Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].C1C=C[C:5]2N(O)N=[N:8][C:6]=2C=1.CCN(C(C)C)C(C)C.[N:21]1[CH:26]=C[C:24]([N:27]2[CH2:32]CC3(CCNCC3)C[CH2:28]2)=[CH:23][CH:22]=1>C(Cl)Cl>[CH3:5][CH2:6][N:8]=[C:26]=[N:21][CH2:22][CH2:23][CH2:24][N:27]([CH3:28])[CH3:32].[ClH:1]
Reactant: On1nnc2ccccc21
Reactant: c1cc(N2CCC3(CCNCC3)CC2)ccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN=C=NCCCN(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
HCl (503 mg, 2.62 mmol), HOBT (177 mg, 1.311 mmol) and DIPEA (0.6 ml) were added to a solution of the product just obtained in step 5 (400 mg, 1.3114 mmol) in methylene chloride (10 ml). The reaction mixture was stirred at 25° C. for 30 min and then cooled to 0° C. and 3-pyridin-4-yl-3,9-diaza-spiro[5.5]undecane (364 mg, 1.57 mmol) was added. The reaction mixture was stirred at 25° C. for 12 h, subsequently diluted with methylene chloride and washed with sat. NH4Cl solution and with NaHCO3 solution. The organic phase was washed with water and sat. NaCl solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[O:3][C:4]1[CH:5]=[C:6]([CH2:10][N:11]2[C:23]3[CH:22]=[CH:21][CH:20]=[C:19]([OH:24])[C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][C:16]=3[C:25](=[O:27])[NH2:26])[CH:7]=[CH:8][CH:9]=1.Br[CH2:31][C:32]([O:34][CH3:35])=[O:33]>CN(C=O)C.C(OCC)(=O)C>[F:29][C:2]([F:28])([F:1])[O:3][C:4]1[CH:5]=[C:6]([CH2:10][N:11]2[C:23]3[CH:22]=[CH:21][CH:20]=[C:19]([O:24][CH2:31][C:32]([O:34][CH3:35])=[O:33])[C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][C:16]=3[C:25](=[O:27])[NH2:26])[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)CBr
Reactant: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(OC(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1cccc(OC(F)(F)F)c1
Reaction time: 0.05 h
Yield: 82.5 %

Procedure:
40% Methanolic Triton B (0.15 mL, 0.34 mM) was added to a solution of the 9-[(3-trifluoromethoxyphenyl)methyl]-4-hydroxy-5-carbamoyl carbazole (115 mg, 0.28 mM) in 8 mL DMF at room temperature. After 3 minutes, methyl bromoacetate (65 mg, 0.41 mM) was added and the resultant mixture stirred at room temperature for 23 hours. The mixture was diluted with ethyl acetate, washed with H2O, and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with ethyl acetate) to afford 112 mg (83%) of the {9-[(3-trifluoromethoxyphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester as a white solid. 1H NMR (DMSO-d6) δ 7.6 (d, 1H, J=8 Hz), 7.55 (br s, 1H), 7.5-7.0 (m, 9H), 6.6 (d, 1H, J=8 Hz), 5.7 (s, 2H), 4.9 (s, 2H), and 3.75 (s, 3H). IR (KBr, cm−1) 3488, 3141, 1763, 1674, 1501, 1444, 1269, 1215, 1178, 1102, 772, and 714. MS (FD) m/e 472.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7](Br)=[CH:8][S:9][C:4]2=[CH:3][CH:2]=1.[Li]CCCC.[C:16](=[O:18])=[O:17]>CCOCC>[S:9]1[CH:8]=[C:7]([C:16]([OH:18])=[O:17])[C:5]2[CH:6]=[CH:1][CH:2]=[CH:3][C:4]1=2
Reactant: O=C=O
Reactant: Brc1csc2ccccc12
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=C(O)c1csc2ccccc12
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
3-bromothianaphthene (1.63 g, 7.65 mmol) was dissolved in anhydrous ether (30 ml) and n-BuLi (2.5 M, 3.5 ml, 8.65 mmol) was added to the solution at −78° C. The mixture was stirred at −78° C. for 10 min, and then the reaction solution was slowly added to an excessive amount of dry ice dissolved in anhydrous ether (140) under nitrogen conditions. The mixture was heated to room temperature for 1 hour, and then stirred at room temperature for another 2 hours. After the reaction was completed, the product was washed, filtered, and dried to obtain benzo[b]thiophene-3-carboxylic acid (805 mg, 4.51 mmol).
