Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]1([C:28](=[O:36])[NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:18][CH2:17][CH2:16][N:15](C(OCC[Si](C)(C)C)=O)[CH2:14]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH2:12][C:13]1([C:28](=[O:36])[NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOC(=O)N1CCCC(CNC(=O)OCc2ccccc2)(C(=O)Nc2ccccc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(NCC1(C(=O)Nc2ccccc2)CCCNC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.5 %

Procedure:
The reaction mixture of 2-(trimethylsilyl)ethyl 3-((((benzyloxy)carbonyl)amino)methyl)-3-(phenylcarbamoyl)piperidine-1-carboxylate (1200.00 mg; 2.35 mmol; 1.00 eq.) and TBAF (10.00 ml; 9.38 mmol; 4.00 eq.) in THF was stirred at RT overnight. The crude was purified by prep HPLC to afford the title compound (600 mg, 69.6%)
Reaction SMILES: Cl.[Br:2][C:3]1[C:11]([F:12])=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([NH:13]N)[CH:4]=1.O=[C:16]1[CH2:21][CH2:20][CH2:19][CH:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:17]1.C(O)(=O)C>C1(C)C=CC=CC=1>[Br:2][C:3]1[C:11]([F:12])=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]2[C:4]=1[C:21]1[CH2:20][CH2:19][CH:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:17][C:16]=1[NH:13]2
Reactant: CCOC(=O)C1CCCC(=O)C1
Reactant: NNc1cc(Br)c(F)cc1C(=O)O
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C1CCc2c([nH]c3c(C(=O)O)cc(F)c(Br)c23)C1
Temperature: 110 °C
Reaction time: 8 h
Yield: 46.8 %

Procedure:
A mixture of 4-bromo-5-fluoro-2-hydrazinylbenzoic acid hydrochloride (5.37 g, 18.8 mmol), ethyl 3-oxocyclohexanecarboxylate (3.52 g, 20.7 mmol) and acetic acid (3.23 mL, 56.4 mmol) in toluene (90 mL) was heated at 110° C. for 20 h. The solvent was removed under reduced pressure, and the residue was diluted with toluene (43 mL) and trifluoroacetic acid (11 mL). The mixture was stirred at 90-94° C. overnight. The cooled mixture was diluted with EtOAc, sonicated, and the precipitate was collected by filtration. The filtrate was concentrated and resuspended in EtOAc with sonication, resulting in another precipitate which was also collected by filtration and washed with EtOAc. The combined solids were triturated twice with MeOH to give a solid. The combined filtrates were concentrated and the residue was triturated with MeOH to give additional solid. The solids were combined to give 5-bromo-2-ethoxycarbonyl-6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid as a pale yellow solid (3.38 g). Mass spectrum m/z 384, 386 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH2:17])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CC(O)C>[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH:17][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: COc1ccc(CN)cc1
Reactant: N#Cc1cnccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: COc1ccc(CNc2ccncc2C#N)cc1
Yield: 93.2 %

