Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([C:4]1[N:9]([CH2:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8](=[O:19])[C:7]2[C:20]([O:33][CH3:34])=[C:21]([C:24]([NH:26][CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[O:25])[N:22]([CH3:23])[C:6]=2[CH:5]=1)[CH3:3].C(N(CC)CC)C.C1COCC1.C([O:50][CH2:51][C:52](Cl)=[O:53])(=O)C>C(OCC)(=O)C>[CH2:2]([C:4]1[N:9]([CH2:10][C:11](=[O:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:8](=[O:19])[C:7]2[C:20]([O:33][CH3:34])=[C:21]([C:24]([NH:26][CH:27]3[CH2:28][CH2:29][N:30]([C:51](=[O:50])[CH2:52][OH:53])[CH2:31][CH2:32]3)=[O:25])[N:22]([CH3:23])[C:6]=2[CH:5]=1)[CH3:3]
Reactant: CCc1cc2c(c(OC)c(C(=O)NC3CCNCC3)n2C)c(=O)n1CC(=O)c1ccccc1
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCc1cc2c(c(OC)c(C(=O)NC3CCN(C(=O)CO)CC3)n2C)c(=O)n1CC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 65 %

Procedure:
To a mixture of the compound of Example 130 (90.0 mg, 0.185 mmol), triethylamine (76.9 μL, 0.555 mmol) and THF (5 mL) was added acetoxyacetyl chloride (23.8 μL, 0.221 mmol) at 0° C., and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by aminosilica gel chromatography (eluate; ethyl acetate), and the obtained solid was dissolved in THF (1.2 mL)-ethanol (2.5 mL). 8N Aqueous sodium hydroxide solution (250 μL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with water, acidified with 6N hydrochloric acid (0.5 mL), and extracted twice with ethyl acetate. The extract was combined, washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by aminosilica gel chromatography (eluate; ethyl acetate/methanol=10/0-9/1), and the obtained solid was recrystallized from ethyl acetate to give the title compound (61.2 mg, 65%) as white crystals.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=[O:9])[CH2:7][CH2:8][C:2]1=2.[H-].[Na+].C([O:14][C:15](=O)[C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=1)C.Cl>C(OCC)(=O)C.O>[F:23][C:22]([F:24])([F:25])[C:20]1[CH:21]=[C:16]([CH:17]=[C:18]([C:26]([F:29])([F:27])[F:28])[CH:19]=1)[C:15]([CH:7]1[CH2:8][C:2]2[S:1][CH:5]=[CH:4][C:3]=2[C:6]1=[O:9])=[O:14]
Reactant: CCOC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C1CCc2sccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1Cc2sccc2C1=O
Temperature: 100 °C
Yield: 41 %

