Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.C[O:7][CH:8](OC)[C:9]1[C:10]([O:16][CH3:17])=[N:11][CH:12]=[C:13](Br)[CH:14]=1.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:30])(=O)=O)=CC=1.Cl.N.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.[Cl-].[Na+].O.CC(C)=O>[F:30][C:13]1[CH:14]=[C:9]([CH:8]=[O:7])[C:10]([O:16][CH3:17])=[N:11][CH:12]=1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: COc1ncc(Br)cc1C(OC)OC
Agent: Cl
Agent: N
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)=O
Product: COc1ncc(F)cc1C=O
Reaction time: 0.42 h
Yield: 26.4 %

Procedure:
20 ml of tetrahydrofuran was cooled to −78° C., 2.41 ml of n-butyllithium (2.6 M, hexane solution) was added thereto, and the mixture was stirred. A solution of 1.50 g of 5-bromo-2-methoxy-3-pyridinecarboxaldehyde dimethyl acetal dissolved in 5 ml of tetrahydrofuran was added dropwise thereinto. After 25 minutes, a solution of 2.16 g of N-fluorobenzenesulfonimide dissolved in 20 ml of tetrahydrofuran was added dropwise thereinto over 20 minutes and the mixture was further stirred for 55 minutes. To the reaction mixture were added brine and 20 ml of 2N-hydrochloric acid, followed by stirring at room temperature. After 40 minutes, a diluted ammonia was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, to give a yellow oil. The oil was dissolved in 16 ml of acetone, 4 ml of 5N-hydrochloric acid was added thereto, and the mixture was left for 30 minutes at room temperature. An aqueous potassium carbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified by silica gel column chromatography (n-hexane:ethyl acetate=15:1), to give 234 mg of the title compound as a slight yellow solid.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][CH2:11]Br)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[N-:13]=[N+:14]=[N-:15].[Na+]>CC(C)=O>[CH2:1]([O:3][P:4]([CH2:9][CH2:10][CH2:11][N:13]=[N+:14]=[N-:15])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOP(=O)(CCCBr)OCC
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOP(=O)(CCCN=[N+]=[N-])OCC
Temperature: 25 °C
Yield: 98.3 %

Procedure:
(3-Bromopropyl)phosphonic acid diethyl ester (300 mg, 1.15 mmol) and sodium azide (150 mg, 2.3 mmol) were dissolved in acetone (10 ml) and the solution was refluxed for 12 hours under nitrogen atmosphere, then cooled to room temperature, filtered, and dried under vacuum to afford (3-azidopropyl)phosphonic acid diethyl ester (250 mg, 98% yield) as a colorless liquid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:27]=[CH:26][C:8]([CH2:9][C@H:10]2[CH2:15][C@H:14]([C:16]3[O:20][NH:19][C:18](=[O:21])[CH:17]=3)[CH2:13][CH2:12][N:11]2C(OC)=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br>>[CH3:1][S:2]([C:5]1[CH:27]=[CH:26][C:8]([CH2:9][C@H:10]2[CH2:15][C@H:14]([C:16]3[O:20][NH:19][C:18](=[O:21])[CH:17]=3)[CH2:13][CH2:12][NH:11]2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccc(S(C)(=O)=O)cc1
Agent: Br
Product: CS(=O)(=O)c1ccc(C[C@H]2C[C@H](c3cc(=O)[nH]o3)CCN2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.8 %

Procedure:
Trans-methyl 2-(4-(methylsulfonyl)benzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (185 mg, 0.47 mmol) was dissolved in HBr (33% in acetic acid, 4 mL, 22.84 mmol) and the mixture was stirred at room temperature overnight. The solvent was evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-(trans-2-(4-(methylsulfonyl)benzyl)piperidin-4-yl)isoxazol-3(2H)-one (161 mg, 102%). 1H NMR (600 MHz, dmso) δ 1.65-1.97 (m, 4H), 2.34-2.63 (omitted signals), 2.80-3.15 (m, 5H), 3.18 (s, 3H), 5.84 (s, 1H), 7.51 (d, 2H), 7.87 (d, 2H). HRMS Calcd for [C16H20N2O4S+H]+: 337.1222. Found: 337.1236
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Na+].[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]Br>O1CCCC1>[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:11]([S:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1)([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:12]#[N:13]
Reactant: COc1ccc(C(C#N)Sc2ccc(C)cc2)cc1OC
Reactant: BrCCCCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(C(C#N)(CCCCCCCCCCCBr)Sc2ccc(C)cc2)cc1OC
Reaction time: 1.5 h
Yield: 73.1 %

