Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([N+:24]([O-:26])=[O:25])=[CH:21][CH:22]=3)[N:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].C(N(CC)CC)C.[F:41][C:42]1[CH:47]=[CH:46][C:45]([N:48]=C=O)=[CH:44][CH:43]=1>C(Cl)Cl>[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[F:41][C:42]1[CH:47]=[CH:46][C:45]([NH:48][C:6]([N:8]2[CH2:9][CH2:10][N:11]([C:14]3[C:23]4[C:18](=[CH:19][C:20]([N+:24]([O-:26])=[O:25])=[CH:21][CH:22]=4)[N:17]=[CH:16][CH:15]=3)[CH2:12][CH2:13]2)=[O:7])=[CH:44][CH:43]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccnc3cc([N+](=O)[O-])ccc23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(F)cc1)N1CCN(c2ccnc3cc([N+](=O)[O-])ccc23)CC1

Procedure:
To a solution of 4-[4-(tert-butoxycarbonyl)piperazin-1-yl]-7-nitroquinoline (360 mg, 1 mmol) in CH2Cl2 (1 mL) is added trifluoroacetic acid (1 mL). After 1½ h at room temp., the mixture is concentrated, and the residue is dissolved in CH2Cl2 (20 mL) and treated with triethylamine (0.56 mL, 4 mmol) and 4-fluorophenyl isocyanate (0.16 mL, 1.4 mmol). After 1½ h stirring at room temp., the reaction mixture is washed with water and brine, dried (Na2SO4), and concentrated. The residue is purified by reversed phase HPLC with water-MeCN-TFA yielding the title product.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4]C[CH2:2]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:2]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCC2)CC1
Yield: 82 %

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid hydrochloride (example 41, intermediate b)), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide, to give the desired product as a light brown solid (82%).
Reaction SMILES: C([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[N:15]=[C:14]2[N:16]([CH3:19])[CH:17]=[N:18][C:13]2=[C:12]([F:20])[C:11]=1[NH:21][C:22]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:23]=1[F:29])=[O:9])=C.Cl.C([O-])(O)=O.[Na+]>C1COCC1.CCO.CCOC(C)=O>[OH:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[N:15]=[C:14]2[N:16]([CH3:19])[CH:17]=[N:18][C:13]2=[C:12]([F:20])[C:11]=1[NH:21][C:22]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:23]=1[F:29])=[O:9]
Reactant: C=COCCONC(=O)c1nc2c(ncn2C)c(F)c1Nc1ccc(Br)cc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1cnc2c(F)c(Nc3ccc(Br)cc3F)c(C(=O)NOCCO)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3 -methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (2-vinyloxyethoxy)-amide (1.00 equivalent) in THF-EtOH is added 1 N aqueous HCl (2.0 equivalents) at room temperature. After stirring for 1 hour at room temperature, the reaction mixture is neutralized with saturated aqueous NaHCO3 and diluted with EtOAc. The organic layer is washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give the crude material that is purified by trituration or flash column chromatography to afford 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (2-hydroxyethoxy)-amide.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[C@H:15]([NH:21]C(OCC(Cl)(Cl)Cl)=O)[CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:30]([OH:32])=[O:31])[CH2:3]1.[C:33](O)(=O)C>[Zn]>[NH2:21][C@@H:15]1[CH2:14][C@@:12]2([CH3:13])[C@@H:8]([CH2:9][CH2:10][C@@H:11]2[C:30]([O:32][CH3:33])=[O:31])[C@H:7]2[C@H:16]1[C@:17]1([CH3:20])[C@@H:4]([CH2:5][CH2:6]2)[CH2:3][C@H:2]([OH:1])[CH2:19][CH2:18]1
Reactant: C[C@]12CC[C@@H](O)C[C@H]1CC[C@@H]1[C@@H]2[C@H](NC(=O)OCC(Cl)(Cl)Cl)C[C@]2(C)[C@@H](C(=O)O)CC[C@@H]12
Reactant: CC(=O)O
Agent: [Zn]
Product: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3[C@H](N)C[C@]12C

