Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([B:8]([OH:10])[OH:9])=[CH:6][CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:13][CH:12]=2)[N:3]=1.[CH2:26]([CH:34]([CH2:37]O)[CH2:35]O)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[F:1][C:2]1[C:7]([B:8]2[O:9][CH2:35][CH:34]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:37][O:10]2)=[CH:6][CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:13][CH:12]=2)[N:3]=1
Reactant: CCCCCCCCOc1ccc(-c2ccc(B(O)O)c(F)n2)cc1
Reactant: CCCCCCCCC(CO)CO
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(-c2ccc(B3OCC(CCCCCCCC)CO3)c(F)n2)cc1
Yield: 83.1 %

Procedure:
1.00 g (3.00 mmol) of 2-fluoro-6-(4-octyloxyphenyl)pyridine-3-boronic acid (prepared as described in Example 10), 0.56 g (3.00 mmol) of 2-octylpropane-1,3-diol and 1.50 g of sodium sulfate in 30 ml of tetrahydrofuran are stirred at room temperature for 48 hours. Sodium sulfate is then filtered off, the filtrate is concentrated, and the residue is recrystallized from hexane, giving 1.24 g of 2-fluoro-3-(5-octyl-1,3-dioxaborinan-2-yl)-6-(4-octyloxyphenyl)pyridine. ##STR61##
Reaction SMILES: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)C1N2N=CC=C2N=C(C2CCC(CC(OCC)=O)CC2)C=1.[CH3:39][Si:40]([CH3:72])([CH3:71])[CH2:41][CH2:42][O:43][CH2:44][N:45]([CH2:63][O:64][CH2:65][CH2:66][Si:67]([CH3:70])([CH3:69])[CH3:68])[C:46]1[N:51]2[N:52]=[CH:53][CH:54]=[C:50]2[N:49]=[C:48]([CH:55]2[CH2:59][CH2:58][C:57](=[CH:60][C:61]#[N:62])[CH2:56]2)[CH:47]=1.C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)C1N2N=CC=C2N=C(C2CCC(=CC(OCC)=O)CC2)C=1>>[CH3:71][Si:40]([CH3:39])([CH3:72])[CH2:41][CH2:42][O:43][CH2:44][N:45]([CH2:63][O:64][CH2:65][CH2:66][Si:67]([CH3:70])([CH3:69])[CH3:68])[C:46]1[N:51]2[N:52]=[CH:53][CH:54]=[C:50]2[N:49]=[C:48]([CH:55]2[CH2:59][CH2:58][CH:57]([CH2:60][C:61]#[N:62])[CH2:56]2)[CH:47]=1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCC(=CC#N)C2)nc2ccnn12
Agent: CCOC(=O)C=C1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)CC1
Agent: CCOC(=O)CC1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)CC1
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCC(CC#N)C2)nc2ccnn12

Procedure:
2-(3-(7-(Bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)cyclopentyl)acetonitrile was synthesized in a manner similar to the synthesis of ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate, but 2-(3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)cyclopentylidene)acetonitrile substituted for ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexylidene)acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([O:11][CH3:12])[N+:4]=1[O-].[P]>>[CH3:12][O:11][C:5]1[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[N:4]=1
Reactant: COc1cc(OC)[n+]([O-])c(OC)c1
Agent: [P]
Product: COc1cc(OC)nc(OC)c1

Procedure:
2,4,6-Trimethoxypyridine was prepared by reacting 2,4,6-trimethoxypyridine-1-oxide and phosphorus and trichloride by the method of Johnson, Katrizky and Viney (J. Chem. Soc. B, 1211, 1967), and was obtained as a colourless solid. Pmr spectrum (δ in ppm; CDCl3): 3.77 (3H, s); 3.87 (6H, s); 5.85 (2H, s).
Reaction SMILES: [NH:1]([C:8]1[C:9](=[O:20])[C:10](=[N:13][C:14]2[CH:19]=[CH:18]C=CC=2)[C:11]=1[OH:12])[C:2]1[CH:7]=[CH:6]C=CC=1.C[C@H]1CN[CH2:25][C@@H:24]([CH3:28])[N:23]1[CH2:29][CH3:30]>>[OH-:12].[OH:12][C:11]1[C:10](=[N+:13]2[CH2:14][C@H:19]([CH3:18])[N:23]([CH2:29][CH3:30])[C@H:24]([CH3:25])[CH2:28]2)[C:9](=[O:20])[C:8]=1[N:1]1[CH2:2][C@H:7]([CH3:6])[N:1]([CH2:2][CH3:7])[C@H:8]([CH3:9])[CH2:11]1
Reactant: CCN1[C@H](C)CNC[C@@H]1C
Reactant: O=c1c(Nc2ccccc2)c(O)c1=Nc1ccccc1
Product: CCN1[C@H](C)CN(c2c(O)c(=[N+]3C[C@@H](C)N(CC)[C@@H](C)C3)c2=O)C[C@@H]1C
Product: [OH-]
Temperature: 213 °C
Reaction time: 0.17 h

