Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)[C:3]([OH:5])=[O:4].[OH:8][C@H:9]([C:50]1[C:58]2[S:57][C:56](=[O:59])[NH:55][C:54]=2[C:53]([OH:60])=[CH:52][CH:51]=1)[CH2:10][N:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]2[CH2:49][CH2:48][C:32]3([O:37][CH2:36][CH2:35][N:34]([C:38]([C:40]4[N:41]=[C:42]([CH:45]([CH3:47])[CH3:46])[S:43][CH:44]=4)=[O:39])[CH2:33]3)[CH2:31][CH2:30]2)=[CH:22][CH:21]=1)C(=O)OC(C)(C)C.C1(C)C=CC=CC=1>C(Cl)Cl>[CH:3]([OH:5])=[O:4].[OH:60][C:53]1[C:54]2[NH:55][C:56](=[O:59])[S:57][C:58]=2[C:50]([C@@H:9]([OH:8])[CH2:10][NH:11][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][N:29]3[CH2:30][CH2:31][C:32]4([O:37][CH2:36][CH2:35][N:34]([C:38]([C:40]5[N:41]=[C:42]([CH:45]([CH3:47])[CH3:46])[S:43][CH:44]=5)=[O:39])[CH2:33]4)[CH2:48][CH2:49]3)=[CH:24][CH:25]=2)=[CH:51][CH:52]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCOc4ccc(CN(C[C@H](O)c5ccc(O)c6[nH]c(=O)sc56)C(=O)OC(C)(C)C)cc4)CC3)C2)cs1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCOc4ccc(CNC[C@H](O)c5ccc(O)c6[nH]c(=O)sc56)cc4)CC3)C2)cs1
Product: O=CO
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Trifluoroacetic acid (0.7 mL) was added to a solution of (R)-tert-butyl 2-hydroxy-2-(4-hydroxy-2-oxo-2,3-dihydrobenzo[d]thiazol-7-yl)ethyl(4-(2-(4-(2-isopropylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)ethoxy)benzyl)carbamate (example 108, step d) (0.122 g) in DCM (1.5 mL). The resulting mixture was stirred at RT for 10 min. Toluene (15 mL) was added and the reaction mixture was evaporated in vacuo. The residue was azeotroped twice with MeCN. The viscous yellow residue was purified by HPLC (Phenomenex Gemini, Gradient: 5-40% acetonitrile in 0.1% aqueous formic acid). The fractions containing product were combined and freeze dried to give the titled compound as a white solid. Yield 0.052 g.
Reaction SMILES: OS(O)(=O)=O.O.[CH2:7]([OH:9])[CH3:8].[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[C:18](=[CH2:22])[C:19](N)=[O:20]>C(Cl)Cl.[Cu]>[CH2:7]([O:9][C:19](=[O:20])[C:18]([C:12]1[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:11]=1[Cl:10])=[CH2:22])[CH3:8]
Reactant: C=C(C(N)=O)c1ccc(Cl)cc1Cl
Reactant: CCO
Agent: [Cu]
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Product: C=C(C(=O)OCC)c1ccc(Cl)cc1Cl
Temperature: 100 °C

Procedure:
Add the cyanohydrin prepared in Example 5(a), 2,4-dichloroacetophenone cyanohydrin-O-trimethylsilylether, (75 g) dropwise to a solution of concentrated H2SO4 containing 4% SO3 (60 mL) and 250 mg of copper powder at 40° C. During the addition, maintain the reaction temperature between 80°-85° C. (water bath). After all cyanohydrin is added, raise the temperature to 100° C. and heat the reaction mixture at this temperature for 30 min. Cool the reaction mixture to 90° C. and carefully treat with water (26 mL) and ethanol (60 mL). Heat the mixture at 100° C. for 15 hrs, cool and dilute with ice cold water (200 mL). Separate the organic layer, dilute with CH2Cl2 (100 mL) and wash with brine (100 mL). Extract the combined aqueous phase containing solids twice with EtOAc (400 mL), wash with saturated NaHCO3, water (100 mL each) and dry over Na2SO4. Eyaporate EtOAc in vacuo to give an oil containing a crystalline solid. Dilute this residue with a small yolume of CH2Cl2 -separated crystals of α-(2,4-dichlorophenyl)-α-methyleneacetamide which were collected by filtration (26 g). Combine the filtrate with the organic layer obtained earlier and chromatograph the concentrate on silica gel (300 g) to provide ethyl-α-(2,4-dichlorophenyl)-α-methyleneacetate.