Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:16]=[C:15]([NH2:17])[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1.N1C=CC=CC=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:16]=[C:15]([NH:17][S:26]([CH3:25])(=[O:28])=[O:27])[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1
Reactant: CCCN(C)C(=O)c1cc(N)cc(C(=O)OC)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCN(C)C(=O)c1cc(NS(C)(=O)=O)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Dissolve 5-amino-N-methyl-N-propyl-isophthalamic acid methyl ester (1.64 g, 6.55 mmol) in dichloromethane (20 mL) and add pyridine (620 mg, 6.88 mmol) and methanesulfonyl chloride (788 mg, 6.88 mmol). Stir at room temperature for 72 h, dilute with dichloromethane, wash with 0.1 N citric acid and saturated aqueous sodium chloride. Dry (magnesium sulfate) and concentrate to give the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:23][CH2:24][S:25][CH3:26])[NH:5][C:6](=[O:22])[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O.O.Cl[Sn]Cl.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:23][CH2:24][S:25][CH3:26])[NH:5][C:6](=[O:22])[C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc([N+](=O)[O-])cc1-c1ccccc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(N)cc1-c1ccccc1
Yield: 74.4 %

Procedure:
4-nitro-2-phenylbenzoyl methionine methyl ester (0.35 g, 0.90 mmol) was taken up in ethyl acetate (9.0 ml). To this mixture was added SnCl2.2H2O (1.02 g, 4.50 mmol) and the reaction was heated under nitrogen at reflux for 1 h. The mixture was poured onto ice, the solution was made basic using NaHCO3 and the product was extracted into ethyl acetate several times (7-8). The ethyl acetate fractions were combined washed with brine and dried over Na2SO4 and the solvent was removed in vacuo to give 0.24 g (73.4%) of yellow solid. 1H NMR (CDCl3) 1.58-1.70 (1H, m), 1.80-1.92 (1H, m), 1.98 (3H, s), 2.06 (2H, t, J=7.7 Hz), 3.62 (3H, s), 4.00 (2H, br s), 4.56-4.63 (1H, m), 5.84 (1H, d, J=7.7 Hz), 6.50 (1H, s), 6.61 (1H, d, J=8.4 Hz), 7.29-7.42 (5H, m), 7.58 (1H, d, J=8.3 Hz); 13C NMR (CDCl3) 15.02, 29.25, 31.25, 51.57, 52.15, 113.27, 115.88, 123.52, 127.56, 128.37, 128.44, 130.92, 140.66, 141.44, 148.53, 168.58, 171.91.
Reaction SMILES: [CH:1]1([N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([CH:14]4[CH2:16][CH2:15]4)[CH:12]=3)[C:7]([C:17]#[N:18])=[CH:6]2)[CH2:4][CH2:3][CH2:2]1.[B:19](OC(C)C)([O:24]C(C)C)[O:20]C(C)C.[Li+].CC([N-]C(C)C)C>C1COCC1>[C:17]([C:7]1[C:8]2[C:13](=[CH:12][C:11]([CH:14]3[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[N:5]([CH:1]2[CH2:4][CH2:3][CH2:2]2)[C:6]=1[B:19]([OH:24])[OH:20])#[N:18]
Reactant: N#Cc1cn(C2CCC2)c2cc(C3CC3)ccc12
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1c(B(O)O)n(C2CCC2)c2cc(C3CC3)ccc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 105.4 %

Procedure:
Into a solution of 1-cyclobutyl-6-cyclopropyl-1H-indole-3-carbonitrile (2.0 g, 8.47 mmol) and triisopropyl borate (3.52 mL, 15.25 mmol) in THF (35 mL) at −78° C. was added LDA (1.5 M in cyclohexane, 7.3 mL, 11.01 mmol). The mixture was stirred at −78° C. for 30 min, quenched with ice water (60 mL) and stirred for 15 min without cooling. The mixture was extracted with ethyl acetate 1:1 in hexane (20 mL). The aqueous layer was acidified with 2 N aq. HCl to pH 5 and then extracted with CH2Cl2 (60 mL). The organic layer was dried over Na2SO4 and concentrated to give the title compound as a solid (2.5 g, 70% pure by LCMS) that was used in the next step without further purification.
Reaction SMILES: [NH2:1][CH:2]([CH:4]([OH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:3].N([C:16]1[NH:17][CH2:18][CH2:19][N:20]=1)[N+]([O-])=O.C1(C)C(C)=CC=CC=1>CC(C)=O>[NH:20]1[CH2:19][CH2:18][N:17]=[C:16]1[NH:1][CH:2]([CH:4]([OH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:3]
Reactant: O=[N+]([O-])NC1=NCCN1
Reactant: CC(N)C(O)c1ccccc1
Solvent: CC(C)=O
Solvent: Cc1ccccc1C
Product: CC(NC1=NCCN1)C(O)c1ccccc1
Reaction time: 0.5 h

