Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:5]=[C:4]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[N:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:36]1[CH2:40]O[CH2:38][CH2:37]1.IC(CC)C>CN(C=O)C>[CH3:40][CH:36]([CH2:37][CH3:38])[CH:8]([C:7]1[C:2]([CH3:1])=[N:3][C:4]([N:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)=[N:5][C:6]=1[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: C1CCOC1
Reactant: COC(=O)Cc1c(C)nc(N2CCCCC2)nc1-c1ccc(C)cc1
Agent: CCC(C)I
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCC(C)C(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1-c1ccc(C)cc1
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 33.4 %

Procedure:
To a cooled (−15° C.) solution of intermediate 23: methyl 2-(4-methyl-2-(piperidin-1-yl)-6-p-tolylpyrimidin-5-yl)acetate (0.100 g; 0.295 mmol) in dry DMF (1.5 mL) was wadded a 1N solution of LHMDS in THF (0.324 mL; 0.324 mmol) dropwise and the mixture was stirred at (−15° C.) for 15 min, followed by the dropwise addition of 2-iodobutane (0.068 mL; 0.589 mmol). After stirring for 2 h at (−15° C.) the mixture was allowed to warm up to room temperature. After 1 h the reaction was quenched by adding a saturated solution of ammonium chloride and the mixture was extracted twice with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (2-20%) in heptane furnished 0.039 g (33%) of the title compound as a colorless oil.
Reaction SMILES: O[CH:2]([P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.S(Cl)([Cl:19])=O>>[Cl:19][CH:2]([P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: CCOP(=O)(OCC)C(O)c1ccccc1
Product: CCOP(=O)(OCC)C(Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.2 %

Procedure:
A solution of Compound 19 (1.00 g, 0.0041M) in thionyl chloride (1.63 g, 0.014M) is allowed to stir at room temperature for 16 hours. The thionyl chloride is removed in vacuo and the crude is poured over ice-water. The aqueous is extracted with ether (2 times). The ether layer is washed with sodium bicarbonate (saturated solution) (2 times) and water. The organic layer is dried (Na2SO4), filtered and concentrated to obtain 0.712 g of a clear oil. The crude is chromatographed over flash silica gel (0.040-063 mm, 100 g) and eluted with 1% acetone/CH2Cl2 to obtain 0.516 g (0.0020M, 48%) of the title compound as a clear oil. 1H NMR (CDCl3 /TMS): δ 7.56-7.52 (m, 2H, Ar), 4.40 -7.32 (m, 3H, ArH), 4.90 (d, J=14 Hz, 1H, CHCl), 4.23-4.12 (m, 2H, CH2), 4.10-4.00 (m, 1H, CH2), 3.95-3.84 (m, 1H, CH2), 1.32 (dt, J=7.0, 0.6 Hz, 3H, CH3), 1.17 (dt, J=7.0, 0.6 Hz, 3H, CH3); 13C NMR (CDCl3): δ 134.16 (d, J=3.0 Hz, Ar), 129.01-128.55 (m, Ar), 64.13-63.86 (m, CH2), 53.67 (d, J=53.7 Hz, CHCl), 16.45-16.19 (m, CH3); 31P NMR (CDCl3): δ 17.82. Anal. calc'd. for C11H16O3CIP: C, 50.30; H, 6.14; P, 11.79. Found: C, 50.06; H, 6.24; P, 11.66.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=1[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:20])C(F)(F)F)=[CH:10][CH:9]=1)=[O:6].I([O-])(=O)(=O)=O.[Na+].[OH2:31]>>[C:4]([O:20][C:15](=[O:31])[NH:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:21]=[CH:22][CH:23]=[CH:24][C:3]=2[S:2][CH3:1])=[CH:9][CH:10]=1)([CH3:21])([CH3:5])[CH3:3]
Reactant: CSc1ccccc1C(=O)Nc1ccc(NC(=O)C(F)(F)F)cc1
Reactant: O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Product: CSc1ccccc1C(=O)Nc1ccc(NC(=O)OC(C)(C)C)cc1
Reaction time: 12 h

