Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13](=[O:31])[CH2:14][S:15][C:16]2[S:17][CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([O:29]C)=[O:28])[N:22]=3)[N:20]=2)[CH2:8][CH2:7]1.CO.[OH-].[Na+].Cl>[Cl-].[Na+].O.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13](=[O:31])[CH2:14][S:15][C:16]2[S:17][CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([OH:29])=[O:28])[N:22]=3)[N:20]=2)[CH2:8][CH2:7]1
Reactant: COC(=O)c1cccc(-c2csc(SCC(=O)NC3CCN(Cc4ccc(Cl)c(Cl)c4)CC3)n2)n1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(CSc1nc(-c2cccc(C(=O)O)n2)cs1)NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.6 %

Procedure:
N-[1-(3,4-Dichlorobenzyl)piperidin-4-yl]-[4-(6-methoxycarbonylpyridin-2-yl)thiazol-2-ylthio]acetamide (330 mg) was suspended in a mixed solvent of methanol (5 mL), tetrahydrofuran (5 mL) and 1 mol/L aqueous sodium hydroxide solution (1.2 mL), and the suspension was stirred at room temperature for 5 hrs. The reaction mixture was neutralized by adding 1 mol/L hydrochloric acid, and saturated brine was added. The mixture was extracted with chloroform, and the extract was dried. Then, the solvent was evaporated to give the title compound (314 mg) as a slightly yellow powder.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1.[N:12]([CH2:15][CH2:16][CH2:17][CH3:18])=[C:13]=[O:14]>C(#N)C.CN(C)C1C=CN=CC=1>[CH2:15]([NH:12][C:13]([N:1]1[C:9]2[C:4](=[C:5]([CH:10]=[O:11])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)=[O:14])[CH2:16][CH2:17][CH3:18]
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: CCCCN=C=O
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CCCCNC(=O)n1ccc2c(C=O)cccc21

Procedure:
To 1H-Indole-4-carbaldehyde (518, 1.57 g, 10.8 mmol) in acetonitrile (20 mL) was added 1-isocyanatobutane (1.81 mL, 16.2 mmol), followed by 4-dimethylaminopyridine (130 mg, 1.1 mmol). The reaction was refluxed for 48 hours. The reaction solution was quenched with 1 M HCl (aq.) and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, filtrated and concentrated to give a light yellow solid (519, 2.62 g, 45%). MS (ESI) [M+H+]+=245.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:25]=[CH:24][C:11]([CH2:12][O:13][C:14]([CH3:23])([C:19]([F:22])([F:21])[F:20])[C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-].[K+].CO>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:12][O:13][C:14]([CH3:23])([C:19]([F:20])([F:21])[F:22])[C:15]([OH:17])=[O:16])=[CH:24][CH:25]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)(OCc1ccc(-c2ccc(Cl)cc2)cc1)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(OCc1ccc(-c2ccc(Cl)cc2)cc1)(C(=O)O)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of the impure ester fraction from the previous example (fraction A) of (±)-methyl 2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-methylpropionate (15.7 g.), potassium hydroxide (3.0 g.), methanol (300 ml.) and water (30 ml.) is stirred at ambient temperature for 18 hours. The suspension is filtered, and the filtrate is evaporated. The residue is mixed with water, and the mixture is washed with ether. The aqueous phase is acidified with concentrated hydrochloric acid then extracted with ether. The extract is dried with sodium sulphate and evaporated. The residue is crystallised from cyclohexane and from a mixture of toluene and light petroleum (b.p. 60°-80° C.) to give (±)-2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-methylpropionic acid, m.p. 135°-136° C. (5.7 g.). The above process is repeated with (±)-methyl 2-(4-chloro-1-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionate obtained as an oil in Example 16, to give (±)-2-(4-chloro-1-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionic acid, m.p. 120°-121° C. (11.1 g.).
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:17])[C@H:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH2:9])([CH3:5])([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Br[CH2:27][CH:28]([O:32][CH2:33][CH3:34])[O:29][CH2:30][CH3:31]>CN(C)C=O>[C:2]([O:6][C:7](=[O:17])[C@H:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH:9][CH2:27][CH:28]([O:32][CH2:33][CH3:34])[O:29][CH2:30][CH3:31])([CH3:5])([CH3:3])[CH3:4]
Reactant: CCOC(CBr)OCC
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCOC(CN[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C)OCC
Temperature: 100 °C
Reaction time: 24 h
Yield: 65.1 %