Procedure:
A mixture of 1.5 grams of 2-anilino-3-hydroxy-4-(phenylimino)-2-cyclobuten-1-one and 1.2 grams of cis-2,6-dimethyl-1-ethylpiperazine is heated at 213° C. in an atmosphere of dry nitrogen for 10 minutes. It is then mixed thoroughly with 25 ml. of anhydrous ethyl ether and suction filtered and this process is repeated. The solid is then dissolved in 200 ml. of anhydrous ethyl ether at room temperature by stirring for 10 minutes. The solution is then stirred with activated charcoal, filtered, and concentrated to a volume of 25 ml. The solid which forms is separated by filtration to give 1-[2-hydroxy-3-(cis-3,5-dimethyl-4-ethyl-1-piperazinyl)-4-oxo-2-cyclobuten-1-ylidene]-cis-3,5-dimethyl-4-ethylpiperazinium hydroxide inner salt as pale pink crystals melting at about 178°-181° C.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22]C)[C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([C@H:10]2[CH2:15][CH2:14][C@@H:13]([OH:16])[CH2:12][CH2:11]2)[C:6]1=[O:17].C(S)C.[Na].[Cl-].[NH4+]>CN(C=O)C>[Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([C@H:10]2[CH2:11][CH2:12][C@@H:13]([OH:16])[CH2:14][CH2:15]2)[C:6]1=[O:17]
Reactant: COc1cccc(Cl)c1CC1CCN([C@H]2CC[C@@H](O)CC2)C1=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: CCS
Solvent: CN(C)C=O
Product: O=C1C(Cc2c(O)cccc2Cl)CCN1[C@H]1CC[C@@H](O)CC1
Temperature: 25 °C

Procedure:
Dissolve 3-(2-chloro-6-methoxy-benzyl)-1-(cis-4-hydroxy-cyclohexyl)-pyrrolidin-2-one (Example 57) (150 mg, 0.44 mmol) in DMF (5 mL) and purge with nitrogen. Add sodium ethane thiol (110 mg, 1.3 mmol) and heat to 120° C. for 4 hours. Cool to room temperature and pour into ammonium chloride and extract with methylene chloride, dry over sodium sulfate, filter and concentrate. Purify over silica gel (20% hexanes in ethyl acetate) to yield 90 mg (63%) of the title compound as a pale yellow solid: Mass spectrum (apci) m/z=324.1 (M+H).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9](F)=[C:8]([F:13])[CH:7]=1)(=[O:5])=[O:4])[CH3:2].[Cl:14][C:15]1[CH:16]=[C:17]([CH2:22][C:23]([OH:25])=[O:24])[CH:18]=[C:19]([OH:21])[CH:20]=1>>[Cl:14][C:15]1[CH:16]=[C:17]([CH2:22][C:23]([OH:25])=[O:24])[CH:18]=[C:19]([O:21][C:9]2[CH:10]=[CH:11][C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[CH:7][C:8]=2[F:13])[CH:20]=1
Reactant: O=C(O)Cc1cc(O)cc(Cl)c1
Reactant: CCS(=O)(=O)c1ccc(F)c(F)c1
Product: CCS(=O)(=O)c1ccc(Oc2cc(Cl)cc(CC(=O)O)c2)c(F)c1

