Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[O:10])[C:2]1[C:3]([O:8][CH3:9])=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH:11]1([Mg]Br)[CH2:13][CH2:12]1.O1CCCC1.[Cl-].[NH4+]>O1CCCC1>[CH:11]1([CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[O:8][CH3:9])[OH:10])[CH2:13][CH2:12]1
Reactant: COc1ccccc1C=O
Reactant: Br[Mg]C1CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccccc1C(O)C1CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Magnesium (10.7 g) was suspended in tetrahydrofuran (80 ml), and to the suspension was added iodine (5 mg). Bromocyclopropane (32.0 ml) was added dropwise thereto over 1.5 hr and the mixture was heated under reflux for 1.5 hr. Thereto was added tetrahydrofuran to give a 1M cyclopropylmagnesium bromide-tetrahydrofuran solution. Subsequently, o-anisaldehyde (8.17 g) was dissolved in tetrahydrofuran (150 ml), the 1M cyclopropylmagnesium bromide-tetrahydrofuran solution (90 ml) was added dropwise thereto over 50 min under ice-cooling, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was ice-cooled, a saturated aqueous ammonium chloride solution (9 ml) was added, and the reaction mixture was stirred at room temperature for 30 min. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=9:1) to give the title compound (6.13 g).
Reaction SMILES: C[O:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[C:11]([CH:44]=[CH:45][CH:46]=2)[CH2:12][CH:13]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([O:42]C)[N:37]=3)[CH:31]=2)[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27]C)[N:22]=3)[CH:16]=2)[CH:6]=[CH:5][CH:4]=1.Cl.[NH+]1C=CC=CC=1.[OH-].[K+]>O>[OH:27][C:23]1[N:22]=[C:21]([C:17]2[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=2)[CH2:14][CH:13]([CH2:12][C:11]2[CH:44]=[CH:45][CH:46]=[C:9]([C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([OH:2])[N:8]=3)[CH:10]=2)[CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([OH:42])[N:37]=3)[CH:31]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: COc1cccc(-c2cccc(CC(Cc3cccc(-c4cccc(OC)n4)c3)Cc3cccc(-c4cccc(OC)n4)c3)c2)n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Oc1cccc(-c2cccc(CC(Cc3cccc(-c4cccc(O)n4)c3)Cc3cccc(-c4cccc(O)n4)c3)c2)n1
Temperature: 190 °C

Procedure:
A mixture of 4.9 g (8.0 mmol) of tris(3-(6-methoxy-2-pyridyl)benzyl)methane and 7.4 g (64 mmol) of pyridinium hydrochloride was heated at 190° C. for 3 h. After cooling, the mixture was taken up in 200 ml of water and adjusted to pH=7.7 using 1N potassium hydroxide solution. The aqueous phase was extracted five times with 200 ml of dichloromethane. The organic phase was dried over magnesium sulfate and filtered through a short frit with silica gel. After removal of the solvent, the residue was recrystallised from tert-butyl methyl ether:n-heptane (1:2). The yield, with a purity of about 97%, was 3.8 g (6.7 mmol), corresponding to 83.8% of theory.
Reaction SMILES: Br[C:2]1[C:3]([O:11][CH3:12])=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[C:7]#[N:8].[CH2:13]([Sn](CCCC)(CCCC)CCCC)[CH:14]=[CH2:15].[Li+].[Cl-]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:10][C:5]1[CH:4]=[C:3]([O:11][CH3:12])[C:2]([CH2:15][CH:14]=[CH2:13])=[CH:9][C:6]=1[C:7]#[N:8]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: COc1cc(F)c(C#N)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: C=CCc1cc(C#N)c(F)cc1OC

