Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Li].[CH3:3][N:4]([CH3:14])[S:5]([N:8]1[CH:12]=[C:11](Br)[CH:10]=[N:9]1)(=[O:7])=[O:6].[B:15](OCC)([O:19]CC)[O:16]CC>C1COCC1>[CH3:3][N:4]([CH3:14])[S:5]([N:8]1[CH:12]=[C:11]([B:15]([OH:19])[OH:16])[CH:10]=[N:9]1)(=[O:7])=[O:6]
Reactant: CN(C)S(=O)(=O)n1cc(Br)cn1
Reactant: CCOB(OCC)OCC
Agent: [Li]C
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1cc(B(O)O)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.3 %

Procedure:
Methyl lithium (1.6M in Et2O, 12.2 ml, 19.5 mmol) was added to a stirred solution of 4-bromo-pyrazole-1-sulfonic acid dimethylamide (3.18 g, 14.9 mmol) and triethyl borate (3.80 ml, 22.3 mmol) in anhydrous THF (40 ml), such that the internal temperature remained >-60° C. After 30 min, the reaction was allowed to warm to room temperature and stirred for 18 h. The reaction was quenched with 2N HCl (25 ml), then extracted with EtOAc (×3). The organic extracts were combined, dried (Na2SO4), filtered and the solvent removed in vacuo. The material was purified by silica column chromatography to afford a colourless gum (2.1 g). MS: [M+H]+=220
Reaction SMILES: CCN(CC)CC.[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][OH:15])=[CH:12][CH:11]=1.O.C(C1C=C(C(C)(C)C)C=C(C(C)(C)C)C=1)(C)(C)C>ClCCCl>[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1
Reactant: COc1ccc(CO)cc1
Agent: CC(C)(C)c1cc(C(C)(C)C)cc(C(C)(C)C)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COc1ccc(C=O)cc1
Temperature: 60 °C
Yield: 98 %

Procedure:
Complex 8 (8.8 mg, 0.021 mmol) and NEt3 (14 μL, 0.10 mmol) were dissolved in 1,2-dichloroethane (2 mL). The solution was added to a flask containing 4-methoxybenzyl alcohol (140 mg, 1.01 mmol), H2O (91 μL, 5.05 mmol), and a 1,3,5-tri-tert-butylbenzene internal standard (19.2 mg, 0.078 mmol). The flask was equipped with an air condenser and a stir bar and heated at 60° C. for 24 h with stirring (˜700 rpm). The reaction mixture was cooled to room temperature, the solvent removed under vacuum, and the extent of conversion determined by integration of the 1H NMR spectrum against the internal standard. 4-Methoxybenzaldehyde was formed in >98% yield (based on the average of two runs of this type).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:25]=[CH:26][C:27]=2[O:28][CH3:29])[CH2:10][N:11]2[C:19]3[N:18]=[C:17]([CH:20]([CH3:22])[CH3:21])[NH:16][C:15]=3[C:14](=[O:23])[NH:13][C:12]2=S)[CH2:5][CH2:4][CH2:3][CH2:2]1>[OH-].[Na+].[Ni]>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:25]=[CH:26][C:27]=2[O:28][CH3:29])[CH2:10][N:11]2[C:19]3[N:18]=[C:17]([CH:20]([CH3:22])[CH3:21])[NH:16][C:15]=3[C:14](=[O:23])[N:13]=[CH:12]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(Cn2c(=S)[nH]c(=O)c3[nH]c(C(C)C)nc32)cc1OC1CCCC1
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(Cn2cnc(=O)c3[nH]c(C(C)C)nc32)cc1OC1CCCC1
Reaction time: 0.5 h