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([NH:19][CH2:20][C:21]([OH:23])=[O:22])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:24][N:25]1[C:34](=[O:35])[CH:33]2[CH:28]([CH:29]3[CH2:36][CH:32]2[CH:31]=[CH:30]3)[C:26]1=[O:27].[CH:37]1([N:43]=[C:44]=[N:45][CH:46]2[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]2)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>O1CCCC1>[OH:24][N:25]1[C:34](=[O:35])[CH:33]2[CH:28]([CH:29]3[CH2:36][CH:32]2[CH:31]=[CH:30]3)[C:26]1=[O:27].[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([NH:19][CH2:20][C:21]([OH:23])=[O:22])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH:46]1([NH:45][C:44]([NH:43][CH:37]2[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]2)=[O:8])[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)NCC(=O)O
Agent: O=C1C2C3C=CC(C3)C2C(=O)N1O
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 0.67 h

Procedure:
A solution of the N-hydroxy-5-norbornene-2,3-dicarboximide active ester of N-benzyloxycarbonyl-L-leucylglycine was prepared according to the general procedure of M. Fujino, et al. [Chem. Pharm. Bull. Japan, 22, 1857 (1974)]. A solution of 1.27 g. of N-benzyloxycarbonylleucylglycine and 0.72 g. of N-hydroxy-5-norbornene-2,3-dicarboximide in 5 ml. of tetrahydrofuran was cooled in an ice bath and 0.83 g. of N,N'-dicyclohexylcarbodiimide was added to the cold solution together with 1 ml. of tetrahydrofuran. The reaction mixture was stirred at low temperature for 40 minutes and then at room temperature for 21/2 hours. The N,N'-dicyclohexylurea formed during the reaction was collected on a filter and washed with three 1-ml. portions of tetrahydrofuran.
Reaction SMILES: [C:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@:12]4([CH3:21])[C:17](=[CH:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[OH:22])[CH2:16][C@@H:15]([OH:20])[CH2:14][CH2:13]4)#[CH:2].[Al].C1(=O)CCCCC1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@:12]4([CH3:21])[C:17]([CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[OH:22])=[CH:16][C:15](=[O:20])[CH2:14][CH2:13]4)#[CH:2]
Reactant: C#C[C@]12CC[C@H]3[C@@H](CC=C4C[C@@H](O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Agent: [Al]
Solvent: O=C1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C#C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Reaction time: 1 h

Procedure:
A solution of 900 mg of the crude 13-ethinyl-10-methyl-gon-5-ene-3β,17β-diol, obtained according to Example 2E, and 540 mg of aluminium isopropylate in 135 ml of toluene and 5.4 ml of cyclohexanone is boiled under reflux, under a water separator, for 60 minutes. After cooling, the reaction mixture is diluted with ethyl acetate, washed with potassium sodium tartrate solution, water and saturated sodium chloride solution, dried and evaporated. The oily residue is chromatographed on 80 g of silica gel. Using a mixture of hexane/ethyl acetate (3:1), 13-ethinyl-10-methyl-gon-4-ene-3,17-dione is eluted, melting point 148°-150° C; [α]D25 = +63°, after which 13-ethinyl-17β-hydroxy-10-methyl-gon-4-en-3-one, melting point 147°-149° C, [α]D25 =+154°, is obtained by elution with a mixture of the same solvents in a ratio of 2:1.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9](C)[C:10]([C:11]#[N:12])=[C:6]2[N:5]=[C:4]([CH3:14])[C:3]=1[CH2:15][CH2:16]Cl.C(N(CC)CC)C.[C:25]([NH2:29])([CH3:28])([CH3:27])[CH3:26].C(O)C>C(C(C)=O)C>[C:25]([N:29]1[C:2]2[N:7]3[N:8]=[CH:9][C:10]([C:11]#[N:12])=[C:6]3[N:5]=[C:4]([CH3:14])[C:3]=2[CH2:15][CH2:16]1)([CH3:28])([CH3:27])[CH3:26]
