Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[C:19](=O)[C:5]2=[CH:6][C:7]3[C:8]([CH3:18])([CH3:17])[C:9]4[C:14]([C:15]=3[CH:16]=[C:4]2[CH2:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=4.[CH3:21][Mg]Br.Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:21][C:19]1[C:5]2=[CH:6][C:7]3[C:8]([CH3:17])([CH3:18])[C:9]4[C:14]([C:15]=3[CH:16]=[C:4]2[CH2:3][C:2]=1[CH3:1])=[CH:13][CH:12]=[CH:11][CH:10]=4
Reactant: C[Mg]Br
Reactant: CC1Cc2cc3c(cc2C1=O)C(C)(C)c1ccccc1-3
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: Cc1ccccc1
Product: CC1=C(C)c2cc3c(cc2C1)-c1ccccc1C3(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 84.6 %

Procedure:
In a 1000 mL round flask, 2,9,9-trimethyl-2,3-dihydrocyclopenta[b]fluoren-1(9H)-one (50 g, 190.6 mmol) was dissolved in 400 mL of toluene, and then the temperature was lowered to 0° C. Then, 76 mL of 3M methylmagnesium bromide (THF solution) was slowly injected thereto, followed by stirring at room temperature for 12 hours. The reaction product was poured into a mixture of 200 mL of 1N-HCl aqueous solution and 200 g of ice. The mixture was stirred for 1 hour, followed by extraction with toluene, and then the organic layer was dried over magnesium sulfate, followed by removal of volatile materials. The dried reaction product was dissolved in 320 mL of toluene, and then inputted to a 500 mL round flask. After that, p-toluene sulfonic acid (0.2 g) was inputted thereto, and then water was completely removed under reflux with Dean-Stark. The resultant material was cooled to room temperature, and then an aqueous ammonium chloride solution (150 mL) and 200 mL of diethyl ether were injected thereto, followed by separation of the organic layer. The organic layer collected by extracting the residue with diethyl ether was dried over magnesium sulfate, followed by removal of volatile materials, and then purified by using silica gel column chromatography, to thereby obtain 42.0 g of 1,2,9,9-tetramethyl-3,9-dihydrocyclopenta[b]fluorene (yield: 84.6%).
Reaction SMILES: [CH2:1]([C@@H:7]1[C@@H:12]([OH:13])[C:11]([CH3:16])([CH2:14][OH:15])[O:10][C:8]1=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:17][S:18](Cl)(=[O:20])=[O:19].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([C@@H:7]1[C@@H:12]([OH:13])[C:11]([CH3:16])([CH2:14][O:15][S:18]([CH3:17])(=[O:20])=[O:19])[O:10][C:8]1=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC[C@H]1C(=O)OC(C)(CO)[C@@H]1O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCC[C@H]1C(=O)OC(C)(COS(C)(=O)=O)[C@@H]1O

Procedure:
2-(R)-Hexyl-3-(R)-hydroxy-4-methyl-4-hydroxymethylbutyrolactone (prepared as described in example 7) is reacted with 1 eq. of methanesulfonylchloride and 3 eq. of triethylamine in dry methylene chloride at 0° C. to afford 2-(R)-hexyl-3-(R)-hydroxy-4-methyl-4-methanesulfonyloxymethylbutyrolactone
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[C:14](=[O:23])[NH:13][C:12]2=[O:24])[CH2:10][CH2:9]1)=[O:7].Cl[CH2:37][CH:38]1[O:42][C:41](=[O:43])[NH:40][CH2:39]1>>[F:35][C:2]([F:1])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[C:14](=[O:23])[N:13]([CH2:37][CH:38]3[O:42][C:41](=[O:43])[NH:40][CH2:39]3)[C:12]2=[O:24])[CH2:10][CH2:9]1)=[O:7]
Reactant: Cc1ccccc1N1C(=O)NC(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2
Reactant: O=C1NCC(CCl)O1
Product: Cc1ccccc1N1C(=O)N(CC2CNC(=O)O2)C(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2

Procedure:
The title compound, MS: m/e=599.0 (M+), was prepared in accordance with the general method of example 99 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-o-tolyl-1,3,8-triaza-spiro[4.5]decane-2,4-dione and 5-chloromethyl-2-oxazolidinone.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][S:8](Cl)(=[O:10])=[O:9].C(OCC)C.[CH3:17][NH:18][CH3:19]>C(#N)C>[CH3:17][N:18]([CH3:19])[S:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)CCCCCCCl
Reactant: CNC
Solvent: CC#N
Solvent: CCOCC
Product: CN(C)S(=O)(=O)CCCCCCCl
Reaction time: 0.33 h
Yield: 96.4 %

