Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=2[F:16])[CH:5]=[C:4]([Cl:17])[N:3]=1.[CH3:18][C:19]1[N:20]=[C:21]([NH2:24])[S:22][CH:23]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>C1(C)C=CC=CC=1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:17][C:4]1[N:3]=[C:2]([NH:24][C:21]2[S:22][CH:23]=[C:19]([CH3:18])[N:20]=2)[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=2[F:16])[CH:5]=1
Reactant: Cc1csc(N)n1
Reactant: Fc1cccc(F)c1Oc1cc(Cl)nc(Cl)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1csc(Nc2cc(Oc3c(F)cccc3F)cc(Cl)n2)n1
Temperature: 90 °C

Procedure:
A mixture of 2,6-dichloro-4-(2,6-difluorophenoxy)pyridine (552 mg, 2.0 mmol), 4-methylthiazol-2-amine (228 mg, 2.0 mmol), potassium phosphate (466 mg, 2.20 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.092 g, 0.100 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.167 g, 0.100 mmol) in degassed toluene (5 mL) and water (2 mL) is heated at 90° C. for 12 hours and then cooled to room temperature. The reaction mixture is partitioned between water and ethyl acetate to afford N-(6-chloro-4-(2,6-difluorophenoxy)pyridin-2-yl)-4-methylthiazol-2-amine.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.Cl.[CH2:11](O)[CH3:12]>>[CH3:2][N:3]1[CH2:8][CH2:7][C:6]2[NH:3][C:4]3[C:11]([CH3:12])=[CH:8][CH:7]=[CH:6][C:5]=3[C:5]=2[CH2:4]1
Reactant: CCO
Reactant: CN1CCC(=O)CC1
Agent: Cl
Product: Cc1cccc2c3c([nH]c12)CCN(C)C3
Temperature: 80 °C
Reaction time: 5 h

Procedure:
O-Tolyl hydrazine hydrochloride (3.0 g, 18.9 mmol) was dissolved in of ethanol (10 mL), 1-methylpiperidin-4-one hydrochloride (2.8 g, 18.9 mmol) and ethanolic HCl (10 mL) was added (pH acidic) and stirred at 80° C. for 5 h. Reaction was monitored by TLC. After completion of the reaction, reaction mixture was concentrated under vacuum. Residue was dissolved in aq NaHCO3 solution, extracted with EtOAc. Organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford 2.5 g of 2,6-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CDCl3, free base) δ (ppm) 7.65 (s, 1H), 7.01 (t, 1H), 6.9 (d, 1H), 3.61 (s, 2H), 2.89-2.80 (m, 4H), 2.58 (s, 3H), 2.41 (s, 3H).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([O:19][CH3:20])([CH3:18])[CH3:17])[N:11]=1)(C(C)(C)C)(C)C>CC(O)=O.C1COCC1.O>[OH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([O:19][CH3:20])([CH3:17])[CH3:18])[N:11]=1
Reactant: COC(C)(C)c1cccc(CO[Si](C)(C)C(C)(C)C)n1
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: COC(C)(C)c1cccc(CO)n1
Yield: 100.1 %

Procedure:
A solution of 2-tert-butyldimethylsilyloxymethyl-6-(1-methoxy-1-methylethyl)pyridine (1.20 g, 4.08 mmol) in AcOH (45 mL), THF (15 mL) and H2O (15 mL) was stirred for 48 h at room temperature. The solvent was removed in vacuo, the residue was partitioned between DCM and sat aq NaHCO3, the organic portion was separated, dried (MgSO4), filtered and evaporated to give the title compound (740 mg, 100%) as a colourless oil; NMR δH (400 MHz, CDCl3) 7.70-7.66 (1H, m), 7.48-7.45 (1H, m), 7.07-7.04 (1H, m), 4.74 (2H, d, J 5.0 Hz), 4.14 (1H, t, J 5.0 Hz), 3.18 (3H, s), 1.57 (6H, s).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])/[CH:7]=[CH:8]/[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([F:18])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6](=[O:19])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([F:18])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc([N+](=O)[O-])c(F)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CCc1ccc(N)c(F)c1
Yield: 99.7 %

