Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:13]=[C:12]([CH2:14][N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)([O-:4])=[O:3].S(Cl)(Cl)=O.[F:25][C:26]1[CH:27]=[C:28]([CH:40]=[C:41]([F:43])[CH:42]=1)[CH2:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][N:34]=[C:33]2[NH2:39].[NH4+].[OH-]>N1C=CC=CC=1.O.CCOC(C)=O>[F:25][C:26]1[CH:27]=[C:28]([CH:40]=[C:41]([F:43])[CH:42]=1)[CH2:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][N:34]=[C:33]2[NH:39][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:12]([CH2:14][N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:13][C:5]=1[N+:2]([O-:4])=[O:3]
Reactant: Nc1n[nH]c2ccc(Cc3cc(F)cc(F)c3)cc12
Reactant: O=C(O)c1ccc(CN2CCCCC2)cc1[N+](=O)[O-]
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: O=C(Nc1n[nH]c2ccc(Cc3cc(F)cc(F)c3)cc12)c1ccc(CN2CCCCC2)cc1[N+](=O)[O-]
Temperature: 4 °C
Yield: 43.1 %

Procedure:
2-Nitro-4-piperidin-1-ylmethyl-benzoic acid hydrochloride (440 mg, 1.46 mmol) was treated with thionyl chloride (5 mL) and refluxed for 1 hour. Excess of reagent was removed by evaporation followed by evaporation from toluene (2×5 mL). The solid was further died under vacuum. The acid chloride was treated with dry pyridine (7 mL), cooled to 4° C. and added with 5-(3,5-difluoro-benzyl)-1H-indazol-3-ylamine (315 mg, 1.22 mmol) in dry pyridine (3 mL) under a nitrogen atmosphere, with stirring. After stirring for a few hours the reaction was left at 0° C. over-night. EtOAc (50 mL) and water (50 mL) were added, pH was adjusted to 9 with concentrated NH4OH. The organic layer was separated, dried over sodium sulphate, evaporated to dryness and purified over silica gel (DCM: MeOH 95:5) affording 266 mg of title compound in 43% yield.
Reaction SMILES: C1C[O:4][CH2:3]C1.Br[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:9][CH:8]=1.[Li]CCCC.CN(C=O)C>CCCCCC>[F:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][CH2:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([CH:3]=[O:4])=[CH:8][CH:9]=2)=[CH:17][CH:18]=1
Reactant: Fc1ccc(OCCc2ccc(Br)cc2)cc1
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=Cc1ccc(CCOc2ccc(F)cc2)cc1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
To a THF (100 mL) solution of 1-bromo-4-[2-(4-fluorophenoxy)ethyl]benzene (3.05 g) was added 1.6 M solution of n-BuLi in n-hexane (6.80 mL) dropwise at −70° C. under an argon atmosphere. After stirring for 30 minutes, DMF (1.20 mL) was slowly added at −70° C. The resultant mixture was stirred and slowly warmed to −40° C. for 3 hours. The reaction mixture was quenched by addition of saturated aqueous NH4Cl, and extracted with AcOEt. The organic layer was washed with water, saturated aqueous NaCl, dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=9/1 to 1/1) to afford 4-[2-(4-fluorophenoxy)ethyl]benzaldehyde as a light yellow solid (1.63 g).
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]3[N:7]=[C:8]([NH2:14])[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.N(OC(C)(C)C)=O.C[Si]([N:28]=[N+:29]=[N-])(C)C>C(#N)C>[N:14]([C:8]1[S:9][C:10]2[CH2:11][CH2:12][O:13][C:4]3[CH:3]=[C:2]([Br:1])[CH:16]=[CH:15][C:5]=3[C:6]=2[N:7]=1)=[N+:28]=[N-:29]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: Nc1nc2c(s1)CCOc1cc(Br)ccc1-2
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: [N-]=[N+]=Nc1nc2c(s1)CCOc1cc(Br)ccc1-2
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-ylamine (2.38 g, 8 mmol) in acetonitrile at 0° C. was added tert-butyl nitrite (1.43 mL, 12 mmol) followed by trimethylsilyl azide (1.26 mL, 9.6 mmol) dropwise. The reaction mixture was stirred at 0° C. for 90 mins, allowed to warm up to RT and concentrated in vacuo. The resulting residue was purified by flash chromatography (SiO2, 10% ethyl acetate in cyclohexane) to yield the title compound as a red oil which solidified upon standing (956 mg, 37%). 1H NMR (CDCl3): 8.21 (1H, d, J=8.6 Hz), 7.24 (1H, dd, J=8.6, 2.1 Hz), 7.20 (1H, d, J=2.1 Hz), 4.34 (2H, t, J=5.1 Hz), 3.21 (2H, t, J=5.1 Hz).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[C:7]1([C@H:13]2C[C@@H:14]2C(O)=O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)Cl>[C:7]1([C@H:13]2[CH2:14][C@@H:1]2[C:2]([Cl:4])=[O:3])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(O)[C@H]1C[C@@H]1c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: O=C(Cl)[C@H]1C[C@@H]1c1ccccc1
Reaction time: 2.5 h

