Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:5]2[CH:6]=[CH:7][NH:8][C:9]=2[CH:10]=1.[H-].[Na+].Br[CH:18]([CH3:20])[CH3:19].CCCCCC>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:5]2[CH:6]=[CH:7][N:8]([CH:18]([CH3:20])[CH3:19])[C:9]=2[CH:10]=1
Reactant: CC(C)Br
Reactant: COC(=O)c1cc(Br)cc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)cc2c1ccn2C(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 43.6 %

Procedure:
To a cooled (0° C.) solution of methyl 6-bromo-1H-indole-4-carboxylate (1.0 g, 3.94 mmol) solid in N,N-dimethylformamide (25 mL) was added sodium hydride (0.173 g, 4.33 mmol). The reaction was stirred for 15 min, at which time 2-bromopropane (0.554 mL, 5.90 mmol) was added. The reaction was then allowed to warm to RT and was maintained overnight. LCMS showed about 25% starting material remaining. The reaction was heated at 45° C. for 4 h, but no further conversion was noted. The reaction vessel was put back into an ice bath and stirred for 15 min. Then excess NaH (60%) was added, stirred for 10 min, and then 2-bromopropane (excess) was added. The ice bath was removed and the reaction stirred for 1 h. Approximately half of the reaction volume was removed in vacuo and poured into saturated NH4Cl (200 mL). This was extracted with ether (2×) and the combined organics were washed with brine, dried (MgSO4), and concentrated. Purification by column chromatography (80 g Isco silica column; Gradient B: 5-25%, A: hexane, B: ethyl acetate) gave methyl 6-bromo-1-(1-methylethyl)-1H-indole-4-carboxylate (0.53 g, 1.718 mmol, 43.7% yield).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:11]([O:13][C:14]([N:16]1[CH2:20][CH:19]2[CH2:21][C:22](=[O:24])[CH2:23][CH:18]2[CH2:17]1)=[O:15])[CH3:12].[F:25][C:26]([F:37])([F:36])[C:27](=[O:35])[CH2:28][S:29][C:30](=[S:34])[O:31][CH2:32][CH3:33].C(O)(=O)C>C1COCC1.C1(C)C=CC=CC=1.O.[Cl-].[Cl-].[Zn+2]>[CH2:11]([O:13][C:14]([N:16]1[CH2:17][CH:18]2[CH:23]([C:27]([CH2:28][S:29][C:30]([O:31][CH2:32][CH3:33])=[S:34])([OH:35])[C:26]([F:37])([F:36])[F:25])[C:22](=[O:24])[CH2:21][CH:19]2[CH2:20]1)=[O:15])[CH3:12]
Reactant: CCOC(=S)SCC(=O)C(F)(F)F
Reactant: CCOC(=O)N1CC2CC(=O)CC2C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)N1CC2CC(=O)C(C(O)(CSC(=S)OCC)C(F)(F)F)C2C1
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 24.5 %

