Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:6][N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=2)[N:9]([CH:19]2[CH2:24][CH2:23][S:22][CH2:21][CH2:20]2)[C:8]1=[O:25].Br[CH2:32][C:33]#[N:34].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:6][N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH2:32][C:33]#[N:34])[CH:14]=2)[N:9]([CH:19]2[CH2:20][CH2:21][S:22][CH2:23][CH2:24]2)[C:8]1=[O:25]
Reactant: COc1ccc(Cn2c(=O)c3cc(O)ccc3n(C3CCSCC3)c2=O)cc1OC
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)c3cc(OCC#N)ccc3n(C3CCSCC3)c2=O)cc1OC
Yield: 0.1 %

Procedure:
A mixture of 0.16 g of the compound obtained in Step 3.3, 0.054 g of bromoacetonitrile and 0.243 g of Cs2CO3 in 1 ml of DMF is irradiated in a microwave field for 15 minutes at 100° C. The reaction mixture is evaporated under reduced pressure. The residue is taken up in DCM, washed with water, dried over Na2SO4 and filtered, and the filtrate is evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with an EtOAc/DCM mixture from (10/90, v/v) to (20/80, v/v) to give 0.138 mg of the expected product.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:17]([NH:19][CH:20]1[CH2:29][C:28]2[C:23]3=[C:24]([NH:30][C:31](=[O:32])[N:22]3[CH2:21]1)[CH:25]=[CH:26][CH:27]=2)=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)(C)(C)C>Cl>[O:32]=[C:31]1[N:22]2[C:23]3[C:28]([CH2:29][CH:20]([NH:19][C:17](=[O:18])[C@H:9]([CH2:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH2:8])[CH2:21]2)=[CH:27][CH:26]=[CH:25][C:24]=3[NH:30]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)NC1Cc2cccc3[nH]c(=O)n(c23)C1
Agent: Cl
Product: N[C@@H](Cc1ccccc1)C(=O)NC1Cc2cccc3[nH]c(=O)n(c23)C1
Yield: 100.9 %

Procedure:
(-) t-Butoxycarbonyl N-(1,2,5,6-tetrahydro-2-oxo-4H-imidazo(4,5,1-ij)quinolin-5-yl)-L-phenylalaninamide (1.8 g) was stirred in ethanolic hydrogen chloride (50 mL of 4.0 N) for 1 hour. The solvent was removed and the residual oil was partitioned between chloroform and sodium hydroxide solution. Evaporation of the chloroform gave 1.4 g of (-) N-(1,2,5,6-tetrahydro-2-oxo-4H-imidazo(4,5,1-ij)quinolin-5-yl)phenylalaninamide. This was dissolved in acetonitrile:THF (30 mL of 1:1) and phenyl isothiocycanate (675 mg, 5 mmol) was added. After 1 hour, the solvents were removed and the residual oil was chromatographed on silica gel using chloroform as the initial eluant. Elution of the column with 5% methanol:chloroform gave 1.8 g of (-) N-((phenylamino)thiocarbonyl)-N-(1,2,5,6-tetrahydro-2-oxo-4H-imidazo(4,5,1-ij)quinolin-5-yl)phenylalaninamide. This was dissolved in trifluoroacetic acid (25 mL). After 1 hour the solvent was removed and the residue was dissolved in methanol (5 mL). Ether (50 mL) was added, the solution was cooled to - 10° C., and the precipitate was filtered off, washed with ether, and air dried to give 1.2 g of (-) 5-amino-5,6-dihydro-4H-imidazo(4,5,1-ij)quinolin-2(1H)-one trifluoroacetate, mp 247° C. (dec). (α)DMeOH -18°. Anal. Calcd. for C10H11N3O.C2HF3O2 : C, 47.53; H, 3.99; F, 18.80; N, 13.97. Found: C, 47.31; H, 4.26; F, 17.37; N, 13.48.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[C:21](=[O:25])[NH:20][CH:19]=[CH:18]3)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[C:21](=[O:25])[NH:20][CH:19]=[CH:18]3)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](Oc2ccc3c(=O)[nH]ccc3c2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]ccc2cc(O[C@H]3CCCNC3)ccc12
Yield: 51.2 %

