Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]([NH2:6])=[CH:4][N:3]=[N:2]1.N1C=CC=CC=1.Cl[C:14]([O:16][CH2:17][C:18]([Cl:21])([Cl:20])[Cl:19])=[O:15].O>O1CCCC1>[S:1]1[C:5]([NH:6][C:14](=[O:15])[O:16][CH2:17][C:18]([Cl:21])([Cl:20])[Cl:19])=[CH:4][N:3]=[N:2]1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1cnns1
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1cnns1)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1,2,3-thiadiazol-5-amine and pyridine (0.129 ml, 4.00 mmol) in tetrahydrofuran (4.5 ml) was added 2,2,2-trichloroethyl chloroformate (0.220 ml, 2.00 mmol) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane was added to the residue, and 190 mg (51.6%) of the desired product was collected by filtration as a solid.
Reaction SMILES: [O:1]1[CH2:4][CH:3]([N:5]2[CH:9]=[C:8]([NH2:10])[N:7]=[CH:6]2)[CH2:2]1.[C:11]([O:14][CH2:15][C:16]1[C:17]([N:31]2[CH2:42][CH2:41][N:40]3[C:33](=[CH:34][C:35]4[CH2:36][C:37]([CH3:44])([CH3:43])[CH2:38][C:39]=43)[C:32]2=[O:45])=[N:18][CH:19]=[CH:20][C:21]=1[C:22]1[CH:27]=[C:26](Br)[C:25](=[O:29])[N:24]([CH3:30])[CH:23]=1)(=[O:13])[CH3:12].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.C(=O)([O-])[O-].[Cs+].[Cs+]>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].O1CCOCC1>[C:11]([O:14][CH2:15][C:16]1[C:17]([N:31]2[CH2:42][CH2:41][N:40]3[C:33](=[CH:34][C:35]4[CH2:36][C:37]([CH3:44])([CH3:43])[CH2:38][C:39]=43)[C:32]2=[O:45])=[N:18][CH:19]=[CH:20][C:21]=1[C:22]1[CH:27]=[C:26]([NH:10][C:8]2[N:7]=[CH:6][N:5]([CH:3]3[CH2:4][O:1][CH2:2]3)[CH:9]=2)[C:25](=[O:29])[N:24]([CH3:30])[CH:23]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)OCc1c(-c2cc(Br)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: Nc1cn(C2COC2)cn1
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
Product: CC(=O)OCc1c(-c2cc(Nc3cn(C4COC4)cn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 100 °C
Yield: 47.8 %

Procedure:
A 25-mL round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 285b (40 mg, 0.28 mmol), [4-(5-bromo-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-{4,4-dimethyl-9-oxo-1,10-diazatri-cyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-3-yl]methyl acetate 273a (150 mg, 0.28 mmol), Pd2(dba)3 (15 mg, 0.015 mmol), XantPhos (18 mg, 0.03 mmol), cesium carbonate (200 mg, 0.6 mmol), and 1,4-dioxane (6 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with 25:1 dichloromethane/methanol to afford 285c as a yellow solid (80 mg, 47%). MS-ESI: [M+H]+ 598.3.
Reaction SMILES: [N:1]1([CH2:6][N:7]2[CH:11]=[N:10][CH:9]=[N:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([Li])CCC.[CH:17]1([C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.O>O1CCCC1>[CH:25]1([C:23]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)([C:11]2[N:7]([CH2:6][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[N:8]=[CH:9][N:10]=2)[OH:24])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: c1ncn(CN2CCCC2)n1
Reactant: O=C(c1ccccc1)C1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: OC(c1ccccc1)(c1ncnn1CN1CCCC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
1-(pyrrolidin-1-ylmethyl)-1H-1,2,4-triazole (Preparation 16, 12.0 g, 78.84 mmol) was dissolved in tetrahydrofuran (120 mL) and the solution cooled to −78° C. n-Butyl lithium (2.5M in hexanes, 34.7 ml, 86.7 mmol) was then added dropwise over 30 mins. After warming to room temperature and stirring for 1 hour the reaction mixture was cooled to −78° C. and a solution of cyclohexyl(phenyl)methanone (16.3 g, 86.7 mmol) in tetrahydrofuran (30 mL) added dropwise. After warming to room temperature over 18 hr, water (100 ml) was added and the solvent removed in vacuo. The residue was partitioned with ethyl acetate (200 ml), the aqueous phase separated and re-extracted with ethyl acetate (2×200 ml). The combined organic layers were dried over magnesium sulphate, filtered and the solvent removed in vacuo to furnish the title compound as a yellow oil, in 100% yield, 27.28 g.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[N-:13]=[N+]=[N-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CS(O)(=O)=O>[OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8](=[O:12])[NH:13][CH2:7][CH2:6][CH2:5][C:4]=2[CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1CCCc2cc(O)ccc21
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1NCCCc2cc(O)ccc21
Temperature: 0 °C
Reaction time: 15 h