Reaction SMILES: [CH:1]1([CH2:4][C:5]([NH:13][C:14]([C:16]2[CH:21]=[C:20]([O:22][C@@H:23]([CH3:28])[C:24]([F:27])([F:26])[F:25])[C:19](Br)=[CH:18][N:17]=2)=[O:15])([CH3:12])[C:6]2[N:10]=[C:9]([CH3:11])[O:8][N:7]=2)[CH2:3][CH2:2]1.[CH:30]1(B(O)O)[CH2:32][CH2:31]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(OC(=O)C)C>[CH:1]1([CH2:4][C:5]([NH:13][C:14]([C:16]2[CH:21]=[C:20]([O:22][C@@H:23]([CH3:28])[C:24]([F:27])([F:26])[F:25])[C:19]([CH:30]3[CH2:32][CH2:31]3)=[CH:18][N:17]=2)=[O:15])([CH3:12])[C:6]2[N:10]=[C:9]([CH3:11])[O:8][N:7]=2)[CH2:3][CH2:2]1
Reactant: Cc1nc(C(C)(CC2CC2)NC(=O)c2cc(O[C@@H](C)C(F)(F)F)c(Br)cn2)no1
Reactant: OB(O)C1CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1nc(C(C)(CC2CC2)NC(=O)c2cc(O[C@@H](C)C(F)(F)F)c(C3CC3)cn2)no1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of 5-Bromo-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-pyridine-2-carboxylic acid [2-cyclopropyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide (Example 100c, 160 mg, 0.335 mmol) in toluene (4.8 mL) were added cyclopropylboronic acid (43.2 mg, 0.503 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (12.3 mg, 17 μmol) and 2M aqueous solution sodium carbonate (335 μL, 0.670 mmol). Reaction was stirred at 80° C. for 18 hours. The reaction mixture was diluted with ethylacetate and extracted with water. The organic layer was dried on sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/ethyl acetate gradient to yield the mixture of epimers (151 mg, 100%). The mixture of epimers was separated by preparative chiral HPLC (Chiralpak AD, isopropanol/heptane) and the title compound was the first epimer collected and isolated as colorless oil; MS (ESI, m/z): 439.7 (M+H+).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([O:20][CH3:21])=[C:5]([N:9]2[C:13]([CH2:14][NH2:15])=[CH:12][C:11]([C:16]([F:19])([F:18])[F:17])=[N:10]2)[CH:6]=[CH:7][CH:8]=1.[F:22][C:23]1[CH:24]=[C:25]([NH:31][C:32](=O)[O:33]C2C=CC=CC=2)[CH:26]=[CH:27][C:28]=1[CH2:29][OH:30]>C(Cl)Cl.O>[Cl:2][C:3]1[C:4]([O:20][CH3:21])=[C:5]([N:9]2[C:13]([CH2:14][NH:15][C:32]([NH:31][C:25]3[CH:26]=[CH:27][C:28]([CH2:29][OH:30])=[C:23]([F:22])[CH:24]=3)=[O:33])=[CH:12][C:11]([C:16]([F:18])([F:19])[F:17])=[N:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1c(Cl)cccc1-n1nc(C(F)(F)F)cc1CN
Reactant: O=C(Nc1ccc(CO)c(F)c1)Oc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: COc1c(Cl)cccc1-n1nc(C(F)(F)F)cc1CNC(=O)Nc1ccc(CO)c(F)c1
Reaction time: 16 h
Yield: 61.2 %

Procedure:
To a stirred solution of (1-(3-chloro-2-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine hydrochloride (100 mg, 0.38 mmol, 1.0 eq) in DCM (5 mL) was added TEA (0.16 mL, 1.14 mmol, 3.0 eq) followed by phenyl 3-fluoro-4-(hydroxymethyl)phenyl-carbamate (131 mg, 0.38 mmol, 1.0 eq) at RT and stirred for 16 h. The reaction mixture was diluted with water (15 mL), extracted with DCM (2×15 mL). The combined organic layer was washed with brine (15 mL), dried over anhydrous Na2SO4 and evaporated under vacuum. Crude product was purified by CC to get 1-((1-(3-chloro-2-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(3-fluoro-4-(hydroxymethyl)phenyl)urea (110 mg; 61%) as off white solid (TLC system: MeOH/CHCl3 (1:9); Rf: 0.55).
