Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH3:9][C:10]1[N:11]([C@H:16]2[CH2:20][C@@H:19]([C:21]([O:23][CH3:24])=[O:22])[CH:18]=[CH:17]2)[C:12]([CH3:15])=[CH:13][CH:14]=1.FC(F)(F)S(O[CH2:31][CH:32]([F:34])[F:33])(=O)=O.[NH4+].[Cl-]>C1COCC1>[F:33][CH:32]([F:34])[CH2:31][C@@:19]1([C:21]([O:23][CH3:24])=[O:22])[CH2:20][C@H:16]([N:11]2[C:10]([CH3:9])=[CH:14][CH:13]=[C:12]2[CH3:15])[CH:17]=[CH:18]1
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Reactant: COC(=O)[C@H]1C=C[C@@H](n2c(C)ccc2C)C1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)[C@@]1(CC(F)F)C=C[C@@H](n2c(C)ccc2C)C1
Reaction time: 0.5 h

Procedure:
A −40° C. solution of 2 M (in Ethylbenzene/THF/Heptane) LDA (36 ml, 72 mmol) in THF (80 ml) was placed in flask with THF (80 ml) was treated with a solution of methyl (1R,4S)-4-(2,5-dimethyl-1H-pyrrol-1-yl)cyclopent-2-ene-1-carboxylate (7.9 g, 36.3 mmol) in THF (17 ml) while keeping the temperature less than −32° C. The reaction was stirred for 30 min and then 2,2-difluoroethyl trifluoromethanesulfonate was added slowly, keeping the temperature <−28° C. The reaction was stirred with cold bath in place and allow to slowly warm. After 4 hours the reaction was poured into NH4Cl solution and extracted twice with ethyl acetate. The combined organics were washed with brine, dried over MgSO4 and concentrated to give a brown oil. The oil was passed through a column of silica gel with 10% ethyl acetate/hexanes to give methyl (1S,4S)-1-(2,2-difluoroethyl)-4-(2,5-dimethyl-1H-pyrrol-1-yl)cyclopent-2-ene-1-carboxylate as a brown oil. (7.5 g, 73%). 1H NMR (400 MHz, CDCl3) δ ppm 6.07-6.04 (1H), 6.02-6.00 (0.25H) 5.98-5.96 (1H), 5.88-5.86 (0.5H), 5.75-5.72 (2.25H), 5.36-5.30 (1H), 3.74 (3H), 2.53-2.41 (2H), 2.39-2.22 (2H), 2.19 (6H)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:6]=2[CH:23]=1.[Br:24]Br>C(O)(=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:6]=2[C:23]=1[Br:24]
Reactant: BrBr
Reactant: CN1C(=O)C(C)(C)N=C(c2ccccc2Cl)c2cc(N)ccc21
Solvent: CC(=O)O
Product: CN1C(=O)C(C)(C)N=C(c2ccccc2Cl)c2c1ccc(N)c2Br
Reaction time: 1 h

Procedure:
16 g (0.049 mol) of 7-amino-5-(o-chlorophenyl)-1,3-dihydro-1,3,3-trimethyl-2H-1,4-benzodiazepin-2-one in 160 ml of glacial acetic acid are treated slowly while stirring with 8.5 g of bromine in 10 ml of glacial acetic acid. After 60 minutes at room temperature, the reaction mixture is concentrated and the residue is partitioned between aqueous ammonia and methylene chloride. The aqueous phase is extracted several times more with methylene chloride. The combined organic extracts are dried and evaporated. The crude product is purified on 500 g of silica gel with methylene chloride/ethyl acetate (5:1) as the elution agent. From ethyl acetate/ether there is obtained 7-amino-6-bromo-5-(o-chlorophenyl)-1,3-dihydro-1,3,3-trimethyl-2H-1,4-benzodiazepin-2-one of melting point 188°-189°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:16])[CH3:15])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:17][CH3:18].C(N(C(C)C)CC)(C)C.[CH3:28][C:29]1[C:38]2[CH:37]=[N:36][C:35](S(C)=O)=[N:34][C:33]=2[N:32]([C:42]2[CH:43]=[C:44]([NH:48][C:49](=[O:52])[CH:50]=[CH2:51])[CH:45]=[CH:46][CH:47]=2)[C:31](=[O:53])[CH:30]=1>C(O)(C)(C)C.O1CCOCC1>[C:14]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:35]3[N:36]=[CH:37][C:38]4[C:29]([CH3:28])=[CH:30][C:31](=[O:53])[N:32]([C:42]5[CH:43]=[C:44]([NH:48][C:49](=[O:52])[CH:50]=[CH2:51])[CH:45]=[CH:46][CH:47]=5)[C:33]=4[N:34]=3)=[C:3]([O:17][CH3:18])[CH:4]=2)[CH2:9][CH2:10]1)(=[O:16])[CH3:15]
Reactant: C=CC(=O)Nc1cccc(-n2c(=O)cc(C)c3cnc(S(C)=O)nc32)c1
Reactant: COc1cc(N2CCN(C(C)=O)CC2)ccc1N
Solvent: CC(C)(C)O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cccc(-n2c(=O)cc(C)c3cnc(Nc4ccc(N5CCN(C(C)=O)CC5)cc4OC)nc32)c1
Temperature: 110 °C
Reaction time: 0.17 h
Yield: 34.7 %

