Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH2:10]([O:14][C:15]1[CH:20]=[C:19](Cl)[N:18]=[CH:17][N:16]=1)[C:11]#[C:12][CH3:13].[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[SH:29].[Cl-].[NH4+]>C(Cl)(Cl)Cl>[CH2:10]([O:14][C:15]1[CH:20]=[C:19]([S:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[F:22])[N:18]=[CH:17][N:16]=1)[C:11]#[C:12][CH3:13]
Reactant: CC#CCOc1cc(Cl)ncn1
Reactant: Fc1ccccc1S
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CC#CCOc1cc(Sc2ccccc2F)ncn1
Temperature: 25 °C
Reaction time: 7 h
Yield: 23.3 %

Procedure:
To 2.2 ml of chloroform were added 0.29 ml of diisopropylethylamine, 0.2 g of 4-(2-butynyloxy)-6-chloropyrimidine, and 0.17 g of 2-fluorothiophenol, followed by stirring at room temperature for 7 hours. Then, a saturated aqueous ammonium chloride solution was poured into the reaction mixture, which was extracted three times with t-butyl methyl ether. The organic layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.07 g of 4-(2-butynyloxy)-6-(2-fluorophenylthio)pyrimidine (the present compound (146)).
Reaction SMILES: [CH:1]([NH:3][C:4]1[C:5]([C:9]([O:11]C)=O)=[CH:6][S:7][CH:8]=1)=O.C([O-])=O.[NH4+:16]>O>[N:3]1[C:4]2=[CH:8][S:7][CH:6]=[C:5]2[C:9](=[O:11])[NH:16][CH:1]=1
Reactant: COC(=O)c1cscc1NC=O
Reactant: [NH4+]
Agent: O=C[O-]
Solvent: O
Product: O=c1[nH]cnc2cscc12
Temperature: 140 °C

Procedure:
A stirred mixture of methyl 4-formamido-3-thenoate (see below) (3.39 g) and ammonium formate (3.4 g) in formamde (5 ml) was heated at 140° C. for 7 hours. On cooling, the mixture was poured into water, and the mixture filtered to give a solid which was washed with water followed by light petroleum (b.p. 60-80° C.) and air dried to give the title product, m.p. 275-278° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([NH:20][C:21]3[N:22]=[CH:23][C:24]4[CH:30]=[C:29]([F:31])[C:28](=[O:32])[N:27]([CH:33]5[CH2:37][CH2:36][CH2:35][CH2:34]5)[C:25]=4[N:26]=3)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(Cl)(Cl)[Cl:39].CO>>[ClH:39].[CH:33]1([N:27]2[C:25]3[N:26]=[C:21]([NH:20][C:17]4[CH:18]=[CH:19][C:14]([N:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)=[CH:15][N:16]=4)[N:22]=[CH:23][C:24]=3[CH:30]=[C:29]([F:31])[C:28]2=[O:32])[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: ClC(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc4cc(F)c(=O)n(C5CCCC5)c4n3)nc2)CC1
Solvent: CO
Product: Cl
Product: O=c1c(F)cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 88 %

Procedure:
4-[6-(8-Cyclopentyl-6-fluoro-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (0.195 g, 0.38 mmol) prepared as in Example 17, was dissolved in 1:1 chloroform/methanol (8 ml), purged with anhydrous hydrogen chloride gas and stirred for 2.5 hours at room temperature. To the mixture was added diethyl ether (15 ml) giving a precipitate that was filtered, washed with ether and dried in vacuo to provide 8-cyclopentyl-6-fluoro-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one hydrochloride as a yellow solid (0.177 g, 88%). MS (APCI); M++1: Calc, 410.46, Found, 410.3. Analyses for C21H24N7O.1.0 H2O.2.0HCl: Calc'd: C, 50.73; H, 5.75; N, 19.46, Cl (ionic), 13.77; H2O, 1.41. Found: C, 50.41; H, 5.64; N, 19.59; Cl (ionic), 14.16; H2O, 3.60.
Reaction SMILES: [Sn:1]([CH2:14][CH2:15][CH2:16]Br)([CH2:10][CH2:11][CH2:12][CH3:13])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH2:4][CH3:5].[NH:18]([CH3:20])[CH3:19]>>[CH3:19][N:18]([CH3:20])[CH2:16][CH2:15][CH2:14][Sn:1]([CH2:10][CH2:11][CH2:12][CH3:13])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCC[Sn](CCCC)(CCCC)CCCBr
Reactant: CNC
Product: CCCC[Sn](CCCC)(CCCC)CCCN(C)C
Yield: 86 %