Procedure:
(S)-3-(Oxo-1,2-dihydroisoquinolin-6-yloxy)piperidine-1-carboxylic acid tert-butyl ester (1.25 g, 3.6 mmol) was mixed with dichloromethane (30 ml) and trifluoroacetic acid (10 ml) at ambient temperature for 15 minutes. Volatiles were removed under reduced pressure and excess trifluoroacetic acid was azeotroped with toluene. The residue was dissolved in methanol and purified using an SCX cartridge. Concentration gave (S)-6-(piperidin-3-yloxy)-2H-isoquinolin-1-one (450 mg, 51%), El-MS: m/z=245.4 [M+H]+.
Reaction SMILES: C([S:4][CH2:5][CH2:6][CH:7]1[CH2:11][C:10]2[C:12]([CH3:19])=[C:13]([OH:18])[C:14]([CH3:17])=[C:15]([CH3:16])[C:9]=2[O:8]1)(=O)C.N>CC(C)=O>[SH:4][CH2:5][CH2:6][CH:7]1[CH2:11][C:10]2[C:12]([CH3:19])=[C:13]([OH:18])[C:14]([CH3:17])=[C:15]([CH3:16])[C:9]=2[O:8]1
Reactant: CC(=O)SCCC1Cc2c(C)c(O)c(C)c(C)c2O1
Agent: N
Solvent: CC(C)=O
Product: Cc1c(C)c2c(c(C)c1O)CC(CCS)O2
Reaction time: 16 h
Yield: 99.2 %

Procedure:
A solution of 5.1 g of 2-(RS)-(2-acetylthioethyl)-2,3-dihydro-5-hydroxy-4,6,7-trimethylbenzofurane in 90 ml of acetone is treated with 20 ml of a 25% NH3 solution under nitrogen and stirred for 16 hours. After acidification, the mixture is extracted with ethyl acetate, and the extracts are dried and evaporated. The obtained 4.3 g of a white solid is obtained that can be crystallized with benzene. m.p. 163°-165° C.; IR (KBr): 3351 (νOH), 1237 cm-1 (νAr--O--CH); 1H-NMR (DMSO-d6): δ5.1-4.4 (1H,m), 3.5 (1H, sb), 3.2-2.6 (4H,m), 2.1 (2H,m), 2.0 (6H,s), 1.95 (3H,s), 1.2 (1H,m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([C:16]([OH:18])=O)=[CH:12][N:11]3[CH:19]=2)=[CH:4][CH:3]=1.[C:20]([NH2:24])([CH3:23])([CH3:22])[CH3:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[C:20]([NH:24][C:16]([C:13]1[CH:14]=[CH:15][C:10]2[N:11]([CH:19]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:9]=2)[CH:12]=1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)N
Reactant: O=C(O)c1ccc2nc(-c3ccc(F)cc3)cn2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1ccc2nc(-c3ccc(F)cc3)cn2c1
Yield: 100.9 %

Procedure:
2-(4-Fluoro-phenyl)-imidazo[1,2-a]pyridine-6-carboxylic acid (example 45; 40 mg, 0.14 mmol), tert-butylamine (73.1 mg, 0.0.27 mmol), HATU (O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate; 57.2 mg, 0.15 mmol) and triethylamine (56.8 μl, 0.41 mmol) in 3 ml DMF were stirred at room temperature for 2 hours. The mixture was evaporated. ethyl acetate and water were added, the organic layer was separated, washed with water, dried and evaporated. The crude product was purified by preparative HPLC (RP18, acetonitrile/water 0.1% TFA) to yield 44 mg (99%) of the desired product. MS: M+H+=312.15.
Reaction SMILES: [NH2:1][C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:3]=1[CH:4]=O.[N+:12]([CH2:15][C:16](OCC)=[O:17])([O-:14])=[O:13].N1CCCCC1>C(O)C>[N+:12]([C:15]1[C:16](=[O:17])[NH:1][C:2]2[C:3]([CH:4]=1)=[C:6]([CH3:11])[CH:7]=[C:8]([CH3:10])[N:9]=2)([O-:14])=[O:13]
Reactant: CCOC(=O)C[N+](=O)[O-]
Reactant: Cc1cc(C)c(C=O)c(N)n1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C)c2cc([N+](=O)[O-])c(=O)[nH]c2n1