Procedure:
A solution of (E)-3-(3-fluoro-4-nitro-phenyl)-acrylic acid tert-butyl ester (804 mg, 3.01 mmol) in ethyl acetate (10 ml) was hydrogenated on 10% palladium on charcoal for 30 min at 1.5 bar. The suspension was filtered, the filter cake washed with ethyl acetate and the filtrate evaporated and dried under high vacuum to give the product as light brown solid (713 mg, 3 mmol; 99%). This material was pure enough for the next step. MS: m/e=240.0 [M+H+].
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH2:6][S:7][C@@H:8]2[CH:15]([NH:16][C:17](=[O:46])[C:18]([C:21]3[N:22]=[C:23]([NH:26]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[S:24][CH:25]=3)=[N:19][OH:20])[C:14](=[O:47])[N:9]2[C:10]=1[C:11]([OH:13])=[O:12])=[N+:2]=[N-:3].C(O)=O.O>O>[N:1]([CH2:4][C:5]1[CH2:6][S:7][C@@H:8]2[CH:15]([NH:16][C:17](=[O:46])[C:18]([C:21]3[N:22]=[C:23]([NH2:26])[S:24][CH:25]=3)=[N:19][OH:20])[C:14](=[O:47])[N:9]2[C:10]=1[C:11]([OH:13])=[O:12])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NO)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Solvent: O=CO
Solvent: O
Product: [N-]=[N+]=NCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NO)c3csc(N)n3)[C@H]2SC1

Procedure:
A mixture of the product of Step B and 6 ml of 2-1 formic acid-water mixture was stirred at 45°-50° C. was stirred for 10 minutes and was diluted with 7 ml of water. The mixture was vacuum filtered and the filtrate was evaporated to dryness. The residue was added all at once to 10 ml of water and the mixture was triturated and vacuum filtered to obtain 0.95 g of the raw syn isomer of 3-azidomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylic acid.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:28][C:29]([CH3:38])([CH3:37])[CH2:30][C:31]1[N:32]=[C:33]([CH3:36])[NH:34][CH:35]=1>C(Cl)Cl>[CH3:28][C:29]([CH3:38])([CH3:37])[CH2:30][C:31]1[N:32]=[C:33]([CH3:36])[N:34]([C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:35]=1
Reactant: Cc1nc(CC(C)(C)C)c[nH]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(CC(C)(C)C)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Triethylamine (70 mL, 0.5 mol) followed by trityl chloride (90 g, 0.32 mol) were added to an ambient temperature solution of 4-(2,2-dimethylpropyl)-2-methyl-1H-imidazole (49 g, 0.32 mmol) in methylene chloride (1 L). After stirring at ambient temperature for 30 min, the reaction mixture was washed with water and brine, dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 10-20% ethyl acetate/hexane afforded the title compound.
Reaction SMILES: [C:1]1([C:7]2[CH:34]=[CH:33][C:10]([O:11][CH2:12][CH2:13][CH:14]3[CH2:20][CH2:19][C:18]4[C:21]([O:31]C)=[C:22]([O:29][CH3:30])[C:23]([O:27][CH3:28])=[C:24]([O:25]C)[C:17]=4[CH2:16][CH2:15]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C(C(O)=O)=CC=CC=1C(O)=O.C1COCC1.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>O>[CH3:28][O:27][C:23]1[C:24](=[O:25])[C:17]2[CH2:16][CH2:15][CH:14]([CH2:13][CH2:12][O:11][C:10]3[CH:9]=[CH:8][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:34][CH:33]=3)[CH2:20][CH2:19][C:18]=2[C:21](=[O:31])[C:22]=1[O:29][CH3:30]
Reactant: COc1c2c(c(OC)c(OC)c1OC)CCC(CCOc1ccc(-c3ccccc3)cc1)CC2
Agent: O=C(O)c1cccc(C(=O)O)n1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Solvent: C1CCOC1
Solvent: O
Product: COC1=C(OC)C(=O)C2=C(CCC(CCOc3ccc(-c4ccccc4)cc3)CC2)C1=O
Reaction time: 0.25 h
Yield: 38.4 %

