Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:18][O:17][C@@H:16]([CH2:19][OH:20])[CH2:15][C@H:14]1[CH2:13][S:12][C:11]([NH:21][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[N:10]2.O.C[N+]1([O-])CC[O:35]CC1.CC(O)C>C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[C:22]([NH:21][C:11]1[S:12][CH2:13][C@@H:14]2[CH2:15][C@H:16]([C:19]([OH:35])=[O:20])[O:17][CH2:18][C@:9]2([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[N:10]=1)(=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: O=C(NC1=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](CO)C[C@H]2CS1)c1ccccc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Solvent: CC(C)O
Solvent: CC#N
Solvent: O
Product: O=C(NC1=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](C(=O)O)C[C@H]2CS1)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Tetrapropylammonium perruthenate (1.09 g, 3.10 mmol) was added to a mixture of N-[(4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(hydroxymethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (P1) (13.0 g, 31.1 mmol) and 4-methylmorpholine N-oxide monohydrate (25.2 g, 186 mmol) in acetonitrile (207 mL), and the reaction mixture was stirred for 90 minutes at room temperature. After addition of 2-propanol (100 mL), it was stirred for an additional 2 hours and then concentrated in vacuo. The residue was partitioned between ethyl acetate and 0.5 M aqueous sodium hydroxide solution. The organic layer was extracted twice with 0.5 M aqueous sodium hydroxide solution, and the combined aqueous layers were acidified to a pH of approximately 1 with 2 M aqueous hydrochloric acid, then extracted three times with ethyl acetate. The combined ethyl acetate layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure; the residue was dissolved in dichloromethane, washed with water and with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification via chromatography on silica gel (Gradient: 0% to 20% methanol in dichloromethane) provided the product as a reddish solid. Yield: 12.36 g, 28.58 mmol, 92%. LCMS m/z 433.2 [M+H+]. 1H NMR (400 MHz, CD3OD) δ 8.09-8.13 (m, 2H), 7.52-7.57 (m, 1H), 7.43-7.51 (m, 3H), 7.03-7.11 (m, 2H), 4.35 (dd, J=11.2, 3.4 Hz, 1H), 4.19 (dd, J=12.0, 1.4 Hz, 1H), 3.97 (d, J=12.1 Hz, 1H), 3.20-3.27 (m, 1H), 2.96 (dd, half of ABX pattern, J=13.1, 4.0 Hz, 1H), 2.78 (dd, half of ABX pattern, J=13.2, 2.8 Hz, 1H), 2.03-2.15 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:24]([O:26][CH3:27])=[O:25])=[N:4][C:5]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.N([O-])=O.[Na+].[N-:32]=[N+:33]=[N-].[Na+].C(OCC)C>FC(F)(F)C(O)=O>[N:1]([C:2]1[C:3]([C:24]([O:26][CH3:27])=[O:25])=[N:4][C:5]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[N:6][C:7]=1[C:8]1[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1)=[N+:32]=[N-:33]
Reactant: COC(=O)c1nc(-c2ccc(OC)cc2)nc(-c2ccc(OC)cc2)c1N
Reactant: [N-]=[N+]=[N-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1nc(-c2ccc(OC)cc2)nc(-c2ccc(OC)cc2)c1N=[N+]=[N-]
Reaction time: 0.17 h
Yield: 82.8 %

Procedure:
Methyl 5-amino-2,6-bis(4-methoxyphenyl)pyrimidine-4-carboxylate (393 mg, 1.08 mmol) was dissolved in trifluoroacetic acid (5 mL) and the yellow solution was cooled in an ice bath. Solid sodium nitrite (148 mg, 2.15 mmol) was added with stirring to give a dark red mixture. After 10 minutes, solid sodium azide (699 mg, 10.8 mmol) was added followed by diethyl ether (5 mL). After and additional 20 minutes the reaction was partitioned between EtOAc and sufficient saturated aqueous NaHCO3 solution (gas evolution) to neutralize the acid. The organic phase was separated, washed with brine, dried with sodium sulfate, and the solvent removed to leave methyl 5-azido-2,6-bis(4-methoxyphenyl)pyrimidine-4-carboxylate (350 mg) as a solid. 1H NMR (CDCl3) δ ppm 8.42 (2H, d, J=9.16 Hz), 8.02 (2H, d, J=9.16 Hz), 7.03 (2H, d, J=8.85 Hz), 6.96 (2H, d, J=9.16 Hz), 4.07 (3H, s), 3.88 (3H, s), 3.85 (3H, s).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[C:17]([CH2:18][C:19]([O:21]CC)=[O:20])=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1>C(O)(=O)C.O>[C:1]1([C:7]2[O:8][C:9]3[C:17]([CH2:18][C:19]([OH:21])=[O:20])=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CCOC(=O)Cc1cccc2c(=O)cc(C3=CCCCC3)oc12
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)Cc1cccc2c(=O)cc(C3=CCCCC3)oc12
Reaction time: 4 h
Yield: 68 %

