Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C@@H:6]1[CH2:10][C@@H:9]([OH:11])[CH2:8][N:7]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:5].[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>N1C=CC=CC=1>[CH3:1][CH2:2][O:3][C:4]([C@@H:6]1[CH2:10][C@@H:9]([O:11][S:25]([C:22]2[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=2)(=[O:27])=[O:26])[CH2:8][N:7]1[C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])=[O:5]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Solvent: c1ccncc1
Product: CCOC(=O)[C@@H]1C[C@@H](OS(=O)(=O)c2ccc(C)cc2)CN1C(=O)OC(C)(C)C
Reaction time: 48 h
Yield: 89.8 %

Procedure:
To the solution of (2S,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid-1-tert-butyl ester-2-ethyl ester (27) (1.8 g, 7 mmol) in dry pyridine (40 ml) was added p-toluenesulfonyl chloride (4.0 g, 21 mmol) under nitrogen at 0° C. The reaction mixture was kept refrigerated at 0° C. for 2 days. The reaction was then concentrated under reduced pressure. The residue was dissolved in ethyl acetate: water (10:1) (150 ml). The organic was washed with water (30 ml, 2×), dried over MgSO4 and evaporated to dryness. The resulting residue was purified by column chromatography using pet ether: EtOAc (1:1) to give 2.6 g of desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][CH:11]=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[N+:22]([C:25]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:26]=1[S:34]Cl)([O-:24])=[O:23]>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:10][C:11]([S:34][C:26]3[CH:27]=[CH:28][C:29]([N+:31]([O-:33])=[O:32])=[CH:30][C:25]=3[N+:22]([O-:24])=[O:23])=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:7][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(SCl)c([N+](=O)[O-])c1
Reactant: COc1ccc(-c2ccsc2-c2ccc(OC)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2cc(Sc3ccc([N+](=O)[O-])cc3[N+](=O)[O-])sc2-c2ccc(OC)cc2)cc1
Yield: 85.2 %

Procedure:
A suspension of 2,3-bis(4-methoxyphenyl)thiophene (6.6 g, 22.3 mmoles) and 2,4-dinitrobenzenesulfenyl chloride (5.5 g, 22.3 mmoles) in 55 ml of trifluoroacetic acid was heated at reflux for 15 minutes. The reaction mixture was cooled in ice; the lustrous crystals were collected and washed with cold ether to give the title compound (9.4 g), m.p. 143°-145°
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:21]N1C(=O)CCC1=O>C(O)(=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:12]=2[Cl:21])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1cc(-c2ccc(C(C)(C)C)cc2)on1
Solvent: CC(=O)O
Product: CCOC(=O)c1noc(-c2ccc(C(C)(C)C)cc2)c1Cl
Temperature: 25 °C
Yield: 35.9 %

Procedure:
A mixture of ethyl 5-(4-tert-butylphenyl)isoxazole-3-carboxylate (2.0 g, 7.32 mmol) and N-chlorosuccinimide (2.44 g, 18.3 mmol) in acetic acid (50 mL) was heated to reflux for 3 days. The reaction mixture was then allowed to cool to room temperature, poured over ice and the resulting white solid was collected, dissolved in ethyl acetate and the organics washed with water, brine and dried with sodium sulphate before being filtered, and evaporated in vacuo. The resultant residue was re-dissolved in dichloromethane, this was then extracted with sodium carbonate solution, and dried using a hydrophobic frit. The organics were removed in vacuo to obtain ethyl 5-(4-tert-butylphenyl)-4-chloroisoxazole-3-carboxylate (0.81 g, 2.63 mmol).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([N:26]4[C:30](=[O:31])[CH2:29][NH:28][C:27]4=[O:32])=[CH:22][C:21]=3[F:33])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:34][CH3:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:36](Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1.CN(C=O)C>[CH2:36]([N:28]1[CH2:29][C:30](=[O:31])[N:26]([C:23]2[CH:24]=[CH:25][C:20]([O:19][C:13]3[C:12]4[C:17](=[CH:18][C:9]([O:8][CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)=[C:10]([O:34][CH3:35])[CH:11]=4)[N:16]=[CH:15][CH:14]=3)=[C:21]([F:33])[CH:22]=2)[C:27]1=[O:32])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: COc1cc2c(Oc3ccc(N4C(=O)CNC4=O)cc3F)ccnc2cc1OCc1ccccc1
Reactant: BrCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc2c(Oc3ccc(N4C(=O)CN(Cc5ccccc5)C4=O)cc3F)ccnc2cc1OCc1ccccc1
Reaction time: 3 h

