Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C@H](C(O)=O)CCCCN.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C[O:26][C:27](=[O:34])[C@H:28]([CH2:30][CH:31]([CH3:33])[CH3:32])[NH2:29].CN1CCOCC1>CN(C=O)C>[NH2:29][C@H:28]([C:27]([OH:34])=[O:26])[CH2:30][CH:31]([CH3:33])[CH3:32]
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: NCCCC[C@H](N)C(=O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: CC(C)C[C@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 29 %

Procedure:
L-Lysine, N-ε-(carbobenzoxy)-[N-α-[N-[4-[4-(2-methyl-1H-imidazol-1-yl) -butyl]phenyl]acetyl]-L-(O-benzyl)-seryl]-, (0.46 g. 6.46 mmol), HOBT (0.089 g, 6.78 mmol), and EDC (0.13 g, 6.78 mmol) were dissolved in 15 mL of DMF. The solution was stirred for 40 minutes at room temperature. L-Leucine methyl ester (0.13 g, 7.11 mmol) was dissolved in 5 mL of DMF containing N-methylmorpholine (0.20 g, 1.94 mol) and then added to this solution. The reaction mixture was stirred overnight at room temperature, and the DMF was removed in vacuo. The concentrated residue was brought up in 150 mL of dichloromethane, and the organic phase was washed with saturated aqueous NaHCO3 (2×100 mL), brine (2×100 mL), dried over MgSO4, filtered and concentrated. The concentrated residue was purified by silica gel flash column chromatography eluting with 5% methanol in methylene chloride to give 0.27 g (49.8%) of L-leucine, N-[N2 -[N-[[4-[4-(2-methyl-1H-imidazol-1-yl)butyl]phenyl]acetyl]-L-(O-benzyl)-seryl]-N-ε-(carbobenzoxy)-L-lysyl]-, methyl ester as a white solid. FAB-MS m/z=839 (M+H). HRMS: calcd for C47H63N6O8 (M+H) 839.4707, found: 839.4706.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:7]=[C:6]([O:16][CH2:17][CH2:18][CH2:19][OH:20])[CH:5]=1.[CH3:22]N(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.F[B-](F)(F)F.C[O+](C)C>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:7]=[C:6]([O:16][CH2:17][CH2:18][CH2:19][O:20][CH3:22])[CH:5]=1
Reactant: COC(=O)c1cc(OCCCO)cc(N2CCCC2=O)c1
Reactant: CN(C)c1cccc2cccc(N(C)C)c12
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COCCCOc1cc(C(=O)OC)cc(N2CCCC2=O)c1
Reaction time: 3 h
Yield: 57.5 %

Procedure:
3-(3-Hydroxy-propoxy)-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid methyl ester (B15) (127 mg, 0.43 mmol, 1 equiv) in CH2Cl2 (2 ml) was treated with proton sponge (279 mg, 1.30 mmol, 3 equiv) and trimethyloxonium tetrafluoroborate (192 mg, 1.30 mmol, 3 equiv). After 3 hrs, further quantities of proton sponge (93 mg, 0.43 mmol, 1 equiv) and trimethyloxonium tetrafluoroborate (65 mg, 0.43 mmol, 1 equiv) were added and stirring was continued for a further 2 h. The mixture was then partitioned between AcOEt and 2N aqueous HCl solution. The two layers were separated and the aqueous phase extracted with AcOEt. The combined organic layers were washed with saturated aqueous NaHCO3 solution, 2N aqueous HCl solution and brine and then dried over Na2SO4 and concentrated in vacuo. Purification by flash chromatography on silica gel (ethyl acetate/iso-hexane: 1/4 to 1/3) gave 3-(3-methoxy-propoxy)-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid methyl ester (B17) (76 mg, 58%). [M+H]+=308.1
Reaction SMILES: [CH3:1]/[C:2](/[CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])=[CH:3]\[CH2:4]O.N1C(C)=CC(C)=CC=1C.[Cl-].[Li+].CS([Cl:27])(=O)=O>CN(C=O)C>[Cl:27][CH2:4]/[CH:3]=[C:2](\[CH3:1])/[CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10]
Reactant: CC(C)=CCC/C(C)=C/CO
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1cc(C)nc(C)c1
Solvent: CN(C)C=O
Product: CC(C)=CCC/C(C)=C/CCl
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 89.4 %

