Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:5][C:6](=[O:26])[CH:7]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:15]=1)[C:8]([CH3:12])([CH3:11])[CH2:9][OH:10])([CH2:3][CH3:4])[CH3:2].[CH3:27][S:28](Cl)(=[O:30])=[O:29]>N1C=CC=CC=1.ClCCl>[CH:1]([NH:5][C:6]([CH:7]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[C:16]([C:22]([F:24])([F:25])[F:23])[CH:15]=1)[C:8]([CH3:11])([CH3:12])[CH2:9][O:10][S:28]([CH3:27])(=[O:30])=[O:29])=[O:26])([CH2:3][CH3:4])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCC(C)NC(=O)C(Oc1ccc(C#N)c(C(F)(F)F)c1)C(C)(C)CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(C)NC(=O)C(Oc1ccc(C#N)c(C(F)(F)F)c1)C(C)(C)COS(C)(=O)=O
Reaction time: 3.5 h

Procedure:
To a stirring solution comprised of two(2) N-sec-butyl-2-(4-cyano-3-trifluoromethyl-phenoxy)-4-hydroxy-3,3-dimethyl-butyramide diastereomers (1.63 g; 4.38 mmol) in pyridine (10 mL) at 0° C. under a nitrogen atmosphere is added methanesulfonyl chloride (0.75 g; 6.5 mmol). The reaction mixture is stirred cold for 3.5 hours. The reaction mixture is diluted with dichloromethane and is washed with 1N aqueous hydrochloric acid and with brine. The organic phase is dried over anhydrous magnesium sulfate and is concentrated in vacuo (the water bath temperature is not raised above 23° C.) to afford 1.892 g of a foam; HPLC UV purity: 99.3% (two diastereomers.)
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:21]2=[CH:22][CH:23]=[N:24][CH:25]=[C:20]2[C:5]2[C:6]([OH:19])=[CH:7][C:8]([CH:10]([CH:12]([CH3:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:11])=[CH:9][C:4]=2[O:3]1.[ClH:27].[N:28]1([CH2:34][CH2:35][CH2:36][C:37](O)=[O:38])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[ClH:27].[CH3:26][C:2]1([CH3:1])[C:21]2=[CH:22][CH:23]=[N:24][CH:25]=[C:20]2[C:5]2[C:6]([O:19][C:37](=[O:38])[CH2:36][CH2:35][CH2:34][N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:7][C:8]([CH:10]([CH:12]([CH3:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:11])=[CH:9][C:4]=2[O:3]1
Reactant: O=C(O)CCCN1CCCCC1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)c1ccncc1-2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: CCCCCC(C)C(C)c1cc(OC(=O)CCCN2CCCCC2)c2c(c1)OC(C)(C)c1ccncc1-2
Temperature: 5 °C
Reaction time: 8 h

