Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:12][C:13]([C:17]#[N:18])=[CH:14][C:15]=1[CH3:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]1([CH2:25][C:26]([NH:28][NH2:29])=O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)CCC>[CH2:1]([NH:8][C:9]([C:11]1[S:12][C:13]([C:17]2[N:18]=[C:26]([CH2:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[NH:28][N:29]=2)=[CH:14][C:15]=1[CH3:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNC(=O)Cc1ccccc1
Reactant: Cc1cc(C#N)sc1C(=O)NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: Cc1cc(-c2n[nH]c(Cc3ccccc3)n2)sc1C(=O)NCc1ccccc1
Temperature: 150 °C
Reaction time: 18 h
Yield: 43.6 %

Procedure:
A mixture of N-benzyl-5-cyano-3-methylthiophene-2-carboxamide (0.15 g, 0.59 mmol), phenylacetic hydrazide (0.09 g, 0.59 mmol) and potassium carbonate (0.12 g, 0.87 mmol) in 1-butanol (4 mL) was stirred in a sealed tube at 150° C. for 18 h. The reaction mixture was allowed to cool to ambient temperature and concentrated. The residue was purified by column chromatography (0-70% ethyl acetate in hexanes) to afford the title compound as a light yellow solid (0.10 g, 42%): mp 168-171° C.; 1H NMR (300 MHz, CDCl3) δ 7.40-7.18 (m, 12H), 6.20 (t, J=5.6 Hz, 1H), 4.57 (d, J=5.6 Hz, 2H), 4.11 (s, 2H), 2.47 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 162.8, 142.2, 137.8, 135.2, 130.7, 130.6, 129.0, 128.8, 128.8, 127.7, 127.6, 127.4, 44.1, 33.1, 15.9; MS (ES+) m/z 389.3 (M+1).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:9][C:10](=[O:12])[CH3:11])=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].Cl[CH2:14][C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=1)=[O:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:10]([NH:9][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:8][N:7]([CH2:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)=[O:16])[N:6]=1)(=[O:12])[CH3:11]
Reactant: O=C(CCl)Nc1cccc(F)c1
Reactant: CC(=O)Nc1n[nH]cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1nn(CC(=O)Nc2cccc(F)c2)cc1[N+](=O)[O-]
Temperature: 50 °C
Yield: 55 %

Procedure:
A mixture of N-(4-nitro-1H-pyrazol-3-yl)acetamide (0.380 g, 2.25 mmol), 2-chloro-N-(3-fluorophenyl)acetamide (0.420 g, 2.25 mmol) and potassium carbonate (00.370 g, 2.7 mmol) in dimethyl formamide (10 ml) was heated at 50° C. for 1 hour. The mixture was filtered and the filtrate was evaporated. The residue was triturated with a mixture of 2% methanol in dichloromethane and then with diethyl ether to give 2-[3-(acetylamino)-4-nitro-1H-pyrazol-1-yl]-N-(3-fluorophenyl)acetamide
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH3:17])([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CN(C(F)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH2:41]1[C:50]2[C:45](=[CH:46][C:47]([C:51]([O:53][CH3:54])=[O:52])=[CH:48][CH:49]=2)[CH2:44][CH2:43][NH:42]1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([C:14]([N:42]2[CH2:43][CH2:44][C:45]3[C:50](=[CH:49][CH:48]=[C:47]([C:51]([O:53][CH3:54])=[O:52])[CH:46]=3)[CH2:41]2)=[O:16])([CH3:17])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc2c(c1)CCNC2
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(=O)O)CC1
Agent: CN(C)C(F)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)CCN(C(=O)C1(C)CCN(C(=O)OC(C)(C)C)CC1)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.1 %