Procedure:
5,6-Dihydro-cyclopenta[b]thiophen-4-one in 13 mL of THY was treated with NaH (60 percent, 1.1 g, 27 mmol). After the addition of 3,5-Bis-trifluoromethyl-benzoic acid ethyl ester, the reaction mixture was heated at 100° C. for 8 hr. The solution was cooled to room temperature and poured into water. The resulting mixture was acidified with concentrated HCl and was added with ethyl acetate (70 mL). The organic layer was collected, brined, dried over MgSO4(s), and concentrated under reduced pressure. The resultant precipitate was collected and recrystallized from ethanol to provide the corresponding 5-(3,5-Bis-trifluoromethyl-benzoyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (1.07 g, 4.1 mmol) as yellow solid in 41% yield.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([CH3:13])[C@@H:10]([C:14]([OH:16])=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17]1([NH2:20])[CH2:19][CH2:18]1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[CH2:1]([N:8]1[CH2:12][C@H:11]([CH3:13])[C@@H:10]([C:14]([NH:20][CH:17]2[CH2:19][CH2:18]2)=[O:16])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CC1
Reactant: C[C@H]1CN(Cc2ccccc2)C[C@@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: C[C@H]1CN(Cc2ccccc2)C[C@@H]1C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(3R,4R)-1-Benzyl-4-methyl-3-pyrrolidine carboxylic acid (6.27 g) was suspended in dichloromethane (250 mL). To this suspension, cyclopropylamine (1.76 mL) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (12.2 g) were sequentially added and the mixture was stirred at room temperature for 4 hours. Subsequently, the reaction mixture was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: methanol=10:1) to give (3R,4R)-1-benzyl-N-cyclopropyl-4-methyl-3-pyrrolidine carboxamide (3.32 g) as white crystals.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][C@@:10]12[C:17]([CH3:19])([CH3:18])[CH:14]([CH2:15][CH2:16]1)[CH2:13][NH:12][CH2:11]2.[OH:20][CH:21]1[CH:28]2[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:30][CH:22]1[CH:23]3[CH2:31][C:32](O)=[O:33])[CH2:27]2.CCN=C=NCCCN(C)C>C(Cl)Cl>[OH:20][CH:21]1[CH:28]2[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:30][CH:22]1[CH:23]3[CH2:31][C:32]([N:12]1[CH2:13][CH:14]3[C:17]([CH3:19])([CH3:18])[C@:10]([CH3:9])([CH2:16][CH2:15]3)[CH2:11]1)=[O:33])[CH2:27]2
Reactant: CC1(C)C2CC[C@]1(C)CNC2
Reactant: O=C(O)CC1C2CC3CC(C2)C(O)C1C3
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C2CC[C@]1(C)CN(C(=O)CC1C3CC4CC(C3)C(O)C1C4)C2
Reaction time: 0.5 h

Procedure:
Triethylamine 0.23 ml was added to a methylene chloride 5 ml solution of (IS)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane hydrochloride 0.26 g and stirred at O@C for 30 min. 4-hydroxy-2-adamantyl acetic acid 0.26 g and WSC 0.31 g were added therein, then temperature of the reaction mixture was gradually changed to room temperature and stirred for 25 hours. The reaction mixture was washed with saturated aqueous sodium chloride solution and dried by anhydrous sodium sulfate. After filtering the drying agent, the filtrate was concentrated in vacuo to obtain crude (IS)-3-(4-hydroxy-2-adamantylacetyl)1,8,8-trimethyl-3-azabicyclo[3.2.1]octane. The concentrate was added to THF 25 ml solution of lithium aluminum hydride 70.5 mg and refluxed under heating for 1.5 hours. The reaction mixture was cooled, then water was added thereto and the insoluble material was removed by filtration. The filtrate was concentrated in vacuo. The thus obtained residue was purified by means of silica gel column chromatography (Wako gel, C200, chloroform methanol=150:1) to obtain the product.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]([S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[C:4](=[O:20])[N:3]=1.[C:21](=O)([O-])[O-].[K+].[K+].CN(C)C=O.IC>CCOC(C)=O>[F:8][C:7]1[C:2](=[NH:1])[N:3]([CH3:21])[C:4](=[O:20])[N:5]([S:9]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)(=[O:10])=[O:11])[CH:6]=1
Reactant: COc1ccc(S(=O)(=O)n2cc(F)c(N)nc2=O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)n2cc(F)c(=N)n(C)c2=O)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 11.7 %