Procedure:
A solution of the product of Preparation 3 (2.4 g) in glacial acetic acid (25 ml) was stirred with zinc (2.5 g) for 4 hours. The zinc was removed by filtration and washed with water (50 ml) and ether (50 ml). The filtrate and washings were brought to pH 10 with 0.88 NH3 solution and extracted with ester (×4). The extract was washed with water, dried and evaporated to leave a solid (1.65 g). A portion was crystallised from ether to give the title compound, m.p. 113°-116°, [α]D +38°
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][N:3]=1.B>C1COCC1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:6][OH:7])=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: COc1cc(C(=O)O)cnc1Cl
Agent: B
Solvent: C1CCOC1
Product: COc1cc(CO)cnc1Cl
Reaction time: 5 h

Procedure:
To a suspension of 6-chloro-5-methoxynicotinic acid (0.54 g, 2.9 mmol) in THF (5 mL) at 25° C. was added borane (1.0 M in THF, 5.8 mL, 5.8 mmol) dropwise. The mixture was let stir for 5 h, after which TLC showed complete conversion. The reaction was quenched with 2 M HCl until bubbling subsided and mixture extracted with dichloromethane (3×). The combined organic layers were dried over MgSO4 and concentrated to furnish the product (6-chloro-5-methoxypyridin-3-yl)methanol as a white solid (0.49 mg (97%); mp 60-63° C.; 1H NMR (400 MHz, CDCl3) δ 7.95 (d, 1H), 7.30 (d, 1H), 4.74 (s, 2H), 3.94 (s, 3H): LC-MS (ELSD): Exact mass calcd for C7H8ClNO2 [M]+, 173. Found 173.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.C1(S([N:22]2[CH:26]=[C:25]([NH2:27])[CH:24]=[N:23]2)(=O)=O)C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[CH3:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([NH:27][C:25]2[CH:26]=[N:22][NH:23][CH:24]=2)[N:3]=[C:4]([S:11][CH3:12])[N:5]=1
Reactant: CSc1nc(C)c(C#N)c(Cl)n1
Reactant: Nc1cnn(S(=O)(=O)c2ccccc2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: CSc1nc(C)c(C#N)c(Nc2cn[nH]c2)n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 45.4 %

Procedure:
To a solution of 4-chloro-6-methyl-2-(methylthio)pyrimidine-5-carbonitrile (6.45 g, 32.2 mmol) and 1-(phenylsulfonyl)-1H-pyrazol-4-amine (7.2 g, 32.2 mmol) in 1,4-dioxane (150 mL) was added 4-methylbenzenesulfonic acid (3.06 g, 16.1 mmol). The reaction mixture was stirred overnight at 90° C. After cooling to room temperature, the precipitate was filtered, washed with saturated NaHCO3 solution and then water, dried and washed with petroleum and the mixture solvent (petroleum ether:ethyl acetate=4:1) successively to give 4-methyl-2-(methylthio)-6-(1H-pyrazol-4-ylamino)-5-pyrimidinecarbonitrile (intermediate 30, 3.6 g) as a pale solid. MS: M(C10H10N6S)=246.30, (M+1)+=247.1; 1HNMR (300 mHz, DMSO-d6) δ ppm 12.69 (1H, s), 9.87 (1H, s), 7.97 (1H, s), 3.33 (3H, m), 2.42 (3H, s). The organic eluents were concentrated under reduced pressure and the residue was treated with the same method above to afford 4-methyl-2-(methylthio)-6-{[1-(phenylsulfonyl)-1H-pyrazol-4-yl]amino}-5-pyrimidinecarbonitrile (intermediate 29, 4.26 g, 34.4% yield) as a yellow solid.
Reaction SMILES: [I-].[CH2:2]([N+:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:7]=1[CH3:13])[CH2:3][CH2:4][CH3:5].[F:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:24])=[C:19]([CH:23]=1)[C:20](Cl)=[O:21]>CN(C1C=CN=CC=1)C>[CH2:2]([N:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8]/[C:7]/1=[CH:13]\[C:20]([C:19]1[CH:23]=[C:15]([F:14])[CH:16]=[CH:17][C:18]=1[CH3:24])=[O:21])[CH2:3][CH2:4][CH3:5]
Reactant: CCCC[n+]1c(C)sc(C)c1C
Reactant: Cc1ccc(F)cc1C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: [I-]
Product: CCCCN1C(C)=C(C)S/C1=C\C(=O)c1cc(F)ccc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 3-butyl-2,4,5-trimethylthiazol-3-ium iodide (48 mg in 0.5 mL DMA, 0.16 mmol, 1 equiv.) was added, followed by TEA (38 mg in 0.5 mL DMA, 0.37 mmol, 2.4 equiv.) and the solution went black. DMAP (2 mg in 0.5 mL DMA, 0.016 mmol, 0.1 equiv) was added next, followed by 5-fluoro-2-methylbenzoyl chloride (0.9 mL of 0.2M in DMA, 1.2 equiv). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.91 (t, 3 H) 1.30-1.41 (m, 2 H) 1.55-1.68 (m, 2 H) 2.20 (s, 3 H) 2.22 (s, 3 H) 2.33 (s, 3 H) 3.96-4.04 (m, 2 H) 6.09 (s, 1 H) 7.08-7.14 (m, 1 H) 7.19-7.27 (m, 2 H); MS (ESI) m/z 320 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:46])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]([CH2:34][CH2:35][CH2:36][N:37]([CH3:39])[CH3:38])[CH:21]3[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]3)[N:9]=2)[C:6]2[CH:40]=[CH:41][CH:42]=[C:43]([O:44][CH3:45])[C:5]=2[N:4]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:46][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH2:34][CH2:35][CH2:36][N:37]([CH3:38])[CH3:39])[N:9]=2)[C:6]2[CH:40]=[CH:41][CH:42]=[C:43]([O:44][CH3:45])[C:5]=2[N:4]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N(CCCN(C)C)C2CCN(C(=O)OC(C)(C)C)CC2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N(CCCN(C)C)C2CCNCC2)n1
Yield: 99 %