Procedure:
A solution of 1-(tert-butoxycarbonyl)-4-methylpiperidine-4-carboxylic acid (0.830 g, 3.41 mmol) and triethylamine (0.792 mL, 5.68 mmol) in DMF (11.0 mL) was treated with TFFH (1.13 g, 4.26 mmol). The resulting mixture was stirred at rt for 30 min and then methyl 1,2,3,4-tetrahydroisoquinoline-6-carboxylate hydrochloride (0.647 g, 2.84 mmol) and triethylamine (0.792 mL, 5.68 mmol) were added. The reaction mixture was stirred at rt for 2 days and then extracted with EtOAc three times. The combined organic phases were washed with water and brine, dried over Na2SO4, filtered and concentrated. Purification of the resulting residue by column chromatography (SiO2, 0-100% EtOAc in hexane) provided methyl 2-{[1-(tert-butoxycarbonyl)-4-methylpiperidin-4-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline-6-carboxylate (0.959 g, 82%). LC-MS: (FA) ES+ 439 (M+Na); 1H NMR (400 MHz, CDCl3) δ 7.85 (dd, J=10.1, 2.2 Hz, 2H), 7.19 (d, J=8.0 Hz, 1H), 4.79 (s, 2H), 3.95-3.77 (m, 5H), 3.67 (d, J=38.1 Hz, 2H), 3.21 (s, 2H), 2.92 (t, J=5.7 Hz, 2H), 2.24-2.10 (m, 2H), 1.61 (d, J=10.8 Hz, 1H), 1.44 (d, J=5.0 Hz, 10H), 1.33 (d, J=3.6 Hz, 3H).
Reaction SMILES: P([N:17]=[N+:18]=[N-:19])(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1.C1CCN2C(=NCCC2)CC1.[N:31]1[C:40]2[C:35](=[CH:36][C:37]([CH:41](O)[CH3:42])=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1>C1(C)C=CC=CC=1>[N:17]([CH:41]([C:37]1[CH:36]=[C:35]2[C:40](=[CH:39][CH:38]=1)[N:31]=[CH:32][CH:33]=[CH:34]2)[CH3:42])=[N+:18]=[N-:19]
Reactant: CC(O)c1ccc2ncccc2c1
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(N=[N+]=[N-])c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
In a 50 mL round bottom flask under N2 was dissolved diphenyl phosphorazidate (2.44 ml, 11.3 mmol), DBU (1.69 ml, 11.3 mmol) and 1-(quinolin-6-yl)ethanol (1.65 g, 9.53 mmol) (Prepared according to B. P. Lugovkin,/Zhurnal Obshchei Khimii 25 (1955) 392-397) in 20 mL of PhMe stirred at rt for 10 h. The crude mixture was directly purified by MPLC (ISCO) with Hexanes:AcOEt 100:0 to 0:100. MS m/z=199.2 [M+1]+. Calc'd for C11H10N4: 198.1.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:24](=[O:25])[N:11]3[N:12]=[CH:13][C:14]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=4)=[C:15](Cl)[C:10]3=[N:9]2)=[CH:5][CH:4]=1.[CH2:30]([OH:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CC(C)([O-])C.[K+]>CN1CCCC1=O.C1COCC1>[F:29][C:2]([F:28])([F:1])[C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:24](=[O:25])[N:11]3[N:12]=[CH:13][C:14]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=4)=[C:15]([O:37][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:10]3=[N:9]2)=[CH:26][CH:27]=1
Reactant: OCc1ccccc1
Reactant: O=c1n(Cc2ccc(C(F)(F)F)cc2)nc2c(Cl)c(-c3ccc(Cl)cc3)cnn12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: O=c1n(Cc2ccc(C(F)(F)F)cc2)nc2c(OCc3ccccc3)c(-c3ccc(Cl)cc3)cnn12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(4-(trifluoromethyl)benzyl)-8-chloro-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (20 mg, 46 μmol), prepared as described in Example 361, in 1-methylpyrrolidone (1 mL) in a 1 dram vial was added benzyl alcohol (10.8 mg, 100 μmol), and 1M solution of potassium t-butoxide in THF (100 uL). The reaction vessel was capped and stirred at room temperature for 16 h. Reaction mixture was quenched with 100 uL of methanol, filtered through a Whatman 0.45 μm syringe filter and the crude product was purified using preparative HPLC (Xterra MS-C18, 30×50 mm); Eluted with 10% to 100% B, 8 min gradient, (A=water+0.1% TFA and B=acetonitrile+0.1% TFA); Flow rate at 30 mL/min. UV detection at 220 nm) to give the title compound 2-(4-(Trifluoromethyl)benzyl)-8-(benzyloxy)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one. (4.9 mg, 16% yield), as a yellow crystalline solid. MS (M+H)=511; 1H NMR MeOD: δ 8.25 (1H, s), 7.60-7.7 (4H, m), 7.47-7.55 (4H, m), 7.13-7.31 (5H, m), 5.81 (2H, s), 5.39 (2H, s). Analytical HPLC purity: 99% at 2.31 min (retention time), (Xterra MS-C18, 4.6×50 mm); Eluted with 10% to 100% B, 4.5 min gradient, (A=water+0.1% TFA and B=acetonitrile+0.1% TFA); Flow rate at 2.5 mL/min. UV detection at 220 nm.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH3:15].[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(NC(C)C)(C)C.CN(C)C=O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Na+].[Na+].[Na+].P(C1C=C(S([O-])(=O)=O)C=CC=1)(C1C=C(S([O-])(=O)=O)C=CC=1)C1C=C(S([O-])(=O)=O)C=CC=1.C(OCC)(=O)C.O>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[C:7]3[C:3]=2[CH:4]=[CH:5][N:6]3[CH3:15])=[CH:19][CH:18]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: COC(=O)c1cc(Br)c2ccn(C)c2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=S(=O)([O-])c1cccc(P(c2cccc(S(=O)(=O)[O-])c2)c2cccc(S(=O)(=O)[O-])c2)c1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: COC(=O)c1cc(-c2ccc(F)cc2)c2ccn(C)c2c1
Temperature: 80 °C
Yield: 85.6 %

