Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[S:5][C:6]([CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:7](/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]=1)([CH3:3])[CH3:2].CO[CH:24](OC)[N:25]([CH3:27])[CH3:26]>>[CH3:24][N:25]([CH:27]=[C:17]([C:6]1[S:5][C:4]([CH:1]([CH3:3])[CH3:2])=[N:8][C:7]=1/[CH:9]=[CH:10]/[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:18]([O:20][CH3:21])=[O:19])[CH3:26]
Reactant: COC(OC)N(C)C
Reactant: COC(=O)Cc1sc(C(C)C)nc1/C=C/c1ccccc1
Product: COC(=O)C(=CN(C)C)c1sc(C(C)C)nc1/C=C/c1ccccc1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A mixture of 3.1 g of the product of Step E and 30 ml of dimethylformamide dimethyl acetal was heated to 50° C. and after 5 hours at this temperature, the mixture was allowed to return to 20° to 25° C. The mixture was stirred for 16 hours and then was brought to dryness. The residue was chromatographed on silica, eluting with a hexane-ethyl acetate mixture (8-2) to obtain after evaporation of the solvents, 2 g of the desired product. Thin layer chromatography; Rf=0.15 [eluant: hexane-ethyl acetate (8-2)]
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[C:3]([O:5][CH2:6][CH2:7][O:8][C:9](OC1C=CC(S(C)(=O)=O)=CC=1)=[O:10])=[O:4].[CH2:23]1[CH2:28][CH2:27][C:26]([CH2:33][NH2:34])([CH2:29][C:30]([OH:32])=[O:31])[CH2:25][CH2:24]1.C(=O)(O)[O-].[K+]>C(#N)C.C(OCC)C>[CH3:1][CH:2]([CH3:22])[C:3]([O:5][CH2:6][CH2:7][O:8][C:9]([NH:34][CH2:33][C:26]1([CH2:29][C:30]([OH:32])=[O:31])[CH2:25][CH2:24][CH2:23][CH2:28][CH2:27]1)=[O:10])=[O:4]
Reactant: NCC1(CC(=O)O)CCCCC1
Reactant: CC(C)C(=O)OCCOC(=O)Oc1ccc(S(C)(=O)=O)cc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: CC(C)C(=O)OCCOC(=O)NCC1(CC(=O)O)CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.9 %

Procedure:
A 50 mL, single-neck, round-bottomed flask equipped with a magnetic stir bar and a nitrogen inlet was charged with sulfone D3 (300 mg, 1 mmol) and gabapentin (171 mg, 1 mmol) in acetonitrile (1 mL). To the resulting slurry, saturated aqueous potassium bicarbonate (1 mL) was slowly added over a period of two minutes. The reaction mixture was stirred overnight at room temperature. The reaction mixture was then poured into a separatory funnel, diluted with diethyl ether (20 mL), washed with 5% aqueous sulfuric acid (10 mL), water (10 mL), and brine (100 mL). The organic phase was dried over sodium sulfate and evaporated under vacuum to give a viscous oil. The crude product was purified by column chromatography using ethyl acetate and hexane to give the title compound E4 as a viscous oil (250 mg, 75% yield). 1H NMR (CDCl3, 400 MHz): δ 1.16 (d, J=6.8 Hz, 6H), 1.35-1.55 (m, 10H), 1.46 (d, J=5.2 Hz, 3H), 2.32 (s, 2H), 2.52 (m, 1H), 3.23 (d, J=6.8 Hz, 2H), 5.27 (t, J=6.4 Hz, 1H, —NH) 6.76 (q, J=5.6 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:15]O>[Pd]>[NH2:12][C:9]1[CH:10]=[CH:11][C:2]([O:1][CH3:15])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: CO
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1O
Agent: [Pd]
Product: COC(=O)c1cc(N)ccc1OC

