Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([NH:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11])=O)(C)(C)C.CCOCC.[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29]>>[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].[CH2:14]([O:13][NH:12][C:10](=[O:11])[CH2:9][NH2:8])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)NOCc1ccccc1
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: NCC(=O)NOCc1ccccc1
Temperature: 25 °C

Procedure:
T-Butyloxycarbonyl-O-benzyl glycine hydroxamic acid [(17.5 g, 62.5 mMol) see Step A] was dissolved in trifluoroacetic acid (25 ml), stirred at room temperature thirty minutes, and ether (200 ml) added. The product was filtered and dried to yield: 9.0 g, m.p. 122°-124°.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[CH2:13](O)[CH2:14][OH:15]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:15][CH2:14][CH2:13][O:6]1
Reactant: OCCO
Reactant: O=C(CCCCl)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: ClCCCC1(c2ccccc2)OCCO1
Yield: 61.2 %

Procedure:
Add 4-chlorobutyrophenone (50 g, 274 mmol), ethylene glycol (28 g, 452 mmol) and p-toluenesulfonic acid (1.04 g, 5.48 mmol) to benzene (600 mL) and heat at reflux for 16 h under a water trap. Cool the reaction to RT and wash with 1 N NaOH (500 mL) and brine (750 mL). Dry (sodium sulfate) and concentrate to give a solid. Recrystallize the solid from hot hexanes to give the title compound as a white powder (38 g, 61%).
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:18](O)=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([I:17])[CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>C1COCC1.CC(N(C)C)=O>[C:4]([O:3][C:1](=[O:2])[NH:8][C@@H:9]([CH2:18][OH:19])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([I:17])[CH:12]=1)([CH3:5])([CH3:7])[CH3:6]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1cccc(I)c1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CO)Cc1cccc(I)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of Boc-3-iodo-D-phenylalanine (6.32 g, 16.2 mmol) and 4-methyl-morpholine (1.87 ml, 17 mol) in THF (13 mL) was added dropwise to a −15° C. solution of isobutyl chloroformate (2.22 mL, 17 mmol) in THF (13 mL) and the resulting suspension was stirred for 1 h. The cold reaction mixture was filtered and the filter cake was rinsed with THF. The filtrate was added dropwise to a 0° C. solution of NaBH4 (0.92 g, 24.2 mmol) in dimethylacetamide (7 mL) and the resulting suspension was warmed to RT and stirred for 1 h. The reaction mixture was cooled back to 0° C. and quenched with 1M aq. citric acid. Additional water was added and the mixture was concentrated in vacuo. The remaining aqueous phase was acidified with 1M aq. HCl before being filtered. The filter cake was rinsed with water and dried under HV to give the title compound as an orange solid that was used further without purification. LC-MS A: tR=0.84 min; [M-Me]+=362.93.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([CH2:13][S:14]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C:6]=1[NH2:27].Cl.[N:29]([O-])=O.[Na+].C(=O)(O)[O-].[Na+]>C1COCC1.O>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]2[C:6]=1[NH:27][N:29]=[C:13]2[S:14]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15]
Reactant: COc1cc(CS(=O)(=O)c2cccc3ccccc23)c(N)c(OCCCl)c1
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(OCCCl)c2[nH]nc(S(=O)(=O)c3cccc4ccccc34)c2c1
Temperature: 3 °C

