Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2].[H-].[Na+].[F:25][C:26]([F:37])([F:36])[CH2:27]OS(C(F)(F)F)(=O)=O>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:27][C:26]([F:37])([F:36])[F:25])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2[nH]1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2n1CC(F)(F)F
Temperature: 70 °C
Reaction time: 0.83 h
Yield: 65.8 %

Procedure:
A solution of 5-benzyloxyindole-2-carboxylic acid ethyl ester (purchased at Biosynth, ref B2000, 2.26 g, 1.0 eq.) in dimethylformamide (15 mL) was added to a suspension of sodium hydride (60% dispersion in oil, 367 mg, 1.2 eq.) in dimethylformamide. The reaction mixture was stirred 50 min at 70° C. 2,2,2-Trifluoroethyltrifluoromethanesulfonate (3.0 g, 1.7 eq.) was added and the reaction mixture was stirred overnight at 70° C. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic fractions were washed with water and brine, evaporated to dryness and purified on silica eluting with 9:1 cyclohexane/ethyl acetate to yield 1.9 g (66%) of the desired product as light yellow solid. MS (m/e): 378.5 (MH+, 100%).
Reaction SMILES: C(=O)(O)[O-].[Na+].[C:6]1(O)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](O)=[N:8][N:7]=1.[CH2:18]([S:26][S:27]C(=N)N)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>O.CO>[CH2:18]([S:26][S:27][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([S:27][S:26][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[N:8][N:7]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: Oc1nnc(O)c2ccccc12
Reactant: CCCCCCCCSSC(=N)N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCCCCCSSc1nnc(SSCCCCCCCC)c2ccccc12
Temperature: 25 °C
Yield: 91 %

Procedure:
A solution of sodium bicarbonate (4.30 g, 0.05 mole) in water (60 ml) was added dropwise to a stirred suspension of the phthalazine-1,4-diol prepared as above (2.91 g, 0.015 mole) and S-n-octylthioisothiourea obtained in step (A) (7.695 g, 0.03 mole) in methanol (70 ml) at 60°-65° C. over 30 minutes. The mixture was stirred at room temperature for a further hour, then filtered giving a yellow solid, which was washed with water and dried giving the product as yellow crystals (6.56 g, 91%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].ClCCl.C([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([N:24]2[C:28]3=[N:29][CH:30]=[N:31][C:32]([O:33][C:34]4[CH:39]=[CH:38][C:37]([N:40]5[C:44]([CH3:45])=[N:43][N:42]=[N:41]5)=[CH:36][CH:35]=4)=[C:27]3[CH:26]=[N:25]2)[CH2:20][CH2:19]1)=[O:17])(C)(C)C>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:45][C:44]1[N:40]([C:37]2[CH:36]=[CH:35][C:34]([O:33][C:32]3[N:31]=[CH:30][N:29]=[C:28]4[N:24]([CH:21]5[CH2:22][CH2:23][N:18]([C:16]([OH:17])=[O:15])[CH2:19][CH2:20]5)[N:25]=[CH:26][C:27]=34)=[CH:39][CH:38]=2)[N:41]=[N:42][N:43]=1
Reactant: Cc1nnnn1-c1ccc(Oc2ncnc3c2cnn3C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nnnn1-c1ccc(Oc2ncnc3c2cnn3C2CCN(C(=O)O)CC2)cc1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 98 %

