Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([O:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([CH:24]5[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]5)[CH:21]=[CH:20][C:18]=4[N:19]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([O:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([CH:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[CH:21]=[CH:20][C:18]=4[N:19]=3)[CH2:10][CH2:9]2)=[N:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc3nc(OC4CCN(c5ncc(Cl)cn5)CC4)sc3c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1cnc(N2CCC(Oc3nc4ccc(C5CCNCC5)cc4s3)CC2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.4 %

Procedure:
To a solution of tert-butyl 4-(2-((1-(5-chloropyrimidin-2-yl)piperidin-4-yl)oxy)benzo[d]thiazol-6-yl)piperidine-1-carboxylate (133 mg, 0.251 mmol) in CH2Cl2 (2.5 mL) was added TFA (0.2 mL, 2.5 mmol). The reaction mixture was stirred at rt for 3 h. The reaction mixture was diluted with CH2Cl2 (5 mL) and washed with aq. NaOH (1 N, 3 mL) and brine. The organic layer was dried (Na2SO4), filtered, and concentrated to afford 2-((1-(5-chloropyrimidin-2-yl)piperidin-4-yl)oxy)-6-(piperidin-4-yl)benzo[d]thiazole (102 mg, 0.237 mmol, 95% yield) as a pale yellow solid. LCMS (m/z)=430 (M+H)+.
Reaction SMILES: O.[CH2:2]([O:6][CH2:7][CH2:8][CH2:9][Si:10](OCC)(OCC)[O:11]CC)[CH:3]1[O:5][CH2:4]1>C(O)(=O)C>[CH2:2]([O:6][CH2:7][CH2:8][CH2:9][SiH2:10][OH:11])[CH:3]1[O:5][CH2:4]1
Reactant: CCO[Si](CCCOCC1CO1)(OCC)OCC
Solvent: O
Solvent: CC(=O)O
Product: O[SiH2]CCCOCC1CO1
Temperature: 90 °C

Procedure:
In a three-necked flask equipped with a stirrer, dropping funnel and reflux condenser, 500 g water were adjusted with dilute acetic acid to a pH value of 4 to 4.5. 15 g glycidoxypropyl triethoxysilane were then added dropwise, the mixture being heated to 90° C. This temperature was maintained for 1 hour.
Reaction SMILES: C[O:2][C:3]1[C:20]([O:21]C)=[CH:19][C:6]2[S:7][C:8]([C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[O:12])=[C:9]([CH3:10])[C:5]=2[CH:4]=1.CO>ClCCl>[OH:2][C:3]1[C:20]([OH:21])=[CH:19][C:6]2[S:7][C:8]([C:11]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[O:12])=[C:9]([CH3:10])[C:5]=2[CH:4]=1
Reactant: COc1cc2sc(C(=O)N3CCOCC3)c(C)c2cc1OC
Solvent: ClCCl
Solvent: CO
Product: Cc1c(C(=O)N2CCOCC2)sc2cc(O)c(O)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (5,6-dimethoxy-3-methylbenzo[b]thiophen-2-yl)morpholin-4-yl-methanone (0.80 g) in dichloromethane (8 ml) boron tribromide (5.2 ml, 2 M solution in dichloromethane) was added at 0° C. The mixture was allowed to warm to room temperature. After 2 hours at room temperature methanol (16 ml) was added and solvents were evaporated. To the residue sodium sulfite solution (16 ml, 5% in water) was added and after stirring for 0.5 hour the precipitate was filtered.
Reaction SMILES: [CH3:1][C@:2]12[CH2:21][CH2:20][C@H:19]3[C@@H:8]([CH2:9][CH2:10][C:11]4[C@:17]3([CH3:18])[CH2:16][CH2:15][C:13](=[O:14])[CH:12]=4)[C@@H:7]1[CH2:6][CH2:5][C:3]2=[O:4].C[C@@]12C(=[O:40])CC[C@H]1[C@H]1[C@@H](C3C=CC(O)=CC=3CC1)CC2>>[CH3:1][C@@:2]12[C:3](=[O:4])[CH2:5][CH2:6][C@H:7]1[C@@H:8]1[CH2:9][CH2:10][C:11]3[C@@:17]([CH:18]=[O:40])([C@H:19]1[CH2:20][CH2:21]2)[CH2:16][CH2:15][C:13](=[O:14])[CH:12]=3
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C=O)[C@@H]1CCC2=O

