Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4](=[O:13])[NH:5][C:6]([CH3:12])=[CH:7][C:8]=1[CH2:9][CH2:10]C.[CH3:14]C(C)/C=C/C(=O)C>>[NH2:1][CH2:2][C:3]1[C:4](=[O:13])[NH:5][C:6]([CH3:12])=[CH:7][C:8]=1[CH:9]([CH3:10])[CH3:14]
Reactant: CC(=O)/C=C/C(C)C
Reactant: CCCc1cc(C)[nH]c(=O)c1CN
Product: Cc1cc(C(C)C)c(CN)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described for 3-(aminomethyl)-6-methyl-4-propyl-2(1H)-pyridinone (Intermediate 2, steps 1 and 2) from (3E)-5-methyl-3-hexen-2-one (20 g, 137 mmol). LCMS E-S (M+H)=181.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.8-11.9 (br s, 1H), 7.86-7.96 (br s, 3H), 6.10 (s, 1H), 3.82-3.86 (m, 2H), 3.02-3.09 (m, 1H), 2.17 (s, 3H), 1.08 (d, 6H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.[CH3:6][Si:7](Cl)([CH3:9])[CH3:8]>C1C=CC=CC=1>[Si:7]([C:5]1[N:1]=[N:2][NH:3][CH:4]=1)([CH3:9])([CH3:8])[CH3:6]
Reactant: c1c[nH]nn1
Reactant: C[Si](C)(C)Cl
Solvent: c1ccccc1
Product: C[Si](C)(C)c1c[nH]nn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1H-1,2,3-triazole (4.98 g, 72.10 mmol, 1 equiv.) in dry benzene (145 mL) at rt under nitrogen, is added TEA (11.05 mL, 79.31 mmol, 1.1 equiv.) followed by the dropwise addition of TMSCl (9.15 mL, 72.10 mmol, 1 equiv.). A white precipitate develops. Reaction mixture is stirred at rt under nitrogen for 1 hour. The resultant precipitate is removed by filtration and washed thoroughly with dry benzene. The filtrate is gently concentrated to avoid evaporating the highly volatile product to give a quantitative yield of TMS-triazole with a trace of benzene.
Reaction SMILES: [CH2:1]=O.[C:3]1([N:9]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11]3[CH2:18][CH2:19][NH:20][CH2:21][CH2:22][C:10]2=3)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>[Ni].C(O)C>[CH3:1][N:20]1[CH2:19][CH2:18][C:11]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[N:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:10]=2[CH2:22][CH2:21]1
Reactant: C=O
Reactant: c1ccc(-n2c3c(c4ccccc42)CCNCC3)cc1
Agent: [Ni]
Solvent: CCO
Product: CN1CCc2c(n(-c3ccccc3)c3ccccc23)CC1

Procedure:
19.8 ml of a 35% formaldehyde solution and a spoonful of Raney Nickel are added to 20.4 g 1,2,3,4,5,6-hexahydro-6-phenylazepino[4,5-b]indole in 385 ml ethanol. The mixture is hydrogenated at room temperature. The mixture is then filtered and the filtrate concentrated to give a residue which is partitioned between ether and water. The ether phase is dried over sodium sulphate and concentrated to give the title compound as an oil which is converted into the hydrochloride, m.p. 236°-238° (from ether/ethanol).
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[S:11][C:7]=2[C:6]([OH:18])=[C:5]([C:19]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:20])[N:4]=1)#[CH:2].S(=O)(=O)(O)[OH:27]>CC(C)=O.S([O-])([O-])(=O)=O.[Hg+2]>[C:1]([C:3]1[C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[S:11][C:7]=2[C:6]([OH:18])=[C:5]([C:19]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:20])[N:4]=1)(=[O:27])[CH3:2]
Reactant: C#Cc1nc(C(=O)NCC(=O)O)c(O)c2sc(-c3ccccc3)nc12
Reactant: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Hg+2]
Solvent: CC(C)=O
Product: CC(=O)c1nc(C(=O)NCC(=O)O)c(O)c2sc(-c3ccccc3)nc12
Temperature: 25 °C
Yield: 43.1 %