Procedure:
A mixture of 3.53 g. (0.01 mole) of 5,5-dimethyl-10-hydroxy-8-(3-methyl-2-octyl)-5H-[1]benzopyrano[3,4-d]pyridine, 2.07 g. (0.01 mole) of γ-piperidinobutyric acid hydrochloride, 2.16 g. (0.0105 mole) of N,N'-dicyclohexylcarbodiimide, and 160 ml. of dried methylene chloride was stirred overnight at room temperature. The reaction mixture was cooled at approximately 5° C. for several hours and was filtered to remove dicyclohexylurea. The filtrate was evaporated in vacuo and the residue was dissolved in 12.5 ml. of methylene chloride and 50 ml. of cyclohexane. After standing overnight in the cold room (approximately 5° C.), the mixture was filtered again and the filtrate was evaporated in vacuo. The residue was recrystallized from methylene chloride/ether, giving 4.1 g. of the product, m.p. 134°-137°.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[CH3:6][C:7]1[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=1[O:9][CH2:10][C:11]1[C:16]([NH:17][OH:18])=[CH:15][CH:14]=[CH:13][N:12]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:18][N:17]([C:16]1[C:11]([CH2:10][O:9][C:8]2[CH:19]=[CH:20][CH:21]=[CH:22][C:7]=2[CH3:6])=[N:12][CH:13]=[CH:14][CH:15]=1)[C:2](=[O:3])[O:4][CH3:5]
Reactant: COC(=O)Cl
Reactant: Cc1ccccc1OCc1ncccc1NO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)N(O)c1cccnc1COc1ccccc1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2.1 g (22 mmol) of methyl chloroformate were added dropwise at -10° C. to a mixture of 4.3 g (mmol) of N-[2-(2-methylphenoxymethyl)pyridin-3-yl]hydroxylamine (Example 3.e), 3.3 g (39 mmol) of NaHCO3 (solid) and 50 ml of methylene chloride. After the reaction mixture had been stirred for 4 hours at room temperature (approximately 25° C.), it was washed with water, dried and freed from solvent under reduced pressure. The residue was purified by column chromatography (cyclohexane/ethyl acetate). This gave 0.6 g (10%) of the title compound as a yellow oil.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[O:12][C:13]([Cl:17])=[C:14]([CH3:16])[N:15]=2)[CH2:7][CH2:6]1)=[O:4].[OH-].[Na+]>O1CCOCC1>[Cl:17][C:13]1[O:12][C:11]([C@H:8]2[CH2:7][CH2:6][C@H:5]([C:3]([OH:4])=[O:2])[CH2:10][CH2:9]2)=[N:15][C:14]=1[CH3:16]
Reactant: COC(=O)[C@H]1CC[C@H](c2nc(C)c(Cl)o2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1nc([C@H]2CC[C@H](C(=O)O)CC2)oc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of trans-4-(5-chloro-4-methyl-oxazol-2-yl)-cyclohexanecarboxylic acid methyl ester (285 mg, 1.11 mmol) in 1,4-dioxane (5.5 ml) and 2 M aqueous sodium hydroxide solution (5.5 ml, 11 mmol) was stirred for 4 h at room temperature. The reaction mixture was partitioned between ethyl acetate (25 ml) and water (25 ml). The aqueous layer was acidified to pH 2. The layers were separated. The aqueous layer was extracted with two 25-ml portions of ethyl acetate. The combined organic layers were washed with one 10-ml portion of brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (245 mg, 91%) as white solid. MS m/e: 242 ([M−H]−)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8]Cl)[N:3]=1.C[O-].[Na+].[SH:13][CH2:14][CH2:15][N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26]>CO>[NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][S:13][CH2:14][CH2:15][N:16]2[C:20](=[O:21])[C:19]3=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]3[C:17]2=[O:26])[N:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCS
Reactant: Nc1ccnc(CCl)n1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Nc1ccnc(CSCCN2C(=O)c3ccccc3C2=O)n1
Reaction time: 1 h

