Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[CH:9]=[CH:10][C:11]([CH3:17])=[N:12]3)=[N:5][NH:4][C:3]1=[S:18].Br[CH2:20][CH2:21][CH2:22][Cl:23].[H-].[Na+]>C(O)C>[Cl:23][CH2:22][CH2:21][CH2:20][S:18][C:3]1[N:2]([CH3:1])[C:6]([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[CH:9]=[CH:10][C:11]([CH3:17])=[N:12]3)=[N:5][N:4]=1
Reactant: ClCCCBr
Reactant: Cc1ccc2c(-c3n[nH]c(=S)n3C)cccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc2c(-c3nnc(SCCCCl)n3C)cccc2n1

Procedure:
To 4-methyl-5-(2-methyl-5-quinolinyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (3.6 g, preparation reported in WO 02/40471) in ethanol (60 ml) containing 1-bromo-3-chloropropane (2.0 ml) was carefully added with stirring sodium hydride (0.60 g, 60% in mineral oil). The mixture was heated at reflux for 45 min. Volatiles were evaporated under reduced pressure and the residue submitted to column chromatography (EtOAc—acetone gradient). The material thus obtained was precipitated from hot EtOAc (20 ml) by adding petroleum ether (40-60, 50 ml), cooled and collected by filtration to provide the title compound as colourless crystals (2.1 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:18][CH:17]=2)[C:7]=1[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:5])[CH3:2].[F:32][C:33]([F:45])([F:44])[O:34][C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:37]3[CH:38]=[CH:39][CH:40]=[C:35]([O:34][C:33]([F:32])([F:44])[F:45])[CH:36]=3)[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:24])[CH3:25])=[CH:18][CH:17]=2)[C:7]=1[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:5])[CH3:2]
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc(OC(C)C)cc1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3cccc(OC(F)(F)F)c3)ccc2n1-c1ccc(OC(C)C)cc1

Procedure:
The sub-title compound was prepared in accordance with step (a) Example 24 from 1-(4-isopropoxyphenyl)-2-ethoxycarbonylmethyl-5-hydroxyindole-3-carboxylic acid ethyl ester (212 mg, 0.50 mmol, see (b) Example 12) and 3-trifluoromethoxyphenylboronic acid. Yield 142 mg (48%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1.O1CCC[CH2:14]1.CN(C)C=O.C(Cl)(=O)C([Cl:26])=O>CO>[ClH:26].[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([O:12][CH3:14])=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: C1CCOC1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2[nH]cnc2c1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.00 g of 1H-benzimidazole-5-carboxylic acid was suspended in a mixed solvent of 10 mL of tetrahydrofuran and 20 μL of N,N-dimethylformamide, to which 1.6 mL of oxalyl chloride was added dropwise at room temperature, and this suspension was stirred for one hour at room temperature. The reaction mixture, to which 10 mL of methanol was added, was stirred for another one hour at room temperature and then for 30 minutes at 50° C., and this mixture was concentrated under reduced pressure. The resultant solid was washed with diisopropyl ether to yield 1.25 g of methyl 1H-benzimidazole-5-carboxylate hydrochloride as gray solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].O1[C:22]2([CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[O:21]CC1.C(#N)C>O>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([N:25]2[CH2:26][CH2:27][C:22](=[O:21])[CH2:23][CH2:24]2)=[CH:3][CH:4]=1
Reactant: C1CC2(CCN1)OCCO2
Reactant: Fc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C1CCN(c2ccc(C(F)(F)F)cc2)CC1
Yield: 2.4 %

