Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][CH2:14][C:15]3[N:19]4[N:20]=[C:21]([C:24]#[C:25][Si](CC)(CC)CC)[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[N:5][CH:4]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C(O)(=O)C>[C:24]([C:21]1[CH:22]=[CH:23][C:18]2[N:19]([C:15]([CH2:14][NH:13][C:7]3[C:6]4[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][N:5]=4)[N:10]=[CH:9][CH:8]=3)=[N:16][N:17]=2)[N:20]=1)#[CH:25]
Reactant: CC[Si](C#Cc1ccc2nnc(CNc3ccnc4cc(OC)cnc34)n2n1)(CC)CC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Product: C#Cc1ccc2nnc(CNc3ccnc4cc(OC)cnc34)n2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7-methoxy-N-((6-(2-(triethylsilyl)ethynyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-1,5-naphthyridin-4-amine (0.360 g, 0.808 mmol) in acetic acid (8 mL) was added TBAF (1.21 ml, 1.21 mmol). The mixture was stirred at room temperature overnight, additional TBAF (1.21 ml, 1.21 mmol) was added and the mixture was heated to 50° C. for five hours. The mixture was concentrated and purified via MPLC (eluted with 0-10% (1:10:90 NH4OH:MeOH:DCM) in dichloromethane) to yield the product as an off-white solid. MS m/z=332.0 [M+1]+. Calc'd for C17H13N7O: 331.1.
Reaction SMILES: [C:1]1([S:7][C@@H:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]2O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)C(C)C)(C)C.CS(Cl)(=O)=O.C1OCCOCCOCCOCCOC1.[N-:44]=[N+:45]=[N-:46].[Na+]>ClCCl.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[N:44]([C@@H:9]1[CH2:10][CH2:11][CH2:12][CH2:13][C@H:8]1[S:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[N+:45]=[N-:46]
Reactant: [N-]=[N+]=[N-]
Reactant: O[C@@H]1CCCC[C@H]1Sc1ccccc1
Agent: C1COCCOCCOCCOCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: [N-]=[N+]=N[C@@H]1CCCC[C@H]1Sc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 0° C. solution of Example 7A (1.04 g, 5.0 mmol), and N,N-diisopropylethylamine (1.1 mL, 6.5 mmol) in dichloromethane (20 mL) was treated with methanesulfonyl chloride (0.46 mL, 6.0 mmol), warmed to room temperature, stirred for 16 hours, diluted with hexanes (20 mL), filtered through a pad of silica gel (15 g) with 10% diethyl ether in hexanes, and concentrated. The concentrate was dissolved in DMF (10 mL), treated with tetrabutylammonium iodide (400 mg, 1.1 mmol), 15-crown-5 (100 mg, 0.40 mmol), and sodium azide (1.0 g, 15.4 mmol), heated to 100° C., and stirred for 16 hours. The mixture was diluted with ethyl acetate (100 mL), washed with water (15 mL) and brine (15 mL), dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 5% ethyl acetate/hexanes to provide the desired product. MS (DCI) m/e 234 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[Br-].[CH2:23]([Zn+])[CH:24]([CH3:26])[CH3:25].[OH-].[Na+].CO>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].[Cu]I.C1COCC1>[CH2:23]([C:2]1[CH:3]=[CH:4][C:5]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8])[CH:24]([CH3:26])[CH3:25]
Reactant: COC(=O)c1cc(Br)ccc1NS(=O)(=O)c1ccccc1
Reactant: CC(C)C[Zn+]
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)Cc1ccc(NS(=O)(=O)c2ccccc2)c(C(=O)O)c1
Temperature: 160 °C

