Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:36]=[CH:35][C:5]([C:6]([NH:8][C@@:9]([C:21]2[CH:26]=[C:25]([O:27][C:28]([F:33])([F:32])[CH:29]([F:31])[F:30])[CH:24]=[C:23]([F:34])[CH:22]=2)([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:10][C:11]([OH:13])=[O:12])=[O:7])=[CH:4][C:3]=1[C:37]([F:40])([F:39])[F:38].[CH:41]1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.CO.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:36]=[CH:35][C:5]([C:6]([NH:8][C@@:9]([C:21]2[CH:26]=[C:25]([O:27][C:28]([F:32])([F:33])[CH:29]([F:31])[F:30])[CH:24]=[C:23]([F:34])[CH:22]=2)([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)[CH2:10][C:11]([O:13][CH3:41])=[O:12])=[O:7])=[CH:4][C:3]=1[C:37]([F:40])([F:39])[F:38]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)C[C@@](NC(=O)c1ccc(F)c(C(F)(F)F)c1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)C[C@@](NC(=O)c1ccc(F)c(C(F)(F)F)c1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Temperature: 100 °C
Yield: 15.2 %

Procedure:
To a solution of (R)-3-(4-fluoro-3-(trifluoromethyl)benzamido)-3-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-3-(4-fluorophenyl)propanoic acid (32 mg, 0.055 mmol) in toluene (0.5 mL) was added DPPA (18 mg, 0.066 mmol) and TEA (7 mg, 0.066 mmol). The reaction mixture was heated at 100° C. for 1 h followed by the addition of MeOH and TEA. The reaction was heated at 65° C. overnight. Excess K2CO3 was added and the reaction was heated to reflux for 3 h. The reaction mixture was concentrated and the resulting residue was purified by preparative HPLC (phenominex 30×100 mm column, 30-100% MeOH (90% in water, 0.1% TFA) gradient over 12 min with flow rate 40 mL/min and UV detection at 220 nm) to yield (R)-methyl 3-(4-fluoro-3-(trifluoromethyl)benzamido)-3-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-3-(4-fluorophenyl)propanoate (Example 318) as a white solid (5 mg, 15% yield). LCMS: RT=3.92 min [M+H] 613.3 (4 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm). 1H NMR (400 MHz, CDCl3) ppm 3.74 (s, 3H), 3.87-4.11 (m, 2H), 4.89 (m, 1H), 5.86 (t, 1H), 6.95 (d, 1 H), 6.99-7.13 (m, 5H), 7.28-7.40 (m, 3H), 8.09-8.16 (m, 1H), 8.26 (d, 1H), 8.94 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[S:10]([OH:13])(=[O:12])=[O:11].[C:14]([O:18][C:19](=[O:39])[NH:20][CH2:21][CH2:22][N:23]1[CH2:30][CH:29]2[O:31][CH:25]([CH2:26][N:27](CC3C=CC=CC=3)[CH2:28]2)[CH2:24]1)([CH3:17])([CH3:16])[CH3:15].CC(C)CC(O)C.[H][H]>[Pd].CO>[CH3:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[C:3]=1[S:10]([OH:13])(=[O:12])=[O:11].[C:14]([O:18][C:19](=[O:39])[NH:20][CH2:21][CH2:22][N:23]1[CH2:24][CH:25]2[O:31][CH:29]([CH2:28][NH:27][CH2:26]2)[CH2:30]1)([CH3:17])([CH3:15])[CH3:16]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NCCN1CC2CN(Cc3ccccc3)CC(C1)O2
Agent: [Pd]
Agent: Cc1cc(C)c(S(=O)(=O)O)c(C)c1
Solvent: CC(C)CC(C)O
Solvent: CO
Product: CC(C)(C)OC(=O)NCCN1CC2CNCC(C1)O2
Temperature: 55 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
[2-(7-Benzyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-ethyl]-carbamic acid tert-butyl ester 2,4,6-trimethylbenzenesulfonic acid salt (150 g prepared as described below), 4-methyl-2-pentanol (MIBC) (300 mL) and methanol (300 mL) were combined in a metal hydrogenation vessel. Solid 5% Pd/C catalyst (4.5 g, 61% water wet, Johnson Matthey type 440L) was added. The mixture was then hydrogenated under 2.5 bar of hydrogen pressure and was simultaneously heated to 55° C. Gas uptake measurement showed the reaction to be complete after 2 hours. After cooling to 40° C. the catalyst was removed by filtration through a glass fibre filter paper. The catalyst was washed on the filter with MIBC (300 mL) and the washings added to the main filtrate. Solvent (185 mL) was removed by distillation at atmospheric pressure. More solvent (243 mL) was then removed by reduced pressure (<100 mmHg) distillation. Isopropyl ether (IPE) (1050 mL) was added quickly at 70° C., which caused the temperature to fall to 45° C. An unstirrable precipitate formed in the reaction vessel. The mixture was re-heated and solvent distilled and collected (268 mL). MIBC (150 mL) was added and at 80° C. all material dissolved. The ratio of MIBC:IPE was now approximately 4:5. The solution was allowed to cool and was seeded (86 mg) at 70° C. The reaction was left to cool overnight to ambient temperature. The mixture was cooled to 8° C. and then the solid product collected by filtration. The solid was washed on the filter with IPE (450 mL) and then sucked dry. Further drying in vacuo at 60° C. gave the title compound as a white solid (115.0 g, 91%).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][N:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[N:31]1([CH2:6][CH2:7][C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[N:18]=[CH:19][C:20]([C:23]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[O:24])=[CH:21][CH:22]=4)=[CH:13][C:11]=3[CH:12]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1
Reactant: C1CCNCC1
Product: O=C(c1ccc(-c2ccc3oc(CCN4CCCCC4)cc3c2)nc1)N1CCOCC1

