Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:29])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[S:19](=[O:27])(=[O:26])[NH:18]2)=[C:9]1[CH3:28])(C)(C)C.[CH2:30](Br)[CH:31]=[CH2:32]>>[CH2:32]([N:18]1[CH:17]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:8]([CH2:7][C:6]([OH:5])=[O:29])[C:9]=2[CH3:28])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[S:19]1(=[O:26])=[O:27])[CH:31]=[CH2:30]
Reactant: Cc1c(C2NS(=O)(=O)c3ccccc32)c2ccccc2n1CC(=O)OC(C)(C)C
Reactant: C=CCBr
Product: C=CCN1C(c2c(C)n(CC(=O)O)c3ccccc23)c2ccccc2S1(=O)=O

Procedure:
The title compound was prepared by the method described for example 14 using the product from example 3, step c) and allyl bromide. MS: ESI (negative): 395 (M−H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:17])([CH3:16])[C:13](O)=[O:14])=[CH:8][CH:7]=1.C[N:19](C=O)C.C(Cl)(=O)C(Cl)=O>C(Cl)Cl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:17])([CH3:16])[C:13]([NH2:19])=[O:14])=[CH:8][CH:7]=1
Reactant: CN(C)C=O
Reactant: CC(C)(C(=O)O)c1ccc(-c2ccco2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC(C)(C(N)=O)c1ccc(-c2ccco2)cc1
Reaction time: 2.5 h

Procedure:
To a solution of 2-(4-(furan-2-yl)-phenyl)-2-methyl-propionic Acid (reference example 28) (115 mg, 0.5 mmol) in CH2Cl2 (3 mL) is added DMF (10 mL) followed by oxalyl chloride (0.3 mL, 2M in CH2Cl2). The resulting solution is stirred for 2.5 hours then concentrated. The residue is taken up in methanolic ammonia (7N) and stirred for 14.5 hours, then concentrated to give 124 mg of the title compound as a tan solid. 1H NMR (CDCl3) d 1.58 (s, 6H), 5.2 (bs, 1H), 5.3 (bs, 1H), 6.45 (dd, J=3, 1 Hz, 1H), 6.63 (m, 1H), 7.39 (m, 2H), 7.45 (bs, 1H), 7.65 (m, 2H). MS (EI), m/z 229 (M+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C@H:12]2[C:21]3[C:16](=[CH:17][C:18]([O:22]CC4C=CC=CC=4)=[CH:19][CH:20]=3)[O:15][CH2:14][C@H:13]2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:8][CH:7]=1>O1CCCC1CO.C(O)=O.[Pd]>[CH3:1][O:2][C:3](=[O:36])[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C@H:12]2[C:21]3[C:16](=[CH:17][C:18]([OH:22])=[CH:19][CH:20]=3)[O:15][CH2:14][C@H:13]2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)COc1ccc([C@H]2c3ccc(OCc4ccccc4)cc3OC[C@H]2c2ccccc2)cc1
Agent: [Pd]
Solvent: OCC1CCCO1
Solvent: O=CO
Product: COC(=O)COc1ccc([C@H]2c3ccc(O)cc3OC[C@H]2c2ccccc2)cc1

Procedure:
(+,−) cis [4-(7-Benzyloxy-3-phenyl-chroman-4-yl)-phenoxy]-acetic acid methyl ester(100 mg, 0.21 mmol) was dissolved in a solvent mixture of tetrahydrofuran-methanol-formic acid (8+1+1, 10 ml). The solution was added to a 5% Palladium on carbon catalyst (20 mg), and hydrogenated (1 atm.) overnight. The reaction mixture was filtered and evaporated to give a dark oil, which was dissolved and evaporated from EtOH (×3), triturated with toluene, and recrystallised from toluene.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH:5]([CH3:7])[OH:6])[CH3:2].[Br:9][CH2:10][CH2:11][CH2:12][CH2:13]Br.[H-].[Na+]>C1COCC1>[CH2:1]([O:3][C:4](=[O:8])[CH:5]([CH3:7])[O:6][CH2:13][CH2:12][CH2:11][CH2:10][Br:9])[CH3:2]
Reactant: CCOC(=O)C(C)O
Reactant: BrCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)OCCCCBr