Procedure:
To a mixture of 7-[2-(4-phenylphenoxy)ethyl]-1,2,3,4-tetramethoxy-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene (1.53 g), 2,6-pyridinedicarboxylic acid (1.66 g), THF (60 ml), and water (15 ml) was dropwise added a solution of CAN (7.24 g) in water (15 ml) with cooling with ice. After the reaction mixture was stirred for 15 min, water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and dried. The solvent was removed in vacuo. The residue was purified by alumina column chromatography (ethyl acetate) and then with recrystallization from hexane-ethyl acetate to yield the entitled compound (550 mg) as crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:11]O>Cl>[CH3:11][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Br:1])[CH:3]=[N:4][CH:5]=1
Reactant: O=C(O)c1cncc(Br)c1
Reactant: CO
Agent: Cl
Product: COC(=O)c1cncc(Br)c1
Reaction time: 60 h

Procedure:
5-Bromo-nicotinic acid (5,00 g, 24.7 mmol) was dissolved in methanol (50 mL) and saturated with hydrochloric acid gas. The reaction mixture was allowed to stand for 2.5 days and then filtered. The filtrate was concentrated under reduced pressure and methylene chloride was added. The solution was washed with saturated sodium bicarbonate solution. The aqueous wash was back-extracted with methylene chloride (2×). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo to afford 5-bromo-nicotinic acid methyl ester (4.72 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[NH2:16]>>[Cl:12][C:13]1[CH:14]=[C:15]([NH:16][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: COc1ccc(N)cc1Cl
Product: COc1ccc(Nc2ccccc2CC(=O)O)cc1Cl

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 3-chloro-4-methoxyaniline to yield 2-[(3-chloro-4-methoxyphenyl)amino]phenylacetic acid.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=2)[C:9]([O:11]C)=O)[CH:5]=[CH:4][N:3]=[CH:2]1.N1(C2C=C(C=CC=2)C(O)=O)C=CN=C1.[C:30]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])(=[O:32])[CH3:31].[Li]>OS(O)(=O)=O.CO>[C:34]([O:33][C:30](=[O:32])[CH2:31][C:9]([C:8]1[CH:13]=[CH:14][CH:15]=[C:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH:7]=1)=[O:11])([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(=O)OC(C)(C)C
Reactant: COC(=O)c1cccc(-n2ccnc2)c1
Agent: O=C(O)c1cccc(-n2ccnc2)c1
Agent: O=S(=O)(O)O
Agent: [Li]
Solvent: CO
Product: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2ccnc2)c1

Procedure:
The title compound was prepared from methyl 3-(1H-imidazol-1-yl)benzoate [prepared from 3-(1H-imidazol-1-yl)benzoic acid (J. Med. Chem. 1987, 30, 1342; CAS-No. [108035-47-8] by refluxing in conc. H2SO4/MeOH ] by treatment with lithium tert.-butyl acetate according to general procedure K (method b). Obtained as an orange-brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[NH:10][C:11](=[O:15])[O:12][CH2:13][CH3:14].C(N(CC)CC)C.Cl[C:24]([O:27]C(Cl)=O)(Cl)Cl>ClCCl>[CH3:9][O:8][C:4]1[C:3]2[N:10]([C:11]([O:12][CH2:13][CH3:14])=[O:15])[C:24](=[O:27])[NH:1][C:2]=2[CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)Nc1c(N)cccc1OC
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)n1c(=O)[nH]c2cccc(OC)c21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
13.0 g (0.062 mol) ethyl (2-amino-6-methoxy-phenyl)-carbamate and 10.3 mL (0.074 mol) triethylamine in 100 mL dichloromethane are added to a solution of 8.20 mL (0.068 mol) trichloromethylchloroformate in 50 mL dichloromethane while cooling with ice. After 4 hours stirring at ambient temperature the reaction mixture is poured onto ice and extracted with dichloromethane. The combined organic phases are washed with water, dried and freed from the solvent. The residue is stirred in diethyl ether.
Reaction SMILES: [CH2:1]([N:3]([CH3:16])[C:4]1[O:5][C:6]2[C:7](=[C:9]([C:13]([O-:15])=O)[CH:10]=[CH:11][CH:12]=2)[N:8]=1)[CH3:2].[Li+].Cl.Cl.[NH2:20][C@H:21]1[CH:26]2[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]2)[CH2:22]1>>[N:23]12[CH2:22][C@@H:21]([NH:20][C:13]([C:9]3[CH:10]=[CH:11][CH:12]=[C:6]4[O:5][C:4]([N:3]([CH2:1][CH3:2])[CH3:16])=[N:8][C:7]=34)=[O:15])[CH:26]([CH2:27][CH2:28]1)[CH2:25][CH2:24]2
Reactant: N[C@@H]1CN2CCC1CC2
Reactant: CCN(C)c1nc2c(C(=O)[O-])cccc2o1
Agent: Cl
Agent: [Li+]
Product: CCN(C)c1nc2c(C(=O)N[C@@H]3CN4CCC3CC4)cccc2o1