Procedure:
To an 8-mL screw capped vial were added 4-amino-5-fluoro-1-(4-methoxyphenylsulfonyl)pyrimidin-2(1H)-one (0.293 g, 0.979 mmol), anhydrous potassium carbonate (K2CO3; 0.271 g, 1.96 mmol), and N,N-dimethylformamide (DMF; 4 mL), followed by iodomethane (CH3I; 0.208 g, 1.47 mmol). The reaction vessel was sealed, and the reaction mixture was warmed to 60° C. and stirred for 4 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (20 mL), and washed with water (H2O; 3×10 mL). The organic phase was dried over MgSO4, filtered, and the solvent was evaporated under reduced pressure. Purification by flash chromatography (silica gel (SiO2), EtOAc/Hexanes gradient) afforded the title compound as a pale yellow solid (36 milligrams (mg), 12%): mp 158-162° C.; 1H NMR (400 MHz, DMSO-d6) δ 8.01 (d, J=9.22 Hz, 2H), 7.74 (d, J=5.27 Hz, 1H), 7.04 (d, J=9.23 Hz, 2H), 3.90 (s, 3H), 3.31 (s, 3H); ESIMS m/z 314 ([M+H]+).
Reaction SMILES: C([O:5][C:6](=[O:26])[CH2:7][CH2:8][N:9]([CH2:11][CH2:12][CH:13]1[C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH3:10])(C)(C)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>ClCCl>[CH:15]1[C:14]2[CH:13]([CH2:12][CH2:11][N:9]([CH3:10])[CH2:8][CH2:7][C:6]([OH:26])=[O:5])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[CH:18]=[CH:17][CH:16]=1
Reactant: CN(CCC(=O)OC(C)(C)C)CCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(CCC(=O)O)CCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Yield: 119 %

Procedure:
A solution of 3-{[2-(9H-fluoren-9-yl)-ethyl]-methyl-amino}-propionic acid tert-butyl ester (11.4 g) in 20 ml dichloromethane is cooled to 0°. Trifluoroacetic acid (20 ml) is added and the solution stirred at room temperature over night. To this mixture a 1 M aq. NaHCO3 solution (262 ml) is added dropwise under vigorous stirring. The phases are separated, the water phase acidified with 14 ml 2N HCl and extracted several times with dichloromethane. The combined extracts are dried over sodium sulfate, filtered and evaporated to afford 11.4 g (100%) of a light brown foam which is used without purification. TLC (silicagel, dichloromethane/methanol 85:15): rf 0.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[C:15]([CH:17]([O:22][CH3:23])[C:18]([O:20]C)=[O:19])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[C:15]([CH:17]([O:22][CH3:23])[C:18]([OH:20])=[O:19])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)C(OC)c1ccc2nc(-c3ccc(Cl)cc3)oc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COC(C(=O)O)c1ccc2nc(-c3ccc(Cl)cc3)oc2c1
Reaction time: 3 h

Procedure:
Methyl 2-p-chlorophenyl-α-methoxy-6-benzoxazolyl-acetate (4.0 g.) was dissolved in dioxan (50 ml.) and a solution of sodium hydroxide (0.7g) in water was added. The solution was stirred for three hours then evaporated to dryness. The residue was stirred with dilute hydrochloric acid for thirty minutes. The solid was filtered off and recrystallised from water-ethanol to give 2-p-chlorophenyl-α-methoxy-6-benzoxazolylacetic acid, m.pt. 164°-6° C.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7].[CH2:14]([OH:16])[CH3:15]>>[ClH:1].[CH3:2][O:3][C:4]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:5]=1[C:6](=[NH:7])[O:16][CH2:14][CH3:15]
Reactant: COc1ccc(C#N)c(OC)c1
Reactant: CCO
Agent: Cl
Product: CCOC(=N)c1ccc(OC)cc1OC
Temperature: 25 °C
Reaction time: 7 h
Yield: 57 %

Procedure:
Hydrogen chloride gas was passed through a solution of 2,4-dimethoxy-benzonitrile (5.20 g, 32 mmol) in anhydrous ethanol (200 mL) at 0° C. After 7 h, hydrogen chloride gas was stopped and the reaction mixture was stirred at room temperature overnight. The solvent was removed and the residue was triturated in diethyl ether to afford ethyl 2,4-dimethoxy-benzimidate hydrochloride (4.5 g, 57%). It was used without further purification.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].O1CCCC1.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][OH:26])=[N:23][CH:24]=1>O>[CH3:8][S:9]([O:26][CH2:25][C:22]1[CH:21]=[CH:20][C:19]([Cl:18])=[CH:24][N:23]=1)(=[O:11])=[O:10]
Reactant: OCc1ccc(Cl)cn1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)OCc1ccc(Cl)cn1
Reaction time: 0.5 h
Yield: 99 %