Procedure:
A mixture of 2.58 g of L-phenylalanine t-butyl ester hydrochloride, 2.76 g of potassium carbonate, 0.1 g of sodium iodide, 2.2 g of 2-bromo-1,1-diethoxyethane and 30 ml of N,N-dimethylformamide was stirred for 24 hours at 100° C. The reaction mixture was poured into ice-water, which was subjected to extraction with hexane. The organic layer was washed with water, dried over anhydrous magnesium sulfate, then concentrated under reduced pressure. The concentrate was purified by means of a silica gel column chromatography (eluent: ethyl acetate-hexane=1:4→1:2) to afford 2.2 g of the title compound as a pale yellow oily product.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=1)(=[O:10])=[O:9].I[CH3:19].O>C1COCC1>[CH3:3][O:4][CH2:5][CH2:6][N:7]([CH3:19])[S:8]([C:11]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=1)(=[O:10])=[O:9]
Reactant: COCCNS(=O)(=O)c1ccc(I)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCCN(C)S(=O)(=O)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68.5 %

Procedure:
Sodium hydride (144 mg, 3.6 mmol) was added in portions to a solution of N-(2-methoxyethyl)-4-iodobenzenesulphonamide (Method 40, 1 g, 3 mmol) in THF (10 ml) and the mixture stirred at ambient temperature for 15 minutes. Iodomethane (230 μl, 3.6 mmol) was added and the reaction stirred for 18 hours. Water (30 ml) was added cautiously and the mixture extracted with ether (40 ml). The combined organics were washed with brine (50 ml), dried and the volatiles evaporated. The residue was purified by flash chromatography on silica gel eluting with iso-hexane/EtOAc (100:0 increasing in polarity to 10:1) to give the title compound (730 mg, 69%) as a clear oil. NMR 2.78 (s, 3H), 3.16 (t, 2H), 3.22 (s, 3H), 3.45 (t, 3H), 7.42 (d, 2H), 7.80 (d, 2H); m/z 356.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:9][C:10]2[CH:19]=[C:18]([NH:20][CH:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[C:13]([C:14]([O:16]C)=[O:15])=[CH:12][N:11]=2)=[N:7][CH:8]=1)#[N:2].[I-].[Li+]>N1C=CC=CC=1>[C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:9][C:10]2[CH:19]=[C:18]([NH:20][CH:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[C:13]([C:14]([OH:16])=[O:15])=[CH:12][N:11]=2)=[N:7][CH:8]=1)#[N:2]
Reactant: COC(=O)c1cnc(Nc2cnc(C#N)cn2)cc1NC1CCN(C)CC1
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: CN1CCC(Nc2cc(Nc3cnc(C#N)cn3)ncc2C(=O)O)CC1
Yield: 10.4 %

Procedure:
Methyl 6-(5-cyanopyrazin-2-ylamino)-4-(1-methylpiperidin-4-ylamino)nicotinate (Synthesis 66) (50 mg, 0.136 mmol) and lithium iodide (36 mg, 2 eq.) in dry pyridine (1.4 mL) were heated at 150° C. in a sealed Biotage microwave vial for 2.5 hr. The volatiles were removed in vacuo and the crude mixture was partitioned between EtOAc and 1M aqueous NaHCO3. The aqueous layer was retained, washed with fresh EtOAc and then carefully neutralised with 1M HCl. The volatiles were then removed and a portion of the residue was purified by HPLC to give the title compound as a yellow powder (5 mg, 10%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[N:22][CH:21]=1.[OH-].[Na+]>CO.O.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7]/[C:8](=[CH:19]\[C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)/[C:9]2=[O:12])=[CH:5][C:4]=1[N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: COc1cc2c(cc1N1CCOCC1)CCC2=O
Reactant: O=Cc1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cc2c(cc1N1CCOCC1)C/C(=C\c1cccnc1)C2=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 13 (0.1 g, 0.404 mmol) in MeOH/H2O (1:1) was added nicotinaldehyde 241 (0.052 g, 0.484 mmol) and NaOH (0.032 g, 0.808 mmol). The reaction was stirred at RT for 6 h, diluted with chloroform and washed with water (3×25 mL). The organic layer was dried over sodium sulphate and concentrated to get the crude, which was purified through flash chromatography by using 100-200 mesh silica gel. The compound 242 was eluted at 30% ethyl acetate in hexane to afford yellow coloured solid (E)-6-methoxy-5-morpholino-2-(pyridin-3-ylmethylene)-2,3-dihydro-1H-inden-1-one 242.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.Cl.[NH2:11][OH:12].N1C=CC=CC=1.Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:11][OH:12])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: NO
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: ON=Cc1ccc(Cl)cc1

