Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH2:20])[CH2:10][CH2:9]1)(OC(C)(C)C)=O.[CH3:21][N:22]1[CH:26]=[CH:25][N:24]=[C:23]1[CH:27]=O.[BH4-].[Na+]>CO>[CH3:21][N:22]1[CH:26]=[CH:25][N:24]=[C:23]1[CH2:27][NH:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: Cn1ccnc1C=O
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2N)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1ccnc1CNc1ccccc1N1CCNCC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 23.5 %

Procedure:
To a solution of 1-boc-4-(2-aminophenyl) piperazine (554 mg, 2.0 mmol, 1.0 eq.) in methanol was added (1-methyl-1H-imidazole-2-carbaldehyde (220 mg, 2.0 mmol, 1.0 eq.). The mixture was reflux for about 1 hour and then cool to about 0° C. Sodium borohydride on alumina (10 wt % on basic alumina, 1.13 g, 3.0 mmol, 1.5 eq.) was added. The solution was warmed to r.t. and then stirred overnight. The reaction mixture was filtered through celite and then concentrated. Purification by flash chromatography (35 g SiO2, 40 mL/min, linear gradient, 0-8% MeOH/CH2Cl2 for 25 minutes and then 8% MeOH for 7 minutes) afforded Boc protected title compound (176 mg, 0.47 mmol, 24%). LRMS (ESI+): 372.3 [M+1].
Reaction SMILES: CCCCCC.[H-].[K+].[CH3:9][C:10]1[NH:11][C:12]2[C:17]([C:18]=1[CH3:19])=[CH:16][CH:15]=[CH:14][CH:13]=2.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([CH3:30])=[C:25]([N:27]=[C:28]=[S:29])[CH:26]=1>C1COCC1>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([CH3:30])=[C:25]([NH:27][C:28]([N:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]([CH3:19])=[C:10]2[CH3:9])=[S:29])[CH:26]=1
Reactant: Cc1[nH]c2ccccc2c1C
Reactant: Cc1ccc(Cl)cc1N=C=S
Agent: [H-]
Agent: [K+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(Cl)cc1NC(=S)n1c(C)c(C)c2ccccc21
Reaction time: 16 h
Yield: 66.1 %

Procedure:
A stirred slurry of hexane washed potassium hydride (1.38 g, 34.5 mmol) in 10 mL of dry THF was treated dropwise with a solution of 2,3-dimethylindole (5.0 g, 34.5 mmol) in 30 mL THF. The mixture was stirred until a clear solution was obtained. A solution of 5-chloro-2-methylphenylisothiocyanate (6.3 g, 34.5 mmol) in 5 mL THF was slowly added and stirring was continued for 16 hours. The reaction mixture was concentrated in vacuo and the residue partitioned between EtOAc and 1N HCl. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residual solid was triturated with Et2O-hexane overnight to provide 7.5 g of the title compound as a light yellow solid, m.p. 115° C. (67% of theory).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])=[O:3].C(=O)([O-])[O-].[Na+].[Na+].[F:16][CH2:17][C:18]([C:22]1[CH:23]=[C:24]([NH2:34])[N:25]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)[N:26]=1)([CH2:20][F:21])[CH3:19].O>C1COCC1>[Cl:7][C:6]([Cl:9])([Cl:8])[CH2:5][O:4][C:2](=[O:3])[NH:34][C:24]1[N:25]([C:27]2[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=2)[N:26]=[C:22]([C:18]([CH2:17][F:16])([CH3:19])[CH2:20][F:21])[CH:23]=1
Reactant: Cc1ccc(-n2nc(C(C)(CF)CF)cc2N)cc1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-n2nc(C(C)(CF)CF)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reaction time: 24 h