Procedure:
A mixture of 25 g (0.1523 mol) of p-fluorobenzotrifluoride, 31 g (0.224 mol) of K2CO3, 65 g (0.4539 mol) of 1,4-dioxa-8-azaspiro[4.5]decane, and 150 ml of acetonitrile is stirred at reflux for 3 days. The reaction mixture is cooled, diluted with water, and extracted with methylene chloride. The combined extracts are washed with water, dried over Na2SO4 and concentrated in vacuo. The residue, 600 ml of 10% sulfuric acid solution and 300 ml of tetrahydrofuran is stirred at ambient temperature for 7 days, diluted with water and extracted with methylene chloride. The extracts are washed with brine, dried over Na2SO4, and concentrated in vacuo. Trituration with ether gives 0.9 g of title compound: IR (KBr) 1715, 1610, 1520 and 1330 cm-1 ; NMR (CDCl3) δ7.55 (d, 2H), 6.95 (d, 2H)m 3.73 (t, 4H), and 2.59 (t, 4H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][CH2:13][N:14]=[N+]=[N-])[C:5]=2[O:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][CH2:13][NH2:14])[C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: [N-]=[N+]=NCCOc1cccc2c1OCCO2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCCOc1cccc2c1OCCO2
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.8 %

Procedure:
A solution of 2-(2,3-dihydrobenzo[1,4]dioxin-5-yloxy)ethylazide (3.43 g, 0.016 mol) and triphenylphosphine (6.3 g, 0.023 mol) in tetrahydrofuran (50 ml) and water (2 ml) was allowed to stir for 18 hours at room temperature. The solvent was removed under vacuum. Chromatography (30% methanol-methylene chloride plus ammonium hydroxide) afford 1.93 g (62%) of product as a yellow oil. MS FAB m/e 196 (M+H)+
Reaction SMILES: CS(O[CH:6]([C:16]1[C:21]([F:22])=[C:20]([Cl:23])[CH:19]=[C:18]([C:24](=[O:26])[CH3:25])[C:17]=1[O:27][CH2:28][CH3:29])[CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])(=O)=O.[N-:30]=[N+:31]=[N-:32].[Na+]>CS(C)=O.[Cl-].[Na+].O>[N:30]([CH:6]([C:16]1[C:17]([O:27][CH2:28][CH3:29])=[C:18]([C:24](=[O:26])[CH3:25])[CH:19]=[C:20]([Cl:23])[C:21]=1[F:22])[CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])=[N+:31]=[N-:32]
Reactant: CCOc1c(C(C)=O)cc(Cl)c(F)c1C(CO[Si](C)(C)C(C)(C)C)OS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOc1c(C(C)=O)cc(Cl)c(F)c1C(CO[Si](C)(C)C(C)(C)C)N=[N+]=[N-]
Temperature: 50 °C
Yield: 100 %

Procedure:
1-(3-Acetyl-5-chloro-2-ethoxy-6-fluorophenyl)-2-{[tert-butyl(dimethyl)silyl]oxy}ethyl methanesulfonate (0.83 g, 1.77 mmol) (from Step 4) was stirred in dimethyl sulfoxide (10 mL) and sodium azide (0.12 g, 1.8 mmol) was added. The mixture was heated to 50° C. for 1 hour and cooled to rt. The mixture was poured into brine and extracted with ethyl acetate. The extracts were dried over sodium sulfate, filtered and evaporated to give the desired compound 736 mg, 100%. LCMS calculated for C18H27ClFN3O3SiNa (M+Na)+: m/z=438.1; found: 438.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([S:20]([CH3:22])=[O:21])=[CH:16][CH:15]=3)[CH2:12][CH2:11][CH2:10][C:9]2=[O:23])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:32])C=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([S:20]([CH3:22])(=[O:32])=[O:21])=[CH:16][CH:15]=3)[CH2:12][CH2:11][CH2:10][C:9]2=[O:23])=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CS(=O)c1ccc(C2CCCC(=O)N2c2ccc(Cl)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C2CCCC(=O)N2c2ccc(Cl)cc2)cc1
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
To a solution of 1.70 g of 1-(4-chlorophenyl)-6-(4-methylsulfinylphenyl)-2-piperidone in 50 ml of methylene chloride was added 1.02 g of m-chloroperbenzoic acid with stirring at 5° to 10° C. over 30 minutes. After stirring at 5° to 10° C. for 1 hour and at room temperature for 1 hour, the mixture was made alkaline with a saturated aqueous sodium hydrogen carbonate solution. The methylene chloride layer was washed with water, dried, and concentrated. The residue was recrystallized from nitroethane to give 1.54 g of 1-(4-chlorophenyl)-6-(4-methylsulfonylphenyl)-2-piperidone as colorless prisms.
Reaction SMILES: [N+](C1C=CC([C:10]2[C:15]3[C:16]4[C:22]([C:23]([O-:25])=O)=[CH:21][CH:20]=[C:19]([O:26][CH3:27])[C:17]=4[O:18][C:14]=3[CH:13]=[CH:12][N:11]=2)=CC=1)([O-])=O.[NH2:28][C:29]1[C:34]([Cl:35])=[CH:33][N:32]=[CH:31][C:30]=1[Cl:36].[H-].[Na+].C(O)(=O)C>CN(C=O)C.O>[Cl:36][C:30]1[CH:31]=[N:32][CH:33]=[C:34]([Cl:35])[C:29]=1[NH:28][C:23]([C:22]1[C:16]2[C:15]3[CH:10]=[N:11][CH:12]=[CH:13][C:14]=3[O:18][C:17]=2[C:19]([O:26][CH3:27])=[CH:20][CH:21]=1)=[O:25]
Reactant: COc1ccc(C(=O)[O-])c2c1oc1ccnc(-c3ccc([N+](=O)[O-])cc3)c12
Reactant: Nc1c(Cl)cncc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1oc1ccncc12
Reaction time: 50.67 h
Yield: 46.4 %

