Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[N:13]2[C:14]3[N:5]([C:6](=[O:16])[CH:7]=[CH:8][C:9]=3[N:10]=[CH:11][C:12]2=[O:15])[CH2:4]1.[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN(CC)CC.CN(C)CCO>C(Cl)Cl.CC(OC)(C)C>[C:17]1([S:23]([O:1][CH2:2][C@H:3]2[N:13]3[C:14]4[N:5]([C:6](=[O:16])[CH:7]=[CH:8][C:9]=4[N:10]=[CH:11][C:12]3=[O:15])[CH2:4]2)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=c1ccc2ncc(=O)n3c2n1C[C@H]3CO
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)CCO
Solvent: COC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1ccc2ncc(=O)n3c2n1C[C@H]3COS(=O)(=O)c1ccccc1
Temperature: 42 °C
Reaction time: 0.5 h
Yield: 85.2 %

Procedure:
To the suspension of (2S)-2-(hydroxymethyl)-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione (26.5 g, 121 mmol) in DCM (320 ml) was added benzenesulfonyl chloride (23.38 ml, 181 mmol) followed by Et3N (39.6 ml, 284 mmol). The reaction mixture was heated at gentle reflux at 42° C. for 2 h. Then, the reaction was cooled to 5° C. and 2-(dimethylamino)ethanol (7.30 ml, 72.5 mmol) was added dropwise. The crude was stirred at room temperature for 30 min and TBME (600 ml) was added. The obtained solid was filtered. The resulting solid was suspended in 100 ml 1N HCl and washed with water and TBME, dried to give [(2S)-3,8-dioxo-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylen-2-yl]methyl benzenesulfonate (37.04 g, 85%) as a cream solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[N:17][CH:18]=1)=[C:8]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:7][CH2:6]2>C(O)(=O)C.[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C@@H:9]([C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][N:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)=[N:17][CH:18]=1)[C@@H:8]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCC(c1ccccc1)=C2c1ccc(OCCN2CCCC2)nc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CC[C@H](c1ccccc1)[C@@H]2c1ccc(OCCN2CCCC2)nc1
Reaction time: 16 h
Yield: 71.9 %

Procedure:
Pd(OH)2 (20%, 77 mg) was flame dried under vacuum and was added to a solution of 5-(6-methoxy-2-phenyl-3,4-dihydronaphthalen-1-yl)-2-(2-pyrrolidin-1-ylethoxy)pyridine (286.4 mg, 0.6714 mmol) in acetic acid (50 mL). The mixture was hydrogenated on a Parr shaker at 50 psi and at 50° C. for 16 h. The catalyst was filtered off with the aid of celite and the acetic acid was removed in vacuo. 1H NMR indicated that the reaction was incomplete and the residue was resubjected to the reaction conditions (50 psi and 60° C.) for an additional 6 h. The catalyst was removed via filtration through celite and the solvent was removed in vacuo. Radial chromatography (solvent gradient, CH2Cl2 to 10% MeOH in CH2Cl2) provided the desired material (207 mg, 72%). 1H NMR (250 MHz, CDCl3): δ7.19 (m, 4H), 6.84 (m, 3H), 6.75 (d, J=2.4 Hz, 1H), 6.68 (dd, J=2.4, 8.4 Hz, 1H), 6.59 (dd, J=2.4, 8.4 Hz, 1H), 6.40 (d, J=8.4 Hz, 1H), 4.35 (t, J=5.7 Hz, 2H), 4.21 (d, J=4.8 Hz, 1H), 3.82 (s, 3H), 3.38 (m, 1H), 3.06 (m, 2H), 2.90 (t, J=5.7 Hz, 2H), 2.69 (m, 4H), 2.11 (m, 2H), 1.84 (m, 4H).
Reaction SMILES: [CH3:1][N:2]1[CH2:11][CH2:10][C:9]2([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[C:4]([CH3:21])([CH2:5][CH2:6][CH:7](O)[CH2:8]2)[CH:3]1C.Cl.[NH2:24][OH:25]>CCO>[CH3:1][N:2]1[CH2:11][CH2:10][C:9]2([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[C:4]([CH3:21])([CH2:5][CH2:6][C:7](=[N:24][OH:25])[CH2:8]2)[CH2:3]1
Reactant: COc1cccc(C23CCN(C)C(C)C2(C)CCC(O)C3)c1
Reactant: NO
Agent: Cl
Solvent: CCO
Product: COc1cccc(C23CCN(C)CC2(C)CCC(=NO)C3)c1
Temperature: 25 °C
Yield: 96.5 %

