Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([C:11]2[N:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[C:13]([NH:28][S:29]([C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][N:33]=3)(=[O:31])=[O:30])[N:12]=2)[CH:8]=[CH:7][N:6]=1)=[NH:4].[C:39](OC(=O)C)(=O)[CH3:40]>C(O)(=O)C>[CH3:18][O:17][C:15]1[N:16]=[C:11]([C:9]2[CH:8]=[CH:7][N:6]=[C:5]([C:3]3[N:4]=[C:39]([CH3:40])[O:1][N:2]=3)[CH:10]=2)[N:12]=[C:13]([NH:28][S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][N:33]=2)(=[O:31])=[O:30])[C:14]=1[O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccnc(C(=N)NO)c2)nc1OC
Solvent: CC(=O)O
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccnc(-c3noc(C)n3)c2)nc1OC

Procedure:
A solution of 108 mg of N-hydroxy-4-[4-methoxy-5-(2-methoxy-phenoxy)-6-(5-methyl-pyridine-2-sulfonylamino)-pyrimidin-2-yl]-pyridine-2-carboxamidine, product of example 34, in acetic acid (3 ml) was treated at RT with 0.057 ml of acetic anhydride then and refluxed for 12 h. The reaction mixture was partitioned between CH2Cl2 and diluted aqueous KHCO3, the organic layer was dried over Na2SO4 and the solvent was removed in a vacuo. The residue was purified on a silica gel chromatography column (eluted with AcOEt). Combination of the purified fractions and evacuation in vacuo afforded 5-methyl-pyridine-2-sulfonic acid {6-methoxy-5-(2-methoxy-phenoxy)-2-[2-(5-methyl-[1,2,4]oxadiazol-3-yl)-pyridin-4-yl]-pyrimidin-4-yl}-amide as a light yellow solid. ISN mass spectrum, m/e 560.1 (M−1 calculated for C26H23N7O6S: 560).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[N:5]2[N:21]=[CH:22][CH:23]=[C:4]2[N:3]=1.[CH3:24][O-:25].[Na+]>CO>[CH3:24][O:25][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[N:5]2[N:21]=[CH:22][CH:23]=[C:4]2[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(Cl)nc3ccnn23)CC1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)n2nccc2n1
Yield: 98 %

Procedure:
tert-Butyl 4-(5-chloro-pyrazolo[1,5-a]pyrimidin-7-yl)piperazine-1-carboxylate (1.23 g, 3.65 mmol) was dissolved under an argon atmosphere in anhydrous methanol (6 ml). Sodium methanolat (3.65 ml of a 1M solution in methanol) was added and the mixture was heated under reflux for 9 hours. The solvent was removed under reduced pressure, the residue taken up in dichloromethane, the resulting solution was washed with water, dried over magnesium sulfate, the solvent removed under reduced pressure to yield 1.186 g of a solid (3.56 mmol, 98%). MS (APCI): m/z=334.3 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1([C@@H:5]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[OH:6])[CH2:4][O:3]1.[CH2:17]([O:19][CH:20]=[CH2:21])[CH3:18].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.CCN(CC)CC>C(Cl)Cl>[CH2:17]([O:19][CH:20]([O:6][CH:5]([C@@:2]1([CH3:1])[CH2:4][O:3]1)[C:7]1[CH:8]=[CH:9][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:11][CH:12]=1)[CH3:21])[CH3:18]
Reactant: CC1([C@H](O)c2ccc(S(C)(=O)=O)cc2)CO1
Reactant: C=COCC
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(C)OC(c1ccc(S(C)(=O)=O)cc1)[C@@]1(C)CO1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of the product from Step 4 (7.2 g) and ethylvinyl ether (50 mL) in 200 mL of CH2Cl2 cooled to 0° C. was added 50 mg of camphorsulfonic acid. The reaction mixture was stirred at r.t. for 20 min. and then treated with 1 mL of Et3N, concentrated to give the crude title compound (9 g).
Reaction SMILES: [S:1]([O:5][C:6]1[CH:11]=[C:10]([N+:12]([O-])=O)[C:9]([O:15][CH3:16])=[CH:8][C:7]=1[CH3:17])(=[O:4])(=[O:3])[CH3:2]>[Pd].C(O)C>[S:1]([O:5][C:6]1[CH:11]=[C:10]([NH2:12])[C:9]([O:15][CH3:16])=[CH:8][C:7]=1[CH3:17])(=[O:4])(=[O:3])[CH3:2]
Reactant: COc1cc(C)c(OS(C)(=O)=O)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: COc1cc(C)c(OS(C)(=O)=O)cc1N
Reaction time: 1 h
Yield: 80.9 %

