Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40]O)=[CH:33][CH:32]=2)=[C:28]([CH:42]([CH3:44])[CH3:43])[NH:27][N:26]=1)(=O)C.[NH2:45][CH:46]([CH2:49][OH:50])[CH2:47][OH:48].NC(C)(C)CO>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([O:37][CH2:38][CH2:39][CH2:40][NH:45][CH:46]([CH2:49][OH:50])[CH2:47][OH:48])=[CH:35][CH:36]=3)=[C:28]([CH:42]([CH3:44])[CH3:43])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCO)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: NC(CO)CO
Agent: CC(C)(N)CO
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(OCCCNC(CO)CO)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 57 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)phenyl]-methyl}-5-isopropyl-1H-pyrazole and 2-amino-1,3-propanediol instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and 2-amino-2-methyl-1-propanol, respectively.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[S:3]([C:5]1[CH:19]=[CH:18][C:8]2[CH2:9][CH2:10][N:11]3[CH:17]=[CH:16][CH:15]=[C:12]3[C:13](=[O:14])[C:7]=2[CH:6]=1)=[O:4].[OH:22]O>C(O)(=O)C>[F:21][C:2]([F:1])([F:20])[S:3]([C:5]1[CH:19]=[CH:18][C:8]2[CH2:9][CH2:10][N:11]3[CH:17]=[CH:16][CH:15]=[C:12]3[C:13](=[O:14])[C:7]=2[CH:6]=1)(=[O:22])=[O:4]
Reactant: O=C1c2cc(S(=O)C(F)(F)F)ccc2CCn2cccc21
Reactant: OO
Solvent: CC(=O)O
Product: O=C1c2cc(S(=O)(=O)C(F)(F)F)ccc2CCn2cccc21

Procedure:
A solution of 2 gm. of 9-trifluoromethylsulfinyl-6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepin-11-one in 20 ml. of acetic acid containing 5 ml. of 90% hydrogen peroxide is stirred at 25° C. for 4 days. The solvent is evaporated and the residue dissolved in 100 ml. of methylene chloride. After washing the organic solution with 2 × 25 ml. of 1N Na2CO3, it is dried and evaporated, and the residue chromatographed on silica gel to yield 9-trifluoromethylsulfonyl-6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepin-11-one.
Reaction SMILES: [NH2:1][C@H:2]([CH2:7][C:8]#[C:9][C:10]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[CH3:23])[C:13]([N:24]([C:26](=[O:44])[C:27]([C:30]2[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[C:32]([C:40]([F:43])([F:42])[F:41])[CH:31]=2)([CH3:29])[CH3:28])[CH3:25])=[CH:12][N:11]=1)[C:3]([O:5][CH3:6])=[O:4]>C(#N)C.FC(F)(F)S([O-])(=O)=O.[Ag+]>[F:37][C:36]([F:38])([F:39])[C:34]1[CH:35]=[C:30]([C:27]([CH3:28])([CH3:29])[C:26]([N:24]([CH3:25])[C:13]2[C:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=3[CH3:23])=[CH:15][C:10]([C:9]3[CH2:8][CH2:7][C@H:2]([C:3]([O:5][CH3:6])=[O:4])[N:1]=3)=[N:11][CH:12]=2)=[O:44])[CH:31]=[C:32]([C:40]([F:41])([F:43])[F:42])[CH:33]=1
Reactant: COC(=O)[C@H](N)CC#Cc1cc(-c2ccc(F)cc2C)c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CC#N
Product: COC(=O)[C@H]1CCC(c2cc(-c3ccc(F)cc3C)c(N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 118.8 %