Procedure:
6-Chlorohexanesulfonyl chloride (6.57g, 30 mmol) was added dropwise to a solution of diethyl ether (60 ml) and a 12% acetonitrile solution of dimethylamine (24.8 g, 66 mmol) with stirring under ice-cooling. Thereafter, the mixture was stirred at the same temperature for 20 minutes. The reaction mixture was concentrated in vacuo. Thereafter, the concentrate was diluted with diethyl ether (60 ml). The resulting solution was washed twice with water (10 ml) and then with brine (10 ml), and thereafter dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The crude product was purified by column chromatography on silica gel with ethyl acetate-n-hexane (1:4), to give N,N-dimethyl-6-chlorohexanesulfonamide (6.59 g) as a pale yellow oil.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:16])[C:8]3[N:9]2[C:12](=[O:15])[NH:13][N:14]=3)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[CH2:20]([C:23]1[NH:24][CH:25]=[CH:26][N:27]=1)[CH2:21][CH3:22]>>[CH2:20]([C:23]1[N:24]([C:2]2[CH:11]=[C:10]3[C:5]([NH:6][C:7](=[O:16])[C:8]4[N:9]3[C:12](=[O:15])[NH:13][N:14]=4)=[CH:4][C:3]=2[N+:17]([O-:19])=[O:18])[CH:25]=[CH:26][N:27]=1)[CH2:21][CH3:22]
Reactant: O=c1[nH]c2cc([N+](=O)[O-])c(F)cc2n2c(=O)[nH]nc12
Reactant: CCCc1ncc[nH]1
Product: CCCc1nccn1-c1cc2c(cc1[N+](=O)[O-])[nH]c(=O)c1n[nH]c(=O)n12

Procedure:
The title compound was prepared from 8-fluoro-7-nitro[1,2,4]triazolo[4,3-a]quinoxaline-1,4(2H,5H)-dione and 2-n-propylimidazole by a method analogous to the method described in example 11. M.p. 260° C. decomp.
Reaction SMILES: [CH3:1][N:2]([CH:15](Cl)[CH:16]([CH3:18])C)[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1.[C-:20]#[N:21].[K+].C1OCCOCCOCCOCCOCCOC1.O>C(#N)C>[CH3:1][N:2]([CH:15]([CH2:16][CH3:18])[C:20]#[N:21])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1
Reactant: COc1ccc(CCN(C)C(Cl)C(C)C)cc1OC
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCC(C#N)N(C)CCc1ccc(OC)c(OC)c1
Yield: 87 %

Procedure:
4.67 g of 3-((N-methyl-N-(2-(3,4-dimethoxyphenyl)ethyl)-amino-2-methylpropyl chloride was dissolved in 40 ml of acetonitrile, followed by the addition of 2.13 g of potassium cyanide and 0.1 g of 18-crown-6. The obtained mixture was heated under reflux for 40 hours, followed by the addition of water. The obtained mixture was extracted with ethyl acetate. The ethyl acetate phase was washed with water and a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was purified by silica gel column chromatography [solvent: n-hexane/ethyl acetate (1:1)] to obtain 3.93 g of the title compound as a pale yellow oil (yield: 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][CH2:9][NH:8]2)=[CH:4][CH:3]=1.[CH:14]1[C:19]([C:20]([CH2:22][CH2:23][CH2:24]Cl)=[O:21])=[CH:18][CH:17]=[C:16]([F:26])[CH:15]=1.C(=O)([O-])[O-].[K+].[K+].C(C(C)=O)C>C(OCC)C.O>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][CH2:9][N:8]2[CH2:24][CH2:23][CH2:22][C:20](=[O:21])[C:19]2[CH:14]=[CH:15][C:16]([F:26])=[CH:17][CH:18]=2)=[CH:4][CH:3]=1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Reactant: Clc1ccc(CC2CCCN2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCC(C)=O
Solvent: O
Product: O=C(CCCN1CCCC1Cc1ccc(Cl)cc1)c1ccc(F)cc1
Yield: 27.2 %

