Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.[CH3:35][C:36]1([NH2:40])[CH2:39][O:38][CH2:37]1>CN(C=O)C.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:40][C:36]5([CH3:35])[CH2:39][O:38][CH2:37]5)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: CC1(N)COC1
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(F)cc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC4(C)COC4)c3n2)c2ccc(F)cc21
Reaction time: 16 h
Yield: 38.7 %

Procedure:
To a stirred solution of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (105 mg, 0.34 mmol) in 6 mL of DMF were added EDCI (128 mmol, 0.67 mmol), DMAP (82 mg, 0.67 mmol) and 3-methyloxetan-3-amine (44 mg, 0.50 mmol) in one portion at room temperature. Then the mixture was stirred for 16 hours. The solvent was evaporated at 70° C. under reduced pressure and the residue was triturated with water (10 mL), dichloromethane (10 mL), methanol (15 mL) then decanted and dried to give 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-N-(3-methyloxetan-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (50 mg, 38.9%) as a yellow solid. MS: (M+H)+=381; 1H NMR (300 MHz, DMSO): δ 12.90 (brs, 1H), 9.13 (s, 1H), 8.53-8.47 (m, 3H), 7.72 (d, 1H, J=7.8 Hz), 7.26-7.21 (m, 1H), 4.91 (d, 2H, J=6.0 Hz), 4.55 (d, 2H, J=6.3 Hz), 4.18 (s, 3H), 1.77 (s, 3H).
Reaction SMILES: [Br:1]C1C=C2C(=CC=1)NN=C2.ClC1C=C2C(=NC=1)NC=C2.FC1C=C2C(=NC=1)NC=C2.N1C2C(=CC=CN=2)C=C1.[F:40][C:41]1[C:46]([C:47]([C:49]2[C:57]3[C:52](=[N:53][CH:54]=[C:55](F)[CH:56]=3)[NH:51][CH:50]=2)=[O:48])=[CH:45][CH:44]=[CH:43][C:42]=1[NH:59][S:60]([CH2:63][CH2:64][CH3:65])(=[O:62])=[O:61]>>[Br:1][C:55]1[CH:56]=[C:57]2[C:49]([C:47]([C:46]3[C:41]([F:40])=[C:42]([NH:59][S:60]([CH2:63][CH2:64][CH3:65])(=[O:62])=[O:61])[CH:43]=[CH:44][CH:45]=3)=[O:48])=[CH:50][NH:51][C:52]2=[N:53][CH:54]=1
Reactant: Brc1ccc2[nH]ncc2c1
Reactant: CCCS(=O)(=O)Nc1cccc(C(=O)c2c[nH]c3ncc(F)cc23)c1F
Agent: Clc1cnc2[nH]ccc2c1
Agent: Fc1cnc2[nH]ccc2c1
Agent: c1cnc2[nH]ccc2c1
Product: CCCS(=O)(=O)Nc1cccc(C(=O)c2c[nH]c3ncc(Br)cc23)c1F

Procedure:
Using the protocol of Scheme 14, substituting 5-bromo-azaindole with either 5-chloro-7-azaindole (80, prepared as described in Example 9), 5-fluoro-7-azaindole (81, prepared as described in Example 9) or 7-azaindole in Step 6, propane-1-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide P-1013 (MS(ESI) [M−H+]−=394.1), propane-1-sulfonic acid [2-fluoro-3-(5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide P-1028 (MS(ESI) [M−H+]−=378.1), and propane-1-sulfonic acid [2-fluoro-3-(1H-1-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide P-1056 (MS(ESI) [M+H+]+=362.2) were prepared, respectively:
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=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.Cl.[N:56]1[N:57]=[CH:58][N:59]2[CH2:64][CH2:63][NH:62][CH2:61][C:60]=12>CN(C=O)C>[N:56]1[N:57]=[CH:58][N:59]2[CH2:64][CH2:63][N:62]([C:19]([C:18]3[CH:17]=[N:16][C:15]([O:14][CH2:13][C:3]4[C:4]([C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=5)=[N:5][O:6][C:2]=4[CH3:1])=[CH:23][CH:22]=3)=[O:21])[CH2:61][C:60]=12
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: c1nnc2n1CCNC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)N2CCn3cnnc3C2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.8 %