Procedure:
Triethylamine (12 mL) and methanesulfonyl chloride (5.7 mL) were added to tetrahydrofuran (150 mL) solution of 5-chloro-2-hydroxymethylpyridine (12.77 g) under cooling with ice, and stirred for 30 minutes under cooling with ice. After addition of water (150 mL), the reaction liquid was extracted with ethyl acetate (150 mL+150 mL), and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Concentrating the solvent under reduced pressure, the residue was crystallized from ethyl acetate-diisopropyl ether mixed solvent to provide the title compound (14.65 g, 99%).
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[NH2:8][C:9]1[N:14]=[C:13]([O:15][CH3:16])[CH:12]=[C:11]([O:17][CH3:18])[N:10]=1.[NH2:19][C:20]1[CH:30]=[CH:29][CH:28]=[CH:27][C:21]=1[CH:22]([OH:26])[CH:23]1[CH2:25][CH2:24]1.C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C>[CH:23]1([CH:22]([OH:26])[C:21]2[CH:27]=[CH:28][CH:29]=[CH:30][C:20]=2[NH:19][S:2]([NH:5][C:6]([NH:8][C:9]2[N:10]=[C:11]([O:17][CH3:18])[CH:12]=[C:13]([O:15][CH3:16])[N:14]=2)=[O:7])(=[O:4])=[O:3])[CH2:24][CH2:25]1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Nc1ccccc1C(O)C1CC1
Reactant: COc1cc(OC)nc(N)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)Nc2ccccc2C(O)C2CC2)n1
Reaction time: 0.5 h
Yield: 21.3 %

Procedure:
Chlorosulfonyl isocyanate (0.53 mL, 0.86 g, 6.1 mmol) is added to a solution of 2-amino-4,6-dimethoxypyrimidine (0.95 g, 6.1 mmol) in methylene chloride at 0° C. The resulting mixture is stirred for 30 minutes and a solution of o-amino-α-cyclopropylbenzyl alcohol (1.00 g, 6.1 mmol) and triethylamine (1.45 mL, 1.05 g, 10.4 mmol) in methylene chloride is slowly added to the mixture. The resulting solution is stirred at room temperature for hours, concentrated in vacuo and dissolved in methanol. The methanol solution is adjusted to about pH 1 with 10% hydrochloric acid and extracted with methylene chloride. The combined organic extracts are dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a residue. Flash column chromatography of the residue using silica gel and 30% to 50% ethyl acetate in hexanes solutions gives the title product as a white solid (0.55 g, 21%, mp 66°-69° C.) which is identified by 1HNMR and MS spectral analyses.
Reaction SMILES: [CH2:1]([N:4]([CH2:25][CH2:26][CH3:27])[C:5]1[N:6]([CH3:24])[C:7](=[O:23])[C:8]2[C:13]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[CH3:22])=[CH:12][NH:11][C:9]=2[N:10]=1)[CH2:2][CH3:3].[H-].[Na+].[C:30](Cl)(=[O:32])[CH3:31]>C(#N)C.O>[C:30]([N:11]1[C:9]2[N:10]=[C:5]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:25][CH2:26][CH3:27])[N:6]([CH3:24])[C:7](=[O:23])[C:8]=2[C:13]([C:14]2[C:15]([CH3:22])=[CH:16][C:17]([CH3:21])=[CH:18][C:19]=2[CH3:20])=[CH:12]1)(=[O:32])[CH3:31]
Reactant: CC(=O)Cl
Reactant: CCCN(CCC)c1nc2[nH]cc(-c3c(C)cc(C)cc3C)c2c(=O)n1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCCN(CCC)c1nc2c(c(-c3c(C)cc(C)cc3C)cn2C(C)=O)c(=O)n1C
Reaction time: 0.5 h
Yield: 77.1 %