Procedure:
Boil 4 g of 2-(4-chlorobenzyl)pyrrolidine, 6.8 g of ω-chloro-4-fluorobutyrophenone, 4.2 g of potassium carbonate and 20 ml of methyl ethyl ketone under reflux for 68 hours. After cooling the resulting reaction mixture to ambient temperature, add 50 ml of water and 50 ml of diethyl ether. Collect the ether phase and dry it over sodium sulfate. Concentrate the dried ether phase to a brown oil before distilling it under a high vacuum to obtain 2.0 g of the title compound as viscous light-brown oil of b.p. 188° to 192° at 0.02 mm of Hg.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8](C=O)[CH2:7][CH2:6]1)#[N:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:24](N)[CH2:25][NH2:26]>>[NH:26]1[CH2:25][CH2:24][N:2]=[C:1]1[CH2:3][CH2:4][CH:5]1[CH2:6][CH2:7][NH:8][CH2:9][CH2:10]1
Reactant: N#CCCC1CCN(C=O)CC1
Reactant: NCCN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: C1CNC(CCC2CCNCC2)=N1
Temperature: 200 °C

Procedure:
A mixture containing 4-(2-cyanoethyl)-1-piperidinecarboxaldehyde (10 g, 0.06 M) and ethylenediamine p-toluenesulfonate (30 g, 0.129 M) were heated at 200° C. for 41/2 hours. Crystallization of the crude reaction mixture from isopropanol (70 ml) yielded the desired product as the di-p-toluenesulfonate salt (14 g). The salt was then basified with 2 equivalents of MeONa and distilled (0.2 mmHg, 170° C.) to give 4-[2-(4,5-dihydro-1H-imidazol-2-yl)ethyl]piperidine (4.1 g, 37% yield).
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C@H:3]([N:29]1[CH2:33][CH2:32][C@H:31]([NH:34]C(=O)OC(C)(C)C)[CH2:30]1)[C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([C:13]3[C:22]([F:23])=[CH:21][C:20]4[C:15](=[CH:16][C:17]([O:24][CH2:25][CH2:26][O:27][CH3:28])=[CH:18][CH:19]=4)[N:14]=3)=[N:11][N:12]=2)[CH:9]=1.Cl>C(Cl)Cl.CC(O)C>[F:43][C:2]([F:1])([F:42])[C@H:3]([N:29]1[CH2:33][CH2:32][C@H:31]([NH2:34])[CH2:30]1)[C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([C:13]3[C:22]([F:23])=[CH:21][C:20]4[C:15](=[CH:16][C:17]([O:24][CH2:25][CH2:26][O:27][CH3:28])=[CH:18][CH:19]=4)[N:14]=3)=[N:11][N:12]=2)[CH:9]=1
Reactant: COCCOc1ccc2cc(F)c(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc2c1
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)O
Product: COCCOc1ccc2cc(F)c(-c3nnc4ccc([C@@H](N5CC[C@H](N)C5)C(F)(F)F)cn34)nc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
To a solution of tert-butyl (3S)-1-((1R)-2,2,2-trifluoro-1-(3-(3-fluoro-7-(2-methoxyethoxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-ylcarbamate (0.096 g, 0.159 mmol) in DCM (0.5 mL) was added 5 N HCl (0.530 mL, 2.65 mmol) in IPA. The reaction mixture was stirred at ambient temperature for 2 hours. The solvent was removed under reduced pressure. The crude residue was suspended in ACN (5 mL) and stirred at ambient temperature for 10 minutes. The solid was collected by filtration to give (3S)-1-((1R)-2,2,2-trifluoro-1-(3-(3-fluoro-7-(2-methoxyethoxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-amine (0.078 g, 0.135 mmol, 85% yield) as a solid. LCMS APCI (+) m/z 505 (M+H).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[CH:7]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O)([CH3:9])[CH3:8].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:7]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:2]1[N:3]=[CH:4][NH:5][CH:6]=1)([CH3:9])[CH3:8]
Reactant: CC(C)Oc1ccccc1B(O)O
Reactant: Brc1c[nH]cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)Oc1ccccc1-c1c[nH]cn1
Yield: 72.9 %

