Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]([CH2:10][C:11]([OH:13])=O)[CH3:9])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][OH:20]>C(O)C>[C:4]([O:3][C:1](=[O:2])[N:8]([CH2:10][C:11](=[O:13])[NH:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][OH:20])[CH3:9])([CH3:5])([CH3:6])[CH3:7]
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: NCCOCCO
Solvent: CCO
Product: CN(CC(=O)NCCOCCO)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
BOC-sarcosine (900 mg, 4.76 mmol) was dissolved in ethanol (10 ml). 2-(2-Aminoethoxy)ethanol (0.477 ml, 4.76 mmol) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride n-hydrate (DMT-MM) (1.79 g, 5.71 mmol) were added and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and water was added to the resulting residue, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (dichloromethane-methanol) to give {[2-(2-hydroxy-ethoxy)-ethylcarbamoyl]-methyl}-methyl-carbamic acid tert-butyl ester. This was used in the next reaction without complete purification.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([NH:9][CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]([C:15]#[C:16][CH2:17][N:18]2[CH2:23][CH2:22][N:21](C(O)=O)[CH2:20][CH2:19]2)=[CH:5][N:4]=1)#[N:2]>O1CCOCC1.Cl>[CH3:12][C:11]([CH3:14])([CH3:13])[CH2:10][NH:9][C:7]1[C:6]([C:15]#[C:16][CH2:17][N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[CH:5][N:4]=[C:3]([C:1]#[N:2])[N:8]=1
Reactant: CC(C)(C)CNc1nc(C#N)ncc1C#CCN1CCN(C(=O)O)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)CNc1nc(C#N)ncc1C#CCN1CCNCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 72 %

Procedure:
To a solution of 4-{3-[2-cyano-4-(2,2-dimethyl-propylamino)-pyrimidin-5-yl]-prop-2-ynyl}-piperazine-1-carboxylic acid .tert.-butyl ester (2.9 mmol) in dioxane (5 ml), 4N hydrogenchloride in dioxane(15 ml) is added at 0° C. The reaction mixture is stirred at room temperature for 1 day and then evaporated under reduced pressure. To a solution of residual solid, CH2Cl2 is added at room temperature, pH is adjusted to 9.0 by triethylamine. The mixture is quenched with ammonium chloride and extracted with CH2Cl2. The combined extracts are washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue is purified by silica gel column chromatography to afford title compound in 72% yield. Rf=0.11 (MeOH:CH2C2=1:9)
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]([C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1.N1(C2CCCCCCCCCC2)CCCCCC[CH2:18][CH2:17][CH2:16]N1.BrC(C)C>C1C=CC=CC=1>[CH:17]([N:3]1[C:4]([C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=[C:2]1[Br:1])([CH3:18])[CH3:16]
Reactant: C1CCCCCC(N2CCCCCCCCCN2)CCCC1
Reactant: Cc1nc(Br)[nH]c1C(=O)OC(C)C
Solvent: CC(C)Br
Solvent: c1ccccc1
Product: Cc1nc(Br)n(C(C)C)c1C(=O)OC(C)C
Temperature: 25 °C
Yield: 68.3 %

Procedure:
To a solution of 2 g (8.1×10-3 moles) of isopropyl 2-bromo-4-methyl-5-imidazolecarboxylate in 20 ml of benzene was added 1.2 ml (8.2×10-3 moles) of diazabicycloundecane, followed by 1.0 g. (8.1×10-3 moles) of 2-bromopropane. The resulting mixture was heated to reflux overnight, cooled to room temperature and filtered. Concentration in vacuo gave a golden oil. This residue was purified by medium pressure liquid chromatography on silica gel to yield 1.6 g (70%) isopropyl 1-isopropyl-2-bromo-4-methyl-5-imidazolecarboxylate as a yellow oil, but only 466 milligrams (20%) of the desired product, isopropyl 2-bromo-3-isopropyl-4-methyl-5-imidazolecarboxylate (also a yellow oil), wherein S1 and S3 and R were all CH(CH3)2.
Reaction SMILES: O=P(Cl)(Cl)Cl.[Cl:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([NH2:13])=O)=[C:9]([O:16][CH2:17][CH:18]([F:20])[F:19])[N:8]=1.[OH-].[Na+]>C(#N)C>[Cl:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]#[N:13])=[C:9]([O:16][CH2:17][CH:18]([F:19])[F:20])[N:8]=1
Reactant: NC(=O)c1ccc(Cl)nc1OCC(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1ccc(Cl)nc1OCC(F)F
Temperature: 60 °C