Procedure:
The lactic acid ethyl ester and 1,4-dibromo-butane were reacted in THF in the presence of NaH to obtain 7-bromo-2-methyl-3-oxaheptanoic acid ethyl ester and subsequently, the exchange of bromine and iodine was carried out, as described in 4(d).
Reaction SMILES: [O:1]([Si:9]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[CH:10]([CH3:12])[CH3:11])S(C(F)(F)F)(=O)=O.[Br:19][CH2:20][C@H:21]([CH3:25])[CH2:22][CH2:23]O.N1C(C)=CC=CC=1C.Cl>C(Cl)Cl>[CH:10]([Si:9]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[O:1][CH2:23][CH2:22][C@@H:21]([CH3:25])[CH2:20][Br:19])([CH3:12])[CH3:11]
Reactant: C[C@@H](CBr)CCO
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Agent: Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)[Si](OCC[C@@H](C)CBr)(C(C)C)C(C)C
Temperature: 0 °C

Procedure:
15.4 ml of triisopropylsilyl triflate are added to a solution of 8.7 g of (R)-4-bromo-3-methylbutan-1-ol in 320 ml of methylene chloride at 0° C., and 6.6 ml of 2,6-lutidine are then added in the course of 30 min. The reaction mixture is subsequently poured onto 100 ml of ice-water and the aqueous phase is acidified by addition of 2N hydrochloric acid (pH 3). It is extracted with methylene chloride and the organic phase is washed with a 5% sodium bicarbonate solution and saturated sodium chloride solution and dried over sodium sulfate. After purification of the crude product by FC over 200 g of silica gel (mobile phase J), the title compound is obtained: Rf (J)=0.48.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:28][O:29][CH2:30][CH2:31][NH:32][CH2:33][CH:34]([C:44]1[CH:49]=[CH:48][C:47]([Cl:50])=[C:46]([Cl:51])[CH:45]=1)[CH2:35][CH2:36][O:37][CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][O:39]1.C(N(CC)CC)C.[CH:59]([O:62][C:63]1[CH:64]=[C:65]([CH2:69][C:70](O)=[O:71])[CH:66]=[CH:67][CH:68]=1)([CH3:61])[CH3:60]>C(Cl)Cl>[CH:59]([O:62][C:63]1[CH:64]=[C:65]([CH2:69][C:70]([N:32]([CH2:33][CH:34]([C:44]2[CH:49]=[CH:48][C:47]([Cl:50])=[C:46]([Cl:51])[CH:45]=2)[CH2:35][CH2:36][O:37][CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][O:39]2)[CH2:31][CH2:30][O:29][CH3:28])=[O:71])[CH:66]=[CH:67][CH:68]=1)([CH3:61])[CH3:60]
Reactant: CC(C)Oc1cccc(CC(=O)O)c1
Reactant: COCCNCC(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCN(CC(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1)C(=O)Cc1cccc(OC(C)C)c1
Reaction time: 1 h
Yield: 80.6 %

Procedure:
2.6 g of BOP are added to a solution cooled at 0° C. of 1.9 g of the product prepared in step 2, 1.2 g of triethylamine and 0.96 g of 3-isopropoxyphenylacetic acid in 50 ml of CH2Cl2. The reaction mixture is stirred for one hour and is then concentrated under vacuum. The residue is taken up in ethyl acetate, washed with water, dried over Na2SO4 and concentrated under vacuum. 2.2 g of the expected product is obtained, which is directly used in the next step.
Reaction SMILES: [CH3:1][Mg]Br.CON(C)[C:7]([C:9]1[N:10]([S:22](=[O:27])(=[O:26])[N:23]([CH3:25])[CH3:24])[N:11]=[C:12]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:13]=1)=[O:8]>C1(C)C=CC=CC=1.C1COCC1.[NH4+].[Cl-]>[CH3:25][N:23]([CH3:24])[S:22]([N:10]1[C:9]([C:7](=[O:8])[CH3:1])=[CH:13][C:12]([CH2:14][O:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[N:11]1)(=[O:26])=[O:27]
Reactant: CON(C)C(=O)c1cc(COc2ccccc2)nn1S(=O)(=O)N(C)C
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(=O)c1cc(COc2ccccc2)nn1S(=O)(=O)N(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
A 1.4M solution of methylmagnesium bromide in toluene and THF (3.88 mL, 5.43 mmol) was added to a solution of 2-dimethylsulfamoyl-5-phenoxymethyl-2H-pyrazole-3-carboxylic acid methoxy-methyl-amide (1.54 g, 4.17 mmol) in THF (20 mL) at −78° C. and under nitrogen. The mixture was stirred at −78° C. for 1 hour and then at room temperature for 16 hours. Then, a second portion of methylmagnesium bromide in toluene and THF (3.58 mL, 5.01 mmol) was added at 0° C. and the mixture was stirred at room temperature for 3 hours. The mixture was diluted with a saturated solution of NH4Cl and extracted with AcOEt. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in heptane 0/100 to 50/50). The desired fractions were collected and the solvents evaporated in vacuo to yield 5-acetyl-3-phenoxymethyl-pyrazole-1-sulfonic acid dimethylamide (1.2 g, 89% yield) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([C:23]2([OH:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=1.[CH2:30]([Sn](CCCC)(CCCC)C=C)[CH2:31]CC>C1(C)C=CC=CC=1.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>[OH:29][C:23]1([CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH:30]=[CH2:31])[CH:3]=2)[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N1CCN(CC(c2cccc(Br)c2)C2(O)CCCCC2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1cccc(C(CN2CCN(C(=O)OC(C)(C)C)CC2)C2(O)CCCCC2)c1
Yield: 90 %

