Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[CH3:2][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li]CCCC.[O:27]=[C:28]1[N:36]([CH2:37][CH2:38][CH3:39])[C:35]2[NH:34][C:33]([C:40]34[CH2:47][CH2:46][C:43]([CH:48]=O)([CH2:44][CH2:45]3)[CH2:42][CH2:41]4)=[N:32][C:31]=2[C:30](=[O:50])[N:29]1[CH2:51][CH2:52][CH3:53]>C1COCC1>[CH2:51]([N:29]1[C:30](=[O:50])[C:31]2[N:32]=[C:33]([C:40]34[CH2:47][CH2:46][C:43]([CH:48]=[CH2:2])([CH2:44][CH2:45]3)[CH2:42][CH2:41]4)[NH:34][C:35]=2[N:36]([CH2:37][CH2:38][CH3:39])[C:28]1=[O:27])[CH2:52][CH3:53]
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCn1c(=O)c2nc(C34CCC(C=O)(CC3)CC4)[nH]c2n(CCC)c1=O
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CC12CCC(c3nc4c(=O)n(CCC)c(=O)n(CCC)c4[nH]3)(CC1)CC2
Reaction time: 0.5 h
Yield: 37.8 %

Procedure:
To a stirred suspension of methyl triphenylphosphonium chloride (1.07 g, 3.0 mmol) in THF (20 ml) at 0° C. was added n-BuLi (1.4 M in hexane, 2.14 ml, 3.0 mmol). The resulting reddish-brown mixture was stirred at this temperature for 0.5 h and then at rt for 0.5 h. A solution of 4-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carbaldehyde (372 mg, 1.0 mmol) in THF (10 ml) was added over a period of 20 minutes and the resulting mixture was stirred overnight (12 h). The reaction mixture was partitioned between saturated aqueous NH2Cl2 (20 ml) and EtOAc (20 ml) and the aqueous phase was extracted with EtOAc (20 ml). The combined organic extracts were washed with saturated aqeuous NaCl (50 ml), dried (MgSO4), filtered and evaporated in vacuo to afford an oil that was purified by radial chromatography (2 mm plate) using a gradient of 0-5% MeOH in CH2Cl2 as eluent. Product-containing fractions were combined and concentrated to afford 140 mg (38%) of a white solid. MS: 371 (MH+).
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[N+:21]([CH2:23][C:24]([O:26][CH3:27])=[O:25])#[C-:22].C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1>CN(C=O)C.C1(C)C=CC=CC=1.CCOC(C)=O>[N:1]1([C:6]2[CH:7]=[C:8]([C:9]3[O:11][CH:22]=[N:21][C:23]=3[C:24]([O:26][CH3:27])=[O:25])[CH:12]=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1cccc(N2CCCC2)c1
Reactant: [C-]#[N+]CC(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)c1ncoc1-c1cccc(N2CCCC2)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a suspension of 3-(pyrrolidin-1-yl)benzoic acid (1.0 g, 5.23 mmol) and K2CO3 1.75 g (12.55 mmol) in DMF (10.8 ml) was added methyl isocyanoacetate (551 mg, 5.23 mmol) in DMF (6.8 mL). The resulting mixture was stirred at rt for 5 min and then cooled to 0° C. A solution of DPPA (1.13 mL, 5.23 mmol) in DMF (6.8 mL) was added dropwise. The resulting mixture was stirred at 0° C. for 2 h and then at rt overnight. It was then diluted with toluene-EtOAc 1:1 (110 mL) and the organic layer was washed with water (55 mL) and aq. sat. NaHCO3-solution (45 mL), dried (MgSO4), filtered and concentrated to dryness. The residue was purified by FC (DCM/MeOH 9:1; Rf=0.41) to afford methyl 5-(3-(pyrrolidin-1-yl)phenyl)oxazole-4-carboxylate as a orange oil. LC-MS conditions A: tR=0.93 min, [M+H]+=273.04.
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[N:10][C:11](Cl)=[C:12]([CH3:15])[C:13]=1[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH:26]=2)O1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.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:34]([O:33][C:31]([N:28]1[CH2:27][CH:26]=[C:25]([C:11]2[N:10]=[N:9][C:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:13]([CH3:14])[C:12]=2[CH3:15])[CH2:30][CH2:29]1)=[O:32])([CH3:37])([CH3:35])[CH3:36]
Reactant: Cc1c(Cl)nnc(Cc2ccccc2)c1C
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(Cc2ccccc2)nnc(C2=CCN(C(=O)OC(C)(C)C)CC2)c1C
Temperature: 100 °C
Yield: 76.6 %

