Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:6][N:5]([C:7]2[N:12]=[C:11]([NH:13][C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH3:15])[N:10]=[C:9]([NH:23][C:24]3[CH:29]=[N:28][CH:27]=[CH:26][N:25]=3)[CH:8]=2)[CH2:4]1.[CH2:30]([S:32](Cl)(=[O:34])=[O:33])[CH3:31].C(N(CC)C(C)C)(C)C>ClCCCl>[F:22][C:19]1[CH:18]=[CH:17][C:16]([C@@H:14]([NH:13][C:11]2[N:12]=[C:7]([N:5]3[CH2:4][CH:3]([CH2:2][NH:1][S:32]([CH2:30][CH3:31])(=[O:34])=[O:33])[CH2:6]3)[CH:8]=[C:9]([NH:23][C:24]3[CH:29]=[N:28][CH:27]=[CH:26][N:25]=3)[N:10]=2)[CH3:15])=[CH:21][CH:20]=1
Reactant: C[C@H](Nc1nc(Nc2cnccn2)cc(N2CC(CN)C2)n1)c1ccc(F)cc1
Reactant: CCS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCS(=O)(=O)NCC1CN(c2cc(Nc3cnccn3)nc(N[C@@H](C)c3ccc(F)cc3)n2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.9 %

Procedure:
23 mg of (S)-6-[3-(aminomethyl)azetidin-1-yl]-N2-[1-(4-fluorophenyl)ethyl]-N4-(pyrazin-2-yl)pyrimidine-2,4-diamine was dissolved in 2 ml of 1,2-dichloroethane, and 8.1 mg of ethanesulfonyl chloride and 22 μl of N,N-diisopropylethylamine were added thereto, and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 15 mg of the objective compound as a brown amorphous solid.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C([O:17][C:18]([CH:20]1[CH2:22][CH:21]1[C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([F:30])[CH:24]=1)=[O:19])C>>[CH:10]1([S:9][C:4]2[C:3]([CH2:2][O:29][C:26]3[CH:27]=[CH:28][C:23]([CH:21]4[CH2:22][CH:20]4[C:18]([OH:19])=[O:17])=[CH:24][C:25]=3[F:30])=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CCOC(=O)C1CC1c1ccc(O)c(F)c1
Reactant: ClCc1cccnc1SC1CCCC1
Product: O=C(O)C1CC1c1ccc(OCc2cccnc2SC2CCCC2)c(F)c1
Yield: 101.7 %

Procedure:
3-Chloromethyl-2-cyclopentylsulfanyl-pyridine (0.040 g, 0.17 mmol) obtained in Step C of Preparation Example 8 and 2-(3-fluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid ethyl ester (0.040 g, 0.17 mmol) obtained in Step C of Preparation Example 44 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.067 g, 98%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][OH:10].[H-].[Na+].Cl[C:14]1[C:19]([C:20]#[N:21])=[CH:18][N:17]=[C:16]([Cl:22])[CH:15]=1>CN(C=O)C>[Cl:22][C:16]1[CH:15]=[C:14]([O:10][CH2:9][CH2:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[C:19]([C:20]#[N:21])=[CH:18][N:17]=1
Reactant: N#Cc1cnc(Cl)cc1Cl
Reactant: OCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cnc(Cl)cc1OCCOC1CCCCO1
Reaction time: 1 h
Yield: 60 %