Procedure:
A 1M solution of Lithium bis(trimethylsilyl)amide in THF (LHMDS) (6.10 ml, 6.10 mmol) was added to anhydrous THF (4 ml) and the mixture was cooled to −30° C. under N2. Next, a solution of 5-Oxo-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid ethyl ester (1.0 g, 5.07 mmol) in THF (1 ml) was added dropwise over 15 minutes and the mixture was stirred for an additional 15 minutes. Next, a 0.5M solution of ZnCl2 (15.2 ml, 7.6 mmol) was added over 15 minutes and the reaction mixture was stirred for an additional 30 minutes. The reaction temperature was lowered to −70° C. and a solution of dithiocarbonic acid O-ethyl ester S-(3,3,3-trifluoro-2-oxo-propyl) ester (1.3 g, 5.59 mmol) in THF (1 ml) was added dropwise over 25-30 minutes. After 3 hours at −70° C., a solution of acetic acid (2.5 ml) in toluene (7.5 ml) was added and the reaction mixture was warmed to 0° C. The reaction mixture was diluted with H2O (7.5 ml) and the organic layer separated, dried (MgSO4), and concentrated providing a oily brown residue that was purified by silica-gel chromatography using a gradient of ethyl acetate/hexanes (0% to 100% ethyl acetate) to give the subtitle product as an oil (533 mg, 24%).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[CH2:5][CH2:4]1.Cl[C:20]1[N:25]=[CH:24][N:23]=[C:22]([C:26]([N:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]([CH3:37])=[CH:29]2)=[O:27])[CH:21]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:37][C:30]1[C:31]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:28]([C:26]([C:22]2[N:23]=[CH:24][N:25]=[C:20]([N:3]3[CH2:4][CH2:5][CH:6]([N:9]4[C:17]5[C:12](=[N:13][CH:14]=[CH:15][CH:16]=5)[NH:11][C:10]4=[O:18])[CH2:7][CH2:8]3)[CH:21]=2)=[O:27])[CH:29]=1
Reactant: Cc1cn(C(=O)c2cc(Cl)ncn2)c2ccccc12
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cn(C(=O)c2cc(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)ncn2)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
227 mg (0.78 mmol) 1-piperidin-4-yl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one dihydrochloride were added to 200 mg (0.74 mmol) (6-chloropyrimidin-4-yl)-(3-methyl-indol-1-yl)-methanone and 413 μL (2.40 mmol) DIPEA in 5 mL DMF. The reaction mixture was stirred overnight at RT and then purified by preparative HPLC. The product fractions were combined and concentrated by rotary evaporation using the rotary evaporator. The residue was taken up in methanol and purified through a silica gel column. The product fractions were combined and concentrated by rotary evaporation using the rotary evaporator.
Reaction SMILES: [CH3:1][N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])=O.CC(O)=O.C(N)=[NH:23].C[O-].[Na+]>CO>[N:2]1[CH:3]=[CH:4][C:5]([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=2)[C:10]([O:12][CH3:13])=[O:11])=[N:23][CH:1]=1
Reactant: COC(=O)c1cccc(C(=O)C=CN(C)C)c1
Reactant: N=CN
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cccc(-c2ccncn2)c1
Yield: 62.2 %

Procedure:
The mixture of methyl 3-(3-dimethylaminopropenoyl)benzoate (1.4 g), formamidine-acetate (2.8 g) and 28% methanolic sodium methoxide (5.2 ml) in methanol (38 ml) was heated under reflux for 64 hours under stirring. The solvent was removed by concentration and to the residue was added water. The mixture was adjusted to pH 9 with 20% aqueous potassium carbonate solution and the mixture was extracted with ethyl acetate. The extract layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with the solution of diisopropyl ether and n-hexane and the precipitate was collected by filtration to give methyl 3-(pyrimidin-4-yl)benzoate (0.8 g).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][C:9](=S)[NH:8][C:6]=2[N:7]=1.[OH2:12].Cl[O-].[Na+].Cl>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][C:9](=[O:12])[NH:8][C:6]=2[N:7]=1
Reactant: Nc1ncc2sc(=S)[nH]c2n1
Reactant: O
Agent: Cl
Agent: [Na+]
Agent: [O-]Cl
Product: Nc1ncc2sc(=O)[nH]c2n1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 27.4 %

