Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:18][CH2:17][CH2:16][N:15]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O.CO.[BH4-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:18][CH2:17][CH2:16][N:15]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[NH2:9]
Reactant: COc1cc(N2CCCN(S(C)(=O)=O)CC2)ccc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(N2CCCN(S(C)(=O)=O)CC2)ccc1N
Yield: 50.7 %

Procedure:
1-[3-(methyloxy)-4-nitrophenyl]-4-(methylsulfonyl)hexahydro-1H-1,4-diazepine (0.737g, 2.24 mmol) was suspended in 5 mL THF and 10 mL MeOH in a 100 mL round bottom flask. NiCl2-6H2O (159 mg, 0.672 mmol) was added followed by slow addition of NaBH4 (254 mg, 6.72 mmol). Reaction mixture was adsorbed onto SiO2 and purified via column chromatography to afford 2-(methyloxy)-4-[4-(methylsulfonyl)hexahydro-1H-1,4-diazepin-1-yl]aniline (340 mg, 51%) 1H NMR (400 MHz, DMSO-d6) δ ppm 1.82-1.94 (m, 2 H) 2.80 (s, 3 H) 3.17 (t, J=5.82 Hz, 2 H) 3.36-3.43 (m, 2 H) 3.49 (dd, J=10.68, 3.99 Hz, 4 H) 3.75 (br. s., 3 H) 4.01-4.15 (m, 2 H) 6.10-6.20 (m, 1 H) 6.26-6.35 (m, 1 H) 6.48-6.59 (m, 1 H). ESIMS (M+H)+301
Reaction SMILES: [CH2:1]([C:4]1[N:5]=[C:6]([C@@H:26]2[C@H:30]([CH2:31][CH3:32])[CH2:29][C@H:28]([NH:33][S:34]([CH:37]3[CH2:39][CH2:38]3)(=[O:36])=[O:35])[CH2:27]2)[N:7]2[C:12]3[CH:13]=[CH:14][N:15](S(C4C=CC(C)=CC=4)(=O)=O)[C:11]=3[N:10]=[CH:9][C:8]=12)[CH:2]=C.I([O-])(=O)(=O)=[O:41].[Na+].[BH4-].[Na+].Cl.[OH-].[Na+]>O1CCOCC1.O.CCOC(C)=O.[NH4+].[Cl-].[Os](=O)(=O)(=O)=O>[CH2:31]([C@H:30]1[C@@H:26]([C:6]2[N:7]3[C:12]4[CH:13]=[CH:14][NH:15][C:11]=4[N:10]=[CH:9][C:8]3=[C:4]([CH2:1][CH2:2][OH:41])[N:5]=2)[CH2:27][C@@H:28]([NH:33][S:34]([CH:37]2[CH2:39][CH2:38]2)(=[O:36])=[O:35])[CH2:29]1)[CH3:32]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCc1nc([C@H]2C[C@@H](NS(=O)(=O)C3CC3)C[C@H]2CC)n2c1cnc1c2ccn1S(=O)(=O)c1ccc(C)cc1
Agent: O=[Os](=O)(=O)=O
Agent: Cl
Agent: [BH4-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CC[C@@H]1C[C@H](NS(=O)(=O)C2CC2)C[C@@H]1c1nc(CCO)c2cnc3[nH]ccc3n12
Temperature: 80 °C
Reaction time: 4 h
Yield: 20 %

Procedure:
To a solution of N-((1S,3S,4R)-3-(3-allyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-ethylcyclopentyl)cyclopropanesulfonamide (0.170 g, 0.299 mmol, prepared using H with Preparation #12, Preparation #Z.1, HATU and DIEA, Q with Lawesson's reagent and mercury (II) trifluoroactate) in 1,4-dioxane (5 mL) and water (1.67 mL) was added sodium periodate (0.26 g, 1.198 mmol) followed by osmium tetroxide (4 wt % in water, 0.12 mL, 0.015 mmol). After about 4 h at ambient temperature, the reaction mixture was diluted with water (about 50 mL) and the resulting precipitate was collected by filtration. The crude aldehyde was dissolved in EtOH (10 mL) and NaBH4 (0.023 g, 0.60 mmol) was added to the reaction mixture. After about 2 h at ambient temperature, HCl (1 N aqueous, about 3 mL) was added to the reaction mixture. After stirring for about 30 min, the reaction mixture was concd in vacuo. The residue was partitioned between EtOAc (20 mL) and saturated aqueous NaHCO3 (20 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concd in vacuo. The crude alcohol was dissolved in 1,4-dioxane (10 mL) and NaOH (2 N aqueous, 1.50 mL, 2.99 mmol) was added. The reaction mixture was heated to about 80° C. After about 