Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:14]=[CH:13]O[C:11](=O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]1(=[O:31])[C:29]2[C:20](=[CH:21][C:22]3[C:27]([CH:28]=2)=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:19](=[O:30])[CH:18]=C1>C1C(Cl)=CC=C(Cl)C=1.O=[Mn]=O>[CH2:1]([S:8][C:9]1[CH:14]=[CH:13][C:18]2[C:19](=[O:30])[C:20]3[C:29](=[CH:28][C:27]4[C:22]([CH:21]=3)=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:16](=[O:31])[C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1cc(SCc2ccccc2)cco1
Reactant: O=C1C=CC(=O)c2cc3ccccc3cc21
Agent: O=[Mn]=O
Solvent: Clc1ccc(Cl)cc1
Product: O=C1c2ccc(SCc3ccccc3)cc2C(=O)c2cc3ccccc3cc21
Temperature: 180 °C

Procedure:
A mixture of 0.27 g (0.0012 mol) of 4-benzylthio-2-oxo-2H-pyrane, 0.25 g (0.0012 mol) of 1,4-anthraquinone and 0.10 g (0.0012 mol) of MnO2 in 5 ml of dichlorobenzene is heated for 24 hours under reflux (180° C.), then cooled and chromatographed over silica gel. Using cyclohexane as eluant, dichlorbenzene is first extracted, then the crude product is chromatographed with CH2Cl2. The pre-purified product is chromatographed once more, using CH2Cl2 as eluant, and the solvent is removed by evaporation. Yield: 0.09 g (20%). Melting point: 200°-203° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:26]([F:29])([F:28])[F:27])[O:14][N:13]=[C:12]([C:15]3[S:19][C:18]([C:20](O)=[O:21])=[C:17]4[CH2:23][CH2:24][CH2:25][C:16]=34)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].C(N(CC)C(C)C)(C)C.Cl.[NH2:40][CH2:41][C:42]([NH:44][CH2:45][C:46]#[CH:47])=[O:43].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:26]([F:29])([F:28])[F:27])[O:14][N:13]=[C:12]([C:15]3[S:19][C:18]([C:20]([NH:40][CH2:41][C:42](=[O:43])[NH:44][CH2:45][C:46]#[CH:47])=[O:21])=[C:17]4[CH2:23][CH2:24][CH2:25][C:16]=34)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8]
Reactant: O=C(O)c1sc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)c2c1CCC2
Reactant: C#CCNC(=O)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C#CCNC(=O)CNC(=O)c1sc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)c2c1CCC2
Yield: 88.9 %