Procedure:
To a solution of 2-(tetrahydro-pyran-2-yloxy)-ethanol (6.32 g, 43.30 mmol) in DMF (15 mL) at 0° C. was added sodium hydride (95% in mineral oil, 1.09 g, 43.30 mmol) portion-wise. After 1 h at room temperature, this mixture was slowly added to a solution of 4,6-dichloro-nicotinonitrile (5.0 g, 28.90 mmol) in DMF (25 mL) at 0° C. After overnight, DMF was removed under reduced pressure, and the resulting mixture was diluted with EtOAc (50 mL). The organic layer was washed with water (20 mL) and brine (3×20 mL) solution, dried over anhydrous Na2SO4, filtered, and concentrated. Purification was accomplished by flash chromatography on silica gel using 5-25% EtOAc/hexanes gradient elution to yield the title compound (4.9 g, 60%) as a transparent oil. 1H NMR (400 MHz, CDCl3) δ ppm 8.47 (s, 1H), 7.10 (s, 1H), 4.70 (t, J=3.3 Hz, 1H), 4.32-4.45 (m, 2H), 4.19-4.08 (m, 1H), 3.91-3.80 (m, 2H), 3.59-3.50 (m, 1H), 1.83-1.68 (m, 2H), 1.65-1.50 (m, 4H).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH:10]([CH2:20][OH:21])[CH2:11][P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[N:22]([CH2:25][CH2:26][O:27][C:28](=[O:32])[C:29]([CH3:31])=[CH2:30])=[C:23]=[O:24]>ClCCl.[Sn]>[CH2:14]([O:13][P:12]([CH2:11][CH:10]([CH2:20][O:21][C:23](=[O:24])[NH:22][CH2:25][CH2:26][O:27][C:28](=[O:32])[C:29]([CH3:31])=[CH2:30])[CH2:9][P:4](=[O:8])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])(=[O:19])[O:16][CH2:17][CH3:18])[CH3:15]
Reactant: C=C(C)C(=O)OCCN=C=O
Reactant: CCOP(=O)(CC(CO)CP(=O)(OCC)OCC)OCC
Agent: [Sn]
Solvent: ClCCl
Product: C=C(C)C(=O)OCCNC(=O)OCC(CP(=O)(OCC)OCC)CP(=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.7 %

Procedure:
A solution of 2-hydroxymethyl-1,3-propylene-bisphosphonic acid tetraethylester (4.8 g, 13.8 mmol) in anhydrous dichloromethane (6.0 ml) was added to a 1% solution of the tin catalyst Metatin 712 in anhydrous dichloromethane (4.0 ml). Then isocyanatoethyl-methacrylate (1.96 ml, 13.8 mmol) was added dropwise, and the reaction mixture was stirred for 3 h at room temperature. After concentrating in vacuo the obtained crude product was purified by column chromatography (eluent: ethyl acetate/methanol 95:5). 6.0 g (86% yield) of the product was obtained as a colorless oil.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N+:20]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH:26]=O)([O-:22])=[O:21]>>[N+:20]([C:23]1[CH:24]=[C:25]([CH2:26][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)[CH:28]=[CH:29][CH:30]=1)([O-:22])=[O:21]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: O=[N+]([O-])c1cccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 3-nitrobenzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(3-nitrophenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:38](I)[CH3:39]>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:38][CH3:39])[CH:28]=1)[C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCI
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Agent: Cl
Product: CCn1cc(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccc(C(C)C)nc2)cn1

Procedure:
By the reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.79 g) and ethyl iodide (0.12 mL) as starting materials, 5-benzyloxy-N-[(1-ethylpyrazol-4-yl)methyl]-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.43 g) was obtained.
Reaction SMILES: [CH:1]1([S:4][C:5]([F:18])([F:17])[C:6]2([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=3[F:16])[CH2:8][O:7]2)[CH2:3][CH2:2]1.[NH:19]1[CH:23]=[N:22][CH:21]=[N:20]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH:1]1([S:4][C:5]([F:18])([F:17])[C:6]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])([OH:7])[CH2:8][N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)[CH2:3][CH2:2]1
Reactant: c1nc[nH]n1
Reactant: Fc1ccc(C2(C(F)(F)SC3CC3)CO2)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: OC(Cn1cncn1)(c1ccc(F)cc1F)C(F)(F)SC1CC1
Temperature: 55 °C
Reaction time: 1.5 h
Yield: 39.8 %