Procedure:
Silver trifluoromethanesulfonate (0.381 g, 1.483 mmol) was added portionwise to a solution of methyl (2R)-2-amino-5-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl)amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-4-pentynoate (Intermediate 13, 1.85 g, 2.97 mmol) in anhydrous Acetonitrile (25 ml) and the resulting reaction mixture was stirred at room temperature overnight. Volatiles were evaporated under vacuo at room temperature. The residue was taken-up in dichloromethane and filtered through a plug of celite to afford 2.2 g of the title compound as a brown solid (the material contained some residual acetonitrile, therefore overall recovered amount was higher than the theoretical amount).
Reaction SMILES: C([N:8]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([C:17]([O:19][CH3:20])=[O:18])[N:10]=[C:9]1[CH:21]([O:23][CH3:24])[CH3:22])C1C=CC=CC=1.Cl>>[CH3:24][O:23][CH:21]([C:9]1[NH:10][C:11]([C:17]([O:19][CH3:20])=[O:18])=[C:12]([C:13]([O:15][CH3:16])=[O:14])[N:8]=1)[CH3:22]
Reactant: COC(=O)c1nc(C(C)OC)n(Cc2ccccc2)c1C(=O)OC
Agent: Cl
Product: COC(=O)c1nc(C(C)OC)[nH]c1C(=O)OC

Procedure:
Following a procedure similar to that described in Preparation 42(iv), but using 3.30 g of dimethyl 1-benzyl-2-(1-methoxyethyl)imidazole-4,5-dicarboxylate [prepared as described in step (iii) above], 2.02 g of the hydrochloride of the title compound were obtained as a syrup.
Reaction SMILES: [Ni:1].CO.[C:4]([CH:8]1[C:15](C(C)(C)C)(O)[CH:14]=[CH:13][C:10]([CH2:11][OH:12])=[CH:9]1)(C)(C)[CH3:5].CC(O)C>C1C=CC=CC=1>[Ni:1].[CH3:11][OH:12].[CH3:5][CH2:4][CH2:8][CH2:9][CH2:10][CH2:13][CH2:14][CH3:15]
Reactant: CC(C)(C)C1C=C(CO)C=CC1(O)C(C)(C)C
Agent: [Ni]
Solvent: CO
Solvent: CC(C)O
Solvent: c1ccccc1
Product: CCCCCCCC

Procedure:
[2,2'-thiobis-(4-t-octylphenolato)]-2-propanol nickel II (83.9 g) prepared as described in Example 4 was dissolved in benzene (250 ml) and 3,4-di-t-butyl-4-hydroxybenzyl alcohol (35.5 g) was added. The temperature of the mixture was raised to reflux and the resulting solution was refluxed for 2.25 hr. Displaced 2-propanol and benzene (150 ml) were then distilled from the reaction mixture. Remaining solvent was removed by rotary evaporation. From the residue the complex [2,2'-thiobis-(4-t-octylphenolato)]-3,4-di-t-butyl-4-hydroxybenzyl alcohol nickel II was obtained by recrystallization from n-octane as a green solid m.p. 253°-255° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=3)[N:10]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=2[CH3:30])=[CH:4][CH:3]=1.[CH2:31]([O:33][C:34](=[O:39])[C:35](Br)([CH3:37])[CH3:36])[CH3:32]>>[CH2:31]([O:33][C:34](=[O:39])[C:35]([O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:9]([CH3:30])=[C:8]2[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)([CH3:37])[CH3:36])[CH3:32]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CCCCCCCCCCCCn1c(C)c(-c2ccc(Cl)cc2)c2cc(O)ccc21
Product: CCCCCCCCCCCCn1c(C)c(-c2ccc(Cl)cc2)c2cc(OC(C)(C)C(=O)OCC)ccc21