Procedure:
To a solution of 2-methylsulfanyl-N-[4-(2,2,2-trifluoro-acetylamino)-phenyl]-benzamide (234 mg) is added a saturated solution of sodium periodate (5 mL) and the mixture is stirred for 12 hours. The purple mixture is poured into water, extracted with ethyl acetate, dried over anhydrous potassium carbonate and evaporated to yield a red solid, 101 mg.
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][N:6]1[C:10]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)([CH3:11])[C:9](=[O:20])[N:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[C:7]1=[O:27])C.[OH-].[Na+]>C1COCC1.CS(C)=O>[F:18][C:16]1[CH:17]=[C:12]([C:10]2([CH3:11])[N:6]([CH2:5][C:4]([OH:28])=[O:3])[C:7](=[O:27])[N:8]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[C:9]2=[O:20])[CH:13]=[C:14]([F:19])[CH:15]=1
Reactant: CCOC(=O)CN1C(=O)N(c2ccccn2)C(=O)C1(C)c1cc(F)cc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC1(c2cc(F)cc(F)c2)C(=O)N(c2ccccn2)C(=O)N1CC(=O)O
Reaction time: 16 h

Procedure:
To a stirred solution of ethyl[5-(3,5-difluorophenyl)-5-methyl-2,4-dioxo-3-pyridin-2-ylimidazolidin-1-yl]acetate, isomer A from Step A (67.0 mg, 0.172 mmol) in THF (2 mL) was added a solution of 1 N NaOH (0.516 mL, 0.516 mmol) and stirring continued for 16 h. The reaction mixture was diluted with DMSO (1 mL) and purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. Lyophilization provided the racemic title compound. MS: m/z=362 (M+1).
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]=[C:9]([CH:14]([CH3:29])[CH2:15][C:16]3[CH:28]=[CH:27][C:19]([O:20][CH2:21][C:22]([O:24]CC)=[O:23])=[CH:18][CH:17]=3)[NH:8][C:7]=2[N:6]([CH2:30][CH2:31][CH3:32])[C:5]1=[O:33])[CH2:2][CH3:3].[OH-].[K+].Cl>C(O)C.O>[CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]=[C:9]([CH:14]([CH3:29])[CH2:15][C:16]3[CH:28]=[CH:27][C:19]([O:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:18][CH:17]=3)[NH:8][C:7]=2[N:6]([CH2:30][CH2:31][CH3:32])[C:5]1=[O:33])[CH2:2][CH3:3]
Reactant: CCCn1c(=O)c2nc(C(C)Cc3ccc(OCC(=O)OCC)cc3)[nH]c2n(CCC)c1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCn1c(=O)c2nc(C(C)Cc3ccc(OCC(=O)O)cc3)[nH]c2n(CCC)c1=O
Reaction time: 3 h
Yield: 72 %

Procedure:
Dissolve (+)-2-[4-[2-(2,3,6,9-tetrahydro-1,3-dipropyl 2,6-dioxo-1H-purin-8-yl)propyl]phenoxy]acetic acid, ethyl ester (0.49 g, 1.07 mmol) in ethanol (10 mL) and treat with a solution of potassium hydroxide (0.072 g, 1.29 mmol) in water (10 mL). Stir for 3 hours, then dilute with water (200 mL) and acidify with 10% hydrochloric acid. Extract into chloroform (2×400 mL), then ether (400 mL) and dry (MgSO4). Evaporate the solvent in vacuo to give the title compound as a white solid (0.33 g, 72%); [α]d 20 =+81° (C=0.069, DMSO).
Reaction SMILES: Br[CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1)[OH:4].[CH:13]([NH2:16])([CH3:15])[CH3:14]>CCOC(C)=O>[CH:13]([NH:16][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1)[OH:4])([CH3:15])[CH3:14]
Reactant: OC(CBr)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)N
Solvent: CCOC(C)=O
Product: CC(C)NCC(O)c1ccc(Cl)c(Cl)c1
Temperature: 80 °C

