Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([Br:23])[CH:17]=1)[C:10]([CH3:25])([CH3:24])[CH:9]2O)=[O:5])[CH3:2].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([Br:23])[CH:17]=1)[C:10]([CH3:24])([CH3:25])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1cc(C)cc(Br)c1)N2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(C)cc(Br)c1)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.1 %

Procedure:
To a mixture of 2-(3-bromo-5-methyl-phenyl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (6.1 g, 14.6 mmol) and triethylsilane (20 mL) at 25° C. was added trifluoroacetic acid (10 mL) dropwise. The resulting mixture was stirred at 25° C. for 1 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×100 mL), washed with saturated aqueous sodium bicarbonate solution (2×50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (10% ethyl acetate/hexanes) to afford 2-(3-bromo-5-methyl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (3.12 g, 42%) as a white solid: LC/MS m/e calcd for C21H24BrNO2 M+: 402.3, observed: 402.1, 404.1.
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[CH:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:8]=2)[CH2:3]1.[Br:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Br:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH:1][CH:2]2[CH2:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:11]([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)=[CH:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:8]=3)[CH2:3]2)(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: COC(=O)CCCC=C(c1cccnc1)c1ccc2c(c1)CC(N)C2
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)CCCC=C(c1cccnc1)c1ccc2c(c1)CC(NS(=O)(=O)c1ccc(Br)cc1)C2

Procedure:
3.4 g of methyl 6-(2-aminoindan-5-yl)-6-(3-pyridyl)hex-5-enoate is placed in 40 ml of chloroform together with 3.3 g of 4-bromobenzenesulphonic acid chloride and 1.8 g of triethylamine are added in batches at ambient temperature. After 30 minutes the solution is washed with water, dried and rotary evaporated. The yellow oil is then chromatographed over a silica gel column using cyclohexane/ethyl acetate (1:2).
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][C:6](O[Si](C)(C)C)=[C:5](O[Si](C)(C)C)[CH2:4]1)[CH3:2].Cl.Cl.[NH2:20][CH2:21][C:22]([NH2:24])=[NH:23]>>[CH2:1]([N:3]1[CH2:7][C:6]2[C:5](=[N:23][C:22]([NH2:24])=[CH:21][N:20]=2)[CH2:4]1)[CH3:2]
Reactant: CCN1CC(O[Si](C)(C)C)=C(O[Si](C)(C)C)C1
Reactant: N=C(N)CN
Agent: Cl
Product: CCN1Cc2ncc(N)nc2C1

Procedure:
This compound was prepared analogous to Example 22 from 1-ethyl-2,5-dihydro-3,4-bis(trimethylsilyloxy)-pyrrole and α-amino-acetamidine dihydrochloride.
Reaction SMILES: C(O[N:7]([CH2:10][CH3:11])[CH2:8][CH3:9])(=O)C(C)=C.[C:12]([O:17][CH3:18])(=[O:16])[C:13]([CH3:15])=[CH2:14].Cl.Cl.N(C(C(=N)N)(C)C)=N[C:23](C(=N)N)(C)C>O>[C:12]([O:17][CH2:18][CH2:23][N:7]([CH2:8][CH3:9])[CH2:10][CH3:11])(=[O:16])[C:13]([CH3:15])=[CH2:14].[C:12]([O:17][CH3:18])(=[O:16])[C:13]([CH3:15])=[CH2:14]
Reactant: CC(C)(N=NC(C)(C)C(=N)N)C(=N)N
Reactant: C=C(C)C(=O)ON(CC)CC
Agent: C=C(C)C(=O)OC
Agent: Cl
Solvent: O
Product: C=C(C)C(=O)OCCN(CC)CC
Temperature: 60 °C