Procedure:
To a mixture of methyl 4-bromo-1-methyl-1H-indole-6-carboxylate (0.45 g, 1.69 mmol), (4-fluorophenyl)-boronic acid (0.36 g, 2.53 mmol), 3,3′,3″-phosphinidynetris (benzensulfonic acid) trisodium salt (81.0 mg, 0.13 mmol), palladium(II) acetate (9.5 mg, 0.04 mmol) and diisopropylamine (0.60 mL, 4.22 mmol) were added N,N-dimethylformamide (6.3 mL) and water (2.1 mL). The mixture was heated to 80° C. for 1 h. The mixture was cooled to ambient temperature and ethyl acetate was added. The organic layer was washed with water (3×10 mL), saturated aqueous sodium chloride (1×10 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (100% hexanes→50% hexanes/ethyl acetate) gave the title compound (0.41 g): LC-MS [M+1]=284.1.
Reaction SMILES: [P:1]([CH2:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]([OH:17])=[O:16])[CH:10]=1)=[O:7])([OH:4])([OH:3])=[O:2]>O.[Pt]=O>[P:1]([CH2:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH:11]([C:15]([OH:17])=[O:16])[CH2:10]1)=[O:7])([OH:3])([OH:4])=[O:2]
Reactant: O=C(CP(=O)(O)O)Nc1ccnc(C(=O)O)c1
Agent: O=[Pt]
Solvent: O
Product: O=C(CP(=O)(O)O)NC1CCNC(C(=O)O)C1

