Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:42][CH3:43])=[C:10]([CH2:19][NH:20][C:21](=[O:41])[CH2:22][C:23]([NH:25][CH2:26][C:27]3[CH:28]=[C:29]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([CH:39]=O)[CH:34]=4)[CH:30]=[CH:31][CH:32]=3)=[O:24])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[NH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>CS(C)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:42][CH3:43])=[C:10]([CH2:19][NH:20][C:21](=[O:41])[CH2:22][C:23]([NH:25][CH2:26][C:27]3[CH:28]=[C:29]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][N:44]5[CH2:49][CH2:48][O:47][CH2:46][CH2:45]5)[CH:34]=4)[CH:30]=[CH:31][CH:32]=3)=[O:24])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: C1COCCN1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(=O)NCc1cccc(-c2cccc(C=O)c2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(=O)NCc1cccc(-c2cccc(CN3CCOCC3)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.7 %

Procedure:
To N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(3′-formyl-3-biphenylyl)methyl]propanediamide (30 mg, 0.051 mmol) was added morpholine (4.49 mg, 0.051 mmol) followed by NaB(OAc)3H (36.4 mg, 0.172 mmol) and AcOH (4.91 μL, 0.086 mmol) in dimethyl sulfoxide (DMSO) (0.5 mL). The mixture was stirred overnight at room temperature. The reaction was quenched with saturated NaHCO3 and extracted with EtOAc (3×1 mL). Combined organic layers were washed with saturated NaCl, dried (Na2SO4) and concentrated. The crude products were redissolved in MeOH/DMSO (1/1) and purified using a Gilson HPLC (acidic conditions) and basified with an amine cartridge to afford 11.9 mg (34%) of the title compound. LC-MS m/z 654 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[CH:10]=[CH:11][C:12]([OH:14])=O.CN(C)C=O.S(Cl)([Cl:22])=O>>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1/[CH:10]=[CH:11]/[C:12]([Cl:22])=[O:14]
Reactant: Cc1cc(C)c(C=CC(=O)O)c(Br)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1cc(C)c(/C=C/C(=O)Cl)c(Br)c1
Yield: 99 %

Procedure:
A solution of 5.07 g (19.9 mmol) of 3-(2-bromo-4,6-dimethylphenyl)-2-propenoic acid in 50 mL of thionyl chloride containing 50 μl of dimethylformamide (DMF) was stirred under nitrogen at room temperature for 20 hours. The volatiles were removed under reduced pressure to give 5.40 g (99%) of (E)-3-(2-bromo-4,6-dimethylphenyl)-2-propenoyl chloride as a dark brown solid: IR (film) 2960, 2920, 1750, 1620 and 1605 cm-1 ; NMR (CDCl3) δ 2.32 (3H, s), 2.40 (3H, s), 6.44 (1H, d, J=16 Hz).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2.[F:16][C:17]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][C:18]=1[O:32][CH3:33]>>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]3)=[CH:19][C:18]=1[O:32][CH3:33]
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2n1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1F
Product: COc1cc(-c2ccnc3nc(C(F)(F)F)ccc23)ccc1F
Yield: 82.2 %