Procedure:
In a flask equipped with a stirring blade and a tube for nitrogen introduction were charged 1,500 parts of ion-exchanged water and heated to 60° C. Twenty parts of diethylamino methacrylate and 60 parts of methyl methacrylate were added thereto while stirring. To the mixture were further added 20 parts 2,2'-azobis(2-amidinopropane) dihydrochloride ("V-50" produced by Wako Pure Chemical Ind. Ltd.) and 10 parts of 2,2'-azobis(2-methyl-N-(1,1'-bis(hydroxymethyl)-2-hydroxyethyl)propionamide) ("V-080" produced by Wako Pure Chemical Ind. Ltd.), followed by heating to 65° C., at which the mixture was subjected to soap-free polymerization for 24 hours. After completion of the reaction, the fine particles thus produced were washed with 5,000 parts of ion-exchanged water by means of a centrifugal separator to obtain fine particles of a diethylaminoethyl methacrylate/methyl methacrylate copolymer having an amidino hydrochloride group and a hydroxyl group on the surface thereof and having an average particle size of 0.5 μm.
Reaction SMILES: [C:1]1([OH:9])[C:2]([CH3:8])=[CH:3][CH:4]=[C:5]([CH3:7])[CH:6]=1.S(=O)(=O)(O)O.[CH3:15][C:16](=[CH2:18])[CH3:17]>O.C([O-])(O)=O.[Na+]>[C:16]([C:4]1[CH:3]=[C:2]([CH3:8])[C:1]([OH:9])=[CH:6][C:5]=1[CH3:7])([CH3:18])([CH3:17])[CH3:15]
Reactant: Cc1ccc(C)c(O)c1
Reactant: C=C(C)C
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1cc(C(C)(C)C)c(C)cc1O
Yield: 49 %

Procedure:
2,5-Xylenol (90 g, 0.73 mol) was melted at 80° C., 1 mL of concentrated sulfuric acid was added, and the mixture was heated at 90° C. while isobutylene gas was introduced subsurface over 4 hours. The reaction appeared to stall at about 80% conversion. The reaction mass was diluted with water and neutralized with NaHCO3, and some starting xylenol was removed by steam-distillation. Since the steam-distillation did not completely remove the starting material, the residue was dissolved in hot hexanes, separated from the aqueous phase, and cooled in an ice-bath. The precipitated product was filtered and washed with cold hexanes to give 64 g (49%) of 4-t-Butyl-2,5-xylenol; lit.(Stevens, Ind. Eng. Chem. 1943, 655; Parc, Rev. Inst. Fr. Pet. 1960, 680) mp 70-72° C. 1H-NMR (CDCl3) δ 1.37, (s, 9H), 2.20 (s, 3H), 2.43 (s, 3H), 4.85 (s, 1H), 6.53 (s, 1H), 7.08 (s, 1H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-].[Na+].[OH-].[Na+].[O:10]1[CH:19]2[CH:11]1[CH2:12][C:13]1[C:18]2=[CH:17][CH:16]=[CH:15][CH:14]=1>O>[N:1]1([CH:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:19][CH:11]2[OH:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CC1OC21
Reactant: C1CCNC1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OC1Cc2ccccc2C1N1CCCC1

Procedure:
10.8 ml of pyrrolidine in 6.75 g of 2,3-epoxy-indane [described by Mousseron et al. Bulletin de la, Societe Chimique de France, 1946, p. 629-630] in 10.8 ml of demineralized water. The temperature rose to 65° C. and the solution was stirred for 90 minutes at this temperature and 20 ml of demineralized water were added when the reaction was finished. Excess pyrrolidine was distilled off under reduced pressure to obtain an oily phase and an aqueous phase. These are saturated with sodium chloride at 20° C. and 1 ml of 32% sodium hydroxide was added. Extraction was done with ether and after drying and concentrating by distilling under reduced pressure, the oil obtained was purified by chromatography over silica (eluent:ethyl acetate with 5% of triethylamine) to obtain 8.31 g of [trans (±)] 2,3-dihydro-1-(1-pyrrolidinyl)-1H inden-2-ol.
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:9]Br>C(Cl)Cl>[Br:9][C:3]1[CH:2]=[C:1]([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=1
Reactant: Cc1ccccc1O
Reactant: BrBr
Solvent: ClCCl
Product: Cc1cc(Br)ccc1O
Temperature: 2 °C
Yield: 78 %

