Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3[CH2:17][S:16][C:15](=[O:18])[NH:14][N:13]=3)=[CH:11][C:6]=2[N:5]=[C:4]1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1)[CH3:2].Br[CH2:28][CH2:29][O:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][O:32]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3[CH2:17][S:16][C:15](=[O:18])[N:14]([CH2:28][CH2:29][O:30][CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][O:32]4)[N:13]=3)=[CH:11][C:6]=2[N:5]=[C:4]1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1)[CH3:2]
Reactant: CCn1c(-c2cccc(OC)c2)nc2cc(C3=NNC(=O)SC3)ccc21
Reactant: BrCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(-c2cccc(OC)c2)nc2cc(C3=NN(CCOC4CCCCO4)C(=O)SC3)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
To 200 mg (0.55 mM) of 5-[1-ethyl-2-(3-methoxyphenyl)-1H-benzimidazol-5-yl]-3,6-dihydro-2H-1,3,4-thiadiazin-2-one in 4 ml of dimethylformamide are added 91 μl (0.6 mM) of 2-(2-bromoethoxy)tetrahydro-2H-pyran and 533.5 mg (1.64 mM) of caesium carbonate. The reaction medium is then stirred at room temperature for 16 hours. Demineralised water is added and the organic phase is isolated, washed with demineralised water and then dried over anhydrous sodium sulfate. The solvent is then evaporated off under vacuum and the residue is purified by chromatography on silica, using a dichloromethane/acetone mixture (90/10) as eluent, to give 200 mg of 5-[1-ethyl-2-(3-methoxyphenyl)-1H-benzimidazol-5-yl]-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-3,6-dihydro-2H-1,3,4-thiadiazin-2-one in the form of an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]#[N:13])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH:14](Br)([CH3:16])[CH3:15].[H-].[Na+]>CN(C=O)C>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH:11]([CH:14]([CH3:16])[CH3:15])[C:12]#[N:13])[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(CC#N)cc(OC)c1
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OC)cc(C(C#N)C(C)C)c1

Procedure:
This is prepared by reacting a solution of 2-(3,5-dimethoxyphenyl)-acetonitrile (4 g, 0.022 mol) in 10 cc of DMF with 2.86 g of isopropyl bromide in 5 cc of DMF, in the presence of a 50% suspension of 1.1 g of sodium hydride in 25 cc of DMF.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[F:15][C:16]1[CH:17]=[C:18]([CH:28]=[CH:29][C:30]=1[N+:31]([O-:33])=[O:32])[CH2:19]P(=O)(OCC)OCC.[H-].[Na+].O>O1CCCC1>[F:15][C:16]1[CH:17]=[C:18]([CH:28]=[CH:29][C:30]=1[N+:31]([O-:33])=[O:32])[CH:19]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])c(F)c1)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(=Cc2ccc([N+](=O)[O-])c(F)c2)CC1
Reaction time: 4 h
Yield: 64.8 %

Procedure:
tert-Butyl 4-oxopiperidine-1-carboxylate (126 mmol, 25.04 g) and diethyl 3-fluoro-4-nitrobenzylphosphonate (126 mmol, 36.6 g) in tetrahydrofuran (220 mL) were stirred and sodium hydride (163 mmol, 6.54 g, 60% in oil) was added. The reaction was stirred for 4 hours and then water was added. The reaction was extracted with dichloromethane and the organics were dried (magnesium sulfate), filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with dichloromethane to give a bright yellow solid. This solid was filtered, washed with heptane and vacuum dried to afford the title compound (27.47 g). 1H NMR (CDCl3, 400 MHz): δ 8.1 (t, 1H), 7.1 (s, 1H), 7.05 (s, 1H), 6.35 (s, 1H), 3.55 (m, 2H), 3.45 (m, 2H), 2.52 (m, 2H), 2.4 (m, 2H), 1.49 (s, 9H)
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][O:7][CH2:8][C:9]2[CH:10]=[CH:11][C:12]([NH2:16])=[N:13][C:14]=2[CH3:15])=[CH:4][CH:3]=1.[F:19][C:20]([F:32])([F:31])[C:21]1[CH:22]=[C:23]([S:27](Cl)(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][CH2:8][C:9]2[CH:10]=[CH:11][C:12]([NH:16][S:27]([C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([C:20]([F:19])([F:31])[F:32])[CH:22]=3)(=[O:29])=[O:28])=[N:13][C:14]=2[CH3:15])=[CH:17][CH:18]=1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: Cc1nc(N)ccc1COCc1ccc(F)cc1
Product: Cc1nc(NS(=O)(=O)c2cccc(C(F)(F)F)c2)ccc1COCc1ccc(F)cc1