Procedure:
To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (500 mg, 1.6 mmol) in DMF (10 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (569 mg, 1.8 mmol), N,N-diisopropyl ethyl amine (1.38 mL, 8.1 mmol) and 5,6,7,8-tetrahydro-(1,2,4)triazolo(4,3-a)-pyrazine hydrochloride (1.8 mmol). The resulting reaction mixture was stirred overnight at room temperature. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1 and then dichloromethane:methanol=9:1) afforded the title compound (605 mg, 86%) which was obtained as a white foam. MS: m/e=417.4 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1([CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH:12]2[N:7]([CH2:8][CH2:9][C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][C:11]=32)[CH2:6][CH2:5][CH:4]1CCC(OC)=O)[CH3:2]>[Pd].CO>[CH2:1]([C:3]1([CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH:12]2[N:7]([CH2:8][CH2:9][C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][C:11]=32)[CH2:6][CH2:5][CH2:4]1)[CH3:2]
Reactant: CCC1(CCC(=O)OC)C(CCC(=O)OC)CCN2CCc3c([nH]c4ccccc34)C21
Agent: [Pd]
Solvent: CO
Product: CCC1(CCC(=O)OC)CCCN2CCc3c([nH]c4ccccc34)C21

Procedure:
An isomer mixture of a ratio described in Example 2 is obtained when dissolving 147 g. of 1-ethyl-(methoxycarbonylethyl)--(methoxycarbonylethyl)-1,2,3,4,6,7-hexahydro-12H-indolo[2,3-a]quinolizine in 16 ml. of methanol and hydrogenating in the presence of 100 mg. palladium on charcoal catalyst.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([N:7]=[C:8]=[O:9])=[CH:3][CH:2]=1.Br.[NH2:12][CH2:13][C:14]([NH:16][C:17]1[CH:30]=[CH:29][CH:28]=[CH:27][C:18]=1[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20])=[O:15].C(N(CC)CC)C.Cl>O1CCCC1.O>[C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:9])[NH:12][CH2:13][C:14]([NH:16][C:17]2[CH:30]=[CH:29][CH:28]=[CH:27][C:18]=2[C:19]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:20])=[O:15])=[CH:3][CH:2]=1
Reactant: NCC(=O)Nc1ccccc1C(=O)c1ccccc1
Reactant: Cc1ccc(N=C=O)cc1
Agent: Br
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(NC(=O)NCC(=O)Nc2ccccc2C(=O)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.5 %

Procedure:
A solution of p-tolylisocyanate (655 mg, 4.92 mmol) in tetrahydrofuran (8 ml) is added to a solution of the salt 3a (1.341 g, 4 mmol) prepared in Preparation 3 in tetrahydrofuran (50 ml). Triethylamine (558 μl, 4 mmol) is added at 0° C., and the mixture is stirred at 0° C. for 30 minutes, and then at room temperature overnight. Water and then 10% hydrochloric acid are added, and the mixture is extracted with ethyl acetate. The extract is washed with water, dried (sodium sulfate), and then the solvent is distilled off under reduced pressure. The residue is recrystallized from dichloromethane/diisopropylether to obtain the objective compound 6z (1.31 1 g, 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:5][NH:6][C:7](=[O:17])[NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14]([OH:16])=O)[N:13]=1.CCN(C(C)C)C(C)C.CN([C:34]([O:38][N:39]1N=NC2C=CC=C[C:40]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.CNOC>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:5][NH:6][C:7](=[O:17])[NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14]([N:39]([O:38][CH3:34])[CH3:40])=[O:16])[N:13]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(NCc1ccc(Cl)c(Cl)c1)Nc1nc(C(=O)O)cs1
Agent: CNOC
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1csc(NC(=O)NCc2ccc(Cl)c(Cl)c2)n1
Reaction time: 8 h