Procedure:
Following general procedure GP-C1, a mixture of lithium 2-(ethyl(methyl)amino)benzoxazole-4-carboxylate and (S)-(−)-3-aminoquinuclidine dihydrochloride were coupled and to afford (S)—N-(quinuclidine-8-yl)-2-(ethyl(methyl)amino)benzoxazole-4-carboxamide, which was converted to the hydrochloride salt following general procedure GP-D1. 1H NMR and MS consistent.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:25][CH3:26])[CH:21]=3)[CH:16]=2)[NH:12][CH:13]=1.F[C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:25][CH3:26])[CH:21]=3)[CH:16]=2)[N:12]([C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=2)[CH:13]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: COc1ccc2cc(Cc3nc(-c4ccc(Cl)cc4Cl)c[nH]3)ccc2c1
Product: COc1ccc2cc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3ccc([N+](=O)[O-])cc3)ccc2c1

Procedure:
4-(2,4-Dichloro-phenyl)-2-(6-methoxy-naphthalen-2-ylmethyl)-1H-imidazole (383 mg, 1 mmol) was treated as described in general procedure B using 1-fluoro-4-nitrobenzene to give 4-(2,4-dichloro-phenyl)-1-(4-nitro-phenyl)-2-(6-methoxy-naphthalen-2-ylmethyl)-1H-imidazole.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:31]([C:30]3[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][CH:29]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3ccncc3)CC2)c1[N+](=O)[O-]
Reactant: COc1ccc(C=O)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-c2nc3c(N4CCN(Cc5ccncc5)CC4)c(Br)cnc3[nH]2)cc1
Temperature: 70 °C
Reaction time: 8.5 h

Procedure:
To a mixture of 5-bromo-3-nitro-4-(4-pyridin-4-ylmethyl-piperazin-1-yl)-pyridin-2-ylamine (0.047 g, 0.12 mmol) and ethanol (3.0 ml) was added 4-methoxybenzaldehyde (0.026 g, 0.18 mmol) with the aid of ethanol (1.0 ml), followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.50 ml, 0.50 mmol). The reaction mixture was stirred at 70° C. for 8.5 h, then allowed to cool to room temperature and concentrated in vacuo. The residue was absorbed on silica gel, and the free-running powder was placed on a 10 g isolute silica column which was eluted with a gradient of methanol (0 to 4%) in ethyl acetate/dichloromethane (v/v; 1:1). The title compound was obtained as a pale yellow solid after trituration with diethyl ether (0.018 g, 31%). 1H-NMR (500 MHz, DMSO-d6) 2.63 (br s, 4H, piperazine N(CH2)2), 3.68 (br s, 4H, piperazine N(CH2)2), 3.62 (s, 2H, NCH2-pyridyl), 3.84 (s, 3H, OCH3), 7.10 (d, J=8.9 Hz, 2H) and 8.14 (d, J=8.8 Hz, 2H) (3,5-C6H4OMe and 2,6-C6H4OMe), 7.40 (d, J=5.9 Hz, 2H, pyridine 3-H and 5-H), 8.20 (s, 1H, imidazo[4,5-b]pyridine 5-H), 8.54 (d, J=5.9 Hz, 2H, pyridine 2-H and 6-H), 13.38 (br s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])[C:12]2[N:17]=[CH:16][C:15]([CH2:18][NH2:19])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N:28]1[CH:33]=[CH:32][C:31](/[CH:34]=[CH:35]/[C:36](O)=[O:37])=[CH:30][CH:29]=1.N1(O)C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>C(OCC)(=O)C.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])[C:12]2[N:17]=[CH:16][C:15]([CH2:18][NH:19][C:36](=[O:37])/[CH:35]=[CH:34]/[C:31]3[CH:32]=[CH:33][N:28]=[CH:29][CH:30]=3)=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: NCc1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Reactant: O=C(O)/C=C/c1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(/C=C/c1ccncc1)NCc1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 65 %