Procedure:
A mixture pf 6.5 parts of α-(1-aminoethyl)benzyl alcohol (also known as morephedrine), 5.2 parts of 2-(nitramino)-2-imidazoline and 8 parts of xylene is stirred for 30 minutes while heating at 160°-170°C. The reaction mixture is cooled and diluted with acetone. The latter is removed in vacuo, yielding α-[1-(2-imidazolin-2-ylamino)-ethyl]benzyl alcohol as an oily residue.
Reaction SMILES: [CH3:1][CH:2]([CH3:30])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22](=O)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].C(N)(=O)CC.Cl.[CH3:37][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[NH:45]N>>[CH3:37][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]2[C:40]=1[NH:45][C:22]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[C:21]2[CH2:20][CH2:19][CH2:18][N:15]1[CH2:16][CH2:17][CH:12]([C:8]2[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH:2]([CH3:1])[CH3:30])[CH:11]=[CH:10][CH:9]=2)[CH2:13][CH2:14]1
Reactant: COc1ccccc1NN
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3)CC2)c1
Agent: CCC(N)=O
Agent: Cl
Product: COc1cccc2c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c(-c3ccccc3)[nH]c12

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-{3-[1-(5-oxo-5-phenylpentyl)-4-piperidinyl]phenyl)propanamide and 1-5-phenylpentyl)-4-piperidinyl]phenyl}propanamide and 1-(2-methoxyphenyl)hydrazine hydrochloride: ESMS m/e: 510.2 (M+H)+.
Reaction SMILES: [Cl:1]C1C=CC=C(C(OO)=[O:9])C=1.Cl.Cl.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.[OH-].[Na+]>O>[ClH:1].[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:9]
Reactant: c1ccc(SC2CCNCC2)nc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=S(c1ccccn1)C1CCNCC1
Temperature: 0 °C
Reaction time: 7.5 h
Yield: 75.8 %

Procedure:
m-Chloroperbenzoic acid (0.77 g) was added to an ice-cooled solution of 4-[(2-pyridyl)thio]piperidine dihydrochloride (1.0 g) in water (20 ml) and the mixture was stirred at the same temperature for 7.5 hours. After additional m-chloroperbenzoic acid (0.07 g) and water (5 ml) were added, the mixture was stirred at the same temperature for 1 hour, adjusted to alkaline pH with sodium hydroxide solution, and extracted several times with chloroform. The extracts were combined, dried over magnesium sulfate, and concentrated in vacuo. The oily residue was dissolved in chloroform. The solution was treated with ethanolic hydrochloric acid and concentrated in vacuo. The crystalline residue was washed with isopropanol to give 4-[(2-pyridyl)sulfinyl]piperidine hydrochloride (0.70 g).
Reaction SMILES: [C:1]([C:3]1[C:20]([F:21])=[CH:19][C:6]([O:7][CH2:8][C@@H:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH3:10])=[CH:5][C:4]=1[F:22])#[CH:2].Br[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH:32]2[CH2:34][CH2:33]2)=[CH:26][N:25]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1.[Cu](I)I.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:32]1([CH2:31][O:30][C:27]2[CH:28]=[CH:29][C:24]([C:2]#[C:1][C:3]3[C:4]([F:22])=[CH:5][C:6]([O:7][CH2:8][C@@H:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:16])([CH3:17])[CH3:15])[CH3:10])=[CH:19][C:20]=3[F:21])=[N:25][CH:26]=2)[CH2:33][CH2:34]1
Reactant: C#Cc1c(F)cc(OC[C@H](C)NC(=O)OC(C)(C)C)cc1F
Reactant: Brc1ccc(OCC2CC2)cn1
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C[C@@H](COc1cc(F)c(C#Cc2ccc(OCC3CC3)cn2)c(F)c1)NC(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 8 h
Yield: 35.9 %