Procedure:
To a solution of 3-benzyl-6-chloro-4,5-dimethylpyridazine (800 mg, 3.44 mmol) in 20 mL DMF is added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1.3 g, 4.1 mmol), followed with potassium carbonate (1.43 g, 10.3 mmol) and Pd(PPh3)4 (397 mg, 0.344 mmol) in a round bottom flask. The vial is evacuated and flushed with nitrogen. The reaction mixture is heated to 100° C. for 16 h. The mixture is filtered through Celite and the filtrate is concentrated to afford the crude material. The mixture is purified by flash chromatography on silica gel, eluting with 3%-15% MeOH:DCM. Fractions containing the desired product are combined and concentrated to afford a brown solid (1.0 g, 77%).
Reaction SMILES: [CH:1]1([C:7]2[CH:21]=[CH:20][C:10]([C:11]([CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.Cl>CO.[OH-].[K+]>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:11]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])=[CH:20][CH:21]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CCC(=O)c1ccc(C2CCCCC2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCC(=O)c1ccc(C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 61 %

Procedure:
To a solution of ethyl 3-(4-cyclohexylbenzoyl)propionate (19.6 g) in methanol (150 ml), 2N KOH (102 ml) was added, followed by stirring at room temperature for 1.5 hours. The reaction mixture was poured into water (200 ml), acidified with concentrated hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), after which the solvent was evaporated off, to yield 3-(4-cyclohexylbenzoyl)propionic acid (10.8 g, 61%), which was then recrystallized from isopropyl ether to yield colorless prisms having a melting point of 140°-141° C.
Reaction SMILES: C(OC(=O)C)(=O)C.[F:8][C:9]1[C:10]([NH:18][CH3:19])=[C:11]([C:15](=[O:17])[CH3:16])[CH:12]=[CH:13][CH:14]=1.[CH:20]([OH:22])=O>>[C:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([F:8])[C:10]=1[N:18]([CH3:19])[CH:20]=[O:22])(=[O:17])[CH3:16]
Reactant: CNc1c(F)cccc1C(C)=O
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Product: CC(=O)c1cccc(F)c1N(C)C=O
Temperature: 25 °C
Reaction time: 2.25 h

Procedure:
A mixture of acetic anhydride (27 ml) and formic acid (18.4 ml) was stirred at 50° for 135 minutes and then cooled to ambient temperature. 3'-Fluoro-2' (methylamino)acetophenone (20.48 g) was then added and the solution stirred overnight. Excess acetic formic anhydride was removed under reduced pressure at 30° and the residue then cooled to 5°. Water (92 ml) followed by aqueous sodium hydroxide (specific gravity 1.5) were then added dropwise to pH 7 whilst maintaining the temperature below 5°. The mixture was extracted with dichloromethane (3×35 ml) and the combined extracts were washed with saturated aqueous sodium carbonate (50 ml) then aqueous sodium chloride (6M, 50 ml) and dried over magnesium sulphate to give a solution of 2'-acetyl-6'-fluoro-N-methylformanilide.
Reaction SMILES: [OH:1][CH:2]([C:32]1[O:33][C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[N:35][N:36]=1)[CH:3]([NH:8][C:9]([CH:11]([NH:23][C:24]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:25])[CH2:12][S:13]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:15])=[O:14])=[O:10])[CH2:4][CH2:5][CH2:6][CH3:7].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:17]1([CH2:16][S:13]([CH2:12][CH:11]([NH:23][C:24]([N:26]2[CH2:27][CH2:28][O:29][CH2:30][CH2:31]2)=[O:25])[C:9](=[O:10])[NH:8][CH:3]([C:2]([C:32]2[O:33][C:34]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)=[N:35][N:36]=2)=[O:1])[CH2:4][CH2:5][CH2:6][CH3:7])(=[O:15])=[O:14])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCCCC(NC(=O)C(CS(=O)(=O)Cc1ccccc1)NC(=O)N1CCOCC1)C(O)c1nnc(-c2ccccc2)o1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: CCCCC(NC(=O)C(CS(=O)(=O)Cc1ccccc1)NC(=O)N1CCOCC1)C(=O)c1nnc(-c2ccccc2)o1
Reaction time: 1 h
Yield: 56.2 %