Procedure:
4.15 g (10 mM) of 3-(3-Cyclopentyloxy-4-methoxy-benzyl)-8-isopropyl-2-thioxanthine was dissolved in 42 ml of 1N NaOH and treated with three portions of 3 g of Raney-nickel with 0.5 hour intervals. After a further 0.5 hour, the nickel was filtered off and the solution acidified with 8 ml of 5N HCl to pH 3 and then neutralized with sodium bicarbonate solution to pH 7. The solid was collected, washed and dried: 3.62 g (94.5%) of hypoxanthine having a melting point of 243°-4° C.
Reaction SMILES: CC([N:5]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:41])[CH2:16][C@@H:17]1[N:23]=[C:22]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:21]2[CH:31]=[C:32]([O:35][CH3:36])[CH:33]=[CH:34][C:20]=2[N:19]2[C:37]([CH3:40])=[N:38][N:39]=[C:18]12)C(=O)[O-])(C)C.[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45]>ClCCl>[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45].[NH2:5][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:41])[CH2:16][C@@H:17]1[N:23]=[C:22]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:21]2[CH:31]=[C:32]([O:35][CH3:36])[CH:33]=[CH:34][C:20]=2[N:19]2[C:37]([CH3:40])=[N:38][N:39]=[C:18]12
Reactant: COc1ccc2c(c1)C(c1ccc(Cl)cc1)=N[C@@H](CC(=O)NCCCCCN(C(=O)[O-])C(C)(C)C)c1nnc(C)n1-2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)C(c1ccc(Cl)cc1)=N[C@@H](CC(=O)NCCCCCN)c1nnc(C)n1-2
Reaction time: 3 h

Procedure:
To a solution of 1,1-dimethylethyl[5-({[(4S)-6-(4-chlorophenyl)-1-methyl-8-(methyloxy)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]acetyl}amino)pentyl]carbamate (for a preparation see Reference compound H) (0.2 g, 0.34 mmol) in dichloromethane (3 ml) was added trifluoroacetic acid (0.053 ml, 0.68 mmol) dropwise at 0° C. The reaction mixture was stirred for 3 h from 0° C. to room temperature. The reaction mixture was concentrated to dryness to afford the title compound as a hygroscopic yellow oil (200 mg)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[C:13]([O:15]C)=[O:14])=[CH:5][CH:4]=1.[H-].[Na+].[CH2:19](Br)[CH:20]=[CH2:21].[OH-].[K+]>CCO.O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2([C:13]([OH:15])=[O:14])[CH2:21][CH:20]=[CH2:19])=[CH:5][CH:4]=1
Reactant: COC(=O)C1CCCc2ccc(OC)cc21
Reactant: C=CCBr
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C=CCC1(C(=O)O)CCCc2ccc(OC)cc21

Procedure:
The sub-title compound was prepared according to the method described in Example 10(ii) above from 7-methoxytetralin-1-yl-carboxylic acid, methyl ester (0.80 g; 3.6 mmol; see Example 10(i) above), NaH (55% in oil; 0.23 mg; 5.4 mmol), and allyl bromide (0.65 g, 5.4 mmol), whereafter the crude product was hydrolysed directly according to the method described in Example 10(iii) above with KOH (3 g) in EtOH:H2O (40 mL; 1:1). Yield 0.39 g (44%).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([S:15](Cl)(=[O:17])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl.[NH2:22][C@@H:23]1[CH2:27][C:26](=[O:28])[N:25]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:24]1=[O:37].CCN(CC)CC.S(Cl)(Cl)(=O)=O>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH2:30]([O:29][N:25]1[C:26](=[O:28])[CH2:27][C@@H:23]([NH:22][S:15]([N:12]2[CH2:13][CH2:14][N:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:20])([F:19])[F:1])=[CH:4][CH:5]=3)[CH2:10][CH2:11]2)(=[O:17])=[O:16])[C:24]1=[O:37])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=S(=O)(Cl)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Reactant: N[C@@H]1CC(=O)N(OCc2ccccc2)C1=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O=S(=O)(Cl)Cl
Solvent: CN(C)C=O
Product: O=C1C[C@@H](NS(=O)(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)C(=O)N1OCc1ccccc1
Temperature: 25 °C

