Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[C:6]1([CH2:12][O:13][C:14]2[C:15]([NH2:20])=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:21]([CH:24]1[CH2:28][CH2:27][O:26][C:25]1=O)(=O)[CH3:22].[OH-].[NH4+]>CC1C=CC=CC=1>[Cl:3][CH2:27][CH2:28][C:24]1[C:25](=[O:26])[N:16]2[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH2:12][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:15]2=[N:20][C:21]=1[CH3:22]
Reactant: CC(=O)C1CCOC1=O
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1ncccc1OCc1ccccc1
Agent: [NH4+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1nc2c(OCc3ccccc3)cccn2c(=O)c1CCCl
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 62.3 %

Procedure:
To a stirred mixture of 84 parts of phosphoryl chloride and 540 parts of methylbenzene were added 20 parts of 3-(phenylmethoxy)-2-pyridinamine. The mixture was stirred at 50° C. and 22 parts of 3-acetyl-4,5-dihydro-2(3H)-furanone were added. The reaction mixture was stirred for 5 hours at 90° C. Another portion of 22 parts of 3-acetyl-4,5-dihydro-2(3H)-furanone was added and stirring was continued for 30 minutes at 90° C. The solution was allowed to stand overnight at 90° C. The whole was poured into crushed ice and treated with an ammonium hydroxide solution 25%. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was stirred in 2-propanol. The product was filtered off, washed with a mixture of 2-propanol and 1,1′-oxybisethane and dried at 50° C., yielding 20.5 parts (62.3%) of 3-(2-chloroethyl)-2-methyl-9-(phenylmethoxy)-4H-pyrido[1,2-a]pyrimidin-4-one; mp. 141.1° C. (intermediate 1) b) A mixture of 3.3 parts of 3-(2-chloroethyl)-2-methyl-9-(phenylmethoxy)-4H-pyrido[1,2-a]pyrimidin-4-one and 120 parts of methanol was hydrogenated at normal pressure and at room temperature with 2.0 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated to dry, yielding 2.4 parts (99%) of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one as an oily residue. (intermediate 2)
Reaction SMILES: [OH:1][CH2:2]/[CH:3]=[CH:4]\[CH2:5][O:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[N:8]=1.C(N(CC)CC)C.[C:30](Cl)(=[O:39])[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)Cl.C(Cl)(Cl)Cl>[CH2:32]([O:31][C:30]([N:20]1[CH2:21][CH2:22][N:17]([C:9]2[N:8]=[C:7]([O:6][CH2:5]/[CH:4]=[CH:3]\[CH2:2][OH:1])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH2:18][CH2:19]1)=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OC/C=C\COc1nc(N2CCNCC2)nc2ccccc12
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCN(c2nc(OC/C=C\CO)c3ccccc3n2)CC1

Procedure:
To a solution of 4-[cis-(4-hydroxybut-2-en-1-yl)oxy]-2-(1-piperazinyl)quinazoline (1.09 g) in dry methylene chloride (25 ml) is added triethylamine (1.52 ml) with stirring under ice-cooling, and thereto is further added dropwise a solution of benzyl chlorocarbonate (0.62 ml) in dry methylene chloride (5 ml). The mixture is stirred under ice-cooling for 1.5 hour. The reaction mixture is diluted with chloroform, washed with water, and dried over anhydrous magnesium sulfate. The solution is evaporated to dryness under reduced pressure, and the residue is purified by medium pressure liquid column chromatography (eluent, chloroform:methanol=50:1, v/v) to give 2-[4-(benzyloxycarbonyl)piperazin-1-yl]-4-[cis-(4-hydroxybut-2-en-1-yl)oxy]quinazoline (1.52 g) as oil.
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[C@@H:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]2([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:18][CH2:17]2)[CH2:11][C@@H:10]1[NH2:24])=O)(C)(C)C.C(O)C.[ClH:35]>ClCCl>[ClH:35].[CH2:22]([O:21][C:19]([C:16]1([NH:15][CH:12]2[CH2:13][CH2:14][C@@H:9]([NH2:8])[C@@H:10]([NH2:24])[CH2:11]2)[CH2:17][CH2:18]1)=[O:20])[CH3:23]
Reactant: CCOC(=O)C1(NC2CC[C@@H](N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)[C@@H](N)C2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)C1(NC2CC[C@@H](N)[C@@H](N)C2)CC1
Reaction time: 1.5 h

