Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH:3]=[CH:2]1.[C:8]([O-:11])(=[S:10])[CH3:9]>>[C:8]([O:11][CH:2]1[CH2:3][C:4](=[O:6])[NH:5][C:1]1=[O:7])(=[S:10])[CH3:9]
Reactant: CC([O-])=S
Reactant: O=C1C=CC(=O)N1
Product: CC(=S)OC1CC(=O)NC1=O
Temperature: 0 °C
Reaction time: 1.17 h
Yield: 43.1 %

Procedure:
Maleimide (5.0 g., 0.051 mole) was added to 10 ml. (0.14 mole) thioacetate acid cooled to 0° C. under nitrogen. The mixture was stirred at 0° C. for 70 min., then filtered. The filtrate was diluted with 70 ml. ethyl acetate and the resulting solution was washed with 50 ml. saturated aqueous sodium bicarbonate solution and 50 ml. saturated aqueous sodium chloride solution. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated in vacuo to a yellow oil (5.4 g). The crude product was purified by flash chromatography on silica gel (350 g.), eluting with 1:3 ethyl acetate-hexane, to yield 3.81 g (43%) of the title compound as a white solid. The NMR spectrum of the title compound as a deuterochloroform solution had peaks at 2.38 (s) and 2.3-3.54 (m) (total 5H); 4.24 (m, 1H); and 8.86 (b, 1H)ppm.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][S:5][C:6]=1[CH2:7][OH:8].[C:9](Cl)(=[O:11])[CH3:10].C(N(CC)CC)C.[Cl-].[Na+]>O1CCCC1>[C:9]([O:8][CH2:7][C:6]1[S:5][N:4]=[N:3][C:2]=1[CH3:1])(=[O:11])[CH3:10]
Reactant: CC(=O)Cl
Reactant: Cc1nnsc1CO
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)OCc1snnc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 107 %

Procedure:
In 10 ml of tetrahydrofuran were dissolved 0.50 g (3.8 mmol) of 4-methyl-1,2,3-thiadiazol-5--ylmethanol, 0.50 g (5.7 numol) of acetyl chloride and 0.80 g (7.6 mmol) of triethylamine. The solution thus obtained was stirred at room temperature for 18 hours. Then, a saturated aqueous solution of sodium chloride was added to the reaction mixture to stop the reaction, the objective product was extracted with ethyl acetate, the organic layer was washed with water and dried, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography using 3:1 mixture of n-hexane and ethyl acetate. Thus, 0.70 g of the objective compound was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.CCCCCC.C([Li])CCC.Cl[P:21]([C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=1)[C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1>O1CCCC1>[CH3:28][C:25]1[CH:24]=[CH:23][C:22]([P:21]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=2)=[CH:27][CH:26]=1
Reactant: Cc1cccc(Br)n1
Reactant: Cc1ccc(P(Cl)c2ccc(C)cc2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(P(c2ccc(C)cc2)c2cccc(C)n2)cc1
Reaction time: 0.17 h
Yield: 50.2 %

Procedure:
After dissolving 2-bromo-6-methylpyridine (23.5 mmol) in 40 ml of tetrahydrofuran, the mixture was cooled in a dry ice-ethanol bath, 1.59 M hexane solution of n-butyllithium (23.5 mmol) was added dropwise while stirring, and stirring was continued for 10 minutes to obtain a reaction mixture. To the obtained reaction mixture there was added chlorobis(4-methylphenyl)phosphine (17.5 mmol) dissolved in 40 ml of tetrahydrofuran, and stirring was continued at room temperature for 2 hours. The reaction solution was quenched with water and extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, purification was performed twice by silica gel column chromatography (developing solution: hexane/ethyl acetate=5/1, 9/1), to obtain 2.68 g of bis(4-methylphenyl)(6-methyl-2-pyridyl)phosphine (50% yield).
Reaction SMILES: C(O[C:4]([C:6]1[C:11](=[O:12])[NH:10][C:9]2[CH:13]=[CH:14][S:15][C:8]=2[C:7]=1[OH:16])=[O:5])C.[CH3:17][C:18]([NH2:22])([C:20]#[CH:21])[CH3:19]>CCO>[CH3:17][C:18]([NH:22][C:4]([C:6]1[C:11](=[O:12])[NH:10][C:9]2[CH:13]=[CH:14][S:15][C:8]=2[C:7]=1[OH:16])=[O:5])([CH3:19])[C:20]#[CH:21]
Reactant: CCOC(=O)c1c(O)c2sccc2[nH]c1=O
Reactant: C#CC(C)(C)N
Solvent: CCO
Product: C#CC(C)(C)NC(=O)c1c(O)c2sccc2[nH]c1=O