Procedure:
5-Chloro-2-trifluoromethyl[1,8]naphthyridine (923 mg, 4.0 mmol) was coupled to 2-(4-fluoro-3-methoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (1.30 g, 5.2 mmol) as described in Example 3 part g), affording 5-(4-fluoro-3-methoxyphenyl)-2-trifluoromethyl[1,8]naphthyridine (1.06 g, 83%). δH (360 MHz, CDCl3) 3.95 (3H, s), 6.99-7.04 (1H, m), 7.06 (1H, dd, J 7.7 and 2.1), 7.30 (1H, dd, J 2.5 and 8.4), 7.56 (1H, d, J 4.2), 7.82 (1H, d, J 8.4), 8.52 (1H, d, J 8.4), 9.27 (1H, d, J 4.2). m/z (ES+) 323 [MH]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH2:12][CH3:13])=[CH:4][C:3]=1F.C([O-])([O-])=O.[K+].[K+].Cl.[CH3:22][S:23]([CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)(=[O:25])=[O:24]>CS(C)=O.C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH2:12][CH3:13])=[CH:4][C:3]=1[N:31]1[CH2:30][CH2:29][N:28]([CH2:27][CH2:26][S:23]([CH3:22])(=[O:24])=[O:25])[CH2:33][CH2:32]1
Reactant: CCOc1cc(F)c(C)cc1[N+](=O)[O-]
Reactant: CS(=O)(=O)CCN1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCOc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(C)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
1-Methyl-2-fluoro-4-(ethyloxy)-5-nitrobenzene (Example 215, step A) (5.74 g, 28.8 mmol) was dissolved in DMSO (60 mL). K2CO3 (11.9 g, 86.4 mmol) and 1-[2-(methylsulfonyl)ethyl]piperazine hydrochloride (Example 148, step B) (9.85 g, 43.2 mmol) were added and the reaction mixture was heated to 100° C. and allowed to stir overnight. The mixture was cooled to rt then diluted with DCM and filtered. The filtrate was poured into H2O and extracted with DCM. The combined organics were dried with MgSO4, filtered, and concentrated in vacuo to give the title compound of Step A (9.70 g, 26.1 mmol, 90%) as an orange solid. 1H NMR (400 MHz, CDCl3) δ 7.75 (s, 1H), 6.51 (s, 1H), 4.11 (q, J=7.0 Hz, 2H), 3.16 (t, J=6.5 Hz, 2H), 3.03 (s, 3H), 3.00-2.91 (m, 6H), 2.72-2.62 (m, 4H), 2.21 (s, 3H), 1.44 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=O)=O)=[CH:5][CH:4]=1.[NH2:21][NH:22][C:23]([NH2:25])=[S:24]>C(O)(=O)C.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[N:21][NH:22][C:23](=[S:24])[N:25]=2)=[CH:5][CH:4]=1
Reactant: NNC(N)=S
Reactant: COc1ccc(C(=O)C(=O)c2ccc(OC)cc2)cc1
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(-c2n[nH]c(=S)nc2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Yield: 62.1 %

Procedure:
A mixture of 4,4′-dimethoxybenzil (13.6 g, 50 mmol) and 6.06 g of thiosemicarbazide (66.5 mmol) in 50 mL of glacial acetic acid were stirred at room temperature then refluxed overnight. The cooled reaction mixture was diluted with 150 mL of water and filtered. The solids were washed with water and dried. The crude product was heated with 55 mL of ethyl acetate, cooled, filtered and dried to give 10.1 g of 5,6-bis-(4-methoxyphenyl)-1,2,4-triazin-3-thione, mp 228–232° C.
Reaction SMILES: N([CH2:3]NC(N)=O)=O.[OH-].[K+].[Cl:10][C:11]1[N:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:12]=1[C:13]([OH:15])=[O:14]>C(OCC)C.CO>[Cl:10][C:11]1[N:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:12]=1[C:13]([O:15][CH3:3])=[O:14]
Reactant: O=C(O)c1c(Cl)ccnc1Cl
Reactant: NC(=O)NCN=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Product: COC(=O)c1c(Cl)ccnc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
Nitrosomethyl urea (8 g, 78.16 mmol), taken in diethyl ether (30 ml) was cooled to 0° C. and 25% aqueous KOH solution was added slowly under cooling. The ether layer was collected, dried over KOH and added dropwise to a stirring solution of 2,4-Dichloronicotinic acid (3 g, 15.62 mmol) in methanol (5 mL) at 0° C. The reaction mixture was allowed to come to room temperature within 1 hour. The organic solvent was removed under reduced pressure and the crude residue was purified by column chromatography (5-10% EtOAc in hexane) to obtain the pure methyl 2,4-dichloronicotinate (3.00 g, 99%) as colorless oil. 1H NMR (400 MHz, CDCl3): δ 8.34 (d, J=5.3 Hz, 1H), 7.33 (d, J=5.4 Hz, 1H), 3.99 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:11]=[C:4]2[N:3]=1.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:5]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:11]=[C:4]2[N:3]=1
Reactant: Clc1cc(Cl)n2nc(-c3ccccc3)cc2n1
Reactant: C1COCCN1
Solvent: C1COCCO1
Product: Clc1cc(N2CCOCC2)n2nc(-c3ccccc3)cc2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
There was dissolved, in 1,4-dioxane (4 mL), 5,7-dichloro-2-phenyl-pyrazolo-[1,5-a]pyrimidine (168 mg, 0.637 mM), morpholine (111 μL, 1.27 mM) was added to the resulting solution and the mixture was stirred at room temperature for 15 minutes. The solvent was distilled off from the reaction mixture, the resulting residue was diluted with water and then extracted with methylene chloride. The extracts thus obtained were combined, dried over anhydrous sodium sulfate, the solvent was distilled off, and the resulting solid was washed with methanol to thus obtain the title compound (200 mg, yield: 100%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:33]=[CH:32][C:8]([C:9]([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][S:16][C:17]3[N:26]([CH3:27])[C:25](=[O:28])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][C:23]=4[CH3:29])[N:18]=3)=[CH:13][CH:12]=2)=[O:10])=[CH:7][CH:6]=1.[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37][NH2:38]>CN(C=O)C>[ClH:1].[ClH:1].[CH3:27][N:26]1[C:25](=[O:28])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][C:23]=2[CH3:29])[N:18]=[C:17]1[S:16][CH2:15][C:14]1[CH:30]=[CH:31][C:11]([C:9](=[O:10])[C:8]2[CH:32]=[CH:33][C:5]([O:4][CH2:3][CH2:2][NH:38][CH2:37][CH2:36][N:35]([CH3:39])[CH3:34])=[CH:6][CH:7]=2)=[CH:12][CH:13]=1
Reactant: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(OCCCl)cc4)cc3)n(C)c(=O)c12
Reactant: CN(C)CCN
Solvent: CN(C)C=O
Product: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(OCCNCCN(C)C)cc4)cc3)n(C)c(=O)c12
Product: Cl