Procedure:
N-Methyl-4aβ-(3-methoxyphenyl)octahydro-6-oxadecahydroisoquinoline 17 (1.41 g, 4.9 mmol) and hydroxylamine hydrochloride (1.70 g, 24.5 mmol) in EtOH (absolute, 100 mL) were heated to reflux for 5 h. The reaction mixture was allowed to cool to room temperature. Ethanol was removed under reduced pressure. The crude product was taken in to aqueous 2N NaOH solution (100 mL) and extracted with 3:1 CH2Cl2/THF (4×50 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure yielding crude product. The crude product was purified by flash chromatography (neutral alumina, Brockmann activity II-III) eluting with 9:1 ethyl acetate/hexane to afford 1.43 g (96%) of 19 as a white solid (mixture of E/Z): LCMS (ESI): m/z 303.5 (M+H)+.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:10]=[CH:11][C:12]([N+:19]([O-:21])=[O:20])=[C:13]([CH:18]=1)[C:14]([NH:16][CH3:17])=[O:15].C=O.[C:24]([BH3-])#N>C(#N)C.C(O)(=O)C>[CH3:17][NH:16][C:14](=[O:15])[C:13]1[CH:18]=[C:9]([N:2]2[CH2:3][CH:4]3[CH:5]([CH2:6][N:7]([CH3:24])[CH2:8]3)[CH2:1]2)[CH:10]=[CH:11][C:12]=1[N+:19]([O-:21])=[O:20]
Reactant: [BH3-]C#N
Reactant: CNC(=O)c1cc(N2CC3CNCC3C2)ccc1[N+](=O)[O-]
Agent: C=O
Solvent: CC(=O)O
Solvent: CC#N
Product: CNC(=O)c1cc(N2CC3CN(C)CC3C2)ccc1[N+](=O)[O-]
Temperature: 130 °C
Yield: 48.3 %

Procedure:
5-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-N-methyl-2-nitrobenzamide (1.78 g, 6.13 mmol) (Intermediate 10B) was dissolved in acetonitrile (45 mL) before addition of formaldehyde (0.6 g, 7.36 mmol) and MP-cyanoborohydride (3.6 g, 9.25 mmol) followed by 6 drops of acetic acid. The resulting mixture was split into 3 microwave vials and heated at 130° C. for 20 minutes. The reaction mixture was filtered and concentrated. The resultant crude material was purified by a 50 g silica column in 100% dichloromethane, 20% methanol in dichloromethane, 100% methanol (Biotage Snap cartridge). Fractions of the product were combined and reduced to dryness under reduced pressure to afford N-methyl-5-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-2-nitrobenzamide (900 mg, 2.96 mmol).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].Cl[S:17]([N:20]=C=O)(=[O:19])=[O:18]>C1(C)C=CC=CC=1>[C:5]([C:4]1[CH:3]=[C:2]([O:1][S:17](=[O:19])(=[O:18])[NH2:20])[CH:15]=[CH:14][CH:13]=1)(=[O:6])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(c1ccccc1)c1cccc(O)c1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: Cc1ccccc1
Product: NS(=O)(=O)Oc1cccc(C(=O)c2ccccc2)c1
Yield: 30.3 %

Procedure:
This compound was prepared according to the procedure used in Example 84. A mixture of 9.9 g (0.05 mole) of 3-hydroxybenzophenone and 4.4 ml (7.1 g, 0.0505 mole) of chlorosulfonyl isocyanate in 75 ml of toluene gave a solid as residue. This residue was recrystallized successively from benzene and then methylene chloride to yield 4.2 g (30%) of the title compound as a white solid, mp 72°-74° C.
Reaction SMILES: [C:1]1([C:6]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[C:13]([OH:15])=O)=O)[S:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:17][NH2:18]>C(O)C>[S:5]1[CH:4]=[CH:3][CH:2]=[C:1]1[C:6]1[C:8]2[S:9][CH:10]=[CH:11][C:12]=2[C:13](=[O:15])[NH:18][N:17]=1
Reactant: O=C(O)c1ccsc1C(=O)c1cccs1
Reactant: NN
Solvent: O
Solvent: CCO
Product: O=c1[nH]nc(-c2cccs2)c2sccc12
Yield: 88.6 %

