Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10](=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:15]1([C:20]2[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=2)[CH:19]=[CH:18][N:17]=[CH:16]1.[BH3-]C#N.[Na+].O>C(O)C.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[N:15]1([C:20]2[CH:26]=[CH:25][C:23]([NH:24][CH:10]3[CH2:11][CH2:12][CH2:13][N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH2:9]3)=[CH:22][CH:21]=2)[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: Nc1ccc(-n2ccnc2)cc1
Reactant: O=C1CCCN(Cc2ccccc2)C1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: c1ccc(CN2CCCC(Nc3ccc(-n4ccnc4)cc3)C2)cc1
Reaction time: 20 h
Yield: 17.1 %

Procedure:
1-Benzyl-3-piperidinone (2.07 g, 10 mmol), 4-(imidazol-1-yl)aniline (1.73 g, 1.0 eq.), and Ti(OiPr)4 (3.72 mL, 1.25 eq.) were stirred at ambient temperature for 1.25 hours. The mixture was then diluted with absolute ethanol (10 mL) and NaCNBH3 (0.44 g, 0.67 eq.) was added. The resulting mixture was stirred for 20 hours. Water (2 mL) was added to the mixture with stirring and the resulting precipitate was filtered. Flash column chromatography on silical gel with 1-5% methanol in methylene chloride gave a crude product. Further purification by HPLC afforded 3-[(4-(imidazol-1-yl)phenyl)amino]-1-benzylpiperidine (569 mg), which was dissolved in methanol (10 mL) and treated with 10% Pd/C (400 mg) and ammonium formate (800 mg). The resulting mixture was heated at reflux for 4 hours. After cooling to ambient temperature, the mixture was filtered. Evaporation of the solvent in vacuo gave 3-[(4-(imidazol-1-yl)phenyl)amino]piperidine (330 mg, 1.36 mmol).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:21][CH2:22]O.[CH3:24][CH:25]1[CH2:29][CH2:28][CH2:27][NH:26]1>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:21][CH2:22][N:26]1[CH2:27][CH2:28][CH2:29][CH:25]1[CH3:24]
Reactant: CC1CCCN1
Reactant: Cc1oc(-c2ccc(OCc3ccccn3)cc2)nc1CCO
Product: Cc1oc(-c2ccc(OCc3ccccn3)cc2)nc1CCN1CCCC1C

Procedure:
2-(4-{5-Methyl-4-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-oxazol-2-yl}-phenoxymethyl)-pyridine is prepared in a manner substantially similar to Example 53 from 2-{5-Methyl-2-[4-(pyridin-2-ylmethoxy)-phenyl]-oxazol-4-yl}-ethanol and 2-methylpyrrolidine. MS (m/e): 378.3 (M+1)
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5]([Cl:6])=[N:4][C:2]=1Cl.[CH2:10]([NH2:14])[CH2:11][CH2:12][CH3:13].C(=O)([O-])O.[K+].[NH3:20]>O.C(#N)C>[NH2:20][C:8]1[N:1]=[C:2]([NH:14][CH2:10][CH2:11][CH2:12][CH3:13])[N:4]=[C:5]([Cl:6])[N:7]=1
Reactant: CCCCN
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: N
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCCCNc1nc(N)nc(Cl)n1
Temperature: 5 °C
Reaction time: 2 h