Procedure:
A mixture of Example 4A (0.09 g, 0.24 mmol), Pd(dppf)Cl2 (5 mol %), and CuI (6 mol %) was sealed using a crimper and treated with a solution of isobutylzinc bromide (0.5M in THF, 0.96 mL, 0.48 mmol). The reaction was heated in a single-mode microwave cavity in the Smith synthesizer at 160° C. for 600 seconds and filtered through a 1 micron PTFE syringe filter. The filtrate was concentrated, dissolved in 1:1 CH3OH:DMSO (1.5 mL), and purified using a C18 reverse-phase HPLC with acetonitrile/water/1% TFA. The purified ester was saponified by treatment with 10 equivalents of 2N NaOH in 1:1 CH3OH:THF at 70° C. for 48 hours. The mixture was extracted with ethyl acetate and the extract was concentrated to provide the desired product. MS (ESI(+)) m/e 334 (M+H)+, 351 (M+NH4)+, 356 (M+Na)+; 1H NMR (300 MHz, DMSO-d6) δ 10.90 (s, 1H), 7.80 (m, 2H), 7.40 (m, 3H), 7.10 (s, 1H), 6.80 (m, 1H), 6.50 (m, 1H), 2.20 (d, 2H), 1.70 (m, 1H), 0.80 (d, 6H).
Reaction SMILES: C([O:3][C:4](=[O:28])[CH:5]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:6][C:7]1[N:8]([CH2:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[CH:14]=2)[CH:9]=[CH:10][N:11]=1)C.Cl>C1COCC1>[CH2:21]([CH:5]([CH2:6][C:7]1[N:8]([CH2:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[CH:14]=2)[CH:9]=[CH:10][N:11]=1)[C:4]([OH:28])=[O:3])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)C(Cc1ccccc1)Cc1nccn1Cc1cc(Cl)cc(Cl)c1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(O)C(Cc1ccccc1)Cc1nccn1Cc1cc(Cl)cc(Cl)c1
Temperature: 75 °C
Yield: 55.7 %

Procedure:
To a solution of 2-benzyl-3-[1-(3,5-dichloro-benzyl)-1H-imidazol-2-yl]-propionic acid ethyl ester (50 mg, 0.12 mmol) in THF (3 mL) was added 6 N HCl (3 mL). The mixture was heated at 75° C. for 14 h with vigorous stirring. The reaction was concentrated in vacuo and the residue washed with Et2O then dried in vacuo to provide the hydrochloride salt of 2-benzyl-3-[1-(3,5-dichloro-benzyl)-1H-imidazol-2-yl]-propionic acid (26 mg, 84%) as a white solid: ESI MS m/z 389 [C20H18Cl2N2O2+H]+.
Reaction SMILES: O=C1CCC(=O)N1O[C:9]([C:11]1[O:15][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])=[N:13][C:12]=1[CH3:23])=[O:10].[N:24]1([C:30]2[N:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=2)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[N:24]1([C:30]2[N:35]=[CH:34][C:33]([NH:36][C:9]([C:11]3[O:15][C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[CH3:22])=[N:13][C:12]=3[CH3:23])=[O:10])=[CH:32][CH:31]=2)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: Nc1ccc(N2CCOCC2)nc1
Reactant: Cc1ccccc1-c1nc(C)c(C(=O)ON2C(=O)CCC2=O)o1
Product: Cc1ccccc1-c1nc(C)c(C(=O)Nc2ccc(N3CCOCC3)nc2)o1

Procedure:
With a procedure similar to example 50 above, 4-methyl-2-o-tolyl-oxazole-5-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide was prepared from 4-methyl-2-o-tolyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester and 6-morpholin-4-yl-pyridin-3-ylamine. LCMS calcd for C21H22N4O3 (m/e) 378, obsd 379 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][C:5]#[N:6].[N:11]([O-])=O.[Na+]>Cl>[C:5]([C:4]1[C:3]2[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=2)[NH:1][N:11]=1)#[N:6]
Reactant: N#CCc1ccccc1N
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Product: N#Cc1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of o-aminobenzyl cyanide (0.5 g) in aqueous hydrochloric acid 1N (9.6 mL), was treated with a solution of aqueous sodium nitrite 1N (3.85 mL). After stirring at room temperature for 15 minutes, the reaction mixture was filtered. The solid was recrystallised from ethanol to give the title compound (0.4 g) as a yellow solid, m.p. 138-140° C. 1H NMR [(CD3)2SO]: δ 7.89 (d, 1H, J=7.7Hz); 7.76 (d, 1H, J=7.9Hz); 7.48 (t, 1H) ; 7.41 (t, 1H).
Reaction SMILES: CS([C:5]1[N:10]=[CH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][N:6]=1)(=O)=O.[NH2:16][C@H:17]1[CH2:21][CH2:20][NH:19][CH2:18]1>COCCOC>[NH2:16][C@H:17]1[CH2:21][CH2:20][N:19]([C:5]2[N:10]=[CH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][N:6]=2)[CH2:18]1
Reactant: N[C@H]1CCNC1
Reactant: CCOC(=O)c1cnc(S(C)(=O)=O)nc1
Solvent: COCCOC
Product: CCOC(=O)c1cnc(N2CC[C@H](N)C2)nc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90.3 %