Procedure:
4-Chlorobenzaldehyde (45.6 g; 0.325 mol), hydroxylamine hydrochloride (27.9 g; 0.401 mol) and pyridine (64 mL; 0.791 mol) in methylene chloride (600 mL) were stirred overnight at room temperature. The reaction mixture was poured into aqueous hydrochloric acid (2N; 300 mL) and extracted. The organic layer was washed with additional aqueous hydrochloric acid (2×300 mL), water (300 mL), dried (MgSO4), filtered and evaporated to yield oxime 1a as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=1.[F:15][C:16]([F:30])([F:29])[C:17]1[C:18]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[N:19][CH:20]=[CH:21][CH:22]=1>ClC1C=CC=CC=1>[Cl:8][C:6]1[CH:5]=[C:4]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=[C:2]([N:26]2[CH2:27][CH2:28][N:23]([C:18]3[C:17]([C:16]([F:30])([F:15])[F:29])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:24][CH2:25]2)[N:7]=1
Reactant: Clc1cc(N2CCCCC2)nc(Cl)n1
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Solvent: Clc1ccccc1
Product: FC(F)(F)c1cccnc1N1CCN(c2nc(Cl)cc(N3CCCCC3)n2)CC1
Temperature: 140 °C

Procedure:
A mixture of 2,4-dichloro-6-(1-piperidinyl)pyrimidine (100 mg, 0.43 mmol) and 1-[3-(trifluoromethyl)pyrid-2-yl]piperazine (119 mg, 0.52 mmol) in chlorobenzene (1 mL) was heated at 140° C. in a sealed tube for 24 hours. The solvent was removed and the crude material was purified by preparative TLC, eluting with hexane/ethyl acetate (9:1). 4-chloro-6-(1-piperidinyl)-2-{4-[3-(trifluoromethyl)-2-pyridinyl]-1-piperazinyl}pyrimidine was obtained as a solid (79 mg, 0.19 mmol, 44%).
Reaction SMILES: O.[CH3:2][N:3]([CH3:36])[C@@H:4]1[CH2:8][CH2:7][N:6]([C:9]2[C:14]([N+:15]([O-])=O)=[CH:13][C:12]([NH:18][C:19]3[N:24]=[C:23]([C:25]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[NH:27][CH:26]=4)[CH:22]=[CH:21][N:20]=3)=[C:11]([O:34][CH3:35])[CH:10]=2)[CH2:5]1.[NH4+].[Cl-]>[Fe].C(O)C>[CH3:36][N:3]([CH3:2])[C@@H:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[C:11]([O:34][CH3:35])[C:12]([NH:18][C:19]3[N:24]=[C:23]([C:25]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[NH:27][CH:26]=4)[CH:22]=[CH:21][N:20]=3)=[CH:13][C:14]=2[NH2:15])[CH2:5]1
Reactant: COc1cc(N2CC[C@@H](N(C)C)C2)c([N+](=O)[O-])cc1Nc1nccc(-c2c[nH]c3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1cc(N2CC[C@@H](N(C)C)C2)c(N)cc1Nc1nccc(-c2c[nH]c3ccccc23)n1
Temperature: 105 °C
Reaction time: 3 h
Yield: 117.2 %

Procedure:
Water (4 mL) was added to a stirred mixture of N-{4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-2-methoxy-5-nitrophenyl}-4-(1H-indol-3-yl)pyrimidin-2-amine (Intermediate 165, 286 mg, 0.60 mmol), iron (202 mg, 3.62 mmol), NH4Cl (22.6 mg, 0.42 mmol) and ethanol (24 mL). The resulting mixture was stirred at 105° C. for 3 h and was then filtered through diatomaceous earth (Celite™) and concentrated in vacuo. Part-purification by ion exchange chromatography, using an SCX column and eluting with 0.35M methanolic ammonia gave the title compound (312 mg, 116%) as a brown gum, which was used without further purification; 1H NMR: 2.13 (2H, d), 2.32 (2H, d), 2.80 (6H, d), 2.87-2.98 (2H, m), 3.19 (2H, d), 3.77 (3H, s), 6.74 (1H, s), 7.17 (4H, ddd), 7.46 (1H, d), 7.56 (1H, s), 7.77 (1H, s), 8.28 (2H, dd), 8.43 (1H, d), 11.76 (1H, s); m/z: ES+ MH+ 444.
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[CH3:17][NH:18][O:19][CH3:20].CN1CCOCC1>>[N:8]1([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([N:18]([O:19][CH3:20])[CH3:17])=[O:12]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: Cl
Solvent: CN1CCOCC1
Product: CON(C)C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C