Procedure:
The hydrogenation of methyl 2-hydroxy-5-nitrobenzoate (700 mg, 3.3 mmol) using 10% Pd—C (100 mg) and Na7SO4 (100 mg) in MeOH at 50 psi gave methyl 5-amino-2-methoxybenzoate (600 mg).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[O:10]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]3[N:21]=[C:22]([NH2:24])[N:23]=[C:19]3[CH:18]=[CH:17][CH:16]=2)=[CH:11]1.CC(C)([O-])C.[Na+].CCOCC>C1COCC1>[O:10]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]3[N:21]=[C:22]([NH:24][C:1](=[O:9])[C:2]4[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=4)[N:23]=[C:19]3[CH:18]=[CH:17][CH:16]=2)=[CH:11]1
Reactant: O=C(O)c1cccnc1
Reactant: Nc1nc2cccc(-c3ccoc3)n2n1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(Nc1nc2cccc(-c3ccoc3)n2n1)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.3 %

Procedure:
A solution of nicotinic acid (74 mg, 0.6 mmol, 1.2 eq.) and 1,1-carbonyldiimidazole (122 mg, 0.75 mmol, 1.5 eq.) in dry THF (1 mL) was stirred for 45 min. at rt. In parallel, a solution of 5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 100 mg; 0.50 mmol; 1.0 eq.) and sodium tert-butoxide (96 mg, 1.0 mmol, 2.0 eq.) in dry THF (2 mL) was stirred for 45 min. at rt. The two solutions were then combined and the reaction mixture was stirred overnight at rt. Et2O was then added and the precipitate obtained was filtered, washed with Et2O, THF, a 5N solution of NaOH and water. It was resuspended in an acidic aqueous solution (pH 1) and filtered to give the title compound as a white powder (52.4 mg, 31%). HPLC, Rt: 1.98 min. (purity 95.1%). LC/MS, M+(ESI): 306.1, M−(ESI): 304.1.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[C:14]1[N:15]([CH3:19])[N:16]=[CH:17][CH:18]=1.[Cl:21][C:22]1[CH:23]=[C:24]([N:28]=[C:29]=[O:30])[CH:25]=[CH:26][CH:27]=1>C(Cl)Cl>[Cl:21][C:22]1[CH:23]=[C:24]([NH:28][C:29]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:20])=[C:8]([C:14]3[N:15]([CH3:19])[N:16]=[CH:17][CH:18]=3)[CH:9]=2)=[O:30])[CH:25]=[CH:26][CH:27]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: CN(C)CCCOc1ccc(N)cc1-c1ccnn1C
Solvent: ClCCl
Product: CN(C)CCCOc1ccc(NC(=O)Nc2cccc(Cl)c2)cc1-c1ccnn1C
Reaction time: 2 h
Yield: 41.9 %

Procedure:
To a solution of 4-(3-dimethylamino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (47.4 mg, 0.173 mmol) in CH2Cl2 (2 mL) was added 3-chlorophenyl isocyanate (0.24 μL, 0.197 mmol) and stirred for two hours. The resulting material was purified by solid phase extraction (SCX, 1 gram cartridge), eluting with methanol (30 mL) followed by 2M NH3 in methanol (30 mL). The NH3 containing fractions were dried in vacuo to afford Compound 134 as a colorless solid (31.0 mg, 42%). LCMS m/z (%)=428 (M+H35Cl, 100), 430 (M+H37Cl, 39), 1H NMR (400 MHz, DMSO-d6) δ: 8.64 (bs, 1H), 8.59 (bs, 1H), 7.47-7.41 (m, 3H), 7.45 (d, J=1.79 Hz, 1H), 7.37 (d, J=2.71 Hz, 1H), 7.30-7.23 (m, 2H), 7.09 (d, J=8.97 Hz, 1H), 6.98-6.92 (m, 1H), 6.24 (d, J=1.85 Hz, 1H), 3.97 (t, J=6.36 Hz, 2H), 3.66 (s, 3H), 2.19 (t, J=7.04 Hz, 2H), 2.07 (s, 6H), 1.77-1.69 (m, 2H).
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[N:12]=[CH:11][NH:10][C:9]3=O)[CH:5]=[CH:4][N:3]=[CH:2]1.P(Cl)(Cl)([Cl:19])=O>CN(C=O)C>[Cl:19][C:9]1[C:8]2[C:13](=[CH:14][CH:15]=[C:6]([N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)[CH:7]=2)[N:12]=[CH:11][N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2ccc(-n3ccnc3)cc12
Solvent: CN(C)C=O
Product: Clc1ncnc2ccc(-n3ccnc3)cc12