Procedure:
In a reaction vessel provided with a carbon dioxide condenser, a mixture of 6.18 g (0.015 mol) of Bu3Sn(CH2)3Br and 20 ml of Me2NH was refluxed for 7 h. The residue obtained after evaporation of the excess of Me2NH was taken up in 30 ml of diethyl ether and treated for 15 min with 50 ml of a 10% aqueous solution of NaHCO3. Distillation gave 4.95 g (86%) of (3-dimethylaminopropyl)tributyltin.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5](O)=[CH:4][C:3]=1[NH:10][C:11]([CH3:13])=[O:12].[CH2:14](Br)[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>[OH-].[K+].C(O)C>[C:11]([NH:10][C:3]1[CH:4]=[C:5]([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14])[C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])(=[O:12])[CH3:13]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: CC(=O)Nc1cc(O)c(Cl)cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCCCCCc1cc(NC(C)=O)c(Cl)cc1Cl
Temperature: 25 °C
Yield: 74.8 %

Procedure:
In a solution of 5.6 g of potassium hydroxide in 200 ml of ethanol was dissolved 22 g of 4,6-dichloro-3-acetaminophenol (which was synthesized using the method described in Beilstein, 13, I, 135). To the solution was added 30.5 g of hexadecyl bromide. After the mixture was stirred for an hour at room temperature (about 20-30° C.), the mixture was heated at reflux for 8 hours. The reaction mixture was poured into water. The resulting precipitate was recovered by filtration and washed with methanol to obtain 32 g of the desired product. The melting point thereof was 92 to 93.5° C.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:9]([F:10])=[CH:8][C:7]([C:11](=[O:17])[CH2:12][NH:13][CH:14]2[CH2:16][CH2:15]2)=[CH:6][C:5]=1[Cl:18].[BH4-].[Na+]>>[NH2:3][C:4]1[C:9]([F:10])=[CH:8][C:7]([CH:11]([OH:17])[CH2:12][NH:13][CH:14]2[CH2:16][CH2:15]2)=[CH:6][C:5]=1[Cl:18]
Reactant: Nc1c(F)cc(C(=O)CNC2CC2)cc1Cl
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: Nc1c(F)cc(C(O)CNC2CC2)cc1Cl

Procedure:
m.p. of the hydrochloride: 175°-177° C. (decomp.), was prepared from 4'-amino-3'-chloro-2-cyclopropylamino-5'-fluoro-acetophenone hydrochloride and sodium borohydride analogous to Example 1.
Reaction SMILES: [BrH:1].[NH:2]([C:4]1[NH:5][CH2:6][CH2:7][N:8]=1)[NH2:3].[CH:9]([C@@H:11]1[C@:19]2([CH3:20])[C@@:14]([OH:27])([CH2:15][C@@H:16]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17][CH2:18]2)[CH2:13][CH2:12]1)=O>O.O1CCOCC1>[BrH:1].[NH:8]1[CH2:7][CH2:6][N:5]=[C:4]1[NH:2]/[N:3]=[CH:9]/[C@@H:11]1[C@:19]2([CH3:20])[C@@:14]([OH:27])([CH2:15][C@@H:16]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:17][CH2:18]2)[CH2:13][CH2:12]1
Reactant: C[C@]12CC[C@H](c3ccccc3)C[C@@]1(O)CC[C@@H]2C=O
Reactant: NNC1=NCCN1
Agent: Br
Solvent: O
Solvent: C1COCCO1
Product: C[C@]12CC[C@H](c3ccccc3)C[C@@]1(O)CC[C@@H]2/C=N/NC1=NCCN1
Reaction time: 2 h
Yield: 53.7 %

