Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.O[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21](=[O:28])[C:20](=[O:29])[CH:19]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCOCC1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21](=[O:28])[C:20](=[O:29])[CH:19]=2)=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(O)cc1
Reactant: O=C1C=C(OCCCCCCO)c2ccccc2C1=O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: N#Cc1ccc(OCCCCCCOC2=CC(=O)C(=O)c3ccccc32)cc1
Temperature: 10 °C
Reaction time: 10 h
Yield: 62.4 %

Procedure:
A mixture of 4-hydroxybenzonitrile (87 mg, 0.73 mmol), naphthoquinone 504 (200 mg, 0.73 mmol), PPh3 (191 mg, 0.73 mmol) in dioxane (10 mL) was cooled to 10° C. and treated with DEAD (140 mg, 0.80 mmol). The reaction mixture was stirred for 10 h, concentrated in vacuo and purified by chromatography (5% EtOAc in benzene) to afford 511 as a yellow solid (171 mg, 53%), 1H NMR (CDCl3) 8.13 (dd, J=7.3, 1.4 Hz, 1H), 8.86 (dd, J=7.7, 1.1 Hz, 1H), 7.67 (dt, J=7.5, 1.5 Hz 1H), 7.60 (dt, J=7.5, 1.5 Hz, 1H), 7.57 (d, J=8.8 Hz, 2H), 6.93 (d, J=8.9 Hz, 2H), 5.96 (s, 1H), 4.17 (t, J=6.4 Hz, 2H), 4.03 (t, J=6.3 Hz, 2H), 1.80-2.05 (m, 4H), 1.58-1.68 (m, 4H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([NH2:12])[CH3:11])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:22]=1[C:23](Cl)=[O:24].[Cl-].[NH4+]>ClCCl>[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:22]=1[C:23]([NH:12][CH:10]([CH3:11])[CH2:9][C:6]1[CH:5]=[CH:4][C:3]([Cl:2])=[CH:8][CH:7]=1)=[O:24]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: CC(N)Cc1ccc(Cl)cc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Cc1ccc(Cl)cc1)NC(=O)c1c(Cl)cccc1Cl
Reaction time: 24 h

Procedure:
100 mg of 1-(4-chlorophenyl)propan-2-amine hydrochloride (0.728 mmol) and 0.10 ml of triethylamine (0.728 mmol) are diluted in 3 ml of dichloromethane at room temperature, 152 mg of 2,6-dichlorobenzoyl chloride (0.728 mmol) are added to the reaction mixture. After 24 hours of stirring, 20 ml of DCM an 10 ml of saturated solution of ammonium chloride are added to the reaction mixture.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([F:10])[CH:3]=1.[N:11]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:14]2[CH2:13][CH2:12][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15]2)=[C:4]([F:10])[CH:3]=1
Reactant: O=Cc1ccc(Br)cc1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Br)cc2F)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.8 %

Procedure:
A 500 mL round-bottom flask was charged with 4-bromo-2-fluorobenzaldehyde (12.0 g, 59.1 mmol, 1.10 equiv), tert-butyl piperazine-1-carboxylate (10.0 g, 53.7 mmol, 1.00 equiv), triethylamine (8.10 g, 80.0 mmol, 1.49 equiv) and dichloroethane (100 mL). The resulting solution was stirred for 30 min at room temperature. Solid sodium triacetoxyborohydride (34.2 g, 161 mmol, 3.01 equiv) was added. The resulting solution was stirred 5 h at room temperature. The reaction progress was monitored by LCMS. The reaction was then quenched by the addition of water (200 mL). The resulting solution was extracted with dichloromethane (3×200 mL) and the organic layers were combined, washed with brine (2×200 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (2/3) to yield 16.0 g (80% yield) of tert-butyl 4-[(4-bromo-2-fluorophenyl)methyl]piperazine-1-carboxylate as yellow oil. LCMS (ESI, m/z): 373 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:12]([NH2:16])[CH:13]([CH3:15])[CH3:14]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:16][CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CC(C)CN
Solvent: ClCCl
Product: CC(C)CNS(=O)(=O)c1ccc(Br)cc1
Yield: 26.3 %