Reaction SMILES: C[O:2][C:3]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:6]([O:7]C)=[CH:5][C:4]=1[CH:14]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH3:15].C(O)(=O)C.Br>O>[CH:14]([C:4]1[CH:5]=[C:6]([OH:7])[C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:3]=1[OH:2])([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH3:15]
Reactant: CCCCCCCCCCCCCCCCC(C)c1cc(OC)c([N+](=O)[O-])cc1OC
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCCCC(C)c1cc(O)c([N+](=O)[O-])cc1O

Procedure:
To 5.0 g of 2-sec-octadecyl-5-nitrohydroquinone dimethyl ether and 135 ml of glacial acetic acid were added 15 ml of 47% hydrobromic acid and the mixture was heated with reflux for 10 hours. After being allowed to cool, the mixture was added to water and then extracted with ether. After washing with water and drying, the solvent was distilled off under reduced pressure and the residue was purified through silica gel column chromatography. As the developing solvent,benzene/n-hexane (1:1) was used. The end product was obtained in 1.7 g as yellowish brown semisolid. The structure was determined by means of IR, NMR and elemental analysis data. Elemental analysis:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([NH2:17])=[N:14][C:13]=2[CH3:18])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[CH2:19]([N:21]=[C:22]=[O:23])[CH3:20]>CN(C=O)C>[CH2:19]([NH:21][C:22]([NH:17][C:15]1[S:16][C:12]([C:4]2[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[C:2]([F:1])[CH:3]=2)=[C:13]([CH3:18])[N:14]=1)=[O:23])[CH3:20]
Reactant: CCN=C=O
Reactant: Cc1nc(N)sc1-c1ccc(S(C)(=O)=O)c(F)c1
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(F)c2)s1
Temperature: 85 °C

Procedure:
A mixture of 5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (0.40 g, 1.4 mmol) and ethyl isocyanate (0.121 ml, 1.5 mmol) in dry DMF (3 ml) is heated at 85° C. for 1 hour. The solvent is removed and the product is purified by chromatography on silica eluting with hexane-ethyl acetate (1:1) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@@H:15]([NH:22][C:23]([C:25]3[NH:29][C:28](=[O:30])[N:27]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:26]=3)=[O:24])[CH2:16][C@@H:17]([OH:21])[C:18]([OH:20])=[O:19])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:37](=[O:44])([O:41][CH2:42][CH3:43])[O:38][CH2:39]Cl.N1C(C)=CC=CC=1C.[Na+].[I-]>CN(C=O)C>[CH2:42]([O:41][C:37]([O:38][CH2:39][O:19][C:18](=[O:20])[C@H:17]([OH:21])[CH2:16][C@H:15]([NH:22][C:23]([C:25]1[NH:29][C:28](=[O:30])[N:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:26]=1)=[O:24])[CH2:14][C:11]1[CH:10]=[CH:9][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[CH:13][CH:12]=1)=[O:44])[CH3:43]
Reactant: O=C(N[C@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C[C@@H](O)C(=O)O)c1nn(-c2ccccc2)c(=O)[nH]1
Reactant: CCOC(=O)OCCl
Agent: [I-]
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Product: CCOC(=O)OCOC(=O)[C@H](O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1nn(-c2ccccc2)c(=O)[nH]1
