Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:15][O:16][C:17](=[O:27])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1>CC(C)=O>[CH3:15][O:16][C:17](=[O:27])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)CCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)CCc1ccc(OCc2ccccc2)cc1

Procedure:
Benzyl bromide (12.9 mL, 108 mmol), K2CO3 (15.0 g, 109 mmol) and the 3-(4-hydroxyphenyl)propionic acid methyl ester from Step 1 above were combined in acetone (300 mL) and refluxed 40 h. The crude reaction mixture was filtered and the cake washed with acetone (2×100 mL). The filtrate was evaporated and the residue was triturated with MeOH (50 mL, 6 mL, 4 mL) to provide the product as a solid which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:8]=[O:9])[S:5][C:6]=1[CH3:7].[BH4-].[Na+]>C(O)C>[Br:1][C:2]1[C:3]([CH3:10])=[C:4]([CH2:8][OH:9])[S:5][C:6]=1[CH3:7]
Reactant: Cc1sc(C=O)c(C)c1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1sc(CO)c(C)c1Br
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
11.8 G. of 4-bromo-3,5-dimethylthiophene-2-carboxaldehyde was dissolved in 250 ml. of dry ethanol and stirred at 20° C. 0.52 G. of sodium borohydride was added and the resulting solution was stirred for 30 minutes, then poured into ice water and extracted with ethyl ether. The combined ether extracts were washed with a solution of 50% sodium carbonate and a saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated. Crystallization from cold hexane yielded 4-bromo-3,5-dimethyl-2-hydroxymethylthiophene, m.p. 85°-90° C.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]2[N:9](S(C3C=CC(C)=CC=3)(=O)=O)[C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[CH:14][CH:13]=3)=[CH:11][C:3]=12.C([Sn](CCCC)(CCCC)[C:39]1[CH:40]=[CH:41][C:42]([C:45]2([OH:49])[CH2:48][CH2:47][CH2:46]2)=[N:43][CH:44]=1)CCC>CN(C)C=O.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>[Cl:8][C:7]1[C:2]([C:39]2[CH:40]=[CH:41][C:42]([C:45]3([OH:49])[CH2:48][CH2:47][CH2:46]3)=[N:43][CH:44]=2)=[C:3]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[CH:14][CH:13]=3)[NH:9][C:4]2=[N:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(-c3ccc(CN4CCCC4)cc3)cc3c(Cl)c(Cl)cnc32)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C2(O)CCC2)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: OC1(c2ccc(-c3c(Cl)cnc4[nH]c(-c5ccc(CN6CCCC6)cc5)cc34)cn2)CCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4,5-dichloro-2-(4-(pyrrolidin-1-ylmethyl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (198 mg, 0.396 mmol) (Example 128B), 1-(5-(tributylstannyl)pyridin-2-yl)cyclobutanol (Example 143A) (260 mg, 0.593 mmol), and bis(triphenylphosphine)palladium dichloride (19.43 mg, 0.028 mmol) in N,N-dimethylformamide (1.318 mL) was heated to 100° C. for 16 hours. The reaction was cooled to room temperature and quenched by the addition of an aqueous potassium fluoride solution (3 g potassium fluoride in 6 mL water) and ethyl acetate (10 mL). The mixture was stirred vigorously for 16 hours and filtered through diatomaceous earth, eluting with ethyl acetate. The eluent was washed with aqueous saturated sodium bicarbonate solution, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in a solvent mixture of 2 N aqueous sodium hydroxide solution (1.0 mL) and methanol (3 mL). The solution was heated to 105° C. by microwave irradiation (Biotage, Initiator) for 5 minutes. The reaction was cooled to room temperature and diluted with dimethyl sulfoxide (1 mL). The resulting solution was purified by reverse phase high performance liquid chromatography (RP HPLC, 19×150 mm Atlantis Prep T3 OBD 5 m column, eluting with a gradient of 5% B in A to 75% B in A over 25 minutes, wherein A is water containing 0.1% v/v trifluoroacetic acid and B is acetonitrile containing 0.1% v/v trifluoroacetic acid) to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 12.50 (bs, 1H), 8.77 (dd, J=2.3, 0.8 Hz, 1H), 8.34 (s, 1H), 8.02 (dd, J=8.1, 2.3 Hz, 1H), 7.94-7.86 (m, 2H), 7.78 (dd, J=8.1, 0.8 Hz, 1H), 7.40-7.33 (m, 2H), 6.72 (s, 1H), 5.86 (s, 1H), 3.59 (s, 2H), 2.74-2.61 (m, 2H), 2.46-2.39 (m, 4H), 2.35-2.22 (m, 2H), 2.05-1.82 (m, 2H), 1.78-1.61 (m, 4H); MS ESI(+) m/z 459.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:23])[CH:11]=2)[CH:6]=1.[N:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[C:26]=[O:27]>C(O)C>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:26]([NH:25][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:27])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:23])[CH:11]=2)[CH:6]=1
Reactant: O=C=Nc1ccccc1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(N)cc2)c1C
Solvent: CCO
Product: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(NC(=O)Nc3ccccc3)cc2)c1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 33.1 %