Procedure:
1.55 g of 10% palladium-on-carbon, 18.8 g (71.9 mmol) of 2-methyl-4-methoxy-5-nitrophenyl mesylate and 120 ml of ethanol were fed into an autoclave (200 ml), and the mixture was then hydrogenated at 50° C. under 50 g/cm2 for 1 hours with stirring. After allowing to cool, palladium-on-carbon was filtered off and the solvent was distilled off under reduced pressure to obtain brown crystals. The crystals thus obtained were recrystallized from ethanol to thereby give 13.4 g (58.2 mmol) of 2-methyl-4-methoxy-5-aminophenyl mesylate in the form of yellow needle-like crystals. The yield was 81%.
Reaction SMILES: [O:1]=[C:2]1[N:7]=[C:6]([NH:8]C(=O)C)[CH:5]=[CH:4][N:3]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1>N.CO>[NH2:8][C:6]1[CH:5]=[CH:4][N:3]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[C:2](=[O:1])[N:7]=1
Reactant: CC(=O)Nc1ccn(CCCCCCOC2CCCCO2)c(=O)n1
Agent: N
Solvent: CO
Product: Nc1ccn(CCCCCCOC2CCCCO2)c(=O)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.1 %

Procedure:
N-{2-Oxo-1-[6-(tetrahydro-pyran-2-yloxy)-hexyl]-1,2-dihydro-pyrimidin-4-yl}-acetamide (H) (0.44 g, 1.3 mmol) was dissolved in a solution of ammonia in MeOH (7 N) (50 ml). The mixture was stirred at room temperature for 16 h. After completion of the reaction the solvent was evaporated under reduced pressure and the crude material was purified over flash silica gel chromatography (CHCl3/MeOH, 10:1) to give compound 4-Amino-1-[6-(tetrahydro-pyran-2-yloxy)-hexyl]-1H-pyrimidin-2-one (I) as a semi-solid (0.25 g, 65%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10]#[N:11].[NH2:12][C:13]1[N:18]=[C:17]([NH2:19])[C:16]([CH:20]=O)=[CH:15][N:14]=1>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:10]([NH2:11])=[N:19][C:17]2[N:18]=[C:13]([NH2:12])[N:14]=[CH:15][C:16]=2[CH:20]=1
Reactant: N#CCc1c(Cl)cccc1Br
Reactant: Nc1ncc(C=O)c(N)n1
Product: Nc1ncc2cc(-c3c(Cl)cccc3Br)c(N)nc2n1