Procedure:
A mixture of 3.9 g (14 mmol) 2-bromo-1-(3,4-dichlorophenyl)ethanol and 10 ml isopropylamine was sealed and heated to 80° C. for 16 h, then cooled to room temperature, diluted with 500 mL EtOAc, washed with 400 mL saturated aqueous NaHCO3, and 500 mL brine, then dried over Na2SO4, filtered and concentrated. Purification by flash chromatography (5×8 cm silica gel, elute with 250 mL 3%MeOH/CH2Cl2, 100 mL 50% EtOH/CH2Cl2, then 200 mL EtOH) afforded 2.7 g 2-isopropylamino-1-(3,4-dichlorophenyl)ethanol. 1H NMR(400 mHz, CDCl3) 7.48 (d, 1H, J=1.92 Hz); 7.40 (d, 1H, J=8.22 Hz); 7.20 (dd, 1H, J=8.23and 1.92 Hz); 4.59 (dd, 1H, J=8.96 and 3.75 Hz); 2.94 (dd, 1H, J=12.2 and 3.66 Hz); 2.83 (sept, 1H, J=6.31 Hz); 2.57 (dd, 1H, J=12.3 and 8.87 Hz); 1.09 (d, 3H, J=6.31 Hz); 1.08 (d, 3H, J=6.22 Hz).
Reaction SMILES: S(C1C=CC(C)=CC=1)(O[CH2:5][CH:6]1[CH2:10][CH2:9][O:8][CH2:7]1)(=O)=O.[C:18]1(=[O:28])[NH:22][C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12.[K].CN(C=O)C>O>[O:8]1[CH2:9][CH2:10][CH:6]([CH2:5][N:22]2[C:18](=[O:28])[C:19]3=[CH:27][CH:26]=[CH:25][CH:24]=[C:20]3[C:21]2=[O:23])[CH2:7]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCOC2)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CC1CCOC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
A mixture comprising 30.0 g of (tetrahydro-3-furanyl)methyl tosylate, 23.0 g of potassium phthalimide and 150 ml of DMF was stirred at 80° C. for 8 hours. Water was poured into the reaction mixture, and crystals precipitated out was separated by filtration to obtain 27.0 g of N-{(tetrahydro-3-furanyl)methyl}phthalimide.
Reaction SMILES: [CH:1]1([N:4]([C:12]2[C:17]([CH3:18])=[C:16]([O:19][C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][C:21]=3[F:30])[N:15]=[CH:14][N:13]=2)[CH2:5][CH:6]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:39]([O:41][CH:42]([CH3:44])[CH3:43])=[O:40]>C1COCC1>[CH:42]([O:41][C:39]([N:9]1[CH2:10][CH2:11][CH:6]([CH2:5][N:4]([CH:1]2[CH2:3][CH2:2]2)[C:12]2[C:17]([CH3:18])=[C:16]([O:19][C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:27])=[O:28])=[CH:22][C:21]=3[F:30])[N:15]=[CH:14][N:13]=2)[CH2:7][CH2:8]1)=[O:40])([CH3:44])[CH3:43]
Reactant: Cc1c(Oc2ccc(S(C)(=O)=O)cc2F)ncnc1N(CC1CCNCC1)C1CC1
Reactant: CC(C)OC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1c(Oc2ccc(S(C)(=O)=O)cc2F)ncnc1N(CC1CCN(C(=O)OC(C)C)CC1)C1CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83.2 %