Procedure:
To a mixture of 18.5 g (0.1 mol) of cyanuric chloride and 150 mL of acetonitrile was added a mixed solution of 7.3 g (0.1 mol) of n-butylamine and 20 mL of water over 2 hours by keeping the reaction temperature not to exceed 5° C. Thereafter, while maintaining the temperature at 5° C. or lower, a solution of 10.0 g (0.1 mol) of potassium hydrogen carbonate in 40 mL of water was dropwise added over 1 hour, and stirring was continued for additional 2 hours. Subsequently, 15.2 g (0.25 mol) of an aqueous 28% ammonia solution was dropwise added at the same temperature, followed by gradually elevating the temperature and stirring the mixture at 50° C. for 4 hours. Crystals were collected by filtration from the slurry solution thus obtained, washed well with water, and dried to obtain 2-amino-4-n-butylamino-6-chloro-1,3,5-triazine, as intermediate. The total amount of the crystals obtained was suspended in 100 mL of water, to which was added 8.1 g (0.11 mol) of n-butylamine, and allowed to react at a reflux temperature for 2 hours. Thereafter, a solution of 4.0 g (0.1 mol) of sodium hydroxide in 20 mL of water was dropwise added over 1 hour, and allowed to react at a reflux temperature for 2 hours. The reaction mixture was cooled and 100 mL of toluene was added thereto to extract the product, which was then washed 5 times with 80 mL of water. The solvent was distilled off from the organic layer thus obtained under reduced pressure to obtain 27.0 g (yield 92%) of the titled compound. Melting point: 73° C.
Reaction SMILES: C[O:2]C1C=C(OC2C=CC(O)=CC=2)C2CC(C3C=CC(OC)=CC=3)CCC=2C=1.Cl.ClCCN1CCCCC1.CO[C:41]1[CH:42]=[C:43]([O:59][C:60]2[CH:74]=[CH:73][C:63]([O:64][CH2:65][CH2:66][N:67]3[CH2:72][CH2:71][CH2:70][CH2:69][CH2:68]3)=[CH:62][CH:61]=2)[C:44]2[CH2:45][CH:46]([C:51]3[CH:56]=[CH:55][C:54]([O:57]C)=[CH:53][CH:52]=3)[CH2:47][CH2:48][C:49]=2[CH:50]=1>>[OH:57][C:54]1[CH:53]=[CH:52][C:51]([CH:46]2[CH2:47][CH2:48][C:49]3[C:50]([OH:2])=[CH:41][CH:42]=[C:43]([O:59][C:60]4[CH:61]=[CH:62][C:63]([O:64][CH2:65][CH2:66][N:67]5[CH2:72][CH2:71][CH2:70][CH2:69][CH2:68]5)=[CH:73][CH:74]=4)[C:44]=3[CH2:45]2)=[CH:56][CH:55]=1
Reactant: COc1ccc(C2CCc3cc(OC)cc(Oc4ccc(O)cc4)c3C2)cc1
Reactant: COc1ccc(C2CCc3cc(OC)cc(Oc4ccc(OCCN5CCCCC5)cc4)c3C2)cc1
Agent: Cl
Agent: ClCCN1CCCCC1
Product: Oc1ccc(C2CCc3c(O)ccc(Oc4ccc(OCCN5CCCCC5)cc4)c3C2)cc1

Procedure:
Synthesized from 4-[3-methoxy-7-(4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-1-yloxy]phenol and 1-(2-chloroethyl)piperidine hydrochloride according to an analogous synthetic method to Preparation Example 40, 1-{2-{4-[3-methoxy-7-(4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-1-yloxy]phenoxy}ethyl}piperidine (180 mg) was used according to an analogous synthetic method to Example 779 described below to provide the title compound (104 mg).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][C:3]#[CH:4].[O:6]1[CH:11]=[CH:10][CH2:9][CH2:8][CH2:7]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>ClCCl>[CH2:1]([O:5][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][O:6]1)[CH2:2][C:3]#[CH:4]
Reactant: C1=COCCC1
Reactant: C#CCCO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: ClCCl
Product: C#CCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 96 h
Yield: 97.8 %

Procedure:
A solution of but-3-yn-1-ol (10.00 g, 143 mmol) in dichloromethane (310 mL) was treated with dihyropyran (18.10 g, 215 mmol) and pyridinium p-toluene sulfonate (3.60 g, 14.30 mmol). The reaction mixture was stirred at room temperature for 4 days. Water was added and the layers were partitioned. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The crude material was purified by flash chromatography on silica gel using 1:1 ethyl acetate: heptane to give 21.57 g (98%) of the title compound. 1H NMR (CDCl3, 400 MHz) δ 4.65 (m, 1H), 3.90-3.80 (m, 2H), 3.60-3.50 (m, 2H), 2.50-2.45 (m, 2H), 1.95 (m, 1H), 1.90-1.80 (m, 1H), 1.79-1.10 (m, 1H), 1.65-1.50 (m, 4H).
Reaction SMILES: [Br-].[CH:2]1([C:8]2([CH2:13][CH2:14][P+:15]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][CH2:11][CH2:10][O:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH:34]1(C2(CC[Br:47])OCCO2)CCCCC1>>[Br-:47].[C:7]1([CH2:2][C:8]2([CH2:13][CH2:14][P+:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[O:9][CH2:10][CH2:11][O:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:34]=1
Reactant: c1ccc([P+](CCC2(C3CCCCC3)OCCO2)(c2ccccc2)c2ccccc2)cc1
Reactant: BrCCC1(C2CCCCC2)OCCO1
Agent: [Br-]
Product: c1ccc(CC2(CC[P+](c3ccccc3)(c3ccccc3)c3ccccc3)OCCO2)cc1