Procedure:
Ethyl [2-(1-cyclohexenyl)-4-oxo-4H-[1]-benzopyran-8-yl]acetate (2.5 g) was dissolved in acetic acid (35 ml) and to the solution was added 50% sulfulic acid (30 ml). The mixture was relfuxed for 4 hours. The reaction mixture was diluted with water and crystals deposited were filtered off and recrystallized from the mixed solvent of ethyl acetate and methanol to obtain the title compound, yield 68%.
Reaction SMILES: [Cl-].[Na+].[Cl:3][S:4]([OH:7])(=O)=[O:5].[CH3:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1>>[Cl:3][S:4]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:9]=1[CH3:8])[C:13]([OH:15])=[O:14])(=[O:7])=[O:5]
Reactant: Cc1ccc(C(=O)O)cc1
Reactant: O=S(=O)(O)Cl
Agent: [Cl-]
Agent: [Na+]
Product: Cc1ccc(C(=O)O)cc1S(=O)(=O)Cl
Temperature: 122 °C

Procedure:
Sodium chloride (8 g, 138 mmol) is added to chlorosulfonic acid (30 mL, 451 mmol) and in small portions 4-methyl-benzoic acid (4 g, 29 mmol) is added to the stirred mixture. After complete addition, the reaction is heated at 122° C. for 16 h. The reaction mixture is cooled and poured into ice-water. The organic material is extracted with ethyl acetate. The organic layer is washed with a saturated sodium chloride solution, dried over magnesium sulfate, filtered, and the solvent is removed in vacuo. The residue is used as is in the next step.
Reaction SMILES: C1(C)C=CC(S([CH2:10][N+:11]#[C-])(=O)=O)=CC=1.CC(C)([O-])C.[K+].[CH3:20][C:21]1[O:25][C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:23][C:22]=1[CH2:32][O:33][C:34]1[CH:52]=[CH:51][C:37]([CH2:38][N:39]2[CH:43]=[C:42]([CH:44]=O)[C:41]([C:46]3[S:47][CH:48]=[CH:49][CH:50]=3)=[N:40]2)=[CH:36][CH:35]=1.[Cl-].[NH4+]>C(COC)OC.CO>[CH3:20][C:21]1[O:25][C:24]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[N:23][C:22]=1[CH2:32][O:33][C:34]1[CH:52]=[CH:51][C:37]([CH2:38][N:39]2[CH:43]=[C:42]([CH2:44][C:10]#[N:11])[C:41]([C:46]3[S:47][CH:48]=[CH:49][CH:50]=3)=[N:40]2)=[CH:36][CH:35]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(C=O)c(-c3cccs3)n2)cc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: COCCOC
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(CC#N)c(-c3cccs3)n2)cc1
Reaction time: 0.08 h
Yield: 82.1 %