Procedure:
0.70 g of 2-(2-thenoyl)-3-thiophene carboxylic acid and 0.22 g of hydrazine hydrate were dissolved in 20 ml of ethanol, and the solution was refluxed for 5 hours. After cooling the solution, it was crystallized by adding ether, thereby obtaining 0.61 g of 7-(2-thienyl)thieno[2,3-d]-pyridazine-4(5H)-one.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>CN(C=O)C>[N:1]1([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: CCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
To a solution of piperidine (3.4 g, 40.7 mmol, 1.0 eq) in DMF were added K2CO3 (14 g, 101.0 mmol, 2.5 eq.) and ethyl 2-chloroacetate (4.83 ml, 48.9 mmol, 1.2 eq). The mixture was stirred at RT for 16 h. The mixture was quenched and extracted as in Intermediate Example 5(a). The solvent was distilled off to give the product in 72% yield (5 g). LC-MS (ESI): Calculated mass: 171.1; Observed mass 172.3 [M+H]+ (rt: 0.1 min).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]1.[C:25]([OH:31])([C:27]([F:30])([F:29])[F:28])=[O:26]>>[F:28][C:27]([F:30])([F:29])[C:25]([OH:31])=[O:26].[NH:15]1[CH2:16][CH2:17][CH:12]([CH2:11][NH:10][C:2]2[NH:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2nc3ccccc3[nH]2)CC1
Solvent: O=C(O)C(F)(F)F
Product: c1ccc2[nH]c(NCC3CCNCC3)nc2c1

Procedure:
) tert-Butyl 4-[(1H-benzimidazol-2-ylamino)methyl]piperidine-1-carboxylate 21b (2.65 g; 8.02 mmol) was treated with 10 ml of TFA under standard conditions. Concentration and trituration of the crude prodcut with n-pentane afforded 2.3 g; ESI-MS [M+H+]=231.15.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:15])[C:7]([C:12](O)=[O:13])=[CH:8][NH:9]2)=[CH:4][C:3]=1[O:16][CH3:17].[OH-].[NH4+:19]>CN(C)C=O>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:15])[C:7]([C:12]([NH2:19])=[O:13])=[CH:8][NH:9]2)=[CH:4][C:3]=1[O:16][CH3:17]
Reactant: COc1cc2c(=O)c(C(=O)O)c[nH]c2cc1F
Reactant: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1cc2c(=O)c(C(N)=O)c[nH]c2cc1F
Temperature: 65 °C
Reaction time: 8 h

Procedure:
A mixture of 7-fluoro-6-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (1.0 g, 4.21 mmol) and N,N′-carbonyldiimidazole (1.51 g, 9.28 mmol) in 14 mL of N,N-dimethylformamide is heated at 65° C. for 2 hours then cooled to room temperature and poured into 200 mL of aqueous ammonium hydroxide in an ice water bath. The solution is allowed to stir at room temperature overnight and then concentrated to a small volume. Ice cold water is added followed by acidification with acetic acid. The resultant solid is collected by filtration washing with water to provide 821 mg of 7-fluoro-6-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxamide as a white solid, mp>300° C.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:16][CH:15]([CH2:17][OH:18])[CH2:14]3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:20]1[N:25]=[CH:24][CH:23]=[CH:22][N:21]=1>C1COCC1>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:14][CH:15]([CH2:17][O:18][C:20]4[N:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[CH2:16]3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Clc1ncccn1
Reactant: OCC1CC(c2ccc(CN3CCCC3)cc2)C1
Solvent: C1CCOC1
Product: c1cnc(OCC2CC(c3ccc(CN4CCCC4)cc3)C2)nc1

Procedure:
To a stirring solution of [3-(4-pyrrolidin-1-ylmethyl-phenyl)-cyclobutyl]-methanol (38.0 mg, 0.16 mmol) prepared above (Step F) in 1.5 mL of THF was added 2-chloropyrimidine (21.3 mg, 0.19 mmol) followed by a solution of KotBu (310 uL, 0.31 mmol, 1 M THF). The reaction immediately turned to a dark pink/milky solution. When mass spectral analysis indicated complete consumption of starting alcohol (15 minutes) the reaction was quenched with an aqueous solution of NH4Cl. The reaction was diluted with a 3:1 mixture of chloroform/isopropyl alcohol. The layers were separated and the organic layer was dried over MgSO4, filtered through a fritted glass filter, and concentrated under reduced pressure to yield the title compound as a mixture of cis:trans isomers. Conversion to the HCl salt was accomplished by dissolving the free base in EtOAc, and then adding 1 eq of a solution of HCl (1 M THF). The colorless solid was collected and dried under reduced pressure to yield 45 mg of a colorless solid, and as a mixture of isomers.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1Cl.[NH4+:10].[OH-]>CCO>[Cl:1][C:2]1[N:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[NH2:10]
Reactant: [NH4+]
Reactant: Clc1cnnc(Cl)c1Cl
Agent: [OH-]
Solvent: CCO
Product: Nc1c(Cl)cnnc1Cl
Temperature: 120 °C
Yield: 36 %