Procedure:
Add 2,2,2-trichloroethyl chloroformate (8.1 mmol, 1.1 mL) and aqueous sodium carbonate solution (4.8 mL) over a solution of 5-(2-fluoro-1-fluoromethyl-1-methyl-ethyl)-2-p-tolyl-2H-pyrazol-3-ylamine (7.3 mmol, 1.9 g) in 37 mL of THF. Stir for 24 hours. Pour the solution over water and extract in ethyl acetate. Combine organic layers and wash with saturated aq. sodium chloride. Dry over sodium sulfate, filter, and concentrate under reduced pressure to give [5-(2-fluoro-1-fluoromethyl-1-methyl-ethyl)-2-p-tolyl-2H-pyrazol-3-yl]-carbamic acid 2,2,2-trichloro-ethyl ester. LCMS ES+ (m/z) 440 [M+H].
Reaction SMILES: [C:1]([NH:9][NH:10][C@@H:11]1[C:16]2[CH:17]=[C:18]([C:21]#[N:22])[CH:19]=[CH:20][C:15]=2[O:14][C:13]([CH3:24])([CH3:23])[C@H:12]1[OH:25])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:32](Cl)(=[O:34])[CH3:33]>C(Cl)(Cl)Cl>[C:32]([N:10]([C@@H:11]1[C:16]2[CH:17]=[C:18]([C:21]#[N:22])[CH:19]=[CH:20][C:15]=2[O:14][C:13]([CH3:23])([CH3:24])[C@H:12]1[OH:25])[NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](NNC(=O)c2ccccc2)[C@@H]1O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(=O)N(NC(=O)c1ccccc1)[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O

Procedure:
Trans-4-(2-benzoylhydrazino)-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol (320 mg) was dissolved in 1 ml of chloroform, 0.5 ml of pyridine was added, and 0.28 ml of acetyl chloride was added with stirring under ice cooling. After stirring at room temperature for 80 minutes, the solvent was distilled off under reduced pressure and the residue was dissolved in 5 ml of methanol. The solution was treated with 5 ml of 1N-sodium hydroxide at room temperature for 30 minutes. After the methanol had been distilled off, the residue was shaken together with ethyl acetate-water and the organic layer was washed with an aqueous solution of sodium chloride and subsequently concentrated. This was recrystallized from hexane-ethanol (1:1) to give 170 mg of trans-4-(1-acetyl-2-benzoylhydrazino)-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol.monohydrate as white crystals, m.p. 212°-213° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[C:5]([F:10])=[CH:4][CH:3]=1.[NH2:11][C@H:12]([CH:15]([CH3:17])[CH3:16])[CH2:13][OH:14].[BH4-].[Na+]>CO>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][NH:11][C@H:12]([CH:15]([CH3:17])[CH3:16])[CH2:13][OH:14])[C:5]([F:10])=[CH:4][CH:3]=1
Reactant: O=Cc1nc(Br)ccc1F
Reactant: CC(C)[C@@H](N)CO
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)[C@H](CO)NCc1nc(Br)ccc1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
6-bromo-3-fluoropicolinaldehyde (4.0 g, 19.61 mmol) and (R)-2-amino-3-methylbutan-1-ol (2.281 mL, 20.59 mmol) were dissolved in methanol (100 mL) and stirred at ambient temperature for 1 hour and 15 minutes. Sodium borohydride (0.742 g, 19.61 mmol) was added and the mixture was stirred for another 1 hour and 30 minutes. The volume of the reaction mixture was reduced, and the mixture was quenched with 200 mL 1.0 N NaOH, and extracted with 200 mL dichloromethane (2×). The organic phase was extracted with 1.0 N HCl and partitioned. The aqueous phase was separated, neutralized with 3.0 N NaOH, extracted with EtOAc, organic phase separated and washed with brine. The organic phase was dried over Na2SO4, filtered, and concentrated to obtain the title compound as an orange solid. MS (ESI+) m/z 291.0 (M+H); 1H NMR (300 MHz, DMSO-d6) δ 7.69 (t, J=8.8, 1H), 7.60 (dd, J=8.6, 3.7, 1H), 4.42 (t, J=5.2, 1H), 3.92-3.75 (m, 2H), 3.43 (dt, J=10.7, 4.8, 1H), 2.34-2.24 (m, 1H), 2.08 (s, 1H), 1.87-1.71 (m, 1H), 0.83 (dd, J=8.5, 6.9, 6H).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][NH:11][CH2:12][CH2:13][NH:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([CH2:21][C:22]([NH:24][C@H:25]2[CH2:30][C:29]3[CH:31]=[CH:32][CH:33]=[C:34]([C:35]([OH:37])=[O:36])[C:28]=3[O:27][B:26]2[OH:38])=[O:23])[CH2:17][CH2:16]1)(C(C)(C)C)(C)C.C(O)(C(F)(F)F)=O>O>[OH:38][B:26]1[C@@H:25]([NH:24][C:22](=[O:23])[CH2:21][C@H:18]2[CH2:19][CH2:20][C@H:15]([NH:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9][OH:8])[CH2:16][CH2:17]2)[CH2:30][C:29]2[CH:31]=[CH:32][CH:33]=[C:34]([C:35]([OH:37])=[O:36])[C:28]=2[O:27]1
Reactant: CC(C)(C)[Si](C)(C)OCCNCCN[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(C[C@H]1CC[C@H](NCCNCCO)CC1)N[C@H]1Cc2cccc(C(=O)O)c2OB1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the compound from step 1 was added a mixture of TFA (2 mL) and H2O (0.2 mL). The resultant reaction mixture was stirred at RT for 2 hr. The solvents were then removed in vacuo and the residue purified by reverse phase preparative HPLC and dried using lyophilization. ESI-MS m/z 434 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[F:13][C:14]([F:21])([F:20])[C:15](OCC)=[O:16].C(N(CC)CC)C.Cl>CO>[F:13][C:14]([F:21])([F:20])[C:15]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:11][CH:12]=1)=[O:16]
Reactant: CCOC(=O)C(F)(F)F
Reactant: Nc1ccc(C=CC(=O)O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(O)C=Cc1ccc(NC(=O)C(F)(F)F)cc1
Yield: 94 %

