Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[C:12]([CH2:13][CH2:14][C:5]2=[N:4][N:3]=1)=[CH:11][C:10](B1OC(C)(C)C(C)(C)O1)=[CH:9][CH:8]=3.Br[C:25]1[CH:26]=[N:27][CH:28]=[C:29]([C:31]([C:34]2[O:35][C:36]([CH:39]3[CH2:41][CH2:40]3)=[N:37][N:38]=2)([CH3:33])[CH3:32])[CH:30]=1.C(=O)([O-])[O-].[K+].[K+].C(O)(C)(C)C>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl.O>[CH:39]1([C:36]2[O:35][C:34]([C:31]([C:29]3[CH:30]=[C:25]([C:10]4[CH:11]=[C:12]5[C:7](=[CH:8][CH:9]=4)[N:6]4[C:2]([CH3:1])=[N:3][N:4]=[C:5]4[CH2:14][CH2:13]5)[CH:26]=[N:27][CH:28]=3)([CH3:33])[CH3:32])=[N:38][N:37]=2)[CH2:41][CH2:40]1
Reactant: Cc1nnc2n1-c1ccc(B3OC(C)(C)C(C)(C)O3)cc1CC2
Reactant: CC(C)(c1cncc(Br)c1)c1nnc(C2CC2)o1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC(C)(C)O
Product: Cc1nnc2n1-c1ccc(-c3cncc(C(C)(C)c4nnc(C5CC5)o4)c3)cc1CC2
Temperature: 80 °C

Procedure:
To a vial containing the title compound from Example 53 Step J (0.025 g, 0.080 mmol), the title compound from Example 70 Step A (0.025 g, 0.080 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (1.1 mg, 1.6 μmol), and potassium carbonate (0.033 g, 0.241 mmol) were added tert-butanol (0.89 mL) and water (0.11 mL). The vial was flushed with nitrogen, sealed tightly and heated to 80° C. overnight. The reaction solution was then cooled to room temperature and concentrated under reduced pressure. The resulting material was diluted with acetonitrile and purified by HPLC (C18 column, 10 to 100% acetonitrile/water, both 0.1% v/v trifluoroacetic acid). Fractions containing product were combined, aqueous 1 N HCl solution was added, and the resulting solution concentrated under reduced pressure to afford the title compound: LCMS m/z 413.02 [M+H]+; 1H NMR (500 MHz, CD3OD) δ 8.90 (s, 1H), 8.64 (s, 1H), 8.30 (s, 1H), 7.90-7.81 (m, 3H), 3.22 (s, 4H), 2.90 (s, 3H), 2.20-2.14 (m, 1H), 1.92 (s, 6H), 1.18-1.16 (m, 2H), 1.07-1.04 (m, 2H).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][CH2:13][C:14]([O:16]C)=[O:15])=[CH:9][CH:10]=2)[CH2:5][C:4]1=[O:18])[CH3:2].[OH-].[Na+].Cl>CO>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:9][CH:10]=2)[CH2:5][C:4]1=[O:18])[CH3:2]
Reactant: CCN1C(=O)Cc2cc(CCC(=O)OC)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCN1C(=O)Cc2cc(CCC(=O)O)ccc21
Reaction time: 1 h
Yield: 93 %

Procedure:
To a solution of 12.9 g. (52.2 mmoles) of 1-ethyl-5-(2-carbomethoxyethyl)oxindole in 53 ml. of methanol was added 112.5 ml. of 1N sodium hydroxide solution. After stirring for 1 hour the reaction mixture was acidified by the addition of 165 ml. of 1N hydrochloric acid. The precipitated product was filtered and dried, 11.39 g. (93% yield).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl-].[Cl-].[Cl-].[Al+3].[O:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1.Cl>C(Cl)Cl>[O:9]1[C:18]2[C:13](=[CH:14][C:15]([C:1](=[O:3])[CH3:2])=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1
Reactant: CC(=O)Cl
Reactant: c1ccc2c(c1)CCCO2
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)CCCO2
Reaction time: 0.25 h
Yield: 63.6 %