Procedure:
To a well stirred solution of 4-nitrophenyl-6-methoxybenzo[4,5]furo[3,2-c]pyridine-9-carboxylate (from step 14) (55 mg, 0.15 mmol) and 4-amino-3,5-dichloropyridine (50 mg, 0.30 mmol) in DMF (2.0 mL) was added sodium hydride (60% dispersion in mineral oil) (18 mg, 0.45 mmol) at −5° C. and stirred for 3040 minutes. Excess of DMF was removed under reduce pressure, the residue obtained was diluted with water (5 mL) and acidified to pH 5-6 with acetic acid. The solid obtained was filtered, washed with water and dried to afford product (27 mg) as off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH:5]=O.Cl.[CH3:12][O:13][NH2:14]>C(O)C.N1C=CC=CC=1>[CH3:12][O:13][N:14]=[CH:5][C:4]1[CH:3]=[C:2]([Cl:1])[CH:9]=[C:8]([Cl:10])[CH:7]=1
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Reactant: CON
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CON=Cc1cc(Cl)cc(Cl)c1
Yield: 93.6 %

Procedure:
A solution of 3,5-dichlorobenzaldehyde (0.0571 mol) and methoxyamine hydrochloride (0.0629 mol) in ethanol (50 ml) and pyridine (50 ml) was stirred 18 hours at room temperature. The reaction was concentrated and partitioned between methylene chloride and water. The organic phase was washed with 3N aqueous hydrogen chloride, dried over sodium sulfate and was concentrated to yield 10.9 g (94%) white solid, mp 53°.
Reaction SMILES: [CH3:1][C@@:2]12[C:8]([CH3:10])([CH3:9])[C@@H:5]([CH2:6][CH2:7]1)[C:4](=O)[C:3]2=O.COP([CH2:19][C:20]([C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[O:29][CH3:30])=O)(=O)OC.O.[NH2:32][NH2:33]>>[F:28][C:26]1[CH:25]=[CH:24][C:23]([O:29][CH3:30])=[C:22]([C:20]2[CH:19]=[C:4]3[C:3]([C@:2]4([CH3:1])[C:8]([CH3:10])([CH3:9])[C@H:5]3[CH2:6][CH2:7]4)=[N:33][N:32]=2)[CH:27]=1
Reactant: COc1ccc(F)cc1C(=O)CP(=O)(OC)OC
Reactant: NN
Reactant: CC1(C)[C@H]2CC[C@]1(C)C(=O)C2=O
Solvent: O
Product: COc1ccc(F)cc1-c1cc2c(nn1)[C@@]1(C)CC[C@@H]2C1(C)C