Procedure:
This compound is the postulated reaction intermediate of the second hydroxylation step of androstenedione-to-estrone catalysis by Aromatase.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:22][CH2:21][C:20]3[C:15](=[C:16]([O:23][CH3:24])[CH:17]=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[NH:25]1[CH2:30][CH:29]=[C:28]([C:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[NH:33][CH:32]=2)[CH2:27][CH2:26]1>CS(C)=O.C(OCC)(=O)C>[CH3:24][O:23][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[O:14][C@@H:13]([CH2:12][N:25]1[CH2:26][CH:27]=[C:28]([C:31]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[NH:33][CH:32]=3)[CH2:29][CH2:30]1)[CH2:22][CH2:21]2
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Reactant: COc1cccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CC2
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1cccc2c1O[C@@H](CN1CC=C(c3c[nH]c4ccccc34)CC1)CC2
Temperature: 80 °C
Yield: 67.8 %

Procedure:
To a solution of [(2R)-8-methoxy-3,4-dihydro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate (0.348 g, 1.00 mmol) in methyl sulfoxide (20 mL) was added 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (0.793 g, 4.00 mmol) and the reaction mixture was heated to 80° C. for 12 h. The reaction mixture was allowed to cool to room temperature and was diluted with ethyl acetate (200 mL), washed with water (2×100 mL), aqueous sodium chloride (100 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude solid. Purification by flash column chromatography (silica, ethyl acetate:hexanes 4:1) followed by recrystallization from ethanol provided 0.254 g (68%, 40% ee) of 3-(1-{[(2R)-8-methoxy-3,4-dihydro-2H-chromen-2-yl]methyl}-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole as a yellow crystalline powder. [α]D25=−28.22 (c 9.92 in chloroform, 40% ee); Rf=0.34 (silica, ethyl acetate:hexanes 4:1); mp 190-194° C. dec; Anal. Calcd. for C24H26N2O2.0.1 H2O: C, 76.61; H, 7.02; N, 7.44. Found: C, 76.42; H, 6.99 N, 7.43.
Reaction SMILES: [CH2:1]([C:3]1([CH2:7][O:8][C:9](=[O:22])/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][C:16]2([CH2:20][CH3:21])[CH2:19][O:18][CH2:17]2)=[O:13])[CH2:6][O:5][CH2:4]1)[CH3:2].[SH:23][CH2:24][CH2:25][CH2:26][Si:27]([O:34][CH2:35][CH3:36])([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30]>C1(C)C=CC=CC=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH2:20]([C:16]1([CH2:15][O:14][C:12](=[O:13])[CH:11]([S:23][CH2:24][CH2:25][CH2:26][Si:27]([O:34][CH2:35][CH3:36])([O:28][CH2:29][CH3:30])[O:31][CH2:32][CH3:33])[CH2:10][C:9]([O:8][CH2:7][C:3]2([CH2:1][CH3:2])[CH2:6][O:5][CH2:4]2)=[O:22])[CH2:17][O:18][CH2:19]1)[CH3:21]
Reactant: CCC1(COC(=O)/C=C/C(=O)OCC2(CC)COC2)COC1
Reactant: CCO[Si](CCCS)(OCC)OCC
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCO[Si](CCCSC(CC(=O)OCC1(CC)COC1)C(=O)OCC1(CC)COC1)(OCC)OCC
Yield: 68.8 %