Procedure:
6-(1-Imidazolyl)-3,4-dihydroquinazolin-4-one (1.0 g) was dissolved in phosphorus oxychloride (15 ml). DMF (2 drops) was added and the mixture was heated at reflux for 1 hour. The mixture was evaporated, the residue was dissolved in methylene chloride, washed with sodium bicarbonate solution and the organic layer was dried (MgSO4) and evaporated to give 4-chloro-6-(1-imidazolyl)quinazoline (0.36 g) which was used without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[I:9].[F:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[OH:18].C1CCN2C(=NCCC2)CC1.[OH-].[Na+]>CN1C(=O)CCC1>[F:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[O:18][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[I:9]
Reactant: Nc1nccc(Cl)c1I
Reactant: Oc1cc(F)ccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1nccc(Oc2cc(F)ccc2F)c1I
Temperature: 170 °C
Reaction time: 6 h
Yield: 62.1 %

Procedure:
4-chloro-3-iodopyridin-2-amine (3.00 g, 11.79 mmol), 2,5-difluoro phenol (4.60 g, 35.4 mmol), DBU (1.777 ml, 11.79 mmol) were combined in NMP (15 mL) and solution was stirred at 170° C. for 6 h under microwave irradiation. The crude reaction mixture was poured into 1N NaOH solution (70 mL), the resultant suspension was filtered, washed with water (5×10 mL) and dried to afford crude product which was purified by silica gel chromatography (EtOAc-hexanes) to afford 4-(2,5-difluorophenoxy)-3-iodopyridin-2-amine as white solid. (2.55 g, 62.1% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.74 (d, J=7.6 Hz, 1H), 7.47 (m, 1H), 7.28 (m, 1H), 7.18 (On, 1H), 6.25 (br s, 2H), 5.88 (dd, J=5.6 Hz, 1H); MS (ESI) m/z: 349.03 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([N:12]2[C:21]3[C:16](=[CH:17][C:18]([CH:27]([F:29])[F:28])=[C:19]([CH:22](OC)[O:23]C)[N:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])=[N:7][CH:8]=1)#[N:2].Cl.C([O-])(O)=O.[Na+]>C1COCC1.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([N:12]2[C:21]3[C:16](=[CH:17][C:18]([CH:27]([F:28])[F:29])=[C:19]([CH:22]=[O:23])[N:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])=[N:7][CH:8]=1)#[N:2]
Reactant: COC(OC)c1nc2c(cc1C(F)F)CCCN2C(=O)Nc1ccc(C#N)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(NC(=O)N2CCCc3cc(C(F)F)c(C=O)nc32)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-(5-cyanopyridin-2-yl)-6-(difluoromethyl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 35, 11 mg, 0.027 mmol) in THF (0.5 ml) and H2O (0.1 ml) was added conc. HCl (0.017 ml), the reaction mixture was stirred at room temperature for 8 h, then conc. HCl (0.033 ml) was added and the reaction mixture was stirred for 20 h. The reaction mixture was poured into sat. aq. NaHCO3 and extracted with DCM (3×). The organic phase was then dried over Na2SO4, filtered and evaporated to give the title compound as a colorless solid.
Reaction SMILES: O=[C:2]([CH2:7][C:8](=[O:10])[CH3:9])[C:3]([O:5][CH3:6])=[O:4].C[O-].[Na+].Br[C:15](=[N:20][NH:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[CH2:24][CH2:23]1)[C:16]([F:19])([F:18])[F:17].C([O-])(O)=O.[Na+]>CO.CCOC(C)=O>[C:8]([C:7]1[C:15]([C:16]([F:19])([F:18])[F:17])=[N:20][N:21]([CH:22]2[CH2:23][CH2:24][N:25]([C:28]([O:30][CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[O:29])[CH2:26][CH2:27]2)[C:2]=1[C:3]([O:5][CH3:6])=[O:4])(=[O:10])[CH3:9]
Reactant: O=C(OCc1ccccc1)N1CCC(NN=C(Br)C(F)(F)F)CC1
Reactant: COC(=O)C(=O)CC(C)=O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1c(C(C)=O)c(C(F)(F)F)nn1C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 38.6 %