Procedure:
A solution of 20% trifluoroacetic acid/dichloromethane (12 mL) was added to a solution of 4-{4-[4-(5-methyl-tetrazol-1-yl)-phenoxy]-pyrazolo[3,4-d]pyrimidin-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (Example 84; 486 mg, 1.02 mmol) in dichloromethane (2 mL) and the mixture was stirred at room temperature for 25 min. The volatiles were evaporated and the residue held at high vacuum and then triturated with ether to give 4-{4-[4-(5-methyl-tetrazol-1-yl)-phenoxy]-pyrazolo[3,4-d]pyrimidin-1-yl}-piperidine-1-carboxylic acid trifluoro-acetate salt (493 mg, 98%) as a white solid. This was taken up in dichloromethane (3 mL) and diisopropylethylamine (243 μL, 1.37 mmol) was added. The mixture was cooled to 0° C., and isopropyl chloroformate (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA; 1 M in toluene; 458 μL, 0.46 mol) was added dropwise. The mixture was stirred at room temperature for 1.5 h. Water (5 mL) was added and the layers were separated. The organic layers was washed with brine, dried (sodium sulfate), filtered, and evaporated. The residue was purified on a Supelco 11 g column, eluting with 6% methanol/dichloromethane to give 4-{4-[4-(5-methyl-tetrazol-1-yl)-phenoxy]-pyrazolo[3,4-d]pyrimidin-1-yl}-piperidine-1-carboxylic acid isopropyl ester (136 mg, 64%) as a white powder. 1H NMR (DMSO-d6) δ 1.20 (d, 6H, J=6.4 Hz), 1.93-2.05 (m, 4H), 2.59 (s, 3H), 2.96-3.14 (m, 2H), 4.04-4.18 (m, 2H), 4.79 (pentet, 1H, J=6.3 Hz), 4.96-5.08 (m, 1H), 7.61-7.64 (m, 2H), 7.79-7.82 (m, 2H), 8.36 (s, 1H), 8.57 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]=[O:10])=[C:4]([Cl:11])[N:3]=1.S(Cl)([Cl:15])(=O)=O>>[Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]([C:9]([Cl:15])=[O:10])=[C:6]([Cl:8])[N:7]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: O=Cc1c(Cl)nc(Cl)nc1Cl
Product: O=C(Cl)c1c(Cl)nc(Cl)nc1Cl

Procedure:
In a first step, 2,4,6-trichloro-pyrimidine-5-carbaldehyde (I) is reacted with sulfuryl chloride to form 2,4,6-trichloropyrimidine-5-carboxylic acid chloride (II). The acyl chloride (II) is reacted, by a Friedel-Crafts-reaction, with an appropriately substituted benzene to form a 2,4,6-trichloro-pyrimidine-5-yl-aryl-ketone (III). Compound III is reacted with an aromatic amine in the presence of a tertiary amine to form a 2,4-dichloro-5-aroyl-6-arylamino-pyrimidine (IV).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](O)=[O:19])[C:9]([CH3:25])([CH3:24])[CH2:8]2)=[O:4].ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.Cl.CN1CCOCC1.[CH3:55][N:56]1[CH2:59][CH:58]([NH2:60])[CH2:57]1>ClCCl>[CH3:24][C:9]1([CH3:25])[CH2:8][C:7]2[C:12](=[CH:13][CH:14]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=2)[NH:11][CH:10]1[C:15]1[CH:23]=[CH:22][CH:21]=[C:17]([C:18](=[O:19])[NH:60][CH:58]2[CH2:59][N:56]([CH3:55])[CH2:57]2)[CH:16]=1
Reactant: CN1CC(N)C1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)O)c1)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)NC3CN(C)C3)c1)N2
Reaction time: 1 h
Yield: 109.2 %

Procedure:
To a suspension of 3-(6-(methoxycarbonyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinolin-2-yl)benzoic acid (100 mg, 0.29 mmol) in dichloromethane (6.7 mL) was added N-hydroxybenzotriazole (59.7 mg, 0.44 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.hydrochloric acid (169.7 mg, 0.88 mmol), followed by 4-methylmorpholine (89.5 mg, 0.88 mmol) and the resultant mixture was stirred at room temperature for 40 min. Then 1-methylazetidin-3-amine (30.5 mg, 0.35 mmol) was added to the flask and the reaction mixture was stirred for an additional 60 min, LC-MS showed the reaction was complete. The reaction was quenched with water, separated, and the aqueous layer was extracted with dichloromethane (twice). The combined organic layers were washed with 2% sodium hydroxide aqueous solution (twice) and brine (3 times), dried over anhydrous magnesium sulfate. Removal of the solvent in vacuo gave 129 mg of methyl 3,3-dimethyl-2-(3-(1-methylazetidin-3-ylcarbamoyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate as a white solid, which was washed with ether to afford 103 mg desired product as a white powder, yield: 85.8%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][C:16](Cl)=[N:17][OH:18])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([C:22]1[C:23]([NH2:29])=[N:24][C:25]([NH2:28])=[CH:26][CH:27]=1)#[CH:21].C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[CH2:15][C:16]1[CH:21]=[C:20]([C:22]2[C:23]([NH2:29])=[N:24][C:25]([NH2:28])=[CH:26][CH:27]=2)[O:18][N:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(N)nc1N
Reactant: ON=C(Cl)Cc1cccc(OCc2ccccc2)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ccc(-c2cc(Cc3cccc(OCc4ccccc4)c3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.2 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (3-benzyloxy-phenyl)-acetohydroximoyl chloride (200 mg, 0.724 mmol) described in Manufacturing Example 61-1-4 and 3-ethynyl-pyridin-2,6-diamine (61.5 mg, 0.462 mmol) described in Manufacturing Example 13-1-3 was added triethylamine (252 μL, 1.81 mmol). This mixture was stirred for 4 hours at room temperature. This mixture was partitioned into water and ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane: ethyl acetate=1:1˜ethyl acetate) to obtain the title compound (138 mg, 51%).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[N:22][C:23]#[N:24])OC2C=CC=CC=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(#N)C.[CH:30]1([NH2:35])[CH2:34][CH2:33][CH2:32][CH2:31]1>>[C:23]([NH:22][C:14]([NH:13][C:5]1[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=[C:3]([C:2]([F:1])([F:25])[F:26])[CH:4]=1)=[N:35][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)#[N:24]
Reactant: NC1CCCC1
Reactant: N#CN=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Oc1ccccc1
Solvent: CC#N
Product: N#CNC(=NC1CCCC1)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 85 °C
Reaction time: 3.5 h
Yield: 82 %