Procedure:
To a solution of 0.93 g of 2-hydrazino-2-imidazoline hydrobromide in 45 ml of water and 30 ml of dioxane a solution of 0.89 g of (1S,3aS,5S,7aR)-1-formyl-5-phenyl-7a-methylperhydroinden-3a-ol in 30 ml of dioxane was added dropwise at room temperature and the mixture was stirred for 2 hrs. The solution was evaporated to dryness under reduced pressure and the residue was ground with ethanol/water then with ethanol to give 0.78 g of the title compound (I-al) as a white solid.
Reaction SMILES: [CH2:1]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[C:8]([O:17][CH3:18])=[CH:7][C:6]=1/[CH:19]=[CH:20]/[C:21]([OH:23])=[O:22])[CH2:2][CH2:3][CH3:4].[N+:24]([C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=1)([O-:26])=[O:25].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:24]([C:27]1[CH:32]=[CH:31][C:30]([O:22][C:21](=[O:23])/[CH:20]=[CH:19]/[C:6]2[CH:7]=[C:8]([O:17][CH3:18])[C:9]3[C:14](=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=3)[C:5]=2[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:29][CH:28]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCCCc1c(/C=C/C(=O)O)cc(OC)c2ccc(OC)cc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCc1c(/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)cc(OC)c2ccc(OC)cc12

Procedure:
As in Example 113, (E)-3-(1-butyl-4,7-dimethoxy-2-naphthalenyl)-2-propenoic acid (0.71 g) was treated with 4-nitrophenol (0.35 g) in dichloromethane (10 mL) in the presence of 1,3-dicyclohexylcarbodiimide (0.475 g) to furnish, after the normal work up and crystallization of the crude product from 2-propanol, 1.17 g of (E)-3-(1-butyl-4,7-dimethoxy-2-naphthalenyl)-2-propenoic acid 4-nitrophenyl ester., mp 144°-145.5° C. Anal. Calcd for C25H25NO6 : C, 68.95; H, 5.79; N, 3.22 Found: C, 69.05; H, 5.74; N, 3.25
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH2:9][C:10]1[S:11][C:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])C)=[O:16])=[CH:13][CH:14]=1.[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26].Cl.OC1C=[CH:39][C:35]([C:36]([NH2:38])=[NH:37])=[CH:34]C=1.CCN=C=NCCCN(C)C.Cl>N1C=CC=CC=1>[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26].[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26].[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26].[CH3:1][O:2][C:3](=[O:22])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH2:9][C:10]1[S:11][C:12]([C:15]([O:17][C:18]2[CH:20]=[CH:39][C:35]([C:36](=[NH:37])[NH2:38])=[CH:34][CH:21]=2)=[O:16])=[CH:13][CH:14]=1
Reactant: COC(=O)[C@@H]1CCCN1Cc1ccc(C(=O)OC(C)(C)C)s1
Reactant: N=C(N)c1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1CCCN1Cc1ccc(C(=O)Oc2ccc(C(=N)N)cc2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29 %

Procedure:
To the compound (0.55 g, 1.7 mmol) obtained in step 1 was added trifluoroacetic acid (10 ml), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, pyridine (10 ml), 4-hydroxybenzamidine hydrochloride (0.35 g, 2.0 mmol), and WSC hydrochloride (0.48 g, 2.5 mmol) were added to the obtained residue, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by high performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to give the title compound (0.30 g, 0.49 mmol, 29%).
Reaction SMILES: C(P(=O)(OCC)OCC)#[N:2].FC(F)(F)[C:13]1[CH:14]=[C:15]2C=C(C(O)=O)[N:19]([CH2:25][C:26]3[CH:31]=CC=C(F)C=3)[C:16]2=[N:17][CH:18]=1>>[NH2:2][C:13]1[CH:18]=[N:17][C:16]([N:19]2[CH2:25][CH2:26][CH2:31]2)=[CH:15][CH:14]=1
Reactant: O=C(O)c1cc2cc(C(F)(F)F)cnc2n1Cc1cccc(F)c1
Reactant: CCOP(=O)(C#N)OCC
Product: Nc1ccc(N2CCC2)nc1
Yield: 120 %