Procedure:
A mixture of 3,4,5-trichloropyridazine (Preparation 3, 500 mg, 2.73 mmole) in EtOH (5.5 mL) and NH4OH (5.5 mL) was heated under microwave irradiation 120° C. for 25 minutes. Concentration under reduced pressure and purification via silica gel column chromatography eluting with acetone:dichloromethane (0-15% acetone), provided the title product in 36% yield, 163 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[CH:6][NH:5][C:4]=1[CH:8]=O.[C:10]1([C:16]2[S:17][C:18]3[C:26]([N:27]=2)=[CH:25][CH:24]=[C:23]2[C:19]=3[CH2:20][C:21](=[O:28])[NH:22]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N1CCCCC1.Cl>CC(O)C.O>[CH3:1][O:2][C:3]1[CH:7]=[CH:6][NH:5][C:4]=1/[CH:8]=[C:20]1\[C:21](=[O:28])[NH:22][C:23]2[CH:24]=[CH:25][C:26]3[N:27]=[C:16]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[S:17][C:18]=3[C:19]\1=2
Reactant: COc1cc[nH]c1C=O
Reactant: O=C1Cc2c(ccc3nc(-c4ccccc4)sc23)N1
Agent: Cl
Solvent: C1CCNCC1
Solvent: CC(C)O
Solvent: O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc3nc(-c4ccccc4)sc3c21

Procedure:
3-Methoxypyrrole-2-carboxaldehyde (13 mg, 0.105 mmol) (Bellamy, supra) and 2-phenyl-6,8-dihydro-thiazolo[5,4-e]indol-7-one (20 mg, 0.075 mmol) (from Example 5) were suspended in a solution of 10% piperidine in 2-propanol (1 mL). The mixture was heated at reflux for 3 h. The mixture was cooled, poured into water, and the aqueous mixture was made acidic with concentrated hydrochloric acid. The aqueous layer was extracted with ethyl acetate, and the combined organic extracts were washed with water, brine, and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo, and the crude product was purified by reverse phase HPLC using acetonitrile-water as solvent. (Yield 10 mg, 36%).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:27][C:18]4([CH2:26][C:20]5([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH2:19]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[CH:28]([N:31](CC)C(C)C)(C)C.BrC#N.O>ClCCl>[C:28]([N:23]1[CH2:22][CH2:21][C:20]2([CH2:19][C:18]3([O:17][C:14]4=[CH:15][N:16]=[C:11]([C:8]5[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH:7]=5)[CH:12]=[C:13]4[CH2:27]3)[CH2:26]2)[CH2:25][CH2:24]1)#[N:31]
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)OC2(C3)CC3(CCNCC3)C2)CC1
Reactant: CCN(C(C)C)C(C)C
Agent: N#CBr
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)N1CC=C(c2cc3c(cn2)OC2(C3)CC3(CCN(C#N)CC3)C2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-dispiro[2,3-dihydrofuro[2,3-c]pyridine-2,1′-cyclobutane-3′,4″-piperidine] (HCl salt, 0.22 g) and N,N-diisopropyl-ethylamine (0.22 mL) in dichloromethane (20 mL) is stirred at room temperature for 5 min. Bromocyanide (60 mg) is added and the solution is stirred at room temperature for 2 h. Water is added and the mixture is extracted with dichloromethane. The combined extracts are dried (Na2SO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate/methanol 5:5:0→5:4:1) to give the title compound. Mass spectrum (ESI+): m/z=415 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[O:7][C:6]2[C:8]([O:14]C(=O)C)=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:5]=2[C:4]=1[C:18](=[O:31])[C:19]1[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=1)#[N:2].[N-:32]=[N+:33]=[N-:34].[Na+]>CN(C=O)C>[OH:14][C:8]1[C:6]2[O:7][C:3]([C:1]3[N:2]=[N:32][NH:33][N:34]=3)=[C:4]([C:18](=[O:31])[C:19]3[CH:20]=[C:21]([O:29][CH3:30])[C:22]([O:27][CH3:28])=[C:23]([O:25][CH3:26])[CH:24]=3)[C:5]=2[CH:11]=[CH:10][C:9]=1[O:12][CH3:13]
Reactant: COc1cc(C(=O)c2c(C#N)oc3c(OC(C)=O)c(OC)ccc23)cc(OC)c1OC
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C(=O)c2c(-c3nn[nH]n3)oc3c(O)c(OC)ccc23)cc(OC)c1OC
Temperature: 110 °C
Reaction time: 4 h

