Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2](=[N:8][NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>C1C=CC=CC=1>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([N:9]2[CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:17][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N:8]2)=[CH:11][CH:12]=1
Reactant: CCOC(=O)C(Cl)=NNc1ccc(Cl)cc1
Reactant: C=Cc1ccccc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=NN(c2ccc(Cl)cc2)C(c2ccccc2)C1
Temperature: 25 °C
Yield: 94 %

Procedure:
Part B: To a stirred boiling solution of ethyl 2-chloro[(4-chlorophenyl) hydrazono]acetate (22.95 gram, 0.088 mol) and styrene (30.3 ml, 0.264 mol) in benzene (140 ml) is added triethylamine (34.3 ml, 0.247 mol) and the resulting solution is heated at reflux temperature for 1 hour. The resulting solution is cooled to room temperature and the formed precipitate is removed by filtration and washed with toluene. The filtrate is concentrated in vacuo and purified by flash chromatography (silica gel, dichloromethane) to give ethyl 1-(4-chlorophenyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxylate (27.2 gram, 94% yield) as a syrup which slowly solidifies on standing. 1H-NMR (200 MHz, CDCl3): 1.38 (t, J=7 Hz, 3H), 3.06 (dd, J=18 and 7 Hz, 1H), 3.73 (dd, J=18 and 13 Hz, 1H), 4.33 (q, J=7 Hz, 2H), 5.38 (dd, J=13 and 7 Hz, 1H), 7.02 (br d, J=8 Hz, 2H), 7.08-7.40 (m, 7H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([OH:16])=O)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.S(Cl)(Cl)=O.[NH2:28][C:29]1[CH:44]=[CH:43][C:32]([O:33][C:34]2[CH:39]=[CH:38][N:37]=[C:36]([C:40]([NH2:42])=[O:41])[CH:35]=2)=[C:31]([F:45])[CH:30]=1>O1CCCC1>[F:45][C:31]1[CH:30]=[C:29]([NH:28][C:14]([C:11]2([C:9](=[O:10])[NH:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:12][CH2:13]2)=[O:16])[CH:44]=[CH:43][C:32]=1[O:33][C:34]1[CH:39]=[CH:38][N:37]=[C:36]([C:40]([NH2:42])=[O:41])[CH:35]=1
Reactant: NC(=O)c1cc(Oc2ccc(N)cc2F)ccn1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NC(=O)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41.2 %

Procedure:
To a solution of 1-(4-fluorophenylaminocarbonyl)cyclopropanecarboxylic acid (5.58 g) in tetrahydrofuran (60 ml) was added dropwise triethylamine (4.18 ml) while cooling in an ice water bath under a nitrogen atmosphere, followed by stirring for 15 min. To the reaction mixture, was then added thionyl chloride (2.0 ml), followed by stirring at the same temperature for 60 min. To the reaction mixture was added a suspension of 4-(4-amino-2-fluorophenoxy)pyridine-2-carboxamide (4.945 g) and triethylamine (4.18 ml) in tetrahydrofuran (50 ml) while cooling in an ice water bath under a nitrogen atmosphere, followed by stirring for 2 hr. The reaction was allowed to warm up to room temperature, followed by stirring overnight. The reaction mixture was partitioned after addition of ethyl acetate (100 ml) and a 1N aqueous solution of sodium hydroxide (100 ml). The organic layer was washed with a 2N aqueous solution of sodium hydroxide (100 ml, 3 times), 1N hydrochloric acid (100 ml, twice) and brine (100 ml) in this order, and dried over anhydrous sodium sulfate. The organic layer was filtered and the filtrate was concentrated under reduced pressure. To the resultant residue (8.3 g) were added ethyl acetate (20 ml) and heptane (5 ml) to precipitate a solid. After diluting with addition of ethyl acetate (20 ml), the solid was collected by filtration with suction, washed with ethyl acetate-heptane (16 ml-2 ml). Drying under aeration with suction on a paper filter provided the titled compound as pale brown powder (3.73 g, 41%). The filtrate was concentrated under reduced pressure, and ethyl acetate (20 ml) and heptane (4 ml) were again added to the residue (3.6 g) to precipitate a solid. The solid was collected by filtration with suction. Drying under aeration with suction on a paper filter provided the titled compound as pale brown powder (216 mg, 2.4%). The filtrate was further concentrated under reduced pressure, and the residue (3.06 g) was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate). Fractions containing the target compound were concentrated under reduced pressure to provide the titled compound as pale brown powder (885 mg, 9.8%).
Reaction SMILES: [C:1]([C:5]1[C:6]([OH:17])=[C:7]([CH3:16])[C:8]([CH3:15])=[C:9]([CH2:11][C:12]([OH:14])=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:19]O>>[C:1]([C:5]1[C:6]([OH:17])=[C:7]([CH3:16])[C:8]([CH3:15])=[C:9]([CH2:11][C:12]([O:14][CH3:19])=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CO
Reactant: Cc1c(CC(=O)O)cc(C(C)(C)C)c(O)c1C
Agent: Cl
Product: COC(=O)Cc1cc(C(C)(C)C)c(O)c(C)c1C
Temperature: 68 °C