Procedure:
To a stirred solution of 30.0 g (0.194 mol) of (E)-3,7-dimethyl-2,6-octadien-1-ol and 28.27 mL (0.213 mol) of 2,4,6-collidine under argon at room temperature was added dropwise 8.23 g (0.194 mol) of lithium chloride in 100 mL of DMF. The mixture was cooled to 0° C. and treated with 16.56 mL (0.213 mol) of methanesulfonyl chloride dropwise over 10 minutes. The reaction was stirred at 0° C. for 1.5 hours (solid present), then poured into 500 mL of ice/water. The aqueous solution was washed three times with 200 mL portions of hexane, the organic layers were combined and washed with 5% KHSO4, water, NaHCO3, brine, dried (MgSO4) and evaporated to provide 29.95 g of a pale yellow oil. Rapid flash chromatography was performed on 400 g of silica gel, eluting with 3:9 EtOAc/hexane. Pure product fractions were combined and evaporated to provide 25.20 g (75%) of title compound as a pale yellow oil.
Reaction SMILES: [O-:1]O.[CH:3]1(C2C=CC=CC=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.C([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)CCCC.[O-]O>>[C:3]1([OH:1])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:20]1(=[O:1])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: [O-]O
Reactant: c1ccc(C2CCCCC2)cc1
Reactant: CCCCCc1ccccc1
Product: O=C1CCCCC1
Product: Oc1ccccc1
Temperature: 25 °C

Procedure:
All cyclohexylbenzene hydroperoxide cleavage reactions were carried out in a 100 mL round bottom flask equipped with a magnetic stir bar. Generally, about 14 g of crude oxidation product (see Example I), 0.4 g of internal standard (n-pentylbenzene), 0.1-3.0 g of catalyst and about 10 mL of solvent were charged to the vessel. The reactor contents were stirred at room temperature for 30 minutes to about 2 hours, then sampled for analysis by gas liquid chromatography (glc). The product yields are corrected for the fact that only 90% of the hydroperoxide in the CHBHP feed is the correct hydroperoxide, i.e. ##STR3## Other isomeric hydroperoxides are incapable of cleavage to give the desired ultimate products, phenol and cyclohexanone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].O.[C:11]([OH:15])(=[O:14])[CH:12]=O.[CH:16]1[CH2:20][CH:19]=[CH:18][CH:17]=1>C(#N)C>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]2[CH:18]3[CH:17]=[CH:16][CH2:20][CH:19]3[CH:12]([C:11]([OH:15])=[O:14])[NH:5][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: O=CC(=O)O
Reactant: C1=CCC=C1
Solvent: CC#N
Solvent: O
Product: O=C(O)C1Nc2cc(Cl)cc(Cl)c2C2C=CCC12
Temperature: 50 °C