Procedure:
8.4 g (26.9 mmol) of fumaric acid-bis-[(3-ethyloxetan-3-yl)methyl]ester, 5.3 g (26.9 mmol) of 3-mercaptopropyltriethoxysilane and 0.33 g (1.3 mmol) of dibenzoyl peroxide were stirred for 5 hours in 20 ml of toluene at 100° C. When the solvent was distilled off, a white deposit precipitated which produced 10.2 g (70% yield) of (10) after filtering off and drying.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH2:10][N:11]2C(=O)C3C(=CC=CC=3)C2=O)[CH:9]=1)[C:5]#[N:6].Cl>CCO.CO>[NH2:11][CH2:10][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([Br:1])[CH:9]=1)[C:5]#[N:6]
Reactant: N#Cc1cc(Br)cc(CN2C(=O)c3ccccc3C2=O)c1
Agent: Cl
Solvent: CO
Solvent: CCO
Product: N#Cc1cc(Br)cc(CN)c1
Yield: 64.4 %

Procedure:
To a suspension of 3-bromo-5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]benzonitrile (3.50 g, 10.3 mmol) in EtOH (60 mL) was added N2H4H2O (85%, 1.31 g). The mixture was refluxed for 3 h. At room temperature 2 N HCl (20 mL) was added (pH=3), and the mixture was filtered and rinsed with water (20 mL×2). The filtrate was concentrated to about 50 mL and filtered again. After addition of NaHCO3 (pH=9), the filtrate was extracted with CH2Cl2 (50 mL×3). The combined extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give a mixture of colorless solid and colorless oil. 2N HCl in MeOH (50 mL) was added and concentrated to afford crude material as a white solid. Recrystallization from MeOH-Et2O yielded the product 3-(aminomethyl)-5-bromobenzonitrile (1.40 g, 55%) as colorless fine needles. 1H NMR (400 MHz, D2O): δ 7.92 (m, 1 H), 7.84 (m, 1 H), 7.69 (m, 1 H), 4.11 (s, 2 H); 13C NMR (400 MHz, D2O): δ 137.1, 135.9, 135.8, 131.7, 123.0, 117.7, 113.8, 42.0; MS: m/z 209.0 (M+−HCl); HPLC: retention time: 9.313 min; purity: 98.4%.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:17][C@H:11]2[CH2:12][N:13]([C:15]#[N:16])[CH2:14][C@@:10]2([C:18]([N:20]2[CH2:29][CH2:28][C:27]3[C:22](=[CH:23][C:24]([C:30]([F:33])([F:32])[F:31])=[CH:25][CH:26]=3)[CH2:21]2)=[O:19])[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=[O:36]>C(Cl)Cl>[NH2:7][C@@H:8]1[CH2:17][C@H:11]2[CH2:12][N:13]([C:15]([NH2:16])=[O:36])[CH2:14][C@@:10]2([C:18]([N:20]2[CH2:29][CH2:28][C:27]3[C:22](=[CH:23][C:24]([C:30]([F:32])([F:31])[F:33])=[CH:25][CH:26]=3)[CH2:21]2)=[O:19])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]2CN(C#N)C[C@@]2(C(=O)N2CCc3ccc(C(F)(F)F)cc3C2)C1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)N1C[C@@H]2C[C@@H](N)C[C@]2(C(=O)N2CCc3ccc(C(F)(F)F)cc3C2)C1

Procedure:
A solution of the product from Step A (0.03 g, 0.627 mmol) in TFA (1 mL) and DCM (1 mL) was stirred at rt for 1.5 h. The volatile organic compounds were removed by evaporation, and the residue was diluted with DCM and evaporated again to give the product as a TFA salt. LC/MS: C19H23F3N4O2: m/z 397.2 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][O:11]2)=[CH:6][C:5]=1[NH:14]C(=O)C)([O-:3])=[O:2].[CH]Cl.N>CCO>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][O:11]2)=[CH:6][C:5]=1[NH2:14])([O-:3])=[O:2]
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])OCCC2
Agent: N
Agent: [CH]Cl
Solvent: CCO
Product: Nc1cc2c(cc1[N+](=O)[O-])OCCC2
Yield: 100.5 %