Procedure:
[2-(2-cyclohexyl-1,3-dioxolane-2-yl)ethyl]triphenylphosphonium bromide from 2-cyclohexyl-2-(2-bromoethyl)-1,3-dioxolane (ex. 27): Liq., IR (microcell) ν cm-1 : 2920-2850, 1440-1110;
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=O)(C)(C)C.ClC[C:16](Cl)=[O:17].[CH3:19][O:20][CH2:21][CH2:22][NH2:23]>>[CH3:19][O:20][CH2:21][CH2:22][NH:23][C:16](=[O:17])[CH2:6][N:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COCCN
Reactant: O=C(Cl)CCl
Product: COCCNC(=O)CN1CCNCC1

Procedure:
The title compound was prepared from 1-tert-butyloxycarbonyl-piperazine, chloroacetylchloride and 2-methoxyethylamine in an analogous manner as described in example 21.
Reaction SMILES: BrC1C=CC(S(O[CH2:12][C@@H:13]2[O:27][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[C:21]([CH3:26])[CH:20]=[CH:19]4)(=O)=O)=CC=1.Cl.Cl.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)=[CH:33][CH:32]=1.C(N(CC)C(C)C)(C)C>CS(C)=O.C(=O)(O)[O-].[Na+]>[Cl:30][C:31]1[CH:32]=[CH:33][C:34]([N:37]2[CH2:42][CH2:41][N:40]([CH2:12][C@@H:13]3[O:27][C:17]4=[C:18]5[C:23](=[CH:24][CH:25]=[C:16]4[O:15][CH2:14]3)[N:22]=[C:21]([CH3:26])[CH:20]=[CH:19]5)[CH2:39][CH2:38]2)=[CH:35][CH:36]=1
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](COS(=O)(=O)c1ccc(Br)cc1)O3
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1ccc2c3c(ccc2n1)OC[C@H](CN1CCN(c2ccc(Cl)cc2)CC1)O3
Temperature: 75 °C
Yield: 49.6 %

Procedure:
To a mixture of [(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl 4-bromobenzenesulfonate (577 mg, 1.28 mmol) and 4-chlorophenylpiperazine dihydrochloride (1.03 g, 3.81 mmol) in anhydrous DMSO (10 mL) was added N,N-diisopropylethylamine (1.33 mL, 3.81 mmol). The reaction mixture was heated at 75° C. overnight. The cooled reaction mixture was diluted with saturated aqueous sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. Flash chromatography on silica gel (50% hexanes/EtOAc) afforded 260 mg (15%) of the title compound as a tan solid: MS EI m/z 410.09 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]([C:5]1[N:6]=[CH:7][C:8]([O:11][C:12]2[CH:13]=[C:14]([CH:19]=[C:20]([OH:22])[CH:21]=2)[C:15]([O:17][CH3:18])=[O:16])=[N:9][CH:10]=1)=[O:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:43][C:44]([O:47][CH2:48][C@H:49](O)[CH3:50])([CH3:46])[CH3:45].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:23][N:2]([CH3:1])[C:3]([C:5]1[N:6]=[CH:7][C:8]([O:11][C:12]2[CH:13]=[C:14]([CH:19]=[C:20]([O:22][C@@H:49]([CH3:50])[CH2:48][O:47][C:44]([CH3:46])([CH3:45])[CH3:43])[CH:21]=2)[C:15]([O:17][CH3:18])=[O:16])=[N:9][CH:10]=1)=[O:4]
Reactant: C[C@@H](O)COC(C)(C)C
Reactant: COC(=O)c1cc(O)cc(Oc2cnc(C(=O)N(C)C)cn2)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(Oc2cnc(C(=O)N(C)C)cn2)cc(O[C@@H](C)COC(C)(C)C)c1
Temperature: 0 °C