Procedure:
To a solution of 2-[(cyclopropylthio) (difluoro)-methyl]-2-(2,4-difluorophenyl)oxirane (5.0 g, 0.017 mol) in DMSO (70 ml), 1,2,4-triazole (3.48 g, 0.05 mol) and potassium carbonate (6.95 g, 0.05 mol) were added, followed by stirring at 55° C. for 1.5 hours. After the completion of the reaction, water was added to the reaction mixture. The resulting mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated saline and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure. The residue so obtained was crystallized from isopropyl ether—ethyl acetate, whereby 1-(cyclopropylthio)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol (2.35 g, yield: 32%) was obtained as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:14]=3[N:15]=2)=[C:5]([O:21][CH2:22][O:23][CH3:24])[CH:4]=1.[Br:25]N1C(=O)CCC1=O.N#N>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:25][CH2:20][C:16]1[C:14]2[N:15]=[C:11]([C:6]3[CH:7]=[C:8]([O:9][CH3:10])[C:3]([O:2][CH3:1])=[CH:4][C:5]=3[O:21][CH2:22][O:23][CH3:24])[O:12][C:13]=2[CH:19]=[CH:18][CH:17]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COCOc1cc(OC)c(OC)cc1-c1nc2c(C)cccc2o1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: N#N
Solvent: ClC(Cl)(Cl)Cl
Product: COCOc1cc(OC)c(OC)cc1-c1nc2c(CBr)cccc2o1
Temperature: 0 °C
Yield: 66 %

Procedure:
A mixture of 5 (1.39 g, 4.23 mmol), N-bromosuccinimide (0.75 g, 4.23 mmol) and AIBN (33 mg, 0.2 mmol) in CCl4 (70 mL) was refluxed for 15 hours under a flow of dry N2 gas. The reaction mixture was cooled to 0° C. and the precipitate was removed by filtration while maintaining the temperature at 0° C. After the solvent was evaporated, the residue was washed with small amount of ethanol several times to afford a pinkish solid 6 (1.14 g, 66%): 1H-NMR (500 MHz, CDCl3) δ3.60 (s, 3H), 3.97 (s, 3H), 3.99 (s, 3H), 4.96 (s, 2H), 5.31 (s, 2H), 6.85 (s, 1H), 7.30 (t, 1H, J=8.0 Hz), 7.40 (d, 1H, J=8.0 Hz), 7.51 (d, 1H, J=8.0 Hz), 7.66 (s, 1H).
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][N:20]=3)=[O:18])[CH2:13][CH2:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.[NH2:53][CH2:54][C:55]1[CH:56]=[N:57][CH:58]=[CH:59][CH:60]=1>C(Cl)Cl.O1CCCC1>[CH:1]([NH:4][C:5]1[C:6]([N:11]2[CH2:12][CH2:13][N:14]([C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([NH:53][CH2:54][C:55]4[CH:56]=[N:57][CH:58]=[CH:59][CH:60]=4)=[O:25])=[CH:21][N:20]=3)=[O:18])[CH2:15][CH2:16]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:2])[CH3:3]
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cn2)CC1
Reactant: NCc1cccnc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)NCc3cccnc3)cn2)CC1
Reaction time: 2 h
Yield: 75 %

Procedure:
6-[1-[3-(isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]nicotinic acid (2 g) was added to a co-solvent of tetrahydrofuran (30 ml) and methylene chloride (30 ml) and with the successive addition of 1,3-dicyclohexylcarbodimide (2.4 g) and 1-hydroxybenzotriazole (0.85 g) at 15° C.˜20° C., the mixture was reacted at the same temperature for 2 hours. With the addition of 3-(aminomethyl)pyridine (0.65 g) at 20° C., the reaction mixture was stirred at 20° C.˜25° C. for 2 hours. With the addition of methylene chloride (60 ml). The mixture was washed with water 3 times, dried over magnesium sulfate and concentrated under reduced pressure. The concentrated residue was chromatographed on column (hexane/chloroform/ethanol=5/2/1, v/v/v). The purified solution was concentrated under reduced pressure, and then, the residue was treated with ether for crystallization to give a desired compound of 1.87 g (yield: 75%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N12CCN(CC1)CC2.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>COC(C)(C)C>[CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][S:28]([C:25]2[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=2)(=[O:30])=[O:29])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@H]1CCN(Cc2ccccc2)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: C1CN2CCN1CC2
Solvent: COC(C)(C)C
Product: Cc1ccc(S(=O)(=O)O[C@H]2CCN(Cc3ccccc3)C2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
To a stirred solution of (S)-1-benzyl-3-pyrrolidinol (44.3 g, 0.25 mol) and 1,4-diazabicyclo[2.2.2]octane (33.7 g, 0.3 mol) in 250 mL of tert-butyl methyl ether under an atmosphere of nitrogen at 0° C., was added p-toluenesulfonyl chloride (52.4 g, 0.275 mol) portion-wise over 20 min. The reaction mixture was stirred at 0° C. for 1 h. The ice bath was removed and the mixture was stirred at ambient temperature overnight (20±5 h). Ethyl acetate (100 mL) was added, followed by saturated aqueous sodium bicarbonate solution (250 mL). The resulting mixture was stirred at ambient temperature for 1 h. The layers were separated and the organic layer was washed with saturated aqueous sodium bicarbonate solution (250 mL); saturated aqueous ammonium chloride solution (250 mL); saturated aqueous sodium chloride solution (250 mL); and then dried over sodium sulfate (80 g). The sodium sulfate was filtered off and washed with ethyl acetate (20 mL) and the solvent was removed in vacuo to give 78.2 g of the title intermediate as an off-white solid (94% yield; 95% purity by HPLC).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[N+:15]([O-])=O)=[CH:9][CH:8]=1.Cl>CCO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH2:15])=[CH:9][CH:8]=1
Reactant: O=[N+]([O-])/C=C/c1ccc(OCc2cccc(F)c2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: NCCc1ccc(OCc2cccc(F)c2)cc1
Yield: 81.5 %