Procedure:
A suspension of acetamide 232 (2.49 g, 10.5 mmol) and cHCl (10 mL) in EtOH (50 mL) was heated at reflux temperature for 16 h. The solution was cooled, carefully neutralized with aqueous NH3 solution, extracted with EtOAc (2×50 mL), the combined organic fraction dried and the solvent evaporated to give nitroaniline 238 (2.05 g, 100%) as an orange solid: mp (EtOAc) 145-148° C. [lit. (Brancaccio, G.; Lotteiri, G.; Viterbo, R. J. Het. Chem. 1973, 10, 623-629) mp (H2O) 139-140° C.]; 1H NMR δ 7.54 (s, 1H, H-8), 6.50 (s, 1H, H-5), 5.62 (br s, 2H, NH2), 4.14 (br t, J=5.2 Hz, 2H, H-2), 2.77 (br t, J=6.5 Hz, 2H, H-4), 1.95-2.02 (m, 2H, H-3).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=2)=[N:7][C:6]=1Cl)[CH3:2].[C:25]([C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1)#[N:26]>>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=2)=[N:7][C:6]=1[O:33][C:30]1[CH:31]=[CH:32][C:27]([C:25]#[N:26])=[CH:28][CH:29]=1)[CH3:2]
Reactant: N#Cc1ccc(O)cc1
Reactant: CCOC(=O)c1ccc(Oc2ccc(OC(F)(F)F)cc2)nc1Cl
Product: CCOC(=O)c1ccc(Oc2ccc(OC(F)(F)F)cc2)nc1Oc1ccc(C#N)cc1
Yield: 62.4 %

Procedure:
2-Chloro-6-(4-trifluoromethoxy phenoxy)nicotinic acid ethyl ester (0.3 g, 0.83 mmol) and 4-cyanophenol (98.8 mg, 0.83 mmol) were coupled using the procedure of Example 17(b) to afford 0.23 g of the required product. Percentage purity (LCMS): 82.35%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:3]=1.C1C(=O)N([Cl:25])C(=O)C1>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[Cl:25])=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Oc1ccc(Br)cc1-c1cc2ccccc2[nH]1
Solvent: CN(C)C=O
Product: Oc1ccc(Br)cc1-c1[nH]c2ccccc2c1Cl
Temperature: 25 °C
Yield: 97.4 %

Procedure:
To a solution of 4-bromo-2-(1H-indol-2-yl)phenol (100 mg, 0.35 mmol) in DMF (1 mL) was added NCS (46 mg, 0.35 mmol), it was allowed to stir at room temperature until LCMS showed the starting material was consumed completely. The reaction solution was extracted with EtOAc, and the combined organic layers were washed with H2O (3×10 mL), brine and dried over Na2SO4. The solvent was removed and the crude product was purified using prep-TLC to provide the desired product of 4-bromo-2-(3-chloro-1H-indol-2-yl)phenol (110 mg, yield: 98.2%). 1H-NMR (CDCl3, 400 MHz) δ 9.25 (s, 1H), 7.80 (d, J=2.4 Hz, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.40˜7.43 (m, 1H), 7.20˜7.30 (m, 2H), 7.12 (t, J=4.0 Hz, 1H), 6.86 (t, J=6.0 Hz, 1H), 5.93 (s, 1H). MS (M+H)+: 322/324.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[CH:16]=1)=[C:9]2[CH2:23][CH2:24][NH2:25])=[O:5])[CH3:2].[N:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][CH2:34][CH:35]=O)=[CH:28][CH:27]=1.S([O-])([O-])(=O)=O.[Mg+2].[Na]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([C:15]1[CH:16]=[C:17]([CH3:22])[CH:18]=[C:19]([CH3:21])[CH:20]=1)=[C:9]2[CH2:23][CH2:24][NH:25][CH2:35][CH2:34][CH2:33][CH2:32][C:29]1[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=1)=[O:5])[CH3:2]
Reactant: O=CCCCc1ccncc1
Reactant: CCOC(=O)c1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCN)c2c1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Agent: [Na]
Product: CCOC(=O)c1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCNCCCCc3ccncc3)c2c1
Temperature: -10 °C
Yield: 50.3 %