Procedure:
POCl3 (7.5 mL, 81 mmol) was added to a solution of 6-chloro-2-(2,2-difluoro-ethoxy)-nicotinamide (6.39 g, 27.0 mmol) in acetonitrile (100 mL) at 14° C. over 5 minutes. The reaction mixture was heated to 60° C. for 1.5 hours then cooled to room temperature. The mixture was poured into an ice cold solution of aqueous NaOH (0.6M, 800 mL) and extracted with EtOAc (4×800 mL). The organic extracts were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash column chromatography (20% ethyl acetate/hexanes) to give the title compound as a light yellow oil which solidified upon standing (5.10 g, 86%).
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[C:7]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17](=[O:26])[NH:18][C:19]1[S:20][CH:21]=[C:22]([S:24][CH3:25])[N:23]=1)(=[O:9])[CH3:8]>O.CO>[C:7]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17](=[O:26])[NH:18][C:19]1[S:20][CH:21]=[C:22]([S:24]([CH3:25])=[O:1])[N:23]=1)(=[O:9])[CH3:8]
Reactant: CSc1csc(NC(=O)c2ccccc2OC(C)=O)n1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(=O)Oc1ccccc1C(=O)Nc1nc(S(C)=O)cs1
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 100 %

Procedure:
A solution of Oxone® (2.71 g, 4.44 mmol) dissolved in a minimum amount of water (15.0 mL) was added to a cold solution (0° C.) of 509 (0.514 g, 1.47 mmol) dissolved in a minimum amount of methanol (200 mL). On addition of the Oxone® solution a white solid precipitated. Additional methanol (100 mL) was added to the reaction. After stirring 25 min at 0° C., a saturated aqueous solution of Na2S2O3 was added to the reaction. The reaction was concentrated to remove excess methanol. The aqueous residue was washed four times with dichloromethane. The combined dichloromethane layers were washed with brine, dried over sodium sulfate and concentrated in vacuo to give crude 1 (0.66 g, >100%) as a white foam. This residue was dissolved in ethyl acetate and loaded onto a 90 g silica gel column that had been pre-equilibrated with ethyl acetate. The column was eluted with ethyl acetate. Like fractions of pure product were combined and concentrated in vacuo. The residue was stirred with ether and evaporated in vacuo to give 1 (0.288 g, 60%) as a white solid. 1H-NMR showed clean desired product contaminated with traces of residual dichloromethane and ethyl acetate. HPLC analysis indicated the product to be 95% pure (tR=5.01 min, Condition C) contaminated with 3% of 2 (tR=5.33 min, Condition C).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.Cl.[F:10][C:11]1([F:15])[CH2:14][NH:13][CH2:12]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:13]2[CH2:14][C:11]([F:15])([F:10])[CH2:12]2)=[N:6][CH:7]=1
Reactant: FC1(F)CNC1
Reactant: Clc1ncc(Br)cn1
Agent: Cl
Product: FC1(F)CN(c2ncc(Br)cn2)C1

Procedure:
The title compound was prepared following a procedure analogous to that described for Intermediate 27 using 5-bromo-2-chloropyrimidine and 3,3-difluoroazetidine hydrogen chloride salt. LC (method 5): tR=1.57 min; Mass spectrum (ESI+): m/z=250/252 (Br) [M+H]+.
Reaction SMILES: Cl.O.[NH2:3][CH:4]([C:11]([OH:13])=[O:12])[CH2:5][C:6]1[N:10]=[CH:9][NH:8][CH:7]=1.Cl.O>O>[NH2:3][C@H:4]([C:11]([OH:13])=[O:12])[CH2:5][C:6]1[N:10]=[CH:9][NH:8][CH:7]=1
Reactant: NC(Cc1c[nH]cn1)C(=O)O
Agent: Cl
Solvent: O
Product: N[C@@H](Cc1c[nH]cn1)C(=O)O
Reaction time: 20 h

Procedure:
HCl.H2O: D,L-His.HCl.H2O (3.2 g) and the appropriate polymer were slurried in water (5 ml) and the slurry was heated to complete dissolution. The hot solution was filtered and allowed to stand at 50° C. for 20 hrs without agitation. The crystals were collected by filtration and the enantiomeric excess was determined. The results are summarized in Table VI.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].O.[C:13]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:13][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[F:11]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)c1cc(Br)ccc1F
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(Br)ccc1F
Yield: 91.9 %

