Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:15]2[O:19][N:18]=[C:17]([C:20]3[S:24][C:23]([CH2:25]O)=[CH:22][C:21]=3[CH3:27])[N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[NH:53]1[CH2:56][CH:55]([C:57]([O:59][CH3:60])=[O:58])[CH2:54]1.C(N(CC)C(C)C)(C)C>>[F:1][C:2]1[CH:3]=[C:4]([C:15]2[O:19][N:18]=[C:17]([C:20]3[S:24][C:23]([CH2:25][N:53]4[CH2:56][CH:55]([C:57]([O:59][CH3:60])=[O:58])[CH2:54]4)=[CH:22][C:21]=3[CH3:27])[N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COC(=O)C1CNC1
Reactant: Cc1cc(CO)sc1-c1noc(-c2ccc(Oc3ccccc3)c(F)c2)n1
Agent: BrC(Br)(Br)Br
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CN(Cc2cc(C)c(-c3noc(-c4ccc(Oc5ccccc5)c(F)c4)n3)s2)C1

Procedure:
The crude product of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 1 (1f) using {5-[5-(3-fluoro-4-phenoxyphenyl]-1,2,4-oxadiazol-3-yl)-4-methyl-2-thienyl}methanol (0.21 g, 0.55 mmol) that was obtained in Example 11 (11f), carbon tetrabromide (0.22 g, 0.66 mmol), triphenylphosphine (0.17 g, 0.66 mmol), methyl 3-azetidinecarboxylate hydrochloride (0.13 g, 0.83 mmol), and N,N-diisopropylethylamine (0.30 mL, 1.7 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography using a mixed solvent of ethyl acetate and hexane (5:5) to afford the title compound (0.23 g) in a yield of 86% as a colourless oily product.
Reaction SMILES: C(O[CH2:4][CH2:5][C:6]#[N:7])C.C(O)C.[NH:11]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)[NH2:12].OCC[N+](C)(C)C>CO>[NH2:7][C:6]1[CH2:5][CH2:4][N:11]([C:13]2[S:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)[N:12]=1
Reactant: NNc1nc2ccccc2s1
Reactant: CCOCCC#N
Agent: C[N+](C)(C)CCO
Solvent: CCO
Solvent: CO
Product: NC1=NN(c2nc3ccccc3s2)CC1

Procedure:
A mixture of 5.0 g. of β-ethoxypropionitrile, 100 ml. of absolute ethanol, 8.25 g. of 2-hydrazinobenzothiazole and 2.5 g. of 50% w/v choline in methanol is refluxed on a steam bath for 16 hours, then the solvent is removed in vacuo. Water is added and the solid is collected by filtration. The solid is recrystalized twice from ethanol to give 5.75 g. of the product of the Example as grey prisms, m.p. 231.5°-235° C.
Reaction SMILES: [Cl:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH2:11][NH:12][CH3:13].[CH3:14][C:15]1([CH3:31])[O:20][C:19]2[CH:21]=[C:22]([CH:25]=[CH:26][C:27]([OH:29])=O)[CH:23]=[N:24][C:18]=2[NH:17][C:16]1=[O:30].ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.CN(C)CCCN=C=NCC>CN(C=O)C.O>[Cl:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH2:11][N:12]([CH3:13])[C:27](=[O:29])/[CH:26]=[CH:25]/[C:22]1[CH:23]=[N:24][C:18]2[NH:17][C:16](=[O:30])[C:15]([CH3:14])([CH3:31])[O:20][C:19]=2[CH:21]=1
Reactant: CNCc1oc2ccccc2c1Cl
Reactant: CC1(C)Oc2cc(C=CC(=O)O)cnc2NC1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CN(Cc1oc2ccccc2c1Cl)C(=O)/C=C/c1cnc2c(c1)OC(C)(C)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.1 %