Yield: 4.3 %

Procedure:
A solution of (2R,4R)-5-(3′-chlorobiphenyl-4-yl)-2-hydroxy-4-[(5-oxo-1-phenyl-4,5-dihydro-1H-[1,2,4]triazole-3-carbonyl)amino]pentanoic acid (253 mg, 0.5 mmol), chloromethyl ethyl carbonate (69 mg, 0.5 mmol), 2,6-lutidine (165 mg, 1.5 mmol) and NaI (150 mg, 1 mmol) in DMF (20 mL) was stirred for 15 hours at 50° C. The mixture was quenched with water (20 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were collected and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether/EtOAc=3:1) to yield the title compound as a white solid (13 mg). LC-MS: 608.8 [M+H]+. 1H NMR: (CDCl3, 400 MHz) δ 1.27 (t, J=8.0 Hz, 3H), 2.03-2.33 (m, 2H), 3.02-3.05 (m, 2H), 4.18 (q, J=8.0 Hz, 2H), 4.49 (br, 1H), 4.85 (br, 1H), 5.57-5.76 (m, 2H), 7.03 (d, J=12 Hz, 1H), 7.25-7.40 (m, 4H), 7.42-7.51 (m, 3H), 7.53-7.61 (m, 3H), 7.93 (d, J=8.0 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4](Br)=[CH:5][CH:6]=1.C([Li])CCC.[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([CH:22]=[O:23])=[CH:21][C:16]=2[CH:15]=[CH:14]1.O>O1CCCC1>[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([CH:22]([C:4]3[S:3][C:2]([Br:1])=[CH:6][CH:5]=3)[OH:23])=[CH:21][C:16]=2[CH:15]=[CH:14]1
Reactant: O=Cc1ccc2occc2c1
Reactant: Brc1ccc(Br)s1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: OC(c1ccc2occc2c1)c1ccc(Br)s1
Reaction time: 0.67 h
Yield: 81 %

Procedure:
To a solution of 2,5-dibromothiophene (2.05 g, 8.48 mmol) in tetrahydrofuran (25 mL) was added n-butyl lithium (3.48 mL, 8.48 mmol) at −78° C., and the solution was stirred for 40 minutes. Then, benzofuran-5-carbaldehyde described in Preparation Example 175 (1.24 g, 8.48 mmol) was added to this reaction solution at −78° C., and the solution was stirred at room temperature for 75 minutes. Water was added to the reaction solution, which was then extracted with ethyl acetate, and the organic layer was washed with brine. Anhydrous magnesium sulfate was added to the organic layer for drying, which was then filtered, the filtrate was concentrated in vacuo, the residue was purified by NH silica gel column chromatography (heptane/ethyl acetate=3/1), and the title compound (2.11 g, 81%) was obtained as a light brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]([OH:14])=[O:13])[CH:11]=1)[NH:8][CH2:7][CH2:6][CH2:5]2.[OH-].[Na+].[C:17](Cl)(=[O:19])[CH3:18]>O1CCOCC1>[C:17]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]([OH:14])=[O:13])[CH:11]=1)[NH:8][CH2:7][CH2:6][CH2:5]2)(=[O:19])[CH3:18]
Reactant: Nc1cc2c(c(C(=O)O)c1)NCCC2
Reactant: CC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(=O)Nc1cc2c(c(C(=O)O)c1)NCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.8 %

Procedure:
A solution of 6-amino-1,2,3,4-tetrahydroquinoline-8-carboxylic acid (4.80 g) in dioxane (60 ml) was added 1N aqueous sodium hydroxide solution (60 ml) and acetyl chloride (2.5 ml), the mixture was stirred for 8 hours at room temperature. After salting out, extracted with ethyl acetate, washed with water and saturated aqueous sodium chloride solution successively and dried over anhydrous sodium sulfate. After solvent was distilled away and the resulting residue was purified by silica gel column chromatography eluting with dichloromethane-ethanol (9:1) to yield 0.98 g (16.8%) of the title compound. This compound was recrystallized from ethanol to give yellow crystals, mp 258°-259° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[CH:7]=[CH:8][CH:9]1[CH2:16][N:15]2[C:17]3[CH:18]=[C:19]([C:30]([O:32][CH3:33])=[O:31])[CH:20]=[CH:21][C:22]=3[C:23]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[C:14]2[C:13]2[CH:34]=[CH:35][CH:36]=[CH:37][C:12]=2[O:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO.O.O.O.O.O.O.[Co](Cl)Cl.[Co](Cl)Cl>[C:1]([O:5][C:6](=[O:38])[CH2:7][CH2:8][CH:9]1[CH2:16][N:15]2[C:17]3[CH:18]=[C:19]([C:30]([O:32][CH3:33])=[O:31])[CH:20]=[CH:21][C:22]=3[C:23]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[C:14]2[C:13]2[CH:34]=[CH:35][CH:36]=[CH:37][C:12]=2[O:11][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C=CC(=O)OC(C)(C)C)COc1ccccc1-3
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CCC(=O)OC(C)(C)C)COc1ccccc1-3

Procedure:
Cobalt chloride hexahydrate (cat.; 0.12 eq) was added to a solution of methyl 7-[3-tert-butoxy-3-oxoprop-1-en-1-yl]-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate in MeOH (0.02 M). Once the cobalt chloride was in solution, NaBH4 (5.4 eq) was introduced. Vigorous effervescence was noted, along with a darkening of the solution to grey/black. After circa 5 min, effervescence had subsided and the dark colour in the reaction began to dissipate with the reaction returning to yellow within 10 min. The reaction mixture was partitioned between EtOAc and 1N HCl (aq). The organics were washed with sat. aq. NaHCO3, water and brine before being dried (Na2SO4), filtered and concentrated in vacuo. The product was taken on without further purification (97%). (ES+) m/z 518 (M+H)+; 540 (M+Na)+.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][CH3:15])[CH2:12][O:11][C@H:10]([C:16]([OH:18])=O)[CH2:9]1)=[O:7])([CH3:4])[CH3:3].[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[CH2:14]([C@H:13]1[N:8]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[CH2:9][C@@H:10]([C:16]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:18])[O:11][CH2:12]1)[CH3:15]
Reactant: Nc1ccccc1
Reactant: CC[C@@H]1CO[C@H](C(=O)O)CN1C(=O)OC(C)(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CC[C@@H]1CO[C@H](C(=O)Nc2ccccc2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
To (2S,5R)-4-{[(1,1-dimethylethyl)oxy]carbonyl}-5-ethyl-2-morpholinecarboxylic acid (0.250 g, 0.964 mmol) in CH2Cl2 (10 mL) were added aniline (0.088 mL, 0.964 mmol), HOAt (0.131 g, 0.964 mmol) and EDC (0.222 g, 1.157 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with water (2×), and the organics were dried over Na2SO4 and concentrated to afford the title compound (0.247 g) as a brown oil. LC-MS (ES) m/z=240 [M+H]+.