Procedure:
To a solution of 2.50 g of 3,4-dimethoxy-α-[(4-methylphenyl)thio]benzeneacetonitrile in 50 mL of tetrahydrofuran, under an argon atmosphere with stirring, is added 0.367 g of 60% sodium hydride in oil. After 1.5 hours, 10.0 g of 1,11-dibromoundecane is added and stirring is continued for 43 hours. The reaction mixture is evaporated and the residue partitioned between diethyl ether and water. The organic phase is separated, washed with water, dried with magnesium sulfate, filtered and evaporated leaving an oil. The oil is purified via column chromatography, using hexane/ether (1:1) to afford 3.25 g of the desired product as a colorless oil.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][N:5]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][C:22]=1[Cl:28])(=[O:20])=[O:19])[CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH2:14][CH2:13][CH2:12]2.O.[OH-].[Na+].Cl>C1COCC1>[Br:27][C:24]1[CH:25]=[CH:26][C:21]([S:18]([N:5]([CH2:4][C:3]([OH:29])=[O:2])[CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][CH2:13][CH2:12]3)(=[O:19])=[O:20])=[C:22]([Cl:28])[CH:23]=1
Reactant: COC(=O)CN(CCOc1ccc2c(c1)CCC2)S(=O)(=O)c1ccc(Br)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CN(CCOc1ccc2c(c1)CCC2)S(=O)(=O)c1ccc(Br)cc1Cl
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A stirred solution of {(4-bromo-2-chloro-benzenesulfonyl)-[2-(indan-5-yloxy)-ethyl]-amino}-acetic acid methyl ester (2.8 g) in THF (22 ml)-water (22 ml) at 15° C. is treated dropwise with 1 M aqueous sodium hydroxide solution (28 ml), and the resulting mixture stirred for 3 hours. The mixture is then diluted with ice-cold water (200 ml), acidified to pH 1 with 1 M hydrochloric acid, and extracted with ethyl acetate (2×100 ml). The combined extracts are washed successively with water (100 ml) and then brine, dried over magnesium sulfate, filtered and evaporated. The resulting solid is triturated with hexane, collected by filtration and dried, to afford {(4-bromo-2-chloro-benzenesulfonyl)-[2-(indan-5-yloxy)-ethyl]-amino}-acetic acid [retention time 7.6 min/HPLC conditions: Kingsorb 3 micron, 30×4.6 mm C 18 column, Gradient elution 10 to 100% acetonitrile in water (+0.1% trifluoroacetic acid) over 10 min]. 1H NMR (DMSO-d6) δ=12.88 (broad s, 1H), 7.94 (d, 1H), 7.90 (d, 1H), 7.71 (dxd, 1H), 7.03 (d, 1H), 6.50 (s, 1H), 6.43 (dxd, 1H), 4.26 (s, 2H), 3.97 (t, 2H), 3.65 (t, 2H), 2.79 (t, 2H), 2.75 (t, 2H), 1.98 (m, 2H).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[C:7]([O:25][C:26]2[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=2)[CH:8]=[C:9]2[C:13]=1[NH:12][C:11]([C:14]1[S:15][CH:16]([CH2:19][C:20](OCC)=[O:21])[CH2:17][N:18]=1)=[CH:10]2)[CH3:3].[BH4-].[Li+].O>O1CCCC1.CO>[CH3:3][CH:2]([O:4][C:5]1[CH:6]=[C:7]([O:25][C:26]2[CH:27]=[CH:28][C:29]([S:32]([CH3:35])(=[O:33])=[O:34])=[CH:30][CH:31]=2)[CH:8]=[C:9]2[C:13]=1[NH:12][C:11]([C:14]1[S:15][CH:16]([CH2:19][CH2:20][OH:21])[CH2:17][N:18]=1)=[CH:10]2)[CH3:1]
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)cc4)cc(OC(C)C)c3[nH]2)S1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C3=NCC(CCO)S3)[nH]c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.9 %