Procedure:
In a dry 100 ml round-bottomed flask was added oxalyl chloride (2.0 ml, 23 mmol) to 8B (0.25 g, 1.5 mmol) in CH2Cl2 at room temperature to give a yellow solution. In 2.5 hours, the reaction was complete. The crude mixture was concentrated in vacuo and residual TFA was removed azeotropically with toluene 3 times to give the desired product (1S,2S)-2-phenylcyclopropanecarbonyl chloride (8B-1), which was used in the next step without further purification.
Reaction SMILES: [O:1]1[C@@H:3]2[CH2:4][C@H:5]([C:22]3[CH:26]=[CH:25][O:24][CH:23]=3)[C@:6]3([CH2:8][CH2:9][C@H:10]4[C@H:19]([C@@:2]123)[CH2:18][CH2:17][C@H:16]1[C@:11]4([CH3:21])[CH2:12][CH2:13][C:14](=[O:20])[CH2:15]1)[CH3:7].C(O[Al](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[H-].O>O1CCCC1C([O-])=O.O1CCCC1>[O:24]1[CH:25]=[CH:26][C:22]([C@H:5]2[CH2:4][C@H:3]3[O:1][C@@:2]43[C@H:19]3[C@H:10]([CH2:9][CH2:8][C@:6]24[CH3:7])[C@:11]2([CH3:21])[C@@H:16]([CH2:15][C@H:14]([OH:20])[CH2:13][CH2:12]2)[CH2:17][CH2:18]3)=[CH:23]1
Reactant: C[C@]12CCC(=O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccoc3)C[C@H]3O[C@]132
Agent: CC(C)(C)O[Al](OC(C)(C)C)OC(C)(C)C
Agent: O=C([O-])C1CCCO1
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@]12CC[C@@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccoc3)C[C@H]3O[C@]132
Temperature: 25 °C
Reaction time: 20 h
Yield: 95 %