Procedure:
A mixture of 2-(2-chloro-ethoxy)-4-methoxy-6-(naphthalene-1-sulfonylmethyl)-phenylamine (1.0 g, 2.46 mmoles) in THF (7 mL), and 4M HCl (15 mL) was stirred in a round bottom flask, under nitrogen, at 3° C. A solution of sodium nitrite (0.17 g, 2.6 mmoles) in H2O (1 mL) was added dropwise. The reaction mixture was poured into a cold solution of saturated sodium bicarbonate (100 mL) and extracted with EtOAc. Compound was dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off white solid (1.0 g, 2.39 mmoles).
Reaction SMILES: Cl.[CH3:2][S:3][CH2:4][CH2:5][NH:6][CH:7]([C:9]1([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:12][CH2:11][CH2:10]1)[CH3:8].ClC1C=CC=C(C(OO)=[O:29])C=1>ClCCl>[CH3:2][S:3]([CH2:4][CH2:5][NH:6][CH:7]([C:9]1([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:10][CH2:11][CH2:12]1)[CH3:8])=[O:29]
Reactant: CSCCNC(C)C1(c2ccc(Cl)c(Cl)c2)CCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cl
Solvent: ClCCl
Product: CC(NCCS(C)=O)C1(c2ccc(Cl)c(Cl)c2)CCC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of the product of Example 78 in the form of its free base (5.7 g), m-chloroperbenzoic acid (3.7 g-85% purity) and dichloromethane (300 ml) was stirred at ambient temperature for 12 hours. The reaction solution was washed with 5N aqueous sodium hydroxide solution and water and then dried. Evaporation of the solvent gave an oil from which N-[2-(methylsulphinyl)ethyl]-1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine was separated by high pressure liquid chromatography. The amine was dissolved in dry ether and hydrogen chloride gas passed through the solution to give a gum which was dissolved in ethyl acetate. Heating this solution to 80° C. caused the precipitation of N-[2-(methylsulphinyl)ethyl]-1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine hydrochloride (m.p. 170°-171° C.).
Reaction SMILES: [Cl-].[CH3:2][O:3]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[CH:30]1([CH2:35][CH2:36][CH:37]=O)[CH2:34][CH2:33][CH2:32][CH2:31]1.Cl>O1CCCC1.C(OCC)C>[CH:30]1([CH2:35][CH2:36][CH2:37][CH:2]=[O:3])[CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: O=CCCC1CCCC1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=CCCCC1CCCC1
Reaction time: 0.17 h
Yield: 54 %

Procedure:
Methoxymethyl triphenylphosphonium chloride (36 g, 0.11 mol) was suspended in anhydrous tetrahydrofuran (400 mL) and treated with potassium tert-butoxide (12.8 g, 0.11 mol). The reaction stirred for 10 minutes and 3-cyclopentyl-propionaldehyde (10.29 g, 0.082 mol, Example 76) was added dropwise as a solution in anhydrous tetrahydrofuran (100 mL). After 24 hours the reaction was quenched with water. The reaction was diluted with diethyl ether (600 mL) and washed with water (3×300 mL). The organic phase was dried (MgSO4) and concentrated to afford an oil. The oil was taken up in tetrahydrofuran (50 mL) and concentrated hydrochloric acid (20 mL) was added. After six hours, the reaction was diluted with diethyl ether and washed with water (2×200 mL). The organic phase was dried (MgSO4), filtered, and concentrated to yield an oil. The oil was filtered through a pad of silica gel to yield 4-cyclopentyl-butyraldehyde as an oil (6.21 g, 54%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:10]([S:11]([NH2:14])(=[O:13])=[O:12])=[C:9]([NH2:15])[CH:8]=[CH:7][CH:6]=1)[CH:2]=[CH2:3].Cl[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=2)[N:18]=1>CC(O)C.Cl>[CH2:1]([O:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([NH:15][C:21]2[CH:22]=[CH:17][N:18]=[C:19]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=3)[N:20]=2)[C:10]=1[S:11]([NH2:14])(=[O:13])=[O:12])[CH:2]=[CH2:3]
Reactant: COc1ccc(Nc2nccc(Cl)n2)cc1OC
Reactant: C=CCOc1cccc(N)c1S(N)(=O)=O
Agent: Cl
Solvent: CC(C)O
Product: C=CCOc1cccc(Nc2ccnc(Nc3ccc(OC)c(OC)c3)n2)c1S(N)(=O)=O

Procedure:
A solution of 6-Allyloxy-2-aminophenyl-sulfonamide (38 mg, 0.166 mmol) and 4-chloro-2-(3,4-dimethoxy-phenylamino)pyrimidine (44.2 mg, 0.166 mmol) in 2-propanol (5 ml) and 1N HCl (333 μl) is refluxed for 105 min. The reaction mixture is partitioned between ammonia (pH 10-11) and EtOAc. The organic layer is dried (Na2SO4) and concentrated. Precipitation with ether/hexanes gives the desired 2-Allyloxy-6-[2-(3,4-dimethoxy-phenylamino)-pyrimidin-4-ylamino]-benzenesulfonamide.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8])([O-])=O.O.N.[Cl-].[Na+]>O>[NH2:2][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: N
Agent: [Cl-]
Solvent: O
Product: Nc1ccccc1C=O
Yield: 60.3 %