Procedure:
Ethyl (2-{7-(1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetate (330 mg) was dissolved in a mixture of tetrahydrofuran (15 mL) and methanol (3 mL). Lithium borohydride (30 mg) was added to the mixture at room temperature and the mixture was stirred at room temperature for 30 min. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90 to 80/20, volume ratio) to give the title compound (112 mg, 37%) as a pale yellow amorphous solid. MS 475 (MH+).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH3:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[C:12]([NH:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>>[CH3:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([N:23]2[CH2:22][CH2:21][CH:20]([NH:19][C:12](=[O:13])[O:14][C:15]([CH3:17])([CH3:16])[CH3:18])[CH2:25][CH2:24]2)[CH:3]=1
Reactant: Cc1ccc([N+](=O)[O-])c(F)c1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Product: Cc1ccc([N+](=O)[O-])c(N2CCC(NC(=O)OC(C)(C)C)CC2)c1
Yield: 97 %

Procedure:
Method 1 was followed using 3-fluoro-4-nitrotoluene (1.0 eq), 4-(N-Boc-amino) piperidine (1.2 eq), and TEA (2.0 eq) at 55° C. for 48 hours yielding tert-butyl 1-(5-methyl-2-nitrophenyl)piperidin-4-ylcarbamate (97%). LCMS (m/z): 336.1 (MH+); LC Rt=3.32 min
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[NH2:13][C:14]1[CH:15]=[C:16]([C:20]2[NH:24][N:23]=[N:22][N:21]=2)[CH:17]=[CH:18][CH:19]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[NH:24][N:23]=[N:22][N:21]=2)[CH:15]=1)(=[O:11])=[O:10]
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(Cl)cc1Cl
Yield: 8 %

Procedure:
The product was prepared according to General Procedure 6, described in Example 65, with 2,4-dichlorobenzenesulfonyl chloride (13.5 mg, 0.055 mmol) and 5-(3-aminophenyl)tetrazole (8.0 mg, 0.050 mmol). The title compound was obtained in 8% yield (1.5 mg). MS (ESI+) calcd mass for C13H9Cl2N5O2S 368.985401, found 368.984681.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[NH:10][C:11]([N:13]1[CH:17]=[CH:16]N=C1)=[S:12].[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1CCN.C(OCC)(=O)C>CN(C)C=O>[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:16][CH2:17][NH:13][C:11]([NH:10][C:2]1[NH:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)=[S:12]
Reactant: NCCc1ccccc1Cl
Reactant: S=C(Nc1nc2ccccc2[nH]1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: S=C(NCCc1ccccc1Cl)Nc1nc2ccccc2[nH]1
Temperature: 25 °C
Yield: 40.5 %

Procedure:
A solution of 1-[(2-benzimidazolyl)thiocarbamoyl]imidazole (1.22 g, 5.0 mmol) and 2-(2-chlorophenyl)ethylamine (0.81 g, 5.0 mmol) in N,N- dimethylformamide (20 mL) was stirred at 90° C. for 2 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, 1N aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was crystallized from EtOAc to provide 0.67 g (40%) of the titled product as a white solid:
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:28])=[C:8]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[N:19][S:18][C:9]2=[C:10]([C:12]#[C:13][Si](C)(C)C)[N:11]=1)=[O:5])C.[NH2:29][CH2:30][C:31]([OH:33])=[O:32]>>[C:12]([C:10]1[N:11]=[C:6]([C:4]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:5])[C:7]([OH:28])=[C:8]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[N:19][S:18][C:9]=12)#[CH:13]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(C#C[Si](C)(C)C)c2snc(-c3ccc(F)cc3)c2c1O
Product: C#Cc1nc(C(=O)NCC(=O)O)c(O)c2c(-c3ccc(F)cc3)nsc12