Procedure:
Morpholine-4-carboxylic acid (1-{1-[hydroxy-(5-phenyl-[1,3,4]oxadiazol-2-yl)-methyl]-pentylcarbamoyl}-2-phenylmethane-sulfonyl-ethyl)-amide (150 mg, 0.25 mmol), in MeCl2 (5 ml), was treated with Dess-Martin periodinane (183 mg, 0.43 mmol) at room temperature. After stirring for 1 hour, 5 ml of saturated Na2S2O3—NaHCO3 were added. After a further 0.5 hours, the reaction mixture was extracted with ethyl acetate, washed with brine, dried with MgSO4 and concentrated. The residue was purified with silica gel column chromatography to yield morpholine-4-carboxylic acid {2-phenylmethanesulfonyl-1-[1-(5-phenyl-[1,3,4]oxadiazole-2-carbonyl)-pentylcarbamoyl]-ethyl}-amide (84 mg); H1 NMR(DMSO-d): 8.71 (1H, d, J=6.6 Hz, NH), 8.12-8.05 (2H, m), 7.75-7.59 (3H, m), 7.38-7.36 (5H, m), 7.04 (1H, d, J=8.1 Hz, NH), 5.12-5.01 (1H, m), 4.8-4.65 (1H, m), 4.47 (2H, s), 3.58-3.46 (4H, m), 3.35-3.2 (6H, m), 2.05-1.85 (1H, m), 1.8-1.65 (1H, m), 1.5-1.2 (4H, m), 0.87 (3H, t, J=6.9 Hz, CH3); MS: 596.8 9M−1), 598.6 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:20](O)(=O)[CH2:21][OH:22].[OH-].[NH4+]>Cl>[C:14]1([CH2:13][N:12]2[C:11]3[C:10]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=4[N:4]=[CH:3][C:2]=3[N:1]=[C:20]2[CH2:21][OH:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1cnc2ccccc2c1NCc1ccccc1
Reactant: O=C(O)CO
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: OCc1nc2cnc3ccccc3c2n1Cc1ccccc1
Temperature: 150 °C
Yield: 82 %

Procedure:
3-amino-4-(benzylamino) quinoline (9.5 g; 0.038 mol) and glycolic acid (6.8 g; 0.089 mol) were mixed and the mixture was heated at 150° C. for about 4 hr. The dark mixture was then dissolved in dilute hydrochloric acid with heating. Upon cooling a precipitate formed and was filtered from the mixture. The solid was dissolved in hot water. The solution was then made basic with ammonium hydroxide to precipitate the product. A second, less pure, small crop was obtained from the original filtrate by making it basic with ammonium hydroxide. The solid was triturated in ethyl acetate to give a green colored powder. Total yield was 82%. The product was recrystallized from methanol to give a pure sample m.p. 211-213° C. Analysis: Calculated: C, 74.7; H, 5.2; N, 14.5. Found: C, 74.4; H, 5.1; N, 14.4.
Reaction SMILES: C([NH:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[CH:15][CH:16]=[C:17]2[N:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)=[CH:12][CH:11]=1)(=O)C1C=CC=CC=1.C(O)C.[OH-].[Na+]>Cl>[NH2:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[CH:15][CH:16]=[C:17]2[N:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)=[CH:12][CH:11]=1
Reactant: CN1CCN(c2cccc3ccc(NC(=O)c4ccccc4)cc23)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN1CCN(c2cccc3ccc(N)cc23)CC1
Yield: 92 %