Procedure:
Prepared as described in Example 1, starting from 1.0 g of 2 -bromo-6-chlorophenylacetonitrile and 0.57 g of 2,4 -diamino-5-pyrimidine-carboxaldehyde, mp 264-280° C.; MS(CI).
Reaction SMILES: [C:1]([C:4]1[CH:22]=[CH:21][C:7]2[S:8][C:9]([CH3:20])=[C:10]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[C:6]=2[CH:5]=1)([OH:3])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:35]([S:40]([NH2:43])(=[O:42])=[O:41])[CH2:36][CH2:37][CH2:38][CH3:39].C1CCN2C(=NCCC2)CC1>CN(C)C=O>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[CH2:11][C:10]1[C:6]2[CH:5]=[C:4]([C:1](=[O:3])[NH:43][S:40]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])(=[O:42])=[O:41])[CH:22]=[CH:21][C:7]=2[S:8][C:9]=1[CH3:20]
Reactant: CCCCCS(N)(=O)=O
Reactant: Cc1sc2ccc(C(=O)O)cc2c1Cc1ccc(Cl)cc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCCCCS(=O)(=O)NC(=O)c1ccc2sc(C)c(Cc3ccc(Cl)cc3Cl)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.7 %

Procedure:
In the same manner as in Example 1, 5-carboxy-3-(2,4-dichlorobenzyl)-2-methylbenzo[b]thiophene (440 mg, 1.25 mmol) was suspended in dimethylformamide and carbonyldiimidazole (305 mg, 1.88 mmol) was added, which was followed by stirring at room temperature for 1 hr. Then, 1-n-pentanesulfonamide (284 mg, 1.88 mmol) and DBU (286 mg, 1.88 mmol) were added and the mixture was refluxed under heating at 100° C. for 15 hr. The reaction mixture was concentrated under reduced pressure and water and 3N hydrochloric acid were added to acidify the mixture. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The residual oil was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=3/2) and recrystallized from 2-propanol-n-hexane to give 3-(2,4-dichlorobenzyl)-2-methyl-5-(1-n-pentanesulfonylcarbamoyl)benzo[b]thiophene (410 mg, 68%) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21](OCC)=[O:22])[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[NH2:35][CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH:37]1[OH:42]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21]([NH:35][CH:36]4[CH2:41][CH2:40][CH2:39][CH2:38][CH:37]4[OH:42])=[O:22])[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(C)c1=O
Reactant: NC1CCCCC1O
Agent: Cl
Solvent: CCN(CC)CC
Product: Cn1c(=O)c(C(=O)NC2CCCCC2O)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Yield: 37.6 %

Procedure:
In a similar manner to that described in example 196, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (18 mg, 0.050 mmol) described in example 92, triethylamine (0.3 mL, 1.95 mmol), and 2-aminocyclohexanol hydrochloride (100 mg, 0.66 mmol), was prepared 7-[(4-fluorophenyl)methyl]-4-hydroxy-N-(2-hydroxycyclohexyl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (8 mg, 38% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.29 (d, J=7.6 Hz, 1 H), 8.54 (s, 1 H), 7.37 (s, 1 H), 7.17-7.13 (m, 2 H), 7.04-6.99 (m, 2 H), 4.12 (s, 2 H), 3.86 (m, 1 H), 3.56-3.47 (m, 4 H), 2.07 (m, 2 H), 1.75 (m, 2 H), 1.42-1.23 (m, 4 H); HRMS m/z calcd for C23H25N3O4F: 426.1829 Found: 426.1834.
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4]([C:12]([O:14][CH3:15])=[O:13])=[CH:3]1.COC(C1CCC2C(=CC=C(S(Cl)(=O)=O)C=2)O1)=O>[Pd]>[CH3:15][O:14][C:12]([CH:4]1[CH2:3][CH2:2][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5]1)=[O:13]
Reactant: COC(=O)c1cc(=O)c2ccccc2o1
Agent: [Pd]
Agent: COC(=O)C1CCc2cc(S(=O)(=O)Cl)ccc2O1
Product: COC(=O)C1CCc2ccccc2O1
Yield: 93 %