Procedure:
A solution of 4-amino-2-chloromethylpyrimidine (11.6 g.) in methanol (20 ml.) was added over 15 minutes to a stirred mixture of sodium methoxide (4.32 g.), N-(2-mercaptoethyl)phthalimide (16.6 g.) and methanol (100 ml.), and the mixture stirred for 1 hour after the addition was complete and then evaporated to dryness. The residue was partitioned between 1N hydrochloric acid and ethyl acetate, and the aqueous phase separated and neutralised by the addition of sodium bicarbonate. The mixture was extracted with ethyl acetate and the extracts dried and evaporated to dryness, and the residue was recrystallised from acetonitrile to give 4-amino-2-[(2-phthalimidoethyl)thiomethyl]pyrimidine, m.p. 131°-133°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N+:25]([O-])([OH:27])=[O:26]>ClCCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3[CH:19]=[C:20]([N+:25]([O-:27])=[O:26])[C:21]([O:23][CH3:24])=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)OC[C@H](COS(=O)(=O)c1ccc(C)cc1)O2
Reactant: O=[N+]([O-])O
Solvent: ClCCCl
Product: COc1cc2c(cc1[N+](=O)[O-])OC(COS(=O)(=O)c1ccc(C)cc1)CO2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 5.91 g (16.9 mmole) of {(2R)-6-methoxy-2,3-dihydro-1,4-benzodioxin-2-yl}methyl 4-methylbenzenesulfonate in 200 mL of 1,2-dichloroethane in an ice/water bath was added dropwise a solution of 2.50 mL (59.1 mmole) of fuming nitric acid (d 1.49) in 75 mL of 1,2-dichloroethane and the mixture was stirred for 2 hours at 0° C. After the reaction was complete, it was quenched with ice and diluted with 500 mL of methylene chloride. After the ice had melted, the organic layer was separated and washed with equal volumes of saturated aqueous sodium bicarbonate and saturated brine, dried over magnesium sulfate, filtered and concentrated in vacuum to give 6.19 g of the (R)-enantiomer of the title compound as a light yellow solid. 1H-NMR (CDCl3): doublet 7.8 δ(2 H); multiplet 7.4 δ(3 H); singlet 6.5 δ(1 H); multiplet 4.10-4.5 δ(5 H); singlet 3.85 δ(3 H); singlet 2.5 δ(3 H).
Reaction SMILES: [F:1][C:2]1([F:32])[CH2:5][CH:4]([C:6]2[O:10][N:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH3:31])=[C:15]([NH:17][C:18]([C:20]4[N:24]5[CH:25]=[C:26]([CH2:29][OH:30])[CH:27]=[CH:28][C:23]5=[N:22][CH:21]=4)=[O:19])[CH:16]=3)[N:7]=2)[CH2:3]1.CCN(C(C)C)C(C)C.CS(Cl)(=O)=O.C([O-])([O-])=O.[K+].[K+].[F:53][CH2:54][CH2:55]O>C(Cl)Cl>[F:32][C:2]1([F:1])[CH2:5][CH:4]([C:6]2[O:10][N:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH3:31])=[C:15]([NH:17][C:18]([C:20]4[N:24]5[CH:25]=[C:26]([CH2:29][O:30][CH2:55][CH2:54][F:53])[CH:27]=[CH:28][C:23]5=[N:22][CH:21]=4)=[O:19])[CH:16]=3)[N:7]=2)[CH2:3]1
Reactant: Cc1ccc(-c2noc(C3CC(F)(F)C3)n2)cc1NC(=O)c1cnc2ccc(CO)cn12
Reactant: OCCF
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(-c2noc(C3CC(F)(F)C3)n2)cc1NC(=O)c1cnc2ccc(COCCF)cn12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)-6-(hydroxymethyl)imidazo[1,2-a]pyridine-3-carboxamide (F159) (95 mg, 0.216 mmol) was dissolved in DCM (1 mL) and DIEA (0.65 mmol). MsCl (0.65 mmol) was added dropwise and the resulting mixture was stirred for 15 minutes at room temperature. The reaction mixture was subjected to aqueous workup, extracted with DCM (2 mL), dried over Na2SO4 and concentrated to give a crude which was dissolved in 0.8 mL of 2-fluoroethanol followed by addition of K2CO3(90 mg, 0.65 mmol). The resulting mixture was heated at 120° C. for 20 minutes. The reaction mixture was subjected to standard aqueous workup and purified by silica chromatography to yield N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)-6-((2-fluoroethoxy)methyl)imidazo[1,2-a]pyridine-3-carboxamide (F176). 1H NMR (400 MHz, CDCl3) δ 9.56 (s, 1H), 8.60 (d, J=1.6, 1H), 8.21 (s, 1H), 7.89 (dd, J=1.7, 7.9, 1H), 7.77 (d, J=9.2, 1H), 7.62 (s, 1H), 7.53 (dd, J=1.7, 9.2, 1H), 7.42 (d, J=8.1, 1H), 4.72-4.64 (m, 3H), 4.59-4.52 (m, 1H), 3.86-3.79 (m, 1H), 3.79-3.73 (m, 1H), 3.68 (m, 1H), 3.16 (m, 4H), 2.47 (s, 3H). MS m/z 486.1 (M+1)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[NH:17]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>CC(N(C)C)=O>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:17]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: C1CNCCNC1
Reactant: Clc1ccccn1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc(N2CCCNCC2)nc1
Yield: 72.9 %