Procedure:
A solution of p-toluenesulfonylmethylisocyanide (0.95 g) in dimethoxyethane (10 ml) was added to a mixture of potassium tert-butoxide (1.01 g) and dimethoxyethane (10 ml) at −78° C., and the mixture was stirred for 5 minutes. A solution of 1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-(2-thienyl)-1H-pyrazole-4-carbaldehyde (2.01 g) in dimethoxyethane (20 ml) was added to the mixture, and then stirred at the same temperature for 1 hour, and at room temperature for 1 hour. Methanol (40 ml) was added to the mixture, and reflux was conducted for 1 hour. After cooling, the reaction mixture was poured into saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel chromatography to obtain [1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-(2-thienyl)-1H-pyrazol-4-yl]acetonitrile (1.69 g, yield: 78%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:3, volume ratio).
Reaction SMILES: [C:1]([C:5]1[CH:23]=[C:22]([O:24][SiH:25]([CH3:27])[CH3:26])[C:8]2[N:9]=[C:10]([C:12]3[S:13][C:14]([CH3:21])([CH3:20])[CH:15]([C:17](O)=[O:18])[N:16]=3)[S:11][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:31])=O.CN(C)C=O>C(Cl)Cl>[C:1]([C:5]1[CH:23]=[C:22]([O:24][SiH:25]([CH3:27])[CH3:26])[C:8]2[N:9]=[C:10]([C:12]3[S:13][C:14]([CH3:21])([CH3:20])[CH:15]([C:17]([Cl:31])=[O:18])[N:16]=3)[S:11][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[SiH](C)Oc1cc(C(C)(C)C)cc2sc(C3=NC(C(=O)O)C(C)(C)S3)nc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[SiH](C)Oc1cc(C(C)(C)C)cc2sc(C3=NC(C(=O)Cl)C(C)(C)S3)nc12
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
2-(6-tert.-butyldimethylsilyloxybenzothiazole-2-yl)-4,5-dihydro-5,5-dimethyl-4-thiazole carboxylic acid is dissolved under argon atmosphere in 8 ml dry methylene chloride, the clear solution is cooled to −15° C. and a mixture of 0.162 ml (1,875 mmol) oxalyl chloride and 500 μl of freshly distilled dimethyl formamide are added dropwise to the reaction under vigorous stirring. Slight gas emission can be observed during this step. The reaction mixture is stirred for additional 30 minutes at −15° C. and subsequently diluted with freshly destilled methylene chloride to a final volume of 30 ml.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=O)[CH:10]=1)[NH:7][CH:6]=[CH:5]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:45]([C:49]1[CH:68]=[CH:67][C:52]([CH2:53][NH:54][CH2:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([O:63][CH:64]([F:66])[F:65])[CH:58]=2)=[CH:51][CH:50]=1)([CH3:48])([CH3:47])[CH3:46]>CN(C=O)C.O>[C:45]([C:49]1[CH:68]=[CH:67][C:52]([CH2:53][N:54]([CH2:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([O:63][CH:64]([F:66])[F:65])[CH:58]=2)[C:11]([C:9]2[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:13])=[CH:51][CH:50]=1)([CH3:48])([CH3:46])[CH3:47]
Reactant: O=C(O)c1cc(Cl)cc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2cccc(OC(F)F)c2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(CN(CCc2cccc(OC(F)F)c2)C(=O)c2cc(Cl)cc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 74.4 %

Procedure:
To a solution of 59 mg (0.3 mmol) of 5-chloro-1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 3 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 100 mg (0.3 mmol) of (4-tert-butyl-benzyl)-[2-(3-difluoromethoxy-phenyl)-ethyl]-amine in 2 ml DMF were added. After stirring for 4 h at rt, the reaction mixture was diluted with 50 ml water and extracted with EtOAc (2×). The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; EtOAc/heptane 1:6) to give 114 mg white solid (67%). MS(ISP) 512.2 (M+H)+.
Reaction SMILES: C(C1C=CC=CC=1)(=O)C.C(NCCCCCCNCC1C=CC=CC=1)C1C=CC=CC=1.C([N:39]([CH2:75][C:76]([C:78]1[CH:83]=[CH:82][C:81]([O:84]CC2C=CC=CC=2)=[C:80]([NH:92][C:93]([NH2:95])=[O:94])[CH:79]=1)=[O:77])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][N:46](CC1C=CC=CC=1)[CH2:47][C:48](=[O:67])[C:49]1[CH:54]=[CH:53][C:52]([O:55]CC2C=CC=CC=2)=[C:51]([NH:63][C:64]([NH2:66])=[O:65])[CH:50]=1)C1C=CC=CC=1>CC(C)=O>[OH:55][C:52]1[CH:53]=[CH:54][C:49]([CH:48]([OH:67])[CH2:47][NH:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][NH:39][CH2:75][CH:76]([OH:77])[C:78]2[CH:83]=[CH:82][C:81]([OH:84])=[C:80]([NH:92][C:93]([NH2:95])=[O:94])[CH:79]=2)=[CH:50][C:51]=1[NH:63][C:64]([NH2:66])=[O:65]
Reactant: NC(=O)Nc1cc(C(=O)CN(CCCCCCN(CC(=O)c2ccc(OCc3ccccc3)c(NC(N)=O)c2)Cc2ccccc2)Cc2ccccc2)ccc1OCc1ccccc1
Agent: c1ccc(CNCCCCCCNCc2ccccc2)cc1
Solvent: CC(C)=O
Solvent: CC(=O)c1ccccc1
Product: NC(=O)Nc1cc(C(O)CNCCCCCCNCC(O)c2ccc(O)c(NC(N)=O)c2)ccc1O

