Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6][C@H:5]1[O:11][C:12](=[O:39])[NH:13][C@H:14]1[C:20](=[O:21])[N:19]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:18]2[CH:31]=[CH:32][CH:33]=[CH:34][C:17]=2[C:16]2[CH:35]=[CH:36][CH:37]=[CH:38][C:15]1=2)([CH3:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[Cl-].[Na+].O.O>C1COCC1.CCOC(C)=O>[CH:1]([C@@H:4]1[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6][C@H:5]1[O:11][C:12](=[O:39])[NH:13][C@@H:14]1[C:20](=[O:21])[N:19]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[C:18]2[CH:31]=[CH:32][CH:33]=[CH:34][C:17]=2[C:16]2[CH:35]=[CH:36][CH:37]=[CH:38][C:15]1=2)([CH3:2])[CH3:3]
Reactant: COc1ccc(CN2C(=O)[C@H](NC(=O)O[C@@H]3C[C@H](C)CC[C@H]3C(C)C)c3ccccc3-c3ccccc32)cc1
Agent: CC(C)[N-]C(C)C
Agent: C[Si](C)(C)Cl
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)[C@@H](NC(=O)O[C@@H]3C[C@H](C)CC[C@H]3C(C)C)c3ccccc3-c3ccccc32)cc1
Temperature: -75 °C
Reaction time: 5 h
Yield: 31.4 %

Procedure:
To a solution of [(R)-5-(4-methoxy-benzyl)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-carbamic acid (1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl ester (5.58 g) in THF (20 mL) cooled to −75° C. was added lithium diisopropylamide (2M solution in THF, 15 mL) within 60 minutes. The reaction mixture was stirred for 5 hours at −75° C., chlorotrimethylsilane (4.6 mL) was added within 35 minutes and the reaction mixture was stirred for 15 hours at room temperature. An ice-water mixture (50 mL) was added and, after 2.5 hours stirring, EtOAc (200 mL) and brine:water 1:1 (400 mL) were added. The phases were separated, the organic phase was washed with brine:water 1:1 (300 mL) twice and the aqueous phases were extracted with EtOAc (100 mL) twice. The combined organic layers were dried (MgSO4) and concentrated under reduced pressure until a weight of 15.8 g was obtained. The suspension obtained was filtered off and the precipitate was dried under vacuum at room temperature affording [(S)-5-(4-methoxy-benzyl)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-carbamic acid (1R,2S,5R) -2-isopropyl-5-methyl-cyclohexyl ester (1.75 g, 31.5%), with d.e.=99.2:0.8 (HPLC), as a white powder. Heptane (132 mL) was added to the filtrate and, after 2 days at room temperature, the precipitate was filtered off affording a ca. 1:1 mixture of [(R)-5-(4-methoxy-benzyl)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-carbamic acid (1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl ester and of [(S)-5-(4-methoxy-benzyl)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-carbamic acid (1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl ester. The filtrate was concentrated under reduced pressure and dried under high vacuum affording [(R)-5-(4-methoxy-benzyl)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-carbamic acid (1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl ester (3.5 g, 64% HPLC ISTD, 40%), d.e.=96.9:3.1 as a yellow oil.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[C:8]1[C:13](=[O:14])[N:12]([CH3:15])[CH:11]=[C:10]2[CH2:16][N:17]([CH2:20][CH2:21][C:22]3[N:30]=[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][N:24]4[N:23]=3)[C:18](=[O:19])[C:9]=12.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33](B(O)O)[CH:32]=1.O>CN(C=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:15][N:12]1[C:13](=[O:14])[C:8]([C:33]2[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=2)=[C:9]2[C:18](=[O:19])[N:17]([CH2:20][CH2:21][C:22]3[N:30]=[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][N:24]4[N:23]=3)[CH2:16][C:10]2=[CH:11]1
Reactant: OB(O)c1cccnc1
Reactant: Cn1cc2c(c(Cl)c1=O)C(=O)N(CCc1nc3ccccn3n1)C2
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc2c(c(-c3cccnc3)c1=O)C(=O)N(CCc1nc3ccccn3n1)C2
Temperature: 120 °C
Yield: 44.8 %

