Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:4][C@@H:5]1[C@@H:10]([OH:11])[C@@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@H:6]1NC(=O)CCCCCNC(=O)C=C)(=O)C.[C:28]([NH2:32])(=[O:31])[CH:29]=[CH2:30]>O>[OH:31][CH:6]1[O:7][C@H:8]([CH2:13][OH:14])[C@H:9]([OH:12])[C@H:10]([OH:11])[C@H:5]1[NH2:4].[C:28]([NH2:32])(=[O:31])[CH:29]=[CH2:30]
Reactant: C=CC(=O)NCCCCCC(=O)N[C@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1NC(C)=O
Agent: C=CC(N)=O
Solvent: O
Product: N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O
Temperature: 60 °C
Reaction time: 24 h
Yield: 249.8 %

Procedure:
Monomer 52 (150 mg, 0.4 mmol) and acrylamide (1.15 g, 1.6 mmol) were dissolved in 3 mL of water and purged with nitrogen for 5 min. The radical initiator V-50 (2.5 mg) was added to the reaction mixture and the solution was heated to 60° C. for 30 min. The solution became viscous during this period. The heating was discontinued and the reaction mixture was stirred for 24 hr at room temperature. The viscous solution was poured into 50 mL of isopropanol while stirring, causing the polymer to precipitate. The polymer was collected by filtration and dried under vacuum at room temperature to give 53 as a white powder (250 mg).
Reaction SMILES: C[Si](C)(C)[C:3](=[O:5])[CH3:4].C1CCN2C(=NCCC2)CC1.[C:19]1([CH:25]=[CH:26][C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CC(O)C>[Br-].C([N+]1C(C)=C(CCO)SC=1)C.C1COCC1>[C:29]1([C:27](=[O:28])[CH2:26][CH:25]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:3](=[O:5])[CH3:4])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(C=Cc1ccccc1)c1ccccc1
Reactant: CC(=O)[Si](C)(C)C
Agent: CC[n+]1csc(CCO)c1C
Agent: [Br-]
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)C(CC(=O)c1ccccc1)c1ccccc1
Temperature: 70 °C
Reaction time: 24 h

Procedure:
1-Trimethylsilanyl-ethanone (1.15 mL; 8.02 mmol) followed by DBU (0.18 mL; 1.2 mmol) were added to a suspension of 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide (304 mg; 1.21 mmol) in dry THF (5 mL). The mixture was heated at 70° C. for 4 min, cooled near rt, then chalcone (833 mg; 4.00 mmol) and 2-propanol (1.22 mL; 15.9 mmol) were added. The reaction was degassed and reacted under nitrogen at 70° C. After 24 h, the reaction was concentrated on a rotary evaporator. Ethyl acetate (25 mL) was added and this washed with H2O (3×3 mL) and satd NaCl (2×3 mL). The organic portion was dried (MgSO4) and filtered through silica with an EtOAc wash. Crude product was adsorbed onto silica (2 g) then purified by MPLC (40 g of silica using a 0→20% EtOAc in hexanes gradient). Pure product was obtained as a clear, colorless viscous liquid (980 mg; 97%). 1H NMR (CDCl3) d 7.98-7.94 (m, 2H), 7.56 (m, 1H), 7.47-7.42 (m, 2H), 7.39-7.27 (m, 5H), 4.44 (dd, J=3.6, 10.0 Hz, 1H), 4.02 (dd, J=10.0, 18.0 Hz, 1H), 3.14 (dd, J=3.6, 18.0 Hz, 1H); GC-MS 252 ([M]+).
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[Br-].[Na+].CC1[CH:13]=[CH:12][C:11]([C:14]([C:16]23[CH2:25][CH:20]4[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]4)[CH2:17]2)[CH2:23]3)=[O:15])=[CH:10][CH:9]=1>O.O.O.O.C([O-])(=O)C.[Co+2].C([O-])(=O)C.O.O.O.O.C([O-])(=O)C.[Mn+2].C([O-])(=O)C.O>[C:16]12([C:14]([C:11]3[CH:12]=[CH:13][C:2]([C:1]([OH:4])=[O:3])=[CH:9][CH:10]=3)=[O:15])[CH2:23][CH:22]3[CH2:21][CH:20]([CH2:19][CH:18]([CH2:24]3)[CH2:17]1)[CH2:25]2
Reactant: CC(=O)O
Reactant: Cc1ccc(C(=O)C23CC4CC(CC(C4)C2)C3)cc1
Agent: [Co+2]
Agent: [Mn+2]
Agent: CC(=O)[O-]
Solvent: O
Product: O=C(O)c1ccc(C(=O)C23CC4CC(CC(C4)C2)C3)cc1
Temperature: 25 °C
Yield: 78 %