Procedure:
A mixture of cyclopropyl-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yl]-piperidin-4-ylmethyl-amine (65 mg, 0.15 mmole) and triethylamine (23 mg, 0.225 mmole) in 2 mL THF was stirred at room temperature for 10 minutes. Into this mixture was added drop-wise isopropyl chloroformate (0.225 mmole). The mixture was quenched with water, extracted with ethyl acetate, and dried in vacuum to give Compound D2 as a yellow solid (65 mg, 83%). 1H NMR (CDCl3, 400 MHz) δ 0.69-0.64 (m, 2H), 0.83-0.88 (m, 2H), 1.12-1.15 (m, 2H), 1.23 (d, J=6.3 Hz, 6H), 1.72 (d, J=13.1 Hz, 2H), 1.94-2.02 (m, 1H), 2.04 (s, 3H), 2.73 (t, J=12.4 Hz, 2H), 2.97-3.17 (m, 1H), 3.10 (s, 3H), 3.49-3.55 (m, 2H), 4.09-4.23 (m, 2H), 4.90 (sept, J=6.3 Hz, 1H), 7.45 (t, J=8.3 Hz, 1H), 7.76-7.80 (m, 2H), 8.12 (s, 1H). Exact mass calculated for C25H33FN4O5S 520.2, found 521.5 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH3:11])=[CH:5][C:3]=1[NH2:4].[H-].[Na+].Cl[C:15]1[C:20]([C:21]#[N:22])=[CH:19][N:18]=[C:17]2[CH:23]=[C:24]([I:26])[S:25][C:16]=12>O1CCCC1>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH3:11])=[CH:5][C:3]=1[NH:4][C:15]1[C:20]([C:21]#[N:22])=[CH:19][N:18]=[C:17]2[CH:23]=[C:24]([I:26])[S:25][C:16]=12
Reactant: N#Cc1cnc2cc(I)sc2c1Cl
Reactant: COc1cc(N)c(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(Nc2c(C#N)cnc3cc(I)sc23)c(Cl)cc1Cl
Temperature: 25 °C
Yield: 50.4 %

Procedure:
A mixture of 2,4-dichloro-5-methoxyaniline (380 mg, 2.0 mmol) and 60% sodium hydride (80 mg, 2.0 mmol) in 20 mL of tetrahydrofuran is heated at reflux for 1 hour. The solution is cooled and 7-chloro-2-iodothieno[3,2-b]pyridine-6-carbonitrile (320 mg, 1.0 mmol) is added and the reaction mixture is heated at reflux overnight. The reaction mixture is cooled to room temperature and partitioned between ethyl acetate and water. The organic layer is washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with 2% methanol in chloroform to provide 240 mg of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-iodothieno[3,2-b]pyridine-6-carbonitrile as yellow crystals, mp 233-234° C.; 1H NMR (DMSO-d6) δ 3.85 (s, 3H), 7.38 (s, 1H), 7.77 (s, 1H), 7.79 (s, 1H), 8.56 (s, 1H), 9.74 (s, 1H); MS 475.9 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]([C:6]([O:8][CH:9]([CH3:11])[CH3:10])=[O:7])[CH2:4][CH2:3][C:2]1=[O:12].[C:13](Cl)(=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:13]([N:1]1[CH:5]([C:6]([O:8][CH:9]([CH3:10])[CH3:11])=[O:7])[CH2:4][CH2:3][C:2]1=[O:12])(=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CC(C)OC(=O)C1CCC(=O)N1
Reactant: CCCCCCCCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCC(=O)N1C(=O)CCC1C(=O)OC(C)C
Yield: 17.9 %

Procedure:
10.0 g of isopropyl 2-pyrrolidone-5-carboxylate was dissolved in 58.4 g of toluene, and 13.04 g of lauroyl chloride was added thereto. Further, 6.03 g of triethylamine was dropwise added, and reacted under reflux for 2 hours. Toluene was concentrated under reduced pressure, then the reaction mixture was purified through silica gel column chromatography (hexane/ethyl acetate=5/1 to 3/1) to obtain 3.69 g of isopropyl N-lauroyl-2-pyrrolidone-5-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[OH:10].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([O:21]CC)=[O:20]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[O:10][CH2:18][C:19]([OH:21])=[O:20]
Reactant: CCOC(=O)CBr
Reactant: Oc1c(Cl)cc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(O)COc1c(Cl)cc(F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.8 %