Procedure:
4-(4-Trifluoromethyl-phenyl)-piperazine-1-sulfonyl chloride (164 mg; 0.50 mmol), (3R)-3-Amino-1-benzyloxy-pyrrolidine-2,5-dione hydrochloric acid (102 mg; 0.40 mmol), Et3N (180 ul; 1.30 mmol) and DMAP (25 mg; 0.20 mmol) was dissolved in DMF (1 ml). The mixture was heated in a microwave oven at 200 W for 10 seconds and allowed to cool to room temperature. Another portion of the sulfonyl chloride (164 mg; 0.50 mmol) and Et3N (180 ul; 1.30 mmol) in DMF (1 ml) was added followed by heating for 10 seconds at 200 W. Reaction mixture were evaporated and filtered through Si-60 gel with EtOAC:Heptane as eluent. This crude product was purified on a C-18 column with an HPLC system using a gradient: 70% (H2O+0.1% TFA):30% (MeCN+0.1% TFA) to 100% (MeCN+0.1% TFA), gradient time=35 min, flow=10 ml/min, UV=220 nm. Fractions containing the product was evaporated to a small volume, the water phase was neutralised with 5% NaHCO3 and the product was extracted with EtOAc. The organic phase was dried (Na2SO4), filtered and evaporated to give the title compound as a colourless solid. Obtained 94 mg (45%)
Reaction SMILES: [O:1]1[C:5]2[CH2:6][CH2:7][CH2:8][C:9](=[O:10])[C:4]=2[CH:3]=[CH:2]1.[BH4-].[Na+].N1C=CN=C1.[C:18]([Si:22]([CH3:25])([CH3:24])Cl)([CH3:21])([CH3:20])[CH3:19]>CO.CCOCC.O>[C:18]([Si:22]([CH3:25])([CH3:24])[O:10][CH:9]1[C:4]2[CH:3]=[CH:2][O:1][C:5]=2[CH2:6][CH2:7][CH2:8]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1CCCc2occc21
Agent: [BH4-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: O
Solvent: CCOCC
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC1CCCc2occc21
Yield: 77 %

Procedure:
To a solution of 6,7-dihydro-4-(5H)-benzofuranone (5.0 g, 37 mmol) in methanol (50 ml) was added sodium borohydride (1.4 g, 37 mmol) at 0° C. with stirring, and the resulting mixture was stirred for 1 hour. After evaporating the reaction mixture in vacuo, the residue obtained was diluted with ether, poured into water (40 ml), and extracted with ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo. Subsequently, to a solution of the residue thus obtained in dimethylformamide (30 ml) were added successively imidazole (4.0 g, 59 mmol) and t-butyldimethylchlorosilane (4.9 g, 32 mmol) with stirring, and the resulting mixture was stirred for 2 hours. After stirring, the reaction mixture was poured into water (50 ml) to quench the reaction and extracted with ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:49 to 3:97) as the eluent to afford the title compound (7.2 g) in a yield of 77% as a colourless oily product.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.Cl.[NH2:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[N:15]=[CH:16][NH:17][C:18]=1[CH3:19].[CH3:20][N:21]=[C:22]=[S:23]>O>[CH3:20][NH:21][C:22]([NH:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[N:15]=[CH:16][NH:17][C:18]=1[CH3:19])=[S:23]
Reactant: CN=C=S
Reactant: Cc1[nH]cnc1CSCCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CNC(=S)NCCSCc1nc[nH]c1C
Temperature: 25 °C

Procedure:
Potassium carbonate (7.75 g.) was added to a solution of 14.6 g. of 4-(2-aminoethyl)thiomethyl-5-methylimidazole dihydrochloride in 120 ml. of water. The solution was maintained at ambient temperature for 15 minutes and 5.15 g. of methyl isothiocyanate was added. After heating under reflux for 0.5 hour, the solution was slowly cooled to 5°. The product was collected and recrystallized from water to give N-methyl-N'-[2-(5-methyl-4-imidazolylmethylthio)ethyl]thiourea, m.p. 150°-152°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:14](O)=O)[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:17][NH2:18]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][NH:18][CH3:17])[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)C1(c2ccc(Cl)c(Cl)c2)CCCC1
Reactant: CN
Product: CNCC1(c2ccc(Cl)c(Cl)c2)CCCC1
Yield: 49 %

Procedure:
The title compound was synthesized from 1-(3,4-dichlorophenyl)-cyclopentanecarboxylic acid and methyl amine using General Procedure G1, followed by General Procedure E in 49% yield. LCMS Rt=11.16 min, m/z=258 (M+1). 1H NMR (CDCl3, δ): 7.4 (m, 2H), 7.17 (dd, J=2.2, 8.4 Hz, 1H), 2.65 (s, 2H), 2.34 (s, 3H), 2.1-1.6 (m, 8H). 13C NMR (CDCl3, δ, mult): 148.3(0), 132.1(0), 129.9(1), 129.7(0), 129.1(1), 126.5(1), 62.1(2), 51.6(0), 37.3(3), 36.2(2), 23.5(2).
Reaction SMILES: [CH:1]([C:3]1[C:4]([N+:13]([O-:15])=[O:14])=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=O.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCCCCC.CCOC(C)=O>CCO>[N+:13]([C:4]1[C:3]([CH:1]=[N:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])([O-:15])=[O:14]
Reactant: COC(=O)c1cccc(C=O)c1[N+](=O)[O-]
Reactant: Nc1ccccc1
Solvent: CCO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(C=Nc2ccccc2)c1[N+](=O)[O-]