Reactant: Cc1nc2c(C#N)c(C)nn2c(Cl)c1CCCl
Reactant: CC(C)(C)N
Solvent: CCN(CC)CC
Solvent: CCC(C)=O
Solvent: CCO
Product: Cc1nc2c(C#N)cnn2c2c1CCN2C(C)(C)C
Temperature: 85 °C
Yield: 80 %

Procedure:
(ii-1) 2.7 g (0.01 mol) of Compound (VI) [R2 =CH3, R3 =CN], 2 ml of triethylamine, 3.2 ml of tert-butylamine, and 15 ml of anhydrous ethanol were placed in a closed tube and heated at 85° C. in a water bath for 8 hours. Then the tube was opened, and 100 ml of methyl ethyl ketone was added to the reaction solution. The mixed solution was warmed and subjected to filtration. The filtrate was purified over a chromatographic column packed with 10 g of silica gel (pH=7, 200 mesh) using methyl ethyl ketone in advance. The eluant was then evaporated to obtain 2.4 g of 8-tert-butyl-3-cyano-6,7-dihydro-2,5-dimethyl-8H-pyrrolo[3,2-e]pyrazolo[1,5-a]pyrimidine [R1 =C(CH3)3, R2 =CH3, R3 =CN in formula (I)] (Compound 2 of this invention) as yellowish orange plate crystals having a melting point of 229°-230° C. at a yield of 80.0%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[N:7]([C@H:11]1[CH2:19][CH2:18][CH2:17][C@H:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C@@H:15]([OH:29])[C@H:14]([CH3:30])[O:13][C:12]1=[O:31])[CH2:8][O:9][CH3:10])([CH3:4])([CH3:3])[CH3:2].[CH3:33][C:34](=[O:37])[C:35]#[CH:36]>C(Cl)Cl.C1N2CCN(CC2)C1>[C:1]([O:5][C:6](=[O:32])[N:7]([C@H:11]1[CH2:19][CH2:18][CH2:17][C@H:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C@@H:15]([O:29][CH:36]=[CH:35][C:34](=[O:37])[CH3:33])[C@H:14]([CH3:30])[O:13][C:12]1=[O:31])[CH2:8][O:9][CH3:10])([CH3:2])([CH3:4])[CH3:3]
Reactant: COCN(C(=O)OC(C)(C)C)[C@H]1CCC[C@H](Cc2ccc(OC)cc2)[C@@H](O)[C@H](C)OC1=O
Reactant: C#CC(C)=O
Agent: C1CN2CCN1CC2
Solvent: ClCCl
Product: COCN(C(=O)OC(C)(C)C)[C@H]1CCC[C@H](Cc2ccc(OC)cc2)[C@@H](OC=CC(C)=O)[C@H](C)OC1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 55.8 %

Procedure:
A round bottomed flask was charged with tert-butyl((3S,7R,8R,9S)-8-hydroxy-7-(4-methoxybenzyl)-9-methyl-2-oxooxonan-3-yl)(methoxymethyl)carbamate (400 mg, 0.886 mmol) in CH2Cl2 (4429 μl). To the solution was added DABCO (4.97 mg, 0.044 mmol) and the reaction mixture was cooled to 0° C. under N2. Upon addition of but-3-yn-2-one (83 μl, 1.063 mmol), the colorless solution became dark brown-orange. After stirring for 2 h, the reaction mixture was concentrated and purified directly by column chromatography on SiO2 (0→10%, hold, 10→20%, hold, 20→50% hold EtOAc/hexanes gradient) to afford the title compound as a thick colorless oil (257 mg, 55.8%): 1H NMR (400 MHz, CDCl3) δ 7.43 (d, J=12.2 Hz, 1H), 7.03 (d, J=8.6 Hz, 2H), 6.81 (d, J=8.6 Hz, 2H), 5.75 (d, J=12.4 Hz, 1H), 5.06-4.85 (m, 2H), 4.82-4.73 (m, 1H), 4.61-4.50 (m, 1H), 4.26-4.14 (m, 1H), 3.78 (s, 3H), 3.37-3.26 (m, 3H), 2.82 (dd, J=13.6, 4.0 Hz, 1H), 2.41-2.28 (m, 1H), 2.24-2.01 (m, 1H), 2.18 (s, 3H), 1.62-1.39 (m, 12H), 1.34 (d, J=6.4 Hz, 3H), 1.26 (t, J=7.1 Hz, 2H), 0.92 (dt, J=13.6, 4.6 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 197.24, 173.18, 163.24, 158.03, 155.34, 131.19, 129.61, 113.83, 108.08, 88.73, 88.61, 81.19, 76.86, 76.23, 75.39, 72.61, 72.49, 58.42, 56.97, 55.41, 55.14, 44.87, 35.82, 30.38, 29.45, 28.43, 28.27, 28.16, 26.38, 26.18, 19.16, 18.24; ESIMS m/z 542.4 ([M+Na)]+).