Procedure:
A mixture of tert-butyl [(1S)-2-(4-ethynyl-3,5-difluorophenoxy)-1-methylethyl]carbamate (2.5 g), 2-bromo-5-(cyclopropylmethoxy)pyridine (1.8 g), copper iodide (I) (0.15 g), dichloropalladium-triphenylphosphine (1:2) (0.56 g) and triethylamine (2.2 mL) in toluene (20 mL) was stirred at 100° C. overnight under argon atmosphere. After cooling to room temperature, the mixture was filtered through a pad of Celite. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to afford the title compound (1.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8]CC[Si](C)(C)C)[N:3]=1.C(O[CH:19]1[O:41][C@H:40]([CH2:42][O:43][C:44](=[O:51])[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C@@H:30]([O:31][C:32](=[O:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C@H:20]1[O:21][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=O)C.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>C(#N)C.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C@@H:19]2[O:41][C@H:40]([CH2:42][O:43][C:44](=[O:51])[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C@@H:30]([O:31][C:32](=[O:39])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C@H:20]2[O:21][C:22](=[O:29])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:4](=[O:8])[N:3]=1
Reactant: C[Si](C)(C)CCOc1nccc(Cl)n1
Reactant: CC(=O)OC1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CC#N
Product: O=C(OC[C@H]1O[C@@H](n2ccc(Cl)nc2=O)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reaction time: 2 h

Procedure:
A solution of 12 (8.17 g. 35.4 mmol) in 200 mL anhydrous acetonitrile is treated with 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose (Pfanstiehl) at room temperature and under an atmosphere of argon. To this mixture is added TMS-triflate (6.11 mL, 35.4 mmol) and the mixture stirred at this temperature for 2 hr. Evaporation of the solvents in vacuo yielded an amber syrup which was immediately redissolved in 300 mL CH2Cl2, washed with cold, saturated NaHCO3 (2×150 mL), dried over magnesium sulfate, filtered and evaporated to a tan residue. Trituration of this residue with cold, anhydrous acetonitrile yielded analytically pure 13, 14.4 g (71%). 1H-NMR (DMSO-d6): δ 8.39 (d, 1 H, 6-H, J6,5 =11.8 Hz); 8.0-7.4 (m, 15 H, aromatic); 6.68 (d, 1 H, H-5); 6.11 (d, 1H, H-1', J1,2=2 Hz); 5.95 (m, 2 H, H-2',3'); 4.85 (m, 1 H, H-4'); 4.70 (m, 2 H, H-5',5"). Anal. Calcd for C30H23N2O8Cl: C, 62.67; H, 4.03; N, 4.87. Found: C, 62.21; H, 3.92; N, 4.80.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH2:12]([CH:14]([NH2:17])[CH2:15][CH3:16])[CH3:13].C(N(CC)C(C)C)(C)C>CCO>[Cl:1][C:2]1[N:7]=[C:6]([NH:17][CH:14]([CH2:15][CH3:16])[CH2:12][CH3:13])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: CCC(N)CC
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCC(CC)Nc1nc(Cl)ncc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 59.5 %