Procedure:
Add tetrakis(triphenylphosphine)palladium(0) (500 mg) to a degassed suspension of 4-bromo-1H-imidazole (5.0 g, 34 mmol) and 2-isopropoxyphenyl boronic acid (9.19 g, 51 mmol) in dioxane (250 mL) and 2 M sodium carbonate solution (10.81 g, 102 mmol) at room temperature under nitrogen and heat the mixture at reflux for 21 hours. Remove the solvent under reduced pressure, dilute the residue with ethyl acetate (500 mL) and filter through a plug of Celite. Dry the filtrate over sodium sulfate, treat with silica gel (20 g) and remove the solvent under reduced pressure. Purify the residue by flash column chromatography on silica gel, eluting with ethyl acetate, to afford crude 4-(2-isopropoxyphenyl)-1H-imidazole (5.01 g, 73%) which is used without further purification in the next step.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[CH2:9]([NH2:13])[CH:10]([CH3:12])[CH3:11].[BH4-].[Na+]>CO>[Br:1][C:2]1[O:6][C:5]([CH2:7][NH:13][CH2:9][CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)o1
Reactant: CC(C)CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CNCc1ccc(Br)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.4 %

Procedure:
To a stirred solution of 5-bromo-2-furaldehyde (500 mg) in methanol (5 mL) was added isobutylamine (209 mg). The mixture was stirred overnight at r.t. Sodium borohydride (162 mg) was added and the mixture was stirred for 2 h. The solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed with water. The organic phase was dried (MgSO4), filtered and concentrated under reduced pressure to give the crude (5-bromo-furan-2-ylmethyl)-isobutyl-amine (686 mg) as a colorless oil which was used in the next step without further purification.
Reaction SMILES: C(OC([N:8]1[CH:17]([C:18](=[O:52])[NH:19][CH:20]([CH2:44][C:45]2[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][CH:46]=2)[C:21]([N:23]2[CH2:28][CH2:27][N:26]([CH:29]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[F:43])[CH2:30][NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH2:25][CH2:24]2)=[O:22])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>>[ClH:51].[Cl:51][C:48]1[CH:47]=[CH:46][C:45]([CH2:44][CH:20]([NH:19][C:18]([CH:17]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][NH:8]2)=[O:52])[C:21]([N:23]2[CH2:24][CH2:25][N:26]([CH:29]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[F:43])[CH2:30][NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH2:27][CH2:28]2)=[O:22])=[CH:50][CH:49]=1
Reactant: CC(C)C(=O)NCC(c1ccccc1F)N1CCN(C(=O)C(Cc2ccc(Cl)cc2)NC(=O)C2Cc3ccccc3CN2C(=O)OC(C)(C)C)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(=O)NCC(c1ccccc1F)N1CCN(C(=O)C(Cc2ccc(Cl)cc2)NC(=O)C2Cc3ccccc3CN2)CC1
Product: Cl
Reaction time: 16 h
Yield: 42 %

Procedure:
3-(1-(4-Chloro-benzyl)-2-{4-[1-(2-fluoro-phenyl)-2-isobutyrylamino-ethyl]-piperazin-1-yl}-2-oxo-ethylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester: To a mixture of 0.26 g (0.56 mmol) of product from Preparation SM3, 0.15 g (0.51 mmol) of material from part B and 0.21 g (0.56 mmol) of O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate in 2 ml of dichlorormethane is added 0.10 mL (0.56 mmol) of N,N-diisopropylethylamine. The mixture is stirred for 16 hr and washed with 10% aqueous sodium bisulfate. After the organic portion is separated, the aqueous portion is saturated with sodium chloride and extracted three times with dichloromethane. The combined organics are dried (Na2SO4), filtered and concentrated in vacuo. Chromatography (Biotage, 5% ethanol, ethyl acetate) affords 0.17 g (42%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[NH:11][C:10]2[C:9](=O)[NH:8][C:7]([NH2:13])=[N:6][C:5]=2[N:4]=1.P(Cl)(Cl)([Cl:18])=O>>[NH2:13][C:7]1[N:6]=[C:5]2[C:10]([NH:11][C:3]([C:2]([F:15])([F:14])[F:1])=[N:4]2)=[C:9]([Cl:18])[N:8]=1
Reactant: Nc1nc2nc(C(F)(F)F)[nH]c2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Nc1nc(Cl)c2[nH]c(C(F)(F)F)nc2n1

