Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1(/[CH:7]=[C:8](\[CH2:14][P:15]([O:21]CC)([CH2:17][CH:18]([CH3:20])[CH3:19])=[O:16])/[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(Cl)Cl.CO.C(O)(=O)C>Cl.C(OCCCC)(=O)C>[CH:1]1(/[CH:7]=[C:8](\[CH2:14][P:15]([OH:21])([CH2:17][CH:18]([CH3:20])[CH3:19])=[O:16])/[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)/C(=C/C1CCCCC1)CP(=O)(CC(C)C)OCC
Agent: Cl
Solvent: CCCCOC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)/C(=C/C1CCCCC1)CP(=O)(O)CC(C)C
Yield: 92.8 %

Procedure:
A solution of 107 mg (0.31 millimole) of ethyl (Z)-3-cyclohexyl-2-(ethoxyisobutylphosphinoyl)methylpropenoate in 1.0 ml of 4N HCl-butyl acetate was heated in a sealed tube at 100° C for 2 hours. After cooling, the solvent was evaporated under reduced pressure, and the residue was purified by "dry-column" flash chromatography 15 g of silica gel 60 made by E. Merck & Co.; chloroform-methanol-acetic acid (50:1:1)] to give 91 mg (yield 94%) of the captioned compound as a colorless oil.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]1.[ClH:23].CC[O:26]C(C)=O>>[ClH:23].[NH:13]1[CH2:14][CH2:15][CH:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]([OH:26])[CH3:2])[CH2:11][CH2:12]1
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2CCO)CC1
Agent: Cl
Product: CC(O)c1ccccc1C1CCNCC1

Procedure:
The title compound was prepared according to the procedure described in Example 1 (Step e) using tert-butyl 4-(2-(hydroxyethyl)phenyl]piperidinecarboxylate (Step b) (1.22 g, 4.0 mmol) and satd anhydrous HCl in EtOAc (50 mL). The title compound was obtained as a white solid (0.96 g). MS (ESI, pos. ion) m/z: 206 (M+1); MS (ESI, neg. ion) m/z: 204 (M−1). Calc'd for C13H19NO: 205.15.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:15])([C:11]([F:14])([F:13])[F:12])[CH2:9][OH:10])=[CH:4][CH:3]=1.[CH3:16][C@@H:17]1[NH:22][CH2:21][CH2:20][N:19]([S:23]([C:26]2[S:27][CH:28]=[CH:29][CH:30]=2)(=[O:25])=[O:24])[CH2:18]1.CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1>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].C1(C)C=CC=CC=1>[CH3:16][C@H:17]1[CH2:18][N:19]([S:23]([C:26]2[S:27][CH:28]=[CH:29][CH:30]=2)(=[O:25])=[O:24])[CH2:20][CH2:21][N:22]1[C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:15])([C:11]([F:14])([F:13])[F:12])[CH2:9][OH:10])=[CH:4][CH:3]=1
Reactant: OCC(O)(c1ccc(Br)cc1)C(F)(F)F
Reactant: C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(O)(CO)C(F)(F)F)cc1
Temperature: 100 °C
Yield: 4.7 %

