Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:39])[CH2:15][NH:16][C:17]([C:19]2[C:20]([O:37][CH3:38])=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][N:23]=[C:22]3/[CH:28]=[CH:29]/[C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[O:18])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[O:39]=[C:14]([N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[CH2:15][NH:16][C:17]([C:19]1[C:20]([O:37][CH3:38])=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][N:23]=[C:22]2/[CH:28]=[CH:29]/[C:30]1[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=1)=[O:18]
Reactant: COc1c(C(=O)NCC(=O)N2CCN(C(=O)OC(C)(C)C)CC2)ccc2[nH]nc(/C=C/c3ccc(F)cc3)c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1c(C(=O)NCC(=O)N2CCNCC2)ccc2[nH]nc(/C=C/c3ccc(F)cc3)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-[2-({3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carbonyl}-amino)-acetyl]-piperazine-1-carboxylic acid tert-butyl ester obtained by Example 1215 was dissolved in 1 mL of dichloromethane, added with 1 mL of trifluoroacetic acid, and stirred at room temperature for 2 hours. The solvent was evaporated, followed by purification by LC-MS, to afford the title compound.
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[Cl:23][C:24]1[CH:25]=[CH:26][C:27]2[C:33](=[O:34])[C:32](I)=[C:31]([O:36][CH3:37])[C:30](=[O:38])[NH:29][C:28]=2[CH:39]=1.[C:40]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])(=[O:43])[CH:41]=[CH2:42].C(N(CC)CC)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:45]([O:44][C:40](=[O:43])/[CH:41]=[CH:42]/[C:32]1[C:33](=[O:34])[C:27]2[CH:26]=[CH:25][C:24]([Cl:23])=[CH:39][C:28]=2[NH:29][C:30](=[O:38])[C:31]=1[O:36][CH3:37])([CH3:48])([CH3:47])[CH3:46]
Reactant: COc1c(I)c(=O)c2ccc(Cl)cc2[nH]c1=O
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1c(/C=C/C(=O)OC(C)(C)C)c(=O)c2ccc(Cl)cc2[nH]c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 76.3 %

Procedure:
A solution of tris(dibenzylidenacetone)dipalladium (O) (0.0163 g) in toluene (39 mL) was treated with tri-orthotolylphosphine (0.0815 g). The solution was stirred under argon at room temperature for 15 minutes and then it was treated with 8-chloro-4-iodo-3-methoxy-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (1.22 g) followed by tert-butyl acrylate (7.30 mL, 6.45 g). The mixture was then treated with triethylamine (0.47 mL, 0.34 g) and it was heated to 105° C. for 35 minutes. The mixture was cooled and concentrated to a dark solid. The solid was dissolved in chloroform and chromatographed on a silica gel column (5.5 cm diameter×20 cm long) using 25% ethyl acetate in hexane to give a light yellow solid (0.932 g). A portion of the solid (0.294 g) was dissolved in warm ethyl acetate (5 mL) and then it was concentrated to 3 mL volume. Hexane (1 mL) was added to the solution and crystals formed. The solid was filtered off, washed with cold ethyl acetate, washed with hexane, and dried to give a white solid (0.21 g); mp 213.2°-213.8° C. (dec); 1H NMR (CDCl3) 7.67 (d,1, J=16), 6.61 (d,1, J=16) for trans olefin protons; MS: m/z=308 (base peak), 364 (M+1). Analysis for C18H18ClNO5 : Calculated: C, 59.43; H, 4.99; N, 3.85; Found: C, 59.22; H, 4.92; N, 3.79.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([NH:12][S@](C(C)(C)C)=O)[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([Br:11])[CH:5]=1.N1C=CC=CC=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].Cl>C(Cl)Cl>[NH2:12][C@@H:3]([C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([Br:11])[CH:5]=1)[CH2:2][NH:1][C:25](=[O:27])[CH3:26]
Reactant: CC(C)(C)[S@](=O)N[C@H](CN)c1cc(F)cc(Br)c1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)NC[C@@H](N)c1cc(F)cc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)—N—((S)-2-amino-1-(3-bromo-5-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (100 mg, 0.297 mmol) was dissolved in DCM (988 μl), followed by pyridine (71.9 μl, 0.890 mmol) and acetic anhydride (28.0 μl, 0.297 mmol). The reaction mixture was stirred at room temperature for 1 h, extracted by EtOAc, washed by water and brine, dried over Na2SO4and concentrated. The residue was dissolved in Et2O (1 mL), then HCl (4 M in dioxane) (148 μl, 0.593 mmol) was added. The reaction mixture was stirred at room temperature for 30 min. After the solvent was decant out, the residue solid was used in next step reaction without purification. LCMS (m/z): 275.1/277.1 (MH+), 0.41 min.
Reaction SMILES: [C:1]([O:6][OH:7])([CH2:4][CH3:5])([CH3:3])[CH3:2].OC([C:12]1[CH:17]=[CH:16][C:15]([C:18]([OH:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=1)(C)C.S(=O)(=O)(O)O>O>[C:1]([O:6][O:7][C:12]([C:13]1[CH:12]=[CH:17][CH:16]=[C:15]([C:18]([O:21][O:21][C:18]([CH2:15][CH3:14])([CH3:20])[CH3:19])([CH3:19])[CH3:20])[CH:14]=1)([CH3:17])[CH3:13])([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(O)c1ccc(C(C)(C)O)cc1
Reactant: CCC(C)(C)OO
Agent: O=S(=O)(O)O
Solvent: O
Product: CCC(C)(C)OOC(C)(C)c1cccc(C(C)(C)OOC(C)(C)CC)c1