Procedure:
The methylsulfone 149 (450 mg, 1.95 mmol) was added to a solution of 3-(S)(−) aminopyrrolidine (253 mg, 2.93 mmol) in DME (10 ml). The reaction mixture was stirred for 10 min at room temperature and the solvent was evaporated. The remaining solid was dissolved in dichloromethane, the solution was washed with saturated aqueous NaHCO3 and brine, dried over MgSO4, filtered and concentrated in vacuo to afford the title compound 150 as a yellow solid (416 mg, 90% yield). 1H NMR: (DMSO) δ (ppm): 8.76 (s, 2H), 4.26 (q, J=7.1 Hz, 2H), 3.70-3.53 (m, 4H), 3.26 (dd, J=11.3, 3.9 Hz, 1H), 2.07-1.98 (m, 1H), 1.75-1.67 (m, 3H), 1.29 (t, J=7.0 Hz, 3H). LRMS (ESI): (calc.) 236.1; (obt.) 237.2 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].O.[OH-].[Na+].[CH3:11][O:12][C:13]1[CH:18]=[C:17]([CH2:19][O:20][C:21](Cl)=[O:22])[C:16]([N+:24]([O-:26])=[O:25])=[CH:15][C:14]=1[O:27][CH3:28]>O1CCOCC1>[CH3:28][O:27][C:14]1[C:13]([O:12][CH3:11])=[CH:18][C:17]([CH2:19][O:20][C:21]([NH:1][CH:2]([CH3:7])[CH2:3][C:4]([OH:6])=[O:5])=[O:22])=[C:16]([N+:24]([O-:26])=[O:25])[CH:15]=1
Reactant: CC(N)CC(=O)O
Reactant: COc1cc(COC(=O)Cl)c([N+](=O)[O-])cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(COC(=O)NC(C)CC(=O)O)c([N+](=O)[O-])cc1OC
Temperature: 0 °C
Yield: 36 %

Procedure:
3-Amino-butyric acid (147 mg, 1.43 mmol) was mixed with water (10 mL), dioxane (10 mL) and 2 M NaOH (10 mL). The mixture was cooled to 0° C. and treated with Nvoc-Cl (1.58 mmol). 2 M NaOH was added in small portions (8×1.25 mL) during 75 minutes. The cooling bath was removed and the reaction mixture was left at room temperature o/n. Water (30 mL) was added and the mixture was filtered. The aqueous phase was adjusted to pH=4 with 2 M HCl (aq.) and extracted with diethyl ether (3×50 mL). The solid was dissolved in water (50 mL) and diethyl ether (50 mL). The combined organic phases were dried over MgSO4 and evaporated in vacuo affording 176 mg (36%) pure 3-(4,5-dimethoxy-2-nitro-benzyloxycarbonylamino)-butyric acid. 1H-NMR (CDCl3): 7.72 (s, 1H), 7.02 (s, 1H), 5.51 (s, 2H), 5.40-5.30 (br s, 1H), 4.15 (m, 1H), 3.96 (s, 3H), 3.92 (s, 3H), 2.60 (d, 2H), 1.31 (d, 3H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([NH2:9])[CH:6]=[CH:5][N:4]=1.C(N(CC)CC)C.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>C(O)C>[N:17]1([CH2:2][C:3]2[N:8]=[C:7]([NH2:9])[CH:6]=[CH:5][N:4]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: Nc1ccnc(CCl)n1
Reactant: C1COCCN1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1ccnc(CN2CCOCC2)n1