Procedure:
To a solution of 2,4-dichloro-5-nitro-pyrimidine (2 g, 10.3 mmol) in anhydrous EtOH (20 mL) is added 1-ethylpropylamine (1.3 mL, 11.3 mmol) and N,N-diisopropylethylamine (2.7 mL, 15.5 mmol) at 0° C. The reaction mixture is stirred for 8 h and concentrated in vacuo. The residue is dissolved with EtOAc, washed with saturated NaHCO3 and brine, dried over Na2SO4, and concentrated in vacuo. Purification with column chromatography (SiO2, EtOAC/Hexane 1:3) gives 1.5 g of (2-chloro-5-nitro-pyrimidin-4-yl)-(1-ethyl-propyl)-amine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](O)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].C(=O)(O)[O-].[Na+].P(Cl)(Cl)([Cl:35])=O>>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:35])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(O)ccnc2cc1OCc1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
Phosphorus oxychloride (300 mL) was added to 7-benzyloxy-6-methoxyquinolin-4-ol (40 g, 140 mmol) and the mixture heated to reflux for 2 h. The mixture was carefully poured into a mixture of ice and sodium carbonate. The solution was adjusted to pH 8 with the addition of solid sodium bicarbonate and stirred at room temperature overnight. The solid was filtered and washed with water and dried to give 7-benzyloxy-4-chloro-6-methoxyquinoline as a pale brown solid (40.2 g, 95%). 1H NMR (400 MHz, d6-DMSO): δ 8.61 (s, 1H), 7.57-7.37 (m, 8H), 5.32 (s, 2H), 3.98 (s, 3H); 13C NMR (100 MHz, d6-DMSO): δ 152.4, 151.5, 148.5, 146.2, 139.6, 137.0, 129.2, 128.8, 121.7, 120.4, 110.1, 101.9, 70.8, 56.5; IR (cm−1): 2359, 2341, 1506, 1456, 1435, 1252, 1227, 1146, 999, 845, 752, 698, 667; LC/MS (M+H=300).
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@:5]2([C:19]3[C:14](=[N:15][CH:16]=[C:17]([OH:20])[CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([Br:21])=[CH:10][CH:11]=3)[N:6]=1.CN(C=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:39][C:40]([F:43])([CH3:42])[CH3:41])(=O)=O>>[Br:21][C:9]1[CH:8]=[C:7]2[C@@:5]3([CH2:4][O:3][C:2]([NH2:1])=[N:6]3)[C:19]3[C:14](=[N:15][CH:16]=[C:17]([O:20][CH2:39][C:40]([F:43])([CH3:42])[CH3:41])[CH:18]=3)[O:13][C:12]2=[CH:11][CH:10]=1
Reactant: NC1=N[C@@]2(CO1)c1cc(Br)ccc1Oc1ncc(O)cc12
Reactant: CC(C)(F)COS(=O)(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(F)COc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(Br)ccc1O2
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A vial was charged with (S)-2′-amino-7-bromo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-3-ol (750 mg, 2.154 mmol), DMF (8617 μL, 2.154 mmol) and cesium carbonate (2106 mg, 6.46 mmol). The mixture was cooled to 0° C. and 2-fluoro-2-methylpropyl trifluoromethanesulfonate (966 mg, 4.31 mmol) was added. The reaction was removed from the ice bath and stirred at RT for 45 minutes. The reaction was diluted with water (250 mL) and poured into a separatory funnel containing ethyl acetate (250 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with water and then brine, dried over sodium sulfate, filtered and concentrated in vacuo to provide a light yellow solid that was purified by silica gel chromatography (Redi-Sep pre-packed silica gel column (40 g), 0-10% methanol in methylenechloride with 0.1% ammonium hydroxide) to provide (S)-7-bromo-3-(2-fluoro-2-methylpropoxy)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine as a light yellow solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:37])[NH:27][C:28]4[CH:36]=[CH:35][C:31]([C:32]([OH:34])=O)=[CH:30][CH:29]=4)=[CH:21][CH:20]=3)[N:8]=2)[CH2:3][CH2:2]1.C[CH2:39][N:40](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN>CN1C(=O)CCC1>[O:16]1[CH2:15][CH2:14][N:13]([C:11]2[N:12]=[C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)[N:8]=[C:9]([C:19]3[CH:20]=[CH:21][C:22]([NH:25][C:26](=[O:37])[NH:27][C:28]4[CH:36]=[CH:35][C:31]([C:32]([NH:40][CH3:39])=[O:34])=[CH:30][CH:29]=4)=[CH:23][CH:24]=3)[N:10]=2)[CH2:18][CH2:17]1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Nc1ccc(C(=O)O)cc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Agent: CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Product: CNC(=O)c1ccc(NC(=O)Nc2ccc(-c3nc(N4CCOCC4)nc(N4CCOCC4)n3)cc2)cc1
Yield: 76.6 %

Procedure:
To the stirred solution of 4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzoic acid (150 mg; 0.297 mmol), Hunig's base (303 μL, 1.782 mmol), HBTU (563 mg, 1.485 mmol) in 2 mL of NMP was reacted according to example 68 with methylamine (594 μL, 2M solution. in THF) to give the product as a white solid (118 mg, 77% yield); MS (ESI) m/z=519.3.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[CH2:7]([O:14][C:15]([N:17]1[C:21]2([C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=3)[C:22]2=[O:39])[C:20](=[O:40])[NH:19][C:18]1=[O:41])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.CCOCC>[CH2:7]([O:14][C:15]([N:17]1[C:21]2([C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=3)[C:22]2=[O:39])[C:20](=[O:40])[N:19]([C:2]([O:4][CH2:5][CH3:6])=[O:3])[C:18]1=[O:41])=[O:16])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C1NC(=O)C2(C(=O)N(Cc3ccc(Cl)c(Cl)c3)c3ccccc32)N1C(=O)OCc1ccccc1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOCC
Product: CCOC(=O)N1C(=O)N(C(=O)OCc2ccccc2)C2(C1=O)C(=O)N(Cc1ccc(Cl)c(Cl)c1)c1ccccc12
Reaction time: 16 h
Yield: 61.9 %