Procedure:
A mixture of compound 5-bromo-2-fluoro-4-methoxybenzonitrile (10.0 mmol), allyl-tributyl-stannane (12.0 mmol), LiCl (20.0 mmol) and Pd(PPh3)4 (0.2 g) in anhydrous toluene was refluxed under N2 overnight. Distilled off the solvent under reduce pressure, the residue was purified with silica gel cloumn chromatography to give the product 2-fluoro-4-methoxy-5-(prop-2-en-1-yl)benzonitrile.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[S:17][C:16]=2[C:24]([O:26]C)=[O:25])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O>O1CCCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[S:17][C:16]=2[C:24]([OH:26])=[O:25])(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1sc2ncccc2c1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2c(C(=O)O)sc3ncccc23)cc1
Temperature: 50 °C
Yield: 100.9 %

Procedure:
To a solution of 94 (0.070 g; 0.17 mmol) in tetrahydrofuran (2 mL), aqueous sodium hydroxide (2 mL; 4 mmol; 2N) and water (4 mL) were added. The reaction mixture was heated at 50° C. for 5 hours, cooled to room temperature, and then extracted with diethyl ether (2×). The ether solution was discarded. The aqueous layer was acidified with aqueous hydrochloric acid (2N) and extracted with ethyl acetate. The organic layer was separated and washed with aqueous saturated sodium chloride, dried over magnesium sulfate filtered, and evaporated under reduced pressure to yield the title compound as an off-white solid (0.067 g).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[OH-].[Na+].[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>ClC(Cl)C>[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14]([N:1]2[CH:5]=[CH:4][CH:3]=[CH:2]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: c1cc[nH]c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)n2cccc2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 75.8 %

Procedure:
Pyrrole (18 g, 0.27 mol) was added to a well-agitated suspension of NaOH (36 g, 0.9 mol. NaOH should be ground and stirred in dichloroethane for 30 min.) in 180 mL of dichloroethane. This mixture was then cooled to 0° C. and stirred for 10 min, following which a solution of 6 (57.3 g, 0.3 mol) in 150 mL of dichloroethane was added over a period of 30 min. Thirty minutes after the completion of addition, the reaction was allowed to come to room temperature and left stirring overnight. The reaction was quenched by pouring onto 600 mL of ice and water. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (3×20 mL). The combined organic extract was washed with brine to neutrality and dried over Na2SO4. Removal of the solvent in vacuo gave 7 (45.3 g, 76%) as light grey solid. This solid was subsequently purified by passing a concentrated solution in dichloromethane through an alumina column (35.4 g). 1H NMR (CDCl3, δ/ppm), 7.75 (m, 2H), 7.29 (m, 2H), 7.15 (t, 2H), 6.28 (t, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([N:7]2[CH2:12][CH2:11][CH2:10][C@H:9]([NH:13]C(=O)OC(C)(C)C)[CH2:8]2)=[C:5]([NH2:21])[CH:4]=[N:3]1.C(OC([NH:29][C:30]1[S:34][C:33]([C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])=[N:32][C:31]=1[C:43](O)=[O:44])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[NH2:29][C:30]1[S:34][C:33]([C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])=[N:32][C:31]=1[C:43]([NH:21][C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[N:7]1[CH2:12][CH2:11][CH2:10][C@H:9]([NH2:13])[CH2:8]1)=[O:44]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: Cn1ncc(N)c1N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1N1CCC[C@H](N)C1
Yield: 11 %