Procedure:
The title compound was prepared by the method of example 2 step (iii) using the product of example 10 step (ii) and the product of example 18 step (iv).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]1([C:12]2[NH:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CN([CH:24]=[O:25])C>>[C:6]1([C:12]2[NH:13][C:14]3[C:19]([C:20]=2[CH:24]=[O:25])=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: c1ccc(-c2cc3ccccc3[nH]2)cc1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c(-c2ccccc2)[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of DMF (11.0 mL, 142 mmol) and phosphorous oxychloride (3.63 mL, 39 mmol) is stirred at 0° C. for 1 h, a 0.2 mL portion is pipetted into a solution of 2-phenylindole (96 mg, 0.5 mmol) in DMF at 5° C. This reaction mixture is stirred at 5°-10° C. for 1 h, quenched with water, stored at −200 for 16 h and filtered. The filtercake is washed with water and dried in vacuo to afford the 2-phenylindole-3-carboxaldehyde intermediate. A suspension of the thus-obtained 2-phenylindole-3-carboxaldehyde (44.2 mg, 0.2 mmol) in isopropanol and concentrated HCl (50 μL) is treated with aminoguanidine bicarbonate (27 mg, 0.2 mmol), heated at 80° C. for 2 h, cooled to room temperature and concentrated in vacuo. The resultant residue is purified by HPLC to afford the title product, 28 mg (20% yield), identified by mass spectral and HPLC analyses (M+H) 277; retention time 3.76 min.
Reaction SMILES: [F:1][C:2]([F:14])=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13].[OH-:15].[Na+].OO.O>C(Cl)Cl>[F:1][C:2]([F:14])=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:15]
Reactant: [OH-]
Reactant: C=CCCCCCCCCC=C(F)F
Agent: OO
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: OCCCCCCCCCCC=C(F)F
Temperature: 20 °C
Reaction time: 60 h

Procedure:
With stirring, 14.5 grams (0.072 mole) of 1,1-difluorododec-1,11-diene was cooled to 0° C., and 25 ml (0.025 mole--1M in tetrahydrofuran) of borane·tetrahydrofuran complex was added dropwise. Upon completion of addition the reaction mixture was stirred for 30 minutes during which time the reaction mixture temperature was at 8°-12° C. After this time 25 ml of aqueous 3N sodium hydroxide was added dropwise. This was followed by 30 ml of aqueous 30% hydrogen peroxide. During the initial peroxide addition the exothermic reaction caused the reaction mixture temperature to rise to 30°-35° C. The reaction mixture was cooled to approximately 20° C., and the peroxide addition was continued. Upon completion of addition the reaction mixture was stirred at ambient temperature for 30 minutes, and then it was warmed to 45°-50° C. where it stirred for one hour. After this time it was allowed to cool to ambient temperature where it stood for 60 hours. The reaction mixture was shaken with 100 ml of water and 50 ml of methylene chloride. The methylene chloride layer was separated, and the water layer was extracted with two 50 ml portions of methylene chloride. The combined methylene chloride extracts were washed with 25 ml of water and 25 ml of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was distilled under reduced pressure yielding 7.6 grams of 12,12-difluoro-11-dodecenol; b.p. 80-85/0.2 mm. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][S:25]3(=[O:30])=[O:29])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:31])[CH3:9])=[CH:4][CH:3]=1.[CH3:32][C:33]1[CH:38]=[C:37](B(O)O)[CH:36]=[CH:35][N:34]=1>>[CH3:32][C:33]1[CH:38]=[C:37]([C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]3[CH2:15][CH2:14][C@:13]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)([CH2:22][CH2:23][N:24]4[CH2:28][CH2:27][CH2:26][S:25]4(=[O:30])=[O:29])[O:12][C:11]3=[O:31])[CH3:9])=[CH:4][CH:3]=2)[CH:36]=[CH:35][N:34]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCN2CCCS2(=O)=O)(c2ccccc2)OC1=O
Reactant: Cc1cc(B(O)O)ccn1
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@@](CCN4CCCS4(=O)=O)(c4ccccc4)OC3=O)cc2)ccn1

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-(1,1-dioxo-isothiazolidin-2-yl)ethyl)-6-phenyl-1,3-oxazinan-2-one and 2-methylpyridine-4-boronic acid following a procedure analogous to that described in Example 459 Step 1.
Reaction SMILES: [CH:1]([O:14][C:15]1[C:16]2[C:29](=[O:30])[N:28]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)[CH2:27][C:17]=2[C:18]([CH2:25]O)=[C:19]2[C:24]=1[N:23]=[CH:22][CH:21]=[CH:20]2)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:41].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH:1]([O:14][C:15]1[C:16]2[C:29](=[O:30])[N:28]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)[CH2:27][C:17]=2[C:18]([CH2:25][Br:41])=[C:19]2[C:24]=1[N:23]=[CH:22][CH:21]=[CH:20]2)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: COc1ccc(CN2Cc3c(c(OC(c4ccccc4)c4ccccc4)c4ncccc4c3CO)C2=O)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(CN2Cc3c(c(OC(c4ccccc4)c4ccccc4)c4ncccc4c3CBr)C2=O)cc1