4 h, the reaction mixture was cooled to ambient temperature and diluted with EtOAc (30 mL) and saturated aqueous NH4Cl (30 mL). The organic layer was separated, concd in vacuo, and purified by chromatography on silica gel (40 g) eluting with 5% MeOH in DCM to provide N-((1S,3R,4S)-3-ethyl-4-(3-(2-hydroxyethyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide (0.025 g, 20%) as a yellow solid: LC/MS (Table 1, Method a) Rt=1.67 min; MS m/z: 418 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:24][CH2:25][S:26][CH3:27])[NH:5][C:6](=[O:23])[C:7]1[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][C:8]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[NH3:29]>ClCCl>[CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:24][CH2:25][S:26][CH3:27])[NH:5][C:6](=[O:23])[C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH2:29])(=[O:15])=[O:14])=[CH:9][C:8]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(S(=O)(=O)Cl)cc1-c1ccccc1
Reactant: N
Solvent: ClCCl
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(S(N)(=O)=O)cc1-c1ccccc1

Procedure:
To a solution of 4-chlorosulfonyl-2-phenylbenzoyl methionine methyl ester from Example 5E in dichloromethane is added aqueous ammonia and the mixture is stirred until the reaction is judged complete by TLC analysis. The organic phase is separated, dried and evaporated and the product is purified by chromatography on silica gel.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1)([CH3:5])[C:3]#[N:4].[H][H]>C1COCC1.CO.[Ni]>[NH2:12][C:9]1[CH:8]=[CH:7][C:6]([C:2]([CH3:5])([CH3:1])[C:3]#[N:4])=[CH:11][CH:10]=1
Reactant: CC(C)(C#N)c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C#N)c1ccc(N)cc1

Procedure:
2-Methyl-2-(4-nitrophenyl)propanenitrile (Compound of step 1, 16 g, 84.1 mmol) and Raney-Ni (4.16 g) were shaken in THF-MeOH [(1:1), 160 mL] under 40 psi of hydrogen for 10 hours at RT, After completion of reaction, the catalyst was filtered-off and the solvent was evaporated to dryness. The crude product was purified by column chromatography (silica gel, ethyl acetate in hexane) to obtain the title compound as oil.
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[CH:8]=[C:9](Br)[CH:10]=[C:11]2[C:16]=1[O:15][C:14]([CH3:18])([CH3:17])[CH2:13][C:12]2([CH3:20])[CH3:19])=[O:6])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:29][Si:30]([C:33]#[CH:34])([CH3:32])[CH3:31].C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:1]([O:4][C:5]([C:7]1[CH:8]=[C:9]([C:34]#[C:33][Si:30]([CH3:32])([CH3:31])[CH3:29])[CH:10]=[C:11]2[C:16]=1[O:15][C:14]([CH3:18])([CH3:17])[CH2:13][C:12]2([CH3:20])[CH3:19])=[O:6])([CH3:3])[CH3:2]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)OC(=O)c1cc(Br)cc2c1OC(C)(C)CC2(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)OC(=O)c1cc(C#C[Si](C)(C)C)cc2c1OC(C)(C)CC2(C)C
Yield: 69.4 %

Procedure:
Following General Procedure D and using 6-bromo-2,2,4,4-tetramethylchroman-8-carboxylic acid isopropyl ester (Intermediate 42, 0.32 g, 0.89 mmol), triethyl amine (2 mL), copper(I)iodide (0.060 g, 0.33 mmol), trimethylsilyl acetylene (0.5 mL, 3.56 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.16 g, 0.22 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 20% ethyl acetate in hexane as the eluent, the title compound (0.23 g, 69%) was obtained as a yellow oil.