Procedure:
A solution of 4-chloronicotinonitrile (1.00 g, 7.22 mmol), 4-methoxybenzylamine (1.03 ml, 7.94 mmol) and potassium carbonate (1.20 g, 8.66 mmol) in propan-2-ol (20 mL) was heated under reflux for 18 hours. The solvent was concentrated in vacuo and the residue partitioned between EtOAc (150 mL) and water (50 mL). The organic phase was dried (Na2SO4), filtered and evaporated to give a brown oil. The oil was pre-adsorbed onto H-MN and purified by flash column chromatography (Si-PPC, cyclohexane:EtOAc, gradient 80:20 to 0:100) to provide the title compound as a white solid (1.61 g, 93%). 1H NMR (CDCl3, 300 MHz) 8.46 (d, J=0.7 Hz, 1H), 8.30 (dd, J=6.1 Hz, 0.7 Hz, 1H), 7.24 (dd, J=8.6 Hz, 2.1 Hz, 2H), 6.92 (dd, J=8.6 Hz, 2.1 Hz, 2H), 6.55 (d, J=6.1 Hz, 1H), 5.35 (br t, 1H), 4.40 (d, J=5.6 Hz, 2H), 3.82 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:15][C:14](=[O:16])[O:13][C:11](=[O:12])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][NH:18]1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:10][C:11](=[O:12])[CH:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][CH2:19][NH:18]2)[CH2:15][C:14]([OH:13])=[O:16])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1CC(c2ccc(Cl)c(Cl)c2)CC(=O)O1
Reactant: c1ccc2c(c1)CCNC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)CC(CC(=O)C1NCCc2ccccc21)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3-(3,4-Dichlorophenyl)glutaric anhydride (10 g, Example 1, Step C) in CH2Cl2 (300 mL) at 0° C. was treated sequentially with 1,2,3,4-tetrahydroisoquinoline (6.0 mL), triethylamine (6.7 mL) and N,N-dimethylaminopyridine (472 mg). The mixture was stirred at 0° C. for two hours then allowed to warm to room temperature and stirred for 12 hours. The reaction mixture was diluted with CH2Cl2 (500 mL) and washed with 1N HCl (1×200 mL) and water (1×200 mL). The organic layers were dried over MgSO4, filtered and concentrated to afford the title compound (14 g).
Reaction SMILES: [NH:1]1[C:10]2[CH:9]=[C:8]3[O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][C:7]3=[CH:6][C:5]=2[C:4](=[O:21])[CH:3]=[CH:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].F[C:29]1[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][C:30]=1[F:38]>CN(C=O)C.CC#N>[F:38][C:30]1[CH:31]=[C:32]([N+:35]([O-:37])=[O:36])[CH:33]=[CH:34][C:29]=1[O:21][C:4]1[C:5]2[CH:6]=[C:7]3[O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][C:8]3=[CH:9][C:10]=2[N:1]=[CH:2][CH:3]=1
Reactant: O=c1cc[nH]c2cc3c(cc12)OCCOCCOCCO3
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(Oc2ccnc3cc4c(cc23)OCCOCCOCCO4)c(F)c1
Yield: 39.7 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar was added 7,8,10,11,13,14-Hexahydro-1H-6,9,12,15-tetraoxa-1-aza-cyclododeca[b]naphthalen-4-one (12.2 g, 43.3 mmol, 1.0 eq.), acetonitrile (150 ml), DMF (150 ml) and cesium carbonate (28.2 g, 86.5 mmol, 2.0 eq). The mixture was stirred at room temperature for 30 minutes at which time 1,2-difluoro-4-nitro-benzene (7.57 g, 47.6 mmoL, 1.1 eq) was added over a 10 minute period. After 2 hours the reaction was complete at which time 75% of the MeCN and DMF were removed and the resulting solution was poured over into ice water. The solid was filtered and dried and further columned with a biotage system. The eluent was 1:3 ethyl acetate/hexane. Removal of the solvent afforded 4-(2-Fluoro-4-nitro-phenoxy)-7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxa-1-aza-cyclodo-deca[b]naphthalene as a pale green solid (7.4 g, 41% yield). 1HNMR (400 MHz, DMSO): 8.58 (s, 1H), 7.80 (s, 1H), 7.50 (s, 1H), 7.04 (t, 1H), 6.88 (m, 1H), 6.50 (m, 2H), 4.35 (s, 4H), 3.87 (d, 4H), 3.62 (s, 4H). LC/MS Calcd for (M+H)+431.4. found 431.5.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[CH:9][N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=4)=[CH:15][CH:14]=3)[N:11]=[C:5]2[N:4]([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:3]1=[O:30].[Cl:31]C(Cl)(Cl)C(Cl)(Cl)Cl.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.O>C(Cl)Cl.C1COCC1>[Cl:31][C:9]1[N:10]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[CH:17][CH:18]=2)[N:11]=[C:5]2[C:6]=1[C:7](=[O:8])[N:2]([CH3:1])[C:3](=[O:30])[N:4]2[CH2:25][C:26]([CH3:27])([CH3:29])[CH3:28]
Reactant: Cn1c(=O)c2cn(Cc3ccc(-c4ccncc4)cc3)nc2n(CC(C)(C)C)c1=O
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cn1c(=O)c2c(Cl)n(Cc3ccc(-c4ccncc4)cc3)nc2n(CC(C)(C)C)c1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92.1 %