Procedure:
1.14 g of 3,5-dichloroaniline (10 mmol), 0.97 g of glyoxylic acid hydrate (15 mmol) and 1.40 g of cyclopentadiene (freshly distilled) (30 mmol) were dissolved in 20 ml of acetonitrile in a closable Teflon vessel and heated to 50° C. within one minute in a microwave oven with a power of 800 watts and kept at this temperature for five minutes with further microwave irradiation. The vessel was then placed in ice water, cautiously opened and evaporated in a rotary evaporator. The mass of crystals obtained was washed with hexane and dried. A colourless mass of crystals was obtained in a quantity of 1.95 g (98% of theoretical).
Reaction SMILES: [ClH:1].[C:2]([O:5][C:6]1[C:7]([CH3:32])=[C:8]2[C:13](=[C:14]([CH3:17])[C:15]=1[CH3:16])[O:12][C:11]([CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27](N)=[CH:26][CH:25]=1)([CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:10][C:9]2=[O:31])(=[O:4])[CH3:3].N([O-])=O.[Na+].[C:37]([O:41][CH2:42][CH3:43])(=[O:40])[CH:38]=[CH2:39]>O.CC(C)=O>[C:2]([O:5][C:6]1[C:7]([CH3:32])=[C:8]2[C:13](=[C:14]([CH3:17])[C:15]=1[CH3:16])[O:12][C:11]([CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:39][CH:38]([Cl:1])[C:37]([O:41][CH2:42][CH3:43])=[O:40])=[CH:26][CH:25]=1)([CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:10][C:9]2=[O:31])(=[O:4])[CH3:3]
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)C(=O)CC(COc1ccc(N)cc1)(CC(C)C)O2
Reactant: Cl
Reactant: C=CC(=O)OCC
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)C(Cl)Cc1ccc(OCC2(CC(C)C)CC(=O)c3c(C)c(OC(C)=O)c(C)c(C)c3O2)cc1
Reaction time: 1 h

Procedure:
1.5 ml of concentrated hydrochloric acid was added to mixture of 1.1 g of 6-acetoxy-2-(4-aminophenoxymethyl)-2-isobutyl-5,7,8-trimethylchroman-4-one (prepared as described in Preparation 8) and 20 ml of acetone under a nitrogen stream and at room temperature. This was followed by 0.8 g of sodium nitrite and 0.3 ml of water, and then by 4 g of ethyl acrylate. 0.1 g of cuprous oxide was added at room temperature to the reaction mixture, which was then stirred for 1 hour. Water was then added, and the mixture was extracted with benzene. The benzene extract was washed with water and dried over anhdyrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography using a 5.1 by volume mixture of hexane and ethyl acetate as eluent, to give the title compound.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[C:5]=1[NH2:6])([CH3:3])[CH3:2].[CH2:14]1[C:27]2[C:18](=[N:19][C:20]3[C:21](=O)[CH2:22][CH2:23][CH2:24][C:25]=3[CH:26]=2)[C:17](=O)[CH2:16][CH2:15]1>>[CH:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[N:6]=[C:17]1[C:18]2[C:27](=[CH:26][C:25]3[CH2:24][CH2:23][CH2:22][C:21](=[N:6][C:5]4[C:7]([CH:11]([CH3:12])[CH3:13])=[CH:8][CH:9]=[CH:10][C:4]=4[CH:1]([CH3:3])[CH3:2])[C:20]=3[N:19]=2)[CH2:14][CH2:15][CH2:16]1)([CH3:13])[CH3:12]
Reactant: O=C1CCCc2cc3c(nc21)C(=O)CCC3
Reactant: CC(C)c1cccc(C(C)C)c1N
Product: CC(C)c1cccc(C(C)C)c1N=C1CCCc2cc3c(nc21)C(=Nc1c(C(C)C)cccc1C(C)C)CCC3

Procedure:
was synthesized by methods similar to those in Examples 3 and 4:: 2,6-di-iso-propylaniline was condensed with 2,3,7,8-tetrahydro-1H,6H-acridine-4,5-dione to yield 4,5-bis[2,6-di-iso-propylphenylimino]-1,2,3,4,5,6,7,8-octahydroacridine (4). The complexation of (4) with FeCl2.4H2O was carried out with azeotropic removal of methanol in benzene. The structure of the final complex was proved by direct probe GC. Exact mass direct probe calculated for C37H47Cl2FeN3: 659.25. Found: 659.25.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:17])[C@:10]([OH:16])([CH3:15])[C:11]([F:14])([F:13])[F:12])=[C:4]([Cl:18])[C:3]=1[Cl:19].[SH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1.CCOC(C)=O.O>CN(C=O)C>[C:25]([C:24]1[CH:28]=[CH:29][C:21]([S:20][C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:17])[C@:10]([OH:16])([CH3:15])[C:11]([F:14])([F:13])[F:12])=[C:4]([Cl:18])[C:3]=2[Cl:19])=[CH:22][CH:23]=1)([OH:27])=[O:26]
Reactant: C[C@@](O)(C(=O)Nc1ccc(I)c(Cl)c1Cl)C(F)(F)F
Reactant: O=C(O)c1ccc(S)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@](O)(C(=O)Nc1ccc(Sc2ccc(C(=O)O)cc2)c(Cl)c1Cl)C(F)(F)F
Temperature: 25 °C
Yield: 82.3 %