Procedure:
A mixture of (A3) (1.0 eq.) and aniline (1.05 eq.) in EtOH (0.2 M) was stirred at reflux under N2 atmosphere for 2 hr until TLC revealed completation of the reaction (Hexane/EtOAc=75:25). Evaporation of the solvent gave (A4) as a white solid which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3, 300K) δ 8.51 (1H, d, J=7.3 Hz), 8.41 (1H, s), 8.11 (1H, d, J=7.8 Hz), 7.67 (1H, t, J=7.8 Hz), 7.43 (2H, t, J=7.8 Hz), 7.31 (1H, t, J=7.3 Hz), 7.16 (2H, d, J=7.8 Hz), 3.94 (3H, s).
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8](=[O:16])OC2C=CC=CC=2)=[CH:5][C:4]([C:17]([F:20])([F:19])[F:18])=[N:3]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[N:29]=[CH:28][N:27]=[C:26]2[O:35][C:36]1[CH:37]=[C:38]([CH:40]=[CH:41][CH:42]=1)[NH2:39].C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[N:29]=[CH:28][N:27]=[C:26]2[O:35][C:36]1[CH:37]=[C:38]([NH:39][C:8]([NH:7][C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:17]([F:18])([F:19])[F:20])[CH:5]=2)=[O:16])[CH:40]=[CH:41][CH:42]=1
Reactant: Cn1nc(C(F)(F)F)cc1NC(=O)Oc1ccccc1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(F)(F)F)nn4C)c3)c2cc1OC
Temperature: 50 °C
Yield: 24 %

Procedure:
Using the procedure described in Example 159B, phenyl 1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamate from the previous step (0.114 g, 0.4 mmol), 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (0.119 g, 0.4 mmol), and N,N-diisopropylethylamine (0.3 mL) in THF (6 mL) were heated at 50° C. for 3 hours, to afford 1-[3-(6,7-Dimethoxyquinazolin-4-yloxy)phenyl]-3-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]urea as solid (0.047 g, 24%). 1H NMR (300 MHz, CDCl3) δ 9.6 (br, 1H), 8.64 (s, 1H), 7.63 (m, 1H), 7.57 (s, 1H), 7.43 (t, 1H), 7.33 (m, 2H), 7.01 (d, 1H), 6.94 (s, 1H), 6.26 (s, 1H), 4.08 (s, 6H), 3.93 (s, 3H); LC-MS (ESI) m/z 489 (M+H)+.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[O:17]1[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18]1.CCOCC>C1C=CC=CC=1>[O:17]1[CH:21]=[CH:20][C:19](/[CH:22]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:18]1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=Cc1ccoc1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCOCC
Product: CCOC(=O)/C=C/c1ccoc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 17.7 g (78.8 mmol) of ethyl diethylphosphonoacetate in 150 ml of benzene, 2.89 g (72.2 mmol) of sodium hydride (60% in oil) was added under ice-cooling, followed by stirring for 30 minutes. To this solution, a solution of 6.308 g (65.65 mmol) of 3-furaldehyde in 50 ml of benzene was added dropwise, followed by stirring at room temperature for 30 minutes and refluxing for 30 minutes. After the reaction mixture was cooled to room temperature, ether was added; the mixture was then washed with water. The ether solution was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane to hexane/ethyl acetate=9/1) to yield the desired product.
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:43])[O:11][CH2:12][C:13]2([C:32](=[O:42])[NH:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[Cl:41])[CH2:18][CH2:17][N:16]([C:19](=[O:31])[C@@H:20]([NH:23]C(OC(C)(C)C)=O)[CH2:21][OH:22])[CH2:15][CH2:14]2)=[CH:5][CH:4]=1.Cl.O1CCOCC1>CO>[F:45][C:2]([F:1])([F:44])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:43])[O:11][CH2:12][C:13]2([C:32](=[O:42])[NH:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[Cl:41])[CH2:18][CH2:17][N:16]([C:19](=[O:31])[C@@H:20]([NH2:23])[CH2:21][OH:22])[CH2:15][CH2:14]2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)N1CCC(COC(=O)Nc2ccc(C(F)(F)F)cc2)(C(=O)NCc2ccccc2Cl)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: N[C@@H](CO)C(=O)N1CCC(COC(=O)Nc2ccc(C(F)(F)F)cc2)(C(=O)NCc2ccccc2Cl)CC1
Reaction time: 2 h
Yield: 106.1 %