Procedure:
2-Chloropyridine (3.00 g, 26.4 mmol), DIPEA (9.20 mL, 52.8 mmol) and homopiperazine (7.90 g, 79.3 mmol) were dissolved in DMA (10 mL) and heated using a microwave (180-200° C., absorption high) for 40 min. The reaction mixture was diluted with DCM (150 mL), washed with sat aq Na2CO3 (100 mL), brine (100 mL), dried (MgSO4) and concentrated in vacuo to give the title compound (3.41 g, 72%) as a brown liquid. LCMS (ES+): 178.6 [MH]+.
Reaction SMILES: [N+](=[CH:3][C:4]([O:6][C@@H:7]([C:12]([Cl:15])([Cl:14])[Cl:13])[CH:8]=[C:9]([CH3:11])[CH3:10])=[O:5])=[N-]>O1CCOCC1.CC(CC(C)=O)=O.CC(CC(C)=O)=O.[Cu]>[CH3:10][C:9]1([CH3:11])[C@H:3]2[C@@H:8]1[C@H:7]([C:12]([Cl:15])([Cl:14])[Cl:13])[O:6][C:4]2=[O:5]
Reactant: CC(C)=C[C@@H](OC(=O)C=[N+]=[N-])C(Cl)(Cl)Cl
Agent: [Cu]
Solvent: CC(=O)CC(C)=O
Solvent: C1COCCO1
Product: CC1(C)[C@H]2[C@H](C(Cl)(Cl)Cl)OC(=O)[C@H]21
Yield: 90 %

Procedure:
A solution of (1R)-3-methyl-1-trichloromethyl-2-butenyl diazoacetate (0.90 g, 3.33 mmole) from Example IA.4.(a) in 15 ml of dry dioxane was added dropwise over a period of 2.6 hours to a catalytic amount (approximately 2 mole %) of cupric acetylacetonate in 65 ml of refluxing dry dioxane under a nitrogen atmosphere. After refluxing for an additional hour, the mixture was evaporated, and an etheral solution of the residue was washed with 1 N HCl, saturated NaHCO3, and saturated NaCl, then dried over MgSO4 and evaporated to give (1R,4R,5S)-6,6-dimethyl-2-oxo-4-trichloromethyl-3-oxabicyclo[3.1.0]hexane (0.73 g, 90% crude yield) as a green-yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:29])=[C:6]([C:8]2([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:7]=1.[CH3:30][S:31]([C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[N:38][CH:39]=1)(=[O:33])=[O:32]>>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[C:10]([NH2:18])=[N:9][C:8]2([C:6]1[CH:7]=[C:2]([C:36]2[CH:37]=[N:38][CH:39]=[C:34]([S:31]([CH3:30])(=[O:33])=[O:32])[CH:35]=2)[CH:3]=[CH:4][C:5]=1[F:29])[C:19]1[CH:24]=[CH:23][N:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=1
Reactant: NC1=NC(c2ccnc(C(F)(F)F)c2)(c2cc(Br)ccc2F)c2cccc(F)c21
Reactant: CS(=O)(=O)c1cncc(B(O)O)c1
Product: CS(=O)(=O)c1cncc(-c2ccc(F)c(C3(c4ccnc(C(F)(F)F)c4)N=C(N)c4c(F)cccc43)c2)c1
Yield: 58 %