Procedure:
To a solution of (3-chloro-benzofuran-2-ylmethyl)-methyl-amine (151 mg, 0.77 mmol) in DMF (5 mL) were added in sequential order 3-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-acrylic acid (174 mg, 0.7 mmol), 1-hydroxybenzotriazole (107 mg, 0.77 mmol), diisopropylethylamine (366 uL, 2.1 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (154 mg, 0.77 mmol). The mixture was stirred at room temperature overnight, cooled in an ice bath and treated with water under rapid stirring. The precipitated product was filtered and dried, triturated with diethyl ether to yield the title compound (218 mg, 73%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.43 (s, 1H), 8.21 (s, 1H), 7.96 (s, 1H), 7.53-7.67 (m, 3H), 7.40-7.44 (m, 3H), 4.89-5.11 (m, 2H), 2.97-3.23 (m, 3H), 1.46 (s, 6H); MS (ESI) m/e 426 (C22H20ClN3O4+H)+.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([N+:21]([O-:23])=[O:22])[CH:14]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH3:24].[CH:25](/B(O)O)=[CH:26]\[CH3:27].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][S:11][C:9]2[N:8]=[C:7]3[C:3]([N:4]=[CH:5][N:6]3[CH3:24])=[C:2](/[CH:25]=[CH:26]/[CH3:27])[N:10]=2)=[CH:14][C:15]=1[N+:21]([O-:23])=[O:22]
Reactant: C/C=C/B(O)O
Reactant: COc1ccc(CSc2nc(Cl)c3ncn(C)c3n2)cc1[N+](=O)[O-]
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: O
Solvent: COCCOC
Product: C/C=C/c1nc(SCc2ccc(OC)c([N+](=O)[O-])c2)nc2c1ncn2C
Yield: 86.3 %

Procedure:
6-chloro-2-(4-methoxy-3-nitrobenzylsulfanyl)-9-methyl-9H-purine (100 mg, 0.273 mmol) was dissolved in dimethoxyethane (4 ml), then trans-propenylboronic acid (70 mg, 0.815 mmol) and tetrakis(triphenylphosphine)palladium (0) (30 mg, 0.025 mmol) were added. Then 106 mg (1.0 mmol) of sodium carbonate dissolved in water (2 ml) was added, and the mixture was heated to reflux for 2 hours. After cooling it, the insolubles were filtered off with Celite, the filtrate was distilled away under reduced pressure, ethyl acetate (20 ml) and water (20 ml) were added to the residue and extraction was performed. After washing with water, drying was carried out with anhydrous magnesium sulfate, the insolubles were filtered off, the filtrate was distilled away under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate: methanol=50:1) to obtain 2-(4-methoxy-3-nitrobenzylsulfanyl)-9-methyl-6-(1-trans-propenyl)-9H-purine (87.5 mg, 86%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([NH2:22])[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1)[C:8]#[N:9])[CH:2]=[CH2:3].[C:23]([C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]>>[CH2:1]([O:4][C:5]1[C:12]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)=[C:11]([NH:22][S:33]([C:30]2[CH:31]=[CH:32][C:27]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:28][CH:29]=2)(=[O:35])=[O:34])[CH:10]=[C:7]([C:8]#[N:9])[CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(C#N)cc(N)c1Oc1cccc(OC)c1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Product: C=CCOc1cc(C#N)cc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1Oc1cccc(OC)c1

Procedure:
Analogously to Example 143e), from 3-allyloxy-5-amino-4-(3-methoxy-phenoxy)-benzonitrile by coupling with 4-tert-butyl-benzenesulphonyl chloride there was obtained N-[3-allyloxy-5-cyano-2-(3-methoxy-phenoxy)-phenyl]-4-tert-butyl-benzenesulphonamide as a crystalline solid.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[NH:20]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[CH2:21]1>>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:19])=[C:2]([N:20]4[CH2:24][CH2:23][CH:22]([C:25]5[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=5)[CH2:21]4)[N:11]=3)[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: c1cc(C2CCNC2)ccn1
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Product: O=C(O)c1cn(C2CC2)c2nc(N3CCC(c4ccncc4)C3)c(F)cc2c1=O
Yield: 67 %