Procedure:
The product from Example 44E and piperidine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ 8.70 (m, 1H), 8.22 (d, J=1.8 Hz, 1H), 7.95 (m, 3H), 7.58 (d, J=8.7 Hz, 1H), 6.82 (s, 1H), 3.3-3.8 (m, 12H), 3.05 (m, 2H), 1.5-2.0 (m, 8H); MS (DCI) m/z 420 (M+H)+;
Reaction SMILES: CN(C(ON1N=N[C:11]2[CH:12]=CC=N[C:10]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH:37]=[CH:36][C:35]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=3)=[CH:34][C:33]2=[O:47])=[CH:28][C:27]=1[NH:48][CH3:49].[CH:50](N(CC)C(C)C)(C)C.C(O)(=O)CCC>CN(C=O)C>[Cl:46][C:43]1[CH:44]=[CH:45][C:40]([CH2:39][O:38][C:35]2[CH:36]=[CH:37][N:32]([C:29]3[CH:30]=[CH:31][C:26]4[N:25]=[C:49]([CH2:10][CH2:11][CH3:12])[N:48]([CH3:50])[C:27]=4[CH:28]=3)[C:33](=[O:47])[CH:34]=2)=[CH:41][CH:42]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CNc1cc(-n2ccc(OCc3ccc(Cl)cc3)cc2=O)ccc1N
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCCC(=O)O
Solvent: CN(C)C=O
Product: CCCc1nc2ccc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)cc2n1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
HATU (321 mg) was added to a solution of 1-(4-amino-3-(methylamino)phenyl)-4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one (250 mg), N,N-diisopropylethylamine (0.367 ml) and butyric acid (68.1 mg) in DMF (3 ml) at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was quenched with brine and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4, and concentrated in vacuo. The resulting residue in AcOH (1 ml) was stirred at 80° C. for 1 h. After evaporation of the solvent, the residue was purified by NH silica gel column chromatography (hexane/EtOAc to MeOH/EtOAc). The resulting solid was recrystallized twice from EtOH followed by THF to give the title compound (126 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:11])[C:9]=1[OH:10])[CH:5]=O.C(O)C.[C-:15]#[N:16].[K+].[CH3:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:20]=1[OH:26]>S(=O)(=O)(O)O.O>[OH:10][C:9]1[C:2]([CH3:1])=[CH:3][C:4]([CH:5]([C:23]2[CH:22]=[C:21]([CH3:25])[C:20]([OH:26])=[C:19]([CH3:18])[CH:24]=2)[C:15]#[N:16])=[CH:7][C:8]=1[CH3:11]
Reactant: Cc1cccc(C)c1O
Reactant: Cc1cc(C=O)cc(C)c1O
Reactant: [C-]#N
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cc1cc(C(C#N)c2cc(C)c(O)c(C)c2)cc(C)c1O
Reaction time: 1 h
Yield: 62 %