Reaction SMILES: C([C:3]1[C:4]([B:21]2[O:25]C(C)(C)[C:23]([CH3:29])(C)[O:22]2)=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=O.C[N+:31]([O-:33])=[O:32].[OH-].[Na+].Cl>CCCCCCCCCCCCCCCC[N+](C)(C)C.[Br-].C1COCC1.O>[OH:25][B:21]1[C:4]2[C:5]([O:6][CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[CH:18][CH:19]=[CH:20][C:3]=2[CH:23]([CH2:29][N+:31]([O-:33])=[O:32])[O:22]1
Reactant: C[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)NCCCOc1cccc(C=O)c1B1OC(C)(C)C(C)(C)O1
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: Cl
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCCCOc1cccc2c1B(O)OC2C[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.5 %

Procedure:
A mixture of tert-butyl 3-(3-formyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propylcarbamate (3.1 g, 8.47 mmol), MeNO2 (775 mg, 12.7 mmol), CTAB (310 mg, 0.85 mmol) and NaOH (407 mg, 10 mmol) in THF (35 mL) and H2O (8 mL) was stirred at room temperature for 3 h. The mixture was adjusted to pH 2-3 using 2N HCl and then stirred for 30 min. The mixture was extracted with EtOAc (2×80 mL). The organic layer was washed with water (30 mL) and brine (30 mL), dried over anhydrous Na2SO4 and then concentrated. The residue was purified by column chromatography on silica gel (PE/EtOAc=5/1) to give the product (2 g, yield 64.5%). 1H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 7.47 (t, J=7.8 Hz, 1H), 7.07 (d, J=7.4 Hz, 1H), 6.91 (m, 2H), 5.72 (dd, J=9.0, 2.7 Hz, 1H), 5.31 (dd, J=13.3, 2.7 Hz, 1H), 4.54 (dd, J=13.3, 9.4 Hz, 1H), 4.05 (t, J=6.3 Hz, 2H), 3.09 (m, 2H), 1.83 (m, 2H), 1.37 (s, 9H); MS (ESI) m/z=367 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:12][C:13]([N:15]1[CH2:20][CH2:19][S:18][C:17]2[CH:21]=[C:22]([N+:25]([O-:27])=[O:26])[CH:23]=[CH:24][C:16]1=2)=O)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].B>C1COCC1>[OH:1][CH2:2][CH2:3][N:4]([CH2:12][CH2:13][N:15]1[CH2:20][CH2:19][S:18][C:17]2[CH:21]=[C:22]([N+:25]([O-:27])=[O:26])[CH:23]=[CH:24][C:16]1=2)[C:5](=[O:11])[O:6][C:7]([CH3:9])([CH3:10])[CH3:8]
Reactant: CC(C)(C)OC(=O)N(CCO)CC(=O)N1CCSc2cc([N+](=O)[O-])ccc21
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CCO)CCN1CCSc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A solution of tert-butyl 2-hydroxyethyl(2-(7-nitro-2H-benzo[b][1,4]thiazin-4(3H)-yl)-2-oxoethyl)carbamate (250 mg, 0.629 mmol) in THF (10 mL) was cooled to 0° C. then treated with borane in THF (1M) (6.29 mL, 6.29 mmol). The resulting bright yellow solution was allowed to warm to room temperature and then stirred at this temperature for 2.5 days. The mixture was cooled to 0° C., and the reaction was then carefully quenched with MeOH (dropwise addition at first; 20 mL total). The cooling bath was removed, and the yellow solution was stirred for 20 minutes then concentrated. The orange residue was dissolved in MeOH (50 mL) and concentrated to dryness. This residue was dissolved in EtOAc (20 mL) and filtered through a pad of silica gel. The silica pad was eluted with EtOAc (100 mL). The filtrate was concentrated to give an orange residue which was dried under reduced pressure for 4 hours (230 mg, 95%). 