Procedure:
A mixture of [(4-ethynyl-7-hydroxy-2-phenyl-thiazolo[4,5-c]pyridine-6-carbonyl)-amino]-acetic acid (52 mg, 0.15 mmole), mercury sulfate (44 mg, 0.15 mmole), concentrated sulfuric acid (19 mg, 0.19 mmole) in 80% aqueous acetone (1.6 ml) was refluxed for 2 h before it was cooled to room temperature and concentrated. The residue was washed with water and filtered. The remaining solid was dissolved in 0.5 N NaOH (15 ml) and extracted with dichloromethane (2×20 ml). The remaining aqueous layer was acidified with 1N HCl (8 ml) to pH=2. The suspension was extracted with ethyl acetate (20 ml) and dichloromethane (20 ml). The organic layer was combined, concentrated and purified by column chromatography on a C18 column with a gradient of water and acetonitrile in formic acid to give the title compound as a yellow solid (24 mg): MS: (+) m/z 372.24 (M+1), MS: (−) m/z 370.27 (M−1).
Reaction SMILES: [I:1]Cl.[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([S:12]([Cl:15])(=[O:14])=[O:13])=[CH:11][C:6]=2[CH2:5][CH2:4]1.C(#N)C>C(Cl)Cl>[I:1][C:8]1[C:7]2[O:3][CH2:4][CH2:5][C:6]=2[CH:11]=[C:10]([S:12]([Cl:15])(=[O:13])=[O:14])[CH:9]=1
Reactant: ClI
Reactant: O=S(=O)(Cl)c1ccc2c(c1)CCO2
Solvent: CC#N
Solvent: ClCCl
Product: O=S(=O)(Cl)c1cc(I)c2c(c1)CCO2
Temperature: 25 °C
Yield: 100.9 %

Procedure:
A solution of ICl (7.7 g, 47 mmol) in DCM (100 mL) was added dropwise to a solution of 2,3-dihydro-benzofuran-5-sulfonyl chloride (5 g, 23 mmol; Intermediate 54) in DCM (100 mL) at reflux temperature under nitrogen atmosphere. The reaction was heated at reflux overnight. The reaction mixture was cooled at room temperature and acetonitrile (50 mL) was added. The resultant mixture was washed with a saturated solution of NaHCO3 and the organic phase was separated followed by elimination of the volatiles under vacuum to give 8 g of brown oil which was used to the next step without further purification. 1H NMR 270 MHz (CDCl3) δ ppm 3.45 (t, J=8.91 Hz, 2H) 4.82 (t, J=8.91 Hz, 2H) 7.79 (d, J=1.48 Hz, 1H) 8.16 (d, J=1.98 Hz, 1H).
Reaction SMILES: [NH2:1][C@H:2]([CH2:7][OH:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[H-].[Na+].Cl[CH2:12][C:13]([CH3:15])=[CH2:14]>C1COCC1>[CH3:14][C:13](=[CH2:12])[CH2:15][O:8][CH2:7][C@@H:2]([NH2:1])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)C[C@H](N)CO
Reactant: C=C(C)CCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C(C)COC[C@@H](N)CC(C)C
Temperature: 50 °C
Reaction time: 2 h
Yield: 69.4 %

Procedure:
To a solution of L-leucinol (20.0 g, 0.17 mol) in an anhydrous THF (200 mL) was portionwise added 60% NaH (7.92 g, 0.198 mol). The resulting mixture was stirred for 30 min. at room temperature and further for 2 hours at 50° C. The mixture was then cooled to room temperature. To the resulting suspension was dropwise added a solution of 3-chloro-2-methylpropene (15.45 g, 0.17 mol) in an anhydrous THF (50 mL). The resulting mixture was stirred for 20 hours at room temperature. The THF was distilled off under reduced pressure. To the residue were successively added a mixture of ice and water and diethyl ether. The mixture was stirred for 5 min. at room temperature, and the organic portion was separated. The aqueous portion was subjected to extraction with diethyl ether. The extract was combined with the organic portion. The combined organic portion was washed with 1 mol/L aqueous hydrochloric acid (7 mL) and subjected to extraction with 1 mol/L aqueous hydrochloric acid (153 mL). The resulting hydrochloric acid extract was made to approx. pH 10 by addition of potassium carbonate and subjected to extraction with diethyl ether. The organic portion was washed with water, dried over sodium sulfate, and placed under reduced pressure to distill the solvent off. There was obtained the titled compound (20.22 g, 69.2%) as an oily product.
Reaction SMILES: [C:1]([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])[C@H:7]([C:16]([OH:18])=O)[CH2:6]1)(=[O:3])[CH3:2].[NH2:19][C:20]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:21]=1[C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23].C(OC1C=CC2C(=CC=CC=2)N1C(OCC)=O)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])[C@H:7]([C:16](=[O:18])[NH:19][C:20]2[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:21]=2[C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: C=CCOC(=O)c1c(C)cccc1N
Reactant: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1C(=O)O
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=CCOC(=O)c1c(C)cccc1NC(=O)[C@@H]1C[C@H](SC(C)=O)CN1C(=O)OCC=C
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.1 %