Procedure:
According to general procedure C, 4-Bromobenzene sulfonyl chloride (0.40 g, 1.56 mmol) and isobutylamine (0.39 mL, 3.90 mmol) were stirred together with dry dichloromethane (5 mL) for 16 hours. 4-bromo-N-isobutylbenzenesulfonamide (0.12 g, 28%) was provided after purification. MS (ESI) m/z 292.HPLC purity 100.0% at 210-370 nm, 9.4 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([CH3:16])([CH3:15])[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1.O[CH2:18][CH2:19][C:20]1[N:25]=[C:24]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH:23]=[CH:22][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:29]([O:28][C:27]([NH:26][C:24]1[N:25]=[C:20]([CH2:19][CH2:18][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C:9]([CH3:16])([CH3:15])[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:7]=2)[CH:21]=[CH:22][CH:23]=1)=[O:33])([CH3:32])([CH3:31])[CH3:30]
Reactant: COC(=O)CC(C)(C)Cc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)Nc1cccc(CCO)n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)CC(C)(C)Cc1ccc(OCCc2cccc(NC(=O)OC(C)(C)C)n2)cc1
Temperature: 22 °C
Reaction time: 16 h

Procedure:
To a stirred solution of the product of STEP 4 (0.45 g), the product of STEP 6 (0.723 g), triphenyl phosphine (0.80 g, Aldrich) in THF (10 mL) at −78° C. was added diisopropyl azodicarboxylate (Aldrich, 0.63 mL) over 3 minutes. The mixture was stirred at −78° C. for 3 hours and at 22° C. for 16 hours. The mixture was concentrated in vacuo and the residue was chromatographed over silica gel using 20% ethyl acetate in hexane as eluant. The fractions containing the desired product were pooled and concentrated to provide the above product as a thick gum.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.[CH3:11][Sn:12](Cl)([CH3:14])[CH3:13].O>CCOCC>[CH3:11][Sn:12]([CH3:14])([CH3:13])[C:2]1[O:1][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccoc1
Reactant: C[Sn](C)(C)Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: C[Sn](C)(C)c1ccco1
Temperature: -30 °C
Yield: 96.3 %

Procedure:
To a solution of 6.8 g furan in 100 ml dry ether at 0° C. under nitrogen was added 10.5 ml 9.5M n-butyllithium. The reaction mixture was heated at reflux for 15 min., then cooled to -30° C. and 19.9 g trimethyltin chloride was added. The reaction mixture was allowed to warm to room temperature and then poured into water. The ether layer was separated, washed with water and passed through an alumina column, eluting with hexane. Removal of the solvent provided 22.2 g (96%) 2-(trimethylstannyl)furan as a pale-yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:4]3[CH2:5][C@@H:6]([CH2:15][CH2:16][OH:17])[CH2:7][CH2:8][C:9]=3[S:10][C:11]=2[N:12]=[CH:13][N:14]=1.[CH3:18][C:19]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])[CH3:20].N1C=CN=C1>CN(C=O)C>[Si:22]([O:17][CH2:16][CH2:15][C@@H:6]1[CH2:5][C:4]2[C:3]3[C:2]([Cl:1])=[N:14][CH:13]=[N:12][C:11]=3[S:10][C:9]=2[CH2:8][CH2:7]1)([C:19]([CH3:21])([CH3:20])[CH3:18])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCC[C@H]1CCc2sc3ncnc(Cl)c3c2C1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC[C@H]1CCc2sc3ncnc(Cl)c3c2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
To a solution of 2-[(12S)-3-chloro-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-12-yl]ethan-1-ol (300 mg, 1.12 mmol, 1.00 equiv) in 5 mL of distilled DMF was added TBSCl (252 mg, 1.50 equiv) and imidazole (137 mg, 2.01 mmol, 1.80 equiv) at room temperature under nitrogen. The resulting solution was stirred for 1 h at ambient temperature and then quenched with water, extracted with 3×50 mL of ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5) to provide (12S)-12-[2-[(tert-butyldimethylsilyl)oxy]ethyl]-3-chloro-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraene (420 mg, 98%) as a light yellow solid. MS: m/z 384, 386 (M+H)+.
Reaction SMILES: [OH:1][NH:2][C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[CH2:15][C:16]1[N:17]=[C:18]([C:21]([F:24])([F:23])[F:22])[S:19][CH:20]=1>>[F:22][C:21]([F:24])([F:23])[C:18]1[S:19][CH:20]=[C:16]([CH2:15][O:1][NH:2][C:3]2[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=2[C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:17]=1
Reactant: CCOC(=O)c1ccccc1NO
Reactant: FC(F)(F)c1nc(CBr)cs1
Product: CCOC(=O)c1ccccc1NOCc1csc(C(F)(F)F)n1
Yield: 52 %