Procedure:
To a stirring suspension of 3-(4-(7-(benzyloxy)-6-methoxyquinolin-4-yloxy)-3-fluorophenyl)imidazolidine-2,4-dione (Example 50, 200 mg, 0.42 mmol) and benzyl bromide (0.06 mL, 0.51 mmol) in THF (2 mL) and DMF (1 mL) was added 1 M LiHMDS in THF (0.51 mL). After 3 h at RT, the solvents were removed under reduced pressure and the residue was purified on a silica gel to afford the title compound. Calc'd Mass for C33H26FN3O5, 563, MS (M+1) 564.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[C:15]([Cl:21])=[N:16][CH:17]=[C:18]([Br:20])[CH:19]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:22][Mg]Br.N#N>C1COCC1>[Br:20][C:18]1[CH:19]=[C:14]([NH:13][S:10]([C:7]2[CH:8]=[CH:9][C:4]([C:1]([OH:3])([CH3:22])[CH3:2])=[CH:5][CH:6]=2)(=[O:12])=[O:11])[C:15]([Cl:21])=[N:16][CH:17]=1
Reactant: C[Mg]Br
Reactant: CC(=O)c1ccc(S(=O)(=O)Nc2cc(Br)cnc2Cl)cc1
Agent: N#N
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(S(=O)(=O)Nc2cc(Br)cnc2Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
To a 100 mL, round-bottomed flask was added 4-acetyl-N-(5-bromo-2-chloropyridin-3-yl)benzenesulfonamide from Step 1 (250 mg, 642 μmol) and THF (10 mL). To this solution, methylmagnesium bromide (3.0 N, 4 mL, 12 mmol) was added in under N2 protection. The suspension was stirred at 25° C. for 3 h. The mixture was quenched by aqueous saturated NH4Cl. The aqueous part was extracted by 10% methanol-DCM (3×), and the combined organic was dried over MgSO4, and concentrated in vacuo to provide the title product as a yellow oil (250 mg), which was taken on to the next step without further purification. MS (ESI positive ion) m/z: 407 (M+1).
Reaction SMILES: [S:1]([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([CH2:20][NH:21][C:22]([C@@H:24]3[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]3)=O)[N:19]=[C:14]2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:46])=CC=1>O1CCOCC1.CCOC(C)=O>[S:1]([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([CH2:20][NH:21][C:22]([C@@H:24]3[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]3)=[S:46])[N:19]=[C:14]2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(CNC(=O)[C@@H]4CCCN(C(=O)OC(C)(C)C)C4)cnc32)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(CNC(=S)[C@@H]4CCCN(C(=O)OC(C)(C)C)C4)cnc32)cc1
Temperature: 60 °C
Yield: 127.1 %