Procedure:
To a solution of 6-hydroxy-1-tetralone (6.5 g) in methanesulfonic acid (140 ml) was added sodium azide (3.4 g) under cooling with ice and the mixture was stirred for 30 minutes at 0° C. and for 15 hours at room temperature. The reaction mixture was poured into ice-water and thereto was added potassium carbonate to alkalify and was extracted with methylene chloride. The organic layer was washed with water, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride successively, dried over anhydrous magnesium sulfate and was concentrated to give the title compound having the following physical data as a crude product. The crude product was used in the next reaction without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[CH2:24][CH2:23][N:22]([CH:25]2[CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH2:26]2)[CH2:21][CH2:20]1>C(OCC)C.O1CCCC1>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:28]2([OH:31])[CH2:29][CH2:30][CH:25]([N:22]3[CH2:23][CH2:24][N:19]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=4)[CH2:20][CH2:21]3)[CH2:26][CH2:27]2)[CH:3]=1
Reactant: Brc1cccnc1
Reactant: O=C1CCC(N2CCN(c3ccccn3)CC2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC1(c2cccnc2)CCC(N2CCN(c3ccccn3)CC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4.74 g (30 mmol) of 3-bromopyridine in 100 ml of diethyl ether is cooled to --78° C. under a nitrogen atmosphere. n-Butyllithium (18.75 ml, 30 mmol) is added dropwise. The resulting suspension is stirred for 30 minutes. To this solution is added a solution of 5.19 g of 4-[4-(2-pyridinyl)-1-piperazinyl]cyclohexanone in 175 ml of tetrahydrofuran dropwise. The cold bath is removed and the mixture is allowed to warm to room temperature and quenched with 50 ml of saturated ammonium chloride solution. The tetrahydrofuran is evaporated under vacuum and the residue is partitioned into water/dichloromethane. The organic phase is separated and dried over magnesium sulfate and evaporated in vacuo to give the title compound as a mixture of cis and trans isomers.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.B([O-])([O-])O[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)=[CH:37][CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.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>[CH3:31][N:24]([CH2:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:14]([C:8]2[CH2:9][CH2:10][S:11](=[O:13])(=[O:12])[C:5]3[CH:4]=[CH:3][C:2]([C:35]4[CH:40]=[CH:39][C:38]([O:41][CH:42]5[CH2:43][CH2:44][O:45][CH2:46][CH2:47]5)=[CH:37][CH:36]=4)=[CH:32][C:6]=3[CH:7]=2)=[O:15])=[CH:18][CH:19]=1)[CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: [O-]B([O-])Oc1ccc(OC2CCOCC2)cc1
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: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc(OC5CCOCC5)cc4)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.9 %