Procedure:
K2CO3 (60.3 mg, 0.436 mmol) and bis(triphenylphosphine) palladium(II) dichloride (10.21 mg, 0.015 mmol) were each rapidly added in sequence to a suspension of 7-chloro-5-methyl-2-(2-[1,2,4]triazolo[1,5-a]pyridin-2-yl-ethyl)-3,5-dihydro-2H-pyrrolo[3,4-c]pyridine-1,6-dione (50 mg, 0.145 mmol, see Example c6)) and pyridin-3-ylboronic acid (19.67 mg, 0.160 mmol) in DMF (1 ml)/water (0.200 ml). The reaction mixture was heated in a microwave at about 120° C. for about 20 min. The mixture was purified by preparative HPLC (system: Waters 2767 PHW003, eluent: MeCN/ammonium acetate buffer (gradient: 5:95 to 30:70 over 15 min), column: Boston Analytics, C-18, 10 μm, 21×250 mm) to afford the title compound (25 mg, 0.065 mmol, 44.5% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH2:14])[C@H:10]([C:15]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:18]2)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(=O)(O)[O-].[Na+]>B.O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH2:14])[C@H:10]([CH2:15][N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:18]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](C(=O)N2CCC[C@@H](Cc3ccc(F)cc3)C2)C1
Agent: B
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](CN2CCC[C@@H](Cc3ccc(F)cc3)C2)C1
Reaction time: 19 h
Yield: 76.9 %

Procedure:
In a dry flask (3R,4R)-4-amino-3-[(S)-3-(4-fluoro-benzyl)-piperidine-1-carbonyl]-piperidine-1-carboxylic acid t-butyl ester (500 mg, 1.19 mmol) was dissolved in borane (50 mL of a 1M solution in tetrahydrofuran, 50 mmol). The reaction was stirred 19 hours. The reaction was poured into hydrochloric acid (70 mL of a 1M aqueous solution) and stirred vigorously for 4 hours. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried with magnesium sulfate, filtered and concentrated in vacuo. The mixture was purified by flash chromatography using 5-20% methanol in chloroform to give a yellow solid (371 mg, 77%). 1H NMR (300 MHz, CDCl3), δ: 7.08 (m, 2H), 6.97 (t, 2H, J=8), 4.08 (bs, 2H), 3.70 (bs, 1H), 3.34 (bs, 1H), 3.02 (bt, 1H, J=9), 2.68 (bm, 2H), 2.32 (bm, 7H), 1.98 (m, 1H), 1.75 (m, 5H), 1.44 (s, 9H), 0.89 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([OH:16])([CH3:15])[CH3:14])=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:17]([NH2:19])=[O:18].Cl[C:21]1[N:26]=[C:25]([CH3:27])[C:24]([C:28]([OH:31])([CH3:30])[CH3:29])=[CH:23][CH:22]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[K+].[K+].C(O)(CC)(C)C>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]>[OH:31][C:28]([C:24]1[CH:23]=[CH:22][C:21]([NH:1][C:2]2[S:6][C:5]([C:7]3[CH:8]=[CH:9][C:10]([C:13]([OH:16])([CH3:15])[CH3:14])=[CH:11][CH:12]=3)=[N:4][C:3]=2[C:17]([NH2:19])=[O:18])=[N:26][C:25]=1[CH3:27])([CH3:30])[CH3:29]
Reactant: CC(C)(O)c1ccc(-c2nc(C(N)=O)c(N)s2)cc1
Reactant: Cc1nc(Cl)ccc1C(C)(C)O
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCC(C)(C)O
Product: Cc1nc(Nc2sc(-c3ccc(C(C)(C)O)cc3)nc2C(N)=O)ccc1C(C)(C)O