Procedure:
A solution of 200 mg of 4-(α-phosphonoacetamido)-picolinic acid in 50 ml of water is hydrogenated over 1.0 g of platinum oxide at 3 atmospheres pressure for 8 hours. After filtration and evaporation to dryness the residue is triturated with ethanol to afford 4-(α-phosphonoacetamido)-piperidine-2-carboxylic acid as a mixture of cis and trans isomers.
Reaction SMILES: [F:1][C:2]([F:19])([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][C@H:4]([N:9]=[C:10]=[O:11])[C:5]([O:7][CH3:8])=[O:6].FC(F)(F)C(O)=O.[CH2:27]1[C:29]2([CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH2:28]1>>[CH2:28]1[C:29]2([CH2:34][CH2:33][N:32]([C:10]([NH:9][C@@H:4]([CH2:3][C:2]([F:19])([F:1])[CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:5]([O:7][CH3:8])=[O:6])=[O:11])[CH2:31][CH2:30]2)[CH2:27]1
Reactant: COC(=O)[C@H](CC(F)(F)Cc1ccccc1)N=C=O
Reactant: C1CC2(CCN1)CC2
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H](CC(F)(F)Cc1ccccc1)NC(=O)N1CCC2(CC1)CC2

Procedure:
Methyl (S)-2-[(6-azaspiro[2.5]octane-6-carbonyl)amino]-4,4-difluoro-5-phenylpentanoate was prepared analogously to example 61, starting from 904 mg of methyl (S)-4,4-difluoro-2-isocyanato-5-phenylpentanoate (3.36 mmol) and 907 mg of 6-azaspiro[2.5]octane trifluoroacetate (1.2 eq.). Chromatographic separation by preparative HPLC (gradient: acetonitrile/water and addition of 0.05% TFA) gave methyl (S)-2-[(6-azaspiro[2.5]octane-6-carbonyl)amino]-4,4-difluoro-5-phenylpentanoate as a yellow oil. Yield: 234 mg (18% of theory)
Reaction SMILES: O[C@H:2]([CH3:15])[C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)=[O:4].CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[NH2:47][C:48]([CH3:52])([CH3:51])[CH2:49][OH:50]>C(#N)C>[CH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[CH:14][C:5]=1[C@:3]1([OH:4])[O:50][CH2:49][C:48]([CH3:52])([CH3:51])[NH:47][C@H:2]1[CH3:15]
Reactant: CC(C)(N)CO
Reactant: C[C@@H](O)C(=O)c1ccc2ccccc2c1
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Product: C[C@@H]1NC(C)(C)CO[C@@]1(O)c1ccc2ccccc2c1
Yield: 62.4 %

Procedure:
Compound 4r was synthesized by a procedure similar to that described for (2S,3S)-4a using (R)-2-hydroxy-1-(naphthalen-2-yl)propan-1-one (10i, 2.5 g, 0.013 mol), Proton sponge (3.24 g, 0.0151 mol), triflic anhydride (2.4 mL, 137 mmol), and 2-amino-2-methyl-1-propanol (2.4 g, 0.027 mol) in acetonitrile (40 mL). After purification, 2.2 g (65%) of the free base 4r was isolated and converted to the hemi-D-tartrate salt: mp 179-180° C.; [α]20D −1.5° (c 0.55, CH3OH); 1H NMR (methanol-d4) δ 8.13-8.12 (m, 1H), 7.95-7.88 (m, 3H), 7.75-7.71 (m, 1H), 7.57-7.50 (m, 2H), 4.33 (s, 1H), 4.25 (d, 1H, J=11.9 Hz), 3.66-3.57 (m, 2H), 1.65 (s, 3H), 1.37 (s, 3H), 1.09 (d, 3H, J=6.6 Hz); 13C NMR (methanol-d4) δ 178.7, 139.9, 135.3, 134.6, 129.8, 129.33, 129.00, 128.0, 127.8, 127.4, 125.4, 97.4, 75.2, 67.7, 55.1, 24.5, 21.6, 14.6; LCMS (ESI) m/z 272.5 [(M-tartrate)+, M=C19H24NO5]; Anal. (C19H24NO5.0.5H2O) calcd: C, 65.88; H, 6.98; N, 4.04. found: C, 65.75; H, 7.03; N, 4.06.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:11](Cl)(=[O:13])=[O:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[OH-].[NH4+:16]>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([S:11]([NH2:16])(=[O:13])=[O:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: [NH4+]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1F
Agent: [OH-]
Solvent: CC#N
Product: NS(=O)(=O)c1ccc([N+](=O)[O-])c(F)c1
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a solution of 5.00 g 3-fluoro-4-nitrobenzenesulfonyl chloride in 20 mL acetonitrile cooled in an ice bath was added dropwise 4.40 mL of a 30% ammonium hydroxide solution. After removal of the ice bath, stirring was continued for 30 min. at room temperature. Water was added and the mixture was extracted with DCM. The combined organic layers were dried over MgSO4 and evaporated to dryness to give 4.65 g (99%) of a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 7.51 (s, 2H), 7.89 (d, J=9.33 Hz, 1H), 7.92 (dd, J=10.23, 1.81 Hz, 1H), 8.14-8.21 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5](Cl)=[N:6][CH:7]=1.[F:10][C:11]([F:18])([F:17])[C:12]1[CH:13]=[N:14][NH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([N:14]2[CH:13]=[C:12]([C:11]([F:18])([F:17])[F:10])[CH:16]=[N:15]2)=[N:6][CH:7]=1
Reactant: Cc1cc(Br)cnc1Cl
Reactant: FC(F)(F)c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Br)cnc1-n1cc(C(F)(F)F)cn1
Temperature: 107.5 °C
Yield: 30 %