1H-NMR (CDCl3) δ 7.97 (brs, 1H), 7.87 (brd, J=8.7 Hz, 1H), 6.85-6.71 (m, 1H), 3.81 (brs, 5H), 3.61 (brs, 2H), 4.54-3.31 (m, 4H), 3.02 (overlapping t, 2H), 1.47 (brs, 9H); ESI-MS (m/z, %): 406 (M+Na, 60), 384 (MH+, 10), 328 (60), 284 (100).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[N:7][C:6]([NH2:9])=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[C:21]1[N:26]=[C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[N:24]=[C:23]([N:33]2[C:37]3[CH:38]=[CH:39][CH:40]=[C:41]([O:42][CH3:43])[C:36]=3[N:35]=[C:34]2[CH:44]([F:46])[F:45])[N:22]=1.C(O)(=O)C>C1COCC1.O>[F:46][CH:44]([F:45])[C:34]1[N:33]([C:23]2[N:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:26]=[C:21]([NH:9][C:6]3[N:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:22]=2)[C:37]2[CH:38]=[CH:39][CH:40]=[C:41]([O:42][CH3:43])[C:36]=2[N:35]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: COc1ccc(N)nn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(Nc2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(OC)cccc43)n2)nn1
Reaction time: 0.17 h
Yield: 30 %

Procedure:
To 0.216 g (1.73 mmol) of 6-methoxy-3-pyridazinamine (J. Med. Chem. 2006, 49, 4409-4424) in THF (3 mL) was added 0.97 mL of NaHMDS (2 M solution in THF), and the mixture was stirred for 10 min. A solution of 0.233 g (0.59 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole (Example 2) was added and the resulting mixture was stirred for 10 min. The resulting mixture was neutralized with acetic acid, diluted with water, and extracted with EtOAc. The organic layer was washed successively with water and aqueous NH3, dried, and concentrated. Recrystallization from ethanol/CH2Cl2 gave 0.086 g (30% yield) of 4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-(6-methoxy-3-pyridazinyl)-6-(4-morpholinyl)-1,3,5-triazin-2-amine: mp 256-259° C.; 1H NMR (DMSO-d6) δ 10.85 (s, 1H), 8.24 (d, J=9.2 Hz, 1H), 8.15 (d, J=7.7 Hz, 1H), 7.99 (t, JHF=52.6 Hz, 1H), 7.40 (t, J=8.2 Hz, 1H), 7.29 (d, J=9.5 Hz, 1H), 6.96 (d, J=8.0 Hz, 1H), 4.00 (s, 3H), 3.97 (s, 3H), 3.84-3.79 (m, 4H), 3.72 (s, 4H); Anal. Calcd. For C21H21F2N9O30.5H2O: C, 51.1; H, 4.5; N, 25.5. Found: C, 51.4; H, 4.6; N, 25.0%.
Reaction SMILES: [CH3:1][C:2]1[CH2:6][C:5](=[O:7])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)[N:3]=1.[ClH:17]>[Pd].CO>[ClH:17].[ClH:17].[NH2:14][C:11]1[CH:10]=[CH:9][C:8]([N:4]2[C:5](=[O:7])[CH2:6][C:2]([CH3:1])=[N:3]2)=[CH:13][CH:12]=1
Reactant: CC1=NN(c2ccc([N+](=O)[O-])cc2)C(=O)C1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC1=NN(c2ccc(N)cc2)C(=O)C1
Yield: 68 %

Procedure:
Into 310 ml of methanol, 500 mg of 3-methyl-1-(4-nitrophenyl)-2-pyrazolin-5-one was dissolved, 50 mg of 5% Pd/C and 0.6 ml of conc. hydrochloric acid were added to the solution, and the mixture was stirred under hydrogen atmosphere to consume the calculated amount of hydrogen. Then, the catalyst was filtered off and the filtrate was concentrated. The residue was recrystallized from methanol-ethyl ether to give 409 mg of 1-(4-aminophenyl)-3-methyl-2-pyrazolin-5-one dihydrochloride (Compound No. 50) as pale brown crystals.