Procedure:
Reaction of tert-butyl 4-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl][3-(dimethylamino)propyl]amino}-1-piperidine-carboxylate from the last step with TFA in CH2Cl2 gave N1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N3,N3-dimethyl-N1-(4-piperidinyl)-1,3-propanediamine in 99% yield: 1H NMR (DMSO-d6) (rotamers) δ 7.96 and 7.93 (d, J=8.3 Hz, 1H), 7.77 and 7.70 (t, JHF=53.1, 53.0 Hz, 1H), 7.40-7.35 (m, 1H), 6.95 (d, J=8.1 Hz, 1H), 4.63-4.56 and 4.50-4.43 (2m, 1H), 3.98 (s, 3H), 3.82-3.77 (m, 4H), 3.70 (br, 4H), 3.55-3.45 (m, 2H), 3.08-3.05 (m, 2H), 2.59-2.52 (m, 3H), 2.28 (t, J=6.8 Hz, 2H), 2.14 and 2.12 (2s, 6H), 1.76-1.61 (m, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([C:10]2[N:11]=[C:12]([NH:18][CH3:19])[S:13][C:14]=2[C:15](O)=[O:16])[CH3:9])[CH:5]=[CH:4][C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CN(C)C=O.C(Cl)(=O)C(Cl)=O.Cl.[NH2:38][OH:39].C(N(CC)CC)C.S1C=CN=C1C(O)=O.Cl>C(Cl)Cl.O.O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([C:10]2[N:11]=[C:12]([NH:18][CH3:19])[S:13][C:14]=2[C:15]([NH:38][OH:39])=[O:16])[CH3:9])[CH:5]=[CH:4][C:3]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: NO
Reactant: CNc1nc(C(C)c2ccc(-c3ccccc3)c(F)c2)c(C(=O)O)s1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)c1nccs1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNc1nc(C(C)c2ccc(-c3ccccc3)c(F)c2)c(C(=O)NO)s1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 48.1 %

Procedure:
To an ice-cooled and stirred solution of 4-(1-(2-fluoro-4-biphenylyl)ethyl)-2-methylamino-5-thiazolecarboxylic acid (5.00 g, 14.0 mmoles) and dimethylformamide (1.03 g, 14.1 mmoles) in methylene chloride (200 ml) was added dropwise oxalyl chloride (3.93 g, 31.0 mmoles) and the mixture was stirred for 40 minutes. On the other hand, hydroxylamine hydrochloride (3.91 g, 56.3 mmoles) in water (5 ml) and triethylamine (8.55 g, 84.5 mmoles) were dissolved in tetrahydrofuran (100 ml), and to the mixture was added dropwise the above-mentioned reacted solution of thiazolecarboxylic acid. After stirring for 30 minutes, the reaction mixture was acidified to pH 4 with 1M hydrochloric acid and extracted with methylene chloride. The organic layer was washed with water, dried and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the desired 4-(1-(2-fluoro-4-biphenylyl)ethyl)-2-methylamino-5-thiazolecarbohydroxamic acid (2.50 g, 6.73 mmoles, 48%) as a light brown amorphous product.
Reaction SMILES: [C:1]1([N:7]([CH2:19][CH2:20][C:21]#[N:22])[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=2[N+:16]([O-])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>O1CCCC1.[C].[Pd]>[C:1]1([N:7]([CH2:19][CH2:20][C:21]#[N:22])[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=2[NH2:16])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc(N(CCC#N)c2ccccc2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1ccc(N(CCC#N)c2ccccc2)c(N)c1
Reaction time: 9 h
Yield: 100.2 %