Procedure:
Following the procedures of Example 14, the above prepared acetophenone and N,N'-dibenzyl-hexamethylenediamine are refluxed in acetone for 12 hours and the resulting N,N'-dibenzyl-N,N'-bis[2-(4-benzyloxy-3-ureidophenyl)-2-oxoethyl]-hexamethylenediamine is hydrogenated to yield N,N'-bis[2-(4-hydroxy-3-ureidophenyl)-2-hydroxyethyl]-hexamethylenediamine.
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]([CH3:35])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]([C:18]2[S:22][C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[N:20][C:19]=2[CH3:33])[CH2:16][CH3:17])=[CH:10][C:9]=1[CH3:34])[CH3:6])C.[OH-].[Na+].Cl>C1COCC1.C(O)C>[CH3:6][C:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]([C:18]2[S:22][C:21]([C:23]3[CH:24]=[CH:25][C:26]([C:29]([F:31])([F:30])[F:32])=[CH:27][CH:28]=3)=[N:20][C:19]=2[CH3:33])[CH2:16][CH3:17])=[CH:10][C:9]=1[CH3:34])([CH3:35])[C:4]([OH:36])=[O:3]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OC(CC)c2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCC(Oc1ccc(OC(C)(C)C(=O)O)c(C)c1)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 63.6 %

Procedure:
To a solution of example 26 (1.1 g, 2.17 mmol) in THF/ethanol (1/1) was added 1N NaOH (10 mmol, 4.6 eq). The resulting mixture was stirred at 80° C. for 1.5 hour, and after cooling at room temperature 1N HCl (10 mmol, 4.6 eq) was added. The resulting mixture was concentrated in vacuo, and the residue was sonicated in water/EtOH. The resulting solid was filtered off and washed with water, diluted HCl, and water to give the title compound (680 mg, 1.38 mmol) in a 64% yield as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][CH2:7][C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[CH2:10][CH2:11][NH2:12])=[CH:4][CH:3]=1.[CH:19](OCC)=[O:20]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[CH2:10][CH2:11][NH:12][CH:19]=[O:20])=[CH:17][CH:18]=1
Reactant: CCOC=O
Reactant: NCCc1ccccc1CCc1ccc(Br)cc1
Product: O=CNCCc1ccccc1CCc1ccc(Br)cc1

Procedure:
A solution of 0.60 g. (0.00197 mole) of 2-(4-bromophenethyl)-phenethylamine in 20 ml. of ethyl formate is heated to refluxing for about 19 hours. The solution is evaporated to dryness under reduced pressure and the residue dissolved in dry benzene. Evaporation of the solvent under reduced pressure leaves the product as the residual yellow oil.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[Cl:18][C:19]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:20]=1[CH2:21]Br>>[Cl:18][C:19]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:20]=1[CH2:21][N:12]1[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2
Reactant: Clc1ccc(CBr)c(Cl)c1
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1ccc(Cl)cc1Cl