Procedure:
5-methyl-7-neopentyl-2-(4-(pyridin-4-yl)benzyl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (500 mg, 1.24 mmol) and hexachloroethane (587 mg, 2.48 mmol) are dissolved in 8 mL of methylene chloride, and then 1.0 M LiHMDS (2.48 mL, 2.48 mmol) in THF is added dropwise. After the reaction mixture is stirred at room temperature for 10 min, 100 mL of deionized water is added, and then extracted with methylene chloride four times (30 mL×4). The combined organic phase is dried over anhydrous sodium sulfate. After filtration, the filtrate is evaporated to dryness to give 500 mg of crude product as brown solids, which is used in the next step without further purification. MS (ESI) m/z 438.2 [M+H]+.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[Na].Cl[C:7]1[N:12]2[C:13]([CH:16]([CH3:18])[CH3:17])=[N:14][CH:15]=[C:11]2[CH:10]=[C:9]([Cl:19])[N:8]=1.O>C(O)C>[Cl:19][C:9]1[N:8]=[C:7]([O:1][CH2:2][CH3:3])[N:12]2[C:13]([CH:16]([CH3:18])[CH3:17])=[N:14][CH:15]=[C:11]2[CH:10]=1
Reactant: CC(C)c1ncc2cc(Cl)nc(Cl)n12
Reactant: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCOc1nc(Cl)cc2cnc(C(C)C)n12

Procedure:
To a stirred solution of sodium ethoxide prepared in ethanol from 0.18 g (7.8 mmole) of sodium metal under nitrogen was added 1.50 g (6.52 mmole) of 5,7-dichloro-3-isopropylimidazo[1,5-c]pyrimidine (from Example 37). After three hours at room temperature the mixture was poured into 50 ml of water and extracted thrice with 30 ml portions of chloroform. The combined extracts were washed thrice with 40 ml portions of water, dried over magnesium sulfate and evaporated to provide crude 7-chloro-5-ethoxy-3-isopropylimidazo[1,5-c]pyrimidine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:10])[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].B(O)(O)[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH3:22])=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH3:10])[NH:9][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH3:22])=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(N)C(=O)OC(C)(C)C
Reactant: Cc1ccc(B(O)O)c2ccccc12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(NN(C)C(=O)OC(C)(C)C)c2ccccc12
Temperature: 50 °C
Yield: 9.2 %

Procedure:
A mixture of N-methyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 1; 450 mg, 3.1 mmol), (4-methyl-1-naphthalene)boronic acid (Aldrich; 561 mg, 3.0 mmol), copper(II) acetate (559 mg, 3.1 mmol) and triethylamine (430 μL, 3.1 mmol) in 1,2-dichloroethane (4 mL) was heated in an oil bath at 50° C. for 3 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 40 g column, eluting with 5% ethyl acetate/hexanes, to give N-methyl-N′-(4-methyl-naphthalen-1-yl)-hydrazinecarboxylic acid tert-butyl ester (79 mg, 9%) as a yellow solid.
Reaction SMILES: [CH:1]1([N:7]([C@H:29]2[CH2:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30]2)[C:8](=[O:28])[NH:9][C:10]2[S:11][C:12]([S:15]([N:18](C)[CH2:19][C:20]([N:22](CC)[CH2:23]C)=[O:21])(=[O:17])=[O:16])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(N([C@H]2CC[C@H](C)CC2)C(=O)NC2SC(S(NCC(O)=O)(=O)=O)=CN=2)CCCCC1.CN>>[CH:1]1([N:7]([C@H:29]2[CH2:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30]2)[C:8](=[O:28])[NH:9][C:10]2[S:11][C:12]([S:15]([NH:18][CH2:19][C:20]([NH:22][CH3:23])=[O:21])(=[O:16])=[O:17])=[CH:13][N:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCN(CC)C(=O)CN(C)S(=O)(=O)c1cnc(NC(=O)N(C2CCCCC2)[C@H]2CC[C@H](C)CC2)s1
Agent: CN
Agent: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(S(=O)(=O)NCC(=O)O)s2)C2CCCCC2)CC1
Product: CNC(=O)CNS(=O)(=O)c1cnc(NC(=O)N(C2CCCCC2)[C@H]2CC[C@H](C)CC2)s1