Procedure:
To a suspension of N-(3,5-bis(trifluoromethyl)phenyl)-N'-cyano-O-phenylisourea (0.400 g, 1.1 mmol) in dry acetonitrile (2.5 ml) triethylamine (0.164 ml, 1.2 mmol) and cyclopentylamine (0.116 ml, 1.2 mmol) was added. The homogenous solution was stirred at 85° C. under N2 for 3.5 h. The solvent was evaporated, and the residue was dissolved in ethyl acetate and washed with water twice. The organic layer was dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography using ethyl acetate/heptane 1:2 to give the title compound. Yield 82% (0.320 g). mp 156-159° C.
Reaction SMILES: [CH3:1][C:2]1=[C:3]([CH3:9])[C:4]([O:6][C:7]1=O)=[O:5].[F:10][C:11]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:12]=1[NH2:13].O>CN(C)C1C=CN=CC=1.CC1C=CC=CC=1C>[F:10][C:11]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:12]=1[N:13]1[C:7](=[O:6])[C:2]([CH3:1])=[C:3]([CH3:9])[C:4]1=[O:5]
Reactant: CC1=C(C)C(=O)OC1=O
Reactant: Nc1ccc(Cl)cc1F
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Cc1ccccc1C
Product: CC1=C(C)C(=O)N(c2ccc(Cl)cc2F)C1=O

Procedure:
A mixture of 126 g (1.0 mol) of dimethylmaleic anhydride, 145.5 g (1.0 mol) of 2-fluoro-4-chloroaniline and 2 g of 4-dimethylaminopyridine is heated under reflux in 800 ml of o-xylene for 16 hours using a water separator. The whole is then evaporated to dryness in vacuo and the residue is dissolved in a 1:1 mixture of ethyl acetate:ether and washed with each of 1N hydrochloric acid, 1N sodium hydroxide solution and water. Afer drying over sodium sulphate and evaporating off the solvent, the residue (227.5 g) is recrystallised from methanol. In this manner there are obtained 211.1 g (84% of the theoretical yield) of the title product in the form of colourless crystals which melt at 96°-97°.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH2:19]([NH:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1ccc(O)c(C(=O)O)c1
Reactant: BrCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(O)c1cc(NCc2ccccc2)ccc1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 113.8 %