Procedure:
A flask was charged with 5-bromo-2-chloro-3-methylpyridine (250 mg, 1.21 mmol), 4-(trifluoromethyl)-1H-pyrazole (165 mg, 1.21 mmol), potassium carbonate (512 mg, 3.63 mmol), and anhydrous dimethylformamide (1.21 mL). The reaction was heated at 85 to 130° C. for 36 h. The reaction was concentrated to give 690 mg of crude material. Purification by silica gel flash chromatography (0-5% ethyl acetate in heptane) afforded 5-bromo-3-methyl-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridine (containing approximately 30% starting material) was carried forth to the next reaction. MS (M+1) 308.1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[NH:13][C:12](=S)[CH2:11][N:10]=[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])[C:8]=2[CH:22]=1)([O-:3])=[O:2].[OH:23][CH2:24][C:25]([NH:27][NH2:28])=O>C(O)CCC>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:25]([CH2:24][OH:23])=[N:27][N:28]=[C:12]3[CH2:11][N:10]=[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])[C:8]=2[CH:22]=1)([O-:3])=[O:2]
Reactant: NNC(=O)CO
Reactant: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1F)=NCC(=S)N2
Solvent: CCCCO
Product: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1F)=NCc1nnc(CO)n1-2

Procedure:
In the manner given in Preparation 1, a solution of 1,3-dihydro-7-nitro-5-(o-fluorophenyl)-2H-1,4-benzodiazepine-2-thione in n-butyl alcohol is heated to reflux with hydroxyacetic acid hydrazide to give 8-nitro-1-(hydroxymethyl)-6-(o-fluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine. Preparation 4 8-(Trifluoromethyl)-1-(hydroxymethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine
Reaction SMILES: [NH2:1][C@@H:2]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[C:3]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)[OH:4].[CH3:27][O:28][B:29](OC)OC>O1CCCC1>[CH:21]1([C@H:2]2[C:3]([C:5]3[CH:6]=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=3)([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[O:4][B:29]([O:28][CH3:27])[NH:1]2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: COc1ccc(C(O)(c2ccc(OC)cc2)[C@@H](N)C2CCCCC2)cc1
Reactant: COB(OC)OC
Solvent: C1CCOC1
Product: COB1N[C@@H](C2CCCCC2)C(c2ccc(OC)cc2)(c2ccc(OC)cc2)O1
Reaction time: 1.5 h