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]=[CH:5][N:4]([S:8]([C:11]2[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[C@@H:3]1[CH2:18][C:19]([OH:21])=O.[NH2:22][C@@H:23]1[CH2:32][CH2:31][CH2:30][C:29]2[CH:28]=[C:27]([CH2:33]O)[CH:26]=[CH:25][C:24]1=2.C1C=C[C:38]2N(O)N=[N:41][C:39]=2[CH:40]=1.CCN=C=NCCCN(C)C>CN(C=O)C.CCOC(C)=O>[CH:39]1([NH:41][CH2:33][C:27]2[CH:28]=[C:29]3[C:24](=[CH:25][CH:26]=2)[C@H:23]([NH:22][C:19](=[O:21])[CH2:18][C@@H:3]2[C:2](=[O:1])[NH:7][CH:6]=[CH:5][N:4]2[S:8]([C:11]2[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:32][CH2:31][CH2:30]3)[CH2:40][CH2:38]1
Reactant: On1nnc2ccccc21
Reactant: Cc1ccc(S(=O)(=O)N2C=CNC(=O)[C@H]2CC(=O)O)cc1
Reactant: N[C@@H]1CCCc2cc(CO)ccc21
Agent: CCN=C=NCCCN(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2C=CNC(=O)[C@H]2CC(=O)N[C@@H]2CCCc3cc(CNC4CC4)ccc32)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
(R)-2-(3-oxo-1-tosyl-1,2,3,4-tetrahydropyrazin-2-yl)acetic acid (6 g, 19.33 mmol) was dissolved in anhydrous DMF (100 mL). (R)-(5-Amino-5,6,7,8-tetrahydronaphthalen-2-yl)methanol (3.77 g, 21.27 mmol) and HOBt (Aldrich, 3.14 g, 23.20 mmol) were added followed by EDCI (Aldrich, 4.45 g, 23.20 mmol). The mixture was stirred at RT for 5 h. EtOAc (250 mL) was added and the solution was washed with saturated sodium bicarbonate/brine (2×200 mL), then with 10% HCl/brine (200 mL), then with brine (200 mL). It was concentrated and dried in vacuo to give the desired product.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]([C:13]2[CH:17]=[CH:16][N:15]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[N:14]=2)=[C:6]2[CH2:11][CH2:10][NH:9][C:8](=[O:12])[C:7]=12.[H-].[Na+].I[CH:29]([CH3:31])[CH3:30]>CN(C=O)C>[CH3:1][S:2][C:3]1[S:4][C:5]([C:13]2[CH:17]=[CH:16][N:15]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:24])([CH3:23])[CH3:25])[N:14]=2)=[C:6]2[CH2:11][CH2:10][N:9]([CH:29]([CH3:31])[CH3:30])[C:8](=[O:12])[C:7]=12
Reactant: CC(C)I
Reactant: CSc1sc(-c2ccn(COCC[Si](C)(C)C)n2)c2c1C(=O)NCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1sc(-c2ccn(COCC[Si](C)(C)C)n2)c2c1C(=O)N(C(C)C)CC2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-(methylsulfanyl)-1-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-3-yl)-6,7-dihydrothieno[3,4-c]pyridin-4(5H)-one (30 mg, 0.076 mmol) in DMF (0.7 mL) at 0° C. was added NaH (1.8 mg, 0.076 mmol). After 10 min, 2-iodopropane (13 mg, 0.076 mmol) was added and the reaction mixture was stirred at rt overnight, The resulting mixture was concentrated and purified directly by silica gel chromatography (gradient elution, 0-40% EtOAc/hexanes) to afford the title compound. LRMS (ESI) m/z 438.0 [(M+H)+; calcd for C20H31N3O2S2Si: 438].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8](C(Cl)(Cl)Cl)[N:7]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[N:15]=3)[C:6]=2[CH:21]=1.[F:22][C:23]([F:27])([F:26])[CH2:24][OH:25].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([O:25][CH2:24][C:23]([F:27])([F:26])[F:22])[N:7]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[N:15]=3)[C:6]=2[CH:21]=1