Procedure:
The above compound was prepared from 3-(4chlorophenyl)-1-dodecyl-2-methyl-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester using a procedure analogous to that of Example 10.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:9][C:10]1[CH:15]=[C:14](Cl)[C:13]([N+:17]([O-:19])=[O:18])=[CH:12][N:11]=1.C([N:22](CC)CC)C.O>C1COCC1>[Cl:9][C:10]1[CH:15]=[C:14]([NH:22][C:4]2[CH:5]=[CH:6][C:1]([O:7][CH3:8])=[CH:2][CH:3]=2)[C:13]([N+:17]([O-:19])=[O:18])=[CH:12][N:11]=1
Reactant: O=[N+]([O-])c1cnc(Cl)cc1Cl
Reactant: CCN(CC)CC
Reactant: COc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Nc2cc(Cl)ncc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Anisole (908 mg, 7.4 mmol) was added to a solution of 2,4-dichloro-5-nitropyridine (1.30 g, 6.7 mmol) and triethylamine (1.02 mL, 7.4 mmol) in THF (5 mL). The mixture was allowed to stir at rt for 1 h, then was poured into H2O and extracted with EtOAc. The organic layers were washed with H2O and brine, dried, filtered and concentrated to a residue which was purified by column chromatography (5-50% EtOAc in hex) to give the title compound as an orange solid, 1.46 g (78%). MS (ES+) m/e 280 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([NH2:11])=[CH:4][CH:3]=1.C[Li].[Cl-].[NH4+].[C:16](OCC)(=O)C>C1COCC1>[NH2:11][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:10][C:6]=1[C:7](=[O:9])[CH3:16]
Reactant: CCOC(C)=O
Reactant: Nc1ccc(Br)cc1C(=O)O
Agent: [Cl-]
Agent: [Li]C
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)c1cc(Br)ccc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
To a solution of 5-bromo anthranilic acid (50 g, 0.231 mol) in anhydrous THF (500 mL) at 0° C. under nitrogen was added in a dropwise manner methyllithium (1.4 M in diethyl ether, 661 mL, 0.926 mol). After addition, the reaction mixture was slowly allowed to warm to room temperature, stirred overnight, and treated with aqueous saturated ammonium chloride solution (1000 mL). Ethyl acetate (400 mL) was added and organic layer was separated. The aqueous layer was extracted with ethyl acetate (3×200 mL). The combined organic layers were dried (Mg2SO4) and concentrated. The residue was purified by a flash chromatography on silica gel (hexane:ethyl acetate/9:1) to afford the title compound as a brown solid (29.3 g, 59%). MS (ES) m/z 214/216 ([M+H]+, 100%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:11])[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>>[O:15]1[CH2:16][CH2:17][N:12]([C:2]2[CH:3]=[C:4]([NH2:11])[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=2)[CH2:13][CH2:14]1
Reactant: Nc1cc(Br)cnc1[N+](=O)[O-]
Reactant: C1COCCN1
Product: Nc1cc(N2CCOCC2)cnc1[N+](=O)[O-]
Temperature: 140 °C
Yield: 84.2 %

Procedure:
5-Bromo-2-nitropyridin-3-amine (2.32 g, 10.6 mmol) was suspended in morpholine (5 mL, 57.4 mmol) and the solution was heated at 140° C. for 1h. The reaction mixture was cooled to room temperature and the solid crash out was triturated with water and filtered. The solid this obtained was washed with water, EtOH, and dried, obtaining 5-morpholino-2-nitropyridin-3-amine (2.0 g, 8.92 mmol, 84%) as a bright yellow powder. Depending on the outcome of the previous step, this solid may still contain the ethoxy derivative from the previous step, and the two compounds can be separated by column chromatography on silica gel (analogix, 20% EtOAc in heptane for 2 min, to 100% EtOAc to 15 min, then 100% EtOAc to 20 min). LCMS (m/z): 225.1 (MH+), 0.43 min; 1H NMR (400 MHz, CDCl3) δ ppm 10.54 (s, 1H) 8.57 (d, J=2.7 Hz, 1H) 7.85 (d, J=2.7 Hz, 1H) 7.70 (d, J=2.3 Hz, 1H) 6.32 (d, J=2.3 Hz, 1H) 6.00 (br. s., 1H) 3.93-3.83 (m, 7H) 3.83-3.74 (m, 3H) 3.63-3.55 (m, 3H) 3.51-3.43 (m, 3H) 3.41-3.31 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:10]([O:12]C)=[O:11])[C:7]2([CH2:9][CH2:8]2)[CH2:6]1)=[O:4].[OH-].[K+].Cl>CO.O>[CH3:1][O:2][C:3]([C:5]1([C:10]([OH:12])=[O:11])[C:7]2([CH2:9][CH2:8]2)[CH2:6]1)=[O:4]
Reactant: COC(=O)C1(C(=O)OC)CC12CC2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)C1(C(=O)O)CC12CC2
Temperature: 25 °C
Reaction time: 48 h
Yield: 82 %