Procedure:
11.8 grams of 5-tert.-butyl-2,3-dimethyl-4-hydroxyphenylacetic acid was added at 20° C. to 200 ml of methanol previously saturated with hydrogen chloride gas. The slightly pinkish solution was heated at reflux (68° C.) for 3 hours after which about one-half of the solvent was removed at reduced pressures and the reaction mixture then poured into about 500 ml of an ice-water mixture with stirring until all the ice had melted. The precipitated crystals were filtered, washed with water and dissolved in benzene. The benzene solution was successively washed with water, saturated sodium bicarbonate solution and finally with water to pH 7, the benzene solution being dried over anhydrous sodium sulfate. The clear benzene solution, freed of drying agent by filtration, was concentrated at reduced pressure. The resulting solid residue was triturated with hexane to remove color bodies. After recrystallization from methanol, the desired product was obtained as white crystals melting at 117° to 119° C. (Compound 14).
Reaction SMILES: [CH2:1]=[O:2].[N+:3]([CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:11][CH:10]=1)([O-:5])=[O:4].[CH2:24]([OH:26])C>>[OH:2][CH2:1][C:6]([CH2:24][OH:26])([N+:3]([O-:5])=[O:4])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15](=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:13][CH:14]=1
Reactant: CCO
Reactant: C=O
Reactant: CCCCCCCC(=O)c1ccc(CCC[N+](=O)[O-])cc1
Product: CCCCCCCC(=O)c1ccc(CCC(CO)(CO)[N+](=O)[O-])cc1

Procedure:
Compound (18) was prepared by Henry addition of formaldehyde (37% aqueous solution) to 1-(4-(3-nitropropyl)phenyl)octan-1-one (17) in ethanol, in the presence of strongly basic anion exchange resin Amberlite IRA-401(0H-), according to the procedure described by Astle and Abbot [J. Org. Chem. 21, 1228 (1956)]. The yield of the desired product was 65%.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH:29]=[CH:28][N:27]([CH3:30])[C:26]4=[O:31])=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1.O.[OH-].[NH4+]>ClCCl.CO>[OH:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:14][CH2:15][N:16]([C:19]3[CH:20]=[CH:21][C:22]([N:25]4[CH:29]=[CH:28][N:27]([CH3:30])[C:26]4=[O:31])=[CH:23][CH:24]=3)[CH2:17][CH2:18]2)=[CH:11][CH:12]=1
Reactant: COc1ccc(N2CCN(c3ccc(-n4ccn(C)c4=O)cc3)CC2)cc1
Agent: BrB(Br)Br
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: Cn1ccn(-c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)c1=O
Reaction time: 120 h
Yield: 68.5 %