Procedure:
N-Phenyl-N-(2-cyanoethyl)-2-nitro-4-methoxyaniline (39.5 g) was dissolved in tetrahydrofuran (200 ml), 10% palladium carbon (4.0 g) was added, the mixture was stirred for 9 hours under hydrogen atmosphere. Palladium carbon was removed by filtration, the filtrate was concentrated under reduced pressure, to thereby obtain 35.6 g of the titled compound (Yield: 100%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][C:30]=1[CH2:31][OH:32])[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:26][CH3:27])=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:23])[CH2:21][CH3:22])=[CH:16][C:15]=2[CH2:24][CH3:25])[CH:13]=1.[CH2:33]([Mg]Br)[CH3:34]>>[CH2:26]([C:11]1[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH2:33][CH3:34])([OH:23])[CH2:21][CH3:22])=[CH:16][C:15]=2[CH2:24][CH3:25])=[CH:13][C:8]([O:7][CH2:6][C:5]2[CH:28]=[CH:29][C:30]([CH2:31][OH:32])=[C:3]([CH2:2][OH:1])[CH:4]=2)=[CH:9][CH:10]=1)[CH3:27]
Reactant: CC[Mg]Br
Reactant: CCC(=O)c1ccc(-c2cc(OCc3ccc(CO)c(CO)c3)ccc2CC)c(CC)c1
Product: CCc1cc(C(O)(CC)CC)ccc1-c1cc(OCc2ccc(CO)c(CO)c2)ccc1CC

Procedure:
In a manner similar to that of Example 1(q), by reacting 840 mg (1.9 mmol) of 1-{5′-[3,4-bis(hydroxymethyl)benzyloxy]-2,2′-diethylbiphenyl-4-yl}-1-propanone with 5.2 ml (16 mmol) of ethylmagnesium bromide (3M/ether), and after purification by chromatography on a column of silica eluted with a mixture of heptane and ethyl acetate (40/60), 254 mg (29%) of {5-[6,2′-diethyl-4′-(1-ethyl-1-hydroxypropyl)biphenyl-3-yloxymethyl]-2-hydroxymethylphenyl}methanol are obtained in the form of white crystals with a melting point of 93° C.
Reaction SMILES: N(C(OCC)=O)=N[C:3](OCC)=[O:4].[OH:13][C@H:14]1[CH2:18][N:17]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[O:20])[C@@H:16]([C:32]([N:34]2[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][O:42][C:43]([O:45][CH2:46][C:47]3[CH:52]=[CH:51][C:50]([N+:53]([O-:55])=[O:54])=[CH:49][CH:48]=3)=[O:44])[CH2:36][CH2:35]2)=[O:33])[CH2:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)=O>O1CCCC1>[CH:3]([O:13][C@@H:14]1[CH2:18][N:17]([C:19]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=2)=[O:20])[C@@H:16]([C:32]([N:34]2[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][O:42][C:43]([O:45][CH2:46][C:47]3[CH:52]=[CH:51][C:50]([N+:53]([O-:55])=[O:54])=[CH:49][CH:48]=3)=[O:44])[CH2:36][CH2:35]2)=[O:33])[CH2:15]1)=[O:4]
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: O=C(OCCN1CCN(C(=O)[C@H]2C[C@@H](O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1)OCc1ccc([N+](=O)[O-])cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=CO
Solvent: C1CCOC1
Product: O=CO[C@H]1C[C@H](C(=O)N2CCN(CCOC(=O)OCc3ccc([N+](=O)[O-])cc3)CC2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 0.17 h
Yield: 45.2 %

