Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][O:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][O:4]1.[NH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](/[CH:18]=[CH:19]/[C:20](O)=[O:21])=[CH:10]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C1COCC1>[NH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH:18]=[CH:19][C:20]([NH:1][O:2][CH:3]2[CH2:8][CH2:7][CH2:6][CH2:5][O:4]2)=[O:21])=[CH:10]1
Reactant: O=C(O)/C=C/c1c[nH]c2ccccc12
Reactant: NOC1CCCCO1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(C=Cc1c[nH]c2ccccc12)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
NH2OTHP (0.38 g, 3.21 mmol) was added to a solution of trans-3-indoleacrylic acid (17) (0.50 g, 2.67 mmol), PyBOP (1.47 g, 2.83 mmol), triethylamine (0.74 ml, 6.41 mmol) in THF (25 mL). The mixture was stirred at room temperature for 2 h and then was concentrated under reduced pressure. The residue was dissolved in EtOAc and quenched with water, followed by extraction with EtOAc (20 mL×3). The combined organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (EtOAc:n-hexane=1.5:1:1% NH3(aq)) to afford 18. 1H NMR (500 MHz, CD3OD): δ 1.58-1.70 (m, 3H), 1.79-1.90 (m, 3H), 3.63-3.65 (m, 1H), 4.03-4.08 (m, 1H), 4.97-4.98 (m, 1H), 6.47 (d, J=14.9 Hz, 1H), 7.15-7.21 (m, 2H), 7.41 (d, J=7.8 Hz, 1H), 7.59 (s, 1H), 7.84-7.87 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[N:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][N:8]=1)=[O:5]>C(O)C.C(OCC)(=O)C.[Pt]=O>[Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[N:8]=[CH:9][C:10]([NH2:13])=[CH:11][N:12]=1)=[O:5]
Reactant: O=C(Nc1ncc([N+](=O)[O-])cn1)c1ccccc1Cl
Agent: O=[Pt]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1cnc(NC(=O)c2ccccc2Cl)nc1
Reaction time: 3 h
Yield: 48.7 %

Procedure:
Platinum oxide (60 mg, 0.22 mmol) was added to a solution 2-(N-2-chlorobenzoyl)amino-5-nitropyrimidine (278 mg, 1.0 mmol) in ethanol (1 ml) and ethyl acetate (10 ml) at ambient temperature and the reaction stirred for 3 hours under an atmosphere of hydrogen. The reaction was filtered through a pad of celite and the solvents were evaporated in vacuo. Purification by flash chromatography on silica gel, eluting with 5% methanol in ethyl acetate yielded 2-(N-2-chlorobenzoyl)amino-5-aminopyrimidine (121 mg, 50% yield) as brown solid:
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:8][C:9]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:10][N:11]=2)[O:6]CCO1.[F:19][C:20]([F:33])([F:32])[C:21]1[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29](O)=[O:30])=[CH:23][CH:22]=1>>[C:2]([C:7]1[S:8][C:9]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:32])([F:33])[F:19])=[CH:26][CH:25]=3)[CH:15]=[N:14]2)=[CH:10][N:11]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ncc(Cn3ncc(N)n3)s2)OCCO1
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1
Product: CC(=O)c1ncc(Cn2ncc(NC(=O)/C=C/c3ccc(C(F)(F)F)cc3)n2)s1

Procedure:
Following general procedure A followed by B, starting from 2-[2-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-5-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and (E)-3-(4-trifluoromethyl-phenyl)-acrylic acid.
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[C:7]1([CH2:19]O)[CH:8]=[N:9][N:10]2[CH:15]=[CH:14][C:13]3[O:16][CH:17]=[CH:18][C:12]=3[C:11]=12>ClCCl.C(=O)([O-])O.[Na+]>[C:7]1([CH2:19][C:5]#[N:6])[CH:8]=[N:9][N:10]2[CH:15]=[CH:14][C:13]3[O:16][CH:17]=[CH:18][C:12]=3[C:11]=12
Reactant: C[Si](C)(C)C#N
Reactant: OCc1cnn2ccc3occc3c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: N#CCc1cnn2ccc3occc3c12
Reaction time: 0.5 h
Yield: 54.5 %