Procedure:
0.58 g of 2-(3-(3,4-dichlorobenzyl)ureido)thiazole-4-carboxylic acid was dissolved in 15 ml of DMF and 3.0 eq. of DIEA and 1.05 eq. of TBTU was added. To the mixture, 1.2 eq. of N,O-dimethylhydroxylamine HCl salt was added and the reaction was stirred at room temp. overnight. The product was precipitated from water, filtered, washed with water and dried to give 2-(3-(3,4-dichlorobenzyl)ureido)-N-methoxy-N-methylthiazole-4-carboxamide.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N:7]2[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH2:8]2)=[C:5]([N+:14]([O-:16])=[O:15])[CH:4]=[N:3]1.CCN(CC)CC.Cl[Si:25]([CH3:28])([CH3:27])[CH3:26]>CN(C=O)C>[CH3:1][N:2]1[C:6]([N:7]2[CH2:8][CH:9]=[C:10]([O:13][Si:25]([CH3:28])([CH3:27])[CH3:26])[CH2:11][CH2:12]2)=[C:5]([N+:14]([O-:16])=[O:15])[CH:4]=[N:3]1
Reactant: Cn1ncc([N+](=O)[O-])c1N1CCC(=O)CC1
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1ncc([N+](=O)[O-])c1N1CC=C(O[Si](C)(C)C)CC1
Temperature: 90 °C
Yield: 59 %

Procedure:
Three identical solutions of piperidin-4-one hydrochloride hydrate (1.84 g, 12.0 mmol), 5-chloro-1-methyl-4-nitro-1H-pyrazole from Example 1 (1.3 g, 8.0 mmol) and potassium fluoride (1.86 g, 32 mmol) in dry DMSO (20 mL) were heated in a microwave at 100° C. for 12 hr. The mixtures were combined, poured into water (700 mL) and extracted into EtOAc (3×100 mL). The combined organic layers were passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (0-5% MeOH/DCM) gave 1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidin-4-one as a yellow solid (1.97 g, 36%). To a solution of this ketone in DMF (40 mL) was added NEt3 (3.05 mL, 21.9 mmol) and chlorotrimethylsilane (1.55 mL, 12.3 mmol). The reaction vessel was sealed and the mixture heated at 90° C. for 16 hr. The mixture was cooled and the product extracted into EtOAc (2×50 mL). The combined organic layers were passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% Et2O/isohexane) gave 1-(1-methyl-4-nitro-1H-pyrazol-5-yl)-4-(trimethylsilyloxy)-1,2,3,6-tetrahydropyridine as a yellow gum (1.53 g, 59%). This gum was dissolved in MeCN (130 mL) and cooled to 0° C. A solution of SelectFluor® (1.99 g, 5.61 mmol) in 2:1 MeCN:DMF (10 mL) was added dropwise over 20 min and the mixture stirred at between −5° C. and 0° C. for 2 hr. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc (50 mL) and water (40 mL). The product was extracted into EtOAc (50 mL) and DCM (50 mL), and the combined organic layers passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave 3-fluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidin-4-one as a pale yellow solid (1.23 g, 99%). 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 5.04 (ddd, J=48.3, 8.2, 5.7 Hz, 1H), 3.89 (s, 3H), 3.77-3.64 (m, 2H), 3.64-3.51 (m, 1H), 3.50-3.43 (m, 1H), 2.88-2.72 (m, 2H).
Reaction SMILES: [CH2:1]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][N:3]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:2]1.[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][C:21]=1[O:29][CH3:30].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.O>[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([N:9]2[CH2:10][CH2:11][C:6]3([CH2:1][CH2:2][N:3]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:4][CH2:5]3)[CH2:7][CH2:8]2)=[O:25])=[CH:22][C:21]=1[O:29][CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)CC1
Reactant: COc1cc(C(=O)O)ccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)N2CCC3(CCN(C(=O)OC(C)(C)C)CC3)CC2)ccc1F

Procedure:
A solution of tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (30 mg, 0.12 mmol; U.S. Pat. No. 5,451,578), 4-fluoro-3-methoxybenzoic acid (20 mg, 0.12 mmol; Aldrich), N,N-diisopropylethylamine (0.025 mL, 0.14 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU; 54 mg, 0.14 mmol; Aldrich) in anhydrous N,N-dimethylformamide (1 mL) was stirred overnight at room temperature. The reaction was diluted with water (10 mL) and extracted with dichloromethane (2×10 mL). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo to provide the title compound which was carried on to the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.[CH2:13]1[O:15][CH2:14]1.CC(C)=O>C1COCC1.CCOCC>[OH:15][CH2:14][CH2:13][C:7]1[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1CO1
Reactant: Fc1ccccn1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: OCCc1cccnc1F
Temperature: 25 °C