Procedure:
Stir a mixture of 3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylic acid (0.8 g, 1.7 mmol), N,N-diisopropylethylamine (663 mg, 5.1 mmol), 2-amino-N-(prop-2-yn-1-yl) acetamide hydrochloride (305 mg, 2.0 mmol) and HATU (974 g, 2.6 mmol) in CH2Cl2 (10 mL) at room temperature for 2 hours. The reaction mixture is diluted with CH2Cl2 (40 mL) and is washed with water (10 mL×3) and brine. Then the organic layer is dried over anhydrous Na2SO4 and concentrated under vacuum. Purify the residue by preparative HPLC to afford 3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-oxo-2-(prop-2-ynylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxamide as a white solid (850 mg, 88.4%). MS (m/z): 584.1 (M+Na).
Reaction SMILES: [C:1]([CH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([NH:17][C@@H:18]([CH2:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH2:19][N:20]([CH3:30])[C:21](=[O:29])[O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])=[O:16])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:38][O:39][CH2:40][CH2:41][CH2:42][CH2:43][Mg]Cl.C([O-])(O)=O.[Na+].[NH4+].[Cl-]>C1COCC1>[OH:8][C:1]([CH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([NH:17][C@@H:18]([CH2:31][CH:32]2[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]2)[CH2:19][N:20]([CH3:30])[C:21](=[O:29])[O:22][CH2:23][CH2:24][Si:25]([CH3:27])([CH3:28])[CH3:26])=[O:16])[CH2:10]1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:43][CH2:42][CH2:41][CH2:40][O:39][CH3:38]
Reactant: CN(C[C@H](CC1CCCCC1)NC(=O)C1CCCC(C(=O)c2ccccc2)C1)C(=O)OCC[Si](C)(C)C
Reactant: COCCCC[Mg]Cl
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCCCCC(O)(c1ccccc1)C1CCCC(C(=O)N[C@@H](CC2CCCCC2)CN(C)C(=O)OCC[Si](C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
A stirred solution of 2-(trimethylsilyl)ethyl (S)-2-(3-benzoylcyclohexanecarboxamido)-3-cyclohexylpropylmethylcarbamate (111 mg, 0.21 mmol) in dry THF (2 mL) was cooled to −70° C. and methoxybutylmagnesium chloride in THF (0.5 mL of 2 M, 1.0 mmol) was added dropwise over 2 min. The cooling bath was allowed to expire and the mixture was stirred as it warmed to rt. After 2 h, the mixture was poured into sat'd aqueous NaHCO3 (20 mL) and sat'd aqueous NH4Cl (20 mL) was added. The mixture was extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine (15 mL), dried over Na2SO4 and evaporated under reduced pressure to leave crude 2-(trimethylsilyl)ethyl (S)-2-(3-(1-hydroxy-5-methoxy-1-phenylpentyl)cyclohexanecarboxamido)-3-cyclohexylpropyl-methylcarbamate as an oil (124 mg, 95%). MS ESI +ve m/z 617 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([F:12])[C:3]=1[C:13]1[S:17][C:16]([NH:18][C:19]2[N:20]=[N:21][C:22]([O:25]CC[Si](C)(C)C)=[CH:23][CH:24]=2)=[C:15]([C:32]([NH2:34])=[O:33])[CH:14]=1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:12][C:4]1[CH:5]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:7]=[C:2]([F:1])[C:3]=1[C:13]1[S:17][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22](=[O:25])[NH:21][N:20]=2)=[C:15]([C:32]([NH2:34])=[O:33])[CH:14]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3ccc(OCC[Si](C)(C)C)nn3)s2)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3ccc(=O)[nH]n3)s2)c(F)c1
Reaction time: 0.5 h

Procedure:
5-[2,6-Difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-2-({6-[2-(trimethylsilyl)ethoxy]pyridazin-3-yl}amino)thiophene-3-carboxamide (0.61 g, 1.20 mmol) was taken up in DCM (12 mL) and TFA (0.4 mL) was added. After 30 minutes at room temperature, saturated NaHCO3 was added. The resulting precipitate was collected by filtration and triturated in DCM to give the title compound as a yellow solid.
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.Cl[C:18](Cl)([O:20]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[N:2]([C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5])=[C:18]=[O:20]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)C(C)(C)N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)N=C=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of the methyl 2-amino-2-methylpropanoate hydrochloride(65.5 g) in THF (650 mL) was treated with triethylamine (60 mL), heated to reflux, stirred for 30 minutes, cooled to room temperature, treated dropwise with a solution of triphosgene (43.2 g) in THF (250 mL) over 5 minutes, heated to reflux, stirred for 4 hours, cooled to 15° C., treated with triethylamine (120 mL) over 7 minutes, heated to reflux, stirred for 40 minutes, cooled to room temperature, and filtered. The solid was washed with THF and the filtrate was collected to provide a solution of methyl 2-isocyanato-2-methylpropanoate in THF.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][C:8](=[O:18])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:23][CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>CN(C)C=O>[CH3:30][C:29]([Si:26]([CH3:28])([CH3:27])[O:25][CH2:24][CH2:23][CH:7]([C:8](=[O:18])[CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([Br:17])=[CH:15][CH:16]=1)[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:19])([CH3:32])[CH3:31]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: CC(C)(C)OC(=O)CC(=O)CCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(CCO[Si](C)(C)C(C)(C)C)C(=O)CCc1ccc(Br)cc1
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 66 %

