Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9](=[O:36])[CH2:10][C@@H:11]([C:24]1[CH:28]=[CH:27][N:26]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH:25]=1)[C:12]([NH:14][C@H:15]([C:20](=[O:23])[NH:21][CH3:22])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])C1C=CC=CC=1.CC(OC)(C)C>CCO>[CH3:17][C:16]([CH3:19])([CH3:18])[C@H:15]([NH:14][C:12](=[O:13])[C@H:11]([C:24]1[CH:28]=[CH:27][N:26]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH:25]=1)[CH2:10][C:9]([OH:36])=[O:8])[C:20](=[O:23])[NH:21][CH3:22]
Reactant: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)c1ccn(-c2ccc(F)cc2)c1)C(C)(C)C
Solvent: COC(C)(C)C
Solvent: CCO
Product: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)O)c1ccn(-c2ccc(F)cc2)c1)C(C)(C)C

Procedure:
As described in Example 1(a), N-[2,2-dimethyl-1(S)-(methylcarbamoyl)propyl]-3 (S)-[1-(4-fluorophenyl)-1H-pyrrol-3-yl]succinamic acid benzyl ester was hydrogenolyzed in EtOH after 1.5 hours. Trituration with MTBE/hex gave in quantitative yield N-[2,2- dimethyl-1(S)-(methylcarbamoyl)propyl]-3(S)-[1-(4-fluorophenyl)-1H-pyrrol-3-yl]succinamic acid as a colorless amorphous solid. 1H NMR: δ7.27-7.23 (m, 2H), 7.07 (t, 2H, J=8.6 Hz), 6.90-6.89 (m, 2H), 6.21 (t, 1H, J=2.2 Hz), 6.13-6.10 (m, 1H), 4.24 (d, 1H, J =9.6 Hz), 4.03 (dd, 1H, J=5.2, 8.5 Hz), 3.14 (dd, 1H, J=8.5, 16.6 Hz), 2.80 (dd, 1H, J=5.7, 16.7 Hz), 2.72 (d, 3H, J=4.8 Hz), 0.94 (s, 9H). Anal. Calculated for C21H26N3O4F: C, 63.17; H, 6.80; N, 10.09. Found: C, 62.89; H, 6.93; N, 9.81.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]4[CH2:29][CH2:28][CH2:27]4)[CH2:23][CH2:22][C:21]([C:30]([O:32]C)=[O:31])=[CH:20][C:19]=3[CH:34]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO.C1COCC1>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]4[CH2:27][CH2:28][CH2:29]4)[CH2:23][CH2:22][C:21]([C:30]([OH:32])=[O:31])=[CH:20][C:19]=3[CH:34]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3CC2CCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3CC2CCC2)cc1
Temperature: 50 °C
Yield: 87.8 %

Procedure:
In methanol (25 ml) and THF (25 ml) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-1-cyclobutylmethyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.47 g). To the solution was added 1N sodium hydroxide solution (10 ml), and the mixture was heated at 50° C. overnight, concentrated, neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give 7-[4-(2-butoxyethoxy)phenyl]-1-cyclobutylmethyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.40 g) as yellow crystals.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([OH:38])=O)[C:31]2=[O:39])=[CH:26][CH:25]=1.[NH2:40][C:41]1[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=1.C(N(CC)CC)C>CN(C=O)C>[C:44]1([CH3:47])[CH:45]=[CH:46][C:41]([NH:40][C:36]([C:32]2[C:31](=[O:39])[N:30]([C:27]3[CH:26]=[CH:25][C:24]([F:23])=[CH:29][CH:28]=3)[CH:35]=[CH:34][CH:33]=2)=[O:38])=[CH:42][CH:43]=1
Reactant: O=C(O)c1cccn(-c2ccc(F)cc2)c1=O
Reactant: Cc1ccc(N)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cccn(-c3ccc(F)cc3)c2=O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 273.6 %