Procedure:
This material was prepared in analogy to example 1 from 5-(4-fluoro-benzyloxymethyl)-6-methyl-pyridin-2-ylamine (0.08 g) and 3-(trifluoromethyl)-benzenesulfonyl chloride (0.087 g) as an amorphous orange solid (0.1 g). MS (ESI−): 453.2 ([M−H]−)
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[CH2:14][C@@H:13]([N:15]2[CH:23]=[N:22][C:21]3[C:16]2=[N:17][CH:18]=[N:19][C:20]=3Cl)[CH2:12][C@@H:11]1[OH:25])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:33]1([C:39]#[CH:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Si:1]([O:8][CH2:9][C@H:10]1[CH2:14][C@@H:13]([N:15]2[CH:23]=[N:22][C:21]3[C:16]2=[N:17][CH:18]=[N:19][C:20]=3[C:40]#[C:39][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:12][C@@H:11]1[OH:25])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C#Cc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1C[C@@H](n2cnc3c(Cl)ncnc32)C[C@@H]1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC[C@H]1C[C@@H](n2cnc3c(C#Cc4ccccc4)ncnc32)C[C@@H]1O
Reaction time: 3 h
Yield: 82.3 %

Procedure:
A solution of (1S,2R,4R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-(6-chloro-9H-purin-9-yl)cyclopentanol (0.1 g, 0.26 mmol), Pd(PPh3)2Cl2 (0.006 g, 0.0089 mmol), CuI (0.004 g, 0.02 mmol) and triethylamine (0.145 mL, 1.04 mmol) in DMF (5 mL) was heated at 70° C. under argon for 1 h. Phenylacetylene (0.057 mL, 0.52 mmol) was added, the reaction mixture was stirred for 3 h, and the reaction was concentrated. The residue was dissolved in DCM and washed with saturated aq NaHCO3 and saturated aq EDTA.Na2 acid. The organic layer was dried (Na2SO4), concentrated and purified by flash chromatography (0 to 50% EtOAc/DCM) to afford the title compound (0.096 g, 82%).
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.Cl[CH2:18][C:19]1[CH:37]=[CH:36][C:22]([O:23][CH2:24][C:25]2[N:26]=[C:27]([C:31]3[O:32][CH:33]=[CH:34][CH:35]=3)[O:28][C:29]=2[CH3:30])=[C:21]([O:38][CH3:39])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:32]1[CH:33]=[CH:34][CH:35]=[C:31]1[C:27]1[O:28][C:29]([CH3:30])=[C:25]([CH2:24][O:23][C:22]2[CH:36]=[CH:37][C:19]([CH2:18][O:1][C:2]3[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:4]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[N:3]=3)=[CH:20][C:21]=2[O:38][CH3:39])[N:26]=1
Reactant: COC(=O)c1cc(O)nn1-c1ccccc1
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccco2)oc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(OCc2ccc(OCc3nc(-c4ccco4)oc3C)c(OC)c2)nn1-c1ccccc1
Temperature: 90 °C
Reaction time: 15 h
Yield: 93.7 %