Procedure:
A suspension of 1-(4-(4-amino-3-methoxyphenyl)piperazin-1-yl)ethanone (20b; 351 mg, 1.40 mmol), diisopropylethylamine (0.41 mL, 2.34 mmol) and N-(3-(5-methyl-2-(methylsulfinyl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (5b; 288 mg, 0.78 mmol) in tert-butanol (2 mL) and dioxane (1 mL) in a sealed glass tube was heated in an oil bath at 110° C. for 72 h. It was concentrated under reduced pressure. The brown residue was stirred in 5 mL of ether for 10 min. The liquid was decanted; the remaining solid was loaded on a silica gel column and eluted with 2-10% MeOH in DCM followed by 5% 2 M NH3 in MeOH in DCM to give the title compound (20) (150 mg, 34% yield) as a yellow crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.33 (1H, s), 8.81 (1H, s), 8.12 (1H, s), 7.88 (1H, d, J=8.0 Hz), 7.42-7.61 (2H, m), 7.28 (1H, d, J=9.0 Hz), 6.98 (1H, d, J=7.8 Hz), 6.56 (1H, m), 6.44 (1H, m), 6.33 (1H, s), 6.24 (1H, m), 6.04 (1H, br. s.), 5.75 (1H, m), 3.78 (3H, s), 3.56 (4H, m), 3.04 (2H, m), 2.97 (2H, m), 2.46 (3H, s), 2.03 (3H, s). m/z (ESI, +ve ion) 554.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[O:7]=[C:8]1[CH2:13][N:12]([C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH2:11][CH2:10][N:9]1[C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>N1C=CC=CC=1>[O:7]=[C:8]1[CH2:13][N:12]([C:14](=[O:19])[C:15]([F:17])([F:16])[F:18])[CH2:11][CH2:10][N:9]1[C:20]1[CH:21]=[CH:22][C:23]([S:26]([NH:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)(=[O:28])=[O:27])=[CH:24][CH:25]=1
Reactant: O=C1CN(C(=O)C(F)(F)F)CCN1c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nccs1
Solvent: c1ccncc1
Product: O=C1CN(C(=O)C(F)(F)F)CCN1c1ccc(S(=O)(=O)Nc2nccs2)cc1
Yield: 48.3 %

Procedure:
Synthesized according to general procedure 12, method A. The reaction was set up with 2-aminothiazole (2.4 g, 24.2 mmol), anhydrous pyridine (10 mL), and 4-(2-oxo-4-(2,2,2-trifluoroacetyl)piperazin-1-yl)benzene-1-sulfonyl chloride (9.0 g, 24.2 mmol). The dark oil was purified via silica gel chromatography using 5% MeOH in CH2Cl2 followed by a second purification on silica gel using 80% EtOAc in hexanes to obtain the desired sulfonamide as a white solid (5.1 g, 11.7 mmol, 48% yield). LC/MS (10%/99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=435.2; tR=2.35 min.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[O:13]1[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][OH:20])[CH2:14]1.O>ClCCl>[O:13]1[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][O:20][S:9]([CH3:8])(=[O:11])=[O:10])[CH2:14]1
Reactant: CS(=O)(=O)Cl
Reactant: OCCC1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCC1CCOC1
Reaction time: 0.33 h