Procedure:
(R)-N-[4-Iodo-2,3-dichlorophenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Method 4) (4.58 g, 10.7 mmol) was heated in DMF (30 ml) with stirring under argon for 4 hours with 4-mercaptobenzoic acid (2.31 g, 14.98 mmol) and cuprous oxide (765 mg) and allowed to cool to room temp. EtOAc and water were added, and the reaction mixture was filtered through a bed of diatomaceous earth, and washed with EtOAc/water. The organic layer was separated, washed with water, brine, dried and evaporated down to dryness. The resulting solid was purified using a Mega Bond Elut column, eluting with 5-50% EtOAc/isohexane to give the title compound (4.0 g) as a pale pink solid. NMR: 1.6 (s, 3H), 7.3 (d, 2H), 7.5 (d, 1H), 7.9 (m, 3H), 8.0 (d, 1H), 9.9 (s, 1H), 13.0 (s, 1H); m/z: 452.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][C:15](=[O:17])[N:14]([C:18]3[CH:22]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[S:20][C:19]=3[C:29]([OH:31])=[O:30])[C@H:13]([CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[N:46]1[CH:51]=[C:50](B(O)O)[CH:49]=[N:48][CH:47]=1>C(#N)C>[CH:32]1([C@@H:13]2[CH2:12][N:11]([S:8]([C:5]3[CH:6]=[N:7][C:2]([C:50]4[CH:51]=[N:46][CH:47]=[N:48][CH:49]=4)=[CH:3][CH:4]=3)(=[O:10])=[O:9])[CH2:16][C:15](=[O:17])[N:14]2[C:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[S:20][C:19]=2[C:29]([OH:31])=[O:30])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: OB(O)c1cncnc1
Reactant: O=C(O)c1sc(-c2ccccc2)cc1N1C(=O)CN(S(=O)(=O)c2ccc(Cl)nc2)C[C@H]1C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(O)c1sc(-c2ccccc2)cc1N1C(=O)CN(S(=O)(=O)c2ccc(-c3cncnc3)nc2)C[C@H]1C1CCCCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 18.4 %

Procedure:
To a solution of 3-[(R)-4-(6-chloro-pyridine-3-sulfonyl)-2-cyclohexyl-6-oxo-piperazin-1-yl]-5-phenyl-thiophene-2-carboxylic acid (1.20 g, 2.14 mmol, 1.0 equiv) in acetonitrile (15.0 mL) was added potassium phosphate (8.58 ml, 1.0 M aqueous solution, 4.0 equiv) and chloro(2-dicyclohexyl phosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)[2-(2-amino ethyl)phenyl] Pd(II) Me-t-butyl ether adduct (0.32 g, 0.43 mmol, 0.2 equiv) at room temperature. The mixture was stirred at room temperature for 10 minutes to form a stock solution. To 0.8 mL of above solution was added 5-pyrimidinyl boronic acid (17.7 mg, 0.143 mmol, 2.0 equiv) and acetonitrile (0.5 mL) at room temperature. The mixture was stirred at 80° C. for 4 hours. The mixture was purified by HPLC (0.1% NH4OH) to afford the product (15.9 mg, 36.9%). MS: 603.2 [M−H+].
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8](=O)[C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=2F)[CH2:4][CH2:3]1.[OH-:18].[K+].[ClH:20].[NH2:21]O.C(O)(C)C>CCOCC.O>[ClH:20].[F:15][C:14]1[C:9]2[C:8]([CH:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[N:21][O:18][C:10]=2[CH:11]=[CH:12][CH:13]=1
Reactant: [OH-]
Reactant: NO
Reactant: CN1CCC(C(=O)c2c(F)cccc2F)CC1
Agent: Cl
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Solvent: CCOCC
Product: CN1CCC(c2noc3cccc(F)c23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.4 %