Procedure:
To the mixture of spiro[2.2]pentane-1,1-dicarboxylic acid dimethyl ester 800 mg (4.3 mmol) in 8 mL of MeOH and 2 mL of water was added KOH (240 mg, 4.3 mmol). This solution was stirred at rt for 2 days. It was then acidified with dilute HCl to pH 3 and extracted two times with ether. The combined organic phases were dried (MgSO4) and concentrated to yield 600 mg (82%) of spiro[2.2]pentane-1,1-dicarboxylic acid methyl ester as a white solid. 1H NMR (300 MHz, CDCl3) δ 3.82 (s, 6 H), 2.35 (d, 1 H, J=3 Hz), 2.26 (d, 1 H, J=3 Hz), 1.20 (m, 1 H), 1.15 (m, 1 H), 1.11 (m, 1 H), 1.05 (m, 1 H). LRMS: MS m/z 169 (M+−1).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[Na+].S(OC)(O[CH3:19])(=O)=O>CO.O>[CH3:19][O:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[CH:5]=[CH:4][NH:3][C:2]2=[O:1]
Reactant: COS(=O)(=O)OC
Reactant: Oc1cccc2c(O)nccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cccc2c(=O)[nH]ccc12
Yield: 64 %

Procedure:
To 3.0 g (18.6 mmol) of 1,5-dihydroxyisoquinoline in 80 ml methanol and 20 ml of water was added 0.78 g of 50% sodium hydroxide (39 mmol) and 2 ml of dimethyl sulfate. The mixture was heated under reflux for two hours. An additional 4.0 ml of dimethyl sulfate and 10 ml of 50% sodium hydroxide was then added and refluxing continued for an additional hour. The mixture was diluted with 200 ml of water and concentrated to half the original volume. The resulting solid was collected and washed with water. Recrystallization from ethanol gave 2.1 g (64%) of the desired product; mp 215°-217°.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[O:7][C:6]=2[CH:5]=[C:4](Br)[C:3]=1[OH:16].[K+].[Br-]>>[C:2]1([C:2]2[C:10]3[C:9]4[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=4[O:7][C:6]=3[CH:5]=[C:4]([C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:9]=3)[C:3]=2[OH:16])[CH:10]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1c(Br)cc2oc3ccccc3c2c1Br
Agent: [Br-]
Agent: [K+]
Product: Oc1c(-c2ccccc2)cc2oc3ccccc3c2c1-c1ccccc1

Procedure:
The title compound was prepared as a light yellow-orange solid (0.058 g, 59%) from 1,3-dibromodibenzofuran-2-ol using a procedure similar to step 2 of Example 39, mp>46° C. (decomp.); 1H NMR (CDCl3) δ 5.14 (s, 1H), 6.99–7.08 (m, 2H), 7.35–7.44 (m, 2H), 7.48–7.68 (m, 11H); IR (KBr) 3530, 3060, 1600, 1500, 1460, 1450, 1420, 1320, 1260, 1220, 1160, 1130, 1070, 890, 800, 750, and 700 cm−1; mass spectrum [EI], m/z 336 (M)+; Anal. Calcd. for C24H16O2.1.0H2O: C, 81.34; H, 5.12; N, 0.00. Found: C, 81.12; H, 4.79; N, −0.03.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:17])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>N1C=CC=CC=1>[I:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:17][C:18](=[O:20])[CH3:19])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: OC(Cc1ccc(I)cc1)c1ccc(I)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC(Cc1ccc(I)cc1)c1ccc(I)cc1
Reaction time: 48 h