Procedure:
1,4-Bis(2-t-amylperoxy-2-propyl)benzene (para III) was prepared by reacting 28.1 grams (0.231 mole) of aqueous 85.7% t-amyl hydroperoxide diluted with 3.2 grams of water with 20.4 grams (0.105 mole) of 1,4-bis(2-hydroxy-2-propyl)benzene in the presence of 44.1 grams (0.316 mole) of 70% sulfuric acid according to the procedure of Example VII. The stripped product was a yellow liquid which remained liquid at 15° C. The product weighed 32.0 grams.
Reaction SMILES: [C:1]1([S:7]([C:10]#[N:11])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]1([CH3:18])[CH:17]=CC=[CH:14][CH:13]=1>C(O)CCC>[C:1]1([S:7]([C:10]2[CH:14]=[CH:13][C:12]([CH3:18])=[CH:17][N:11]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CS(=O)(=O)c1ccccc1
Reactant: Cc1ccccc1
Solvent: CCCCO
Product: Cc1ccc(S(=O)(=O)c2ccccc2)nc1
Temperature: 110 °C
Yield: 88 %

Procedure:
First, 8.40 g (100 mmol) tiglic aldehyde (trans-2-methyl-2-butenal) and 8.35 g (50.0 mmol) of benzenesulfonyl cyanide were introduced to the same reaction vessel as in Example 1. Toluene (15 ml) as the solvent and butanol (1.5 ml) were added, and the mixture was heated under reflux for 3 hours while agitating at an internal temperature of 110° C. in a nitrogen atmosphere, separating and removing water that was produced. After this solution was cooled to room temperature, the low-boiling components, such as solvent, etc., were removed under reduced pressure and the resulting concentrate was cooled in an ice bath to precipitate crystals. The crystals were filtered with a glass filter and washed with 10 ml of toluene that had been cooled to 5° C. or lower. Then the crystals were dried for 2 hours in vacuo to give 10.5 g of 2-benzenesulfonyl-5-methylpyridine with the following properties as colorless crystals (purity of 99%, yield of 88% based on benzenesulfonyl cyanide).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:22]Cl)[CH2:10][CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[I:33])[C:28]#[N:29].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:22][O:24][C:25]1[CH:26]=[C:27]([C:28]#[N:29])[CH:30]=[CH:31][C:32]=1[I:33])[CH2:10][CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1ccc(I)c(O)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCl)CCC(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](CCC(=O)OCc1ccccc1)COc1cc(C#N)ccc1I