Procedure:
To a dichloromethane (1 ml) solution of the [6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methylamine (41 mg, 0.10 mmol) obtained in Example 63, (E)-3-(pyridin-4-yl)acrylic acid (15 mg, 0.10 mmol), benzotriazol-1-ol (14 mg, 0.10 mmol) and N-methylmorpholine (0.011 ml, 0.10 mmol) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (19 mg, 0.10 mmol) at 0° C. The resulting mixture was stirred at room temperature for 19 hours. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel chromatography. The fraction obtained from the ethyl acetate eluate was concentrated under reduced pressure. The solid thus obtained was washed with diethyl ether and collected by filtration to give the title compound (35 mg, 0.065 mmol, 65%) as a white solid.
Reaction SMILES: [O:1]([C:8]1[CH:12]=[CH:11][S:10][C:9]=1[CH:13]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]1([S:21]([CH2:24][C:25]#[N:26])(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[O:1]([C:8]1[CH:12]=[CH:11][S:10][C:9]=1/[CH:13]=[C:24](/[S:21]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:22])=[O:23])\[C:25]#[N:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCS(=O)(=O)c1ccccc1
Reactant: O=Cc1sccc1Oc1ccccc1
Product: N#C/C(=C\c1sccc1Oc1ccccc1)S(=O)(=O)c1ccccc1

Procedure:
Reaction of 3-phenoxythiophen-2-carboxaldehyde and phenylsulfonylacetonitrile as in Example 1 gave (E)-3-(3-phenoxythien-2-yl)-2-(phenylsulfonyl)acrylonitrile.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[CH:19]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:17])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[F:25][C:26]1[C:31](B(O)O)=[CH:30][CH:29]=[CH:28][N:27]=1>>[Cl:24][C:20]1[CH:19]=[C:18]([C:8]2([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:31]4[C:26]([F:25])=[N:27][CH:28]=[CH:29][CH:30]=4)[CH:3]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:17])=[N:9]2)[CH:23]=[CH:22][N:21]=1
Reactant: OB(O)c1cccnc1F
Reactant: NC1=NC(c2cccc(Br)c2)(c2ccnc(Cl)c2)c2ccccc21
Product: NC1=NC(c2cccc(-c3cccnc3F)c2)(c2ccnc(Cl)c2)c2ccccc21
Yield: 35 %