Procedure:
A solution of the compound (9.7 g) obtained from step 1 above in dimethylformamide (25 ml) was added dropwise over 20 minutes to a stirred suspension of sodium hydride (1.42 g) in dimethylformamide (25 ml) at 0° C. under nitrogen atmosphere and stirred the reaction mixture for 20 minutes. To it was added (2-bromoethoxy)-t-butyldimethylsilane (8.50 g) dropwise over 20 minutes at 0° C. then the reaction mixture was heated to 70° C. for about 3-4 hour. On cooling to room temperature the reaction was quenched with water. The residue was partitioned between saturated aqueous ammonium chloride solution and dichloromethane. The organic phases were combined, washed with water and brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue thus obtained was purified by column chromatography using 8% ethyl acetate in hexane as eluant to furnish the title compound (9.5 g).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[F:18][C:19]([F:29])([F:28])[C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1>>[CH3:16][C:13]1([CH3:17])[N:12]([CH2:24][C:23]2[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:28])[F:29])=[CH:27][CH:26]=2)[N:11]([CH:2]2[CH:3]3[CH2:4][CH:5]4[CH2:6][CH:7]([CH2:8][CH:1]2[CH2:10]4)[CH2:9]3)[C:14]1=[O:15]
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Reactant: FC(F)(F)c1ccc(CBr)cc1
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1ccc(C(F)(F)F)cc1

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 4-(trifluoromethyl)benzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[O:6][CH2:7][C:8]([OH:10])=[O:9].[CH3:15][S:16]([C:19]1[CH:24]=[CH:23][C:22](F)=[C:21]([Cl:26])[CH:20]=1)(=[O:18])=[O:17].[OH-].[Na+]>CN(C=O)C>[Cl:26][C:21]1[CH:20]=[C:19]([S:16]([CH3:15])(=[O:18])=[O:17])[CH:24]=[CH:23][C:22]=1[O:3][C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[O:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc(F)c(Cl)c1
Reactant: O=C(O)COc1ccccc1O
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Oc2ccccc2OCC(=O)O)c(Cl)c1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% disp. oil, 0.24 g) was added to a solution of (2-hydroxyphenoxy) acetic acid (0.5 g) in DMF (20 ml) and stirred at 40° C. for 30 min. The product from example 7 step (ii) (0.62 g) was added, then the mixture heated at 75° C. for 30 h. 2M Sodium hydroxide solution was added and extracted with ethylacetate. The aqueous layer was acidified with 2M hydrochloric acid and extracted with ethyl acetate. The organics were dried, evaporated under reduced pressure and the residue purified by RPHPLC, yield 0.21 g.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]([C:14]3[C:15]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.Br[CH2:31][CH2:32][C:33]#[N:34].C(OCC)(=O)C>CN(C)C1C=CN=CC=1.CN(C=O)C.C(Cl)Cl.CCCCCC>[C:33]([CH2:32][CH2:31][N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]3[C:15]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][CH:21]=4)=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:13])[CH:6]=2)[CH2:1]1)#[N:34]
Reactant: N#CCCBr
Reactant: O=C(Nc1ccc2c(c1)CCNC2)c1ccccc1-c1ccc(C(F)(F)F)cc1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: N#CCCN1CCc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2C1
Temperature: 70 °C