Reaction SMILES: OC(C)(C)CNC(N)=N.[NH2:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:27][C:28]([OH:51])([CH3:50])[CH2:29][NH:30][C:31]1[N:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[C:34]([C:41]2[CH:46]=[CH:45][N:44]=[C:43](S(C)=O)[N:42]=2)=[CH:33][N:32]=1>C1COCC1>[CH3:50][C:28]([OH:51])([CH3:27])[CH2:29][NH:30][C:31]1[N:36]=[C:35]([C:37]([F:39])([F:38])[F:40])[C:34]([C:41]2[CH:46]=[CH:45][N:44]=[C:43]([NH:10][C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)[N:42]=2)=[CH:33][N:32]=1
Reactant: Nc1ccncc1
Reactant: CS(=O)c1nccc(-c2cnc(NCC(C)(C)O)nc2C(F)(F)F)n1
Agent: CC(C)(O)CNC(=N)N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(O)CNc1ncc(-c2ccnc(Nc3ccncc3)n2)c(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.8 %

Procedure:
This compound was synthesized in an analogous manner to 22 utilizing 1-(2-hydroxy-2-methylpropyl)guanidine in step 3. To a solution of 4-aminopyridine (80 mg, 0.852 mmol) in THF (426 μl) cooled at −78° C. under nitrogen, LiHMDS (852 μl, 0.852 mmol) was added dropwise. The reaction mixture was warmed up to rt, then was stirred for 30 minutes. To the reaction mixture cooled back to −78° C., 2-methyl-1-(2-(methylsulfinyl)-4′-(trifluoromethyl)-4,5′-bipyrimidin-2′-ylamino)propan-2-ol (80 mg, 0.213 mmol) was added, and the reaction mixture was warmed up to rt, then was stirred for 1 hour. The crude product was purified by reverse-phase HPLC [30-100% organic phase over 15 minutes] followed by Biotage™ silica gel chromatography [10 g SNAP column, 100% DCM to 12% MeOH/DCM] to obtain the desired product as a pale yellow solid (25.7 mg, 30% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.14 (s, 6H) 3.40 (br. s., 2H) 4.51 (s, 1H) 7.13 (d, J=5.05 Hz, 1H) 7.76 (s, 2H) 8.01 (br. s., 1H) 8.34 (d, J=5.56 Hz, 2H) 8.66 (d, J=4.93 Hz, 1H) 10.19 (s, 1H). HRMS (ES+) for C18H18F3N7O.H+ [MH+]: calcd, 406.1603; found, 406.1612. UV-LC: 100/100% UV purity at 214/254 nm; tR=2.95 minutes over 7.75 minutes.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[C:16]([O:20][C:21]([N:23]1[C:31]2[C:26](=[N:27][CH:28]=[CH:29][CH:30]=2)[C:25]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)=[C:24]1[C:39]1[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17].[CH3:45][S:46]SC>O1CCCC1>[C:16]([O:20][C:21]([N:23]1[C:31]2[C:26](=[N:27][CH:28]=[CH:29][C:30]=2[S:46][CH3:45])[C:25]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)=[C:24]1[C:39]1[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CSSC
Reactant: CC(C)(C)OC(=O)n1c(-c2ccncc2)c(-c2ccc(F)cc2)c2ncccc21
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1ccnc2c(-c3ccc(F)cc3)c(-c3ccncc3)n(C(=O)OC(C)(C)C)c12
Temperature: -78 °C
Reaction time: 1 h

Procedure:
2,2,6,6-Tetramethylpiperidine (1.76 ml, 10.40 mmol) was dissolved in tetrahydrofuran (39 ml) and placed under an atmosphere of nitrogen. The solution was cooled to −78° C. and n-butyllithium (3.96 ml, 9.91 mmol, 2.5 M solution of in hexanes) was added at such a rate that the internal temperature did not exceed −70° C. The reaction mixture was warmed to −10° C. for 30 min., then re-cooled to −78° C. A solution of 1-tert-butoxycarbonyl-3-(4-fluorophenyl)-2-(pyridin-4-yl)-pyrrolo[3,2-b]pyridine (0.965g, 2.47 mmol) in tetrahydrofuran (32 ml) was cooled to −78° C. and then added via cannula at such a rate that the internal temperature did not exceed −70+ C. After 1 h, dimethyldisulfide (0.29 ml, 3.22 mmol) was added and the resulting solution was stirred for an additional 1 h at −78° C. The reaction mixture was quenched with saturated ammonium chloride solution and the product was extracted into ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude residue was purified by flash chromatography using 20% acetone/hexanes as the eluant to give 1-tert-butoxycarbonyl-3-(4-fluorophenyl)-7-methylthio-2-(pyridin-4-yl)-pyrrolo[3,2-b]pyridine. MS: 435 (M).