Procedure:
A solution of 2-(dipropylamino)-5-mesityl-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (20 mg, 0.054 mmol) in acetonitrile (1.5 ml) was added sodium hydride (60% in oil, 5 mg, 0.125 mmol) at 0° C. and stirred for 0.5 hour. After stirring at room temperature for 0.5 hour, to the mixture was added a solution of acetylchloride (20 mg, 0.25 mmol) and acetonitrile (0.5 ml) at 0° C. and stirred for 0.5 hour. After stirring at 80° C. for 1 hour, the mixture was diluted with water (20 ml) and extracted with ethyl acetate (20 ml×3). The extracts were combined, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate (10:1) to give 17 mg (77%) of the title compound.
Reaction SMILES: Cl.Cl.Cl.[CH3:4][C:5]1[N:9]([CH:10]2[CH2:16][C@H:15]3[N:17]([CH2:18][CH2:19][C:20]4([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[O:25][CH2:24][CH2:23][NH:22][CH2:21]4)[C@H:12]([CH2:13][CH2:14]3)[CH2:11]2)[C:8]2[CH:32]=[CH:33][CH:34]=[CH:35][C:7]=2[N:6]=1.[OH:36][CH2:37][C:38]([CH3:43])([CH3:42])[C:39](O)=[O:40].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(Cl)Cl>[CH3:42][C:38]([CH3:43])([C:37]([N:22]1[CH2:23][CH2:24][O:25][C:20]([CH2:19][CH2:18][N:17]2[C@H:12]3[CH2:13][CH2:14][C@@H:15]2[CH2:16][CH:10]([N:9]2[C:8]4[CH:32]=[CH:33][CH:34]=[CH:35][C:7]=4[N:6]=[C:5]2[CH3:4])[CH2:11]3)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:21]1)=[O:36])[CH2:39][OH:40]
Reactant: CC(C)(CO)C(=O)O
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2ccccc2)CNCCO1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2ccccc2)CN(C(=O)C(C)(C)CO)CCO1
Temperature: 25 °C
Reaction time: 24 h
Yield: 55.2 %

Procedure:
To a stirred solution of 2-methyl-1-{(1R,5S)-8-[2-(2-phenylmorpholin-2-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole trihyrdochloride (59.3 mg, 0.10 mmol), 3-hydroxy-2,2-dimethylpropanoic acid (18 mg, 0.15 mmol), and diisopropylethylamine (70 μL, 0.40 mmol) in 1 mL DMF was added HATU (57 mg, 0.15 mmol). The resulting mixture was stirred at ambient temperature for 24 h and then diluted with methylene chloride and washed with saturated aqueous NaHCO3. The organic phase was dried (Na2SO4), concentrated by evaporation, and purified by chromatography (5% (2M NH3/MeOH) in CHCl3) to afford 2,2-dimethyl-3-(2-{2-[(1R,5S)-3(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-2-phenylmorpholin-4-yl)-3-oxopropan-1-ol (29.3 mg. 55%) as amorphous solid. 1H NMR (400 MHz, CDCl3), δ 7.65 (m, 1H), 7.44-7.26 (m, 6H), 7.19-7.10 (m, 2H), 4.80 (br., 1H), 4.69 (m, 1H), 3.75-3.37 (m, 8H), 3.35-3.16 (m, 3H), 2.58 (s, 3H), 2.46-2.34 (m, 2H), 2.13-1.84 (m, 8H), 1.68-1.59 (m, 2H), 1.23 (s, 3H), 1.02 (s, 3H); ESI-MS 531 (M+H), 553 (M+Na).
Reaction SMILES: [C:1]([O:5][C:6]1[CH:7]=[C:8]([C@@H:19]2[CH2:21][O:20]2)[C:9]2[S:13][C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[N:11][C:10]=2[CH:18]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:22]([O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]([NH2:37])([CH3:36])[CH3:35])=[CH:29][CH:28]=1)[CH2:23][CH2:24][CH3:25].O.CC(OC)(C)C>CS(C)=O>[C:1]([O:5][C:6]1[CH:7]=[C:8]([C@@H:19]([OH:20])[CH2:21][NH:37][C:34]([CH3:35])([CH3:36])[CH2:33][C:30]2[CH:31]=[CH:32][C:27]([O:26][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:28][CH:29]=2)[C:9]2[S:13][C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[N:11][C:10]=2[CH:18]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCCCOc1ccc(CC(C)(C)N)cc1
Reactant: CC(C)Oc1nc2cc(OC(C)(C)C)cc([C@@H]3CO3)c2s1
Solvent: CS(C)=O
Solvent: COC(C)(C)C
Solvent: O
Product: CCCCOc1ccc(CC(C)(C)NC[C@H](O)c2cc(OC(C)(C)C)cc3nc(OC(C)C)sc23)cc1
Temperature: 80 °C
Reaction time: 27 h