Procedure:
7-Benzamido-1-(4-methyl-1-piperazinyl)-naphthalene (the product from example 1, 3.75 g, 10.87 mmol) was slurried in 6N HCl (a mixture of concentrated HCl (25 mL) and ethanol (25 mL)) (50 mL) and refluxed for 3.5 hours. The mixture was cooled and brought to pH 10 with 1N sodium hydroxide. The aqueous mixture was extracted with methylene chloride. The organic layer was washed with brine, dried over calcium sulfate and concentrated to afford 2.44 g (92%) of the title product which was suitable for use in further reactions without purification. A sample was recrystallized from isopropyl alcohol for analysis: mp 157°-159° C.; 1H NMR δ 7.65 (d, J=8.5 Hz, 1H), 7.44 (d, J=8 Hz, 1H), 7.35 (d, J=2 Hz, 1H), 7.17 (t, J=8 Hz, 1H), 7.04 (d with long range coupling, J=7 Hz, 1H), 6.94 (dd, J=2.5, 8.5 Hz, 1H), 3.88 (br s, 3H), 3.12 (br s, 4H), 2.42 (s, 3H). Analysis calculated for C15H19N3:C, 74.65; H, 7.94; N, 17.41. Found: C, 74.79; H, 8.14; N, 17.41.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:19][C:20]([CH3:22])=[CH2:21])[CH2:9][C:8](=[O:10])[N:7]([C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:18])[CH2:6]1)=[O:4].[Li+].[OH-]>CO>[CH3:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=1[N:7]1[C:8](=[O:10])[CH2:9][C:5]([CH2:19][C:20]([CH3:22])=[CH2:21])([C:3]([OH:4])=[O:2])[CH2:6]1
Reactant: C=C(C)CC1(C(=O)OC)CC(=O)N(c2c(C)cccc2C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: C=C(C)CC1(C(=O)O)CC(=O)N(c2c(C)cccc2C)C1
Temperature: 70 °C

Procedure:
To a solution of 1-(2,6-dimethylphenyl)-3-(2-methylallyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (prepared from step a, 10.9 g, 36.21 mmol) in MeOH (100 mL) was added 1M LiOH (100 mL, 100 mmol) and the resulting clear solution was refluxed (70° C.) for an hour. The reaction mixture was then cooled to room temperature, MeOH was removed under reduced pressure and the obtained basic aqueous solution was added to a cooled (0° C.) 2N HCl (200 mL) with vigorous stirring. The resulting white solid was filtered, washed with water (3×300 mL), heptane (200 mL) and dried under high vacuum to obtain 1-(2,6-dimethylphenyl)-3-(2-methylallyl)-5-oxo-pyrrolidine-3-carboxylic acid (10 g, quantitative yield). LC-MS: Rt (retention time): 1.98 min, MS: (ES) m/z 288.1 (M+H+).
Reaction SMILES: [S:1]1[CH2:4][S:3][C:2]1=[C:5]([C:12](C(OOCC)=O)=[O:13])[C:6]([O:8][CH:9]([CH3:11])[CH3:10])=[O:7].[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1>>[S:3]1[CH2:4][S:1][C:2]1=[C:5]([C:12](=[O:13])[NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:23][CH:22]=1)[C:6]([O:8][CH:9]([CH3:10])[CH3:11])=[O:7]
Reactant: CCOOC(=O)C(=O)C(C(=O)OC(C)C)=C1SCS1
Reactant: Nc1ccc(C(F)(F)F)cc1
Product: CC(C)OC(=O)C(C(=O)Nc1ccc(C(F)(F)F)cc1)=C1SCS1