Procedure:
Into a 5-liter reaction flask was charged 324g of o-cresol (3 moles) and 1200 g of methylene chloride. The reaction was cooled to 2° C. and 480 g (3 moles) of bromine dissolved in 960 g of methylene chloride was run in slowly over a 7-hour period. The next day, the cooling bath was removed and a heating mantle was attached. 1 liter of Isopar G (trademark of Exxon for a hydrocarbon fraction) was added and distillation of the methylene chloride was begun under water aspirator vacuum. Eventually the distillation rate slowed and the pot temperature rose to 70° C. The still head temperature dropped from 35° C. to 28° C. The solution was poured into a beaker and cooled to room temperature without stirring. In the morning, the solution was cooled to -5° C. and filtered. There was recovered 440 g of 4-bromo-o-cresol melting at 61-64° C. in 78% yield.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6](Br)[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[F:14])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl.[CH:23]1([N:26]2[CH2:31][C:30]3([CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[O:29][CH2:28][C:27]2=[O:37])[CH2:25][CH2:24]1>CN(C)C=O.O>[C:1]([O:4][CH2:5][CH:6]([C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[F:14])[N:34]1[CH2:35][CH2:36][C:30]2([O:29][CH2:28][C:27](=[O:37])[N:26]([CH:23]3[CH2:24][CH2:25]3)[CH2:31]2)[CH2:32][CH2:33]1)(=[O:3])[CH3:2]
Reactant: O=C1COC2(CCNCC2)CN1C1CC1
Reactant: CC(=O)OCC(Br)c1ccc(Br)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCC(c1ccc(Br)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
A solution of 2-bromo-2-(4-bromo-2-fluorophenyl)ethyl acetate (0.971 mmol) in N,N-dimethylformamide (5 mL) was treated with potassium carbonate (2.91 mmol) and 4-cyclopropyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one hydrochloride (1.019 mmol). The reaction was allowed to stir at room temperature overnight. The reaction solution was then diluted with water (50 mL) and was extracted four times with ethyl acetate. The combined organic layer was washed four times with water, twice with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound as an oil (385 mg, 76% yield). MS(ES)+ m/e 469.1/471.2 [M+H]+ (bromide isotope pattern).
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:9](OCC)(=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11]>CCOCC.C1COCC1>[CH:1]1([C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Br[Mg]C1CCCCC1
Reactant: CCOC(=O)C(=O)OCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)C(=O)C1CCCCC1
Temperature: 0 °C
Yield: 86 %

Procedure:
Cyclohexyl magnesium bromide (Aldrich) in ether (2 M, 150 mL) was pumped under vacuum to remove ethyl ether, at rt, the residue obtained was then dissolved in anhydrous THF (100 mL) while cooled with an ice water bath. The solution was then added to a solution of diethyl oxalate (60 g ) in THF (150 mL) at -30--40° C. in 10 min. The reaction mixture was warmed to 0° C. for 5 min, and quenched with 10% HCl (100 mL), extracted with ethyl acetate (200 mL), the extract was washed with water (30 mL), brine (50 mL) and dried with sodium sulfate, then filtered. The filtrate was concentrated to give an oil. It was distilled 40-50° C. at 1 mm Hg to remove the starting material and the left over is the product (total of 46 g, 86% yield, purity >90%, it can be distilled at 1 mm Hg, 75-80° C.). 1H NMR δ: 1.20-1.40 (m, 8H), 1.62-1.94 (m, 5H), 3.02 (broad s, 1H), 4.30 (q, J=8 Hz, 2H). 13C-NMR δ 13.91, 25.11, 25.58, 27.36, 46.13, 62.07, 161.84, 197.51.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=3)[C:12]([F:23])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]>>[NH2:22][C:18]1[CH:17]=[C:16]([NH:15][C:13]2[C:12]([F:23])=[CH:11][N:10]=[C:9]([NH:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([N:1]=[CH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:3]=3)[N:14]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: Nc1cccc(Nc2ncc(F)c(Nc3cccc(N)c3)n2)c1
Reactant: CC(C)(C)OC(=O)CBr
Product: CC(C)(C)OC(=O)C=Nc1cccc(Nc2ncc(F)c(Nc3cccc(N)c3)n2)c1

Procedure:
In like manner to the preparation of N2,N4-bis(3-tert-butoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine, N2,N4-bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine and tert-butyl bromoacetate were reacted together to give N4-(3-aminophenyl)-N2-(3-tert-butoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 18.33 min.; purity: 94.5%; MS (m/e): 369.09 (MH+).
Reaction SMILES: [CH3:1]/[CH:2]=[C:3](/[C:5]([O:7][C@@H:8]1[C@:16]23[C@H:20]([C@@:21]([C@:25]45[O:30][C@@:29]4([CH3:31])[C@H:28]4[C@:32]6([OH:38])[C@H:36]([O:37][C@@H:26]5[CH2:27]4)[O:35][CH:34]=[CH:33]6)([CH3:24])[C@H:22]([OH:23])[C@H:14]4[C@H:15]2[C@:11]([C:44]([O:46][CH3:47])=[O:45])([CH2:12][O:13]4)[C@H:10]([O:48][C:49]([CH3:51])=[O:50])[CH2:9]1)[C@@:19]([OH:43])([C:39]([O:41][CH3:42])=[O:40])[O:18][CH2:17]3)=[O:6])\[CH3:4]>CCCCCC>[CH3:1]/[CH:2]=[C:3](/[C:5]([O:7][C@@H:8]1[C@:16]23[C@H:20]([C@@:21]([C@:25]45[O:30][C@@:29]4([CH3:31])[C@@H:28]4[C@:32]6([OH:38])[C@H:36]([O:37][C@H:26]5[CH2:27]4)[O:35][CH:34]=[CH:33]6)([CH3:24])[C@H:22]([OH:23])[C@H:14]4[C@H:15]2[C@:11]([C:44]([O:46][CH3:47])=[O:45])([CH2:12][O:13]4)[C@H:10]([O:48][C:49]([CH3:51])=[O:50])[CH2:9]1)[C@@:19]([OH:43])([C:39]([O:41][CH3:42])=[O:40])[O:18][CH2:17]3)=[O:6])\[CH3:4]
Reactant: C/C=C(\C)C(=O)O[C@H]1C[C@@H](OC(C)=O)[C@@]2(C(=O)OC)CO[C@H]3[C@@H](O)[C@@](C)([C@]45O[C@@]4(C)[C@@H]4C[C@H]5O[C@@H]5OC=C[C@@]54O)[C@H]4[C@]1(CO[C@]4(O)C(=O)OC)[C@@H]32
Solvent: CCCCCC
Product: C/C=C(\C)C(=O)O[C@H]1C[C@@H](OC(C)=O)[C@@]2(C(=O)OC)CO[C@H]3[C@@H](O)[C@@](C)([C@]45O[C@@]4(C)[C@H]4C[C@@H]5O[C@@H]5OC=C[C@@]54O)[C@H]4[C@]1(CO[C@]4(O)C(=O)OC)[C@@H]32
Yield: 25 %

Procedure:
Govindachari, Sandhya and Ganeshraj (Govindachari, T. R., Sandhya, G, and Ganeshraj, S. P., Chromatographia, 31, 303, 1991) have prepared azadirachtin A involving the following steps; (1), defatting of powdered neem seed kernels (1 kg.) with hexane (31.); (2), extraction of defatted powdered neem kernels with refluxing 95% ethanol (a), (1 1.) and (b), (0.5 1.), (3), partition of ethanol concentrate (95 g.) obtained after removal of solvent from combined ethanol extract dissolved in 90% methanol with petroleum ether (100 ml.) thrice; (4), treatment of residue after removal of solvent from methanol extract from step 3, with ethylacetate; (5), washing of ethylacetate extract with water to remove proteins, carbohydrates; (6), removal of solvent from ethylacetate extract to give azadirachtin (25%, 24.5 g.); (7), preparative HPLC of azadirachtin (25%, 4 g.) on RP 18 column to give azadirachtin A+D (340 mg.); (8), preparative HPLC of azadirachtin A+D to give azadirachtin A (160 mg.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[C:10](OC(=O)C)(=[O:12])[CH3:11]>S(=O)(=O)(O)O.O>[C:10]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH3:9])[CH:4]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(O)ccc1Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)Oc1ccc(Cl)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
43.0 g (0.30 mol) of 4-chloro-3-methylphenol, 34 ml (0.36 mol) of acetic anhydride and a few drops of concentrated sulfuric acid were stirred for 2 h at 60° C. in a 250 ml flask equipped with a reflux condenser. The reaction mixture was cooled to room temperature, poured into 200 ml of water and stirred for 1 h at room temperature. The mixture was then extracted with 400 ml of diethyl ether. The organic phase was dried over magnesium sulfate and the ether was distilled off. The raw product is subsequently distilled under reduced pressure (b.p. 65-68° C., 20 mbar).
Reaction SMILES: [NH2:1][NH:2][C:3]([NH:5][NH2:6])=[S:4].[CH2:7]([C:22]1[CH:23]=[C:24]([CH:32]=[CH:33][CH:34]=1)[O:25][CH:26]([CH2:30][CH3:31])[C:27](O)=O)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[N+](C1C=C(B(O)O)C=CC=1)([O-])=O>C1(C)C=CC=CC=1>[NH2:6][N:5]1[C:3]([SH:4])=[N:2][N:1]=[C:27]1[CH:26]([O:25][C:24]1[CH:32]=[CH:33][CH:34]=[C:22]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:23]=1)[CH2:30][CH3:31]
Reactant: CCCCCCCCCCCCCCCc1cccc(OC(CC)C(=O)O)c1
Reactant: NNC(=S)NN
Agent: O=[N+]([O-])c1cccc(B(O)O)c1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCc1cccc(OC(CC)c2nnc(S)n2N)c1
Reaction time: 0.25 h
Yield: 62.5 %

Procedure:
To a mixture of 2.65 g (25 mmol) of thiocarbohydrazide and 9.77 g (25 mmol) of 2-(3-pentadecylphenoxy)butanoic acid in 30 mL of toluene was added 0.42 g (2.5 mmol) of 3-nitrobenzene boronic acid was heated at reflux for 24 hr. The reaction was cooled and the reaction was allowed to settle. The supernatant liquid was decanted. To the residual solid was added 20 mL of acetonitrile. The mixture was stirred for 15 minutes. The solid was collected, rinsed with 5 mL of cold acetonitrile and dried in vacuo to afford 7.20 g (60.4%) of the desired product as a white solid. Analytical data are consistent with the assigned structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:40])([CH2:32][Si](OC(C)C)(C)C)[C@H:10]([N:12]1[CH:16]=[CH:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([F:30])([F:29])[CH:26]([F:28])[F:27])=[CH:19][CH:18]=2)[C:13]1=[O:31])[CH3:11].C(=O)([O-])[OH:42].[Na+]>CO.O1CCCC1.OO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:40])([CH2:32][OH:42])[C@H:10]([N:12]1[CH:16]=[CH:15][N:14]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:24][C:25]([F:29])([F:30])[CH:26]([F:28])[F:27])=[CH:21][CH:22]=2)[C:13]1=[O:31])[CH3:11]
Reactant: O=C([O-])O
Reactant: CC(C)O[Si](C)(C)C[C@](O)(c1ccc(F)cc1F)[C@@H](C)n1ccn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H](n1ccn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O)[C@](O)(CO)c1ccc(F)cc1F
Yield: 88.3 %

Procedure:
1-[(1R,2S)-2-(2,4-Difluorophenyl)-2-hydroxy-3-(isopropoxydimethylsilyl)-1-methylpropyl]-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2(1H,3H)-imidazolone (1.8 g) was dissolved in a mixture of methanol and tetrahydrofuran (1:1, 20 ml), to which 3.21 ml of 30% aqueous hydrogen peroxide and 0.262 g of sodium hydrogencarbonate were added. The mixture was heated at 70° to 80° C. for 90 minutes, cooled and extracted with 100 ml of ethyl acetate. The extract was washed with 50 ml of water, an aqueous solution of Na2S2O3 (50 ml×2) and 50 ml of an aqueous solution of sodium chloride successively, and dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel chromatography (silica gel: 50 g, eluent; hexane:ethyl acetate=2:3) and recrystallized from diisopropyl ether to give 1.32 g of 1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-dihydroxy-1-methylpropyl]-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2(1H,3H)-imidazolone (yield: 88%) as colorless prisms.
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3[N:15]=[N:14][C:13]([C:16]4[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=4)=[CH:12][CH:11]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:30](Cl)(=[O:32])[CH3:31]>C(Cl)Cl>[CH:1]1([N:4]2[CH2:5][CH2:6][N:7]([C:10]3[N:15]=[N:14][C:13]([C:16]4[CH:17]=[C:18]([NH:22][C:30](=[O:32])[CH3:31])[CH:19]=[CH:20][CH:21]=4)=[CH:12][CH:11]=3)[CH2:8][CH2:9]2)[CH2:3][CH2:2]1
Reactant: CC(=O)Cl
Reactant: Nc1cccc(-c2ccc(N3CCN(C4CC4)CC3)nn2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1cccc(-c2ccc(N3CCN(C4CC4)CC3)nn2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-[6-(4-cyclopropyl-piperazin-1-yl)-pyridazin-3-yl]-phenylamine (400 mg, 1.36 mmol) in CH2Cl2 (25 mL) was added triethylamine (275 mg, 2.72 mmol). Then acetyl chloride (171 mg, 2.18 mmol) was added dropwise and the resulting mixture was stirred overnight at rt. The reaction was quenched with water (15 mL) and the phases were separated. The organic phase was washed with brine, dried (Na2SO4) and concentrated to give a crude product, which was recrystallized from MeOH. This afforded 201 mg (48%) of the title compound.
Reaction SMILES: C([O:5][C:6](=[O:53])[CH2:7][C@H:8]([NH:27][C:28]([C@@H:30]1[CH2:35][CH2:34][CH2:33][N:32]([C:36](=[O:52])[CH2:37][CH2:38][CH:39]2[CH2:44][CH2:43][N:42](C(OC(C)(C)C)=O)[CH2:41][CH2:40]2)[CH2:31]1)=[O:29])[C:9]1[CH:10]=[N:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][CH2:25][F:26])[CH:18]=2)[CH:14]=1)(C)(C)C>C(O)=O>[F:26][CH2:25][CH2:24][O:23][C:19]1[CH:18]=[C:17]([CH2:16][CH2:15][C:13]2[CH:14]=[C:9]([C@@H:8]([NH:27][C:28]([C@@H:30]3[CH2:35][CH2:34][CH2:33][N:32]([C:36](=[O:52])[CH2:37][CH2:38][CH:39]4[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]4)[CH2:31]3)=[O:29])[CH2:7][C:6]([OH:53])=[O:5])[CH:10]=[N:11][CH:12]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(CCc2cccc(OCCF)c2)c1
Solvent: O=CO
Product: O=C(O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCNCC2)C1)c1cncc(CCc2cccc(OCCF)c2)c1
Yield: 68.6 %

Procedure:
Tert-butyl 4-{3-[(3R)-3-{[(1S)-3-tert-butoxy-1-(5-{2-[3-(2-fluoroethoxy)phenyl]ethyl}pyridin-3-yl)-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (20 mg, 30 μmol) was heated to 60° C. in formic acid for 50 minutes. The solution was then concentrated in vacuum and the residue purified by preparative HPLC to yield 12 mg of (3S)-3-(5-{2-[3-(2-fluoroethoxy)phenyl]ethyl}pyridin-3-yl)-3-[({(3R)-1-[3-(piperidin-4-yl)propanoyl]piperidin-3-yl}carbonyl)amino]propanoic acid.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH2:11][CH:12]2[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]2)[CH:3]=1.[NH3:23]>CO.C(Cl)Cl>[NH2:23][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH2:11][CH:12]2[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]2)[CH:3]=1
Reactant: CCOC(=O)C1CCC(Cc2cc(Cl)n3nccc3n2)CC1
Reactant: N
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)C1CCC(Cc2cc(N)n3nccc3n2)CC1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To a 10-20 mL microwave vessel was charged ethyl 4-((7-chloropyrazolo[1,5-a]pyrimidin-5-yl)methyl)cyclohexanecarboxylate (Int-4g, 2.29 g, 7.12 mmol). To this was added ˜7N NH3 in methanol (15 mL). The resulting solution was stirred at 90° C. for 4 hours. After 4 hours, the reaction was cooled to room temperature and diluted with DCM (100 mL). This solution was washed with H2O and the organic layer was extracted. The aqueous phase was again extracted with DCM. The combined organics were dried over Na2SO4 and then the solvent was removed in vacuo. The resulting solid was taken on without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][CH3:17])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18]O>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][CH3:17])[C:13]([O:15][CH3:18])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CO
Solvent: Cc1ccccc1
Product: CC[C@H](NC(=O)OCc1ccccc1)C(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
To a solution of (S)-2-(((benzyloxy)carbonyl)amino)butanoic acid (10.0 g, 42.1 mmol) in methanol (100 mL) and toluene (300 mL) was added dropwise at room temperature under argon trimethylsilyldiazomethane (23.2 mL, 46.4 mmol). After stirring at room temperature for 1 hour, the reaction mixture was concentrated and the residue was extracted with a solution of EtOAc and brine. The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by column chromatography (120 g SiO2) using EtOAc in hexane from 0% to 30% in order to give the title compound (5.2 g, 48%) as a colorless oil. LC-MS: [M+H] 252.1; Rt 0.93 min; (LCMS method 1).