Procedure:
A solution of 2-[4-[4-(2-chloroethoxy)benzoyl]-benzylthio]-3,5-dimethyl-4(3H)-quinazolinone (237 mg) and 2-dimethylaminoethylamine (1.1 ml) in DMF (5 ml) was stirred at 100° C. for 7 hours. This reaction mixture was concentrated and the residue was purified by silica gel column chromatography (dichloromethane: methanol: aqueous ammonia =9:1:0.1) and treated with hydrogen chloride/ethyl acetate to provide the title compound as colorless solid (104 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[NH:8][C:9](=[O:18])[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[CH:5]=[C:4]([CH3:19])[N:3]=1.C([O-])(=O)C.[Na+].[Br:25]Br>C(O)(=O)C.O>[NH2:1][C:2]1[C:7]2[NH:8][C:9](=[O:18])[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[C:5]([Br:25])=[C:4]([CH3:19])[N:3]=1
Reactant: BrBr
Reactant: Cc1cc2c([nH]c(=O)n2Cc2ccccc2)c(N)n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1nc(N)c2[nH]c(=O)n(Cc3ccccc3)c2c1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Amino-1-benzyl-6-methyl-1,3-dihydro-imidazo[4,5-c]pyridin-2-one (20 mg, 0.08 mmol) was suspended in 5 mL of acetic acid then sodium acetate (5 mg, 0.08 mmol) was added followed by bromine (4□L, 0.08 mmol) dropwise. The mixture was stirred at room temperature for 30 minutes. The mixture was diluted in water (50 mL) and extracted with ethyl acetate (50 mL), the organic layer was separated, dried over magnesium sulfate and the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel using 10% of methanol in ethyl acetate to give 15 mg of the title compound as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.OS(O)(=O)=O.[CH3:26]O>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([O:16][CH3:26])=[O:15])=[CH:12][CH:13]=2)=[C:4]([C:17]([F:18])([F:19])[F:20])[CH:3]=1
Reactant: CO
Reactant: Nc1ccc(-c2ccc(C(=O)O)cc2)c(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(-c2ccc(N)cc2C(F)(F)F)cc1
Yield: 50 %

Procedure:
Crude 4'-amino-2'-trifluoromethylbiphenyl-4-carboxylic acid (D33, 0.31 g, 0.078 mol) was dissolved in methanol (200 ml) and treated with conc. H2SO4 acid (1 ml). The mixture was heated at reflux under argon for 2 hrs, then concentrated in vacuo. The resultant yellow solid was basified with 10% aqueous Na2CO3 solution, extracted with dichloromethane, then the extract dried (Na2SO4) and concentrated in vacuo. The resultant yellow solid was purified by preparative TLC on silica gel plates eluting with 1:1 pet ether/ether to afford the title compound as an off-white solid (161 mg, 50%).
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][C:4]([N:7]2[C:11]([NH2:12])=[CH:10][C:9]([C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=3)=[N:8]2)=[CH:3][CH:2]=1.C(N([CH2:26][CH3:27])CC)C.[C:28]1([S:34](Cl)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(Cl)Cl>[NH2:12][C:11]1[N:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:20])=[CH:6][CH:5]=2)[N:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([N:19]([S:34]([C:27]3[CH:26]=[CH:30][CH:29]=[CH:28][CH:33]=3)(=[O:36])=[O:35])[S:34]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:36])=[O:35])=[CH:15][CH:14]=2)[CH:10]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCN(CC)CC
Reactant: Cc1ccc(-n2nc(-c3ccc(N)cc3)cc2N)cc1
Solvent: ClCCl
Product: Cc1ccc(-n2nc(-c3ccc(N(S(=O)(=O)c4ccccc4)S(=O)(=O)c4ccccc4)cc3)cc2N)cc1