Procedure:
A solution of the product of Step B (0.29 g; 1.0 mmol), 36% HCl (0.16 ml) and 10% Pd/C (0.17 g) in EtOH (15 ml) was stirred for 3 h at 0° C. under H2 (balloon). The catalyst was removed by filtration through Celite pad, washed with EtOH (2×10 ml) and combined filtrates were evaporated to dryness under reduced pressure and the dark residue was diluted to 10 ml with CH3CN and the white precipitate was filtered off, washed with fresh CH3CN (2 ml) and dried to give the title compound (0.2 g; 70%) as off white solid. 1H-NMR (D2O) (2.86 (tr, 2H, J=7.2 Hz); 3.15 (tr, 2H, J=7.2 Hz); 4.66 (HDO); 5.07 (s, 2H); 6.85-6.89 (m, 3H); 7.02 (m, 1H); 7.11-7.34 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].C([Li])CCC.[CH2:14]([Sn:18](Cl)([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH3:17]>O1CCCC1.CCCCCC>[CH2:23]([Sn:18]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:19][CH2:20][CH2:21][CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8])[CH2:24][CH2:25][CH3:26]
Reactant: Cc1ccccc1Br
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1ccccc1C
Reaction time: 0.5 h
Yield: 92.4 %

Procedure:
To a stirred solution of 3.4 g of 2-bromotoluene in 100 ml of dry tetrahydrofuran at -78° C. is slowly added 8 ml of 2.5M butyl lithium in hexane. The reaction mixture is stirred for 30 minutes and 6.5 g of tri-n-butyl tin chloride in 25 ml of tetrahydrofuran added. The reaction mixture is stirred an additional 1 hour, quenched with water and extracted with ether. The ether extract is dried over Na2SO4, filtered and the filtrate evaporated in vacuo to give 7.0 g of a residue. Mass spectrum: M+H:381.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH2:9]Br)[CH:3]=1.C([S:14][CH2:15][C@@H:16]([CH3:20])[C:17]([OH:19])=[O:18])(=O)C.[OH-].[Na+].CCOC(C)=O>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([CH3:8])[CH:7]=1)[CH2:9][S:14][CH2:15][C@@H:16]([CH3:20])[C:17]([OH:19])=[O:18]
Reactant: Cc1cc(Br)cc(CBr)c1
Reactant: CC(=O)SC[C@@H](C)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc(Br)cc(CSC[C@@H](C)C(=O)O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 5.55 g (21 mmol) 1-bromo-3-bromomethyl-5-methyl-benzene and 2.90 ml (21 mmol) (S)-3-acetylsulfanyl-2-methyl-propionic acid in 32 ml methanol is cooled in an ice bath and 4N aqueous sodium hydroxide (15.8 ml, 63 mmol) are added. The reaction mixture is stirred at rt for 3 hrs. EtOAc is added to the mixture and the organic layer is washed with water and brine and evaporated. Filtration over silica gel (flashmaster, hexane to hexane/EtOAc 4/6) gives the title compound.
Reaction SMILES: Cl.[C:2]1([CH:8]2[NH:13][C:12]([NH2:14])=[N:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:15]1[CH:20]=[CH:19][C:18]([C:21](=O)[CH2:22][C:23](OCC)=[O:24])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[C:2]1([CH:8]2[CH2:9][CH2:10][N:11]3[C:23](=[O:24])[CH:22]=[C:21]([C:18]4[CH:19]=[CH:20][N:15]=[CH:16][CH:17]=4)[N:14]=[C:12]3[NH:13]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)c1ccncc1
Reactant: NC1=NCCC(c2ccccc2)N1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=c1cc(-c2ccncc2)nc2n1CCC(c1ccccc1)N2
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
A suspension containing 4 g (16.12 mmoles) of 6-phenyl-1,4,5,6-tetrahydro-2-pyrimidinamine hydrochloride (1:2), 3.11 g (16.12 mmoles) of ethyl 3-(pyridin-4-yl)-3-oxopropionate, 6.68 g (48.36 mmoles) of anhydrous potassium carbonate in 50 ml of ethanol were refluxed for 18 h. The cooled solution was evaporated and the residue was treated with water and allowed to stir at 0° C. during 2 h. The precipitate which formed was recovered by filtration and dried at 90° C. during 18 h. 4.80 g (98%) of product was thus obtained.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[OH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[C:18]([OH:20])=[O:19].[CH2:21](Cl)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[CH2:21]([O:19][C:18]([C:9]1[CH:10]=[CH:11][C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]=1[O:7][CH2:18][C:9]1[CH:10]=[CH:11][CH:12]=[CH:17][CH:8]=1)=[O:20])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(O)c1ccc2ccccc2c1O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1ccc2ccccc2c1OCc1ccccc1
Yield: 38.5 %