Procedure:
To a solution of boron trifluoride diethyl ether complex (200 μL, 1.58 mmol) and trimethylsilyl cyanide (280 μL, 2.10 mmol) in dichloromethane (5 mL) was added a solution of furo[3,2-c]pyrazolo[1,5-a]pyridin-1-ylmethanol (100 mg, 0.531 mmol) in dichloromethane (5 mL) under ice-cooling and an argon atmosphere, and the mixture was stirred for 30 min. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90→30/70) to give the title compound (57.1 mg, yield 55%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][CH:10]=1)=[O:5])[CH3:2].[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[CH2:21][C:22](Cl)=[O:23]>>[CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([C:22](=[O:23])[CH2:21][C:12]2[CH:13]=[CH:14][C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:11]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc[nH]1
Reactant: O=C(Cl)Cc1ccc2ccccc2c1
Product: CCOC(=O)c1cc(C(=O)Cc2ccc3ccccc3c2)c[nH]1

Procedure:
4-(2-Naphthalen-2-yl-acetyl)-1H-pyrrole-2-carboxylic acid ethyl ester (141) was synthesized from 1H-pyrrole-2-carboxylic acid ethyl ester and naphthalen-2-yl-acetyl chloride following the procedure described in Example 32. Reaction Conditions: 1,2-dichloromethane/−40° C.→RT. Purification: no purification. LC/MS: 78%.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:13]=[C:12](S(C)(=O)=O)[N:11]=[C:10]([C@@H:18]3[CH2:20][C@H:19]3[C:21]3[N:25]([CH3:26])[C:24]4[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=4[N:22]=3)[CH:9]=2)[N:3]=1.[C-:31]#[N:32].[Na+].O>CS(C)=O>[CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:9]=[C:10]([C@@H:18]3[CH2:20][C@H:19]3[C:21]3[N:25]([CH3:26])[C:24]4[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=4[N:22]=3)[N:11]=[C:12]([C:31]#[N:32])[N:13]=2)[N:3]=1
Reactant: [C-]#N
Reactant: Cc1nc(C)n(-c2cc([C@@H]3C[C@H]3c3nc4ccccc4n3C)nc(S(C)(=O)=O)n2)n1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1nc(C)n(-c2cc([C@@H]3C[C@H]3c3nc4ccccc4n3C)nc(C#N)n2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of trans-2-(2-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-(methylsulfonyl)pyrimidin-4-yl)cyclopropyl)-1-methyl-1H-benzo[d]imidazole (1-6, 750 mg, 1.77 mmol, 1.0 eq) and sodium cyanide (173 mg, 3.54 mmol, 2.0 eq) in DMSO (5.3 mL) was allowed to stir at room temperature for 1 hour. The reaction appeared complete by LCMS. Water was added to the reaction mixture and the resulting precipitate was isolated by suction filtration and washed with water. The precipitate was then triturated with ethyl acetate to afford trans-4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-6-(2-(1-methyl-1H-benzo[d]imidazol-2-yl)cyclopropyl)pyrimidine-2-carbonitrile (21) as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 8.12 (s, 1H), 7.69 (ddd, 1H, J=6.3, 5.1, 1.8 Hz), 7.37-7.18 (m, 3H), 3.85 (s, 3H), 3.03 (ddd, 1H, J=9.3, 4.5, 3.9 Hz), 2.94 (m, 1H), 2.91 (s, 3H), 2.41 (s, 3H), 2.13-1.98 (m, 2H). LRMS m/z (M+H) 371.0 found, 371.2 required. m.p. 229-231° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[N:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=1>>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]([NH:9][C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([NH:1][C:24](=[O:25])[C:23]3[CH:27]=[CH:28][C:20]([Cl:19])=[CH:21][CH:22]=3)[CH:3]=2)=[O:18])=[CH:12][N:13]=1
Reactant: Nc1cc(NC(=O)c2ccc(Cl)nc2)ccc1Cl
Reactant: O=C(O)c1ccc(Cl)cc1
Product: O=C(Nc1ccc(Cl)c(NC(=O)c2ccc(Cl)cc2)c1)c1ccc(Cl)nc1