Procedure:
To a solution of (S)-(1-(2-(tert-butoxycarbonyl)amino-3-hydroxypropanoyl)-4-(2-chlorobenzylcarbamoyl)piperidin-4-yl)methyl 4-(trifluoromethyl)phenylcarbamate (145 mg, 0.22 mmol) in CH3OH (1 mL) was added 4M HCl in dioxane (200 μL, 0.8 mmol, 3.6 equiv.), which was stirred for 2 h. The reaction mixture was concentrated to dryness by co-evaporating with toluene to give (S)-(1-(2-amino-3-hydroxypropanoyl)-4-(2-chlorobenzylcarbamoyl)piperidin-4-yl)methyl 4-(trifluoromethyl)phenylcarbamate (130 mg, quant.). LRMS (M+H+) m/z 557.1.
Reaction SMILES: Cl[C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[OH:17])=O)=[CH:4][N:3]=1.O.[CH3:21][N:22](C=O)[CH3:23]>S(=O)(=O)(O)O>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]2[N:8]=[C:6]([C:5]3[CH:18]=[CH:19][C:2]([N:22]([CH3:23])[CH3:21])=[N:3][CH:4]=3)[O:17][C:10]=2[CH:11]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(NC(=O)c2ccc(Cl)nc2)c(O)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: COc1ccc2nc(-c3ccc(N(C)C)nc3)oc2c1
Reaction time: 0.33 h

Procedure:
6-Chloro-N-(2-hydroxy-4-methoxyphenyl)nicotinamide (40 mg, 0.14 mmol) was dissolved in DMF (1.5 mL) and one drop of sulfuric acid was added. The reaction was run at 230° C. for 20 minutes in a microwave reactor. The mixture was added to water, the solid was collected, rinsed with water and dried. The crude product was purified by flash column chromatography using 40% ethyl acetate in hexane, giving the title compound (14 mg) as an orange solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.96 (d, 1H) 8.19 (dd, 1 H) 7.57 (d, 1H) 7.10 (d, 1H) 6.92 (dd, 1H) 6.60 (d, 1H) 3.88 (s, 3H) 3.20 (s, 6H); MS m/z (M+H) 270.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[CH2:21]([NH:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH2:21]([N:28]([CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:15]([CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=1)=[O:17])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Reactant: c1ccc(CCNCc2ccccc2)cc1
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCC(=O)N(CCc2ccccc2)Cc2ccccc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and benzyl-phenethyl-amine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a yellow oil. MS (ES) for C27H29NO5 [M+H]+: 448.
Reaction SMILES: [CH2:1]([C:4]1([CH:20]([CH3:22])[CH3:21])[O:9][C:8](=[O:10])[N:7]([CH:11]([C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([C:4]1([CH:20]([CH3:22])[CH3:21])[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:27]3[CH:26]=[CH:25][C:24]([F:23])=[CH:29][C:28]=3[F:30])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCC1(C(C)C)CCN(C(C)c2ccc(Br)cc2)C(=O)O1
Reactant: OB(O)c1ccc(F)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C=CCC1(C(C)C)CCN([C@@H](C)c2ccc(-c3ccc(F)cc3F)cc2)C(=O)O1
Yield: 72.8 %