Procedure:
To methyl 3-[5-(dimethylcarbamoyl)pyrazin-2-yl]oxy-5-hydroxy-benzoate (10 g, 32 mmol) was added triphenylphosphine (10.3 g, 39.4 mmol), THF (100 mL) and (2R)-1-[(2-methylpropan-2-yl)oxy]propan-2-ol (CAS no. 136656-73-0) (5.21 g, 39.4 mmol). The resulting slurry was cooled to 0° C. and diethylazodicarboxylate (50% w/v in toluene, 13.7 mL, 39.4 mmol) was charged dropwise keeping the temperature below 10° C. After 2 hours the solvent was evaporated under reduced pressure and taken up with ethyl acetate (23 mL). A solid crashed out which was filtered and the mother liquors were evaporated under reduced pressure, taken up into ethyl acetate (23 mL) and isohexane (53 mL) and the resulting solid filtered, the mother liquors were evaporated under reduced pressure and the resulting residue was purified by flash chromatography eluting with 80% ethyl acetate/ 20% isohexane to afford the product (13.5 g).
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[OH:12])[CH2:5][CH2:4][CH2:3][CH2:2]1.[BrH:13].CS(C)=O>C(O)(=O)C.O>[Br:13][C:10]1[CH:9]=[CH:8][C:7]([OH:12])=[C:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:11]=1
Reactant: Oc1ccccc1C1CCCC1
Reactant: Br
Solvent: CS(C)=O
Solvent: CC(=O)O
Solvent: O
Product: Oc1ccc(Br)cc1C1CCCC1
Yield: 89.4 %

Procedure:
To a stirring solution of 2-cyclopentyl phenol (7.9 g, 48.7 mmol) in acetic acid (32 mL) and water (16 mL) was added HBr (33% in AcOH, 50.45 mL, 292.2 mmol) followed by the dropwise addition of DMSO (34.8 g, 31.6 mL, 445.0 mmol) over 10 min. The reaction was quenched with saturated aqueous NaHCO3 and concentrated in vacuo to remove gasses. The residue was brought up in ether (200 mL), washed with water (2×100 mL) and brine (100 mL) then dried over Na2SO4. The solution was filtered and concentrated in vacuo to produce an oil which was purified by silica gel chromatography (0-10% ethyl acetate/hexane) to provide 4-bromo-2-cyclopentylphenol (10.5 g, 89% yield) as a colorless oil. 1H NMR (400.0 MHz, DMSO-d6) δ 9.59 (s, 1H), 7.20 (d, J=2.5 Hz, 1H), 7.13 (dd, J=2.5, 8.5 Hz, 1H), 6.73 (d, J=8.5 Hz, 1H), 3.21-3.13 (m, 1H), 1.95-1.88 (m, 2H), 1.77-1.69 (m, 2H), 1.65-1.44 (m, 4H).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[N:12][CH:11]=1)=[O:9].[Br:16][C:17]1[N:22]=[C:21]([C:23](OCC)=[O:24])[CH:20]=[CH:19][CH:18]=1.O>O1CCCC1.C(O)(=O)C>[Br:16][C:17]1[N:22]=[C:21]([C:23](=[O:24])[CH2:7][C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:9])[CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1cccc(Br)n1
Reactant: CC(=O)c1cccnc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: O=C(CC(=O)c1cccc(Br)n1)c1cccnc1
Temperature: 25 °C

Procedure:
3.71 g (33.0 mmol) of potassium tert-butoxide were added to a mixture of 4.00 g (33.0 mmol) of 3-acetopyridine and 7.60 g (33.0 mmol) of ethyl 6-bromo-2-pyridinecarboxylate in 100 ml of tetrahydrofuran. The solution was stirred at room temperature until a solid mixture has formed. 100 ml of water and 10 ml of acetic acid were then added, and the aqueous phase was subsequently extracted with dichloromethane. The combined organic phases were dried over magnesium sulfate, and the solvent was then removed under reduced pressure. The residue that remained was purified chromatographically (mobile phase: cyclohexane/ethyl acetate), the solid was then washed with diethyl ether. This gave 6.91 g (69% of theory) of 1-(6-bromopyridin-2-yl)-3-(pyridin-3-yl)propane-1,3-dione.
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16](/[CH:20]=[CH:21]/[C:22]3[S:23][CH:24]=[C:25]([CH:27]4[CH2:30][CH2:29][CH2:28]4)[N:26]=3)[CH:15]=2)=[O:12])=[CH:6][CH:5]=1.O1CCCCC1.CO.O.[OH-].[Li+]>O>[CH:27]1([C:25]2[N:26]=[C:22](/[CH:21]=[CH:20]/[C:16]3[CH:15]=[C:14]([NH:13][C:11](=[O:12])[CH2:10][C:7]4[CH:6]=[CH:5][C:4]([C:3]([OH:31])=[O:2])=[CH:9][CH:8]=4)[CH:19]=[CH:18][CH:17]=3)[S:23][CH:24]=2)[CH2:28][CH2:29][CH2:30]1
Reactant: COC(=O)c1ccc(CC(=O)Nc2cccc(/C=C/c3nc(C4CCC4)cs3)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOCC1
Solvent: O
Product: O=C(Cc1ccc(C(=O)O)cc1)Nc1cccc(/C=C/c2nc(C3CCC3)cs2)c1
Reaction time: 20 h