Procedure:
A solution of 4-aminocinnamic acid (1.88 g), ethyl trifluoroacetate (6.8 ml) and triethylamine (4.8 ml) in 20 ml methanol was stirred at room temperature for 4 hours, and 0.3 mol/l hydrochloric acid was added thereto, on ice, to precipitate a solid, which was then filtered, washed with water, and then dried by heating under reduced pressure to give 4-(trifluoroacetylamino)cinnamic acid (2.81 g, 94%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]=1[N:11]1[CH2:14][CH2:13][CH2:12]1.[H][H]>CO.[Pt]=O>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[N:11]1[CH2:14][CH2:13][CH2:12]1
Reactant: C1=C(N2CCC2)CCc2ccccc21
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CO
Product: c1ccc2c(c1)CCC(N1CCC1)C2

Procedure:
The crude product from Step 1 was dissolved in methanol (1 litre) and reduced at room temperature over platinum oxide (5 g) with hydrogen at 120 p.s.i. (about 8.3×105Pa). After 21/2 h, the solution was filtered and evaporated in vacuo. The residue was purified by chromatography (silica; methanol) to give the product (2.5 g as an oil).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:34][CH3:35])=[C:6]([S:8]([N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[C:26]([F:33])[CH:25]=4)=[O:22])[CH:19]=3)[CH2:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:7]=1.Cl[C:37]1C=CC(OC)=C(S(Cl)(=O)=O)[CH:42]=1>>[CH2:37]([O:29][C:28](=[O:30])[C:27]1[CH:31]=[CH:32][C:24]([NH:23][C:21]([C:18]2[CH:19]=[C:20]3[C:15]([CH2:14][CH2:13][CH2:12][N:11]3[S:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:34][CH3:35])(=[O:10])=[O:9])=[CH:16][CH:17]=2)=[O:22])=[CH:25][C:26]=1[F:33])[CH3:42]
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CCCc2ccc(C(=O)Nc3ccc(C(=O)O)c(F)c3)cc21
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CCC3)cc1F

Procedure:
4-{[1-(5-Chloro-2-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-2-fluoro-benzoic acid, m/z (ES+): 519.26 (M+H+.), was prepared in analogy to example 48, steps 1 to 5. Step 4 was performed using 5-chloro-2-methoxy-benzenesulfonyl chloride, yielding 4-{[1-(5-chloro-2-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-2-fluoro-benzoic acid ethyl ester, which was hydrolyzed in step 5.
Reaction SMILES: C([N:14]1[CH2:17][C:16]([NH:21][CH2:22][CH3:23])([C:18]([NH2:20])=[O:19])[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.[ClH:24].CCOCC>CO>[ClH:24].[CH2:22]([NH:21][C:16]1([C:18]([NH2:20])=[O:19])[CH2:17][NH:14][CH2:15]1)[CH3:23]
Reactant: CCNC1(C(N)=O)CN(C(c2ccccc2)c2ccccc2)C1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CCNC1(C(N)=O)CNC1