Procedure:
Under argon atmosphere, a mixture of 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg), 4-(tetrahydropyran-4-yloxy)phenyl borate (141 mg) and potassium carbonate (160 mg) in toluene/ethanol/water (10/1/1 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (33 mg), and the mixture was refluxed for 6 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (ethanol/ethyl acetate=1:3) to give crystals, which were recrystallized from ethanol to give colorless crystals of N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-7-[4-(tetrahydropyran-4-yloxy)phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 68) (274 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH3:9].C([Li])CCC.[C:15](=[O:17])=[O:16]>C(OCC)C>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]([OH:17])=[O:16])=[C:3]([CH3:9])[CH:4]=1
Reactant: O=C=O
Reactant: Cc1cc(F)ccc1Br
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1cc(F)ccc1C(=O)O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 0.1 %

Procedure:
To a cooled (−78° C.) solution of 2-bromo-5-fluorotoluene (10.0 g, 52.9 mmol) in diethyl ether (100 mL) was added dropwise n-butyllithium (1.6 M in hexane, 21.2 mL, 52.9 mmol). The mixture was stirred for 5 min, and slowly warmed to 0° C. Dry ice (100 g, 2.27 mol) was slowly added to the mixture while stirring, and it was allowed to warm to rt over 16 h. The mixture was adjusted to pH=2, and extracted with ethyl acetate (3×20 mL). The organic phase was concentrated and the resulting yellow residue suspended in water (100 mL). The suspension was adjusted to pH=12 with 2 N NaOH, and washed with diethyl ether. The aqueous phase was then acidified to pH=2 with 2 N HCl, and extracted with diethyl ether (3×50 mL). The organic extract was washed with water, dried (MgSO4), and concentrated under reduced pressure to afford the product (5.0 mg, 61%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 2.53 (s, 3H), 7.06-7.17 (m, 2H), 7.87 (dd, 1H), 12.85 (s, 1H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]1[C:13]3[S:19][C:18]([C:20](O)=[O:21])=[CH:17][C:14]=3[NH:15][N:16]=1)=[CH:6]2.ON1C2C=CC=CC=2N=N1.N=C=N.[CH2:36]([O:38][CH2:39][CH2:40][CH2:41][NH2:42])[CH3:37].C(O)C(N)(CO)CO>ClCCl.CO.CN(C)C=O>[CH2:36]([O:38][CH2:39][CH2:40][CH2:41][NH:42][C:20]([C:18]1[S:19][C:13]2[C:12]([C:7]3[NH:8][C:9]4[C:5]([CH:6]=3)=[CH:4][C:3]([CH2:2][OH:1])=[CH:11][CH:10]=4)=[N:16][NH:15][C:14]=2[CH:17]=1)=[O:21])[CH3:37]
Reactant: O=C(O)c1cc2[nH]nc(-c3cc4cc(CO)ccc4[nH]3)c2s1
Reactant: CCOCCCN
Agent: N=C=N
Agent: NC(CO)(CO)CO
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOCCCNC(=O)c1cc2[nH]nc(-c3cc4cc(CO)ccc4[nH]3)c2s1
Reaction time: 4 h
Yield: 17.3 %