Procedure:
The title compound was prepared in a similar manner to 2-({2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonyl}-methyl-amino)-N,N-diethyl-acetamide using {2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonylamino}-acetic acid and methylamine.
Reaction SMILES: [CH2:1](Br)[CH3:2].C([NH:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:23])=[C:13]([C:18]([O:20]CC)=[O:19])[CH:14]=[N:15]2)=[CH:10][C:9]=1[F:24])(=O)C>O.C(O)C.[OH-].[Na+]>[F:24][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:8]=1[NH2:7])[N:15]([CH2:1][CH3:2])[CH:14]=[C:13]([C:18]([OH:20])=[O:19])[C:12]2=[O:23]
Reactant: CCOC(=O)c1cnc2cc(NC(C)=O)c(F)cc2c1O
Reactant: CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N)cc21

Procedure:
1.5 ml of ethyl bromide is added to a solution of 1 gram of ethyl 7-acetamido-4-hydroxy-6-fluoro-3-quinolinecarboxylate in 25 ml of water, 60 ml of ethanol and 2.5 ml of 10% sodium hydroxide solution, and the mixture is maintained under reflux for 4 hours. The mixture is then concentrated to half its volume, 5 ml of 10% sodium hydroxide solution are added and refluxing is maintained for 1 hour. The mixture is allowed to cool and is acidified with hydrochloric acid, and the precipitate formed is filtered off. The precipitate is washed with water, dried, and recrystallized in a dimethylformamide/water (10:1) mixture.
Reaction SMILES: C(C(C(OCC)=O)C(OCC)=[O:10])C1C=CC=CC=1.C(C(C(OCC)=O)C(OCC)=O)CCC.CC(CCCCCCCC)C(O)=O.C(C(CCCC)(CCCCCCCCCC)C(O)=O)CCC.C(C(CCCCCCCCCC)C(O)=O)CCC.[CH3:87][CH:88]([CH2:90][CH2:91][CH2:92][C@H:93]([CH2:95][CH2:96][CH2:97][C@H:98]([CH2:100][CH2:101][CH2:102]/[C:103](=[CH:105]/[CH2:106][OH:107])/[CH3:104])[CH3:99])[CH3:94])[CH3:89]>C(O)(=O)C.[O-2].[O-2].[O-2].[Cr+6]>[CH3:104][CH:103]([CH2:102][CH2:101][CH2:100][CH:98]([CH3:99])[CH2:97][CH2:96][CH2:95][CH:93]([CH3:94])[CH2:92][CH2:91][CH2:90][CH:88]([CH3:87])[CH3:89])[CH2:105][C:106]([OH:10])=[O:107]
Reactant: C/C(=C\CO)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Reactant: CCOC(=O)C(Cc1ccccc1)C(=O)OCC
Agent: [Cr+6]
Agent: CCCCC(C(=O)OCC)C(=O)OCC
Agent: CCCCCCCCC(C)C(=O)O
Solvent: CC(=O)O
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)CC(=O)O

Procedure:
The 2-benzylalkanoic and 2-butylalkanoic acids were prepared by the malonic ester method starting from diethyl benzylmalonate or diethyl butylmalonate and the appropriate alkyl bromide. The procedure used was analogous to that for the preparation of 2-methyldecanoic acid. Preparation of 2,2-dibutyldodecanoic acid was accomplished by alkylation of 2-butyldodecanoic acid using the method of Pfeffer, Silbert, and Chirinko. Hydrogenation of phytol followed by oxidation of the resulting saturated alcohol with a solution of chromium trioxide in acetic acid gave 3,7,11,15-tetramethylhexadecanoic acid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[OH:10].Br[C:12]([CH3:18])([CH3:17])[C:13]([O:15][CH3:16])=[O:14].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[O:10][C:12]([CH3:18])([CH3:17])[C:13]([O:15][CH3:16])=[O:14]
Reactant: Cc1cc(C)c(C)c(O)c1
Reactant: COC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)C(C)(C)Oc1cc(C)cc(C)c1C
Reaction time: 36 h
Yield: 87.2 %