Procedure:
8.29 g (24.3 mmol) of benzyl (4R)-4-t-butoxycarbonylamino-5-chloropentanoate, 6.9 g (28.0 mmol) of 3-hydroxy-4-iodobenzonitrile, 6.9 g (50 mmol) of potassium carbonate and 4.15 g (25 mmol) of potassium iodide were stirred together in 80 ml of DMF at 70° C. for 3 days. The solvent was evaporated, and the crude product obtained by an ordinary method with ethyl acetate as the extracting solvent was purified by the silica gel chromatography (ethyl acetate/hexane) to obtain the title compound.
Reaction SMILES: O[CH:2]([C:12]1[CH:13]=[C:14]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[C:15]([NH:17][C:18]1([C:27]([OH:29])=[O:28])[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1)=[O:16])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=1.Cl.[H][H]>C(O)C.CO.[Pd]>[CH3:34][O:33][C:32]1[CH:31]=[CH:30][C:14]([C:15]([NH:17][C:18]2([C:27]([OH:29])=[O:28])[CH2:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:26]2)=[O:16])=[CH:13][C:12]=1[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=1
Reactant: COc1ccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)cc1C(O)COc1cccc(C)c1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCO
Product: COc1ccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)cc1CCOc1cccc(C)c1

Procedure:
The compound of example 114 (20 mg, 0.043 mmol) was dissolved in ethanol (2 ml), a 0.5 M solution of hydrogen chloride in methanol (0.2 ml) was added and the mixture was hydrogenated overnight in the presence of palladium on charcoal (10%) at room temperature at a hydrogen pressure of 5 bar (complete conversion of the starting compound). After filtration over a small plug of silica gel and evaporation, the residue was purified by preparative RP HPLC (water/ACN gradient).
Reaction SMILES: CCN(CC)CC.[O:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]([NH2:21])=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:10][CH2:9]1.[C:22]([O:26][C:27]([NH:29][C@@H:30]([CH3:34])[C:31](O)=[O:32])=[O:28])([CH3:25])([CH3:24])[CH3:23].C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:22]([O:26][C:27](=[O:28])[NH:29][C@H:30]([C:31](=[O:32])[NH:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[NH:14][CH:11]1[CH2:10][CH2:9][O:8][CH2:13][CH2:12]1)[CH3:34])([CH3:23])([CH3:24])[CH3:25]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ccccc1NC1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccccc1NC1CCOCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83.5 %

Procedure:
Et3N (2.6 mL, 18.9 mmol) was added to a stirred mixture of N-(tetrahydropyran-4-yl)benzene-1,2-diamine (1.21 g, 6.29 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (1.31 g, 6.92 mmol), HOAt (0.94 g, 6.92 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.33 g, 6.92 mmol) in anhydrous DCM (30 mL) at 0° C. under a nitrogen atmosphere. Stirring was continued for 10 min at 0° C. then the mixture was slowly warmed to RT and stirred at RT for 4 h. The reaction mixture was partitioned between DCM and a saturated solution of NaHCO3. The aqueous phase was further extracted with DCM and the combined organic layers were then washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-4% 2M NH3/MeOH in DCM) affording {(S)-1-[2-(Tetrahydropyran-4-ylamino)phenylcarbamoyl]ethyl}carbamic acid tertbutyl ester as a white solid (1.91 g, 83%). LCMS: RT 2.78 min [M+H-tBu]+ 308.1.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:20]=[CH:19][C:9]([CH2:10]P(=O)(OCC)OCC)=[CH:8][CH:7]=1)([O-:5])=[O:4].[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O.C(OCC)(=O)C>CN(C)C=O>[F:21][C:22]1[CH:29]=[CH:28][CH:27]=[C:24](/[CH:25]=[CH:10]/[C:9]2[CH:8]=[CH:7][C:6]([N+:3]([O-:5])=[O:4])=[CH:20][CH:19]=2)[CH:23]=1
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])cc1)OCC
Reactant: O=Cc1cccc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(/C=C/c2cccc(F)c2)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 81.9 %