Procedure:
Compound 3A was prepared by hydrogenation of the methyl 4-oxo-4H-chromene-2-carboxylate catalyzed by 10% Pd/C in 93% yield. MS: MS: 193 (M+1)+. Preparation of 6-Chlorosulfonyl-chroman-2-carboxylic acid methyl ester (Compound 3B)
Reaction SMILES: C[C:2]1[N:6]2[C:7]([NH2:15])=[C:8]([Cl:14])[CH:9]=[C:10]([C:11]([OH:13])=O)[C:5]2=[N:4][C:3]=1[CH3:16].[CH3:17][O:18][CH2:19][C:20]([CH3:31])([CH3:30])[CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][NH2:29])[CH2:24][CH2:23]1>>[NH2:15][C:7]1[N:6]2[CH:2]=[C:3]([CH3:16])[N:4]=[C:5]2[C:10]([C:11]([NH:29][CH2:28][CH:25]2[CH2:24][CH2:23][N:22]([CH2:21][C:20]([CH3:31])([CH3:30])[CH2:19][O:18][CH3:17])[CH2:27][CH2:26]2)=[O:13])=[CH:9][C:8]=1[Cl:14]
Reactant: Cc1nc2c(C(=O)O)cc(Cl)c(N)n2c1C
Reactant: COCC(C)(C)CN1CCC(CN)CC1
Product: COCC(C)(C)CN1CCC(CNC(=O)c2cc(Cl)c(N)n3cc(C)nc23)CC1

Procedure:
The title compound was prepared according to the procedure described in the Step 6 in EXAMPLE 1 from 5-amino-6-chloro-2-methylimidazo[1,2-a]pyridine-8-carboxylic acid (EXAMPLE 1, Step 5) and {[1-(3-methoxy-2,2-dimethylpropyl)piperidin-4-yl]methyl}amine (EXAMPLE 9, Step 1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH:12]([N:15](C(C)C)CC)(C)C.CN>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:15][CH3:12])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: CN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNc1nc(Cl)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.7 %

Procedure:
To a solution of 2,4-dichloro-5-nitropyrimidine (5 g, 26 mmol) in THF (50 mL) was added diisopropylethylamine (3.36 g, 26 mmol) at −78° C., followed by the dropwise addition of methylamine (13 mL, 2 mol/L in methanol, 26 mmol). After the addition, the mixture was warmed to RT and stirred for 3 h. The reaction mixture was then diluted with ethyl acetate and washed with brine (50 mL*3). The organic layer was dried over sodium sulfate, filtered and concentrated to give the title compound (4.4 g, 100%) as a yellow solid. MS (ES+) C5H5ClN4O2 requires: 188, 190. found: 189, 191 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)=O.[CH3:22][NH:23][CH3:24].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1.C(Cl)CCl>[CH3:22][N:23]([CH2:1][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)[CH3:24]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2C=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CN(C)Cc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To tert-butyl 4-(2-formylphenyl)piperazinecarboxylate (Step 1) (0.6 g, 2.1 mmol), was added dimethylamine (Aldrich) (1.6 mL of a 2.0 M soln in THF, 3.2 mmol) in ClCH2CH2Cl (15 mL) and NaBH(OAc)3 (Aldrich) (0.66 g, 3.2 mmol). The reaction was stirred at RT for 2 h. The mixture was partitioned between CH2Cl2 and satd NaHCO3. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give tert-butyl 4-{2-[(dimethylamino) methyl]phenyl}piperazinecarboxylate (0.68 g) as a yellow oil. MS m/z: 320 (M+H). Calc'd for C18H29N3O2: 319.44.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[F:19][C:20]1[CH:28]=[C:27]([OH:29])[CH:26]=[CH:25][C:21]=1[C:22]([OH:24])=[O:23].C(Cl)Cl.Cl>N1C=CC=CC=1>[F:19][C:20]1[CH:28]=[C:27]([O:29][C:14](=[O:15])[C:13]2[CH:12]=[CH:11][C:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:18][CH:17]=2)[CH:26]=[CH:25][C:21]=1[C:22]([OH:24])=[O:23]
Reactant: O=C(O)c1ccc(O)cc1F
Reactant: CCCCCCCCOc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCOc1ccc(C(=O)Oc2ccc(C(=O)O)c(F)c2)cc1
Yield: 78 %