Procedure:
For example, 9-benzhydryloxy-5-hydroxymethyl-7-(4-methoxy-benzyl)-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one A11.5 prepared by the method shown in Example 50, is reacted in dichloromethane with one molar equivalent of carbon tetrabromide and triphenylphosphine to produce 9-benzhydryloxy-5-bromomethyl-7-(4-methoxy-benzyl)-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one A11.6. The product is then heated at 120° C. with an excess of a trialkyl phosphite A11.3. The resulting phosphonate is then deprotected to afford the phenolic product A11.7.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[C:3]1[CH3:10].ClC(N(C)C)=C(C)C.[CH2:19]([O:26][C:27]1[CH:34]=[CH:33][C:30]([NH:31][CH3:32])=[CH:29][CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(C(C)C)C(C)C)C>ClCCCl.ClCCl>[CH2:19]([O:26][C:27]1[CH:28]=[CH:29][C:30]([N:31]([CH3:32])[C:7]([C:4]2[CH:5]=[CH:6][N:2]([CH3:1])[C:3]=2[CH3:10])=[O:9])=[CH:33][CH:34]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Cc1c(C(=O)O)ccn1C
Reactant: CNc1ccc(OCc2ccccc2)cc1
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(C(=O)N(C)c2ccc(OCc3ccccc3)cc2)ccn1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of 1,2-dimethylpyrrole-3-carboxylic acid (2.085 g; 15 mmol) in 1,2-dichloroethane (40 mL) there is added 1-chloro-N,N,2-trimethyl-prop-1-en-1-amine (2.37 mL; 17.9 mmol), and the solution formed is stirred for 1 hour. To the resulting solution there is added, dropwise, an ice-cold solution of 4-benzyloxy-N-methyl-aniline (3.73 g; 15 mmol) and N-ethyl-N-isopropyl-propan-2-amine (7.75 mL; 45 mmol) in 1,2-dichloroethane (40 mL). The reaction mixture is stirred at ambient temperature for 1 hour; it is then diluted with dichloromethane (250 mL) and washed with water (2×30 mL), dried over Na2SO4 and evaporated. The crude product is triturated with diethyl ether and the solid formed is filtered off to yield the title compound.
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]1)=[O:5].[Br-].[CH2:20]1[CH2:24]OC[CH2:21]1>>[C:4]([CH:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:7]1)(=[O:5])[C:21]#[C:20][CH3:24]
Reactant: C1CCOC1
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)C1
Agent: [Br-]
Product: CC#CC(=O)C1CCN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a stirred mixture of tert-butyl 3-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate (2 g, 7.75 mmol) in dry THF (10 mL) was added 1-propynylmagnesinm bromide (30 mL, 15 mmol) under N2 at −78° C. The reaction mixture was stirred at −78° C. for 0.5 h, allowed to warm to rt slowly and stirred for another 10 h. The mixture was quenched with 2 N aq HCl (20 mL) at 0° C. and extracted with EtOAc (50 mL×3). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SO4 and concentrated. The residue was purified by preparative TLC (PE/EA=1:1) to afford tert-butyl 3-(but-2-ynoyl)pyrrolidine-1-carboxylate (1.6 g, 86%) as a white oil.
Reaction SMILES: F[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[O:17]([CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Oc1ccccc1
Reactant: O=C(CF)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(COc1ccccc1)c1ccccc1
Temperature: 120 °C
Reaction time: 7 h
Yield: 65 %