Procedure:
3.1 g (13 mmol) of 6-ethoxycarbonyl-7-hydroxy-thieno[3,2-b]pyridin-5(4H)-one and 1.3 g (1.2 eq.) of 1,1-dimethylpropargylamine in 80 ml of EtOH were stirred for 8 hours at 150° C. in an autoclave. The solvent was removed under reduced pressure and the solid residue was stirred with diethyl ether. The solid was filtered off and purified chromatographically (silica gel, methylene chloride/methanol =8/1).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].N.[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CO>[CH2:7]([S:5][CH2:4][CH2:3][NH2:2])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCc1ccccc1
Reactant: NCCS
Agent: Cl
Agent: N
Solvent: CO
Product: NCCSCc1ccccc1
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a suspension of 0.1 mole cysteamine hydrochloride in 20 mL methanol were added 13.6 mL of 25% ammonia solution, followed by dropwise addition of 0.12 mole benzyl bromide at room temperature. The mixture was stirred for 0.5 h, and the formed precipitate of S-dibenzylcysteamine was collected by filtration. The product was extracted with ether (3×100 mL) and the organic phase was successively washed with brine (2×100 mL), dried over MgSO4 and the solvent evaporated in vacuo. The crude product was essentially pure enough for the next step. It could, however be recrystallized from ethyl acetate. Yield 86%, of white solid. m.p. 85°-6° C. NMR (CDCl3) in agreement with the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:39][CH3:40])=[C:17]([O:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:28][CH:27]5[CH2:29][N:30](C(OC(C)(C)C)=O)[CH2:31][CH:26]5[CH2:25]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].Cl>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:39][CH3:40])=[C:17]([O:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:28][CH:27]5[CH:26]([CH2:31][NH:30][CH2:29]5)[CH2:25]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CC2CN(C(=O)OC(C)(C)C)CC2C1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CC2CNCC2C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 92.7 %

Procedure:
To a solution of tert-butyl 5-(3-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)propyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (1.70 g) in DCM (30 mL) was added a solution of HCl in EtOAc. The reaction mixture was stirred at room temperature for 6 h and filtered to obtain the crude product. The crude product was recrystallized from MeOH/EA to give the title compound as a white solid (1.30 g, 80.00%), HPLC: 85.68%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 472.2 (M+1); 1H NMR (400 MHz, CDCl3) δ: 1.81-1.88 (m, 4H), 2.35-2.43 (m, 6H), 2.68-2.74 (m, 4H), 3.99 (s, 3H), 4.13 (t, J=7.2 Hz, 2H), 7.16 (s, 1H), 7.26 (s, 1H), 7.45 (s, 1H), 7.57-7.62 (m, 1H), 7.91-7.93 (m, 1H), 8.64 (s, 1H) ppm.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CC(OC)(C)C>[F:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:2]2[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)=[CH:12][CH:11]=1
Reactant: Oc1ccc(Br)nc1
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COC(C)(C)C
Product: Oc1ccc(Oc2ccc(F)cc2)nc1
Temperature: 170 °C

Procedure:
A mixture of 6-bromo-pyridin-3-ol (8.0 g), 4-fluorophenol (15.5 g) and cesium carbonate (30 g) was heated to 170° C. for 6 hours. After the mixture reached room temperature, it was distributed between water and MTBE. The organic phase was dried (Na2SO4) and concentrated. The residue was purified by chromatography (SiO2; EA/heptane 1:1.5) to provide the subtitle compound. MS ESI+: m/z=206 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][N:12]([N:14]([CH2:22][C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)C(=O)CC(C)(C)C)[C:11](=[O:29])[N:10]2[CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][N:12]([NH:14][CH2:22][C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[C:11](=[O:29])[N:10]2[CH2:30][CH2:31][C:32]2[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: COc1ccc(CCN2C(=O)N(N(Cc3ccncc3)C(=O)CC(C)(C)C)CC2c2ccc(C)c(C)c2)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(CCN2C(=O)N(NCc3ccncc3)CC2c2ccc(C)c(C)c2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 104.7 %