Procedure:
Add, dropwise, 4.26 g (24.83 mmol) of diethyl cyanophosphonate to a solution, stirred at 20° C. under a nitrogen atmosphere, of 7 g (20.69 mmol) of 5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid as obtained in Stage 1.3 and 3.7 g (24.83 mmol) of 3-amino-6-(azetidin-1-yl)-pyridine prepared in the preceding stage in 140 mL of dimethylformamide. Then add, dropwise, 4.6 mL (45.53 mmol) of triethylamine, then stir the reaction mixture for 70 hours at 20° C. After this time, the mixture is concentrated at reduced pressure and then taken up in 700 mL of ethyl acetate and 300 mL of water. The aqueous phase is separated and then extracted with 200 mL of ethyl acetate. The organic phases are combined, washed three times with 200 mL of a saturated sodium bicarbonate solution, then dried over sodium sulfate and concentrated at reduced pressure. The product thus obtained is purified in a silica column, eluting with a mixture of dichloromethane and ethyl acetate, then recrystallized from a mixture of ethanol and methanol. In this way we isolate 5.7 g of the expected product in the form of white crystals.
Reaction SMILES: CS(O[C:6]1([CH2:9][O:10][C:11]2[C:16]([C:17]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:18]=3[CH2:19][CH2:20][C:21]4=[O:26])=[CH:15][CH:14]=[C:13]([O:27][CH3:28])[C:12]=2[O:29][CH3:30])[CH2:8][CH2:7]1)(=O)=O.[N-:31]=[N+:32]=[N-:33].[Na+].[CH3:35]N(C)C=O>>[N:31]([CH2:35][C:6]1([CH2:9][O:10][C:11]2[C:12]([O:29][CH3:30])=[C:13]([O:27][CH3:28])[CH:14]=[CH:15][C:16]=2[C:17]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:18]=2[CH2:19][CH2:20][C:21]3=[O:26])[CH2:7][CH2:8]1)=[N+:32]=[N-:33]
Reactant: CN(C)C=O
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(OS(C)(=O)=O)CC2)c1OC
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CN=[N+]=[N-])CC2)c1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirring solution of 1-((2,3-dimethoxy-6-(1-oxo-2,3-dihydro-1H-inden-4-yl)phenoxy)methyl)cyclopropyl methanesulfonate (3 g, 6.72 mmol) in dimethylformamide (20 mL), was added sodium azide (2.18 g, 33.63 mmol) and the resultant reaction mixture was stirred at RT for 16 h. The reaction mixture was quenched with ice water and extracted with ethyl acetate (3×). The combined ethyl acetate layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification by column chromatography (silica gel, 0-5% ethyl acetate in pet ether) to afforded 4-(2-((1-(azidomethyl)cyclopropyl)methoxy)-3,4-dimethoxyphenyl)-2,3-dihydro-1H-inden-1-one as a liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](F)[CH:6]=[CH:5][C:4]=1[N+:10]([O-:12])=[O:11].[N:13]1([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+].CS(C)=O>O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:22]2[CH2:23][CH2:24][CH:19]([N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:20][CH2:21]2)[CH:6]=[CH:5][C:4]=1[N+:10]([O-:12])=[O:11]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: C1CCN(C2CCNCC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(N2CCC(N3CCCCC3)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 72 h
Yield: 98.7 %

Procedure:
To 5-fluoro-2-nitrophenyl methyl ether (26.0 g, 152 mmol), 1,4′-bipiperidine (25.5 g, 152 mmol) and K2CO3 (22.9 g, 166 mmol) was added DMSO (260 mL). The mixture was stirred at room temperature for 3 days. The mixture was poured into H2O (1000 mL) and the H2O washed with EtOAc (2×500 mL). The EtOAc washes were combined and washed with H2O (2×500 mL). The ether layer was dried (MgSO4), filtered, and rotovaped down to give the title compound (47.9 g, 150 mmol, 99%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J=9.5 Hz, 1H), 6.40 (dd, J=9.5 and 2.6 Hz, 1H), 6.29 (d, J=2.6 Hz, 1H), 3.99-3.93 (m, 2H), 3.93 (s, 3H), 2.98-2.89 (m, 2H), 2.58-2.48 (m, 5H), 1.99-1.90 (m, 2H), 1.70-1.55 (m, 8H), 1.48-1.40 (m, 2H).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C2C(=CC=CC=2)C=CC=1>CCCCCC.[Pd]>[C:9]([O:11][CH2:12][CH3:13])(=[O:10])/[CH:8]=[CH:7]\[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C#Cc1ccccc1
Agent: [Pd]
Solvent: c1ccc2ncccc2c1
Solvent: CCCCCC
Product: CCOC(=O)/C=C\c1ccccc1
Temperature: 25 °C
Yield: 92.3 %