Procedure:
The titled compound was prepared using similar procedure as that of Example-1 (step-2) using ethyl 2-(hydroxyamino)benzoate and product of step 3 described above in 52% yield.
Reaction SMILES: [F:1][C:2]1[C:3]([S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:14][C:13]=2[N+]([O-])=O)(=[O:11])=[O:10])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C1(O)C=CC=CC=1.CC(C)([O-])C.[K+]>CN(C=O)C>[F:1][C:2]1[C:3]2[S:9](=[O:11])(=[O:10])[C:12]3[C:17](=[CH:16][C:15]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:14][CH:13]=3)[O:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)Oc1ccc(S(=O)(=O)c2c(O)cccc2F)c([N+](=O)[O-])c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Oc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc2c(c1)Oc1cccc(F)c1S2(=O)=O
Yield: 70 %

Procedure:
From 3-fluoro-2-((4-isopropoxy-2-nitrophenyl)sulphonyl)phenol (Example 21): A stirred solution of 3-fluoro-2-((4-isopropoxy-2-nitrophenyl))sulphonyl)phenol (0.35 g, 0.98 mmol) and potassium tert-butoxide (0.13 g, 1.18 mmol) in 25 mL anhydrous DMF was heated at 80° C. for 1 h during which time the reaction color changed from orange to light yellow. After the reaction had been cooled 10% aqueous HCL (100 mL) was added and the mixture extracted with EtOAc (2×100 mL). The combined organics were washed with 10% aqueous HCl (100 mL) and brine (100 mL), dried (Na2SO4) and concentrated in vacuo to a yellow solid (290 mg). Recrystallization from etOAC/hexane gave 210 mg (70%) of the title compound which was identical in all aspects to material prepared from 1-Fluoro-7-isopropoxyphenoxathiin (Example 20).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:27]=1[CH3:33])(=[O:25])=[O:24].[N:34]1[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40][NH2:41])[CH:35]=1>>[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:41][CH2:40][C:36]3[CH:35]=[N:34][CH:39]=[CH:38][CH:37]=3)=[O:19])=[CH:20][CH:21]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:27]=1[CH3:33])(=[O:25])=[O:24]
Reactant: NCc1cccnc1
Reactant: Cc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)O)cc3)oc2C)c(C)c1
Agent: O=C(Cl)C(=O)Cl
Product: Cc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)NCc4cccnc4)cc3)oc2C)c(C)c1
Yield: 23.7 %

Procedure:
Method E. Reaction of oxalyl chloride (31 λL, 0.35 mmol) and benzoic acid 44 (92 mg, 0.24 mmol) with subsequent coupling to 3-pyridinylmethylamine (27 λL, 0.26 mmol) gave benzamide 45 (27 mg, 24%) as a clear gum: 1H NMR δ 9.22 (t, J=5.8Hz, 1.H, CONH), 8.57 (d, J=1.5Hz, 1.H, H-2′), 8.47 (dd, J=4.7, 1.5Hz, 1 H, H-6′), 8.00 (d, J=8.4Hz, 2 H, H-2, H-6), 7.88 (d, J=8.4Hz, 2 H, H-3, H-5), 7.74 (br d, J=7.8Hz, 1 H, H-4′), 7.57 (d, J=8.1Hz, 1H, H-5″) 7.37 (dd, J=7.8, 4.7Hz, 1 H, H-5′), 7.27 (br s, 1 H, H-3″), 7.18 (d, J=8.1Hz, 1 H, H-6″), 4.61 (s, 2 H, CH2SO2), 4.51 (d, J=5.8Hz, 2 H, CH2N), 2.55 (s, 3 H, CH3), 2.34 (s, 3 H, CH3), 2.15 (s, 3 H, CH3); MS m/z 476.6 (MH+, 100%). Anal. calcd for C26H25N3O4S.½CH3CO2CH2CH3: C, 64.72, H, 5.63; N, 8.09. Found: C, 64.72; H, 5.60; N, 7.75%.
Reaction SMILES: [N+:1]([CH2:4][CH2:5][C:6]1[C:14]2[C:13]([C:15]([O:17]C)=O)=[CH:12][CH:11]=[CH:10][C:9]=2[NH:8][CH:7]=1)([O-])=O.N1[C:27]2[CH:26]=[CH:25][CH:24]=[C:23](C(OC)=O)[C:22]=2C=C1.[N+](C=CC1C=CC=CC=1)([O-])=O>>[C:22]1([CH:5]2[C:6]3=[CH:7][NH:8][C:9]4[CH:10]=[CH:11][CH:12]=[C:13]([C:14]=43)[C:15](=[O:17])[NH:1][CH2:4]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)c1cccc2[nH]cc(CC[N+](=O)[O-])c12
Reactant: COC(=O)c1cccc2[nH]ccc12
Agent: O=[N+]([O-])C=Cc1ccccc1
Product: O=C1NCC(c2ccccc2)c2c[nH]c3cccc1c23
Temperature: 160 °C