Procedure:
Following the procedure of Example 18, the titled compound was prepared as a white solid (67%) from isopropyl 2-(1,3-dithietan-2-ylidene)-2-(ethoxycarboxycarbonyl)acetate and 4-aminobenzotrifluoride.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:12](O)[CH2:13][OH:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[I:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:7]2[O:14][CH2:13][CH2:12][O:8]2)[CH:9]=1
Reactant: COc1ccc(I)cc1C=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(I)cc1C1OCCO1

Procedure:
A solution of 1.0 grams (3.82 mmol) of the above aldehyde, 0.85 mL of ethylene glycol, 20 mg of p-toluenesulfonic acid and 42 mL of toluene was refluxed under nitrogen for 18 hours, cooled and concentrated in vacuo. The residue was redissolved in 50 mL of CH2Cl2, washed with saturated aqueous NaHCO3, dried over MgSO4 and concentrated to an oil. Chromatography on silica gel (10% ethyl acetate (EtOAc): 90% hexane) gave 2-(5-iodo-2-methoxyphenyl)-1,3-dioxolane as a clear oil, 0.68 grams (58%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[N:8]=1)(=O)=O.Cl.[NH2:20][C@H:21]1[CH2:24][C@H:23]([N:25]2[C:29]3[N:30]=[CH:31][N:32]=[CH:33][C:28]=3[C:27]([CH3:35])([CH3:34])[C:26]2=[O:36])[CH2:22]1.C(N(CC)C(C)C)(C)C>CS(C)=O.O>[N:8]1[C:9]2[C:14](=[N:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[CH:16][C:7]=1[NH:20][C@H:21]1[CH2:24][C@H:23]([N:25]2[C:29]3[N:30]=[CH:31][N:32]=[CH:33][C:28]=3[C:27]([CH3:34])([CH3:35])[C:26]2=[O:36])[CH2:22]1
Reactant: CC1(C)C(=O)N([C@H]2C[C@H](N)C2)c2ncncc21
Reactant: O=S(=O)(Oc1ccc2ncccc2n1)C(F)(F)F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: CC1(C)C(=O)N([C@H]2C[C@H](Nc3ccc4ncccc4n3)C2)c2ncncc21
Temperature: 100 °C

Procedure:
To suspension of 1,5-naphthyridin-2(1H)-one (0.200 g, 1.368 mmol) in Pyridine (1 mL) was added slowly trifluoromethanesulfonic anhydride (0.050 mL, 0.298 mmol). After the addition, the reaction mixture was stirred at room temperature for 18 h. The solvent was evaporated under high vacuum and residue diluted with water and extracted with EtOAc. EtOAc was washed with water, brine, dried over Na2SO4 and concentrated to give crude 1,5-naphthyridin-2-yl trifluoromethanesulfonate. To this crude 1,5-naphthyridin-2-yl trifluoromethanesulfonate (100 mg) in DMSO (0.5 mL) was added 7-(trans-3-aminocyclobutyl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one hydrochloride, INTERMEDIATE 62, (0.05 g, 0.186 mmol) and N,N-diisopropylethylamine (0.032 mL, 0.186 mmol). The mixture was heated to 100° C. for 2 hours, diluted with water and extracted with EtOAc. EtOAc was concentrated and residue purified with ISCO using silical gel column eluting with 0-100% EtOAc/hexanes to give the title compound 7-(trans-3-((1,5-naphthyridin-2-yl)amino)cyclobutyl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one (0.048 g, 0.133 mmol, 71.6% yield). m/z: 361.2; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.85 (s, 1 H) 8.62 (dd, J=4.21, 1.27 Hz, 1 H) 8.33 (s, 1 H) 8.07 (d, J=9.00 Hz, 1 H) 7.98 (d, J=8.22 Hz, 1 H) 7.45 (dd, J=8.51, 4.21 Hz, 1 H) 6.88 (d, J=9.00 Hz, 1 H) 5.46 (d, J=4.50 Hz, 1 H) 5.17-5.35 (m, 1 H) 4.79 (dd, J=7.92, 3.62 Hz, 1 H) 3.32-3.58 (m, 2 H) 2.44 (tt, J=10.03, 3.08 Hz, 2 H) 1.45 (s, 6 H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][CH2:12][CH2:13][CH2:14][S:15]([NH:18][CH2:19][CH:20]([CH2:44][CH:45]([OH:47])[CH3:46])[CH2:21][O:22][C:23](=[O:43])[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])(=[O:17])=[O:16].C(N(CC)CC)C>ClCCl>[Cl:11][CH2:12][CH2:13][CH2:14][S:15]([NH:18][CH2:19][CH:20]([CH2:44][C:45](=[O:47])[CH3:46])[CH2:21][O:22][C:23](=[O:43])[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])(=[O:17])=[O:16]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCCl)CC(C)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCCl)CC(C)=O
Reaction time: 0.08 h