Procedure:
To a dry flask were added 5.0 g (14.9 mmol) of 3-(2-aminoethyl)-2-(3,5-dimethylphenyl)-1H-indole-5-carboxylic acid ethyl ester, 1.98 g (13.5 mmol) of 4-(pyridin-4-yl)butyraldehyde (diluted with 0.5 mL of CDCl3), 8.12 g (67.7 mmol) of anhydrous magnesium sulfate, and a magnetic stirring bar. The flask was purged with nitrogen, cooled to −10° C., and stirred as 11.5 mL of dry CDCl3 was introduced gradually by syringe. The mixture was stirred under nitrogen for about 20 minutes. Next, the septum was removed, and 670 mg (17.6 mmol) of sodium borohyrdide was added rapidly. The septum was immediately replaced, and the system was again purged with nitrogen. The mixture was stirred under nitrogen at about −5° C. as 10 mL of dry methanol was added gradually by syringe. After a few minutes at this temperature, the reaction was removed from the cooling bath and partitioned between 80 mL of ethyl acetate and 100 mL of water. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with a gradient of 4-9% methanol in methylene chloride; repeated using 5-15% methanol in methylene chloride) to give the title compound (3.19 g). 500 MHz 1H NMR (CDCl3) was consistent with the assigned structure. Mass spectrum (PB-NH3/CI): m/e=470.4 (M+H). An additional 1.91 g of less pure material was also isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)=[C:4]([N+:16]([O-])=O)[CH:3]=1.[H][H]>[Ni].C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)=[C:4]([NH2:16])[CH:3]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1COC1CCCCO1
Agent: [Ni]
Solvent: CCO
Product: Nc1cc(Cl)ccc1COC1CCCCO1
Yield: 98.1 %

Procedure:
A Parr bottle containing 4-chloro-2-nitro-1-[[(tetrahydro-2H-pyran-2-yl)oxy]methyl]benzene (22.6 g, 82.8 mmol) and ethanol (150 mL) was treated with Raney nickel (50% slurry in water, 2.0 g), charged with hydrogen (60 psi) and rocked until hydrogen uptake ceased (3 h). The resultant suspension was filtered through celite, and the celite cake thoroughly washed with fresh ethanol (5×150 mL). The combined organic extracts were concentrated in vacuo to give an orange oil that crystallized on standing. Recrystallization (ethyl acetate/hexane) gave the title compound as a white solid (19.64 g, 98%). 1H NMR (CDCl3) δ7.00 (d, J=8 Hz, 1H), 6.65-6.60 (m, 2H), 4.72 (A of ABq, J=12 Hz, 1H), 4.79-4.77 (m, 1H), 4.45 (B of ABq, J=12 Hz, 1H), 4.27 (bs, 2H), 3.94-3.85 (m, 1H), 3.58-3.50 (m, I), 1.88-1.65 (m, 2H), 1.58-1.46 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[CH:12][C:3]=1[C:4]([NH:6][C@@H:7]([CH3:11])[C:8]([OH:10])=[O:9])=[O:5]>CC(O)=O.[Fe]>[NH2:16][C:14]1[CH:13]=[CH:12][C:3]([C:4]([NH:6][C@@H:7]([CH3:11])[C:8]([OH:10])=[O:9])=[O:5])=[C:2]([F:1])[CH:15]=1
Reactant: C[C@H](NC(=O)c1ccc([N+](=O)[O-])cc1F)C(=O)O
Agent: [Fe]
Solvent: CC(=O)O
Product: C[C@H](NC(=O)c1ccc(N)cc1F)C(=O)O
Temperature: 65 °C
Reaction time: 0.33 h
Yield: 75.6 %

Procedure:
To a suspension of iron powder (175 mg, 3.12 mmol) in AcOH (2 mL) was added (S)-2-(2-fluoro-4-nitrobenzamido)propanoic acid (80 mg, 0.31 mmol) at rt and stirred at 60-70° C. for 20 min. Work-up of the reaction mixture as described in example 6 gave the product as a pale brown color solid (53 mg, 75%), mp 244-248° C. 1H NMR (400 MHz, DMSO-d6): δ 7.69 (1H, br s), 7.55 (1H, t, J=8.8 Hz), 6.41 (1H, d, J=8.4 Hz), 6.30 (1H, d, J=14.8 Hz), 5.97 (2H, br s), 4.15 (1H, br s), 1.31 (3H, d, J=6.8 Hz); LC-MS (positive ion mode): m/z 227 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10](Cl)=[O:11].[C:13]([CH:15]1[CH2:17][NH:16]1)#[N:14]>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([N:16]1[CH2:17][CH:15]1[C:13]#[N:14])=[O:11]
Reactant: N#CC1CN1
Reactant: O=C(Cl)c1cc2ccccc2o1
Product: N#CC1CN1C(=O)c1cc2ccccc2o1