Procedure:
In a manner similar to that described for the preparation of methyl 3-(nitroethyl)-indole-4-carboxylate D above, methyl indole-4-carboxylate (85 mg, 0.49 mmol) and nitrostyrene (80 mg, 0.54 mmol) were heated at 160° C. in a sealed tube for 12 h. The product was isolated by silica gel chromatography as a brown oil, 132 mg (83%). The intermediate nitro alkane was reduced/cyclized as described to give (rac)-3-phenyl-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-one as a white solid, 51.4 mg (48%, after chromatography and recrystallization). mp 201-203° C.; 1H NMR (300 MHz, d6-DMSO) δ 3.73 (m, 2H), 4.42 (m, 1H), 7.28 (br m, 8H), 7.64 (d, 1H, J=7.9 Hz), 7.77 (d, 1H, J=7.9 Hz), 11.32 (br s, 1H); HRMS (FAB, MH+) Calcd for C17H15N2O: 263.1184, Found: 263.1180; Anal. (C17H14N2O.0.25 H2O) C, H, N.
Reaction SMILES: I[CH2:2][CH:3]1[CH2:12][CH2:11][C:6]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:5][CH2:4]1.[C:13]1([N:19]2[C:23]([SH:24])=[N:22][N:21]=[N:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[K+].O>CCO>[O:10]1[C:6]2([CH2:11][CH2:12][CH:3]([CH2:2][S:24][C:23]3[N:19]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:20]=[N:21][N:22]=3)[CH2:4][CH2:5]2)[O:7][CH2:8][CH2:9]1
Reactant: ICC1CCC2(CC1)OCCO2
Reactant: Sc1nnnn1-c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: c1ccc(-n2nnnc2SCC2CCC3(CC2)OCCO3)cc1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
A solution of 8-iodomethyl-1,4-dioxa-spiro[4.5]decane (prepared according to WO 2003/095438, 26 g, 92 mmol) was dissolved in EtOH (200 ml), 1-phenyl-1H-tetrazole-5-thiol (18.9 g, 106 mmol) and KOH (6.7 g, 120 mmol) was added and the mixture stirred at 80° C. for 2.5 h. A little water was added and the mixture concentrated in vacuo. The residue was taken up in water and EA. The yield after work up was 30.9 g (100%; yellowish oil).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:15])[C:5]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].Br[C:17]1C=C(C)C(F)=C([CH:24]=1)C#N.C([O-])([O-])=O.[K+].[K+].N1C=NC=N1>CN(C=O)C.O>[CH3:15][C:4]1[C:5]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[C:6]([CH:9]=[C:2]([CH:17]=[CH2:24])[CH:3]=1)[C:7]#[N:8]
Reactant: Cc1cc(Br)cc(C#N)c1F
Reactant: Cc1cc(Br)cc(C#N)c1-n1cncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1nc[nH]n1
Solvent: CN(C)C=O
Solvent: O
Product: C=Cc1cc(C)c(-n2cncn2)c(C#N)c1
Temperature: 140 °C
Yield: 49 %