Procedure:
In a four-necked flask, there were placed 175 ml of water, 10.5 g of ferrous sulfate heptahydrate, 0.5 ml of concentrated hydrochloric acid and 6 g of o-nitrobenzaldehyde, then the flask was heated at 90° C. on a water-bath. Into the reaction mixture in the flask, 25 ml of a concentrated ammonia water was added in one-time with stirring, further 30 ml of ammonia water was added in three times in every 2 minutes. After finished the addition of ammonia water, the reaction mixture was subjected to steam distillation immediately. The distillate in an amount of 250 ml was collected in two times separately. The first distillate was cooled and the crystals precipitated were collected by filtration. The mother liquor obtained from the first distillate was combined with second distillate, and this mixture was saturated with sodium chloride, then was extracted with ether extract was dried with sodium sulfate, and ether was removed by distillation. The residue thus obtained was combined with the crystals precipitated from the first distillate and the mixture was dried to obtain 2.9 g of o-aminobenzaldehyde in the form of yellowish flake-like crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[C:11](N1C=CN=C1)(N1C=CN=C1)=[S:12].C(N(CC)CC)C.Cl>CCCCCCC.C(Cl)Cl>[N:1]([C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6])=[C:11]=[S:12]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1cccc(C(=O)O)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCCCCCC
Solvent: CCN(CC)CC
Product: O=C(O)c1cccc(N=C=S)c1
Temperature: -10 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
3-aminobenzoic acid (5.00 g, 36.5 mmol) was added to a methylene chloride solution (51 mL) of thiocarbonyldiimidazole (7.8 g, 43.8 mmol) and triethylamine (5.6 mL, 40.2 mmol) at an internal temperature of at most 5° C., followed by stirring at −10° C. for one hour. The mixture was dropped to a separately prepared mixed solution of concentrated hydrochloric acid (11.6 mL, 133.0 mmol) and n-heptane (51 mL) as that the internal temperature became from 20° C. to 30° C., followed by stirring for one hour as it was. Then, the mixture was stirred under cooling with ice for 2 hours, and the obtained colorless solid was collected by filtration, washed with water (20 mL) four times and dried under reduced pressure to obtain 3-isothiocyanatobenzoic acid as a creamy solid (6.01 g, yield: 93%, HPLC purity: 99.8%).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[N:6]([CH2:16][CH2:17][CH2:18][N:19]([CH3:26])[C:20](=[O:25])[O:21][CH:22](Cl)[CH3:23])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:27]([OH:35])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=1.C(N(CC)CC)C>CN(C)C=O>[N:30]1[CH:31]=[CH:32][CH:33]=[C:28]([C:27]([O:35][CH:22]([O:21][C:20]([N:19]([CH2:18][CH2:17][CH2:16][N:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][CH2:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)[CH3:26])=[O:25])[CH3:23])=[O:34])[CH:29]=1
Reactant: CC(Cl)OC(=O)N(C)CCCN1c2ccccc2CCc2ccccc21
Reactant: O=C(O)c1cccnc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(OC(=O)c1cccnc1)OC(=O)N(C)CCCN1c2ccccc2CCc2ccccc21
Yield: 38.9 %

Procedure:
Following the general procedure of Example 52, but using 1.05 g (0.0028 mol) of the product of Example 51, 0.45 g (0.036 mol) of nicotinic acid and 0.36 g of triethylamine in 10 mL dimethylformamide and carrying out the reaction at 25°-30° C. for 48 hours, gave 0.5 g of the title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH2:10]C[C:8]1=[O:14])=[O:6].C1(=O)NCCCC1>>[Cl:18][C:16]1[CH:15]=[C:4]([CH:3]=[C:2]([Cl:1])[CH:17]=1)[C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH2:10][C:8]1=[O:14])=[O:6]
Reactant: O=C1CCCCCN1C(=O)c1cc(Cl)cc(Cl)c1
Agent: O=C1CCCCN1
Product: O=C1CCCCN1C(=O)c1cc(Cl)cc(Cl)c1

Procedure:
Synthesized as for N-(3,5-dichlorobenzoyl)caprolactam (Example XXI) using valerolactam (Aldrich) in place of caprolactam.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([NH:15][C:16]2[CH:17]=[C:18]([NH:34]CC3C=CC(OC)=CC=3)[C:19]3[N:20]([C:22]([C:25]([NH:27][C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)=[O:26])=[CH:23][N:24]=3)[N:21]=2)[CH2:11][CH2:10]1>>[NH2:34][C:18]1[C:19]2[N:20]([C:22]([C:25]([NH:27][C:28]3[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=3)=[O:26])=[CH:23][N:24]=2)[N:21]=[C:16]([NH:15][CH:12]2[CH2:13][CH2:14][CH:9]([NH2:8])[CH2:10][CH2:11]2)[CH:17]=1
Reactant: COc1ccc(CNc2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C(=O)Nc4ccncc4)cnc23)cc1
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(NC2CCC(N)CC2)nn2c(C(=O)Nc3ccncc3)cnc12
Temperature: 40 °C
Reaction time: 0.67 h
Yield: 15.44 %