Procedure:
Following the procedures as described in Example 113, (S)-tert-butyl 1-(1-methyl-4-amino-1H-pyrazol-5-yl)piperidin-3-ylcarbamate, 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid, and HATU were reacted to give 106 as a white solid (32 mg, 11%) over two steps. 1H NMR (400 MHz, DMSO) δ 8.80 (s, 1H), 7.60-7.42 (m, 4H), 7.27 (t, J=8.7, 2H), 3.62 (d, J=10.3, 3H), 3.09 (dd, J=11.1, 3.3, 1H), 3.03-2.88 (m, 2H), 2.83 (t, J=8.7, 1H), 2.69 (dd, J=11.0, 8.5, 1H), 1.87-1.64 (m, 2H), 1.55 (d, J=8.9, 1H), 1.17 (dd, J=19.9, 9.3, 1H). ESIMS m/z=434.1 (M+1)
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:28])[C:7](=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:8])([CH3:4])[CH3:3].[CH:29]1[CH:30]=[CH:31][C:32]([CH:37]=[O:38])=[C:33]([CH:35]=O)[CH:34]=1>>[CH3:1][C:2]([O:5][C:6](=[O:28])/[C:7](/[CH3:8])=[CH:35]/[C:33]1[CH:34]=[CH:29][CH:30]=[CH:31][C:32]=1[CH:37]=[O:38])([CH3:4])[CH3:3]
Reactant: O=Cc1ccccc1C=O
Reactant: CC(C(=O)OC(C)(C)C)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: C/C(=C\c1ccccc1C=O)C(=O)OC(C)(C)C

Procedure:
From 2-(triphenylphosphoranylidene)propanoic acid 1,1-dimethylethyl ester and ortho phthalaldehyde
Reaction SMILES: Cl[C:2]1[N:6]([C@@H:7]2[O:13][C@H:12]([CH2:14][OH:15])[C@@H:10]([OH:11])[C@H:8]2[OH:9])[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[N:3]=1.[CH2:20]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH2:36][NH2:37])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>C(O)C(C)C>[CH2:20]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH2:36][NH:37][C:2]1[N:6]([C@@H:7]2[O:13][C@H:12]([CH2:14][OH:15])[C@@H:10]([OH:11])[C@H:8]2[OH:9])[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[N:3]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: NCc1cccc(NCCCCOCc2ccccc2)c1
Reactant: OC[C@H]1O[C@@H](n2c(Cl)nc3ccccc32)[C@H](O)[C@@H]1O
Solvent: CC(C)CO
Solvent: CCN(CC)CC
Product: OC[C@H]1O[C@@H](n2c(NCc3cccc(NCCCCOCc4ccccc4)c3)nc3ccccc32)[C@H](O)[C@@H]1O
Yield: 30.5 %

Procedure:
2-Chloro-1-(β-D-ribofuranosyl)-1H-benzimidazole (0.14 g) and 3-(4-benzyloxybutylamino)benzylamine (0.36 g) were suspended in isobutanol (5 mL). To the mixture was added triethylamine (0.56 mL), and the mixture was refluxed for 16 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by preparative reverse phase column chromatography (Shiseido CAPSELL PAC C18UG80, 5 μm, 20×50 mm, flow rate 30 mL/minutes linear gradient, water/methanol=70/30-10/90) to give the title compound (0.08 g).
Reaction SMILES: [CH2:1]([C:9]1[N:13]=[C:12]([C:14]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=2)[O:11][N:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][NH2:31]>>[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][NH:31][CH2:18][C:17]1[CH:20]=[CH:21][C:14]([C:12]2[O:11][N:10]=[C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[N:13]=2)=[CH:15][CH:16]=1
Reactant: NCCc1ccccc1F
Reactant: CCCCCCCCc1noc(-c2ccc(C=O)cc2)n1
Product: CCCCCCCCc1noc(-c2ccc(CNCCc3ccccc3F)cc2)n1

Procedure:
The same procedure as employed in the preparation of Example 357 (step a) but using 4-(3-octyl-1,2,4-oxadiazol-5-yl)benzaldehyde and 2-(2-fluorophenyl)ethylamine gave the title compound as an oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:19](C1C=C(NC2C=CC=CC=2)C=CC=1)[CH3:20].N1C=CC=CC=1C=O>>[CH2:19]([C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1)[CH3:20]
Reactant: CCc1cccc(Nc2ccccc2)c1
Reactant: Clc1cccc(-n2nnc(-c3ccccn3)n2)c1
Agent: O=Cc1ccccn1
Product: CCc1cccc(-n2nnc(-c3ccccn3)n2)c1

Procedure:
Following the procedure described in EXAMPLE 1 for the synthesis of 2-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]pyridine, 3-ethylphenylaniline (36.4 mg, 0.3 mmol) and 2-pyridinecarboxaldehyde (32.1 mg, 0.3 mmol) were employed to obtain 2-[2-(3-ethylphenyl)-2H-tetrazol-5-yl]pyridine as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:27]=[CH:26][N:25]([CH3:28])[CH:24]=[CH:23]3)=[CH:18][CH:17]=2)[C:5]([C:12]([NH2:14])=[O:13])=[N:6][C:7]=1[C:8](O)([CH3:10])[CH3:9]>C(O)(=O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([N:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)=[CH:20][CH:21]=2)[C:5]([C:12]([NH2:14])=[O:13])=[N:6][C:7]=1[C:8]([CH3:10])=[CH2:9]
Reactant: CN1C=CN(c2ccc(Nc3nc(Cl)c(C(C)(C)O)nc3C(N)=O)cc2)C=C1
Solvent: CC(=O)O
Product: C=C(C)c1nc(C(N)=O)c(Nc2ccc(N3CCN(C)CC3)cc2)nc1Cl
Temperature: 120 °C
Reaction time: 5 h
Yield: 63.9 %

Procedure:
A mixture of 5-chloro-6-(1-hydroxy-1-methylethyl)-3-{[4-(4-methylpyrazin-1-yl)phenyl]amino}pyrazine-2-carboxamide (Preparation Example 416) (430 mg) and acetic acid (10 mL) was stirred at 120° C. for 5 hours. After the reaction liquid was cooled, the solvent was distilled off, and water and saturated aqueous sodium hydrogen carbonate were added to neutralize. After extraction with ethyl acetate, the extract was washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was washed with diisopropyl ether to give 5-chloro-6-isopropenyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide (265 mg) as an orange solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[S:15][C:14]([CH2:16][NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:29])[F:28])(=[O:20])=[O:19])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].IC.[C:33](=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[S:15][C:14]([CH2:16][N:17]([CH3:33])[S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:28])[F:29])(=[O:20])=[O:19])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1cccc(-c2ccc(CNS(=O)(=O)c3ccccc3C(F)(F)F)s2)c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: CI
Product: CN(Cc1ccc(-c2cccc(S(C)(=O)=O)c2)s1)S(=O)(=O)c1ccccc1C(F)(F)F

Procedure:
In analogy to example 10, step 3, N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-2-trifluoromethyl-benzenesulfonamide (example 27, step 1) was reacted with iodomethane and cesium carbonate in N,N-dimethylacetamide to give N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-N-methyl-2-trifluoromethyl-benzenesulfonamide as a light yellow semi-solid. MS: 506.9 ([M+H]+)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:19][CH3:20])=[N:15][C:16]([CH:17]=O)=[C:10]2[CH:9]1[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:34]O.C(OC(=O)C)(=O)C.O>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:19][CH3:20])=[N:15][C:16]([C:17]#[N:34])=[C:10]2[CH:9]1[CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:27][CH:28]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCc1nc(C=O)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)cc1
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCc1nc(C#N)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 3-ethyl-1-formyl-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (6.000 g; 13.289 mmol) in pyridine (100 ml) was added hydroxylamine hydrochloride (1.015 g; 14.618 mmol). The resulting mixture was first stirred at rt (4 h), and was then heated to 60° C. for 1 h before acetic anhydride (1.9 ml; 20.099 mmol; 1.5 eq.) was added at this temperature. After further heating at 60° C. (30 min.), the reaction mixture was then heated at 80° C. for 16 h. A second addition of acetic anhydride (0.3 ml; 3.173 mmol) was performed at 60° C., and the resulting mixture was additionally stirred at 80° C. for 10 h. The resulting yellow solution was then allowed to cool to rt before water was added. Extractions with DCM, washing with aq. 2N HCl, drying of the organic layer over magnesium sulfate, filtration, and concentration to dryness under reduced pressure afforded the crude product (yellow oil; 7.50 g). Purification by FC (EA/heptane=4/1) gave the expected pure product 1-cyano-3-ethyl-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester as a yellow oil (5.000 g; 84%). LC-MS: tR=1.09 min.; [M+H]+=449.40 g/mol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C1C(=O)N([Br:23])C(=O)C1>C(Cl)Cl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])=[O:9])=[CH:4][C:3]=1[Br:23]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(N)cc1
Solvent: ClCCl
Product: CC(C)(C)NS(=O)(=O)c1ccc(N)c(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.1 %

Procedure:
To a solution of 4-amino-N-tert-butyl-benzenesulfonamide (J. Med. Chem. (2003), 46(16), 3463-3475, 228 mg, 1.00 mmol) in DCM (10 mL), NBS (178 mg, 1.00 mmol) was added. The resulting mixture was stirred at RT for 30 min and washed with satd NaHCO3 (10 mL) and 10% aq Na2S2O3 (10 mL). The organic layer was separated, dried and concentrated to obtain 4-amino-3-bromo-N-tert-butyl-benzenesulfonamide (163 mg, 53%).
Reaction SMILES: [F:1][C:2]1[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:5][N:4]2[CH:13]=[CH:14][N:15]([C:16]3[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=3[CH3:23])[NH2:19])[C:3]=12.[F:24][S:25]([F:38])([F:37])([F:36])([F:35])[C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](O)=[O:30]>>[F:1][C:2]1[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:5][N:4]2[CH:13]=[CH:14][N:15]([C:16]3[CH:17]=[C:18]([NH:19][C:29](=[O:30])[C:28]4[CH:32]=[CH:33][CH:34]=[C:26]([S:25]([F:38])([F:24])([F:35])([F:36])[F:37])[CH:27]=4)[CH:20]=[CH:21][C:22]=3[CH3:23])[C:3]=12
Reactant: O=C(O)c1cccc(S(F)(F)(F)(F)F)c1
Reactant: Cc1ccc(N)cc1-n1ccn2nc(-c3cccnc3)c(F)c12
Product: Cc1ccc(NC(=O)c2cccc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cccnc3)c(F)c12

Procedure:
Analogously to the process described in Example 126, 60 mg (0.195 mmol) of the compound of Example 83A and 48 mg (0.195 mmol) of 3-(pentafluoro-λ6-sulphanyl)benzoic acid gave 35 mg (33% of theory) of the title compound. The product obtained from the preparative HPLC purification was dissolved in a little methanol and passed through a bicarbonate cartridge (from Polymerlabs, Stratospheres SPE, PL-HCO3 MP SPE, capacity 0.9 mmol). After concentration of the eluate, the residue was dried under high vacuum.
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12]CC)=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15](=[O:18])(O)[O-].[Na+]>C(O)C>[C:2]1([C:1]2[O:8][C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:9][C:15](=[O:18])[C:9]=2[C:10]([OH:12])=[O:11])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=C(O)c1c(-c2ccccc2)oc(-c2ccccc2)cc1=O

Procedure:
A 250 ml round-bottom flask is equipped with a mechanical stirrer, thermometer, and a distillation head and condenser set up to remove distillate. The flask is charged with 100 g (0.52 moles) ethyl benzoylacetate and 0.075 g sodium bicarbonate. The flask and its contents are heated by means of an oil bath over a period of about 5 hours at temperature from ambient to a maximum of 200° C. while the ethanol formed is continuously removed. Unreacted ethyl benzoylacetate is removed by vaccum distillation. The residue consisting of crude 3-benzoyl-6-phenyl-2H-pyran-2,4-(3H)-dione is then heated at 80°-85° C. with 500 g of 85% sulfuric acid for 4 hours. This mixture is poured into 1 liter of ice-water and the water extracted three times with 150 ml portions of chloroform. The combined chloroform extracts are stripped of volatiles on a rotary evaporator and the residue of 2,6-diphenyl-4-oxopyran-3-carboxylic acid isolated by fractional crystallization. A toluene solution of this pyrone is then treated with an equal molar quantity of 4-amino-2,2,6,6-tetramethylpiperidine and refluxed with removal of water by means of a Dean-Stark trap. When water has ceased to separate, the toluene is removed on a rotary evaporator and the residue cooled and treated with hexane to promote crystallization of the crude product. The product is further purified by fractional crystallization.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[CH:9]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]>C(#N)C>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([CH:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:4][CH2:3]1
Reactant: CCOC(=O)C(Br)c1ccccc1
Reactant: CC1CCNCC1
Solvent: CC#N
Product: CCOC(=O)C(c1ccccc1)N1CCC(C)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 70 %