Procedure:
(1R*,2S*)-N,N-Bis(tert-butoxycarbonyl)-4-[(1-ethoxycarbonyl)cyclopropan-1-yl]amino-1,2-cyclohexane-diamine (Stereoisomer A) (1.34 g) was dissolved in dichloromethane (20 ml), a saturated ethanol solution (20 ml) of hydrochloric acid was added, and the mixture was stirred for 90 minutes. The solvent was distilled off under reduced pressure to obtain (1R*,2S*)-4-[(1-ethoxycarbonyl)cyclopropan-1-yl]amino-1,2-cyclohexane-diamine hydrochloride (Stereoisomer A) (1.07 g) as a colorless solid.
Reaction SMILES: C(O[CH:5]([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8])(=O)C.[CH:12]([O:15][CH2:16][CH3:17])=[CH:13][CH3:14].[CH2:18]([OH:20])[CH3:19].C(OCC)(OCC)OCC.B(F)(F)F.CCOCC>CCOCC>[CH2:10]([O:9][CH:5]([O:6][CH2:7][CH3:8])[CH:13]([CH3:14])[CH:12]([O:20][CH2:18][CH3:19])[O:15][CH2:16][CH3:17])[CH3:11]
Reactant: CC=COCC
Reactant: CCOC(OCC)OC(C)=O
Reactant: CCO
Agent: FB(F)F
Solvent: CCOCC
Solvent: CCOC(OCC)OCC
Product: CCOC(OCC)C(C)C(OCC)OCC
Temperature: 5 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
A solution of one equivalent of diethoxymethyl acetate and one equivalent of a ethyl propenyl ether/ethanol mixture is stirred at ambient temperature for 30 min. followed by the addition of 1.3 equivalents of triethyl orthoformate. After cooling to 5° C. 1.5 ml. of boron trifluoride etherate is added and the resulting exotherm (5° to 37° C.) is controlled with an ice bath. After stirring at ambient temperature overnight the yellow reaction solution is diluted with ether and washed with water, saturated aqueous sodium bicarbonate and again with water. Drying (MgSO4) followed by solvent removal afforded a 92% yield of oil which is shown by glc to be ~80% pure product, δ(TMS, CDCl3) 4.44 (d, 2H, CH--O); 3.3-4.0 (complex, 8H, ethyl methylene), ~2.1 (m, 1H, CH3 --CH), 1.1 (t, 12H, ethyl methyls), and 1.0 (d, 3H, CH3 --CH).
Reaction SMILES: [Br:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[CH:8]=2)[C:3]1=[O:17].[C:18]([NH2:26])(=[S:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[BrH:1].[C:19]1([C:18]2[S:25][CH:2]3[CH2:10][C:9]4[CH:8]=[C:7]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[CH:6]=[CH:5][C:4]=4[C:3]3([OH:17])[N:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NC(=S)c1ccccc1
Reactant: O=C1c2ccc(OCC(F)(F)F)cc2CC1Br
Product: Br
Product: OC12N=C(c3ccccc3)SC1Cc1cc(OCC(F)(F)F)ccc12

Procedure:
This compound is prepared analogously to the process described in Example 1c using 2-bromo-5-(2,2,2-trifluoroethoxy)indan-1-one and thiobenzamide; melting point: 240-246° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([CH3:10])[CH:3]=1.C[C:12]1([CH3:20])[O:19][C:17](=[O:18])[CH2:16]C(=O)O1.N1CCCC1C(O)=O.[CH3:29][S:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]2[C:40]=1[NH:39][CH:38]=[CH:37]2>C(#N)C.[Cu].C(O)C.N1C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([C:37]2[C:36]3[C:40](=[C:32]([CH2:31][S:30][CH3:29])[CH:33]=[CH:34][CH:35]=3)[NH:39][CH:38]=2)[CH2:16][C:17]([O:19][CH2:12][CH3:20])=[O:18])=[C:4]([CH3:10])[CH:3]=1
Reactant: CSCc1cccc2cc[nH]c12
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: Cc1cc(Cl)ccc1C=O
Agent: [Cu]
Agent: O=C(O)C1CCCN1
Solvent: CCO
Solvent: CC#N
Solvent: c1ccncc1
Product: CCOC(=O)CC(c1ccc(Cl)cc1C)c1c[nH]c2c(CSC)cccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.44 g (9.31 mmol) of 4-chloro-2-methylbenzaldehyde, 1.34 g (9.31 mmol) of Meldrum's acid and 48.7 mg (0.42 mmol) of D,L-proline were added to a solution of 1.50 g (8.46 mmol) of the compound from Example 8A in 70 ml of acetonitrile. The reaction mixture was stirred at RT overnight. It was concentrated, and the residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. 3.43 g of a crude product were obtained and were introduced into 53 ml of pyridine and 14 ml of ethanol, and 4.8 mg (75 μmol) of copper powder were added. The reaction mixture was heated under reflux for 1 h. It was concentrated, and the residue was taken up in ethyl acetate, washed with 1N hydrochloric acid, dried over magnesium sulfate, filtered through silica gel and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 1.68 g (49% of theory) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2Cl.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: Clc1ccnc2ccc(Br)cc12
Reactant: C1COCCN1
Solvent: O
Product: Brc1ccc2nccc(N3CCOCC3)c2c1
Temperature: 150 °C
Reaction time: 48 h
Yield: 87.8 %