Procedure:
Triethylamine (2.1 mL, 15 mM) and methanesulfonyl chloride (0.85 mL, 11 mM) were added drop wise to a cold (−5 to −10° C.) solution of 2-(tetrahydro-furan-3-yl)-ethanol (1.14 g, 10 mM) in dichloromethane (15 mL). The reaction was stirred for 20 min at this temp then water (10 mL) was added and the reaction was stirred an additional 10 min then the phases were separated and the aqueous phase was extracted with dichloromethane (3×20 mL). The combined organics were washed with 50% aqueous HCl, sat. NaHCO3, dried (MgSO4), filtered and concentrated to give a quantitative yield of methanesulfonic acid 2-(tetrahydrofuran-3-yl)-ethyl ester.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].Br[CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1>C(COC)OC.CCOCC>[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(Br)CC1
Reactant: Sc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(Sc2ccccn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.1 %

Procedure:
To a slurry of sodium hydride (about 60% oil suspension, 397 mg) in dimethoxyethane (4 ml) was added a solution of 2-pyridinethiol (1.05 g) in dimethoxyethane (6 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. To the mixture was added tert-butyl 4-bromo-1-piperidinecarboxylate (2.74 g), and the mixture was refluxed for 2 hours. After cooling, the resulting suspension was diluted with ether and filtered through a pad of Celite. The filtrate was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent; 14% ethyl acetate in n-hexane) to give the title compound (2.2 g) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:11]([O:12][CH2:13][C:14]#[N:15])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:16][NH:17][C:18]([C:20]1[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[O:22][C:21]=1[CH3:29])=[O:19])=[CH:7]2.[N-:30]=[N+:31]=[N-:32].[Na+].[Cl-].[NH4+].[OH-].[Na+]>CN(C=O)C.O>[Br:1][C:2]1[C:11]([O:12][CH2:13][C:14]2[NH:32][N:31]=[N:30][N:15]=2)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:16][NH:17][C:18]([C:20]1[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[O:22][C:21]=1[CH3:29])=[O:19])=[CH:7]2
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1oc2ccccc2c1C(=O)NCc1ccc2c(Br)c(OCC#N)ccc2c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1oc2ccccc2c1C(=O)NCc1ccc2c(Br)c(OCc3nnn[nH]3)ccc2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 84.4 %

Procedure:
A mixture of 2-methyl-benzofuran-3-carboxylic acid (5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-amide (233 mg, 0.52 mmol), prepared in the previous step, sodium azide (101 mg, 1.56 mmol) and ammonium chloride (83 mg, 1.55 mmol) in 15 mL of DMF was stirred under nitrogen at 100° C. for 8 h. The reaction was diluted with 35 mL of water, made basic by the addition of 3 mL of 1 N NaOH and extracted five times with ethyl acetate. The aqueous layer was acidified by the addition of 5 mL of 1 N HCl. The solid that precipitated was collected by filtration and dried under reduced pressure to give the title compound (216 mg, 85%) as a white solid, mp 242-244° C.
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)[CH2:4][N:3]=[N:2]1.[CH3:11][N:12]=[C:13]=[S:14]>C(O)C>[CH3:11][NH:12][C:13]([N:2]1[N:3]=[CH:4][C:5]2([CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)[CH2:1]1)=[S:14]
Reactant: C1CC2(CCO1)CN=NC2
Reactant: CN=C=S
Solvent: CCO
Product: CNC(=S)N1CC2(C=N1)CCOCC2
Yield: 0.2 %