Procedure:
light yellow solid. MS (ESI): 312.9 (MH+). Prepared from (1S,4R)-1,7,7-trimethyl-bicyclo[2.2.1]heptane-2,3-dione, [2-(5-Fluoro-2-methoxy-phenyl)-2-oxo-ethyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:27]1[CH:32]=[C:31]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([N:40]3[CH2:47][CH:46]4[N:48]([CH3:49])[CH:42]([CH2:43][O:44][CH2:45]4)[CH2:41]3)=[CH:36][N:35]=2)[C:30](=[O:50])[N:29]([CH3:51])[CH:28]=1)(=O)C.O[Li].O>CC(O)C.C1COCC1.O>[F:26][C:9]1[CH:8]=[C:7]([C:27]2[CH:32]=[C:31]([NH:33][C:34]3[CH:39]=[CH:38][C:37]([N:40]4[CH2:41][CH:42]5[N:48]([CH3:49])[CH:46]([CH2:45][O:44][CH2:43]5)[CH2:47]4)=[CH:36][N:35]=3)[C:30](=[O:50])[N:29]([CH3:51])[CH:28]=2)[C:6]([CH2:5][OH:4])=[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])[CH:10]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CC5COCC(C4)N5C)cn3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li]O
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: O
Product: CN1C2COCC1CN(c1ccc(Nc3cc(-c4cc(F)cc(N5CCn6c(cc7c6CCCC7)C5=O)c4CO)cn(C)c3=O)nc1)C2
Temperature: 30 °C
Reaction time: 1 h
Yield: 32.8 %

Procedure:
A mixture of 112l (340 mg, 0.489 mmol) and LiOH hydrate (445 mg, 24.45 mmol) in iPrOH (4 mL), THF (4 mL) and H2O (4 mL) was stirred at 30° C. for 1 h. The mixture was evaporated in vacuo, and the residue was purified on prep-HPLC to give 112 as a low yellow solid (105 mg, 32.85%). MS: [M+H]+ 654. 1H NMR (500 MHz, CDCl3) δ 8.46 (d, J=2.5 Hz, 1H), 7.87 (d, J=3.0 Hz, 1H), 7.69 (s, 1H), 7.42 (d, J=2.0 Hz, 1H), 7.23-7.14 (m, 2H), 6.94 (d, J=2.5 Hz, 1H), 6.84 (m, 2H), 4.52 (d, J=11.5 Hz, 1H), 4.31 (m, 2H), 4.12 (m, 5H), 3.89 (m, 3H), 3.69 (s, 3H), 3.43 (m, 4H), 2.84 (s, 2H), 5.62-2.54 (m, 7H), 1.88 (m, 2H), 1.78 (m, 2H)
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([N:8]([CH2:16][C:17]2([O:23][CH3:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:4][CH:3]=1.[Cl:25][C:26]1[C:27](B(O)O)=[CH:28][C:29]([F:32])=[N:30][CH:31]=1.C(Cl)Cl.COCCOC>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:25][C:26]1[C:27]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([N:8]([CH2:16][C:17]3([O:23][CH3:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:14])[CH3:12])[N:7]=2)=[CH:28][C:29]([F:32])=[N:30][CH:31]=1
Reactant: COC1(CN(C(=O)OC(C)(C)C)c2cccc(Br)n2)CCOCC1
Reactant: OB(O)c1cc(F)ncc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC1(CN(C(=O)OC(C)(C)C)c2cccc(-c3cc(F)ncc3Cl)n2)CCOCC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 56.6 %