Procedure:
To a stirred solution of Methyl 2,4-dioxopentanoate (892 mg, 6.19 mmol) in MeOH (11.5 mL) at room temperature was added Sodium methoxide (25% in MeOH, 0.891 mL, 4.13 mmol). Then a solution of 111 (842 mg, 2.063 mmol) in MeOH (2.3 mL) was added drop-wise and the suspension was stirred for 10 min at room temperature, then for 2 h at 65° C. After cooling, the mixture was taken to dryness and AcOEt and saturated NaHCO3 were added, the organic layer was separated, dried over MgSO4, filtrated and evaporated and the residue was purified via Biotage (10% to 40% EtOAc/Hexane; 25S column) to afford 112 (361 mg, 38.6% yield) as red oil. LRMS (ESI): calc. 453.4; found 454.2 (MH)+.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][NH:16][CH2:15][C:14]3=[O:19])=[CH:10][C:5]=2[CH2:4][O:3]1.O=[C:21]1[CH2:30][CH2:29][C:28]2[CH:27]=[C:26]([C:31]#[N:32])[CH:25]=[CH:24][C:23]=2[CH2:22]1>>[O:19]=[C:14]1[N:13]([CH2:12][CH2:11][C:9]2[CH:8]=[CH:7][C:6]3[C:2](=[O:1])[O:3][CH2:4][C:5]=3[CH:10]=2)[CH2:18][CH2:17][N:16]([CH:21]2[CH2:30][CH2:29][C:28]3[CH:27]=[C:26]([C:31]#[N:32])[CH:25]=[CH:24][C:23]=3[CH2:22]2)[CH2:15]1
Reactant: N#Cc1ccc2c(c1)CCC(=O)C2
Reactant: O=C1OCc2cc(CCN3CCNCC3=O)ccc21
Product: N#Cc1ccc2c(c1)CCC(N1CCN(CCc3ccc4c(c3)COC4=O)C(=O)C1)C2

Procedure:
The title compound was prepared from 1-[2-(1-Oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-2-one and 6-Oxo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile following essentially the same procedure as Example 6. The product was purified by mass-directed reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 416 [M+1]+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:11]1[CH:15]=[C:14]([CH2:16][CH2:17][C:18](O)=[O:19])[N:13]=[CH:12]1>>[C:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:18](=[O:19])[CH2:17][CH2:16][C:14]2[N:13]=[CH:12][NH:11][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCc1c[nH]cn1
Reactant: NCCCc1ccccc1
Product: O=C(CCc1c[nH]cn1)NCCCc1ccccc1

Procedure:
The preparation is carried out as in Example 1 with 3-phenylpropanamine and 3-(1H-imidazol-4-yl)propanoic acid, the acid being here added after the reaction of the amine component with N,N′-carbonyldiimidazole. The title compound is extracted from water with diethyl ether, purified by chromatography and recrystallized in the hydrogenmaleate form from ethanol/diethyl ether.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]([NH2:25])=[N:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=1[F:24])=O)[CH3:2].O>N1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:5]1[NH:25][C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=2[F:24])=[N:7][N:6]=1)=[O:26])[CH3:2]
Reactant: CCOC(=O)C(N)=NNC(=O)c1ccncc1Nc1ccc(I)cc1F
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)c1nnc(-c2ccncc2Nc2ccc(I)cc2F)[nH]1

Procedure:
Amino-{[3-(2-fluoro-4-iodo-phenylamino)-pyridine-4-carbonyl]-hydrazono}-acetic acid ethyl ester (1.6 g, 3.4 mmo) in pyridine (10 mL) was stirred at 140° C. for 3 hrs. Cooled, poured into water, Extracted with EtOAc, Combined the organic layer, and washed with Brine, dried over MgSO4, filtered, removed off solvent, got crude product, which was subjected to silica gel column (Hex:EtOAc=1:1). Collected final product 1.02 g. [5.23 min, 454 (M+1)]
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:4]=1[NH2:5])[CH3:2].[Br:11][CH2:12][CH2:13][C:14](Cl)=[O:15].O.O.O.C([O-])(=O)C.[Na+]>C(O)(=O)C.O>[Br:11][CH2:12][CH2:13][C:14]([NH:5][C:4]1[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:3]=1[CH2:1][CH3:2])=[O:15]
Reactant: O=C(Cl)CCBr
Reactant: CCc1cccc(C)c1N
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCc1cccc(C)c1NC(=O)CCBr
Reaction time: 0.5 h

Procedure:
In a glass-stoppered bottle, a solution of 2-ethyl-6-methylaniline (15.0 g, 0.111 mole) in glacial acetic acid (95 ml) was cooled to 13° C. and 3-bromo-propionyl chloride (21.1 g, 0.122 mole) was added. The mixture was mixed and was combined immediately with a cooled (3° C.) solution of sodium acetate trihydrate (36.9 g) in water (150 ml). The mixture was shaken vigorously for 30 min. The white product that formed was filtered off, washed carefully with water, and dried. This product, i.e., 3-bromo-2'-ethyl-6'-methylpropionanilide (27.4 g, 91%), melted at 149°-150° C. and was sufficiently pure for the next step.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:21][C:22]2[CH:26]=[C:25]([O:27][CH:28]([CH3:30])[CH3:29])[NH:24][N:23]=2)=[N:4][C:5]([NH:10][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:12][OH:13])=[C:6]([CH:9]=1)[C:7]#[N:8].[OH-:31].[K+].OO>CO>[F:1][C:2]1[C:3]([NH:21][C:22]2[CH:26]=[C:25]([O:27][CH:28]([CH3:30])[CH3:29])[NH:24][N:23]=2)=[N:4][C:5]([NH:10][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:12][OH:13])=[C:6]([CH:9]=1)[C:7]([NH2:8])=[O:31]
Reactant: CC(C)Oc1cc(Nc2nc(N[C@@H](CO)c3ccc(F)cc3)c(C#N)cc2F)n[nH]1
Reactant: [OH-]
Agent: OO
Agent: [K+]
Solvent: CO
Product: CC(C)Oc1cc(Nc2nc(N[C@@H](CO)c3ccc(F)cc3)c(C(N)=O)cc2F)n[nH]1
Temperature: 65 °C
Yield: 85.6 %

Procedure:
(R)-5-Fluoro-2-(1-(4-fluorophenyl)-2-hydroxyethylamino)-6-(5-isopropoxy-1H-pyrazol-3-ylamino)nicotinonitrile (Example 11; 0.06 g, 0.1 mmol) was placed in MeOH (5 ml) at 25° C. A 25% aqueous solution (0.2 ml) of KOH (0.05 g, 0.7 mmol) was then added, followed by the addition of 0.05 ml of 30% H2O2. The resulting dark red solution was heated to 65° C. for 1 h, cooled to 25° C., and concentrated. The resulting residue was dissolved in EtOAc (50 ml), washed with water (30 ml), dried, filtered, and concentrated. The resulting solid was purified by column chromatography (DCM-MeOH=30:1) to give the title compound (0.037 g, 60%). 1H NMR (400 MHz, CD3OD) δ 7.75 (d, J=11.9 Hz, 1H), 7.43-7.39 (m, 2H), 7.06-7.02 (m, 2H), 5.37 (br s, 1H), 5.10-5.02 (m, 1H), 4.60-4.54 (m, 1H), 3.90-3.86 (m, 1H), 3.79-3.74 (m, 1H), 1.32 (d, J=6.0 Hz, 6H). MS: Calcd.: 432. Found: [M+H]+433.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)=[N:15][N:16]4[C:21]([NH:22][CH2:23][C:24]([O:26]C)=[O:25])=[CH:20][CH:19]=[CH:18][C:17]=34)[CH:10]=[C:9]([CH3:35])[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Li+]>O1CCCC1.CO>[CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:28]4[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=4)=[N:15][N:16]4[C:21]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:20][CH:19]=[CH:18][C:17]=34)[CH:10]=[C:9]([CH3:35])[N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)CNc1cccc2c(-c3cc(C)nc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nn12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(-c2c(-c3ccc(F)cc3)nn3c(NCC(=O)O)cccc23)nc(NC2CCCC2)n1
Yield: 95 %