Procedure:
2-(4-bromophenyl)-3,3,3-trifluoro-1,2-propanediol (0.35 g, 1.2 mmol), (3S)-3-methyl-1-(2-thiophenylsulfonyl)piperazine (0.20 g, 0.81 mmol), sodium tert-butoxide (0.27 g, 2.8 mmol), dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPhos) (0.076 g, 0.16 mmol, Strem Chemical Inc, Newburyport, Mass.), tris(dibenzylideneacetone)dipalladium (0) (0.074 g, 0.081 mmol, Strem Chemical Inc, Newburyport, Mass.), and toluene (3.3 mL) were added to a high-pressure reaction vessel. The vessel was sealed and heated at 100° C. for 24 h. After cooling to room temperature, was purified via flash chromatography on silica gel (twice, 2% MeOH in CH2Cl2 then 33% EtOAc in hexanes) to afford 2-(4-((2S)-2-methyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-3,3,3-trifluoro-1,2-propanediol (0.017 g) as a mixture of two isomers.
Reaction SMILES: [O:1]=[C:2]1[N:8]2[CH:4]([O:5][CH:6]([CH2:9][C:10]([O-:12])=O)[CH2:7]2)[CH2:3]1.[Na+].ClC(OCC)=O.Cl.[CH2:21]([O:28][C:29](=[O:35])[C@@H:30]1[CH2:34][CH2:33][CH2:32][NH:31]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>CS(C)=O.ClCCl.C(Cl)(Cl)Cl>[CH2:21]([O:28][C:29](=[O:35])[C@@H:30]1[CH2:34][CH2:33][CH2:32][N:31]1[C:10]([CH2:9][CH:6]1[O:5][CH:4]2[N:8]([C:2](=[O:1])[CH2:3]2)[CH2:7]1)=[O:12])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: O=C([O-])CC1CN2C(=O)CC2O1
Agent: CCOC(=O)Cl
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Product: O=C(OCc1ccccc1)[C@@H]1CCCN1C(=O)CC1CN2C(=O)CC2O1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 22.3 %

Procedure:
To solution of sodium 2-(7-oxo-4-oxa-1-azabicyclo [3,2,0] heptan-3-yl)-acetate (194 mg, 1 mmol) in 2 ml of DMSO and 10 ml of dichloromethane, ethyl chloroformate (109 mg, 1 mmol) was added at -15° C. After stirring at -15° C. for 30 mins, a precooled (ca. -10° C.) solution of L-proline benzyl ester hydrochloride (242 mg, 1 mmol), triethylamine (110 mg, 1.1 mmol) in chloroform (8 ml) was added at -10° C. The resulting mixture was stirred at -10 to 0° C. for 2 hrs and at room temperature overnight, and then diluted with chloroform, washed with water, dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography using hexane-ethyl acetate (1:2) as eluent and 80 mg of the title compound was obtained.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([OH:11])=O)=[N:7][CH:8]=1.[B-](F)(F)(F)F.CN(C(O[N:25]1[C:30](=O)[CH:29]=[CH:28]C=C1)=[N+](C)C)C.CCN(C(C)C)C(C)C.C1(N)CC1>CN(C=O)C>[CH:30]1([NH:25][C:9]([C:6]2[CH:5]=[CH:4][C:3]([CH2:2][OH:1])=[CH:8][N:7]=2)=[O:11])[CH2:28][CH2:29]1
Reactant: O=C(O)c1ccc(CO)cn1
Reactant: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: NC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC1CC1)c1ccc(CO)cn1

Procedure:
5-Hydroxymethyl-pyridine-2-carboxylic acid (0.23 g, 1.5 mmol) was dissolved in DMF (3 ml) and activated with TPTU (0.45 g, 1.5 mmol), Hünig's base (0.51 ml, 3.0 mmol) and reacted with cyclopropyl amine (0.12 ml, 1.65 mmol) for 1 h at r.t during which a precipitate was formed. Solvent was removed and the residue dissolved in acetonitrile/water and purified by prep.RP(C18)HPLC: 60 mg;
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:22][O:23][C:24]1[CH:29]=[C:28]([C:30]#[N:31])[CH:27]=[CH:26][C:25]=1I)[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].[C:33]([O:37][CH2:38][CH3:39])(=[O:36])[CH:34]=[CH2:35].C(N(CC)CC)C.C(OCC)(=O)C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([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])[CH2:22][O:23][C:24]1[CH:29]=[C:28]([C:30]#[N:31])[CH:27]=[CH:26][C:25]=1[CH:35]=[CH:34][C:33]([O:37][CH2:38][CH3:39])=[O:36])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)OCc1ccccc1)COc1cc(C#N)ccc1I
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1ccc(C#N)cc1OC[C@H](CCC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 8 h