Procedure:
TBTU (276 mg, 0.851 mmol) was added to the mixture of 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (147 mg, 0.567 mmol), p-toluidine (73.7 mg, 0.681 mmol), and triethylamine (120 μl, 0.851 mmol) in DMF (3 ml) at rt. The combined mixture was stirred at rt for 16 h. After that time, the solvent was removed to give a black solid (500 mg). It was purified by chromatography on silica gel (15 g) eluting with 40% (100 ml), 50% (100 ml), 60% (100 ml) and 70% (100 ml) EtOAc/hexane to give the title compound as a light-brown solid. 1H NMR (400 MHz, CDCl3): δ=2.31 (s, 3H), 6.58 (dd, J=6.8 & 7.2 Hz, 1H), 7.13 (d, J=8.4 Hz, 2H), 7.23-7.29 (m, 2H), 7.38-7.42 (m, 2H), 7.56-7.63 (m, 3H), 8.74 (dd, J=2.0 & 6.8 Hz, 1H), 11.69 (brs, 1H). MS (ES+): m/z 323.09 [MH+]. HPLC: tR=3.69 min (polar—5 min, ZQ3).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[H][H]>C(O)(C)C.[Pd]>[OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][CH2:9][CH2:8][C:7]2=[O:12]
Reactant: Oc1cccc2c(O)cccc12
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: O=C1CCCc2c(O)cccc21
Temperature: 25 °C
Yield: 59.3 %

Procedure:
To a mixture of 1,5-dihydroxynaphthalene (25.0 g, 156 mmol) in isopropanol (150 mL) and an aqueous (40 mL) solution of sodium hydroxide (6.3 g, 157 mmol) was added 10% palladium on carbon (3.9 g) at room temperature. The reaction mixture was put under 100 psi hydrogen in a Parr autoclave (from Parr Instrument Company) at 80° C. for 20 hours. After being cooled to room temperature, the reaction mixture was filtered through a pad of Celite® (a diatomite filter from World Minerals Inc.), and then washed with isopropanol (200 mL). The combined filtrates were treated with charcoal at 50° C. for 1 hour, and then were filtered through a pad of Celite® (diatomite filter). Isopropanol was removed, and the resulting solution was adjusted to a pH of about 2 by the slow addition of concentrated hydrochloric acid, during which a solid precipitate appeared. The solid was collected, and washed with water (100 mL×2), and then dried under high vacuum at 50° C. to give 5-hydroxy-3,4-dihydro-2H-naphthalen-1-one (15.0 g, 60%) as a dark brown solid, which was used in the next step without further purification. MS cald. (calculated) for C10H10O2 162, obsd. (observed) 163 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]3)[CH2:9][N:8]([C:23]3[C:24]4[C@H:31]([CH3:32])[CH2:30][CH:29]([OH:33])[C:25]=4[N:26]=[CH:27][N:28]=3)[C:5]2=[CH:6][CH:7]=1.[N+:34]([C:37]1[CH:45]=[CH:44][C:40]([C:41](Cl)=[O:42])=[CH:39][CH:38]=1)([O-:36])=[O:35]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]3)[CH2:9][N:8]([C:23]3[C:24]4[C@H:31]([CH3:32])[CH2:30][C@@H:29]([O:33][C:41](=[O:42])[C:40]5[CH:39]=[CH:38][C:37]([N+:34]([O-:36])=[O:35])=[CH:45][CH:44]=5)[C:25]=4[N:26]=[CH:27][N:28]=3)[C:5]2=[CH:6][CH:7]=1
Reactant: C[C@@H]1CC(O)c2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4cc(Cl)ccc43)c21
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H]1C[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)c2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4cc(Cl)ccc43)c21
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 23 %

