Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]([O:13][CH3:14])[CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[H-].[Na+].Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>>[CH3:14][O:13][CH:3]([O:2][CH3:1])[CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:8][CH:7]=1
Reactant: COC(CSc1ccc(O)cc1)OC
Reactant: CCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Product: CCCCCCCCOc1ccc(SCC(OC)OC)cc1
Yield: 87 %

Procedure:
This phenol is alkylated again by the same method, but using sodium hydride and 1-bromooctane, to provide 1-((2,2-dimethoxyethyl)thio)-4-(octyloxy)benzene as a colorless oil after chromatography (87% yield). By the method of example 2, this is converted into the title compound, obtained as a pale yellow solid, mp 70°-72° after recrystallization from hexane-dichloromethane.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[H-].[Na+].O.[CH3:20]N(C=O)C>>[CH3:20][O:16][CH2:15][CH2:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COCCC1CCNCC1

Procedure:
To a solution of 825 mg (3.6 mmol) of 1-t-butoxycarbonyl-4-hydroxyethylpiperidine in 2.5 mL of DMF was added 0.21 g (7.2 mmol) of NaH (80% dispersion in mineral oil) in 3 portions over a period of 30 min. After 16 h 10 mL of H2O was added to the reaction mixture and it was extracted with ethyl acetate. The combined organic fractions were washed with sat'd NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, hexanes:ethyl acetate=4:1) to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[CH3:25][S:26]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)(=[O:28])=[O:27]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].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>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:32]4[CH:33]=[CH:34][C:29]([S:26]([CH3:25])(=[O:28])=[O:27])=[CH:30][CH:31]=4)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(-c4ccc(S(C)(=O)=O)cc4)cc32)N=C1N
Temperature: 120 °C
Yield: 75 %

Procedure:
Pd(PPh3)2Cl2 (10 mg) in a 10 mL tube under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 4-(methylsulfonyl)phenylboronic acid (20.8 mg, 0.1 mmol). The mixture was heated in a microwave reactor at 120° C. for 30 min. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give pure 2′-amino-1′-methyl-6-(4-(methylsulfonyl)phenyl)-2-phenylspir-o[chroman-4,4′-imidazol]-5′(1′H)-one (18 mg, 80%). 1H-NMR (CDCl3+MeOD): 2.07 (dd, 1H), 2.41 (t, 1H), 3.01 (s, 3H), 3.12 (s, 3H), 5.25 (d, 0.5H), 5.89 (d, 1H), 6.90 (d, 1H), 7.31 (s, 2H), 7.32 (t, 2H), 7.39 (d, 3H), 7.60 (t, 2H), 7.87 (d, 2H).
Reaction SMILES: [C:1]([NH:4][C:5]([NH2:7])=[S:6])(=[NH:3])[NH2:2].Cl[CH2:9][C:10](=O)[CH3:11]>CC(C)=O>[CH3:11][C:10]1[N:7]=[C:5]([NH:4][C:1]([NH2:2])=[NH:3])[S:6][CH:9]=1
Reactant: CC(=O)CCl
Reactant: N=C(N)NC(N)=S
Solvent: CC(C)=O
Product: Cc1csc(NC(=N)N)n1
Temperature: 25 °C
Yield: 83 %

Procedure:
A mixture of amidinothiourea (2.0 g, 16.9 mmol), chloroacetone (1.56 g, 16.9 mmol) was heated at reflux in acetone (12 mL) for 4 h. The mixture was cooled to room temperature and removed half of the solvent. The precipitate was filtered, washed with dry acetone, and dried to give N-(4-methyl-1,3-thiazol-2-yl)guanidine (2.19 g, 83%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2O.O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][CH:7]=1
Reactant: COc1cc2nccc(O)c2cc1OC
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cc2nccc(Cl)c2cc1OC
Temperature: 85 °C