Procedure:
To a solution of 5-aminosalicylic acid (2.0 g, 13 mmole, purchased from Aldrich Chemical Company, USA) and triethylamine in dried DMF (25 ml) was added benzyl bromide (2.68 g, 1.90 ml, 15.6 mmole) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred for 4 hr at room temperature. Ice chips were added to the reaction mixture and then solvent was removed in vacuo. The reaction mixture was diluted with water and then extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over anhydrous MgSO4. After evaporation of the solvent, the residue was purified by column chromatography and recrystallized from methanol/ethyl acetate/hexane (1:3:1) to give 3.6 g (73% yield) of 5-benzylaminosalylic acid as a white solid.: mp 173.5-174.5° C. (decompose).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]#[N:13])=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:7]=1.CC(C)([O-])C.[K+].[C:20]([O:23][CH2:24][CH2:25]Br)(=[O:22])[CH3:21].C(OCC)(=O)C>C1COCC1>[CH2:24]([O:23][C:20]([C:21]1[N:8]([C:9](=[O:11])[CH3:10])[C:6]2[C:5]([C:12]=1[NH2:13])=[CH:4][CH:3]=[C:2]([Cl:1])[CH:7]=2)=[O:22])[CH3:25]
Reactant: CC(=O)Nc1cc(Cl)ccc1C#N
Reactant: CC(=O)OCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(N)c2ccc(Cl)cc2n1C(C)=O
Temperature: 0 °C
Yield: 45 %

Procedure:
Stir and cool to 0° C. a mixture of N-(5-chloro-2-cyanophenyl)acetamide (see Example 8, 1.0 g, 5.14 mmol) and THF (10 mL) and add potassium tert-butoxide (6.2 mL, of a 1M solution in THF) and stir at 0° C. for 30 min. Add bromoethyl acetate (0.6 mL) in one portion. Stir at room temperature for 2 h. Quench the reaction with water (40 mL) and stir with ethyl acetate. Separate the layers and reextract the aqueous with ethyl acetate. Combine the organic extracts and wash with water and brine. Dry over MgSO4 and concentrate under reduced pressure to obtain a brown solid. Triturate the solid with ether and collect a beige solid. Chromatograph the solid on silica gel with 2% ethyl acetate/dichloromethane followed by 10% ethyl acetate/dichloromethane to obtain 0.65 g (45%) of the title compound as a beige solid: MS 281(M+H), HPLC: Rt=3.20 min., TLC (silica gel, 10% ethyl acetate/dichloromethane) Rf=0.53.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([NH2:9])[C:3]=1[NH2:10].[CH:11](O)=O>>[Br:1][C:2]1[C:3]2[N:10]=[CH:11][NH:9][C:4]=2[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Nc1cc(F)cc(Br)c1N
Reactant: O=CO
Product: Fc1cc(Br)c2nc[nH]c2c1
Temperature: 110 °C

Procedure:
A mixture of 3-bromo-5-fluorobenzene-1,2-diamine (10.1 g, 49 mmol) in formic acid (20 mL) was heated at 110° C. overnight. The reaction mixture was concentrated, and to the residue was added MeOH (5 mL) to form a precipitate. The precipitate was filtered and washed with MeOH (2 mL) to afford 4-bromo-6-fluoro-1H-benzo[d]imidazole as a yellow solid (10 g, yield, 73%). MS (ESI): m/z=215 [M+1]+.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]2[CH:14]=[CH:15][C:16]([OH:19])=[N:17][CH:18]=2)=[N:5]1)[CH3:3].[H-].[Na+].[CH3:22][N:23]1[C:27]2=[N:28][CH:29]=[CH:30][CH:31]=[C:26]2[N:25]=[C:24]1S(C)(=O)=O.O>CN(C=O)C>[CH3:3][CH:2]([N:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]2[CH:18]=[N:17][C:16]([O:19][C:24]3[N:23]([CH3:22])[C:27]4=[N:28][CH:29]=[CH:30][CH:31]=[C:26]4[N:25]=3)=[CH:15][CH:14]=2)=[N:5]1)[CH3:1]
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Reactant: CC(C)n1nc(-c2ccc(O)nc2)c2ncccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1nc(-c2ccc(Oc3nc4cccnc4n3C)nc2)c2ncccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20 %