Procedure:
The title compound was synthesized as described for Example 1 in 58% yield, starting from 1-(5-bromo-2-fluorophenyl)-4-fluoro-1-(2-(trifluoromethyl)pyridin-4-yl)-1H-isoindol-3-amine (64.8 mg, 0.14 mmol) and 5-(methylsulfonyl)pyridin-3-ylboronic acid (30.6 mg, 0.15 mmol).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6](I)=[C:5]([O:10][CH:11]([CH3:13])[CH3:12])[CH:4]=1)[CH3:2].O.[CH3:15][N:16](C)C=O>[C-]#N.[Zn+2].[C-]#N.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:15]#[N:16])=[C:5]([O:10][CH:11]([CH3:13])[CH3:12])[CH:4]=1)[CH3:2]
Reactant: CN(C)C=O
Reactant: CCc1ccc(I)c(OC(C)C)c1
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: CCc1ccc(C#N)c(OC(C)C)c1
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 56 %

Procedure:
4-Ethyl-1-iodo-2-isopropoxy-benzene (0.93 g, 3.2 mmol) was dissolved in dimethylformamide (5 mL). Zinc cyanide (226 mg, 1.92 mmol) was added. Argon gas was passed through the mixture for 10 min. Tetrakis(triphenylphosphine)-palladium(184 mg, 0.16 mmol) was added and the mixture was heated at 90° C. for 5 h. The reaction mixture was cooled to room temperature and poured into water. The mixture was extracted with diethyl ether. The organic extracts were washed with brine and dried over anhydrous magnesium sulfate. The solid was then filtered off, and the filtrate was concentrated in vacuo. Purification of the residue by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 10% diethyl ether in hexanes yielded 4-ethyl-2-isopropoxy-benzonitrile (0.34 g, 56%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26](O)=[O:27])[N:9]=2)[CH:7]=1.[N:33]1([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:36]3[CH2:35][CH2:34][N:33]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:38][CH2:37]3)=[O:27])[N:9]=2)[CH:7]=1
Reactant: O=C(O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 105.3 %

Procedure:
To a solution of {3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}acetic acid (200 mg) in DMF (5 mL) was added tert-butyl piperazine-1-carboxylate (77.5 mg, 0.42 mmol), DIEA (89.6 mg, 0.69 mmol), HATU (158.3 mg, 0.42 mmol). The resulting solution was stirred at room temperature for 3 h and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with 3% MeOH in DCM to afford 279 mg of tert-butyl 4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperazine-1-carboxylate as a yellow solid. LCMS (Method 22) [M+H]+=631.4, RT=1.49 min.
Reaction SMILES: [OH:1][CH2:2][C:3]([N-:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])([CH2:6][OH:7])[CH2:4][OH:5].[H]1[BH2][H][BH2]1>C1COCC1>[CH2:9]([NH:8][C:3]([CH2:6][OH:7])([CH2:4][OH:5])[CH2:2][OH:1])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCCCCCCC[N-]C(CO)(CO)CO
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCNC(CO)(CO)CO
Temperature: 0 °C
Reaction time: 8 h