Procedure:
To a mixture of 3-(5-hydroxymethyl-1H-indol-2-yl)-1H-thieno[3,2-c]pyrazole-5-carboxylic acid [159 mg, 0.507 mmol, Example 37], 1-hydroxybenzotriazole (116 mg, 0.858 mmol), PS-carbodiimide (1.2 mmol/g, 845 mg) in Dichioromethane (8 mL) and dimethyl formamide (2 mL) is stirred at room temperature for 25 minutes before addition of 3-ethoxypropylamine (45 mg, 0.436 mmol). After 4 h, PS-trisamine (4.03 mmol/g, 500 mg) is added and stirred for 6 hours. The reaction mixture is filtered and the resin washed under suction with Dichloromethane (3×15 mL). The filtrate is evaporated in vacuo. The crude is purified by chromatography on 10 g silica gel cartridge (ethyl acetate then 1% methanol in ethyl acetate) to give thick semi solid. It is redissolved in methanol and triturated with water to give 3-(5-hydroxymethyl-1H-indol-2-yl)-1H-thieno[3,2-c]pyrazole-5-carboxylic acid (3-ethoxy-propyl)-amide [30 mg, Example 39] as pale yellow solid; 1H NMR [(CD3)2SO)]: δ 13.490 (1H, s, NH), 11.56 (1H, NH, s), 8.70 (1H, t), 7.88 (1H, s), 7.51 (1H, s), 7.38 (1H, d), 7.10 (1H, s), 6.66 (1H, s), 5.01 (1H, t, OH), 4.55 (2H, HOCH2—), 3.44 (6H, m), 1.80 (2H), 1.12 (3H, t); LC/MS: 399 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3([C:20]4[N:21]=[N:22][NH:23][N:24]=4)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH:11]=[CH:10][C:9]=2[NH2:25])=[CH:4][CH2:3]1.[K+].[C:28]([C:30]1[N:31]=[C:32]([C:43]([O-])=[O:44])[N:33]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[CH:34]=1)#[N:29].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:1][C:2]1([CH3:26])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3([C:20]4[N:21]=[N:22][NH:23][N:24]=4)[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[CH:11]=[CH:10][C:9]=2[NH:25][C:43]([C:32]2[N:33]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[CH:34]=[C:30]([C:28]#[N:29])[N:31]=2)=[O:44])=[CH:4][CH2:3]1
Reactant: CC1(C)CC=C(c2cc(C3(c4nn[nH]n4)CCOCC3)ccc2N)CC1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC1(C)CC=C(c2cc(C3(c4nn[nH]n4)CCOCC3)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 41.5 %

Procedure:
To the crude product of 2-(4,4-dimethyl-cyclohex-1-enyl)-4-[4-(2H-tetrazol-5-yl)-tetrahydro-pyran-4-yl]-phenylamine (76 mg, ca. 0.22 mmol) in 2.5 mL of DMF was added potassium 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate (as prepared in Example 1, step (d), 72 mg, 0.24 mmol), PyBroP (110 mg, 0.236 mmol) and DIEA (112 μL, 0.645 mmol). After stirring at RT for 2 d, the mixture was treated with 20 mL of H2O and extracted with EtOAc (2×20 mL). The combined organic layers were washed with H2O (2×10 mL) and brine (10 mL). After drying over Na2SO4 and concentrating in vacuo, the residue was purified by silica gel chromatography (1-3 MeOH/DCM) to afford the title compound (55 mg, 42% for 2 steps) as a faint brown solid. Mass spectrum (ESI, m/z): Calcd. for C31H42N8O3Si, 603.3 (M+H). found 602.9.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1>>[OH:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])=[CH:13][CH:14]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1ccc(O)cc1
Product: O=S(=O)(Nc1ccc(O)cc1)c1ccccc1

Procedure:
The preparation is carried out as in Example 1(a) from 353 g (2 mol) of benzenesulphonyl chloride and 229.2 g of 4-aminophenol (2.1 mol).
Reaction SMILES: C([O:8][C:9]1[CH:33]=[CH:32][C:31]([CH:34]2[CH2:39][CH2:38][N:37]([CH:40]([CH3:42])[CH3:41])[CH2:36][CH2:35]2)=[CH:30][C:10]=1[C:11]([NH:13][C:14]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])=[O:12])C1C=CC=CC=1.C(Cl)(Cl)Cl>C(OCC)(=O)C.CO.[C].[Pd]>[OH:8][C:9]1[CH:33]=[CH:32][C:31]([CH:34]2[CH2:35][CH2:36][N:37]([CH:40]([CH3:42])[CH3:41])[CH2:38][CH2:39]2)=[CH:30][C:10]=1[C:11]([NH:13][C:14]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])=[O:12]
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(C2CCN(C(C)C)CC2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(C2CCN(C(C)C)CC2)ccc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
To a solution mixture of the obtained methyl 2-(2-(benzyloxy)-5-(1-isopropylpiperidin-4-yl)benzamido)-4-phenylbenzoate (0.12 g) in ethyl acetate (1.5 mL) and methanol (1.5 mL), 10% palladium-carbon (0.12 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 1 hour. Chloroform was added to the reaction mixture, and the insoluble substance was removed by filtration. The solvent was evaporated under reduced pressure to obtain 0.086 g of methyl 2-(2-hydroxy-5-(1-isopropylpiperidin-4-yl)benzamido)-4-phenylbenzoate as an orange solid.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3](=O)[CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[C:13]([CH3:20])[CH:12]=1)[C:5](OCC)=[O:6].O.[NH2:25][NH2:26].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:20][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=1[N+:17]([O-:19])=[O:18])[CH2:10][CH:4]1[C:3]([C:2]([F:23])([F:22])[F:1])=[N:26][NH:25][C:5]1=[O:6]
Reactant: CCOC(=O)C(Cc1ccc([N+](=O)[O-])c(C)c1)C(=O)C(F)(F)F
Reactant: NN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(CC2C(=O)NN=C2C(F)(F)F)ccc1[N+](=O)[O-]
Yield: 55.3 %