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][CH2:3][C:4]([O-])=[O:5].C1N=CN(C(N2C=NC=C2)=O)C=1.O/[N:23]=[C:24](\[NH2:32])/[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C>[CH2:25]([C:24]1[N:32]=[C:4]([CH2:3][CH2:2][C:1]([O:8][CH3:9])=[O:7])[O:5][N:23]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)CCC(=O)[O-]
Reactant: N/C(Cc1ccccc1)=N\O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: COC(=O)CCc1nc(Cc2ccccc2)no1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.7 %

Procedure:
Butanedioic acid, monomethyl ester (4.0 g, 30.3 mmole) and CDI (5.40 g, 33.3 mmole) were dissolved in anhydrous DMF (15 ml). After stirring the solution at room temperature for 3 hours, (1Z)—N′-hydroxy-2-phenylethanimidamide (5.0 g, 33.3 mmole) was added and the solution heated at 90° C. for 20 hours. After evaporation of solvent, the residue was dissolved in EtOAc. The organic phase was washed with water and brine, dried over Na2SO4. After filtration and evaporation of solvent, the residue was purified by flash chromatography on silica gel eluted with EtOAc/Hexane (25/75). The purification gave 5.2 g (69.7%) of product as light yellowish oil. LCMS calculated for C13H15N2O3 (M+H): 247.1. found 247.0.
Reaction SMILES: C(OCC1C2C(=CN=C(C([NH:21][OH:22])=O)C=2)N(CC2C=CC(F)=CC=2F)C=1)C1C=CC=CC=1.[Cl:32][C:33]1[CH:56]=[C:55]([F:57])[CH:54]=[CH:53][C:34]=1[O:35][CH2:36][C:37]1[C:41]2[CH:42]=[N:43][C:44]([C:46]([O:48]CC)=O)=[CH:45][C:40]=2[N:39]([CH2:51][CH3:52])[CH:38]=1.ClC1C(O)=C(C=C(F)C=1)CC1C2C=NC(C(OCC)=O)=CC=2N(CC)C=1>>[Cl:32][C:33]1[CH:56]=[C:55]([F:57])[CH:54]=[CH:53][C:34]=1[O:35][CH2:36][C:37]1[C:41]2[CH:42]=[N:43][C:44]([C:46]([NH:21][OH:22])=[O:48])=[CH:45][C:40]=2[N:39]([CH2:51][CH3:52])[CH:38]=1
Reactant: O=C(NO)c1cc2c(COCc3ccccc3)cn(Cc3ccc(F)cc3F)c2cn1
Reactant: CCOC(=O)c1cc2c(cn1)c(COc1ccc(F)cc1Cl)cn2CC
Agent: CCOC(=O)c1cc2c(cn1)c(Cc1cc(F)cc(Cl)c1O)cn2CC
Product: CCn1cc(COc2ccc(F)cc2Cl)c2cnc(C(=O)NO)cc21

Procedure:
Ethyl 3-(2-chloro-4-fluoro-phenoxymethyl)-1-ethyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate and ethyl 3-(3-chloro-5-fluoro-2-hydroxy-benzyl)-1-ethyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate. The title compound can be prepared from ethyl 3-hydroxymethyl-1-ethyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate and 2-chloro-4-fluorophenol using methods similar to step (e) of Example 54. (b) 3-(2-Chloro-4-fluoro-phenoxymethyl)-1-ethyl-N-hydroxy-1H-pyrrolo[3,2-c]pyridine-6-carboxamide. The title compound can be prepared from a mixture of ethyl 3-(2-chloro-4-fluoro-phenoxymethyl)-1-ethyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate and ethyl 3-(3-chloro-5-fluoro-2-hydroxy-benzyl)-1-ethyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate in a manner similar to step (e) of Example 11. Purification by HPLC can provide the pure title compound.