Procedure:
TFA (1 mL) was added to a 2 dram vial containing 6-((trans)-4-aminocyclohexylamino)-8-(4-methoxybenzylamino)-N-(pyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide 39A and the mixture was heated at 40° C. After 40 min, the mixture was concentrated to dryness under a stream of nitrogen. The residue was dissolved in 3 mL of methanol and 3 mL of Solvent B (90% MeOH, 10% water, 0.1% TFA). One drop of TFA was added to the solution, the sample was split into 3 equal volumes and purified by reverse phase preparative HPLC on a Phenx Luna Axia Column 5u (21.2×100 mm) Solvent A (10% MeOH, 90% water, 0.1% TFA), Solvent B (90% MeOH, 10% water, 0.1% TFA) 10-80% solvent B gradient, 20 mL/min, 220 nM UV detection to provide 8-amino-6-(4-aminocyclohexylamino)-N-(pyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (0.0419 g, 0.059 mmol, 15.44% yield). 1H NMR (500 MHz, CD3OD) δ ppm 8.65 (3H, d, J=7.15 Hz), 8.26 (3H, d, J=7.15 Hz), 8.08 (1H, s), 5.87 (1H, s), 3.66 (1H, m), 3.10 (1H, m), 2.22-2.27 (2H, m), 2.08 (2H, m), 1.53 (2H, m), 1.36-1.44 (2H, m). LC/MS: HPLC Retention time: 1.38 min, MS: 367 (M+1) (Shimidazu LC, Waters Sunfire C-18 column (4.65×50 mm, 5 um, 0-100% Solvent B, 4 min gradient, 4 mL/min, 220 UV detection. Solvent A: 10% MeOH/90% Water/0.1% TFA, Solvent B 90% MeOH/10% Water/0.1% TFA.)
Reaction SMILES: [NH2:1][CH:2]([CH:6]([OH:15])[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1)[C:3](O)=[O:4].[B-].[Na+]>C(O)C>[NH2:1][CH:2]([CH:6]([C:7]1[CH:8]=[CH:9][C:10]([S:13][CH3:14])=[CH:11][CH:12]=1)[OH:15])[CH2:3][OH:4]
Reactant: CSc1ccc(C(O)C(N)C(=O)O)cc1
Agent: [B-]
Agent: [Na+]
Solvent: CCO
Product: CSc1ccc(C(O)C(N)CO)cc1

Procedure:
The L-threo 2-amino-3-hydroxy-3- (4-methylthiophenyl)propionic acid thus obtained then can be esterified and reduced with sodium borohydrate according to known methods to produce D-threo 2-amino-3-(4-methylthiophenyl)propane-1,3-diol, m.p. 151.9°-152.9° C., [α]D25 -21° (1% in ethanol).
Reaction SMILES: [F:1][C:2]([F:11])([CH:8]([F:10])[F:9])/[CH:3]=[CH:4]/[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.[CH3:18][C:19]1[CH:24]=[C:23]([NH:25][CH2:26][CH2:27][NH2:28])[CH:22]=[C:21]([O:29][CH2:30][CH:31]([CH3:34])[CH2:32][CH3:33])[N:20]=1>C(Cl)Cl.CN(C=O)C.C(OCC)(=O)C>[F:11][C:2]([F:1])([CH:8]([F:10])[F:9])/[CH:3]=[CH:4]/[C:5]([NH:28][CH2:27][CH2:26][NH:25][C:23]1[CH:22]=[C:21]([O:29][CH2:30][CH:31]([CH3:34])[CH2:32][CH3:33])[N:20]=[C:19]([CH3:18])[CH:24]=1)=[O:7]
Reactant: O=C(O)/C=C/C(F)(F)C(F)F
Reactant: CCC(C)COc1cc(NCCN)cc(C)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC(C)COc1cc(NCCNC(=O)/C=C/C(F)(F)C(F)F)cc(C)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 39 %