Procedure:
Boc-Proline (2.00 g, 9.29 mmol) and N,O-Dimethylhydroxylaminehydrochloride (0.91 g, 9.29 mmol) were treated as described for 1 using NMM (2 ml, 18.4 mmol) and CAIBE (1.47 ml, 9.29 mmol).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O)#[N:2].[Cl:11][C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[CH:17][C:18]([CH3:22])=[N:19]2)=[CH:14][CH:13]=1.C([O-])(=O)C.[Na+]>C(OC(=O)C)(=O)C>[Cl:11][C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[CH:17][C:18]([CH:22]=[CH:6][C:5]3[CH:4]=[C:3]([CH:10]=[CH:9][CH:8]=3)[C:1]#[N:2])=[N:19]2)=[CH:14][CH:13]=1
Reactant: N#Cc1cccc(C=O)c1
Reactant: Cc1ccc2ccc(Cl)cc2n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: N#Cc1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Temperature: 130 °C
Yield: 91.8 %

Procedure:
Under the protection by nitrogen, meta-cyanobenzaldehyde (137.6 g, 1.05 mol), 7-chloroquinaldine (177 g, 1.0 mol) and sodium acetate (82 g) are added into 1000 ml of acetic anhydride, and the resulted mixture solution is stirred and heated to 125-135° C. for 24 hours. After distilling out the most of acetic anhydride, 300 ml of water is added into the residue, and then extracted by ethyl acetate (500 ml×3), washed with saturated saline water, dried with anhydrous sodium sulfate and condensed in the vacuum. The resulted residue is then purified through Flash Column Chromatography to obtain 266.8 g of the title compound, with a yield of 92%.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]O)=[CH:13][CH:12]=1)[CH:2]=[CH2:3].O=S(Cl)[Cl:21]>C(Cl)Cl>[CH2:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][Cl:21])=[CH:13][CH:12]=1)[CH:2]=[CH2:3]
Reactant: C=CCOCCOCCOc1ccc(CO)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: C=CCOCCOCCOc1ccc(CCl)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
All four compounds were prepared by the same method. An example is presented below. 4-[2-(2-Allyloxyethoxy)ethoxy]benzyl alcohol (7.57 g, 0.03 mol) was dissolved in methylene chloride (100 mL), and SOCl2 (4.28 g, 0.036 mol) was added dropwise. After the addition was completed the reaction mixture was stirred at 40° C. for 1 hr. washed with water, 2% NaHCO3 aqueous solution, and water and dried over anhydrous MgSO4. The solvent was evaporated and the residual oil was purified by column chromatography (silica gel, a mixture of 1:3 ethyl acetate to n-hexane as eluent) to yield 6.52 g (80%) of a colorless oily product 14. 1H-NMR (CDCl3, TMS, δ in ppm): 3.55-4.19 (m, 10H, --CH2 --(O--CH2 --CH2)2), 4.55 (s, 2H, Ph--CH2 --), 5.23 and 5.78 (m, 3H, CH2 =CH--), 5.92 and 7.25 (2d, 4 aromatic protons).
Reaction SMILES: [CH2:1]([C:5]([CH3:26])([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20]OS(C)(=O)=O)=[CH:14][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:2][CH2:3][CH3:4].[N-:27]=[N+:28]=[N-:29].[Na+]>>[N:27]([CH2:20][CH2:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH3:26])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:13][CH:14]=1)=[N+:28]=[N-:29]
Reactant: CCCCC(C)(Cc1ccc(OCCOS(C)(=O)=O)cc1)C(=O)OCC
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: CCCCC(C)(Cc1ccc(OCCN=[N+]=[N-])cc1)C(=O)OCC
Yield: 102.4 %

