][C:12]([SH:15])=[CH:11][CH:10]=1.ICC>O1CCCC1>[CH2:1]([S:15][C:12]1[CH:13]=[CH:14][C:9]([F:8])=[CH:10][CH:11]=1)[CH3:2]
Reactant: Fc1ccc(S)cc1
Reactant: CCN(CC)CC
Solvent: CCI
Solvent: C1CCOC1
Product: CCSc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.8 %

Procedure:
Triethylamine (5.44 mL, 39 mmol) was added to a solution of 4-fluorobenzenethiol (5 g, 39 mmol) and iodoethane (3.78 mL, 46.8 mmol) in tetrahydrofuran (50 mL). The resulting mixture was stirred at ambient temperature for 2 hours and then filtered. The filtrate was concentrated, triturated with hexane, and dried under vacuum to afford the title compound (4.8 g, 76%).
Reaction SMILES: [N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]([CH3:5])=[CH:3][CH:2]=1.B.C1COCC1.[H-].[H-].COCCO[Al+]OCCOC.[Na+].O>C1COCC1.C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:5][C:4]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[NH:1][CH2:2][CH:3]=1
Reactant: Cc1ccnc2ccccc12
Agent: B
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1=CCNc2ccccc21
Reaction time: 2 h
Yield: 43.4 %

Procedure:
A solution of lepidine (10.0 g) in THF was cooled down to −78° C., after which a solution of BH3.THF in THF (1 M, 70 ml) was added. After 2 h, a solution of sodium bis(2-methoxy-ethoxy)aluminum dihydride in toluene (3.5 M, 40 ml) was added and the reaction mixture was stirred for an additional 2 h. Water was added and the mixture diluted with ethyl acetate. The organic layer was separated, dried (MgSO4) and partially concentrated in vacuo causing crystallization of the title compound. The crystals were collected by filtration to yield 3.5 g after drying in vacuo. The remaining mother liquor was concentrated in vacuo and the residue was purified by chromatography on silicagel using heptane/ethyl acetate=0/1=>1/0 ( (v/v) as the eluent to give an additional 4.4 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([C:18](OCC)=[O:19])=[CH:5]2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH2:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=2)[CH:5]=[C:6]1[CH2:18][OH:19])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1cc2cc(Br)ccc2n1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCc1cc2cc(Br)ccc2n1Cc1ccccc1

Procedure:
The title compound was prepared from ethyl 5-bromo-1-benzyl-1H-indole-2-carboxylate and lithium aluminum hydride in substantially the same manner, as described in step 3 of Example 1. The product was obtained as a semi-solid. Mass spectrum (ESI, [M−H]−) m/z 314. 1H NMR (400 MHz, DMSO-d6) δ 7.67 (s, 1H), 7.58-7.15 (m, 4H), 7.12 (d, 1H, J=8.69 and 1.97 Hz), 6.98 (d, 2H, J=8.34 Hz) 6.41 (s, 1H), 5.43 (s, 2H), 5.33 (t, 1H, J=5.57 Hz), and 4.54 ppm (d, 2H, J=5.43 Hz).
Reaction SMILES: FC1C=C(C2C3C(=CC=C(OC)C=3)C(NCCO)=NC=2C#N)C=CC=1.Cl[C:27]1[C:36]2[C:31](=[CH:32][C:33]([O:37][CH3:38])=[CH:34][CH:35]=2)[C:30]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[F:45])=[C:29]([C:46]#[N:47])[N:28]=1.[NH2:48][CH2:49][CH:50]([OH:53])[CH2:51][OH:52]>>[OH:53][CH:50]([CH2:51][OH:52])[CH2:49][NH:48][C:27]1[C:36]2[C:31](=[CH:32][C:33]([O:37][CH3:38])=[CH:34][CH:35]=2)[C:30]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[F:45])=[C:29]([C:46]#[N:47])[N:28]=1
Reactant: NCC(O)CO
Reactant: COc1ccc2c(Cl)nc(C#N)c(-c3ccccc3F)c2c1
Agent: COc1ccc2c(NCCO)nc(C#N)c(-c3cccc(F)c3)c2c1
Product: COc1ccc2c(NCC(O)CO)nc(C#N)c(-c3ccccc3F)c2c1