Procedure:
A solution of 2.0 g (20.6 mmol) of 2-fluoropyridine in 25 ml of dry THF was cooled to -78° C. was added 25 ml (1.6M in hexanes, 41.6 mmol) n-BuLi under an atmosphere of nitrogen. The mixture was stirred at this temperature for 2 hours before an addition of 4 ml ethylene oxide in 7 ml ether. The mixture was warmed to room temperature, 150 ml ether and 25 ml acetone was added. The precipitate was removed by filtration, and the filtrate was concentrated to 1/3 of volume in vacuo. The remainder was washed once with brine, dried with Na2SO4, and concentrated in vacuo. The chide material was purified by dry column flash chromatography (hexane/EtOAc) to afford 0.42 g of 3-(2-hydroxyethyl)-2-fluoropyridine as a brown oil.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[OH:10][C@H:11]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C@H:12]([N:14]([CH3:26])[C:15](=[O:25])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([S:23][CH3:24])[CH:18]=1)[CH3:13].C(OC(=O)NC1C=CC=C(CN2C=CC(NC(=O)[C@@H](C3C=CC(S(C)(=O)=O)=C(Cl)C=3)[CH2:55][CH:56]3[CH2:60][CH2:59][CH2:58][CH2:57]3)=N2)C=1)(C)(C)C.O>O1CCCC1>[CH:56]1([CH2:55][C@H:16]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([S:23][CH3:24])[CH:18]=2)[C:15]([N:14]([C@H:12]([CH3:13])[C@H:11]([OH:10])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH3:26])=[O:25])[CH2:60][CH2:59][CH2:58][CH2:57]1
Reactant: CSc1cccc(CC(=O)N(C)[C@H](C)[C@H](O)c2ccccc2)c1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Cn2ccc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)n2)c1
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: CSc1cccc([C@@H](CC2CCCC2)C(=O)N(C)[C@H](C)[C@H](O)c2ccccc2)c1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
To a solution of 1,1,1,3,3,3-Hexamethyldisilazane (1.81 g, 11.19 mmol) in tetrahydrofuran (15 mL) cooled to −20° C. under nitrogen was added n-butylithium (6.4 mL of a 1.6 M solution, 10.21 mmol) slowly keeping the temperature at −20° C. for 30 min. N-((1R,2R)-2-hydroxy-1-methyl-2-phenyl-ethyl)-N-methyl-2-(3-methylsulfanyl-phenyl)-acetamide (1.60 g, 4.86 mmol) in tetrahydrofuran (15 mL) was added slowly to the reaction maintaining the temperature at −20° C. After the addition was complete the reaction was warmed to 0° C. and stirred for 30 min. A solution of 2,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1.31 g, 10.21 mmol) and iodomethylcyclopentane (prepared in PCT WO2004/052869 A1 Example 1, 1.23 g, 5.84 mmol) were added to the reaction at 0° C. and stirring continued for 3 h. The reaction was poured into water (60 mL) and extracted with ethyl acetate. The ethyl acetate fractions were washed with water, 2 N aqueous hydrochloric acid solution, saturated sodium bicarbonate and saturated sodium chloride solution and then dried over magnesium sulfate. Filtration and concentration afforded the crude product which was purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 0% ethyl acetate/hexanes to 50% ethyl acetate/hexanes) to yield (R)-3-cyclopentyl-N-((1R,2R)-2-hydroxy-1-methyl-2-phenyl-ethyl)-N-methyl-2-(3-methylsulfanyl-phenyl)-propionamide (1.16 g, 58%) as a clear sticky solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:19][C:20]([N:22]2[CH2:31][CH2:30][C:29]3[CH:28]=[N:27][C:26]([NH:32][CH:33]([CH3:35])[CH3:34])=[N:25][C:24]=3[CH2:23]2)=[O:21])[CH2:9][N:10](C)[C:11](=O)OC(C)(C)C)=[CH:4][C:3]=1[F:36].C(Cl)Cl.Cl.O1CCOCC1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH2:9][NH:10][CH3:11])[CH2:19][C:20]([N:22]2[CH2:31][CH2:30][C:29]3[CH:28]=[N:27][C:26]([NH:32][CH:33]([CH3:35])[CH3:34])=[N:25][C:24]=3[CH2:23]2)=[O:21])=[CH:4][C:3]=1[F:36]
Reactant: CC(C)Nc1ncc2c(n1)CN(C(=O)C[C@H](CN(C)C(=O)OC(C)(C)C)c1ccc(Cl)c(F)c1)CC2
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: C1COCCO1
Product: CNC[C@@H](CC(=O)N1CCc2cnc(NC(C)C)nc2C1)c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 106 (106 mg, 0.204 mmol) in MeOH (2 mL) and a small amount of DCM was added 4 M HCl in dioxane (764 μL, 3.06 mmol). The reaction was stirred at RT for 4 h. The reaction was concentrated and purified by reverse phase column chromatography (SP4) eluting with a MeCN/H2O gradient (0-80% MeCN) to afford 50.7 mg (54.5%) of I-17: LCMS (ACPI-pos) m/z 420.3 (M+H)+.
Reaction SMILES: C(O)(=O)C.C(O)(=O)C.[N+:9]([C:12]1[S:16][C:15]([CH:17]=O)=[CH:14][CH:13]=1)([O-:11])=[O:10].[CH3:19][C:20](=[O:25])[CH2:21][C:22](=[O:24])[CH3:23]>>[N+:9]([C:12]1[S:16][C:15]([CH:17]=[C:21]([C:20](=[O:25])[CH3:19])[C:22](=[O:24])[CH3:23])=[CH:14][CH:13]=1)([O-:11])=[O:10]
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Reactant: CC(=O)CC(C)=O
Solvent: CC(=O)O
Product: CC(=O)C(=Cc1ccc([N+](=O)[O-])s1)C(C)=O