Procedure:
6,7-Dimethoxy-4-hydroxyquinoline (Step A, 7.8 g) was dissolved in POCl3 (45 mL) and heated at 85° C. for 3 h. The mixture was cooled down to RT, POCl3 was evaporated and the resulting oil was quenched by adding ice at 0° C. The aqueous phase was basified to pH 8 and a solid precipitated. The solid was filtered and dried under vacuum to give 4-chloro-6,7-dimethoxyquinoline.
Reaction SMILES: [NH2:1][CH:2]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)[C:3]([N:5]1[CH2:10][CH2:9][N:8]([CH:11]([CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)[C:12]([NH:14][CH3:15])=[O:13])[CH2:7][CH:6]1[CH2:27][CH3:28])=[O:4].CC(OC([N:44]1[C@H:47]([C:48](O)=[O:49])[CH2:46][CH2:45]1)=O)(C)C.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C.O.CCOC(C)=O>[CH2:27]([CH:6]1[CH2:7][N:8]([CH:11]([C:12](=[O:13])[NH:14][CH3:15])[CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)[CH2:9][CH2:10][N:5]1[C:3](=[O:4])[CH:2]([NH:1][C:48]([CH:47]1[CH2:46][CH2:45][NH:44]1)=[O:49])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)[CH3:28]
Reactant: CCC1CN(C(Cc2ccc3ccccc3c2)C(=O)NC)CCN1C(=O)C(N)Cc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CCC1CN(C(Cc2ccc3ccccc3c2)C(=O)NC)CCN1C(=O)C(Cc1ccc(F)cc1)NC(=O)C1CCN1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
2-{4-[2-Amino-3-(4-fluorophenyl)-propionyl]-3-ethyl-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propioamide, 41, (0.78 g, 0.83 mmol) and Boc-L-azetidine-2-carboxylic acid (0.17 g, 0.83 mmol), 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide (0.19 g, 1.0 mmol) and 1-hydroxybenzotriazole (0.22 g, 1.66 mmol) are dissolved in anhydrous DMF (2 mL). The reaction mixture is cooled to 0° C., then N-methylmorpholine (0.6 mL, 5.46 mmol) is added. The reaction mixture is stirred for 4 hrs. EtOAc (30 mL) and water (100 mL) are added, and the organic layer is separated. The aqueous layer is extracted with EtOAc (3×30 mL). All organic layers are combined and washed with water (2×50 mL), and dried over Na2SO4. The solution is concentrated in vacuo to afford the desired product which is used without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[CH2:3][CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH:9]1[S:13][C:12]2[C:14]([CH3:24])=[C:15]([O:20]COC)[C:16]([CH3:19])=[C:17]([CH3:18])[C:11]=2[O:10]1.S(=O)(=O)(O)O>C(O)(=O)C>[CH3:25][N:2]([CH3:1])[CH2:3][CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH:9]1[S:13][C:12]2[C:14]([CH3:24])=[C:15]([OH:20])[C:16]([CH3:19])=[C:17]([CH3:18])[C:11]=2[O:10]1
Reactant: COCOc1c(C)c(C)c2c(c1C)SC(CCCOCCN(C)C)O2
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1c(C)c2c(c(C)c1O)SC(CCCOCCN(C)C)O2

Procedure:
330 mg of 2-[3-(2-dimethylaminoethoxy)propyl]-5-methoxymethoxy-4,6,7-trimethyl-1,3-benzoxathiole (prepared as described in Example 88) were dissolved in 5 ml of acetic acid, and then 5 drops of 10% v/v aqueous sulfuric acid was added using a Komagome pipette; the mixture was then heated for 5 hours at 70°-75° C. The acetic acid solution and then condensed by evaporation under reduced pressure, and the condensate was poured into ice-water, neutralized with potassium carbonate and extracted with ethyl acetate. The ethyl acetate solution was washed with water and the dried over anhydrous sodium sulfate. The ethyl acetate was then distilled off under reduced pressure. The resulting residue was then subjected to silica gel column chromatography, and the title compound was obtained from the fraction eluted with a 20:1 by volume mixture of ethyl acetate and triethylamine.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=O)[N:2]=1.[NH:13]1[CH:17]=[CH:16][N:15]=[C:14]1[NH:18][C:19]([C:21]1[C:29]2[NH:28][C:27]([NH2:30])=[N:26][C:25]=2[CH:24]=[CH:23][CH:22]=1)=[O:20].[BH4-].[Na+]>ClCCCl.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[NH:15]1[CH:16]=[CH:17][N:13]=[C:14]1[NH:18][C:19]([C:21]1[C:29]2[N:28]=[C:27]([NH:30][CH2:11][C:3]3[N:2]=[CH:1][C:10]4[C:5]([CH:4]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)[NH:26][C:25]=2[CH:24]=[CH:23][CH:22]=1)=[O:20]
Reactant: O=Cc1cc2ccccc2cn1
Reactant: Nc1nc2cccc(C(=O)Nc3ncc[nH]3)c2[nH]1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCCl
Product: O=C(Nc1ncc[nH]1)c1cccc2[nH]c(NCc3cc4ccccc4cn3)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 7.3 %