Procedure:
A mixture of 6-allyl-3-[1-(4-bromo-phenyl)-ethyl]-6-isopropyl-[1,3]oxazinan-2-one (200 mg, 0.55 mmol), 2,4-difluorophenylboronic acid (104 mg, 0.66 mmol), PdCl2(PPh3)2 (20 mg), aqueous Cs2CO3 solution (2 M, 2 mL) in 1,4-dioxane (8 mL) was heated to reflux for 2 h. The mixture was filtered, and the filtrate was extracted with EtOAc for 3 times. The combined organic layer was washed with brine, dried over Na2SO4 and concentrated to give the crude product, which was purified by preparative TLC to give 6-allyl-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-isopropyl-1,3-oxazinan-2-one (160 mg, 73%). 1H NMR (CDCl3): 0.96 (m, 6H), 1.61 (m, 3H), 1.68-2.09 (m, 3H), 2.32-2.47 (m, 2H), 2.84 (m, 1H), 3.18 (m, 1H), 5.02-5.19 (m, 2H), 5.84 (m, 2H), 6.93 (m, 2H), 7.41 (m, 3H), 7.50 (m, 2H).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Cl:10][C:11]1[CH:12]=[CH:13][C:14]2[N:18]=[CH:17][N:16]([C:19]3[N:24]=[C:23](SC#N)[C:22]([N+:28]([O-:30])=[O:29])=[CH:21][N:20]=3)[C:15]=2[CH:31]=1.Cl.[C:33]([O:37][C:38](=[O:42])[C@@H:39]([CH3:41])[NH2:40])([CH3:36])([CH3:35])[CH3:34]>C1COCC1>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]2[N:18]=[CH:17][N:16]([C:19]3[N:24]=[C:23]([NH:40][C@H:39]([CH3:41])[C:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:42])[C:22]([N+:28]([O-:30])=[O:29])=[CH:21][N:20]=3)[C:15]=2[CH:31]=1
Reactant: N#CSc1nc(-n2cnc3ccc(Cl)cc32)ncc1[N+](=O)[O-]
Reactant: C[C@@H](N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[C@@H](Nc1nc(-n2cnc3ccc(Cl)cc32)ncc1[N+](=O)[O-])C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.7 %

Procedure:
Diisopropylethylamine (2.6 mL) was added to a mixture of 6-chloro-1-(5-nitro-4-thiocyanatopyrimidin-2-yl)-1H-benzo[d]imidazole (1.66 g, 5 mmol) and D-alanine t-butyl ester hydrochloride (1.1 g, Chem-Impex Int.) in THF (50 mL). The combined mixture was stirred at RT overnight, partitioned between ethyl acetate and water then separated. The aqueous layer was extracted once again with ethyl acetate and the combined organics were concentrated and purified by column chromatography. Elution with DCM and 0.5% MeOH in DCM provided the above compound (0.58 g), MH+=419, 421.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[C:7]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:6]=1)(=[O:4])=[O:3]>CO.[Pd]>[CH3:17][S:14]([C:7]1[CH:8]=[C:9]([NH2:11])[CH:10]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=1)(=[O:16])=[O:15]
Reactant: CS(=O)(=O)c1cc([N+](=O)[O-])cc(S(C)(=O)=O)c1
Agent: [Pd]
Solvent: CO
Product: CS(=O)(=O)c1cc(N)cc(S(C)(=O)=O)c1
Reaction time: 1 h

Procedure:
To a slurry of 1,3-bis(methylsulfonyl)-5-nitrobenzene (0.7 g) in methanol (10 mL) was added palladium on charcoal (0.1 g) and the mixture was hydrogenated at atmospheric pressure and 25° C. for 1 hour. The reaction mixture was filtered and evaporated. The residue was suspended in ethyl acetate (25 mL) and HCl in ethyl acetate (5 mL, appr. 2M) was added. Filtration afforded the desired aniline as its hydrochloride salt, which was converted into an isocyanate using diphosgene as described previously.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][N:4]=[C:5]=[S:6].[NH2:9][C:10]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][OH:17])[N:11]=1>C(#N)C>[OH:17][CH2:16][CH2:15][N:12]1[CH:13]=[CH:14][C:10]([NH:9][C:5]([NH:4][CH2:3][C:2]([F:8])([F:7])[F:1])=[S:6])=[N:11]1
Reactant: FC(F)(F)CN=C=S
Reactant: Nc1ccn(CCO)n1
Solvent: CC#N
Product: OCCn1ccc(NC(=S)NCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 46.1 %

Procedure:
A mixture of 2,2,2-trifluoroethylisothiocyanate (13.8 g.) and 3-amino-1-(2-hydroxyethyl)pyrazole (12.5 g.) in acetonitrile dried over 4A molecular sieve (30 ml.) was stirred at room temperature for 4 hours. A precipitate formed after 30 minutes. Filtration gave 1-(2-hydroxyethyl)-3-[3-(2,2,2-trifluoroethyl)thioureido]pyrazole (12.1 g.; 46%), m.p. 145°-146°.