Procedure:
Ethyl phenylpropiolate (10.8 g, 0.062 mol) was dissolved in hexane (540 ml), followed by addition of quinoline (11.2 g) and palladium on calcium carbonate (Lindlax catalyst, 3.6 g). The resulting reaction mixture was stirred under hydrogen (1 atm) at room temperature, and the progress of the reaction was monitored closely by GC analysis. The reaction was stopped by displacement of the hydrogen atmosphere with nitrogen once the rate of absorption of hydrogen was observed to decrease abruptly. The resulting mixture was filtered through a pad of diatomaceous earth and the filtrate was dried over Na2SO4. Solvent was removed under reduced pressure. Then the residue was distilled under vacuum (2.5 mm Hg, at 98°-100° C.) to provide 10.08 g of cis-ethyl cinnamate, for a yield of nearly 95%. By GC analysis, this product mixture was found to contain 5.7% over-reduced alkane and 3.5% trans-ethyl cinnamate, but was used without further purification.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]2[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:8]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)=[N:7][C:6]=12.[CH3:25][Si:26]([C:29]#[CH:30])([CH3:28])[CH3:27].C(N(CC)CC)C>CN(C)C=O>[F:12][C:11]([F:14])([F:13])[C:10]1[N:5]2[N:4]=[CH:3][C:2]([C:30]#[C:29][Si:26]([CH3:28])([CH3:27])[CH3:25])=[C:6]2[N:7]=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[CH:9]=1
Reactant: C#C[Si](C)(C)C
Reactant: FC(F)(F)c1cccc(-c2cc(C(F)(F)F)n3ncc(I)c3n2)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cnn2c(C(F)(F)F)cc(-c3cccc(C(F)(F)F)c3)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 102.2 %

Procedure:
A mixture of 3-iodo-7-trifluoromethyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (6.49 g, 14.2 mmol), trimethylsilylacetylene (3.54 mL, 25.6 mmol) and triethylamine (3.94 mL, 28.4 mmol) in N,N-dimethylformamide (15 mL) was stirred for 10 min at room temperature while being purged with Argon, then PdCl2(PPh3)2 (100 mg, 1 mol %), PPh3 (37 mg, 1 mol %) and CuI (8 mg, 0.3 mol %) were added. Stirring was continued at 90° C. for 4.5 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (150 mL), washed with water (2×50 mL) and brine (70 mL), dried (MgSO4) and evaporated to give 7-trifluoromethyl-5-(3-trifluoromethyl-phenyl)-3-trimethylsilanylethynyl-pyrazolo[1,5-a]pyrimidine (6.2 g, 102%) as a light brown solid, which was dissolved in THF (30 mL) and MeOH (70 mL), while stirring at 0° C. potassium carbonate (200 mg, 1.45 mmol) was added and the mixture was stirred at 0° C. for 5 h. The mixture was diluted with ice water (200 mL) and extracted with TBME (3×200 mL). The combined organic layers were washed with brine (300 mL), dried (MgSO4) and evaporated. The crude product was further purified by silica gel column chromatography (heptane/EtOAc 9:1) followed by trituration with heptane to give 3-ethynyl-7-trifluoromethyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (3.23 g, 63%) as an orange solid. MS (EI) 355.0[(M)+]; mp 154° C.
Reaction SMILES: C(OC([N:11]([C:23]1[C:24]([C:35]([O:37][CH3:38])=[O:36])=[C:25]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[S:26][CH:27]=1)[C:12]([C:14]1[O:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[CH:18]=1)=[O:13])=O)C1C=CC=CC=1>C(O)C.C(OCC)(=O)C.ClCCl.[Pd]>[O:15]1[C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[CH:18]=[C:14]1[C:12]([NH:11][C:23]1[C:24]([C:35]([O:37][CH3:38])=[O:36])=[C:25]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[S:26][CH:27]=1)=[O:13]
Reactant: COC(=O)c1c(N(C(=O)OCc2ccccc2)C(=O)c2cc3ccccc3o2)csc1-c1ccc(Cl)cc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)c1c(NC(=O)c2cc3ccccc3o2)csc1-c1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
10% Pd/C (5.8 mg, 5 μmol, 20 mol % Pd) was added to compound 9 (14.8 mg, 27 μmol) in ethanol:ethyl acetate:dichloromethane (2:1:1, 1.5 mL). The mixture was degassed and placed under H2 (1 atm) and stirred for 30 min. The mixture was filtered through a 0.45 μm syringe filter and concentrated under reduced pressure to provide 10 (11.1 mg, 99%) as a solid: 1H NMR (500 MHz, d6-DMSO) δ11.12 (s, 1H), 8.15 (s, 1H), 7.84 (d, J=7.9 Hz, 1H), 7.78 (m, 2H), 7.55-7.50 (m, 5H), 7.39 (t, J=7.6 Hz, 1H), 3.69 (s, 3H); LRESIMS m/z 412.0 [M+H]+, calcd. for C21H15Cl1N1O4S1 412.0.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:12][CH2:11][C:10]2=[O:13])=[CH:5][CH:4]=1.FC(F)(F)S(O)(=O)=O.C(N(CC)CC)C.[BH4-].[Na+]>ClCCCl.C(O)C>[F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][CH2:12][CH2:11][CH:10]2[OH:13]
Reactant: O=C1CCN1c1ccc(C(F)(F)F)cc1
Agent: O=S(=O)(O)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: ClCCCl
Product: OC1CCNc2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15 %