Procedure:
Alternatively, a solution of 1-benzhydryl-3-ethylaminoazetidine-3-carboxylic acid amide (I-2A-1g; 9.2 g, 30 mmol) in methanol (150 ml) at 0° C. was added 1 M HCl in ether (75 ml, 75 mmol). The mixture was concentrated to ⅔ volume to remove the ether, in vacuo, and then methanol was added to bring the reaction volume to 150 mL. This was repeated a second time. After the addition of 20% Pd(OH)2 on carbon (50% water; 2.3 g), the mixture was placed on a Parr® shaker and then reduced (45 psi H2) at room temperature overnight. The mixture was diluted with methanol (350 ml) filtered through Celite®, rinsing with additional methanol. The methanol fractions were filtered through a 0.45 μm filter disk, and then concentrated under reduced pressure to give a solid residue that was triturated from diethyl ether, collected by vacuum filtration, washed with ether and then dried, in vacuo, to afford I-(13A-9)f (6.3 g, 91%) as a tan solid.
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:10]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]2[C:11]=1[N:12]=[CH:13][CH:14]=[N:15]2.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([S:8][C:10]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]2[C:11]=1[N:12]=[CH:13][CH:14]=[N:15]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: SCc1ccccc1
Reactant: Clc1cc(Br)c2nccnc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Clc1cc(SCc2ccccc2)c2nccnc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Benzyl mercaptan (0.51 g, 4.1 mmol) was added dropwise to a mixture of 5-bromo-7-chloroquinoxaline (1 g, 4.1 mmol), cesium carbonate (1.6 g, 4.92 mmol) at 0° C. in DMF (25 ml) under nitrogen. The reaction mixture was allowed to warm to room temperature, stirred for 2 hours and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried with sodium sulfate and concentrated. Purification by column chromatography gave 5-(benzylthio)-7-chloroquinoxaline (rf=0.39 in 9:1 hexanes/ethyl acetate) as a yellow solid. The undesired regioisomer elutes afterwards (rf=0.27 in 9:1 hexanes/ethyl acetate).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33].C[O-].[Na+]>>[OH:15][C:14]1[C:13]2[C:8](=[CH:9][C:10]([O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:11][CH:12]=2)[C:7]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[N:6][C:5]=1[C:3]([NH:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:4]
Reactant: NCCC(=O)O
Reactant: COC(=O)c1nc(-c2ccccc2)c2cc(Oc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1nc(-c2ccccc2)c2cc(Oc3ccccc3)ccc2c1O
Temperature: 25 °C
Yield: 91.4 %

Procedure:
A mixture of 4-hydroxy-7-phenoxy-1-phenyl-isoquinoline-3-carboxylic acid methyl ester (46 mg, 0.12 mmol), β-alanine (552 mg, 6.2 mmol) and NaOMe (9.3 mL, 4.65 mmol, 0.5 M in MeOH) was refluxed for 16 h. After cooling to r.t., the solvent was evaporated. The residue was partitioned between EtOAc (50 mL) and water (50 mL). 1 M HCl was added with stirring until pH was ˜2. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by column chromatography (0-35% EtOAc/hexanes+2% AcOH) to give 47 mg of the title compound as a light yellow solid. MS: (+) m/z 429.13 (M+1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:16]=[C:15]3[C:10]([N:11]=[CH:12][CH:13]=[N:14]3)=[C:9]([O:17][C@@H:18]3[CH2:23][CH2:22][C@H:21]([NH2:24])[CH2:20][CH2:19]3)[CH:8]=2)[CH2:3][CH2:2]1.CS([C:29]1[N:34]=[CH:33][CH:32]=[CH:31][N:30]=1)(=O)=O.CCN(C(C)C)C(C)C>>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:16]=[C:15]3[C:10]([N:11]=[CH:12][CH:13]=[N:14]3)=[C:9]([O:17][C@@H:18]3[CH2:23][CH2:22][C@H:21]([NH:24][C:29]4[N:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[CH2:20][CH2:19]3)[CH:8]=2)[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)c1ncccn1
Reactant: N[C@H]1CC[C@@H](Oc2cc(N3CCOCC3)cc3nccnc23)CC1
Solvent: CCN(C(C)C)C(C)C
Product: c1cnc(N[C@H]2CC[C@@H](Oc3cc(N4CCOCC4)cc4nccnc34)CC2)nc1
Temperature: 100 °C