Procedure:
To a cooled solution of 0.0645 ml (0.75 mM) of oxalyl chloride in 50 ml of dichloromethane at -78° C., is added 0.106 ml (1.5 mM) of dimethylsulfoxide dropwise and the mixture is stirred for another 5 minutes. To this mixture is added a solution of 285 mg (0.5 mM) of 1-(3-chloropropylsulfonylamino)-2-(2-hydroxypropan-1-yl)-3-octadecylcarbamoyloxypropane m10 in 2 ml of dichloromethane at -70° C. with vigorous stirring. The mixture is allowed to react at -70° C. for 15 minutes and 0.836 ml (6 mM) of triethylamine is added. After allowing the temperature of the reaction mixture to rise to room temperature, the product is isolated with dichloromethane extraction. The dichloromethane layer is washed with 2N aqueous hydrochloric acid, water and saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate and evaporated to obtain crude product of the titled compound IIIm1.
Reaction SMILES: [N:1]([C@@H:4]([C@H:8]([CH3:14])[CH2:9][C:10]([F:13])([F:12])[F:11])[C:5]([OH:7])=[O:6])=[N+]=[N-].C(O)(=O)C>[Pd].O>[F:11][C:10]([F:12])([F:13])[CH2:9][C@@H:8]([CH3:14])[C@@H:4]([C:5]([OH:7])=[O:6])[NH2:1]
Reactant: C[C@H](CC(F)(F)F)[C@H](N=[N+]=[N-])C(=O)O
Agent: [Pd]
Solvent: O
Solvent: CC(=O)O
Product: C[C@H](CC(F)(F)F)[C@H](N)C(=O)O
Reaction time: 20 h
Yield: 84.4 %

Procedure:
(2S,3R)-2-azido-5,5,5-trifluoro-3-methylpentanoic acid (3.2 g, 17.27 mmol), 10% palladium on carbon (0.79 g), glacial acetic acid (37 mL) and water (90 mL) was placed under an atmosphere of hydrogen (40 psi) and shaken on Parr hydrogenator. After 20 h, the reaction mixture was filtered through a pad of the Celite® reagent which was rinsed well with H2O (20 mL). The filtrate was concentrated under reduced pressure to produce a white solid. The solid was triturated with EtOAc (200 mL), filtered and washed once more with EtOAc (200 mL) then air dried to give 5,5,5-trifluoro-L-alloisoleucine as a white solid (2.7 g, 96%). Mass Spectrum (−ESI): 184 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:10][CH2:11][C:12](=[O:15])[NH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[OH:8].C([O-])([O-])=O.[K+].[K+].Br[CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>CN(C=O)C>[C:26]([CH2:25][CH2:24][CH2:23][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[CH2:10][CH2:11][C:12](=[O:15])[NH:13][N:14]=2)=[CH:3][C:2]=1[Cl:1])([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)CCCBr
Reactant: O=C1CCC(c2ccc(O)c(Cl)c2)=NN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccc(C2=NNC(=O)CC2)cc1Cl
Yield: 75.7 %