Procedure:
A solution of tert-butyl 5-chloro-1-((5R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (0.065 g, 0.14 mmol) and TEA (0.038 ml, 0.28 mmol) in DCM was cooled to about 0° C. To the mixture was added 4-nitrobenzoyl chloride (0.031 g, 0.17 mmol). The reaction was stirred at about 0° C. for about 5 minutes, then warmed to about room temperature and stirred for 1.5 hours. The reaction was diluted with DCM and saturated NaHCO3. The combined extracts were washed with brine, dried over MgSO4, filtered and concentrated. The crude residue was purified by column chromatography (30-50% EtOAc/Hexane) to yield tert-butyl 5-chloro-1-((5R,7R)-5-methyl-7-(4-nitrobenzoyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (0.020 g, 23%). LCMS (APCI+) m/z 620, 622 [M+H]+; Rt=4.65 min, and to yield tert-butyl 5-chloro-1-((5R,7S)-5-methyl-7-(4-nitrobenzoyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (0.029 g, 29%). LCMS (APCI+) m/z 620, 622 [M+H]+; Rt=4.66 min.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][NH:8][N:7]=1)[CH3:4].Cl[CH2:19][C:20]1[O:24][N:23]=[C:22]([O:25][CH2:26][C:27]2[N:28]=[C:29]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[O:30][C:31]=2[CH3:32])[CH:21]=1.O>CN(C)C=O>[CH2:3]([O:5][C:6]1[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][N:8]([CH2:19][C:20]2[O:24][N:23]=[C:22]([O:25][CH2:26][C:27]3[N:28]=[C:29]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[O:30][C:31]=3[CH3:32])[CH:21]=2)[N:7]=1)[CH3:4]
Reactant: CCOC(=O)CCc1c[nH]nc1OCC
Reactant: Cc1oc(-c2ccccc2)nc1COc1cc(CCl)on1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2cc(OCc3nc(-c4ccccc4)oc3C)no2)nc1OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
Sodium hydride (60%, oily, 60.0 mg) was added to a solution of ethyl 3-(3-ethoxy-1H-pyrazol-4-yl)propionate (318 mg) and 5-chloromethyl-3-(5-methyl-2-phenyl-4-oxazolylmethoxy)isoxazole (457 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[3-ethoxy-1-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-isoxazolylmethyl]-1H-pyrazol-4-yl]propionate (653 mg, yield: 91%) as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 82–83° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH3:6].[F:7][C:8]([F:36])([F:35])[C:9]1[N:13]2[N:14]=[C:15]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:34]=[CH:33][C:27]([O:28][CH2:29][C:30]([OH:32])=O)=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)[CH2:16][CH2:17][C:12]2=[N:11][N:10]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH3:6])[C:30](=[O:32])[CH2:29][O:28][C:27]1[CH:26]=[CH:25][C:24]([CH:21]2[CH2:22][CH2:23][N:18]([C:15]3[CH2:16][CH2:17][C:12]4[N:13]([C:9]([C:8]([F:7])([F:36])[F:35])=[N:10][N:11]=4)[N:14]=3)[CH2:19][CH2:20]2)=[CH:34][CH:33]=1
Reactant: CNCCOC
Reactant: O=C(O)COc1ccc(C2CCN(C3=Nn4c(nnc4C(F)(F)F)CC3)CC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCN(C)C(=O)COc1ccc(C2CCN(C3=Nn4c(nnc4C(F)(F)F)CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 32 %

Procedure:
N-(2-methoxyethyl)methylamine (25 mg, 0.28 mmol) was added to 2-[4-[1-[3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenoxy]acetic acid (100 mg, 0.24 mmol), HATU (108 mg, 0.28 mmol) and DIPEA (0.123 mL, 0.71 mmol) in DMF (2 mL). The resulting solution was stirred at ambient temperature for 3 hours then purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford N-(2-methoxyethyl)-N-methyl-2-(4-{1-[3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)acetamide (38 mg, 32%) as a solid.
Reaction SMILES: C(O)C.[F:4][C:5]([F:19])([F:18])[C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:13][O:14][C:15](=[O:17])[N:16]=2)[CH:7]=1.[CH:20]([CH:22]=[CH2:23])=[O:21]>C(N(CC)CC)C>[F:19][C:5]([F:4])([F:18])[C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[N:16]([CH2:23][CH2:22][CH:20]=[O:21])[C:15](=[O:17])[O:14][N:13]=2)[CH:7]=1
Reactant: C=CC=O
Reactant: O=c1nc(-c2cc(C(F)(F)F)ccn2)[nH]o1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=CCCn1c(-c2cc(C(F)(F)F)ccn2)noc1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.4 %

Procedure:
To 1 ml of ethanol were added 0.12 g of triethylamine, 0.2 g of 3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-one, and 0.05 g of acrolein, the mixture was stirred at room temperature for 18 hours, and concentrated, and the residue was subjected to silica gel column chromatography to obtain 0.16 g of 3-[3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-on-4-yl]propionaldehyde (present compound (22)).
Reaction SMILES: [C:1]([NH:7][C:8]1[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11])([O:3][CH:4]([CH3:6])[CH3:5])=[O:2].[H][H]>C(O)C.[C].[Pd]>[NH2:17][C:15]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([NH:7][C:1]([O:3][CH:4]([CH3:6])[CH3:5])=[O:2])[CH:16]=1
Reactant: CC(C)OC(=O)Nc1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)OC(=O)Nc1cc(N)ccc1C(=O)O

Procedure:
A solution was prepared by dissolving 13.08 g of 2-carboisopropoxyamino-4-nitrobenzoic acid in 200 ml of ethyl alcohol and was mixed with 3 g of a 10% palladium-carbon catalyst. The resultant reaction mixture was stirred at room temperature in a hydrogen gas atmosphere for 2 hours. Then, the reaction mixture was filtered through a Celite filter and the catalyst on the Celite filter was washed with ethyl alcohol. The entire amount of the filtrate was collected, concentrated and dried under a reduced pressure, and the resultant crude product was recrystallized from an ethyl alcohol-water mixed solvent. The resultant 4-amino-2-carboisopropoxyaminobenzoic acid was obtained in a yield of 11.3 g and exhibited a melting point of 197° C.
Reaction SMILES: Cl.O1CCOCC1.[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][N:15]1[C:23]2[C:18](=[CH:19][C:20]([NH2:24])=[CH:21][CH:22]=2)[CH:17]=[N:16]1.Cl[C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][C:34]=2[F:36])[N:29]=[CH:28][N:27]=1>C(#N)C>[F:36][C:34]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:35]=1[C:26]([NH:24][C:20]1[CH:19]=[C:18]3[C:23](=[CH:22][CH:21]=1)[N:15]([CH2:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][N:8]=1)[N:16]=[CH:17]3)=[N:27][CH:28]=[N:29]2
Reactant: Nc1ccc2c(cnn2Cc2ccccn2)c1
Reactant: Fc1cccc2ncnc(Cl)c12
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Product: Fc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Temperature: 75 °C
Reaction time: 1.5 h
Yield: 71.7 %

Procedure:
4N Hydrogen chloride in dioxane (9.6 ml, 38.4 mmol) was added to a mixture of 1-(pyridin-2-ylmethyl)-1H-indazol-5-amine (8.78 g, 39.2 mmol) and 4-chloro-5-fluoroquinazoline (7 g, 38.4 mmol; prepared as described in WO 2001/094341) in acetonitrile (100 ml). The mixture was stirred at 75° C. for 1.5 hours. After cooling, the mixture was evaporated to dryness. The residue was diluted in 6N methanolic ammonia. The mixture was evaporated to dryness and was diluted in DCM. After filtration of the solids, the filtrate was evaporated to dryness. The residue was purified by chromatography on silica gel (eluant: methanol in DCM) to give 5-fluoro-N-[1-(pyridin-2-ylmethyl)-1H-indazol-5-yl]quinazolin-4-amine as a beige solid (10.2 g, 72%); NMR spectrum (CDCl3) 5.76 (s, 2H), 6.89 (d, 1H), 7.22-7.18 (m, 2H), 7.58-7.45 (m, 3H), 7.72 (m, 2H), 8.11 (s, 1H), 8.21 (s, 1H), 8.47 (m, 1H), 8.60 (d, 1H), 8.68 (s, 1H); Mass spectrum MH+ 371.
Reaction SMILES: [C:1]1([CH2:7][O:8][P:9]([CH2:26][C:27](O)=[O:28])([CH:11]([NH:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(#N)C.[NH:33]1[CH2:47][CH2:46][CH2:45][C@H:34]1[C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36]>C(OCC)(=O)C>[C:1]1([CH2:7][O:8][P:9]([CH2:26][C:27]([N:33]2[CH2:47][CH2:46][CH2:45][C@H:34]2[C:35]([O:37][CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)=[O:36])=[O:28])([CH:11]([NH:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)NC(CCc1ccccc1)P(=O)(CC(=O)O)OCc1ccccc1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)NC(CCc1ccccc1)P(=O)(CC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)OCc1ccccc1
Reaction time: 1 h

Procedure:
1,1-Carbonyldiimidazole (1.8 g., 0.011 mole) is added to a chilled (0°) solution of the product from part (c) (4.6 g., 0.011 mole) in 50 ml. of acetonitrile. The mixture is stirred for one hour at 0° and a solution of L-proline, benzyl ester (2.3 g., 0.011 mole) in 25 ml. of acetonitrile is added. The mixture is stirred at ambient temperature for 16 hours. The solvent is removed in vacuo. The residue is dissolved in 200 ml. of dichloromethane, washed with 5% potassium bisulfate, saturated sodium bicarbonate solution, brine, and dried (MgSO4). The solvent is removed in vacuo to give an oil residue of 6.5 g. Tlc, silica gel, ethyl acetate, shows a major spot at Rf 0.50 visualized with PMA. The residue is chromatographed on silica gel, eluted with dichloromethane/ethyl acetate (9:1) and (4:1) to give 5.4 g. of (±)-1-[(phenylmethoxy)[1-[(ethoxycarbonyl)amino]-3-phenylpropyl]phosphinyl]acetyl]-L-proline, phenylmethyl ester. Tlc shows a single spot at Rf 0.50.
Reaction SMILES: [CH:1]([S:4][C:5]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:6]=1/[CH:7]=[N:8]/[CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])([CH3:3])[CH3:2].C(N(CC)CC)C>ClCCl.[Cl-].[Ti+4].[Cl-].[Cl-].[Cl-]>[CH:1]([S:4][C:5]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:6]=1[CH:7]1[CH:11]([C:12]([O:14][CH3:15])=[O:13])[CH2:10][CH2:9][NH:8]1)([CH3:3])[CH3:2]
Reactant: COC(=O)CCC/N=C/c1cc([N+](=O)[O-])ccc1SC(C)C
Agent: [Ti+4]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1CCNC1c1cc([N+](=O)[O-])ccc1SC(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.8 %