Procedure:
5-Amino-3H-thiazolo[4,5-d]pyrimidin-2-thione (0.24 g, 1.3 mmol, 1.0 eq) was dissolved in 8 ml water containing 0.1 g NaOH (2.5 mmol, 2.5 eq). The resulting solution was heated to 80° C. A solution of sodium hypochlorite (NaClO) (4.4 ml, 10-13% solution, 5 eq) was added slowly to the above solution at about 80° C. and stirring was continued at 80-90° C. for 30 minutes. The solution was cooled down to about 70° C. and a concentrated HCl solution (0.3 ml, 37%, 2.3 eq.) was added, after which the resulting solution was heated to 80-90° C. for one hour. The reaction mixture was cooled down to room temperature and filtered through a pad of celite. The pH of the filtrate was adjusted to 5-5.5 using 10% NaOH solution. The resulting mixture was heated up to 60° C. for 1 hour, cooled to room temperature and stirred for at least two hours, filtered and washed with water and acetonitrile to afford 0.06 g (27%) of 5-amino-3H-thiazolo[4,5-d]pyrimidin-2-one as a pale yellow solid. 1H NMR, HPLC and LCMS analyses of this product are identical to the product described in Step 3 of Example 1.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4](=[O:29])[C@@H:5]([NH:21]C(OC(C)(C)C)=O)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]#[N:20])=[CH:9][CH:8]=1>O1CCOCC1>[ClH:1].[CH3:2][O:3][C:4](=[O:29])[C@@H:5]([NH2:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]#[N:20])=[CH:9][CH:8]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2C#N)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@@H](N)Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
3 ml of a saturated solution of HCl in dioxane were added to a solution of (S)-2-tert-butoxycarbonylamino-3-(2′-cyano-biphenyl-4-yl) propionic acid methyl ester (513 mg, 1.35 mmol) in dioxane (4 ml) and the resulting mixture was stirred at room temperature for 3 h. The solvent was concentrated in vacuo to yield the title compound (425 mg, 99%) that was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[N:19]1([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH:35]=[CH:34][NH:33][C:32]3=[O:36])=[CH:27][CH:26]=2)[CH:23]=[N:22][CH:21]=[N:20]1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:10])([CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[C@H:11]([N:33]1[CH:34]=[CH:35][N:31]([C:28]2[CH:27]=[CH:26][C:25]([CH2:24][N:19]3[CH:23]=[N:22][CH:21]=[N:20]3)=[CH:30][CH:29]=2)[C:32]1=[O:36])[CH3:12]
Reactant: O=c1[nH]ccn1-c1ccc(Cn2cncn2)cc1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Product: C[C@@H](n1ccn(-c2ccc(Cn3cncn3)cc2)c1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
(2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane was reacted with 1-[4-(1H-1,2,4-triazol-1-ylmethyl)phenyl]-2(1H,3H)-imidazolone in the same manner as in Working Example 11 to give 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1,2,4-triazol-1-ylmethyl)phenyl]-2(1H,3H)-imidazolone (Compound 17).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl-].[Cl-].[Cl-].[Al+3].[CH2:11]([O:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24]2[C:20]=1[C:21]([CH2:31][C:32]([N:34]1[CH2:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH2:35]1)=O)=[CH:22][N:23]2[CH2:29][CH3:30])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[CH2:11]([O:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24]2[C:20]=1[C:21]([CH2:31][CH2:32][N:34]1[CH2:35][C:36]3[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:42]1)=[CH:22][N:23]2[CH2:29][CH3:30])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCn1cc(CC(=O)N2Cc3ccccc3C2)c2c(OCc3ccccc3)cc(F)cc21
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CCn1cc(CCN2Cc3ccccc3C2)c2c(OCc3ccccc3)cc(F)cc21
Reaction time: 0.17 h
Yield: 57.4 %

Procedure:
To a solution of LiAlH4 (100 mg, 2.6 mmol) in THF (30 mL) was added aluminum trichloride (463 mg, 3.51 mmol) at 0° C. After stirring for 10 min, a solution of 31-2 (180 mg, 0.42 mmol) in THF (5 mL) was added dropwise. The reaction mixture was stirred for 5 min before Na2SO4.10H2O was added to quench the reaction. The solid was filtered off and the filtrate was evaporated. The resulting residue was purified on silica gel column chromatography eluting with dichloromethane/methanol (10:1) to get 31-3 (100 mg, 57%) as a yellow solid. 1H-NMR (400 MHz, CDCl3): δ (ppm) 7.46 (d, J=7.2 Hz, 2H), 7.31-7.26 (m, 4H), 7.27 (t, J=3.6 Hz, 1H), 7.09-7.06 (m, 2H), 6.93 (s, 1H), 6.65 (d, J=7.2 Hz, 1H), 6.42 (d, J=7.2 Hz, 1H), 5.06 (s, 2H), 4.02-4.00 (m, 6H), 3.27 (s, 4H), 1.41 (t, J=7.4 Hz, 3H). LRMS: calc 414.2 and found: 414.9 [M+1].
Reaction SMILES: [C:1]([CH2:7][C:8]#[N:9])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C([N:12](CC)CC)C.S(O)(O)(=O)=O.NO>O>[NH2:9][C:8]1[CH:7]=[C:1]([C:2]([CH3:5])([CH3:4])[CH3:3])[O:6][N:12]=1
Reactant: CC(C)(C)C(=O)CC#N
Reactant: CCN(CC)CC
Agent: NO
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)(C)c1cc(N)no1
Yield: 81.7 %