Procedure:
To a solution of (R)-tert-butyl 3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamoyl)-piperidine-1-carboxylate (7.58 g, 13.8 mmol) in 1,4-dioxane (130 mL) was added Lawesson's reagent (3.37 g, 8.32 mmol) and the reaction mixture was heated to about 60° C. for about 2 h then cooled to ambient temperature and concd under reduced pressure. The crude residue was dissolved in EtOAc (40 mL) and washed with saturated aqueous NaHCO3, (3×40 mL), brine (30 mL), dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The crude material was purified by silica gel chromatography eluting with a gradient of 0-5% MeOH in DCM to afford (R)-tert-butyl 3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamothioyl)piperidine-1-carboxylate (5.6 g, 74%, UV purity 97%): LC/MS (Table 1, Method b) Rt=2.60 min; MS m/z: 530 (M+H)+.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.O[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=2)[N:10]=[CH:9][CH:8]=1.[OH-].[Na+]>CN(C=O)C>[Cl:3][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=2)[N:10]=[CH:9][CH:8]=1
Reactant: N#Cc1ccc2nccc(O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: N#Cc1ccc2nccc(Cl)c2c1

Procedure:
Phosphorus oxychloride (0.518 ml) was added to DMF (9 ml) at an inner temperature of 5-7° C. while stirring under ice-cooling, and the mixture was stirred at room temperature for 0.5 hr. 4-Hydroxy-6-quinolinecarbonitrile (860 mg) was added while stirring under ice-cooling and the mixture was stirred under ice-cooling for 1 hr. 1N aqueous sodium hydroxide solution (18 ml) was added and the mixture was stirred at room temperature for 10 min. The precipitate was collected by filtration and washed with water to give a pale brown powder. The obtained powder was purified by silica gel column chromatography (eluent: chloroform-methanol=50/1) to give the object compound (800 mg) as a pale yellow powder.
Reaction SMILES: [C:1]1([C:7]2[CH2:8][O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].O>C(O)C>[C:1]1([CH:7]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[O:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C2=Nc3ccccc3OC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: c1ccc(C2COc3ccccc3N2)cc1
Temperature: 90 °C
Yield: 93 %

Procedure:
To a slurry of 3-phenyl-2H-1,4-benzoxazine (17 g, 81.2 mmol) in 100 mL absolute ethanol is added sodium borohydride (6.07 g, 162.4 mmol) and water (25 mL). The mixture is heated at 90° C. for 2 h. The mixture is cooled and concentrated, then partitioned between CH2C2 and water. The organic layer is washed twice with water (200 mL), dried over magnesium sulfate and concentrated. The resulting oil is dried under high vacuum to give 15.95 g (93%) of 3-phenyl-3,4-dihydro-2H-1,4-benzoxazine.
Reaction SMILES: [C:1]([CH2:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=O)#[N:2].O.[NH2:20][NH2:21]>CCO>[NH2:2][C:1]1[NH:21][N:20]=[C:4]([CH:6]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH:3]=1
Reactant: NN
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)CC#N)CC1
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2cc(N)[nH]n2)CC1
Temperature: 80 °C

Procedure:
A 5 mL conical reaction vial was charged with tert-butyl 4-(2-cyanoacetyl)piperidine-1-carboxylate (348 mg, 1.379 mmol), hydrazine monohydrate (329.4 μL, 6.896 mmol) and EtOH (4 mL). The reaction vessel was sealed and heated to 80° C. for 20 hours. The volatiles were removed to afford tert-butyl 4-(5-amino-1H-pyrazol-3-yl)piperidine-1-carboxylate as a foam (367 mg. 99%).
Reaction SMILES: [NH2:1][CH2:2][C:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][C:5]([C:13]([OH:15])=[O:14])([CH2:6]3)[CH2:4]1)[CH2:10]2.Cl.[CH3:17]O>O1CCOCC1>[NH2:1][CH2:2][C:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][C:5]([C:13]([O:15][CH3:17])=[O:14])([CH2:6]3)[CH2:4]1)[CH2:10]2
Reactant: CO
Reactant: NCC12CC3CC(C1)CC(C(=O)O)(C3)C2
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)C12CC3CC(CC(CN)(C3)C1)C2
Yield: 82 %