Procedure:
To a solution of 4.5 g of 14β,15β-epoxy-17β-(3-furyl)-5β-androstan-3-one in 30 ml of dry tetrahydrofuran at-78° C, a solution of 9.8 g of tri-tert-butoxyaluminum-hydride in tetrahydrofuran was added dropwise. The mixture was stirred for 20 hrs, then 40 ml of water were added and the temperature raised to 25° C. The aluminum salts were filtered on a celite cake and washed with methanol. The solution was concentrated under reduced pressure and extracted with methylene chloride. The organic layer was dried over sodium sulfate and evaporated to dryness under reduced pressure to give 4.3 g of the title compound (II-b) as a white solid.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]2[N:15]=[C:14]([NH2:16])[C:13]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[CH:12][N:11]=2)=[N:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH:29]1([CH2:35]Br)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.O>CN(C=O)C>[CH:29]1([CH2:35][N:1]2[C:5]3=[N:6][CH:7]=[CH:8][CH:9]=[C:4]3[C:3]([C:10]3[N:15]=[C:14]([NH2:16])[C:13]([C:17]4[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=4)=[CH:12][N:11]=3)=[N:2]2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: BrCC1CCCCC1
Reactant: Nc1nc(-c2n[nH]c3ncccc23)ncc1-c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc(-c2nn(CC3CCCCC3)c3ncccc23)ncc1-c1ccncc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
200 mg (0.691 mmol) of 2-(1H-pyrazolo[3,4-b]pyridin-3-yl)-5-(pyridin-4-yl)pyrimidine-4-amine (preparation: see WO 03/097063, Example 35A) were dissolved in 5 ml of DMF, and 248 mg (0.760 mmol) of cesium carbonate and 136 mg (0.760 mmol) of cyclohexylmethyl bromide were added. The mixture was stirred at RT overnight. Water was added, and the mixture was extracted three times with dichloromethane. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated on a rotary evaporator. The residue was fractionated by preparative HPLC (Method 5). The product-containing fractions were combined and concentrated on a rotary evaporator, and the residue was dried under high vacuum. This gave 29 mg (11% of theory) of the target compound.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=2)[CH:3]=1.[NH2:19][C@@H:20]1[CH2:25][CH2:24][O:23][CH2:22][C@@H:21]1[NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30].C(N(CC)C(C)C)(C)C.O>O1CCOCC1.C(OCC)(=O)C>[C:29]([O:28][C:27](=[O:33])[NH:26][C@@H:21]1[C@H:20]([NH:19][C:2]2[N:7]=[N:6][C:5]([C:8](=[O:9])[NH2:10])=[C:4]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=3)[CH:3]=2)[CH2:25][CH2:24][O:23][CH2:22]1)([CH3:32])([CH3:30])[CH3:31]
Reactant: Cc1cccc(Nc2cc(Cl)nnc2C(N)=O)n1
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1COCCO1
Product: Cc1cccc(Nc2cc(N[C@@H]3CCOC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)n1
Temperature: 150 °C
Reaction time: 96 h
Yield: 23.7 %

Procedure:
6-Chloro-4-(6-methyl-pyridin-2-ylamino)-pyridazine-3-carboxylic acid amide (150 mg, 0.57 mmol) and tert-butyl (3R,4R)-4-aminotetrahydro-2H-pyran-3-ylcarbamate (185 mg, 0.85 mmol) were dissolved in 1,4-dioxane (2.8 mL) and N,N-diisopropylethylamine (0.25 mL, 1.4 mmol). The reaction mixture was stirred at 150° C. for 4 d. Further tert-butyl (3R,4R)-4-aminotetrahydro-2H-pyran-3-ylcarbamate (50 mg, 0.23 mmol) and N,N-diisopropylethylamine (0.04 mL, 0.23 mmol) was added in four portions (every 36 h for 144 h). The mixture was cooled, and then water and ethyl acetate were added. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with sodium chloride solution and dried over sodium sulfate. After concentration, the residue was purified by chromatography (silica, 0 to 7% methanol in dichloromethane) to give {(3R,4R)-4-[6-carbamoyl-5-(6-methyl-pyridin-2-ylamino)-pyridazin-3-ylamino]-tetrahydro-pyran-3-yl}-carbamic acid tert-butyl ester (60 mg, 18%) as a clear amorphous residue. This was 83% pure and was used directly without further purification. MS (EI/CI) m/z: 444 [M+H].
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[C:7]([OH:9])[C:6]([O:10][CH2:11][CH2:12][CH3:13])=[CH:5][N:4]=1.S(Cl)([Cl:16])=O>C(Cl)(Cl)Cl>[Cl:16][CH2:2][C:3]1[CH:8]=[C:7]([OH:9])[C:6]([O:10][CH2:11][CH2:12][CH3:13])=[CH:5][N:4]=1
Reactant: O=S(Cl)Cl
Reactant: CCCOc1cnc(CO)cc1O
Solvent: ClC(Cl)Cl
Product: CCCOc1cnc(CCl)cc1O