Procedure:
The procedure described in Example 12 was repeated by using 2.59 g of 5-nitro-2-thiophenecarboxaldehyde diacetate, 1.5 g of 2,4-pentanedione. Yield 0.5 g, yellow viscous oil.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]3[CH:14]=[C:15]([C:18]([NH:20][NH2:21])=[O:19])[CH:16]=[CH:17][C:12]3=[N:11][CH:10]=2)=[CH:5][CH:4]=1.[C:22](Cl)(=[O:24])[CH3:23].C(OCC)(=O)C>CN(C)C(=O)C>[C:22]([NH:21][NH:20][C:18]([C:15]1[CH:16]=[CH:17][C:12]2[N:13]([C:9]([C:6]3[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=3)=[CH:10][N:11]=2)[CH:14]=1)=[O:19])(=[O:24])[CH3:23]
Reactant: CSc1ccc(-c2cnc3ccc(C(=O)NN)cn23)cc1
Reactant: CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CSc1ccc(-c2cnc3ccc(C(=O)NNC(C)=O)cn23)cc1
Reaction time: 1.5 h
Yield: 73.9 %

Procedure:
To a solution of 3-[4-(methylthio)phenyl]imidazo[1,2-a]pyridine-6-carbohydrazide (505 mg, 1.69 mmol) in N,N-dimethylacetamide (4 mL) was added acetyl chloride (0.132 mL, 1.86 mmol) at room temperature, and the resulting mixture was stirred for 1.5 hr. Ethyl acetate was added to the reaction mixture, and the precipitate was collected by filtration to give N′-acetyl-3-[4-(methylthio)phenyl]imidazo[1,2-a]pyridine-6-carbohydrazide (425 mg) as colorless crystals.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:37]=[C:36]2[C:32]([C:33]([C:41]([OH:43])=O)=[CH:34][N:35]2[CH:38]([CH3:40])[CH3:39])=[CH:31][CH:30]=1.[NH2:44][C:45]1[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][N:46]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.O.C(OCC)(=O)C>[Cl:51][C:48]1[CH:49]=[CH:50][C:45]([NH:44][C:41]([C:33]2[C:32]3[C:36](=[CH:37][C:29]([Cl:28])=[CH:30][CH:31]=3)[N:35]([CH:38]([CH3:39])[CH3:40])[CH:34]=2)=[O:43])=[N:46][CH:47]=1
Reactant: CC(C)n1cc(C(=O)O)c2ccc(Cl)cc21
Reactant: Nc1ccc(Cl)cn1
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)n1cc(C(=O)Nc2ccc(Cl)cn2)c2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 28.7 %