Procedure:
To a mixture of [4-(4-amino-phenyl)-6-chloro-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (115 mg, 0.34 mmol) and isocyanato-benzene (36 mg, 0.29 mmol) was added ethanol (5 mL) under nitrogen. The resulting suspension was stirred at room temperature for 4 hours and the precipitated solids were collected by filtration, washed with cold ethanol, and air-dried to give {6-chloro-3-methyl-4-[4-(3-phenyl-ureido)-phenyl]-naphthalen-2-yl}-acetic acid methyl ester (44 mg, 28%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.86 (s, 1 H), 8.77 (s, 1 H), 7.95 (d, J=8.8 Hz, 1 H), 7.86 (s, 1 H), 7.64 (d, J=8.5 Hz, 2 H), 7.42-7.53 (m, 3 H), 7.30 (t, J=7.8 Hz, 2 H), 7.20 (d, J=1.8 Hz, 1 H), 7.15 (d, J=8.5 Hz, 2 H), 6.94-7.03 (m, 1 H), 3.96 (s, 2 H), 3.66 (s, 3 H), 2.10 (s, 3 H). HRMS calcd. for C27H24ClN2O3 [(M+H)+] 459.1470, obsd. 459.1470.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]([CH3:23])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2([CH2:19][C:20]#[CH:21])[CH2:18][CH2:17]2)=[CH:10][C:9]=1[CH3:22])[CH3:6])[CH3:2].I[C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=1>>[CH2:1]([O:3][C:4](=[O:24])[C:5]([CH3:23])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2([CH2:19][C:20]#[C:21][C:26]3[CH:27]=[CH:28][C:29]([O:32][C:33]([F:34])([F:35])[F:36])=[CH:30][CH:31]=3)[CH2:18][CH2:17]2)=[CH:10][C:9]=1[CH3:22])[CH3:6])[CH3:2]
Reactant: C#CCC1(COc2ccc(OC(C)(C)C(=O)OCC)c(C)c2)CC1
Reactant: FC(F)(F)Oc1ccc(I)cc1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCC2(CC#Cc3ccc(OC(F)(F)F)cc3)CC2)cc1C

Procedure:
In analogy to the procedure described in example 24E), reaction of 2-methyl-2-[2-methyl-4-(1-prop-2-ynyl-cyclopropylmethoxy)-phenoxy]-propionic acid ethyl ester (example 35I]) and 1-iodo-4-trifluoromethoxybenzene gave the title compound as light yellow oil.
Reaction SMILES: CON(C)[C:4](=[O:15])[C@@H:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH3:6].[CH2:17]([C:19]1[CH:20]=[C:21]([Mg]Br)[CH:22]=[CH:23][CH:24]=1)[CH3:18].C1COCC1>>[CH2:17]([C:19]1[CH:24]=[C:23]([C:4](=[O:15])[C@@H:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:12])[CH3:13])[CH3:6])[CH:22]=[CH:21][CH:20]=1)[CH3:18]
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Reactant: CCc1cccc([Mg]Br)c1
Solvent: C1CCOC1
Product: CCc1cccc(C(=O)[C@H](C)NC(=O)OC(C)(C)C)c1

Procedure:
The subtitle compound was prepared analogous to the method described in Example 19 (step 19d). Starting from (S)-tert-butyl 1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (0.7 g, 3.01 mmol) and freshly made (3-ethylphenyl)magnesium bromide 0.9M solution in THF (5 mL, 4.50 mmol). Yield 817 mg (97%)
Reaction SMILES: [C:1]1([OH:9])[CH:6]=[CH:5][CH:4]=[C:3]([OH:7])[C:2]=1[OH:8].CO[C:12](OC)([CH3:14])[CH3:13]>C1(C)C=CC=CC=1>[CH3:13][C:12]1([CH3:14])[O:7][C:3]2[CH:4]=[CH:5][CH:6]=[C:1]([OH:9])[C:2]=2[O:8]1
Reactant: COC(C)(C)OC
Reactant: Oc1cccc(O)c1O
Solvent: Cc1ccccc1
Product: CC1(C)Oc2cccc(O)c2O1
Yield: 40.4 %