Procedure:
Mixture of 2-cyano-7-acetoxy-6-methoxy-3-(3,4,5-trimethoxybenzoyl)-benzo[b]furan (15 mg, 0.04 mmol) ammonium chloride (11 mg, 0.2 mmol) and sodium azide (13 mg, 0.2 mmol) in dry DMF (400 μL) was stirred at 110° C. for 4 hours. More sodium azide (15 mg, 0.23 mmol) was added and stirring was continued for 1 hour (tlc), quenched with saturated ammonium chloride solution and extracted with ethyl-acetate (10 mL×2). The organic layer was dried over magnesium sulfate and solvent was distilled and the crude was purified by silica gel plate to afford the title compound as creamy solid; (3.5 mg, 21%; 1H NMR (300 MHz, CDCl3) δ: 7.85(1H, NH), 7.26(d, J=8.54 Hz, 1H), 7.02(s, 2H, benzoyl Hs), 6.95(d, J=8.54 Hz, 1H), 5.74(b, 1H, OH), 3.97(s, 3H, OMe), 3.88(s, 3H, OMe), 3.82(s, 6H, 2×OMe).
Reaction SMILES: [NH:1]([C:18]([O:20][CH2:21][CH:22]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[C@@H:2]([C:15](O)=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>COCCOC.O>[CH:24]1[C:23]2[CH:22]([CH2:21][O:20][C:18]([NH:1][C@@H:2]([CH2:15][OH:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:9])[O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[O:19])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]=2[CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)NCCCC[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)NCCCC[C@H](CO)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: -5 °C
Reaction time: 0.03 h

Procedure:
A solution of Fmoc-D-Lys(BOC)—OH (2.102 g, 4.5 mmol) in DME (5 mL) at −15° C. was treated successively with N-methylmorpholine (0.56 mL, 5.0 mmol) and isobutyl chloroformate (0.7 mL, 5 mmol), stirred for 2 minutes, and filtered. The filter cake was washed with DME (3×5 mL) and the combined filtrate and washings were cooled to −5° C. and treated with NaBH4 (0.3 g, 7.5 mmol) in water (5 mL) and additional water(250 mL) immediately afterwards. The mixture was stirred for 15 minutes and filtered. The filter cake was washed with water and dried to provide the desired product. MS (APCI) m/e 455 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1)[C:5]([N:7]([O:9][CH3:10])[CH3:8])=[O:6].N1C=CN=C1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>C(Cl)Cl.CCOC(C)=O>[C:26]([Si:23]([CH3:25])([CH3:24])[O:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:13]=1)[C:5]([N:7]([O:9][CH3:10])[CH3:8])=[O:6])([CH3:29])([CH3:28])[CH3:27]
Reactant: CON(C)C(=O)c1cc(O)cc(C(F)(F)F)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CON(C)C(=O)c1cc(O[Si](C)(C)C(C)(C)C)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.8 %