Procedure:
To a mixture of 2-hydroxymethyl-5-propoxy-pyridin-4-ol (5.56 g, 30.3 mmole) and 30 mL of chloroform stirred cooled with an ice bath is added 30 mL of thionyl chloride (x g, 0.x mole). This is stirred for 15 minutes at ice bath temperature and then refluxed for 1 hour. The reaction mixture is cooled, evaporated to dryness in vacuo and then treated with isopropanol. The solid is filtered, washed with fresh isopropanol, then ether and air dried to give an off-white solid, 3.4 g, (48%), m.p. 165-7° C.; MS (ES+): m/z 202.3 (M+H).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([N:16]2[CH:20]=[CH:19][C:18]([C:21]([OH:23])=O)=[N:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:46][CH2:47][C:48]([N:50]1[CH2:55][CH2:54][N:53]([C:56](=[O:67])[C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=2[C:63]([F:66])([F:65])[F:64])[CH2:52][CH2:51]1)=[O:49]>CN(C=O)C.O>[O:49]=[C:48]([N:50]1[CH2:51][CH2:52][N:53]([C:56](=[O:67])[C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=2[C:63]([F:66])([F:65])[F:64])[CH2:54][CH2:55]1)[CH2:47][NH:46][C:21]([C:18]1[CH:19]=[CH:20][N:16]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:17]=1)=[O:23]
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reactant: O=C(O)c1ccn(-c2ccccc2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccn(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 30.5 %

Procedure:
DIPEA (130 mg, 0.17 mL, 1.0 mmol) was added to a stirred solution of 1-phenyl-1H-pyrazole-3-carboxylic acid (47 mg, 0.25 mmol) in DMF (5 mL). HOBT (37 mg, 0.27 mmol) and EDCI (120 mg, 0.62 mmol) were then added at room temperature. After 2 minutes, 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (prepared by the method as described above) (97 mg, 0.27 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using silica gel of 60-120 mesh and 70% EtOAc in Hexane as eluent) to afford 37 mg (30.5% yield) of 1-phenyl-1H-pyrazole-3-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity: 96.28%. 1H NMR (CDCl3): δ 7.9 (d, 2H), 7.7 (d, 3H), 7.68-7.54 (m, 2H), 7.44 (t, 2H), 7.32 (d, 2H), 6.8 (d, 1H), 4.42-4.2 (m, 2H), 4.1-3.86 (m, 2H), 3.82-3.4 (m, 4H), 3.2 (s, 2H).
Reaction SMILES: [Cl:1][CH2:2][C:3]([O:5][C@H:6]1[CH2:25][C@@:24]2([CH3:26])[C@@H:17]([CH2:18][CH2:19][C@@H:20]2[C:21](=[O:23])[CH3:22])[C@H:16]2[C@H:7]1[C@:8]1([CH3:28])[C@@H:13]([CH2:14][CH2:15]2)[CH2:12][C@@H:11]2[O:27][C@@H:10]2[CH2:9]1)=[O:4].C(=O)(O)[O-].[Na+].[C:34]([OH:37])(=[O:36])[CH3:35]>>[C:34]([O:37][C@H:10]1[CH2:9][C@@:8]2([CH3:28])[C@@H:13]([CH2:14][CH2:15][C@@H:16]3[C@@H:7]2[C@@H:6]([O:5][C:3](=[O:4])[CH2:2][Cl:1])[CH2:25][C@@:24]2([CH3:26])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[C:21](=[O:23])[CH3:22])[CH2:12][C@@H:11]1[OH:27])(=[O:36])[CH3:35]
Reactant: CC(=O)O
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3[C@@H](OC(=O)CCl)C[C@]12C
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(=O)O[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2[C@@H](OC(=O)CCl)C[C@]2(C)[C@@H](C(C)=O)CC[C@@H]32)C[C@@H]1O