Reaction SMILES: [N:1]1([C@H:13]2[CH2:17][CH2:16][C@H:15]([NH2:18])[CH2:14]2)[C:12]2[C:4](=[CH:5][N:6]=[C:7]3[C:11]=2[CH:10]=[CH:9][NH:8]3)[N:3]=[N:2]1.[F:19][C:20]([F:26])([F:25])[CH2:21][C:22](O)=[O:23].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.CN(C1C=CN=CC=1)C.O>[F:19][C:20]([F:26])([F:25])[CH2:21][C:22]([NH:18][C@H:15]1[CH2:16][CH2:17][C@H:13]([N:1]2[C:12]3[C:4](=[CH:5][N:6]=[C:7]4[C:11]=3[CH:10]=[CH:9][NH:8]4)[N:3]=[N:2]2)[CH2:14]1)=[O:23]
Reactant: O=C(O)CC(F)(F)F
Reactant: N[C@H]1CC[C@H](n2nnc3cnc4[nH]ccc4c32)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CC(F)(F)F)N[C@H]1CC[C@H](n2nnc3cnc4[nH]ccc4c32)C1
Reaction time: 18 h
Yield: 46.2 %

Procedure:
To a stirred solution of racemic trans 3-(6H-1,2,3,5,6-pentaaza-as-indacen-1-yl)-cyclopentylamine (120 mg, 0.49 mmol) in DMF (3 mL), 3,3,3-trifluoropropionic acid (53.0 μL, 0.60 mmol), DMAP (103 mg, 0.84 mmol), HOBt (100 mg, 0.74 mmol) and EDCI (161 mg, 0.84 mmol) were added. Stirring was continued for 18 hours at ambient temperature. The mixture was diluted with water and purified by column chromatography (SCX-2, gradient: methanol to 2M NH3 in methanol). The isolated product was triturated (DCM), washed with water and dried in vacuo at 40° C. for 18 hours affording 79.8 mg (45%) of racemic trans 3,3,3-trifluoro-N-[3-(6H-1,2,3,5,6-pentaaza-as-indacen-1-yl)-cyclopentyl]-propionamide as a grey powder. LCMS (Method A, ESI): RT=3.14 min, m+H=353.3; 1H NMR (400 MHz, DMSO) δ: 12.37 (s, 1H), 9.00 (s, 1H), 8.53 (d, 1H), 7.61 (t, 1H), 7.00 (dd, 1H), 5.67 (m, 1H), 4.48 (m, 1H), 3.26 (q, 2H), 2.55 (m, 2H), 2.33-2.18 (m, 3H), 1.71 (m, 1H).
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=O)[CH:3]=1.CCN=C=NCCCN(C)C.Cl.C[NH:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:42][C:41]([CH3:44])([CH3:43])[O:40][C:38](=[O:39])[CH2:37][CH2:36][O:35][CH2:34][CH2:33][O:32][CH2:31][CH2:30][O:29][CH2:28][CH2:27][NH:26][C:5]([C:4]1[CH:3]=[C:2]([CH:10]=[CH:9][CH:8]=1)[C:1]([OH:12])=[O:11])=[O:7]
Reactant: O=C(O)c1cccc(C(=O)O)c1
Reactant: CNCCOCCOCCOCCC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCOCCOCCOCCNC(=O)c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.2 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of isophthalic acid (1.7 g, 10.24 mmol, 2.98 equiv) in dichloromethane (10 mL), EDC.HCl (660 mg, 3.44 mmol, 1.00 equiv), 4-dimethylaminopyridine (420 mg, 3.44 mmol, 1.00 equiv), and tert-butyl 3-(2-(2-(2-(methylamino)ethoxy)ethoxy)ethoxy)propanoate 8b (1 g, 3.44 mmol, 1.00 equiv). The resulting solution was stirred for 2 h at room temperature. The resulting mixture was washed with 2×20 mL of water and 1×20 mL of NH4Cl (aq). The mixture was dried over sodium sulfate and concentrated under vacuum. The crude product (1 g) was purified by reverse phase chromatography with a water/methanol gradient to yield 500 mg (33%) of 3-((14,14-dimethyl-12-oxo-3,6,9,13-tetraoxapentadecyl)carbamoyl)benzoic acid. as yellow oil. 1H-NMR (300 MHz, CD3OD, ppm): δ 8.087 (s, 2H), 7.664-7.560 (m, 2H), 3.785-3.499 (m, 14H), 3.144-3.705 (m, 3H), 2.489-2.448 (m, 2H), 1.469-1.456 (s, 9H). MS (ES, m/z): 440 [M+H]+.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH2:14][C:15]2[C:16](=[S:52])[NH:17][C:18](=[O:51])[N:19]([CH:50]=2)[C@@H:20]2[O:49][C@H:39]([CH2:40][O:41][Si](C(C)(C)C)(C)C)[C@@H:30]([O:31][Si](C(C)(C)C)(C)C)[C@H:21]2[O:22][Si](C(C)(C)C)(C)C)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(#N)C>[O:1]([C:8]1[CH:9]=[C:10]([CH2:14][C:15]2[C:16](=[S:52])[NH:17][C:18](=[O:51])[N:19]([CH:50]=2)[C@@H:20]2[O:49][C@H:39]([CH2:40][OH:41])[C@@H:30]([OH:31])[C@H:21]2[OH:22])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(Cc3cccc(Oc4ccccc4)c3)c(=S)[nH]c2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Solvent: CC#N