Procedure:
A suspension of 677 mg of sodium hydride (55% dispersion in oil) in 10 ml of N,N-dimethylformamide is cooled to 0° C. Thereupon, 5.61 g (20.5 mmol) of diethyl (4-nitrobenzyl)phosphonate are added portionwise. The reaction mixture is left to warm to RT and stirred for 1.5 hours. Thereafter, the mixture is cooled to −10° C. and a solution of 1.5 g (12.1 mmol) of 3-fluorobenzaldehyde in 5 ml N,N-dimethylformamide is added dropwise. Stirring is continued for 30 min at 0° C., then at RT. For the working-up, ice and ethyl acetate are added to the reaction mixture. The organic layer is separated, dried over magnesium sulfate and evaporated under reduced pressure to yield the crude crystalline product, which after recrystallisation from a mixture of ether and heptane gives 2.41 g (82% of theory) of (E)-1-fluoro-3-[2-(4-nitrophenyl)ethenyl]-benzene as a yellow solid; MS: m/e=243(M)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:11]2[N:12]=[C:13]([NH:15][C:16]([NH:18][CH2:19][CH3:20])=[O:17])[N:14]=[C:10]2[CH:9]=[C:8]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[CH:7]=1)=O)C.[BH4-].[Na+]>C1COCC1.CO>[CH2:19]([NH:18][C:16]([NH:15][C:13]1[N:14]=[C:10]2[CH:9]=[C:8]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:7]=[C:6]([CH2:4][OH:3])[N:11]2[N:12]=1)=[O:17])[CH3:20]
Reactant: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(C(=O)OCC)n2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(CO)n2n1
Reaction time: 1 h

Procedure:
To a stirring suspension of the product of Step 2, (0.88 g, 2.5 mmol) in THF (40 mL) and MeOH (5 mL) was added sodium borohydride (1.02 g, 27 mmol). After 1 h the reaction was quenched by the addition of ca. 50 mL water and stirred 1 h to allow formation of a precipitate. The solid was rinsed with water (3×10 mL) and dried in vacuo to give the alcohol, 1-ethyl-3-(5-hydroxymethyl-7-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-urea as a solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[OH:8][C:9]1[C:17]2[N:16]=[C:15]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:14]([CH2:27][CH2:28][CH2:29][CH:30]3[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]3)[C:13]=2[CH:12]=[CH:11][CH:10]=1.[H-].[Na+].[CH:45](Br)([CH3:47])[CH3:46]>CN(C)C=O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:45]([O:8][C:9]1[C:17]2[N:16]=[C:15]([CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)[N:14]([CH2:27][CH2:28][CH2:29][CH:30]3[CH2:31][CH2:32][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34][CH2:35]3)[C:13]=2[CH:12]=[CH:11][CH:10]=1)([CH3:47])[CH3:46]
Reactant: CC(C)(C)OC(=O)N1CCC(CCCn2c(COc3ccc(Cl)cc3)nc3c(O)cccc32)CC1
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)Oc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C

Procedure:
A solution of 4-hydroxy-2-[(4-chlorophenoxy)methyl]-1-[3-[1-(t-butoxycarbonyl)piperidin-4-yl]propyl]benzimidazole trifluoroacetate (300 mg, 0.6 mmol, 1 eq) in anhydrous N,N-dimethylformamide (3 m) was treated with sodium hydride (60% in mineral oil, 26 mg, 0.66 mmol, 1.1 eq). The resulting mixture was stirred for thirty minutes at room temperature. Isopropyl bromide (0.66 mmol, 1 eq) was added to the reaction and the resulting mixture was stirred for two hours at room temperature. The reaction was quenched with the addition of water (5 ml). The aqueous fraction was extracted with ethyl acetate (3×10 ml). The organic fractions were combined, washed with water (2×10 ml), then brine (1×10 ml), and then dried over sodium sulfate. The solvents were removed in vacuo. The residue was further purified by flash column chromatography to yield the title product as a crystalline product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH2:23])=[C:16]2[N:15]=1.[OH:24][C@@H:25]1[CH2:29][CH2:28][C@H:27]([C:30](O)=[O:31])[CH2:26]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH:23][C:30]([C@H:27]3[CH2:28][CH2:29][C@@H:25]([OH:24])[CH2:26]3)=[O:31])=[C:16]2[N:15]=1
Reactant: O=C(O)[C@H]1CC[C@@H](O)C1
Reactant: Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: O=C(Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12)[C@H]1CC[C@@H](O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.2 %