Procedure:
A mixture of methyl 3-hydroxy-1-phenyl-1H-pyrazole-5-carboxylate (5.60 g), 4-(4-chloromethyl-2-methoxyphenoxymethyl)-2-(2-furyl)-5-methyloxazole (9.45 g), potassium carbonate (3.55 g) and N,N-dimethylformamide (200 ml) was stirred at 90° C. for 15 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to give methyl 3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxybenzyloxy]-1-phenyl-1H-pyrazole-5-carboxylate (12.40 g, yield 94%). The crystals were recrystallized from ethyl acetate-hexane. melting point: 146–147° C.
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]3[CH:15]=[C:14]([C:16]([O:18]CC)=[O:17])[CH:13]=[CH:12][C:10]=3[N:11]=2)C=CC=CC=1.[Li+].[OH-].Cl>C1COCC1.O>[S:8]1[CH:9]=[CH:10][N:11]=[C:1]1[C:7]1[S:8][C:9]2[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[CH:13]=[CH:12][C:10]=2[N:11]=1
Reactant: CCOC(=O)c1ccc2nc(-c3ccccc3)sc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc2nc(-c3nccs3)sc2c1
Yield: 186.4 %

Procedure:
Ethyl 2-phenyl-benzothiazole-6-carboxylate 9q (130 mg, 0.45 mmol) was stirred with LiOH (43 mg, 1.8 mmol) in THF (4 mL) and H2O (2 mL) for 6 h. Aqueous 1N HCl solution was added to the mixture to adjust pH to 3-4. The resulting mixture was extracted with EtOAc (2×). The organic solution was washed with aq. NaCl, dried over Na2SO4 and concentrated to give 9r (110 mg).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[C:35]([CH2:39][C:40]#[N:41])[CH:36]=[CH:37][CH:38]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.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>[CH:18]1([N:9]2[C:10]3[CH:15]=[CH:14][N:13]=[C:12]([O:16][CH3:17])[C:11]=3[C:7]([C:33]3[CH:34]=[C:35]([CH2:39][C:40]#[N:41])[CH:36]=[CH:37][CH:38]=3)=[N:8]2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: COc1nccc2c1c(OS(=O)(=O)C(F)(F)F)nn2C1CCCC1
Reactant: CC1(C)OB(c2cccc(CC#N)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1nccc2c1c(-c1cccc(CC#N)c1)nn2C1CCCC1
Yield: 87.2 %

Procedure:
A solution of 1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (160 mg) obtained in Step C of Example 12, (3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetonitrile (160 mg), tetrakis(triphenylphosphine)palladium(0) (50.6 mg) and 2M aqueous sodium carbonate solution (1.10 mL) in DME (10 mL) was heated overnight with reflux under nitrogen atmosphere. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (127 mg).
Reaction SMILES: Br.[NH2:2][CH2:3][C:4]([NH:6][C@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[NH:13][C:14](=[O:25])[C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1)=[O:5].[Cl:26][C:27]1[CH:28]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1.CCOC(C)=O>CN(C=O)C>[NH2:24][S:21]([C:18]1[CH:17]=[CH:16][C:15]([C:14]([NH:13][C@@H:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C@@H:7]2[NH:6][C:4](=[O:5])[CH2:3][NH:2][S:33]([C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([Cl:26])[CH:28]=2)(=[O:35])=[O:34])=[O:25])=[CH:20][CH:19]=1)(=[O:23])=[O:22]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: NCC(=O)N[C@H]1CCCC[C@H]1NC(=O)c1ccc(S(N)(=O)=O)cc1
Agent: Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1ccc(C(=O)N[C@@H]2CCCC[C@@H]2NC(=O)CNS(=O)(=O)c2cccc(Cl)c2)cc1
Reaction time: 8 h
Yield: 29.4 %

Procedure:
N-(cis)-{2-[(aminoacetyl)amino]cyclohexyl}-4-(aminosulfonyl)benzamide hydrogen bromide, (61b), (70 mg) was dissolved in DMF (2.5 mL) prior to the addition of 3-chlorobenzenesulfonyl chloride (51 mg). After stirring overnight, EtOAc was added and the solution was washed with 1N HCl. The EtOAc was dried, filtered, and concentrated. Reverse phase HPLC purification (gradient elution, water/acetonitrile/TFA) of the resulting residue provided the title benzamide (25 mg). MS found: (M+H)+=530.1.
Reaction SMILES: [H-].[Na+].[CH:3]1([C:8]([O:10]C)=O)[CH2:7][CH2:6][CH2:5][CH2:4]1.[C:12](#[N:14])[CH3:13]>C1COCC1.C(OCC)(=O)C.Cl>[CH:3]1([C:8](=[O:10])[CH2:13][C:12]#[N:14])[CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CC#N
Reactant: COC(=O)C1CCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#CCC(=O)C1CCCC1
Temperature: 71 °C
Reaction time: 16 h