Procedure:
A mixture of 6-bromo-4-chloro-quinoline (1.0 g, 4.12 mmol) and morpholine (9.98 g, 114.6 mmol) was heated to 150° C. in a sealed tube and stirred for 2 days. Then, the brown suspension was diluted with water and extracted with ethyl acetate (3×50 mL). The combined extracts were washed with brine solution and dried over anhydrous magnesium sulfate. After filtration of the drying agent, the filtrate was removed under the vacuum and the residue was purified by using a Biotage silica gel column chromatography to afford 1.06 g (87.7% yield) of 6-bromo-4-morpholin-4-yl-quinoline as a light brown solid: EI-LRMS m/e calcd for C13H13BrN2O (M+) 293.1, found 293.1.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[N:27]1([C:32]2[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=2)[CH:31]=[CH:30][CH:29]=[CH:28]1>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:36](=[O:37])[C:35]5[CH:39]=[CH:40][C:32]([N:27]6[CH:31]=[CH:30][CH:29]=[CH:28]6)=[CH:33][CH:34]=5)[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: O=C(O)c1ccc(-n2cccc2)cc1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1)c1ccc(-n2cccc2)cc1

Procedure:
The title compound, light brown solid (90 mg, 73%), MS (ISP) m/z=498.4 [(M+H)+], mp 228° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and 4-pyrrol-1-yl-benzoic acid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.Cl.[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]2[CH2:43][N:42]3[CH:44]=[C:45]([C:47]([OH:49])=O)[N:46]=[C:41]3[CH2:40][CH2:39]2)=[CH:34][C:33]=1[CH3:50].[CH2:51]([CH:58]1[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]1)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>CN(C=O)C>[CH2:51]([CH:58]1[CH2:63][CH2:62][N:61]([C:47]([C:45]2[N:46]=[C:41]3[CH2:40][CH2:39][CH:38]([C:35]4[CH:36]=[CH:37][C:32]([F:31])=[C:33]([CH3:50])[CH:34]=4)[CH2:43][N:42]3[CH:44]=2)=[O:49])[CH2:60][CH2:59]1)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: Cc1cc(C2CCc3nc(C(=O)O)cn3C2)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1cc(C2CCc3nc(C(=O)N4CCC(Cc5ccccc5)CC4)cn3C2)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
TBTU (295 mg; 0.92 mmol) and N-methylmorpholine (253 μl; 232 mg; 2.3 mmol) were added to a solution of 6-(4-fluoro-3-methylphenyl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridine-2-carboxylic acid hydrochloride (210 mg; 0.68 mmol) in DMF (1 ml). The reaction mixture was stirred vigorously for 30 min at room temperature and then 4-benzylpiperidine (162 μl; 161 mg; 0.9 mmol) was added. The reaction mixture was stirred for 4 h at room temperature and then poured onto water. The precipitated solid was filtered out and washed with petroleum ether. Yield: 205 mg (72%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].S(Cl)([Cl:14])=O>CCCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([Cl:14])=[O:8]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: O=S(Cl)Cl
Solvent: CCCCCCC
Product: O=C(Cl)c1cc(Cl)ccc1O
Temperature: 60 °C
Yield: 99.3 %