Procedure:
The title compound was synthesized from 1-(3-bromophenyl)-1-(2-chloropyridin-4-yl)-1H-isoindol-3-amine (Example 120) as described in Example 67 Scheme #10, D in 35% yield using 2-fluoropyridine-3-boronic acid. 1H NMR (DMSO-d6) δ 8.32 (d, J=5.31 Hz, 1 H), 8.27-8.19 (m, 1 H), 8.08-7.99 (m, 1 H), 7.96-7.81 (m, 2 H), 7.61-7.31 (m, 9 H), 7.01 (br s, 2 H); MS (ESI) m/z 415 [M+1]+.
Reaction SMILES: [H-].[Na+].Br[C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][NH:10]2)=[CH:6][CH:5]=1.[Li]C(CC)C.[NH4+].[Cl-].C1C[O:23][CH2:22]C1>CN(C=O)C>[NH:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([CH:22]=[O:23])[CH:12]=2)[CH:8]=[N:9]1
Reactant: Brc1ccc2cn[nH]c2c1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [H-]
Agent: [Li]C(C)CC
Solvent: CN(C)C=O
Product: O=Cc1ccc2cn[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
To a suspension of 60% NaH (10.0 g, 0.24 mol) in THF (240 mL) was added a suspension of 6-bromo-1H-indazole (39.4 g, 0.2 mol) in THF (280 mL) dropwise over 45 min. After addition, the resulting mixture was stirred for 1 h at rt to give a dark red clear solution which was cooled to −78° C. s-BuLi (1.4 M in hexane, 300 mL, 0.42 mol) was added dropwsie over 1 h. During this addition, additional THF (130 mL) was added to keep the mixture stirring. After the addition, the resulting mixture was stirred for 75 min at −78° C.; DMF (90 mL) was added dropwise (note: reaction solidified upon addition of DMF, occasional warming was needed to keep the mixture stirring). The resulting mixture was stirred at rt overnight and cooled to 0° C. Solid NH4Cl and saturated NH4Cl were added to quench the reaction and bring the pH to about 7. The product was extracted with EtOAc (800 mL+200 mL+300 mL, 1.3 L in total) and the combined extracts were washed with H2O (300 mL×3) and dried (Na2SO4). Evaporation of the solvent gave a dark red solid which was triturated by EtOAc (4 times, the last filtrate was purified by flash chromatography) to give the title compound (16.96 g in total, 58%) as yellow brown solid. 1H NMR (400 MHz, DMSO-d6) δ 13.62 (s, 1H, NH), 10.12 (s, 1H, CHO), 8.23 (s, 1H), 8.17 (s, 1H), 7.93 (d, J=8.4 Hz, 1H), 7.59 (d, J=8.4 Hz, 1H); MS ESI 147.0 [M+H]+, calcd for [C8H6N2O+H]+ 147.0.
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4](=[O:26])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[C:7]([Cl:25])[CH:6]=1.[OH-].[Na+]>CO.O1CCCC1.O>[Cl:25][C:7]1[CH:6]=[C:5]([C:4](=[O:26])[C:3]([OH:27])=[O:2])[CH:10]=[CH:9][C:8]=1[O:11][CH2:12][CH2:13][O:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1
Reactant: COC(=O)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)c(Cl)c1
Yield: 93.4 %

Procedure:
A solution of 3-chloro-4-[2-(2-naphthalenyloxy)ethoxy]-alpha-oxobenzeneacetic acid methyl ester (0.7 g) in warm methanol (10 mL) and tetrahydrofuran (10 mL) was treated with 1N sodium hydroxide (2.5 mL) and after 10 minutes the mixture was diluted with water and concentrated to remove the organic solvents. The residue was acidified with excess hydrochloric acid and extracted with dichloromethane containing a little tetrahydrofuran. The organic layer was washed with water, dried (Na2SO4), filtered and evaporated to give crude product. Crystallization from acetone-hexane provided 0.63 g of purified 3-chloro-4-[2-(2-naphthalenyloxy)ethoxy]-alpha-oxobenzeneacetic acid as a colorless solid, mp 167°-168° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]=O)[CH:7]=[CH:6]2.[OH-].[Na+].O.[CH3:18][C:19]([CH3:21])=[O:20]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]=[CH:18][C:19](=[O:20])[CH3:21])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc(C=O)ccc2c1
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc2cc(C=CC(C)=O)ccc2c1
Reaction time: 1 h
Yield: 98.2 %

Procedure:
6-Methoxy-2-naphthaldehyde (1 g, 5.4 mmol) in acetone (5.0 g), with aqueous NaOH (0.25 g of 2.8% NaOH; 3.3 mol %) was stirred for 1 hour at 20° C. followed by 1 hour at reflux. Water (10 g) was added to precipitate the product which was filtered and dried to give 1.2 g (98% of theory) of 4-(6-methoxy-2-naphthyl)-3-buten-2-one. GC showed 99% conversion and 4% of a heavy co-product (95% of butenone).