Procedure:
The title compound was prepared as described in Example 1, Step 2 using 5-amino-2-[4-(1-hydroxy-1-methylethyl)phenyl]-1,3-thiazole-4-carboxamide (Example 5, Step 3) (150 mg, 0.54 mmol), 2-(6-chloro-2-methylpyridin-3-yl)propan-2-ol (100 mg, 0.54 mmol), Pd2(dba)3 (30 mg, 0.032 mmol), X-PHOS (77 mg, 0.16 mmol), potassium carbonate (82 mg, 0.60 mmol), and tert-amyl alcohol (1.1 ml) as starting materials. 1H NMR (500 MHz, d6-DMSO) δ 11.17 (s, 1H), 7.87 (d, 2H), 7.34 (d, 1H), 7.69 (s, 1H), 7.58 (s, 1H), 7.55 (d, 2H), 6.95 (d, 1H), 5.11 (s, 1H), 5.02 (s, 1H), 2.76 (s, 3H), 1.49 (s, 6H), 1.44 (s, 6H). LRMS (APCI) calc'd for C22H27N4O3S [M+H]+ 427.2, found 427.0.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)[CH3:2].[CH2:13]([NH:20][C:21](=[O:42])[CH2:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[O:29][C:28]([CH3:34])([CH3:33])[CH:27]([OH:35])[CH:26]2[NH:36][CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.O>ClCCl>[CH2:13]([NH:20][C:21](=[O:42])[CH2:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[O:29][C:28]([CH3:34])([CH3:33])[CH:27]([OH:35])[CH:26]2[N:36]([S:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=1)(=[O:11])=[O:10])[CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)CNC1c2cc(CC(=O)NCc3ccccc3)ccc2OC(C)(C)C1O
Reactant: CCc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1ccc(S(=O)(=O)N(CC(C)(C)C)C2c3cc(CC(=O)NCc4ccccc4)ccc3OC(C)(C)C2O)cc1
Temperature: 65 °C
Reaction time: 1.5 h

Procedure:
4.1 ml 4-ethyl benzenesulfonyl chloride was added dropwise to a solution of 10.8 g of the N-benzyl-2-[3-hydroxy-2,2-dimethyl-4-(neopentylamino)-3,4-dihydro-2H-chromen-6-yl]acetamide obtained above in Example 3 and 5 ml triethylamine in 100 ml dichloromethane. Dichloromethane was immediately substantially completely evaporated at reduced pressure, and the resulting reaction mixture was stirred for 90 minutes at 65° C. and 180 bar. The entire batch was poured into 150 ml water, and the aqueous phase was extracted once with 200 ml ethyl acetate. The solvent was largely evaporated at reduced pressure, the remaining residue was dried over sodium sulfate, and the remaining residue was chromatographed on silica gel (mobile phase: petroleum ether/ethyl acetate 3:1 v/v). Drying the product fractions in an oil pump vacuum yielded 3.6 g of the title compound (2 conformers) as colorless oil.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12](O)=[O:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN1CCOCC1.ClC(OCC)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>C1COCC1.O>[C:1]1([C:7]2[O:8][C:9]([C:15]([F:17])([F:18])[F:16])=[C:10]([CH2:12][OH:13])[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: CCOC(=O)Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: OCc1nc(-c2ccccc2)oc1C(F)(F)F
Temperature: -10 °C
Reaction time: 1 h

Procedure:
500 mg (1.94 mmol) of 2-phenyl-5-(trifluoromethyl)-1,3-oxazole-4-carboxylic acid are dissolved in 40 ml of dry THF and cooled to −10° C. 197 mg (1.94 mmol) of 4-methylmorpholine and 211 mg (1.94 mmol) of ethyl chloroformate are added. The reaction solution is stirred at −10° C. for 1 h. 3.9 ml (3.89 mmol) of a 1 M solution of lithium aluminum hydride in THF are then slowly added dropwise. The reaction mixture is stirred overnight and slowly allowed to warm to RT. The mixture is then once more cooled to 0° C., and 0.6 ml of water and 1.2 ml of 1 N aqueous sodium hydroxide solution are added carefully. The mixture is then stirred at RT overnight. After filtration, the solvent is removed on a rotary evaporator. The residue is used without further purification in the subsequent reaction.
Reaction SMILES: [CH3:1][C:2]1[CH2:6][CH:5]([CH3:7])[N:4]([CH2:8][C:9]([O:11]CC)=[O:10])[N:3]=1.[OH-].[Li+].CO.[Cl-].[NH4+]>O.O1CCCC1>[CH3:1][C:2]1[CH2:6][CH:5]([CH3:7])[N:4]([CH2:8][C:9]([OH:11])=[O:10])[N:3]=1
Reactant: CCOC(=O)CN1N=C(C)CC1C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC1=NN(CC(=O)O)C(C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of ethyl 4,5-dihydro-3,5-dimethyl-1H-pyrazole-1-acetate (i.e. the product of Step A) (0.26 g, 0.0014 mol) and lithium hydroxide (0.072 g, 3 mmol) in a solution of methanol (2 mL), tetrahydrofuran (2 mL) and water (2 mL) was stirred overnight at room temperature. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate, and the organic layer was concentrated under reduced pressure to provide the title compound as a colorless oil (0.10 g).
Reaction SMILES: [CH2:1](I)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[Na].[C:14]([O:20][CH2:21][CH3:22])(=[O:19])[CH2:15][C:16]([CH3:18])=[O:17]>C(O)C>[CH2:1]([CH:15]([C:16]([CH3:18])=[O:17])[C:14]([O:20][CH2:21][CH3:22])=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCOC(=O)CC(C)=O
Reactant: CCCCCCCCCCCI
Agent: [Na]
Solvent: CCO
Product: CCCCCCCCCCCC(C(C)=O)C(=O)OCC