Procedure:
2-Fluoroacetophenone (2.0 mg, 14.5 mmol) was dissolved in DMF (50 mL), phenol (1.4 g, 14.5 mmol) and potassium carbonate (2.0 g, 14.5 mmol) were added thereto, and then the mixture was stirred at 120° C. for 7 hours. To the reaction solution was added water, and the reaction mixture was extracted with ethyl acetate. The extract was dried, and then concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane/ethyl acetate=100:0 to 85:15) to give the title compound (2.0 g, yield 65%).
Reaction SMILES: [CH:1]1(O)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][CH:3]3[CH2:2]1.C1(P([N:28]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1.O>C1(C)C=CC=CC=1>[CH:1]1([NH2:28])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][CH:3]3[CH2:2]1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: OC1CC2CCCc3cccc1c32
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: NC1CC2CCCc3cccc1c32
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a cooled (0° C.) solution of 2a,3,4,5-tetrahydro-2H-acenaphthylen-1-ol and diphenylphosphoryl azide (9.31 g) in toluene (90 ml) was added DBU (diazabicycloundecene) (5.04 mL), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was poured into water, and the mixture was extracted with toluene. The combined organic layer was washed with water, dried over magnesium sulfate, and concentrated. The crude product was dissolved in a mixed solvent (77 ml) of THF/water (10:1), triphenylphosphine (9.61 g) was added, and the mixture was heated under reflux for 1 hr. After cooling to room temperature, the solvent was evaporated, 1N hydrochloric acid (100 ml) was added to the residue, and unnecessary substances were removed by extraction with ethyl acetate. The aqueous phase was alkalified with potassium carbonate, and extracted with chloroform. The extract was washed with water and saturated brine, dried over magnesium sulfate, and concentrated to give 1,2,2a,3,4,5-hexahydroacenaphthylen-1-ylamine.
Reaction SMILES: [C:1]1([C:7]2[N:15]=[C:14]3[C:10]([NH:11][C:12](=[O:16])[NH:13]3)=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N12CCN(CC1)CC2.CN(C)C=O.[N:30]1([C:35](Cl)=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31]1>O>[C:1]1([C:7]2[N:15]=[C:14]3[C:10]([N:11]([C:35]([N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)=[O:36])[C:12](=[O:16])[NH:13]3)=[CH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)N1CCCC1
Reactant: O=c1[nH]c2cnc(-c3ccccc3)nc2[nH]1
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: CN(C)C=O
Product: O=C(N1CCCC1)n1c(=O)[nH]c2nc(-c3ccccc3)ncc21
Reaction time: 10 h

Procedure:
To a mixture of 2-phenyl-7,9-dihydro-8H-purine-8-one <prepared according to the similar method to those of Reference Example 19> (4.0 g), 1,4-diazabicyclo[2.2.2]octane (2.2 g) and N,N-dimethylformamide (50 ml) was added dropwise 1-pyrrolidinecarbonyl chloride (2.6 g) at room temperature and the mixture was stirred for 10 hours. To the reaction mixture was added water (100 ml), and the crystals precipitated were collected by filtration and was dried to give the title compound 4.8 g.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[CH:12]1[CH2:17][C:16](=[O:18])[NH:15][CH:14]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[CH3:26])[C:13]21[C:34]1[C:29](=[CH:30][C:31]([Cl:35])=[CH:32][CH:33]=1)[NH:28][C:27]2=[O:36].[CH:37]1([C:41](O)=[O:42])[CH2:40][CH2:39][CH2:38]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:35][C:31]1[CH:30]=[C:29]2[NH:28][C:27](=[O:36])[C:13]3([CH:12]([C:6]4[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=4[O:4][CH2:3][CH2:2][NH:1][C:41]([CH:37]4[CH2:40][CH2:39][CH2:38]4)=[O:42])[CH2:17][C:16](=[O:18])[NH:15][CH:14]3[C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[CH3:26])[C:34]2=[CH:33][CH:32]=1
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OCCN)C12C(=O)Nc1cc(Cl)ccc12
Reactant: O=C(O)C1CCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OCCNC(=O)C2CCC2)C12C(=O)Nc1cc(Cl)ccc12
Reaction time: 8 h
Yield: 16.5 %