Procedure:
A solution of 5-chloro-2-hydroxy-benzoic acid (20.0 g, 116 mmol) in heptane (232 mL, 0.5 M) was treated with thionyl chloride (25.4 mL, 348 mmol) and heated to 60° C. for 6 h. After cooling to room temperature, the solution was concentrated under reduced pressure to give 5-chloro-2-hydroxy-benzoyl chloride as a thick yellow oil (22 g) which was used without further purification.
Reaction SMILES: P(OP(O)(O)=O)(O)(O)=O.[CH3:10][C:11]([C:13]1[C:18]([NH2:19])=[CH:17][C:16]2[O:20][CH2:21][O:22][C:15]=2[CH:14]=1)=[O:12].[O:23]1[CH:27]=[C:26]([C:28](Cl)=[O:29])[C:25]2[CH:31]=[CH:32][CH:33]=[CH:34][C:24]1=2>>[C:11]([C:13]1[C:18]([NH:19][C:28]([C:26]2[C:25]3[CH:31]=[CH:32][CH:33]=[CH:34][C:24]=3[O:23][CH:27]=2)=[O:29])=[CH:17][C:16]2[O:20][CH2:21][O:22][C:15]=2[CH:14]=1)(=[O:12])[CH3:10]
Reactant: CC(=O)c1cc2c(cc1N)OCO2
Reactant: O=C(Cl)c1coc2ccccc12
Agent: O=P(O)(O)OP(=O)(O)O
Product: CC(=O)c1cc2c(cc1NC(=O)c1coc3ccccc13)OCO2

Procedure:
The synthetic procedure of target compounds 158 is illustrated in Scheme 12. The starting 2-amino-4,5-methylenedioxy acetophenone (148) was first reacted with benzo[b]furan-3-carbonyl chloride (154) to give N-(6-Acetyl-1,3-benzodioxol-5-yl)-1-benzofuran-3-carboxamide (155). Then, the intermediates (155) was subjected to cyclization in dioxane, in the presence of NaOH, to afford 2-(3-Benzo[b]furyl)-6,7-methylenedioxyquinolin-4-one (156). Compound 156 was first reacted with tetrabenzylpyrophosphate in THF, in the presence of NaH, to yield dibenzyl 2-(3-benzo[b]furyl)-6,7-methylenedioxyquinolin-4-yl phosphate (157). Compound 157 was then subjected to catalytic hydrogenation in MeOH to give its diphosphoric acid (158).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5][NH2:6].Cl[CH2:12][C:13]([O:15][CH3:16])=[O:14].C(N(CC)CC)C>CN(C)C=O.CCOCC>[CH3:16][O:15][C:13](=[O:14])[CH2:12][NH:6][CH2:5][C:4]1[CH:3]=[C:2]([F:1])[CH:9]=[C:8]([F:10])[CH:7]=1
Reactant: COC(=O)CCl
Reactant: NCc1cc(F)cc(F)c1
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CNCc1cc(F)cc(F)c1
Yield: 41 %

Procedure:
A solution of 3,5-difluorobenzylamine (12.3 g, 0.0863 mole), methyl chloroacetate (7.6 ml, 0.0863 mole) and triethylamine (12.0 ml, 0.0863 mole) in dry dimethylformamide (85 ml) was heated at 60° C. for 3 hours. The mixture was diluted with an equal volume of ether and the triethylamine hydrochloride filtered. The filtrate was concentrated under vacuum and the resultant oil triturated with ethyl acetate and the solution decanted from a small amount of residual oil. The solvent was removed and the product was purified by flash chromatography (silica) by eluting with hexane-ethyl acetate (70:30) to give an oil (7.61 g, 41%).
Reaction SMILES: Cl.[C:2]([CH:5]1[CH2:10][CH:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][CH2:7][NH:6]1)(=[O:4])[NH2:3].CCN(C(C)C)C(C)C.[C:25](Cl)(=[O:34])[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl>[C:2]([CH:5]1[CH2:10][CH:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][CH2:7][N:6]1[C:25]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:34])(=[O:4])[NH2:3]
Reactant: CCOC(=O)C1CCNC(C(N)=O)C1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCN(C(=O)OCc2ccccc2)C(C(N)=O)C1
Reaction time: 1 h
Yield: 75.7 %

Procedure:
Ethyl 2-carbamoylpiperidine-4-carboxylate hydrochloride (2 g, 7.86 mmol) was slurried in dichloromethane (25 mL) and DIPEA (3.43 mL, 19.65 mmol) was added followed by benzyl carbonochloridate (1.161 mL, 8.25 mmol) dropwise. The reaction was stirred for 1 h then washed with 25 mL of 2 M HCl and water, dried over Na2SO4 and evaporated. The crude product was purified on a 100 g Biotage column with heptane/EtOAc over 4 CV followed by 100% EtOAc over 10 CV. 1-Benzyl 4-ethyl 2-carbamoylpiperidine-1,4-dicarboxylate (1.99 g, 76%) was isolated. 1H NMR (400 MHz, dmso) δ 1.16 (t, 3H), 1.57-1.69 (m, 1H), 1.81-1.92 (m, 1H), 1.95-2.07 (m, 1H), 2.21-2.32 (m, 1H), 2.58-2.67 (m, 1H), 3.29-3.45 (m, 1H), 3.69-3.77 (m, 1H), 3.92-4.06 (m, 2H), 4.34 (t, 1H), 4.99-5.08 (m, 2H), 6.95 (s, 1H), 7.25-7.38 (m, 6H). MS m/z 335 (M+H)+
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7]([CH3:24])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[NH:20][N:19]=[C:18]([C:21](O)=[O:22])[CH:17]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.Cl.[Cl:35][CH2:36][CH2:37][NH2:38].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>CN(C=O)C.C(Cl)Cl>[C:1]([NH:5][C:6]1[C:7]([CH3:24])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[NH:20][N:19]=[C:18]([C:21]([NH:38][CH2:37][CH2:36][Cl:35])=[O:22])[CH:17]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1nc2cccc(-c3cc(C(=O)O)n[nH]3)c2nc1NC(C)(C)C
Reactant: NCCCl
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cccc(-c3cc(C(=O)NCCCl)n[nH]3)c2nc1NC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a 50-mL round-bottomed flask was added 5-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrazole-3-carboxylic acid (467b) (69 mg, 0.21 mmol), DCM (4 mL), DMF (1 mL), DIPEA (0.15 mL, 0.85 mmol), 2-chloroethanamine hydrochloride (49 mg, 0.42 mmol) (Sigma-Aldrich), and (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (110 mg, 0.21 mmol) (Sigma-Aldrich). The reaction mixture was stirred at RT for 16 h and the solvent was completely remover under vacuum. 5-(3-(tert-Butylamino)-2-methylquinoxalin-5-yl)-N-(2-chloroethyl)-1H-pyrazole-3-carboxamide (471a) was taken to next step without purification. m/z (ESI, +ve) 387.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[N:7]([C@H:11]1[CH2:19][CH2:18][CH2:17][C@H:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C@@H:15]([OH:29])[C@H:14]([CH3:30])[O:13][C:12]1=[O:31])[CH2:8][O:9][CH3:10])([CH3:4])([CH3:3])[CH3:2].C(=O)(OC(C)(C)C)O[CH2:35][CH:36]=[CH2:37]>C1COCC1.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.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.[Pd]>[C:1]([O:5][C:6](=[O:32])[N:7]([C@H:11]1[CH2:19][CH2:18][CH2:17][C@H:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C@@H:15]([O:29][CH2:37][CH:36]=[CH2:35])[C@H:14]([CH3:30])[O:13][C:12]1=[O:31])[CH2:8][O:9][CH3:10])([CH3:2])([CH3:4])[CH3:3]
Reactant: C=CCOC(=O)OC(C)(C)C
Reactant: COCN(C(=O)OC(C)(C)C)[C@H]1CCC[C@H](Cc2ccc(OC)cc2)[C@@H](O)[C@H](C)OC1=O
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CCO[C@@H]1[C@@H](Cc2ccc(OC)cc2)CCC[C@H](N(COC)C(=O)OC(C)(C)C)C(=O)O[C@H]1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.5 %

Procedure:
A solution of tert-butyl((3S,7R,8R,9S)-8-hydroxy-7-(4-methoxybenzyl)-9-methyl-2-oxooxonan-3-yl)(methoxymethyl)carbamate (350 mg, 0.775 mmol), palladium tetrakis(triphenylphosphine) (90 mg, 0.078 mmol), and allyl tert-butyl carbonate (758 mg, 4.79 mmol) in degassed THF (3876 μl) was heated to 60° C. and stirred for 4 h. The reaction mixture was cooled to room temperature and purified directly by column chromatography on SiO2 (EtOAc/Hex gradient) to afford the title product as a light yellow oil (200 mg, 52.5%): IR (neat) 2977, 2934, 2836, 1746, 1702, 1511, 1367, 1297, 1246, 1175 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.07 (d, J=8.5 Hz, 2H), 6.81 (d, J=8.6 Hz, 2H), 6.02-5.88 (m, 1H), 5.33 (dd, J=17.2, 1.6 Hz, 1H), 5.20 (dd, J=10.4, 1.5 Hz, 1H), 4.94-4.81 (m, 2H), 4.76 (t, J=10.3 Hz, 1H), 4.60-4.50 (m, 1H), 4.28 (dd, J=11.8, 5.6 Hz, 1H), 4.22-4.15 (m, 1H), 4.09 (dd, J=11.9, 5.3 Hz, 1H), 3.78 (s, 3H), 3.30 (d, J=14.5 Hz, 3H), 3.21 (t, J=9.0 Hz, 1H), 3.03 (dd, J=13.5, 3.4 Hz, 1H), 2.34-2.22 (m, 1H), 2.15-1.98 (m, 1H), 1.80 (s, 1H), 1.65-1.59 (m, 2H), 1.50-1.39 (m, 13H), 0.90-0.76 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 173.53, 157.82, 134.40, 134.36, 132.63, 129.69, 117.12, 113.73, 84.28, 84.24, 81.09, 74.62, 58.57, 57.06, 55.24, 55.22, 46.01, 35.97, 28.32, 28.23, 26.57, 19.22, 18.26; HRMS-ESI (m/z) ([M]+) calcd for C27H41NO7, 491.2883; found, 491.2862.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][C:11]1[CH:23]=[CH:22][C:14]([CH2:15][NH:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1>CCCCCC>[CH3:10][C:11]1[CH:23]=[CH:22][C:14]([CH2:15][N:16]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[S:9])=[CH:13][CH:12]=1
Reactant: Cc1ccc(CNC2CCCC2)cc1
Reactant: S=C=Nc1ccccc1
Solvent: CCCCCC
Product: Cc1ccc(CN(C(=S)Nc2ccccc2)C2CCCC2)cc1
Yield: 92.1 %

Procedure:
A solution of 14 g of phenyl isothiocyanate in 50 ml of hexane was added dropwise to 19 g of N-4-methylbenzyl-N-cyclopentyl amine in 400 ml of hexane while cooling and stirring. After the addition, the temperature of the reaction mixture was gradually raised, and the solution was stirred at 40° C. for about 5 hours. The mixture was cooled and filtered. The residue was recrystallized from a mixture of hexane and ethyl alcohol. 30 g of N-4-methylbenzyl-N-cyclopentyl-N'-phenylthiourea were obtained. Melting point: 109°-111° C.
Reaction SMILES: C(OC(=O)C)(=O)C.[N+:8]([O-:11])(O)=[O:9].[CH3:12][O:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[CH3:24])[C:15]=1[C:25]([F:28])([F:27])[F:26]>O>[CH3:12][O:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([N+:8]([O-:11])=[O:9])[C:20]=2[CH3:24])[C:15]=1[C:25]([F:26])([F:28])[F:27]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc2c(C)cccc2c1C(F)(F)F
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COc1ccc2c(C)c([N+](=O)[O-])ccc2c1C(F)(F)F
Temperature: 5 °C
Yield: 41 %

Procedure:
To a cooled solution (3° to 4° C.) of acetic anhydride (640 mL) was added fuming nitric acid (90%, specific gravity=1.5, 160 mL) dropwise via an addition funnel at such a rate as to keep the internal temperature at or below 8° C. (~1 hour 20 minutes total addition time). After the internal temperature had again cooled to 3°-4° C., 2-methoxy-5-methyl-1-trifluoromethylnaphthalene (200 g, 0.833 mol) was added portion wise. The portions added were small enough such that the internal temperature did not rise above 10° C. and each portion was added when the temperature had cooled to 5° C. (addition time ~1 hour 15 minutes). After an additional 15 minutes the reaction mixture was added to water (3 L). The resulting amorphous solid was filtered, washed with water and the lumps broken up and dried in vacuo overnight. The dry solid (~225 g) was recrystallized from 95:5 ethanol:isopropanol (3 L). The resulting long yellow needles were filtered and washed with ethanol (2×50 mL) to provide the product (97.5 g, 41%), m.p. 141°-142° C. A small amount of the desired product was recrystallized from 4:1 petroleum ether:ethyl acetate.