Product: O=c1[nH]c(=S)c(Cc2cccc(Oc3ccccc3)c2)cn1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 76.1 %

Procedure:
The product of step (iii) (3.5 g) was dissolved in acetonitrile (70 ml) and treated with a 1:1 hydrofluoric acid-pyridine complex (20 ml). After 3 hours the mixture was quenched with saturated aqueous sodium carbonate solution (100 ml) and the product extracted into ethyl acetate. The organic phase was collected, dried over magnesium sulphate and the solvent was removed under reduced pressure. The residue was purified by flash silica-gel chromatography eluting with chloroform-methanol mixtures to afford 5-((3-phenoxy)phenylmethyl)-4-thiouridine as a yellow powder (1.5 g).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:14][C:13]([N:15]3[CH2:19][CH2:18][CH2:17][C:16]3=[O:20])=[N:12][C:11]=2[CH3:21])=[O:9])=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:34]1([CH:37]=O)[CH2:36][CH2:35]1.[Cl-].[NH4+]>CN1CCCN(C)C1=O.O1CCCC1>[CH:34]1([CH2:37][CH:17]2[CH2:18][CH2:19][N:15]([C:13]3[S:14][C:10]([C:8]([NH:7][CH2:6][C:5]4[CH:22]=[CH:23][C:2]([F:1])=[CH:3][CH:4]=4)=[O:9])=[C:11]([CH3:21])[N:12]=3)[C:16]2=[O:20])[CH2:36][CH2:35]1
Reactant: Cc1nc(N2CCCC2=O)sc1C(=O)NCc1ccc(F)cc1
Reactant: O=CC1CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: Cc1nc(N2CCC(CC3CC3)C2=O)sc1C(=O)NCc1ccc(F)cc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 17 %

Procedure:
To a solution of N-(4-fluorobenzyl)-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamide (0.13 g, 0.38 mmol) in a mixture of anhydrous tetrahydrofuran and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (8/1, v/v) at −78° C. was added lithium bis(trimethylsilyl)amide in tetrahydrofuran (0.83 mL, 0.83 mmol) dropwise. The reaction mixture was stirred at −78° C. for 5 minutes, followed by the addition of cyclopropanecarbaldehyde (0.028 mL, 0.38 mmol) dropwise. The reaction mixture was warmed to ambient temperature after 3 hours followed by the addition of aqueous saturated ammonium chloride (10 mL) solution. The mixture was extracted with dichloromethane (3×10 mL). The combined organic solutions were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in ethyl acetate and hydrogenated in the presence of catalytic amount of Pd/C (20% w/w) at ambient temperature and atmospheric pressure for 1 hour. The reaction mixture was filtered through a bed of celite and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/hexanes (1/1)) to afford the title compound as a white solid (0.025 g, 17%): mp 153-155° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.34-7.23 (m, 2H), 7.01 (t, J=8.6 Hz, 2H), 5.95 (t, J=5.6 Hz, 1H), 4.52 (d, J=5.6 Hz, 2H), 4.23-4.14 (m, 1H), 3.99-3.90 (m, 1H), 2.87-2.78 (m, 1H), 2.62 (s, 3H), 2.53-2.42 (m, 1H), 2.08-1.94 (m, 1H), 1.79-1.69 (m, 1H), 1.52-1.42 (m, 1H), 0.84-0.69 (m, 1H), 0.53-0.39 (m, 2H), 0.16-0.03 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 175.9, 162.4, 162.3, 155.5, 152.9, 133.7, 129.6, 118.2, 115.7, 46.2, 43.3, 35.5, 24.9, 17.3, 8.6, 4.8, 4.3; MS (ES+) m/z 388.2 (M+1).
Reaction SMILES: [C:1]1([C:7](=[O:11])[C:8](O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.COC(Cl)[Cl:15]>>[C:1]1([C:7](=[O:11])[C:8]([Cl:15])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C(=O)c1ccccc1
Reactant: COC(Cl)Cl
Product: O=C(Cl)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
In a 50 mL-volume flask, 12.2 g of phenyl glyoxylic acid was placed, and then 9.26 g of dichloromethyl methyl ether was dropwise added at room temperature. The mixture was stirred at room temperature for 1 hour. The reaction mixture was placed under reduced pressure (62° C./2 torr) to give 13.4 g of phenylglyoxylic acid chloride. The obtained phenylglyoxylic acid chloride was dropwise added to a mixture of 7.86 g of phenol, 7.26 g of pyridine and 10 mL of toluene. The resulting mixture was stirred at 50° C. for 2 hours.
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]#[N:17])[CH:14]=3)[NH:9][CH:8]=2)[CH2:3]1.[CH3:18][NH:19][CH3:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.C(=O)([O-])[O-].[Na+].[Na+]>CCO.O>[CH3:18][N:19]([CH3:20])[CH:2]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]#[N:17])[CH:14]=3)[NH:9][CH:8]=2)[CH2:3]1
Reactant: N#Cc1ccc2[nH]cc(C3CCC(=O)C3)c2c1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Product: CN(C)C1CCC(c2c[nH]c3ccc(C#N)cc23)C1
Reaction time: 0.25 h
Yield: 98.7 %

Procedure:
3-(3-oxocyclopentyl)-1H-indole-5-carbonitrile (2.24 g, 10 mMol) and dimethylamine (2.0 M solution in THF, 50 mL, 100 mMol) were dissolved in EtOH (150 mL). After stirring for 15 min, sodium triacetoxyborohydride (8.50 g, 40 mMol) was added and the reaction stirred for 4 h. The reaction was then diluted with water (100 mL) and made acidic (pH 3) with HCl (6 M). The reaction was then adjusted to pH 10 with sodium carbonate. It was extracted three times with ethyl acetate (100 mL) and the organic extracts were dried over sodium sulfate, concentrated in vacuo, and dried under high vacuum to give 3-(3-dimethylaminocyclopentyl)-1H-indole-5-carbonitrile (Compound 3, 2.5 g, 100%) as mixture of cis/trans diastereomers. 1H NMR (500 MHz, d4-MeOH) δ 8.02 (0.7 H s), 7.99 (0.3 H, s), 7.46 (0.4 H, s), 7.44 (0.6 H, s), 7.35 (1 H, dd, J=8.55 1.53), 7.24 (0.7 H, s), 7.21 (0.3 H, s), 3.49 (0.4 H, m), 3.37 (0.6 H, m), 2.92 (0.3 H, m), 2.83 (0.7 H, m), 2.41 (0.7 H, m), 2.36 (6 H, s), 2.22 (1.3 H, m), 2.07 (1 H, m), 1.80 (2 H, m), 1.67 (1 H, m). MS m/e 254.2 (M+H)+, 252.2 (M−H)+. LCMS (YMC ODS-A C18 S7 3.0×50 mm) tR, 0.857 min., MH+ 254.19.