Procedure:
To 20B (12.0 g, 28.2 mmol) and triethylamine (7.86 mL, 56.4 mmol) in dichloromethane at −10° C. was added titanium chloride (113 mL, 1 M in dichloromethane) dropwise under argon. The reaction was stirred at rt for 4 h and then quenched with saturated potassium carbonate. The mixture was filtered through celite and the aqueous layer was extracted with dichloromethane (2×). The organic extracts were combined, washed with brine and dried over sodium sulfate. The solvent was evaporated to give 7.3 g of crude pyrrolidine 20C.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C@H:10]2[CH2:14][N:13]([CH2:15][C:16](=[O:32])[NH:17][C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]4=[O:30])=[CH:20][C:19]=3[F:31])[C@H:12]([C:33](O)=[O:34])[CH2:11]2)=[O:8])=[CH:4][CH:3]=1.[NH2:36][CH2:37][CH2:38][OH:39]>>[OH:39][CH2:38][CH2:37][NH:36][C:33]([C@@H:12]1[CH2:11][C@@H:10]([NH:9][C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:8])[CH2:14][N:13]1[CH2:15][C:16](=[O:32])[NH:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]2=[O:30])=[CH:20][C:19]=1[F:31])=[O:34]
Reactant: O=C(CN1C[C@H](NC(=O)c2ccc(Cl)s2)C[C@H]1C(=O)O)Nc1ccc(-n2ccccc2=O)cc1F
Reactant: NCCO
Product: O=C(CN1C[C@H](NC(=O)c2ccc(Cl)s2)C[C@H]1C(=O)NCCO)Nc1ccc(-n2ccccc2=O)cc1F

Procedure:
Using general procedure D (2S,4R)-4-[(5-chloro-thiophene-2-carbonyl)-amino]—1-{[2-fluoro-4-(2-oxo-pyridin-1-yl)-phenylcarbamoyl]-methyl}-pyrrolidine-2-carboxylic acid (example 12) was coupled with 2-aminoethanol to give (2S,4R)-4-[(5-chloro-thiophene-2-carbonyl)-amino]-1-{[2-fluoro-4-(2-oxo-pyridin-1-yl)-phenylcarbamoyl]-methyl}-pyrrolidine-2-carboxylic acid (2-hydroxy-ethyl)-amide. White solid. MS 562.5 ([M+H]+)
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][N:17]=2)[N:12]=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20].[CH2:22]([O:24][CH:25]([O:30][CH2:31][CH3:32])[CH2:26][CH2:27][CH2:28][NH2:29])[CH3:23]>ClCCl.C(=O)(O)[O-].[Na+]>[CH2:31]([O:30][CH:25]([O:24][CH2:22][CH3:23])[CH2:26][CH2:27][CH2:28][NH:29][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][N:17]=2)[N:12]=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20])[CH3:32]
Reactant: CCOC(CCCN)OCC
Reactant: O=[N+]([O-])c1cnc2cccnc2c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(CCCNc1c([N+](=O)[O-])cnc2cccnc12)OCC
Temperature: 5 °C
Reaction time: 2 h
Yield: 101.8 %