Procedure:
Compound (II) (780 mg, 1.97 mmole), 3-bromopropionitrile (290 mg, 2.17 mmole) and 4-dimethylaminopyridine (264 mg, 2.16 mmole) were combined in 10 mL of DMF and heated to 70° C. for 72 hrs. The reaction was diluted with methylene chloride, washed with water and brine, and then dried over magnesium sulfate. Purification of the residue obtained on evaporation was carried out with silica gel chromatography using a gradient of 10-100% ethyl acetate in hexane as the eluent.
Reaction SMILES: [CH3:1][O:2][C:3](/[C:5](/NC(=O)OC(C)(C)C)=[CH:6]/[C:7]1[CH:15]=[C:14]([CH3:16])[C:13]2[C:9](=[CH:10][N:11]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[N:12]=2)[CH:8]=1)=[O:4].FC(F)(F)C(O)=[O:36].C([BH3-])#N.[Na+].O1CCCC1>ClCCl.C(OCC)(=O)C>[CH3:22][Si:21]([CH3:24])([CH3:23])[CH2:20][CH2:19][O:18][CH2:17][N:11]1[CH:10]=[C:9]2[C:13]([C:14]([CH3:16])=[CH:15][C:7]([CH2:6][CH:5]([OH:36])[C:3]([O:2][CH3:1])=[O:4])=[CH:8]2)=[N:12]1
Reactant: O=C(O)C(F)(F)F
Reactant: COC(=O)/C(=C/c1cc(C)c2nn(COCC[Si](C)(C)C)cc2c1)NC(=O)OC(C)(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)C(O)Cc1cc(C)c2nn(COCC[Si](C)(C)C)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl (Z)-1-(methoxycarbonyl)-2-(2-((2-(trimethylsilyl)ethoxy)methyl)-7-methyl-2H-indazol-5-yl)vinylcarbamate (200 mg, 0.43 mmol) in dichloromethane (2 mL) at 0° C. was added trifluoroacetic acid (1 mL). The ice bath was removed. After 30 min, the reaction was poured into a separatory funnel containing ethyl acetate and water, neutralized with solid sodium bicarbonate, and the layers were separated. The organic phase was washed with saturated sodium bicarbonate, then brine, dried over magnesium sulfate, and concentrated. The yellow residue was treated with sodium cyanoborohydride (200 mg, 7.4 equiv) and tetrahydrofuran (2 mL). The reaction was stirred at room temperature overnight, diluted with ethyl acetate, washed with water (2×), then brine, dried over magnesium sulfate, and concentrated. Column chromatography on silica gel (25% ethyl acetate/hexanes) gave 20.4 mg (13%) as a light yellow oil. Mass spec.: 365.40 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[S:10][C:9]([C:11](O)([CH3:13])[CH3:12])=[C:8]([CH2:15][CH2:16][OH:17])[C:6]=2[N:7]=1.C1(C)C=CC=CC=1.FC(F)(F)C(O)=O>O>[Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[C:5]2[S:10][C:9]3[C:11]([CH3:12])([CH3:13])[O:17][CH2:16][CH2:15][C:8]=3[C:6]=2[N:7]=1
Reactant: CC(C)(O)c1sc2c(N3CCOCC3)nc(Cl)nc2c1CCO
Solvent: Cc1ccccc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)OCCc2c1sc1c(N3CCOCC3)nc(Cl)nc21
Temperature: 120 °C
Yield: 35.1 %

Procedure:
Impure 2-(2-chloro-7-(2-hydroxyethyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)propan-2-ol (30 mg) was dissolved in toluene (5 mL, 50 mmol). Trifluoroacetic acid (0.5 mL, 6 mmol) was added and the reaction mixture was heated at 120° C. for two h. Complete reaction was confirmed by LCMS. Diluted with water and extracted with ethyl acetate, dried over magnesium sulfate, concentrated in vacuo and was purified by silica gel chromatography (0 to 100% ethyl acetate/heptanes) on the CombiFlash® Rf system using an amine column and concentrated in vacuo to give 3-Chloro-8,8-dimethyl-1-morpholin-4-yl-5,8-dihydro-6H-7-oxa-9-thia-2,4-diaza-fluorene (10 mg, 10% yield)
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([C:17]#[N:18])[CH:11]=[CH:10]2)(=O)=O.[CH2:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[C:23]1(/[CH:22]=[CH:21]/[C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[CH:13]=[C:12]([C:17]#[N:18])[CH:11]=[CH:10]3)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C=Cc1ccccc1
Reactant: N#Cc1ccc2cc(OS(=O)(=O)C(F)(F)F)ccc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#Cc1ccc2cc(/C=C/c3ccccc3)ccc2c1
Yield: 54 %

Procedure:
A solution of Example 28B (350 mg, 1.16 mmol), styrene (157 mg, 1.51 mmol), palladium (II) acetate (26 mg, 0.12 mmol), triphenylphosphine (61 mg, 0.23 mmol), triethylamine (2 mL) and acetonitrile (1 mL) in a sealed tube with minimal head volume was heated at 100° C. for 19 h, diluted with ethyl acetate (20 mL), washed with water, dried (MgSO4) and concentrated with silica gel (4 g). The mixture was chromatographed on silica gel with 10% ethyl acetate/hexane to provide 160 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[C:5]#[N:6].[OH:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH:22]=[O:23])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH:22]=[O:23])=[CH:14][CH:13]=1)[C:5]#[N:6]
Reactant: N#Cc1ccc(F)c(Cl)c1
Reactant: O=Cc1ccc(O)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: N#Cc1ccc(Oc2ccc(C=O)c3ccccc23)c(Cl)c1
Temperature: 80 °C