Procedure:
11β-Chloroacetoxy-2α,3α-epoxy-5α-pregnan-20-one (5 g) was dissolved in glacial acetic acid (25 ml) and heated on a steam bath for 3.1/2 hrs. The solution was poured into saturated sodium bicarbonate solution, the white precipitate filtered off, washed well with water and dried. Preparation thick layer chromatography in ethyl acetate-petrol gave the title compound as a white foam (3.26 g). [α]D +93.2°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][C:18]1=[O:26]>>[CH3:1][O:2][C:3]1[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][C:6]([CH:7]=[C:19]2[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[NH:17][C:18]2=[O:26])=[CH:9][CH:10]=1
Reactant: O=C1Cc2ccccc2N1
Reactant: COc1ccc(C=O)cc1-c1ccccc1
Product: COc1ccc(C=C2C(=O)Nc3ccccc32)cc1-c1ccccc1

Procedure:
4-Methoxy-3-phenylbenzaldehyde was condensed with 2-oxindole to give 0.3 g of 3-(6-methoxybiphenyl-3-ylmethylene)-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=3)=[C:13]([CH3:22])[S:12][C:11]=2[CH:23]=1.[CH3:24][NH:25][CH3:26]>>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[C:10]3[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:25]([CH3:26])[CH3:24])=[CH:23][C:11]=3[S:12][C:13]=2[CH3:22])=[CH:16][CH:17]=1
Reactant: CNC
Reactant: Cc1sc2cc(OCCCCBr)ccc2c1-c1ccc(Br)cc1
Product: Cc1sc2cc(OCCCCN(C)C)ccc2c1-c1ccc(Br)cc1

Procedure:
According to the method in example 31, 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-2-methyl-benzo[b]thiophene and dimethylamine were converted to yield {4-[3-(4-Bromo-phenyl)-2-methyl-benzo[b]thiophen-6-yloxy]-butyl}-dimethyl-amine as yellowish oil, MS: 418 (MH+, 1Br).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].C(N(CC)C(C)C)(C)C.[CH3:21][C@H:22]1[N:27]([C:28]2[C:29]3[CH:36]=[CH:35][S:34][C:30]=3[N:31]=[CH:32][N:33]=2)[C@@H:26]([CH3:37])[CH2:25][N:24]([CH2:38][C:39](O)=[O:40])[CH2:23]1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>O1CCOCC1.CN(C)C1C=CN=CC=1>[CH3:21][C@H:22]1[N:27]([C:28]2[C:29]3[CH:36]=[CH:35][S:34][C:30]=3[N:31]=[CH:32][N:33]=2)[C@@H:26]([CH3:37])[CH2:25][N:24]([CH2:38][C:39]([NH:5][C:4]2[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=2[C:2]([F:10])([F:11])[F:1])=[O:40])[CH2:23]1
Reactant: Nc1ccccc1C(F)(F)F
Reactant: C[C@@H]1CN(CC(=O)O)C[C@H](C)N1c1ncnc2sccc12
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C[C@@H]1CN(CC(=O)Nc2ccccc2C(F)(F)F)C[C@H](C)N1c1ncnc2sccc12
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A mixture of the product from step (i) (0.2 g), 2-trifluoromethylaniline (0.11 g) and N,N-diisopropylethylamine in 1,4-dioxane (5 ml) was heated at 80° C. for 18 hours. LC mass spectrum analysis showed cis-(3,5-dimethyl-4-(thieno[2,3-d]pyrimidin-4-yl)piperazin-1-yl]acetic acid present. PyBroP (0.18 g) and 4-dimethylaminopyridine (0.05 g) were added and the mixture further stirred at room temperature for 18 hours. The solvent was evaporated under reduced pressure and the residue purified by high pressure liquid chromatography (acetonitrile/0.1% aqueous ammonium acetate, gradient elution 25% to 75% organic phase) to give the title product as a white solid. Yield 0.08 g.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[C:10]([O:15]CC3C=CC(OC)=CC=3)=[CH:9]2)[CH:5]=[CH:4][CH:3]=1.[NH:25]1[C:33]2[C:28](=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=2)[CH:27]=[N:26]1>C1COCC1.C([O-])([O-])=O.[Cs+].[Cs+].[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[OH:15][C:10]1[C:11](=[O:14])[CH:12]=[CH:13][N:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:29]3[CH:30]=[CH:31][CH:32]=[C:33]4[C:28]=3[CH:27]=[N:26][NH:25]4)[N:7]=2)[CH:9]=1
Reactant: OB(O)c1cccc2[nH]ncc12
Reactant: COc1ccc(COc2cn(-c3cccc(Br)n3)ccc2=O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: O=c1ccn(-c2cccc(-c3cccc4[nH]ncc34)n2)cc1O
Temperature: 160 °C
Reaction time: 1 h