Procedure:
To a room temperature solution of methyl {[3-[2-(cyclopentylamino)-6-methyl-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-7-yl]amino}acetate (76 mg, 0.16 mmol) in tetrahydrofuran (3 mL) and methanol (1 mL) was added lithium hydroxide (1 mL, 1.0 M in water, 1 mmol). The resultant mixture was stirred at room temperature for 24 hours then concentrated in vacuo. The residue was suspended in ether and acidified with aqueous hydrochloric acid (4N). The solids were filtered and azeotroped twice with methanol in vacuo to provide the hydrochloride salt of {[3-[2-(cyclopentylamino)-6-methyl-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-7-yl]amino}acetic acid (70 mg, 95%) as a yellow solid.1H NMR (CDCl3) δ 7.72–7.34 (m, 7H), 6.40–6.26 (m, 2H), 4.17–4.04 (m, 3H), 2.20 (s, 3H), 1.88 (m, 2H), 1.69 (m, 2H), 1.54 (m, 4H); 19F NMR (CDCl3) δ −112.96; MS m/z 461 (M+1).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:23])([O:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=1)[C@@H:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[OH:6].[F:24][C:25]([F:31])([F:30])[S:26](Cl)(=[O:28])=[O:27]>CCCCC.C(OCC)C>[F:23][C:4]([F:3])([O:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=1)[C@H:5]([O:6][S:26]([C:25]([F:31])([F:30])[F:24])(=[O:28])=[O:27])[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1
Reactant: CSc1ccc(OC(F)(F)[C@H](O)c2ccc(F)cc2)cc1
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCCCC
Product: CSc1ccc(OC(F)(F)[C@H](OS(=O)(=O)C(F)(F)F)c2ccc(F)cc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 77 %

Procedure:
NaH (60% in oil, 1.54 g, 4.9 mmol) was washed several times with pentane, under nitrogen and then suspended in anhydrous ethyl ether (10 m) and cooled at 0° C. A solution of 2,2-difluoro-1(R)-(4-fluorophenyl)-2-(4-methylsulfanylphenoxy)ethanol in ethyl ether (10 ml) was added. After stirring the reaction mixture for 15 min, trifluoromethylsulfonyl chloride was added and the resulting mixture was stirred for 2 h at 0° C. The reaction mixture was diluted with hexanes (20 ml) and washed with saturated solution of NaHCO3 and brine. After drying over magnesium sulfate, the solution was concentrated to give trifluoromethanesulfonic acid 2,2-difluoro-1(R)-(4-fluorophenyl)-2-(4-methylsulfanylphenoxy)ethyl ester (1.70 g, 77%) as an oil.
Reaction SMILES: [Br:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:27]=[CH:26][C:14]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:13][CH:12]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:10][C:11]1[CH:27]=[CH:26][C:14]([O:15][C:16]2[CH:17]=[CH:18][C:19]([S:22]([NH:8][C:7]3[C:2]([Br:1])=[N:3][CH:4]=[C:5]([Br:9])[CH:6]=3)(=[O:24])=[O:23])=[CH:20][CH:21]=2)=[CH:13][CH:12]=1
Reactant: Nc1cc(Br)cnc1Br
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccc(Cl)cc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1cc(Br)cnc1Br)c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 25 °C