Procedure:
To a solution of 2,3,5-trimethylphenol (20.0 g, 147 mmol) in dimethylsulfoxide (100 ml) was added methyl 2-bromoisobutyrate (52.2 g, 288 mmol) and potassium carbonate (40.0 g, 289 mmol) at room temperature. The mixture was stirred for 36 hours. The resulting mixture was poured into water and extracted with ethyl acetate. The organic extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified using basic silica gel column chromatography (hexane/ethyl acetate=50/1) to obtain 30.3 g (yield 87%) of oily title compound.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([O:21]C)=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1)(=O)=O.[Cl:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][NH2:27]>>[Cl:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][NH:27][CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1
Reactant: NCc1ccccc1Cl
Reactant: COC(=O)c1ccnc(-c2cn(CCOS(C)(=O)=O)cn2)c1
Product: O=C(O)c1ccnc(-c2cn(CCNCc3ccccc3Cl)cn2)c1
Yield: 8 %

Procedure:
The title compound was prepared in 8% yield from methyl 2-(1-{2-[(methylsulfonyl)oxy]ethyl}-1H-imidazol-4-yl)pyridine-4-carboxylate (PREPARATION 6) and 2-chlorobenzylamine according to the procedure for the preparation of Example 58. 1HNMR (400 MHz, DMSO): δ 2.90 (2H, t, J=6.0 Hz), 3.80 (2H, s), 4.11 (2H, t, J=6.0 Hz), 7.23-7.27 (2H, m), 7.38 (1H, dd, J=4.5 and 1.5 Hz), 7.45 (1H, dd, J=4.6 and 2.2 Hz), 7.55 (1H, dd, J=3.2 and 1.5 Hz), 7.76 (1H, s), 7.81 (1H, s), 8.27 (1H, s), 8.56 (1H, d, J=5.0 Hz). [M+H] Calc'd for C18H17ClN4O2, 358. Found, 358.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].C(=O)(O[C:14]([CH3:18])([CH3:17])[C:15]#[CH:16])OC.C1CCN2C(=NCCC2)CC1>C(#N)C.[Cu]>[CH3:17][C:14]([O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)([CH3:18])[C:15]#[CH:16]
Reactant: C#CC(C)(C)OC(=O)OC
Reactant: N#Cc1ccc(O)cc1
Agent: [Cu]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: C#CC(C)(C)Oc1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 23 h

Procedure:
To a solution of 4-cyanophenol (3.0 g, 25.18 mmol) and methyl 1,1-dimethyl-2-propynyl carbonate (3.93 g, 27.64 mmol) in acetonitrile (24 mL) at 0° C. under argon was added DBU (5.0 mL, 33.43 mmol). To the resulting solution at 0° C. was added cuprous chloride (7.47 mg, 0.003 eq., 0.3 mol %) and copper bronze (83 mg). After stirring at 0° C. for 23 hours, the reaction mixture was filtered and the filtrate was diluted with toluene (~400 mL). The resulting solution was washed with 1N HCl (×2), 1N NaOH (×2), and brine. After drying (magnesium sulfate), the solvent was removed at reduced pressure to give crude title compound as a pale yellow oil (4.18 g). Distillation of the crude material (bulb-to-bulb) afforded the title compound as a colorless, low melting (mp 28°-29° C.) solid (4.02 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[N+:12]([O-])=O>C(O)C.[Ni]>[NH2:12][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:6]=1[NH:5][CH2:4][CH2:3][CH2:2][OH:1]
Reactant: O=[N+]([O-])c1cnccc1NCCCO
Agent: [Ni]
Solvent: CCO
Product: Nc1cnccc1NCCCO
Reaction time: 72 h

Procedure:
4-(3-Hydroxypropylamino)-3-nitropyridine (4.12 g, 20.9 mmol) was dissolved in ethanol (130 ml) and Raney nickel (411 mg, 7.0 mmol) added. The stirred mixture was hydrogenated for 3 days. The catalyst was removed by filtration under argon and the solvent removed under reduced pressure to give 3-amino-4-(3-hydroxypropylamino)pyridine as a brown oil which was used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Br:24]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:24])[N:6]2[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: BrBr
Reactant: CCCCCSc1nc(N)c2ncn(Cc3ccccc3)c2n1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCSc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 7 h
Yield: 15 %