Procedure:
A mixture of 2-amino-4,6-dimethylnicotinaldehyde (2.40 g., 16 mmole), ethyl nitroacetate (5.12 g., 32 mmole), piperidine (336 mg., 4 mmole) and ethanol (4 ml.) is heated under reflux with stirring for an hour. The mixture then is cooled, treated with petroleum ether, the solid removed by filtration and recrystallized from methanol yielding 1.55 g. (44%) of product, m.p. 270°-272° C. (dec.). Following recrystallization from the same solvent the product melts at 272°- 274° C. (dec.).
Reaction SMILES: C[O-].[Na+].[C:4]([O:8][CH3:9])(=[O:7])[CH2:5][SH:6].Cl[C:11]([CH:15]([CH3:17])[CH3:16])=[CH:12][C:13]#[N:14]>CO>[NH2:14][C:13]1[CH:12]=[C:11]([CH:15]([CH3:17])[CH3:16])[S:6][C:5]=1[C:4]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)CS
Reactant: CC(C)C(Cl)=CC#N
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1sc(C(C)C)cc1N
Temperature: 20 °C
Reaction time: 0.08 h
Yield: 16 %

Procedure:
To a solution of NaOMe (14 g) in MeOH (1 L) was added methyl thioglycolate (22.3 mL). The mixture was stirred for 5 min, then a solution of 3-chloro-4-methyl-2-pentenenitrile (32.4 g) in MeOH (200 mL) was added and the solution was heated at the reflux temp. for 90 min. After cooling to 20° C., the mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc, washed with a 1N HCl solution, dried (MgSO4), and concentrated under reduced pressure. The residue was purified by flash chromatography (EtOAc/hexane) to yield methyl 3-amino-5-isopropylthiophene-2-carboxylate (8.0 g, 16%).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[C:12](=[O:13])[NH:11][C:10](=[O:14])[CH2:9][NH:8]2)=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20](Cl)=[O:21])[CH3:18]>>[CH2:17]([O:19][C:20]([N:8]1[CH2:9][C:10](=[O:14])[NH:11][C:12](=[O:13])[N:7]1[CH2:6][C:5]1[CH:15]=[CH:16][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:21])[CH3:18]
Reactant: CCOC(=O)Cl
Reactant: O=C1CNN(Cc2ccc(Cl)cc2)C(=O)N1
Product: CCOC(=O)N1CC(=O)NC(=O)N1Cc1ccc(Cl)cc1
Yield: 50 %

Procedure:
Into a 50 ml round bottomed flask equipped with an efficient condenser sealed with a calcium chloride tube were placed 10 ml of ethylchloroformate and 1 g of 2-(4'-chlorobenzyl)-hexahydro-1,2,4-triazine-3,5-dione. The mixture was refluxed for 3 hours, the solvent was removed in vacuum and ice water was added cautiously to the residue. The solution was adjusted to a neutral pH with a saturated solution of sodium bicarbonate. The crystals thus formed were filtered off by suction and recrystallized from isopropanol to yield 0.8 g (50%) of 1-ethoxycarbonyl-2-(4'-chlorobenzyl)-hexahydro-1,2,4-triazine-3,5-dione; m.p. 135°.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)[C:10]([C:28](=[O:34])[C:29]([O:31]CC)=[O:30])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C1COCC1.O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:25])[F:26])=[CH:19][CH:18]=2)[C:10]([C:28](=[O:34])[C:29]([OH:31])=[O:30])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)c1cn(Cc2ccccc2)c2c(-c3ccc(OC(F)(F)F)cc3)cccc12
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(=O)c1cn(Cc2ccccc2)c2c(-c3ccc(OC(F)(F)F)cc3)cccc12