Procedure:
As shown in step 9-iv of Scheme 9, to a solution so (cis) 4-(7-morpholinoquinoxalin-5-yl)oxycyclohexanamine (415 mg, 1.264 mmol) and 2-methylsulfonylpyrimidine (400 mg, 2.53 mmol) was added DIEA (490 mg, 661 μL, 3.79 mmol) and the reaction mixture was sealed in a vessel and heated to 100° C. for 16 hours. After this time, the volatiles were removed under a stream of nitrogen gas and the crude residue dissolved in minimal amount of DCM. Purification by medium pressure silica gel chromatography (0-10% MeOH/DCM, 1% Et3N] produced N-((cis)-4-((7-morpholinoquinoxalin-5-yl)oxy)cyclohexyl)pyrimidin-2-amine containing triethylamine hydrochloride as an impurity. Dissolved product in DCM and stirred with a silica-supported amine (Silabond Amine® 40-63 μm). The scavenger mixture was filtered, concentrated under reduced pressure, and dried under high vacuum to provide N-((cis)-4-((7-morpholinoquinoxalin-5-yl)oxy)cyclohexyl)pyrimidin-2-amine (Compound 28, 435 mg): 1H-NMR (400 MHz, CDCl3) δ 8.68 (d, J=1.9 Hz, 1H), 8.61 (d, J=1.9 Hz, 1H), 8.27 (s, 1H), 8.26 (s, 1H), 6.94 (d, J=2.4 Hz, 1H), 6.90 (d, J=2.4 Hz, 1H), 6.50 (t, J=4.8 Hz, 1H), 4.78 (s, 1H), 4.08-3.97 (m, 1H), 3.94-3.86 (m, 4H), 3.37-3.28 (m, 4H), 2.20 (d, J=9.1 Hz, 2H), 1.95-1.85 (m, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:19]([O:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26](F)=[CH:25][CH:24]=1)[CH3:20].O>CN(C)C=O>[CH2:19]([O:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26]([N:10]2[C:11]3[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=3)[CH:8]=[CH:9]2)=[CH:25][CH:24]=1)[CH3:20]
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(-n2ccc3ccc([N+](=O)[O-])cc32)cc1
Temperature: 75 °C
Reaction time: 8 h
Yield: 66.9 %

Procedure:
To a solution of 6-nitro-1H-indole (0.5 g) in N,N-dimethylformamide (10 mL) were added cesium carbonate (1.2 g) and 4-fluoro benzoic acid ethyl ester (0.62 g), and this mixture was stirred at 75° C. overnight. This reaction mixture was poured into water and the precipitated solid was collected by filtration, and washed with water and n-hexane, dried under reduced pressure to give the title compound (0.64 g).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][C@@H:9]([NH:12][C:13](=[O:16])[CH2:14][NH2:15])[CH2:8]2)=[CH:4][CH:3]=1.[Br:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[CH3:29])[C:23](O)=[O:24].C(N=C=NC(C)C)(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)(Cl)Cl.C(O)(C)(C)C>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][C@@H:9]([NH:12][C:13](=[O:16])[CH2:14][NH:15][C:23](=[O:24])[C:22]3[CH:26]=[CH:27][C:28]([CH3:29])=[C:20]([Br:19])[CH:21]=3)[CH2:8]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)O)cc1Br
Reactant: NCC(=O)N[C@@H]1CCN(Cc2ccc(Cl)cc2)C1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CC(C)(C)O
Product: Cc1ccc(C(=O)NCC(=O)N[C@@H]2CCN(Cc3ccc(Cl)cc3)C2)cc1Br
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of (R)-1-(4-chlorobenzyl)-3-(glycylamino)pyrrolidine (0.050 mmol) in CHCl3 (1.35 mL) and tert-butanol (0-15 mL) was treated with 3-bromo-4-methylbenzoic acid (0.060 mmol), diisopropylcarbodiimide (0.060 mmol), and HOBt (0.060 mmol). The reaction mixture was stirred at room temperature for 15 h. The mixture was loaded onto Varian™ SCX column, and washed with CH3OH/CHCl3 1:1 (12 mL) and CH3OH (12 mL). Product was eluted off using 2 N NH3 in CH3OH (5 mL) and concentrated to afford (R)-1-(4-chlorobenzyl)-3-[{N-(3-bromo-4-methylbenzoyl)glycyl}amino]pyrrolidine (Compound No. 1098) (11.6 mg, 50%): The purity was determined by RPLC/MS (94%); ESI/MS m/e 466.0 (C21H23BrClN3O2).
Reaction SMILES: [SH:1][C@@H:2]([CH3:13])[C:3]([N:5]1[C@H:9]([C:10]([OH:12])=[O:11])[CH2:8][S:7][CH2:6]1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[C:20]1([CH3:29])[CH:25]=[CH:24][C:23]([C:26](Cl)=[O:27])=[CH:22][CH:21]=1>O>[CH3:29][C:20]1[CH:25]=[CH:24][C:23]([C:26]([S:1][C@@H:2]([CH3:13])[C:3]([N:5]2[C@H:9]([C:10]([OH:12])=[O:11])[CH2:8][S:7][CH2:6]2)=[O:4])=[O:27])=[CH:22][CH:21]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: C[C@H](S)C(=O)N1CSC[C@H]1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1ccc(C(=O)S[C@@H](C)C(=O)N2CSC[C@H]2C(=O)O)cc1
Temperature: 25 °C