Procedure:
A solution composed of 0.5 g of (E)-4-[2-[3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]phenylamino]-2-oxoethyl]benzoic acid methyl ester, 20 ml of tetrahydropyran, 3 ml of methanol, 3 ml of water and 0.35 g of lithium hydroxide monohydrate was allowed to stand at room temperature for 20 hr. The solvents were removed by rotary evaporation and the residual materials were taken up in 30 ml of water. Addition of an excess of acetic acid caused the precipitation of 0.5 g of (E)-4-[2-[3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]phenylamino]-2-oxoethyl]benzoic acid; m.p. 262°-263° C. after recrystallization from 2-propanol.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH2:32][C:33](O)=[O:34])=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.Cl.[NH:37]1[CH2:40][CH2:39][CH2:38]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O.C(N(CC)CC)C>[N:37]1([C:33](=[O:34])[CH2:32][C:29]2[CH:28]=[CH:27][C:26]([C:24]3[NH:25][C:21]([CH:13]([C:10]4[CH:11]=[CH:12][C:7]([S:4]([CH:1]5[CH2:3][CH2:2]5)(=[O:5])=[O:6])=[CH:8][CH:9]=4)[CH2:14][CH:15]4[CH2:16][CH2:17][O:18][CH2:19][CH2:20]4)=[CH:22][CH:23]=3)=[N:31][CH:30]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: C1CNC1
Reactant: O=C(O)Cc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1)N1CCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.3 %

Procedure:
To a solution of [6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridin-3-yl]acetic acid (0.200 g) in N,N-dimethylformamide (5 mL) were added azetidine hydrochloride (57 mg), triethylamine (0.169 mL), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (116 mg) and 1-hydroxybenzotriazole (93 mg), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:methanol=100:0-80:20, volume ratio) and recrystallized from hexane-ethyl acetate to give the title compound (0.115 g, yield 53%) as colorless crystals. MS: 534 (MH+). melting point 94-98° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[N:6][CH:7]=1.[F:9][C:10]1[CH:11]=[C:12]([OH:17])[CH:13]=[CH:14][C:15]=1[F:16].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][C:12]2[CH:13]=[CH:14][C:15]([F:16])=[C:10]([F:9])[CH:11]=2)=[N:6][CH:7]=1
Reactant: Oc1ccc(F)c(F)c1
Reactant: Fc1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: Fc1ccc(Oc2ccc(Br)cn2)cc1F
Temperature: 80 °C
Reaction time: 2 h
Yield: 61.5 %

Procedure:
To a solution of 5-bromo-2-fluoropyridine (19 g, 108 mmol) and 3,4-difluorophenol (14.05 g, 108 mmol) in dimethyl sulfoxide (DMSO) (150 mL) was added potassium carbonate (26.9 g, 194 mmol). The reaction mixture was stirred at 80° C. for 2 hr, then H2O (200 ml) and EtOAc (200 ml) were added. The organic layer was separated, and then concentrated under reduced pressure. The crude product was purified by a silica gel chromatography eluting with Hex/EtOAc (10:1) to provide 5-bromo-2-(3,4-difluorophenoxy)pyridine (19 g, 55.4%).
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH:5]([CH3:7])[CH3:6].I(C1C=CC=CC=1C(O)=O)(=O)=O.O>CS(C)=O>[CH3:6][CH:5]([CH3:7])[CH2:4][CH:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:2]=[O:1]
Reactant: CC(C)CC(CO)NC(=O)OC(C)(C)C
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: CS(C)=O
Solvent: O
Product: CC(C)CC(C=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl (1-hydroxy-4-methylpentan-2-yl)carbamate (2.7 g) in DMSO (60 mL) was added 2-iodoxybenzoic acid (3.5 g), and the mixture was stirred at room temperature for 3 hr. Water was added thereto, the resulting insoluble matter was filtered off, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. After the dessicant was filtered off, the filtrate was concentrated under reduced pressure to afford a crude product of tert-butyl (4-methyl-1-oxopentan-2-yl)carbamate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3[N:24]2[CH2:37][CH2:36][C:27]3([N:31]([CH:32]([CH3:34])[CH3:33])[CH2:30][NH:29][C:28]3=[O:35])[CH2:26][CH2:25]2)=[CH:4][CH:3]=1.[CH3:38]I.[H-].[Na+]>O1CCCC1.CN(C)C=O>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3[N:24]2[CH2:37][CH2:36][C:27]3([N:31]([CH:32]([CH3:33])[CH3:34])[CH2:30][N:29]([CH3:38])[C:28]3=[O:35])[CH2:26][CH2:25]2)=[CH:6][CH:7]=1
Reactant: CC(C)N1CNC(=O)C12CCN(c1ncnc3c1nc(-c1ccccc1Cl)n3-c1ccc(Cl)cc1)CC2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)N1CN(C)C(=O)C12CCN(c1ncnc3c1nc(-c1ccccc1Cl)n3-c1ccc(Cl)cc1)CC2
Product: Cl
Reaction time: 2 h