Procedure:
Following the procedure for 4-(3-fluorophenyl)-1-[(2-hydroxyethyl)amino]-6-methoxyisoquinoline-3-carbonitrile, using 1-chloro-4-(2-fluorophenyl)-6-methoxyisoquinoline-3-carbonitrile in place of 1-chloro-4-(3-fluorophenyl)-6-methoxyisoquinoline-3-carbonitrile, and using racemic 1-amino-2,3-propanediol in place of 2-aminoethanol, the title compound was synthesized.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:14])([C:8]#[C:9][Si](C)(C)C)[CH3:7])[CH:3]=[N:2]1.O.O.[F-].[K+]>CO>[NH:1]1[CH:5]=[C:4]([C:6]([OH:14])([C:8]#[CH:9])[CH3:7])[CH:3]=[N:2]1
Reactant: CC(O)(C#C[Si](C)(C)C)c1cn[nH]c1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C#CC(C)(O)c1cn[nH]c1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
In a 20-mL sealed tube, a suspension of 2-(1H-pyrazol-4-yl)-4-(trimethylsilyl)but-3-yn-2-ol (1.4 g, 6.72 mmol, 1.00 equiv) and potassium fluoride dihydrate (2.0 g) in methanol (10 mL) was stirred for 1.5 h at 50° C. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 20 mL of water. The resulting solution was extracted with 3×20 mL of tetrahydrofuran/ethyl acetate (2/1) and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 1 g (98%) of 2-(1H-pyrazol-4-yl)but-3-yn-2-ol as a solid.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]1([CH2:13][SH:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.F[C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([I:24])[C:17]=1[C:18]#[N:19].[Cl-].[NH4+]>C1COCC1>[CH2:13]([S:14][C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([I:24])[C:17]=1[C:18]#[N:19])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: SCc1ccccc1
Reactant: N#Cc1c(F)cccc1I
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1c(I)cccc1SCc1ccccc1
Reaction time: 0.17 h
Yield: 68.6 %

Procedure:
A suspension of potassium tert-butoxide (1.12 g, 10.0 mmol) and phenyl-methanethiol (1.24 g, 10 mmol) in THF (30 mL) at room temperature was stirred for 10 minutes before treating with 2-fluoro-6-iodo-benzonitrile (2.47 g, 10 mmol). The solution was stirred for 1 hour at room temperature, poured into a saturated ammonium chloride solution and filtered. The filter cake was recrystallized from hexanes to provide 2.41 g (53% yield) of the desired product. MS (ESI(−)) m/e 350.0 (M−H)−.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[S:21][C:22]1[CH:23]=[C:24]([NH:28][C:29](=[O:31])[CH3:30])[CH:25]=[CH:26][CH:27]=1>>[CH3:20][C:18]1[CH:17]=[CH:16][C:15]([S:21][C:22]2[CH:23]=[C:24]([NH:28][C:29](=[O:31])[CH3:30])[CH:25]=[CH:26][CH:27]=2)=[C:14]([NH:13][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:19]=1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: CC(=O)Nc1cccc(Sc2ccc(C)cc2N)c1
Product: CC(=O)Nc1cccc(Sc2ccc(C)cc2Nc2ccnc3nc(C)ccc23)c1

Procedure:
The product from Example 1d (100 mg, 0.559 mmol) was reacted with the product from Example 71c (152 mg, 0.559 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (45 mg, 18%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.97 (s, 3H), 2.38 (s, 3H), 2.74 (s, 3H), 6.26 (d, J=6.99 Hz, 1H), 6.84 (d, J=8.46 Hz, 1H), 7.06 (t, J=8.09 Hz, 1H), 7.25 (d, J=8.09 Hz, 1H), 7.33-7.41 (m, 2H), 7.41-7.54 (m, 2H), 7.74 (d, J=8.82 Hz, 1H), 8.33 (d, J=6.99 Hz, 1H), 8.89 (d, J=8.82 Hz, 1H), 9.81 (s, 1H), 10.91 (s, 1H); MS (ESI+) m/z 415 (M+H)+, (ESI−) m/z 413 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12]([NH:14][C@H:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:16][CH3:17])=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.C1C(=O)N([Br:37])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:37][CH2:1][C:2]1[C:3]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12]([NH:14][C@H:15]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:16][CH3:17])=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: CC[C@H](NC(=O)c1c(C)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC[C@H](NC(=O)c1c(CBr)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Yield: 24.3 %

