Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][NH:12][C:13]([C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)=[O:14])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[Cl:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:29].ClN1C(=O)CCC1=O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:1]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][NH:12][C:13]([C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][C:16]=2[O:29][CH2:28][CH2:27][CH2:26][CH2:25][Cl:24])=[O:14])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: OCCCCCl
Reactant: CCCCN1CCC(CNC(=O)c2c[nH]c3ccccc23)CC1
Agent: O=C([O-])[O-]
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCCCN1CCC(CNC(=O)c2c(OCCCCCl)[nH]c3ccccc23)CC1
Reaction time: 0.67 h
Yield: 49.9 %

Procedure:
A stirred suspension of N-[(l-n butyl-4-piperidyl)methyl] indole-3-carboxamide (Description 1b, 1.0 g, 0.0032 mole) in chloroform (25 ml) was treated with 4-chlorobutanol (0.69 ml, 0.0064 mole) followed by N-chlorosuccinimide (470 mg, 0.0035 mole) and a yellow solution was produced inside 5 minutes. After a further 40 minutes the solution was observed to darken in colour to orange. The mixture was kept at room temperature for a further 1 h then treated with 10% Na2CO3 solution (30 ml) and extracted with chloroform (2×30 ml). The combined extracts were dried (Na2SO4) and concentrated in vacuo to afford an orange oil, which was chromatographed on silica gel eluting with 5% methanol/chloroform to give N-[(1-n butyl-4-piperidyl)methyl] 2-(4-chlorobutoxy)indole-3-carboxamide (0.67 g, 50%) as a yellow oil.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14](=[O:22])[N:15]([CH3:21])[N:16]=[CH:17][C:18]=2[O:19][CH3:20])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[CH3:23]OC(OC)(C)C.Cl>CO.O1CCOCC1>[CH3:23][O:4][C:3](=[O:5])[CH:2]([NH2:1])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[C:14](=[O:22])[N:15]([CH3:21])[N:16]=[CH:17][C:18]=2[O:19][CH3:20])=[CH:11][CH:12]=1
Reactant: COc1cnn(C)c(=O)c1-c1ccc(C[C@H](N)C(=O)O)cc1
Reactant: COC(C)(C)OC
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)C(N)Cc1ccc(-c2c(OC)cnn(C)c2=O)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-(S)-Amino-3-[4-(5-methoxy-2-methyl-3-oxo-2,3-dihydro-pyridazin-4-yl)-phenyl]-propionic acid (0.40 g, 1.0 mmol) was dissolved in MeOH (2.6 mL). Dimethoxypropane (0.26 mL) and 1N HCl in dioxane (0.33 mL) were added and stirred at room temperature for 24 h. The mixture was concentrated in vacuo to give 2-Amino-3-[4-(5-methoxy-2-methyl-3-oxo-2,3-dihydro-pyridazin-4-yl)-phenyl]-propionic acid methyl ester. MS (ES+) 318.