Procedure:
1 ,2-di(p-bromophenyl)-hydroxyethane (17.8 g, 0.05 mol), potassium iodide (165 g), copper (I) iodide (95 g) and hexamethylphosphoramide (200 mL) was stirred at 150-160° C. for 48 h and then cooled. Work-up was as described in Example IV to provide a light yellow solid (10 g), which was the expected 1,2-di(p-iodophenyl)-1-hydroxyethane. A portion of this compound (7.2 g, 0.016 mol), acetic anhydride (16 mL), pyridine (16 mL) were heated at 60° C. for 30 min, followed by standing for 2 days. The resulting solution was worked up as in Example IlIl to provide an oil which solidified upon standing. The solid was crystallized from hexanes to provide the title compound as a light yellow solid (4.3 g).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]([CH2:9][O:10][C:11]3[CH:19]=[CH:18][CH:17]=[C:16]4[C:12]=3[CH:13]=[C:14]([C:20](O)=[O:21])[NH:15]4)=[CH:7][O:8][C:4]=2[CH:3]=1.[NH2:25][CH:26]1[CH2:31][CH2:30][C:29]([CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][C@H:38]([OH:41])[C@@H:37]([CH3:42])[CH2:36]2)([OH:32])[CH2:28][CH2:27]1>>[OH:32][C:29]1([CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][C@H:38]([OH:41])[C@@H:37]([CH3:42])[CH2:36]2)[CH2:30][CH2:31][CH:26]([NH:25][C:20]([C:14]2[NH:15][C:16]3[C:12]([CH:13]=2)=[C:11]([O:10][CH2:9][C:6]2[C:5]4[CH:23]=[CH:24][C:2]([F:1])=[CH:3][C:4]=4[O:8][CH:7]=2)[CH:19]=[CH:18][CH:17]=3)=[O:21])[CH2:27][CH2:28]1
Reactant: O=C(O)c1cc2c(OCc3coc4cc(F)ccc34)cccc2[nH]1
Reactant: C[C@H]1CN(CCC2(O)CCC(N)CC2)CC[C@@H]1O
Product: C[C@H]1CN(CCC2(O)CCC(NC(=O)c3cc4c(OCc5coc6cc(F)ccc56)cccc4[nH]3)CC2)CC[C@@H]1O

Procedure:
This compound is synthesized analogously to example 1 from 4-(6-fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (synthesis described in WO2005077932A2, cmpd 106) and amine 14.
Reaction SMILES: O[CH:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8])[CH2:3]1.N1C(C)=CC=CC=1C.[S:21]([O:28]S(C(F)(F)F)(=O)=O)([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22].[O-]S(C(F)(F)F)(=O)=O.[N:44]12[CH2:51][CH2:50][N:47]([CH2:48][CH2:49]1)[CH2:46][CH2:45]2>C(Cl)Cl.CC#N>[O-:28][S:21]([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22].[CH2:10]([O:9][C:7]([N:4]1[CH2:5][CH2:6][CH:2]([N+:44]23[CH2:51][CH2:50][N:47]([CH2:48][CH2:49]2)[CH2:46][CH2:45]3)[CH2:3]1)=[O:8])[CH:11]=[CH2:12]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: C1CN2CCN1CC2
Reactant: C=CCOC(=O)N1CCC(O)C1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CC#N
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: C=CCOC(=O)N1CCC([N+]23CCN(CC2)CC3)C1
Reaction time: 0.67 h
Yield: 75.4 %