Procedure:
A stirred mixture of 10.0 grams (0.079 mole) of benzene-1,2,3-triol, 20 mL (0.163 mole) of 2,2-dimethoxypropane and 1.0 gram (catalyst) of Amberlite® IR-120 (plus) ion exchange resin in 50 mL of toluene was warmed to 100° C., where it was maintained during an 18 hour period. After this time the reaction mixture was concentrated under reduced pressure to a residual solid. The solid was triturated with three 50 mL portions of methylene chloride. The combined organic extracts were concentrated under reduced pressure to a residual solid, which was then dissolved in methylene chloride and subjected to column chromatography on silical gel. Elution was accomplished with 1:4 ethyl acetate:hexane. A second column chromatography as described above was needed to purify the solid. In each chromatography, the appropriate fractions were combined and concentrated under reduced pressure, ultimately yielding 5.3 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][N:19]=[C:18]([NH:25][CH:26]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:17]=2)[CH2:10][CH2:9]1)(C)(C)C.Cl>O1CCOCC1>[NH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][NH:15][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][N:19]=[C:18]([NH:25][CH:26]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:17]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CCC(CNc2nc(NC(Cc3ccccc3)c3ccccc3)ncc2[N+](=O)[O-])CC1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H]1CC[C@H](CNc2nc(NC(Cc3ccccc3)c3ccccc3)ncc2[N+](=O)[O-])CC1
Reaction time: 18 h
Yield: 67.2 %

Procedure:
(4-{[2-(1,2-Diphenyl-ethylamino)-5-nitro-pyrimidin-4-ylamino]-methyl}-cyclohexyl)-carbamic acid tert-butyl ester (105 mg, 0.19 mmol) was dissolved in dioxane (5 mL). An HCl solution (2 mL of a 4M solution) was added. After 18 h, an oil separated from the solvent. The solvent was decanted and the oil was dissolved in water and lyopholized yielding 57 mg of the title compound as a pale yellow solid, m/z 447.3 [M+1]+.
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C@@H:9]([C:15](=[O:18])[CH2:16][CH3:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+].[Cl-].[BH4-].[Na+].[CH3:30]CO>O>[CH2:19]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@@H:9]([C@H:15]([OH:18])[CH:16]([CH3:30])[CH3:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)[C@H](C(=O)CC)N(Cc1ccccc1)Cc1ccccc1
Reactant: CCO
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: CCOC(=O)[C@H]([C@H](O)C(C)C)N(Cc1ccccc1)Cc1ccccc1
Yield: 48 %

Procedure:
To a stirred solution of ethyl (2S*)-2-(dibenzylamino)-3-oxo-pentanoate [prepared as for example 47, step 1] (2.76 g, 7.8 mmol) in EtOH (90 mL), at rt, a solution of NH4Cl (8.34 g, 156 mmol) in H2O (23 mL) was added. NaBH4 (2.95 g, 78 mmol) was then added in small portions. After 1 h from the last addition, the reaction was quenched with H2O and the solvent evaporated. The crude mixture was taken up with H2O and CH2Cl2 and pH corrected to 9 with 20% NH4OH aqueous solution. After extraction, the organic phase was dried over Na2SO4, filtered, and concentrated in vacuo to give a crude product, as an oil. Purification by column chromatography using a Teledyne ISCO apparatus, eluting with Cy:AcOEt (90:10), gave the title compound (1.33 g, 48% over 2 steps), as a pure syn diastereoisomer, as a colorless oil. MS (ESI) m/z: 356 [M−H]+. 1H NMR (DMSO-d6) δ 0.66 (d, J=6.69 Hz, 3H), 0.71 (d, J=6.68 Hz, 3H), 1.26 (t, J=7.09 Hz, 3H), 1.66 (h, J=6.63 Hz, 1H), 3.24 (d, J=7.12 Hz, 1H), 3.63 (d, J=13.94 Hz, 2H), 3.63 (m, 1H) 4.06 (d, J=14.06 Hz, 2H), 4.10-4.27 (m, 2H), 4.61 (d, J=4.60 Hz, 1H), 7.15-7.45 (m, 10H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:5]=[C:4]([NH:17][CH:18]2[NH:22][C:21](=[O:23])[N:20]([CH3:24])[C:19]2=[O:25])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:32][O:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1>CN(C)C=O.O>[CH3:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][NH:8][C:6]2[N:7]=[C:2]([NH:39][CH2:38][C:37]3[CH:40]=[CH:41][C:34]([O:33][CH3:32])=[CH:35][CH:36]=3)[N:3]=[C:4]([NH:17][CH:18]3[NH:22][C:21](=[O:23])[N:20]([CH3:24])[C:19]3=[O:25])[N:5]=2)=[CH:11][CH:12]=1
Reactant: Cc1ccc(CNc2nc(Cl)nc(NC3NC(=O)N(C)C3=O)n2)cc1
Reactant: COc1ccc(CN)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CNc2nc(NCc3ccc(C)cc3)nc(NC3NC(=O)N(C)C3=O)n2)cc1
Reaction time: 20 h
Yield: 77.6 %