Procedure:
To a stirred and cooled (ice-bath) amount of 200 ml of a boron tribromide solution in dichloromethane 1M was added dropwise a solution of 14.6 parts of 1,3-dihydro-1-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-3-methyl-2H-imidazol-2-one in 665 parts of dichloromethane. Stirring was continued for 5 days at room temperature and then the reaction mixture was poured into a mixture of 200 parts of water, 158 parts of methanol and 180 parts of ammonium hydroxide. After stirring for 1 hour, the precipitate was filtered off, washed with dichloromethane and water and dried (=first fraction of product). The organic layer of the filtrate was separated and evaporated. The residue was triturated in dichloromethane. The solid was filtered off and dried (=second fraction). The two fractions were combined and crystallized from N,N-dimethylformamide, yielding 9.6 parts (68.5%) of 1,3-dihydro-1-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-3-methyl-2H-imidazol-2-one; mp. 283.1° C. (interm. 14).
Reaction SMILES: C(OC([NH:8][C@:9]1([C:14]([NH:16][S:17]([CH:20]2[CH2:22][CH2:21]2)(=[O:19])=[O:18])=[O:15])[CH2:11][C@H:10]1[CH:12]=[CH2:13])=O)(C)(C)C.[Cl:23]CCl>C(O)(C(F)(F)F)=O>[ClH:23].[NH2:8][C@:9]1([C:14]([NH:16][S:17]([CH:20]2[CH2:22][CH2:21]2)(=[O:19])=[O:18])=[O:15])[CH2:11][C@H:10]1[CH:12]=[CH2:13]
Reactant: ClCCl
Reactant: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)NS(=O)(=O)C1CC1
Solvent: O=C(O)C(F)(F)F
Product: C=C[C@@H]1C[C@]1(N)C(=O)NS(=O)(=O)C1CC1
Product: Cl

Procedure:
A solution of the product of Step 2 (3.5 g, 10.6 mmol) in dichloromethane (35 mL) and TFA (32 mL) was stirred at room temperature for 1.5 hours. The volatiles were removed in vacuo and the residue was suspended in 1N HCl in diethyl ether (20 mL) and concentrated in vacuo. This procedure was repeated once. The resulting mixture was triturated from pentane and filtered to provide the desired product as a hygroscopic, off-white solid (2.60 g, 92%). 1H NMR: (DMSO-d6) δ 1.01-1.15 (m, 4H), 1.69-1.73 (m, 1H), 1.99-2.02 (m, 1H), 2.38 (q, J=9 Hz, 1H), 2.92-2.97 (m, 1H), 5.20 (d, J=11 Hz, 1H), 5.33 (d, J=17 Hz, 1H), 5.52-5.59 (m, 1H), 9.17 (br s, 3H) LC-MS (retention time: 0.24 minutes, method B), MS m/z 231 (M++H).
Reaction SMILES: C[Mg]Br.[CH2:4](OCC)C.[C:9]1([CH:19]=[O:20])[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[CH:12]=[CH:11][N:10]=1>O1CCCC1>[OH:20][CH:19]([C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[CH:12]=[CH:11][N:10]=1)[CH3:4]
Reactant: O=Cc1nccc2c1CCCC2
Reactant: CCOCC
Agent: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)c1nccc2c1CCCC2
Temperature: 25 °C
Yield: 87.4 %

Procedure:
Methylmagnesium bromide in diethyl ether (9.3 ml, 28 mmole) is dissolved in 10 ml tetrahydrofuran at 0° C. in an oven dried 100 ml two neck round bottom flask under nitrogen. The solution is treated with 5,6,7,8,-Tetrahydroisoquinoline-1-carbaldehyde (3.61 g, 22.4 mmole) followed by 10 ml diethyl ether. The reaction mixture is warmed to room temperature and then to reflux for 1 h. The mixture is cooled, is quenched with 20 ml 10% hydrochloric acid, and the pH is adjusted to 9 with 2N sodium hydroxide. The layers are separated, the aqueous layer is washed with 4×50 ml dichloromethane, and the combined organics are dried over potassium carbonate. The dried organics are concentrated in vacuo to give 3.47 g (87%) of 1-(1-hydroxyethyl)-5,6,7,8-tetrahydroisoquinoline.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:13][C:14]2[CH:18]=[C:17]([CH3:19])[NH:16][N:15]=2)[N:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.C([O-])([O-])=O.[Na+].[Na+].CN(C)C=O>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.O>[CH3:20][O:21][C:22]1[CH:27]=[C:26]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:13][C:14]3[CH:18]=[C:17]([CH3:19])[NH:16][N:15]=3)[N:3]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: Cc1cc(Nc2cc3cc(O)ccc3c(Br)n2)n[nH]1
Reactant: COc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(-c2nc(Nc3cc(C)[nH]n3)cc3cc(O)ccc23)c1
Temperature: 180 °C
Yield: 55.3 %