Procedure:
In a similar manner to that described in Reference example 3(h), a reaction was carried out using ethyl 2-butyl-3-[4-(2-methanesulfonyloxyethoxy)phenyl]-2-methylpropionate (3.17 g), which is the product of Reference example 10(e), and sodium azide (1.60 g) and the reaction mixture was treated to afford the desired compound (2.80 g) as a syrup.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH3:11].[CH2:12]=[C:13]1[O:17][C:15](=[O:16])[CH2:14]1>C(#N)C>[CH3:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:15](=[O:16])[CH2:14][C:13](=[O:17])[CH3:12])[CH:3]=2)[NH:7][N:6]=1
Reactant: C=C1CC(=O)O1
Reactant: Cc1n[nH]c2ccc(N)cc12
Solvent: CC#N
Product: CC(=O)CC(=O)Nc1ccc2[nH]nc(C)c2c1
Reaction time: 8 h

Procedure:
5-Amino-3-methylindazole (300 mg, 2.04 mmol, 1.00 equiv) was dissolved in acetonitrile (4 mL) and diketene (151 uL, 2.04 mmol, 1.00 equiv) was added. The reaction mixture was stirred overnight, and the reaction mixture was purified directly by silica gel chromatography (50→100% EtOAc/hexanes)
Reaction SMILES: [CH2:1]([CH:19]([N:38]=[N+:39]=[N-:40])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:41][N:42]([CH3:46])[CH2:43][C:44]#[CH:45].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>O.C(O)(C)(C)C>[CH3:18][CH2:17][CH2:16][CH2:15][CH2:14]/[CH:13]=[CH:12]\[CH2:11]/[CH:10]=[CH:9]\[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][CH:19]([N:38]1[CH:45]=[C:44]([CH2:43][N:42]([CH3:46])[CH3:41])[N:40]=[N:39]1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: C#CCN(C)C
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCC(CCCCCCCC/C=C\C/C=C\CCCCC)N=[N+]=[N-]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CCCCC/C=C\C/C=C\CCCCCCCCC(CCCCCCCC/C=C\C/C=C\CCCCC)n1cc(CN(C)C)nn1
Reaction time: 96 h
Yield: 91.4 %

Procedure:
A solution of dilinoleyl methyl azide (500 mg, 0.90 mmol) and 3-dimethylamino-1-propyne (75 mg, 0.90 mmol) in H2O and tert-butyl alcohol (1:1, 12 mL) was treated with sodium ascorbate (0.090 mmol, 17.94 taken from a 1M solution in water), followed by CuSO4.5H2O (2.3 mg, dissolved in 30 μL of water) and stirred (96 h). The solution was then diluted with H2O (50 mL) and extracted with CH2Cl2 (3×), dried (Na2SO4), filtered, concentrated and purified via column chromatography (2%→4% MeOH/CH2Cl2) to yield the title compound as a colorless oil (524 mg, 91%). 1H NMR (400 MHz, CDCl3, δH) 7.76 (br. s, 1H), 5.47-5.25 (m, 8H), 4.48 (p, 1H), 3.80 (br. s, 2H), 2.75 (app. t, 4H), 2.49 (s, 6H), 2.15-2.00 (m, 8H), 1.91-1.75 (m, 4H), 1.40-1.12 (m, 34H), 1.11-0.98 (m, 2H), 0.85 (t, 6H). FW 637.08, C42H76N4.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:12]2C(=O)OC(C)(C)[O:14][C:13]2=[O:21])[C:9]#[C:10][CH3:11])=[CH:4][CH:3]=1.O.Cl>C(C(CC)=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:9]#[C:10][CH3:11])[CH2:12][C:13]([OH:21])=[O:14])=[CH:6][CH:7]=1
Reactant: CC#CC(c1ccc(O)cc1)C1C(=O)OC(C)(C)OC1=O
Agent: Cl
Solvent: O
Solvent: CCC(=O)CC
Product: CC#CC(CC(=O)O)c1ccc(O)cc1
Yield: 100 %

Procedure:
To a 250 mL 3-necked RB flask fitted with magnetic stirrer was charged with 5-[1-(4-hydroxyphenyl)but-2-yn-1-yl]-2,2-dimethyl-1,3-dioxane-4,6-dione (5.8 g, 20.13 mmol) in diethyl ketone was added water (13 mL), the reaction mixture was heated to refluxed for 48 h. The RM was acidified with 1N HCl and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulphat. Finally removal of solvent under reduced pressure to obtain the product (4.11 g, yield: 100.0%).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([O:14][CH2:15][CH3:16])(=[O:13])[CH:10]([CH3:12])[CH3:11].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]Cl>O1CCCC1>[CH2:15]([O:14][C:9](=[O:13])[C:10]([CH3:12])([CH3:11])[CH2:22][C:21]1[CH:24]=[CH:25][CH:26]=[C:19]([O:18][CH3:17])[CH:20]=1)[CH3:16]
Reactant: COc1cccc(CCl)c1
Reactant: CCOC(=O)C(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)Cc1cccc(OC)c1
Reaction time: 1 h
Yield: 106.4 %