Procedure:
N-(3-amino-4-chlorophenyl)-6-chloronicotinamide (0.71 mmol) was used in general procedure 2 with 4-chlorobenzoic acid (0.78 mmol). The product was purified by RP-HPLC to give 6-chloro-N-(4-chloro-3-(4-chlorobenzamido)phenyl)nicotinamide. MS (Q1) 419.8 (M)+
Reaction SMILES: [H][H].[F:3][C@H:4]1[CH2:9][C@H:8]2[C@H:10]3[C@H:20]([CH2:21][CH2:22][C@:6]2([CH3:7])[C:5]1=[O:23])[C@:18]1([CH3:19])[C@H:13]([CH2:14][CH2:15][CH2:16][CH2:17]1)[CH2:12][CH2:11]3.CO.[OH-].[K+]>C(O)C.[Pd]>[F:3][C@@H:4]1[CH2:9][C@H:8]2[C@H:10]3[C@H:20]([CH2:21][CH2:22][C@:6]2([CH3:7])[C:5]1=[O:23])[C@:18]1([CH3:19])[C@H:13]([CH2:14][CH2:15][CH2:16][CH2:17]1)[CH2:12][CH2:11]3
Reactant: C[C@]12CCCC[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)[C@@H](F)C[C@@H]12
Reactant: [H][H]
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: C[C@]12CCCC[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)[C@H](F)C[C@@H]12

Procedure:
250 mg of 16βfluoro-5-α-androsten-17-one in 50 ml of ethanol was treated with 50 mg of 5% palladium on carbon and hydrogen gas for 21/2 hours. The reaction mixture, as indicated by the IR, is compatible with 16β-fluoro-5α-androstan-17-one. This crude product was treated with 5 ml methanol and 5 ml of 1N methanolic KOH for one hour. The mixture was partitioned between methylene chloride and water and subjected to HPLC as indicated above. Crystallization of the less mobile component from methanol gave 30 mg of 16α-fluoro-5α-androstan-17-one as prismatic needles, melting point 148°-150° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].Cl.Cl.[N+:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[N:30]=[C:31]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[S:32][CH:33]=1)([O-:22])=[O:21]>>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([N:37]1[CH2:38][CH2:39][N:34]([C:31]2[S:32][CH:33]=[C:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[N+:20]([O-:22])=[O:21])[N:30]=2)[CH2:35][CH2:36]1)=[O:9])([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: O=[N+]([O-])c1ccccc1-c1csc(N2CCNCC2)n1
Agent: Cl
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2nc(-c3ccccc3[N+](=O)[O-])cs2)CC1
Yield: 61 %

Procedure:
Prepared in analogy to example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 1-[4-(2-nitro-phenyl)-thiazol-2-yl]-piperazine dihydrochloride. The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as a yellow crystalline solid (yield 61%). MS (m/e): 531.3 (M+H+, 100%).
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([C:22](=[O:29])[CH2:23][NH:24][C:25](=[O:28])[CH2:26]Br)[CH3:21])[C:14]=3[Cl:30])[C:5]2=[N:4][C:3]=1[CH3:31].[CH3:32][NH2:33]>CO>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([C:22](=[O:29])[CH2:23][NH:24][C:25](=[O:28])[CH2:26][NH:33][CH3:32])[CH3:21])[C:14]=3[Cl:30])[C:5]2=[N:4][C:3]=1[CH3:31]
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)CBr)c3Cl)cccn2c1Br
Reactant: CN
Solvent: CO
Product: CNCC(=O)NCC(=O)N(C)c1ccc(Cl)c(COc2cccn3c(Br)c(C)nc23)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3-bromo-8-[2,6-dichloro-3-[N-(bromoacetylglycyl)-N-methylamino]benzyloxy]-2-methylimidazo[1,2-a]pyridine (150 mg) and 30% solution of methylamine in methanol (2 ml) was stirred for 1 hour at ambient temperature. The mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (methylene chloride:methanol=10:1, V/V) to give 3-bromo-8-[2,6-dichloro-3-[N-(sarcosylglycyl)-N-methylamino]benzyloxy]-2-methylimidazo[1,2-a]pyridine (103 mg).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([N+:11]([O-:13])=[O:12])=[CH:9][N:10]=2)[N:7]=1.[Cl:14][C:15]1[C:16]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=[N:17][CH:18]=[N:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:14][C:15]1[C:16]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:2]3[CH:3]=[CH:4][C:5]4[N:6]([C:8]([N+:11]([O-:13])=[O:12])=[CH:9][N:10]=4)[N:7]=3)=[CH:25][CH:24]=2)=[N:17][CH:18]=[N:19][CH:20]=1
Reactant: Oc1ccc(CNc2ncncc2Cl)cc1
Reactant: O=[N+]([O-])c1cnc2ccc(Cl)nn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cnc2ccc(Oc3ccc(CNc4ncncc4Cl)cc3)nn12
Temperature: 80 °C
Reaction time: 3 h
Yield: 76.8 %

Procedure:
0.18 g (3.6 mmol) of 6-chloro-3-nitro-imidazo[1,2-b]pyridazine are added to a solution of 0.85 g (3.6 mmol) of 4-[(5-chloro-pyrimidin-4-ylamino)-methyl]-phenol (from example A14) and 2.5 g (18 mmol) of potassium carbonate in 10 ml of dry N,N-dimethylformamide and the reaction mixture is stirred at 80° C. for 3 h. The temperature is allowed to raise to room temperature and the mixture is poured into water (100 ml). The precipitate is filtered off and purified by silica gel chromatography (toluene/dioxane=2:1) to yield 1.1 g (78%) of the title compound as a beige powder of m.p. 185° C.
Reaction SMILES: Br.[N:2]1([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[C:25]1([N:31]=[C:32]=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>ClCCl>[C:25]1([NH:31][C:32]([N:5]2[CH2:4][CH2:3][N:2]([NH:8][C:9](=[O:17])[C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[CH2:7][CH2:6]2)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(NN1CCNCC1)c1ccc(F)cc1
Reactant: O=C=Nc1ccccc1
Agent: Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NN1CCN(C(=O)Nc2ccccc2)CC1)c1ccc(F)cc1
Reaction time: 1 h

Procedure:
To a solution of N-piperazinyl-p-fluorobenzamide hydrobromide (300 mg) and triethylamine (0.412 ml) in dichloromethane (6 ml) was added phenyl isocyanate (0.186 ml) at ambient temperature, and the reaction mixture was stirred at the same temperature for 1 hour. The precipitate was filtered, then washed with dichloromethane and water. The residue was dried to give N-(4-phenylcarbamoyl-1-piperazinyl)-p-fluorobenzamide (0.23 g).
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[CH3:6][O:7][C:8]1[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=1[O:10][CH2:11][CH2:12][OH:13].C>C(Cl)Cl>[CH3:6][O:7][C:8]1[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=1[O:10][CH2:11][CH2:12][O:13][S:1](=[O:4])(=[O:3])[NH2:2]
Reactant: COc1ccccc1OCCO
Reactant: NS(=O)(=O)Cl
Solvent: ClCCl
Product: COc1ccccc1OCCOS(N)(=O)=O

Procedure:
The title compound was prepared by the procedure of Example 28 from sulfamoyl chloride and 2-(2-methoxyphenoxy)ethanol. The solid obtained was dissolved in 150 ml of methylene chloride, and the solution was treated with charcoal and filtered through Celite®. The filtrate was evaporated under reduced pressure and the solid residue was recrystallized from methylene chloride-petroleum ether (bp range 30°-60° C.) to give the title compound in 25% yield as white solid, mp 102°-104° C.
Reaction SMILES: OC(C(F)(F)F)=O.[Cl:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:22]=1[C:16]1([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[N:15]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)[C:14]2=[S:32].C([O-])([O-])=O.[K+].[K+].[CH:39]12[CH2:48][CH:43]3[CH2:44][CH:45]([CH2:47][CH:41]([CH2:42]3)[CH:40]1[N:49]=[C:50]=[O:51])[CH2:46]2.NC(N)=O>CC#N>[Cl:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:22]=1[C:16]1([CH2:21][CH2:20][N:19]([C:50]([NH:49][CH:40]3[CH:39]4[CH2:48][CH:43]5[CH2:44][CH:45]([CH2:47][CH:41]3[CH2:42]5)[CH2:46]4)=[O:51])[CH2:18][CH2:17]1)[N:15]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1)[C:14]2=[S:32]
Reactant: COc1ccc(CN2C(=S)c3cccc(Cl)c3C23CCNCC3)cc1
Reactant: O=C=NC1C2CC3CC(C2)CC1C3
Agent: NC(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COc1ccc(CN2C(=S)c3cccc(Cl)c3C23CCN(C(=O)NC2C4CC5CC(C4)CC2C5)CC3)cc1
Reaction time: 2 h
Yield: 84.5 %

Procedure:
To a solution of crude 7-chloro-2-(4-methoxybenzyl)spiro[isoindoline-1,4′-piperidine]-3-thione TFA salt (prepared from TFA deprotection of tert-butyl 7-chloro-2-(4-methoxybenzyl)-3-thioxospiro[isoindoline-1,4′-piperidine]-1′-carboxylate (52 mg, 0.11 mmol)) in 1:1 MeCN:10% aq K2CO3 (10 mL), was added 2-adamantylisocyanate (50 mg, 0.30 mmol, 2.6 equiv) and the mixture stirred was for 2 h. After this time LC-MS analysis showed formation of the desired urea. The mixture was concentrated to ˜50% of its original volume and diluted with EtOAc. The mixture was washed with 1.0 M aq HCl and brine, dried over Na2SO4, and evaporated. The residue was purified by flash chromatography on silica gel (4 g), eluting with 20-80% EtOAc in hexanes, affording 7-chloro-N-(2-adamantyl)-2-(4-methoxybenzyl)-3-thioxospiro[isoindoline-1,4′-piperidine]-1′-carboxamide (51 mg, 0.093 mmol, 85% yield) of the desired thiolactam-urea as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:11](Cl)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.O.[NH2:14][NH2:15]>C(O)C>[Cl:1][C:2]1[C:11]([NH:14][NH2:15])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1nc2ccccc2nc1Cl
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNc1nc2ccccc2nc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.5 %

Procedure:
To a suspension of 2,3-dichloroquinoxaline (33.5 g; 0.168 mole) in 500 ml ethanol, hydrazine hydrate (18.5 g; 0.37 mole) was added and the reaction mixture was stirred vigorously at room temperature for 16 hours. The thick slurry was filtered, washed with ethanol to give 23.7 g of 2-chloro-3-hydrazinoquinoxaline having a mp of 181°-182° C. (dec.).
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4](O)=[O:5].O=S(Cl)Cl.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCN(CC)CC>>[C:13]1([NH:12][C:4](=[O:5])[CH:3]=[C:2]([CH3:7])[CH3:1])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccccc1
Reactant: CC(C)=CC(=O)O
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)=CC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
A mixture of 3-methyl-but-2-enoic acid (100 g, 1 mol) and SOCl2 (119 g, 1 mol) was heated at reflux for 3 h. The excess SOCl2 was removed under reduced pressure. CH2Cl2 (200 mL) was added followed by the addition of aniline (93 g, 1.0 mol) in Et3N (101 g, 1 mol) at 0° C. The mixture was stirred at room temperature for 1 h and quenched with HCl (5%, 150 mL). The aqueous layer was separated and extracted with CH2Cl2. The combined organic layers were washed with water (2×100 mL) and brine (100 mL), dried over Na2S O4 and concentrated to give 3-methyl-but-2-enoic acid phenylamide (120 g, 80%).
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH3:16])[CH:13]([CH3:15])[CH3:14])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.[CH3:21][C:22]1[NH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[C:26](B1OC(C)(C)C(C)(C)O1)[CH:25]=2.C([O-])([O-])=O.[K+].[K+]>COCCOC.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>[CH3:16][N:12]([CH:13]([CH3:15])[CH3:14])[C:11]1[C:2]([C:27]2[CH:28]=[C:29]3[C:24](=[CH:25][CH:26]=2)[NH:23][C:22]([CH3:21])=[CH:30]3)=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([C:17]([O:19][CH3:20])=[O:18])=[CH:6][CH:5]=2
Reactant: Cc1cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2[nH]1
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
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: O
Solvent: COCCOC
Product: COC(=O)c1ccc2nc(-c3ccc4[nH]c(C)cc4c3)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 68.1 %

Procedure:
To a solution of methyl 2-chloro-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate (200 mg, 0.68 mmol) in DME (5.0 mL) and water (2 drops) was added 2-methyl-6-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (352 mg, 1.37 mmol), Pd(PPh3)4 (39 mg, 0.03 mmol), and K2CO3 (189 mg, 1.37 mmol) with stirring for 1 hour at 90° C. under atmosphere of nitrogen. The resulting mixture was concentrated in vacuo to give a residue, which was purified by silica gel column chromatography (1% ethyl acetate in petroleum ether) to give methyl 3-[methyl(propan-2-yl)amino]-2-(2-methyl-1H-indol-5-yl)quinoxaline-6-carboxylate as a light yellow solid (180 mg, 68%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:7]=[C:6]([CH2:17][O:18][CH3:19])[C:3]=1[CH:4]=[O:5].[O:20](S(C(F)(F)F)(=O)=O)[S:21]([C:24]([F:27])([F:26])[F:25])(=O)=[O:22]>ClCCl.O>[CH:4]([C:3]1[C:6]([CH2:17][O:18][CH3:19])=[CH:7][C:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[CH:9][C:2]=1[O:1][S:21]([C:24]([F:27])([F:26])[F:25])(=[O:22])=[O:20])=[O:5]
Reactant: COCc1cc(OC2CCCCO2)cc(O)c1C=O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: COCc1cc(OC2CCCCO2)cc(OS(=O)(=O)C(F)(F)F)c1C=O
Yield: 67.3 %

Procedure:
A solution of 2-hydroxy-6-methoxymethyl-4-(tetrahydro-pyran-2-yloxy)-benzaldehyde (5.18 g, 19.5 mmol) and TEA (10.9 mL, 78.0 mmol) in dichloromethane (100 mL) was treated with Tf2O (7.20 mL, 42.8 mmol) at −78° C. for 1 h. The mixture was diluted with water (150 mL) and extracted with dichloromethane. The organic phases were separated, dried (Na2SO4), and concentrated to dryness. The residue was purified by the flash column chromatography (silica, hexanes/ethyl acetate=4:1), affording the title compound (5.23 g, 67%). 1H NMR (300 MHz, CDCl3) δ 10.29 (s, 1H), 7.44 (s, 1H), 6.99 (s, 1H), 5.60-5.58 (m, 1H), 4.84 (s, 2H), 3.78-3.74 (m, 1H), 3.68-3.62 (m, 1H), 3.51 (s, 3H), 1.91-1.88 (m, 2H), 1.74-1.68 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:24])[CH2:9][CH:10]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.[N+:25]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)([O-:27])=[O:26].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[N+:25]([C:28]1[CH:33]=[CH:32][C:31]([C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:24])[CH2:9][CH:10]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=2)=[CH:30][CH:29]=1)([O-:27])=[O:26]
Reactant: CCOC(=O)C(CCc1ccccc1)CC(=O)c1ccc(Br)cc1
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)C(CCc1ccccc1)CC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 85 °C
Yield: 75.2 %

Procedure:
Ethyl 4-(4-bromophenyl)-4-oxo-2-(2-phenylethyl)butanoate (4.32 g, 11.1 mmol) and 4-nitrophenylboronic acid (2.22, 13.3 mmol) was added to a dry flask under argon. Toluene (100 mL), dioxane (25 mL), saturated aqueous sodium carbonate (30 mL), and [1,1′-bis(diphenyl-phosphino)-ferrocene]dichloro palladium(II) (1:1 complex with dichloromethane, 453 mg, 0.55 mmol) were added and the mixture was thoroughly degassed. The resulting mixture was then heated at 85° C. for 16 h before it was cooled to rt. Water was added and the mixture was extracted twice with ethyl acetate. The combined extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage flash 75, 5:1 ethyl acetate/hexane) to afford ethyl 4-(4′-nitro-1,1′-biphenyl-4-yl)-4-oxo-2-(2-phenylethyl)butanoate (3.6 g, 75%). HPLC ret. time 3.99 min, 1H NMR (300 MHz, CDCl3) δ 1.29 (t, 3H), 1.85-2.08 (m, 2H), 2.71 (t, 2H), 3.05-3.20 (m, 2H), 3.45-3.52 (m, 1H), 4.20 (q, 2H), 7.18-7.31 (m, 5H), 7.72 (d, 2H), 7.78 (d, 2H), 8.05 (d, 2H), 8.33 (d, 2H).