Procedure:
Heat a solution of 5-bromo-2-fluorobenzoic acid (20 g, 92 mmol) and p-toluenesulfonic acid monohydrate (52 g, 275 mmol) in methanol (200 mL) at reflux overnight. Concentrate and dissolve the residue in ethyl acetate, wash twice with an aqueous saturated solution of sodium bicarbonate, once with an aqueous saturated solution of sodium chloride, dry (sodium sulfate), filter and concentrate to give the title compound as a clear liquid (19.7 g, 92%).
Reaction SMILES: Br.[Br:2][C:3]1[CH:4]=[C:5]([CH2:10]Br)[C:6]([NH2:9])=[N:7][CH:8]=1.Cl.[CH3:13][O:14][C:15](=[O:19])[C@@H:16]([CH3:18])[NH2:17].C(N(CC)CC)C>CN(C=O)C>[NH2:9][C:6]1[C:5]([CH2:10][NH:17][C@H:16]([CH3:18])[C:15]([O:14][CH3:13])=[O:19])=[CH:4][C:3]([Br:2])=[CH:8][N:7]=1
Reactant: COC(=O)[C@@H](C)N
Reactant: Nc1ncc(Br)cc1CBr
Agent: Br
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](C)NCc1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.5 %

Procedure:
To a solution of 5-bromo-3-(bromomethyl)pyridin-2-amine hydrobromide (2.5 g, 7.3 mmol) in DMF (10 mL) was added D-alanine methyl ester hydrochloride (1.67 g, 10.9 mmol) and triethylamine (5 mL, 36 mmol) and the reaction was stirred at room temperature overnight. The reaction is quenched with water (20 mL) and the product was extracted with ethyl acetate (4×20 mL), the combined organic layers dried over sodium sulfate and concentrated. The crude reaction mixture was purified using a silica gel column eluting with ethyl acetate to give the final product as a white solid (1 g, 50%): 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 7.35 (s, 1H), 5.54 (bs, 2H), 3.73 (d, 1H, J=13.2 Hz), 3.54 (d, 1H, J=13.2 Hz), 3.36-3.34 (m, 1H), 2.96 (s, 3H), 1.35 (d, 3H, J=6.8 Hz).
Reaction SMILES: [O:1]=[S:2]1(=[O:19])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=2)[CH2:9][CH2:8]1.[CH3:20][C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH3:20][C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=1[N:28]1[CH2:29][CH2:30][N:31]([C:14]([C:13]2[CH:17]=[CH:18][C:10]([C:7]3([N:3]4[CH2:4][CH2:5][CH2:6][S:2]4(=[O:1])=[O:19])[CH2:8][CH2:9]3)=[CH:11][CH:12]=2)=[O:16])[CH2:32][CH2:33]1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Reactant: O=C(O)c1ccc(C2(N3CCCS3(=O)=O)CC2)cc1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(C4(N5CCCS5(=O)=O)CC4)cc3)CC2)c(C)c1
Yield: 80.7 %

Procedure:
Using 4-[1-(1,1-dioxo-1λ6-isothiazolidin-2-yl)cyclopropyl]benzoic acid (141 mg) described in Preparation Example 31 and 1-(2,4-dimethylphenyl)piperazine (95.1 mg) and by the reaction and treatment in the same manner as in Example 87, the title compound (183 mg) was obtained.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19][OH:20])=[C:17]([O:23][CH:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)[CH:16]=1)([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl>[C:11]([C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[C:17]([O:23][CH:24]2[CH2:25][CH2:26][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:28][CH2:29]2)[CH:16]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(C(C)(C)C)ccc2CO)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(C(C)(C)C)ccc2C=O)CC1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 101 %