Procedure:
3-methyl-2-phenyl-N-[(1S)-1-phenylpropyl]quinoline-4-carboxamide (9.8 g, 26 mmol) was dissolved in 200 mL hot CCl4 (with stirring) under N2 and heated at a gentle reflux. NBS (6.9 g, 39 mmol) was added and solution irradiated with long wave UV light for 0.5 h. Additional NBS (1.9 g, 11 mmol) was added and solution irradiated and refluxed for another 0.5 h. It was then allowed to cool and concentrated under reduced pressure to remove most of the CCl4. The residue was then dissolved in CH2Cl2 and washed with aqueous NaHCO3 containing a few crystals of sodium thiosulfate. The organic layer was then dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting material was then purified using silica gel chromatography (0-15% EtOAc/CH2Cl2) to give 2.9 g of desired product (24%) as a yellow-white solid. 1H NMR (300 MHz, CDCl3, 52° C.) δ 8.11 (d, J=8.1 Hz, 1H), 7.81-7.67 (m, 2H), 7.67-7.58 (m, 2H), 7.55-7.26 (m, 9H), 6.39 (d, J=7.8 Hz, 1H), 5.28 (q, J=7.6 Hz, 1H), 4.74-4.50 (m, 2H), 2.23-1.91 (m, 2H), 1.03 (t, J=7.4 Hz, 3H); LCMS: m/z 459 (MH+).
Reaction SMILES: [N:1]1[C:2]2[C:14](=[O:15])[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:3]=2[NH:4][C:5](=[O:7])[CH:6]=1.[BH4-].[Na+]>>[OH:15][CH:14]1[C:2]2[N:1]=[CH:6][C:5](=[O:7])[NH:4][C:3]=2[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]1=2
Reactant: O=C1c2ccccc2-c2[nH]c(=O)cnc21
Agent: [BH4-]
Agent: [Na+]
Product: O=c1cnc2c([nH]1)-c1ccccc1C2O
Yield: 104.7 %

Procedure:
9H-Indeno[1,2-b]pyrazine-3,9(4H)-dione (5.0 g, 25.23 mmol) was reduced with sodium borohydride (1.72 g, 45.5 mmol) as described in example 11. Yield 5.29 g (96%) of the title compound. M.p. 251°-253° C. 1H-NMR (DMSO-d6, δ): 5.32 (d, 1H), 5.92 (d, 1H), 7.47 (m, 2H), 7.64 (m, 1H), 7.8 (m, 1H) 7.9 (s, 1H), 12.5 (s, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[N:6]=[C:7]([C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)[O:8][C:9]=1[CH3:10].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30].O>C(OCC)(=O)C>[CH3:28][S:29]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[N:6]=[C:7]([C:11]2[CH:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:19][CH:20]=2)[O:8][C:9]=1[CH3:10])(=[O:31])=[O:30]
Reactant: COC(=O)c1ccc(-c2nc(CCCO)c(C)o2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2nc(CCCOS(C)(=O)=O)c(C)o2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
To a solution of methyl 4-[4-(3-hydroxypropyl)-5-methyl-1,3-oxazol-2-yl]benzoate (500 mg, 1.82 mmol, 1.00 equiv) and triethylamine (370 mg, 3.66 mmol, 2.01 equiv) in ethyl acetate (20 mL) at −5° C. was added methane sulfonyl chloride (0.27 g) dropwise with stiffing. The resulting solution was warmed to room temperature naturally and stirred at room temperature for 1 h. Water (20 mL) was added and the mixture was extracted with 1×30 mL of ethyl acetate. The organic layer was washed sequentially with 1×10 mL of 1 N hydrochloric acid, 1×10 mL of 5% sodium bicarbonate solution and 1×30 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give 0.55 g (86%) of methyl 4-[4-[3-(methanesulfonyloxy)propyl]-5-methyl-1,3-oxazol-2-yl]benzoate as a white solid. LC-MS: (ES, m/z): 354 [M+H]+, 258, 146, 105.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])([OH:10])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1.[CH2:19]([S:21](Cl)(=[O:23])=[O:22])[CH3:20]>>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C:3]([OH:10])([CH2:2][NH:1][S:21]([CH2:19][CH3:20])(=[O:23])=[O:22])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1
Reactant: NCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Reactant: CCS(=O)(=O)Cl
Product: CCS(=O)(=O)NCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl

Procedure:
Following the procedure described in example 1 but using 3-amino-2-(2,4-dichlorophenyl)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol and ethanesulfonylchloride, the title compound was obtained in a similar yield: mp 144°-145° C.; 1H NMR (80 MHz, CDCl3)δ(TMS) 7.96 (s, 1H, CH=N), 7.83 (s, 1H, CH=N), 7.62 (d, J=8.5 Hz, 1H, arom), 7.4-7.1 (m, 2H, atom), 5.00 (AB system, Δv=0.56, J=14.5 Hz, 2H, CH2 -Tr), 4.79 (t, J=6.4 Hz, 1H, NH), 4.1-3.5 (m, 2H, CH2NH 3.00 (q, J=7.5 Hz, 2H, Et), 1.29 (t, J=7.5 Hz, 3H, Et). Anal calcd. for C13H16Cl2N4O3S: C 41.17%; H 4.25%; N 14.77%. Found: C 41.24%; H 4.27%; N 14.48%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([N:13]2[CH2:18][CH2:17][O:16][C:15]3[N:19]=[CH:20][C:21]([C:23]4[CH:31]=[CH:30][CH:29]=[C:28]5[C:24]=4[CH:25]=[CH:26][NH:27]5)=[CH:22][C:14]2=3)=[O:12])[CH:5]=[C:6]([Br:10])[C:7]=1[O:8]C.[Br-].[Li+].N1CCNCC1.Cl>CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([N:13]2[CH2:18][CH2:17][O:16][C:15]3[N:19]=[CH:20][C:21]([C:23]4[CH:31]=[CH:30][CH:29]=[C:28]5[C:24]=4[CH:25]=[CH:26][NH:27]5)=[CH:22][C:14]2=3)=[O:12])[CH:5]=[C:6]([Br:10])[C:7]=1[OH:8]
Reactant: COc1c(Br)cc(C(=O)N2CCOc3ncc(-c4cccc5[nH]ccc45)cc32)cc1Br
Agent: C1CNCCN1
Agent: Cl
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1cc(Br)c(O)c(Br)c1)N1CCOc2ncc(-c3cccc4[nH]ccc34)cc21
Temperature: 100 °C
Reaction time: 2 h
Yield: 63.3 %

Procedure:
In a 10 ml flask, (3,5-dibromo-4-methoxy-phenyl)-[7-(1H-indol-4-yl)-2,3-dihydro-pyrido[2,3-b][1,4]oxazin-1-yl]-methanone (124 mg, 0.23 mmol), lithium bromide (246 mg, 2.83 mmol) and piperazine (29 mg, 0.34 mmol) were dissolved in 5 ml of N,N-dimethyl formamide (DMF), and then stirred at 100° C. for 2 hours. After completion of the reaction by adding water dropwise, the mixture was adjusted to weak acidic condition (pH=6) with 1N hydrochloric acid. The formed solid was filtered and washed with distilled water. The resulting solid was recrystallized from methanol to obtain the target compound 70, i.e., (3,5-dibromo-4-hydroxy-phenyl)-[7-(1H-indol-4-yl)-2,3-dihydro-pyrido[2,3-b][1,4]oxazin-1-yl]-methanone (77 mg, 64%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[CH2:33][C@@H:14]2[O:15][Si](C(C)C)(C(C)C)O[Si](C(C)C)(C(C)C)[O:19][CH2:20][C@H:13]2[CH2:12]1.F.N1C=CC=CC=1>C1COCC1.N1C=CC=CC=1>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[CH2:33][C@H:14]([OH:15])[C@@H:13]([CH2:20][OH:19])[CH2:12]1
Reactant: CC(C)[Si]1(C(C)C)OC[C@H]2C[C@@H](n3cnc4c(Cl)ncnc43)C[C@@H]2O[Si](C(C)C)(C(C)C)O1
Agent: F
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: OC[C@H]1C[C@@H](n2cnc3c(Cl)ncnc32)C[C@@H]1O
Reaction time: 14 h
Yield: 63.6 %