Procedure:
K2CO3 (9.26 g, 67 mmol), dry DMF (20 mL), commercially available 1-hydroxy-2-naphthoic acid (1.88 g, 10 mmol), and benzyl chloride (5.6 mL). Yield: 1.41 g of yellow-orange viscous product (38.5% yield). Rf=0.38 (SiO2, 50% Hexanes/50% CH2Cl2). 1H NMR (400 MHz, CDCl3) δ 5.13 (s, 2H), δ 5.39 (s, 2H), δ 7.32-7.41 (m, 7H), δ 7.43-7.52 (m, 5H) δ 7.57 (d, J=7.8 Hz, 1H), δ 7.63 (d, J=8.7 Hz, 1H), δ 7.84 (d, J=8.2 Hz, 1H), δ 7.92 (d, J=8.7 Hz, 1H), δ 8.24 (d, J=8.2 Hz, 1H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[N:18]=[C:17]([NH2:19])[CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1.C(N(CC)CC)C>C1COCC1>[CH3:5][N:6]1[CH2:7][CH2:8][CH:9]([O:12][C:13]2[N:18]=[C:17]([NH:19][C:1](=[O:3])[CH3:2])[CH:16]=[CH:15][CH:14]=2)[CH2:10][CH2:11]1
Reactant: CN1CCC(Oc2cccc(N)n2)CC1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc(OC2CCN(C)CC2)n1
Temperature: 40 °C
Yield: 76.4 %

Procedure:
Add acetyl chloride (118 mg, 0.11 mL, 1.50 mmol) slowly to a solution of 6-(1-methyl-piperidin-4-yloxy)-pyridin-2-ylamine (preparation 72, 260 mg, 1.25 mmol) in triethylamine (190 mg, 0.26 mL, 1.88 mmol) and THF (10 mL), heat at 40° C. overnight. Quench the reaction with 0.1N NaOH, extract with methylene dichloride three times. Combine the organic layers, dry over Na2SO4, filter and concentrate to give a residue. Chromatography (silica gel) eluting with 4.5% 2M NH3-methanol in methylene dichloride provides 238 mg (76%) of the title compound as an oil: mass spectrum (ion spray): m/z=250.0 (M+1); 1H NMR (CDCl3, ppm): 7.70 (m, 2H), 7.56 (t, 1H), 6.44 (d, 1H), 4.91 (m, 1H), 2.68 (m, 2H), 2.34 (m, 5H), 2.20 (s, 3H), 2.00 (m, 2H), 1.81 (m, 2H).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]([CH2:21][CH2:22][CH3:23])[CH:10]2[CH2:19][C:18]3[CH:17]=[C:16]([OH:20])[CH:15]=[CH:14][C:13]=3[CH2:12][CH2:11]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[NH:24]1[C:32]2[C:27](=[CH:28][C:29]([CH:33]=O)=[CH:30][CH:31]=2)[CH:26]=[CH:25]1>>[NH:24]1[C:32]2[C:27](=[CH:28][C:29]([CH2:33][N:4]3[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][N:9]([CH2:21][CH2:22][CH3:23])[CH:10]4[CH2:19][C:18]5[CH:17]=[C:16]([OH:20])[CH:15]=[CH:14][C:13]=5[CH2:12][CH2:11]4)[CH2:2][CH2:3]3)=[CH:30][CH:31]=2)[CH:26]=[CH:25]1
Reactant: O=Cc1ccc2[nH]ccc2c1
Reactant: CCCN(CCN1CCNCC1)C1CCc2ccc(O)cc2C1
Product: CCCN(CCN1CCN(Cc2ccc3[nH]ccc3c2)CC1)C1CCc2ccc(O)cc2C1
Yield: 32.5 %