Procedure:
This compound is obtained in a yield of 1.3 g., analogously to Example 75, from 1.8 g. benzofuran-2-carbonyl chloride and 0.68 g. 2-cyanoaziridine. It has a melting point of 92°-94° C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][NH2:7].CS[C:10]1[NH:11][C:12](=[O:21])[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][N:15]=1>CO>[O:21]=[C:12]1[NH:11][C:10]([NH:7][CH2:6][CH:2]2[CH2:3][CH2:4][CH2:5][O:1]2)=[N:15][CH:14]=[C:13]1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)c1cnc(SC)[nH]c1=O
Reactant: NCC1CCCO1
Solvent: CO
Product: CCOC(=O)c1cnc(NCC2CCCO2)[nH]c1=O
Reaction time: 8 h
Yield: 47 %

Procedure:
(tetrahydrofuran-2-yl)methanamine (142 mg, 1.40 mmol) was added into ethyl 2-(methylthio)-6-oxo-1,6-dihydropyrmidine-5-carboxylate (300 mg, 1.40 mmol) in methanol and refluxed overnight. After half of the starting material was consumed, the reaction mixture was reheated again overnight. Then the reaction mixture was cooled and the precipitate filtered. 1H-NMR confirmed the product as ethyl 6-oxo-2-(((tetrahydrofuran-2-yl)methyl)amino)-1,6-dihydropyrimidine-5-carboxylate (HGN-0017) (176 mg, 47% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[Cl-].[CH2:11]([C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[O:19][CH2:18][CH2:17][CH:16]2[NH3+:23])[CH3:12].C(N(CC)CC)C>CN(C)C(=O)C>[CH2:11]([C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[O:19][CH2:18][CH2:17][CH:16]2[NH:23][C:2]1[CH:3]=[N:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1)[CH3:12]
Reactant: CCc1ccc2c(c1)C([NH3+])CCO2
Reactant: N#Cc1ncc(Br)cn1
Agent: [Cl-]
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CCc1ccc2c(c1)C(Nc1cnc(C#N)nc1)CCO2
Yield: 9.8 %

Procedure:
0.20 g (1.09 mmol) of 5-bromo-2-cyanopyrimidine (ABCR 245244), 0.325 g (1.52 mmol) of 6-ethyl-3,4-dihydro-2H-chromen-4-aminium chloride and 0.35 g (3.3 mmol) of triethylamine in 1.5 ml of N,N-dimethylacetamide are heated in a closed cuvette in the microwave at 200° C. for 120 minutes (Biotage Initiator, http://www.biotage.com/DynPage.aspx?id=22001). The crude mixture obtained in this manner is applied to silica gel and purified by column chromatography using the mobile phase heptane/ethyl acetate. Concentration gives 0.03 g of 5-[(6-ethyl-3,4-dihydro-2H-chromen-4-yl)amino]pyrimidine-2-carbonitrile (wax-like) (yield 8% at a purity of 80%).
Reaction SMILES: [F-].[K+].[CH:3]1([O:8][C:9]2[CH:10]=[C:11]([C:17]3([C:24]#[C:25][Si](C)(C)C)[CH2:22][CH2:21][CH2:20][C:19](=[O:23])[CH2:18]3)[CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH2:7][CH2:6][CH2:5][CH2:4]1.O>CN(C)C=O>[CH:3]1([O:8][C:9]2[CH:10]=[C:11]([C:17]3([C:24]#[CH:25])[CH2:22][CH2:21][CH2:20][C:19](=[O:23])[CH2:18]3)[CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: COc1ccc(C2(C#C[Si](C)(C)C)CCCC(=O)C2)cc1OC1CCCC1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CC1(c2ccc(OC)c(OC3CCCC3)c2)CCCC(=O)C1
Reaction time: 18 h