Procedure:
(E)-4,4,5,5-tetrafluoropent-2-enoic acid (21 mg, 0.12 mmol) was dissolved in DCM (1 ml), oxalyl chloride was added (10 μl, 0.12 mmol) followed by a drop of DMF. The mixture was stirred for 10 minutes at room temperature. N-[2-methyl-6-(2-methylbutoxy)-4-pyridyl]-ethane-1,2-diamine (18 mg, 0.1 mmol) was dissolved in DMF (0.5 ml), the mixtures were combined, TEA (42 μl, 0.3 mmol) was added and the resulting mixture was stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate, washed with water and saturated sodium bicarbonate solution, dried over magnesium sulfate, the solvent was removed under reduced pressure. The residue was purified by preparative HPLC (gradient of water containing 0.1% NH3 and acetonitrile) to yield 13 mg of a white solid (0.039 mmol, 39%).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@@H:13]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C@H:12]([N:22]2[CH:27]=[CH:26][C:25](=[O:28])[N:24](CC3C=CC(OC)=CC=3)[C:23]2=[O:38])[O:11][CH:10]1[C@H:39]([OH:71])[C@@H:40]([C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[NH:41][CH2:42][CH2:43][CH2:44][NH:45][C:46](=[O:63])[C@H:47]([CH2:59][CH:60]([CH3:62])[CH3:61])[NH:48][C:49](=[O:58])[O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N+]([O-])([O-])=O.[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[Cl-].[Na+]>C(#N)C.O>[Si:1]([O:8][C@H:9]1[C@@H:13]([O:14][Si:15]([C:18]([CH3:20])([CH3:19])[CH3:21])([CH3:17])[CH3:16])[C@H:12]([N:22]2[CH:27]=[CH:26][C:25](=[O:28])[NH:24][C:23]2=[O:38])[O:11][CH:10]1[C@H:39]([OH:71])[C@@H:40]([C:64]([O:66][C:67]([CH3:68])([CH3:70])[CH3:69])=[O:65])[NH:41][CH2:42][CH2:43][CH2:44][NH:45][C:46](=[O:63])[C@H:47]([CH2:59][CH:60]([CH3:61])[CH3:62])[NH:48][C:49](=[O:58])[O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: COc1ccc(Cn2c(=O)ccn([C@@H]3OC([C@H](O)[C@H](NCCCNC(=O)[C@H](CC(C)C)NC(=O)OCc4ccccc4)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [Cl-]
Solvent: CC#N
Solvent: O
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)NCCCN[C@H](C(=O)OC(C)(C)C)[C@@H](O)C1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 24.6 %

Procedure:
To a solution of tert-butyl (5S,12S)-12-[(R)-[(3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl](hydroxy)methyl]-5-isobutyl-3,6-dioxo-1-phenyl-2-oxa-4,7,11-triazatridecan-13-oate (420 mg, 0.409 mmol, obtained from Example 4) in acetonitrile (20 ml) was added a solution of ammonium cerium(IV) nitrate (898 mg, 1.6 mmol) in water (4 ml). The resulting solution was stirred for 48 hours at room temperature, and saturated sodium chloride aqueous solution was added. The aqueous layer was extracted with ethyl acetate (3×75 mL). The combined extracts were washed with saturated sodium chloride, dried over sodium sulfate, filtered and concentrated in vacuo. The resultant residue was chromatographed (flash column, silica gel, 5% methanol in methylene chloride) to provide tert-butyl (5S,12S)-12-[(R)-[(3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(2,4-dioxo -3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl](hydroxy)methyl]-5-isobutyl-3,6-dioxo-1-phenyl-2-oxa-4,7,11-triazatridecan-13-oate (91 mg, 25%) as a pale tan amorphous solid.
Reaction SMILES: [OH:1][C@@H:2]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[N:8]=[C:7]([C:25](O)=[O:26])[CH:6]=1)[CH2:3][OH:4].[NH2:28][C@@H:29]([CH2:33][C:34]([NH2:36])=[O:35])[C:30]([NH2:32])=[O:31].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][C@@H:2]([C:5]1[CH:10]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)=[CH:15][CH:16]=2)[N:8]=[C:7]([C:25]([NH:28][CH:29]([CH2:33][C:34]([NH2:36])=[O:35])[C:30]([NH2:32])=[O:31])=[O:26])[CH:6]=1)[CH2:3][OH:4]
Reactant: O=C(O)c1cc([C@H](O)CO)cc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Reactant: NC(=O)C[C@H](N)C(N)=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)CC(NC(=O)c1cc([C@H](O)CO)cc(-c2ccc(Oc3ccc(F)cc3)cc2)n1)C(N)=O
Reaction time: 8 h
Yield: 59 %