Procedure:
73 mg (0.30 mmol) of 3-(aminomethyl)adamantane-1-carboxylic acid were initially charged in 1.48 ml of methanol, and 1.48 ml of 4 N hydrogen chloride solution in dioxane were added. The mixture was stirred under reflux for 5 h. The mixture was concentrated by evaporation and the residue was admixed with saturated sodium hydrogencarbonate solution. The mixture was extracted three times with ethyl acetate, and the combined organic phases were dried over sodium sulphate and then concentrated by evaporation and dried. 55 mg of the target compound (82% of theory) were obtained, which were used in the subsequent stage without further purification.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[CH:21]1[C:29]2[C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[O:26][C:25]=2[CH:24]=[CH:23][C:22]=1[CH:34]=O>>[CH:21]1[C:29]2[C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[O:26][C:25]=2[CH:24]=[CH:23][C:22]=1[CH2:34][N:1]1[CH:2]([C:11]2[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=2[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]1=[O:9]
Reactant: O=Cc1ccc2oc3ccccc3c2c1
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1ccc2oc3ccccc3c2c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with commercially available dibenzo[b,d]furan-2-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions I): tR=1.53 min.; [M+H]+: 430.13 g/mol.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[N+:21]([C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[C:27](O)=O)([O-:23])=[O:22]>>[N+:21]([C:24]1[CH:25]=[C:26]([C:27]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:17]([F:19])([F:20])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)[N:16]=2)[CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:32]=1)([O-:23])=[O:22]
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3cc([N+](=O)[O-])cc(C(F)(F)F)c3)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 65 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 3-nitro-5-(trifluoromethyl)benzoic acid: MS (ESI): m/z 482 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10](=[O:27])[CH:11]=[C:12]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:16]2[CH:23]=[CH:24][CH:25]=[CH:26][C:15]=2[CH:14]=[CH:13]1.CO.[Li+].[OH-].Cl>O>[CH:22]1[C:17]2[C:16]3[CH:23]=[CH:24][CH:25]=[CH:26][C:15]=3[CH:14]=[CH:13][C:12](=[CH:11][C:10]([NH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:28])=[O:2])=[O:27])[C:18]=2[CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)CCCCCNC(=O)C=C1C=Cc2ccccc2-c2ccccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCCCCNC(=O)C=C1C=Cc2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.8 %

Procedure:
6-(2-(5H-dibenzocyclohepten-5-ylidene)acetamido)hexanoic acid methyl ester (375 mg, 1 mmol) and 300 ml of CH3OH were stirred at room temperature while 25 ml of 4 N solution of LiOH in H2O was added. The mixture was stirred for 24 hours at room temperature. The mixture was neutralized with concentrated hydrochloric acid to pH 7 and evaporated under vacuum to remove methanol. The residue was adjusted to pH 3 with concentrated hydrochloric acid. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (310 mg, 86% yield) as a white solid. LC-MS (m/z) 362 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2(O)[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(S(F)(F)[F:35])CC)C.[ClH:38]>>[ClH:38].[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2([F:35])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cccc(OCc3ccccc3)c2)CC1
Reactant: CCN(CC)S(F)(F)F
Agent: Cl
Product: FC1(c2cccc(OCc3ccccc3)c2)CCNCC1