Procedure:
A solution of triphenylphosphine (243 mg, 0.92 mmol) in methylene chloride (3 mL) cooled to 0° C. was treated with N-bromosuccinimide (165 mg, 0.92 mmol). This solution was stirred at 0° C. for 15 min. At this time, the reaction was treated with 6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (200 mg, 0.84 mmol). This solution was stirred at 0° C. for 15 min and then was allowed to warm to 25° C. where it was stirred for 30 min. The reaction was then treated with 2-amino-5-chloropyridine (270 mg, 2.10 mmol) and was then stirred at 25° C. for 40 h. At this time, the reaction was diluted with water (25 mL) and ethyl acetate (25 mL). This mixture was treated with a saturated aqueous sodium bicarbonate solution (10 mL). The organic layer was separated and was washed with a saturated aqueous sodium chloride solution (1×25 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 5/1 hexanes/ethyl acetate) afforded 6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (5-chloro-pyridin-2-yl)-amide (84 mg, 29%) as a pale yellow solid: mp 131-134° C.; EI-HRMS m/e calcd for C17H15Cl2N3O (M+) 347.0592, found 347.0594.
Reaction SMILES: Cl.O1CCOCC1.C(O[C:13](=O)[N:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[N:25]([C:32]3[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:33]=3[Cl:39])[N:26]=[CH:27][C:28]=2[CH:29]([CH3:31])[CH3:30])=[CH:18][C:17]=1[CH3:40])C)(C)(C)C>ClCCl>[Cl:38][C:37]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:39])[C:32]=1[N:25]1[C:24]([CH2:23][O:22][C:19]2[CH:20]=[CH:21][C:16]([NH:14][CH3:13])=[C:17]([CH3:40])[CH:18]=2)=[C:28]([CH:29]([CH3:31])[CH3:30])[CH:27]=[N:26]1
Reactant: Cc1cc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)ccc1N(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CNc1ccc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
A solution of 4.0 M HCl in 1,4-dioxane (2.8 mL, 11.0 mmol) is added to a solution of {4-[2-(2,6-dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-methyl-carbamic acid tert-butyl ester (1.85 g, 3.7 mmol) in dichloromethane (25.0 mL) at 0° C. The reaction mixture is then stirred at room temperature for 2.0 h. The solvents are removed by evaporation under reduced pressure. The residue is partitioned between EtOAc (50 mL) and 5% aqueous sodium bicarbonate (30 mL). The organic layer is washed with brine (40 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to a residue. The residue is purified by flash chromatography (EtOAc/Hexane) to afford the title compound as a foamy solid (1.25 g, 84%). LC-ES/MS m/e 404.0 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:43])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]([N:14]2[CH2:18][C@@H:17]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C@@:16]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[F:33])([C:24]#[N:25])[C@H:15]2[C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:35]=2[F:41])=[O:13])=[CH:6][C:5]=1[F:42].O[Li].O>C1COCC1.O>[Cl:40][C:36]1[C:35]([F:41])=[C:34]([C@@H:15]2[C@:16]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[F:33])([C:24]#[N:25])[C@H:17]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:18][N:14]2[C:12]([NH:11][CH2:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:43])=[O:2])=[C:5]([F:42])[CH:6]=2)=[O:13])[CH:39]=[CH:38][CH:37]=1
Reactant: COC(=O)c1ccc(CNC(=O)N2C[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1F
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)C[C@@H]1CN(C(=O)NCc2ccc(C(=O)O)c(F)c2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.1 %

Procedure:
To a mixture of rac-4-({[(2S,3S,4S)-2-(3-Chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]amino}-methyl)-2-fluoro-benzoic acid methyl ester (53.0 mg, 0.0838 mmol) in THF (6 mL) was added a solution of LiOH.H2O (Aldrich, 26 mg, 0.615 mmol) in water (3 mL) and the reaction mixture was stirred at rt overnight. The reaction mixture was partly concentrated and quenched with 1 N HCl (pH 5), extracted with EtOAc, and washed with water, saturated NaCl. The organic phase was separated, and dried over Na2SO4. The mixture was then concentrated to give rac-4-({[(2S,3S,4S)-2-(3-Chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-methyl)-2-fluoro-benzoic acid (38.9 mg, 75%). HRMS (ES+) m/z Calcd C31H28Cl2F3N3O3+H (M+H): 618.1533; Found: 618.1532