Procedure:
A suspension of 8-trifluoromethylguanine (Pfleiderer and Shanshal, Liebigs Ann. Chem., 726, 201-215 (1969)) (2.0 g, 9.1 mmol) in phosphorous oxychloride (20 mL) was refluxed for 3 h. Excess phosphorous oxychloride was evaporated under reduced pressure. The resulting residue was mixed with ice-water (100 g), and the pH was adjusted to 3-4 with a concentrated aqueous NaOH solution. The resulting solution was mixed with MeOH (100 mL) and approximately half (i.e., 100 mL) of the aqueous methanol solution was loaded on a 3×80 cm Sephadex LH-20 column eluted with methanol/water (1:1) at 1 mL/min. Column eluent was continuously monitored at 280 nm and fractions (10 mL) were collected. The remainder of the reaction mixture in MeOH/H2O was chromatographed separately under identical conditions. The desired product eluted in fractions 73-85. Evaporation of solvent from the pooled fractions 73-85 from both chromatographic runs afforded analytically pure 2-amino-6-chloro-8-trifluoromethylpurine: yield,0.94 g (43%); mp >225° C. dec.; UV (pH 1) λmax 245 nm (ε=0.501×104), 314 (0.746××104); (pH 6.9) 270 (0.265 ×104), 315 (0.612×104); (pH 13) 272 (0.269×104 ), 314 (0.612×104); 1H NMR δ 7.19 (s, 2 H, NH2, exchange with D2O), 14.25 (br s, 1 H, NH, exchanges with D2O); MS (EI) calcd. m/z for C6H3 N5F335Cl 237.0029, found 237.0011; calcd. m/z for C6H3N5F337Cl 239.0000, found 238.9987; Anal. (C6H3N5F3C) C, H, N, F, Cl.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:32]/[OH:33])/[C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([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.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:53][C@H:54]1[CH2:59][CH2:58][C@H:57](O)[CH2:56][CH2:55]1.N(C(OCC)=O)=NC(OCC)=O>C1C=CC=CC=1>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:32]/[O:33][C@H:57]2[CH2:58][CH2:59][C@@H:54]([Cl:53])[CH2:55][CH2:56]2)/[C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O[C@H]1CC[C@H](Cl)CC1
Reactant: CCOC(=O)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CCOC(=O)/C(=N\O[C@H]1CC[C@@H](Cl)CC1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1

Procedure:
Ethyl 2-(2-tritylaminothiazol-4-yl)-(Z)-2-(hydroxyimino)acetate (0.91 g), triphenylphosphine (0.58 g) and trans-4-chlorocyclohexanol (0.54 g) were dissolved together in anhydrous benzene (20 ml). Diethyl azodicarboxylate (0 35 ml) was added and the solution heated at reflux for 16 h with exclusion of moisture. Evaporation of solvent followed by chromatography afforded the title compound as a near colourless gum (225 mg, 20%); νmax (KBr) 1737, 1595 (w), 1529, 1491 and 1446 cm-1 ; δHH (CDCl3) 1.39 (3H, t, J 7 Hz), 1.69, 1.96 and 2.06 (8H, 3m), 4.04 (1H, qt, J 6 Hz), 4.39(2H, q, J 7Hz), 4.44 (1H, qt, J 3 Hz), 6.49 (1H, s), 6.97 (1H, brs, D2O exch), and 7.32 (15H, s). [Mass spectrum: +ve ion (thioglycerol) MH+ (574), MNa+ (596)].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:7](=[O:8])[O:6][CH2:5]2.[CH3:12][O:13][C:14]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:15]=1[CH:16]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CC(O)=O.CN(C=O)C.CCOC(C)=O>[CH3:12][O:13][C:14]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:15]=1[CH2:16][NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:7](=[O:8])[O:6][CH2:5]2
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: Nc1ccc2c(c1)COC2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COc1ccc(CNc2ccc3c(c2)COC3=O)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.4 %