Procedure:
{1-Benzyl-7-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetic acid was prepared from ethyl {1-benzyl-7-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetate (0.318 g, 0.680 mmol), and potassium hydroxide (0.123 g, 2.19 mmol) in THF (3 mL) and water (3 mL) according to the procedure described in Step 4 of Example 5. Purification by crystallization from isopropanol and drying for 12 hours at 80° C. yielded the title compound as a white solid. (0.171 g, 57%), mp: 177-178° C. Mass spectrum (−ESI, [M−H]−) m/z 438; 1HNMR (500 MHz, DMSO-d6): δ 13.8-14.2 (br s, 1H), 8.65 (s, 1H), 8.35 (dd, 1H, J=7.9 Hz and 1.1 Hz), 7.35 (t, 1H, J=7.6 Hz), 7.2-7.25 (m, 4H), 7.1 (t, 1H, J=7.3 Hz), 7.0-7.05 (m, 3H), 6.25 (d, 2H, J=7.3 Hz), and 5.6 ppm (s, 2H). Elemental Analysis for C24H16F3NO4: Calculated: C, 65.61; H, 3.67; N, 3.19. Found: C, 65.48; H, 3.44; N, 3.16.
Reaction SMILES: [BH4-].[Na+].[OH-].[CH3:4][N+:5]1[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[N:7][C:6]=1[NH:15][CH2:16][C:17]1[CH:26]=[CH:25][C:22]([O:23][CH3:24])=[C:19]([O:20][CH3:21])[CH:18]=1>C(O)C>[CH3:4][N:5]1[CH2:10][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][N:7]=[C:6]1[NH:15][CH2:16][C:17]1[CH:26]=[CH:25][C:22]([O:23][CH3:24])=[C:19]([O:20][CH3:21])[CH:18]=1
Reactant: COC(=O)c1cnc(NCc2ccc(OC)c(OC)c2)[n+](C)c1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)C1=CN=C(NCc2ccc(OC)c(OC)c2)N(C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 122.6 %

Procedure:
0.170 g (3 eq) of sodium borohydride is added to 0.400 g of 1-methyl-2-veratrylamino-5-methoxycarbonylpyrimidinium hydroxide dissolved in 50 ml of ethanol. The mixture is stirred under argon at room temperature for three hours. After evaporation of the ethanol, the medium is extracted with dichloromethane and water. The organic phases are washed with a saturated sodium chloride solution and then dried over sodium sulfate. The oil resulting from evaporation of the organic phases, purified on silica gel under medium pressure (eluent: 15% MeOH/CH2Cl2) gives 467 mg (yield: 98%) of the corresponding 1,6-dihydropyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3](=[NH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11]([N:13]=[C:14]=[O:15])[CH3:12]>>[CH2:11]([NH:13][C:14]([N:10]=[C:3]([O:2][CH3:1])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:15])[CH3:12]
Reactant: COC(=N)c1ccccc1
Reactant: CCN=C=O
Product: CCNC(=O)N=C(OC)c1ccccc1
Temperature: 50 °C
Reaction time: 24 h
Yield: 95.1 %

Procedure:
A neat mixture of benzimidic acid methyl ester (750 mg, 5.56 mmol) and ethyl isocyanate (808 mg, 11.3 mmol) was stirred at 50° C. for 24 h. Excess isocyanate was removed under vacuum to provide the desired product as a colorless viscous oil (1.09 g, 95%). This material was used without further purification. 1H NMR (400 MHz, CDCl3) δ 1.07 (t, J=7.3 Hz, 3H), 3.25 (q, J=7.3 Hz, 2H), 3.87 (s, 3H), 4.97 (br s, 1), 7.26–7.40 (m, 2H), 7.45 (d, J=7.4 Hz, 1H), 7.69–7.71 (m, 2H). MS, m/z 207=M+1.
Reaction SMILES: [N:1]1([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH:17]3[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]3)[N:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[N:1]1([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH:17]3[CH2:22][CH2:21][CH2:20][N:19]([S:24]([CH3:23])(=[O:26])=[O:25])[CH2:18]3)[N:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: c1ccc2c(c1)nnn2-c1ccnc(NC2CCCNC2)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)N1CCCC(Nc2nccc(-n3nnc4ccccc43)n2)C1
Temperature: 25 °C

Procedure:
To DCM (8 mL) was added (4-benzotriazol-1-yl-pyrimidin-2-yl)-piperidin-3-ylamine (0.15 g), methanesulfonyl chloride (35 μL) and TEA (0.285 mL), and the mixture stirred at RT. The product was purified by column chromatography on silica, using 100% DCM to 15% MeOH/DCM, then recrystallized from EtOAc to provide (4-benzotriazol-1-yl-pyrimidin-2-yl)-(1-methanesulfonyl-piperidin-3-yl)-amine. Mp=196.0-197.0° C., 1H nmr (300 MHz, DMSO-d6): δ ppm 1.40-1.76 (m, 2H), 1.78-2.14 (m, 2H), 2.72-2.86 (m, 2H), 2.89 (s, 3H), 3.49 (m, 1H), 3.78 (m, 1H), 4.02 (m, 1H), 7.41 (d, J=5.27 Hz, 1H), 7.58 (t, J=7.35 Hz, 1H), 7.73 (m, 1H), 8.22 (d, J=8.29 Hz, 1H), 8.55 (d, J=5.27 Hz, 1H), 8.88 (d, 1H).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][C:12]([C:16]([OH:18])=[O:17])=[CH:11][C:10]=3[N+:19]([O-:21])=[O:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[OH-].[Na+].[CH2:29](O)[CH3:30]>>[CH2:29]([O:17][C:16]([C:12]1[CH:13]=[C:14]2[C:9](=[C:10]([N+:19]([O-:21])=[O:20])[CH:11]=1)[NH:8][C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[CH:15]2)=[O:18])[CH3:30]
Reactant: CCO
Reactant: O=C(O)c1cc([N+](=O)[O-])c2[nH]c(-c3ccccc3)cc2c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)c1cc([N+](=O)[O-])c2[nH]c(-c3ccccc3)cc2c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
2-Phenyl-7-nitro-1H-indole-5-carboxylic acid (14.1 g, 50 mmol) prepared in Preparation 30 was dissolved in ethanol (40 mL). Conc. sulfuric acid (10 mL) was added thereto, and the mixture was stirred for 2 h at 50° C. After completion of the reaction, 1N NaOH was added to the reaction mixture, which was then extracted with EtOAc, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed under reduced pressure, and the residue was recrystallized from EtOAc and hexane to give the title compound (14.1 g, Yield 95%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@@H:9]1[CH2:21][CH2:22][O:23]S(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-].[Na+].[C:30]1(O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C)C=O.C(=O)(O)[O-].[Na+]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@@H:9]1[CH2:21][CH2:22][O:23][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)C[C@@H]1CCOS(C)(=O)=O
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)C[C@@H]1CCOc1ccccc1
Yield: 25 %

Procedure:
Combine (S)-4-benzyl-2-(2-methanesulfonyloxyethyl)piperazine-1-carboxylic acid tert-butyl ester (2.82 g, 7.08 mmol), sodium iodide (0.106 g, 0.708 mmol), and phenol (3.33 g, 35.4 mmol) in dimethyl formamide (40 mL) and stir at 100° C. for 20 hours. Dilute the mixture with saturated aqueous sodium bicarbonate and extract three times with dichloromethane. Combine the organic layers, dry over sodium sulfate and concentrate under reduced pressure. Purify by flash chromatography, eluting with a step gradient (100% dichloromethane to 5% 2N ammonia-methanol in dichloromethane) to obtain (S)-4-benzyl-2-(2-phenoxyethyl)piperazine-1-carboxylic acid tert-butyl ester (0.703 g, 25%): mass spectrum (APCI): m/z=397.2 (M+1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][N:8]1[C@@H:11]([CH3:12])[C@@H:10]([CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:9]1=[O:23].[OH-:24].[Na+]>O1CCOCC1>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][CH2:13][C@H:10]([C@@H:11]([NH:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[CH3:12])[C:9]([OH:23])=[O:24])=[CH:17][CH:18]=1
Reactant: C[C@H]1[C@@H](CCCc2ccc(Cl)cc2)C(=O)N1OC1CCCCO1
Reactant: [OH-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@H](NOC1CCCCO1)[C@@H](CCCc1ccc(Cl)cc1)C(=O)O
Temperature: 23 °C
Reaction time: 72 h
Yield: 99 %

Procedure:
To a solution of (3R,4S)-1-(2-tetrahydropyranyloxy)-3-(3-(4-chlorophenyl)-1-propyl)-4-methylazetidin-2-one (360 mg, 1.07 mmol) in dioxane (3.2 mL) is added 1 M aqueous sodium hydroxide (1.6 mL). The solution is stirred at 23° C. for 72 h, then extracted with hexanes (20 mL). The aqueous layer is acidified to pH 3 with saturated aqueous sodium bisulfate solution, and is extracted with two 30 mL portions of EtOAc. The combined organics are washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to provide (2R,3S)-2-(3-(4-chlorophenyl)-1-propyl)-3-(2-tetrahydropyranyloxyamino)butanoic acid as an oil (380 mg, 99% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:11][C:12]2[CH:13]=[C:14]([CH2:18][C@H:19]([NH:21][CH2:22][CH2:23][CH3:24])[CH3:20])[CH:15]=[CH:16][CH:17]=2)=[O:10])=[CH:5][CH:4]=1.ClC(Cl)C.[N:29]1([C:35]([N:37]2[CH2:42][CH2:41][CH:40]([CH:43]=O)[CH2:39][CH2:38]2)=[O:36])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(OCC)C.[OH-].[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([NH:11][C:12]2[CH:13]=[C:14]([CH2:18][C@H:19]([N:21]([CH2:43][CH:40]3[CH2:41][CH2:42][N:37]([C:35]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[O:36])[CH2:38][CH2:39]3)[CH2:22][CH2:23][CH3:24])[CH3:20])[CH:15]=[CH:16][CH:17]=2)=[O:10])=[CH:7][CH:8]=1
Reactant: O=CC1CCN(C(=O)N2CCOCC2)CC1
Reactant: CCCN[C@H](C)Cc1cccc(NC(=O)c2ccc(OC)cc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: CCOCC
Product: CCCN(CC1CCN(C(=O)N2CCOCC2)CC1)[C@H](C)Cc1cccc(NC(=O)c2ccc(OC)cc2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 79.8 %

Procedure:
(R)-N-{2-[3-(4-Methoxyphenylcarbonylamino)phenyl]-1-methylethyl}-propylamine (0.32 g), dichloroethane (20 ml) and 1-(morpholine-4-carbonyl)piperidine-4-carboxaldehyde (0.32 g) and were stirred under nitrogen for 30 minutes. Sodium triacetoxyborohydride (0.5 g) was added, and the mixture stirred at room temperature for about 72 hours. The mixture was diluted with diethyl ether (50 ml) and 10% sodium hydroxide solution (20 ml). The organic layer was dried with sodium sulfate, filtered, and the solvent evaporated in vacuo. The residue was chromatographed, eluting with methanol/dichloromethane to give (R)-N-{2-[3-(4-methoxyphenylcarbonylamino)phenyl]-1-methylethyl}-N-propyl-[1-(morpholine-4-carbonyl)piperidine-4-ylmethyl]amine, (0.42 g), [α]D25−42° (c 1.0 CH3OH); M+H 537.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].[CH:19]([NH2:21])=O.CN(C)C=O>O>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[C:7]([N+:10]([O-:12])=[O:11])[CH:6]=2)[N:1]=[CH:19][N:21]=1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1N
Reactant: NC=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncnc2ccc([N+](=O)[O-])cc12
Temperature: 150 °C
Reaction time: 0.83 h

Procedure:
A mixture of 2-amino-5-nitrobenzonitrile (48.9 g), anhydrous potassium carbonate (45.6 g), formamide (240 ml) and N,N-dimethylformamide (200 ml) was stirred for 50 minutes at 150° C. and then cooled to ambient temperature. To the resultant mixture was added a small volume of water with stirring. Precipitated crystals were separated by filtration, washed three times with water and dried under reduced pressure to give crystalline 4-amino-6-nitroquinazoline (50.1 g).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.[Cl:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]I>C1COCC1>[Cl:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccsc1
Reactant: ClCCCCCCI
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: ClCCCCCCc1cccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
To a stirred solution of thiophene (5.0 g, 59.5 mmol) in dry THF (50 ml) was added n-butyllithium (2.5 M in hexanes, 20.0 ml, 50.0 mmol) dropwise at −78° C. under nitrogen. After complete addition, the mixture was allowed to warm to room temperature, with stirring, over 2 h, followed by the addition of 1-chloro-6-iodohexane (12.3 g, 50.0 mmol). The resultant mixture was stirred overnight at room temperature. The reaction was quenched with sat. aq. ammonium chloride, and the reaction mixture was extracted with ethyl acetate (3×70 ml). The combined organic extracts were washed with water, brine, and dried over magnesium sulphate. The solvent was removed under reduced pressure and the residue was chromatographyed (silica gel, petroleum ether), to afford the product as a pale yellow oil (9.3 g, 92%). 1H NMR (300 MHz, CDCl3): δ (ppm) 7.06 (dd, J=5.1 Hz, 1.2 Hz, 1H, Ar—H), 6.87 (dd, J=5.1 Hz, 3.4 Hz, 1H, Ar—H), 6.75 (m, 1H, Ar—H), 3.48 (t, J=6.6 Hz, 2H, ClCH2), 2.80 (t, J=7.4 Hz 2H, ArCH2), 1.61-1.78 (m, 4H, CH2), 1.29-1.50 (m, 4H, CH2); 13C NMR (75 MHz, CDCl3): δ (ppm) 145.5 (quat.), 126.7 (CH), 124.1 (CH), 122.9 (CH), 45.1 (CH2), 32.6 (CH2), 31.7 (CH2), 29.9 (CH2), 28.4 (CH2) 26.7 (CH2); MS (m/e) 204 (M+, 9%), 202 (M+, 3%), 97 (100).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.O>C(Cl)Cl>[CH3:14][O:13][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([CH2:2][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:12]=1
Reactant: COC(=O)c1ccc(OC)cc1CBr
Reactant: C1COCCN1
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc(OC)cc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.9 %

Procedure:
To a solution of methyl 2-(bromomethyl)-4-methoxybenzoate (960 mg, 3.7 mmol) in DCM (18.5 mL) was added morpholine (0.68 mL, 7.8 mmol). The reaction mixture was stirred at room temperature overnight and poured onto iced water. The aqueous mixture was extracted with DCM (3×), and the combined organics were dried over MgSO4, filtered, and concentrated in vacuo to provide a yellow oil. The crude material was purified by flash chromatography on silica using a gradient of EtOAc in hexane (0 to 50%) as eluant. The tittle product was obtained as a clear oil (490 mg, 50%)