Procedure:
0.8 g (1 mol equiv.) 8-Oxa-2,3-diaza-spiro[4.5]dec-2-ene (synthesized as described in WO 2008/034863) and 0.54 g (1.3 mol equiv.) methyl isothiocyanate were added to 10 mL ethanol, and the reaction mixture was refluxed for 5 hours. Silica gel was added and volatiles were removed under reduced pressure. Purification by flash chromatography on silica gel (Et2O) afforded 0.52 g (35%) 8-oxa-2,3-diaza-spiro[4.5]dec-3-ene-2-carbothioic acid methylamide. 1H NMR (400 MHz, CDCl3) δ 1.52-1.59 (m, 3H), 1.82-1.90 (m, 2H), 3.17 (d, J=5.0, 3H), 3.56-3.64 (m, 2H), 3.86-3.92 (m, 2H), 4.11 (s, 2H), 6.80 (s, 1H), 7.21 (br.s., 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[OH-].[Na+].Cl[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:12](=[O:13])[O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Br)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(Nc1cccc(Br)c1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a mixture of 3-bromoaniline (0.500 g), 2 mol/L aqueous sodium hydroxide (2.18 mL) and tetrahydrofuran (3.63 mL) was added dropwise benzyl chloroformate (0.498 mL), and the resulting mixture was stirred at room temperature for 3.5 hours. The reaction mixture was partitioned between ethyl acetate (35 mL) and water (10 mL). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=8/1) to give the title compound (0.897 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.C(O[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])C>CC#N>[N+:19]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:13]=1[NH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)([O-:21])=[O:20]
Reactant: CCOc1ccncc1[N+](=O)[O-]
Reactant: NCCN1CCNCC1
Solvent: CC#N
Product: O=[N+]([O-])c1cnccc1NCCN1CCNCC1
Temperature: 25 °C

Procedure:
A mixture of 1-(2-aminoethyl)piperazine and 4-ethoxy-3-nitropyridine in CH3CN was heated at reflux for 40 hours. The reaction mixture was cooled to ambient temperature and concentrated to give 3-nitro-4-[2-(piperazine-1-yl)ethyl]aminopyridine which was used without further purification.
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3]1.[N-:31]=[N+:32]=[N-:33].[Na+].O>CN(C)C=O>[N:31]([CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3]1)=[N+:32]=[N-:33]
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(Cl)c3ccccc32)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(N=[N+]=[N-])c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
5-Chloro-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.8 g) is dissolved in dimethylformamide and thereto is added sodium azide (0.18 g) at room temperature. The mixture is stirred at room temperature overnight, and further reacted with heating at 50° C. for 5 hours. Water is added to the reaction mixture and the precipitated crystal is collected by filtration to give 5-azido-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.68 g) as light brown powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[N:12]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([F:20])=[CH:15][CH:14]=3)=[O:10])[CH:5]=[CH:4][N:3]=1.Br[CH:30]([CH3:39])[C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=O>C(#N)C>[CH3:39][C:30]1[N:1]=[C:2]2[CH:7]=[C:6]([NH:8][C:9]([C:11]3[N:12]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=4)[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([F:20])=[CH:15][CH:14]=4)=[O:10])[CH:5]=[CH:4][N:3]2[C:31]=1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Nc1cc(NC(=O)c2cc3cc(F)ccc3n2Cc2cccc(F)c2)ccn1
Reactant: CC(Br)C(=O)c1ccccc1
Solvent: CC#N
Product: Cc1nc2cc(NC(=O)c3cc4cc(F)ccc4n3Cc3cccc(F)c3)ccn2c1-c1ccccc1
Temperature: 150 °C
Yield: 23.4 %