Procedure:
To a stirred suspension of 5-[4-chloro-6-(4-methyl-benzylamino)-[1,3,5]-triazin-2-ylamino]-3-methyl-imidazolidine-2,4-dione (Example 1.5, Part A) (80 mg, 0.22 mmol) and potassium carbonate (67 mg, 0.49 mmol) in dimethylformamide (5 mL) at 35° was added 4-methoxybenzylamine (0.03 mL, 0.24 mmol). The reaction mixture was stirred at 35° for 20 h and then diluted with water and extracted with ethyl acetate. The ethyl acetate layer was dried and concentrated to give the crude product as a foam (79 mg, 77%). NMR spectrum δH (300 MHz, CD3CN): 7.2-7.0 (br m, 7H, Ar+NH), 6.8 (br d, 2H, Ar), 6.5 (br, 1H, NH), 6.1-5.8 (br m, 2H, NH), 5.45 (br d, 1H, CH), 4.5-4.3 (br, 4H, CH2), 4.15 (d, 2H, CH2) 3.74 (s, 3H, OMe), 2.9-2.7 (br, 3H, NMe), 2.3 (s, 3H, Me). Mass spectrum (ESI) m/z 463 [M+H].
Reaction SMILES: N#N.[CH3:3][O:4][C:5]([C:7]1[O:8][C:9]([CH2:12][N:13]2[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]2)=[CH:10][CH:11]=1)=[O:6].CCN(C(C)C)C(C)C.[CH:28]1[CH:33]=[C:32]([CH2:34][O:35][C:36](Cl)=[O:37])[C:31]([Cl:39])=[CH:30][CH:29]=1>C(Cl)Cl>[CH3:3][O:4][C:5]([C:7]1[O:8][C:9]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:36]([O:35][CH2:34][C:32]3[CH:33]=[CH:28][CH:29]=[CH:30][C:31]=3[Cl:39])=[O:37])[CH:15]=[N:14]2)=[CH:10][CH:11]=1)=[O:6]
Reactant: O=C(Cl)OCc1ccccc1Cl
Reactant: COC(=O)c1ccc(Cn2cc(N)cn2)o1
Agent: N#N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(Cn2cc(NC(=O)OCc3ccccc3Cl)cn2)o1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-(4-amino-pyrazol-1-ylmethyl)-furan-2-carboxylic acid methyl ester (2.90 g, 13.10 mmol) in CH2Cl2 (58.0 mL) was treated with DIPEA (3.37 mL, 19.66 mmol) followed by 2-chlorobenzylchloroformate (2.69 mL, 17.04 mmol). The reaction mixture was stirred at rt for 4 h before being quenched with water (100 mL), extracted with CH2Cl2 (3×50 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (50:50 hept-EA) gave the title compound as a solid. TLC: rf (50:50 hept-EA)=0.22. LC-MS-conditions 02: tR=0.94 min; [M+H]+=390.37. 1H NMR (400 MHz, CDCl3) δ 3.89 (s, 3H), 5.29 (s, 2H), 5.31 (s, 2H), 6.39 (d, J=2.5 Hz, 1H), 6.75 (s, 1H), 7.12 (d, J=3.0 Hz, 1H), 7.23-7.31 (m, 2H), 7.38-7.42 (m, 1H), 7.43-7.46 (m, 2H), 7.75 (s, 1H).
Reaction SMILES: C(O/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][N:9]=[C:8]([S:12][CH3:13])[N:7]=1)C.BrN1C(=O)CCC1=O.[CH3:22][O:23][C:24](=[O:32])[C:25]1[CH:30]=[CH:29][CH:28]=[N:27][C:26]=1[NH2:31]>O1CCOCC1.O>[CH3:13][S:12][C:8]1[N:7]=[C:6]([C:5]2[N:27]3[CH:28]=[CH:29][CH:30]=[C:25]([C:24]([O:23][CH3:22])=[O:32])[C:26]3=[N:31][CH:4]=2)[CH:11]=[CH:10][N:9]=1
Reactant: COC(=O)c1cccnc1N
Reactant: CCO/C=C/c1ccnc(SC)n1
Agent: O=C1CCC(=O)N1Br
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cccn2c(-c3ccnc(SC)n3)cnc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.7 %