Procedure:
(2S,4S)-4-Acetylthio-1-allyloxycarbonyl-2-carboxypyrrolidine (2.3 g, 8.6 mM), allyl 2-amino-6-methylbenzoate (1.5 g, 7.8 mM), and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (2.5 g, 10 mM) were dissolved in toluene (30 ml) and stirred for 18 hours at ambient temperature. The reaction mixture was diluted with ethyl acetate (150 ml) and washed with a 2M aqueous solution of HCl (3 by 30 ml), water, a saturated aqueous solution of NaHCO3, and brine. Drying over MgSO4 and evaporation of the solvent gave (2S,4S)-4-acetylthio-1-allyloxycarbonyl-2-(2-allyloxycarbonyl-3-methylphenylcarbamoyl)pyrrolidine as a gum (3.4 g, 97%) which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH:10]([N:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1)[CH3:11])([CH3:4])([CH3:3])[CH3:2].[NH2:20][CH2:21][C:22]1[N:27]=[C:26]([C:28]#[N:29])[CH:25]=[CH:24][CH:23]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH:10]([N:12]1[CH2:17][CH2:16][CH:15]([NH:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[C:26]([C:28]#[N:29])[N:27]=2)[CH2:14][CH2:13]1)[CH3:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1cccc(CN)n1
Reactant: CC(CCNC(=O)OC(C)(C)C)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(CCNC(=O)OC(C)(C)C)N1CCC(NCc2cccc(C#N)n2)CC1
Yield: 77 %

Procedure:
Using general procedure A, [3-(4-oxo-piperidin-1-yl)-butyl]-carbamic acid tert-butyl ester (0.361 g, 1.34 mmol), 6-aminomethyl-pyridine-2-carbonitrile (0.178 g, 1.34 mmol), sodium triacetoxyborohydride (0.425 g, 2.01 mmol) and acetic acid (0.2 ml, cat.) in CH2Cl2 (15 ml) at rt for 16 h gave the crude product as a pale yellow oil. Purification by column chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 86:12:2, v/v/v) afforded (3-{4-[(6-cyano-pyridin-2-ylmethyl)-amino]-piperidin-1-yl}-butyl)-carbamic acid tert-butyl ester (0.400 g, 77%) as a colorless oil. 1H NMR (CDCl3) δ 0.93 (d, 3H, J=6.0 Hz), 1.40 (s+m, 13H), 1.65 (m, 1H), 1.92 (m, 2H), 2.13 (br t, 1H, J=9.0 Hz), 2.45 (m, 2H), 2.69-2.81 (m, 3H), 3.07 (m, 1H), 3.30 (m, 1H), 3.97 (s, 2H), 5.95 (br s, 1H), 7.56 (d, 1H, J=9.0 Hz), 7.59 (d, 1H, J=9.0 Hz), 7.77 (t, 1H, J=7.5 Hz).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[C:16]([CH3:23])[CH:15]=1.[C:24](=O)([O:27]C)[O:25]C>C1COCC1>[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[C:16]([CH2:23][C:24]([OH:27])=[O:25])[CH:15]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: COC(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(O)Cc1cc(Br)ccc1C(=O)O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 93.8 %