Procedure:
Ethyl chloroformate (0.6 g.) was added slowly to a stirred mixture of 3-benzyloxycarbonyl-1'-(3,4-dichlorobenzyl)-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione (2.55 g.) and sodium carbonate (2.0 g.) in 1,2-dimethoxyethane (60 ml.). The mixture was stirred for 16 hours and the solid then removed by filtration. The filtrate was evaporated to give an oil which solidified on treatment with a few drops of ether. This solid was recrystallised from ethyl acetate/petrol 60-80 to give 3-benzyloxycarbonyl-1-ethoxycarbonyl-1'(3,4-dichlorobenzyl)-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione (1.8 g.), m.p. 128°-131° C.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([CH:7]=[CH2:8])[CH2:5][OH:6].[CH3:9][O:10][CH:11]([O:14][CH3:15])[CH2:12]Br.[Cl-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH3:9][O:10][CH:11]([O:14][CH3:15])[CH2:12][O:6][CH2:5][CH:4]([CH3:3])[CH:7]=[CH2:8]
Reactant: C=CC(C)CO
Reactant: COC(CBr)OC
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CC(C)COCC(OC)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60 wt %, 928 mg) was added to a solution of 2-methyl-3-buten-1-ol (2 g) in DMF (30 mL) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. Bromoacetaldehyde dimethyl acetal (5.45 mL) was added dropwise to the reaction solution at the same temperature. The reaction solution was stirred for 16 hours with gradual heating to room temperature. Ethyl acetate and aqueous sodium chloride were added to the reaction solution, and the organic layer was separated. The same operation was performed on the same scale. The combined organic layers were washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (4.92 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:6](=[O:7])[CH2:5][C:4]([CH3:9])([CH3:8])[O:3]1.C[O-].[Na+].[Br:14][C:15]1[CH:16]=[CH:17][C:18]([O:23][CH:24]([F:26])[F:25])=[C:19]([CH:22]=1)[CH:20]=O>COCCOC.CCOCC>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([O:23][CH:24]([F:25])[F:26])=[C:19]([CH:20]=[C:5]2[C:4]([CH3:9])([CH3:8])[O:3][C:2]([CH3:10])([CH3:1])[C:6]2=[O:7])[CH:22]=1
Reactant: O=Cc1cc(Br)ccc1OC(F)F
Reactant: CC1(C)CC(=O)C(C)(C)O1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: COCCOC
Product: CC1(C)OC(C)(C)C(=Cc2cc(Br)ccc2OC(F)F)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 103 %

Procedure:
To an ice-cold solution of 2,2,5,5-tetramethyldihydrofuran-3-one (3.60 g, 0.025 mol) in anhydrous 1,2-dimethoxyethane (8 ml) is added sodium methoxide (1.51 g, 0.028 mol) in one portion. After stirring at this temperature for 5 minutes a solution of 5-bromo-2-difluoromethoxy-benzaldehyde (5.66 g, 0.023 mol) in 1,2-dimethoxyethane (8 ml) is added dropwise over 10 mins, followed by stirring at 0° C. for a further 1 hour. After warming to room temperature the reaction mixture is diluted with ether and washed with 2M hydrochloric acid (×2). Organic fractions are combined, dried over magnesium sulfate and evaporated in vacuo to afford 4-[1-(5-bromo-2-difluoromethoxyphenyl)methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one (8.89 g) as an orange oil.
Reaction SMILES: [NH2:1][CH:2]([C:7]([OH:9])=O)[CH2:3][CH2:4][S:5][CH3:6].NCC(O)=O.[NH2:15][C@H:16]([C:21]([OH:23])=[O:22])[CH2:17]CSC.N[C@H](C(O)=O)C>O>[NH2:1][C@H:2]([C:7]([NH:15][C@H:16]([C:21]([OH:23])=[O:22])[CH3:17])=[O:9])[CH2:3][CH2:4][S:5][CH3:6]
Reactant: CSCC[C@H](N)C(=O)O
Reactant: CSCCC(N)C(=O)O
Agent: C[C@H](N)C(=O)O
Agent: NCC(=O)O
Solvent: O
Product: CSCC[C@H](N)C(=O)N[C@@H](C)C(=O)O