Procedure:
1-[4-(Trifluoromethyl)phenyl]azetidin-2-one (2.3 g, 10.7 mmol) was dissolved in 1,2-dichloroethane (20 mL), trifluoromethanesulfonic acid (1 mL) was added at 0° C., and the mixture was stirred at room temperature for 30 min. Triethylamine (2.2 mL) was added to the reaction mixture, and the mixture was worked-up according to a conventional method to give a crude product. The obtained crude product was dissolved in ethanol (10 mL), sodium borohydride (0.81 g, 21.4 mmol) was added, and the mixture was stirred for 4 hrs. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound (0.35 g, 1.6 mmol, 15%).
Reaction SMILES: C[C:2]1[C:8]([CH3:9])=[C:7]([OH:10])[CH:6]=[CH:5][C:3]=1[OH:4].C([O-])([O-])=O.[K+].[K+].[I-].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC(C)=O>[CH2:19]([O:10][C:7]1[CH:6]=[CH:5][C:3]([OH:4])=[CH:2][C:8]=1[CH3:9])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1c(O)ccc(O)c1C
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(O)ccc1OCc1ccccc1
Temperature: 25 °C

Procedure:
To a mixture of 2,3-dimethylhydroquinone (1.38 g, 10 mmol), K2CO3 (2.76 g, 20 mmol), potassium iodide (0.83 g, 5 mmol) in 50 mL dry acetone was added benzyl bromide (1.88 g, 11 mmol). The resulting suspension was vigorously stirred for 48 at RT. The solid was filtered off and the liquid was concentrated. The residue was chromatographed to afford the benzyl derivative, 4-benzyloxy-3-methyl-phenol, as a light brown solid (1.15 g). 1H-NMR (300 MHz, CDCl3) δ (ppm): 7.49-7.35 (m, 5H), 6.70 (d, J=8.7, 1H), 6.61 (d, J=8.7, 1H), 5.03 (s, 2H), 4.43 (s, 1H), 2.26 (s, 3H), 2.22 (s, 3H); MS (ESI) m/z: 229 (M+H+, 100%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:22])[CH2:5][S:6][C:7]=1[CH:8]1[CH:13]=[CH:12][N:11](C(OCC(Cl)(Cl)Cl)=O)[CH:10]=[CH:9]1>C(O)=O.[Zn]>[CH3:1][C:2]1[NH:3][C:4](=[O:22])[CH2:5][S:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1
Reactant: CC1=C(C2C=CN(C(=O)OCC(Cl)(Cl)Cl)C=C2)SCC(=O)N1
Agent: [Zn]
Solvent: O=CO
Product: CC1=C(c2ccncc2)SCC(=O)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.2 %

Procedure:
Zinc powder (1 g) was added to a stirred solution of 5-methyl-6-[1-(2,2,2-trichloroethoxycarbonyl)-1,4-dihydro-4-pyridinyl]-2H-1,4-thiazin-3(4H)-one (1 g) in formic acid (14 ml), and the reaction mixture was stirred at room temperature for 3 hours. The insoluble solid was removed by filtration. The filtrate was evaporated to dryness and the residue was dissolved in water (30 ml). The solution was adjusted to pH 7.0 by addition of 1N sodium hydroxide aqueous solution. The precipitates were extracted with chloroform (although the solution was converted into an emulsion at this extracting step, the operation was facilitated by using a filter aid such as "Avicel"). The extract was dried over anhydrous magnesium sulfate and was evaporated under reduced pressure. The crude product was purified by the preparative thin layer chromatography [Merck TLC plate, silica gel 60F254 t (particles average porous diameter 60A, Fluorescent substance Zn2SiO4 /Mn), 20×20 cm, t=1 mm, chloroform/methanol= 20/1] to give 200 mg of 5-methyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one. The physical properties were as described above.