Procedure:
To a solution of 2,5-dibromo-3-aminopyridine (0.51 g, 2.0 mmol) and 4-(4-chloro-phenoxy)-benzenesulfonyl chloride (0.76 g, 2.0 mmol) in dry CH2Cl2 (10 mL) was added pyridine (1 mL) at 0 C. The resulting mixture was allowed to warm to room temperature and stirred until TCL showed the completion of the reaction. The reaction mixture was diluted with CH2Cl2 and washed with aqueous HCl solution. After the pyridine was neutralized, the organics were washed with water, brine and dried over anhydrous Na2SO4. The filtration (Celite) and concentration under vacuo gave a crude material, which was purified by silica column (30% EtOAc/hexanes). MS: 516, 518 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[NH:9][CH:10]=[CH:11][C:3]=12.[I:12]N1C(=O)CCC1=O>CN(C)C=O>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[NH:9][CH:10]=[C:11]([I:12])[C:3]=12
Reactant: Fc1cnc2[nH]ccc2c1Cl
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: Fc1cnc2[nH]cc(I)c2c1Cl

Procedure:
To a solution of 4-chloro-5-fluoro-1H-pyrrolo[2,3-b]pyridine (1.8 g, 10.5 mmol) in N,N-dimethylformamide (25 mL) at 0° C. was added N-iodosuccinimide (2.37 g, 10.55 mmol). The mixture was slowly brought to room temperature, quenched with brine and extracted with ethyl acetate (twice). The organic phase was concentrated and purified by column chromatography (silica gel, 30% ethyl acetate in hexane) to afford the title compound. MS (ESI+) m/z 297 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([P:16]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:20][CH:19]=3)Cl)=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1COCC1>[C:27]1([CH2:26][CH2:25][CH2:24][C:21]2[CH:22]=[CH:23][C:18]([PH:16][C:13]3[CH:12]=[CH:11][C:10]([CH2:9][CH2:8][CH2:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:15][CH:14]=3)=[CH:19][CH:20]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: ClP(c1ccc(CCCc2ccccc2)cc1)c1ccc(CCCc2ccccc2)cc1
Solvent: C1CCOC1
Product: c1ccc(CCCc2ccc(Pc3ccc(CCCc4ccccc4)cc3)cc2)cc1

Procedure:
Di[p-(3-phenylpropyl)phenyl]chlorophosphine 1 (6.0 g, 13.1 mmol) was dissolved in 150 ml THF and Li (0.185 g, 26.2 mmol) was chopped directly into the reaction flask under Ar. A deep red solution was resulted in 10 min and all the lithium was consumed in 4 h. The solvent was removed by vacuum and 100 ml diethyl ether was added. The organic phase was washed 3×20 ml H2O and dried over MgSO4. Ether was then removed by vacuum and the final product was obtained as a pale yellow oil with quantitative yield. 2 was characterized by 31P NMR. -42.5, 'JH-P =211 Hz.
Reaction SMILES: C(OC([NH:11][CH:12]([CH2:23][CH2:24][P:25]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][C:37]([O:39]CC2C=CC=CC=2)=[O:38])[CH:31]=1)([O:27][CH3:28])=[O:26])[C:13]([O:15]CC1C=CC=CC=1)=[O:14])=O)C1C=CC=CC=1.[H][H]>CO.O.[C].[Pd]>[NH2:11][CH:12]([CH2:23][CH2:24][P:25]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][C:37]([OH:39])=[O:38])[CH:31]=1)([O:27][CH3:28])=[O:26])[C:13]([OH:15])=[O:14]
Reactant: COP(=O)(CCC(NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)Oc1cccc(CC(=O)OCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: O
Product: COP(=O)(CCC(N)C(=O)O)Oc1cccc(CC(=O)O)c1
Yield: 51.2 %

Procedure:
Next, 0.72 g (1.12 mmol) of benzyl 2-(N-benzyloxycarbonylamino)-4-{[3-(benzyloxycarbonylmethyl)phenyl](methyl)phosphono}butanoate was dissolved in 24 mL of a solvent mixture of methanol and water at 5:1 and mixed with 200 mg of 5% palladium-carbon, and hydrogen gas was introduced at room temperature for 2.5 hours. Thereafter, the palladium-carbon was removed by Celite filtration and the filtrate was vacuum-concentrated and the residue was freeze-dried from water to obtain 2-amino-4-{[3-(carboxymethyl)phenyl] (methyl)phosphono}butanoic acid (0.19 g, yield 51%) as a colorless solid.