Procedure:
3-Hydroxy-1-allyloxycarbonylpyrrolidine (0.34 g, 1.99 mmol) was dissolved in CH2Cl2 (40 mL). 2,6-Lutidine (0.7 mL, 6 mmol) was added at -20° C. followed by adding triflic anhydride (0.5 mL, 2.97 mmol). The mixture was kept at -20° C. for 40 min, diluted with CH2Cl2, washed with water, 0.1 N HCl aqueous solution, water and brine, dried over Na2SO4 and concentrated to give the trifalte (0.63 g). The triflate (0.43 g, 1.42 mmol) was reacted with 1,4-diazabicyclo[2.2.2]octane (0.15 g, 1.34 mmol) in CH3CN overnight. The solvent was removed and the residue was dried under vacuum to give the product (0.42 g).
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]1.[ClH:23].CC[O:26]C(C)=O>>[ClH:23].[NH:13]1[CH2:14][CH2:15][CH:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]([OH:26])[CH3:2])[CH2:11][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2CCO)CC1
Reactant: CCOC(C)=O
Agent: Cl
Product: CC(O)c1ccccc1C1CCNCC1

Procedure:
The title compound was prepared according to the procedure described in Example 1 (Step e) using tert-butyl 4-(2-(hydroxyethyl)phenyl]piperidinecarboxylate (Step b) (1.22 g, 4.0 mmol) and satd anhydrous HCl in EtOAc (50 mL). The title compound was obtained as a white solid (0.96 g). MS (ESI, pos. ion) m/z: 206 (M+1); MS (ESI, neg. ion) m/z: 204 (M−1). Calc'd for C13H19NO: 205.15.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[O:32]1[C:36]2[C:37]([S:41](Cl)(=[O:43])=[O:42])=[CH:38][CH:39]=[CH:40][C:35]=2[CH:34]=[CH:33]1.N1C=CC=CC=1>ClCCl>[F:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH:8][S:41]([C:37]1[C:36]2[O:32][CH:33]=[CH:34][C:35]=2[CH:40]=[CH:39][CH:38]=1)(=[O:42])=[O:43]
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Reactant: O=S(=O)(Cl)c1cccc2ccoc12
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1cccc2ccoc12
Temperature: 50 °C
Reaction time: 2 h

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. benzofuran-7-sulfonyl chloride (15 mg, 0.07 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that the target compound was obtained.
Reaction SMILES: Cl[C:2]1[C:3]([CH3:21])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH3:20])=[CH:14][CH:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[NH2:22][C@H:23]1[CH2:28][CH2:27][C@@H:26]([NH2:29])[CH2:25][CH2:24]1>CO>[NH2:22][C@@H:23]1[CH2:28][CH2:27][C@H:26]([NH:29][C:2]2[C:3]([CH3:21])=[C:4]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH3:20])=[CH:14][CH:13]=3)[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=2)[CH2:25][CH2:24]1
Reactant: N[C@H]1CC[C@@H](N)CC1
Reactant: CCOc1ccc(Nc2c(C)c(Cl)nn3ccnc23)cc1
Solvent: CO
Product: CCOc1ccc(Nc2c(C)c(N[C@H]3CC[C@@H](N)CC3)nn3ccnc23)cc1
Temperature: 165 °C