Procedure:
A solution of 1.31 g of diethyl azodicarboxylate in 5 ml of tetrahydrofuran was added dropwise, whilst ice-cooling, to a solution of 3.0 g of (2R,4R)-4-hydroxy-2-{4-[2-(4-nitrobenzyloxycarbonyl)oxyethyl]-1-piperazinylcarbonyl}-1-(4-nitrobenzyloxycarbonyl)-pyrrolidine [prepared as described in Preparation 57(i)] and 1.97 g of triphenylphosphine in 25 ml of tetrahydrofuran, and the resulting mixture was stirred at the same temperature for 10 minutes. 283 μl of formic acid were then added dropwise to the mixture, and the mixture was stirred at the same temperature for 5 minutes and at room temperature for 1 hour. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 20:1 by volume mixture of ethyl acetate and methanol as the eluent, to give 1.42 g of the title compound, as a colorless powder.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH:19][C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][N:27]=[C:26]3[NH:30][CH:31]=[CH:32][C:25]=23)=[S:21])[CH:13]=1)=[O:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:30]1[C:26]2=[N:27][CH:28]=[CH:29][C:24]([CH2:23][NH:22][C:20](=[S:21])[NH:19][CH2:18][C:14]3[CH:13]=[C:12]([NH:11][C:9](=[O:10])[CH2:8][NH2:7])[CH:17]=[CH:16][CH:15]=3)=[C:25]2[CH:32]=[CH:31]1
Reactant: CC(C)(C)OC(=O)NCC(=O)Nc1cccc(CNC(=S)NCc2ccnc3[nH]ccc23)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCC(=O)Nc1cccc(CNC(=S)NCc2ccnc3[nH]ccc23)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.6 %

Procedure:
To a solution of 27-1 (100 mg, 0.32 mmol) and Boc-glycine (68 mg, 0.39 mmol) in DCM (10 mL) was added TEA (98 mg, 0.96 mmol) and HATU (184 mg, 0.48 mmol). the mixture was stirred at rt for 16 h. The mixture then washed with saturated sodium bicarbonate solution (aq), and the organic layer was dried and evaporated. The residue was purified by column chromatography to yield tert-butyl(2-((3-((3-((1H-pyrrolo[2,3-b]pyridin-4-yl)methyl)thioureido)methyl)phenyl)amino)-2-oxoethyl)carbamate (120 mg, 0.26 mmol). To a solution of tert-butyl(2-((3-((3-((1H-pyrrolo[2,3-b]pyridin-4-yl)methyl)thioureido)methyl)phenyl)amino)-2-oxoethyl)carbamate (120 mg, 0.26 mmol) in DCM (10 mL) was added TFA (2 mL). The mixture was stirred at rt for 0.5 h. Solvent was evaporated and the residue was purified by semi-prep HPLC to yield Example 112, N-(3-((3-((1H-pyrrolo[2,3-b]pyridin-4-yl)methyl)thioureido)methyl)phenyl)-2-aminoacetamide (13 mg).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([Cl:21])=[CH:5][C:6]([F:20])=[C:7]([C:9]2[C:13]([Cl:14])=[C:12]([C:15]([F:18])([F:17])[F:16])[N:11]([CH3:19])[N:10]=2)[CH:8]=1.[SH:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:21][C:4]1[CH:5]=[C:6]([F:20])[C:7]([C:9]2[C:13]([Cl:14])=[C:12]([C:15]([F:18])([F:17])[F:16])[N:11]([CH3:19])[N:10]=2)=[CH:8][C:3]=1[CH2:2][S:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: Cn1nc(-c2cc(CBr)c(Cl)cc2F)c(Cl)c1C(F)(F)F
Reactant: CCOC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CSCc1cc(-c2nn(C)c(C(F)(F)F)c2Cl)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
A mixture of 1.62 g (4.0 mmole) 3-[5-(bromomethyl)-4-chloro-2-fluorophenyl]-4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazole, 0.44 mL ethyl mercaptoacetate and 0.55 g K2CO3 was slurried in 25 mL of acetone. The reaction mixture was allowed to stir at room temperature overnight. After dilution with 100 mL of cold water, the mixture was extracted with ethyl acetate, the organic extracts washed with water, dried with MgSO4 and concentrated in vacuo. The residue was purified by chromatography to afford 1.7 g (96%) of (((2-chloro-5-(4-chloro-1-methyl-5-(trifluoromethyl) -1H-pyrazol-3-yl) -4-fluorophenyl)methyl)thio)acetic acid, ethyl ester as a white solid; mp 63° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:12]2[N:13]([S:23]([N:26]([CH3:28])[CH3:27])(=[O:25])=[O:24])[CH:14]=[C:15]([CH2:17][C:18]([CH3:22])([CH3:21])[CH2:19][CH3:20])[N:16]=2)([OH:11])[CH3:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB([C:43]2[CH:44]=[N:45][NH:46][CH:47]=2)O1.O>CN(C)C=O.O>[CH3:21][C:18]([CH3:22])([CH2:19][CH3:20])[CH2:17][C:15]1[N:16]=[C:12]([C:9]([OH:11])([CH3:10])[CH2:8][C:5]2[CH:6]=[CH:7][C:2]([C:43]3[CH:44]=[N:45][NH:46][CH:47]=3)=[CH:3][CH:4]=2)[N:13]([S:23]([N:26]([CH3:28])[CH3:27])(=[O:25])=[O:24])[CH:14]=1
Reactant: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(C)(O)Cc2ccc(Br)cc2)n1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(C)(O)Cc2ccc(-c3cn[nH]c3)cc2)n1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (57 mg, 0.07 mmol) was added to a degassed, ambient temperature solution of 2-[2-(4-bromophenyl)-1-hydroxy-1-methylethyl]-4-(2,2-dimethylbutyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (329 mg, 0.70 mmol), sodium carbonate (222 mg, 2.1 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (217 mg, 1.4 mmol) in N,N-dimethylformamide/water (2:1) (30 mL). After stirring at 80° C. overnight, the reaction mixture was cooled, poured into water and extracted with diethyl ether. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-40% ethyl acetate/hexane afforded 4-(2,2-dimethylbutyl)-2-{1-hydroxy-1-methyl-2-[4-(1H-pyrazol-4-yl)phenyl]ethyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][CH2:6][C:7]([C:9]1[C:17]2[C:12](=[C:13]([O:18][CH3:19])[CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:10]=1)=[O:8])=O.[CH2:27]([NH:29][CH2:30][CH3:31])[CH3:28].Cl>O1CCCC1.[OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O.ClCCl>[ClH:1].[CH:21]1([CH2:20][N:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][CH3:19])[C:9]([C:7]3[O:8][C:3]([CH2:2][N:29]([CH2:30][CH3:31])[CH2:27][CH3:28])=[N:5][CH:6]=3)=[CH:10]2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: COc1cccc2c(C(=O)CNC(=O)CCl)cn(CC3CCCCC3)c12
Reactant: CCNCC
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: Cl
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCN(CC)Cc1ncc(-c2cn(CC3CCCCC3)c3c(OC)cccc23)o1