Procedure:
A mixture of tert-butyl 6-bromo-pyridin-2-yl((4-methoxytetrahydro-2H-pyran-4-yl)methyl)carbamate (50 mg, 0.125 mmol), 5-chloro-2-fluoropyridin-4-ylboronic acid (43.7 mg, 0.249 mmol), PdCl2(dppf).CH2Cl2 adduct (15.2 mg, 0.019 mmol), DME (1.5 Ml) and 2M aqueous Na2CO2 (0.25 Ml, 0.5 mmol) was sealed and stirred at 100° C. for 3 hours. After cooling to room temperature the mixture was diluted with EtOAc (15 Ml), filtered and concentrated in vacuo. The crude material was purified by column chromatography [silica gel, 12 g, EtOAc/hexane=5/100 to 50/50] to provide tert-butyl 5′-chloro-2′-fluoro-2,4′-bipyridin-6-yl((4-methoxytetrahydro-2H-pyran-4-yl)methyl)carbamate (32 mg, 57% yield). LCMS (m/z): 452.2 [M+H]+; retention time=1.068 min.
Reaction SMILES: [NH2:1][C:2]1[CH:35]=[CH:34][C:5]([C:6]([N:8]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25](=[O:33])[C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH2:21][CH2:20]2)[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>>[F:32][C:29]1[CH:28]=[CH:27][C:26]([C:25]([CH:22]2[CH2:23][CH2:24][N:19]([CH2:18][CH2:17][N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=3)[C:6](=[O:7])[C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:35][CH:34]=3)[CH2:20][CH2:21]2)=[O:33])=[CH:31][CH:30]=1
Reactant: COc1cccc(N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)C(=O)c2ccc(N)cc2)c1
Reactant: CS(=O)(=O)Cl
Product: COc1cccc(N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)C(=O)c2ccc(NS(C)(=O)=O)cc2)c1
Yield: 95.3 %

Procedure:
Using 4-amino-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(3-methoxyphenyl)benzamide (475.0mg, 1.00 mmol) and methanesulfonyl chloride (0.12 ml, 1.50 mmol), the procedure of inventive Example 94 was repeated to obtain 527.8 mg (95.4%) of the title compound in a colorless amorphous form.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C@@H:10]([O:14][CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[C@@H:9]1[C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCC[CH2:38]1.C1(C)C=CC=CC=1>C[C-]1C=CC=C1.[C-]1(C)C=CC=C1.[Ti+2].C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([O:14][C:15]([C:16]2[CH:17]=[C:18]([C:26]([F:27])([F:28])[F:29])[CH:19]=[C:20]([C:22]([F:23])([F:25])[F:24])[CH:21]=2)=[CH2:38])[C@@H:9]1[C:30]1[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc([C@H]2[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)OCCN2Cc2ccccc2)cc1
Reactant: C1CCOC1
Agent: [Ti+2]
Agent: C[c-]1cccc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C=C(O[C@H]1OCCN(Cc2ccccc2)[C@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 69 %

Procedure:
A solution of 4-benzyl-2-(R)-[3,5-bis(trifluoromethyl)benzyloxy]-3-(S)-(4-fluorophenyl)morpholine (2.50 g, 4.9 mmol) and dimethyl titanocene (2.50 g, 12.0 mmol) in 35 ml of a 1:1 v/v tetrahydrofuran:toluene mixture is stirred in an oil bath at 80° C. for sixteen hours. The reaction mixture is cooled and centrated in vacuo. Flash chromatography on 150 grams of silica gel using 3:1 v/v hexanes:methylene chloride as the eluant affords 1.71 grams (69%) of the title compound as a solid. If desired, an anlytical sample may be obtained by recrystallization from isopropanol.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[S:9][CH:10]=[CH:11][N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:13][C:14]1[C:15](Cl)=[C:16]([N+:21]([O-:23])=[O:22])[C:17]([NH2:20])=[N:18][CH:19]=1>CC(O)C.CCN(C(C)C)C(C)C>[Br:13][C:14]1[C:15]([N:4]2[CH2:3][CH2:2][N:1]([CH2:7][C:8]3[S:9][CH:10]=[CH:11][N:12]=3)[CH2:6][CH2:5]2)=[C:16]([N+:21]([O-:23])=[O:22])[C:17]([NH2:20])=[N:18][CH:19]=1
Reactant: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Reactant: c1csc(CN2CCNCC2)n1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncc(Br)c(N2CCN(Cc3nccs3)CC2)c1[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 17 h
Yield: 59 %