Procedure:
To a solution of 150 mg (0.95 mmol) of isoquinoline-3-carbaldehyde in dry DCE (1 mL) was added 60 mg (0.25 mmol) of 2-amino-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide (intermediate B), and Ti(OiPr)4 (3 mL). The mixture was sonciated for 30 min then stirred at room temperature for 6 h. NaBH4 (0.5 g) was added, and the mixture was stirring for 12 h. The reaction was quenched by addition of methanol (2 mL). After usual workup, the residue was purified by column chromatography eluting with DCM then EtOAc/methanol (v/v=100:5) to give 7 mg (7%) of 2-[(isoquinolin-3-ylmethyl)-amino]-1H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide. LCMS: 384 (M+1)+. 1H NMR (DMSO-d6, 400 MHz): δ 12.58 (s, 1H), 11.8 (s, 1H), 11.6 (s, 1H), 9.07 (s, 1H), 8.69 (s, 1H), 8.22 (t, 1H), 7.96 (d, 1H), 7.91 (d, 1H), 7.67 (m, 2H), 7.53 (t, 1H), 7.36 (d, 1H), 7.02 (t, 1H), 6.90 (s, 1H), 6.85 (s, 1H), 4.78 (d, 2H) ppm.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[C:25](Br)=[CH:24][C:23]([Cl:27])=[CH:22][N:21]4[C:28]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][N:37](C)C(=O)C>C(OCC)(=O)C.[Zn].[C-]#N.[Zn+2].[C-]#N>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[C:25]([C:36]#[N:37])=[CH:24][C:23]([Cl:27])=[CH:22][N:21]4[C:28]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)N(C)C
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(Br)cc(Cl)cn4c3-c3ccccc3)cc2)CCC1
Agent: [C-]#N
Agent: [Zn+2]
Agent: [Zn]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(C#N)cc(Cl)cn4c3-c3ccccc3)cc2)CCC1
Reaction time: 1 h

Procedure:
300 mg (0.54 mmol) {1-[4-(8-Bromo-6-chloro-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, intermediate example Int-400-12, 3.5 mg (0.054 mmol) zinc, 44.3 mg (0.054 mmol) 1,1 bis(diphenylphosphino)-ferrocenedichloropalladium(II) and 127.4 mg (1.08 mmol) zinc cyanide in 4.5 mL N,N-dimethylacetamide (degassed) were heated in the microwave at 110° C. for three hours. Due to an incomplete reaction additional zinc, catalyst and zinc cyanide were added, and stirring was continued at 150° C. for one hour. The reaction mixture was diluted with ethyl acetate and washed with water/saturated ammonium chloride. The organic phase was separated, dried (sodium sulfate), filtrated and the solvent was removed. The crude product (530 mg >100%) was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[C:9]([Si:11]([CH3:14])([CH3:13])[CH3:12])#[CH:10].C(N(CC)CC)C>[Cu](I)I.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>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([C:10]#[C:9][Si:11]([CH3:14])([CH3:13])[CH3:12])=[N:3][CH:4]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1ccc(Br)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: Cc1ccc(C#C[Si](C)(C)C)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.3 %