Procedure:
The title compound was prepared according to the procedures of Example 1A and B above by replacing DL-methionine and glycine respectively with L-methionine and L-alanine (Aldrich Chemical Co., Beil. 4,381). The title compound had a melting point of 141° to 143° C (d). The compound was found to be water soluble. The product thus obtained was subjected to amino acid analysis and found to contain 49.40 mole percent alanine and 50.60 mole percent methionine.
Reaction SMILES: [C:1]([CH:3]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:4]1(O)[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)#[N:2].O=S(Cl)Cl>N1C=CC=CC=1>[C:1]([C:3]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[C:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(C(C#N)c2ccccc2)CC1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(=C(C#N)c2ccccc2)CC1
Reaction time: 0.17 h

Procedure:
To tert-butyl 4-[cyano(phenyl)methyl]-4-hydroxypiperidine-1-carboxylate (1.8 g, 5.69 mmol) in pyridine (4 ml) was added SOCl2 (2.076 ml, 28.4 mmol) and the reaction was stirred for 10 min. The reaction mixture was concentrated in vacuo. The resulting crystalline solid was adsorbed onto silica gel and purified by silica gel chromatography in an Isco Companion. The desired fractions were combined and concentrated in vacuo. 1.18 g, 70% over two steps.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[NH2:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([NH:25][C:26]([NH:28][C:29]3[N:33]([C:34]4[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=4)[N:32]=[C:31]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH:30]=3)=[O:27])=[CH:17][CH:16]=2)[CH:11]=[CH:10][N:9]=1.CCN(C(C)C)C(C)C>C1COCC1>[C:41]([C:31]1[CH:30]=[C:29]([NH:28][C:26](=[O:27])[NH:25][C:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:15]([O:14][C:12]3[CH:11]=[CH:10][N:9]=[C:8]([NH:7][C:4](=[O:5])[CH2:3][O:2][CH3:1])[CH:13]=3)=[CH:16][CH:17]=2)[N:33]([C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=2)[N:32]=1)([CH3:44])([CH3:43])[CH3:42]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccnc(N)c3)c3ccccc23)cc1
Reactant: COCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCC(=O)Nc1cc(Oc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc(C)cc3)c3ccccc23)ccn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 60.9 %

Procedure:
Methoxyacetyl chloride (64.2 μl, 0.703 mmol) was added slowly to a mixture of 1-(4-(2-aminopyridin-4-yloxy)naphthalen-1-yl)-3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl) urea (8) (89 mg, 0.176 mmol) and DIPEA (153 μl, 0.878 mmol) in THF (5 mL). The reaction mixture was stirred at 0° C. for a further 20 min and then warmed to RT. After 2.5 hr, the reaction was quenched by the addition of a solution of 1% NH3 in MeOH (3 mL), and the resulting mixture stirred for a further 45 min. The volatiles were removed in vacuo and the residue was dissolved in a mixture of MeOH (5 mL) and AcOH (2 mL) and subjected to SCX capture and release eluting with 1% NH3 in MeOH solution. The crude material was purified by flash column chromatography (SiO2; 12 g) eluting with 0 to 60% [5% MeOH in EtOAc] in iso-hexane to give N-(4-(4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)pyridin-2-yl)-2-methoxyacetamide (1) (62 mg, 61%) as a white solid: m/z 579 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.29 (9H, s), 2.40 (3H, s), 3.31 (3H, s), 3.99 (2H, s), 6.41 (1H, s), 6.70 (1H, dd), 7.32-7.40 (3H, m), 7.44-7.48 (2H, m), 7.55-7.61 (1H, m), 7.63-7.67 (2H, m), 7.84 (1H, dd), 7.97 (1H, d), 8.09 (1H, d), 8.19 (1H, d), 8.79 (1H, s), 9.13 (1H, s), 10.02 (1H, s).