Procedure:
1.64 g (2.98 mmol) of benzyl (4S)-4-t-butoxycarbonylamino-5-(5-cyano-2-iodophenoxy)pentanoate was dissolved in 30 ml of N,N-dimethylformamide (dehydrated). 0.65 ml (5.96 mmol) of ethyl acrylate, 2.1 ml (14.9 mmol) of triethylamine and 14 mg (0.06 mmol) of palladium acetate were added to the obtained solution, and they were stirred at 100° C. overnight. After the treatment with ethyl acetate as the extraction solvent in an ordinary manner, the obtained crude product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=O)[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:18]([O:20][NH2:21])[CH3:19].N1C=CC=CC=1>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[N:21][O:20][CH2:18][CH3:19])[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCON
Reactant: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CCON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Yield: 91.8 %

Procedure:
A solution was made containing (2S)-1-(tert-butoxycarbonyl)-4-oxo-2-pyrrolidinecarboxylic acid (5.0 g, 22 mmol) and O-ethylhydroxylamine hydrochloride (6.4 g, 65.5 mmol) in a 1:1 mixture of pyridine and ethanol (100 ml). The reaction was heated to reflux for 2.5 h before cooling and removal of solvent. The residue was dissolved in ethyl acetate and washed rapidly with 1.3N HCl (40 ml). The acidic layer was then extracted with ethyl acetate (3×20 ml) and the combined organic layers washed with brine before drying over magnesiom sulfate, filtering and removal of solvent in vacuo. The desired product (5.5 g, 93%) was isolated as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH:4]([S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:5]1[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[CH2:6]1.[H-].[Na+].[CH3:24]I.O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:21])[C:4]([S:12]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)(=[O:13])=[O:14])([CH:5]1[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[CH2:6]1)[CH3:24]
Reactant: CI
Reactant: COC(=O)C(C1CCCC(=O)C1)S(=O)(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C1CCCC(=O)C1)S(=O)(=O)c1ccccc1
Reaction time: 1 h
Yield: 37.8 %

Procedure:
To a stirred solution of 2 g (6.44 mmol) of benzenesulfonyl-(3-oxo-cyclohexyl)-acetic acid methyl ester in 40 mL of DMF at 0° C., 283 mg (7.09 mmol, 1.1 eq) of NaH (60%) were added. The reaction mixture was stirred at this temperature for one hour, and 1.37 g (9.66 mmol, 1.5 eq) of methyliodide were added. After 2 hours at RT, the reaction mixture was poured into water and extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and evaporated. The resulting two diastereomers were separated by column chromatography on silica gel with heptane/EtOAc 2:1, yielding 0.79 g (38%) of (RS,SR)-2-benzenesulfonyl-2-(3-oxo-cyclohexyl)-propionic acid methyl ester as a white solid, MS: 325 (MH+) and 0.71 g (34%) of (RR,SS)-2-benzenesulfonyl-2-(3-oxo-cyclohexyl)-propionic acid methyl ester as a white solid, MS: 325 (MH+).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[CH:19]1([C:24]([OH:26])=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20]1.[C:27]([O:31][C:32](=[O:45])[C:33]([CH2:35][CH2:36][O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[CH2:34])([CH3:30])([CH3:29])[CH3:28]>O1CCCC1>[CH2:38]([O:37][CH2:36][CH2:35][CH:33]([C:32]([O:31][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:45])[CH2:34][C:19]1([C:24]([OH:26])=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20]1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C(O)C1CCCC1
Reactant: C=C(CCOCc1ccccc1)C(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)C(CCOCc1ccccc1)CC1(C(=O)O)CCCC1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (2.9 mL, 20.8 mmol) in dry tetrahydrofuran (50 mL) at -50° C. was added a 2.5M solution of n-butyllithium in hexane (8.4 mL, 21 mmol). The mixture was stirred at a temperature from -30° C. to 0° C. over 30 minutes and then cooled again to -40° C. A solution of cyclopentanecarboxylic acid (1.1 mL, 10.1 mmol) in tetrahydrofuran (20 mL) was added and the resulting mixture was allowed to warm to room temperature with stirring over 2 hours. The reaction was cooled to -79° C. and a solution of 2-(2-benzyloxyethyl) acrylic acid tert-butyl ester (2.6 g, 9.9 mmol) in dry tetrahydrofuran (10 mL) was added dropwise; stirring was continued at -40° C. for 2 hours. The mixture was quenched by the addition of 0.5M HCl solution and was extracted with ether. The extract was washed with brine, dried over MgSO4 and evaporated under vacuum to leave an oil from which 1-(4-benzyloxy-2-tert-butoxycarbonylbutyl)cyclopentane carboxylic acid, 2.9 g (78%), was isolated by chromatography on silica gel eluting with methylene chloride and then 1% methanol in methylene chloride.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:13]([O:16]C)=[N:14][N:15]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[C:7]([F:12])[CH:6]=2.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C.CCOC(C)=O.Br.CC(O)=O>[CH2:18]([NH:25][C:2]1[C:3]2[N:4]([C:13](=[O:16])[NH:14][N:15]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[C:7]([F:12])[CH:6]=2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1nnc2c(Cl)nc3ccc(F)cc3n12
Reactant: NCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1[nH]nc2c(NCc3ccccc3)nc3ccc(F)cc3n12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 500 mg of 4-chloro-8-fluoro-1-methoxy-[1,2,4]triazolo[4,3-a]quinoxaline in DMF (6.0 mL) was added 637 mg of benzylamine. This solution was stirred at room temperature for 18 hrs. and then diluted with EtOAc and washed with water and saturated lithium chloride. The extracts were dried over sodium sulfate, filtered, and concentrated and the residue was separated by silica gel chromatography to give a yellow solid. This material was dissolved in a 1:1.5 mixture of 48% HBr/AcOH, and refluxed for 12 hrs. The reaction mixture was concentrated and the residue was recrystallized from MeOH to afford the title compound as a yellow solid. MS (M+H)+=310.0.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][C:12]([O:21][CH3:22])=[CH:13][C:14]=3[O:19][CH3:20])[N:9]=2)=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1.C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C>O1CCOCC1.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].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH3:20][O:19][C:14]1[CH:13]=[C:12]([O:21][CH3:22])[CH:11]=[C:10]2[C:15]=1[C:16](=[O:18])[NH:17][C:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:23][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[CH:3][CH:4]=1)=[N:9]2
Reactant: Nc1cccnc1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(Br)cc3)nc2c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(Nc4cccnc4)cc3)nc2c1
Yield: 51 %

Procedure:
A mixture of 2-(4-bromophenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.200 g, 0.55 mmol), 3-aminopyridine (0.057 g, 0.61 mmol), Cs2CO3 (0.253 g, 0.776 mmol), Xantphos (0.002 g, 0.003 mmol), and Pd2(dba)3 (0.003 g, 0.003 mmol) in dioxane (2 mL) were combined in a microwave tube under nitrogen and irradiated at 300 W, 105° C. for 30 minutes. Then, DMF (1 mL) was added and the flask was irradiated for 1 hour at 300 W, 105° C. Then, the mixture was concentrated and purified by silica gel chromatography, eluting with 92:7:1 CHCl3/MeOH/concentrated NH4OH. The residue was further purified by reverse-phase HPLC, eluting with 10% to 90% CH3CN in H2O with 0.1% TFA, to afford the title compound (0.105 g, 51%) as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 11.83 (s, 1H), 8.82 (s, 1H), 8.44 (d, J=2.4 Hz, 1H), 8.11-8.16 (m, 3H), 7.59-7.62 (m, 1H), 7.31-7.35 (m, 1H), 7.13 (d, J=8.7 Hz, 2H), 6.68 (d, J=1.8 Hz, 1H), 6.46 (d, J=1.8 Hz, 1H), 3.88 (s, 3H), 3.83 (s, 3H). APCI MS m/z 375 [M+H]+.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[CH:11][NH:10][C:9]=2[C:8](=[O:14])[N:7]2[C:15]([CH2:18][O:19][CH3:20])=[N:16][N:17]=[C:6]12)[CH2:2][CH2:3][CH3:4].[Br:21]N1C(=O)CCC1=O>O1CCCC1>[Br:21][C:11]1[NH:10][C:9]2[C:8](=[O:14])[N:7]3[C:15]([CH2:18][O:19][CH3:20])=[N:16][N:17]=[C:6]3[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:13]=2[N:12]=1
Reactant: CCCCn1c2nc[nH]c2c(=O)n2c(COC)nnc12
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: CCCCn1c2nc(Br)[nH]c2c(=O)n2c(COC)nnc12
Temperature: 70 °C
Reaction time: 2 h

Procedure:
The mixture of 9-butyl-3-(methoxymethyl)-6,9-dihydro-5h-[1,2,4]triazolo[4,3-a]purin-5-one (6 mg, 21.7 mmol), N-bromosuccinimide (4.64 mg, 26.0 mmol) in tetrahydrofuran (10 ml) was stirred at 70° C. for 2 hours. The reaction mixture was concentrated in vacuo and the residue was purified by prep LCMS to yield the desired product. LCMS calculated for C13H18BrN6O2(M+H): 369.1; found 371.1.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].C(N(CC)CC)C.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.O>C(#N)C>[N:20]1([CH:2]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([O:5][CH3:6])=[O:4])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: COC(=O)C(Br)c1ccccc1
Reactant: C1COCCN1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)C(c1ccccc1)N1CCOCC1
Reaction time: 18 h

Procedure:
Methyl α-bromophenylacetate (3.79 g, 16.5 mmol) was dissolved in 50 mL of dry ACN, to which triethylamine (3.46 mL, 24.8 mmol) and morpholine (1.73 mL, 19.8 mmol) were added and the mixture was stirred for 18 hours. The mixture was poured into water, extracted twice with EtOAc. The combined organic extracts were dried with Na2SO4, filtered and concentrated in vacuo, providing methyl morpholin-4-yl(phenyl)acetate. ESI+MS: 236.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]12[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.B([C:20]1[N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:22]=[CH:23][CH:24]=1)(O)O.C([O-])([O-])=O.[K+].[K+]>O>[O:11]=[C:6]1[C:5]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:20]3[N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:22]=[CH:23][CH:24]=3)[CH:3]=2)[NH:7]1
Reactant: O=C1Nc2ccc(Br)cc2C12CCCCC2
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(C)(C)OC(=O)n1cccc1-c1ccc2c(c1)C1(CCCCC1)C(=O)N2
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5′-bromo-spiro[cyclohexane-1,3′-indolin]-2′-one (3.4 g, 12 mmol) in 1,2-DME (100 mL) under a nitrogen atmosphere was added tetrakis(triphenylphospine)palladium(0) (70 mg, 5 mol %). After 15 min, 2-borono-1H-pyrrole-1-carboxylic acid, 1-tert butyl ester (1.3 eq, 3.31 g, 15.6 mmol) and a solution of K2CO3 (2.3 eq, 3.83 g, 27.6 mmol) in water (5 mL) were added sequentially. The solution was heated to 80° C. for 3 h and allowed to cool. The reaction mixture was poured into water (200 mL) and extracted with EtOAc (2×100 mL). The organic layers were combined, washed with brine (150 mL) and dried over MgSO4. The solution was filtered, concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with 30% EtOAc/hexane) to give subtitled compound: (3.4 g, 76%) as a white powder, mp 177° C. 1H NMR (CDCl3; 300 MHz) δ 1.38 (s, 9H), 1.59–1.93 (m, 10H), 6.18 (m, 1H) 6.23 (‘t’, 1H, J=3 Hz), 6.91 (d, 1H, J=8 Hz), 7.21 (d, 1H, J=8 Hz), 7.34 (m, 1H), 7.44 (s, 1H), 8.33 (br s, 1H, D2Oex). MS ((+)−APCI) m/z 367 [(M+H)+]. Anal. Calcd for C22H26N2O3: C, 72.11; H, 7.15; N, 7.64. Found: C, 71.7; H, 7.16; N, 7.5.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[CH2:5]Cl)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:14][C:15]1([CH3:20])[CH2:19][CH2:18][CH2:17][NH:16]1>C(O)C.C(OCC)C>[CH2:1]([O:3][C:4](=[O:7])[CH2:5][N:16]1[CH2:17][CH2:18][CH2:19][C:15]1([CH3:20])[CH3:14])[CH3:2]
Reactant: CCOC(=O)CCl
Reactant: CC1(C)CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)CN1CCCC1(C)C
Yield: 61.5 %

Procedure:
Ethylchloroacetate (0.15 ml, 1.37 mmol), potassium carbonate (416 mg, 1.5 mmol) and 2,2-dimethyl-pyrolidine (0.280 mg, 2.06 mmol) were suspended in ethanol (3 ml) and subjected to microwave irradiation at 120° C. for 45 min. The resultant mixture was suspended in diethyl ether (30 ml), extracted with 2M hydrochloric acid (30 ml) and the organic layer discarded. The aqueous layer was treated with a slight excess of 4N sodium hydroxide solution and extracted with diethyl ether (3×30 ml). The organic layers were combined, dried over sodium sulfate, filtered and solvent removed under reduced pressure to afford (2,2-dimethyl-pyrrolidin-1-yl)-acetic acid ethyl ester (156 mg).
Reaction SMILES: [F:1][CH:2]([F:32])[O:3][C:4]1[CH:11]=[C:10]([O:12][CH:13]([C:16]2[S:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)=[N:18][C:17]=2[CH3:31])[CH2:14][CH3:15])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7].C(N(CC)CC)C.Cl.[NH2:41][OH:42].O>CO>[F:32][CH:2]([F:1])[O:3][C:4]1[CH:11]=[C:10]([O:12][CH:13]([C:16]2[S:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)=[N:18][C:17]=2[CH3:31])[CH2:14][CH3:15])[CH:9]=[CH:8][C:5]=1[C:6]([NH:41][OH:42])=[NH:7]
Reactant: NO
Reactant: CCC(Oc1ccc(C#N)c(OC(F)F)c1)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Agent: Cl
Solvent: CO
Solvent: O
Solvent: CCN(CC)CC
Product: CCC(Oc1ccc(C(=N)NO)c(OC(F)F)c1)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Temperature: 140 °C
Yield: 61.6 %

Procedure:
To a solution of 485 mg of 2-difluoromethoxy-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-benzonitrile in 10 mL of methanol was added 4.166 mL of triethylamine followed by 316 mg of hydroxylamine hydrochloride. The resulting mixture was heated in a sealed tube to 140° C. under microwave irradiation for 30 minutes. After allowing it to cool down to room temperature, the mixture was poured into water and extracted with dichloromethane. The organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (gradient from heptane 100 to heptane 60/ethyl acetate 40) to give 320 mg of 2-difluoromethoxy-N-hydroxy-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-benzamidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21]Cl)[CH:16]=1.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[Cl:24])[CH:16]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CCl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: COCCOC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(Cc2ccccc2Cl)c1
Yield: 71 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-3-(2-chlorobenzyl)benzamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(chloromethyl)benzamide (0.060 g; 0.173 mmol), 2-chlorophenylboronic acid (0.028 g; 0.181 mmol), tetrakis(triphenylphosphine)palladium(0) (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.345 mmol), sodium iodide (0.052 g; 0.345 mmol), in dimethoxyethane (3 mL) and water (1 mL), heated in a sealed tube at 130° C. for 18 hours. Flash chromatography on silica gel (eluent 1 to 10% ethyl acetate in dichloromethane) furnished 0.052 g (71%) of the title compound as a white solid.