Procedure:
4-Octyloxybenzoic acid chloride (10.74 g) and 6.24 g of 2-fluoro-4-hydroxybenzoic acid were stirred in 20 ml of pyridine and 50 ml of methylene chloride for 3 hours on refluxing by heating. After the reaction mixture was left to cool, it was neutralized with 10% hydrochloric acid, and the precipitated crystals were separated by filtration, and washed with water and then with cold methanol. The resulting crude crystals were recrystallized from ethanol to obtain 12.11 g of 2-fluoro-4-(4-octyloxybenzoyloxy)benzoic acid (yield 78%) which was liquid crystalline (transition temperatures: m.p. 147° to 148° C., N-I point 217° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH2:9].CN(C)C=O.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[CH2:15]([N:9]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccc(F)cc1F
Reactant: BrCc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(N(Cc2ccccc2)Cc2ccccc2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To 2,4-difluoro-phenylamine (a, 2.0 g, 15.5 mmol) in N,N-dimethylformamide (20 mL) potassium carbonate (6.0 g, 45 mmol) and benzyl bromide (5.49 mL, 35 mmol) were added. The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography eluting with hexane to give dibenzyl-(2,4-difluoro-phenyl)-amine as colourless oil (4.34 g, 90%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=2)[CH:3]=[CH:2]1.[NH:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[CH2:25][C@H:14]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[N:13]1([C:10]([C:7]2[CH:8]=[C:9]3[C:4]([CH:3]=[CH:2][NH:1]3)=[CH:5][CH:6]=2)=[O:12])[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[CH2:25][C@H:14]12
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccc2cc[nH]c2c1)N1CCC[C@@H]2c3ccccc3C[C@@H]21
Yield: 41 %

Procedure:
The title compound is prepared from 1H-indole-6-carboxylic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 41% of theory; LC (method 4): tR=2.00 min; Mass spectrum (ESI+): m/z=317 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:12][CH2:13][C:14]([NH:21][C:22]([C:24]1[N:28]2[CH:29]=[CH:30][CH:31]=[C:32]([O:33][CH2:34][C:35]3[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=3[F:42])[C:27]2=[N:26][C:25]=1[CH3:43])=[O:23])([C:16]1[N:17]=[N:18][NH:19][N:20]=1)[CH3:15])(C)(C)C.Cl[C:57]([F:62])([F:61])C([O-])=O.[Na+].C(OC(C)C)(C)C>CN(C=O)C.C(OCC)(=O)C.O>[F:41][C:40]1[CH:39]=[CH:38][CH:37]=[C:36]([F:42])[C:35]=1[CH2:34][O:33][C:32]1[C:27]2[N:28]([C:24]([C:22]([NH:21][C:14]([C:16]3[N:17]=[N:18][N:19]([CH:57]([F:62])[F:61])[N:20]=3)([CH3:15])[CH2:13][OH:12])=[O:23])=[C:25]([CH3:43])[N:26]=2)[CH:29]=[CH:30][CH:31]=1
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1nn[nH]n1
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)OC(C)C
Solvent: O
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC(C)(CO)c1nnn(C(F)F)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.1 %

Procedure:
To a mixture of 153 mg of potassium carbonate and 5 ml of DMF was added dropwise a solution of 346 mg of N-[1-{[tert-butyl (diphenyl)silyl]oxy}-2-(2H-tetrazol-5-yl)propan-2-yl]-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxamide and 158 mg of sodium chloro(difluoro)acetate in 3 ml of DMF at an inner temperature of 95° C., followed by stirring at the same temperature for 1 hour. After leaving to be cooled to room temperature, water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography. To the obtained crude product were added ethyl acetate and diisopropyl ether, and the insoluble materials were collected by filtration and dried under reduced pressure to obtain 98 mg of 8-[(2,6-difluorobenzyl)oxy]-N-{2-[2-(difluoromethyl)-2H-tetrazol-5-yl]-1-hydroxypropan-2-yl}-2-methylimidazo[1,2-a]pyridine-3-carboxamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=O)=[CH:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:5][CH:4]=1.Cl.[NH2:27][OH:28].C(=O)([O-])O.[Na+]>CO.O>[OH:28][N:27]=[C:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[C:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[CH:10][CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)CC=C(C(=O)c1ccc(OC)cc1)c1ccc(OC)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)CC=C(C(=NO)c1ccc(OC)cc1)c1ccc(OC)cc1
Yield: 89.9 %