Procedure:
Five grams of 3,5-dimethyl-4-hydroxybenzaldehyde is suspended with stirring in 20 ml of 50% by volume aqueous ethanol. 2.6 gm of potassium cyanide is added in one addition. After one hour, a freshly prepared solution of 6 gm 2,6-dimethylphenol in 10 ml of concentrated sulfuric acid is added slowly over a period of about one minute. An exothermic reaction takes place. After stirring for one hour, the mixture is poured into 100 ml of water. A brown solid containing the named product is filtered off and washed with water. It is dissolved in 10 ml tetrahydrofuran and stirred vigorously for several hours with a solution of 10 gm sodium bisulfite in 50 ml of water. The product is subsequently extracted with ether, washed with brine, dried with magnesium sulfate, filtered and concentrated to yield 5.81 grams of the title compound, a yellow solid.
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:10]([CH2:11][CH3:12])=[N:9][C:8]2[N:13]([CH2:16][CH3:17])[N:14]=[CH:15][C:7]=2[C:6]=1[NH:18][CH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[N+]=[N-].CCOCC>C(O)C.[Pd]>[NH2:1][CH2:4][C:5]1[C:10]([CH2:11][CH3:12])=[N:9][C:8]2[N:13]([CH2:16][CH3:17])[N:14]=[CH:15][C:7]=2[C:6]=1[NH:18][CH:19]1[CH2:20][CH2:21][O:22][CH2:23][CH2:24]1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN=[N+]=[N-]
Agent: [Pd]
Solvent: CCO
Solvent: CCOCC
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.6 %

Procedure:
A suspension of 5-(azidomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (10.3 g, 34 mmol, e.g. which can be as prepared in Intermediate 6) in ethanol (200 ml) was added to 10% palladium on carbon (1 g) and stirred under an atmosphere of hydrogen for 3 hours at room temperature. The catalyst was removed by filtration under nitrogen and washed well with ethanol. The filtrate was evaporated to dryness to give a dark oil. Ether was added and then evaporated to give the title compound as a foamy semi-solid (9.35 g).
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[C:51]([C:58]5[C:59]([CH3:63])=[N:60][NH:61][CH:62]=5)[CH:52]=[CH:53][CH:54]=4)[O:49][C:48]=3[C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C.C(O)(C(F)(F)F)=O.[ClH:78]>CO.O>[ClH:78].[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[C:51]([C:58]5[C:59]([CH3:63])=[N:60][NH:61][CH:62]=5)[CH:52]=[CH:53][CH:54]=4)[O:49][C:48]=3[C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)=[CH:45][CH:46]=2)[CH2:38][CH2:39][CH2:40]1
Reactant: Cc1n[nH]cc1-c1cccc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc12
Agent: Cl
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Solvent: O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Cc1n[nH]cc1-c1cccc2c(=O)c(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)oc12
Yield: 74 %

Procedure:
Following the procedure of 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, (1-{4-[8-(3-methyl-1H-pyrazol-4-yl)-4-oxo-2-phenyl-4H-chromen-3-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester was treated with TFA. The resultant free base was dissolved in a mixture of MeOH (7 mL), water (7 mL) and 1 M HCl (0.6 mL) and chromatographed on a 5 g C18 cartridge {gradient 10 to 50% MeOH in water+1 M HCl (60 μL in each 10 mL of eluent)} to give the title compound as a white solid (23 mg, 74%). 1H NMR (400 MHz, DMSO-d6): δ 8.61 (s, 3H), 8.00 (dd, J=8.0 and 1.5 Hz, 1H), 7.84 (s, 1H), 7.77 (dd, J=7.4 and 1.7 Hz, 1H), 7.52 (t, J=7.8 Hz, 1H), 7.42 (d, J=8.4 Hz, 2H), 7.38-7.22 (m, 7H), 3.96 (bs, 1H), 2.57-2.43 (m, 4H), 2.21 (s, 3H), 2.19-2.07 (m, 1H), 1.82-1.69 (m, 1H). LCMS (Method E): RT=3.02 min, [M+H]+=448.
Reaction SMILES: CC(C)([O-])C.[K+].Cl.[C:8]([NH2:11])(=[NH:10])[CH3:9].C[O:13][C:14]([CH:16]1[CH2:21][CH2:20][CH2:19][C:18]([CH3:28])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:17]1=O)=O>C(O)C>[CH3:9][C:8]1[N:11]=[C:14]([OH:13])[C:16]2[CH2:21][CH2:20][CH2:19][C:18]([CH3:28])([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:17]=2[N:10]=1
Reactant: CC(=N)N
Reactant: COC(=O)C1CCCC(C)(c2ccccc2)C1=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: Cc1nc(O)c2c(n1)C(C)(c1ccccc1)CCC2
Yield: 52.4 %

Procedure:
A solution of potassium t-butoxide (8.4 g, 75 mmol), acetamidine hydrochloride (7.1 g, 75 mmol) and 3-methyl-2-oxo-3-phenyl-cyclohexanecarboxylic acid methyl ester (30 mmol) in 150 mL of ethanol was stirred at room temperature for 12 hours and then heated under reflux for 2 hours. The mixture was concentrated under reduced pressure, diluted with water, and washed with ether. The aqueous layer was neutralized with HCl and filtered to afford 4.0 g of 2,8-dimethyl-8-phenyl-5,6,7,8-tetrahydro-quinazolin-4-ol as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.Cl[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:15][CH:16]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CCOC(=O)CCl
Reactant: Oc1ccc(-c2nc3cc(Br)cnc3[nH]2)cc1
Product: CCOC(=O)COc1ccc(-c2nc3cc(Br)cnc3[nH]2)cc1

Procedure:
The title compound was prepared from 4-(6-bromo-3H-imidazo[4,5-b]pyridin-2-yl)phenol and ethyl chloroacetate using the method described in Example 41.
Reaction SMILES: [Br:1]Br.C(Cl)(Cl)(Cl)Cl.[CH3:8][N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:12](=[O:26])[CH2:11][C:10]1=[O:27]>C(Cl)Cl>[Br:1][CH:11]1[C:10](=[O:27])[N:9]([CH3:8])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:12]1=[O:26]
Reactant: CN1C(=O)CC(=O)N(c2ccccc2)c2ccccc21
Reactant: BrBr
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CN1C(=O)C(Br)C(=O)N(c2ccccc2)c2ccccc21

Procedure:
While irradiating with a 500 watt lamp at about 40° C., a solution of 5 ml of bromine and 30 ml of carbon tetrachloride was introduced dropwise into a solution of 25 g of the product of Step A and 750 ml of carbon tetrachloride. At the end of the introduction, the lamp was extinguished, the mixture was cooled and 500 ml of methylene chloride were added. The organic phase was washed with a saturated sodium carbonate solution, then with water and the product obtained was chromatographed on silica. Elution with an ethyl acetate-methylene chloride mixture 7-3-yielded 10.5 g of the sought product melting at 132° C.
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24](O)=[O:25])[N:23]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.Cl.[NH:28]1[CH2:32][CH2:31][N:30]=[C:29]1[C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][NH:41][CH3:42])=[CH:35][CH:34]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:41]([CH2:40][CH2:39][C:36]3[CH:35]=[CH:34][C:33]([C:29]4[NH:30][CH2:31][CH2:32][N:28]=4)=[CH:38][CH:37]=3)[CH3:42])=[O:25])[N:23]=2)[S:5]([C:8]2[C:9]([CH3:17])=[CH:10][C:11]([O:15][CH3:16])=[CH:12][C:13]=2[CH3:14])(=[O:7])=[O:6])[CH2:3][CH2:2]1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)O)co2)C2CC2)c(C)c1
Reactant: CNCCc1ccc(C2=NCCN2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N(C)CCc3ccc(C4=NCCN4)cc3)co2)C2CC2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AH using 2-({cyclopropyl[(4-methoxy-2,6-dimethylphenyl)sulfonyl]amino}methyl)-1,3-oxazole-4-carboxylic acid (100 mg, 0.26 mmol), the bis HCl salt of 2-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]-N-methylethanamine (65 mg, 0.23 mmol), EDCI (60 mg, 0.31 mmol), HOBt (42 mg, 0.31 mmol) and DIPEA (0.2 mL, 1.04 mmol) in DMF (8 mL).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[N:11](CC2C=CC(OC)=CC=2OC)[CH2:10][C:9]2[N:23]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[S:25][C:8]=2[C:7]1=[O:30])=[O:5])[CH3:2].S(Cl)(Cl)=O>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[CH:10][C:9]2[N:23]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[S:25][C:8]=2[C:7]=1[OH:30])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1C(=O)c2sc(C(C)(C)C)nc2CN1Cc1ccc(OC)cc1OC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ncc2nc(C(C)(C)C)sc2c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.3 %