Procedure:
5-Bromo-3-methyl-2-(1H-1,2,4-triazol-1-yl)benzonitrile (DI71): To a stirred solution of 5-bromo-2-fluoro-3-methylbenzonitrile (1.0 g, 47.716 mmol), in DMF (10.0 mL) was added K2CO3 (1.95 g, 14.14 mmol) followed by 1H-1,2,4-triazole (0.811 g, 9.433 mmol) at ambient temperature. The reaction mixture was heated to 140° C. for 18 h. The reaction mixture was cooled to ambient temperature, diluted with water and extracted with EtOAc (2×100 mL). The combined EtOAc layer was washed with brine and dried over Na2SO4 and concentrated under reduced pressure to afford the crude compound purified by flash column chromatography (SiO2, 100-200 mesh; eluting with 30% EtOAc/pet ether) to afford the title compound as a pink solid (0.6 g, 49%): 1H NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 8.23 (s, 1H), 7.91 (d, J=2.4 Hz, 2H), 2.21 (s, 3H), ESIMS m/z 262.57 ([M+H]+); IR (thin film) 2231, 554 cm−1.
Reaction SMILES: C(O[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:15])=[O:7])(C)(C)C.[O:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:30]=[CH:29][C:25](C(O)=O)=[CH:24][CH:23]=2)[CH2:18][CH2:17]1>CN(C=O)C>[NH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[NH:8][C:6](=[O:7])[C:25]1[CH:24]=[CH:23][C:22]([N:19]2[CH2:18][CH2:17][O:16][CH2:21][CH2:20]2)=[CH:30][CH:29]=1
Reactant: O=C(O)c1ccc(N2CCOCC2)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Solvent: CN(C)C=O
Product: Nc1ccccc1NC(=O)c1ccc(N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 11.4 %

Procedure:
A solution of 1-(N-t-butoxycarbonylamino)-2-aminobenzene (Method 17; 104 mg, 0.5 mmol) in DMF (1.6 ml) was added to 4-morpholinobenzoic acid (149 mg, 0.5 mmol) followed by 4-(4,6-dimethoxy-1,3,5-triazinyl-2-yl)-4-methylmorpholinium chloride (Method 18, 138 mg, 0.5 mmol) and the reaction mixture stirred at ambient temperature for 48 hours. The solvent was removed in vacuo and the resultant residue partitioned between ethyl acetate and water. The organic phase was separated, then washed with water, brine and dried over sodium sulfate then filtered. The organic extracts were concentrated by half and a 4M solution of hydrogen chloride in 1,4-dioxane (1 ml) added. The reaction mixture was stirred at ambient temperature for a further 64 hours and the resultant precipitate was collected by filtration. This solid was purified by preparative mass triggered HPLC, eluting with an increasing gradient of acetonitrile in water (which contains 5% (v/v) of a 1% (v/v) solution of formic acid in methanol) to afford the title compound (17 mg, 12%); NMR Spectrum: (DMSO-d6) 3.25 (m, 4H), 3.76 (m, 4H), 4.83 (s, 2H), 6.60 (m, 1H), 6.79 (dd, 1H), 6.96 (m, 1H), 7.01 (d, 2H), 7.16 (dd, 1H), 7.90 (d, 2H), 9.31 (brs, 1H); Mass Spectrum: M+H+ 298.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17](O)=[O:18])[C:10](=[O:22])[CH:9]=2)[CH:7]=1.[CH3:25][C:26]1[O:30][C:29]([C:31]2[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=2)=[N:28][N:27]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17]([NH:35][C:34]3[CH:33]=[CH:32][C:31]([C:29]4[O:30][C:26]([CH3:25])=[N:27][N:28]=4)=[CH:37][CH:36]=3)=[O:18])[C:10](=[O:22])[CH:9]=2)[CH:7]=1
Reactant: Cc1nnc(-c2ccc(N)cc2)o1
Reactant: CCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Product: CCC(C(=O)Nc1ccc(-c2nnc(C)o2)cc1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
100 mg (0.29 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoic acid (racemate) and 76 mg (0.43 mmol, 1.5 eq.) of 4-(5-methyl-1,3,4-oxadiazol-2-yl)aniline were reacted according to General Method 7. The crude product was purified by normal phase chromatography (mobile phase: dichloromethane/methanol 1-10% mixtures). Yield: 144 mg (99% of theory)
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][S:9]([CH2:12][C:13]([O:15]C(C)(C)C)=[O:14])(=[O:11])=[O:10])(=[O:5])[C:2]([CH3:4])=[CH2:3].COC1C=CC(O)=CC=1.CCOC(C)=O>C(O)(C(F)(F)F)=O>[C:1]([O:6][CH2:7][CH2:8][S:9]([CH2:12][C:13]([OH:15])=[O:14])(=[O:11])=[O:10])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OCCS(=O)(=O)CC(=O)OC(C)(C)C
Agent: COc1ccc(O)cc1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: C=C(C)C(=O)OCCS(=O)(=O)CC(=O)O
Temperature: 55 °C
Reaction time: 3 h
Yield: 65.1 %