Procedure:
To a solution of oxalyl chloride (0.30 mL, 3.46 mmol) in dichloromethane (5 mL) stirring at −78° C. under nitrogen atmosphere, dimethylsulfoxide was added dropwise (0.49 mL, 6.93 mmol). After 10 min, a solution of the crude 4-(tert-butyl)-2-(1-Boc-piperidine-4-yloxy)benzyl alcohol (0.42 g, 1.15 mmol) in dichloromethane (6 mL) was added slowly via cannula. After the addition was complete, the reaction mixture was stirred at −78° C. for 1 h. The reaction was then treated with triethylamine (1.6 mL, 11.5 mmol) and allowed to warm up to room temperature overnight. The reaction mixture was partitioned between brine and dichloromethane. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried with magnesium sulfate, filtered, and concentrated in vacuo to a brown residue which was purified on a silica gel chromatotron plate. Elution with ethyl acetate-hexanes (1:5) afforded the title compound (0.42 g, 100%) as a clear oil which foamed up under vacuum.
Reaction SMILES: Cl[CH:2]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:3]1[O:4][C:5]2[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=2[C:7]=1[CH3:8].[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([NH:28][CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])=[O:27])=[CH:22][CH:21]=1>>[CH:13]1([CH:2]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]([NH:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:27])=[CH:24][CH:25]=2)[C:3]2[O:4][C:5]3[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=3[C:7]=2[CH3:8])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Reactant: Cc1c(C(Cl)C2CCCCC2)oc2ccccc12
Product: Cc1c(C(Nc2ccc(C(=O)NCCC(=O)O)cc2)C2CCCCC2)oc2ccccc12
Yield: 37.4 %

Procedure:
Using 2-[chloro(cyclohexyl)methyl]-3-methyl-1-benzofuran (433 mg) synthesized in Example A16(3) and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (390 mg) synthesized in Example 1(2) and in the same manner as, in Example A7(3), the title object compound (268 mg, 37%) was obtained as a white solid.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:24]=[CH:23][C:22]3[C@@H:21]4[C@H:12]([C@H:13]5[C@@:17]([CH2:19][C@@H:20]4[C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][S:37]([CH2:39][CH2:40][CH2:41][C:42]([F:48])([F:47])[C:43]([F:46])([F:45])[F:44])=[O:38])=[CH:27][CH:26]=4)([CH3:18])[C@@H:16]([OH:49])[CH2:15][CH2:14]5)[CH2:11][CH2:10][C:9]=3[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:58])C=1>>[CH:1]1([O:6][C:7]2[CH:24]=[CH:23][C:22]3[C@@H:21]4[C@H:12]([C@H:13]5[C@@:17]([CH2:19][C@@H:20]4[C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][S:37]([CH2:39][CH2:40][CH2:41][C:42]([F:47])([F:48])[C:43]([F:44])([F:45])[F:46])(=[O:58])=[O:38])=[CH:27][CH:26]=4)([CH3:18])[C@@H:16]([OH:49])[CH2:15][CH2:14]5)[CH2:11][CH2:10][C:9]=3[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C[C@]12C[C@H](c3ccc(OCCCCCS(=O)CCCC(F)(F)C(F)(F)F)cc3)[C@@H]3c4ccc(OC5CCCC5)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Product: C[C@]12C[C@H](c3ccc(OCCCCCS(=O)(=O)CCCC(F)(F)C(F)(F)F)cc3)[C@@H]3c4ccc(OC5CCCC5)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Yield: 79.4 %

Procedure:
By operating as in Example 56 using at the start 698 mg of the product obtained in Example 68 and 228 mg of metachloro perbenzoic acid, 567 mg of expected product is obtained. M.p.=166° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[C:6](Cl)[N:5]2[N:16]=[CH:17][N:18]=[C:4]2[N:3]=1.[CH:19]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20]1.C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[C:6]([NH:24][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[N:5]2[N:16]=[CH:17][N:18]=[C:4]2[N:3]=1
Reactant: NC1CCCC1
Reactant: Cc1ccc(-c2c(Cl)nc3ncnn3c2Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(Cl)nc3ncnn3c2NC2CCCC2)cc1
Reaction time: 3 h
Yield: 86.4 %