Procedure:
To a solution of diisopropylamine (13.26 mL, 93 mmol, 4.0 equiv.) in THF (50 mL) was slowly added n-BuLi (37.2 mL, 93 mmol, 4.0 equiv.) at −78° C. The mixture was allowed to warm to 0° C. and stirred at that temperature for 5 min. The reaction was cooled back to −78° C. and to this mixture was slowly added 4-bromo-2-methylbenzoic acid (5.0 g, 23.25 mmol) and dimethyl carbonate (3.91 mL, 46.5 mmol, 2.0 equiv.) in THF (50 mL) and the mixture was stirred at −78° C. for 5 min. The dry ice bath was removed and the reaction was allowed to stir at room temperature for 4 h. Upon completion of the reaction, the mixture was quenched by the addition of 75 mL water and allowed to stir overnight. The aqueous layer was separated from the organic layer. The aqueous layer was acidified with conc. HCl until pH 2, extracted with EtOAc (2×50 mL), dried over Na2SO4, filtered and evaporated to dryness to yield a white solid. The solid was recrystallized from hot EtOAc/hexanes to yield 5.65 g of 4-bromo-2-(carboxymethyl)benzoic acid as a white solid.
Reaction SMILES: [CH:1]1([CH2:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[O-:21][C:22]#[N:23].[Na+]>C(O)(=O)C.O>[CH:1]1([CH2:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:16][CH2:17][N:18]([C:22]([NH2:23])=[O:21])[CH2:19][CH2:20]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C2CCNCC2)cc1CC1CCCC1
Reactant: N#C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(C2CCN(C(N)=O)CC2)cc1CC1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4-(3-cyclopentylmethyl-4-methoxyphenyl)piperidine (1.8 mmol, 0.500 g) in acetic acid (5 mL) was added a solution of sodium cyanate (10.8 mmol, 0.702 g) in water (15 mL) dropwise over 20 minutes at room temperature. The resulting solution was stirred at room temperature overnight, after which the acetic acid was removed in vacuo. The residue was partitioned between EtOAc (200 mL) and H2O (200 mL). The aqueous phase was extracted with EtOAc (1×200 mL), the combined organics dried (Na2SO4), concentrated in vacuo and purified by flash chromatography (SiO2 ; EtOAc) to give the title compound as a white solid, mp=168°-169° C. (0.5 mmol, 1.054 g, 27%).
Reaction SMILES: Br[C:2]1[S:15][C:5]2[C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:17]=1>>[S:15]1[C:5]2[C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[CH:3]=[C:2]1[C:18]1[CH:17]=[N:16][CH:21]=[CH:20][CH:19]=1
Reactant: CC1(C)OB(c2cccnc2)OC1(C)C
Reactant: Brc1cc2c(s1)-c1ccccc1OCC2
Product: c1cncc(-c2cc3c(s2)-c2ccccc2OCC3)c1

Procedure:
2-Bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine from Example 73 was reacted with 3-pyridine boronic acid pinacol ester using standard Suzuki coupling procedure. Purification on silica gave 152. 1H NMR (400 MHz, CDCl3): 3.29 (2H, t), 4.39 (2H, t), 7.05-7.10 (2H, m), 7.18-7.22 (2H, m), 7.32-7.35 (1H, m), 7.74 (1H, dd), 7.89 (1H, dt), 8.55 (1H, dd), 8.91 (1H, s). MS: (ESI+) 280
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]#[C:6][Li].ClCCCC#C.C([Li])CCC.[CH:19]([B:23](OC(C)C)[O:24][CH:25]([CH3:27])[CH3:26])([CH2:21][CH3:22])[CH3:20].Cl.C(OCC)C>O1CCCC1>[CH:19]([B:23]([C:6]#[C:5][CH2:4][CH2:3][CH2:2][Cl:1])[O:24][CH:25]([CH3:27])[CH3:26])([CH2:21][CH3:22])[CH3:20]
Reactant: [Li]C#CCCCCl
Reactant: CCC(C)B(OC(C)C)OC(C)C
Agent: C#CCCCCl
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(C)B(C#CCCCCl)OC(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a tetrahydrofuran (THF) solution of 5-chloro-1-pentynyllithium prepared from 5-chloro-1-pentyne (5.43 g, 53 mmol) and n-butyllithium (20.4 mL, 53 mmol) cooled to -78° C. was added sec-butyldiisopropoxyborane (8.74, 48 mmol) in 48 mL THF. The reaction mixture was stirred at -78° C. for an additional 1 h, then quenched with hydrogen chloride in ethyl ether (15.5 mL, 53 mmol). The cooling bath was removed and the reaction mixture allowed to warm to room temperature. The lithium chloride was allowed to settle and the clear supernatant was decanted via a double-ended needle into a distillation flask. The remaining solid lithium chloride was washed with THF, 2×15 mL, and added to the distillation flask. Volatiles were removed with reduced pressure, followed by high vacuum distillation. Yield: 9.5 g (92%), bp 72°-74° C. (0.1 mm Hg); n20D 1.4496; proton NMR (CDCl3)δ4.63 (septet, J=18 Hz, 1H), 3.60 (triplet, J=18 Hz, 2H), 2.47 (triplet, J=18 Hz, 2H), 1.17 (d, J=18 Hz, 6H), 0.87 (m, 6H); boron NMR (EE)δ+41.3 ppm (s); mass spectrum (chemical ionization, isobutane), m/e 213 (M+H, 8%). IR (thin film) 2185, 1325 cm-1. Anal. Calcd. for C12H28BClO: C, 63.06; H, 9.70; B, 4.73. Found: C, 63.14; H, 9.60; B, 4.48.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].[N+:12]([CH3:15])([O-:14])=[O:13]>O>[OH:5][C:4]1([CH2:15][N+:12]([O-:14])=[O:13])[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[NH:1][C:2]1=[O:3]
Reactant: C[N+](=O)[O-]
Reactant: O=C1Nc2ccccc2C1=O
Solvent: O
Product: O=C1Nc2ccccc2C1(O)C[N+](=O)[O-]
Temperature: 30 °C
Reaction time: 0.17 h