Procedure:
To a solution of 3-chloro-4-fluorobenzonitrile (1.09 g, 7.00 mmol) in DMSO (25 mL) was added 4-hydroxy-1-napthaldehyde (1.20 g, 7.0 mmol) and caesium carbonate (4.55 g, 14.0 mmol). The reaction mixture was heated to 80° C. for 24 h. After cooling to rt the mixture was partitioned between EtOAc (40 mL) and saturated NaHCO3 (50 mL), and the aqueous phase washed with EtOAc (50 mL). Solvent was removed in vacuo and the residue purified by column chromatography (EtOAc:isohexane, 2:8) to give the title compound: RT=4.10 min; m/z (ES+)=NO IONISATION [M+H]+. δH(DMSO) 7.10 (1H, t), 7.46 (1H, d), 7.78 (1H, t), 7.88 (1H, t), 7.94 (1H, d), 8.19 (1H, d), 8.32 (1H, d), 8.37 (1H, d), 9.28 (1H, d), 10.33 (1H, s).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][OH:29])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][O:29][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: BrCc1ccccn1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCO)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCOCc4ccccn4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 34, Step 4, using 1-{4′-[4-(2-hydroxy-ethyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 2-bromomethyl-pyridine.
Reaction SMILES: [CH3:1][C:2]1[CH:7]2[C:8]([CH3:10])([CH3:9])[CH:5]([CH2:6]2)[CH2:4][CH:3]=1.C1C(C(OO)=[O:18])=CC=CC=1>C(Cl)(Cl)Cl>[CH3:9][C:8]1([CH3:10])[CH:7]2[C:2]3([CH3:1])[O:18][CH:3]3[CH2:4][CH:5]1[CH2:6]2
Reactant: CC1=CCC2CC1C2(C)C
Reactant: O=C(OO)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CC1(C)C2CC3OC3(C)C1C2

Procedure:
in a first stage, epoxidizing α-pinene with a 15-30% solution of perbenzoic acid in chloroform at a temperature between -1° C. and -10° C. to obtain α-pinene epoxide
Reaction SMILES: [CH3:1][C@@:2]12[C:8]([CH3:10])([CH3:9])[C@@H:5]([CH2:6][CH2:7]1)[CH:4]([C:11](Cl)=[O:12])[C:3]2=O.C(N(CC)CC)C.C(O[C:27]([N:29](C)[NH:30][C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=1)=O)(C)(C)C.Cl.O1CCOCC1>ClCCCl>[CH3:27][N:29]1[C:3]2[C@:2]3([CH3:1])[C:8]([CH3:10])([CH3:9])[C@@H:5]([CH2:6][CH2:7]3)[C:4]=2[C:11](=[O:12])[N:30]1[C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=1
Reactant: CN(Nc1ccc2ccccc2c1)C(=O)OC(C)(C)C
Reactant: CC1(C)[C@H]2CC[C@]1(C)C(=O)C2C(=O)Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: Cn1c2c(c(=O)n1-c1ccc3ccccc3c1)[C@@H]1CC[C@@]2(C)C1(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 31 %

Procedure:
A solution of (1S,4S)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 25; 530 mg, 2.47 mmol) in 1,2-dichloroethane (12 mL) was added to a cooled (0° C.) solution of triethylamine (470 μL, 3.37 mmol) and N-methyl-N′-naphthalen-2-yl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 36; 450 mg, 1.65 mmol) in 1,2-dichloroethane (6 mL) over 1 min. The reaction mixture was stirred at room temperature for 90 min. A solution of HCl in dioxane (4 M; 10 mL, 40 mmol) was added and the reaction mixture was heated at reflux for 90 min, and allowed to cool. The solvent was evaporated. The residue was purified twice using ISCO 40 g columns. The first column was eluted with 50-100% ethyl acetate and then with 10% methanol/ethyl acetate. The second column was eluted with 60-100% ethyl acetate/hexanes. Fractions homogeneous for the product were evaporated and the residue was co-evaporated with methanol and then with diethyl ether, and dried under high vacuum at room temperature to give (4R,7S)-1,7,8,8-tetramethyl-2-naphthalen-2-yl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (170 mg, 31%) as an off-white foam. ES(+)-MS (M+H) 333.
Reaction SMILES: CN(C=O)C.[F:6][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([F:17])[C:15]=1[F:16])[C:10]([OH:12])=[O:11].[CH2:18](Br)[C:19]#[CH:20].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[F:6][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([F:17])[C:15]=1[F:16])[C:10]([O:12][CH2:20][C:19]#[CH:18])=[O:11]
Reactant: O=C(O)c1cc(F)c(F)c(F)c1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C#CCOC(=O)c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.7 %