Procedure:
A solution of 2-tert-butyl-5-(2,4-dimethoxy-benzyl)-7-oxo-4,5,6,7-tetrahydro-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (1 g, 2.3 mmol) in 23 mL of dichloromethane was cooled to 0° C. with an external ice bath and thionyl chloride (253 μL, 3.47 mmol) was added. The ice bath was removed and the reaction was allowed to stir at room temperature for 16 h. Pyridine (500 μL) was added and the mixture was stirred for 5 min before concentrating on silica gel under reduced pressure and purification by column chromatography. The desired product was eluted from silica gel with a gradient of 10-50% ethyl acetate in hexanes to give 363 mg of pale yellow solid. MS (ESI−): m/z 279.3 (M−1).
Reaction SMILES: [CH:1]([OH:3])=[O:2].C(O[C:8](=[O:10])C)(=O)C.O[CH2:12][CH2:13][NH:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1>O1CCCC1>[CH:1]([O:3][CH2:12][CH2:13][N:14]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH:8]=[O:10])=[O:2]
Reactant: O=CO
Reactant: CC(=O)OC(C)=O
Reactant: OCCNc1cccnc1
Solvent: C1CCOC1
Product: O=COCCN(C=O)c1cccnc1
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
A mixture of formic acid (5.02 g) and acetic anhydride (11.14 g) was stirred for 30 minutes at 40° to 45° C. and cooled in an ice bath. To the cold mixed anhydride was added a solution of 3-(2-hydroxyethyl)aminopyridine (5.80 g) in tetrahydrofuran (20 ml) under cooling in an ice bath and stirring, which was continued for two hours at room temperature. The mixture was evaporated to remove tetrahydrofuran and poured into water (100 ml). The mixture was adjusted to pH 6 to 7 with sodium bicarbonate and extracted with methylene chloride. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated to give 3-[N-(2-formyloxyethyl)formamido]-pyridine (7.47 g) as an oil.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([CH2:21][OH:22])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[C:17]([O:16][C:14]([N:12]1[CH2:13][C@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:10][C@H:11]1[CH2:21][O:22][S:31]([CH3:30])(=[O:33])=[O:32])=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1COS(C)(=O)=O
Temperature: 25 °C
Yield: 91.5 %

Procedure:
To a solution of (2S,4R)-tert-butyl 4-(tert-butyldimethylsilyloxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (4.72 g, 14.2 mmol) and triethylamine (3.97 mL, 28.5 mmol) in DCM (30 mL) cooled to 0° C. was added methanesulfonyl chloride (1.66 mL, 21.9 mmol). The reaction mixture was stirred overnight while the ice bath was allowed to warm to room temperature. The solvent was removed under reduced pressure and the residue partitioned between EtOAc and water. The organic phase was washed with 1N phosphoric acid (100 mL), water (100 mL), saturated sodium bicarbonate solution (100 mL) and brine (100 mL) and then was dried over magnesium sulfate and concentrated to yield (2S,4R)-tert-butyl-4-(tert-butyldimethylsilyloxy)-2-((methylsulfonyloxy)methyl)pyrrolidine-1-carboxylate (5.34 g, 13.0 mmol) as a colorless oil. RP-HPLC (Table 1, Method f) Rt 6.25 min; m/z: (M−H)− 468.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH:4]1[C:9]([OH:11])=[O:10].[OH-:12].[Na+].Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>O.O1CCOCC1>[CH2:18]([O:17][C:15]([N:3]1[CH2:8][CH2:7][N:6]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:12])[CH2:5][CH:4]1[C:9]([OH:11])=[O:10])=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)C1CNCCN1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)C1CN(C(=O)OCc2ccccc2)CCN1C(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 96 %

