Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:5](C(C)(C)C)([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:30])[CH2:17][N:18]([C:20]([C@H:22]2[CH2:27][CH2:26][C@H:25]([C:28]#[N:29])[CH2:24][CH2:23]2)=[O:21])[CH3:19])=[CH:12][C:11]=1[O:31][CH2:32][C:33]([O-:35])=[O:34])[C:6]([O-:8])=[O:7])(C)(C)C.N1C=CC=CC=1.C(N(CC)CC)C.[SH2:53]>C(OCC)(=O)C>[C:28]([C@H:25]1[CH2:24][CH2:23][C@H:22]([C:20]([N:18]([CH2:17][C:16]([C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:5][C:6]([OH:8])=[O:7])=[C:11]([O:31][CH2:32][C:33]([OH:35])=[O:34])[CH:12]=2)=[O:30])[CH3:19])=[O:21])[CH2:27][CH2:26]1)(=[S:53])[NH2:29]
Reactant: S
Reactant: CN(CC(=O)c1ccc(OC(C(=O)[O-])(C(C)(C)C)C(C)(C)C)c(OCC(=O)[O-])c1)C(=O)[C@H]1CC[C@H](C#N)CC1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CN(CC(=O)c1ccc(OCC(=O)O)c(OCC(=O)O)c1)C(=O)[C@H]1CC[C@H](C(N)=S)CC1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
Into the solution of the compound prepared in (a) (655 mg, 1.2 mmole) in the mixture of pyridine (15 ml) and triethylamine (1 ml) was streamed a hydrogen sulfide gas for 1 hour, and the mixture was stirred in a sealed tube at 50° C. for 5 hours. After the reaction mixture was cooled to room temperature, it was diluted with ethyl acetate, and washed twice with each of a 5% aqueous sodium hydrogen carbonate and a 1M potassium hydrogen sulfate solution. After the organic layer was dried over anhydrous magnesium sulfate, the inorganic salt was removed by filtration. The filtrate was concentrated under reduced pressure, and the oily product thus obtained was purified by column chromatography on silica gel with an eluent system of chloroform:methanol=50:1 to give 71 mg of the thioamide derivative as a yellow oily product (yield, 10%).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:41])[CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:38][CH3:39])([C:22]3[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]4([OH:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[C:24]([CH3:37])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:40])[CH:12]=1.[Cl-].[NH4+]>CO>[CH2:20]([C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:11]2[CH:12]=[C:7]([CH2:6][C:5]([OH:41])=[O:4])[CH:8]=[N:9][CH:10]=2)=[C:14]([CH3:40])[CH:15]=1)([C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]2([OH:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[C:24]([CH3:37])[CH:23]=1)[CH2:38][CH3:39])[CH3:21]
Reactant: CCC(CC)(c1ccc(/C=C/C2(O)CCCCC2)c(C)c1)c1ccc(-c2cncc(CC(=O)OC)c2)c(C)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCC(CC)(c1ccc(/C=C/C2(O)CCCCC2)c(C)c1)c1ccc(-c2cncc(CC(=O)O)c2)c(C)c1
Reaction time: 4 h
Yield: 86.4 %

Procedure:
A 2 N sodium hydroxide aqueous solution (0.27 mL) was added to a solution of {5-[4-(1-ethyl-1-{4-[(E)-2-(1-hydroxy-cyclohexyl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic acid methyl ester (Example 92-(1); 47.8 mg, 0.09 mmol) in methanol (1.5 mL), and the mixture was stirred for four hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by thin layer silica gel chromatography (10% methanol/dichloromethane) to give the title compound (39.8 mg, 85%).
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=O)[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH:52]1[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]1>O1CCOCC1.C(OCC)(=O)C>[CH3:1][C:2]1[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[N:5]=[C:6]([N:52]2[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]2)[N:7]=1
Reactant: C1CCNCC1
Reactant: CCOC(=O)c1c(-c2ccc(C)cc2)nc(=O)[nH]c1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(C)nc(N2CCCCC2)nc1-c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a stirred solution of ethyl 6-methyl-2-oxo-4-p-tolyl-1,2-dihydropyrimidine-5-carboxylate (2 g; 7,34 mmol) in dioxane (35 mL) were added PyBrOP (3,77 g; 8,08 mmol), triethyl amine (2,06 mL; 14,69 mmol) and piperidine (0,945 mL; 9,55 mmol) and the mixture was stirred at room temperature for 4 days. The reaction mixture was diluted with ethyl acetate and washed with a saturated solution of ammonium chloride and brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (2-20%) in heptane furnished 2 g (80%) of the title as a yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH:14]=[O:15])=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].[Br:16]Br>>[Br:16][CH:13]([CH2:12][CH2:11][C:8]1[CH:9]=[CH:10][C:5]([C:1]([O:3][CH3:4])=[O:2])=[CH:6][CH:7]=1)[CH:14]=[O:15]
Reactant: COC(=O)c1ccc(CCCC=O)cc1
Reactant: BrBr
Product: COC(=O)c1ccc(CCC(Br)C=O)cc1

Procedure:
performing a bromiantion reaction between 4-(4-carbomethoxyphenyl)butanal and Br2 to give 2-bromo-4-(4-carbomethoxyphenyl)butanal;
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([C:16]([OH:18])=O)[N:6]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[CH:7]=1)#[N:2].[K].CCN(C(C)C)C(C)C.[C:29]1([C:35]2[CH:40]=[C:39]([CH2:41][S:42]([N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)(=[O:44])=[O:43])[CH:38]=[CH:37][C:36]=2[NH2:51])[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:29]1([C:35]2[CH:40]=[C:39]([CH2:41][S:42]([N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)(=[O:44])=[O:43])[CH:38]=[CH:37][C:36]=2[NH:51][C:16]([C:5]2[N:6]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:13])([CH3:14])[CH3:15])[CH:7]=[C:3]([C:1]#[N:2])[N:4]=2)=[O:18])[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]=1
Reactant: Nc1ccc(CS(=O)(=O)N2CCOCC2)cc1C1=CCCCC1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(CS(=O)(=O)N2CCOCC2)cc1C1=CCCCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 95 %

Procedure:
A mixture of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid, potassium salt (as prepared in the Example 1, step (d), 33.6 mg, 0.110 mmol), DIEA (34 μL, 0.20 mmol), 2-cyclohex-1-enyl-4-(morpholine-4-sulfonylmethyl)-phenylamine (as prepared in the previous step, 33.6 mg, 0.110 mmol) and PyBroP (69.9 mg, 0.150 mmol) in DCM (2 mL) was stirred at RT for 12 h. The reaction mixture was diluted with DCM (10 mL) and washed with satd aq NaHCO3 (10 mL) and water (10 mL). The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The residue was purified on silica (20-40% EtOAc/hexane) to afford 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(morpholine-4-sulfonylmethyl)-phenyl]-amide (56 mg, 95%). Mass spectrum (ESI, m/z): Calcd. for C28H39N5O5SSi, 586.2 (M+H). found 586.1.
Reaction SMILES: [N:1]1C2C(=CC=CC=2)[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[O:18]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[O:21][CH2:20][CH:19]1[C:28](Cl)=[O:29]>>[CH2:2]([NH:1][C:28]([C:19]1[O:18][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[O:21][CH:20]=1)=[O:29])[CH2:3][CH3:4]
Reactant: O=C(Cl)C1COc2ccccc2O1
Reactant: c1ccc2ncccc2c1
Solvent: CCN(CC)CC
Product: CCCNC(=O)C1=COc2ccccc2O1
Yield: 110.4 %

Procedure:
This compound was prepared from the amine of Example 11 (1.90 g, 10.0 mmol), triethylamine (2.77 ml, 20.0 mmol) and 2,3-dihydro-1,4-benzodioxin-2-carbonyl chloride (1.88 g, 9.5 mmol) using the method described in Example 6. The crude gum was purified by chromatography (silica; ether) to give the product (2.30 g, 69%) as an oil which was converted into the thioamide of Example 14.
Reaction SMILES: [CH3:1][C:2]1([CH3:38])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([CH2:14][C:15]3[NH:19][N:18]=[N:17][N:16]=3)[CH:11]=[CH:10][C:9]=2[NH:20][C:21]([C:23]2[N:24]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:25]=[C:26]([C:28]#[N:29])[N:27]=2)=[O:22])=[CH:4][CH2:3]1.Cl.Cl[CH2:41][CH2:42][N:43]([CH3:45])[CH3:44].CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH3:44][N:43]([CH3:45])[CH2:42][CH2:41][N:17]1[N:18]=[N:19][C:15]([CH2:14][C:12]2[CH:11]=[CH:10][C:9]([NH:20][C:21]([C:23]3[N:24]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:35])([CH3:37])[CH3:36])[CH:25]=[C:26]([C:28]#[N:29])[N:27]=3)=[O:22])=[C:8]([C:5]3[CH2:6][CH2:7][C:2]([CH3:38])([CH3:1])[CH2:3][CH:4]=3)[CH:13]=2)=[N:16]1
Reactant: CC1(C)CC=C(c2cc(Cc3nnn[nH]3)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Reactant: CN(C)CCCl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCn1nnc(Cc2ccc(NC(=O)c3nc(C#N)cn3COCC[Si](C)(C)C)c(C3=CCC(C)(C)CC3)c2)n1
Temperature: 100 °C
Yield: 24.8 %

Procedure:
A solution of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-4-(1H-tetrazol-5-ylmethyl)-phenyl]-amide (as prepared in Example 42, step (b), 78 mg, 0.14 mmol) and (2-chloro-ethyl)-dimethyl-amine hydrochloride (63 mg, 0.43 mmol) in DMF (1 mL) was treated with DIEA (128 μL, 0.73 mmol) and then heated at 100° C. for 1 h. The reaction was allowed to cool to room temperature, diluted with EtOAc (25 mL) and then washed with water (2×10 mL). The organic phase was dried (Na2SO4) and concentrated in vacuo. Purification by preparative tlc (10% MeOH—CHCl3) afforded 21 mg (24%) of the title compound. Mass spectrum (ESI, m/z): Calcd. for C31H45N9O2Si, 604.3 (M+H), found 604.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.Cl[CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[C:27]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH:26]=1>>[C:19]([O:18][C:16]([N:13]1[CH2:14][CH2:15][CH:10]([N:9]([CH2:24][C:25]2[CH:30]=[CH:29][N:28]=[C:27]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH:26]=2)[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:11][CH2:12]1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: Fc1ccc(-c2cc(CCl)ccn2)cc1
Reactant: COc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Product: COc1ccc(N(Cc2ccnc(-c3ccc(F)cc3)c2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
4-(p-Anisidino)-1-(tert-butoxycarbonyl)piperidine (306 mg) and 4-chloromethyl-2-(4-fluorophenyl)pyridine (222 mg) were condensed in the same manner as described in Example 9 to give the title compound.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.O[C:14]1[C:15]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([NH2:26])=[O:25])[C:16]=2[N:17]=[N:18][N:19]=1>>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][NH:10][C:14]2[C:15]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([NH2:26])=[O:25])[C:16]=3[N:17]=[N:18][N:19]=2)=[CH:7][CH:8]=1
Reactant: NC(=O)c1cccc2c(O)nnnc12
Reactant: NCc1ccc(C(F)(F)F)cc1
Product: NC(=O)c1cccc2c(NCc3ccc(C(F)(F)F)cc3)nnnc12

Procedure:
Compound 8 was prepared following general synthetic scheme 7 wherein (4-(trifluoromethyl)phenyl)methanamine was reacted with 4-hydroxybenzo[d][1,2,3]-triazine-8-carboxamide to give the title compound. LC-MS [348 (M+1)], 1H NMR (400 MHz, DMSO-d): δ 9.40-9.37 (m, 2H), 8.56-8.51 (m, 2H), 8.05 (s, 1H), 8.01 (t, 1H), 7.70 (d, 2H), 7.62 (d, 2H), 4.99 (d, 2H).
Reaction SMILES: [C:1]1([O:8][CH3:9])[C:2](=[CH:4][CH:5]=[CH:6][CH:7]=1)[OH:3].[Br:10][C:11]([F:17])([F:16])[C:12]([F:15])([F:14])Br.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Br:10][C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[O:3][C:2]1[CH:4]=[CH:5][CH:6]=[CH:7][C:1]=1[O:8][CH3:9]
Reactant: FC(F)(Br)C(F)(F)Br
Reactant: COc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccccc1OC(F)(F)C(F)(F)Br
Temperature: 100 °C
Reaction time: 24 h
Yield: 85.1 %

Procedure:
30.0 g of guaiacol, 70.0 g of 1,2-dibromotetrafluoroethane, 50.0 g of anhydrous potassium carbonate and 450 ml of dry DMSO were introduced into a stirred autoclave made of stainless steel. After the autoclave had been flushed with argon, it was sealed and subsequently heated to 100° C. After the reaction mixture had been stirred at this temperature for 24 hours, it was cooled to 20° C., poured into water and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate. The dichloromethane was then evaporated in vacuo and the residue was distilled. 62.3 g of a mixture of 70 area % of 1-(2-bromo-1,1,2,2-tetrafluoroethoxy)-2-methoxybenzene (59.2% of theory) and 30 area % of 1-(1,1,2,2-tetrafluoroethoxy)-2-methoxybenzene (GC analysis) were obtained, distilling over at 80-95° C./14 mbar.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:28])[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][N:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>N1C=CC=CC=1.C(OCC)(=O)C>[OH:22][C:21]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:13](=[O:28])[C:12]=1[C:7]1[NH:6][C:5]2[CH:29]=[CH:30][C:2]([NH:1][S:32]([CH3:31])(=[O:34])=[O:33])=[CH:3][C:4]=2[S:9](=[O:11])(=[O:10])[N:8]=1
Reactant: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(N)ccc3N2)c(O)c2cccnc21
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)c(O)c2cccnc21
Temperature: 100 °C
Yield: 34.9 %

Procedure:
To the product of Example 205 (0.020 g, 0.047 mmol) in pyridine (0.2 mL) was added methanesulfonyl chloride (0.0064 g, 0.0043 mL, 0.056 mmol). The reaction mixture was heated in a microwave reactor at 100° C. for 38 minutes. The reaction was diluted with ethyl acetate (40 mL), washed with 1 N hydrochloric acid, water, and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a yellow solid, which was purified by chromatography on silica gel eluting with 99:1 dichloromethane:methanol to give the title compound (8.3 mg, 35%). 1H NMR (300 MHz, DMSO-d6) δ 0.98 (d, J=6.62 Hz, 6 H) 1.57 (m, 2 H) 1.70 (m, 1 H) 3.10 (s, 3 H) 4.49 (m, 2 H) 7.50 (dd, J=7.91, 4.60 Hz, 1 H) 7.58 (dd, J=8.82, 2.57 Hz, 1 H) 7.64 (d, J=2.21 Hz, 1 H) 7.75 (d, J=8.82 Hz, 1 H) 8.56 (dd, J=8.09, 1.84 Hz, 1 H) 8.89 (dd, J=4.60, 1.65 Hz, 1 H) 10.29 (s, 1 H) 14.17 (s, 1 H). MS (ESI−) m/z 504 (M−H)−.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)O)[CH3:2].COCCN(S(F)(F)[F:25])CCOC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:14])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)[F:25])[CH3:2]
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CCOC(=O)C(O)c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C(F)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 12 h
Yield: 69.3 %

Procedure:
(4-Chlorophenyl)-hydroxy-acetic acid ethyl ester (10.0 g, 46.6 mmol) in DCM (35 mL) was cannulated into a solution of [bis(2-methoxyethyl)amino]sulfur trifluoride (9.45 mL, 51.3 mmol) in DCM (35 mL) cooled at −78° C. After being stirred for 12 hours and allowed to warm to ambient temperature, the mixture was poured into saturated aqueous NaHCO3. The mixture was extracted with DCM and the organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. The crude material was chromatographed (SiO2) using DCM as eluent to give (4-chlorophenyl)-fluoroacetic acid ethyl ester as a colorless oil (7.0 g).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([I:17])[N:8]2C2CCCCO2)=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([I:17])[NH:8]2)=[C:4]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[N:3]=1
Reactant: Clc1nc(N2CCOCC2)c2nc(I)n(C3CCCCO3)c2n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: Clc1nc(N2CCOCC2)c2nc(I)[nH]c2n1
Temperature: 50 °C
Yield: 55.3 %

Procedure:
To a suspension of 4-(2-chloro-8-iodo-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)morpholine (0.655 g, 1.46 mmol) in methanol (6 mL) was added a catalytic amount of p-toluenesulfonic acid (25 mg, 0.14 mmol). The reaction mixture was heated at 50° C. for an overnight period. After this time, the mixture was cooled to room temperature and the volume of methanol was reduced by vacuum evaporation. The resulting residue was diluted with sat. aqueous NaHCO3 solution. The precipitate that formed was collected by filtration. In total, 295 mg (56%) of 4-(2-chloro-8-iodo-9H-purin-6-yl)morpholine was obtained as a white solid which was dissolved in anhydrous DMF (2.5 mL). Cesium carbonate (0.53 g, 1.61 mmol) was added and the mixture was stirred together 10 min at 23° C. Subsequently 1-(2H-3,4,5,6-tetrahydropyran-2-yloxy)-3-bromopropane (0.54 g, 2.42 mmol) was introduced to the mixture. The resulting reaction mixture was heated at 50° C. for 2 h. Complete conversion was observed at the end of this period. The reaction was worked up by dilution with 1 N HCl and EtOAc. The phases were separated and the aqueous layer was extracted twice with EtOAc. The combined organic portions were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by FCC (40 g silica gel column, 0-50% EtOAc in heptane) to give 385 mg (94% yield) of 4-(2-chloro-8-iodo-9-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-9H-purin-6-yl)morpholine as a pale yellow solid. MS (ESI+): m/z 508.0 (M+H+)
Reaction SMILES: C(O)(=O)[C@@H]([C@H](C(O)=O)O)O.[CH2:11]([O:13][C:14](=[O:32])[C:15]([CH3:31])([O:17][C:18]1[CH:23]=[C:22]([CH:24]2[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]2)[CH:21]=[CH:20][C:19]=1[CH3:30])[CH3:16])[CH3:12].CN(C)CCCN=C=NCC.[CH3:44][C:45]1[N:46]=[C:47]([C:53]2[CH:58]=[CH:57][C:56]([C:59]([F:62])([F:61])[F:60])=[CH:55][CH:54]=2)[S:48][C:49]=1[C:50](O)=[O:51]>C(OCC)(=O)C.C(OCC)C>[CH2:11]([O:13][C:14](=[O:32])[C:15]([CH3:31])([O:17][C:18]1[CH:23]=[C:22]([CH:24]2[CH2:29][CH2:28][CH2:27][N:26]([C:50]([C:49]3[S:48][C:47]([C:53]4[CH:54]=[CH:55][C:56]([C:59]([F:62])([F:60])[F:61])=[CH:57][CH:58]=4)=[N:46][C:45]=3[CH3:44])=[O:51])[CH2:25]2)[CH:21]=[CH:20][C:19]=1[CH3:30])[CH3:16])[CH3:12]
Reactant: CCOC(=O)C(C)(C)Oc1cc(C2CCCNC2)ccc1C
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)Oc1cc(C2CCCN(C(=O)c3sc(-c4ccc(C(F)(F)F)cc4)nc3C)C2)ccc1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 91.6 %

Procedure:
2-methyl-2-(2-methyl-5-piperidin-3-yl-phenoxy)-propionic acid ethyl ester L-tartaric acid salt (155 mg, 0.34 mmol) was dissolved in 50 mL ethyl acetate and washed with 50 mL saturated aqueous NaHCO3. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The resultant oil was taken up in 2 mL CH2Cl2 and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide (130 mg, 0.68 mmol) and 4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-carboxylic acid (98 mg, 0.34 mmol) were added. The reaction was stirred at ambient temperature under nitrogen for 72 h. The reaction was diluted with 100 mL diethyl ether and washed with water (100 mL), 0.5 N HCl (2×100 mL), saturated aqueous NaHCO3 (2×100 mL), dried over Na2SO4 and concentrated under reduced pressure to yield 2-methyl-2-(2-methyl-5-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carbonyl]-piperidin-3-yl}-phenoxy)-propionic acid ethyl ester (179 mg, 91%) as a clear oil.
Reaction SMILES: Cl[C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][CH2:9][C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][C:15]([Cl:21])=[CH:16][CH:17]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[CH3:30][NH:31][CH3:32]>>[Cl:21][C:15]1[CH:14]=[C:13]2[C:18]([C:19](=[O:20])[C:10]([CH2:9][NH:8][C:6](=[O:7])[C:5]3[CH:28]=[CH:29][C:2]([N:31]([CH3:32])[CH3:30])=[N:3][CH:4]=3)=[CH:11][N:12]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:17][CH:16]=1
Reactant: CNC
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(Cl)nc1
Product: CN(C)c1ccc(C(=O)NCc2cn(-c3ccccc3)c3cc(Cl)ccc3c2=O)cn1

Procedure:
N-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-6-dimethylamino-nicotinamide was prepared starting from intermediate E and dimethylamine. MS calcd. for C24H21ClN4O2 [(M+H)+] 433.1, obsd. 432.
Reaction SMILES: [I:1][CH:2]=[CH:3][CH:4]([OH:10])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:11]([Mg]Br)#[CH:12].CCOCC>O1CCCC1>[C:11]([C:4]([OH:10])([CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH:3]=[CH:2][I:1])#[CH:12]
Reactant: CCCCCC(O)C=CI
Reactant: C#C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: C#CC(O)(C=CI)CCCCC
Reaction time: 1 h

Procedure:
As shown in FIG. 1, 1-iodo-1-octen-3-ol (II) is treated with an ethynyl Grignard reagent, conveniently ethynyl magnesium bromide, in a suitable Grignard solvent of the ether type, conveniently tetrahydrofuran, at reduced temperature, conveniently 0° C., while stirring for a short time, conveniently 1 hour, to give dl-3-ethynyl-1-iodo-1-octen-3-ol (III).
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][N:14]=[CH:13]2.[C:19]([CH:21]1[CH2:24][N:23]([C:25](=[O:49])[C@H:26]([NH:28][C:29]([C:31]2[C:39]3[C:34](=[N:35][CH:36]=[C:37](I)[N:38]=3)[N:33]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[CH:32]=2)=[O:30])[CH3:27])[CH2:22]1)#[N:20].CN[C@@H]1CCCC[C@H]1NC>[Cu]I.C1(C)C=CC=CC=1>[C:19]([CH:21]1[CH2:22][N:23]([C:25](=[O:49])[C@H:26]([NH:28][C:29]([C:31]2[C:39]3[C:34](=[N:35][CH:36]=[C:37]([N:15]4[C:16]5[C:12](=[CH:11][C:10]([Cl:9])=[CH:18][CH:17]=5)[CH:13]=[N:14]4)[N:38]=3)[N:33]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[CH:32]=2)=[O:30])[CH3:27])[CH2:24]1)#[N:20]
Reactant: Clc1ccc2[nH]ncc2c1
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(I)nc12)C(=O)N1CC(C#N)C1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-n3ncc4cc(Cl)ccc43)nc12)C(=O)N1CC(C#N)C1
Temperature: 110 °C
Yield: 57.6 %

Procedure:
In a 5 mL microwave vial were placed copper(I) iodide (6 mg, 0.033 mmol), K3PO4 (132 mg, 0.62 mmol), 5-chloro-1H-indazole (54 mg, 0.36 mmol), 2-iodo-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (164 mg, 0.30 mmol), toluene (1.2 mL), and trans-N,N′-dimethylcyclohexane-1,2-diamine (9 mg, 0.066 mmol). The vial was purged with a stream of nitrogen then sealed and heated in an oil bath at 110° C. for 24 h. The reaction mixture was cooled to room temperature and diluted with EtOAc then filtered over a Buchner funnel, rinsing with EtOAc. The filtrate was concentrated and the resultant residue was purified by silica gel chromatography with 50% to 80% EtOAc/hexanes to afford 100 mg (58%) of 2-(5-chloro-indazol-1-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a light yellow foam.