Procedure:
A stirred mixture of 209 g of 1-methyl-4-(2,6-difluorobenzoyl)piperidine, 400 g of potassium hydroxide, 102 g of hydroxylamine hydrochloride, 2100 ml of isopropanol and 2100 ml of water was refluxed for 10 hrs and then stirred overnight at ambient temperature. The reaction mixture was poured into water and extracted with hexane. The hexane extracts were dried over anhydrous magnesium sulfate, filtered and the solvent was removed in vacuo to yield a solid. The solid was purified by passing it through a silica gel column (15:1) using 1% methanol in dichloromethane as eluent. Evaporation of the eluent provided a solid, which was dissolved in ether. A hydrochloric acid-ether solution was added dropwise. The precipitate was collected and washed with ether to yield 24.71 g (14%) of product, mp, 221°-223°.
Reaction SMILES: [CH:1]1[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1.[C:17](Cl)([CH3:20])([CH3:19])[CH3:18].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl.O>[C:17]([C:8]1[C:7]2[C:16]3=[C:15]4[C:4](=[CH:5][CH:6]=2)[CH:3]=[CH:2][CH:1]=[C:14]4[CH:13]=[CH:12][C:11]3=[CH:10][CH:9]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)Cl
Reactant: c1cc2ccc3cccc4ccc(c1)c2c34
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1ccc2ccc3cccc4ccc1c2c34
Temperature: 0 °C
Reaction time: 2 h
Yield: 51.1 %

Procedure:
In a reaction vessel, 50.0 g (0.25 mol) of pyrene, 27.6 g (0.30 mol) of tert-butyl chloride, and 200 ml of methylene chloride were charged, and the resulting mixture was cooled to 0° C. Next, 35.3 g (0.27 mol) of aluminum chloride was charged, followed by stirring at room temperature for 2 hours. Then, iced water and methylene chloride were added, and an organic layer was extracted, washed with water, dried over magnesium sulfate, and recrystallized to produce 33 g of tert-butylpyrene crystals in a yield of 51%.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18]Cl.[CH3:20][NH2:21]>C(O)C>[ClH:1].[CH3:20][N:21]1[CH2:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[O:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: ClCCOc1ccccc1Oc1ccccc1CCl
Reactant: CN
Solvent: CCO
Product: CN1CCOc2ccccc2Oc2ccccc2C1
Product: Cl
Reaction time: 8 h
Yield: 35 %

Procedure:
A solution of 6.2 g of 2-(2-chloroethoxy)-1-[2-(chloromethyl)phenoxy]benzene in 310 ml ethanol was added at room temperature in 45 min to a solution of 80 ml of methylamine in 1.2 1 of abs. ethanol. The mixture was stirred overnight, concentrated and dissolved in 100 ml of dimethyl sulphoxide. 18.6 ml of triethylamine were added and the reaction mixture was heated to 90°-100° C. and stirred overnight. After cooling the mixture was poured into 4.5 1 of ice water and extracted with 3×600 ml of dichloromethane. The extract was washed with water, dried over sodium sulphate and concentrated in vacuo. The crude product obtained was purified by silica chromatography with dichloromethane-acetone (9:1), after which the free base was converted into the hydrochloric salt, to obtain 2.12 g (35%) of 6,7,8,9-tetrahydro-8-methyl-dibenzo[b,i][1,4,7]dioxazecine hydrochloride. Mp 223° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1B(O)O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])O.[Na+].Br[C:22]1[CH:30]=[C:29]2[C:25]([CH2:26][C:27](=[O:31])[NH:28]2)=[CH:24][CH:23]=1>COCCOC>[C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:22]1[CH:30]=[C:29]2[C:25]([CH2:26][C:27](=[O:31])[NH:28]2)=[CH:24][CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Reactant: O=C1Cc2ccc(Br)cc2N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)n1cccc1-c1ccc2c(c1)NC(=O)C2
Yield: 71.6 %