Procedure:
137.2 mg of the 4-[(E)-2-ethoxyvinyl]-2-(methylthio)pyrimidine [25-2] was dissolved in a mixture solvent of 5 mL of 1,4-dioxane and 2 mL of water, and 124.1 mg of N-bromosuccinimide was added thereto. After stirring at room temperature for 1 hour, 106 mg of the 2-aminonicotinic acid methylester [25-1] was added, and stirred at 85° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative thin layer chromatography, to obtain 106.1 mg of methyl 3-[2-(methylthio)-4-pyrimidinyl]imidazo[1,2-a]pyridine-8-carboxylate [25-3].
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1B(O)O.Br[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([Br:25])=[CH:17][CH:16]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>[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.C(COC)OC>[Br:25][C:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15]([C:3]2[CH:2]=[CH:1][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=2)=[CH:16][CH:17]=1
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: Brc1ccc(Br)c2ccccc12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: Cc1ccccc1
Product: Brc1ccc(-c2ccc3ccccc3c2)c2ccccc12
Temperature: 78 °C
Reaction time: 20 h
Yield: 25.3 %

Procedure:
Under an argon gas atmosphere, 121 g (700 mmol) of 2-naphthaleneboronic acid, 200.0 g (700 mmol) of 1,4-dibromonaphthalene, 16.2 g (13.4 mmol) of tetrakis(triphenylphosphine) palladium(0), 3.0L of toluene, 3.2L of dimethoxyethane and 1.60L of 2M sodium carbonate solution were mixed, and stirred for 20 hours at 78 degrees C. The reaction mixture experienced filtration to be subsequently cleansed by water and methanol. The obtained solid was added with toluene to be heat-dissolved. Insoluble matter therein was eliminated by filtration, such that the filtrate was distilled away under reduced pressure. By recrystallizing residue by toluene and hexane, 59 g of 4-bromo-1-(2-naphthyl)naphthalene was obtained at an yield of 25%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([Cl:9])=[C:6]([OH:8])[CH:7]=1.CC(C)([O-])C.[K+].Cl[C:18]1[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[N:22][CH:23]=1>CC(N(C)C)=O.O>[NH2:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([Cl:9])=[C:6]([CH:7]=1)[O:8][C:18]1[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[N:22][CH:23]=1
Reactant: N#Cc1ccc(Cl)cn1
Reactant: Nc1cc(O)c(Cl)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(Oc2cc(N)c(F)cc2Cl)cn1
Temperature: 25 °C