Procedure:
6-Amino-9-benzyl-2-pentylthiopurine (260 mg, 0.79 mmol) and bromine (0.5 ml) were dissolved in 100 ml of methylene chloride and the solution was stirred at room temperature for 7 hours. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated, dried on magnesium sulfate and filtered. The solvent of the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (49 mg, yield 15%).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8](I)=[CH:9][CH:10]=3)[C@:5]3([CH2:20][O:19][C:18]([NH2:21])=[N:17]3)[C:4]=2[CH:3]=1.[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCOCC1.O.C(OCC)(=O)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:9][CH:10]=3)[C@:5]3([CH2:20][O:19][C:18]([NH2:21])=[N:17]3)[C:4]=2[CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: NC1=N[C@@]2(CO1)c1cc(Br)ccc1Oc1ccc(I)cc12
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: NC1=N[C@@]2(CO1)c1cc(Br)ccc1Oc1ccc(-c3ccccc3)cc12
Temperature: 100 °C

Procedure:
A 100 ml RBF vial was charged with (S)-2′-bromo-7′-iodo-5H-spiro[oxazole-4,9′-xanthen]-2-amine (3.37 g, 7.37 mmol) in dioxane (30 mL), water (15 mL), phenylboronic acid (0.965 g, 7.91 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.106 g, 0.150 mmol), and potassium phosphate-tribasic (3.17 g, 14.93 mmol). The reaction was heated to 100° C. in an oil-bath for 8 hours. The reaction was diluted with ethyl acetate (100 mL), water (25 mL), and the ethyl acetate layer was separated and dried over anhydrous sodium sulfate. Concentration and purification by silica gel flash column chromatography (hexanes/ethyl acetate) provided (R)-2′-bromo-7′-phenyl-5H-spiro[oxazole-4,9′-xanthen]-2-amine
Reaction SMILES: C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.C(N(CC)CC)C.[C:29]([O:33][CH2:34][CH3:35])(=[O:32])[CH:30]=[CH2:31].Cl[C:37]1[N:42]=[C:41]([O:43][CH3:44])[C:40]([N+:45]([O-:47])=[O:46])=[CH:39][CH:38]=1>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:44][O:43][C:41]1[N:42]=[C:37](/[CH:31]=[CH:30]/[C:29]([O:33][CH2:34][CH3:35])=[O:32])[CH:38]=[CH:39][C:40]=1[N+:45]([O-:47])=[O:46]
Reactant: C=CC(=O)OCC
Reactant: COc1nc(Cl)ccc1[N+](=O)[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc([N+](=O)[O-])c(OC)n1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
Palladium acetate (386 mg), 2-(di-tert-butylphosphino)biphenyl (1.03 g), triethylamine (9.59 mL) and ethyl acrylate (18.6 mL) were added to a solution of 6-chloro-2-methoxy-3-nitropyridine (6.49 g) in DMF (100 mL). The reaction solution was stirred in a nitrogen atmosphere at 120° C. for two hours and then left to cool to room temperature. The reaction solution was concentrated under reduced pressure. Water and ethyl acetate were added to the resulting residue, and the organic layer was separated. The resulting organic layer was washed with water and brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) and crystallized from heptane to obtain 2.1 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].Cl.[NH2:12][C:13]1[CH:19]=[CH:18][C:16]([OH:17])=[CH:15][C:14]=1O.[OH-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][C:14]3[CH:15]=[C:16]([OH:17])[CH:18]=[CH:19][C:13]=3[N:12]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(Cl)c1cccc(Br)c1
Reactant: Nc1ccc(O)cc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Oc1ccc2nc(-c3cccc(Br)c3)oc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.4 %

Procedure:
14.1 ml (107 mmol) of 3-bromobenzoic chloride and 1.7 g (10.5 mmol) of 4-aminoresorcinol hydrochloride were introduced into a three-necked flask provided with a thermometer and a cooling condenser, and the mixture was heated at 90° to 145° C. for 30 minutes. To the residue, an aqueous solution of sodium hydroxide and methanol were added into a homogeneous solution which was then stirred at room temperature for 2 hours. The reaction solution was extracted twice with ethyl acetate and washed with 1N hydrochloric acid then with a saturated sodium chloride solution. Distilling off the excessive ethyl acetate, the obtained precipitate was recrystallized with THF/water. There was obtained 0.68 g (2.35 mmol) of 2-(3-bromophenyl)-6-hydroxybenzoxazole, and the yield was 16.6%.