Procedure:
The mixture of 2,6-dichloro-4-fluorophenol (362 mg, 2.0 mmol), potassium carbonate (910 mg, 6.6 mmol), ethyl bromoacetate (500 mg, 3.0 mmol) and acetone (25 ml) was refluxed for 12 h. After cooling, the mixture was filtered to remove potassium carbonate. The filtrate was concentrated under reduced pressure. To this residue, 10 ml dioxane and 14 ml 5% sodium hydroxide solution were added. After the mixture was stirred at room temperature overnight, it was acidified with concentrated hydrochloric acid to pH 2, and then extracted three times with ethyl acetate (15 ml each). Organic phases were combined, washed with water and brine, dried over magnesium sulfate, filtered, and then evaporated in vacuo. The residue was recrystallized from ethyl acetate and petroleum ether to give 348 mg 2,6-dichloro-4-fluorophenoxyacetic acid as white crystals, mp 155-158° C., yield: 72.8%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[H-].[Na+].[C:13]([O:17][C:18]([N:20]([CH2:24][CH2:25]Cl)[CH2:21][CH2:22]Cl)=[O:19])([CH3:16])([CH3:15])[CH3:14].N1(C#N)CCCCC1>CN(C=O)C>[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:25][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)([C:9]#[N:10])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Reactant: N#CCc1ccc(Cl)cc1
Agent: N#CN1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccc(Cl)cc2)CC1

Procedure:
4-Chlorophenylacetonitrile was reacted with three equivalents of sodium hydride and one equivalent of N-tert-butyloxycarbonyl-bis-(2-chloroethyl)amine in DMF, initially at room temperature and then at 60° C. to give, after work up, the N-protected piperidine nitrile title compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([CH3:25])[CH:12]=[CH:11][C:10]([N:13]2[C:17]3([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:16](=[O:23])[NH:15][C:14]2=[O:24])=[CH:9][CH:8]=1.Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].O>CN(C=O)C>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][N:15]1[C:16](=[O:23])[C:17]2([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:13]([C:10]2[CH:9]=[CH:8][C:7]([CH3:25])=[CH:12][CH:11]=2)[C:14]1=[O:24])[CH3:32]
Reactant: Cc1ccc(N2C(=O)NC(=O)C23CCCCC3)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN1C(=O)N(c2ccc(C)cc2)C2(CCCCC2)C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
17.9 g (0.130 mol; 1.1 eq.) of potassium carbonate are added to a solution of 30.4 g (0.117 mol; 1 eq.) of 1-p-tolyl-1,3-diazaspiro[4.5]decane-2,4-dione in 150 ml of DMF, and 16 ml (0.141 mol; 1.2 eq.) of ethyl bromoacetate are then added dropwise to the reaction medium. The cream-coloured reaction medium suspension is stirred at room temperature for 18 hours. The reaction medium is poured into 300 ml of water and the white precipitate is filtered off, rinsed with water and then dried in an oven under vacuum at 40° C. for 48 hours. The product (2,4-dioxo-1-p-tolyl-1,3-diaza-spiro[4.5]dec-3-yl)acetic acid ethyl ester is obtained in the form of a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8](I)[C:7]([CH2:11][CH3:12])=[CH:6][C:5]=1[NH2:13].[CH3:15][N:16]1[C:20]([Sn](CCCC)(CCCC)CCCC)=[CH:19][CH:18]=[N:17]1.O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CCOC(C)=O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([C:20]2[N:16]([CH3:15])[N:17]=[CH:18][CH:19]=2)[C:7]([CH2:11][CH3:12])=[CH:6][C:5]=1[NH2:13]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnn1C
Reactant: CCc1cc(N)c(C(=O)OC)cc1I
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCc1cc(N)c(C(=O)OC)cc1-c1ccnn1C
Temperature: 100 °C
Reaction time: 18 h
Yield: 68.3 %