Procedure:
To a suspension of NaH (2.75 g, 68.7 mmol) in THF (15 mL) at 70° C. was added dropwise a solution of methyl cyclopentanecarboxylate (8.00 g, 62.4 mmol) and anhydrous acetonitrile (3.91 mL, 74.9 mmol) in THF (5 mL). The mixture was stirred for 16 h at 70-72° C., cooled to rt, and diluted with ethyl acetate and aqueous HCl. The organic layer was washed with water and brine and dried (MgSO4). Removal of the solvent provided 3-cyclopentyl-3-oxopropanenitrile, which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([OH:16])[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4].C([O-])([O-])=O.[K+].[K+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc(O)c2c(c1)OC(C)(C)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCc2ccccc2)c2c(c1)OC(C)(C)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
4-Hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (3e) was dissolved in DMF (50 mL). K2CO3 (6.48 g, 46.9 mmol) and benzyl bromide (2.80 mL, 23.6 mmol) were added. The reaction mixture was stirred at room temperature overnight, quenched with H2O (150 mL), and extracted with EtOAc (2×150 mL). The organic layers were dried over MgSO4 and concentrated to give a white solid (7.18g, 98% yield) which was used as it is for the next step. 1H NMR (400 MHz, CDCl3) δ 7.34-7.46 (m, 5 H) 7.21 (s, 1 H) 7.08 (s, 1 H) 5.13 (s, 2 H) 3.90 (s, 3 H) 3.02 (s, 2 H) 1.49 (s, 6 H); LCMS for C19H20O4 m/z 313.20 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:47][NH:48][CH3:49]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([CH2:40][C:41]([N:48]([CH3:49])[CH3:47])=[O:42])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CNC
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N(C)C)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-Butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with dimethylamine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C38H48Cl2N5O3 [(M+H)+] 692.3129, observed 692.3129.
Reaction SMILES: [F:1][CH:2]([F:18])[C:3]1[N:4]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[S:6][C:7]=1[CH2:8]O.C(N(CC)CC)C.CS([Cl:30])(=O)=O>ClCCl>[Cl:30][CH2:8][C:7]1[S:6][C:5]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[N:4][C:3]=1[CH:2]([F:18])[F:1]
Reactant: COc1ccc(-c2nc(C(F)F)c(CO)s2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-c2nc(C(F)F)c(CCl)s2)cc1
Temperature: 25 °C