Reaction SMILES: [CH3:1][C:2]1([N:13]([CH3:42])[C:14]2[C:15]([C:38]([F:41])([F:40])[F:39])=[CH:16][C:17]3[O:36][CH2:35][C:20]4=[N:21][N:22](COCC[Si](C)(C)C)[C:23](=[O:26])[CH:24]([CH3:25])[N:19]4[C:18]=3[CH:37]=2)[CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[C:43]([OH:49])([C:45]([F:48])([F:47])[F:46])=[O:44]>C(Cl)Cl>[F:46][C:45]([F:48])([F:47])[C:43]([OH:49])=[O:44].[CH3:25][C@@H:24]1[C:23](=[O:26])[NH:22][N:21]=[C:20]2[CH2:35][O:36][C:17]3[CH:16]=[C:15]([C:38]([F:40])([F:39])[F:41])[C:14]([N:13]([CH3:42])[C:2]4([CH3:1])[CH2:3][NH:4][CH2:5]4)=[CH:37][C:18]=3[N:19]12
Reactant: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3cc(C(F)(F)F)c(N(C)C4(C)CN(C(=O)OC(C)(C)C)C4)cc3N21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1C(=O)NN=C2COc3cc(C(F)(F)F)c(N(C)C4(C)CNC4)cc3N21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 7 %

Procedure:
To a solution of tert-butyl 3-methyl-3-(methyl(1-methyl-2-oxo-8-(trifluoromethyl)-3-((2-(tri methylsilyl)ethoxy)methyl)-1,2,3,5-tetrahydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-9-yl)amino)azetidine-1-carboxylate (0.586 g, 0.360 mmol) in DCM (4 mL) was added TFA (0.8 mL) and the mixture was stirred at ambient temperature for 1.5 h. The solvent was removed in vacuo and dioxane (1 mL) and ammonium hydroxide (25%, 1 mL) were added and the reaction mixture was stirred for 1.5 h at ambient temperature. The solvent was removed in vacuo and the residue was purified by HPLC (Table 3, Method 19) and further separated by chiral SFC (Table 2, Method 12) to give (R)-1-methyl-9-(methyl(3-methylazetidin-3-yl)amino)-8-(trifluoromethyl)-3,5-dihydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-2(1H)-one trifluoroacetic acid (SFC (Table 1, Method 17) Rt: 6.57 min, 0.033 g, 7%)) as a pale solid. LC/MS (Table 1, Method 5) Rt=2.319 min.; MS m/z: 384 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]3([C:33]([NH:35][CH2:36][CH2:37][CH2:38][C:39]([O:41]C(C)(C)C)=[O:40])=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:24][CH:23]=2)=[CH:18][CH:17]=1.Cl.O1CCOCC1>>[CH3:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]3([C:33]([NH:35][CH2:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:34])[CH2:29][CH2:30][CH2:31][CH2:32]3)=[CH:24][CH:23]=2)=[CH:20][CH:21]=1
Reactant: C[C@@H]1CCCN1CCc1ccc(-c2ccc(C3(C(=O)NCCCC(=O)OC(C)(C)C)CCCC3)cc2)cc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: C[C@@H]1CCCN1CCc1ccc(-c2ccc(C3(C(=O)NCCCC(=O)O)CCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (R)-tert-butyl 4-(1-(4′-(2-(2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)cyclopentanecarboxamido)butanoate 2,2,2-trifluoroacetate (2.6 mg, 4.11 μmol) was added 4M hydrogen chloride in dioxane (0.103 mL, 0.411 mmol). The reaction was stirred at room temperature overnight. The mixture was concentrated to give the title compound. LCMS m/z=463.4 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]([OH:13])=O)=[CH:8][C:9]=1[CH3:10])=[O:4].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[NH2:55][CH2:56][C:57]1[CH:58]=[CH:59][C:60]([F:64])=[C:61]([OH:63])[CH:62]=1>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11](=[O:13])[NH:55][CH2:56][C:57]2[CH:58]=[CH:59][C:60]([F:64])=[C:61]([OH:63])[CH:62]=2)=[CH:8][C:9]=1[CH3:10])=[O:4]
Reactant: NCc1ccc(F)c(O)c1
Reactant: COC(=O)c1sc(C(=O)O)cc1C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1sc(C(=O)NCc2ccc(F)c(O)c2)cc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 97.6 %

Procedure:
To a solution of 3-Methyl-thiophene-2,5-dicarboxylic acid 2-methyl ester (220 mg, 1.10 mmol) in anhydrous DMF (10 mL) was added triethylamine (0.46 mL, 3.30 mmol), HBTU (0.63 g, 1.65 mmol), HOBT (178 mg, 1.32 mmol), and 5-Aminomethyl-2-fluoro-phenol (187 mg, 1.32 mmol). The mixture was stirred at room temperature 15 h, then quenched by pouring into EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography with 60-80% EtOAc in hexane to afford the desired product (0.3472 g, 98% yield).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[CH3:5][O:6][C:7](=[O:13])[CH:8](Cl)[C:9](=O)[CH3:10]>CCO>[CH3:5][O:6][C:7]([C:8]1[S:3][C:2]([NH2:4])=[N:1][C:9]=1[CH3:10])=[O:13]
Reactant: COC(=O)C(Cl)C(C)=O
Reactant: NC(N)=S
Solvent: CCO
Product: COC(=O)c1sc(N)nc1C

Procedure:
A mixture of thiourea (59.8 mmol) and 2-chloro-3-oxo-butyric acid methyl ester (59.8 mmol) in EtOH (140 mL) is heated at reflux for 14 h and concentrated in vacuo. Water and aq. NaHCO3 are added and the mixture is extracted several times with EtOAc. The combined organic layers are dried and concentrated in vacuo to give the desired amino-thiazole derivative. LC-MS: tR=0.51 min; [M+H]+=173.0.
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[C:20]([NH2:22])=[O:21])[CH2:14][CH2:13]2)=[CH:4]1.[O:29]1[C:38]2[C:33](=[CH:34][C:35](/[CH:39]=[CH:40]/[C:41](O)=[O:42])=[CH:36][CH:37]=2)[CH2:32][CH2:31][CH2:30]1>>[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([CH:23]3[CH2:24][CH2:25][N:26]([C:41](=[O:42])/[CH:40]=[CH:39]/[C:35]4[CH:34]=[C:33]5[C:38](=[CH:37][CH:36]=4)[O:29][CH2:30][CH2:31][CH2:32]5)[CH2:27][CH2:28]3)[C:20]([NH2:22])=[O:21])[CH2:14][CH2:13]2)=[CH:4]1
Reactant: NC(=O)C(NC1CCC(c2c[nH]c3ccccc23)CC1)C1CCNCC1
Reactant: O=C(O)/C=C/c1ccc2c(c1)CCCO2
Agent: Cl
Product: NC(=O)C(NC1CCC(c2c[nH]c3ccccc23)CC1)C1CCN(C(=O)/C=C/c2ccc3c(c2)CCCO3)CC1

Procedure:
The title compound was prepared from the product of Example 1, step J, and (2E)-3-(3,4-dihydro-2H-chromen-6-yl)prop-2-enoic acid, by the method of Example 1, step K, giving a yellow solid that was a mixture of cyclohexyl diastereomers by LCMS. Mass spectrum (LCMS, ESI pos.) calcd. for C33H40N4O3: 541 (M+H). Found: 541
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:14][O:13][C:5]2([CH2:9][C@@H:8]([C:10]([OH:12])=O)[CH2:7][CH2:6]2)[O:4][CH2:3]1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:31][C:32]1[CH2:39][CH2:38][C:35]2([CH2:37][CH2:36]2)[CH2:34][C:33]=1[C:40]([O:42][CH2:43][CH3:44])=[O:41]>C(#N)C>[CH3:15][C:2]1([CH3:1])[CH2:3][O:4][C:5]2([CH2:9][C@@H:8]([C:10]([NH:31][C:32]3[CH2:39][CH2:38][C:35]4([CH2:37][CH2:36]4)[CH2:34][C:33]=3[C:40]([O:42][CH2:43][CH3:44])=[O:41])=[O:12])[CH2:7][CH2:6]2)[O:13][CH2:14]1
Reactant: CCOC(=O)C1=C(N)CCC2(CC2)C1
Reactant: CC1(C)COC2(CC[C@H](C(=O)O)C2)OC1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: CC#N
Product: CCOC(=O)C1=C(NC(=O)[C@H]2CCC3(C2)OCC(C)(C)CO3)CCC2(CC2)C1
Reaction time: 1 h
Yield: 56.6 %

Procedure:
To a stirred solution of (S)-8,8-dimethyl-6,10-dioxaspiro[4.5]decane-2-carboxylic acid (1.5 g, 7.0 mmol) and NMM (1.15 ml, 10.50 mmol) in acetonitrile (35 ml), isobutyl chloroformate (1 ml, 7.70 mmol) was added drop wise at −5 to −10° C. After 1 h, a solution of ethyl 6-aminospiro[2.5]oct-5-ene-5-carboxylate (3.42 g, 17.50 mmol) in acetonitrile (15 ml) was added and the reaction was allowed to stir at 0° C. to −5° C. for 1 h followed by stirring overnight at 25-30° C. Upon completion, the reaction mixture was quenched by addition of water (10 ml). Organic solvent was removed under reduced pressure and the residue was diluted with ethyl acetate (50 ml) and 10% sodium bicarbonate (25 ml). The organic mass was extracted using ethyl acetate (3×50 ml). Combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford a crude solid, which was purified by column chromatography over silica gel using ethyl acetate in hexane as eluents to obtain the title compound (1.55 g, 56.6%).
Reaction SMILES: Br[CH2:2][C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=3)[O:11][C:6]2=[CH:5][CH:4]=1.CCN(CC)CC.[C:28]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>CC#N>[C:31]([O:30][C:28]([N:35]1[CH2:40][CH2:39][N:38]([CH2:2][C:3]2[N:8]=[C:7]3[N:9]=[C:10]([C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=4)[O:11][C:6]3=[CH:5][CH:4]=2)[CH2:37][CH2:36]1)=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: O=[N+]([O-])c1cccc(-c2nc3nc(CBr)ccc3o2)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc3oc(-c4cccc([N+](=O)[O-])c4)nc3n2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
5-Bromomethyl-2-(3-nitro-phenyl)-oxazolo[4,5-b]pyridine (250 mg, 0.75 mmol) was dissolved in 5 mL of CH3CN along with Et3N (0.200 mL, 1.5 mmol) and 140 mg of Boc-piperazine. The reaction mixture was stirred at room temperature for 18 hours. It was then concentrated and the resulting residue was mixed with 25 mL of CH2Cl2 and washed with brine. The organic layer was dried (Na2SO4) and concentrated to afford essentially quantitative yield of 4-[2-(3-nitro-phenyl)-oxazolo[4,5-b]pyridin-5-ylmethyl]-piperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:29]=[CH:30][CH:31]=1)[CH2:9][NH:10][C:11]1[N:15]([C@@H:16]2[O:22][C@H:21]([CH2:23][OH:24])[C@@H:19]([OH:20])[C@H:17]2[OH:18])[C:14]2[CH:25]=[CH:26][CH:27]=[CH:28][C:13]=2[N:12]=1.C(OC([NH:42][C:43](N1C=CC=N1)=[NH:44])=O)C1C=CC=CC=1>O1CCCC1>[NH:1]([CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:29]=[CH:30][CH:31]=1)[CH2:9][NH:10][C:11]1[N:15]([C@@H:16]2[O:22][C@H:21]([CH2:23][OH:24])[C@@H:19]([OH:20])[C@H:17]2[OH:18])[C:14]2[CH:25]=[CH:26][CH:27]=[CH:28][C:13]=2[N:12]=1)[C:43]([NH2:44])=[NH:42]
Reactant: N=C(NC(=O)OCc1ccccc1)n1cccn1
Reactant: NCCCOc1cccc(CNc2nc3ccccc3n2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c1
Solvent: C1CCOC1
Product: N=C(N)NCCCOc1cccc(CNc2nc3ccccc3n2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c1
Temperature: 60 °C
Reaction time: 24 h
Yield: 4.6 %

Procedure:
2-[3-(3-Aminopropoxy)benzylamino]-1-(β-D-ribofuranosyl)-1H-benzimidazole (0.2 g) and N-(benzyloxycarbonyl)-1H-pyrazol-1-carboxamidine (0.55 g) were suspended in tetrahydrofuran (2.5 mL), and the mixture was stirred at 60° C. for 24 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was dissolved in methanol (4 mL). To the solution was added a catalytic amount of 10% palladium-carbon powder, and the mixture was stirred at 40° C. under a hydrogen atmosphere for 2 hour. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by preparative reverse phase column chromatography (Shiseido CAPSELL PAC C18UG80, 5 μm, 20×50 mm, flow rate 30 mL/minutes linear gradient, water/methanol=70/30-10/90) to give the title compound (0.01 g).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:35](O)(=[O:38])[CH2:36][CH3:37].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[F:17][C:15]1[CH:14]=[N:13][C:12]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)=[C:11]([CH:16]=1)[C:10]([NH:9][C@H:6]1[CH2:7][CH2:8][C@@H:3]([NH:2][C:35](=[O:38])[CH2:36][CH3:37])[CH2:4][CH2:5]1)=[O:27]
Reactant: CCC(=O)O
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](N)CC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(=O)N[C@H]1CC[C@@H](NC(=O)c2cc(F)cnc2Oc2cccc(SC)c2)CC1
Temperature: 25 °C
Reaction time: 64 h
Yield: 99.2 %

Procedure:
N-(cis-4-Amino-cyclohexyl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide hydrochloride (100 mg, 0.243 mmol) was dissolved in dimethylformamide (1 ml) and triethylamine (100 μl, 0.729 mmol) was added followed by propionic acid (22 μl, 0.291 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (56 mg, 0.291 mmol) and 1-hydroxybenzotriazole (39 mg, 0.291 mmol). The reaction was stirred under nitrogen at room temperature for 64 h and the solvent was removed under reduced pressure. The residue was partitioned between sat. sodium bicarbonate solution (5 ml) and ethyl acetate (10 ml) and the aqueous phase was extracted with ethyl acetate (3×10 ml). The combined organic extracts were washed with water (2×5 ml), brine (5 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was triturated with diethylether (5 ml) to give 5-Fluoro-2-(3-methylsulfanyl-phenoxy)-N-(cis-4-propionylamino-cyclohexyl)-nicotinamide (104 mg) as a white solid.
Reaction SMILES: [H-].[Na+].[CH:3]([C:5]1[NH:6][CH:7]=[CH:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][CH:11]=1)=[O:4].[O:17](C(OC(C)(C)C)=O)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=O>>[C:21]([O:20][C:18]([N:6]1[CH:7]=[CH:8][C:9]([C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][CH:11]=2)=[C:5]1[CH:3]=[O:4])=[O:17])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: O=Cc1[nH]ccc1-c1ccc(I)cc1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)n1ccc(-c2ccc(I)cc2)c1C=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Following a standard procedure (Tietze, L. F.; Kettschau, G.; Heitmann, K. Synthesis 1996, 851-857), sample of NaH (70 mg, 1.75 mmol, 60% dispersion in mineral oil) in a round-bottomed flask under argon was washed twice with anhydrous pentane (˜5 mL). Anhydrous THF (14 mL) was added followed by 5 (400 mg, 1.35 mmol). After stirring for 30 min at room temperature, (BOC)2O (325 mg, 1.5 mmol) was added and stirring was continued for another 2 h. The reaction was quenched with 50% satd. aq NH4Cl (50 mL). The mixture was extracted with ether, and the combined organic layers were washed with brine, dried (Na2SO4), and filtered [silica, hexanes/ethyl acetate (4:1)] to yield a viscous oil (535 mg, quantitative). 1H NMR δ 1.64 (s, 9H), 6.33 (d, J=3.0 Hz, 1H), 7.30 (d, J=8.1 Hz, 2H), 7.46 (d, J=3.0 Hz, 1H), 7.72 (d, J=8.1 Hz, 2H), 10.22 (s, 1H); 13C NMR δ 27.7, 85.8, 94.2, 113.2, 126.7, 128.5, 131.3, 132.8, 137.0, 137.4, 148.3, 181.6; FAB-MS obsd 397.0176, calcd 397.0175 (C16H16INO3).
Reaction SMILES: [OH-].[Na+].[CH:3]1([C:9]2[C:10]3[CH:11]=[CH:12][C:13]([C:35]([O:37]C)=[O:36])=[CH:14][C:15]=3[N:16]3[CH2:22][CH:21]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])[CH2:20][C:19]4[CH:31]=[CH:32][CH:33]=[CH:34][C:18]=4[C:17]=23)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl>CO.O1CCCC1>[CH:3]1([C:9]2[C:10]3[CH:11]=[CH:12][C:13]([C:35]([OH:37])=[O:36])=[CH:14][C:15]=3[N:16]3[CH2:22][CH:21]([C:23]([N:25]4[CH2:26][CH2:27][O:28][CH2:29][CH2:30]4)=[O:24])[CH2:20][C:19]4[CH:31]=[CH:32][CH:33]=[CH:34][C:18]=4[C:17]=23)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)N1CCOCC1)Cc1ccccc1-3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)N1CCOCC1)Cc1ccccc1-3
Temperature: 90 °C
Yield: 83 %

Procedure:
Sodium hydroxide (200 μL, 0.2 mmol) was added to a solution of the preceding methyl ester (60 mg, 0.127 mmol) in methanol (1.2 mL) and tetrahydrofuran (1.2 mL) in a microwave vial. The vial was sealed and the contents heated at 90° C. for 10 min in a microwave apparatus, at which time the vial was cooled and additional NaOH was added (200 μL, 0.2 mmol). The solution was heated for another 5 min at 90° C. when LC/MS showed complete hydrolysis of the ester. The solution was acidified with dilute hydrochloric acid to precipitate the crude acid. The solid was collected and purified on the Shimadzu preparative liquid chromatograph. The product containing fraction was concentrated on a Speed Vac® to leave the titled compound as a colorless solid (50 mg, 83%). ESI-MS m/z 473 (MH+), 1H NMR (500 MHz, CD3OD) δ 1.24-1.35 (m, 1H), 1.40-1.55 (m, 2H), 1.60-1.68 (m, 1H), 1.77-2.22 (m, 6 H), 2.76 (m, 1 H), 2.88-3.04 (m, 1 H), 3.44-3.51 (m, 1 H), 3.58-3.93 (m, 9 H), 4.47-4.59 (m, 1 H), 4.89 (m, 1 H), 7.31-7.43 (m, 1 H), 7.47 (m, 3 H), 7.72 (m, 1 H), 7.88 (m, 1 H), 8.16 (m, 1 H).
Reaction SMILES: Cl.Cl.Cl.[NH:4]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.C([Li])CCC.F[Si:22]([CH3:25])([CH3:24])[CH3:23]>ClC1C=CC=CC=1>[CH3:23][Si:22]([CH3:25])([CH3:24])[N:4]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][N:10]([Si:22]([CH3:25])([CH3:24])[CH3:23])[CH2:9][CH2:8][N:7]([Si:22]([CH3:25])([CH3:24])[CH3:23])[CH2:6][CH2:5]1
Reactant: C1CCNCCNCCNCC1
Reactant: C[Si](C)(C)F
Agent: Cl
Agent: [Li]CCCC
Solvent: Clc1ccccc1
Product: C[Si](C)(C)N1CCCCCN([Si](C)(C)C)CCN([Si](C)(C)C)CC1
Reaction time: 5.8 h

Procedure:
1,4,7-Tris(trimethylsilyl)-1,4,7-triazacyclododecane was prepared from 1,4,7-triazacyclododecane trishydrochloride with six equivalents of n-butyllithium essentially by the procedure of Example 1 (A). In a 50 ml flask a solution of 0.675 g of the tris silyl compound (distilled bulb-to-bulb at 95°-125°/0.1 mm) in 2.5 ml of chlorobenzene was frozen, evacuated, and pressured with 40 ml of phosphorus oxyfluoride gas. The flask was sealed and the mixture heated overnight at 100°. Then the mixture was refluxed under a nitrogen atmosphere for 4 hours. A sample indicated (by nmr) that two-thirds of the silyl groups had reacted. Refluxing was continued for 5.8 hours under a nitrogen pressure of 960- 1040 mm of mercury. A sample at this time showed almost complete displacement of the silyl groups as fluorotrimethylsilane. The mixture remaining (about 80-85% of the original) was concentrated under vacuum and distilled bulb-to-bulb under vacuum (0.1 mm). The fraction collected at 80°-100° oven temperature consisted of solidified condensate in the mouth of the receiver, mp 78°-86.5°. This sample (~30 mg) was used for ir and mass spectroscopy which identify this material as 13-oxo-1,4,7-triaza-13-phosphatricyclo[5.5.1.04,13 ]-tridecane. It was recrystallized in part from cyclohexane giving needles, mp 86°-87.5°.
Reaction SMILES: CS([C:5]1[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][N:6]=1)(=O)=O.Cl.CN.C[CH2:23][N:24](CC)CC>C1COCC1>[CH3:23][NH:24][C:5]1[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][N:6]=1
Reactant: CS(=O)(=O)c1ncc(C#Cc2ccccc2)cn1
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: C1CCOC1
Product: CNc1ncc(C#Cc2ccccc2)cn1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
(100 mg, 0.38 mmol) 2-Methanesulfonyl-5-phenylethynyl-pyrimidine (Example 8, step 2), methylamine hydrochloride (52 mg, 0.77 mmol, 2 equiv.) and Et3N (220 μl, 1.55 mmol, 4 equiv.) were suspended in 1 ml THF and stirred for 1 hour at 65° C. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography by directly loading the crude material onto a silica gel column and eluting with (heptane:ethyl acetate 100:0->0:100). The desired methyl-(5-phenylethynyl-pyrimidin-2-yl)-amine was obtained as a white solid (38 mg, 47%), MS: m/e=210.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:12])=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:12])=[CH:9][C:10]=1[Cl:11])[C:5]([O:7][CH2:18][CH3:19])=[O:6]
Reactant: CCO
Reactant: Cc1cc(Cl)c(Cl)cc1C(=O)O
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(Cl)c(Cl)cc1C
Yield: 97 %

Procedure:
9.2.1 g (421 mmol) of the 3,4-dichloro-6-methylbenzoic acid obtained in the above step (2) was dissolved in 550 ml of ethanol as both an esterifying agent and a solvent, 20 ml of concentrated sulfuric acid as an acid catalyst was added, and the mixture was refluxed under heat for 7 hours. The ethanol was distilled off under reduced pressure, ice water was added, and the mixture was extracted with ethyl acetate twice. The resultant organic layer was consecutively washed with a sodium carbonate aqueous solution and with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 103.4 g (yield 97%) of ethyl 3,4-dichloro-6-methylbenzoate as a crude product.
Reaction SMILES: [CH2:1]([C@:3]1([OH:38])[C:35]2[CH:34]=[C:33]3[N:9]([CH2:10][C:11]4[C:12]3=[N:13][C:14]3[CH:15]=[C:16]([F:32])[C:17]([CH3:31])=[C:18]5[CH2:23][CH2:22][CH:21]([NH:24]C(=O)C(F)(F)F)[C:20]=4[C:19]=35)[C:8](=[O:36])[C:7]=2[CH2:6][O:5][C:4]1=[O:37])[CH3:2].[ClH:39].CO>O>[ClH:39].[NH2:24][CH:21]1[C:20]2=[C:11]3[CH2:10][N:9]4[C:33](=[CH:34][C:35]5[C@:3]([CH2:1][CH3:2])([OH:38])[C:4](=[O:37])[O:5][CH2:6][C:7]=5[C:8]4=[O:36])[C:12]3=[N:13][C:14]3[CH:15]=[C:16]([F:32])[C:17]([CH3:31])=[C:18]([C:19]=32)[CH2:23][CH2:22]1
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1cc(F)c(C)c3c1c2C(NC(=O)C(F)(F)F)CC3
Agent: Cl
Solvent: O
Solvent: CO
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1cc(F)c(C)c3c1c2C(N)CC3
Temperature: 80 °C
Reaction time: 7 h

Procedure:
625 mg of the compound prepared in (10) above was added to a mixed solution of 7.5 ml of concentrated hydrochloric acid, 18 ml of methanol and 12 ml of water, and stirred at 80° C. for 7 hours. Insoluble substances were removed by filtration and the filtrate was purified with HPLC (CAPCELL PAK C18) using a mixture of acetonitrile-water-1N hydrochloric acid (20:80:1) to obtain 138 mg of Isomer A and 143 mg Isomer B of the title compound.