Procedure:
A mixture of 24.5 g of methyl 4,5bis(4-methoxyphenyl)-5-oxo-3-pentenoate and 51.5 g of hydroxylamine hydrochloride in a mixture of 650 ml of methanol and 72 ml of water was heated under reflux for 3 hours. During this procedure, 0.9 equivalent of sodium hydrogen carbonate was added portionwise to the reaction mixture as the reaction progressed. After completion of the reaction, the methanol was distilled off under reduced pressure. Water and ethyl acetate were added to the residue for dissolution thereof, the organic layer was separated, washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The organic layer was then concentrated under reduced pressure and the residue was separated and purified by silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:4) to give 23 g (yield 90%) of methyl 5-hydroxyimino-4,5-bis(4-methoxyphenyl)-3-pentenoate as an oil.
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:31])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19](Br)[N:20]=3)[N:15]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].[F:32][C:33]1[CH:34]=[CH:35][C:36]2[N:37]([C:39]([S:55][CH3:56])=[N:40][C:41]=2[Sn](CCCC)(CCCC)CCCC)[CH:38]=1>CN(C=O)C.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.[Cu]I>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:31])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:41]4[N:40]=[C:39]([S:55][CH3:56])[N:37]5[CH:38]=[C:33]([F:32])[CH:34]=[CH:35][C:36]=45)[N:20]=3)[N:15]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(SC)n2cc(F)ccc12
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(=O)N1CC(C#N)C1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CSc1nc(-c2cnc3c(n2)c(C(=O)N[C@H](C)C(=O)N2CC(C#N)C2)cn3COCC[Si](C)(C)C)c2ccc(F)cn12
Temperature: 80 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
In a round-bottomed flask, 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (100 mg, 0.20 mmol) and 6-fluoro-3-methylsulfanyl-1-tributylstannanyl-imidazo[1,5-a]pyridine (crude from Step 4) were dissolved in DMF (2 ml). The flask was evacuated and backfilled with argon then tetrakis(triphenylphosphine)palladium (0) (12 mg, 0.010 mmol) and copper (I) iodide (8 mg, 0.042 mmol) were added. The reaction mixture was stirred at 80° C. in an oil bath overnight then cooled to room temperature, quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with MeOH/CH2Cl2/0.5% NH4OH (gradient 0-2.5% MeOH) to afford 109 mg (82%) of 2-(6-fluoro-3-methylsulfanyl-imidazo[1,5-a]pyridin-1-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a brown oil.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=4)[CH:24]=[C:23]([CH2:37][CH3:38])[N:22]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH2:37]([C:23]1[N:22]=[C:21]([C:17]2[CH:16]=[C:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:10]=3)[CH:20]=[CH:19][CH:18]=2)[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:35])([F:36])[F:34])=[CH:29][CH:28]=2)[CH:24]=1)[CH3:38]
Reactant: CCc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(N)(=O)=O)c3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 6.1 %

Procedure:
To a cooled and stirred solution of 3′-[6-ethyl-4-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide (example 265) (0.40 g, 0.742 mmol) in dichloromethane (10 mL) was added TFA (10 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (5 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane/diethyl ether and dried to yield the title compound as a white solid (0.022 g, 12%). MS (ISP) 481.2 [(M+H)+].