Procedure:
64.6 mL of acetic acid, 3.4 mL of water, 333 mg (1.34 mmol) of cobalt acetate tetrahydrate, 33 mg (0.134 mmol) of manganese acetate tetrahydrate and 138 mg (1.34 mmol) of sodium bromide were added to 3.4 g (13.4 mmol) of (4-methylphenyl) (adamantan-1-yl)methanone, and the mixture was stirred at room temperature for a short time. While blowing air into the mixture, the mixture was stirred in an oil bath at 100 to 110° C. for one day. The reaction mixture was cooled to room temperature, and water was added thereto. The precipitated solids were collected by filtration, washed with water, and air-dried, thereby giving 2.99 mg of 4-(adamantan-1-ylcarbonyl)benzoic acid (yield: 78%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].O.[NH2:14][C:15]1[NH:19][N:18]=[N:17][N:16]=1>O1CCCC1.O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([NH:14][C:15]1[NH:19][N:18]=[N:17][N:16]=1)=[O:8])([O-:3])=[O:2]
Reactant: Nc1nnn[nH]1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1nnn[nH]1)c1cccc([N+](=O)[O-])c1
Reaction time: 16 h

Procedure:
In a similar manner, a solution of 46.4 g of 3-nitrobenzoyl chloride in 100 ml of tetrahydrofuran was added to a hot solution of 51.6 g of 5-aminotetrazole monohydrate in 1200 ml of tetrahydrofuran and 50 ml of water. The mixture was allowed to stand for 16 hours and then concentrated, and the resulting slurry was treated with water. The white solid was collected, washed with water and oven-dried to give 3-nitro-N-(1H-tetrazol-5-yl)benzamide melting at about 276° C. with decomposition.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:24])([C:7]3[CH:15]=[CH:14][C:13]([CH:16]=[CH:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:25].CN(C)C=O>C(O)C.[Pd]>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:24])([C:7]3[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:25]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(C=Cc4ccccc4)cc3CC[C@@H]12
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCO
Product: CN1C(=O)CC[C@]2(C)c3ccc(CCc4ccccc4)cc3CC[C@@H]12

Procedure:
A 150 mg portion of the product of Example 279 was hydrogenated on a Parr apparatus at 40 p.s.i. in 50 mL of ethanol containing 5 mL of dimethylformamide and 20 mg of 10% palladium/carbon catalyst. When the starting material had been consumed, the mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by chromatography on silica gel, eluting with 90% ethyl acetate/hexane to obtain a product which was recrystallized from ethyl acetate/hexane to produce the desired product. m.p. 109°-111°.
Reaction SMILES: [C:1](O[C@@H](C1C(C)=CC2N=C(N3CCN(C)C(C4C=C5C(=CC=4)N(C)N=C5)C3=O)SC=2C=1C1C=CC(Cl)=CC=1)C(O)=O)(C)([CH3:3])[CH3:2].[C:45]([O:49][C@@H:50]([C:56]1[C:80]([CH3:81])=[CH:79][C:59]2[N:60]=[C:61]([N:63]3[CH2:68][CH2:67][NH:66][CH:65]([C:69]4[CH:70]=[C:71]5[C:75](=[CH:76][CH:77]=4)[N:74]([CH3:78])[N:73]=[CH:72]5)[CH2:64]3)[S:62][C:58]=2[C:57]=1[C:82]1[CH:87]=[CH:86][C:85]([Cl:88])=[CH:84][CH:83]=1)[C:51]([O:53][CH2:54][CH3:55])=[O:52])([CH3:48])([CH3:47])[CH3:46].COC(OC)(C)C.C=O>CC(C)=O>[C:45]([O:49][C@@H:50]([C:56]1[C:80]([CH3:81])=[CH:79][C:59]2[N:60]=[C:61]([N:63]3[CH2:68][CH2:67][N:66]([CH:1]([CH3:3])[CH3:2])[CH:65]([C:69]4[CH:70]=[C:71]5[C:75](=[CH:76][CH:77]=4)[N:74]([CH3:78])[N:73]=[CH:72]5)[CH2:64]3)[S:62][C:58]=2[C:57]=1[C:82]1[CH:87]=[CH:86][C:85]([Cl:88])=[CH:84][CH:83]=1)[C:51]([O:53][CH2:54][CH3:55])=[O:52])([CH3:46])([CH3:47])[CH3:48]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(N3CCNC(c4ccc5c(cnn5C)c4)C3)sc2c1-c1ccc(Cl)cc1
Reactant: Cc1cc2nc(N3CCN(C)C(c4ccc5c(cnn5C)c4)C3=O)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Agent: C=O
Solvent: COC(C)(C)OC
Solvent: CC(C)=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(N3CCN(C(C)C)C(c4ccc5c(cnn5C)c4)C3)sc2c1-c1ccc(Cl)cc1

Procedure:
(2S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(4-isopropyl-3-(1-methyl-1H-indazol-5-yl)piperazin-1-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (16 mg) was prepared in a similar manner as (2S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(4-methyl-3-(1-methyl-1H-indazol-5-yl)-2-oxopiperazin-1-yl)benzo[d]thiazol-6-yl)acetic acid except using (2S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(3-(1-methyl-1H-indazol-5-yl)piperazin-1-yl)benzo[d]thiazol-6-yl)acetate, and acetone and 2,2-dimethoxypropane instead of (2S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(3-(1-methyl-1H-indazol-5-yl)-2-oxopiperazin-1-yl)benzo[d]thiazol-6-yl)acetic acid and formaldehyde. LCMS-ESI+: calc'd for C37H45ClN5O3S: 674.3 (M+H+); Found: 674.3 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[Cl:17].Br[C:19]1[CH:20]=[N:21][CH:22]=[N:23][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].COCCOC>[Cl:17][C:3]1[CH:4]=[C:5]([C:19]2[CH:20]=[N:21][CH:22]=[N:23][CH:24]=2)[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: CC1(C)OB(c2ccc(N)c(Cl)c2)OC1(C)C
Reactant: Brc1cncnc1
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Nc1ccc(-c2cncnc2)cc1Cl
Temperature: 150 °C
Yield: 84 %

Procedure:
To a mixture of 4-amino-3-chlorophenylboronic acid pinacol ester (0.110 g, 0.434 mmol), 5-bromopyrimidine (0.090 g, 0.56 mmol), 1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) DCM complex (23 mg, 0.028 mmol) was added anhydrous DME (3.0 mL) followed by 2M aqueous sodium carbonate (0.53 mL, 1.06 mmol). The microwave vial was heated at 150° C. for 15 minutes under microwave irradiation. The reaction was partitioned between ethyl acetate (60 mL) and a saturated aqueous NaHCO3 solution (15 mL). The organic layer was washed with a saturated aqueous NaHCO3 solution (15 mL), dried (Na2SO4) and concentrated in vacuo. The residue was purified using preparative TLC eluting with 20% ethyl acetate in CH2Cl2. The product band was recovered and stirred with 2% MeOH in ethyl acetate/CH2Cl2 (v/v; 1:5) (20 mL). The silica was removed by filtration, washed with ethyl acetate/CH2Cl2 (v/v; 1:1) (2×5 mL) and acetone (3×4 mL) to give the title compound as a white solid (0.075 g, 84%). 1H-NMR (500 MHz, DMSO-d6) 5.72 (s, 2H), 6.91 (d, J=8.4, 1H), 7.51 (dd, J=2.2, 8.3 Hz, 1H), 7.72 (d, J=2.2 Hz, 1H), 9.04, 9.05 (2×s, 3H).
Reaction SMILES: [CH3:1][CH:2]([CH3:17])[CH2:3][C@H:4]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:5]([O:7]C(C)(C)C)=[O:6]>Cl.O1CCOCC1>[CH3:1][CH:2]([CH3:17])[CH2:3][C@H:4]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:5]([OH:7])=[O:6]
Reactant: CC(C)C[C@H](NS(C)(=O)=O)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)C[C@H](NS(C)(=O)=O)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)-tert-Butyl 2-amino-4-methylpentanoate hydrochloride (1.53 g, 6.84 mmol) was dissolved in dichloromethane and triethylamine (3.15 mL, 22.57 mmol). Methanesulfonyl chloride (0.638 mL, 8.21 mmol) was added dropwise, and the reaction stirred at room temperature for 1 hour. The reaction was quenched with saturated aqueous NaHCO3 and extracted with dichloromethane (3×50 mL). The solvent was removed in vacuo to give (S)-tert-butyl 4-methyl-2-(methylsulfonamido)pentanoate: 1H NMR (300 MHz, CDCl3) δ ppm 4.71 (d, J=9.7, 1H), 3.98 (td, J=9.5, 5.5, 1H), 2.92 (s, 3H), 1.84 (dt, J=13.1, 6.6, 1H), 1.54 (s, 9H), 1.44-1.48 br s, 1H), 0.96 (dd, J=6.6, 2.4, 6H); MS (ESI−) m/z 264 (M−H)−. (S)-tert-Butyl 4-methyl-2-(methylsulfonamido)pentanoate was dissolved in 10 mL of 4 N HCl in dioxane and stirred at room temperature overnight. The solvent was removed under a stream of nitrogen and under high vacuum to give (S)-4-methyl-2-(methylsulfonamido)pentanoic acid: 1H NMR (300 MHz, CDCl3) δ ppm 4.86 (d, J=9.6, 1H), 4.17 (td, J=9.6, 4.8, 1H), 3.18-3.07 (m, 1H), 2.99 (s, 3H), 1.96-1.80 (m, 1H), 1.64 (dddd, J=23.4, 13.9, 9.1, 5.0, 2H), 1.40 (t, J=7.3, 1H), 0.98 (dd, J=6.6, 3.3, 6H).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[CH3:19][O:20][C:21](=[O:76])[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][C:31]2[C:39]3[C:34](=[CH:35][CH:36]=[C:37]([Cl:40])[CH:38]=3)[N:33]([CH:41]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:32]=2[CH2:54][CH2:55][O:56][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:24][C:23]=1[O:74][CH3:75]>C1COCC1>[CH3:19][O:20][C:21](=[O:76])[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][C:31]2[C:39]3[C:34](=[CH:35][CH:36]=[C:37]([Cl:40])[CH:38]=3)[N:33]([CH:41]([C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:32]=2[CH2:54][CH2:55][OH:56])=[CH:24][C:23]=1[O:74][CH3:75]
Reactant: COC(=O)c1ccc(OCCc2c(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCCc2c(CCO)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.2 %

Procedure:
TBAF (1M in THF) (0.37 mL, 0.37 mmol) was added to a solution of 4-(2-{1-Benzhydryl-2-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-5-chloro-1H-indol-3-yl}-ethoxy)-2-methoxy-benzoic acid methyl ester (0.25 g, 0.31 mmol) in THF (4 mL). Reaction was stirred at room temperature for 30 minutes. Reaction solution was concentrated by rotary evaporation and the resulting residue was purified with silica gel prep plates and 1:9 EtOAc/dichloromethane as eluent. Obtained 0.11 g of 4-{2-[1-Benzhydryl-5-chloro-2-(2-hydroxy-ethyl)-1H-indol-3-yl]-ethoxy}-2-methoxy-benzoic acid methyl ester (white solid) in 62% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[CH3:18][N:19]1[CH2:24][CH2:23][CH:22]([CH2:25][NH2:26])[CH2:21][CH2:20]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:26][CH2:25][CH:22]1[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]1
Reactant: CN1CCC(CN)CC1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Product: CN1CCC(CNc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Yield: 85.2 %

Procedure:
Following general procedure B, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (0.880 g, 2.83 mmol) was reacted with (1-methylpiperidin-4-yl)methanamine (435 mg, 3.39 mmol) to afford the desired product (970 mg, 85%) as a light brown solid: 1H NMR (300 MHz, CDCl3) δ 10.87 (s, 1H), 9.22 (s, 1H), 8.36 (d, J=1.9 Hz, 1H), 7.80 (d, J=8.9 Hz, 1H), 7.73 (dd, J=8.9, 2.0 Hz, 1H), 3.69 (dd, J=6.4, 5.2 Hz, 2H), 2.93 (d, J=11.4 Hz, 2H), 2.79-2.60 (m, 1H), 2.31 (s, J=9.0 Hz, 3H), 2.01 (t, J=11.7 Hz, 2H), 1.89 (d, J=12.7 Hz, 2H), 1.76-1.60 (m, 1H), 1.53-1.30 (m, 2H), 1.30-1.17 (m, 2H), 1.10-0.95 (m, 2H).
Reaction SMILES: [C:1]([O:12][CH3:13])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([O-:8])=[O:7])=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:17])=O>CN(C=O)C.C1(C)C=CC=CC=1>[Cl-:17].[C:1]([O:12][CH3:13])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([O-:8])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Agent: COC(=O)c1ccc(C(=O)[O-])cc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: [Cl-]
Temperature: 45 °C
Reaction time: 16 h

Procedure:
To a stirred solution of mono-methyl terephthalate (1 equivalent), toluene (30 ml/gm of ester) and 3 drops of DMF was added dropwise oxalyl chloride (2.0 equivalents). The reaction mixture was stirred at 45° C. for 16 hours. The solution was concentrated under reduced pressure to give the desired product as a pale yellow solid. The product was used without further purification; yield 82.0%; m.p. 50°-52° C. IR (thin film); 2970, 1775, 1720, 1430, 1400, 1280, 1105, 880 cm-1.
Reaction SMILES: [C:1]1(/[CH:11]=[C:12]2/[CH:13]([OH:22])[C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]#[C:21]/2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:23]([O:30][CH2:31][C:32](Cl)=[O:33])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C1C=CN=CC=1)C>[CH2:23]([O:30][CH2:31][C:32]([O:22][CH:13]1[C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]#[C:21]/[C:12]/1=[CH:11]\[C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)=[O:33])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: OC1C#CCCCCC#C/C1=C\c1cccc2ccccc12
Reactant: O=C(Cl)COCc1ccccc1
Agent: CN(C)c1ccncc1
Product: O=C(COCc1ccccc1)OC1C#CCCCCC#C/C1=C\c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.1 %

Procedure:
To a solution of Compound 20b (12.1 mg, 4.37×10−2 mmol) and DMAP (57.5 mg, 0.44 mmol) in dry Ch2Cl2 (5 mL) cooled in an ice-water bath was added benzyloxyacetyl chloride (16.1 mg, 8.74×10−2 mmol) followed by stirring at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography (silica gel, 20 percent EtOAc in hexane) to give 13.5 mg (73 percent) of Compound 38: pale yellow oil; Rf=0.52 (20 percent EtOAc in hexane); IR (neat) 2956, 2212, 1755, 1188, 1069 cm−1; 1H NMR (300 MHz, CDCl3) δ8.32 (d, J=7.44 Hz, 1H), 8.09-8.00 (m, 1H), 7.92-7.79 (m, 2H), 7.58-7.46 (m, 3H), 7.44-7.28 (m, 6H), 6.33 (t, J=1.35 Hz, 1H), 4.68 (s, 2H), 4.24 and 4.18 (AB q, J=16.59 Hz, 2H), 2.52-2.22 (m, 4H), 1.98-1.66 (m, 4H); 13C NMR (75 MHz, CDCl3) δ170.5, 134.2, 133.4, 132.6, 131.9, 129.8, 129.3, 129.2, 128.9, 128.7, 127.1, 127.0, 126.5, 125.9, 124.1, 123.4, 121.3, 103.4, 94.5, 80.8, 79.0, 74.1, 70.2, 68.0, 28.2, 28.1, 22.5, 21.4; MS (+CI) m/z (relative intensity) 435 (M+, 1), 271 (100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[F:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[F:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:11]=[CH:12][C:3]=2[O:2][CH3:1])=[O:19])=[CH:16][CH:15]=1
Reactant: COc1ccc2ccccc2c1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc2ccccc2c1C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.9 %

Procedure:
A solution of 2-methoxynaphthalene (20.0 g, 120 mmol) and 4-fluorobenzoyl chloride (15 ml, 126 mmol) in methylene chloride (200 ml) was cooled in an ice bath under nitrogen and aluminum chloride (18.5 g, 129 mmol, 1.1 equiv.) was added portionwise over 10 minutes. The reaction mixture was stirred at room temperature for 3 h and then poured into 2N HCl (500 ml). The product was extracted into methylene chloride, and washed with brine, and dried over sodium sulfate. The organic layer was concentrated in vacuo to give 34.6 g of 1-(4-fluoro-benzoyl)-2-methoxynaphthalene as a solid (97% yield) which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N:8]=[C:9]=[S:10])=[C:6]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:5]=[CH:4][CH:3]=1.[NH3:17]>>[CH3:1][C:2]1[C:7]([NH:8][C:9]([NH2:17])=[S:10])=[C:6]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(N2CCOCC2)c1N=C=S
Reactant: N
Product: Cc1cccc(N2CCOCC2)c1NC(N)=S

Procedure:
Reaction of 6-methyl-2-morpholinophenyl isothiocyanate (8.8 g) with 33% alcoholic ammonia solution (60 ml) at room temperature for 5 hours gave 1-(6-methyl-2-morpholinophenyl)thiourea (9 g) as a pale yellow solid, m.p. 199° C. which was recrystallised from a 1:1 mixture of ethylacetate and hexane.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[Cl:14][C:15]1[C:20]([O:21][CH3:22])=[C:19](Cl)[N:18]=[CH:17][N:16]=1.CC(C)([O-])C.[K+]>C1COCC1>[CH:1]([O:4][C:5]([N:7]1[CH2:8][CH2:9][CH:10]([O:13][C:19]2[C:20]([O:21][CH3:22])=[C:15]([Cl:14])[N:16]=[CH:17][N:18]=2)[CH2:11][CH2:12]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCC(O)CC1
Reactant: COc1c(Cl)ncnc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1c(Cl)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Temperature: 7.5 °C
Reaction time: 1 h
Yield: 103.7 %

Procedure:
A solution of 4-hydroxy-piperidine-1-carboxylic acid isopropyl ester (71.0 g, 380 mmol) and 4,6-dichloro-5-methoxypyrimidine (71.6 g, 400 mmol) in anhydrous THF (1 L) was cooled to 5° C. under N2. A solution of potassium t-butoxide (1.0 M in THF, 380 mL, 380 mmol) was added dropwise over 1 h. The reaction temperature was kept under 10° C. during addition. The reaction mixture was stirred at 5-10° C. for 1 h, quenched with saturated NH4Cl (200 mL), and diluted with ether (1 L) and water (1 L). The aqueous phase was separated and discarded. The organic extract was washed with brine (800 mL), dried over MgSO4, and then concentrated. The residue was dissolved in hexane (400 mL) and filtered over Celite™ to remove a small amount of brown solid. The solvent was removed from the filtrate to afford a pale amber oil which gradually crystallized to give the title compound (130 g, 98.6% yield) as a pale amber solid. Exact Mass calculated for C14H20ClN3O4: 329.1. Found: LCMS m/z=330.2 (M+H+); 1H NMR (400 MHz, CDCl3) δ 1.25 (d, J=6.2 Hz, 6H), 1.82 (m, 2H), 2.02 (m, 2H), 3.40 (m, 2H), 3.80 (m, 2H), 3.91 (s, 3H), 4.95 (m, 1H), 5.39 (m, 1H), 8.27 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[C:4]2[N:44](COCC[Si](C)(C)C)[CH:43]=[N:42][C:5]=2[C:6]([CH2:33][C:34]2[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][C:35]=2[Cl:41])=[N:7][C:8]=1[NH:9][C:10]1[CH:30]=[CH:29][C:13]([C:14]([N:16]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)=[O:15])=[CH:12][C:11]=1[O:31][CH3:32])#[N:2].C(=O)(O)[O-].[Na+]>S(=O)(=O)(O)O.O>[Cl:40][C:39]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:41])[C:34]=1[CH2:33][C:6]1[C:5]2[N:42]=[CH:43][NH:44][C:4]=2[C:3]([C:1]#[N:2])=[C:8]([NH:9][C:10]2[CH:30]=[CH:29][C:13]([C:14]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[O:15])=[CH:12][C:11]=2[O:31][CH3:32])[N:7]=1
Reactant: COc1cc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1nc(Cc2c(Cl)cccc2Cl)c2ncn(COCC[Si](C)(C)C)c2c1C#N
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: COc1cc(C(=O)N2CCNCC2)ccc1Nc1nc(Cc2c(Cl)cccc2Cl)c2nc[nH]c2c1C#N
Temperature: 95 °C

Procedure:
To a solution of the product of Example 39D (100 mg, 0.13 mmol) in concentrated sulfuric acid (5 mL) at 0° C. was added water (1 mL) and the mixture was heated at 95° C. for 20 minutes. After cooling, the mixture was diluted with water (3 mL), adjusted to pH 8-9 with saturated sodium bicarbonate solution and extracted with dichloromethane (3×20 mL). The combined organic phase was concentrated and the residue was purified via preparative HPLC using a gradient of 10/90 to 75/25 acetonitrile/water (containing 0.1% trifluoroacetic acid) to give the title compound. 1H NMR (DMSO-d6, 300 MHz): δ 12.18 (s, 1 H), 9.60 (br, 1 H), 8.86 (s, 2 H), 8.64 (s, 1 H), 7.79-7.78 (m, 1 H), 7.77 (s, 1H), 7.72 (s, 1 H), 7.64-7.61 (m, 2 H), 7.48 (d, J=9 Hz, 1 H), 6.98 (s, 1 H), 6.57 (d, J=9 Hz, 1 H), 4.90 (s, 2 H), 3.88 (s, 3 H), 3.23-3.10 (m, 8 H). MS: 554 (M+H+).
Reaction SMILES: C[O:2][C:3](=[O:21])[C@H:4]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[NH:5][C:6](=[O:13])[C@H:7]([CH2:9][C:10](=[O:12])[OH:11])[NH2:8].[CH:22](N[C@@H]1C(=O)OC(=O)C1)=[O:23].N[C@H](C(O)=O)CC1C=CC=CC=1>O>[CH:22]([NH:8][C@H:7]([C:6]([NH:5][C@H:4]([C:3]([OH:2])=[O:21])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:13])[CH2:9][C:10](=[O:12])[OH:11])=[O:23]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(=O)O
Reactant: O=CN[C@H]1CC(=O)OC1=O
Agent: N[C@@H](Cc1ccccc1)C(=O)O
Solvent: O
Product: O=CN[C@@H](CC(=O)O)C(=O)N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
A process for preparing an α-L-aspartyl-L-phenylalanine methyl ester which comprises the steps of reacting formyl-L-aspartic anhydride with L-phenylalanine in the presence of water at a high pH, to produce formyl-α-L-aspartyl-L-phenylalanine; removing the formyl group from the formyl-α-L-aspartyl-L-phenylalanine and esterifying the resultant compound with methanol and hydrogen chloride to produce the hydrogen chloride salt of α-L-aspartyl-L-phenylalanine methyl ester; neutralizing the hydrogen chloride salt of α-L-aspartyl-L-phenylalanine methyl ester; and filtering the neutralized solution to produce α-L-aspartyl-L-phenylalanine methyl ester.