Procedure:
5,7 Dichloro-6-(4-methylphenyl)-1,2,4-triazolo-[1,5-a]pyrimidine (1.8 g, 6 mmol) was dissolved in tetrahydrofuran. A solution of cyclopentylamine (0.51 g, 6 mmol) and triethylamine (0.61 g, 6 mmol) in tetrahydrofuran (2 ml) was then added with stirring and the stirring continued for a further 3 hours at ambient temperature (20° C.). The reaction mixture was then evaporated in vacuo and the residue extracted with dichloromethane and water (100 ml each). The organic layer was dried over sodium sulphate and the solvent evaporated in vacuo. The residue was crystallized from ethyl acetate to give 1.7 g 5-chloro-6-(4-methylphenyl)-7-cyclopentylamino-1,2,4-triazolo[1,5-a]pyrimidine as yellowish crystals, m.pt. 158° C. Yield: 87% of theoretical 1H-NMR: δ=1.3-1.75 (2 m, 8H); 2.43(s,1H); 3.73 (m,1H); 5.97 (d,1H); 7.25 (m,4H); 8.25(s,1H) ppm
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[CH:10][CH:9]=[C:8](I)[N:7]=1.[C:29]1([C:35]#[CH:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[CH:10][CH:9]=[C:8]([C:36]#[C:35][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:7]=1
Reactant: C#Cc1ccccc1
Reactant: COC(=O)CCc1nc(I)ccc1OCCCC/C=C/c1ccc(OC)cc1
Product: COC(=O)CCc1nc(C#Cc2ccccc2)ccc1OCCCC/C=C/c1ccc(OC)cc1
Yield: 56.5 %

Procedure:
Under the conditions of example 5 A, 500 mg of 3-{6-iodo-3-[6-(4-methoxyphenyl)-(5E)-5-hexenyloxy]-2-pyridyl}-propionic acid methyl ester is reacted with 102 mg of phenylacetylene, worked up, and the crude product is chromatographed on silica gel with hexane/0-7% ethyl acetate. 265 mg of 3-{3-[6-(4-methoxyphenyl)-(5E)-5-hexenyloxy]-6-(2-phenylethinyl)-2-pyridyl}-propionic acid methyl ester is obtained as oil.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([N:13]=[C:14]2[NH:18][CH2:17][C:16]3([CH2:22][CH2:21][CH2:20][CH2:19]3)[S:15]2)=[CH:5][CH:4]=1)#[N:2].[CH2:23](Br)[CH:24]([CH3:26])[CH3:25]>>[CH2:23]([N:18]1[CH2:17][C:16]2([CH2:19][CH2:20][CH2:21][CH2:22]2)[S:15][C:14]1=[N:13][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[CH:24]([CH3:26])[CH3:25]
Reactant: N#Cc1ccc(N=C2NCC3(CCCC3)S2)c2ccccc12
Reactant: CC(C)CBr
Product: CC(C)CN1CC2(CCCC2)SC1=Nc1ccc(C#N)c2ccccc12

Procedure:
1-Amino-1-(hydroxymethyl)cyclopentane was synthesized as described in Method B1c. The 2-hydroxyethylamine was reacted with SOCl2 according to Method B7a to give 1-amino-1-(chloromethyl)cyclopentane HCl salt. 1-Amino-4-cyanonaphthalene was converted into 4-cyano-1-naphthyl isothiocyanate according to Method A2a, Step 3. The 2-chloroethylamine was reacted with 4-cyano-1-naphthyl isothiocyanate to Method C1a to give 2-(4-cyano-1-naphthylimino)-1-thia-3-azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2b to give 3-isobutyl-2-(4-cyano-1-naphthylimino)-1-thia-3-azaspiro[4.4]nonane.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:9][C@H:8]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH:6]=1)=[O:4].CO[CH2:20][N:21]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:22][Si](C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:27]([N:21]1[CH2:22][C@@:5]2([C:3]([O:2][CH3:1])=[O:4])[CH2:9][C@H:8]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][C@H:6]2[CH2:20]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)C1=CC[C@@H](NC(=O)OC(C)(C)C)C1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@]12C[C@H](NC(=O)OC(C)(C)C)C[C@H]1CN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product from Step B (5.51 g, 20 mmol) and N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (6.4 mL, 24 mmol, Aldrich) in DCM (40 mL) was added 1M TFA in DCM (2.4 mL, 2.4 mmol) slowly. The resulting mixture was stirred at rt overnight and quenched by the addition of saturated aqueous NaHCO3 solution. The organic phase was washed with brine, dried over Na2SO4. Evaporation and purification by column chromatography (eluent: 10% EtOAc in hexanes to 20%) gave the desired isomer as a colorless gel. 1H-NMR (400 MHz, CDCl3) of the desired isomer: δ 1.38 (s, 9H), 1.66-1.86 (m, 2H), 1.86-1.96 (m, 1H), 1.96-2.08 (m, 1H), 2.29-2.63 (m, 3H), 2.71-2.93 (m, 2H), 3.43-3.56 (m, 2H), 3.58-3.74 (s, 3H), 4.08-4.29 (m, 1H), 4.78 (d, J=6.6 Hz, 1H), 7.11-7.31 (m, 5H). LC/MS: C24H28N2O4: m/z 375.2 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([O:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=2)[CH:3]=1.[BH4-].[Na+].B(F)(F)F.CCOCC>O1CCCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[C:4]([O:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=2)[CH:3]=1
Reactant: COc1cc(OC)cc(Oc2cc(Br)ccc2C(=O)O)c1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc(OC)cc(Oc2cc(Br)ccc2CO)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.5 %