Procedure:
A solution of N-{4-(3,4-dimethylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-2-oxo-imidazolidin-1-yl}-3,3-dimethyl-N-pyridin-4-ylmethyl-butyramide (205 mg, 0.386 mmol) in CH2Cl2 (1.5 mL) is cooled in an ice bath and triethylsilane (0.129 mL, 0.81 mmol) is added, followed by trifluoroacetic acid (1.5 mL). The ice bath is removed and the reaction is stirred at ambient temperature for 2.5 hours. The reaction is concentrated to an oil, dissolved in ethyl acetate, and washed with 10% aqueous NaHCO3, and brine. The organic phase is dried (Na2SO4), treated with 2N HCl/ether (0.7 mL), and concentrated under reduced pressure. The solid which results is re-crystallized from dichloromethane/ether to afford 174 mg (76% yield) of the desired compound. 1H NMR (DMSO-d6) δ 8.92 (d, J=6.0 Hz, 2H), 8.21 (d, J=6.0 Hz, 2H), 7.14 (d, J=7.5 Hz, 1H), 7.00 (m, 4H), 6.82 (d, J=8.1 Hz, 2H), 4.38 (m, 3H), 3.74 (s, 3H), 3.72 (m, 1H), 3.44 (m, 1H), 3.14 (t, J=7.8 Hz, 1H), 2.68 (m, 1H), 2.52 (m, 1H), 2.24 (s, 3H), 2.20 (s, 3H). MS 431 (MH+). Anal. calcd. for C26H30N4O2 2HCl: C, 62.03; H, 6.41; N, 11.13. Found: C, 61.99; H, 6.41; N, 11.13.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:25]#[N:26])=[C:4]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])[C:5]2[C:10](=[O:11])[N:9]([CH3:12])[C:8](=[O:13])[N:7]([CH3:14])[C:6]=2[N:15]=1.Br[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=1>>[NH2:26][CH2:25][C:3]1[C:2]([NH:1][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=2)=[N:15][C:6]2[N:7]([CH3:14])[C:8](=[O:13])[N:9]([CH3:12])[C:10](=[O:11])[C:5]=2[C:4]=1[C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[O:23][CH3:24]
Reactant: COc1cccc(CBr)c1
Reactant: COc1ccc(F)cc1-c1c(C#N)c(N)nc2c1c(=O)n(C)c(=O)n2C
Product: COc1cccc(CNc2nc3c(c(-c4cc(F)ccc4OC)c2CN)c(=O)n(C)c(=O)n3C)c1

Procedure:
The synthesis of title compounds started from Compound 70a and 1-(bromomethyl)-3-methoxybenzene, according to procedures described in the synthesis of Compound 56. MS [m+H] calc'd C25H27FN5O4 480; found 480.
Reaction SMILES: N[C:2]1[NH:3][C:4](=[O:20])[C:5]2[N:6]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:18]#[N:19])[CH:7]=[N:8][C:9]=2[N:10]=1.N([O-])=[O:22].[Na+].O.Cl>C(O)(=O)C>[C:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][N:6]1[C:5]2[C:4](=[O:20])[NH:3][C:2](=[O:22])[NH:10][C:9]=2[N:8]=[CH:7]1)#[N:19]
Reactant: N#Cc1ccccc1Cn1cnc2nc(N)[nH]c(=O)c21
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1ccccc1Cn1cnc2[nH]c(=O)[nH]c(=O)c21

Procedure:
Prepared by treating 16.68 g of 2-amino-7-(2-cyano-benzyl)-1,7-dihydro-purin-6-one with 17.00 g of sodium nitrite in a mixture of 375 ml of conc. acetic acid, 84 ml of water and 5.2 ml of conc. hydrochloric acid at 50° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([CH2:17][CH2:18][N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[N:12]=[CH:11]3)[C:4](=[O:24])[CH:3]=1.Br[CH:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:27]>CN(C=O)C>[C:28]1([CH:26]([O:1][C:2]2[CH:7]=[CH:6][N:5]([C:8]3[CH:9]=[C:10]4[C:14](=[CH:15][CH:16]=3)[N:13]([CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[N:12]=[CH:11]4)[C:4](=[O:24])[CH:3]=2)[CH3:27])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=c1cc(O)ccn1-c1ccc2c(cnn2CCN2CCCC2)c1
Reactant: CC(Br)c1ccccc1
Solvent: CN(C)C=O
Product: CC(Oc1ccn(-c2ccc3c(cnn3CCN3CCCC3)c2)c(=O)c1)c1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 39.5 %

Procedure:
To a solution of 4-hydroxy-1-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-indazol-5-yl)pyridin-2(1H)-one (84 mg, 0.26 mmol) in DMF was added Ag2O (120 mg, 0.52 mmol) followed by 1-bromoethylbenzene (71 uL, 0.52 mmol). The reaction mixture was heated to 80° C. for 4 hours, cooled to room temperature and stirred at room temperature for overnight. The reaction mixture was filtered through a thin layer of Celite, washed with CH2Cl2, and the filtrate was concentrated. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH, 90:10) gave 4-(1-phenylethoxy)-1-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-indazol-5-yl)pyridin-2(1H)-one (44 mg, 40%) as an oil. In accordance with the procedure of Example 1, the HCl salt was made to give the title compound as a white foam: 1H NMR (500 MHz, DMSO-d6) δ 9.82 (s, 1H), 8.15 (s, 1H), 7.75 (d, J=9.0 Hz, 1H), 7.69 (d, J=2.0 Hz, 1H), 7.49 (d, J=7.5 Hz, 1H), 7.38-7.31 (m, 5H), 7.26-7.24 (m, 1H), 6.04 (dd, J=7.5, 2.5 Hz, 1H), 5.69 (d, J=3.0 Hz, 1H), 5.51 (q, J=6.5 Hz, 1H), 4.77-4.75 (m, 2H), 3.66-3.63 (m, 2H), 3.46-3.45 (m, 2H), 3.00-2.99 (m, 2H), 1.93 (m, 2H), 1.78-1.75 (m, 2H), 1.51 (d, J=6.5 Hz, 3H); ESI MS m/z 429 [M+H]+.
Reaction SMILES: O=[C:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[CH2:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=O.O.[NH2:26][NH2:27]>CCO>[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:2]1[CH:3]=[C:4]([CH:6]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[NH:27][N:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)CC(=O)c2ccccn2)CC1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2cc(-c3ccccn3)n[nH]2)CC1
Temperature: 80 °C

Procedure:
Unpurified tert-butyl 4-(3-oxo-3-pyridin-2-ylpropanoyl)piperidine-1-carboxylate (2.00 g, 6.02 mmol) was dissolved in 20 ml of EtOH and hydrazine hydrate (0.321 ml, 6.62 mmol) was added and the reaction was warmed to 80° C. After 15 h the reaction was concentrated in vacuo and the residue was purified by flash column chromatography (dissolve in DCM, elute with 98:2 to 95:5 DCM/MeOH). tert-Butyl 4-(3-pyridin-2-yl-1H-pyrazol-5-yl)piperidine-1-carboxylate was obtained as a yellow oil. 1H NMR (CDCl3): δ 8.60 (m, 1H), 7.73 (dt, J=1.7, 7.6 Hz, 1H), 7.65 (d, J=7.8 Hz, 1H), 7.22 (m, 1H), 6.57 (s, 1H), 4.18 (bs, 2H), 2.89 (m, 4H), 2.00 (d, J=12.5 Hz, 2H), 1.67 (m, 2H), 1.48 (s, 9H). m/z (m+1): 329.2
Reaction SMILES: CN1CCOCC1.[Br:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][CH:10]=1.Cl.Cl.[CH3:19][O:20][C:21](=[O:32])[CH:22]([NH:25][C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[CH2:23][NH2:24].ON1C2C=CC=CC=2N=N1>CN(C=O)C>[CH3:19][O:20][C:21](=[O:32])[CH:22]([NH:25][C:26]1[N:27]=[CH:28][CH:29]=[CH:30][N:31]=1)[CH2:23][NH:24][C:14]([C:12]1[S:13][C:9]([Br:8])=[CH:10][CH:11]=1)=[O:16]
Reactant: O=C(O)c1ccc(Br)s1
Reactant: COC(=O)C(CN)Nc1ncccn1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)C(CNC(=O)c1ccc(Br)s1)Nc1ncccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.5 %

Procedure:
4-methylmorpholine (0.23 mL, 2.10 mmol) was added to a mixture of 5-bromothiophene-2-carboxylic acid (124 mg, 0.60 mmol), 3-amino-2-(pyrimidin-2-ylamino)-propionic acid methyl ester bis-hydrochloride salt (161 mg, 0.60 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarboiimide hydrochloride (115 mg, 0.60 mmol) and 1-hydroxybenzotriazole (81 mg, 0.60 mmol) in dry DMF (2 mL). The mixture was stirred at room temperature overnight. The reaction mixture was concentrated, solvent removed in vacuo and the residue chromatographed. Elution with 5% methanol in dichloromethane gave compound G-2 as a yellow foam (186 mg, 81% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]([CH3:24])([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:17])[CH:12]=[CH:13][C:14]=1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].CN(C)[CH:28]=[O:29]>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]([CH3:24])([CH3:17])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:12]=[CH:13][C:14]=1[CH:28]=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: CCCCCCC(C)(C)c1ccc(Br)c(OCc2ccccc2)c1
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCCC(C)(C)c1ccc(C=O)c(OCc2ccccc2)c1
Temperature: 25 °C

Procedure:
2-(3-benzyloxy-4-bromophenyl)-2-methyloctane (100 g., 0.257 mole) in tetrahydrofuran (500 ml.) was slowly added to 70-80 mesh magnesium (12.3 g., 0.514 mole) at such a rate that reflux was maintained. Upon completion of addition, the reaction mixture was stirred until it cooled to room temperature. It was then further cooled to 0° C. Dimethylformamide (29.8 ml., 0.385 mole) was added dropwise to the reaction mixture over a 25 minute period (reaction temperature <10° C.). The reaction mixture was then allowed to warm and was stirred for 40 minutes at room temperature. The reaction mixture was quenched by addition to a saturated aqueous solution of cold ammonium chloride (1800 ml.) and the product extracted with ether (one liter). The ether extract was washed twice with saturated sodium chloride (1500 ml.), dried over magnesium sulfate and evaporated to a quantitative yield of the title compound as an oil.
Reaction SMILES: [CH2:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][OH:11])[O:8][C@@H:7]([N:12]2[CH:19]=[C:18](I)[C:16](=[O:17])[NH:15][C:13]2=[O:14])[CH2:6]1)[CH:2]=[CH2:3].C(N(CC)CC)C.[CH2:28]([NH:31][C:32](=[O:37])[C:33]([F:36])([F:35])[F:34])[C:29]#[CH:30]>CN(C=O)C.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][OH:11])[O:8][C@@H:7]([N:12]2[CH:19]=[C:18]([C:30]#[C:29][CH2:28][NH:31][C:32](=[O:37])[C:33]([F:36])([F:35])[F:34])[C:16](=[O:17])[NH:15][C:13]2=[O:14])[CH2:6]1)[CH:2]=[CH2:3]
Reactant: C#CCNC(=O)C(F)(F)F
Reactant: C=CCO[C@H]1C[C@H](n2cc(I)c(=O)[nH]c2=O)O[C@@H]1CO
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CCO[C@H]1C[C@H](n2cc(C#CCNC(=O)C(F)(F)F)c(=O)[nH]c2=O)O[C@@H]1CO
Reaction time: 16 h
Yield: 95.4 %

Procedure:
To a solution of (35) (400 mg, 1.0 mmol) in dry DMF (10 ml) was added CuI (38 mg, 20 μmol) and triethylamine (300 μl, 2.0 mmol). The propargyltrifluoroacetamide (453 mg, 3.0 mmol) was added drop wise, followed by Pd(PPh3)4 (110 mg, 9.5 μmol). The reaction was stirred for 16 h in the dark. The reaction was quenched by adding MeOH (10 ml), DCM (10 ml) and bicarbonate dowex. The mixture was stirred for 30 min and then filtered. The solvents were removed under vacuum and the crude product was purified by chromatography on silica (EtOAc:petrol 3:7 to 7:3). The product was isolated as slightly yellow crystals (398 mg, 95%). 1H NMR (d6 DMSO) δ 2.25-2.43 (m, 2H, H-2′), 3.65-3.76 (m, 2H, H-5′), 4.07-4.17 (m, 3H, H-4′, CH2), 4.21-4.23 (m, 1H, H-3′), 4.34 (d, J=5.5 Hz, 2H, CH2N), 5.25-5.27 (m, 2H, ═CH2, OH), 5.38 (dd, J=1.83, 17.3 Hz, 1H, ═CH2), 5.96-6.06 (m, 1H, ═CH), 6.17 (t, J=6.9 Hz, 1H, H-1′), 8.29 (8, 1H, H-6), 10.17 (t, J=5.5 Hz, 1H, NHTFA), 11.78 (s, 1H, NH). Mass (−ve electrospray) calcd for C17H18F3N3O6 417.11, found 416.
Reaction SMILES: [C:1]1([C:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16]C(C)([O-])C.[K+].CI>C1COCC1>[C:1]1([C:7](=[O:8])[CH:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH3:16])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)[O-]
Reactant: O=C(Cc1ccccc1)c1ccccc1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CC(C(=O)c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
To deoxybenzoin (0.500 g, 2.55 mmol) in THF (12 mL) at −78° C. were added a THF solution of potassium tert-butoxide 1M (2.5 mL, 2.55 mmol) and MeI (0.396 mL). After a period of 0.5 h, at room temperature, NH4OAc aqueous was added to the reaction mixture. The organic phase was separated, dried over NaSO4, filtered and evaporated. The residue was purified by flash chromatography to give the title compound.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[C:13]1([P:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1C=CC=CC=1>[C:26]1([P:19](=[CH:2][C:3]([O:5][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4])([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: O=C(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
A 22.9 g quantity of benzyl bromoacetate was dissolved in 100 ml of dry benzene. A 26.2 g quantity of triphenylphosphine was added thereto at room temperature and stirred overnight. The precipitated solids were collected by filtration, washed with benzene and dissolved in 250 ml of dichloromethane. A 14 ml quantity of triethylamine was added with ice-cooling and stirred with ice-cooling for 30 minutes and at room temperature for a further 30 minutes. The reaction mixture was transferred to a separating funnel, washed with water and dried over magnesium sulfate. The solvent was distilled off and diethyl ether was added to the residue. The resulting precipitate was collected by filtration to provide the title compound as white crystals (yield 41%).
Reaction SMILES: [Cl:1][CH:2]([F:9])[C:3]([F:8])([F:7])[C:4](O)=[O:5].C([Cl:18])(=O)C1C=CC=CC=1>>[Cl:1][CH:2]([F:9])[C:3]([F:8])([F:7])[C:4]([Cl:18])=[O:5]
Reactant: O=C(O)C(F)(F)C(F)Cl
Reactant: O=C(Cl)c1ccccc1
Product: O=C(Cl)C(F)(F)C(F)Cl

Procedure:
In a three-necked 2 l flask provided with a Vigreux column, a condenser, and a collecting flask were brought 325 g (2 moles) of 3-chloro-2,2,3-trifluoro-propionic acid (Org.Synth.Coll. 5, 239) and 562 g (4 moles) of benzoyl chloride. The mixture was heated so that the acid chloride distilled over slowly. The collected product was refluxed for 20 min to eliminate any residual hydrochloric acid. Finally the product was distilled at normal pressure. Yield: 280 g. Boiling point: 72°-74° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([NH:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:24][O:25][C:26](=[O:40])[C:27]([C:30]1[CH:35]=[CH:34][C:33]([N:36]=[C:37]=[O:38])=[C:32]([F:39])[CH:31]=1)([CH3:29])[CH3:28].CCN(CC)CC>ClCCCl>[CH3:24][O:25][C:26](=[O:40])[C:27]([C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37]([N:17]([C:16]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=[C:10]3[C:15]=2[CH:14]=[CH:13][CH:12]=[CH:11]3)[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:38])=[C:32]([F:39])[CH:31]=1)([CH3:29])[CH3:28]
Reactant: COC(=O)C(C)(C)c1ccc(N=C=O)c(F)c1
Reactant: Clc1ccc(-n2nc3ccccc3c2NC2CCCCC2)cc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(C)(C)c1ccc(NC(=O)N(c2c3ccccc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c(F)c1

Procedure:
In analogy to the procedure described in example 1.2, [2-(4-chloro-phenyl)-2H-indazol-3-yl]-cyclohexyl-amine (example 9.1) was reacted with 2-(3-fluoro-4-isocyanato-phenyl)-2-methyl-propionic acid methyl ester in 1,2-dichloroethane in the presence of Et3N for 3 days under reflux conditions to give the title compound as yellow solid. MS: m/e=563.5 [M+H+].