Procedure:
Piperazine-2-carboxylic acid dihydrochloride (10.0 g, 49.2 mmol) was dissolved in H2O (125 mL) and 1,4-dioxane (200 mL), and the solution was brought to pH 11 with 50% NaOH in H2O. Benzyl chloroformate (14 mL, 98 mmol) was added while maintaining the pH at 11 with 50% NaOH in H2O. After 1 h, an additional portion of benzyl chloroformate (2 mL, 14 mmol) was added. After 30 min, the solution was extracted with Et2O (3×100 mL). The aqueous layer was brought to pH 2 with concentrated HCl and extracted with EtOAc (3×200 mL). The combined EtOAc extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to give 18.9 g (96%) of the desired product as a thick oil. The material was used without further purification. LC-MS: RT=9.250 min; [M+H]+=421.1.
Reaction SMILES: [CH2:1]([N:4]([CH2:10][CH2:11][CH3:12])[CH2:5][CH2:6][CH2:7][CH2:8][NH2:9])[CH2:2][CH3:3].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[C:35]([O:39][C:40]([N:42]([CH2:49][C:50]1[CH:58]=[CH:57][C:53]([C:54](O)=[O:55])=[CH:52][CH:51]=1)[CH2:43][C:44]1[NH:45][CH:46]=[CH:47][N:48]=1)=[O:41])([CH3:38])([CH3:37])[CH3:36]>CN(C=O)C.C(Cl)(Cl)Cl.C(N(CC)CC)C>[C:35]([O:39][C:40](=[O:41])[N:42]([CH2:49][C:50]1[CH:51]=[CH:52][C:53]([C:54](=[O:55])[NH:9][CH2:8][CH2:7][CH2:6][CH2:5][N:4]([CH2:1][CH2:2][CH3:3])[CH2:10][CH2:11][CH3:12])=[CH:57][CH:58]=1)[CH2:43][C:44]1[NH:48][CH:47]=[CH:46][N:45]=1)([CH3:38])([CH3:36])[CH3:37]
Reactant: CCCN(CCC)CCCCN
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(C(=O)O)cc1)Cc1ncc[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCN(CCC)CCCCNC(=O)c1ccc(CN(Cc2ncc[nH]2)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 29.4 %

Procedure:
The compound (203 mg) obtained in Example 1-2 was dissolved in DMF (5.0 ml) and chloroform (5.0 ml), and then added with triethylamine (0.374 ml), WSCI hydrochloride (382 mg), HOBt (200 mg), and the compound (463 mg) obtained in Example 6-1. The whole was stirred at room temperature for 23 hours. After completion of the reaction, the solvent was distilled off. Then, the resultant was added with chloroform and washed with water and a saturated saline solution, followed by drying with anhydrous sodium sulfate. The solvent was distilled off and the residue was purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining the subject compound (168 mg) as colorless foam.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)=[O:2].ON1C2C=CC=CC=2N=N1.Cl.[CH2:23]([O:25][C:26](=[O:30])[CH2:27][CH2:28][NH2:29])[CH3:24].C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:23]([O:25][C:26](=[O:30])[CH2:27][CH2:28][NH:29][C:7](=[O:9])[C:6]1[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:11][CH:10]=1)[CH3:24]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CCOC(=O)CCN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCNC(=O)c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.6 %

Procedure:
To a solution of 4-formylbenzoic acid (27.4 g, 0.18 mol) in DMF (300 mL) was added N-ethyl-N′-3-dimethylaminopropylcarbodiimide (34.5 g, 0.18 mol) and N-hydroxybenzotriazole (29.9 g, 0.22 mol). The resulting mixture was stirred at room temperature for 1 hour, then β-alanine ethyl ester hydrochloride (65.4 g, 0.42 mol) and diisopropylethylamine (76 mL, 0.44 mol) was added. After 16 hours stirring at ambient temperature the reaction mixture was partitioned between water (600 mL) and ethyl acetate (600 mL). The organic phase was washed successively with hydrochloric acid (1N, 300 mL), saturated aqueous ammonium chloride (300 mL), water (2×300 mL) and brine (300 mL). The solvent was removed by rotary evaporation to leave an oil, which crystallised upon standing to afford 29.0 g (65%) of 3-(4-formylbenzoylamino)propionic acid ethyl ester.