Reactant: Nc1nccc(-n2c(C(Cl)(Cl)Cl)nc3ccc(Br)cc32)n1
Reactant: OCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Nc1nccc(-n2c(OCC(F)(F)F)nc3ccc(Br)cc32)n1
Yield: 54.5 %

Procedure:
A mixture of 4-[6-bromo-2-(trichloromethyl)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine (500 mg, 1.23 mmol), 2,2,2-trifluoroethan-1-ol (500 mg, 5.00 mmol) and cesium carbonate (2.5 g, 7.67 mmol) in N,N-dimethylformamide (5 mL) placed in a 10-mL sealed tube maintained under nitrogen was irradiated with microwave radiation at 70° C. for 2 hr. The residue was purified on a C18 column (acetonitrile/water, 5:95-80:20) to yield 260 mg (46%) of 4-[6-bromo-2-(2,2,2-trifluoroethoxy)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine as a yellow solid. LC-MS: m/z=+388 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2Cl)=[CH:4][CH:3]=1.[CH3:13][O-:14].[Na+]>CO>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[O:14][CH3:13])=[CH:4][CH:3]=1
Reactant: Clc1nccc2ccc(Br)cc12
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nccc2ccc(Br)cc12
Temperature: 130 °C
Yield: 91 %

Procedure:
7-Bromo-1-chloroisoquinoline (570 mg, 2.4 mmol) was combined with methanol (10 mL) and sodium methoxide (25 wt % in methanol, 1.5 mL, 24 mmol) in a microwave vial. The vial was sealed and heated to 130° C. for 3 hours in a microwave. The reaction was concentrated. The crude residue was taken up in ethyl acetate and washed with water and saturated aqueous sodium bicarbonate. The aqueous layer was extracted two times with hot ethyl acetate. The combined organics were dried over sodium sulfate, filtered, and concentrated to give the title compound (520 mg, 93%). +ESI (M+H+1) 240.0; 1H NMR (400 MHz, DMSO-d6, δ): 8.25-8.28 (m, 1H), 8.04 (d, J=5.9 Hz, 1H), 7.86-7.89 (m, 2H), 7.40 (dd, J=6.0, 0.9 Hz, 1H), 4.03 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH:20]=[CH:21][N:22]4[CH2:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[OH-].[Na+:36].O>O1CCOCC1.C(O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH:20]=[CH:21][N:22]4[CH2:27][CH2:28][CH2:29][C:30]([O-:32])=[O:31])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[Na+:36]
Reactant: CCOC(=O)CCCn1ccc2c(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)cccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3ccn4CCCC(=O)[O-])no2)cc1C#N
Temperature: 25 °C
Reaction time: 4 h
Yield: 41.5 %

Procedure:
To a solution of ethyl 4-[4-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl]butanoate (D65) (1.42 g, 3.09 mmol) in a mixture of dioxan (70 ml) and ethanol (70 ml) was treated with 2N sodium hydroxide (1.86 ml, 3.71 mmol) followed by water (35 ml). The solution was stirred at RT for 4 hours. Evaporated off most of the solvent and filtered off the white solid from the remaining solvent. Washed the solid with water followed by ether and dried to give 580 mg of the title compound. δH (400 MHz, methanol-d4) 1.45 (6H, d), 2.09-2.22 (4H, m), 4.30 (2H, t), 4.92-4.98 (1H, m), 7.15 (1H, d), 7.31 (1H, t), 7.38-7.43 (2H, m), 7.69 (1H, d), 7.95 (1H, d), 8.43-8.46 (2H, m). MS (ES) C24H22N4O4 requires 430; found 431 (MH+).