Procedure:
To a solution of 1-(4-tolyl)-3-(4-aminophenyl)-5-aminopyrazole (0.1 g, 0.4 mmol) in CH2Cl2 (5 mL) at room temperature was added triethylamine (0.16 mL, 1.2 mmol) and benzenesulfonyl chloride (0.11 mL, 0.82 mmol). The resultant mixture was stirred at room temperature overnight. The solvent was evaporated and the residue purified by prep TLC eluting with 2:1 hexanes/EtOAc to yield N-[4-[5-amino-1(4-methylphenyl)-1H-pyrazol-3-yl]phenyl]-N-(phenylsulfonyl)-benzenesulfonamide as a solid.
Reaction SMILES: Br(O)(=O)=O.[O:5]1[CH2:10][CH2:9][N:8]([C:11]([NH2:13])=[NH:12])[CH2:7][CH2:6]1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:28]=[CH:29][CH:30]=1)[C:19]([CH:21]1[CH2:26][CH:25]=C[O:23][C:22]1=O)=O.CC(C)([O-:34])C.[Na+]>CC(O)(C)C>[OH:34][CH2:25][CH2:26][C:21]1[C:22]([OH:23])=[N:12][C:11]([N:8]2[CH2:9][CH2:10][O:5][CH2:6][CH2:7]2)=[N:13][C:19]=1[C:18]1[CH:28]=[CH:29][CH:30]=[C:16]([O:15][CH3:14])[CH:17]=1
Reactant: CC(C)(C)[O-]
Reactant: N=C(N)N1CCOCC1
Reactant: COc1cccc(C(=O)C2CC=COC2=O)c1
Agent: [Na+]
Agent: [O-][Br+2]([O-])O
Solvent: CC(C)(C)O
Product: COc1cccc(-c2nc(N3CCOCC3)nc(O)c2CCO)c1

Procedure:
Morpholinoformamidine bromate salt (200 mg, 0.952 mmol), 3-(3-methoxybenzoyl)dihydropyran-2-one (544 mg, 3.6 mmol) and sodium t-butoxide (230 mg, 2.32 mmol) were added into a microwave reaction tube, and dissolved in t-BuOH (3 ml). After irradiation of microwave (200 W, 120° C.) for 1 hour, the solvent was removed under reduced pressure, to obtain a crude product as a brown solid. This was purified by silica gel column chromatography (dichloromethane/methanol=95/5), to obtain 5-(2-hydroxyethyl)-6-(3-methoxyphenyl)-2-(morpholin-4-yl)-pyrimidin-4-ol and 4-(3-methoxyphenyl)-2-(morpholin-4-yl)-5,6-furo[2,3-d]pyrimidine as colorless solid (Yield 16%).
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:29]=[CH:28][C:10]([NH:11][C:12]2[C:17]([NH:18][C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:20])=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=1.C([Si]([O:47][C:48]1[CH:53]=[CH:52][C:51]([O:54][CH2:55][CH:56]2[CH2:58][O:57]2)=[CH:50][CH:49]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[CH2:22]([NH:21][C:19]([NH:18][C:17]1[C:12]([NH:11][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:58][C@H:56]([OH:57])[CH2:55][O:54][C:51]3[CH:52]=[CH:53][C:48]([OH:47])=[CH:49][CH:50]=3)=[CH:29][CH:28]=2)=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:20])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCCNC(=O)Nc1cccnc1Nc1ccc(CCN)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O=CO
Product: CCCCCCNC(=O)Nc1cccnc1Nc1ccc(CCNC[C@H](O)COc2ccc(O)cc2)cc1
Yield: 32.8 %