Procedure:
To a stirred mixture of 5-[1-(1-Methylethyl)-1H-pyrazolo[4,3-b]pyridin-3-yl]pyridin-2-ol (76 mg) in DMF (4 mL) was added NaH (60% in oil, 12.6 mg) at room temperature. The mixture was stirred at room temperature for 30 min and then 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (76 mg) was added. The mixture was exposed to microwave irradiation at 180° C. for 30 min, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane). The product was crystallized from AcOEt/hexane to give the title compound (23.0 mg).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:6][CH:7]=1.[NH:14]1[CH2:19][CH2:18][C:17]2([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[C:21](=[O:28])[O:20]2)[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:13][C:10]1[N:9]=[C:8]([C:5]2[N:4]=[N:3][C:2]([N:14]3[CH2:19][CH2:18][C:17]4([C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[C:21](=[O:28])[O:20]4)[CH2:16][CH2:15]3)=[CH:7][CH:6]=2)[O:12][N:11]=1
Reactant: O=C1OC2(CCNCC2)c2ccccc21
Reactant: Cc1noc(-c2ccc(Cl)nn2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1noc(-c2ccc(N3CCC4(CC3)OC(=O)c3ccccc34)nn2)n1

Procedure:
The object product (187 mg, 52%) was obtained in the same manner as in Example 1 and using 3-chloro-6-(3-methyl-1,2,4-oxadiazol-5-yl)pyridazine (200 mg) obtained in Example 43(2), 3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (240 mg) and potassium carbonate (140 mg).
Reaction SMILES: [Br:1][C:2]1[CH:23]=[C:22]([F:24])[C:5]2[N:6]([CH2:9][C:10]3[CH:21]=[CH:20][C:13]4[N:14]=[C:15](S(C)=O)[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[NH2:25][C@@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]1[OH:32].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[Br:1][C:2]1[CH:23]=[C:22]([F:24])[C:5]2[N:6]([CH2:9][C:10]3[CH:21]=[CH:20][C:13]4[N:14]=[C:15]([NH:25][C@@H:26]5[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]5[OH:32])[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: CS(=O)c1nc2ccc(Cn3cnc4cc(Br)cc(F)c43)cc2s1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(Br)cc(F)c43)cc2s1
Temperature: 110 °C
Yield: 63.8 %

Procedure:
A stirred mixture of 6-((5-bromo-7-fluoro-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (1.33 g, 3.14 mmol), (1R,2R)-2-aminocyclohexanol (1.09 g, 9.43 mmol), DIEA (1.62 g, 12.58 mmol) and DMA (40 mL) was heated in a sealed vial at 110° C. for 15 h. The mixture was cooled to rt and then partitioned between water and EtOAc. The organic layer was separated and washed sequentially with water and brine. The organic layer was separated, dried over MgSO4, filtered, and concentrated under reduced pressure. The residual solid was purified by trituration with a 6:1 mixture of diethyl ether and DCM to afford (1R,2R)-2-((6-((5-bromo-7-fluoro-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (952 mg, 64%) as a tan solid. A 90 mg portion was further purified by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the stationary phase to afford (1R,2R)-2-((6-((5-bromo-7-fluoro-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (15 mg) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 8.52 (s, 1H), 7.98 (d, J=10.0 Hz, 1H), 7.74 (d, J=5.0 Hz, 1H), 7.54 (m, 1H), 7.33 (m, 1H), 7.29 (d, J=10.0 Hz, 1H), 7.08 (m, 1H), 5.52 (s, 2H), 4.75 (d, J=5.0 Hz, 1H), 3.51 (m, 1H), 3.33 (m, 1H), 2.02 (m, 1H), 1.87 (m, 1H), 1.59-1.64 (m, 2H), 1.16-1.30 (m, 4H); LCMS (ESI) m/z 475 and 477 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][N:11]3[C:17]=2[CH2:18][C:19](O)=[O:20])=[CH:4][CH:3]=1.[CH2:22]([NH:29][CH2:30][CH2:31]OC)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([N:29]([CH2:30][CH3:31])[C:19](=[O:20])[CH2:18][C:17]1[N:11]2[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:10]2=[N:9][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COCCNCc1ccccc1
Reactant: Cc1ccc(-c2nc3cc(C)ccn3c2CC(=O)O)cc1
Product: CCN(Cc1ccccc1)C(=O)Cc1c(-c2ccc(C)cc2)nc2cc(C)ccn12
Yield: 54.6 %