Procedure:
At room temperature, a mixture of racemic (2′S,3S,4′R)-4′-[2-(2-amino-ethoxy)5-chloro-phenyl]-6-chloro-2′-(5-fluoro-2-methyl phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (100 mg, 0.189 mmol) prepared in Example 32e, cyclobutanecarboxylic acid (98 mg, 0.948 mmol), EDC.HCl (181 mg, 0.948 mmol), HOBt (128 mg, 0.948 mmol) and DIPEA (245 mg, 1.897 mmol) in anhydrous DMF (4 mL) was stirred overnight. Then the mixture was filtered and the filtrate was concentrated. The residue was purified by Prep-HPLC to give the title compound as a white solid (19 mg).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[N:11]=[C:12]([N:15]=[C:16]([NH2:18])[NH2:17])[S:13][CH:14]=2)[N:9]=1.[C:19]([N:21]=[C:22](SC)SC)#[N:20].[CH2:27]([N:29](CC)CC)C>CN(C)C=O>[NH2:17][C:16](=[N:15][C:12]1[S:13][CH:14]=[C:10]([C:8]2[N:9]=[C:5]([CH2:4][NH:3][C:19]([NH:21][CH3:22])=[N:20][C:27]#[N:29])[S:6][CH:7]=2)[N:11]=1)[NH2:18]
Reactant: NCc1nc(-c2csc(N=C(N)N)n2)cs1
Reactant: CSC(=NC#N)SC
Reactant: CCN(CC)CC
Agent: Cl
Solvent: CN(C)C=O
Product: CNC(=NC#N)NCc1nc(-c2csc(N=C(N)N)n2)cs1
Temperature: 70 °C
Reaction time: 14 h
Yield: 19.5 %

Procedure:
A suspension of 4-(2-aminomethylthiazol-4-yl)-2-(diaminomethyleneamino)thiazole dihydrochloride (1.0 g), dimethyl N-cyanodithiocarbonimidate (0.45 g) and triethyl amine (0.7 g) in N,N-dimethylformamide (40 ml) was heated at 70° C. for 10 hours. 40% methylamino solution (5 ml) was added to the reaction mixture and the mixture was stirred at room temperature for 14 hours. The solvent was removed under reduced pressure. The residue was suspended in water (30 ml) and the mixture was alkalized to pH 10 with a saturated aqueous potassium carbonate solution. The resulting precipitate was collected by filtration. Recrystallization from a mixture of N,N-dimethylformamide and water afforded 2-(diaminomethyleneamino)-4-[2-(2-cyano-3-methylguanidino)methylthiazol-4-yl]thiazole (0.2 g).
Reaction SMILES: O[C:2]1([C:12]([NH2:14])=[O:13])[CH:10](O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.C(N(CC)CC)C.[C:22](Cl)(=[O:24])[CH3:23]>ClC(Cl)Cl>[C:22]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:10][C@H:2]1[C:12]([NH2:14])=[O:13])(=[O:24])[CH3:23]
Reactant: NC(=O)C1(O)Nc2ccccc2C1O
Reactant: CC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)N1c2ccccc2C[C@H]1C(N)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
2,3-Dihydroxy-1H-indole-2-carboxamide (0.030 mol) was suspended in trichloromethane (400 ml). The mixture was cooled to 0° C. Triethylamine (0.045 mol) was added. Acetyl chloride (0.045 mol) was added over 2 minutes. After 30 minutes, TLC showed the reaction was incomplete. While the flask was still cool, more Triethylamine (6.26 ml) was added, followed 15 minutes later with more acetyl chloride (3.21 ml). TLC showed the reaction was still incomplete. The reaction was continued to allow to stir, cooled to 0° C., and more triethylamine (6.26 ml) was added. Over 2 minutes, more acetyl chloride (3.21 ml) was added neat. TLC showed 80% completion after 60 minutes, and no progress after 30 more minutes. A third portion of acetyl chloride and triethylamine was added. After an additional 15 minutes, ice cold water (200 ml) was added. The mixture was stirred for 10 minutes, filtered, and rinsed with water (3×100 ml) and trichloromethane (2×75 ml). The sample was allowed to dry overnight, yielding 4.71 g of (S)-1-acetyl-2,3-dihydro-1H-indole-2-carboxamide (intermediate 1, mp. >260° C.).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][CH:13]=[CH2:14]>[C].[Pd].CO>[OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][CH2:13][CH3:14]
Reactant: C=CCc1cc(C(=O)OC)ccc1O
Agent: [Pd]
Solvent: CO
Product: CCCc1cc(C(=O)OC)ccc1O
Reaction time: 8 h
Yield: 8.9 %

Procedure:
To a mixed solution of methyl 4-hydroxy-3-(2-propen-1-yl)benzoate (12.16 g, 0.63 mol) and methanol (50 mL), 10% palladium carbon catalyst (608 mg) was added, and the mixture was stirred overnight under a hydrogen atmosphere. The catalyst was separated by filtration from the reaction solution which was then concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (hexane/ethyl acetate) and the title compound (10.83 g, yield 88%) was obtained as a colorless powder.