Procedure:
A suspension of pivaloylacetonitrile (12.52 g) and triethylamine (11.27 g) in water (200 ml) is stirred and mixed with hydroxylamine sulfate (9.03 g). pH 8.22. The reaction mixture is treated as in Example 2 to give 3-amino-5-t-butylisoxazole (11.45 g; yield, 81.7%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][NH:27][C:28]([NH2:30])=[S:29])[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:38][C:39](=O)[CH3:40]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][NH:27][C:28]3[S:29][CH:38]=[C:39]([CH3:40])[N:30]=3)[CH2:21][CH2:20]2)=[CH:4][CH:3]=1
Reactant: NC(=S)NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1csc(NCCN2CCC(Nc3nc4ccccc4n3Cc3ccc(F)cc3)CC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a stirred mixture of 4.3 parts of N-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]thiourea, 2.1 parts of potassium carbonate and 45 parts of tetrahydrofuran was added dropwise a solution of 0.9 parts of 1-chloro-2-propanone in a small amount of tetrahydrofuran. Upon completion, stirring at room temperature was continued overnight. The reaction mixture was filtered over Hyflo and the filtrate was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 3.8 parts (81%) of 1-[(4-fluorophenyl)methyl]-N-[1-[2-[(4-methyl-2-thiazolyl)amino]ethyl]-4-piperidinyl]-1H-benzimidazol-2-amine; mp. 184° C. (compound 85).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[N:22]=[C:21](Cl)[C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:19]3[Cl:33])([C:10]2[N:14]([CH3:15])[CH:13]=[N:12][CH:11]=2)[OH:9])=[CH:4][CH:3]=1.[CH3:34][O:35][CH2:36][CH2:37][OH:38].C1(C)C=CC=CC=1.[H-].[Na+]>CCOC(C)=O>[Cl:33][C:19]1[C:18]2[C:23](=[CH:24][CH:25]=[C:16]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)([C:10]3[N:14]([CH3:15])[CH:13]=[N:12][CH:11]=3)[OH:9])[CH:17]=2)[N:22]=[C:21]([O:38][CH2:37][CH2:36][O:35][CH3:34])[C:20]=1[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(Cl)c(-c3ccccc3)c(Cl)c2c1
Reactant: COCCO
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COCCOc1nc2ccc(C(O)(c3ccc(Cl)cc3)c3cncn3C)cc2c(Cl)c1-c1ccccc1
Temperature: 25 °C

Procedure:
(4-Chlorophenyl)(2,4-dichloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol (100 mg, 0.202 mmol, Example 65), 2-methoxyethanol (16.0 μL, 0.202 mmol), toluene (2 mL), and sodium hydride (60% dispersion in mineral oil, 20.2 mg, 0.505 mmol) were combined in a round bottom flask under an N2 atmosphere. The contents were heated to reflux and refluxed overnight. The reaction solution turned from a heterogeneous white mixture to slightly yellowish with a moderate amount of precipitate. The contents were cooled to room temperature then transferred to a separatory funnel with EtOAc dilution, and extracted with saturated, aqueous NH4Cl and saturated, aqueous NaHCO3 solutions. The organic phase was separated then dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 0-10% DCM/(10% of a 2 M NH3 MeOH in DCM)) then further purified via reverse phase chromatography using acetonitrile with ammonium hydroxide in water as eluent to afford the title compound. MS (ESI): mass calcd. for C29H25Cl2N3O3, 533.1; m/z found, 534.2 [M+H]+; 1H NMR (600 MHz, CD3OD) δ ppm 8.96 (d, J=0.9 Hz, 1H), 8.19 (d, J=1.9 Hz, 1H), 7.91 (d, J=8.8 Hz, 1H), 7.70 (dd, J=8.8, 2.2 Hz, 1H), 7.48-7.44 (m, 4H), 7.43-7.39 (m, 3H), 7.36-7.33 (m, 2H), 6.90 (d, J=1.6 Hz, 1H), 4.59-4.54 (m, 2H), 3.70 (s, 3H), 3.68-3.63 (m, 2H), 3.25 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH2:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[N+:12]([O-])([OH:14])=[O:13].OS(O)(=O)=O.[K+].[Br-]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:12]([O-:14])=[O:13])=[C:4]([CH2:8][C:9]([NH2:11])=[O:10])[CH:3]=1
Reactant: NC(=O)Cc1cccc(Cl)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Product: NC(=O)Cc1cc(Cl)ccc1[N+](=O)[O-]
Yield: 30 %