Procedure:
The mixture of 1-Bromo-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-ol (300 mg), 3-methoxy-phenylboronic acid (318 mg), Na2CO3 (400 mg), Tetrakis(triphenylphosphine)palladium(0) (100 mg), N,N-dimethylformamide (DMF) (2 ml) and water (2 ml) was heated at 180° C. for 30 minutes under microwave irradiation. After reaction finished, the mixture was sent to preparative LC-MS and 1-(3-methoxy-phenyl)-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-ol (180 mg) was produced as a solid. LC-MS m/e 347(MH+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:5](Br)=[C:4](Cl)[N:3]=1.C(N(CC)CC)C.[H][H]>[Pd].C(OCC)(=O)C.CO>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:16])([CH3:15])[CH3:17])[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)NCCNc1nc(N)nc(Cl)c1Br
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)NCCNc1ccnc(N)n1

Procedure:
A solution of tert-butyl 2-(2-amino-5-bromo-6-chloropyrimidin-4-ylamino)ethylcarbamate (Example 1A, 18.60 g, 0.0507 mole), triethylamine (135.0 mL, 0.9686 mole), and 10% palladium on charcoal (7.40 g) in 1:1 ethyl acetate/methanol (500 mL) was treated with hydrogen (60 psi) for two days. Insoluble material was removed by filtration through a pad of diatomaceous earth and the filtrate was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and dilute aqueous sodium hydroxide. The organic layer was dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to give tert-butyl 2-(2-aminopyrimidin-4-ylamino)ethylcarbamate as a white, amorphous solid (12.7 g, 98.8% yield). 1H NMR (300 MHz, CD3Cl3) δ ppm 1.44 (s, 9H), 3.27-3.37 (m, 2H), 3.37-3.47 (m, 2H), 5.00 (sbr, 2H), 5.28 (sbr, 1H), 5.52 (sbr, 1H), 5.78 (d, J=6 Hz, 1H), 7.76 (d, J=6 Hz, 1H). MS (DCl—NH3) m/z=254 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[C:6]([Cl:9])[C:7]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].[F:22][C:23]([F:27])([F:26])[CH2:24]I>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[C:6]([Cl:9])[C:7]=1[O:8][CH2:24][C:23]([F:27])([F:26])[F:22]
Reactant: FC(F)(F)CI
Reactant: CCOC(=O)Cc1cc(Cl)c(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cc(Cl)c(OCC(F)(F)F)c(Br)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 29.4 %

Procedure:
To a stirred solution of ethyl 2-(3-bromo-5-chloro-4-hydroxyphenyl)acetate (2 g, 6.8 mmol), potassium carbonate (2.35 g, 17.0 mmol) in dry DMF (20 mL), was slowly added trifluoro ethyl iodide (8.58 g, 4.0 mL, 40.8 mmol) at room temperature, the reaction mixture was slowly heated to 100° C. and heating was continued for 4 h. Upon which the reaction mixture was poured onto water and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with water, dried over Na2SO4 and evaporated under reduced pressure. Purification by column chromatography over silica gel (hexane/EtOAc) to gave compound ethyl 2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-acetate (0.750 g, 30% yield). 1HNMR (CDCl3, 400 MHz): 7.43 (s, 1H); 7.34 (s, 1H); 4.4 (q, 2H), 4.13 (q, 2H); 3.55 (t, 1H); 1.93 (m, 1H), 1.58 (m, 1H); 1.45 (m, 1H); 1.24 (t, 3H), 0.92 (d, 6H);
Reaction SMILES: [C:1]12([CH2:11][OH:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[H-].[Na+].Cl[CH2:16][C:17]([OH:19])=[O:18].O>CN(C=O)C>[C:1]12([CH2:11][O:12][CH2:16][C:17]([OH:19])=[O:18])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: O=C(O)CCl
Reactant: OCC12CC3CC(CC(C3)C1)C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)COCC12CC3CC(CC(C3)C1)C2
Temperature: 80 °C
Yield: 38.4 %