Procedure:
This material was prepared from the reaction of tert-butyl 4-(3-benzyloxyphenyl)-4-hydroxypiperidine-1-carboxylate with diethylaminosulfur trifluoride followed by direct deprotection of the crude product with methanolic hydrogen chloride as described in Step 2 of Example 1 in 75% overall yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:12][C:13]([OH:15])=O)[CH2:9][CH2:10][CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16]12([NH2:26])[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH2:17]1)[CH2:23]2.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl>[C:16]12([NH:26][C:13](=[O:15])[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][CH2:10][CH3:11])[CH2:23][CH:22]3[CH2:21][CH:20]([CH2:19][CH:18]([CH2:24]3)[CH2:17]1)[CH2:25]2
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: CCCN(CC(=O)O)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(CC(=O)NC12CC3CC(CC(C3)C1)C2)C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
Next, methylene chloride (208 ml) was added to a mixture of 2-[N-(t-butoxycarbonyl)-N-propylamino]acetic acid (4.52 g, 20.8 mmol) and 1-adamantaneamine (3.46 g, 22.9 mmol), and the whole was stirred at room temperature. N,N-Diisopropylethylamine (7.25 ml, 41.6 mmol) and then O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (8.71 g, 22.9 mmol) were added thereto, and the whole was stirred overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 7.88 g (quantitatively) of 2-[N′-(t-butoxycarbonyl)-N′-propylamino]acetic acid N-(1-adamantyl)amide as a colorless oily matter. The obtained oily matter solidified at room temperature.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([C:18]3[C:19](=[O:31])[N:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:21]([CH3:24])[C:22]=3[CH3:23])=[O:17])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.[C:38]1([O:44][C:45](Cl)=[O:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(Cl)Cl>[CH3:24][N:21]1[C:22]([CH3:23])=[C:18]([C:16]([NH:15][C:12]2[N:13]=[CH:14][C:9]([O:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:45](=[O:46])[O:44][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH:7]=3)=[CH:10][CH:11]=2)=[O:17])[C:19](=[O:31])[N:20]1[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(N)c3)cn2)c(=O)n(-c2ccccc2)n1C
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(NC(=O)Oc4ccccc4)c3)cn2)c(=O)n(-c2ccccc2)n1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 41.6 %

Procedure:
To a suspension of N-(5-((2-aminopyridin-4-yl)oxy)pyridin-2-yl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (0.25 g, 0.6 mmol) in DCM (20 mL) was added pyridine (0.65 mL, 6 mmol). The suspension was cooled to 0° C., followed by slowly addition of a solution of phenylcarbonochloridate (98 mg, 0.63 mmol) in DCM (5 mL). The reaction was stirred at rt for 2 hours, diluted with DCM (20 mL), and then washed with water (25 mL×2), followed by washing with brine (25 mL). The organic solution was dried over anhydrous Na2SO4, then concentrated in vacuo, and the residue was purified by a silica gel column chromatography (DCM/MeOH (v/v)=100/1) to give the title compound as a white solid (134 mg, 42%).
Reaction SMILES: COC1C=CC(C[O:8][C:9]2[C:18]3[C:13](=[C:14]([Cl:21])[C:15]([O:19][CH3:20])=[CH:16][CH:17]=3)[N:12]=[C:11]([C:22]3[S:23][CH:24]=[C:25]([CH3:27])[N:26]=3)[CH:10]=2)=CC=1>FC(F)(F)C(O)=O>[Cl:21][C:14]1[C:15]([O:19][CH3:20])=[CH:16][CH:17]=[C:18]2[C:13]=1[N:12]=[C:11]([C:22]1[S:23][CH:24]=[C:25]([CH3:27])[N:26]=1)[CH:10]=[C:9]2[OH:8]
Reactant: COc1ccc(COc2cc(-c3nc(C)cs3)nc3c(Cl)c(OC)ccc23)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(O)cc(-c3nc(C)cs3)nc2c1Cl