Procedure:
2.70 g [4-Difluoromethyl-2-(4-methoxy-phenyl)-thiazol-5-yl]-methanol were dissolved in 15 ml dichloromethane and cooled in an ice bath. 2.07 ml triethylamine were added, followed by the addition of 0.92 ml methanesulfonylchloride. The ice bath was removed and the resulting mixture stirred at room temperature over night. Then 2.07 ml triethylamine and 0.92 ml methanesulfonylchloride were added again and the reaction mixture stirred at room temperature for additional four hours. The reaction mixture was then washed with water and brine, dried over MgSO4 and the solvent removed in vacuo to obtain 3.0 g crude 5-chloromethyl-4-difluoromethyl-2-(4-methoxy-phenyl)-thiazole as an oil which was used without further purification.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH:13]([OH:24])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)=[O:7])(C)(C)C.[C:25]([O:29][C:30]([N:32]1[CH2:39][CH2:38][CH2:37][C@H:33]1C(O)=O)=[O:31])([CH3:28])([CH3:27])[CH3:26].CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>Cl.O1CCOCC1>[C:25]([O:29][C:30]([N:32]1[CH2:39][CH2:38][CH2:37][C@H:33]1[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH:13]([OH:24])[CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)=[O:7])=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: COc1ccc(OCC(O)[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: C1COCCO1
Product: COc1ccc(OCC(O)[C@@H]2CCCN2C(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
(2S)-1-(tert-Butoxycarbonyl)-2-[1-hydroxy-2-(4-methoxyphenoxy)ethyl]pyrrolidine (1.57 g) was dissolved in 4N hydrochloric acid/1,4-dioxane (23 ml), and the mixture was stirred at room temperature for 1 hour. The residue obtained by concentration and drying of the reaction mixture was dissolved in DMF (15 ml), and subjected to the condensation reaction using N-(tert-butoxycarbonyl)-L-proline (1.00 g), N-methylmorpholine (0.51 ml), HOBt (0.75 g) and DCC (0.96 g) in the same manner as in Example 46-C) to give 1.41 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]1([CH2:16][C:17]([OH:19])=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(OC(=O)C)(=O)C>C(N(CC)CC)C>[C:10]1([C:16](=[CH:6][C:5]2[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:17]([OH:19])=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: O=C(O)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: O=C(O)C(=Cc1ccc(Cl)cc1)c1ccccc1

Procedure:
A mixture of 56.2 g 4-chlorobenzaldehyde, 54.4 g phenylacetic acid, 80 ml acetic anhydride and 40 ml triethylamine was refluxed for 5 hours. Unreacted 4-chlorobenzaldehyde was removed by steam distillation and the residue dissolved in aqueous alcohol and treated with decolourising carbon. Crystals of α-phenyl-4-chlorocinnamic acid were obtained on acidification of the solution. The product was recrystallised from alcohol and found to have a melting point of 202°-4° C. The chlorosulphonyl derivative was prepared according to the method described in Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:10][C:11]2[C:16]([Cl:17])=[CH:15][N:14]=[C:13]([NH:18][C:19]3[N:23]([CH:24]([CH3:26])[CH3:25])[N:22]=[C:21]([CH3:27])[CH:20]=3)[CH:12]=2)=C([CH:9]=1)C#N.[OH-].[Na+].[C:30]([O:33]CC)(=[O:32])[CH3:31]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:10][C:11]2[C:16]([Cl:17])=[CH:15][N:14]=[C:13]([NH:18][C:19]3[N:23]([CH:24]([CH3:25])[CH3:26])[N:22]=[C:21]([CH3:27])[CH:20]=3)[CH:12]=2)=[C:31]([CH:9]=1)[C:30]([OH:33])=[O:32]
Reactant: Cc1cc(Nc2cc(Nc3ccc(Cl)cc3C#N)c(Cl)cn2)n(C(C)C)n1
Reactant: CCOC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1cc(Nc2cc(Nc3ccc(Cl)cc3C(=O)O)c(Cl)cn2)n(C(C)C)n1
Yield: 90 %