Procedure:
Following a procedure from J. Chem. Soc. Perkin. Trans. I, 1996, 2925, 2-chloromethyl-pyrimidin-4-ylamine (0.35 g, Eur. Pat. Appl. EP 61318 A2, 1982; Eur. Pat. Appl. 60094 A2, 1982) was dissolved in ethanol (10 mL) and triethylamine (0.51 mL) and morpholine (0.21 mL) were added. The mixture was heated to reflux for 48 hours and was then allowed to cool and evaporated in vacuo. The residue was dissolved in ethyl acetate and washed with 3N NaOH saturated with NaCl. The aqueous layer was subsequently re-extracted 5 times with ethyl acetate and the combined organic layers were dried over Na2SO4, filtered and evaporated. Flash chromatography (ethyl acetate/methanol 8:2) furnished the desired product 2-morpholin-4-ylmethyl-pyrimidin-4-ylamine as a light brown solid (0.23 g). 1H NMR (δ, DMSO-d6): 7.99 (d, 1H), 6.79 (br s, 2H), 6.28 (d, 1H), 3.56-3.53 (m, 4H, 3.36 (s, 2H), 2.46-2.43 (m, 4H). MS (ESI): 194.9 (MH+).
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl.[NH2:15][CH:16]([CH2:22][SH:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(Cl)Cl>[CH:1]1([C:4]([NH:15][CH:16]([CH2:22][SH:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CC1
Reactant: CCOC(=O)C(N)CS
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(CS)NC(=O)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cyclopropanecarbonyl chloride (3.1 mL) was added to a suspension of triethylamine (4.68 mL) and ethyl 2-amino-3-mercaptopropanoate hydrochloride (5.2 g) in DCM (200 mL) at 0° C. The resulting mixture was allowed to warm to RT and stirred overnight. The reaction was quenched with ethanol and the solvent evaporated. The residue was suspend in ethyl acetate (200 mL) and washed with saturated sodium bicarbonate solution (2×150 mL), aqueous HCl solution (2M, 2×150 mL) and brine (150 mL), then dried over magnesium sulphate, filtered and evaporated. The resulting white solid was purified by silica gel chromatography eluting with 4:1 isohexane:ethyl acetate to give the subtitled compound as a white solid. Yield 5 g.
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C=O.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH2:25][CH2:26][C@@H:27]2[NH:32][CH2:31][CH2:30][N:29]([C:33]3[C:42]4[N:41]=[C:40]([C:43]([F:46])([F:45])[F:44])[S:39][C:38]=4[NH:37][C:36]4[CH:47]=[CH:48][CH:49]=[CH:50][C:35]=4[N:34]=3)[CH2:28]2)[CH:22]=[CH:23][CH:24]=1>CO.ClC(Cl)C>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH2:25][CH2:26][C@@H:27]2[N:32]([CH3:1])[CH2:31][CH2:30][N:29]([C:33]3[C:42]4[N:41]=[C:40]([C:43]([F:45])([F:46])[F:44])[S:39][C:38]=4[NH:37][C:36]4[CH:47]=[CH:48][CH:49]=[CH:50][C:35]=4[N:34]=3)[CH2:28]2)[CH:22]=[CH:23][CH:24]=1
Reactant: COc1cccc(CC[C@H]2CN(C3=Nc4ccccc4Nc4sc(C(F)(F)F)nc43)CCN2)c1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CO
Product: COc1cccc(CC[C@H]2CN(C3=Nc4ccccc4Nc4sc(C(F)(F)F)nc43)CCN2C)c1
Reaction time: 1.5 h
Yield: 60.1 %