Procedure:
To 6-chloro-N-(4-ethoxyphenyl)-7-methylimidazo[1,2-b]pyridazin-8-amine (40 mg, 0.14 mmol) from Example III(1), step 1d was added cis-1,4-diaminocyclohexane (250 mg, 2.19 mmol). The mixture was allowed to heat at 165° C. for 48 hrs. The reaction mixture then cooled, diluted with methanol and purified by preparative HPLC. The eluent was then concentrated in vacuo, diluted with methanol (2 mL), purified and neutralized by passing through a 500 mg SCX (Cation exchange column). The eluent was concentrated to give 6.0 mg (11.3%) of the titled compound. 1H NMR (500 MHz, MeOH) δ ppm 7.65 (1H, s), 7.25 (1H, s), 6.85 (4 H, m), 3.95 (2H, d, J=7.2 Hz), 3.95 (1H, m), 3.05 (1H, m), 1.95 (2H, m), 1.85 (3H, s), 1.80 (4H, m), 1.65 (2H, m), 1.35 (3H, t, J=7.2 Hz). LC/MS m/e 381 (M+1). HPLC, 1.91 min. Waters Sunfire C18 4.6×50.0%-100% B. B: 90% MeOH, 10% H2O, 0.1% TFA. A: 10% MeOH, 90% H2O, 0.1% TFA, gradient time 4 min, hold at 100% B 1 min, flow rate 4 mL/min.
Reaction SMILES: C([Mg]Br)C.C(NC(C)C)(C)C.[Cl:12][C:13]1[CH:14]=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:16]=[CH:17][C:18]=1[F:19].[C:24](=[O:26])=[O:25].Cl.CC1CCCCC1>C1COCC1>[Cl:12][C:13]1[C:18]([F:19])=[C:17]([CH:16]=[C:15]([C:20]([F:23])([F:21])[F:22])[CH:14]=1)[C:24]([OH:26])=[O:25]
Reactant: O=C=O
Reactant: Fc1ccc(C(F)(F)F)cc1Cl
Agent: CC[Mg]Br
Agent: Cl
Solvent: CC1CCCCC1
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(O)c1cc(C(F)(F)F)cc(Cl)c1F
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 37.9 %

Procedure:
To a mixture of ethyl magnesium bromide solution (6.25 ml, 6.25 mmol, 1.25 equiv., 1M in THF) and diisopropyl amine (77.7 μl, 0.5 mmol, 0.1 equiv.) was added 3-chloro-4-fluoro-benzo trifluoride (0.99 g, 5 mmol in THF (2 ml)) at ambient temperature and the mixture was heated in an oil bath to 50° C. for 13 h. The brown clear reaction mixture was cooled to 0-5° C., was transferred into a syringe and added dropwise to a solution of CO2 (2.2 g, 50 mmol, 10 equiv.) in THF (5 ml) at −70° C. and stirred for 15 min. To the brown suspension was added HCl (1M, 14 ml) and the phases were separated. The aqueous phase was extracted with TBME (10 ml), the combined organic phases were dried over sodium sulfate, filtered, washed with TBME and the solvents were removed under vacuum to yield a dark brown oil (0.97 g of the crude product). The crude product was treated with methyl cyclohexane (4.4 ml) and heated in a pre-heated oil bath to reflux. After 5 min, a brown clear solution was obtained, the oil bath was removed, the reaction mixture was cooled to ambient temperature and the formed suspension was stirred overnight at ambient temperature. After 18 h the brown suspension was stirred in an ice bath (0-5° C.) for two hours, the obtained crystals were filtered off, the crystals were washed with cold methyl cyclohexane (1.6 ml) and the crystals were dried until weight constancy to yield the product as white crystals (0.46 g, 38.2% yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[N:3]=1.[F:16][C:17]([F:27])([F:26])[O:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1.C(N(CC)CC)C>C(O)CCC>[Cl:8][C:6]1[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[N:3]=[C:2]([NH:23][C:22]2[CH:24]=[CH:25][C:19]([O:18][C:17]([F:16])([F:26])[F:27])=[CH:20][CH:21]=2)[CH:7]=1
Reactant: Fc1ccc(-c2nc(Cl)cc(Cl)n2)cc1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: Fc1ccc(-c2nc(Cl)cc(Nc3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Yield: 47.7 %

Procedure:
A mixture of compound 4,6-dichloro-2-(4-fluoro-phenyl)-pyrimidine (1 g, 4.10 mmol), 4-trifluoromethoxy aniline (0.8 g, 4.5 mmol) and triethyl amine (0.83 g, 8.20 mmol) in n-butanol (10 mL) was refluxed for 12 hours under nitrogen. The reaction mixture was then cooled to room temperature and concentrated under vacuum, the crude compound was passed through the silicagel by using 5-6% ethylacetate—petroleum ether to afford the compound [6-chloro-2-(4-fluoro-phenyl)-pyrimidin-4-yl]-(4-trifluoromethoxy-phenyl)-amine (0.75 g, 50%) as light brown solid.