Procedure:
1-t-Butoxycarbonylpyrrol-2-ylboronic acid (1.5 g, 7.1 mmol) and a saturated aqueous solution of sodium hydrogen carbonate (25 ml) were added to a solution of 6-bromooxindole (1.1 g, 5.2 mmol), (prepared as described for the starting material in Example 62), in 1,2-dimethoxyethane (75 ml). The reaction mixture was degassed and placed under argon and tetrakis(triphenylphosphine)palladium(0) (50 mg) was added and the mixture heated at reflux for 6 hours. The organic solvent was removed by evaporation and the reaction mixture partitioned between ethyl acetate and water. The organic phase was separated and the aqueous phase was re-extracted twice with ethyl acetate. The organic phases were combined, washed with brine, dried (MgSO4), and the solvent removed by evaporation. The residue was triturated with ether/isohexanes (1/1) and collected by filtration to give 6-(1-t-butoxycarbonylpyrrol-2-yl)oxindole (1.11 g, 71%).
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=2)=[O:5])[CH2:3][CH2:2]1.[CH3:16][Si](C)(C)N[Si](C)(C)C.[Li].IC.[Cl-].[NH4+]>O1CCCC1>[CH3:16][C:1]1([C:4]([C:6]2[CH:7]=[CH:8][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:14][CH:15]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: COC(=O)c1ccc(C(=O)C2CC2)cc1
Agent: [Cl-]
Agent: [Li]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)c1ccc(C(=O)C2(C)CC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 8 %

Procedure:
To a solution of methyl 4-(cyclopropylcarbonyl)benzoate (500 mg, 2.45 mmol) in tetrahydrofuran (12 mL) was added dropwise a solution of 1 mol/L lithium hexamethyldisilazane in tetrahydrofuran (3.0 mL, 3.00 mmol) at −78° C. under argon atmosphere, and the mixture was stirred for 15 minutes. To the mixture was added dropwise iodomethane (200 μL, 3.21 mmol) at the same temperature, and the reaction solution was slowly warmed to room temperature and stirred overnight. To the reaction solution was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate three times. The organic layer was combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→97:3) to give methyl 4-[(1-methylcyclopropyl)carbonyl]benzoate (45 mg, 8%) as a colorless oil.
Reaction SMILES: C([O:5][C:6](=[O:38])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:25]=[N:26][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[F:36])=[CH:28][CH:29]=3)[S:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH3:37])(C)(C)C.[C:39](O)(C(F)(F)F)=O>C(Cl)Cl.O>[F:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:27]1[N:26]=[CH:25][C:24]([C:20]2[S:21][C:22]([CH3:23])=[C:18]([CH:17]([CH3:39])[CH2:16][O:15][C:12]3[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][C:6]([OH:5])=[O:38])=[C:10]([CH3:37])[CH:11]=3)[N:19]=2)=[CH:29][CH:28]=1
Reactant: Cc1cc(OCCc2nc(-c3ccc(-c4ccccc4F)nc3)sc2C)ccc1CCC(=O)OC(C)(C)C
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: Cc1cc(OCC(C)c2nc(-c3ccc(-c4ccccc4F)nc3)sc2C)ccc1CCC(=O)O
Reaction time: 2 h