Procedure:
To 50 ml of DMF were added 5.0 g of 3,4,5-trifluorobenzoic acid, 4.0 g of propargyl bromide and 4.7 g of potassium carbonate, and the mixture obtained was stirred at room temperature for 30 minutes and then heated with stirring at 80° C. for 1 hour. Then, ethyl acetate was added to the reaction mixture and the mixture was filtered through Celite. Water and dilute hydrochloric acid were added to the filtrate in order and it was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain 6.0 g of 2-propynyl 3,4,5-trifluorobenzoate represented by the formula:
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[Cl:6][C:7]([Cl:27])([Cl:26])[CH:8]1[O:13][CH:12]([C:14]([Cl:17])([Cl:16])[Cl:15])[C:11]2[CH:18]=[C:19]([S:22](Cl)(=[O:24])=[O:23])[CH:20]=[CH:21][C:10]=2[O:9]1>C(O)C>[CH2:1]([N:3]([CH2:4][CH3:5])[S:22]([C:19]1[CH:20]=[CH:21][C:10]2[O:9][CH:8]([C:7]([Cl:6])([Cl:26])[Cl:27])[O:13][CH:12]([C:14]([Cl:17])([Cl:15])[Cl:16])[C:11]=2[CH:18]=1)(=[O:24])=[O:23])[CH3:2]
Reactant: O=S(=O)(Cl)c1ccc2c(c1)C(C(Cl)(Cl)Cl)OC(C(Cl)(Cl)Cl)O2
Reactant: CCNCC
Solvent: CCO
Product: CCN(CC)S(=O)(=O)c1ccc2c(c1)C(C(Cl)(Cl)Cl)OC(C(Cl)(Cl)Cl)O2

Procedure:
Diethylamine (0.8 g.) was added dropwise to a stirred suspension of 2,4-bis(trichloromethyl)benzo[1,3]dioxin-6-sulphonyl chloride (4.7 g.) in absolute ethanol (20 ml.), the mixture was maintained under gentle reflux for 2 hours, and the resulting solution was allowed to cool slowly to give a crystalline product, which was recrystallised from aqueous methanol to give 6-diethylsulphamoyl-2,4-bis(trichloromethyl)benzo[1,3]dioxin, m.p. 125°-126° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:18]#[N:19])[C:5]2[C:6](I)=[N:7][N:8]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[C:9]=2[CH:10]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:28]B1OB(C)OB(C)O1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[CH:3]=[C:4]([C:18]#[N:19])[C:5]2[C:6]([CH3:28])=[N:7][N:8]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[C:9]=2[CH:10]=1
Reactant: CB1OB(C)OB(C)O1
Reactant: N#Cc1cc(Cl)cc2c1c(I)nn2C1CCCCO1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1nn(C2CCCCO2)c2cc(Cl)cc(C#N)c12
Temperature: 100 °C
Yield: 54.9 %

Procedure:
A mixture of 6-chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-carbonitrile (600 mg, 1.550 mmol), K3PO4 (644 mg, 3.037 mmol), PdCl2(dppf) (186 mg, 0.228 mmol), and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (290 mg, 1.52 mmol) in dioxane (2 mL) under nitrogen in a sealed vial was heated at 100° C. in a microwave oven for 18 h. The reaction mixture was quenched with EtOAc and water. The organic layer was concentrated in vacuo to afford 6-chloro-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-carbonitrile as white solid (230 mg, 53.9%). MS (ESI): m/z=276 [M+1]+.