Procedure:
To a solution of 2-chloro-N-[2-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)-2-oxoethyl]-acetamide (200 mg, 0.53 mmol) in tetrahydrofuran (2 ml) was added diethylamine (0.55 ml, 5.3 mmol) and the reaction mixture subjected to microwave irradiation at 150° C. for 15 minutes. The reaction mixture was poured into a separating funnel and dichloromethane (30 ml) added. The organics were washed sequentially with 5% aqueous sodium carbonate and brine. The organics were dried over magnesium sulfate, filtered and the solvent removed in vacuo to give a brown solid. The brown solid was dissolved in tetrahydrofuran (2 ml) and (methoxycarbonylsulfamoyl)triethylammonium hydroxide, inner salt (505 mg, 2.12 mmol) added. The resulting reaction mixture was subjected to microwave irradiation at 150° C. for 15 minutes and quenched with methanol (20 ml). The solvent was removed in vacuo and the residue purified by flash chromatography using 50% (v/v) ethyl acetate in heptane, followed by semi-prep. HPLC [Method (ii)] to afford a white solid. The solid was dissolved in dichloromethane (˜5 ml) and hydrogen chloride (1M solution in diethyl ether; 1 ml) added. The mixture was concentrated in vacuo to afford the title compound as a 1:1 hydrochloride salt (77 mg, 0.2 mmol). 1H NMR (400 MHz, CD3OD) δH 0.97-1.12 (2H, m), 1.15-1.25 (3H, m), 1.44 (6H, t, J 6.9), 1.52-1.62 (2H, m), 1.62-1.77 (3H, m), 1.77-1.9 (1H, m), 3.36 (4H, q, J 6.7), 3.95 (3H, s), 4.26 (2H, d, J 7), 4.64 (2H, s), 6.77 (1H, d, J 8), 7.11 (1H, t, J 8), 7.38 (1H, s), 7.41 (1H, d, J 8), 7.56 (1H, s); EsIMS: m/z 396.1 [M+H]+, 323.4, 268.4.