Procedure:
2 g of the resulted N-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]octadecyl-amide were transferred to a three necks round bottom flask equipped with a dropping funnel, a cooling bath, and a magnetic stirrer. The compound was dissolved in 50 ml dry THF and the solution was cooled to 0° C. 40 ml of 1.0 M solution of B2H6 in THF (borane tetrahydrofuran complex) were added dropwise through the dropping funnel during 2 hours and then the mixture was left to react for another 2 hours at 0° C. The cooling bath was removed and the reaction was left to stir overnight. The next day, 10 ml of H2O were added slowly and the solution was evaporated to dryness, transferred to a separatory funnel, and 100 ml water, 100 ml dichloromethane and 50 ml methanol were added. Following shaking, the lower phase was collected and the upper, aqueous-methanolic phase was extracted twice with 50 ml CH2Cl2:MeOH, 3:1. The combined organic phases were washed with 100 ml H2O, dried for 2 hours over MgSO4, filtered and the solution was evaporated to dryness. The resulted product was crystallized from ethanol:H2O. Yield: 0.9 g.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:5]([CH2:15][CH3:16])=[C:6]([CH3:14])[C:7]2[N:8]([C:10]([NH2:13])=[N:11][N:12]=2)[N:9]=1.[OH2:17].ClCCl>CCC(O)CC.CN(C=O)C>[CH2:15]([C:5]1[C:4]([O:17][CH:5]([CH2:15][CH3:16])[CH2:6][CH3:7])=[N:9][N:8]2[C:10]([NH2:13])=[N:11][N:12]=[C:7]2[C:6]=1[CH3:14])[CH3:16]
Reactant: O
Reactant: CCc1c(Cl)nn2c(N)nnc2c1C
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCC(O)CC
Solvent: CN(C)C=O
Product: CCc1c(OC(CC)CC)nn2c(N)nnc2c1C
Reaction time: 8 h

Procedure:
3-Pentanol (2.5 ml) was initially charged at RT with stirring. Thereafter, sodium hydride (91 mg) was added while cooling with ice. After stirring at 55° C. for 2.5 h, 6-chloro-7-ethyl-8-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine (W2.007; 120 mg), dissolved in 3-pentanol (2 ml) and DMF (4 ml), was added dropwise. After stirring for 1 h, the mixture was left to stand at RT overnight, and the reaction mixture was admixed with water and dichloromethane and then extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and, after the desiccant had been filtered off, dried under reduced pressure. 126 mg of the title compound were obtained.
Reaction SMILES: [C:1]([O:8]CC)(=O)[C:2]([O:4]CC)=O.[CH3:11][NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH2:19]>>[CH3:11][N:12]1[C:13]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:19][C:1](=[O:8])[C:2]1=[O:4]
Reactant: CNc1ccccc1N
Reactant: CCOC(=O)C(=O)OCC
Product: Cn1c(=O)c(=O)[nH]c2ccccc21
Temperature: 25 °C

Procedure:
N-Methyl-1,4-dihydro-2,3-quinoxalinedione was prepared using an adaptation of the method of Cheeseman (J. Chem. Soc. 1171 (1962)). A mixture of diethyl oxalate (3.23 g, 22.1 mmol) and N-methyl-1,2-diaminobenzene (332 mg, 2.72 mmol) was heated to reflux under N2 for 2 h. The reaction was allowed to cool to room temperature and the solid collected by vacuum filtration and rinsed with EtOH. The gray brown solid was further dried under vacuum (0.1 torr, 25° C.) to give 274.3 mg (57.2%). A portion of this solid was further purified by recrystallization from 50 mL EtOH and treatment with activated charcoal to give fluffy pale yellow crystals which were collected by vacuum filtration and rinsed with cold EtOH to yield 104.9 mg. 1H NMR (d6 -DMSO) δ 3.50 (s, 3H, CH3), 7.16 (m, 3H, ArH), 7.36 (m, 1H, ArH), 12.01 (s, 1H, NH). EIMS 176 (M+, 52), 148 (33), 119 (100, bp).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:20]=[CH:19][C:18]2[NH:17][C:16]3[C:11](=[CH:12][C:13]([NH:21][C:22](=[O:26])[CH2:23][CH2:24]Cl)=[CH:14][CH:15]=3)[C:10](=[O:27])[C:9]=2[CH:8]=1)=[O:5].[CH3:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][NH:30]1>>[CH3:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][N:30]1[CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:20]=[CH:19][C:18]2[NH:17][C:16]3[C:11](=[CH:12][C:13]([NH:21][C:22](=[O:26])[CH2:23][CH2:24][N:17]4[CH2:18][CH2:9][CH2:10][CH2:11][CH:16]4[CH3:15])=[CH:14][CH:15]=3)[C:10](=[O:27])[C:9]=2[CH:8]=1)=[O:5]
Reactant: CC1CCCCN1
Reactant: O=C(CCCl)Nc1ccc2[nH]c3ccc(NC(=O)CCCl)cc3c(=O)c2c1
Product: CC1CCCCN1CCC(=O)Nc1ccc2[nH]c3ccc(NC(=O)CCN4CCCCC4C)cc3c(=O)c2c1