Procedure:
Ethyl 4,4,4-trifluoro-2-(3-methyl-4-nitro-benzyl)-3-oxo-butyrate (2.0 g), hydrazine monohydrate (0.5 g) and a small amount of p-toluenesulfonic acid were dissolved in toluene, and the mixture was refluxed for 4 hours. After cooling, the solvent was distilled off under reduced pressure. The residue was suspended in ethyl acetate and washed with 1N aqueous solution of hydrochloric acid. After drying the organic layer with sodium sulfate, the solvent was distilled off and the obtained residue was purified by silica gel column chromatography to obtain 4-(3-methyl-4-nitro-benzyl)-5-trifluoromethyl-2,4-dihydro-pyrazol-3-one (1.0 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].[CH2:8]([C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].Cl>O.O1CCOCC1>[CH2:8]([C:14]1[CH:15]=[CH:16][C:17]([C:18]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[O:19])=[CH:21][CH:22]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCc1ccc(C(=O)Cl)cc1
Reactant: NCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCCCCCc1ccc(C(=O)NCC(=O)O)cc1
Reaction time: 0.5 h
Yield: 83 %

Procedure:
In a 200 ml-three-necked flask, 3.34 g (44.5 mM) of glycine, 0.89 g (22.3 mM) of sodium hydroxide and 16.7 ml of distilled water were placed and mixed. To the solution, 16.7 ml of dioxane was added. To the resultant mixture, a solution of 0.89 g (22.3 mM) of sodium hydroxide in 8.4 ml of distilled water and a solution of 5.00 g (22.2 mM) of 4-hexylbenzoyl chloride in 33.4 ml of dioxane were gradually added simultaneously at -1° to 3° C. by dropping funnels, respectively, followed by stirring for 30 minutes at 1°-2° C. After the reaction, 2.3 ml of concentrated hydrochloric acid was added to the reaction mixture to precipitate a crystal. The crystal was recovered by filtration and washed with water, followed by drying and recrystallization from ethyl acetate to obtain 4.86 g of N-(4-hexylbenzoyl)glycine (Yield: 82.9%).
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=3)[C:18]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10][CH2:9]2)=[O:7])=[CH:4][C:3]=1[F:30].C(N(CC)CC)C.[CH:38]1([C:44](Cl)=[O:45])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>ClCCl>[C:21]([NH:20][C:18](=[O:19])[C:17]1[CH:25]=[CH:26][CH:27]=[C:15]([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:5]3[CH:28]=[CH:29][C:2]([NH:1][C:44]([CH:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)=[O:45])=[C:3]([F:30])[CH:4]=3)[CH2:9][CH2:10]2)[CH:16]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: O=C(Cl)C1CCCCC1
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(N)c(F)c3)CC2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(NC(=O)C4CCCCC4)c(F)c3)CC2)c1
Reaction time: 16 h
Yield: 44.3 %