Procedure:
Isatin (0.073 g) and nitromethane (0.1 ml) were added to water and the reaction mixture was vigorously stirred at a temperature of 30° C. for 10 minutes. The formed solid product was filtered and recrystallized with MeOH to afford pure product.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].Cl.[F:19][C:20]([F:34])([F:33])[CH2:21][C:22]1[S:26][C:25]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:24][CH:23]=1>>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([N:30]1[CH2:31][CH2:32][N:27]([C:25]2[S:26][C:22]([CH2:21][C:20]([F:34])([F:19])[F:33])=[CH:23][N:24]=2)[CH2:28][CH2:29]1)=[O:9])([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: FC(F)(F)Cc1cnc(N2CCNCC2)s1
Agent: Cl
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(CC(F)(F)F)s2)CC1
Yield: 36 %

Procedure:
Prepared in analogy to example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 1-[5-(2,2,2-trifluoro-ethyl)-thiazol-2-yl]-piperazine hydrochloride (Example 69(e)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) to yield the title compound as a white crystalline solid (yield 36%). MS (m/e): 492.4 (M+H+, 100%).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:5]2[CH2:13][C:12](=[O:14])[NH:11][C:6]=2[N:7]=[C:8]([SH:10])[N:9]=1.[F:15][C:16]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Br.O>CN(C=O)C>[NH2:3][C:4]1[C:5]2[CH2:13][C:12](=[O:14])[NH:11][C:6]=2[N:7]=[C:8]([S:10][CH2:18][C:17]2[CH:20]=[CH:21][CH:22]=[C:23]([F:24])[C:16]=2[F:15])[N:9]=1
Reactant: Nc1nc(S)nc2c1CC(=O)N2
Reactant: Fc1cccc(CBr)c1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(SCc2cccc(F)c2F)nc2c1CC(=O)N2
Reaction time: 0.5 h

Procedure:
To a suspension of 60% sodium hydride (125 mg) in dry DMF (5 ml) was added a solution of the product from example 3, step (a) (0.57 g) in DMF (10 ml). The mixture was allowed to stir for 30 mins. To the solution was added 2,3-difluorobenzyl bromide (0.39 ml) and the mixture stirred for 2 hours. Poured into water and the crude product extracted into ethyl acetate. Chromatography on silica eluting with 10% ethyl acetate/dichloromethane afforded the title compound (0.35 g).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([C:11]#[N:12])[CH:3]=1.[CH3:13][C:14]1[C:15]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[N:16][CH:17]=[C:18]([CH3:20])[CH:19]=1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:24]2[CH2:25][CH2:26][N:21]([C:15]3[C:14]([CH3:13])=[CH:19][C:18]([CH3:20])=[CH:17][N:16]=3)[CH2:22][CH2:23]2)=[O:8])=[C:4]([CH:3]=1)[C:11]#[N:12]
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: N#Cc1cc(Br)ccc1C(=O)O
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3C#N)CC2)c(C)c1
Yield: 83.1 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 90 and using 4-bromo-2-cyanobenzoic acid (2.03 g) described in Preparation Example 192 and 1-(3,5-dimethylpyridin-2-yl)piperazine (1.81 g) described in Preparation Example 47, the title compound (2.98 g) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:47][C:48]([F:61])([F:60])[C:49]1[N:53]2[CH2:54][CH2:55][NH:56][CH2:57][C:52]2=[C:51]([C:58]#[N:59])[N:50]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([N:56]1[CH2:55][CH2:54][N:53]2[C:49]([C:48]([F:61])([F:47])[F:60])=[N:50][C:51]([C:58]#[N:59])=[C:52]2[CH2:57]1)=[O:6]
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: N#Cc1nc(C(F)(F)F)n2c1CNCC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1nc(C(F)(F)F)n2c1CN(C(=O)c1cc(Cc3n[nH]c(=O)c4ccccc34)ccc1F)CC2
Reaction time: 12 h
Yield: 21.9 %