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 2,4-dichlorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a colorless oil.
Reaction SMILES: ClC1N=C2C(N=C(OC3CN(C(OC(C)(C)C)=O)C3)N2C2CCCCO2)=C(N2CCOCC2)N=1.[CH2:35]([C:37]1[N:41]([C:42]2[N:50]=[C:49]3[C:45]([N:46]=[C:47]([O:52][CH:53]4[CH2:56][N:55]([C:57](=[O:61])[CH:58]([CH3:60])[CH3:59])[CH2:54]4)[N:48]3C)=[C:44]([N:62]3[CH2:67][CH2:66][O:65][CH2:64][CH2:63]3)[N:43]=2)[C:40]2[CH:68]=[CH:69][CH:70]=[CH:71][C:39]=2[N:38]=1)[CH3:36]>>[CH2:35]([C:37]1[N:41]([C:42]2[N:50]=[C:49]3[C:45]([N:46]=[C:47]([O:52][CH:53]4[CH2:54][N:55]([C:57](=[O:61])[CH:58]([CH3:60])[CH3:59])[CH2:56]4)[NH:48]3)=[C:44]([N:62]3[CH2:67][CH2:66][O:65][CH2:64][CH2:63]3)[N:43]=2)[C:40]2[CH:68]=[CH:69][CH:70]=[CH:71][C:39]=2[N:38]=1)[CH3:36]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(OC3CN(C(=O)C(C)C)C3)n(C)c2n1
Agent: CC(C)(C)OC(=O)N1CC(Oc2nc3c(N4CCOCC4)nc(Cl)nc3n2C2CCCCO2)C1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(OC3CN(C(=O)C(C)C)C3)[nH]c2n1

Procedure:
The compound was prepared from tert-butyl 3-(2-chloro-6-morpholino-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-8-yloxy)azetidine-1-carboxylate in a similar manner to that of 1-(3-(2-(2-ethyl-1H-benzo[d]imidazol-1-yl)-9-methyl-6-morpholino-9H-purin-8-yloxy)azetidin-1-yl)-2-methylpropan-1-one (122) following General Procedures of Boc-deprotection and amide coupling. 1H NMR (400 MHz, DMSO) δ 13.10 (s, 1H), 7.94-7.84 (m, 1H), 7.67-7.57 (m, 1H), 7.29-7.16 (m, 2H), 5.47 (s, 1H), 4.70-4.55 (m, 1H), 4.28 (dd, J=15.8, 9.3 Hz, 2H), 4.11 (s, 4H), 3.91 (d, J=7.9 Hz, 1H), 3.81-3.69 (m, 4H), 3.35 (d, J=3.0 Hz, 1H), 3.21 (q, J=7.4 Hz, 2H), 1.30 (t, J=7.4 Hz, 3H), 0.99 (d, J=6.6 Hz, 6H). LCMS: M+H+=491.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[N:16]=[C:15]([N:17]3[CH2:20][C:19](=O)[CH2:18]3)[CH:14]=[C:13]([NH:22][C:23]3[CH:28]=[N:27][CH:26]=[CH:25][N:24]=3)[N:12]=2)[CH3:9])=[CH:4][CH:3]=1.[CH3:29][NH:30][CH3:31].O1CCCC1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(OCC)(=O)C>[CH3:29][N:30]([CH3:31])[CH:19]1[CH2:20][N:17]([C:15]2[N:16]=[C:11]([NH:10][C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH3:9])[N:12]=[C:13]([NH:22][C:23]3[CH:28]=[N:27][CH:26]=[CH:25][N:24]=3)[CH:14]=2)[CH2:18]1
Reactant: C[C@H](Nc1nc(Nc2cnccn2)cc(N2CC(=O)C2)n1)c1ccc(F)cc1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: ClCCCl
Product: C[C@H](Nc1nc(Nc2cnccn2)cc(N2CC(N(C)C)C2)n1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
300 mg of (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-one was dissolved in 5 ml of 1,2-dichloroethane, and 12 ml of 2M dimethylamine/tetrahydrofuran solution and 290 μl of acetic acid were added thereto, and the mixture was stirred at room temperature for 30 minutes. 340 mg of sodium triacetoxyborohydride was added thereto, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with a saturated aqueous solution of sodium bicarbonate and brine, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 187 mg of the objective compound as brown powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:34]=[CH:33][C:18]([NH:19][CH2:20][C:21]3[CH:30]=[C:29]4[C:24]([CH:25]=[CH:26][C:27]([C:31]#[N:32])=[CH:28]4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:35]1([C:41](Cl)=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([N:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][C:27]([C:31]#[N:32])=[CH:26][CH:25]=4)[CH:30]=3)[C:41]([CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)=[O:42])=[CH:33][CH:34]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)C1CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCc3ccc4ccc(C#N)cc4c3)cc2)CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N(Cc3ccc4ccc(C#N)cc4c3)C(=O)C3CCCCC3)cc2)CC1