Procedure:
0.1 g (0.26 mmol) of N-[2-aminopyrid-4-yl]-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide, prepared according to the protocol described in step 10.1, 0.11 g (0.53 mmol) of 2-bromo-1-phenylpropan-1-one and 4 mL of acetonitrile are placed in a 10 mL pressure tube specific for microwave reactors. The tube is then sealed and heated in the microwave reactor at 150° C. for two 1-hour cycles. After this time, the reaction mixture is concentrated under reduced pressure. The crude reaction product is then purified by chromatography on a column of silica gel, eluting with a mixture of dichloromethane and methanol. 0.03 g of the expected product is thus obtained in the form of a beige-coloured solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:7])[CH2:3][C:4](Cl)=[O:5].[C:8]([O:12][C:13](=[O:35])[CH2:14][N:15]1[C:19]2[CH:20]=[CH:21][C:22]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:23][C:18]=2[N:17]=[C:16]1[CH2:32][CH2:33][CH3:34])([CH3:11])([CH3:10])[CH3:9].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl.Cl>[C:8]([O:12][C:13](=[O:35])[CH2:14][N:15]1[C:19]2[CH:20]=[CH:21][C:22]([N:24]([CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:4](=[O:5])[CH2:3][CH:2]([CH3:7])[CH3:1])=[CH:23][C:18]=2[N:17]=[C:16]1[CH2:32][CH2:33][CH3:34])([CH3:11])([CH3:10])[CH3:9]
Reactant: CCCc1nc2cc(NCc3ccccc3)ccc2n1CC(=O)OC(C)(C)C
Reactant: CC(C)CC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1nc2cc(N(Cc3ccccc3)C(=O)CC(C)C)ccc2n1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Methyl-butyryl chloride (44 μL, 0.36 mmol) was added to a solution of (5-benzylamino-2-propyl-benzoimidazol-1-yl)-acetic acid tert-butyl ester (45 mg, 0.12 mmol), DIEA (41 μL, 0.24 mmol) and DMAP (15 mg, 0.12 mmol) in CH2Cl2 (1 mL), and stirred overnight at room temperature. The reaction solution was diluted with aqueous HCl (1.0 M) and filtered through an Extrelut column. The Extrelut column was washed with CH2Cl2, and the filtrate was concentrated to afford the subtitle compound that was used without further purification. MS calculated for C28H37N3O3+H: 464, observed: 464.
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].[NH2:5][CH2:6][C:7]1([C:17]2[S:18][C:19]([C:22]3[CH:23]=[C:24]([NH:29][C:30]4[N:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][N:31]=4)[CH:25]=[C:26]([CH3:28])[CH:27]=3)=[CH:20][N:21]=2)[CH2:16][CH2:15][C:10]2(OCC[O:11]2)[CH2:9][CH2:8]1.CS(O)(=O)=O>C(Cl)(Cl)Cl>[NH2:5][CH2:6][C:7]1([C:17]2[S:18][C:19]([C:22]3[CH:23]=[C:24]([NH:29][C:30]4[N:35]=[C:34]([C:36]([F:38])([F:37])[F:39])[CH:33]=[CH:32][N:31]=4)[CH:25]=[C:26]([CH3:28])[CH:27]=3)=[CH:20][N:21]=2)[CH2:8][CH2:9][NH:1][C:10](=[O:11])[CH2:15][CH2:16]1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(CN)CCC4(CC3)OCCO4)s2)c1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(CN)CCNC(=O)CC3)s2)c1
Temperature: 65 °C
Reaction time: 1 h
Yield: 2.5 %

Procedure:
Sodium azide (20.45 mg, 0.315 mmol, 3.0 equiv) was added to a stirring solution of the product of Step 1 (53 mg, 0.11 mmol) in chloroform (5 ml). Methanesulfonic Acid (0.082 ml, 1.258 mmol, 12 equiv) was added and the reaction was capped and stirred at 65° C. for 1 h. The yellow mixture was partitioned between EtOAc (2×85 ml) and saturated aqueous NaHCO3 (90 ml), and the combined organic layers were dried over MgSO4 and concentrated. The residual colorless oil was purified via reverse-phase HPLC (Acetonitrile/Water gradient with 0.1% TFA present). The desired fractions were partitioned between EtOAc (2×55 ml) and saturated aqueous NaHCO3 (65 ml). The combined organic layers were dried over Na2SO4 and concentrated, providing the desired title compound (1.3 mg, 2.5%) as a colorless solid-oil. MS ESI: [M+H]+ m/z 477.21. 1H NMR (500 MHz, CD3OD) δ 8.72 (d, 1H, J=4.6 Hz), 8.19 (bs, 1H), 7.98 (s, 1H), 7.44 (s, 1H), 7.16 (s, 1H), 7.13 (d, 1H, J=4.6 Hz), 3.45 (s, 2H), 2.95 (m, 2H), 2.05 (s, 3H), 1.90-1.57 (m, 6H). rhSYK activity=+++
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[N:9]1[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=1>CS(C)=O>[S:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:15]1[C:12]1[CH:13]=[CH:14][N:9]=[CH:10][CH:11]=1
Reactant: Nc1ccccc1S
Reactant: O=Cc1ccncc1
Solvent: CS(C)=O
Product: c1ccc2sc(-c3ccncc3)nc2c1
Yield: 84.8 %