Procedure:
To a stirred solution of acetyl chloride (4.78 mL, 67.1 mmol) in dry CH2Cl2 (20 mL) in a −10° C. bath is added aluminum trichloride (4.76 g, 35.7 mmol) in small portions. The mixture is stirred for 15 min until the solution became homogeneous. The solution is added via canula to a separate solution of chromane (4,79 g, 35.7 mmol) in CH2Cl2 (30 mL) all at −10° C. After complete addition, the solution is stirred at −10° C. for 30 min. The solution is poured over a mixture of crushed ice and concentrated HCl. The mixture is extracted with CH2Cl2. The combined organic layers are washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The remaining residue is purified via crystallization from hexanes to give 4.0 g (64%) of 1-(3,4-dihydro-2H-chromen-6-yl)ethanone as a white solid. 1H NMR (400 MHz, CDCl3) δ7.76-7.73, 6.75, 4.27, 2.86, 2.57, 2.09-2.03.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH:11][C@H:12]([C:14]([OH:16])=[O:15])[CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH:17]1([CH2:20]O)[CH2:19][CH2:18]1>>[CH:17]1([CH2:20][O:15][C:14](=[O:16])[C@H:12]([CH3:13])[NH:11][C:9](=[O:10])[CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH2:19][CH2:18]1
Reactant: C[C@H](NC(=O)Cc1cccc(Cl)c1)C(=O)O
Reactant: OCC1CC1
Product: C[C@H](NC(=O)Cc1cccc(Cl)c1)C(=O)OCC1CC1

Procedure:
Following General Procedure C above, and using N-(3-chlorophenylacetyl alanine (from Example D above) and cyclopropylmethanol (Aldrich), the title compound can be prepared. The reaction was monitored by tlc on silica gel and purification was by liquid chromatography using 3:7 EtOAc:hexane as the eluant.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[O:8])[CH:4]=[CH:3]1>CCCCC.[Pd]>[CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1
Reactant: CC1(C)C=CC(=O)CC1
Agent: [Pd]
Solvent: CCCCC
Product: CC1(C)CCC(=O)CC1

Procedure:
31.1 g of 4,4-dimethylcyclohex-2-enone in 100 ml of pentane are hydrogenated in an autoclave at a pressure of 5 bar in the presence of 1.6 g of 5% palladium on charcoal. The reaction mixture is filtered and the solvents are evaporated off under reduced pressure.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([NH:17]C(OCC[Si](C)(C)C)=O)[C:7]=1[C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1)=[O:5])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(O)(=O)C.C1(C)C=CC=CC=1>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:8]([NH2:17])[C:7]=1[C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(-c2ccccc2)n(NC(=O)OCC[Si](C)(C)C)c1-c1cccc2ccccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(-c2ccccc2)n(N)c1-c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
2-Naphthalen-1-yl-5-phenyl-1-(2-trimethylsilanyl-ethoxycarbonylamino)-1H-pyrrole-3-carboxylic acid ethyl ester (608 mg, 1.3 mmol) was treated with a solution of TBAF in THF (2.66 mL of a 1 M solution, 2.7 mmol). The resulting solution was stirred at rt under Ar overnight. The reaction was quenched with glacial acetic acid (145 μL, 2.5 mmol), and passed through a short plug of silica gel eluting with toluene. The filtrate was concentrated in vacuo to afford 1-Amino-2-naphthalen-1-yl-5-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester (434 mg), which was not purified, but was used immediately for the next reaction.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1([C:15](OC)=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.CCOCC>C1COCC1.C(Cl)Cl>[OH:16][CH2:15][C:10]1([CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: COC(=O)C1(CNC(=O)OC(C)(C)C)CCCC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC1(CO)CCCC1
Temperature: -10 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To a solution of methyl 1-[(tert-butoxycarbonyl)amino]methylcyclopentanecarboxylate (1.50 g, 5.83 mmol) in THF (25.0 mL) at −78° C. was added dropwise 1.0 M diisobutylaluminum hydride in DCM (17.5 mL). The reaction was stirred for 2 hours with slow warming to −10° C. A saturated solution of K/Na tartrate was added, followed by ether. This mixture was stirred for 30 minutes at ambient temperature and the organic layer was separated and washed with water, and brine. The organic layer was then dried over sodium sulfate, and the solvent was removed in vacuo to afford the product (1.03 g, 77%). 1H NMR (300 MHz, CDCl3): 4.90 (br s, 1H), 3.27 (s, 2H), 3.06 (d, 2H), 1.5-1.17 (m, 8H), 1.44 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15](Br)=[C:16]([CH2:17][CH2:18][CH2:19][NH2:20])[C:11]=2[O:10][CH:9]1[CH2:22][CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:24]([Sn](CCCC)(CCCC)CCCC)=[CH2:25]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([CH:24]=[CH2:25])=[C:16]([CH2:17][CH2:18][CH2:19][NH2:20])[C:11]=2[O:10][CH:9]1[CH2:22][CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC1Oc2c(ccc(Br)c2CCCN)N1C(=O)OC(C)(C)C
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc2c(c1CCCN)OC(CC)N2C(=O)OC(C)(C)C
Yield: 52.6 %