Procedure:
To a solution of 75.4 g (F.W. 353.168, 213 mmol) of 4-bromo-2-(3,5-dimethoxyphenoxy)benzoic acid (22) in 300 mL of tetrahydrofuran was added 8.9 g (F.W. 37.83, 235 mmol) of sodium borohydride portionwise at room temperature and then, 31 mL (F.W. 141.93, d=1.154, 252 mmol) of boron trifluoride diethyl etherate was added thereto dropwise. The resulting solution was stirred at room temperature for one hour. To this reaction solution was added 200 mL of ice water slowly. The resulting solution was extracted with ethyl acetate and the extract was washed with a saturated sodium chloride aqueous solution three times. After drying with anhydrous magnesium sulfate, the solvent was removed under reduced pressure. The residue was recrystallized from benzene-diisopropyl ether to obtain 46.6 g (64%) of alcohol (23). (TLC; ethyl acetate:hexane=1:4).
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[CH:2]=[CH2:3].[S:10]1C=CC=C1.O1[CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH:3]12[S:10][CH:17]([CH:18]=[CH:19]1)[CH2:16][CH:2]2[C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: c1ccsc1
Reactant: C1CCOC1
Product: CC(C)(C)OC(=O)C1CC2C=CC1S2
Temperature: 70 °C
Reaction time: 24 h
Yield: 80 %

Procedure:
Tetrahydrofuran solvent (500 g), tert-butyl acrylate (1.2 mole) of Chemical Formula 3c below, and thiophene (1.0 mole) are introduced into a 2-liter flask, and the mixture is stirred at 70° C. for 24 hours. After the reaction is completed, the solvent and excess amount of tert-butyl acrylate are removed by using a rotary evaporator. The residue is distilled in vacuo to obtain pure tert-butyl 7-thiabicyclo[2.2.1]hept-5-ene-2-carboxylate represented by Chemical Formula 117 below (yield: 80%).
Reaction SMILES: [OH:1][CH:2]([CH3:6])[C:3](O)=[O:4].ClC(N(C)C)=C(C)C.[Br:15][C:16]1[CH:17]=[C:18]([NH2:24])[C:19]([O:22][CH3:23])=[N:20][CH:21]=1.CNC>C(Cl)Cl>[Br:15][C:16]1[CH:17]=[C:18]([NH:24][C:3](=[O:4])[CH:2]([OH:1])[CH3:6])[C:19]([O:22][CH3:23])=[N:20][CH:21]=1
Reactant: CC(O)C(=O)O
Reactant: COc1ncc(Br)cc1N
Agent: CC(C)=C(Cl)N(C)C
Agent: CNC
Solvent: ClCCl
Product: COc1ncc(Br)cc1NC(=O)C(C)O
Reaction time: 0.08 h
Yield: 32.5 %

Procedure:
2-Hydroxypropanoic acid (444 mg, 4.93 mmol) was dissolved in DCM (10 ml) and (1-chloro-2-methyl-1-propen-1-yl)dimethylamine (0.652 ml, 4.93 mmol) was added. The mixture was stirred for 5 mins, then 5-bromo-2-(methyloxy)-3-pyridinamine (500 mg, 2.463 mmol, available from Asymchem) was added and the reaction mixture was diluted with further DCM (5 ml). Stirring was continued at room temperature, then after 3 hours a further portion of chloro-2-methyl-1-propen-1-yl)dimethylamine (0.652 mL, 4.93 mmol) was added and the reaction was left stirring at room temperature overnight. The mixture was quenched with water and the separated DCM layer was washed with saturated sodium bicarbonate (aq) before passing through a hydrophobic frit and evaporation to dryness. The residue was stirred with 2M NaOH (aq., 5 ml). After stirring for 4 hours the resulting precipitate was collected by filtration and then dissolved in DCM and washed with 2M HCl (aq). The DCM layer was separated. The remaining aqueous layer was washed with ethyl acetate and the combined organics were evaporated to dryness to afford the title compound (220 mg).