Procedure:
The mixture of 2-bromo-5-methylpyridine (5.0 g, 29.1 mmol), ethynyltrimethylsilane (3.42 g, 34.88 mmol), Copper iodide (0.61 g, 332 mg) and Pd(PPh3)2Cl2 (0.61 g, 0.871 mmol) was dissolved in triethylamine (6.4 mL, 261 mmol). The solution was purged with N2 3 times. The solution was stirred for overnight under 25° C. The solvent was removed under reduced pressure. The residue was separated by silca gel chromatography with the eluent of PE/EA=20/1. The product was obtained as a yellow solid (4.15 g, 76%). 1H NMR (400 MHz, CDCl3) δ 8.41 (s, 1H), 7.46 (dd, J=7.9, 1.5 Hz, 1H), 7.36 (d, J=7.9 Hz, 1H), 2.35 (s, 3H), 0.28 (s, 9H); LRMS (ES) calculated M+H for C11H16NSi: 190.3. Found: 190.2.
Reaction SMILES: Cl.[OH:2][C:3]1([C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[O:18]=[C:19]1[C:24]([CH:25]=O)=[CH:23][CH:22]=[CH:21][NH:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.ClCCl>[OH:2][C:3]1([C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[CH2:4][CH2:5][N:6]([CH2:25][C:24]2[C:19](=[O:18])[NH:20][CH:21]=[CH:22][CH:23]=2)[CH2:7][CH2:8]1
Reactant: O=Cc1ccc[nH]c1=O
Reactant: OC1(C#Cc2ccccc2F)CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=c1[nH]cccc1CN1CCC(O)(C#Cc2ccccc2F)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 9.9 %

Procedure:
After then adding 253 mg of the 4-hydroxy-4-[(2-fluorophenyl)ethynyl]piperidine hydrochloride to 10 ml of dichloromethane, 158 mg of 2-oxo-1,2-dihydropyridine-3-carboxaldehyde was added and the mixture was stirred for 10 minutes at room temperature. Next, 315 mg of sodium triacetoxyborohydride was added and the mixture was stirred overnight at room temperature. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture and extraction was performed with ethyl acetate. After drying the organic layer over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography to obtain the title compound (32 mg, 10% yield).
Reaction SMILES: Br[C:2]1[N:10]([CH3:11])[C:9]2[C:8](=[O:12])[N:7]([CH3:13])[C:6](=[O:14])[N:5]([CH3:15])[C:4]=2[N:3]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][C:23]=1[O:24][CH3:25].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:13][N:7]1[C:8](=[O:12])[C:9]2[N:10]([CH3:11])[C:2]([C:21]3[CH:20]=[CH:19][C:18]([O:17][CH3:16])=[C:23]([O:24][CH3:25])[CH:22]=3)=[N:3][C:4]=2[N:5]([CH3:15])[C:6]1=[O:14]
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: Cn1c(=O)c2c(nc(Br)n2C)n(C)c1=O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ccc(-c2nc3c(c(=O)n(C)c(=O)n3C)n2C)cc1OC
Temperature: 70 °C

Procedure:
A solution of 8-Bromo-1,3,7-trimethyl xanthine (315 mg, 1.15 mmol) and 3,4-dimethoxy phenylboronic acid (230 mg; 1.26 mmol) in 1,4-dioxane (5 ml) was treated tetrakis(triphenyl phosphine) palladium (0) (88 mg, 0.14 mmol) and potassium carbonate (277 mg, 2.0 mmol). The mixture was heated to 70° C. for 12 hrs under argon atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified on a silica gel column eluting with 70% ethyl acetate in hexane to 100% ethyl acetate. The desired product was isolated as off white solid, Yield 297 mg, 78% PRO-04-46
Reaction SMILES: [Br:1]Br.[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1>C(Cl)Cl>[Br:1][C:7]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:5][CH:6]=1
Reactant: BrBr
Reactant: c1ccc(-c2cccs2)nc1
Solvent: ClCCl
Product: Brc1ccc(-c2ccccn2)s1
Reaction time: 0.17 h