Procedure:
To a stirred solution of 5-aminophthalide (11.7 g, 78 mmol) and 2,4-dimethoxybenzaldehyde (15.5 g, 93.6 mmol) in 1% AcOH/DMF (60 ml), was added sodium triacetoxyborohydride (50.0 g, 236 mmol). The mixture was stirred at room temperature for 16 hours, diluted with EtOAc (400 ml), washed with saturated NaHCO3 solution (3×400 ml) and water (400 ml), dried over anhydrous Na2SO4, and evaporated to provide a crude product. Trituration of the crude product with MEOH gave 5-(2,4-dimethoxy-benzylamino)-3H-isobenzofuran-1-one as an off-white powder (19.0 g, 82%).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10](C(Cl)(Cl)Cl)[N:9]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH2:22])[N:17]=3)[C:8]=2[CH:23]=1.[O:24]1[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26][CH2:25]1>CN(C)C=O>[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([O:30][CH:27]3[CH2:28][CH2:29][O:24][CH2:25][CH2:26]3)[N:9]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH2:22])[N:17]=3)[C:8]=2[CH:23]=1
Reactant: Nc1nccc(-n2c(C(Cl)(Cl)Cl)nc3ccc(Br)cc32)n1
Reactant: OC1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1nccc(-n2c(OC3CCOCC3)nc3ccc(Br)cc32)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.4 %

Procedure:
Sodium hydride (200 mg, 5.00 mmol, 60% dispersion in mineral oil) was added in several portions into a solution of 4-[6-bromo-2-(trichloromethyl)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine (500 mg, 1.23 mmol) and oxan-4-ol (1.00 g, 9.79 mmol) in N,N-dimethylformamide (10 mL) under an atmosphere of nitrogen. The reaction mixture was stirred overnight at room temperature and then filtered through a frit filter. The filtrate was purified on a C18 column (acetonitrile/water, 5:95-80:20) to give 170 mg (28%) of 4-[6-bromo-2-(oxan-4-yloxy)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine as a brown solid. LC-MS: m/z=+390 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:10]#[CH:11])[CH:6]=[CH:7][C:8]=1[OH:9].[CH3:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][SH:18])=[CH:15][CH:14]=1.[Na]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[OH:9])/[CH:10]=[CH:11]\[CH:17]([S:18][CH:12](/[CH:11]=[CH:10]\[C:5]1[CH:6]=[CH:7][C:8]([OH:9])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:13]1[CH:20]=[CH:19][C:16]([CH3:17])=[CH:15][CH:14]=1)[C:16]1[CH:19]=[CH:20][C:13]([CH3:12])=[CH:14][CH:15]=1
Reactant: Cc1ccc(CS)cc1
Reactant: C#Cc1ccc(O)c(OC)c1
Agent: [Na]
Product: COc1cc(/C=C\C(SC(/C=C\c2ccc(O)c(OC)c2)c2ccc(C)cc2)c2ccc(C)cc2)ccc1O

Procedure:
A solution of 3-methoxy-4-hydroxyphenylacetylene (0.02 mol), 4-methylbenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) is subjected to the General Procedure to form (Z)-3-methoxy-4-hydroxystyryl-4-methylbenzylsulfide. The title compound is obtained following oxidation of the sulfide, according to the General Procedure.
Reaction SMILES: N1CCCCC1.[CH2:7]([O:10][CH2:11][C:12](=O)[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:8]#[CH:9].[Cl:20][C:21]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]=O.[NH2:30]/[C:31](/[CH3:37])=[CH:32]\[C:33]([O:35][CH3:36])=[O:34]>C(O)(C)C>[Cl:20][C:21]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]1[C:32]([C:33]([O:35][CH3:36])=[O:34])=[C:31]([CH3:37])[NH:30][C:12]([CH2:11][O:10][CH2:7][C:8]#[CH:9])=[C:13]1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: COC(=O)/C=C(/C)N
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: C#CCOCC(=O)CC(=O)OCC
Solvent: C1CCNCC1
Solvent: CC(C)O
Product: C#CCOCC1=C(C(=O)OCC)C(c2cccc(Cl)c2Cl)C(C(=O)OC)=C(C)N1
Temperature: 25 °C
Reaction time: 24 h
Yield: 19.9 %

Procedure:
Piperidine (2.4 g) was added dropwise over 10 minutes to a stirred mixture of ethyl 4-(prop-2-ynoxy)acetoacetate (63 g) and 2,3-dichlorobenzaldehyde (60 g) in isopropanol (600 ml) and the mixture was stirred at room temperature for 24 hours. The mixture was then treated with methyl 3-aminocrotonate (39 g), stirred at room temperature for four days and evaporated. The residual oil was dissolved in methanol (300 ml) and the solution kept at -20° for two days. The resulting solid was collected, washed with cold methanol and dried to give the title compound (29.5 g), m.p. 104°-105°, which was used directly.