Procedure:
A mixture of 6′-bromo-3-[(4-methoxybenzyl)oxy]-4H-1,2′-bipyridin-4-one (40 mg, 0.1 mmol), 1H-indazol-4-ylboronic acid (32.5 mg, 0.2 mmol), and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichchloromethane complex (4 mg) in THF (2 mL) and 1 M aq. Cs2CO3 (1 mL) was heated under microwave irradiation at 160° C. for 10 min. After cooling to rt, the THF and aq. layers were separated and the aq. solution was extracted with THF (2×2 mL). The combined THF solution was treated with QuadraPure TU resin (Aldrich) for 1 h and filtered. The collected THF solution was concentrated. The concentrated residue was dissolved in TFA-DCM (1:1, 1 mL) and stirred for 1 h. The TFA-DCM solution was concentrated and the residue was purified by LCMS to give 3-Hydroxy-6′-(1H-indazol-4-yl)-4H-1,2′-bipyridin-4-one (TFA salt,). 1H NMR (499 MHz, DMSO): δ 8.60-8.55 (m, 2 H); 8.39 (d, J=2.4 Hz, 1 H); 8.18 (t, J=7.9 Hz, 1 H); 8.10 (d, J=7.7 Hz, 1 H); 7.87 (d, J=8.1 Hz, 1 H); 7.82 (d, J=7.2 Hz, 1 H); 7.70 (d, J=8.3 Hz, 1 H); 7.52 (t, J=7.7 Hz, 1 H); 6.50 (d, J=7.6 Hz, 1 H); LC/MS (M+H)+ 305; HRMS Calcd for (C17H12N4O2+H)+ 305.1033 found 305.1032.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][N:5]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:4](=[O:12])[C:3]=1[CH3:13].[N:14]1[CH:19]=[CH:18][C:17]([C:20](Cl)=[O:21])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].CC(C)=O>C(OCC)(=O)C.CCCCCC>[C:8]([N:5]1[C:4](=[O:12])[C:3]([CH3:13])=[C:2]([NH:1][C:20]([C:17]2[CH:18]=[CH:19][N:14]=[CH:15][CH:16]=2)=[O:21])[CH:7]=[N:6]1)([CH3:9])([CH3:11])[CH3:10]
Reactant: Cc1c(N)cnn(C(C)(C)C)c1=O
Reactant: O=C(Cl)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: CCCCCC
Product: Cc1c(NC(=O)c2ccncc2)cnn(C(C)(C)C)c1=O
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
0.72 of 5-amino-2-tert-butyl-4-methylpyridazin-3-(2H)-one, 0.57 g of 4-pyridylcarbonyl chloride, 0.55 g of anhydrous potassium carbonate and 30 ml of dry acetone were mixed and vigorously stirred at room temperature for 40 minutes. Acetone was distilled off under reduced pressure, and the residue was extracted with 150 ml of methylene chloride and washed twice with water. Then, It was dried over anhydrous sodium sulfate and concentrated. The residue thereby obtained was subjected to column chromatography, and using an eluent (n-hexane:ethyl acetate=1:2), 0.56 g of the desired product (Compound No. 1) having a melting point of from 206° to 207° C., was obtained.
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>>[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([S:24]([C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[S:8][C:7]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:26])=[O:25])=[CH:22][CH:23]=1
Reactant: c1ccc(-c2cc3ccccc3s2)cc1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc(S(=O)(=O)c2c(-c3ccccc3)sc3ccccc23)cc1