Procedure:
2-Amino-5-iodo-4-ethyl-benzoic acid methyl ester (280 mg, 0.92 mmol) and 1-methyl-5-tributylstannanyl-1H-pyrazole (409 mg, 1.2 equiv) were weighed in air and added to a flame-dried flask. [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium (75 mg, 0.1 equiv) was added and the flask was closed by a septum. Dioxane (1 mL) was added and the mixture was stirred at 100° C. for 18 h (TLC control). The mixture was dissolved with EtOAc, filtered and evaporated to dryness. The crude product was purified by flash chromatography (hexanes to EtOAc/hexanes (4:6)) to yield 2-amino-4-ethyl-5-(2-methyl-2H-pyrazol-3-yl)-benzoic acid methyl ester (163 mg, 68% yield) as a yellow solid. ESI-MS: m/z 260.3 [M+H]+, rt 6.37 min.
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])=[C:15]([Br:26])[CH:14]=2)[S:11][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([O:34][C:35]([N:37]1[CH2:41][CH2:40][CH2:39][C@@H:38]1[CH:42]=[CH:43][CH2:44]O)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([O:34][C:35]([N:37]1[CH2:41][CH2:40][CH2:39][C@@H:38]1[CH:42]=[CH:43][CH2:44][N:19]([C:16]1[CH:17]=[CH:18][C:13]([C:10]2[S:11][CH:12]=[C:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[N:9]=2)=[CH:14][C:15]=1[Br:26])[C:20](=[O:25])[C:21]([F:22])([F:23])[F:24])=[O:36])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(OCc1ccccc1)N1CCC[C@@H]1C=CCO
Reactant: O=C(Nc1ccc(-c2nc(Cc3ccccc3)cs2)cc1Br)C(F)(F)F
Product: O=C(OCc1ccccc1)N1CCC[C@@H]1C=CCN(C(=O)C(F)(F)F)c1ccc(-c2nc(Cc3ccccc3)cs2)cc1Br
Yield: 97 %

Procedure:
4-(4-Benzyl-1,3-thiazol-2-yl)-2-bromo-1-trifluoroacetylaminobenzene and (R)-1-(N-benzyloxycarbonylpyrrolidin-2-yl)-3-hydroxypropene were used. Chromatography using elution with a 1-5% either gradient in methylene chloride afforded the title compound (97%) as a white foam: FAB LRMS (m/z, relative intensity) 686 (MH2+, 100), 685 (MH+, 60), 684 (M+, 90), 640 (23), 578 (15), 441 (17), 371 (20); FAB HRMS calculated for [C33H29BrF3N3O3S.H]+ [with 79Br and 32S] 664.1145, found 664.1157.
Reaction SMILES: [N:1]1[C:8]([NH2:9])=[N:7][C:5]([NH2:6])=[N:4][C:2]=1[NH2:3].C=O.[OH-].[Na+].[C:14](O)(=O)C(O)=O>CO>[CH3:14][NH:3][C:2]1[N:4]=[C:5]([NH2:6])[N:7]=[C:8]([NH2:9])[N:1]=1
Reactant: Nc1nc(N)nc(N)n1
Reactant: O=C(O)C(=O)O
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CNc1nc(N)nc(N)n1
Temperature: 70 °C

Procedure:
C-2: A mixture of 378 parts by weight of melamine and 810 parts by weight of 37% formalin was adjusted to pH 7-8 with sodium hydroxide. The mixture was heated to about 70° C. and when it became transparent, 1800 parts by weight of methyl alcohol and 1.9 parts by weight of oxalic acid were added thereto. Then, the mixture was boiled for several minutes. The reaction mixture was cooled, then filtrated and concentrated under reduced pressure to obtain polymethoxy methyl melamine (C-2). An analysis showed that the number of methanol bonded was about 3 mols per 1 mol of melamine.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=S(Cl)Cl.[CH:13]1[CH:18]=[C:17]([OH:19])[CH:16]=[C:15]([CH2:20][C@H:21]([NH2:25])[C:22](O)=[O:23])[CH:14]=1>CCOC(C)=O>[NH2:25][CH:21]([CH2:20][C:15]1[CH:14]=[CH:13][CH:18]=[C:17]([OH:19])[CH:16]=1)[C:22]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:23]
Reactant: N[C@@H](Cc1cccc(O)c1)C(=O)O
Reactant: OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: NC(Cc1cccc(O)c1)C(=O)OCc1ccccc1
Temperature: -5 °C
Reaction time: 0.08 h
Yield: 59 %