Procedure:
Compound 40b was prepared according to Procedure A using 39a (65 mg, 0.20 mmol) and indole-5-carboxaldehyde (35 mg, 0.24 mmol) to give 40b (29 mg, 32%) after column chromatography. 1H NMR (400 MHz, CDCl3) δ 0.84 (t, 3H, J=7.2 Hz), 1.33-1.44 (m, 3H), 1.85 (d, 1H, J=10.0 Hz), 2.41-2.82 (m, 19H), 3.60 (s, 2H), 6.35 (d, 1H, J=2.0 Hz), 6.49-6.58 (m, 2H), 6.85 (d, 1H, J=8.4 Hz), 7.14-7.20 (m, 2H), 7.31 (d, 1H, J=8.4 Hz), 7.54 (s, 1H), 8.38 (bs, 1H). The free base of 40b was converted into oxalate salt. m.p. 198-203° C. Anal. [C28H38N4O.2.5(COOH)2.3H2O]C, H, N.
Reaction SMILES: [OH:1]/[N:2]=[C:3](\Cl)/[C:4]1[CH:15]=[CH:14][C:7]2[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=2[CH:5]=1.[Cl:17][C:18]1[CH:23]=[C:22]([C:24]([C:26]([F:29])([F:28])[F:27])=[CH2:25])[CH:21]=[C:20]([Cl:30])[C:19]=1[O:31][CH2:32][C:33]([F:36])([F:35])[F:34].CC(=O)OCC>CN(C=O)C>[Cl:17][C:18]1[CH:23]=[C:22]([C:24]2([C:26]([F:29])([F:27])[F:28])[O:1][N:2]=[C:3]([C:4]3[CH:15]=[CH:14][C:7]4[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=4[CH:5]=3)[CH2:25]2)[CH:21]=[C:20]([Cl:30])[C:19]=1[O:31][CH2:32][C:33]([F:34])([F:36])[F:35]
Reactant: CC1(C)OB(O)c2ccc(/C(Cl)=N/O)cc21
Reactant: C=C(c1cc(Cl)c(OCC(F)(F)F)c(Cl)c1)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)OB(O)c2ccc(C3=NOC(c4cc(Cl)c(OCC(F)(F)F)c(Cl)c4)(C(F)(F)F)C3)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 18.3 %

Procedure:
To a solution of (Z)-N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoyl chloride (253 mg, 1.06 mmol) and 1,3-dichloro-2-(2,2,2-trifluoroethoxy)-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (360 mg, 1.06 mmol) in DMF (10 mL) at rt was added TEA (107 mg, 1.06 mmol). The reaction mixture was stirred at rt for 18 h, poured into ice-water and extracted with EA (20 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluted with PE:EA (6:1) to give the final title compound (105 mg; yield 18.3%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.20 (s, 1H), 7.76-7.69 (m, 5H), 4.80 (q, J=8.8 Hz, 2H), 4.37 (q, J=18.4 Hz, 2H), 1.48 (s, 6H) ppm; HPLC purity: 96.2% at 220 nm and 98.3% at 254 nm; MS: m/z=542.2 (M+, ESI+).