Procedure:
Add sodium triacetoxyborohydride (0.23 g, 1.1 mmol) and aqueous formaldehyde (37% w/w, 0.083 mL, 1.1 mmol) to a solution of (S)-10-{3-[2-(3-methoxy-phenyl)-ethyl]-piperazin-1 yl}-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene (0.36 g, 0.74 mmol) in methanol: dichloroethane (1:1) and stir. After 1.5 hours, concentrate the reaction under reduced pressure to remove methanol, and then dilute with a saturated aqueous solution of sodium bicarbonate and dichloromethane, and separate the layers. Extract the aqueous layer with dichloromethane (2×), combine organics, and dry (sodium sulfate), filter, and concentrate under reduced pressure to a residue. Purify the residue by flash chromatography, eluting with a gradient of a solution of ethyl acetate: hexane (1:1) with 1% 2M ammonia in methanol added (40–100% in hexane over 30 minutes, then 100% for 10 minutes) to give the title compound (0.223 g, 60%): mass spectrum (APCI+, m/e): 502 (M+1); 1H NMR (300 MHz, DMSO-d6), δ (ppm): 8.48 (s, 1H), 7.19–7.10 (m, 1H), 6.97–6.81 (m, 3H), 6.76–6.67 (m, 4H), 3.96–3.76 (br. m, 2H), 3.68 (s, 3H), 3.15–3.02 (m, 1H), 2.93–2.81 (m, 1H), 2.80–2.69 (m, 1H), 2.65–2.34 (m, 2H), 2.27–2.04 (m, 5H), 1.91–1.75 (m, 1H), 1.66–1.48 (m, 1H).
Reaction SMILES: [C:1]1([C:7]2[C:14]3[S:13][C:12]([NH2:15])=[N:11][C:10]=3[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][O:17][CH2:18][C:19](Cl)=[O:20].C(O)C(N)(CO)CO>CN(C1C=CN=CC=1)C.C1COCC1>[CH3:16][O:17][CH2:18][C:19]([NH:15][C:12]1[S:13][C:14]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8][NH:9][C:10]=2[N:11]=1)=[O:20]
Reactant: COCC(=O)Cl
Reactant: Nc1nc2[nH]nc(-c3ccccc3)c2s1
Agent: CN(C)c1ccncc1
Agent: NC(CO)(CO)CO
Solvent: C1CCOC1
Product: COCC(=O)Nc1nc2[nH]nc(-c3ccccc3)c2s1
Temperature: 70 °C
Reaction time: 3.5 h
Yield: 37.4 %

Procedure:
To a vial charged with 3-phenyl-1H-pyrazolo[3,4-d]thiazol-5-ylamine (30 mg, 0.139 mmol), PS-DMAP (Argonaut resin, 0.56 g, 6 equiv.), and a stirring bar was added THF (2 mL) and 2-methoxyacetyl chloride (63 μL, 0.694 mmol). The reaction mixture was stirred at 70° C. for 3.5 hours, then cooled to room temperature and treated with PS-trisamine (Argonaut resin, 0.51 g, 15 equiv.) at 50° C. for 3 hours. The resin was filtered, washed with THF and the solvent was evaporated. Purification on silica gel with 0-10% MeOH in CH2Cl2 as eluent provided 15 mg (37% yield) of 2-methoxy-N-(3-phenyl-1H-pyrazolo[3,4-d]thiazol-5-yl)-acetamide as a white solid. 1H-NMR (d6-DMSO) δ: 13.6 (broad s, 1H), 12.3 (broad s, 1H), 7.73 (broad s, 2H), 7.53 (broad s, 2H), 7.37 (broad s, 1H), 4.20 (s, 2H), 3.37 (s, 3H), 2.18 (s, 3H); HPLC/MS m/z: 289.1 [MH]+.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])[C:14]([OH:16])=O)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[NH2:37][C:38]1[N:43]=[CH:42][C:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[CH:40][CH:39]=1.N1C=CC=CC=1>C(Cl)Cl>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])[C:14]([NH:37][C:38]3[N:43]=[CH:42][C:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[CH:40][CH:39]=3)=[O:16])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)c1ccc(N)nc1
Reactant: O=C(O)C(Oc1ccc(F)cc1F)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(NC(=O)C(Oc2ccc(F)cc2F)c2ccc(S(=O)(=O)C3CC3)cc2)nc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 54.2 %