Procedure:
Bromine, 16 g (0.1 mol), was added to a solution of 8.05 g (0.05 mol) of 2-(2-thienyl)pyridine in 250 ml of methylene chloride. After stirring for 10 minutes, the reaction mixture was washed with 10% aqueous sodium carbonate solution, dried and evaporated. Crystallization from ethanol gave 9.5 g of the title compound with m.p. 85°-87°.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[C:12]4[C:17]([C:18](Br)=[C:19]5[C:24]=3[CH:23]=[CH:22][CH:21]=[CH:20]5)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=1.[C:36]1([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:37](B(O)O)=[CH:38][CH:39]=[CH:40][CH:41]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>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.O.C(O)C>[C:36]1([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:37]=[CH:38][CH:39]=[C:40]([C:18]2[C:19]3[C:24]([C:11]([C:8]4[CH:9]=[C:10]5[C:5]([CH:4]=[CH:3][C:2]([C:26]6[CH:35]=[CH:34][C:33]7[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=7)[CH:27]=6)=[CH:1]5)=[CH:6][CH:7]=4)=[C:12]4[C:17]=2[CH:16]=[CH:15][CH:14]=[CH:13]4)=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:41]=1
Reactant: OB(O)c1ccccc1-c1ccccc1
Reactant: Brc1c2ccccc2c(-c2ccc3ccc(-c4ccc5ccccc5c4)cc3c2)c2ccccc12
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: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: c1ccc(-c2cccc(-c3c4ccccc4c(-c4ccc5ccc(-c6ccc7ccccc7c6)cc5c4)c4ccccc34)c2)cc1
Temperature: 25 °C
Yield: 21.9 %