Procedure:
A mixture of 1.500 mg (6.675 mmol) of 6-(3-chloro-4-hydroxyphenyl)-4,5-dihydro-3(2H)-pyridazinone, prepared by the method of Eur. Pat. Appl. 178,189, 1.010 g (7.34 mmol) K2CO3, and 1.463 g (7.50 mmol) of ethyl 4-bromobutyrate in 30 ml of DMF is heated at 100° C. for 2 hrs under N2. The DMF is removed under vacuum and the residue taken up in 150 ml of EtOAc and 50 ml of water. The organic phase is washed with 50 ml of 5% NaOH, then saturated NaCl solution, dried (MgSO4), and the solvent removed to leave a white solid. This solid is recrystallized from hexane-EtoAc to give 1.711 g of 6-[4-carboethoxypropyloxy-3-chlorophenyl]-4,5-dihydro-3(2H)-pyridazinone as white needles, m.p. 109°-110° C. Yield, 82%.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.N1C=CC=CC=1.[C:30](Cl)(=[O:32])[CH3:31]>ClCCl>[F:23][C:2]([F:1])([F:22])[O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:21]=[CH:20][C:18]([NH:19][C:30](=[O:32])[CH3:31])=[CH:17][CH:16]=3)=[N:11]2)=[CH:8][CH:9]=1
Reactant: CC(=O)Cl
Reactant: Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
To a stirred solution containing 4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)aniline (WO 2009/102736) (0.272 g, 0.849 mmol) and pyridine (0.137 mL, 1.90 mmol) dissolved in dichloromethane (2.1 mL) at 0° C. was added acetyl chloride (0.079 mL, 1.10 mmol) dropwise. The reaction was warmed to room temperature and stirred for 1 hour. The solution was diluted with dichloromethane (20 mL) and washed successively with hydrogen chloride (1 N, 1×15 mL), saturated aqueous sodium bicarbonate (1×15 mL) and saturated sodium chloride solution (15 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated to afford the title compound (0.291 g, 95%): mp 169-171° C.; 1H NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 8.15 (d, J=8.7 Hz, 2H), 7.80 (d, J=9.1 Hz, 2H), 7.63 (d, J=8.6 Hz, 2H), 7.39 (d, J=9.0 Hz, 2H), 7.28 (s, 1H), 2.22 (s, 3H). ESIMS m/z 362 ([M+H]+).
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.C(N(C(C)C)CC)(C)C.[N+:19]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][NH2:26])([O-:21])=[O:20]>C(O)C>[Br:8][C:6]1[N:7]=[C:2]([NH:26][CH2:25][C:24]2[CH:27]=[CH:28][CH:29]=[C:22]([N+:19]([O-:21])=[O:20])[CH:23]=2)[C:3]([NH2:9])=[N:4][CH:5]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: NCc1cccc([N+](=O)[O-])c1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncc(Br)nc1NCc1cccc([N+](=O)[O-])c1
Temperature: 180 °C
Yield: 30.9 %

Procedure:
To a solution of 3,5-dibromopyrazin-2-ylamine (253 mg, 1.0 mmol), diisopropylethyl-amine (0.2 mL, 1.5 mmol) and anhydrous ethanol (2 mL) in a microwave tube (Smith process vial, 2-5 mL) was added m-nitrobenzylamine (192 mg, 1.2 mmol). The tube was sealed and heated at 180° C. in a microwave reactor (Smith Synthesizer) for 1.5 h. The reaction mixture was then concentration under reduced pressure and the resultant residue was purified by flash chromatography [silica gel, hexanes/ethyl acetate (2:1)] to afford 5-bromo-N3-(3-nitrobenzyl)pyrazine-2,3-diamine as a brown solid (100 mg, 31%).