Procedure:
4-Methylpiperidine (0.17 ml, 1.48 mmol), ethyl 2-bromo-2-phenylacetate (0.22 ml, 1.23 mmol), and TEA (0.21 ml, 1.48 mmol) were dissolved in acetonitrile (6 ml) and stirred at room temperature for 48 hours. The volatiles were evaporated and the crude residue was purified by flash chromatography (petroleum ether/AcOEt=95/5) to obtain ethyl 2-(4-methylpiperidin-1-yl)-2-phenylacetate (225 mg, 69.8% yield) as a colourless oil.
Reaction SMILES: [CH3:1][N:2]([CH3:9])[C:3](SC)=[CH:4][C:5]#[N:6].O.[NH2:11][NH2:12]>C(O)C>[CH3:1][N:2]([CH3:9])[C:3]1[NH:12][N:11]=[C:5]([NH2:6])[CH:4]=1
Reactant: CSC(=CC#N)N(C)C
Reactant: NN
Solvent: O
Solvent: CCO
Product: CN(C)c1cc(N)n[nH]1
Temperature: 85 °C
Yield: 68.6 %

Procedure:
A mixture of (2E or Z)-3-(dimethylamino)-3-(methylthio)acrylonitrile (Method 33, 9.525 g, 67 mmol) and hydrazine hydrate (10.06 g, 201 mmol) in ethanol (70 ml) was heated at 85° C. overnight. Solvent was removed. The residue was purified by silica gel column chromatography (by ISCO Combiflash with a gradient of 0-10% methanol in methylenechloride with 1% NH4OH). 5.8 g (69%) product as obtained brownish thick oil. LC-MS, 127 (M+1). NMR (DMSO, 400 MHz) δ9.51 (br, 1H), 4.67 (s, 1H), 2.62 (s, 6H).
Reaction SMILES: [F:1][C:2]([F:13])([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][N:7]=1)[C:3]([O-:5])=O.[Na+].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:39][C:40]1[CH:48]=[CH:47][CH:46]=[CH:45][C:41]=1[C:42]([NH2:44])=[O:43]>CN(C=O)C>[F:13][C:2]([F:1])([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][N:7]=1)[C:3]([NH:39][C:40]1[CH:48]=[CH:47][CH:46]=[CH:45][C:41]=1[C:42]([NH2:44])=[O:43])=[O:5]
Reactant: NC(=O)c1ccccc1N
Reactant: O=C([O-])C(F)(F)c1ccc(F)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)c1ccccc1NC(=O)C(F)(F)c1ccc(F)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
To a mixture of sodium 2,2-difluoro-2-(5-fluoropyridin-2-yl)acetate (100 mg, 0.47 mmol), HATU (213 mg, 0.56 mmol) and 2-aminobenzamide (77 mg, 0.56 mmol) was added DMF (2 mL) and the mixture was stirred overnight at rt. The mixture was partitioned between saturated aq ammonium chloride and EtOAc, and the organic layer was concentrated. The residue was purified by silica gel chromotography eluting with 2-10% MeOH/DCM to afford 2-(2,2-difluoro-2-(5-fluoropyridin-2-yl)acetamido)benzamide as an oil (110 mg, 74%). LC-MS (ESI) m/z 332 (M+Na)+.