Procedure:
(R)-5-tert-butoxy-2-isopropoxy-7-oxiranyl-benzothiazole (145 g, 471.7 mmol) and 2-(4-butoxy-phenyl)-1,1-dimethyl-ethylamine (114.8 g, 518.9 mmol) were dissolved in DMSO (850 ml). The reaction mixture was heated to 80° C. and stirred for 27 h. The mixture was then cooled to 25° C. and added to a stirred mixture of water (1500 ml) and TBME (1500 ml). The aqueous layer was separated and extracted with TBME (1000 ml). The combined organic layers were sequentially washed with water (1500 ml) and brine (1000 ml), dried with anhydrous Na2SO4. After concentration, the residue was purified by column chromatography (eluting with 10% of EtOAc in n-heptane to 33% of EtOAc in n-heptane). Solid product (R)-1-(5-tert-butoxy-2-isopropoxybenzo[d]thiazol-7-yl)-2-(1-(4-butoxyphenyl)-2-methylpropan-2-ylamino)ethanol was obtained (140 g) as off-white solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH2:28][CH2:29][CH3:30]>>[NH2:26][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:24])[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][N:20]([CH2:28][CH2:29][CH3:30])[CH2:19]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCNC3)c2n1
Reactant: CCCI
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCC3CCCN(CCC)C3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[3-(3-piperidinyl)propyl]-9H-purin-6-amine and 1-iodopropane.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:7]1[CH:12]=[C:11]([Cl:13])[N:10]=[N:9][C:8]=1[Cl:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:14][C:8]1[N:9]=[N:10][C:11]([Cl:13])=[CH:12][C:7]=1[N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Clc1cc(Br)c(Cl)nn1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1cc(N2CCCC2)c(Cl)nn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.7 %