Procedure:
Acylation of 2-phenylbenzothiophene with 4-methoxybenzenesulfonyl chloride as described above gives 3-(4-methoxyphenylsulfonyl)-2-phenylbenzothiophene.
Reaction SMILES: [CH2:1]([O:4][CH2:5]Cl)[CH2:2][CH3:3].[OH-].[Na+].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]=[C:19]([C:30]3[NH:31][CH:32]=[CH:33][CH:34]=3)[S:20][C:21]=2[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[CH:13][CH:12]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C=CC=CC=1.O>[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[N:18]=[C:19]([C:30]3[N:31]([CH2:5][O:4][CH2:1][CH2:2][CH3:3])[CH:32]=[CH:33][CH:34]=3)[S:20][C:21]=2[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc(-c2nc(-c3ccc[nH]3)sc2-c2ccc(OC)cc2)cc1
Reactant: CCCOCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CCCOCn1cccc1-c1nc(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)s1
Yield: 83 %

Procedure:
4,5-Bis(4-methoxyphenyl)-2-(pyrrol-2-yl)thiazole obtained in the same manner as described in Reference Example 6 (1.81 g, 5 mmole), chloromethyl n-propyl ether (0.65 g, 6 mmole), and tetra-n-butylammonium bromide (0.16 g, 0.5 mmole) are refluxed in two phases of benzene (20 ml) and 50% aqueous sodium hydroxide (20 ml) for 20 minutes. To the mixture are added water and benzene under ice-cooling, and the mixture is shaken. The benzene layer is taken, washed with water, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to remove the solvent. The residue is subjected to silica gel column chromatography (solvent, ethyl acetate:cyclohexane=1:20) to give oily 4,5-bis(4-methoxyphenyl)-2-(1-n-propoxymethylpyrrol-2-yl)thiazole (1.80 g, yield: 83%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:10]=[C:11]([C:21]#[N:22])[N:12]3[C:17]([S:18][CH3:19])=[CH:16][C:15]([CH3:20])=[N:14][C:13]=23)=[C:4]([CH3:23])[CH:3]=1.[OH-:24].[Na+]>OS(O)(=O)=O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:10]=[C:11]([C:21]([NH2:22])=[O:24])[N:12]3[C:17]([S:18][CH3:19])=[CH:16][C:15]([CH3:20])=[N:14][C:13]=23)=[C:4]([CH3:23])[CH:3]=1
Reactant: [OH-]
Reactant: CSc1cc(C)nc2c(-c3c(C)cc(Br)cc3C)cc(C#N)n12
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CSc1cc(C)nc2c(-c3c(C)cc(Br)cc3C)cc(C(N)=O)n12
Temperature: 60 °C

Procedure:
8-(4-bromo-2,6-dimethyl-phenyl)-2-methyl-4-methylsulfanyl-pyrrolo[1,2-a]pyrimidine-6-carbonitrile (5.70 g) was added into conc. H2SO4 (100 mL) and heated for 60° C. for 5 hours. The reaction mixture was cooled to room temperature, poured into ice-water and then 10% aqueous NaOH solution was added to make the aqueous mixture alkaline (pH=8) and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by a silica gel column chromatography (silica gel: Wako Gel (C200), eluent: ethyl acetate) to give 8-(4-bromo-2,6-dimethyl-phenyl)-2-methyl-4-methylsulfanyl-pyrrolo[1,2-a]pyrimidine-6-carboxylic acid amide (3.12 g).