Procedure:
A solution of N-t-butoxycarbonyl 7-(3-aminopropyl)-6-bromo-2-ethylbenzoxazole (396 mg, 1.03 mmol), vinyltributyltin (360 mg, 1.14 mmol), and tetrakis(triphenylphosphine)palladium (0) (60 mg, 0.052 mmol) in toluene (10 mL) was refluxed for 3 hours. The crude reaction mixture was poured directly on a silica gel column, and the tin by-products were eluted with hexanes. The product was eluted with 25% EtOAc/hexanes to give a clear oil (180 mg, 53%).
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:18][CH3:19])[C:15]([OH:17])=O)[C:9]([OH:11])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][C@H:21]1[CH2:27][CH2:26][S:25][C@H:24]2[CH2:28][CH2:29][CH2:30][C@@H:31]([C:32]([O:34][CH3:35])=[O:33])[N:23]2[C:22]1=[O:36]>>[CH2:1]([C@H:8]([C:9]([NH:20][C@H:21]1[CH2:27][CH2:26][S:25][C@H:24]2[CH2:28][CH2:29][CH2:30][C@@H:31]([C:32]([O:34][CH3:35])=[O:33])[N:23]2[C:22]1=[O:36])=[O:11])[CH2:12][CH2:13][C@H:14]([CH2:18][CH3:19])[C:15]([NH:20][C@H:21]1[CH2:27][CH2:26][S:25][C@H:24]2[CH2:28][CH2:29][CH2:30][C@@H:31]([C:32]([O:34][CH3:35])=[O:33])[N:23]2[C:22]1=[O:36])=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](N)C(=O)N21
Reactant: CC[C@@H](CC[C@H](Cc1ccccc1)C(=O)O)C(=O)O
Product: CC[C@@H](CC[C@H](Cc1ccccc1)C(=O)N[C@H]1CCS[C@H]2CCC[C@@H](C(=O)OC)N2C1=O)C(=O)N[C@H]1CCS[C@H]2CCC[C@@H](C(=O)OC)N2C1=O

Procedure:
Methyl (4S,7S,10aS)-4-(((2S,5R)-5-benzyl-2-ethyl-6-(((4S,7S,10aS)-7-(methoxycarbonyl)-5-oxooctahydro-7H-pyrido[2,1-b][1,3]thiazepin-4-yl)amino)-6-oxohexanoyl)amino)-5-oxooctahydro-7H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure F using Intermediate 82 (33 mg, 0.13 mmol) and (4S,7S,10aS)-methyl 4-amino-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate (121 mg, 0.312 mmol) to give a white solid (25 mg, 27% yield). Anal. Calcd. for C37H52N4O8S2 m/z 744.3. found: 745.3 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.47 (m, 1H), 7.23-7.13 (m, 5H), 5.40-5.30 (m, 2H), 5.19-5.12 (m, 3H), 4.99 (m, 1H), 3.73 (s, 3H), 3.69 (s, 3H), 3.28-3.12 (m, 2H), 2.92-2.71 (m, 14H), 2.41 (m, 3H), 2.24 (m, 1H), 2.05-1.98 (m, 6H), 1.80-1.44 (m, 14H), 0.86 (t, J=7.4 Hz, 3H).
Reaction SMILES: [OH-].[K+].[CH2:3]([OH:6])[C:4]#[CH:5].[CH3:7][CH:8]([CH2:10][CH2:11][CH2:12][CH:13]([CH2:15][CH2:16][CH2:17][C:18]([CH3:20])=[O:19])[CH3:14])[CH3:9].S(=O)(=O)(O)O>O1CCCC1>[CH3:20][C:18]([OH:19])([CH2:17][CH2:16][CH2:15][CH:13]([CH3:14])[CH2:12][CH2:11][CH2:10][CH:8]([CH3:9])[CH3:7])[C:5]#[C:4][CH2:3][OH:6]
Reactant: CC(=O)CCCC(C)CCCC(C)C
Reactant: C#CCO
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)CCCC(C)CCCC(C)(O)C#CCO
Temperature: 0 °C
Yield: 70.9 %