Procedure:
To an ice-cold suspension of 3-hydroxy-5-trifluoromethyl-benzoic acid (1.0 mg, 4.85 mmol) and N,O-dimethylhydroxylamine hydrochloride (520 mg, 5.33 mmol) in CH2Cl2 (20 mL) was added N-methylmorpholine (586 μl, 5.33 mmol). The mixture was stirred for 5 minutes, to which were added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.05 g, 5.33 mmol). The mixture was stirred for 3 hours at room temperature, and then diluted with EtOAc. The organic layer was washed with 1N HCl, water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The product was vacuum-dried to give the 3-hydroxy-N-methoxy-N-methyl-5-trifluoromethyl-benzamide. To a suspension of 3-hydroxy-N-methoxy-N-methyl-5-trifluoromethyl-benzamide (13.7 g, 44.8 mmol) and imidazole (495 mg, 7.27 mmol) in CH2Cl2 (20 mL) was added portionwise tert-butyldimethylsilyl chloride (877 mg, 5.82 mmol) at 0° C. The mixture was stirred for 3 hours at room temperature, and then diluted with EtOAc. The organic layer was washed with 1N HCl, water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography to give 3-(tert-butyl-dimethyl-silanyloxy)-N-methoxy-N-methyl-5-trifluoromethyl-benzamide (1.71 g, 97%).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:28][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[C:21]([CH3:26])[C:20]([CH3:27])=[N:19]4)(=O)=O)=CC=1.[F:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][CH:34]=[C:33]2[C:39]1[CH2:40][CH2:41][NH:42][CH2:43][CH:44]=1>CS(C)=O.C(OCC)(=O)C>[F:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][CH:34]=[C:33]2[C:39]1[CH2:40][CH2:41][N:42]([CH2:12][CH:13]2[O:28][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[C:21]([CH3:26])[C:20]([CH3:27])=[N:19]4)[CH2:43][CH:44]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4nc(C)c(C)nc4c3O2)cc1
Reactant: Fc1ccc2[nH]cc(C3=CCNCC3)c2c1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1nc2ccc3c(c2nc1C)OC(CN1CC=C(c2c[nH]c4ccc(F)cc24)CC1)CO3
Temperature: 80 °C

Procedure:
To a solution of [(2R)-8,9-dimethyl-2,3-dihydro[1,4]dioxino[2,3-f]-quinoxalin-2-yl]methyl 4-methylbenzenesulfonate (0.400 g, 1.000 mmole) in methyl sulfoxide (20 mL) was added 5-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (0.540 g, 2.497 mmole) and the reaction mixture was heated to 80° C. for 12 hours. The reaction mixture was allowed to cool to room temperature and was diluted with ethyl acetate (250 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, methanol:ethyl acetate 1:9) followed by recrystallization from ethanol provided 0.239 g (54%) of the (S)-enantiomer of the title compound as a pale yellow solid. Rf=0.35 (silica, methanol:ethyl acetate 1:9); mp 138–141° C.
Reaction SMILES: [CH3:1][N:2]([C:4]1[S:8][N:7]=[C:6]([C:9]([Cl:12])([Cl:11])[Cl:10])[N:5]=1)[NH2:3].[CH:13](=O)[C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[OH:16]>C(O)C>[CH3:1][N:2]([C:4]1[S:8][N:7]=[C:6]([C:9]([Cl:10])([Cl:12])[Cl:11])[N:5]=1)[N:3]=[CH:13][C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[OH:16]
Reactant: O=Cc1ccccc1O
Reactant: CN(N)c1nc(C(Cl)(Cl)Cl)ns1
Solvent: CCO
Product: CN(N=Cc1ccccc1O)c1nc(C(Cl)(Cl)Cl)ns1
Temperature: 37 °C
Yield: 61 %

Procedure:
A mixture of 2.50 g (0.01 mole) 5-(1-methylhydrazino)-3-trichloromethyl-1,2,4-thiadiazole and 1.30 g (0.01 mole) salicylaldehyde was stirred. An exothermic reaction ensued and the reaction mixture warmed to 37° C. After 15 minutes ethanol was added and the solid product extracted. The product crystallized and was filtered to yield 2.15 g (61% yield) [mp. 207°-209° C. (dec)].
Reaction SMILES: [CH:1]([C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[S:12][C:11]([C:13]#[N:14])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)=[O:2].C([O-])([O-])=[O:18].[K+].[K+].O>CS(C)=O>[CH:1]([C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[S:12][C:11]([C:13]([NH2:14])=[O:18])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)=[O:2]
Reactant: N#Cc1ccc(Oc2ccc(C=O)cc2)s1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)c1ccc(Oc2ccc(C=O)cc2)s1
Reaction time: 1 h

Procedure:
Dissolve 5-(4-formylphenoxy)thiophene-2-carbonitrile (0.818 g, 3.57 mmol) in DMSO (18 mL) in a round bottom flask, then add K2CO3 (0.247 g, 1.78 mmol). Cool the reaction flask in a water bath and add 30% H2O, (0.81 mL, 7.14 mmol) solution. After one hour, add water (25 mL). Filter the resulting precipitate and wash the filter cake with water (25 mL). Collect the filter cake as the title compound: HRMS calcd for C12H10NO3S 248.0381 (M+H)+, found 248.0396, time 0.36 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=13.0 min, 100% purity.