Procedure:
A solution of 1-adamantanemethanol (3.11 g, 18.7 mmol) in dry DMF (50 ml) was added to a suspension of sodium hydride (60% dispersion in oil, 1.55 g, 38.6 mmol) in DMF (20 ml). The mixture was warmed to 80° C. for 1 h, cooled to room temperature and a solution of chloroacetic acid (1.86 g, 19.6 mmol) in DMF (25 ml) was added dropwise. The mixture was heated at 80° C. for 17 h. On cooling, the mixture was poured into water (100 ml), extracted with ethyl acetate (2×80 ml), and the extracts were washed with 5%KHSO4 (150 ml), brine (150 ml) and dried (MgSO4). Filtration and evaporation of the solvent gave a white solid which was washed with diethyl ether and water, isolated by filtration and dried in vacuo at 50° C. The product was obtained as a white fluffy solid (1.61 g, 38%). 1H NMR (300 MHz, CDCl3) 4.08 (2H, s), 3.14 (2H, s), 2.00 (3H, br s), 1.70 (6H, q), 1.57 (6H, br s).
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([NH2:10])[CH2:3]2.[N:11]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[C:12]=[O:13]>CN(C=O)C.C(N(CC)CC)C>[CH2:14]([NH:11][C:12]([NH:10][CH:4]1[CH:5]2[CH2:8][CH2:9][N:2]([CH2:7][CH2:6]2)[CH2:3]1)=[O:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NC1CN2CCC1CC2
Reactant: O=C=NCc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCc1ccccc1)NC1CN2CCC1CC2
Yield: 548.3 %

Procedure:
To a stirred solution of quinuclidin-3-amine hydrochloride (324 mg, 0.199 mmol) in DMF (30 ml) was added triethylamine (3 drops) followed by (isocyanatomethyl)benzene (275 mg, 2.10 mmol) carefully. The resultant mixture was stirred at 25° C. for 18 h. After HPLC separation, 1-benzyl-3-(quinuclidin-3-yl)urea (283 mg, 55%) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4](O)=[O:5].C(O)(=O)C.[O:16]([C:18]#[N:19])[Na].[OH-].[Na+]>O>[Cl:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[NH:1][C:18](=[O:16])[NH:19][C:4]2=[O:5]
Reactant: Nc1ccc(Cl)cc1C(=O)O
Reactant: N#CO[Na]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]c(=O)c2cc(Cl)ccc2[nH]1
Temperature: 30 °C
Reaction time: 0.5 h

Procedure:
Into a 500-mL 3-necked round-bottom flask, was placed a solution of 2-amino-5-chlorobenzoic acid (10 g, 58.48 mmol, 1.00 equiv) in water (100 mL), acetic acid (8 g, 133.33 mmol, 2.24 equiv). This was followed by the addition of NaOCN (8.2 g, 126.15 mmol, 2.13 equiv). The mixture was stirred for 30 mins at 30° C. To this was added sodium hydroxide (86 g, 2.15 mol, 37.00 equiv). The resulting solution was stirred overnight at 30° C. The solids were collected by filtration. The residue was dissolved in water. The pH value of the solution was adjusted to 7 with hydrogen chloride (12 mol/L). The solids were collected by filtration. This resulted in 5 g (44%) of 6-chloroquinazoline-2,4(1H,3H)-dione as a white solid.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:10][C:11]2[CH:22]=[CH:21][C:14]3[N:15]=[C:16](S(C)=O)[O:17][C:13]=3[CH:12]=2)[CH:2]=1.[NH2:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]1[OH:30].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:10][C:11]2[CH:22]=[CH:21][C:14]3[N:15]=[C:16]([NH:23][C@@H:24]4[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]4[OH:30])[O:17][C:13]=3[CH:12]=2)[CH:2]=1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: CS(=O)c1nc2ccc(Cn3cnc4cccnc43)cc2o1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cccnc43)cc2o1
Temperature: 100 °C
Yield: 22.8 %