Procedure:
Lithium diisopropylamide (2 M in tetrahydrofuran, 2.71 mL, 5.42 mmol) was added to a mixture of ethyl isobutyrate (600 mg, 5.17 mmol) in tetrahydrofuran (60 mL) at −78° C. and stirred at this temperature for 1 hour. 3-Methoxybenzyl chloride (1.15 g, 7.34 mmol) was added dropwise and the reaction mixture was stirred at −78° C. for another 1 hour and then at room temperature overnight. The mixture was quenched by water and extracted with ethyl acetate. The combined organic fractions were washed with water, dried over sodium sulfate and concentrated under vacuum to give ethyl-3-(3-methoxyphenyl)-2,2-dimethylpropanoate (1.3 g) as a yellow oil, which was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]([CH3:13])([CH3:12])[CH2:7][CH2:6][C:5]([CH3:15])([CH3:14])[C:4]=2[CH:3]=1.ClCCl.[Cl-].[Al+3].[Cl-].[Cl-].[C:23](Cl)(=[O:27])[CH:24]([CH3:26])[CH3:25]>O>[CH:24]([C:23]([C:11]1[C:2]([OH:1])=[CH:3][C:4]2[C:5]([CH3:15])([CH3:14])[CH2:6][CH2:7][C:8]([CH3:13])([CH3:12])[C:9]=2[CH:10]=1)=[O:27])([CH3:26])[CH3:25]
Reactant: CC1(C)CCC(C)(C)c2cc(O)ccc21
Reactant: CC(C)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CC(C)C(=O)c1cc2c(cc1O)C(C)(C)CCC2(C)C
Temperature: 60 °C
Reaction time: 2 h

Procedure:
The synthesis process is as set forth in the chemical reaction formula below. To 5,6,7,8-tetrahydro-2-hydroxy-5,5,8,8-tetramethylnaphthalene (204 mg, 1.00 mol) were added anhydrous dichloromethane (1 mL), aluminum chloride (148 mg, 1.12 mmol), and isobutyryl chloride (117 mg, 1.10 mmol) followed by stirring at 60° C. for 2 hours. The reaction solution was poured into cold water, and extracted by ethyl acetate. The organic layer was washed by water, a saturated sodium hydrogen carbonate aq. solution, and a saturated saline solution, dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography using hexane/ethyl acetate (20/1) as an elution solvent. The yield was 128 mg (47%).
Reaction SMILES: [Cl:1][C:2]([Cl:9])([Cl:8])[C:3]([N:5]=[C:6]=[O:7])=[O:4].[NH2:10][C:11]1[S:12][CH:13]=[CH:14][C:15]=1[C:16]([NH2:18])=[O:17].C(OCC)C>N1C=CC=CC=1>[Cl:1][C:2]([Cl:9])([Cl:8])[C:3]([NH:5][C:6](=[O:7])[NH:10][C:11]1[S:12][CH:13]=[CH:14][C:15]=1[C:16]([NH2:18])=[O:17])=[O:4]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: NC(=O)c1ccsc1N
Solvent: CCOCC
Solvent: c1ccncc1
Product: NC(=O)c1ccsc1NC(=O)NC(=O)C(Cl)(Cl)Cl
Temperature: 0 °C
Yield: 99.2 %

Procedure:
Trichloroacetyl isocyanate (10 g, 53 mmol) was added dropwise to the solution of 2-amino-thiophene-3-carboxylic acid amide (3.8 g, 26.5 mmol) in pyridine (110 mL) at 0° C. The resulting reaction mixture was stirred at 0° C. The temperature of the reaction mixture was raised to room temperature over a 3 h period until LC-MS showed no remaining starting material. Diethyl ether (100 mL) was added to the reaction mixture and the resulting precipitate was filtered and dried under vacuum to give the above titled compound as a light grey solid (8.7 g, 26.3 mmol, 99% yield).