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:10]1([C:16](Br)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N1C=CC=CC=1.[K+].[Br-]>O>[C:10]1([C:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:9][CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:2]#[CH:1])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C#CC(O)CCCCC
Reactant: BrC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: c1ccncc1
Product: C#CC(CCCCC)OC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
A mixture of 1.26 g. (10.0 mmoles) of 1-octyn-3-ol, 4.85 g. (15.0 mmoles) of triphenylmethyl bromide, and 50 ml. of dry pyridine is heated at 95° C. for 60 minutes with occasional swirling. The solution is cooled, treated with water, and extracted with ether. The extract is washed successively with water and saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. The crude product is purified by chromatography on Florisil and recrysallization from petroleum ether to give white crystals, m.p. 65°-66.5°, νmax. (KBr) 3280 (acetylenic hydrogen), 1605, 1030, and 702 cm-1 (triphenylmethoxy group).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[N:9]1[N:13]2[C:14]([C@@H:18](O)[CH3:19])=[CH:15][CH:16]=[N:17][C:12]2=[N:11][CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C@@H:18]([C:14]2[N:13]3[N:9]=[CH:10][N:11]=[C:12]3[N:17]=[CH:16][CH:15]=2)[CH3:19])=[CH:4][CH:3]=1
Reactant: C[C@H](O)c1ccnc2ncnn12
Reactant: Oc1ccc(Cl)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C[C@@H](Oc1ccc(Cl)cc1)c1ccnc2ncnn12
Temperature: 7.5 °C
Yield: 73 %

Procedure:
The reactor was loaded with 4-chlorophenol (58.5 g), (S)1-(1,2,4-triazolo[1,5-a]pyrimidin-7-yl)ethanol (50 g), triphenylphosphine (85 g) and toluene (900 ml). The suspension was cooled to 5-10° C. and diisopropyl azodicarboxylate (65 ml) was added over 2 hours. After complete addition of diisopropyl azodicarboxylate the solution was stirred while warming to ambient temperature. The reaction mixture was re-cooled to 0° C. and filtered. The filtrate, magnesium chloride (anhydrous; 31.1 g) and celite (25.5 g) were combined in the reactor. Toluene (500 ml) was distilled off and the remaining mixture was cooled to 0° C. The suspension formed was removed by filtration. Further magnesium chloride (2.6 g) and celite (2.5 g) were added to the filtrate. Toluene (200 ml) was removed by distillation. The residue was cooled to 0° C. and filtered. The filtercake was washed with toluene. The reactor was loaded with the filtrate, and toluene was removed by azeotropic distillation with propan-2-ol. The product crystallised from propan-2-ol at 40° C. while cooling to 20° C. The product was collected by filtration and washed with propan-2-ol. After drying, the product (R)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine (61.1 g) was obtained (yield: 73.6%; HPLC analysis: 99.1%; chiral HPLC: ee=100%). No triphenylphosphine oxide was detectable by HPLC analysis.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Si:5]([O:10][CH3:11])([O:8][CH3:9])[O:6][CH3:7].[CH2:12]([NH:30]C)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].[O-][CH2:33]C.[Na+]>C(O)C>[CH3:33][CH:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:13][CH2:12][NH:30][CH2:2][CH2:3][CH2:4][Si:5]([O:10][CH3:11])([O:8][CH3:9])[O:6][CH3:7]
Reactant: CC[O-]
Reactant: CO[Si](CCCBr)(OC)OC
Reactant: CCCCCCCCCCCCCCCCCCNC
Agent: [Na+]
Solvent: CCO