Procedure:
(5-Chloro-2-nitrophenyl)acetamide (35.0 g, 30%) was prepared from 3-chloro phenyl acetamide (90.0 g, 0.53 mol) (obtained in step 1 above), conc. HNO3 (100 mL), conc. H2SO4 (156 mL) and dichloromethane (250 mL), by an analogous procedure to that described in preparation 1 (step 2). mp 115-116° C.; IR (KBr) 3329, 1693, 1504 cm-1 ; 1H NMR (CDCl3) δ 2.30 (s, 3H, CH3), 7.12 (d, J=8.4 Hz, 1H), 7.28 (s, 1H), 8.20 (d, J=8.4 Hz, 1H), 10.48 (brs, 1H, NH); Mass (m/z) 214 (M+.).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:11]1([C:14]2[N:19]=[CH:18][C:17]([CH:20]([CH2:23][C:24]3([C:27]([F:30])([F:29])[F:28])[CH2:26][CH2:25]3)[CH2:21][NH2:22])=[CH:16][CH:15]=2)[CH2:13][CH2:12]1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:22][CH2:21][CH:20]([C:17]1[CH:18]=[N:19][C:14]([CH:11]2[CH2:12][CH2:13]2)=[CH:15][CH:16]=1)[CH2:23][C:24]1([C:27]([F:28])([F:29])[F:30])[CH2:26][CH2:25]1)=[O:6]
Reactant: O=C(O)c1ccccc1Cl
Reactant: NCC(CC1(C(F)(F)F)CC1)c1ccc(C2CC2)nc1
Product: O=C(NCC(CC1(C(F)(F)F)CC1)c1ccc(C2CC2)nc1)c1ccccc1Cl

Procedure:
From 2-chlorobenzoic acid and 2-(6-cyclopropyl-pyridin-3-yl)-3-(1-trifluoromethyl-cyclopropyl)-propylamine. LCMS (MH+): m/z=423.1, tR (minutes, Method G)=2.04
Reaction SMILES: Br[C:2]1[C:3]([O:12][CH2:13][C@H:14]2[CH2:16][C@@H:15]2[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][N:18]=2)=[N:4][C:5]2[C:10]([CH:11]=1)=[N:9][CH:8]=[CH:7][CH:6]=2.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[N:35][N:36]([CH2:38][CH2:39][OH:40])[CH:37]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>C1COCC1.O.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([C@H:15]2[CH2:16][C@@H:14]2[CH2:13][O:12][C:3]2[C:2]([C:33]3[CH:34]=[N:35][N:36]([CH2:38][CH2:39][OH:40])[CH:37]=3)=[CH:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][N:9]=3)[N:4]=2)=[N:18][CH:19]=1
Reactant: CC1(C)OB(c2cnn(CCO)c2)OC1(C)C
Reactant: COc1ccc([C@H]2C[C@@H]2COc2nc3cccnc3cc2Br)nc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc([C@H]2C[C@@H]2COc2nc3cccnc3cc2-c2cnn(CCO)c2)nc1
Temperature: 100 °C

Procedure:
A mixture of 3-bromo-2-{[(1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl]-methoxy}-1,5-naphthyridine (LL2) (130 mg, 0.3 mmol), 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]ethanol (97 mg, 0.4 mmol), tripotassium phosphate (133 mg, 0.6 mmol), S-Phos (12.8 mg, 0.03 mmol), and Pd(OAc)2 (3.5 mg, 0.02 mmol) in THF (1.3 mL) and water (0.3 mL) was heated at 100° C. for 14 hours. The reaction mixture was allowed to cool to room temperature. The mixture was then diluted with EtOAc (10 mL), washed with sodium bicarbonate (2 mL) and brine (2 mL), dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by reverse phase chromatography (Waters Sunfire Prep C18 OBD, 5-60% acetonitrile in water with 0.1% TFA modifier) to afford the title compound as a white solid. 1H NMR (500 MHz, DMSO): δ 8.78 (d, J=4.1 Hz, 1 H), 8.55 (s, 1 H), 8.35 (s, 1 H), 8.22 (s, 1 H), 8.15-8.10 (m, 2 H), 7.61 (dd, J=8.4, 4.3 Hz, 1 H), 7.29 (s, 2 H), 4.94-4.91 (m, 1 H), 4.69-4.65 (m, 1 H), 4.47 (d, J=9.5 Hz, 1 H), 4.14-4.09 (m, 2 H), 3.79 (s, 3 H), 3.73 (d, J=6.5 Hz, 2 H), 2.31-2.27 (m, 1 H), 1.90 (s, 1 H), 1.26-1.22 (m, 1 H), 1.14 (s, 1H); HRMS m/z (M+H) 418.1871 found, 418.1874 required.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:15][OH:16])[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]1=[O:14].C(N(CC)CC)C.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[S:34])[CH:29]=[CH:30][CH:31]=1>O1CCCC1>[OH:16][CH2:15][C:3]1([CH2:2][O:1][C:33](=[S:34])[NH:32][C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([C:25]([F:24])([F:35])[F:36])[CH:27]=2)[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]1=[O:14]
Reactant: O=C1c2ccccc2OCCC1(CO)CO
Reactant: FC(F)(F)c1cccc(N=C=S)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1c2ccccc2OCCC1(CO)COC(=S)Nc1cccc(C(F)(F)F)c1