Procedure:
Into a 2-liter, three-neck, round-bottom flask fitted with a mechanical stirrer, a reflux condenser, and an addition funnel was added 210 g (3.60 mol) of finely powdered potassium hydroxide and 500 ml of anhydrous tetrahydrofuran. The resulting reaction mixture was heated to reflux and then 30.0 g (0.54 mol) of propargyl alcohol was slowly added over a 30 minute period with rapid stirring. The mixture was refluxed for 3 hours before 100 g (0.51 mol) of hexahydropseudoionone in 140 ml of tetrahydrofuran was slowly added over a 2-hour period. After an additional 2 hours at reflux, the reaction was cooled to 0° C. and poured onto 1000 g of ice and 360 g of concentrated sulfuric acid with efficient mixing. The resulting aqueous layer was rinsed with 3×100 ml of ether and the combined organic layers were rinsed with 50 ml of water, 3×50 ml of saturated aqueous sodium bicarbonate, and 50 ml of brine. The resulting ethereal solution was dried with 50 g of magnesium sulfate, and the solvent was removed at aspirator pressure with the aid of a rotary evaporator, leaving 110 g of crude product. Vacuum distillation at 40 μHg and 140° C. afforded 92 g (73%) of pure product, i.e. 4,8,12-trimethyltridec-2-yn-1,4-diol.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH2:18]([N:20]=[C:21]=[O:22])[CH3:19]>>[CH2:18]([NH:20][C:21]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:22])[CH3:19]
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: CCN=C=O
Product: CCNC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2n1
Yield: 69.9 %

Procedure:
Beginning with 0.15 gm (0.65 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.067 mL (0.85 mMol) ethyl isocyanate, 0.137 gm (70%) of the title compound were recovered essentially by the procedure of Example 122. An analytical sample was crystallized from aqueous ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:32]=[CH:31][C:23]([O:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[C:22]([F:33])[CH:21]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=O)=[C:4]([CH3:34])[CH:3]=1.Cl.[NH2:36][OH:37].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:32]=[CH:31][C:23]([O:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[C:22]([F:33])[CH:21]=2)[CH2:9]/[C:10](=[N:36]\[OH:37])/[C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[C:4]([CH3:34])[CH:3]=1
Reactant: NO
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(OCCCC(=O)O)c(F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(Cl)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(OCCCC(=O)O)c(F)c1

Procedure:
In analogy to example 151, step 3, 4-{4-[1-(4-chloro-2-methyl-phenyl)-3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-propyl]-2-fluoro-phenoxy}-butyric acid was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound containing less than 10% of the corresponding Z isomer as a colourless solid, MS (ESI−): m/z=499.2 [M−H]−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[N:7]=[C:8]([C:10]3[CH:11]=C[C:13]([NH2:16])=[N:14][CH:15]=3)[O:9][C:5]=2[CH:4]=1.[NH2:19]C1N=CC(B2OC(C)(C)C(C)(C)O2)=CN=1>>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[N:7]=[C:8]([C:10]3[CH:15]=[N:14][C:13]([NH2:16])=[N:19][CH:11]=3)[O:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2nc(-c3ccc(N)nc3)oc2c1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: COc1ccc2nc(-c3cnc(N)nc3)oc2c1