Procedure:
N-{2-[4-(2-Aminoethyl)anilino]-3-pyridinyl}-N′-hexylurea formate (0.24 g, 0.60 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.242 g, 0.60 mmol) according to Procedure G (eluant: 20:1 going to 10:1 chloroform-methanol) to give the title compound (0.15 g, 0.197 mmol).
Reaction SMILES: [NH2:1][C:2]1[N:26]=[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:12]=[CH:13][C:14]([Cl:25])=[C:15]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:16]=3)=[CH:9][N:4]2[N:3]=1.[CH:27]1([C:30](Cl)=[O:31])[CH2:29][CH2:28]1>CN(C)C(=O)C.C(=O)([O-])O.[Na+]>[Cl:25][C:14]1[CH:13]=[CH:12][C:11]([O:10][C:8]2[CH:7]=[CH:6][C:5]3[N:4]([N:3]=[C:2]([NH:1][C:30]([CH:27]4[CH2:29][CH2:28]4)=[O:31])[N:26]=3)[CH:9]=2)=[CH:16][C:15]=1[NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:21])[CH3:22]
Reactant: O=C(Cl)C1CC1
Reactant: CC(C)(C)OC(=O)Nc1cc(Oc2ccc3nc(N)nn3c2)ccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)ccc1Cl
Temperature: 25 °C
Reaction time: 14 h
Yield: 86.6 %

Procedure:
To a solution of tert-butyl {5-[(2-amino[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy]-2-chlorophenyl}carbamate (5.49 g, 14.60 mmol) in N,N-dimethylacetamide (40 mL) was added cyclopropanecarbonyl chloride (1.50 mL, 16.5 mmol) at 0° C., and the mixture was stirred at room temperature for 14 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was washed with ethyl acetate-hexane to give the title compound (5.61 g, 87%) as a white solid.
Reaction SMILES: CO[C:3](=[O:21])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]1=[O:20].C(O)(=O)C.C(OCC)(=O)C.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[O:20]=[C:6]1[CH:7]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]1[CH2:4][C:3]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)=[O:21]
Reactant: COC(=O)CN1C(=O)C(c2ccccc2)c2ccccc21
Reactant: C1COCCN1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(CN1C(=O)C(c2ccccc2)c2ccccc21)N1CCOCC1

Procedure:
11 g of methyl(2,3-dihydro-2-oxo-3-phenyl-1-indolyl)-acetate were dissolved in 50 ml of morpholine and the mixture was heated under nitrogen on a steam bath for 9 hours and then poured into a mixture of glacial acetic acid and ethyl acetate; the aqueous phase was extracted with methylene chloride and the organic phase was dried and concentrated. The crude product was recrystallized from isopropanol. Melting point 153°-154° C.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]([C:16]#[CH:17])=[CH:14][C:13]([C:18]3[CH:19]=[N:20][C:21]([N:24]4[CH2:29][CH2:28][C:27]([CH3:33])([C:30]([OH:32])=[O:31])[CH2:26][CH2:25]4)=[N:22][CH:23]=3)=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2].Br[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH3:42])[N:36]=1.CCN(C(C)C)C(C)C.CCCCCC>CN(C=O)C.[Cu]I.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>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]([C:16]#[C:17][C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH3:42])[N:36]=3)=[CH:14][C:13]([C:18]3[CH:23]=[N:22][C:21]([N:24]4[CH2:25][CH2:26][C:27]([CH3:33])([C:30]([OH:32])=[O:31])[CH2:28][CH2:29]4)=[N:20][CH:19]=3)=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2]
Reactant: COc1cccc(Br)n1
Reactant: C#Cc1cc(-c2cnc(N3CCC(C)(C(=O)O)CC3)nc2)cc2nc(NC(=O)NCC)sc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)O)CC4)nc3)cc(C#Cc3cccc(OC)n3)c2s1
Temperature: 80 °C
Yield: 4.5 %