Procedure:
Starting compound: 7-[[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]anilino]methyl]-2-naphthalenecarbonitrile, cyclohexanecarbonyl chloride.
Reaction SMILES: Cl.C[O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[C:11]2[CH2:14][CH2:15][NH2:16])=[CH:6][CH:5]=1.[BrH:17]>>[BrH:17].[OH:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[C:11]2[CH2:14][CH2:15][NH2:16])=[CH:6][CH:5]=1
Reactant: COc1ccc2cccc(CCN)c2c1
Agent: Br
Agent: Cl
Product: NCCc1cccc2ccc(O)cc12
Yield: 80 %

Procedure:
13.8 g (5.81×10-2 mol) of 2-(7-methoxy-1-naphthyl)ethylamine hydrochloride and 46 cm3 of 47% hydrobromic acid solution are introduced into a 250-cm3 round- bottom flask with a ground neck. The mixture is brought to reflux for 6.5 hours. After cooling, the reaction medium is filtered. The precipitate is washed with water and then with hexane. Recrystallization of the crude product is carried out in an ethyl acetate/hexane mixture to obtain 2-(7-hydroxy-l-naphthyl)ethylamine hydrobromide (yield 80%; melting point: 174°-175° C.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[F:12][C:13]1[C:19]([F:20])=[C:18]([F:21])[CH:17]=[C:16]([F:22])[C:14]=1[NH2:15]>>[F:12][C:13]1[C:19]([F:20])=[C:18]([F:21])[CH:17]=[C:16]([F:22])[C:14]=1[NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: Nc1c(F)cc(F)c(F)c1F
Reactant: O=C(O)Cc1ccccc1Br
Product: O=C(O)Cc1ccccc1Nc1c(F)cc(F)c(F)c1F

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 2,3,4,6-tetrafluoroaniline to yield 2-[(2,3,4,6-tetrafluorophenyl)amino]phenylacetic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[Cl-].[Cl-].[Mg+2].C(N(CC)CC)C.[CH2:20]=[O:21].Cl>C(#N)C>[OH:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH:20]=[O:21]
Reactant: COc1ccc(O)cc1
Reactant: C=O
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(O)c(C=O)c1
Temperature: 25 °C
Yield: 91 %

Procedure:
To a mixture of compound p-methoxyphenol (3 g, 24.2 mmol), anhydrous magnesium dichloride (3.48 g, 37.0 mmol) and dry triethylamine (12.8 mL, 92.1 mmol) in 100 mL of acetonitrile was added dry paraformaldehyde (5 g, 167 mmol). The reaction mixture was refluxed for 8 hours and cooled down to room temperature. Then the reaction mixture was poured into 5% HCl (300 mL) and extracted with diethyl ether (200 mL) for three times. The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated. The residue was purified by flash column chromatography (20% EtOAc in n-hexane) to yield 3.35 g of 2-hydroxy-5-methoxybenzaldehyde (91% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:8]=1)[NH2:5].Cl[C:16]1[N:21]=[C:20]([O:22][CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)[CH:19]=[CH:18][N:17]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][C:2]1[CH:3]=[C:4]([NH:5][C:16]2[N:21]=[C:20]([O:22][CH:23]3[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:27][CH2:28]3)[CH:19]=[CH:18][N:17]=2)[CH:6]=[C:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccnc(Cl)n2)CC1
Reactant: Cc1cc(N)cc(-c2cccnc2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(Nc2nccc(OC3CCN(C(=O)OC(C)(C)C)CC3)n2)cc(-c2cccnc2)c1
Temperature: 75 °C

Procedure:
3-Methyl-5-(pyridin-3-yl)aniline (50.7 mg, 0.275 mmol) was added a solution of tert-Butyl 4-[(2-chloropyrimidin-4-yl)oxy]piperidine-1-carboxylate (72.0 mg, 0.229 mmol) in dioxane (486 μL). The reaction mixture was flushed and purged with Ar(g) followed by the addition of Pd(OAc)2 (5.15 mg, 0.023 mmol) and Xantphos (19.9 mg, 0.034 mmol). The reaction was heated to 75° C. overnight and then cooled to room temperature. The reaction mixture was diluted with water and extracted with dichloromethane. The organic was dried over sodium sulfate and was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% MeOH in DCM:hexanes, 10:90 to 50:50) to yield tert-butyl 4-[(2-{[3-methyl-5-(pyridin-3-yl)phenyl]amino}pyrimidin-4-yl)oxy]piperidine-1-carboxylate.