Product: CCCCCCCCCCCCCCCC(C)CCNCCC[Si](OC)(OC)OC
Temperature: 103.5 °C

Procedure:
A mixture of 12.0g of gamma-bromopropyltrimethoxysilane and 14.15g of octadecylmethylamine are heated at 94-113° C. for 16 hours and then cooled. The resulting tertiary ammonium salt is dissolved in 100 ml of absolute ethanol and 0.05 moles of freshly prepared sodium ethoxide in 50 ml of ethanol is added. Filtration of the resulting solution and removal of the solvent yield the tertiary amine, gammamethyloctadecylaminopropyltrimethoxysilane.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]([O:15]C)=[N:13][C:12]2[C:7]1=[N:8][C:9]([O:18][CH2:19][CH2:20][CH2:21][CH3:22])=[N:10][C:11]=2[NH2:17].[CH3:23][N:24]([CH3:31])[CH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][NH2:28].C(=O)([O-])[O-].[K+].[K+].Br[CH2:39][C:40]1[CH:41]=[C:42]([CH2:46][C:47]([O:49][CH3:50])=[O:48])[CH:43]=[CH:44][CH:45]=1>>[NH2:17][C:11]1[N:10]=[C:9]([O:18][CH2:19][CH2:20][CH2:21][CH3:22])[N:8]=[C:7]2[C:12]=1[NH:13][C:14](=[O:15])[N:6]2[CH2:5][CH2:4][CH2:3][CH2:2][N:28]([CH2:39][C:40]1[CH:41]=[C:42]([CH2:46][C:47]([O:49][CH3:50])=[O:48])[CH:43]=[CH:44][CH:45]=1)[CH2:27][C:26]([CH3:30])([CH3:29])[CH2:25][N:24]([CH3:31])[CH3:23]
Reactant: COC(=O)Cc1cccc(CBr)c1
Reactant: CN(C)CC(C)(C)CN
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCBr)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCN(Cc3cccc(CC(=O)OC)c3)CC(C)(C)CN(C)C)c2n1

Procedure:
Using the compound obtained in Example 2-13 step (i) (350 mg), N,N,2,2-tetramethylpropane-1,3-diamine (1 ml), potassium carbonate (500 mg) and methyl [3-(bromomethyl)phenyl]acetate (200 mg), the same manner to Example 2-29 was conducted to give the titled compound as a white solid. Yield: 60 mg (13%); MS APCI+ve 570 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]([C:15]2[S:22][C:21]([CH3:23])=[C:20]3[C:16]=2[CH2:17][C@H:18]2[C:24]([CH3:26])([CH3:25])[C@H:19]23)=[O:14])[CH:6]=[C:7](C)[C:8]=1[OH:9])[CH3:2].[CH2:27]([CH:29]1[O:31][CH2:30]1)Cl.[CH:32]([OH:35])(C)C>[OH-].[Na+].CC(=O)OCC>[CH2:1]([C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]([C:15]2[S:22][C:21]([CH3:23])=[C:20]3[C:16]=2[CH2:17][C@H:18]2[C:24]([CH3:26])([CH3:25])[C@H:19]23)=[O:14])[CH:6]=[C:7]([O:35][CH3:32])[C:8]=1[O:9][CH2:27][CH:29]1[CH2:30][O:31]1)[CH3:2]
Reactant: CC(C)O
Reactant: ClCC1CO1
Reactant: CCc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(OC)c1OCC1CO1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 3-(3-ethyl-4-hydroxy-5-methyl-phenyl)-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (600 mg, 1.63 mmol, Intermediate 12) in isopropanol (5 mL) and 3 N aq. NaOH (2 mL) is treated with epichlorohydrine (366 mg, 3.95 mmol). The dark red reaction mixture is stirred at rt for 18 h. The mixture is diluted with EA and washed with water. The organic layer is dried over MgSO4 and evaporated. The crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give 3-(3-ethyl-5-methoxy-4-oxiranylmethoxy-phenyl)-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (524 mg, mixture of diastereoisomers) as a pale yellow oil; LC-MS: tR=1.18 min, [M+1]+=425.26; 1H NMR (CDCl3): δ 6.89-6.85 (m, 2H), 4.00 (dd, J=2.9, 11.1 Hz, 1H), 3.73 (dd, J=5.9, 11.1 Hz, 1H), 3.48 (s, 2H), 3.37-3.32 (m, 1H), 3.02-2.85 (m, 5H), 2.78 (d, J=18.8 Hz, 1H), 2.64 (q, J=7.6 Hz, 2H), 2.37 (s, 3H), 2.26 8s, 3H), 1.91-1.85 (m, 2H), 1.20 (t, J=7.6 Hz, 3H), 1.11 (s, 3H), 0.70 (s, 3H).