Procedure:
The resulting 2-(piperazin-1-ylmethyl)thiazole (supposedly 0.580 g, 3.18 mmol, 1 eq) was suspended in iPrOH (3.1 mL) and DIPEA (2.2 mL). To this solution, 5-bromo-4-chloro-3-nitropyridin-2-amine (0.800 g, 3.18 mmol, 1 eq) was added and the reaction mixture was heated and stirred for 17 h at 65° C. The mixture was filtered, washed with iPrOH (3×3 mL), Et2O (2×3 mL) and dried to give the title compound as a bright yellow powder (0.750 g, 59%); 1H-NMR (500 MHz, DMSO-d6): δ 2.65 (br s, 4H, piperazine N(CH2)2), 3.09 (m, 4H, piperazine N(CH2)2), 3.90 (s, 2H, NCH2), 6.98 (s, 2H, NH2), 7.66 (d, J=3.0 Hz, 1H, thiazole 5-H), 7.72 (d, J=3.0 Hz, 1H, thiazole 4-H), 8.16 (s, 1H, pyridine 6-H); LC (Method B)-MS (ESI, m/z): Rt=2.90 mins-399/401 [(M+H+), Br isotopic pattern, 100%].
Reaction SMILES: C[O:2][C:3]([CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]2[N:13]([CH:15]=[N:16][CH:17]=2)[CH:14]=1)=[O:4]>C(O)C.[OH-].[Na+].O>[C:3]([CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]2[N:13]([CH:15]=[N:16][CH:17]=2)[CH:14]=1)([OH:4])=[O:2]
Reactant: COC(=O)CCCCc1ccc2cncn2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCCCc1ccc2cncn2c1

Procedure:
A solution of 6-(4-methoxycarbonylbutyl)-imidazo[1,5-a]pyridine in 0.3 ml of ethanol and 0.8 ml of 1N sodium hydroxide, is refluxed gently for 2 hours, cooled, diluted with 2 ml of water and extracted with ethyl acetate (5 ml). The aqueous phase is brought to pH=6 and is extracted with chloroform. The extracts are dried and evaporated to yield 6-(4-carboxybutyl)-imidazo[1,5-a]pyridine, melting at 168°-171°.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([N:7]2[CH2:11][CH2:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[C:8]2=[O:23])[S:4][C:3]=1[C:24]([O:26]CC)=[O:25].[OH-].[Na+].Cl>C(O)C>[CH3:1][C:2]1[CH:6]=[C:5]([N:7]2[CH2:11][CH2:10][N:9]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:17][CH:18]=3)[C:8]2=[O:23])[S:4][C:3]=1[C:24]([OH:26])=[O:25]
Reactant: CCOC(=O)c1sc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(=O)O
Temperature: 0 °C
Yield: 91 %

Procedure:
A mixture of ethyl 3-methyl-5-(2-oxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-1-yl)thiophene-2-carboxylate (4.31 g, 10.5 mmol) and 1 N aqueous sodium hydroxide solution (60 mL, 60 mmol) in ethanol (120 mL) was stirred at reflux for 1.5 h, then cooled to 0° C. and acidified with 10% aqueous hydrochloric acid to pH ˜2. The white precipitate was filtered, washed with water and ethanol, and then dried in vacuo to afford the title compound as a colorless solid in 91% yield (3.68 g): 1H NMR (300 MHz, DMSO-d6) δ 12.37 (br s, 1H), 7.74 (d, J=8.1 Hz, 2H), 7.53 (d, J=8.1 Hz, 2 H), 6.30 (s, 1H), 4.50 (s, 2H), 3.90-3.81 (m, 2H), 3.52-3.44 (m, 2H), 2.40 (s, 3H): MS (ES+) m/z 385.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][C:13]2([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][OH:27])=[CH:21][CH:20]=3)[CH2:17][CH2:16][CH2:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.F[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1.C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH2:12][C:13]2([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][O:27][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)=[CH:21][CH:20]=3)[CH2:14][CH2:15][CH2:16][CH2:17]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=S(=O)(NCC1(Cc2ccc(CCO)cc2)CCCC1)c1ccc(Cl)cc1
Reactant: Fc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=S(=O)(NCC1(Cc2ccc(CCOc3ccccn3)cc2)CCCC1)c1ccc(Cl)cc1
Reaction time: 0.07 h
Yield: 22.3 %