Procedure:
Chloroamide 13 (1.0 g, 2.5 mmol) was treated with 2-methylpiperidine (5 mL) according to the general aminolysis procedure to give the desired product JM-ACO-06 (916 mg, 69%) as a pale yellow/green solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)[CH3:2].[CH3:9][C:10]1[CH:18]=[CH:17][C:13]([CH2:14][CH2:15]Br)=[CH:12][CH:11]=1>>[CH3:9][C:10]1[CH:18]=[CH:17][C:13]([CH2:14][CH2:15][CH:1]([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH3:2])=[CH:12][CH:11]=1
Reactant: Cc1ccc(CCBr)cc1
Reactant: CCc1ccncc1
Product: Cc1ccc(CCC(C)c2ccncc2)cc1
Yield: 98.3 %

Procedure:
1.0 g (9.35 mmol) of 4-ethylpyridine and 1.86 g (9.35 mmol) of 4-methylphenethyl bromide were reacted in the same manner as in Example 1. The reaction product was purified to obtain 2.07 g of the desired compound (yield: 98.4%). The resulting compound was identified as 1-(4-methylphenyl)-3-(4-pyridyl)-butane (hereinafter referred to as compound 7) by the following analytical results.
Reaction SMILES: OC1C=CC=C2C=1[NH+]=CC=C2.[O:12]=[C:13]1[C@@H:16]([NH:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[C@H:15]([CH3:28])[N:14]1S([O-])(=O)=O>C(#N)C>[C:22]1([CH2:21][O:20][C:18]([NH:17][C@H:16]2[C@H:15]([CH3:28])[NH:14][C:13]2=[O:12])=[O:19])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C[C@H]1[C@H](NC(=O)OCc2ccccc2)C(=O)N1S(=O)(=O)[O-]
Agent: Oc1cccc2ccc[nH+]c12
Solvent: CC#N
Product: C[C@@H]1NC(=O)[C@H]1NC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 110 %

Procedure:
A solution of (3S-trans)-2-oxo-3-[[(phenylmethoxy)carbonyl]amino]-4-methyl-1-azetidinesulfonic acid, 8-hydroxyquinolinium salt (150 mg, 0.326 mmol) in acetonitrile (10 ml) was brought rapidly to reflux by lowering the reaction vessel into a preheated oil bath. The mixture was refluxed for a total of 9 minutes during which time a precipitate formed. After cooling to room temperature, the mixture was filtered and solvent was removed from the filtrate in vacuo. The resulting residue was partially dissolved in a small amount of acetonitrile and the addition of ethyl acetate caused further precipitation. After decanting the supernatant, the procedure was repeated on the solid. The remaining solid was triturated with ethyl acetate and decanted. The supernatants were filtered through Celite, combined, and solvent was removed under reduced pressure yielding an oil (84 mg). The crude product was purified by column chromatography on silica gel (2 g, Mallinckrodt SilicAR CC-4). Elution with 5% acetonitrile: 95% ethyl acetate afforded the desired product (56 mg).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([SH:27])=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:26]=[CH:25][C:24]([S:27][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=3[CH:19]=2)=[CH:23][CH:22]=1
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCCl)cc21
Reactant: Fc1ccc(S)cc1
Product: CC1(C)OC(=O)Nc2ccc(OCCCCSc3ccc(F)cc3)cc21

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-fluoro-thiophenol.