Procedure:
To a solution of (S)-4-(1,2-dihydroxyethyl)-6-(4-(4-fluorophenoxy)phenyl)picolinic acid (assume 0.44 mmol) in DMF (5 mL) was added (S)-2-aminosuccinamide (0.076 g, 0.45 mmol), DIEA (0.20 mL, 1.1 mmol) and HBTU (0.203 g, 0.54 mmol). The reaction was stirred overnight then partitioned between 50 mL EtOAc and 50 mL brine. The aqueous layer was extracted once more with 25 mL EtOAc and combined. The organics were dried over Na2SO4, filtered and evaporated in vacuo. The residue was crystallized from 4 mL warm acetone, the solid filtered off, rinsed with additional acetone and dried under vacuum at 50° C. to yield the product S)-2-(4-((S)-1,2-Dihydroxyethyl)-6-(4-(4-fluorophenoxy)phenyl)picolinamido)succinamide as a light tan powder (0.125 g, 0.26 mmol, 59% yield, LC/MS: m/z=483.1 [M+H]+, 1H NMR (400 MHz, DMSO-d6): δ 9.29 (d, J=8.4 Hz, 1H), 8.25 (d, J=8.8 Hz, 2H), 8.06 (s, 1H), 7.99 (s, 1H), 7.48 (s, 1H), 7.40 (s, 1H), 7.32-7.25 (m, 2H), 7.21-7.15 (m, 2H), 7.14-7.07 (m, 3H), 6.99 (s, 1H), 5.64 (d, J=4.8 Hz, 1H), 4.85 (t, J=6.0 Hz, 1H), 4.75-4.64 (m, 2H), 3.62-3.49 (m, 2H), 2.79-2.70 (m, 1H), 2.61-2.53 (m, 1H).
Reaction SMILES: Cl.C([O:4][C:5]1[N:14]=[C:13]2[C:8]([C:9]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:11]=[N:12]2)=[CH:7][CH:6]=1)C>[OH-].[Na+]>[CH3:28][O:27][C:24]1[CH:23]=[CH:22][C:21]([NH:20][C:9]2[C:8]3[CH:7]=[CH:6][C:5](=[O:4])[NH:14][C:13]=3[N:12]=[CH:11][C:10]=2[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1cnc2nc(OCC)ccc2c1Nc1ccc(OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)c1cnc2[nH]c(=O)ccc2c1Nc1ccc(OC)cc1

Procedure:
A mixture of ethyl 7-ethoxy-4-(4-methoxyanilino)-1,8-naphthyridine-3-carboxylate hydrochloride (2.6 g) and 5M sodium hydroxide solution (60 ml) was heated on a steam bath for 4 hours. The mixture was cooled and filtered. The residue was dissolved in IMS and hydrogen chloride gas bubbled through this solution. Ether was added to induce crystallisation and the mixture was filtered to give ethyl 4-[4-methoxyanilino]-7-oxo-7,8-dihydro-1,8-naphthyridine-3-carboxylate 0.3 hydrochloride hemihydrate, m.p. 243°-246° C.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([C:28]#CC4C=CN=CC=4)=N[CH:25]=[CH:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:38]([OH:40])[CH3:39]>[Pd]>[F:1][C:2]([F:36])([F:37])[C:3]1[CH:4]=[C:5]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([O:40][CH2:38][C:39]4[CH:20]=[CH:21][N:16]=[CH:17][CH:18]=4)=[CH:28][CH:25]=[CH:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(c2nccnc2C#Cc2ccncc2)CC1
Reactant: CCO
Agent: [Pd]
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(c2ncccc2OCc2ccncc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3′-Pyridin-4-ylethynyl-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid (3,5-bis-trifluoromethylphenyl)amide (˜0.4 mmol) was dissolved in 5 mL ethanol. Then, 50 mg of 10% palladium on carbon was added. The reaction flask was flushed with hydrogen and the reaction was stirred at room temperature for 5 hr under 1 atmosphere of hydrogen. The reaction mixture was filtered through Celite and concentrated under vacuum. The residue was purified by reverse phase HPLC to give N-[3,5-bis(trifluoromethyl)phenyl]-4-{3-[(pyridin-4-ylmethyl)oxy]pyridin-2-yl}piperazine-1-carboxamide (80 mg) as a yellow solid. 1H NMR (DMSO-d6) δ 9.34 (s, 1H), 8.48 (d, 2H), 8.23 (s, 1H), 8.20 (d, 1H), 8.14 (d, 2H), 7.58 (s, 1H), 7.39 (d, 2H), 3.66 (m, 4H), 3.13-3.43 (m, 8H) ppm.