Procedure:
The title compound was synthesised according to the procedure described for 5-(6-methoxy-1,3-benzoxazol-2-yl)pyridin-2-amine starting from 2-aminopyrimidine-5-boronic acid pinacol ester. 1H NMR δ ppm 8.89 (s, 2H) 7.61 (d, 1H) 7.48 (s, 2H) 7.37 (d, 1 H) 6.97 (dd, 1H) 3.83 (s, 3H); MS m/z 243 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:16]=[CH:17][C:18]([OH:22])=[N:19][C:20]=4[CH3:21])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([O:28][CH:29]([F:31])[F:30])[C:24]([F:27])([F:26])[F:25])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:38][C:39]([F:47])(S(F)(=O)=O)C(O)=O>C(#N)C>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:20]([CH3:21])=[N:19][C:18]([O:22][CH:39]([F:47])[F:38])=[CH:17][CH:16]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([O:28][CH:29]([F:30])[F:31])[C:24]([F:27])([F:26])[F:25])=[CH:4][CH:3]=1
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Reactant: Cc1nc(O)ccc1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1nc(OC(F)F)ccc1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 77.8 %

Procedure:
To a solution of 5-{9-chloro-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-3,4-dihydropyrimido[1,2-a]benzimidazol-1(2H)-yl}-6-methylpyridin-2-ol (90.0 mg, 0.194 mmol) in acetonitrile (2.0 mL) was added sodium carbonate (41.1 mg, 0.389 mmol) and 2,2-difluoro-2-fluorosulfonyl-aceticacid (40.2 μL, 0.389 mmol) 0° C. The reaction mixture was stirred at room temperature for 1.5 hrs. The mixture was concentrated. The precipitate was removed by filtration. The filtrate was concentrated and the residue was purified by silica gel column chromatography eluting with a 0-35% ethyl acetate/n-hexane gradient mixture. The resulting solid was recrystallized from ethyl acetate/n-hexane to give the title compound as a colorless powder (77.3 mg, 0.151 mmol, 78%).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[OH:24][CH2:25][C:26]1([CH2:32][NH:33][C:34]2[CH2:38][S:37][C:36](=[O:39])[N:35]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:38]2/[C:34]([NH:33][CH2:32][C:26]3([CH2:25][OH:24])[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)=[N:35][C:36](=[O:39])[S:37]/2)[CH2:8][CH2:7]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: O=C1N=C(NCC2(CO)CCOCC2)CS1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: O=C1N=C(NCC2(CO)CCOCC2)/C(=C/C2CCN(Cc3ccc(C(F)(F)F)cc3C(F)(F)F)CC2)S1
Temperature: 80 °C
Reaction time: 8 h
Yield: 47.8 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (972 mg) in 2-propanol (20 mL) were added 4-({[4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]methyl}amino)thiazol-2(5H)-one (1.05 g) and piperidinium acetate (425 mg). The reaction mixture was stirred at 80° C. overnight and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (774 mg).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:10])[CH:3]=1.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[F:10][C:4]1[CH:3]=[C:2]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: OB(O)c1ccccc1
Reactant: O=Cc1ccc(Br)cc1F
Product: O=Cc1ccc(-c2ccccc2)cc1F

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 2 using 4-bromo-2-fluoro-benzaldehyde instead of tert-butyl N-(4-bromobenzyl)carbamate and phenylboronic acid instead of 3-benzyloxyphenylboronic acid.
Reaction SMILES: [NH2:1][C@@H:2]([C:20]([NH:22][CH2:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10].[CH2:34]([S:41](Cl)(=[O:43])=[O:42])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH2:34]([S:41]([NH:1][C@@H:2]([C:20]([NH:22][CH2:23][C:24]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([CH3:16])=[CH:17][CH:18]=1)(=[O:11])=[O:10])(=[O:43])=[O:42])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@@H](N)C(=O)NCC(=O)OCc2ccccc2)cc1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@@H](NS(=O)(=O)Cc2ccccc2)C(=O)NCC(=O)OCc2ccccc2)cc1
Temperature: 23 °C
Reaction time: 0.42 h
Yield: 97 %