Procedure:
A solution of 5-amino-2-chloro-4-fluorophenol (100 mg, 0.619 mmol) in degassed dimethylacetamide (2 mL) was treated with potassium t-butoxide (83 mg, 0.743 mmol) and 5-chloro-2-cyanopyridine (86 mg, 0.619 mmol). The resultant mixture was heated to 80° C. overnight, then cooled to RT and diluted with water (10 mL). The mixture was extracted with EtOAc (30 mL). The organic phase was washed with water (3×30 mL) and brine (30 mL) dried (Na2SO4) and concentrated in vacuo to provide 5-(5-amino-2-chloro-4-fluorophenoxy)picolinonitrile as a dark oil which was used without further purification. MS (ESI) m/z: 264.0 (M+H+).
Reaction SMILES: Cl.O1CCOCC1.OC(C(F)(F)F)=O.OC(C(F)(F)F)=O.[S:22]1[C:26]2[CH:27]=[C:28]([NH:31][C:32]([N:34]3[CH2:39][CH2:38][N:37](C(OC(C)(C)C)=O)[CH2:36][CH:35]3[CH2:47][O:48][C:49]3[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=3)=[O:33])[CH:29]=[CH:30][C:25]=2[N:24]=[CH:23]1>CO>[S:22]1[C:26]2[CH:27]=[C:28]([NH:31][C:32]([N:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH:35]3[CH2:47][O:48][C:49]3[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=3)=[O:33])[CH:29]=[CH:30][C:25]=2[N:24]=[CH:23]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Nc2ccc3ncsc3c2)C(COc2cccnc2)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc2ncsc2c1)N1CCNCC1COc1cccnc1
Reaction time: 8 h
Yield: 85.1 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of tert-butyl 4-(benzo[d]thiazol-6-ylcarbamoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate di-TFA salt (154 mg, 0.221 mmol) in MeOH (1 mL). After stirring overnight, the reaction mixture was concentrated under reduced pressure, dissolved in 1 N NaOH, and extracted with EtOAc (3×). The combined extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure, yielding 69.5 mg (85%) of the title compound as an off-white solid. LC-MS: RT=3.62 min, [M+H]+=370.1.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([Cl:16])[C:14]=1[Cl:15])[C:11](=O)[C:10]([CH2:20][CH2:21][C:22](=[O:24])[CH3:23])([CH:18]=[CH2:19])[CH2:9]2.[OH-].[Na+]>CO.O>[Cl:16][C:13]1[C:14]([Cl:15])=[C:6]([O:5][CH2:4][C:3]([OH:2])=[O:25])[CH:7]=[C:8]2[C:12]=1[C:11]1[C:10]([CH:18]=[CH2:19])([CH2:9]2)[CH2:20][CH2:21][C:22](=[O:24])[CH:23]=1
Reactant: C=CC1(CCC(C)=O)Cc2cc(OCC(=O)OC)c(Cl)c(Cl)c2C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=CC12CCC(=O)C=C1c1c(cc(OCC(=O)O)c(Cl)c1Cl)C2
Reaction time: 48 h

Procedure:
Methyl{[6,7-dichloro-1-oxo-2-(3-oxobutyl)-2-vinyl-2,3-dihydro-1H-inden-5-yl]oxy}acetate (7.3 gm., 0.02 mole) is dissolved in a solution of methanol (100 ml) and water (50 ml.) containing sodium hydroxide (9.43 gm., 0.236 mole), taking care to keep the temperature below 25° C. The solution is kept at ambient temperature for 48 hours. The solution is concentrated in vacuo to 100 ml. in a rotary evaporator at room temperature and poured into water (250 ml.) containing concentrated hydrochloric acid (26 ml.) with cooling. The product is separated by filtration, washed with water, dried and recrystallized from a mixture of acetic acid and water to obtain [(5,6-dichloro-3-oxo-9a-vinyl-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)oxy]acetic acid.
Reaction SMILES: [CH2:1]([Si:3]([CH3:10])([O:7][CH2:8][CH3:9])OCC)[CH3:2].[Mg].Br[C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=1>O1CCCC1>[CH2:1]([Si:3]([CH3:10])([O:7][CH2:8][CH3:9])[C:13]1[CH:18]=[CH:17][C:16]([Si:3]([CH2:1][CH3:2])([CH3:10])[O:7][CH2:8][CH3:9])=[CH:15][CH:14]=1)[CH3:2]
Reactant: Brc1ccc(Br)cc1
Reactant: CCO[Si](C)(CC)OCC
Agent: [Mg]
Solvent: C1CCOC1
Product: CCO[Si](C)(CC)c1ccc([Si](C)(CC)OCC)cc1
Reaction time: 3 h
Yield: 67.7 %

Procedure:
16.2 g of ethylmethyldiethoxysilane, 2.43 g of magnesium and 10 ml of tetrahydrofuran were charged into a 500-ml, three-necked flask provided with a stirrer, a cooler and a dropping funnel and stirred under a nitrogen gas stream, while 100 ml of a tetrahydrofuran solution containing 11,8 g of p-dibromobenzene was dropwise added thereto from the dropping funnel over about 3 hours. After the dropwise addition, the mixture was further stirred and refluxed for about 5 hours. After the refluxing, the resulting polymer was separated by filtration, and then the solvent was removed therefrom by distillation. The residues were then subjected to distillation under reduced pressure, whereby 10.5 g of p-bis(ethylmethylethoxysilyl)benzene was obtained (yield: 68%, boiling point: 122°-125° C./3 mmHg).