Procedure:
To a stirred solution of 3-((4-(4-amino-3-fluorobenzoyl)piperazin-1-yl)methyl)-N-tert-butylbenzamide (0.121 mmol, 50 mg) and triethylamine (0.485 mmol, 0.068 mL, 49.1 mg) in dichloromethane (1.5 mL) was added cyclohexanecarbonyl chloride (0.133 mmol, 19.55 mg). After 16 hours stirring, the reaction was concentrated under vacuum and purified by acidic reverse phase HPLC to yield the title compound (28 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1.[CH:23]1[C:31]2[C:30]3[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=3[O:28][C:27]=2[C:26]([C:36]2[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=2)=[CH:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.C(OCC)(=O)C.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>[CH3:1][O:2][C:3](=[O:22])[CH:4]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([C:39]2[CH:40]=[CH:41][C:36]([C:26]3[C:27]4[O:28][C:29]5[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=5[C:31]=4[CH:23]=[CH:24][CH:25]=3)=[CH:37][CH:38]=2)=[CH:9][CH:8]=1
Reactant: OB(O)c1ccc(-c2cccc3c2oc2ccccc23)cc1
Reactant: COC(=O)C(CSc1ccc(Br)cc1)NC(=O)OC(C)(C)C
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: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)C(CSc1ccc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 70.7 %

Procedure:
A solution of 2-tert-Butoxycarbonylamino-3-(4-bromophenylsulfanyl)-propanoic acid methyl ester (0.55 g, 1.41 mmol), 4-(4-dibenzofuranyl)benzeneboronic acid (0.44 g, 1.52 mmol) and Pd(PPh3)4 (0.073 g, 5 mol %) in toluene (15 mL) and ethanol (3.0 mL) was treated with 2 M K2CO3 (2.2 mL). The reaction mixture was heated to reflux for 2 h, cooled to room temperature, diluted with ethyl acetate (100 mL). The organic layer was washed successively with 2% aq HCl and sat. aq NaCl, dried over MgSO4 and concentrated. Purification by flash column chromatography (2-10% ethyl acetate in heptane) gave the desired product (552 mg, 72%) as a white solid. 1H NMR (CDCl3), δ 8.01 (d, J=6 Hz, 2 H), 7.96 (dd, J=4 Hz, 8 Hz, 2H), 7.74 (d, J=9 Hz, 2 H), 7.66 (m, 4 H), 7.42 (m, 5 H), 5.41 (d, J=7 Hz, 1 H), 4.62 (m, 1 H), 3.73 (s, 3 H), 3.45 (d, J=4 Hz, 2H), 1.57 (s, 9 H). LCMS 454 (M+−100).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:17]2[C:22](=[O:23])[NH:21][C:20](=[O:24])[CH:19]=[N:18]2)[CH:5]=[CH:6][C:7]=1[C:8](=O)[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1.O.[CH:26]([NH2:28])=[O:27]>C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:17]2[C:22](=[O:23])[NH:21][C:20](=[O:24])[CH:19]=[N:18]2)[CH:5]=[CH:6][C:7]=1[CH:8]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[NH:28][CH:26]=[O:27]
Reactant: NC=O
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(-n2ncc(=O)[nH]c2=O)cc1Cl
Solvent: O
Solvent: O=CO
Product: O=CNC(c1ccc(Cl)cc1)c1ccc(-n2ncc(=O)[nH]c2=O)cc1Cl
Temperature: 160 °C
Reaction time: 16 h
Yield: 22.5 %

Procedure:
A mixture of 2-[3-chloro-4-(4-chlorobenzoyl)phenyl]-1,2,4-triazine-3,5(2H,4H)-dione (0.081 mol) in formic acid (120 ml) and formamide (300 ml) was stirred for 16 hours at 160° C. The reaction mixture was cooled, poured out into water (600 ml) and the resulting precipitate was filtered off and dried. This fraction was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 95/5). The pure fractions were collected and the solvent was evaporated. The residue was stirred in DIPE, filtered off, and dried, yielding 8.78 g (22.5%) of (±)-N-[[2-chloro-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)phenyl](4-chlorophenyl)methyl]formamide (interm. 64).