Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([NH:24][CH2:25][C:26](=O)[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:45])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]1[S:45][C:26]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[CH:25][N:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OCCn2c1nc(C(=O)NCC(=O)Cc1ccc(F)cc1)c(OCc1ccccc1)c2=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CC1(C)OCCn2c1nc(-c1ncc(Cc3ccc(F)cc3)s1)c(OCc1ccccc1)c2=O
Yield: 43 %

Procedure:
A solution of 3-(benzyloxy)-N-(3-(4-fluorophenyl)-2-oxopropyl)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide: (0.12 g, 0.25 mmol) and Lawesson's reagent (0.11 g, 0.275 mmol) in toluene (10 mL) was stirred 15 min at room temperature, 30 min at 60° C. and 2 h at 100° C. The mixture was cooled, concentrated and purified by preparative HPLC on a C18 column using water/MeOH containing 0.1% TFA as eluent to afford the title compound (0.05 g, 43% yield) as a yellow solid. 1HNMR (500 MHz, CDCl3) δ: 7.78 (1H, s), 7.54-7.51 (2H, m), 7.32-7.29 (3H, m), 7.19 (2H, dd, J=8.6, 5.2 Hz), 7.01 (2H, t, J=8.6 Hz), 5.35 (2H, s), 4.15 (2H, s), 4.06-4.00 (4H, m), 1.66 (6H, s). HRMS (M+H) calcd for C26H25N3O3FS: 478.1601. found: 478.1623.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[Cl:23][CH2:24][C:25](Cl)=[O:26]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:25](=[O:26])[CH2:24][Cl:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(Cl)CCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)CCl)CC1
Yield: 78 %

Procedure:
Piperazine-1-carboxylic acid tert-butyl ester (3.0 g, 16.1 mmol) and DIPEA (3.1 ml, 18.0 mmol) were dissolved in DCM (32 ml) and cooled in ice bath. To the above stirred mixture was added a solution of chloroacetyl chloride (1.33 ml, 16.7 mmol) at 0° C. Three hours later, the mixture was washed with water, dried and evaporated under reduced pressure. The residue was purified by column chromatography using EA/PE (4/1) as eluent to afford the title compound (3.3 g, yield 78.0%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]#[N:21])=[C:7]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH:18]=O)[CH:17]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1.[C:22]([O:26][C:27](=[O:34])[NH:28][C@@H:29]1[CH2:33][CH2:32][NH:31][CH2:30]1)([CH3:25])([CH3:24])[CH3:23]>>[C:22]([O:26][C:27](=[O:34])[NH:28][C@@H:29]1[CH2:33][CH2:32][N:31]([CH2:18][C:16]2[CH:15]=[N:14][CH:13]=[C:12]([C:7]3[N:8]([CH3:11])[C:9]4[C:5]([C:6]=3[C:20]#[N:21])=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=4)[CH:17]=2)[CH2:30]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: Cn1c(-c2cncc(C=O)c2)c(C#N)c2ccc(Cl)cc21
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Product: Cn1c(-c2cncc(CN3CC[C@@H](NC(=O)OC(C)(C)C)C3)c2)c(C#N)c2ccc(Cl)cc21

Procedure:
6-Chloro-2-(5-formyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile (Example 126) and (R)-pyrrolidin-3-yl-carbamic acid tert-butyl ester are processed according to the method described in Example 170 to give {(R)-1-[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester. MS (ESI) m/z 466.17 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11](C(OCC1C=CC=CC=1)=O)[C:12]1[C:21]2[N:22]=[C:23]([CH2:30][O:31][CH2:32][CH3:33])[N:24]([CH2:25][C:26]([OH:29])([CH3:28])[CH3:27])[C:20]=2[C:19]2[CH:18]=[CH:17][C:16]([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:15][C:14]=2[N:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:51]([N:58]([CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)[CH2:59][C:60](O)=[O:61])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1.C(N=C=NCCCN(C)C)C>CN(C1C=CN=CC=1)C.ClCCl>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:21]2[N:22]=[C:23]([CH2:30][O:31][CH2:32][CH3:33])[N:24]([CH2:25][C:26]([O:29][C:60](=[O:61])[CH2:59][N:58]([CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[CH2:63][C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)([CH3:28])[CH3:27])[C:20]=2[C:19]2[CH:18]=[CH:17][C:16]([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:15][C:14]=2[N:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CN(Cc1ccccc1)Cc1ccccc1
Reactant: CCOCc1nc2c(N(C(=O)OCc3ccccc3)C(=O)OCc3ccccc3)nc3cc(CCC(=O)OCC)ccc3c2n1CC(C)(C)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOCc1nc2c(NC(=O)OCc3ccccc3)nc3cc(CCC(=O)OCC)ccc3c2n1CC(C)(C)OC(=O)CN(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.8 %

Procedure:
To a suspension of ethyl 3-(4-(bis(benzyloxycarbonyl)amino)-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl)propanoate (300 mg, 439 μmol), 2-(dibenzylamino)acetic acid (337 mg, 1.32 mmol) and DMAP (107 mg, 879 μmol) in dichloromethane (4 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (253 mg, 1.32 mmol) and molecular sieves (300 mg). After 1 h stirring at room temperature starting materials had dissolved, stirring at room temperature continued for 6 h and the mixture was left standing over the weekend. The residue was diluted with dichloromethane (50 mL) and washed with HCl (1 M, 20 mL) and water (20 mL). The aqueous phase was extracted with dichloromethane (50 mL), organic phases were combined, dried with MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0% to 100% ethyl acetate in heptane) to give the title compound (182 mg, 52%) as light yellow oil; LC-MS (UV peak area, ESI) 98%, 784.6 (MH+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[CH:15]=[C:14]([C:16]4[S:17][C:18]5[C:24]([C:25]6[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=6)=[C:23]([C@H:32]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:22]([CH3:43])=[CH:21][C:19]=5[N:20]=4)[CH:13]=[CH:12][N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:51]([F:57])([F:56])C(OC)=O>CN(C=O)C>[C:39]([O:38][C@@H:32]([C:23]1[C:22]([CH3:43])=[CH:21][C:19]2[N:20]=[C:16]([C:14]3[CH:13]=[CH:12][N:11]=[C:10]([C:6]4[CH:5]=[C:4]5[C:9](=[CH:8][CH:7]=4)[N:1]([CH:51]([F:57])[F:56])[N:2]=[CH:3]5)[CH:15]=3)[S:17][C:18]=2[C:24]=1[C:25]1[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=1)[C:33]([O:35][CH2:36][CH3:37])=[O:34])([CH3:42])([CH3:41])[CH3:40]
Reactant: COC(=O)C(F)(F)Cl
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4ccc5[nH]ncc5c4)c3)sc2c1-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4ccc5c(cnn5C(F)F)c4)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 60 °C

Procedure:
To a solution of (S)-ethyl 2-(2-(2-(1H-indazol-5-yl)pyridin-4-yl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (20 mg, 0.0327 mmol) in DMF (1 mL) was added Cs2CO3 (53 mg, 0.163 mmol), methyl 2-chloro-2,2-difluoroacetate (4 μL, 0.039 mmol). The reaction mixture was heated at 60° C. overnight. Then more methyl 2-chloro-2,2-difluoroacetate (6 μL, 0.058 mmol) was added and heated at 60° C. for 1 day. The reaction mixture was washed by water, extracted by EtOAc, the organic phase was dried over MgSO4, filtered, concentrated down, purified by silica gel column, eluting by 0-50% EtOAc in hexanes to give (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-(1-(difluoromethyl)-1H-indazol-5-yl)pyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate LCMS-ESI+: calc'd for C35H31ClF2N4O3S: 661.2 (M+H+); found: 661.2; and (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-(2-(difluoromethyl)-2H-indazol-5-yl)pyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate. LCMS-ESI+: calc'd for C35H31ClF2N4O3S: 661.2 (M+H+); found: 661.3.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:3]=1.[CH3:21][O-:22].[Na+]>CO>[CH3:21][O:22][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:3]=1
Reactant: C[O-]
Reactant: COc1ccc(CCNc2cc(CO)nc(Cl)n2)cc1
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CCNc2cc(CO)nc(OC)n2)cc1
Reaction time: 3 h
Yield: 88 %

Procedure:
A mixture of {2-chloro-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-methanol (6.5 g mg, 22.1 mmol, Intermediate (57)] 25 wt % sodium methoxide in MeOH (15.2 mL, 66.3 mmol), in MeOH (20 mL) is heated to 90° C. and stirred for 3 hours and concentrated by rotary evaporator to remove the solvent. The solid is dissolved in water and the solution is acidified to pH 8 with the addition of saturated ammonium chloride solution. Extracted twice with 150 mL ethyl acetate, combined the extracts, Dried over magnesium sulfate, filtered and concentrated to afford {2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-methanol [5.66 g, 88%, Intermediate (58)] as a solid. LCMS: RT=2.35 minutes, MS: 290 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9](Cl)=[CH:8][C:7]([CH3:11])=[N:6][C:5]=1[O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=1[CH3:21].[NH2:23][CH:24]([CH2:28][CH3:29])[CH:25]([OH:27])[CH3:26]>CS(C)=O>[CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9]([NH:23][CH:24]([CH2:28][CH3:29])[CH:25]([OH:27])[CH3:26])=[CH:8][C:7]([CH3:11])=[N:6][C:5]=1[O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=1[CH3:21]
Reactant: CCC(N)C(C)O
Reactant: COC(=O)c1c(Cl)cc(C)nc1Oc1c(C)cc(C)cc1C
Solvent: CS(C)=O
Product: CCC(Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C(=O)OC)C(C)O
Temperature: 130 °C

Procedure:
A mixture of 4-chloro-2-(2,4,6-trimethyl-phenoxy)-6-methyl-nicotinic acid methyl ester (250 mg, 0.78 mmol) and 3-amino-pentan-2-ol (320 mg, 3.13 mmol) in DMSO was heated in 130° C. oil bath for 24 hr. The mixture cooled to rt and quenched with water and extracted with ethyl acetate. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give 280 mg of crude product as an oil. The oil was purified through silica gel column chromatography using 20% ethyl acetate in hexane as eluent to give the title compound as a yellow solid, mp 116-120° C.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.[NH3:25]>CO.O>[C:20]([O:19][C:17](=[O:18])[NH:16][CH:4]([C:3](=[O:2])[NH2:25])[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: COC(=O)C(CCCc1ccc(OC)cc1)NC(=O)OC(C)(C)C
Reactant: N
Solvent: CO
Solvent: O
Product: COc1ccc(CCCC(NC(=O)OC(C)(C)C)C(N)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-tert-butoxycarbonylamino-5-(4-methoxy-phenyl)-pentanoic acid methyl ester (5.6 g, 16.6 mmol) in MeOH (100 mL) is treated with aqueous ammonia solution (100 mL of a 28% solution in water, 28 mmol) and stirred at RT overnight. The organic solvent is removed in vacuo and the remaining aqueous portion is extracted with EtOAc (×3). The combined organic extracts are washed with brine and then dried (MgSO4) and concentrated in vacuo to afford the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]([OH:18])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N:20]1CCOCC1.ClC(OCC)=O>C(Cl)Cl.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16](=[O:18])[NH2:20])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCOCC1
Reactant: O=C(O)C1CCCN1C(=O)OCc1ccccc1
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: O
Product: NC(=O)C1CCCN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
Pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester (30.0 g, 121 mmol) was dissolved in DCM (180 mL). The solution was cooled to 0° C. and N-methyl-morpholine (12.8 g, 127 mmol) was added over a period of 10 mins. The solution was then cooled to −15° C. and the ethyl chloroformate (13.7 g, 126 mmol) in DCM (30 mL) was added dropwise. The solution was then stirred for 2 hours at −25° C. Next, the solution was placed under NH3 (g) while maintaining the temperature below −20° C. The reaction mixture was then stirred for 1 hour while allowing the temperature to return to 0° C. The solution was poured in H2O (120 mL) and the organic layer was partitioned from the aqueous layer. The organic layer was then washed with 1N HCl (2×50 mL), 1N NaHCO3 (2×50 mL), dried over MgSO4 and concentrated under vacuo to afford 27.8 g (88%) of 2-carbamoyl-pyrrolidine-1-carboxylic acid benzyl ester, as a colorless oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[F:12].[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.CCN(C(C)C)C(C)C>C1COCC1>[F:12][C:4]1[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]=1[CH2:2][N:17]1[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]1
Reactant: O=[N+]([O-])c1ccc(F)c(CBr)c1
Reactant: CN1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(Cc2cc([N+](=O)[O-])ccc2F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.7 %

Procedure:
A solution of ˜80% pure 2-(bromomethyl)-1-fluoro-4-nitrobenzene (0.956 g, 3.27 mmol) in THF (10 mL) was added slowly drop-wise to a −20° C. solution of 1-methylpiperazine (0.393 g, 3.92 mmol) and DIEA (1.142 mL, 6.54 mmol) in THF (20 mL), the mixture allowed to warm slowly to RT and stirred overnight. The resulting solid was removed via filtration and the filtrate was concentrated to dryness and purified via silica gel chromatography (EtOAc, MeOH/DCM) to afford 1-(2-fluoro-5-nitrobenzyl)-4-methylpiperazine (577 mg, 70% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.28 (dd, J=6.2, 3.0 Hz, 1H), 8.21 (ddd, J=9.0, 4.4, 3.0 Hz, 1H), 7.47 (t, J=9.1 Hz, 1H), 3.60 (s, 2H), 2.48-2.25 (br m, 8H), 2.14 (s, 3H); MS (ESI) m/z: 254.1 [M+H]+.
Reaction SMILES: O[CH:2]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH:7]=[CH:6]2.[CH3:23][O:24][C:25]([O:29][Si](C)(C)C)=[C:26]([CH3:28])[CH3:27].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:15][N:14]([CH3:16])[C:12]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([CH:2]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:26]([CH3:28])([CH3:27])[C:25]([O:24][CH3:23])=[O:29])=[CH:11][CH:10]=2)[CH:6]=[CH:7]1)=[O:13]
Reactant: CN(C)C(=O)n1ccc2cc(C(O)c3ccccc3)ccc21
Reactant: COC(O[Si](C)(C)C)=C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C(C)(C)C(c1ccccc1)c1ccc2c(ccn2C(=O)N(C)C)c1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 96 %

Procedure:
To a stirred solution of 5-(hydroxy(phenyl)methyl)-N,N-dimethyl-1H-indole-1-carboxamide (0.72 g, 2.5 mmol) and (1-methoxy-2-methylprop-1-enyloxy)trimethylsilane (8 mL) in anhydrous dichloromethane (6 mL) was added boron trifluoride diethyl ether complex (0.83 mL, 6.6 mmol) dropwise at 0° C. under argon. After stirring at 0° C. for 30 min and rt for 3.5 hr, the mixture was poured into a saturated aqueous sodium bicarbonate solution maintained at 0° C. The reaction mixture was stirred well, extracted with ethyl acetate (20 mL), dried (Na2SO4) and concentrated. Silica gel flash chromatography gave methyl 3-(1-(dimethylcarbamoyl)-1H-indol-5-yl)-2,2-dimethyl-3-phenylpropanoate (0.9 g, 2.4 mmol, 96% yield) as a glassy solid, the NMR spectrum of which was consistent with the desired structure.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[CH2:15][CH2:16][CH:17]=[CH2:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:30]([O:37][C:38]1[CH:39]=[C:40]([CH3:47])[C:41]([CH2:45]Br)=[C:42]([CH3:44])[CH:43]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[C@H:15]([CH2:45][C:41]1[C:42]([CH3:44])=[CH:43][C:38]([O:37][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:39][C:40]=1[CH3:47])[CH2:16][CH:17]=[CH2:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCCC(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: Cc1cc(OCc2ccccc2)cc(C)c1CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC[C@@H](Cc1c(C)cc(OCc2ccccc2)cc1C)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
Cool a solution of (R)-4-Benzyl-3-pent-4-enoyl-oxazolidin-2-one (4.8 g, 19 mmol) in THF (100 mL) to −78° C. Treat the solution dropwise with 10M LiHMDS in THF (20 mL, 20 mmol) and stir at −78° C. for 30 minutes. Treat the solution with 5-Benzyloxy-2-bromomethyl-1,3-dimethyl-benzene (6.8 g, 22 mmol) and allow to slowly warm to room temperature. The reaction stirs 3 hr at room temperature. Quench the reaction with 1N HCl (aqueous) and extract with Et2O. Wash the organic with brine, dry over MgSO4, filter, and remove the solvent. Purify the crude by silica gel column chromatography using Hexanes:EtOAc to elute the pure product. Remove the solvent to afford 7.0 g (78%) of desired product. MS (m/e): 484 (M+1).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[CH2:13][S:14][C:15]2[NH:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH:6]([NH:24][CH3:25])[CH2:5][CH2:4]1)[CH3:2].[CH:26]([CH:28]=O)=[O:27]>CO>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[CH2:13][S:14][C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[CH:6]([N:24]([CH3:25])[CH2:28][CH2:26][OH:27])[CH2:5][CH2:4]1)[CH3:2]
Reactant: O=CC=O
Reactant: CCN1CCC(NC)c2cccc(CSc3nc4ccccc4[nH]3)c21
Solvent: CO
Product: CCN1CCC(N(C)CCO)c2cccc(CSc3nc4ccccc4[nH]3)c21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-ethyl-4-methylamino-8-(2-benzimidazolyl)thiomethyl-1,2,3,4-tetrahydroquinoline (900 mg) in methanol (20 ml) was added glyoxal (10 ml) and the mixture was stirred for 3 hours at room temperature. The solvent was distilled off and the resulting residue was dissolved in methanol, and to this mixture was added gradually sodium borohydride (1 g). After stirring the mixture for 1 hour at room temperature, the reaction mixture was concentrated. The resulting residue was extracted with dichloromethane and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography [eluent:dichloromethane-methanol (99:1)] to give 1-ethyl-4-[N-methyl-N-(2-hydroxyethyl)amino]-8-(2-benzimidazolyl)thiomethyl-1,2,3,4-tetrahydroquinoline (510 mg).
Reaction SMILES: CC([O:5]C(=O)[NH:7][CH2:8][CH2:9][NH:10][C:11](=[O:46])[CH2:12][N:13]([CH2:42][C:43]([OH:45])=[O:44])[CH2:14][CH2:15][N:16]([CH2:38][C:39]([OH:41])=[O:40])[CH2:17][CH2:18][N:19]([CH2:34][C:35]([OH:37])=[O:36])[CH2:20][C:21](=[O:33])[NH:22][CH2:23][CH2:24][NH:25]C(OC(C)(C)C)=O)(C)C.Cl.[OH-:49].[Na+]>O>[OH2:5].[OH2:49].[NH2:25][CH2:24][CH2:23][NH:22][C:21](=[O:33])[CH2:20][N:19]([CH2:34][C:35]([OH:37])=[O:36])[CH2:18][CH2:17][N:16]([CH2:38][C:39]([OH:41])=[O:40])[CH2:15][CH2:14][N:13]([CH2:12][C:11]([NH:10][CH2:9][CH2:8][NH2:7])=[O:46])[CH2:42][C:43]([OH:45])=[O:44]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)CN(CCN(CCN(CC(=O)O)CC(=O)NCCNC(=O)OC(C)(C)C)CC(=O)O)CC(=O)O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NCCNC(=O)CN(CCN(CCN(CC(=O)O)CC(=O)NCCN)CC(=O)O)CC(=O)O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The DTPA-B(tBA)EA prepared above was dissolved in 110 mL DI water, adjustedto pH 7 (5N HCl), and cooled in an ice bath. To the cool stirred solution was added concentrated HCl (39 mL) in one portion. The mixture was stirred10 minutes in the ice bath then for 2 hours at ambient temperature. The solution was then cooled in an ice bath, titrated to pH 7 (50% NaOH), and concentrated by rotary evaporation to a dry solid (50 g). A portion of solid NaCl was removed from this material by suspending the solid in 50 mLDI water and vacuum filtering through a medium fritted glass funnel. The filtrate was adjusted to pH 2.5 (5N HCl), concentrated to a 50 mL suspension, and vacuum filtered through a coarse fritted glass funnel to remove additional solid NaCl. The filtrate was loaded onto a 9.5×2.0" (24.1×5.1 cm) column bed of Bio-Rad AG50-X8 (H+,200-400 mesh). The column was eluted under nitrogen pressure with 0.75 L DIwater followed by 1.25 L of 2N ammonium hydroxide. The product eluted with 2N ammonium hydroxide. The UV active fraction was concentrated by rotary evaporation to an oily residue. The residue was dissolved in 100 mL 1N acetic acid, concentrated by rotary evaporation, reconcentrated repeatedlyfrom water (13×100 mL) to remove ammonium acetate, and lyophilized (10μ, 14 hours) to afford DTPA-B(AE)A.2H2O. 1H NMR (250 MHz, D2O/DCl:pH 2.3): δ 2.95 (t, 4H, J=5.7 Hz), δ 3.09-3.28 (b, 8H), δ 3.35 (t, 4H, J=5.7 Hz), δ 3.51 (s, 4H), δ 3.55 (s, 2H), δ 3.66 (s, 4H).
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([NH:18]C(=O)OC(C)(C)C)[CH2:14][CH2:13]1)#[N:9]>C(Cl)Cl>[NH2:18][CH:15]1[CH2:16][CH2:17][N:12]([CH2:11][CH2:10][C:8]#[N:9])[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCC#N)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CCCN1CCC(N)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
TFA (1.21 g, 10.62 mmol) was added to a solution of tert-butyl [1-(2-cyanoethyl)piperidin-4-yl]carbamate (0.27 g, 1.06 mmol) in DCM (11 mL), and the mixture was stirred at rt for 2 h. The mixture was evaporated and the product was used without any further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][C@H:10]([CH3:12])[NH:9][C@H:8]([CH3:13])[CH2:7]1)=[O:5])[CH3:2].[C:14]1(C)[CH:19]=CC(S(OCCC)(=O)=O)=C[CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+].C(=O)=O>C(O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][C@@H:8]([CH3:13])[N:9]([CH2:15][CH2:14][CH3:19])[C@@H:10]([CH3:12])[CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1C[C@@H](C)N[C@@H](C)C1
Reactant: CCCOS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [Na+]
Solvent: CCO
Product: CCCN1[C@H](C)CN(C(=O)OCC)C[C@@H]1C
Reaction time: 5 h

Procedure:
A mixture of 25.8 grams of 1-ethoxycarbonyl-cis-3,5-dimethylpiperazine, 38.6 grams of propyl 4-toluenesulfonate, 90 ml. of absolute ethanol and 9.5 grams of sodium carbonate is stirred and heated to reflux. After 30 minutes of reflux, vigorous evolution of carbon dioxide begins and continues for about 5 hours. Refluxing is continued for a total of 22 hours. The reaction mixture is then cooled and filtered and the solvent is evaporated. The resulting residue is mixed with 300 ml. of aqueous 1 N sodium hydroxide solution and the mixture is extracted with ethyl ether. The ether extract is washed successively with 100 ml. of aqueous 1 N sodium hydroxide and 100 ml. of water and then dried over anhydrous sodium sulfate. The organic solution is then treated with charcoal and the solvent is evaporated to leave a residue which is purified by chromatography to give 4-ethoxycarbonyl-cis-2,6-dimethyl-1-propylpiperazine.
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH3:12].[CH2:13]([CH2:15][NH2:16])[OH:14].C(N(CC)CC)C>C(O)(C)C>[OH:14][CH2:13][CH2:15][NH:16][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH3:12]
Reactant: Cc1c(Cl)n(C)c(=O)n(C)c1=O
Reactant: NCCO
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Cc1c(NCCO)n(C)c(=O)n(C)c1=O
Reaction time: 8 h

Procedure:
6-chloro-1,3,5-trimethyl-2,4(1H,3H)-pyrimidinedione (3.4 g) was suspended in 30 ml of isopropanol, and the suspension was added with 1.26 ml of ethanolamine and 3.8 ml of triethylamine and then the resultant mixture was refluxed for 3 hours. The reaction mixture was allowed to stand overnight at room temperature, and thereafter crystals formed were collected by filtration, washed with water and then recrystallized using a water-ethanol solution (1:1, v/v), thereby 2.9 g of 6-(2-hydroxyethylamino)-1,3,5-trimethyl-2,4(1H,3H)-pyrimidinedione being obtained.