Procedure:
To a solution of 1-[5-[2-(ethylcarbamoylamino)-7-ethynyl-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-methyl-piperidine-4-carboxylic acid (0.18 g, 0.39 mmol) in DMF (5 mL) was added 2-bromo-6-methoxy pyridine (0.15 g, 0.77 mmol) and DIPEA (0.16 mL, 1.16 mmol). The reaction mass was degassed by purging N2 for 15 min followed by addition of CuI (0.015 g, 0.077 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.067 g, 0.058 mmol). The reaction mixture was again degassed for 10-15 min then heated up to 80° C. for 30 min under microwave irradiation. The mixture was then poured in 100 mL of ice-cold water, extracted with EtOAc (3×100 mL) and the combined organic layer washed with brine, dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. The crude residue was purified over 100-200 M silica-gel using 30% EtOAc:hexane to obtain Compound 152 as an off-white solid (0.01 g, 5% yield). 1H NMR (DMSO-d6): δ 1.09 (t, J=7.20 Hz, 3H), 1.19 (s, 3H), 1.41 (m, 2H), 2.02 (m, 2H), 3.19 (m, 2H), 3.30 (m, 2H), 3.90 (s, 3H), 4.30 (m, 2H), 6.77 (br s, 1H), 6.93 (d, J=8.40 Hz, 1H), 7.34 (d, J=7.20 Hz, 1H), 7.66-7.82 (m, 2H), 7.97 (s, 1H), 8.81 (s, 2H), 10.91 (br s, 1H) and 12.46 (br s, 1H). MS: 572.05 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH:17]1[CH2:19][CH2:18]1)[S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15])(=[O:7])=[O:6].C(N(C(C)C)CC)(C)C.Cl[C:30](OC1C=CC([N+]([O-])=O)=CC=1)=[O:31].[C:42]1([C:48]2([C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)[CH:52]3[CH2:53][NH:54][CH2:55][CH2:56][N:51]3[C:50](=[O:57])[O:49]2)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>O1CCCC1.C(OCC)(=O)C>[CH:17]1([N:4]([S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])(=[O:7])=[O:6])[CH2:3][CH2:2][NH:1][C:30]([N:54]2[CH2:55][CH2:56][N:51]3[C:50](=[O:57])[O:49][C:48]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)([C:58]4[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=4)[CH:52]3[CH2:53]2)=[O:31])[CH2:19][CH2:18]1
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)C2CNCCN12
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: NCCN(C1CC1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCN(C1CC1)S(=O)(=O)c1ccccc1[N+](=O)[O-])N1CCN2C(=O)OC(c3ccccc3)(c3ccccc3)C2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
To a solution of N-(2-aminoethyl)-N-cyclopropyl-2-nitrobenzenesulfonamide (0.47 g, 1.7 mmol) and diisopropylethylamine (0.71 mL, 4.1 mmol) in tetrahydrofuran (15 mL) was added 4-nitrophenyl chloroformate (0.33 g, 1.7 mmol) at 0° C., and the mixture was stirred at room temperature for 1 hour. Hexahydro-1,1-diphenyl-3H-oxazolo[3,4-a]pyrazin-3-one (0.40 g, 1.4 mmol) was added thereto, and the mixture was stirred at room temperature for 60 hours. To the reaction solution was added ethyl acetate, and the resulting mixture was washed with 1 N hydrochloric acid, a 1 N aqueous sodium hydroxide solution, water and saturated brine, and dried over magnesium sulfate. The solid was filtered off, and the filtrate was concentrated. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=98:2 to ethyl acetate). The fractions were collected and concentrated. The residue was washed with diethyl ether and collected by filtration to obtain the title compound (0.76 g, yield 92%).
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([NH2:8])[CH:2]=1.[C:9]1([C:16]2[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=2)[CH:15]=[CH:14][C:12](N)=[CH:11][CH:10]=1>>[NH2:7][C:6]1[CH:5]=[CH:4][C:3]([N:8]([C:3]2[CH:4]=[CH:5][C:6]([NH2:7])=[CH:1][CH:2]=2)[C:12]2[CH:11]=[CH:10][C:9]([C:16]3[CH:22]=[CH:21][C:19]([N:20]([C:16]4[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=4)[C:9]4[CH:15]=[CH:14][C:12]([NH2:8])=[CH:11][CH:10]=4)=[CH:18][CH:17]=3)=[CH:15][CH:14]=2)=[CH:2][CH:1]=1
Reactant: Nc1ccc(-c2ccc(N)cc2)cc1
Reactant: Nc1ccc(N)cc1
Product: Nc1ccc(N(c2ccc(N)cc2)c2ccc(-c3ccc(N(c4ccc(N)cc4)c4ccc(N)cc4)cc3)cc2)cc1

Procedure:
The same reaction as in Synthesis example 1 was carried out except for changing p-phenylenediamine used in Synthesis example 1 to benzidine to obtain 12 parts of orange tetrakis(p-aminophenyl)benzidine.