Procedure:
A mixture of tert-butyl 4-[2-(3-bromophenyl)-2-(1-hydroxycyclohexyl)ethyl]piperazine-1-carboxylate (see Example 135, step 2) (141 mg, 0.300 mmol), tributyl(vinyl)tin (114 mg, 0.360 mmol, 1.2 equivalents, and tetrakis(triphenylphosphine)palladium (17 mg, 0.015 mmol, 5 mol %) in toluene (3 mL) was heated at reflux under nitrogen until all starting material was consumed and precipitation of black palladium occurred (1-2 h). Filtration through Celite® and purification via flash column chromatography (silica, gradient from 0% ethyl acetate/hexane to 10% ethyl acetate/hexane) yielded 111 mg (90%) tert-butyl 4-[2-(1-hydroxycyclohexyl)-2-(3-vinylphenyl)ethyl]piperazine-1-carboxylate as a viscous colorless oil. MS (ES) m/z 415.4 ([M+H]+); HRMS: calcd for C25H38N2O3, 414.2882; found (ESI), 415.2966.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:17]I.O>CN(C=O)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH3:17])[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][N:14]=2)=[CH:6][CH:7]=1
Reactant: CI
Reactant: Ic1ccc(Nc2ncccn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1ccc(I)cc1)c1ncccn1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
Under an argon atmosphere, a solution of N-(4-iodophenyl)pyrimidin-2-amine (1.47 g) in anhydrous DMF (10 ml) was added dropwise to a suspension of sodium hydride (218 mg) in anhydrous DMF (8 ml), and the resulting mixture was stirred at room temperature for 75 minutes. Methyl iodide (0.37 ml) was added dropwise to the reaction solution and the resulting mixture was stirred at room temperature for another 1 hour. Water was added thereto and the resulting mixture was extracted with ethyl acetate. Organic layer was washed twice with water and once with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was recrystallized from hexane to obtain N-(4-iodophenyl)-N-methylpyrimidin-2-amine (1.38 g). NMR (H1, CDCl3): δ 3.49(3H, s), 6.58 (1H, t, J=4.6 Hz), 7.07-7.09 (2H, m), 7.67-7.69 (2H, m), 8.32 (2H, d, J=4.6 Hz)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[S:13][C:12]([NH:14][C:15](=[O:17])[CH3:16])=[N:11][C:10]=2[CH3:18])[CH:5]=[N:6][C:7]=1[Cl:8].[C:19]1([N:25]=[C:26]=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[NH:25]([C:26]([NH:1][C:2]1[CH:3]=[C:4]([C:9]2[S:13][C:12]([NH:14][C:15](=[O:17])[CH3:16])=[N:11][C:10]=2[CH3:18])[CH:5]=[N:6][C:7]=1[Cl:8])=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C=Nc1ccccc1
Reactant: CC(=O)Nc1nc(C)c(-c2cnc(Cl)c(N)c2)s1
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(C)c(-c2cnc(Cl)c(NC(=O)Nc3ccccc3)c2)s1
Yield: 35.5 %

Procedure:
N-[5-(5-Amino-6-chloropyridin-3-yl)-4-methyl-1,3-thiazol-2-yl]acetamide (20 mg, 0.07 mmol) and phenyl isocyanate (0.023 mL, 0.21 mmol) were stirred in THF (0.6 mL) at 40° C. for 2 hours. The reaction product was purified by preparative HPLC (Method A) to give the title product (retention time 8.93 minutes; 10 mg, 36%); 1H NMR Spectrum: (DMSOd6) 12.23 (1H, s); 9.56 (1H, s); 8.69 (1H, d); 8.54 (1H, s); 8.15 (1H, d); 7.48 (2H, d); 7.32 (2H, t); 7.02 (1H, t); 2.40 (3H, s); 2.16 (3H, s); Mass Spectrum: M+H+ 402 and 404.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:13][Si:14]([CH2:17][CH2:18][O:19][CH2:20]Cl)([CH3:16])[CH3:15]>C1COCC1>[Br:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:20][O:19][CH2:18][CH2:17][Si:14]([CH3:16])([CH3:15])[CH3:13])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Brc1cccc2[nH]cnc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cnc2c(Br)cccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a solution of 4-bromo-1H-benzo[d]imidazole (1.1 g, 5.6 mmol) in THF was added NaH (448 mg, 11.2 mmol) at 0° C. After stirring at for 30 minutes at room temperature 0° C., SEM-Cl (1.4 g, 8.4 mmol) was added to the mixture at 0° C. The mixture was then stirred at room temperature for 16 h, at which time TLC showed the completion of the reaction. The reaction was quenched by addition of aq. NH4Cl and the mixture extracted with ethyl acetate with the combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuum to give the desired product and used in the next step without further purification (1.65 g, Yield 90%). LCMS (m/z): 229.0 (M+1)
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[NH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]1>>[CH:9]1[C:10]2[NH:11][C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]=2[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][NH:19][CH2:20][CH:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[CH:7][CH:8]=1
Reactant: c1ccc2c(c1)[nH]c1cccc(OC[C@@H]3CO3)c12
Reactant: CC(C)N1CCC(CN)CC1
Product: CC(C)N1CCC(CNC[C@H](O)COc2cccc3[nH]c4ccccc4c23)CC1
Yield: 34.1 %

Procedure:
Prepared from 4-[(2S)-oxiranylmethoxy]-9H-carbazole (0.239 g, 1.0 mmol) and 4-aminomethyl-1-isopropylpiperidine (0.312 g, 2.0 mmol) of according to the procedure used for Example 2 to give 0.135 g of the title compound as a white solid.
Reaction SMILES: Cl[C:2]([O:4]CC)=[O:3].[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH:13]([CH3:21])[CH:14]3[CH2:18][NH:17][CH2:16][CH:15]3[C:19]=2[CH:20]=1>C1COCC1.O>[CH2:16]([NH:17][C:2](=[O:3])[O-:4])[CH3:15].[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH:13]([CH3:21])[CH:14]3[CH2:18][NH:17][CH2:16][CH:15]3[C:19]=2[CH:20]=1
Reactant: CCOC(=O)Cl
Agent: COc1ccc2c(c1)C1CNCC1C2C
Solvent: O
Solvent: C1CCOC1
Product: CCNC(=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Hydrogen sodium carbonate (11.7 g, 139 mmol) and ethyl chloroformate (3.2 mL, 33.4 mmol) were added to a solution of 5-methoxy-8=methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 1, Step E) (5.6 g, 27.8 mmol) in THF/H2O (140 mL, 1/1, v/v), and stirred overnight at room temperature. The reaction mixture was quenched by addition of an aqueous HCl solution (200 mL, 1.0 M) and the product was extracted with EtOAc (3×100 mL). The combined organic extracts were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (SiO2) using a 0-35% ethyl acetate-hexanes gradient to afford 2.7 g (35%) of the subtitle compound. 1H NMR (CDCl3 300 MHz)*7.07 (d, 1H), 6.78 (m, 2H), 4.09 (m, 2H), 3.79 (m, 5H), 3.63 (m, 1H), 3.52 (m, 1H), 3.32 (m, 1H), 3.07 (m, 1H), 2.95 (m, 1H), 1.26 (m, 6H) ppm. MS calculated for C16H21NO3+H: 276, observed: 276.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH3:9])[CH:3]=1.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=1[F:18].C(=O)([O-])[O-].[K+].[K+]>CCOC(C)=O>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:2]2[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH3:9])[CH:3]=2)=[CH:13][C:12]=1[F:18]
Reactant: Cc1cc(Br)cc(C)n1
Reactant: Oc1ccc(Br)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: Cc1cc(Oc2ccc(Br)c(F)c2)cc(C)n1
Temperature: 150 °C
Yield: 73.8 %

Procedure:
A mixture of 4-bromo-2,6-dimethyl-pyridine (1 g, 5.4 mmol), 4-bromo-3-fluoro-phenol (0.59 g, 5.4 mmol), and potassium carbonate (0.89 g, 6.4 mmol) in xylenes (2 ml) was heated at 150° C. (oil bath temperature) in a sealed tube for 48 hours. After cooling to room temperature the mixture was diluted with EtOAc and filtered through a diatomaceous earth pad. The filtrate was evaporated till dryness and the crude product thus obtained was purified by column chromatography (silica gel; DCM to DCM/EtOAc up to 10% as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate 17 (1.18 g, 72%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH2:10]O)[CH2:4][CH2:3]1.[C:12]([NH:19][C:20]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[N:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([CH2:8][CH2:9][CH2:10][N:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:20]([NH:29][C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])=[N:19][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reactant: CN1CCC(CCCO)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Product: CN1CCC(CCCN(C(=O)OC(C)(C)C)C(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a 100 mL, 3-neck, round bottom flask were added 3-(1-methyl-piperidin-4-yl)-propan-1-ol (1.91 g, 0.012 mol), Polymer Labs (Varian) PL-TPP resin (9.83 g, 0.014 mol), N,N′,N″-tri-Boc-guanidine (4.36 g, 0.012 mol) and THF (anhydrous, 100 mL). The resultant mixture was stirred and cooled to 2° C., at which time DEAD (2.53 g, 0.014 mol) was added drop wise over 10 min. Upon completion of addition, the flask was warmed to room temperature, aged for 4 h and filtered to remove the resin bound oxide. The resultant cake was rinsed with THF (25 mL) and heptane (2×25 mL). The filtrates were combined, extracted with saturated aqueous NaHCO3 (2×25 mL), dried over anhydrous MgSO4, filtered and concentrated. The resultant residue was triturated in hot ethanol (25 mL), cooled to room temperature and filtered. The filtrate was concentrated to yield N-[3-(1-methylpiperidin-4-yl)-propyl]-N,N′,N″-tri-Boc-guanidine.
Reaction SMILES: [F:1][C:2]([F:38])([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([NH:19][C:20]3[N:25]=[C:24]([C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH:23]=[CH:22][N:21]=3)[CH:13]=2)=[O:10])=[CH:5][CH:4]=1.[CH3:39][CH:40]=O>>[CH2:39]([N:35]1[CH2:34][CH2:33][N:32]([C:2]([F:1])([F:38])[C:3]2[CH:4]=[CH:5][C:6]([C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([NH:19][C:20]4[N:25]=[C:24]([C:26]5[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=5)[CH:23]=[CH:22][N:21]=4)[CH:13]=3)=[O:10])=[CH:7][CH:8]=2)[CH2:37][CH2:36]1)[CH3:40]
Reactant: Cc1ccc(NC(=O)c2ccc(C(F)(F)N3CCNCC3)cc2)cc1Nc1nccc(-c2cccnc2)n1
Reactant: CC=O
Product: CCN1CCN(C(F)(F)c2ccc(C(=O)Nc3ccc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc2)CC1

Procedure:
The product from Example 14 was ethylated via reductive amination with CH3CHO/NaBHCN afforded the title compound. Mass: (M+1), 544.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[OH-].[Na+].C[SH-][C:13]([SH-]C)=[N:14][C:15]1[S:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1>CN(C=O)C.O>[S:16]1[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=[C:15]1[NH:14][C:13]1[O:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: C[SH-]C(=Nc1nc2ccccc2s1)[SH-]C
Reactant: Nc1ccccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc2oc(Nc3nc4ccccc4s3)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.1 %

Procedure:
2-aminophenol (21.8 g (0.20 mol)) was dissolved in 944 g of DMF, thereto was added 40 mL of 5 mol/L aqueous sodium hydroxide solution (equivalent to 0.20 mol of sodium hydroxide), the resulting mixture was stirred at room temperature for 30 minutes, and then thereto was added a solution obtained by dissolving 50.9 g (0.20 mol) of the obtained S,S′-dimethyl-N-(2-benzothiazolyl)carbonimidodithioate in 1416 g of DMF. The resulting mixture was then heated to 153° C., refluxed under a nitrogen atmosphere for 6 hours, and then cooled to room temperature, and the reaction liquid was added dropwise in 2000 g of water. A precipitate was filtered off, washed with water, and dried to obtain 30.0 g of 2-(2-benzothiazolylamino)benzoxazole (L5: see Table 1 below). The yield was 56.1% based on 2-aminophenol.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[F:28][C:29]1[C:34]([F:35])=[C:33]([F:36])[CH:32]=[CH:31][C:30]=1[C:37](=[O:41])[C:38]#[C:39][CH3:40].CCN(C(C)C)C(C)C>CO>[CH3:40]/[C:39](/[NH:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4])=[CH:38]/[C:37](=[O:41])[C:30]1[CH:31]=[CH:32][C:33]([F:36])=[C:34]([F:35])[C:29]=1[F:28]
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1
Reactant: CC#CC(=O)c1ccc(F)c(F)c1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: C/C(=C/C(=O)c1ccc(F)c(F)c1F)N[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)O
Yield: 58.6 %

Procedure:
A mixture of 680 mg (1.85 mmol) of Intermediate 45, 367 mg (1.85 mmol) of Intermediate 36, and 0.67 mL (3.7 mmol) of DIEA in 15 mL of MeOH was refluxed overnight (14 h). The solvent was evaporated under reduced pressure and the residue purified directly by silica gel chromatography. Elution with 5%-20% MeOH in CH2Cl2 gave 612 mg (58% yield) of the title compound as a solid: TLC (DCM/MeOH, 4/1): Rf=0.50; 1H NMR (DMSO-d6, 300 MHz) δ11.35 (d, 1H, J=9.0), 7.87 (m, 2H), 7.48 (m, 4H), 7.3 (q, 1H, J=5.4), 7.10 (d, 2H, J=8.7), 6.78 (d, 2H, J=8.7), 5.25 (s, 1H), 4.18 (m, 3H), 3.19 (m, 2H), 2.86 (t, 2H, J=6.3), 2.74 (dd, 1H, J=13.8, 9.0), 2.32 (s, 3H), 1.64 (s, 3H); low resolution MS (ES+)m/e 564.9 (MH+);
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:26]#[N:27])=[C:4]([C:8]([NH:10][C@@H:11]2[CH2:16][CH2:15][N:14](C(OCC)=O)[CH2:13][C@@H:12]2[O:22][CH2:23][CH2:24][CH3:25])=[O:9])[NH:5][C:6]=1[CH3:7].[OH-].[K+].O.NN.O>C(O)CO>[Cl:1][C:2]1[C:3]([C:26]#[N:27])=[C:4]([C:8]([NH:10][C@@H:11]2[CH2:16][CH2:15][NH:14][CH2:13][C@@H:12]2[O:22][CH2:23][CH2:24][CH3:25])=[O:9])[NH:5][C:6]=1[CH3:7]
Reactant: CCCO[C@H]1CN(C(=O)OCC)CC[C@H]1NC(=O)c1[nH]c(C)c(Cl)c1C#N
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: CCCO[C@H]1CNCC[C@H]1NC(=O)c1[nH]c(C)c(Cl)c1C#N
Temperature: 25 °C
Yield: 70.4 %

Procedure:
A solution of ethyl (3S,4R)-4-{[(4-chloro-3-cyano-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-propoxypiperidine-1-carboxylate (Intermediate 75, 2.6 g, 6.56 mmol), potassium hydroxide (3.67 g, 65.6. mmol), and hydrazine hydrate (3.28 g, 65.6 mmol) in ethylene glycol (100 mL) was stirred for 60 h at 120° C. The reaction mixture was cooled to room temperature and poured into water (75 mL) and extracted with ethyl acetate (2×100 mL). The combined organic extracts were dried over anhydrous sodium sulphate, filtered, concentrated under vacuum to afford 4-chloro-3-cyano-5-methyl-N-[(3S,4R)-3-propoxypiperidin-4-yl]-1H-pyrrole-2-carboxamide 1.5 g, 71% as solid.