Procedure:
A solution of 5-chloro-2-[(5-chloro-2-{[3-methyl-1-(1-methylethyl)-1H-pyrazol-5-yl]amino}-4-pyridinyl)amino]benzonitrile (850 mg, 2.118 mmol) in sodium hydroxide-1 M (20 mL, 20.00 mmol) and 1,4-dioxane (20 mL) was refluxed overnight. Ethyl acetate was added and the layers were separated. The organic layer was washed with 1 M NaOH (40 ml). Combined aqueous layers were washed with ethyl acetate. The organic layers were combined, evaporated, dissolved in MeOH and evaporated again. 5-Chloro-2-[(5-chloro-2-{[3-methyl-1-(1-methylethyl)-1H-pyrazol-5-yl]amino}-4-pyridinyl)amino]benzoic acid (800 mg, 1.903 mmol, 90% yield) was isolated as a yellow solid. 1H NMR (400 MHz, DMSO-d6) ppm 1.28 (d, J=6.57 Hz, 6 H) 2.12 (s, 3 H) 4.40 (quin, J=6.51 Hz, 1 H) 5.97 (s, 1 H) 6.79 (s, 1 H) 7.56-7.62 (m, 1 H) 7.62-7.69 (m, 1 H) 7.94 (d, J=2.27 Hz, 1 H) 8.04 (s, 1 H) 8.58 (s, 1 H) 9.94 (br. s., 1 H) 13.97 (br. s., 1 H); HPLC Rt=2.65 min, MS (ESI): 420.2, 421.1 [M+H]+.
Reaction SMILES: Cl.Cl.[CH:3]1([C:6]([CH:8]([N:16]2[CH2:21][CH2:20][C:19]3[S:22][C:23]([N+:25]([O-])=O)=[CH:24][C:18]=3[CH2:17]2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])=[O:7])[CH2:5][CH2:4]1.[Sn]>O>[NH2:25][C:23]1[S:22][C:19]2[CH2:20][CH2:21][N:16]([CH:8]([C:6]([CH:3]3[CH2:5][CH2:4]3)=[O:7])[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[F:15])[CH2:17][C:18]=2[CH:24]=1
Reactant: O=C(C1CC1)C(c1ccccc1F)N1CCc2sc([N+](=O)[O-])cc2C1
Agent: Cl
Agent: [Sn]
Solvent: O
Product: Nc1cc2c(s1)CCN(C(C(=O)C1CC1)c1ccccc1F)C2
Yield: 72 %

Procedure:
5 ml of hydrochloric acid were added to 0.4 g of 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-nitro-4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride (prepared as described in Example 18), and then 0.23 g of tin powder was added to the resulting mixture, whilst stirring, after which the mixture was stirred at room temperature for a further hour. 10 ml of water were added to the reaction mixture, which was then extracted with methylene chloride. The methylene chloride layer was removed, and the aqueous layer was concentrated to dryness by evaporation under reduced pressure, and then crystallized from diethyl ether, to give a complex of the title compound with stannic chloride as a pale yellow powder in a yield of 72%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].[CH:11]1(Br)[CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH:11]1([O:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: BrC1CCCC1
Reactant: O=[N+]([O-])c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccccc1OC1CCCC1
Yield: 46.8 %

Procedure:
2-Nitrophenol (83.5 g, 0.60 mole), cyclopentyl bromide (98.0 g, 0.66 mole), anhydrous potassium carbonate (82.9 g, 0.60 mole) and dry acetone (600 cc) were refluxed for 72 hrs., and filtered to remove the potassium bromide. The residue was washed with acetone and the solvent was removed by rotary evaporation. The residue was partitioned between 200 cc of dichloromethane and water. The dichloromethane layer was washed with 200 cc of 10% potassium hydroxide, separated and the solvent was removed by rotary evaporation. The crude product was fractionally distilled at 144°-146° C. at 1.0 mm. Hg to yield 58.2 g of product (46.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17]CC)=[O:16])[CH:13]=2)[N:8]=[C:7]([CH3:20])[C:6]1=[O:21].[OH-].[Na+].CO.Cl>O>[C:15]([C:12]1[CH:13]=[C:14]2[C:9]([N:8]=[C:7]([CH3:20])[C:6](=[O:21])[N:5]2[CH2:4][C:3]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:2]=2[Cl:1])=[CH:10][CH:11]=1)([OH:17])=[O:16]
Reactant: CCOC(=O)c1ccc2nc(C)c(=O)n(Cc3ccc(Cl)cc3Cl)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1nc2ccc(C(=O)O)cc2n(Cc2ccc(Cl)cc2Cl)c1=O
Yield: 77.6 %

Procedure:
1-(2,4-Dichlorobenzyl)-7-(ethoxycarbonyl)-3-methyl-2(1H)-quinoxalinone (0.50 g) in a mixture of a 5% aqueous sodium hydroxide solution (3 g) and methanol (20 ml) was heated under reflux for 1 hr. After cooling, concentrated hydrochloric acid (4 ml) and water (10 ml) were added to the reaction mixture and the precipitate was collected by filtration. The precipitate was washed with water (30 g) and dried to give the object compound (0.36 g) as yellow crystals.