Procedure:
(S)-2-amino-2-cyclohexyl-1,1-bis-(4-methoxyphenyl)ethanol (71.1 mg, 0.2 mmol), dry tetrahydrofuran (2 mL) and trimethylborate (27.2 μL, 0.24mmol) were added to a dry flask and stirred under an atmosphere of nitrogen for 1.5 hours to form a solution of (S)-4-cyclohexyl-5,5-bis-(4-methoxyphenyl)-2-methoxy-1,3,2-oxazaborolidine. Borane dimethylsulfide complex (100 μL, 1.0 mmol) was added to this solution and the mixture was stirred at room temperature for a further 30 minutes. A solution of 3,5-(bistrifluoromethyl)-acetophenone (180 μL, 1.0 mmol) in tetrahydrofuran (3 mL) was added by means of a syringe pump at a rate of 9 mL/min and the reaction then stirred for a further 1.5 hours. Thin layer chromatography (silica gelhexane/ethyl acetate 4:1) showed no starting material. The reaction was quenched by addition of methanol. The solvent was evaporated under vacuum and the residue was dissolved in ethyl acetate and washed 3 times with 1N HCl. The ethyl acetate solution was dried over magnesium sulfate, filtered through a plug of silica gel and concentrated to give (R)-1-[3,5-(bistrifluoromethyl)phenylethanol. The enantiomer ratio was determined by HPLC using a Chiralcel OD 25 cm×4.6 mm column with hexane/2-propanol (97: 3) mobile phase at 0.7 mL/min at 25° C. Detection with UV was at 254 nm.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12](=[O:15])[CH2:13][CH3:14])=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]1=[O:16].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1C=CC=CC=1>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12](=[O:15])[CH2:13][CH3:14])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]1=[O:16]
Reactant: CCC(=O)c1ccc2c(c1)CCC(=O)N2C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: c1ccccc1
Product: CCC(=O)c1ccc2c(ccc(=O)n2C)c1
Yield: 39 %

Procedure:
A solution of 1-methyl-2-oxo-6-propionyl-1,2,3,4-tetrahydroquinoline (20 g) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (20.9 g) in benzene (250 ml) was refluxed for 1 day. The mixture was filtered by suction and evaporated. The residue was chromatographed on silica gel (400 g) with a mixture of benzene and ethyl acetate (1:1) as an eluent. The eluates were concentrated to give an oil of 1-methyl-2-oxo-6-propionyl-1,2-dihydroquinoline (7.72 g).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15](Br)[N:14]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)#[N:2].[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:1]([CH2:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:14]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)#[N:2]
Reactant: N#CCc1cccc(NC(=O)c2cccc(Br)n2)c1
Reactant: OB(O)c1ccccc1
Product: N#CCc1cccc(NC(=O)c2cccc(-c3ccccc3)n2)c1

Procedure:
The pyridyl bromide (91) (150 mg, 0.47 mmol) was coupled to phenylboronic acid (64 mg, 0.52 mmol) using Method E. The crude residue was purified by column chromatography eluting with 20% EtOAc in heptane to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([N+:17]([O-])=O)[C:11]=2[N:10]=[C:9]1[CH2:20][CH2:21][CH3:22])([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:23])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([NH2:17])[C:11]=2[N:10]=[C:9]1[CH2:20][CH2:21][CH3:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCc1nc2c([N+](=O)[O-])cccc2n1CC(=O)OC(C)(C)C
Agent: [Pd]
Product: CCCc1nc2c(N)cccc2n1CC(=O)OC(C)(C)C

Procedure:
The sub-title compound was prepared by the method of example 1, step c.) using (4-nitro-2-propyl-benzoimidazol-1-yl)-acetic acid tert-butyl ester (regioisomer 2) from step b.) and 10% Pd/C and was used in crude form without purification. MS: ESI (positive): 290 (M+H).
Reaction SMILES: [CH2:1]([SH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:9][OH:10]>>[CH2:1]([S:8][C:1]1[C:9](=[O:10])[CH2:4][CH2:3][CH:2]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCS
Reactant: CO
Product: CCCCCCCSC1=CCCC1=O
Yield: 49 %