Procedure:
To 10 mL of benzyl alcohol at −5° C. was added, with stirring, 0.2 mL of SOCl2 slowly. The clear colorless solution was cooled to −5° C. and 490 mg of meta-Tyrosine was added. After 5 min, the resulting solution was heated to 120° C. overnight. 100 ml of AcOEt are added. The organic phase are washed with saturated NaHCO3 and brine then dried over Na3SO4, filtered and concentrated to afford 170 as a white solid (430 mg, 59%). 1H NMR (DMSO): δ 1.90 (s, 3H), 2.87 (dd, 1H, J=13.1, 6.5 Hz), 2.94 (dd, 1H, J=13.1, 6.5 Hz), 3.73 (t, 1H, J=6.5 Hz), 5.19 (s, 2H), 6.70 (d, 1H, J=7.7 Hz), 6.75 (s, 1H), 7.17 (t, 1H, J=7.7 Hz), 7.41 (d, 1H, J=7.0 Hz), 7.48 (m, 5H), 9.37 (s, 1H).
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[CH:8]=[N:9][N:10]2[CH2:15][CH2:14][CH2:13][NH:12][C:11]=12.C(N(C(C)C)C(C)C)C.[C:25]([O:29][C:30]([NH:32][CH2:33][C:34](ON1C(=O)CCC1=O)=[O:35])=[O:31])([CH3:28])([CH3:27])[CH3:26]>C(Cl)Cl>[C:25]([O:29][C:30]([NH:32][CH2:33][C:34]([NH:6][C:7]1[CH:8]=[N:9][N:10]2[CH2:15][CH2:14][CH2:13][NH:12][C:11]=12)=[O:35])=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: Nc1cnn2c1NCCC2
Reactant: CC(C)(C)OC(=O)NCC(=O)ON1C(=O)CCC1=O
Agent: O=S(=O)(O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)Nc1cnn2c1NCCC2
Temperature: 25 °C
Reaction time: 14 h
Yield: 81.3 %

Procedure:
To a solution of 3-amino-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine sulfuric acid salt (2.96 g) and N-ethyldiisopropylamine (2.59 g) in methylene chloride (70 ml) was added N-[2-(tert-butoxycarbonylamino)acetoxy]succinimide (2.72 g). The mixture was stirred at room temperature for 14 hours. The reaction mixture was washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 6% methanol/chloroform to give 3-[2-(tert-butoxycarbonylamino)acetyl]amino-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (2.4 g) as a solid.
Reaction SMILES: [NH2:1][C:2]([CH3:23])([CH3:22])[CH2:3][O:4][C:5](=[O:21])[C@H:6]([CH:18]([CH3:20])[CH3:19])[NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].N1C=CC=CC=1.Cl[C:31]([O:33][CH2:34][Cl:35])=[O:32]>ClCCl>[Cl:35][CH2:34][O:33][C:31]([NH:1][C:2]([CH3:23])([CH3:22])[CH2:3][O:4][C:5](=[O:21])[C@H:6]([CH:18]([CH3:19])[CH3:20])[NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])=[O:32]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(C)(C)N
Reactant: O=C(Cl)OCCl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(C)(C)NC(=O)OCCl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-amino-2-methyl-1-(N-benzyloxycarbonyl-L-valyloxy)-propane (2.9 g, 9 mmole) and pyridine (2 ml) in dichloromethane (50 ml) was added chloromethyl chloroformate(1.55 g, 12 mmole) and the mixture was stirred for 3 hours at room temperature. The mixture was evaporated under reduced pressure and ethyl acetate was added. The organic phase was washed with water, dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography with hexane/ethyl acetate. Yield: 1.1 g=29%.