Procedure:
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (210 mg, 0.70 mmol) was dissolved in 5 mL of N,N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (350 mg, 0.92 mmol), crude 3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carbonitrile 25a (100 mg, 0.46 mmol), and N,N-diisopropylethylamine (250 μL, 1.18 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain 7-[2-fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoyl]-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-1-carbonitrile 25 (50 mg, yield 21.9%) as a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][N:12]2[C:18](=[O:19])[C@H:17]([NH:20]C(=O)OC(C)(C)C)[CH2:16][S:15][C@@H:14]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:13]2)[CH2:10][CH2:9]1>ClCCl>[NH2:20][C@@H:17]1[CH2:16][S:15][C@@H:14]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:13][N:12]([CH2:11][CH:8]2[CH2:10][CH2:9]2)[C:18]1=[O:19]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CS[C@@H](c2ccccc2)CN(CC2CC2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H]1CS[C@@H](c2ccccc2)CN(CC2CC2)C1=O
Reaction time: 1 h
Yield: 86.3 %

Procedure:
Trifluoroacetic acid (2.0 mL) was added to a solution of tert-butyl (2S,6S)-4-(cyclopropylmethyl)-5-oxo-2-phenyl-1,4-thiazepan-6-ylcarbamate (90 mg, 0.239 mmol) in dichloromethane (5 mL). After 1 h, the mixture was concentrated and aqueous saturated sodium bicarbonate was added. The mixture was extracted with dichloromethane (2×), and the combined organic extracts were dried over magnesium sulfate, filtered, and concentrated to give the crude product (57 mg). 1H NMR (500 MHz, CDCl3) □ 7.38-7.30 (m, 5H), 4.36-4.28 (m, 2H), 4.06 (d, J=9.3 Hz, 1H), 3.74 (dd, J=14.4, 1.5 Hz, 1H), 3.67 (dd, J=13.9, 7.3 Hz, 1H), 3.08 (dd, J=13.9, 6.6 Hz, 1H), 3.00 (dd, J=14.4, 9.8 Hz, 1H), 2.66 (dd, J=14.4, 1.9 Hz, 1H), 1.02-0.99 (m, 1H), 0.57-0.53 (m, 2H), 0.27-0.23 (m, 2H).
Reaction SMILES: BrC1C=[C:4]([C:10]2[O:14]C(=O)NN=2)C=NC=1CC.[Br:16][C:17]1[C:18]([CH2:27][CH3:28])=[N:19][CH:20]=[C:21]([CH:26]=1)[C:22](NN)=[O:23].C(N(C(C)C)CC)(C)C.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Br:16][C:17]1[C:18]([CH2:27][CH3:28])=[N:19][CH:20]=[C:21]([CH:26]=1)[C:22]([O:14][CH2:10][CH3:4])=[O:23]
Reactant: CCc1ncc(-c2n[nH]c(=O)o2)cc1Br
Reactant: CCc1ncc(C(=O)NN)cc1Br
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnc(CC)c(Br)c1
Reaction time: 1 h
Yield: 58 %

Procedure:
Step-3: 5-(5-Bromo-6-ethylpyridin-3-yl)-1,3,4-oxadiazol-2(3H)-one: To a stirred and cooled (0° C.) solution of 5-bromo-6-ethylnicotinohydrazide (2.50 g, 10.24 mmol, 1.0 eq) and diisopropylethylamine (3.58 mL, 20.48 mmol, 2.0 eq) in DCM (20 mL) was added a solution of triphosgene (1.21 g, 4.10 mmol, 0.4 eq) in DCM (10 mL) over a period of 10 min. The resulting mixture was stirred for 1 h at the same temperature. The reaction mixture was then diluted with DCM (50 mL) and washed with water (50 mL), aqueous sodium bicarbonate (10%, 50 mL), brine (50 mL), dried (Na2SO4) and filtered. The filtrate was evaporated under vacuum to afford 1.60 g (58%) of the desired product as a white solid. 1HNMR (400 MHz, DMSO) δ 8.83 (d, J=1.5 Hz, 1H), 8.25 (d, J=1.5 Hz, 1H), 2.92 (q, J=7.0 Hz, 2H), 1.21 (t, J=7.0 Hz, 3H); ESI-MS (m/z) 270, 272 [(MH)+ Br79, 81].