Procedure:
2.2 g of (4R)-3-[(2S)-2-mercaptopropanoyl]-4-thiazolidinecarboxylic acid and 2.8 g of potassium carbonate are dissolved in 50 ml of water. To this solution, 1.6 g of p-toluoyl chloride is added dropwise with stirring under ice-cooling. After the addition, the mixture is stirred under ice-cooling for 1 hour and at room temperature for additional 1 hour. The reaction solution is washed with ethyl acetate, and acidified with conc. hydrochloric acid to give crystals. The crystals (the titled compound) are collected by filtration, yield 3.3 g (97%), mp. 166°-166.5° C. (ethyl acetate), [α]D25 -148.6°(c=1.1, methanol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][CH:5]2O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH:6]=[CH:5]2
Reactant: OC1CCOc2ccc(Br)cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1ccc2c(c1)C=CCO2
Temperature: 50 °C
Yield: 133.4 %

Procedure:
To a solution of 6-bromochroman-4-ol (3.98 kg, 17.4 mol) in toluene (18 L) add p-toluenesulfonic acid monohydrate (95 g, 499.42 mmol) at room temperature. Attach a Dean-Stark trap and reflux for 3 hr. and 50 min. Allow the mixture to cool to 50° C. in air and pour into saturated aqueous sodium bicarbonate (10 L) and ice (about 3 kg) with stirring. Separate the two layers. Back extract the aqueous layer with methyl tert-butyl ether (4 L). Wash the organic layer with saturated sodium bicarbonate (10 L) and brine (1×10 L), and evaporate the solvent under reduced pressure to obtain the title compound as a brown oil (4.90 kg, >100%, contains toluene). LCMS m/z (79Br) 209 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[H][H]>[Pd].C(OCC)(=O)C>[CH2:9]([O:8][C:6](=[O:7])[CH:5]([C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:20])[CH3:10]
Reactant: [H][H]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C(=O)OCC)c1ccc(N)cc1
Yield: 90 %

Procedure:
A mixture of crude 2-(4-nitro-phenyl)-malonic acid diethyl ester and 10% palladium on carbon in ethyl acetate (20 ml) was treated with hydrogen gas (40 psi) on a Parr shaker for 2 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 25% ethyl acetate-hexane to provide 2-(4-amino-phenyl)-malonic acid diethyl ester (450 mg, 90% yield for 2 steps).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([I:21])=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.[C:24](=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([I:21])[CH:17]=3)[N:12]([CH3:24])[CH:11]=2)=[O:9])=[CH:22][CH:23]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(I)cc2c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(I)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
N-(4-Chlorobenzyl)-4-hydroxy-6-iodo-3-quinolinecarboxamide (12.07 g) from Preparation No. 4 and potassium carbonate (5.70 g) are disolved in DMF (90 mL). lodomethane (2.1 mL) is added and the mixture is stirred at room temperature for 1 h. The resulting suspension is poured into water (500 mL) and filtered. The crude solid is washed with water (50 mL) and diethyl ether (100 mL) and then is recrystallized from ethanol to afford 10.6 g (85%) of the title compound as a white solid.