Procedure:
Starting from 7-chloro-1-cyclopropyl-6-fluoro -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (0.85 g, 3.0 mmol) and 4-(3-pyrrolidinyl) pyridine, a procedure analogous to that given in Example 1 provided the title compound (0.79 g, 67%), mp 223°-225° C.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:20]([C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:31])[CH3:30])=[CH:24][CH:23]=1)=O>>[F:19][C:16]([F:17])([F:18])[C:13]1[N:11]2[N:12]=[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:20][C:22]4[CH:23]=[CH:24][C:25]([NH:28][C:29](=[O:31])[CH3:30])=[CH:26][CH:27]=4)[CH2:5][CH2:6]3)[CH:8]=[CH:9][C:10]2=[N:15][N:14]=1
Reactant: CC(=O)Nc1ccc(C=O)cc1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: CC(=O)Nc1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with N-(4-formylphenyl)acetamide was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give N-[4-[[4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]methyl]phenyl]acetamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:20][C:21]1[CH:25]=[C:24]([C:26]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:27])[NH:23][C:22]=1[CH:34]=O>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:34][C:22]4[NH:23][C:24]([C:26]([N:28]5[CH2:29][CH2:30][O:31][CH2:32][CH2:33]5)=[O:27])=[CH:25][C:21]=4[CH3:20])[C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Reactant: Cc1cc(C(=O)N2CCOCC2)[nH]c1C=O
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C(=O)N2CCOCC2)[nH]c1C=C1C(=O)Nc2ncnc(Nc3ccc(F)c(Cl)c3)c21
Temperature: 25 °C
Reaction time: 72 h
Yield: 69.2 %

Procedure:
A mixture of 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (93 mg, 0.33 mmol), 3-methyl-5-(morpholine-4-carbonyl)-1H-pyrrole-2-carbaldehyde (73 mg, 0.33 mmol), and piperidine (1 drop) in ethanol (2 mL) was stirred at room temperature for 3 days. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 110.3 mg (69%) of the title compound. 1H NMR (360 MHz, DMSO-d6) δ 13.43 (br s, 1H, NH), 11.74 (br s, 1H, NH), 9.23 (br s, 1H), 8.33 (s, 1H), 7.73 (dd, J=2.5 & 6.7 Hz, 1H), 7.44 (m, 1H), 7.32-7.37 (m, 2H), 6.61 (d, J=2.28 Hz, 1H), 3.69 (m, 4H, 2×CH2), 3.65 (m, 4H, 2×CH2), 2.22 (s, 3H, CH3). MS 483 [M+].
Reaction SMILES: [CH:1]([NH:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:14]2[C:15]([CH3:20])=[C:16]([CH2:18]O)[O:17][C:13]=2[CH:12]=[CH:11][CH:10]=1)([CH3:3])[CH3:2].[CH2:21]([SH:29])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]([NH:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:14]2[C:15]([CH3:20])=[C:16]([CH2:18][S:29][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:17][C:13]=2[CH:12]=[CH:11][CH:10]=1)([CH3:2])[CH3:3]
Reactant: SCCc1ccccc1
Reactant: Cc1c(CO)oc2cccc(OCCCNC(C)C)c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(CSCCc2ccccc2)oc2cccc(OCCCNC(C)C)c12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 75.5 %

Procedure:
To a solution of [4-(3-isopropylamino-propoxy)-3-methyl-benzofuran-2-yl]-methanol (14 mg, 0.05 mmol) and phenethyl mercaptan (10.3 mg, 0.075 mmol) in anhydrous CH2Cl2 (0.9 ml) was added TFA (0.2 ml). The Mixture was stirred at room temperature for 2.5 hours. The solvent was removed in vacuo. The residue was purified over preparative TLC (CH2Cl2/MeOH=100/1) to give desired compound (15 mg, 74%). FAB-MS: m/z 398 (MH+); 1H-NMR (CDCl3): δ 1.11 (6H, d, J=6.2 Hz), 2.05 (2H, m), 2.34 (3H, s), 2.61-2.96 (7H, m), 3.80 (2H, s), 4.11 (2H, m), 6.56 (1H, m), 6.95-7.28 (7H, m).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:16]=[N:15][C:14]3[C:9](=[CH:10][C:11](B4OC(C)(C)C(C)(C)O4)=[CH:12][CH:13]=3)[N:8]=2)[CH:4]=[N:3]1.Br[C:27]1[CH:28]=[C:29]([NH:33][S:34]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=2[F:44])(=[O:36])=[O:35])[CH:30]=[N:31][CH:32]=1>C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>[F:44][C:38]1[CH:39]=[C:40]([F:43])[CH:41]=[CH:42][C:37]=1[S:34]([NH:33][C:29]1[CH:30]=[N:31][CH:32]=[C:27]([C:11]2[CH:10]=[C:9]3[C:14](=[CH:13][CH:12]=2)[N:15]=[CH:16][C:7]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=2)=[N:8]3)[CH:28]=1)(=[O:36])=[O:35]
Reactant: Cn1cc(-c2cnc3ccc(B4OC(C)(C)C(C)(C)O4)cc3n2)cn1
Reactant: O=S(=O)(Nc1cncc(Br)c1)c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cn1cc(-c2cnc3ccc(-c4cncc(NS(=O)(=O)c5ccc(F)cc5F)c4)cc3n2)cn1
Temperature: 100 °C
Yield: 64.3 %

Procedure:
A mixture of 2-(1-methyl-1H-pyrazol-4-yl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxaline (9.22 mmol), N-(5-bromo-3-pyridinyl)-2,4-difluorobenzenesulfonamide (8.13 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (1:1) (0.404 mmol) in 2M aqueous sodium carbonate (40 mL) and 1,4-dioxane (40 mL) was heated at 100° C. for 1 h. Upon cooling, the reaction mixture separated into two layers (aqueous and organic). The organic layer was partitioned between ethyl acetate (50 mL) and water (25 mL). The two aqueous layers were then combined and the pH was adjusted to ˜7 with 2N aqueous HCl. A solid precipitated and was filtered away from the solution. The solid was dried in vacuo and then desiccated over P2O5 to afford the title product (2.5 g, 64%). MS(ES)+ m/e 479 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:12]3[CH2:15][C:14](=[O:16])[CH2:13]3)=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1.[BH4-].[Na+]>CO.C(Cl)Cl>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:12]3[CH2:13][CH:14]([OH:16])[CH2:15]3)=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1
Reactant: O=C1CC(c2nc(I)c3c(Cl)nccn23)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: OC1CC(c2nc(I)c3c(Cl)nccn23)C1
Reaction time: 4.5 h

Procedure:
3-(8-Chloro-1-iodo-imidazo[1,5-a]pyrazin-3-yl)-cyclobutanone (5.0 g, 14 mmol) was dissolved in a 1:1 mixture of methanol (35.0 mL) and CH2Cl2 (35.0 mL). To the solution mixture sodium tetrahydroborate (560 mg, 14.0 mmol) was added slowly, gas evolution was observed. After 4.5 h at rt under nitrogen, the reaction was concentrated in vacuo. The crude mix was dissolved in EtOAc and washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified using HPFC Jones 50 gram silica gel column eluting with 50% EtOAc: Hex to 100% EtOAc, to yield the title compound as a light yellow solid; MS (ES+): m/z 349.81 (100) [MH+], 351.50 (30) [MH+++]; HPLC: tR=2.49 min (OpenLynx, polar—5 min); 1H NMR (CDCl3, 400 MHz) δ 2.41-2.54 (m, 2H) 2.78-3.05 (m, 1H) 3.12-3.32 (m, 1H) 4.08-4.75 (m, 1H) 5.30 (s, 1H) 7.31 (d, J=5.05 Hz, 1H) 7.57 (d, J=4.80 Hz, 1H)
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:18]2[CH:23]=[C:22]([N:24]3[CH:28]=[C:27]([CH2:29][CH2:30][OH:31])[N:26]=[N:25]3)[CH:21]=[CH:20][C:19]=2[CH3:32])=[O:17])=[C:12]([CH3:33])[CH:11]=1.BrC1C=CC(C(C2C=C(N3C=C(CCO)N=N3)C=CC=2C)=O)=C(C)C=1.[Cl:59]C1C=C(N)C=CC=1F>>[Cl:59][C:7]1[CH:2]=[C:3]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([C:18]3[CH:23]=[C:22]([N:24]4[CH:28]=[C:27]([CH2:29][CH2:30][OH:31])[N:26]=[N:25]4)[CH:21]=[CH:20][C:19]=3[CH3:32])=[O:17])=[C:12]([CH3:33])[CH:11]=2)[CH:4]=[CH:5][C:6]=1[F:8]
Reactant: Cc1cc(Nc2ccc(F)cc2F)ccc1C(=O)c1cc(-n2cc(CCO)nn2)ccc1C
Reactant: Nc1ccc(F)c(Cl)c1
Agent: Cc1cc(Br)ccc1C(=O)c1cc(-n2cc(CCO)nn2)ccc1C
Product: Cc1cc(Nc2ccc(F)c(Cl)c2)ccc1C(=O)c1cc(-n2cc(CCO)nn2)ccc1C

Procedure:
The reaction was carried out similarly as described in the preparation of compound 148, using compound 452 (0.13 mmol) and 3-chloro-4-fluoro-phenylamine (0.13 mmol). The crude product was purified by continuous gradient flash chromatography using MeOH/DCM/petroleum ether (40-60) 0:50:50, 0:100:0 and 5:95:0 as the eluent to afford the title compound as yellow solid. 13C NMR (DMSO-d6) δ 196.4, 152.6 (d), 147.6, 145.8, 142.3, 142.3, 138.6 (d), 135.3 (d), 134.4, 132.2, 126.9, 121.1, 120.7, 120.5, 120.0 (d), 119.9 (d), 118.4, 117.7, 117.5 (d), 111.3, 60.2, 29.2, 22.0, 18.9
Reaction SMILES: C[Mg]Cl.[Cl:4][C:5]1[CH:6]=[C:7](Cl)[C:8]2[C:9](=[CH:11][S:12][CH:13]=2)[N:10]=1.[CH3:15]N1CCCC1=O>C1COCC1.O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Fe+3]>[Cl:4][C:5]1[CH:6]=[C:7]([CH3:15])[C:8]2[C:9](=[CH:11][S:12][CH:13]=2)[N:10]=1
Reactant: Clc1cc(Cl)c2cscc2n1
Reactant: CN1CCCC1=O
Agent: [Fe+3]
Agent: CC(=O)/C=C(/C)[O-]
Agent: C[Mg]Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Cl)nc2cscc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution (0.67 mL) of 3 M methyl magnesium chloride in THF was added dropwise to a mixture of 2,4-dichlorothieno[3,4-b]pyridine (0.37 g), iron(III) acetylacetonate (0.064 g), N-methyl-2-pyrrolidinone (1 mL), and THF (15 mL) with ice cooling, and the mixture was stirred at room temperature for 20 h. The reaction solution was diluted with water, and the mixture was extracted with chloroform. The organic layer was dried with anhydrous magnesium sulfate, then the desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (silica gel and NH silica gel, ethyl acetate/hexane=20:1-10:1) to obtain 2-chloro-4-methylthieno[3,4-b]pyridine (0.027 g).
Reaction SMILES: [C:1]1([CH2:11][NH:12][C:13]([C:15]2O[C:17]([NH:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])=[N:18][N:19]=2)=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH:26][CH:27]1[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]1>ClCCl>[OH:26][CH:27]1[CH2:32][CH2:31][CH2:30][N:29]([C:17]2[N:20]([CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])[C:15]([C:13]([NH:12][CH2:11][C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)=[O:14])=[N:19][N:18]=2)[CH2:28]1
Reactant: CC(C)=CCNc1nnc(C(=O)NCc2cccc3ccccc23)o1
Reactant: OC1CCCNC1
Solvent: ClCCl
Product: CC(C)=CCn1c(C(=O)NCc2cccc3ccccc23)nnc1N1CCCC(O)C1
Temperature: 200 °C
Reaction time: 0.33 h

Procedure:
A mixture of 0.12 g 5-(3-methyl-but-2-enyl)amino-[1,3,4]oxadiazole-2-carboxylic acid-(naphth-1-ylmethyl)-amide and 1.80 g 3-hydroxypiperidine is stirred for 20 min at 200° C. in a microwave. After cooling to ambient temperature dichloromethane is added, the organic phase is washed once with water and once with 1 M hydrochloric acid, dried over sodium sulphate, and the solvent is removed.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[C:19](B(O)O)=[C:20]2[CH2:25][CH2:24][CH2:23][N:21]2[N:22]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C=O)C>O.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>[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[C:19]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)=[C:20]2[CH2:25][CH2:24][CH2:23][N:21]2[N:22]=1
Reactant: Brc1cncc2cccnc12
Reactant: OB(O)c1c(-c2ccccn2)nn2c1CCC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(-c2nn3c(c2-c2cncc4cccnc24)CCC3)nc1
Temperature: 60 °C
Yield: 65.1 %

Procedure:
Add 8-bromo-[1,6]naphthyridine (Spec; 32 mg, 0.152 mmol), 2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronic acid (Preparation 5; 35 mg, 0.153 mmol), and potasium phosphate (97 mg, 0.458 mmol) to DMF (1 mL) and water (0.5 mL). De-gas the solution with argon and add tetrakis(triphenylphosphine)palladium(0) (88 mg, 0.076 mol). Heat the mixture at 60° C. for 18 h under an argon atmosphere. Cool the mixture to room temperature and dilute with water. Filter the mixture, and separate the filtrate. Extract the aqueous layer with dichloromethane. Dry the combined organic layers over sodium sulfate, filter, and concentrate. Purify the crude residue by column chromatography (12 g Redisep column, gradient dichloromethane through CMA over 40 min, 20 mL/min) to provide the title compound (31 mg, 64%) as an off white solid. Mp 180-184° C. MS (APCI) m/e=314 (M+1). 1H NMR (CDCl3) δ 8.88 (dd, J=1.6, 4.2 Hz, 1H), 8.60 (d, J=4.7 Hz, 1H), 8.28 (d, J=8.5 Hz, 1H), 8.19 (d, J=8.9 Hz, 1H), 7.73-7.68 (m, 3H), 7.58 (dd, J=4.2, 8.5 Hz, 2H), 4.30 (t, J=7 Hz, 2H), 3.30 (t, J=7 Hz, 2H), 2.73 (p, J=7 Hz, 2H). HPLC: >99%, Rt=7.1 min.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([Cl:23])=[CH:21][C:20]([Cl:24])=[CH:19][N:18]=4)[CH2:13][C@H:12]3[CH3:25])[NH:7][C:6]=2[CH:5]=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[F:30][C:31]([F:42])([F:41])[C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C([O-])([O-])=O.[Na+].[Na+].O>CC#N.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>[Cl:23][C:22]1[C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:8]3[NH:9][C:10]4[C:2]([C:35]5[CH:36]=[CH:37][C:32]([C:31]([F:42])([F:41])[F:30])=[CH:33][CH:34]=5)=[CH:3][C:4]([C:26]([F:28])([F:27])[F:29])=[CH:5][C:6]=4[N:7]=3)[C@H:12]([CH3:25])[CH2:13]2)=[N:18][CH:19]=[C:20]([Cl:24])[CH:21]=1
Reactant: C[C@@H]1CN(c2ncc(Cl)cc2Cl)CCN1c1nc2c(Br)cc(C(F)(F)F)cc2[nH]1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
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: O
Solvent: CC#N
Product: C[C@@H]1CN(c2ncc(Cl)cc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)c2[nH]1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
A mixture of 4-bromo-2-[(2R)-4-(3,5-dichloro-pyridin-2-yl)-2-methyl-piperazin-1-yl]-6-trifluoromethyl-1H-benzoimidazole (204 mg, 0.4 mmol, Example 149b), 4-trifluoromethylphenylboronic acid (152 mg, 0.8 mmol, Aldrich), Pd(PPh3)4 (46 mg, 0.04 mmol, Aldrich) and Na2CO3 (2 mL, 0.8 mmol, 0.4 M in H2O) in MeCN (4 mL) was heated at 90° C. with stirring for 16 h. Water (10 mL) was added and the mixture was extracted with EtOAc (2×30 mL). The combined organic extracts were washed with brine (5 mL), dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography, eluting with 10% EtOAc/hexane to give the title compound. MS (ESI, pos. ion) m/z: 574 (M+1).
Reaction SMILES: [CH3:1][C:2]([N:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:29])[CH:13]([NH:17][C:18](=[O:28])[CH2:19][C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=2)[CH2:14][CH2:15][CH3:16])[N:8]=[CH:7]1)([CH3:5])[CH:3]=O.[C:30]1([CH:36]([NH2:38])[CH3:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH3:1][C:2]([N:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:29])[CH:13]([NH:17][C:18](=[O:28])[CH2:19][C:20]2[CH:21]=[C:22]([F:27])[CH:23]=[C:24]([F:26])[CH:25]=2)[CH2:14][CH2:15][CH3:16])[N:8]=[CH:7]1)([CH3:5])[CH2:3][NH:38][CH:36]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:37]
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C(C)(C)C=O)cn1
Reactant: CC(N)c1ccccc1
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C(C)(C)CNC(C)c2ccccc2)cn1

Procedure:
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [1-(1,1-dimethyl-2-oxo-ethyl)-1H-imidazol-4-yl]-amide was reacted with 1-phenyl-ethylamine to afford the title compound: C13 NMR (100 MHz, CDCl3) 14.0, 19.0, 24.9, 26.0, 27.0, 36.0, 43.2, 53.2, 57.9, 58.6, 58.9, 102.6, 102.9, 103.1, 105.2, 112.4, 112.6, 112.6, 126.8, 127.1, 128.6, 131.7, 137.8, 138.8, 145.7, 161.9, 164.4, 164.5, 169.3; MS m/z 512.3 (M+1).