Procedure:
A stirred mixture of 6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]oxazole (165 mg, 0.53 mmol) from Step 5 of this Example, (1R,2R)-(−)-2-aminocyclohexanol (122 mg, 1.06 mmol), and DIEA (137 mg, 1.06 mmol) in anhydrous DMA (3 mL) was sealed and heated at 100° C. for 15 h. The reaction mixture was cooled to rt and purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HOAc), CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the stationary phase to afford (1R,2R)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]oxazol-2-yl)amino)cyclohexanol (44 mg, 23%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.60 (s, 1H), 8.39 (dd, J=1.1, 4.7 Hz, 1H), 8.08 (dd, J=1.2, 8.0 Hz, 1H), 7.81 (d, J=7.5 Hz, 1H), 7.40 (s, 1H), 7.29 (dd, J=4.7, 8.1 Hz, 1H), 7.10-7.19 (m, 2H), 5.50 (s, 2H), 4.70 (br s, 1H), 3.25-3.45 (m, 2H), 1.83-1.97 (m, 2H), 1.57-1.67 (m, 2H), 1.14-1.32 (m, 4H). LCMS (ESI) m/z 364 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Mg]Br.[CH2:11]([N:18]1[CH2:26][CH:25]2[CH:20]([CH2:21][CH2:22][CH:23]([CH3:28])[C:24]2=[O:27])[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH2:11]([N:18]1[CH2:26][CH:25]2[CH:20]([CH2:21][CH2:22][CH:23]([CH3:28])[C:24]2([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[OH:27])[CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC1CCC2CN(Cc3ccccc3)CC2C1=O
Reactant: COc1ccccc1[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccccc1C1(O)C(C)CCC2CN(Cc3ccccc3)CC21
Yield: 98.9 %

Procedure:
To a suspension of 2.13 g of 2-methoxyphenylmagnesium bromide in 15 cm3 of tetrahydrofuran is added dropwise, at room temperature and with stirring, a solution of 0.7 g of (3aRS,5RS,7aSR)-2-benzyl-5-methyl-4-perhydroisoindolone in 15 cm3 of tetrahydrofuran. The reaction mixture is stirred at room temperature for 48 hours, treated with 50 cm3 of saturated aqueous ammonium chloride solution, taken up in ethyl acetate and washed with saturated aqueous sodium chloride solution. The organic phase is separated out after settling has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of Merck silica gel (particle size 0.04-0.06 mm, diameter 2 cm, height 15 cm), eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (60/40 by volume) and collecting 25 cm3 fractions. Fractions 10 to 20 are combined and then concentrated to dryness under reduced pressure (2.5 kPa). 1 g of (3aRS,4RS,5RS,7aSR)-2-benzyl-4-(2-methoxyphenyl)-5methyl-4-perhydroisoindolol is obtained in the form of a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.Cl.[NH:13]1[CH2:16][CH2:15][CH2:14]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C.CCOC(C)=O>[N:13]1([C:9](=[O:11])[CH2:8][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[CH2:16][CH2:15][CH2:14]1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: C1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Cc1ccc(Br)cc1)N1CCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 115.9 %

Procedure:
A mixture of (4-bromophenyl)acetic acid (1 g, 4.65 mmol), azetidine hydrochloride (481 mg, 5.12 mmol), HATU (1.95 g, 5.12 mmol) and NMM (1.03 g, 10.23 mmol) in DMF (30 mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with EtOAc and washed with 1N HCl (15 mL×2) and 1M aqueous K2CO3 (15 mL×2). The organic phase was washed with brine, dried over sodium sulfate and concentrated in vacuo to give 1-(azetidin-1-yl)-2-(4-bromophenyl)ethanone (1.37 g) as a solid which was used directly in the next step without purification. 1H NMR (400 MHz, CD3OD) δ 7.47 (d, 2H), 7.197 (d, 2H), 4.26 (t, 2H), 4.01 (t, 2H), δ 3.45 (s, 2H), δ 2.30 (p, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]2[C:13]([O:18][CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[N:14][CH:15]=[CH:16][CH:17]=2)=[C:6]2[C:10]=1[C@@H:9]([OH:11])[CH2:8][CH2:7]2.O[C:25]1[CH:38]=[CH:37][C:28]2[C@H:29]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:30][O:31][C:27]=2[CH:26]=1.BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]2[C:13]([O:18][CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[N:14][CH:15]=[CH:16][CH:17]=2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:25]1[CH:38]=[CH:37][C:28]3[C@H:29]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:30][O:31][C:27]=3[CH:26]=1)[CH2:8][CH2:7]2
Reactant: CC(C)(C)COc1ncccc1-c1ccc(F)c2c1CC[C@@H]2O
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5cccnc5OCC(C)(C)C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from (1S)-7-fluoro-4-(2-(neopentyloxy)pyridin-3-yl)-2,3-dihydro-1H-inden-1-ol and (S)-methyl 2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetate following a procedure analogous to that described in Step 3 of Intermediate 1. LC (method 15): tR=1.32 min.