Procedure:
Ethyl 2-(n-undecyl)-acetoacetate was prepared from undecyl iodide (26.6.g) by reaction with an equivalent amount of the sodium derivative of ethyl acetoacetate in ethanol (5 hours, reflux temperature). After cooling the solvent is removed on a rotary evaporator, 300 ml of hexane is added to the residue, and the precipitate of salt is now easily filtered. The product is of sufficient purity (g.c-m.s.) to dispense with further work-up.Reaction of it (6.80 g) with 3,5-difluoroaniline (3.1 g) and 0.30 g of p-toluenesulfonic acid monohydrate in 100 ml of benzene (water separator, 3 days) produced the anilinocrotonic ester with very little of the starting materials left. After removal of the solvent, the crude product was added quickly to 30 ml of boiling Dowtherm A and kept at boiling temperature for about 10 minutes. The product crystallizes out upon cooling and is isolated by filtration and washing with hexane (50 ml).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:13])[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:6][CH:7]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:17].OO.NC(N)=O.OP([O-])([O-])=O.[K+].[K+].S(=O)(O)[O-].[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([Cl:13])[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N+:6]([O-:17])[CH:7]=1
Reactant: CCOC(=O)c1ncc(Br)cc1Cl
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: NC(N)=O
Agent: O=P([O-])([O-])O
Agent: O=S([O-])O
Solvent: ClCCl
Product: CCOC(=O)c1c(Cl)cc(Br)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of ethyl 5-bromo-3-chloro-pyridine-2-carboxylate (2, 151.0 g, 570.89 mmol) in dichloromethane (1.73 L) was added trifluoroacetic anhydride (30.0 mL, 1.14 mol) and urea hydrogen peroxide (112.69 g, 1.20 mol) at 0° C. The reaction was stirred overnight at room temperature. After completion of the reaction, the reaction mixture was neutralized with a potassium phosphate dibasic solution. A sodium bisulfite solution was added followed by extraction with dichloromethane (2×100 mL). The organic layers were separated, combined, dried with magnesium sulfate, filtered and concentrated to dryness under vacuum to afford ethyl 5-bromo-3-chloro-1-oxido-pyridin-1-ium-2-carboxylate 3 as an off white solid. Yield: 150.5 g, 94%; MS (ESI) m/z 281.8 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.26 (d, J=1.2 Hz, 1H), 7.48 (d, J=1.2 Hz, 1H), 4.50 (q, J=7.12 Hz, 2H), 1.42 (t, J=12.12 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=O)([O-:3])=[O:2].[OH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH2:24])=[CH:18][CH:17]=1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[OH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][N:24]2[C:10](=[O:11])[C:5]3=[C:4]([N+:1]([O-:3])=[O:2])[CH:14]=[CH:13][CH:12]=[C:6]3[C:7]2=[O:9])=[CH:18][CH:17]=1
Reactant: NCCc1ccc(O)cc1
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C1c2cccc([N+](=O)[O-])c2C(=O)N1CCc1ccc(O)cc1
Temperature: 25 °C
Yield: 93.5 %

Procedure:
3-Nitrophthalic anhydride (1.93 g, 0.01 mol, 1 eq) and 2-(4-hydroxyphenyl)-ethylamine (2.06 g, 0.015 mol, 1.5 eq) were refluxed under heating in toluene (20 ml) for 3 hours. The reaction mi i t ure was cooled to room temperature, and ethyl acetate (100 ml) was added to this reaction mixture. The organic layer was washed twice with dil. aqueous hydrochloric acid solution (30 ml), further washed with saturated brine (100 ml), and dried over anhydrous sodium sulfate. After the drying agent was filtered off, the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=1/1) to give N-[2-(4-hydroxyphenyl)ethyl]-3-nitrophthalimide (2.92 g, 92.8%) as a colorless solid. This was further purified by recrystallization from methanol to give colorless crystals (1.9 g, 60.8%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]#[N:6].[NH:7]1[CH:14]=[CH:13][C:11]([NH2:12])=[N:10][C:8]1=[S:9]>CCO.[OH-].[Na+]>[NH2:12][C:11]1[CH:13]=[CH:14][N:7]=[C:8]([S:9][CH2:2][CH2:3][CH2:4][C:5]#[N:6])[N:10]=1
Reactant: Nc1cc[nH]c(=S)n1
Reactant: N#CCCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N#CCCCSc1nccc(N)n1
Reaction time: 18 h
Yield: 78.6 %

Procedure:
4-Chlorobutyronitrile (0.23 g.) in EtOH (2 ml.) was added to a solution of 2-thiocytosine (0.25 g.) in 0.5 N aqueous NaOH (5 ml.) and the mixture stirred for 18 hours. A further portion of 4-chlorobutyronitrile (0.23 g.) was added and the mixture stirred a further 24 hours. The solution was concentrated in vacuo to 2 ml. and cooled and the crystalline precipitate collected to give 4-[4-aminopyrimid-2-ylthio]butyronitrile (0.3 g.), m.p. 99-100°.
Reaction SMILES: [CH:1]([CH2:3][C:4]([OH:6])=O)=[CH2:2].C(Cl)(=O)C(Cl)=O.[N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][C:14]=1[C:23]1[CH:24]=[C:25]([NH2:29])[CH:26]=[CH:27][CH:28]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.C1COCC1.C(OCC)(=O)C.CN(C=O)C>[N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][C:14]=1[C:23]1[CH:24]=[C:25]([NH:29][C:4](=[O:6])[CH2:3][CH:1]=[CH2:2])[CH:26]=[CH:27][CH:28]=1
Reactant: C=CCC(=O)O
Reactant: Nc1cccc(-c2cnc3ccccc3n2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C=CCC(=O)Nc1cccc(-c2cnc3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 26.8 %

Procedure:
To a solution of vinylacetic acid (43 μL, 0.497 mmol) and oxalyl chloride (48 μL, 0.542 mmol) in DCM (5 mL), a drop of DMF was added using a Pasteur pipette. The colourless solution was stirred at room temperature for 15 min, and a solution of (3-quinoxalin-2-ylphenyl)amine (100 mg, 0.452 mmol) and diisopropylethylamine (DIEA, 90 μL, 0.542 mmol) in THF (5 mL) was added. The resulting slurry was stirred at room temperature for 24 hrs, the reaction mixture was then diluted with ethyl acetate (30 mL) and washed with water (2×25 mL), the organic phase dried over sodium sulphate and the solvent evaporated in vacuo. The resulting crude solid was purified by preparative LCMS to afford N-(3-(quinoxalin-2-yl)phenyl)but-3-enamide (35 mg, 22% yield). LCMS calculated for C18H15N3O (M+H): 290.33. found 290.24. 1H-NMR (DMSO-d6, 400 Mhz) δH: 10.59 (1H, br.), 9.52 (1H, s), 8.52 (1H, m), 8.12-8.16 (2H, m), 8.05-8.08 (1H, m), 7.80-7.95 (3H, m), 7.55-7.60 (1H, m), 5.95-6.07 (1H, m), 5.25-5.12 (2H, m), 3.18 (2H, d, J=6.2 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](/[CH:17]=[CH:18]/[C:19]([OH:21])=O)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.C(Cl)(=O)C(C)(C)C.C([Li])CCC.[Li].[C:42]1([C@@H:48]2[CH2:52][O:51][C:50](=[O:53])[NH:49]2)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C1COCC1>[O:21]=[C:19]([N:49]1[C@H:48]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:52][O:51][C:50]1=[O:53])/[CH:18]=[CH:17]/[C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH:9]=1
Reactant: CC(C)(C)OC(=O)n1cc(/C=C/C(=O)O)c2ccccc21
Reactant: O=C1N[C@H](c2ccccc2)CO1
Agent: CC(C)(C)C(=O)Cl
Agent: [Li]
Agent: [Li]CCCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1cc(/C=C/C(=O)N2C(=O)OC[C@H]2c2ccccc2)c2ccccc21
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of (E)-3-(1-(tert-butoxycarbonyl)-1H-indol-3-yl)acrylic acid (7.14 g, 24.85 mmol) in THF (400 mL) at −78° C. were added Et3N (10.39 ml, 74.6 mmol) and pivaloyl chloride (6.12 ml, 49.7 mmol). The mixture was stirred for 15 min at −78° C. then warmed to 0° C. for 1.5 h. The mixture was cooled to −78° C., to which was added n-Butyllithium (1.6 M in Hexanes)(14 mL, 22.4 mmol), then added the lithium salt of (R)-4-phenyl-2-oxazolidinone [prepared by adding n-Butyllithium (1.6 M in Hexanes)(31 ml, 49.7 mmol), to a solution of (R)-4-phenyloxazolidin-2-one (8.11 g, 49.7 mmol)] in THF (200 mL) at −78° C.) via cannula. The reaction was stirred at −78° C. for 2 h then at rt for 16 h. The reaction was quenched with saturated NH4Cl aqueous solution. The organics were removed under vacuum and the aqueous was extracted with EtOAc. The organic layer was collected, washed with brine, dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel chromatography using a gradient of 10-20% EtOAc/Hexanes. The product fractions were collected and the solvent removed under vacuum to give ((R,E)-tert-butyl 3-(3-oxo-3-(2-oxo-4-phenyloxazolidin-3-yl)prop-1-en-1-yl)-1H-indole-1-carboxylate, 7.12 g (66%). ESI-MS (+) m/z 433.4 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C@H:15]2[C@:10]([CH3:23])([CH2:11][CH2:12][C:13]3[C:20]([Cl:21])=[C:19](Br)[CH:18]=[CH:17][C:14]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C(Cl)Cl>[CH2:1]([N:8]1[CH2:16][C@H:15]2[C@:10]([CH3:23])([CH2:11][CH2:12][C:13]3[C:20]([Cl:21])=[C:19]([CH3:24])[CH:18]=[CH:17][C:14]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CB1OB(C)OB(C)O1
Reactant: C[C@]12CCc3c(ccc(Br)c3Cl)[C@H]1CN(Cc1ccccc1)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc2c(c1Cl)CC[C@]1(C)CN(Cc3ccccc3)C[C@H]21
Temperature: 130 °C
Yield: 78.5 %

Procedure:
A mixture of cis-2-benzyl-7-bromo-6-chloro-3a-methyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole (0.154 mmol, 60 mg), tetrakis(triphenylphosphine)Pd(0) (7.68 μmol, 8.96 mg), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (0.184 mmol, 52 μl, 46.3 mg) and potassium carbonate (0.230 mmol, 32.2 mg) in 1,4-Dioxane (1 ml) and Water (0.5 ml) was heated in a microwave reactor at 130° C. for 20 min. The reaction mixture was diluted with DCM and water, the phases were separated and the aqueous was extracted with DCM (using a hydrophobic frit). The combined organic extracts were concentrated in vacuo and purified by silica column chromatography (eluting with neat heptane—2:1 heptane:ethyl acetate). The fractions containing the product compound were concentrated in vacuo and then redissolved in MeOH and then passed through Strata SCX column (1 g) and concentrated in vacuo to afford cis-2-benzyl-6-chloro-3a,7-dimethyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole (39.4 mg), m/z=326.2 [M+H]+.