Procedure:
Cyclopentenone (3.40 g) was oxidized in 15 ml of methanol using 4.4 ml of an aqueous solution of hydrogen peroxide and 4 ml of a 3 N aqueous solution of sodium hydroxide to afford crude 2,3-epoxycyclopentanone. To the crude product was added dropwise slowly 30 ml of a solution of 3.20 g of n-heptylmercaptan in methanol at room temperature over the course of 1.5 hours. Thirty minutes after the end of addition, the reaction mixture was concentrated under reduced pressure, and diethyl ether was added. The organic layer was washed with water, and treated in a customary manner to afford 5.21 g of a crude product. The crude product was chromatographed with cyclohexane/ethyl acetate (=8/2) to afford 2.50 g of 2-n-heptylthiocyclopent-2-en-1-one in a yield of 49%. The product had the following characteristics.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[N:8][N:9]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:19]([F:28])([C:24]([F:27])([F:26])[F:25])[C:20]([F:23])([F:22])[F:21])[CH:16]=3)[NH:11][C:10]2=[O:29])[CH:2]=1.[H-].[Na+].[C:32](OC(=O)C)(=[O:34])[CH3:33]>CC(N(C)C)=O>[C:32]([N:11]1[C:12]2[C:17](=[CH:16][C:15]([C:19]([F:28])([C:24]([F:25])([F:26])[F:27])[C:20]([F:22])([F:21])[F:23])=[CH:14][CH:13]=2)[CH2:18][N:9]([N:8]=[CH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[C:10]1=[O:29])(=[O:34])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1Nc2ccc(C(F)(C(F)(F)F)C(F)(F)F)cc2CN1N=Cc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(=O)N1C(=O)N(N=Cc2cccnc2)Cc2cc(C(F)(C(F)(F)F)C(F)(F)F)ccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
In 10 ml of dimethylacetamide was dissolved 0.84 g (1.8 mmol) of 3-(3-pyridylmethylideneamino)-3,4-dihydro-6-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-2(1H)-quinazolinone, and to the resulting solution was added 0.09 g (2.3 mmol) of sodium hydride (purity: 62.4%). The reaction was carried out at room temperature for 30 minutes, after which 0.25 g (2.4 mmol) of acetic anhydride was added and the reaction was carried out for 4 hours. After completion of the reaction, the reaction solution was poured into ice water and the desired compound was extracted with ethyl acetate (20 ml×3). The extract solution was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated in vacuo. The crude product thus obtained was purified by silica gel column chromatography (ethyl acetate−methanol=10:1) to obtain 0.78 g of the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Cl.Br[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.C(COC)OC.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.C1(P(CCCC[Pd-](Cl)Cl)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:5][CH:4]=1
Reactant: Brc1ccncc1
Reactant: COc1ccc(B(O)O)cc1
Agent: Cl[Pd-](Cl)CCCCP(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ccncc2)cc1
Temperature: 85 °C
Reaction time: 1.5 h

Procedure:
A mixture of 4-methoxybenzene boronic acid (2 g, 13.15 mmol), 4-bromopyridine hydrochloride (3.84 g, 19.72 mmol), diphenylphosphinobutylpalladium (II) dichloride (100 mg), dimethoxyethane (50 ml) and 2M sodium carbonate solution (30 ml) were stirred at 85° C. for 1.5 hours under a nitrogen atmosphere. The solution was allowed to cool to ambient temperature, diluted with ethyl acetate (150 ml) and washed with water (150 ml). The aqueous layer was extracted with ethyl acetate (2×100 ml). The combined organic layers were dried over sodium sulphate and the solvents were removed leaving a white solid, which was chromatographed on silica gel in 70-100% ethyl acetate/hexane giving the title compound as a white solid (1.95 g, 80%). 1H NMR (250 MHz, CDCl3) δ 8.66-8.63 (2H, d, J=6.2 Hz), 7.63-7.59 (2H, d, J=9.0 Hz), 7.50-7.47 (2H, d, J=6.2 Hz), 7.03-6.99 (2H, d, J=9.0 Hz), and 3.87 (3H, s). m/z (ES+) 186 (M+1).