Procedure:
A mixture of 30 mg (0.074 mmol) of 4-chloro-N-({1-[4-(2-hydroxyethyl)benzyl]cyclopentyl}methyl]benzenesulfonamide (EP 472449), 130 μl (1.48 mmol) of 2-fluoropyridine and 16.576 mg (0.148 mmol) of potassium carbonate is irradiated in a microwave oven (600 W max.), at a maximum temperature of 120° C. for 4 minutes. The crude reaction medium is purified by preparative LC-MS to give 8 mg of the expected compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[C:6]([C:8]2[CH:13]=[C:12](Cl)[N:11]=[C:10]([NH2:15])[N:9]=2)[CH:7]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[C:6]([C:8]2[N:9]=[C:10]([NH2:15])[N:11]=[C:12]([NH:28][C:25]3[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=3)[CH:13]=2)[CH:7]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: COCCOc1ccc(Br)cc1-c1cc(Cl)nc(N)n1
Product: COCCOc1ccc(Br)cc1-c1cc(Nc2ccc(Cl)cc2)nc(N)n1
Yield: 79 %

Procedure:
Following the method described in Example 4, 4-[5-bromo-2-(2-methoxy-ethoxy)-phenyl)-6-chloro-pyrimidin-2-ylamine and 4-chloro-phenylamine provided the title compound (79% yield). 1H NMR (DMSO-d6) δ 3.26 (s, 3H, CH3), 3.71 (t, 2H, J=4.7 Hz, CH2), 4.19 (t, 2H, J=4.4 Hz, CH2), 6.36 (s, 2H, NH2), 6.74 (s, 1H, Ar), 7.11 (d, 1H, J=8.8 Hz, Ar), 7.31 (d, 2H, J=8.8 Hz, Ar), 7.52 (dd, 1H, J=8.8 Hz, J=2.6 Hz, Ar), 7.76 (d, 2H, J=8.7 Hz, Ar), 8.01 (d, 1H, J=2.6 Hz, Ar), 9.27 (s, 1H, NH).
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([NH:9][C:10](=[O:20])[C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[O:18][CH3:19])=[N:6][C:5]=1[CH3:21])(=[O:3])[CH3:2].Br[CH2:23][CH2:24][CH2:25][CH3:26].CC(C)([O-])C.[K+]>CN(C)C=O>[C:1]([C:4]1[S:8]/[C:7](=[N:9]\[C:10](=[O:20])[C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[O:18][CH3:19])/[N:6]([CH2:23][CH2:24][CH2:25][CH3:26])[C:5]=1[CH3:21])(=[O:3])[CH3:2]
Reactant: COc1ccc(Cl)cc1C(=O)Nc1nc(C)c(C(C)=O)s1
Reactant: CCCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCn1c(C)c(C(C)=O)s/c1=N\C(=O)c1cc(Cl)ccc1OC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of Example 238A (0.40 g, 1.2 mmol), 1-bromobutane (0.16 mL, 1.5 mmol), and potassium t-butoxide (0.22 g, 1.9 mmol) in 5 mL N,N-dimethylformamide was warmed to 65° C. and stirred for 20 hours. The mixture was cooled to ambient temperature quenched with 5 mL of saturated aqueous NH4Cl and diluted with 5 mL of ethyl acetate. The layers were separated and the aqueous phase was extracted twice with 5 mL of ethyl acetate. The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification via column chromatography (SiO2, 40% hexanes in ethyl acetate) afforded the title compound. 1H NMR (300 MHz, CD3OD) δ ppm 1.04 (t, J=7.3 Hz, 3H), 1.42-1.55 (m, 2H), 1.77-1.90 (m, 2H), 2.51 (s, 3H), 2.76 (s, 3H), 3.889 (s, 3H), 4.32-4.41 (m, 2H), 7.10 (d, J=8.8 Hz, 1H), 7.45 (dd, J=8.8, 2.7 Hz, 1H), 7.99 (d, J=3.1 Hz, 1H); MS (DCI/NH3) m/z 381 (M+H)+. Anal. Calculated for C18H21ClN2O3S: C, 56.76; H, 5.56, N, 7.35. Found: C, 56.68; H, 5.49; N, 7.26.