Procedure:
The title compound was synthesized in analogy to Example 1 from 3-(4-fluoro-phenyl)-4-hydroxy-7-trimethylsilanylethynyl-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester and glycine: MS (m/z) 370.1 (M−1).
Reaction SMILES: [F:1][CH:2]([F:19])[O:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([N:10]2[C:14]([CH3:15])=[C:13]([C:16](O)=[O:17])[CH:12]=[N:11]2)[CH:5]=1.S(Cl)([Cl:22])=O>ClCCCl>[F:1][CH:2]([F:19])[O:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([N:10]2[C:14]([CH3:15])=[C:13]([C:16]([Cl:22])=[O:17])[CH:12]=[N:11]2)[CH:5]=1
Reactant: Cc1c(C(=O)O)cnn1-c1cc(OC(F)F)n(C)n1
Reactant: O=S(Cl)Cl
Solvent: ClCCCl
Product: Cc1c(C(=O)Cl)cnn1-c1cc(OC(F)F)n(C)n1

Procedure:
0.2 g (3.8 mmol) 1-(5-Difluoromethoxy-1-methyl-3-pyrazolyl)-5-methyl-4-pyrazolecarboxylic acid was suspended in 30 ml 1,2-dichloroethane and 1.19 g (10.0 mmol) thionyl chloride was added at room temperature, dropwise. The mixture was heated for 1 hour under reflux and concentrated.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:31])[C:11]([C:28](O)=[O:29])=[CH:12][N:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[C:15](=[O:27])[C:14]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:36][C:37]([Mg]Cl)([CH3:40])[CH2:38][CH3:39].CCOCC.S([O-])(O)(=O)=O.[K+]>O1CCCC1.O.C(OCC)(=O)C.C(N(CC)CC)C>[CH2:1]([O:8][C:9]1[C:10](=[O:31])[C:11]([C:28](=[O:29])[C:37]([CH3:40])([CH3:36])[CH2:38][CH3:39])=[CH:12][N:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[C:15](=[O:27])[C:14]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(C)(C)[Mg]Cl
Reactant: O=C(O)c1cn2c(c(OCc3ccccc3)c1=O)C(=O)N(Cc1cccc(Cl)c1)CC2
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: CCC(C)(C)C(=O)c1cn2c(c(OCc3ccccc3)c1=O)C(=O)N(Cc1cccc(Cl)c1)CC2
Temperature: -78 °C

Procedure:
9-Benzyloxy-2-(3-chlorobenzyl)-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxylic acid (200 mg) obtained in Example 219, Step 2 was suspended in tetrahydrofuran (6 ml), and triethylamine (0.07 ml) and thionyl chloride (0.037 ml) were added at room temperature with stirring. After stirring at room temperature for 10 min, the mixture was cooled to −78° C. and 1.0 M 1,1-dimethylpropylmagnesium chloride/ether solution was added dropwise. After further stirring at the same temperature for 20 min, 5% aqueous potassium hydrogen sulfate solution (5 ml) and ethyl acetate (6 ml) were added, and water (5 ml) was further added. The mixture was extracted twice with ethyl acetate-tetrahydrofuran (1:1, 30 ml each). The organic layer was dried and concentrated, and ethyl acetate was added to the residue. The obtained solid was collected by filtration to give 9-benzyloxy-2-(3-chlorobenzyl)-7-(2,2-dimethylbutyryl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione (59 mg).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[C:5](=[O:13])[O:4][C:3]=1[CH:14]([OH:16])[CH3:15].[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+].Cl>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[OH:16][CH:14]([C:3]1[O:4][C:5](=[O:13])[C:6]2[C:11]([C:2]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:10][CH:9]=[C:8]([CH3:12])[CH:7]=2)[CH3:15]
Reactant: OB(O)c1ccccc1
Reactant: Cc1ccc2c(Br)c(C(C)O)oc(=O)c2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc2c(-c3ccccc3)c(C(C)O)oc(=O)c2c1
Temperature: 90 °C
Yield: 81.2 %