Procedure:
To a solution of 3-[4-(2-{2-[6-(2-Fluoro-phenyl)-pyridin-3-yl]-5-methyl-thiazol-4-yl}-ethoxy)-2-methyl-phenyl]-propionic acid tert-butyl ester (120 mg) in methylene chloride (1 mL) is added TFA (0.8 mL) and two drops of water. The mixture is stirred for 2 h, and concentrated and purified by reversed phase HPLC (water-acetonitrile with 0.1% TFA). MS (ES): 491.4 (M++1).
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12]C(=O)C)(=O)C.Cl>CO>[NH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][OH:4]
Reactant: CC(=O)NCCCCCCCOC(C)=O
Agent: Cl
Solvent: CO
Product: NCCCCCCCO

Procedure:
1-Acetoxy-7-acetamidoheptane (11.8 g, 54.3 mmol) was dissolved in 20 mL of methanol in a 200 mL round bottom flask. To this was added 50 mL of 40% aqueous hydrochloric acid and the mixture was heated at reflux for 60 hours. All volatiles were removed under reduced pressure. The desired 7-amino-1-heptanol was obtained as the crystalline hydrochloride salt, m.p. 74-81° C., MS: 131 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:32][CH2:31]NCC4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.C1[CH:46]=[CH:47][C:48]2N(O)N=[N:51][C:49]=2C=1.C(N(C(C)C)CC)(C)C.[CH3:64][N:65]([CH:67]=[O:68])[CH3:66]>>[NH2:51][CH2:49][C:48]1([C:67]([N:65]2[CH2:66][CH2:31][CH2:32][CH:27]([C:19]3[N:20]4[C:25]([C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)=[C:17]([C:12]4[CH:13]=[CH:14][C:15]5[C:10]([CH:11]=4)=[N:9][N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:16]=5)[CH:18]=3)[CH2:64]2)=[O:68])[CH2:46][CH2:47]1
Reactant: On1nnc2ccccc21
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CN(C)C=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: NCC1(C(=O)N2CCCC(c3cc(-c4ccc5cn(Cc6ccccc6)nc5c4)c4c(N)ncnn34)C2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 8 %

Procedure:
A mixture of 5-(2-benzyl-2H-indazol-6-yl)-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (100 mg, 0.24 mmol), 1-(Boc-aminomethyl)-cyclopropyl-1-carboxylic acid (61 mg, 0.28 mmol), EDCl (50 mg, 0.26 mmol), HOBt (35 mg, 0.26 mmol), and N, diisopropylethylamine (123 μL, 0.71 mmol) in DMF (1.5 mL) was stirred at rt for 17 h. Additional 1-(Boc-aminomethyl)-cyclopropyl-1-carboxylic acid (30 mg), EDCl (25 mg), HOBt (18 mg) and N,N-diisopropylethylamine (62 μL) were added and the mixture continued to stir at rt for 16 hr. The crude mixture was purified by preparative HPLC using a gradient elution from 15% to 45% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated. To a solution of the residue in MeOH (1 mL) was added 4M HCl in dioxane (500 μL). The mixture was stirred at rt for 64 h. The mixture was concentrated and the residue was dissolved in 3:1 CHCl3/isopropanol (15 mL). The mixture was washed with saturated, aqueous NaHCO3 (15 mL), brine, dried (Na2SO4) and concentrated to dryness to afford 9 mg (8%) of the desired product. 1H NMR (400 MHz, CD3OD) δ 8.36 (s, 1 H), 7.78-7.88 (m, 2 H), 7.65 (s, 1 H), 7.29-7.37 (m, 5 H), 7.22 (dd, 1 H), 6.66 (s, 1 H), 5.65 (s, 2 H), 4.69-4.82 (m, 1 H), 4.44 (br s, 1 H), 3.37-3.51 (m, 1 H), 3.05 (dd, 1 H), 2.94 (br s, 2 H), 2.75 (d, 1 H), 2.21 (d, 1 H), 1.83-2.03 (m, 2 H), 1.60-1.75 (m, 1 H), 0.72-1.06 (m, 4 H); ES-MS m/z 521.21 [M+H]+, HPLC RT (min) 2.30.