Procedure:
A DMA (1 mL) solution of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (Preparation B; 50 mg, 0.16 mmol), (1S,3R)-3-hydroxycyclopentanecarboxylic acid (23 mg, 0.17 mmol) [purchased from AFID Therapeutics Inc.] and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) (56 mg, 0.17 mmol) was first cooled in an ice-water bath, then DIEA (0.083 mL, 0.48 mmol) was added to reaction drop-wise. Ice bath was then removed and the reaction was stirred at ambient temperature for 1 hour to reach completion. The reaction mixture was diluted with water (10 mL) and vacuum-filtered, yielding the crude product as a beige solid. The crude was purified by reverse phase column chromatography, eluting with 5 to 57% acetonitrile/water to yield the final product as a solid (20 mg, 30% yield). MS (apci) m/z=428.2 (M+H).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:13][NH:14][C:15]([N:17]1[C:25]2[C:20](=[CH:21][C:22]([O:26][C:27]3[CH:32]=[CH:31][N:30]=[C:29]([N:33](C(OC4C=CC=CC=4)=O)[C:34](=O)[O:35]C4C=CC=CC=4)[CH:28]=3)=[CH:23][CH:24]=2)[CH:19]=[CH:18]1)=[O:16]>CN(C)C=O>[CH3:13][NH:14][C:15]([N:17]1[C:25]2[C:20](=[CH:21][C:22]([O:26][C:27]3[CH:32]=[CH:31][N:30]=[C:29]([NH:33][C:34]([N:2]4[CH2:5][CH2:4][CH2:3]4)=[O:35])[CH:28]=3)=[CH:23][CH:24]=2)[CH:19]=[CH:18]1)=[O:16]
Reactant: CNC(=O)n1ccc2cc(Oc3ccnc(N(C(=O)Oc4ccccc4)C(=O)Oc4ccccc4)c3)ccc21
Reactant: C1CNC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)N4CCC4)c3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.6 %

Procedure:
Azetidine hydrochloride (104 mg, 1.11 mmol) and triethylamine (0.155 ml, 1.11 mmol) were added to a dimethylformamide (1 ml) solution of phenyl N-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate (116 mg, 0.222 mmol) synthesized in Production example 5-2; and the reaction mixture was stirred overnight at room temperature. The reaction mixture was partitioned between ethyl acetate and water; the organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with a solvent mixture of ether-hexane=1:1; and the resultant solid was filtered off to yield the title compound (50 mg) as crystals.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.CN(C)C=O.CS(O[CH:17]1[CH2:20][CH:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:18]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[CH2:22]([O:21][CH:19]1[CH2:18][CH:17]([N:4]2[CH:3]=[C:2]([I:1])[CH:6]=[N:5]2)[CH2:20]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CS(=O)(=O)OC1CC(OCc2ccccc2)C1
Reactant: Ic1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Ic1cnn(C2CC(OCc3ccccc3)C2)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
A 250-mL round-bottom flask was charged with 4-iodo-1H-pyrazole (1.97 g, 10.2 mmol), N,N-dimethylformamide (20 mL), 3-(benzyloxy)cyclobutyl methanesulfonate (2.60 g, 10.2 mmol) and cesium carbonate (9.75 g, 29.9 mmol), and the resulting mixture stirred overnight at 80° C. The reaction mixture was cooled to room temperature, poured into water (50 mL), and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford 1-(3-(benzyloxy)cyclobutyl)-4-iodo-1H-pyrazole (3.00 g, 83%) as yellow oil. MS (ESI, pos. ion) m/z 355 [M+H]+.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[CH2:5]([O:7][C:8]([C:10]1[C:11]([CH3:25])=[N:12][S:13][C:14]=1[NH:15][C:16]([O:18]C1C=CC=CC=1)=O)=[O:9])[CH3:6]>C(O)C>[CH2:5]([O:7][C:8]([C:10]1[C:11]([CH3:25])=[N:12][S:13][C:14]=1[NH:15][C:16]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:18])=[O:9])[CH3:6]
Reactant: CC(C)N
Reactant: CCOC(=O)c1c(C)nsc1NC(=O)Oc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1c(C)nsc1NC(=O)NC(C)C