Procedure:
To a solution of D-Arg(Tos)-Gly-OBn (5.2 mmol; Boc previously removed by treatment with 40% TFA/DCM (0.1M) for 15 min. and then concentrated in vacuo; RP-HPLC: 13.8 min.; C18, 0-100% CH3CN over 25 min., 1.5 mL/min) in 21 mL of DCM is neutralized with DIEA before cooling to −78° C. where 1.19 g (6.24 mmol) of BnSO2Cl is added as a solid followed by 900 uL (10.4 mmol). The solution is allowed to warm to 23° C. and stirr for 18 h. The eaction mixture was extracted twice with 10% citric acid, twice with 5% NaHCO3 (50 mL), brine (50 mL), dried (MgSO4), and concentrated in vacuo to give 3.2 g (97%) of BnSO2-D-Arg(Tos)Gly-OBn as a white solid. RP-HPLC: 18.0 min.;C18, 0-100% CH3CN over 25 min., 1.5 mL/min.
Reaction SMILES: Br[CH2:2][CH:3]([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].[O-:10][CH2:11][CH3:12].[Na+]>C(Cl)Cl>[CH2:5]([O:4][CH:3]([O:7][CH2:8][CH3:9])[CH2:2][O:10][CH2:11][CH3:12])[CH3:6]
Reactant: CCOC(CBr)OCC
Reactant: CC[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOCC(OCC)OCC
Temperature: 120 °C
Reaction time: 8 h

Procedure:
A sealed tube was charged with 2-bromo-1,1-diethoxy-ethane (3.82 mL, 25.4 mmol) and sodium ethoxide (16.44 g, 50.7 mmol). The tube was sealed, heated to 120° C. and stirred overnight. The sealed tube was cooled to room temperature and the contents are dissolved in DCM and washed with water twice. The organic layer was separated, dried over sodium sulfate and concentrated in vacuo to give 1,1,2-triethoxy-ethane, which was taken into the next step without further purification. A portion (1.00 g, 6.16 mmol) was dissolved in THF (4 mL) at 0° C. and 5M aqueous HCl (2.5 mL, 12.3 mmol) was added. The reaction mixture was left to stir at room temperature for 1.5 hrs. The mixture was taken up in DCM and washed with water once. The aqueous layer was extracted twice with DCM. The organic layer was dried over sodium sulfate and concentrated in vacuo to afford ethoxy-acetaldehyde, which was taken into the next step with no further purification.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[N:16]=[CH:15][C:14]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4]CC1.C(O)(C(F)(F)F)=O.[OH-].[Na+]>O>[O:4]=[C:5]1[CH2:10][CH2:9][CH:8]([C:11]2[N:16]=[CH:15][C:14]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1
Reactant: O=C(Nc1ccc(C2CCC3(CC2)OCCO3)nc1)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C1CCC(c2ccc(NC(=O)OCc3ccccc3)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an ice water cooled solution of benzyl [6-(1,4-dioxaspiro[4.5]dec-8-yl)pyridin-3-yl]carbamate, prepared as above, (4.94 g, 13.41 mmol) was added TFA (20 mL) followed by water (1.1 mL). The reaction mixture was allowed to stir at ambient temperature for 2 hours. It was treated with 2M NaOH to adjust the pH to 10 and then the mixture was extracted into EtOAc (3×200 mL), the organic phase was separated, dried (MgSO4) and concentrated to leave a gum, 4.05 g (12.26 mmol, 93%) which was used directly in the next stage; 1H NMR (CDCl3) δ 1.97-2.10 (m, 2H), 2.24-2.29 (m, 2H), 2.49-2.53 (m, 4H), 3.13-3.21 (m, 1H), 5.22 (s, 2H), 6.82 (s, 1H), 7.18 (d, 1H), 7.36-7.40 (m, 5H), 7.96 (s, 1H), 8.41 (s, 1H); MS m/e MH+ 325.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].N1C=CC=CC=1.[CH:15]([CH:18]([C:24](OCC)=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:17])[CH3:16]>>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:24]([CH:18]([CH:15]([CH3:16])[CH3:17])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:25])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)C(C(=O)OCC)C(C)C
Reactant: Nc1cccc(F)c1
Solvent: c1ccncc1
Product: CCOC(=O)C(C(=O)Nc1cccc(F)c1)C(C)C

Procedure:
Prepared according to procedure A using 3-fluoroaniline (8.70 mL, 90 mmol), pyridine (10.92 mL, 135 mmol) and diethyl isopropylmalonate (20.02 mL, 99 mmol). The crude was purified by column chromatography (Hexanes:EtOAc, 1:0 to 4:1) to give ethyl 2-(3-fluorophenylcarbamoyl)-3-methylbutanoate.