Procedure:
According to the method of Example 13, 2-(4-methylphenyl)-7-methylimidazo[1,2-a]pyridine-3-acetic acid and N-benzyl-2-methoxyethylamine were used as raw materials for synthesis, to obtain yellow solid powder, yield 54.6%. m.p. 220-222° C., ESm/z: 398[M+H]+, 1H NMR(CDCl3, 400 MHz)δ: 1.14(t, 1.5H, J=7.00 Hz), 1.17(t, 1.5H, J=7.00 Hz), 2.36(s, 1.5H), 2.37(s, 1.5H), 2.52(s, 1.5H), 2.54(s, 1.5H), 3.35(q, 1H, J=7.00 Hz), 3.52(q, 1H, J=7.00 Hz), 4.15(s, 1H), 4.24(s, 1H), 4.57(s, 1H), 4.61(s, 1H), 7.05-7.19(m, 1H), 7.22-7.36(m, 9H), 7.47-7.62(m, 1H), 8.13-8.29(m, 1H).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][C:6]=1[F:12])([CH3:3])[CH3:2].C([Li])CCC.[C:18](=[O:20])=[O:19]>C1COCC1.CCCCCCC>[F:12][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][C:5]=1[O:4][CH:1]([CH3:3])[CH3:2])[C:18]([OH:20])=[O:19]
Reactant: CC(C)Oc1ccc(Br)cc1F
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(C(=O)O)cc1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
A solution of 639 mg (2.74 mmol) 1-isopropyloxy-2-fluoro-4-bromobenzene (from Step A) in 10 mL of THF at −78° C. was treated with 1.64 mL of 2.0 M n-butyllithium in heptane. After stirring at −78° C. for 30 min, the mixture was poured onto 300 g of crushed dry ice and allowed to warm up to rt. The mixture was partitioned between 100 mL of 2.0 N NaOH and 100 mL of Et2O. The aqueous layer was separated, acidified using 5.0 N HCl to pH 2, and extracted with CH2Cl2 (3×50 mL). The organic layers were combined, dried over MgSO4, and concentrated to afford 380 mg of the title compound: 1H NMR (500 MHz, CDCl3) δ 1.41 (d, J=6.2, 6H), 4.65-4.73 (m, 1H), 7.00 (t, J=8.5, 1H), 7.79-7.87 (m, 2H).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C:7](=[C:8]([CH2:32]Br)[CH2:9][C@@H:10]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:6]1)(=[O:3])[CH3:2].[CH2:34]([O:36][CH2:37][CH2:38][NH:39][CH2:40][CH2:41][O:42][CH2:43][CH3:44])[CH3:35].ClCCl>O>[C:1]([O:4][C@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C:7](=[C:8]([CH2:32][N:39]([CH2:40][CH2:41][O:42][CH2:43][CH3:44])[CH2:38][CH2:37][O:36][CH2:34][CH3:35])[CH2:9][C@@H:10]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=C(CBr)C[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]32)C1
Reactant: CCOCCNCCOCC
Solvent: O
Solvent: ClCCl
Product: CCOCCN(CCOCC)CC1=C2C[C@@H](OC(C)=O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]3[C@@H]2C1

Procedure:
A solution of 10 parts of 3β-acetoxy-6-(bromomethyl)cholest-5-ene and 20 parts of bis(ethoxyethyl)amine in 13 parts of dichloromethane is allowed to stand at room temperatures for 24 hours, whereupon 5 volumes of water is introduced and the oil which separates is extracted with diethyl ether. The extract is washed with water, dried over anhydrous sodium sulfate, and stripped of solvent by vacuum distillation to give 3β-acetoxy-6-[di(2-ethoxyethyl)aminomethyl]cholest-5-ene as the residue. The product, an oil, has the formula ##SPC9##
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][CH:11]1[CH2:28][CH2:27][C:14]2([CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH2:13][CH2:12]1.CCN(CC)CC>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][CH:11]2[CH2:12][CH2:13][C:14]3([CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:16][CH2:15]3)[CH2:27][CH2:28]2)[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(N)CC2)CC1
Reactant: Clc1ncc(Cl)c(Cl)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC2(CCC(Nc3nc(Cl)ncc3Cl)CC2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 34.5 %

Procedure:
To a solution of 2,4,5-trichloropyrimidine (495.9 mg, 2.7 mmol) in ethanol (20 mL) were added tert-butyl 9-amino-3-azaspiro[5.5]undecane-3-carboxylate (1.08 g, 4.0 mmol) and Et3N (413.6 mg, 4.1 mmol). The mixture was stirred at room temperature for 12 h and then concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/10 to 1/7) to give the product as a light yellow solid (387.1 mg, 34.5%).