Procedure:
Triethylamine (3.9 mL, 27.9 mmol, 1.2 eq) was added to a suspension of 4-chloro-3-nitro[1,5]naphthyridine (4.87 g, 23.3 mmol, 1.0 eq) in dichloromethane (100 mL). The resulting solution was cooled to 5° C. and 4,4-diethoxybutylamine (5.36 mL, 27.9 mmol, 1.2 eq) was added dropwise over a period of 5 minutes. The reaction mixture was allowed to stir at ambient temperature for 2 hours and then diluted with saturated aqueous sodium bicarbonate (100 mL). The phases were separated and the aqueous phase was extracted with dichloromethane (2×50 mL). The combined organics were dried over magnesium sulfate, filtered, and then concentrated under reduced pressure to provide 7.93 g of (4,4-diethoxybutyl)(3-nitro[1,5]naphthyridin-4-yl)-amine as a red solid.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([I:9])=[CH:7][N:6]=[C:5](N)[CH:4]=1)[CH3:2].N([O-])=O.[Na+].[OH-].[Na+].[ClH:17]>O>[Cl:17][C:5]1[CH:4]=[C:3]([CH2:1][CH3:2])[C:8]([I:9])=[CH:7][N:6]=1
Reactant: CCc1cc(N)ncc1I
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1cc(Cl)ncc1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 49 %

Procedure:
4-ethyl-5-iodopyridin-2-amine (15.0 g, 60.48 mmol) was dissolved in 140 mL conc. HCl. NaNO2 was dissolved in 40 mL of water and added drop wise to the above solution at 0° C. Care was taken to prevent the temperature of the reaction mixture from rising above 0° C. When all of the NaNO2 solution was added, the reaction mixture was allowed to warm up to room temperature and was stirred for a further 2 h at room temperature. Progress of the reaction was monitored by GC and HPLC. The reaction mixture was then re-cooled to 0° C. and the pH was adjusted to pH=12 by the addition of sat. NaOH. The mixture was extracted with dichloromethane (2×200 mL) and the solvent removed under vacuum. The crude was purified by silica gel column chromatography eluting with 5% ethyl acetate/hexanes. 8.0 g of desired product was obtained after purification (49% yield).
Reaction SMILES: [CH3:1][N:2]([CH3:50])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:47][CH3:48])=[C:12]([NH:15][C:16]3[N:17]=[C:18]([NH:35][C:36]4[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[C:37]=4[C:38]([NH:40][CH3:41])=[O:39])[C:19]4[CH:24]=[CH:23][N:22](S(C5C=CC(C)=CC=5)(=O)=O)[C:20]=4[N:21]=3)[CH:13]=2)[CH2:8][C@@H:7]1[CH3:49])=[O:5].[OH-].[Na+].[Na+].[Cl-]>O1CCOCC1.CCOC(C)=O>[CH3:50][N:2]([CH3:1])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:47][CH3:48])=[C:12]([NH:15][C:16]3[NH:21][C:20]4=[N:22][CH:23]=[CH:24][C:19]4=[C:18]([NH:35][C:36]4[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[C:37]=4[C:38]([NH:40][CH3:41])=[O:39])[N:17]=3)[CH:13]=2)[CH2:8][C@@H:7]1[CH3:49])=[O:5]
Reactant: CNC(=O)c1c(F)cccc1Nc1nc(Nc2cc3c(cc2OC)C[C@H](C)N3C(=O)CN(C)C)nc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CNC(=O)c1c(F)cccc1Nc1nc(Nc2cc3c(cc2OC)C[C@H](C)N3C(=O)CN(C)C)[nH]c2nccc1-2
Temperature: 25 °C
Yield: 72.8 %

Procedure:
A solution of 2-({2-{[(2S)-1-(N,N-dimethylglycyl)-2-methyl-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluoro-N-methylbenzamide (254 mg, 0.362 mmol) in dioxane (10 mL) and a 2M aqueous NaOH solution (2 mL) was heated at 80° C. for 6 h. The resulting mixture was allowed to cool to rt, diluted with EtOAc (50 mL) and a saturated NaCl solution (10 mL). The organic layer was concentrated onto Celite and purified by silica gel chromatography using 1-10% MeOH (containing 0.2% NH3)/CH2Cl2 to afford 2-[(2-{[(2S)-1-(N,N-dimethylglycyl)-2-methyl-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluoro-N-methylbenzamide as a pink solid (144 mg, 73%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.25 (d, J=5.49 Hz, 3H), 2.27 (s, 6H), 2.59 (d, J=15.57 Hz, 1H), 2.80 (d, J=4.40 Hz, 3H), 3.08 (d, J=14.28 Hz, 1H), 3.21-3.46 (m, 2H), 3.80 (s, 3H), 4.71-4.85 (m, 1H), 6.27-6.34 (m, 1H), 6.83-7.08 (m, 3H), 7.26-7.44 (m, 1H), 7.54 (s, 1H), 8.33 (d, J=8.06 Hz, 1H), 547.40; Optical rotation −11.4 (1 mg/mL MeOH, rt).