Procedure:
To a solution of 6-chloro-9-[(6aR,8R,9aS)-2,2,4,4-tetraisopropylhexahydrocyclopenta[f][1,3,5,2,4]trioxadisilocin-8-yl]-9H-purine (0.518 g, 1.0 mmol) in THF/pyridine (5.2 mL, 1:1) was added hydrofluoric acid in pyridine (0.381 mL, 15.2 mmol). The reaction was stirred for 14 h then quenched with saturated aq NaHCO3 and concentrated under reduced pressure. The residue was dissolved in 10% solution of MeOH/DCM, filtered, the organic layer was concentrated and the residue purified by flash chromatography (0 to 10% MeOH/DCM to afford the title compound (0.171 g, 63%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:17]#[N:18])=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-])=O)[NH:8][C:7](=[O:15])[C:6](=[O:16])[NH:5]2.O.O.[Sn](Cl)Cl>C(O)C>[NH2:12][C:11]1[CH:10]=[C:9]2[C:4]([NH:5][C:6](=[O:16])[C:7](=[O:15])[NH:8]2)=[C:3]([C:17]#[N:18])[C:2]=1[Cl:1]
Reactant: N#Cc1c(Cl)c([N+](=O)[O-])cc2[nH]c(=O)c(=O)[nH]c12
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: N#Cc1c(Cl)c(N)cc2[nH]c(=O)c(=O)[nH]c12
Temperature: 25 °C
Yield: 86.7 %

Procedure:
A suspension of 6-chloro-5-cyano-7-nitroquinoxaline-2(1H),3(4H)-dione (0.100 g, 0.38 mmol, as prepared above) and tin (II) chloride dihydrate (0.508 g, 2.25 mmol, Aldrich) in ethanol (4.0 mL) was refluxed for 24 h. The resulting suspension was then cooled to room temperature and the yellow solid was filtered, washed with ethanol (2.0 mL), and dried under vacuum to obtain 0.078 g (88%) of 7-amino-6-chloro-5-cyanoquinoxaline-2(1H),3(4H)-dione as a yellow powder; 1H NMR (DMSO-d6): δ 5.762 (br s, 2H), 6.818 (s, 1H), 11.69 (s, 1H), 12.03 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:17](Cl)(=[O:27])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].Cl>N1C=CC=CC=1>[S:13]1[CH:14]=[N:15][N:16]=[C:12]1[NH:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:17](=[O:27])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: Nc1ccc(S(=O)(=O)Nc2nncs2)cc1
Reactant: CCCCCCCCCC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCC(=O)Nc1ccc(S(=O)(=O)Nc2nncs2)cc1
Temperature: 95 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Compound 100 (50 mg, 0.20 mmol) was suspended in pyridine (0.3 mL). Decanoyl chloride (39.1 mg, 0.21 mmol) was added gradually over 15 min. The reaction mixture was heated to 95° C. and stirred at this temperature for 1 h, then poured into 10% aqueous HCl solution and extracted with EtOAc (3×0.5 mL). The combined organic extracts were washed with water (3×5 mL), brine (3×5 mL), and dried over anhydrous Na2SO4. Evaporation of the solvent yielded the product (80 mg, 0.20 mmol, 95%). It was recrystallized from hexanes/ethyl acetate to yield an analytical sample, mp 151-152° C.; 1H NMR (250 MHz, CD3OD) δ 0.88 (3, t, J=7.5 Hz), 1.24-1.45 (12, m), 1.68 (2, t, J=7.5 Hz), 2.37 (2, t, J=7.5 Hz), 7.72 (2, d, J=8.5 Hz), 7.79 (2, d, J=8.5 Hz), 8.49 (1, S); 13C NMR (125 MHz, CD3OD) δ 14.4, 23.7, 26.7, 30.3, 30.4, 30.5, 30.6, 33.0, 38.1, 102.4, 128.3, 137.5, 144.0, 145.0, 170.0, 174.9; MS (ESI+) 411.1 (M+H)+; HRMS (IonSpec. HiRES ESI+) calcd. for C18H27N4O3S2 (M+H)+411.1525, obsd. 411.1524.