Procedure:
Pyrrolidine (3.36 ml, 40 mmol) was added to a stirred solution/suspension of 4-bromo-3,6-dichloropyridazine (8.3 g, 36 mmol) and potassium carbonate (13.8 g, 0.1 mol) in dry DMF (100 ml) at room temperature under nitrogen. The mixture was stirred at room temperature for 16 hours, then at 60° C. for 3 hours. The reaction was poured into water (250 ml). The aqueous was extracted with ethyl acetate (×3). The combined extracts were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica gel, eluting with 0.5% methanol/dichloromethane to afford the title pyridazine (7.2 g, 92%) as a colourless oil. 1H NMR (250 MHz, CDCl3) 2.00-2.05 (4H, m), 3.61-3.69 (4H, m), 6.46 (1H, s). MS (ES+) 218 [MH]+, 220 [MH]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:60])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[NH:17][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33](=O)[CH2:34][NH:35][C:36]([CH:38]4[CH2:42][C:41]5(CCOCC5)[CH2:40][N:39]4[C:48](=[O:58])[C@@H:49]([NH:53][C:54]([O:56][CH3:57])=[O:55])[CH:50]([CH3:52])[CH3:51])=O)=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)[N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].C([O-])(=O)C.[NH4+:65].[O:66]1[CH2:71][CH2:70]O[CH2:68][CH2:67]1>C(OCC)(=O)C>[CH3:52][CH:50]([CH3:51])[C@H:49]([NH:53][C:54](=[O:55])[O:56][CH3:57])[C:48]([N:39]1[CH2:40][CH2:41][CH2:42][C@H:38]1[C:36]1[NH:35][CH:34]=[C:33]([C:30]2[CH:31]=[CH:32][C:27]([C:24]3[CH:23]=[CH:22][C:21]([C:19]4[N:20]=[C:16]([CH:12]5[CH2:13][C:14]6([CH2:70][CH2:71][O:66][CH2:67][CH2:68]6)[CH2:15][N:11]5[C:9](=[O:10])[C@@H:5]([NH:4][C:3]([O:2][CH3:1])=[O:60])[CH:6]([CH3:7])[CH3:8])[NH:17][CH:18]=4)=[CH:26][CH:25]=3)=[CH:28][CH:29]=2)[N:65]=1)=[O:58]
Reactant: COC(=O)N[C@H](C(=O)N1CC2(CCOCC2)CC1C(=O)NCC(=O)c1ccc(-c2ccc(-c3c[nH]c([C@@H]4CCCN4C(=O)[C@@H](NC(=O)OC)C(C)C)n3)cc2)cc1)C(C)C
Reactant: C1COCCO1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Product: COC(=O)N[C@H](C(=O)N1CC2(CCOCC2)CC1c1nc(-c2ccc(-c3ccc(-c4c[nH]c([C@@H]5CCCN5C(=O)[C@@H](NC(=O)OC)C(C)C)n4)cc3)cc2)c[nH]1)C(C)C
Temperature: 110 °C
Yield: 34 %

Procedure:
A solution of methyl((1S)-2-methyl-1-{[(2S)-2-(4-{4′-[({[2-((2S)-3-methyl-2-{[(methyloxy)carbonyl]amino}butanoyl)-8-oxa-2-azaspiro[4.5]dec-3-yl]carbonyl}amino)acetyl]-4-biphenylyl}-1H-imidazol-2-yl)-1-pyrrolidinyl]carbonyl}propyl)carbamate (Intermediate 104) (131 mg, 0.16 mmol) and ammonium acetate (122 mg, 1.6 mmol) in dioxane (2 mL) was degassed and heated to 110° C. in a sealed tube for 18 h. The reaction was cooled to room temperature and diluted with ethyl acetate and filtered and concentrated in vacuo. The residue was purified by C18 RP chromatography eluting with 10-90% water/acetonitrile/0.2% NH4OH, to afford an off-white solid (44 mg, 34% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.55-7.87 (m, 8H) 7.32 (br. s., 4H) 5.02-5.23 (m, 3H) 4.13-4.34 (m, 4H) 3.93-4.04 (m, 1H) 3.88 (br. s., 2H) 3.49-3.84 (m, 8H) 1.86-2.54 (m, 10H) 1.45-1.84 (m, 4H) 0.69-1.12 (m, 12H). HRMS for C44H57N8O7 (M+H)+ calc: 809.4350. found: 809.4346. Purity (LC-MS): 96%.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=1[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1.[CH:17]1[CH:18]=[CH:19][N:20]2[CH2:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[NH:23][CH2:22][C:21]=12>>[CH:17]1[CH:18]=[CH:19][N:20]2[CH2:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[N:23]([C:12]([C:11]3[CH:10]=[CH:9][C:8]([C:3]4[CH2:4][CH2:5][CH2:6][CH2:7][C:2]=4[CH3:1])=[CH:16][CH:15]=3)=[O:14])[CH2:22][C:21]=12
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: CC1=C(c2ccc(C(=O)O)cc2)CCCC1
Product: CC1=C(c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)CCCC1
Yield: 91.9 %

Procedure:
4-(2-Methyl-cyclohex-1-en-1-yl)-benzoic acid of Step C (0.720 g, 3.33 mmol) and 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.674 g, 3.66 mmol) were reacted according to the procedure of Example 1, Step D. The title compound was purified by recrystallization from petroleum ether to afford white crystals (1.17 g), m.p. 119-120° C.