Procedure:
Compound 275 (750 mg, 1 eq.) in trifluoroacetic acid (5 mL) was stirred at room temperature for 10 min. Then, the acid was evaporated, ethyl acetate added and concentrated again in diminished pressure. The residue was triturated in diethyl ether to give the compound 276 as a white solid in quantitative yield. 1H NMR (CDCl3, 400 MHz) δ (ppm) 2.59 (d, J=0.81 Hz, 3H), 4.10 (s, 3H), 7.19 (d, J=9.25 Hz, 1H), 7.22 (d, J=0.81 Hz, 1H), 7.25 (s, 1H), 8.36 (d, J=9.25 Hz, 1H), 10.51 (br s, 1H); MS (ESI, EI+): m/z=306.93 (MH+).
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:19])[N:7]([CH2:20][CH2:21][C:22]3([OH:25])[CH2:24][CH2:23]3)[C:6](=[O:26])[N:5]([CH3:27])[C:4]=2[N:3]=1.[CH3:28][C:29]1[N:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:10]2[C:9]3[C:8](=[O:19])[N:7]([CH2:20][CH2:21][C:22]4([OH:25])[CH2:24][CH2:23]4)[C:6](=[O:26])[N:5]([CH3:27])[C:4]=3[N:3]=[C:2]2[O:35][C:32]2[CH:33]=[N:34][C:29]([CH3:28])=[CH:30][CH:31]=2)=[CH:13][CH:14]=1
Reactant: Cn1c(=O)n(CCC2(O)CC2)c(=O)c2c1nc(Br)n2Cc1ccc(Cl)cc1
Reactant: Cc1ccc(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2nc3c(c(=O)n(CCC4(O)CC4)c(=O)n3C)n2Cc2ccc(Cl)cc2)cn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 80.9 %

Procedure:
To a solution of 8-bromo-7-(4-chlorobenzyl)-1-(2-(1-hydroxycyclopropyl)ethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (128 mg, 0.282 mmol, intermediate 56) in DMF (5 mL) was added 6-methylpyridin-3-ol (37 mg, 0.338 mmol), followed by potassium carbonate (58 mg, 0.423 mmol). The reaction was stirred at 80° C. for 2 h. The reaction was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give a crude product, which was purified by preparative HPLC to give 7-(4-chlorobenzyl)-1-(2-(1-hydroxycyclopropyl)ethyl)-3-methyl-8-((6-methylpyridin-3-yl)oxy)-1H-purine-2,6(3H,7H)-dione (110 mg, 80.9% yield) as white solid. 1H-NMR (CD3OD) δ 8.457-8.451(d,1H), 7.776-7.748(d,1H), 7.470-7.374(m, 5H), 5.519(s,2H), 4.291-4.256(t,2H), 3.411(s,3H), 2.584(s,3H), 1.867-1.832(t,2H), 0.618-0.610(m, 2H), 0.403-0.387(m,2H). LCMS retention time 2.619 min; LCMS MH+ 482.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18](C)([C:24](OCC)=O)[C:19]([O:21]CC)=[O:20])=[CH:10][C:9]1=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O.Cl>C(O)C>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH:18]([CH3:24])[C:19]([OH:21])=[O:20])=[CH:10][C:9]1=[O:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(C(=O)OCC)c1cc(=O)n(Cc2ccccc2)c2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C(=O)O)c1cc(=O)n(Cc2ccccc2)c2ccccc12
Yield: 66.3 %

Procedure:
A solution of diethyl α-(1-benzyl-1,2-dihydro-2-oxoquinol-4-yl)-α-methylmalonate (3.0 g.) in ethanol (20 ml.) containing sodium hydroxide (3.0 g.) and water (3.0 ml.) was heated under reflux for 1 hour. The solution was then cooled and poured into water (200 ml.). The resultant solution was acidified to pH 3 by addition of concentrated hydrochloric acid to give α-(1-benzyl-1,2-dihydro-2-oxoquinol-4-yl)propionic acid 1.5 g., m.p. 179°-180° C.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1.[C:12]1([CH:18](Br)[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:19][CH:18]([N:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: CC(Br)c1ccccc1
Product: CC(c1ccccc1)n1ccc2c(C=O)cccc21
Yield: 70 %

Procedure:
The same procedures used in Example 4 were repeated except for using 703 mg of indole-4-carbaldehyde and 987 mg of α-phenylethyl bromide instead of the 4-picolyl chloride hydrochloride to give 845 mg of 1-(α-methylbenzyl)indole-4-carbaldehyde as an orange-colored oily substance. The yield thereof was found to be 70%.