Procedure:
2-(4-cyclopropylsulfonylphenyl)-2-(2,4-difluorophenoxy)acetic acid (Preparation 1; 2.0 g, 5.42 mmol) was dissolved in DCM (20 mL). To this solution was added DMF (0.41 mL, 5.42 mmol) and cooled to 0° C., followed by the addition of oxalyl chloride (0.77 mL, 8.14 mmol) and further stirred for 1 hr at room temp. To this mixture, a solution of tert-butyl 6-aminopyridine-3-carboxylate (preparation 54, 1.26 g, 6.51 mmol) and pyridine (2.19 mL, 2.71 mmol) in DCM 20 (mL) was added drop wise at 0° C. and was stirred further for 1 hr at room temperature. The reaction mixture was diluted with DCM (50 mL), organic layer was washed with water, followed by brine, dried over anhydrous sodium sulfate, solvent was removed under reduced pressure to get the crude compound which was purified by silica gel column chromatography to get the title product (1.6 g).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].F[C:8]1[C:16]2[CH:15]=[CH:14][S:13][C:12]=2[C:11]([C:17]#[N:18])=[CH:10][CH:9]=1.[NH2:19][C@@H:20]([C:24]([OH:26])=[O:25])[C@H:21]([CH3:23])[OH:22]>CS(C)=O>[C:17]([C:11]1[C:12]2[S:13][CH:14]=[CH:15][C:16]=2[C:8]([NH:19][C@H:20]([C@@H:21]([OH:22])[CH3:23])[C:24]([OH:26])=[O:25])=[CH:9][CH:10]=1)#[N:18]
Reactant: N#Cc1ccc(F)c2ccsc12
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@H](O)[C@@H](Nc1ccc(C#N)c2sccc12)C(=O)O
Temperature: 80 °C
Reaction time: 15 h
Yield: 76 %

Procedure:
K2CO3 (1.97 g, 14.3 mmol) was added to a mixture of 4-fluorobenzo[b]thiophene-7-carbonitrile [(1.01 g, 5.70 mmol), which was prepared according to the procedures reported in WO 2004016576] and D-threonine (815 mg, 6.84 mmol) in DMSO (15 mL) at room temperature. The resulting mixture was heated to 80° C. and stirred for 15 h. After cooling to room temperature, the reaction mixture was poured into ice-water (150 mL) and extracted with 10% EtOAc in hexanes (2×50 mL). The aqueous phase was acidified to pH=2˜3 with 2N HCl and extracted with EtOAc (2×100 mL). The EtOAc extracts were washed with water, brine and dried with Na2SO4. Removal of the solvent gave the crude (2R,3S)-2-(7-cyanobenzo[b]thiophen-4-ylamino)-3-hydroxybutanoic acid (1.20 g, 76%). 1H NMR (400 MHz, Acetone-d6, δ in ppm) 7.81 (d, J=5.7 Hz, 1H), 7.73 (d, J=5.7 Hz, 1H), 7.63 (d, J=8.4 Hz, 1H), 6.66 (d, J=8.4 Hz, 1H), 6.12 (d, J=8.0 Hz, 1H), 4.46 (m, 1H), 4.33 (m, 1H), 1.34 (d, J=6.2 Hz, 3H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[C:19]([C:20](O)=[O:21])=[C:18]([CH3:23])[N:17]=[C:16]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:15]=1.[CH2:30]([NH:37][CH:38]([CH3:40])[CH3:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.CN(C=O)C>[CH2:30]([N:37]([CH:38]([CH3:40])[CH3:39])[C:20]([C:19]1[C:14]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[F:7])=[N:15][C:16]([N:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)=[N:17][C:18]=1[CH3:23])=[O:21])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)NCc1ccccc1
Reactant: Cc1nc(N2CCOCC2)nc(-c2ccccc2F)c1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nc(N2CCOCC2)nc(-c2ccccc2F)c1C(=O)N(Cc1ccccc1)C(C)C
Reaction time: 0.25 h
Yield: 39.6 %