Procedure:
A solution of isopropylamine in ethanol (33% w/v; 30 ml.) was added, cautiously with swirling, to 4-ethoxycarbonyl-3-methyl-5-phenoxycarbonylaminoisothiazole (prepared according to the method of Goerdeler and Horn, Chemische Berichte, 1963, 96, 1551; 30 g.). When the initial exothermic reaction had subsided the mixture was heated at reflux for 10 minutes, cooled and filtered. The solid was washed with water, and dried to give 1-(4-ethoxycarbonyl-3-methylisothiazol-5-yl)-3-isopropylurea (20.8 g.), m.p. 175°-176° C.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[CH2:11]([O:13][C:14]1[C:19]([C:20]2([OH:33])[C:28]3[C:23](=[CH:24][C:25]([F:31])=[C:26]([C:29]#[N:30])[CH:27]=3)[NH:22][C:21]2=[O:32])=[CH:18][CH:17]=[CH:16][N:15]=1)[CH3:12]>N1C=CC=CC=1.ClCCl>[C:29]([C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][C:25]=1[F:31])[N:22]([C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3])[C:21](=[O:32])[C:20]2([C:19]1[C:14]([O:13][CH2:11][CH3:12])=[N:15][CH:16]=[CH:17][CH:18]=1)[O:33][C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3])#[N:30]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCOc1ncccc1C1(O)C(=O)Nc2cc(F)c(C#N)cc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOc1ncccc1C1(OC(=O)Oc2ccccc2)C(=O)N(C(=O)Oc2ccccc2)c2cc(F)c(C#N)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.7 %

Procedure:
330 μl (2.62 mmol) of phenyl chloroformate were slowly added dropwise to a solution, cooled to 0° C., of 342 mg (0.66 mmol; 60% purity) of 3-(2-ethoxypyridin-3-yl)-6-fluoro-3-hydroxy-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile (mother liquor from example a.2) in 8 ml of pyridine, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and extracted with water. The organic phase was washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (Redisep cartridge, mobile phase gradient from 0 to 5% methanol in dichloromethane). 291 mg of the title compound were obtained.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)[N:3]=1.[NH2:28][C:29]1[CH:39]=[CH:38][CH:37]=[CH:36][C:30]=1[C:31]([N:33]([CH3:35])[CH3:34])=[O:32]>>[CH3:34][N:33]([CH3:35])[C:31]([C:30]1[CH:36]=[CH:37][CH:38]=[CH:39][C:29]=1[NH:28][C:2]1[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)[N:3]=1)=[O:32]
Reactant: CN(C)C(=O)c1ccccc1N
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccccc3C(=O)N(C)C)n2)cc1)OCC

Procedure:
The title compound was prepared using the procedure for Example 102 with diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate and the commercially available 2-amino-N,N-dimethylbenzamide. MS (ES+): m/z 552.38 (100) [MH+]; HPLC: tR=0.96 min (UPLC, purity).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:12]=1[CH:13]([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16].CN([CH:23]=[O:24])C>C1COCC1>[CH2:15]([O:14][CH:13]([O:17][CH2:18][CH3:19])[C:12]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[CH:23]=[O:24])[CH3:16]
Reactant: CN(C)C=O
Reactant: CCOC(OCC)c1ccncc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(OCC)c1ccncc1C=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 78.7 %

Procedure:
BuLi (5.84 mL, 9.35 mmol) was added to a solution of 3-bromo-4-diethoxymethyl-pyridine (2.21 g, 8.50 mmol) in THF (50 mL) at −78° C. After 1 h, DMF (6.58 mL, 85 mmol) was added. The reaction was stirred at −78° C. for 1 hr. It was then warmed to room temperature, quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated in vacuo to afford 1.4 g of 4-diethoxymethyl-pyridine-3-carbaldehyde, which was taken in the next step without further purification. MS (ESI) m/z 210.1 (M+H)+