Procedure:
To a solution of 4,4-bis(hydroxymethyl)-3,4-dihydro-2H-benzo[b]oxepin-5-one (510 mg, 2.3 mmol) in 29 ml tetrahydrofuran were added, at room temperature, triethylamine (0.35 ml, 2.5 mmol) and 3-(trifluoromethyl)phenyl isothiocyanate (872 μl, 5.74 mmol). The mixture was heated to reflux for 72 hours, concentrated and purified by column chromatography on silica gel (eluent: 1:2 ethyl acetate/hexane). The product was obtained in a yield of 483 mg (50%).
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[C:11]([NH:15][C:16]([NH:18][O:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[Cl:27])=[O:17])([CH3:14])([CH3:13])[CH3:12]>C(OCC)(=O)C>[C:11]([NH:15][C:16]([N:18]([O:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[Cl:27])[CH:1]=[O:2])=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)NC(=O)NOc1cc(Cl)ccc1Cl
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)NC(=O)N(C=O)Oc1cc(Cl)ccc1Cl
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 61.1 %

Procedure:
A mixture of 1.53 g (33.3 mmoles) of formic acid and 3.24 g (31.8 mmoles) of acetic anhydride was stirred at 60° C. for 2.5 hours, and 2.20 g (7.94 mmoles) of 1-t-butyl-3-(2,5-dichlorophenoxy)urea was added. The mixture was stirred at 60° C. for 5 hours. The reaction mixture was cooled to room temperature, and 100 ml of ethyl acetate was added The mixture was washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The ethyl acetate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate/hexane) to give 1.48 g of the desired compound as colorless crystals(yield 61 %).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:36])[C@@H:10]([NH2:35])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:22][C:21](=[O:23])[N:20]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[S:19]2(=[O:34])=[O:33])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:37]([NH:40][C@@H:41]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:42](O)=[O:43])(=[O:39])[CH3:38].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CCOC(C)=O>[CH2:1]([O:8][C:9](=[O:36])[C@@H:10]([NH:35][C:42](=[O:43])[C@@H:41]([NH:40][C:37](=[O:39])[CH3:38])[CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[CH2:22][C:21](=[O:23])[N:20]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[S:19]2(=[O:33])=[O:34])=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CN2C(=O)CN(c3ccc(C[C@H](N)C(=O)OCc4ccccc4)cc3)S2(=O)=O)cc1
Reactant: CC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(CN2C(=O)CN(c3ccc(C[C@H](NC(=O)[C@H](Cc4ccccc4)NC(C)=O)C(=O)OCc4ccccc4)cc3)S2(=O)=O)cc1
Reaction time: 1 h

Procedure:
The title A compound, (S)-2-amino-3-{4-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionic acid benzyl ester (79 mg, 0.155 mmol) and (S)-2-acetylamino-3-phenyl-propionic acid (33.7 mg, 0.162 mmol) are dissolved in CH2Cl2 (3.1 mL). HOBt (24.8 mg, 0.162 mmol) is added as a solid, followed by EDCl (31.0 mg, 0.162 mmol) and TEA (0.023 mL, 0.162 mmol) in a slurry of CH2Cl2 (1 mL). After 1 h, EtOAc (100 mL) is added and the mixture is washed three times with 2N aqueous HCl (50 mL) followed by saturated aqueous NaHCO3 (50 mL). The EtOAc layer is dried over anhydrous Na2SO4 and concentrated to yield (S)-2-((S)-2-acetylamino-3-phenyl-propionylamino)-3-{4-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionic acid benzyl ester as a white powder.