Procedure:
A solution of 2 M oxalyl chloride in CH2Cl2 (0.070 mL, 0.14 mmol) was added to a stirred solution of 4-(2-fluorophenyl)-6-methyl-2-morpholin-4-yl-pyrimidine-5-carboxylic acid (0.03 g, 0.09 mmol) in CH2Cl2 (2 mL) and DMF (0.030 mL) at room temperature, and stirring continued for 15 min. A solution of N-benzylisopropylamine (0.013 g, 0.1 mmol) in CH2Cl2(1 mL) and diisopropylethylamine (0.044 mL, 0.25 mmol) were added and stirred for 24 hr. The solvent was removed under reduced pressure, and the residue was purified by Biotage SP1 on packed silica gel column (10%-80% EtOAc/Hexanes gradient) to give 4-(2-fluorophenyl)-6-methyl-2-morpholin-4-yl-pyrimidine-5-carboxylic acid benzyl-isopropyl-amide (0.016 g, 40%). Mass Spec. LCMS 449(M+1).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:11]([NH:13][C@H:14]([C:16]([OH:18])=O)[CH3:15])=[O:12])[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.[NH2:26][CH2:27][CH2:28][CH2:29][OH:30]>C1COCC1>[NH:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[C@H:9]([C:11]([NH:13][C@H:14]([C:16]([NH:26][CH2:27][CH2:28][CH2:29][OH:30])=[O:18])[CH3:15])=[O:12])[CH3:10]
Reactant: C[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)O
Reactant: NCCCO
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)NCCCO
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 84 %

Procedure:
To a vigorously stirring solution of Boc-(Ala)2-OH (1.55 gm, 5.96 mmol) and NMM (0.98 mL, 8.9 mmol) in THF (15 mL) cooled to −15° C. was added under an atmosphere of N2 ethyl chloroformate (ECF) (587 μL, 6.14 mmol). After stirring for 2 min, a solution of H2N(CH2)3OH (546 uL, 7.2 mmol) in THF (5 mL) was added to the mixture followed by NMM (1.64 mL, 14.9 mmol) and the mixture was warmed to r.t. and stirred until silica gel TLC indicated complete consumption of the starting acid (eluting solvent-MeOH:DCM—1:10, Rf—0.5) (˜8 h). The solvent was evaporated, and the residue was diluted with EtOAc and washed with brine, water, saturated solutions of citric acid and NaHCO3, and the organic layer was dried using NaHSO4, and the solvent was removed under vacuum to yield a residue which was purified using silica gel flash column chromatography—Hexanes:EtOAc—1:4; to give the desired product in 84% yield (1.59 g) as a solid, m.p.—142° C.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:10]=1)[C:5]([OH:7])=[O:6].[N-]=[N+]=[N-].[Na+].[OH2:21]>Cl.CO.CCOC(C)=O>[OH:21][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: Nc1cc(C(=O)O)cc(N2CCCC2=O)c1
Reactant: O
Agent: Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(O)c1cc(O)cc(N2CCCC2=O)c1
Temperature: 90 °C
Yield: 40 %

Procedure:
To a solution of 3-amino-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid (D6) (280 mg, 1.25 mmol, 1 equiv) in a mixture of 2N aqueous HCl solution (2.5 ml) and MeOH (5 ml) at 0° C. was added NaN3 (190 mg, 2.75 mmol, 2.2 equiv) portionwise over 20 min. H2O (5 ml) was added and the resulting mixture was heated at 90° C. for 1 h then cooled to room temperature and diluted with AcOEt. The two layers were separated and the aqueous phase was extracted twice with AcOEt (20 ml). The combined organic layers were washed with brine (20 ml), dried over MgSO4 and concentrated in vacuo to give a crude product which was triturated with Et2O/MeOH to give 3-hydroxy-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid (D36) (110 mg, 40%) as a light tan solid.