Procedure:
A mixture of potassium fluoride (900 mg, 15.6 mmol) and 3-(3-cyclopentyloxy-4-methoxyphenyl)-3-trimethylsilylethynylcyclohexan-1-one (0.3 g, 0.78 mmol) were stirred in dry N,N-dimethylformamide (3 mL) under an argon atmosphere. After 18 h, the solvent was removed in vacuo, the residue was partitioned between water and ethyl acetate, the aqueous layer was extracted twice with ethyl acetate, the combined extract was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 4:1 hexanes/ethyl acetate provided a clear colorless oil. Anal. (C20H24O3.1/10 H2O) calcd: C 76.45, H 7.76; found: C 76.32, H 7.60.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[C:10]([O:21]C(=O)C)=[CH:9][C:8]=2[C:25]([O:27]C)=[O:26])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[C:1]1([C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[C:10]([OH:21])=[CH:9][C:8]=2[C:25]([OH:27])=[O:26])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cc(OC(C)=O)c2cc(OC)c(OC)cc2c1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc2c(O)cc(C(=O)O)c(-c3ccccc3)c2cc1OC
Temperature: 25 °C
Yield: 100.7 %

Procedure:
1-Phenyl-2-methoxycarbonyl-4-acetoxy-6,7-dimethoxynaphthalene (66.4 grams) from Step 3, 500 mL of a 10 weight percent aqueous sodium hydroxide solution and 50 mL of methanol were added to a reaction flask and heated to reflux for 3 hours and then cooled to room temperature. The reaction mixture was poured onto an aqueous solution of 4N hydrochloric acid/ice mixture (˜400 mL). A white precipitate formed and was collected by vacuum filtration, washed with water and was air-dried. Recrystallization from ethanol (95 weight percent) gave 57 grams of 1-phenyl-4-hydroxy-6,7-dimethoxy-2-naphthoic acid.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[C:19]([C:23]4[O:27][C:26](=[O:28])[NH:25][N:24]=4)[CH:20]=[CH:21][CH:22]=3)[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:29]=1>CC1OCCN=1>[CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[C:19]([C:23]4[O:27][C:26](=[O:28])[N:25]([CH2:12][CH2:13][NH:14][C:15](=[O:16])[CH3:6])[N:24]=4)[CH:20]=[CH:21][CH:22]=3)[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:29]=1
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3n[nH]c(=O)o3)c1)C2=O
Agent: CC1=NCCO1
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3nn(CCNC(C)=O)c(=O)o3)c1)C2=O
Temperature: 100 °C
Reaction time: 8 h
Yield: 268.3 %

Procedure:
(S)-5-[3-(9-Methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-1,3,4-oxadiazol-2(3H)-one (140 mg, 0.34 mmol) obtained in Step 1 of Example 89 was suspended in 2-methyl-2-oxazoline (1.0 mL), and the mixture was stirred overnight at 100° C. The residue obtained by concentrating the mixture under reduced pressure was then purified by silica gel column chromatography to give (S)—N-(2-{5-[3-(9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-2-oxo-1,3,4-oxadiazol-3(2H)-yl}ethyl)acetamide (226 mg, quantitative).
Reaction SMILES: COC1C=C([C:12]2[O:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)C=C(OC)C=1C.C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.BrN1C(=O)CCC1=O>CCOC(C)=O>[O:13]1[C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=[CH:12]1
Reactant: COc1cc(-c2nc3ccccc3o2)cc(OC)c1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: c1ccc2ocnc2c1

Procedure:
A mixture of 2-(3,5-dimethoxy-4-methylphenyl)-1,3-benzoxazole (260 mg, 1 mmol), carbon tetrachloride (4.2 mL), benzoyl peroxide (15 mg, 0.06 mmol) and N-bromosuccinimide (270 mg, 1.5 mmol) was heated to reflux conditions under argon overnight. Concentration of cooled reaction mixture in vacuo afforded a yellow solid. Flash chromatography on silica gel of crude material using 1:4 EtOAc:hexanes gave the desired intermediate, 2-[4-bromomethyl)-3,5-dimethoxyphenyl]-1,3-benzoxazole, as a colorless solid.