Procedure:
Pure 7 (1.2 g, 3.9 mmol) was dissolved in TFA (15 mL) under nitrogen. A trace amount of MEHQ was added to the mixture and the reaction was stirred for 3 hours at 55° C. Completion of the reaction was confirmed by TLC (EtOAc/Hex/TFA: 60:40:0.1% (v/v), Rf: 0.38). The reaction mixture was purified on a silica gel column (EtOAc/Hex, 3/2). 0.6 g (65% yield) 8 was obtained as yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[O:7][CH2:6][C:5]([CH2:20][N:21]2[CH:25]=[CH:24][N:23]=[C:22]2[N+:26]([O-:28])=[O:27])([CH2:8]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:4][O:3]1.C1N2CCOCCOCCN(CCOCCOCC2)CCOCCOC1.[F-:56].[K+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][C:2]1([CH3:29])[O:7][CH2:6][C:5]([CH2:8][F:56])([CH2:20][N:21]2[CH:25]=[CH:24][N:23]=[C:22]2[N+:26]([O-:28])=[O:27])[CH2:4][O:3]1
Reactant: [F-]
Reactant: Cc1ccc(S(=O)(=O)OCC2(Cn3ccnc3[N+](=O)[O-])COC(C)(C)OC2)cc1
Agent: C1COCCN2CCOCCOCCN(CCO1)CCOCCOCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1(C)OCC(CF)(Cn2ccnc2[N+](=O)[O-])CO1
Temperature: 25 °C
Yield: 48.2 %

Procedure:
30 mg (0.0705 mmol equivalents) of 2,2-dimethyl-5-[(2-nitro-1H-imidazol-1-yl)methyl]-5-(p-toluenesulfonyloxymethyl)-1,3-dioxane was dissolved in 1.0 mL of acetonitrile, 39.8 mg (0.106 mmol equivalents) of Kryptofix 222 (trade name, Merck), 5.1 mg (0.088 mmol equivalents) of potassium fluoride, and 2.0 mg (0.014 mmol equivalents) of potassium carbonate were added thereto, and the mixture was stirred under reflux by heating for 3 hours. After completion of the reaction, the reaction liquid was cooled to room temperature (25° C.), the solvent was then removed by distillation, and the obtained crude product was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (v/v)=2/1) to give 9.2 mg (0.034 mmol equivalents) of 2,2-dimethyl-5-fluoromethyl-5-[(2-nitro-1H-imidazol-1-yl)methyl]-1,3-dioxane.
Reaction SMILES: BrCCCCC(C)(C1C=CC(C)=CC=1)CO.[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([CH3:30])([CH3:29])[C:24](OCC)=[O:25].[Li+].[BH4-].CO>C(Cl)Cl>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([CH3:30])([CH3:29])[CH2:24][OH:25]
Reactant: CCOC(=O)C(C)(C)CCCCCBr
Agent: Cc1ccc(C(C)(CO)CCCCBr)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(CO)CCCCCBr
Yield: 101.4 %

Procedure:
According to the method for the synthesis of 206e, 205g (43.0 g, 0.16 mol) was treated with LiBH4 (5.55 g, 0.25 mol) and methanol (7.75 g, 0.24 mol) in CH2Cl2 (200 mL) to give 206g (36.2 g, 98%) as a colorless, viscous oil. 1H NMR (CDCl3): δ 3.41 (t, 2H, J=6.9), 3.30 (br. s, 2H), 1.90-1.84 (m, 3H), 1.42-1.22 (m, 6H), 0.86 (s, 6H). 13C NMR (CDCl3): δ 71.9, 38.6, 35.1, 34.1, 32.9, 29.2, 24.0, 23.2. HRMS (LSIMS, nba): Calcd for C9H18Br (MH+—H2O): 205.0592, found: 205.0563.