Procedure:
Under the nitrogen atmosphere, ([9-([2,2′-binaphthalen]-7-yl)-10-bromoanthracene (2.0 g) as the tenth intermediate compound, m-biphenylboronic acid (1.4 g), Pd(PPh3)4] (0.1 g), potassium phosphate (1.7 g), and a mixture solvent (16 ml) of toluene and ethanol (toluene/ethanol=4/1 (volume ratio)) were added to a flask and refluxed for 10 hours. Once the heating is completed, the reaction solution was cooled to room temperature and added with water. The precipitates were collected by suction filtration. The obtained solid was washed with water followed by methanol, and washed further with ethyl acetate. The obtained crude product was purified by silica gel column chromatography (solvent: chlorobenzene). Finally, after re-crystallization with chlorobenzene, 9-([1,1′-biphenyl]-3-yl)-10-([2,2′-binaphthalen]-7-yl)anthracene (0.5 g) was obtained as the target compound represented by Formula (1-160). The scheme is shown in the following “Reaction 16”.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC([N:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH:17]([CH3:22])[CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:21][N:18]1[CH2:19][CH2:20][NH:15][CH2:16][CH:17]1[CH3:22]
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1CNCCN1C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (15 mL) was added to 3,4-dimethylpiperazine-1-carboxylic acid tert-butyl ester (3.10 g) obtained from Referential Example 83 in methylene chloride (30 mL) at room temperature, followed by stirring for 1 hour. The residue obtained by removal through evaporation of the reaction solvent under reduced pressure was crystallized from chloroform-ether, and the crystals were recovered by filtration, to thereby give the title compound (2.756 g, 56%).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:47])=[N:14][C:15]2[N:16]([N:33]=[C:34]([CH:36]=[CH:37][CH2:38][C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][C:40]=3O)[CH:35]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][C@H:30]([OH:32])[CH3:31])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:47])=[N:14][C:15]2=[CH:35][C:34]3=[N:33][N:16]2[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:24])([O:25][CH2:26][CH2:27][CH2:28][CH2:29][C@H:30]([CH3:31])[O:32][C:44]2[CH:43]=[C:42]([F:45])[CH:41]=[CH:40][C:39]=2[CH2:38][CH:37]=[CH:36]3)[CH2:20][CH2:19]1)[C:7]([OH:9])=[O:8])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(C=CCc3ccc(F)cc3O)nn2c1N1CCC(C)(OCCCC[C@@H](C)O)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nc2cc3nn2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CC1)OCCCC[C@H](C)Oc1cc(F)ccc1CC=C3
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (S)-ethyl 2-(tert-butoxy)-2-(2-(3-(4-fluoro-2-hydroxyphenyl)prop-1-en-1-yl)-7-(4-(((R)-5-hydroxyhexyl)oxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (240 mg, 0.367 mmol) in THF (50 mL) at 0° C. was added Ph3P (144 mg, 0.550 mmol) followed by DEAD (0.087 mL, 0.550 mmol) and the resulting mixture was stirred at room temp for 3 h. At this point LCMS indicated completion of reaction and desired product as mixture of four isomers. Water (25 mL) was then added and the mixture was extracted with ether (50 mL), dried (Na2SO4), filtered and concentrated. The residue was then purified by Biotage (0-30% EtOAc/hexane) to afford to afford desired ester (165 mg, 0.259 mmol, 70.7% yield) as a inseparable mixture of two isomers which was used in the next step without further purification. LCMS (M+H)=637.3
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[C:18]1(C)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(B(O)O)CCCCC=1.C(=O)([O-])[O-].[K+].[K+]>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.C(O)C>[C:18]1([C:2]2[CH:3]=[C:4]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=1
Reactant: Clc1cc(Nc2ccccn2)c2nccn2n1
Reactant: Cc1ccccc1
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: OB(O)C1=CCCCC1
Solvent: CCO
Product: C1=C(c2cc(Nc3ccccn3)c3nccn3n2)CCCC1
Temperature: 170 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
A mixture of (6-chloro-imidazo[1,2-b]pyridazin-8-yl)-pyridin-2-yl-amine (0.063 g, 0.26 mmol), 2 mL of toluene, 0.5 mL of ethanol, cyclohexen-1-yl boronic acid (0.065 g, 0.51 mmol), Pd(PPh3)4 (0.032 g, 0.027 mmol), and 0.36 mL of a 2 M aq. potassium carbonate solution under N2 was stirred at 170° C. in a microwave for 3 h. The mixture was partitioned between 10 mL of a 10% NaOH solution and 10 mL of dichloromethane. The aqueous layer was further extracted with 10 mL of dichloromethane. The combined organic layers were dried over MgSO4, filtered and concentrated to 0.093 g of a pale yellow oil. Column chromatography (0->33% EtOAc/hexanes) afforded 0.050 g (66%) of (6-cyclohex-1-enyl-imidazo[1,2-b]pyridazin-8-yl)-pyridin-2-yl-amine as a white solid.
Reaction SMILES: [NH2:1][C:2](=[S:13])[C:3]1[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=1[CH3:8].Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[CH:19]=1)=O>CC(C)=O>[Br:24][C:20]1[CH:19]=[C:18]([C:16]2[N:1]=[C:2]([C:3]3[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=3[CH3:8])[S:13][CH:15]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: COC(=S)c1cc(C(N)=S)c(C)s1
Reactant: O=C(CBr)c1cccc(Br)c1
Solvent: CC(C)=O
Product: COC(=S)c1cc(-c2nc(-c3cccc(Br)c3)cs2)c(C)s1
Yield: 40.2 %

Procedure:
99 mg (0.400 mmol) of methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (Maybridge Chemical Co. LTD., Cornwall, U.K.) was dissolved in 25 mL of reagent grade acetone. 2-bromo-3′-Bromo acetophenone (0.4 mmol; 111 mg) was added and the solution was allowed to reflux for 3 h. The solution was allowed to cool and a solid was filtered and dissolved in 5 mL of hot tetrahydrofuran (THF), (Aldrich Chemical Co.) and purified on a 1 mm silica prep plate eluting with 20% ethyl acetate/hexane and dried in vacuo to afford 66 mg (40% yield) of methyl 4-[4-(3-bromophenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate.