Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]2[S:6][CH:7]=[C:8]([CH2:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.C([Li])CCC.[CH2:24]([O:31][C@@H:32]1[C@@H:38]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@H:37]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C@@H:36]([CH2:55][O:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[O:35][C:33]1=[O:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:24]([O:31][C@@H:32]1[C@@H:38]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@H:37]([O:47][CH2:48][C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[C@@H:36]([CH2:55][O:56][CH2:57][C:58]2[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=2)[O:35][C:33]1([C:2]1[CH:18]=[CH:17][C:5]2[S:6][CH:7]=[C:8]([CH2:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1)[OH:34])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: Brc1ccc2scc(CCc3ccccc3)c2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC1(c2ccc3scc(CCc4ccccc4)c3c2)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 95.3 %

Procedure:
To a solution of 5-bromo-3-(2-phenylethyl)benzo[b]-thiophene (0.94 g) in tetrahydrofuran (25 mL) was added n-butyllithium (2.44 mol/L n-hexane solution, 1.24 mL) at −78° C. under an argon atmosphere, and the mixture was stirred at the same temperature for 5 minutes. To the reaction mixture was added a solution of 2,3,4,6-tetra-O-benzyl-D-glucono-1,5-lactone (0.80 g) in tetrahydrofuran (4 mL), and the mixture was warmed to 0° C. and stirred for 30 minutes. The reaction mixture was poured into a saturated ammonium chloride aqueous solution, and the mixture was extracted with diethyl ether. The organic layer was washed with water and brine and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1-3/1) to give the title compound (1.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]#[CH:13])[CH:7]=[C:6]([F:14])[C:3]=1[CH2:4][OH:5].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28](Cl)=[O:29])[C@H:24]([CH2:31][CH3:32])[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]#[CH:13])[CH:7]=[C:6]([F:14])[C:3]=1[CH2:4][O:5][C:28]([N:25]1[CH2:26][CH2:27][N:22]([C:20]([O:19][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:21])[CH2:23][C@H:24]1[CH2:31][CH3:32])=[O:29]
Reactant: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)Cl
Reactant: C#CCOc1cc(F)c(CO)c(Cl)c1
Product: C#CCOc1cc(F)c(COC(=O)N2CCN(C(=O)OC(C)(C)C)C[C@H]2CC)c(Cl)c1
Yield: 80 %

Procedure:
This compound was prepared from 2-chloro-6-fluoro-4-prop-2-ynyloxy-benzylalcohol and (R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid tert-butyl ester according to the procedure described in Example 179 to give the product as a colorless oil (357 mg; 80%); MS (ISP): 472.3 (M+NH4)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:14]=[CH:13][C:10]([CH2:11][OH:12])=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.O[C:16]1[CH:17]=[C:18]([C:22]2([O:28][CH3:29])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1.N1(C2C=CC(COC3C=C(C4(OC)CCOCC4)C=CC=3)=CC=2)C=CN=C1>>[CH3:29][O:28][C:22]1([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([O:12][CH2:11][C:10]3[CH:13]=[CH:14][C:7]([N:3]4[CH:4]=[CH:5][N:6]=[C:2]4[CH3:1])=[CH:8][CH:9]=3)[CH:17]=2)[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1
Reactant: Cc1nccn1-c1ccc(CO)cc1
Reactant: COC1(c2cccc(O)c2)CCOCC1
Agent: COC1(c2cccc(OCc3ccc(-n4ccnc4)cc3)c2)CCOCC1
Product: COC1(c2cccc(OCc3ccc(-n4ccnc4C)cc3)c2)CCOCC1

Procedure:
The title compound was prepared from 4-(2-methylimidazol-1-yl)benzyl alcohol and 4-(3-hydroxyphenyl)-4-methoxy-3,4,5,6-tetrahydro-2H-pyran according to the procedure described for 4-[3-[4-(1-imidazolyl)benzyloxy]phenyl]-4-methoxy-3,4,5,6-tetrahydro-2H-pyran. (Example 1)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[CH2:11][CH3:12]>CO.[Ni]>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[CH2:11][CH3:12])[NH2:8]
Reactant: CCc1ccc([N+](=O)[O-])cc1Br
Agent: [Ni]
Solvent: CO
Product: CCc1ccc(N)cc1Br
Reaction time: 3 h
Yield: 210.4 %

Procedure:
To a solution of 2-bromo-1-ethyl-4-nitro-benzene (25 g, 0.019 mol) in MeOH (100 mL) was added Raney-Ni (2.5 g). The reaction mixture was hydrogenated under hydrogen (1 atm) at room temperature. After stirring for 3 hours, the mixture was filtered and concentrated under reduced pressure. The crude material was purified by preparative HPLC to give 3-bromo-4-ethylaniline (8.0 g, 48%). 1H NMR (400 MHz, CDCl3) δ 6.92 (d, J=8.4 Hz, 1H), 6.83 (d, J=2.4 Hz, 1H), 6.52 (dd, J=2.4, 8.4 Hz, 1H), 2.57 (q, J=7.6 Hz, 2H), 1.10 (t, J=7.6 Hz, 3H). MS (ESI) m/e (M+H+) 200.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]1=[O:11]>CO.CC(O)=O.[Pd]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3](=[O:11])[N:2]([CH3:1])[CH:7]=1
Reactant: Cn1cc([N+](=O)[O-])ccc1=O
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: Cn1cc(N)ccc1=O

Procedure:
A solution of compound 50B (200 mg, 1.298 mmol) and 10% Pd/C (˜5 mg) in MeOH and AcOH was stirred under H2 at 1 atmosphere for 30 minutes. The reaction solution was filtered through a pad of celite eluting with MeOH. The MeOH was removed under reduced pressure to give compound 50C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10](=[O:13])[CH2:11]Br)=[CH:2]1.C([SnH](CCCC)CCCC)CCC.N(C(C)(C)C#N)=NC(C)(C)C#N>C1(C)C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10](=[O:13])[CH3:11])=[CH:2]1
Reactant: O=C(CBr)c1coc2ccccc12
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC(=O)c1coc2ccccc12
Temperature: 25 °C

Procedure:
A solution of 1-benzofuran-3-yl-2-bromo-ethanone (Intermediate I1) (commercially available from Maybridge) (2.1 g, 8.8 mmol) in toluene at reflux was treated with tributyltin hydride (2.9 mL, 10.6 mmol) and 2,2′-azobisisobutyronitrile (AIBN, catalyst) for 2 h. The mixture was cooled to rt and concentrated onto silica gel under reduced pressure. The product was eluted from a column of silica gel with 5% EtOAc: hexane to give 1-benzofuran-3-yl-ethanone (Intermediate I2) as an oil, 1.45 g (99%).
Reaction SMILES: [F:1][C:2]([F:36])([C:14]([F:35])([F:34])[C:15]([F:33])([F:32])[C:16]([F:31])([F:30])[C:17]([F:29])([F:28])[C:18]([F:27])([F:26])[C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])[CH2:3][CH2:4][C:5]([O:8][C:9](=[O:13])N(C)C)([CH3:7])[CH3:6].C(Cl)Cl.C(O)([C:42]([F:45])([F:44])[F:43])=O>>[F:1][C:2]([F:36])([C:14]([F:35])([F:34])[C:15]([F:33])([F:32])[C:16]([F:31])([F:30])[C:17]([F:29])([F:28])[C:18]([F:27])([F:26])[C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])[CH2:3][CH2:4][C:5]([O:8][C:9](=[O:13])[C:42]([F:45])([F:44])[F:43])([CH3:7])[CH3:6]
Reactant: CN(C)C(=O)OC(C)(C)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)OC(=O)C(F)(F)F
Yield: 100 %

Procedure:
Dimethylamine(2-perfluorooctylethyl)isopropyl carbamate 10 (251 mg, 0.44 mmol) was stirred with 1:1 CH2Cl2/TFA at room temperature overnight. After evaporation of solvent, the residue was partitioned between dichloromethane and aqueous K2CO3. The organic phase was dried over MgSO4 and evaporated to give pure product (262 mg, 100%); 1H NMR (CDCl3) δ 2.22-2.08 (m, 4H), 1.63 (s, 6H); 19F NMR (CDCl3) δ −74.6 (3F), −79.6 (2F), −113.3 (2F), −120.8 (6F), −121.6 (2F), −122.1 (2F), −125.0 (2F). 13C NMR (CDCl3) δ 156.4 (t), 121.5-105.1 (m), 86:7, 31.5, 25.7 (t), 25.0; LRMS: m/z (relative intensity) 587 (M+−Me, 70%), 489 (M+−CF3CO2, 68%), 155 (82%); HRMS calcd. for C13H10F17: 489.0511, found: 489.0504; IR (thin film): 2992, 1784, 1371, 1214 cm−1.
Reaction SMILES: [C:1]([NH:24][CH:25]([CH2:40][CH:41]([CH3:43])[CH3:42])[C:26]([NH:28][C:29]1[CH:30]=[CH:31][C:32]([OH:39])=[C:33]([CH:38]=1)[C:34]([O:36]C)=[O:35])=[O:27])(=[O:23])[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH:7]=[CH:8][CH2:9][CH:10]=[CH:11][CH2:12][CH:13]=[CH:14][CH2:15][CH:16]=[CH:17][CH2:18][CH:19]=[CH:20][CH2:21][CH3:22].[OH-].[Na+].Cl>CO>[C:1]([NH:24][CH:25]([CH2:40][CH:41]([CH3:42])[CH3:43])[C:26]([NH:28][C:29]1[CH:30]=[CH:31][C:32]([OH:39])=[C:33]([CH:38]=1)[C:34]([OH:36])=[O:35])=[O:27])(=[O:23])[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH:7]=[CH:8][CH2:9][CH:10]=[CH:11][CH2:12][CH:13]=[CH:14][CH2:15][CH:16]=[CH:17][CH2:18][CH:19]=[CH:20][CH2:21][CH3:22]
Reactant: CCC=CCC=CCC=CCC=CCC=CCC=CCCC(=O)NC(CC(C)C)C(=O)Nc1ccc(O)c(C(=O)OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC=CCC=CCC=CCC=CCC=CCC=CCCC(=O)NC(CC(C)C)C(=O)Nc1ccc(O)c(C(=O)O)c1
Temperature: 47.5 °C
Yield: 61.4 %

Procedure:
To a solution of methyl 5-(2-docosa-4,7,10,13,16,19-hexaenamido-4-methylpentanamido)-2-hydroxybenzoate (155 mg, 0.26 mmol) in MeOH (3 mL) was added 2M aqueous NaOH (5 mL). The mixture was heated (45-50° C., 16 h), and then cooled to RT. 2M aqueous HCl was added dropwise to adjust to pH 1. The mixture was then extracted by EtOAc (3×20 mL). The combined organic layers were washed with brine, dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (MeOH/DCM, 0-10%) to afford of 5-(2-docosa-4,7,10,13,16,19-hexaenamido-4-methylpentanamido)-2-hydroxybenzoic acid as light yellow oil (92 mg, 61%). Mass calculated for C35H48N2O5=576.77; found: [M+H]+=577.3.
Reaction SMILES: [C:1]([C:3]1([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:8][CH2:7][CH:6]([CH:9]2[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]2)[CH2:5][CH2:4]1)#[N:2].O1C2(CCC(C3CCC(=O)CC3)CC2)OCC1.S(C[N+]#[C-])(C1C=CC(C)=CC=1)(=O)=O.[Li+].CC([N-]C(C)C)C.C(Br)CCCCCC.[BH4-].[Na+].[CH2:71]([C@H:76]1[CH2:81][CH2:80][C@H:79]([C:82](O)=[O:83])[CH2:78][CH2:77]1)[CH2:72][CH2:73][CH2:74][CH3:75].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:1]([C:3]1([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:8][CH2:7][CH:6]([CH:9]2[CH2:14][CH2:13][CH:12]([O:15][C:82]([C@H:79]3[CH2:80][CH2:81][C@H:76]([CH2:71][CH2:72][CH2:73][CH2:74][CH3:75])[CH2:77][CH2:78]3)=[O:83])[CH2:11][CH2:10]2)[CH2:5][CH2:4]1)#[N:2]
Reactant: CCCCCCCC1(C#N)CCC(C2CCC(O)CC2)CC1
Reactant: CCCCC[C@H]1CC[C@H](C(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)[N-]C(C)C
Agent: CN(C)c1ccncc1
Solvent: CCCCCCCBr
Solvent: ClCCl
Product: CCCCCCCC1(C#N)CCC(C2CCC(OC(=O)[C@H]3CC[C@H](CCCCC)CC3)CC2)CC1

Procedure:
1 g of 4-dimethylaminopyridine and 30.3 g (0.1 mole) of 4-cyano-4-heptyl-4'-hydroxybicyclohexane (obtainable from 4-(1,4-dioxaspiro[4,5]dec-8-yl)-cyclohexanone by introduction of the nitrile group with tosylmethyl isocyanide (TOSMIC), alkylation with LDA (diisopropylamine/butyl-lithium) and heptyl bromide, detachment of the keto-protective group, reduction of the ketone with NaBH4 to the alcohol and separation of the isomers) are added to 19.8 g (0.1 mole) of trans-4-pentylcyclohexanecarboxylic acid in 75 ml of CH2Cl2, with stirring. A solution of 27.7 g (0.105 mole) of dicyclo-hexylcarbodiimide in 50 ml of methylene chloride is added dropwise at 0°, while controlling the temperature, and the mixture is then stirred at room temperature for a further hour. The urea precipitated is separated off and the methylene chloride phase is washed with dilute HCl and saturated NaHCO3 solution and dried. The product is then purified by filtration over a short silica gel column and by crystallisation. 4-Cyano-4-heptyl-4'-(trans-4-pentylcyclohexylcarbonyloxy)-bicyclohexane is obtained.
Reaction SMILES: C([C:3]([C:10](=O)[CH3:11])([CH2:7][CH2:8][CH3:9])[C:4]([OH:6])=O)C.[Na].[F:14][C:15]([F:20])([F:19])[C:16]([NH2:18])=[NH:17]>CCO>[CH3:11][C:10]1[N:17]=[C:16]([C:15]([F:20])([F:19])[F:14])[NH:18][C:4](=[O:6])[C:3]=1[CH2:7][CH2:8][CH3:9]
Reactant: CCCC(CC)(C(C)=O)C(=O)O
Reactant: N=C(N)C(F)(F)F
Agent: [Na]
Solvent: CCO
Product: CCCc1c(C)nc(C(F)(F)F)[nH]c1=O
Yield: 34.1 %

Procedure:
Ethyl 2-acetylpentanoic acid (17.2 g, 0.1 mol) in absolute EtOH was treated with 2.3 g, 0.1 mol) sodium until the metal was dissolved. Trifluoroacetamidine (11.5 g, 0.1 mol) was added and the mixture was refluxed for 3 h, then evaporated to dryness. The residue was taken up in H2O, acidified with 2N HCl, and extracted with EtOAc. The organic layer was washed with water (twice), dried, and evaporated to give an oil. Purification by flash chromatography (CH2Cl2, CH2Cl2 -EtOAc 5%) afforded 7.5 g (34%) of the desired compound as crystals.
Reaction SMILES: O1CCO[CH:2]1[CH2:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)=O.[C:18]([NH:21][CH2:22][CH2:23][NH2:24])(=[O:20])[CH3:19]>C(O)(=O)C>[CH3:17][O:16][C:13]1[CH:12]=[CH:11][C:10]([C:8]2[N:24]([CH2:23][CH2:22][NH:21][C:18](=[O:20])[CH3:19])[CH:2]=[CH:6][CH:7]=2)=[CH:15][CH:14]=1
Reactant: CC(=O)NCCN
Reactant: COc1ccc(C(=O)CCC2OCCO2)cc1
Solvent: CC(=O)O
Product: COc1ccc(-c2cccn2CCNC(C)=O)cc1
Yield: 65.5 %

Procedure:
3-(1,3-Dioxolan-2-yl)-4'-methoxypropiophenone (38.8 g) was dissolved in 100 ml of acetic acid and added under argon and while stirring to a solution of 33.5 g of N-acetylethylene-diamine in 500 ml of acetic acid. The reaction solution was heated to reflux overnight, the acetic acid was subsequently removed in a vacuum. The residue was taken up in 500 ml of methylene chloride and washed with a mixture of 200 ml of saturated sodium hydrogen carbonate solution and 400 ml of 2N sodium hydroxide solution. The aqueous phase was extracted three times with 100 ml of methylene chloride each time, the organic phases were combined, dried with MgSO4 and freed from solvent. The residue, 49.6 g of brown oil, was chromatographed on 500 g of silica gel with ethyl acetate as the eluent. 27.8 g (66%) of N-[2-[2-(p-methoxyphenyl)-pyrrol-1-yl]ethyl]acetamide were isolated as a yellow-brown oil. MS: m/e=258 (M+).
Reaction SMILES: CO[C:3](=O)[C@H:4]([CH2:6][CH:7]([CH3:9])[CH3:8])[NH2:5].OCCN.[CH3:15][C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=1[N:25]=[C:26]=[S:27]>>[CH3:15][C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=1[N:25]=[C:26]1[NH:5][C@@H:4]([CH2:6][CH:7]([CH3:9])[CH3:8])[CH2:3][S:27]1
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Solvent: NCCO
Product: Cc1cc([N+](=O)[O-])ccc1N=C1N[C@@H](CC(C)C)CS1

Procedure:
(1S)-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-1-methylbutanammonium chloride as described in Method B7a. 2-Methyl-4-nitrophenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-3-methylbutanammonium chloride according to Method C1a to give (4S)-2-(2-methyl-4-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with 5-iodoheptane according to Method D2a to give (4S)-2-(2-methyl-4-nitrophenylimino)-4-isobutyl-3-(5-heptyl)-1,3-thiazolidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[C:5]2[NH:21][CH:22]=[C:23]([C:24](=[O:44])[C:25]([N:27]3[CH2:32][CH2:31][N:30]([C:33]4[N:37]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=5)[N:36]=[N:35][N:34]=4)[CH2:29][CH2:28]3)=[O:26])[C:4]=12.[C:45](Cl)(=[O:50])[O:46][CH:47]([CH3:49])[CH3:48]>C1COCC1.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:16][CH2:17][N:18]([C:45]([O:46][CH:47]([CH3:49])[CH3:48])=[O:50])[CH2:19][CH2:20]3)=[CH:11][CH:10]=2)=[C:5]2[NH:21][CH:22]=[C:23]([C:24](=[O:44])[C:25](=[O:26])[N:27]3[CH2:32][CH2:31][N:30]([C:33]4[N:37]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=5)[N:36]=[N:35][N:34]=4)[CH2:29][CH2:28]3)[C:4]=12
Reactant: COc1cnc(-c2ccc(N3CCNCC3)cc2)c2[nH]cc(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccn4)CC3)c12
Reactant: CC(C)OC(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cnc(-c2ccc(N3CCN(C(=O)OC(C)C)CC3)cc2)c2[nH]cc(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccn4)CC3)c12
Reaction time: 3 h
Yield: 35 %

Procedure:
To a solution of 1-(4-methoxy-7-(4-(piperazin-1-yl)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione (50 mg, 0.084 mmol) in THF (1 mL) and DMF (1 mL) were added TEA (0.023 mL, 0.168 mmol) and isopropyl carbonochloridate (13.42 mg, 0.109 mmol) at room temperature. The reaction was stirred for 3 hours. The reaction mixture was concentrated under reduced pressure. The resulting crude was purified by prep HPLC to give isopropyl 4-(4-(4-methoxy-3-(2-oxo-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)phenyl)piperazine-1-carboxylate (20 mg, 35%) as white solid. LCMS: m/e 680.58 (M+H)+, ret time 2.49 min (method 4). 1H NMR (500 MHz, MeOD) δ ppm 1.30 (d, J=6.10 Hz, 6H) 3.41-3.50 (m, 6H) 3.50-3.58 (m, 2H) 3.65-3.75 (m, 6H) 3.86-3.93 (m, 2H) 4.14 (s, 3H) 4.95-4.99 (m, 1H) 7.28 (d, J=8.85 Hz, 2H) 7.63 (dd, J=7.32, 4.88 Hz, 1H) 7.77 (d, J=8.55 Hz, 2H) 7.89 (d, J=7.93 Hz, 1H) 8.01 (s, 1H) 8.12-8.20 (m, 1H) 8.67 (s, 2H).
Reaction SMILES: C([CH:3]([O:7][C:8]1[CH:12]=[C:11]([C:13](O)=O)[N:10]([CH3:16])[N:9]=1)[C:4]([OH:6])=[O:5])C.CCN=C=NCCCN(C)C.Cl.[CH2:29]([N:32]1[C:39]([NH2:40])=[C:38]([NH2:41])[C:36](=[O:37])[N:35]([CH2:42][CH2:43][CH3:44])[C:33]1=[O:34])[CH2:30][CH3:31]>CO>[CH2:42]([N:35]1[C:36](=[O:37])[C:38]2[NH:41][C:13]([C:11]3[N:10]([CH3:16])[N:9]=[C:8]([O:7][CH2:3][C:4]([OH:6])=[O:5])[CH:12]=3)=[N:40][C:39]=2[N:32]([CH2:29][CH2:30][CH3:31])[C:33]1=[O:34])[CH2:43][CH3:44]
Reactant: CCC(Oc1cc(C(=O)O)n(C)n1)C(=O)O
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CO
Product: CCCn1c(=O)c2[nH]c(-c3cc(OCC(=O)O)nn3C)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl (5-carboxy-1-methylpyrazol-3-yl)oxyacetic acid (0.5 mmol) and EDCl (0.5 mmol) in methanol (20 mL) was added a solution of 1,3-dipropyl-5,6-diaminouracil (0.5 mmol), dissolved in methanol (20 mL). The mixture was stirred at room temperature for two hours, the solvent was then removed in vacuo, water added, and the solid that formed was collected by filtration and washed with additional cold water. The intermediate amide was heated in 20 mL of 2.5 N NaOH at 70° C. for 30 minutes to afford the desired 2-[5-(1,3-dipropyl-xanthin-8-yl)-1-methyl-pyrazol-3-yl)oxyacetic acid.