Procedure:
A suspension of 8-[9-(4-chlorophenyl)-8-(2-chlorophenyl)-9H-purin-6-yl]-1-isopropyl-1,3,8-triazaspiro[4.5]decan-4-one 13A-1 (86 mg, 0.16 mmol) and methyl iodide (2 M in MTBE, 16 μl) in 1:1 tetrahydrofuran/dimethylformamide (2 ml) was treated with sodium hydride (60% dispersion in oil, 12 mg, 0.3 mmol). After stirring for 2 hours, the mixture was extracted from saturated aqueous sodium bicarbonate with ethyl acetate, dried (Na2SO4), concentrated (123 mg), and then purified by flash chromatography using 4% methanol to give title compound 25A-1 as an oil (87 mg, quantitative). A methylene chloride solution of the material was treated with excess 1 M HCl in ether, concentrated under a stream of nitrogen, and then triturated from ether to give the hydrochloride salt of compound 25A-1 (82 mg, 82% overall) as a colorless solid: +ESI MS (M+1) 550.2; 1H NMR (400 MHz, CD3OD) δ 8.34 (s, 1H), 7.60 (d, J=7.9 Hz, 1H), 7.51–7.39 (m, 5H), 7.31 (d, J=8.3 Hz, 2H), 4.76 (s, 2H), 4.14 (brs, 2H), 3.78 (brs, 1H), 2.96 (s, 3H), 2.28 (br s, 4H), 1.32 (d, J=6.2 Hz, 6H).
Reaction SMILES: [CH:1]1([C:4]([OH:6])=O)[CH2:3][CH2:2]1.Cl.CN(C)CCCN=C=NCC.[O:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[N:25]1[C:33]2[C:28](=[CH:29][C:30]([C:34]3[N:38]=[CH:37][N:36]([C:39]([C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[N:35]=3)=[CH:31][CH:32]=2)[C:27]([C:58]2[CH:59]=[C:60]([NH2:64])[CH:61]=[CH:62][CH:63]=2)=[N:26]1>ClCCl>[CH:1]1([C:4]([NH:64][C:60]2[CH:61]=[CH:62][CH:63]=[C:58]([C:27]3[C:28]4[C:33](=[CH:32][CH:31]=[C:30]([C:34]5[N:38]=[CH:37][N:36]([C:39]([C:40]6[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=6)([C:46]6[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=6)[C:52]6[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=6)[N:35]=5)[CH:29]=4)[N:25]([CH:20]4[CH2:21][CH2:22][CH2:23][CH2:24][O:19]4)[N:26]=3)[CH:59]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: O=C(O)C1CC1
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1)C1CC1

Procedure:
To a solution of cyclopropanecarboxylic acid (0.024 g, 0.274 mmol) in 2.5 mL of dichloromethane was added 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDCI) (0.057 g, 0.298 mmol). The reaction was stirred at room temperature for 10 min before 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.150 g, 0.248 mmol), dissolved in 1 mL of dichloromethane was added to the solution. The reaction was stirred at room temperature for 2 days while 2 additions of one equivalent of reagents were necessary. The reaction mixture was then partitioned between water and dichloromethane. The crude material that was obtained from evaporation of the extracts was not purified further. (Yield not calculated) ES-MS (m/z) 672 [M+2H]+.