Procedure:
To a solution of 4-bromo-3-(1-hydroxyethyl)-7-methyl-1H-isochromen-1-one (intermediate A4, 1.04 g, 3.67 mmol) in Dioxane/H2O (5:1) (60 ml), phenylboronic acid (0.67 g, 5.51 mmol) and Na2CO3 (0.779 g, 7.34 mmol) were added followed by Pd(dppf)Cl2 (0.269 g, 0.367 mmol) and the resulting mixture was heated at 90° C. for 2 hrs. 1N HCl was added (pH≈2) and the mixture was partitioned between EtOAc and water. The organic phase was washed twice with brine and dried over sodium sulfate. The solvent was removed under vacuum and the crude was purified by flash column chromatography on Biotage silica gel cartridge (cyclohexane:EtOAc=95:5 to 40:60) to afford title compound as a yellow oil (0.835 g, 2.98 mmol, 81%).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C@H:10]1[NH:15][C:14](=[O:16])[C@@H:13]([C@@H:17]([CH3:20])[CH2:18][CH3:19])[N:12]([CH:21]([C:32]2[C:33]([CH3:39])=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=2)[C:22]([NH:24][C:25]2C=CC=CC=2O)=[O:23])[C:11]1=[O:40].CNC>>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C@H:10]1[NH:15][C:14](=[O:16])[C@@H:13]([C@@H:17]([CH3:20])[CH2:18][CH3:19])[N:12]([C@H:21]([C:32]2[C:33]([CH3:39])=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=2)[C:22]([NH:24][CH3:25])=[O:23])[C:11]1=[O:40]
Reactant: CC[C@H](C)[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1C(C(=O)Nc1ccccc1O)c1ccc(C)nc1C
Agent: CNC
Product: CC[C@H](C)[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1[C@@H](C(=O)NC)c1ccc(C)nc1C

Procedure:
Similarly prepared from intermediate 2 and dimethylamine (2.0M in tetrahydrofuran):
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[C:4]1=[O:17].CO[C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[CH:26]=[C:25]([S:30](Cl)(=[O:32])=[O:31])[CH:24]=[CH:23]2>>[C:12]([C:11]1[CH:10]=[C:9]([CH:16]=[CH:15][CH:14]=1)[CH2:8][N:5]1[CH2:6][CH2:7][C@H:3]([NH:2][S:30]([C:25]2[CH:24]=[CH:23][C:22]3[CH2:21][CH2:20][CH2:29][CH2:28][C:27]=3[CH:26]=2)(=[O:32])=[O:31])[C:4]1=[O:17])#[N:13]
Reactant: COc1ccc2cc(S(=O)(=O)Cl)ccc2c1
Reactant: N#Cc1cccc(CN2CC[C@H](N)C2=O)c1
Agent: Cl
Product: N#Cc1cccc(CN2CC[C@H](NS(=O)(=O)c3ccc4c(c3)CCCC4)C2=O)c1

Procedure:
The title compound is prepared from 3-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)benzonitrile hydrochloride as in EXAMPLE 24, Part B, substituting 5,6,7,8-tetrahydronaphthalene-2-sulfonyl chloride for 6-methoxynaphthalene-2-sulfonyl chloride. The crude product is purified by column chromatography eluting with 70% EtOAc/hexanes afford the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([N:12]([CH2:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:32][CH2:31][N:30](C(OCC4C=CC=CC=4)=O)[CH2:29][CH2:28]3)=[CH:23][CH:22]=2)[CH:18]=[CH:19][CH:20]=1)[CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.C1COCC1.[Pd]>[CH3:13][N:12]([CH2:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:22]=[CH:23][C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[CH:25][CH:26]=2)[CH:18]=[CH:19][CH:20]=1)[C:10](=[O:11])[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(Cc1cccc(-c2ccc(N3CCN(C(=O)OCc4ccccc4)CC3)cc2)c1)C(=O)CNC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CN(Cc1cccc(-c2ccc(N3CCNCC3)cc2)c1)C(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.9 %

Procedure:
Benzyl 4-[3′-({[N-(tert-butoxycarbonyl)glycyl](methyl)amino}methyl)biphenyl-4-yl]piperazine-1-carboxylate (1.5 g) was dissolved in a mixed solution of MeOH (15 ml) and THF (15 ml). 10% Pd—C (150 mg) was added thereto, followed by stirring at room temperature for 1 day under a hydrogen atmosphere. The reaction mixture was filtered using Celite as a filtration assistant, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain tert-butyl (2-{methyl [(4′-piperazin-1-ylbiphenyl-3-yl)methyl]amino}-2-oxoethyl)carbamate (860 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[CH:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]=[C:33]=[O:34])([CH3:25])[CH3:24]>C1(C)C=CC=CC=1>[CH:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][C:33]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:21][CH:20]=1)=[O:34])([CH3:25])[CH3:24]
Reactant: CC(C)c1ccccc1N=C=O
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccccc4C(C)C)cc3)c2cc1OC
Yield: 20 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (44 mg) was dissolved in toluene (5 ml) with heat, 2-isopropylphenyl isocyanate (0.2 ml) was added, and the admixture was refluxed with heat for 80 minutes. The resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 14 mg of the title compound (yield: 20%).
Reaction SMILES: [NH2:1][C:2](=O)[CH2:3][N:4]1[CH:9]([NH:10]S(C2C=CC(C)=CC=2)(=O)=O)[CH:8]=[CH:7][C:6]([O:21][C:22]2[CH:23]=[CH:24][C:25]([F:38])=[C:26]([NH:28][C:29]([C:31]3[N:35]([CH3:36])[N:34]=[C:33]([CH3:37])[CH:32]=3)=[O:30])[CH:27]=2)=[CH:5]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[NH2:1][C:2]1[N:10]=[C:9]2[CH:8]=[CH:7][C:6]([O:21][C:22]3[CH:23]=[CH:24][C:25]([F:38])=[C:26]([NH:28][C:29]([C:31]4[N:35]([CH3:36])[N:34]=[C:33]([CH3:37])[CH:32]=4)=[O:30])[CH:27]=3)=[CH:5][N:4]2[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)NC2C=CC(Oc3ccc(F)c(NC(=O)c4cc(C)nn4C)c3)=CN2CC(N)=O)cc1
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(N)cn4c3)ccc2F)n(C)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 18.1 %

Procedure:
A mixture of N-{5-[(1-(2-amino-2-oxoethyl)-6-{[(4-methylphenyl)sulfonyl]amino}-1,6-dihydropyridin-3-yl)oxy]-2-fluorophenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (5.85 g, 10.6 mmol), trifluoroacetic anhydride (40 mL) and dichloromethane (40 mL) was stirred at room temperature for 6 hr. The reaction solution was concentrated under reduced pressure, ethyl acetate (50 mL) and saturated aqueous sodium hydrogen carbonate solution (50 mL) were added to the residue and the mixture was stirred for 10 min. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, 8N aqueous sodium hydroxide solution (15 mL) and ethanol (60 mL) were added to the residue. The mixture was stirred at room temperature for 2 hr and at 60° C. for 2 hr. The reaction mixture was diluted with water and extracted with ethyl acetate/tetrahydrofuran (×3). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (NH silica gel, ethyl acetate) and recrystallized from ethyl acetate-hexane to give the title compound (730 mg, 18%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH:15]([CH3:19])[C:16](=O)[CH3:17])[C:6]([O:8][CH2:9][CH3:10])=[O:7]>S(=O)(=O)(O)O>[CH3:19][C:15]1[O:14][C:13]2[C:3]([O:2][CH3:1])=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][C:12]=2[C:16]=1[CH3:17]
Reactant: CCOC(=O)c1ccc(OC(C)C(C)=O)c(OC)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(OC)c2oc(C)c(C)c2c1
Temperature: 25 °C

Procedure:
1,600 ml of 70% sulfuric acid are added to 214 g (0.8 mol) of ethyl 3-methoxy-4-(1-methyl-2-oxopropoxy)-benzoate at room temperature. During this addition, the reaction mixture becomes dark-red to brown in colour. Thereafter, the reaction mixture is warmed to 60° for 4 hours. A brown crystalline sludge thereby gradually forms. The reaction mixture is allowed to cool to room temperature and is poured onto 2 kg of ice and extracted with ethyl acetate. The extract is washed twice with water and then 5 times with 500 ml of 0.5 N sodium bicarbonate solution each time and 3 times with 500 ml of 2 N sodium carbonate solution each time, dried over magnesium sulfate and evaporated completely under a waterpump vacuum. Chromatography on 1.5 kg of silica gel using chloroform which contains 2% of methanol gives ethyl 2,3-dimethyl-7-methoxy-5-benzofurancarboxylate, which, after recrystallisation from warm hexane, melts at 67°-68°.