Procedure:
2-Aminothiophenol (6.3 g, 0.05 mol) and 4-pyridinecarboxaldehyde (5.4 g, 0.05 mol) were dissolved in dimethylsulfoxide (35 ml) and heated until vapours distilled off at 180°-186° C. The distillation residue on cooling was partitioned between ethyl acetate and saturated ammonium chloride solution. The combined organic layers were washed with water (100 ml), dried (MgSO4) and concentrated. The solid was triturated with ether to afford the title compound as a pale brown solid (9 g, 85%). δH (CDCl3), 7.42 (1H, m, ArH), 7.51 (1H, m, ArH), 7.93 (3H, m, ArH), 8.13 (1H, d, J 8.7Hz, ArH), 8.78 (2H, m, ArH). m/z (ES+) 213 (M+1)+.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:8]1([NH2:11])[CH2:10][CH2:9]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH:8]1([NH:11][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:10][CH2:9]1
Reactant: NC1CC1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CNC1CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52 %

Procedure:
Ethyl bromoacetate (1 eq.) was added slowly to an ice-cold mixture of cyclopropylamine (17.5 mmol, 3 eq.) and K2CO3 (2 eq.) in DMF (25 ml) and the reaction mixture was then stirred at room temperature for 16 h. For working up, the mixture was diluted with water and extracted with 20% ethyl acetate/hexane solution. The organic phase was washed with water and sat. NaCl solution and dried over Na2SO4. After the solvent had been removed completely, the crude product was employed in the next stage without further purification. Yield: 52%
Reaction SMILES: CCN(C(C)C)C(C)C.OC(C(F)(F)F)=O.[NH2:17][CH2:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:36])[F:35])[CH2:23][CH2:22]1)=[O:20].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[OH:61][C:62]1[CH:70]=[CH:69][C:65]([C:66](O)=[O:67])=[CH:64][N:63]=1>CN(C=O)C.O>[OH:61][C:62]1[CH:70]=[CH:69][C:65]([C:66]([NH:17][CH2:18][C:19](=[O:20])[N:21]2[CH2:22][CH2:23][N:24]([C:27](=[O:38])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:37])([F:35])[F:36])[CH2:25][CH2:26]2)=[O:67])=[CH:64][N:63]=1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reactant: O=C(O)c1ccc(O)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(O)nc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 56.5 %

Procedure:
DIPEA (56 mg, 0.43 mmol) was added to a stirred solution of 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone TFA salt. (74 mg, 0.17 mmol) in DMF (1 mL). HOBT (23 mg, 0.17 mmol) and EDCI.HCl (33 mg, 0.17 mmol) were then added at room temperature. After 2 minutes, 6-hydroxy nicotinic acid (20 mg, 0.14 mmol) was added and the resulting mixture was stirred at room temperature for 4 hrs. Cold water (20 mL) was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to afford 35 mg (56.5% yield) of 6-hydroxy-N-{2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-nicotinamide. LCMS Purity: 99.38%, HPLC Purity: 92.66%, 1H NMR (DMSO-d6): δ 12 (s, 1H), 8.0 (t, 1H), 7.9-7.8 (m, 2H), 7.8-7.7 (d, 1H), 7.7-7.6 (t, 1H), 7.6-7.5 (m, 1H), 6.4-6.3 (dd, 1H), 4.2-4.0 (m, 2H), 3.8-3.7 (m, 2H), 3.6 (m, 2H), 3.4 (m, 2H), 3.2-3.1 (m, 2H).
Reaction SMILES: CO[C:3]([C:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]=1[C:14]([O:16]CC1C=CC=CC=1)=[O:15])=[O:4].[C:24](OCC)(=[O:26])C>[Pd]>[CH3:24][O:26][C:11]1[CH:12]=[CH:13][C:8]2[O:7][CH:6]([C:14]([OH:16])=[O:15])[C:5](=[C:3]=[O:4])[C:9]=2[CH:10]=1
Reactant: CCOC(C)=O
Reactant: COC(=O)c1c(C(=O)OCc2ccccc2)oc2ccccc12
Agent: [Pd]
Product: COc1ccc2c(c1)C(=C=O)C(C(=O)O)O2
Reaction time: 2 h
Yield: 91 %

Procedure:
To a solution of benzyl methoxy-carbonylbenzofuran-2-carboxylate (0.144 g, 0.409 mmol) in ethyl acetate (20 mL) was added 10% palladium on carbon (0.072 g, 50% w/w). After stirring under a hydrogen atmosphere for 2 h, the mixture was filtered through Celite. The filtrate was concentrated to yield the title compound as a white solid (0.098 g, 91%): 1H NMR: