Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[CH3:16]O>S(=O)(=O)(O)O>[CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=[CH:8][C:4]=1[C:5]([O:7][CH3:16])=[O:6]
Reactant: CO
Reactant: COc1ccc(C(=O)O)c(OC)c1OC
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(OC)c(OC)c1OC

Procedure:
To a solution of 2,3,4-trimethoxybenzoic acid (25 g) in dry methanol (250 ml), concentrated sulfuric acid (2.4 ml) was added. The reaction solution was refluxed for 20 hr, concentrated to half its volume by evaporation, and poured into a mixture of ice and water. The solution was extracted with methylene chloride and the organic extract was washed with cold aqueous sodium carbonate solution and water, dried over sodium sulfate and evaporated to give 25.4 g of 2,3,4-trimethoxybenzoic acid, methyl ester: ir (CHCl3) 1720 cm-1 ; and nmr (CDCl3) δ 3.85 (s, 3H), 3.87 (s, 3H), 3.92 (s, 6H), 6.65 (d, 1H) and 7.55 (d, 1H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[O:11]=[C:12]1[NH:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[N:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[C:14](=[O:29])[CH2:13]1.Br[CH2:31][C:32]([N:34]([CH:43]([CH3:45])[CH3:44])[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1)=[O:33].O>C1COCC1.CN(C=O)C>[O:11]=[C:12]1[N:18]([CH2:31][C:32]([N:34]([CH:43]([CH3:45])[CH3:44])[C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)=[O:33])[C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[N:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[C:14](=[O:29])[CH2:13]1
Reactant: COc1ccc(N(C(=O)CBr)C(C)C)cc1
Reactant: O=C1CC(=O)N(c2ccccn2)c2ccccc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3ccccn3)c3ccccc32)C(C)C)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 47.7 %

Procedure:
1.6 mL (1.6 mmol, 1.0 equiv) of 1M NaN(TMS)2 in THF is added dropwise to a solution of 0.40 g (1.6 mmol, 1.0 equiv) of 2,4-dioxo-5-pyrid-2-yl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepine in 20 mL of DMF at 0° C. After 15 min, a solution of 0.47 g (1.6 mmol, 1.0 equiv) of 2-bromo-N-isopropyl-N-(4-methoxy-phenyl) acetamide in 3 mL of DMF is added dropwise and the resulting green solution is stirred at 0° C. for 25 min. The reaction mixture is poured into 100 mL of H2O and extracted with EtOAc (×2). The organic extract is washed with H2O and brine, dried over MgSO4 and concentrated to a brown oil. Purification by silica gel flash chromatography using EtOAc as eluent gave 0.35 g of the title compound as a light yellow foam: 1H NMR (CDCl3, 300 MHz) δ8.4-6.8 (m, 12H), 5.04 (m, 1H), 4.44 (d, 1H, J=17), 3.94 (d, 1H, J=17), 3.80 (s, 3H), 3.65 (d, 1H, J=12), 3.49 (d, 1H, J=12), 1.11 (d, 6H, J=7); low resolution MS (FAB) m/e 459 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[N:9][C:8]([C:12]([NH2:14])=O)=[N:7]1.CCN(CC)CC.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[N:9][C:8]([C:12]#[N:14])=[N:7]1
Reactant: Cc1nc(C(N)=O)nn1Cc1cccc(Br)c1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(C#N)nn1Cc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 82.8 %

Procedure:
To a suspension of 1-(3-bromobenzyl)-5-methyl-1H-1,2,4-triazole-3-carboxamide (50 mg, 0.17 mmol) and Et3N (47 μL, 0.34 mmol) in DCM (2 mL) was slowly added a solution of trifluoroacetic anhydride (29 μL, 0.20 mmol) in DCM (2 mL) at 0° C. The reaction was stirred at 0° C. for 2 h, and was then warmed to RT while stirring overnight. The reaction was then quenched with H2O (3 mL) and washed with NaOH (1N, 5 mL) and brine (2×5 mL) before being concentrated under reduced pressure. The crude product was purified on a Biotage pre-packed silica gel column with a gradient of 12% to 80% EtOAc:Hexanes to afford 1-(3-bromobenzyl)-5-methyl-1H-1,2,4-triazole-3-carbonitrile (39 mg, 83%) as a viscous oil. MS (ES+) C11H9BrN4 requires: 276, 278 found: 277, 279 [M+H]+(1:1).
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH3:9])[C:4](=[O:10])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](I)[CH2:18][CH3:19].O>CN(C=O)C>[Cl:1][C:2]1[N:7]([CH2:17][CH2:18][CH3:19])[C:6](=[O:8])[N:5]([CH3:9])[C:4](=[O:10])[CH:3]=1
Reactant: Cn1c(=O)cc(Cl)[nH]c1=O
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1c(Cl)cc(=O)n(C)c1=O

Procedure:
6-chloro-3-methyl uracil (10 g) and potassium carbonate (10.34 g) in DMF (70 ml) under nitrogen was treated with n-propyl iodide (25.4 g) and heated at reflux for 8 h. The reaction 30 was cooled and then poured into water (700 ml) and extracted with ethyl acetate. The combined organics were dried and evaporated in vacuo to afford the subtitle compound an orange oil, 17.52 g. δ 1HCDCl3 0.98 (3H, t), 1.74 (2H, sextet), 3.33 (3H, s), 4.02 (2H, t), 8.02 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][N:18]2[CH:23]=[CH:22][C:21]([NH:24][CH2:25][CH3:26])=[N:20][C:19]2=[O:27])=[CH:4][CH:3]=1.Cl[C:29]1[CH:34]=CN(CC2N3C=CC=CC3=NC=2C2C=CC(Cl)=CC=2)C(=O)N=1.N1CCCC1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][N:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:34][CH2:29][CH2:26][CH2:25]3)=[N:20][C:19]2=[O:27])=[CH:6][CH:7]=1
Reactant: O=c1nc(Cl)ccn1Cc1c(-c2ccc(Cl)cc2)nc2ccccn12
Reactant: CCNc1ccn(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)c(=O)n1
Solvent: C1CCNC1
Product: O=c1nc(N2CCCC2)ccn1Cc1c(-c2ccc(Cl)cc2)nc2ccccn12

Procedure:
The title compound was prepared according to the experimental for compound 132 from 4-chloro-1-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-2(1H)-one and pyrrolidine. M/e+ 406 for C22H21ClN5O (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 8.44 (d, J=6.6 Hz, 1H), 7.69 (d, J=8.4 Hz, 2H), 7.63 (d, J=8.8 Hz, 1H), 7.47 (d, J=8.4 Hz, 2H), 7.28 (m, 1H), 6.86 (td, J=6.9, 1.1 Hz, 1H), 6.73 (d, J=7.3 Hz, 1H), 5.57 (s, 2H), 5.49 (d, J=7.7 Hz, 1H), 3.65 (t, J=6.6 Hz, 2H), 3.28 (t, J=6.6 Hz, 2H), 1.90 (m, 4H) ppm.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6][C@H](C)CCC)[CH3:3].[OH2:12].C[C:14]([CH3:16])=[O:15]>OS(O)(=O)=O.[Cl-].[Na+].O>[CH3:1][C@H:2]([CH2:4][CH2:5][CH3:6])[CH2:3][CH2:16][C:14]([OH:12])=[O:15]
Reactant: O
Reactant: CCC[C@@H](C)CCC=C(C)C
Reactant: CC(C)=O
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Product: CCC[C@@H](C)CCC(=O)O

Procedure:
To alkene 98 (20 g, 0.13 mol) in acetone (433 mL) was added a solution of CrO3 (39 g, 0.39 mol) in H2SO4 (33 mL)/H2O (146 mL) over 50 minutes. After 6 hours a further amount of CrO3 (26 g, 0.26 mol) in H2SO4 (22 mL)/H2O (100 mL) was added. After 12 hours the solution was diluted with brine and the solution extracted with ether. The combined organic phases were dried (MgSO4) and concentrated. Flash chromatography (gradient of 6:1 to 2:1 hexane/EtOAc) gave the product 99 as an oil. 12.1 g; 65%. MS, m/z (relative intensity): 143 [M−H, 100%].
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[CH:23]=[C:21]([CH3:22])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[CH2:12][C@@H:11]1[OH:24])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:45]1[C:49](=[O:50])[C:48]2=[CH:51][CH:52]=[CH:53][CH:54]=[C:47]2[C:46]1=[O:55].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCOCC>[Si:1]([O:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[CH:23]=[C:21]([CH3:22])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[CH2:12][C@@H:11]1[O:24][N:45]1[C:46](=[O:55])[C:47]2=[CH:54][CH:53]=[CH:52][CH:51]=[C:48]2[C:49]1=[O:50])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O2)c(=O)[nH]c1=O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cn([C@H]2C[C@H](ON3C(=O)c4ccccc4C3=O)[C@@H](CO[Si](C)(C)C(C)(C)C)O2)c(=O)[nH]c1=O
Temperature: 0 °C
Yield: 62 %

Procedure:
To a solution of 5'-O-t-butyldimethylsilylthymidine [1, 21.36 g, 60 mmol, prepared according to the procedure of Nair, V., and Buenger, G. S., Org. Prep. Procedures Int., 22:57 (1990) in dry THF (750 ml)], triphenylphosphine (17.28 g, 66 mmol) and N-hydroxyphthalimide (10.74 g, 66 mmol) were added. The solution was cooled to 0° C. and diisopropylazodicarboxylate (15.15 g, 75 mmol) was added dropwise over a period of 3 hr while stirring under nitrogen. The reaction mixture was then stirred at room temperature for 12 hr. The solution was evaporated and the residue was dissolved in CH2Cl2 (750 ml), extracted with sat. NaHCO3 (200 ml), and water (200 ml), dried (MgSO4), filtered and concentrated to furnish yellow oily residue. Silica gel column chromatography (100% hexanes, and then hexanes:Et2O gradient to 90% Et2O) of the residue gave compound 2 as a colorless glass (18.68 g, 62%); 1H NMR (CDCl3) δ0.05 [2s, 6, (CH3)2 ], 0.91 [s, 9, (CH3)3 ], 2.0 (s, 3, CH3), 2.5-2.65 (m, 2, 2'CH2), 4.05-4.2 (m, 2, 5'CH2), 4.25-4.35 (m, 1, 4'H), 5.0 (m, 1, 3'H), 6.15 (m, 1, 1'H), 8.6 (br s, 1, NH), and aromatic protons.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH:23]=[C:22]4[C:16]([CH2:17][CH2:18][N:19]([C:24](OC(C)(C)C)=O)[CH2:20][CH2:21]4)=[N:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:31]1(=O)[CH2:34]C[CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>FC(F)(F)C(O)=O.CO.ClCCl>[CH:24]1([N:19]2[CH2:20][CH2:21][C:22]3=[CH:23][N:14]([CH:11]4[CH2:10][CH2:9][N:8]([C:5]5[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=5)[CH2:13][CH2:12]4)[N:15]=[C:16]3[CH2:17][CH2:18]2)[CH2:34][CH2:31][CH2:32]1
Reactant: O=C1CCC1
Reactant: Cc1ccc(N2CCC(n3cc4c(n3)CCN(C(=O)OC(C)(C)C)CC4)CC2)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(N2CCC(n3cc4c(n3)CCN(C3CCC3)CC4)CC2)cn1
Reaction time: 17.25 h

Procedure:
1,1-Dimethylethyl 2-[1-(6-methyl-3-pyridinyl)-4-piperidinyl]-4,5,7,8-tetrahydropyrazolo[3,4-d]azepine-6(2H)-carboxylate (may be prepared as described in Description 50) (27 mg, 0.065 mmol) was stirred in trifluoroacetic acid (0.5 ml)/dichloromethane (1 ml) for 2 hours. Mixture was then diluted with methanol and passed through an SCX cartridge. A mixture of the product in dichloromethane (1.3 ml) was treated with cyclobutanone (0.010 ml, 0.13 mmol) followed by sodium triacetoxyborohydride (28 mg, 0.13 mmol) (about 5 min later). The resulting mixture was then stirred under Argon for 17.25 h. After an additional 1.25 hours, more dichloromethane (2.5 ml), cyclobutanone (0.030 ml) and then sodium triacetoxyborohydride (28 mg) were added and the mixture stirred for an additional 3.75 hours and then for an additional 2.5 hours. After a further 1 hour, more cyclobutanone (0.030 ml) followed by sodium triacetoxyborohydride (2 eq) were added and the resulting mixture left at room temperature under Ar for 16.75 hours. Then dichloromethane (2 ml) was added. Methanol was then added and the mixture purified by SCX eluting with methanol and then methanol/ammonia (2M). This material was purified by Mass Directed Autopreparation to give a product which was purified further by SCX eluting with methanol and then methanol/2M NH3 in methanol to afford the title compound (E44).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH3:6].[C:7]([O-])([O-])=O.[K+].[K+].[OH:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][CH:23]([C:26]3[CH:31]=[CH:30][C:29]([C@@H:32]([NH:34][C:35](=[O:37])[CH3:36])[CH3:33])=[CH:28][CH:27]=3)[CH2:22][CH2:21]2)=[CH:16][CH:15]=1>C(#N)C>[O:4]1[CH2:5][CH2:6][CH:7]([O:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:27]=[CH:28][C:29]([C@@H:32]([NH:34][C:35](=[O:37])[CH3:36])[CH3:33])=[CH:30][CH:31]=4)[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[CH2:2][CH2:3]1
Reactant: CC(=O)N[C@@H](C)c1ccc(C2CCN(c3ccc(O)cc3)CC2)cc1
Reactant: CCOCCBr
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)N[C@@H](C)c1ccc(C2CCN(c3ccc(OC4CCOCC4)cc3)CC2)cc1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
17 μL (0.15 mmol) 1-Bromo-2-ethoxy-ethane and 35 mg (0.25 mmol) K2CO3 are added to 34 mg (0.10 mmol) (S)-N-{1-(4-[1-(4-hydroxyphenyl)-piperidin-4-yl]-phenyl}-ethyl)-acetamide (compound 1.48) in 2 mL ACN. The mixture is stirred at 90° C. for 4 h followed by addition of 11 μL (0.10 mmol) 1-bromo-2-ethoxy-ethane. Stirring is continued at 90° C. over night. The solvent is removed in vacuo and the residue is purified using reversed phase HPLC (water/MeOH, 0.1% TFA) to yield the desired product.
Reaction SMILES: Br[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.CON(C)[C:13](=[O:23])[CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].[Cl-].[NH4+].O>O1CCCC1>[Cl:8][C:7]1[C:2]([C:13](=[O:23])[CH2:14][NH:15][C:16](=[O:17])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[N:3][CH:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: Clc1cnc(Br)c(Cl)c1
Reactant: CON(C)C(=O)CNC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(=O)c1ncc(Cl)cc1Cl
Temperature: -20 °C
Yield: 59.6 %

Procedure:
To 35.1 g of 2-bromo-3,5-dichloropyridine in 10 ml of tetrahydrofuran, 116.3 ml of a 1.3 M tetrahydrofuran solution of isopropylmagnesium chloride-lithium chloride complex was added dropwise with stirring at −20° C., and after the addition, the mixture was stirred at the same temperature for 15 minutes. Then, to the reaction mixture, 15.0 g of N-methoxy-N-methyl-2-(tert-butoxycarbonylamino)acetamide in 114 ml of tetrahydrofuran was added dropwise, and after the addition, the mixture was stirred at the same temperature for another 2 hours. After completion of the reaction, the reaction mixture was mixed with 100 ml of saturated aqueous ammonium chloride and 100 ml of water and extracted with ethyl acetate (200 ml×2), the resulting organic layers were combined, washed with water (100 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 0:10 to 3:7) as the eluent to obtain 12.5 g of the desired product as pale yellow crystals.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:13][C:14](=[O:27])[CH2:15][CH:16]([C:20]1[CH:21]=[N:22][C:23]([CH3:26])=[N:24][CH:25]=1)[CH2:17][CH2:18][OH:19])[CH3:12].CCN(CC)CC>C(Cl)Cl>[CH2:11]([O:13][C:14](=[O:27])[CH2:15][CH:16]([C:20]1[CH:21]=[N:22][C:23]([CH3:26])=[N:24][CH:25]=1)[CH2:17][CH:18]=[O:19])[CH3:12]
Reactant: CCOC(=O)CC(CCO)c1cnc(C)nc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCOC(=O)CC(CC=O)c1cnc(C)nc1
Reaction time: 0.5 h

Procedure:
To a solution of oxalyl chloride (73 μL, 0.84 mmol) in CH2Cl2 at −78° C. was added DMSO (80 μL, 1.0 mmol) dropwise. After gas evolution ceased, 4-5 (100 mg, 0.42 mmol) in CH2Cl2 was added. After 30 minutes, the cooling bath was removed and NEt3 (290 μL, 2.1 mmol) was added. After 20 minutes, the reaction mixture was diluted with CH2Cl2 and washed sat. NaHCO3 and brine, dried (MgSO4), and concentrated to give 4-6 as a yellow oil.
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]1=[O:12].IC[CH2:15][CH2:16][C:17]([CH3:22])([N+:19]([O-:21])=[O:20])[CH3:18]>CN(C=O)C>[CH3:18][C:17]([N+:19]([O-:21])=[O:20])([CH3:22])[CH2:16][CH2:15][N:5]1[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:3][C:4]1=[O:12]
Reactant: O=c1[nH]c2ccccc2o1
Reactant: CC(C)(CCCI)[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(CCn1c(=O)oc2ccccc21)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 132 %

Procedure:
1.70 g (42.5 mmol) sodium hydride (60%) are added batchwise to a solution of 4.50 g (33.3 mmol) benzoxazol-2-one in 50 mL DMF, while the temperature is kept below 0° C. by cooling. After one hour's stirring a solution of 9.61 g (37.4 mmol) 1-iodo-4-methyl-4-nitro-pentane in 20 mL DMF is added dropwise so that the temperature does not exceed 5° C. The mixture is stirred overnight at ambient temperature and the solvent is distilled off. The residue is taken up in ethyl acetate and washed successively with water and sodium chloride solution, dried with sodium sulphate and evaporated down. 11.0 g oil are obtained. Mass spectroscopy: [M+H]+=265.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:9]2[C:19](=[O:23])[N:20]([CH3:22])[N:21]=[C:8]2[NH:7][C:6]=1[CH3:24])=[O:4].[F:25][C:26]([F:37])([F:36])[C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1.CCN(CC)CC>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:12]=[CH:13][C:14]([C:17]#[N:18])=[CH:15][CH:16]=2)[N:9]2[C:19](=[O:23])[N:20]([CH3:22])[N:21]=[C:8]2[N:7]([C:31]2[CH:30]=[CH:29][CH:28]=[C:27]([C:26]([F:37])([F:36])[F:25])[CH:32]=2)[C:6]=1[CH3:24])=[O:4]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)C1=C(C)Nc2nn(C)c(=O)n2C1c1ccc(C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nn(C)c(=O)n2C1c1ccc(C#N)cc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 3.6 %

Procedure:
Intermediate 8 (900 mg, 2.77 mmol), 3-trifluoromethylphenylboronic acid (1.05 g, 5.54 mmol), Et3N (925 μl, 6.6 mmol), and copper (II) acetate (1.0 g, 5.54 mmol) were dissolved in DCE (25 mL), and the reaction mixture was stirred at 80° C. for 18 hours. After cooling to RT the reaction mixture was partitioned between DCM and water. The organic layer was separated, washed with water, followed by brine, then dried (MgSO4) and evaporated in vacuo. The resulting residue was purified by silica gel chromatography eluting with a gradient of 3-10% MeOH in DCM and then using HPLC system 1 to yield the title compound as an orange solid (47 mg).
Reaction SMILES: [F:1][C:2]([F:52])([F:51])[C:3]1[CH:4]=[C:5]([CH:48]=[CH:49][CH:50]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[CH:19]=[CH:18][C:17]=2[NH:28][C:29]([C:31]2[CH:32]=[C:33]([CH:45]=[CH:46][CH:47]=2)[CH2:34][S:35][CH2:36][CH2:37][C:38]([O:40]C(C)(C)C)=[O:39])=[O:30])[CH:11]=1)=[O:9].FC(F)(F)C(O)=O>ClCCl>[F:52][C:2]([F:1])([F:51])[C:3]1[CH:4]=[C:5]([CH:48]=[CH:49][CH:50]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([O:22][CH2:23][C:24]([F:26])([F:25])[F:27])[CH:19]=[CH:18][C:17]=2[NH:28][C:29]([C:31]2[CH:32]=[C:33]([CH:45]=[CH:46][CH:47]=2)[CH2:34][S:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:30])[CH:11]=1)=[O:9]
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(OCC(F)(F)F)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(OCC(F)(F)F)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.4 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of tert-butyl 3-(3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(2,2,2-trifluoroethoxy)phenyl)-carbamoyl)benzylthio)propanoate (200 mg, 0.27 mmol, 1.00 equiv) in dichloromethane (5 mL), and trifluoroacetic acid (2 mL). The resulting solution was stirred overnight at room temperature. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum. The crude product (200 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 68 mg (37%) of a light yellow solid. 1H-NMR (300 MHz, DMSO-d6, ppm): δ 12.61 (s, 1H), 9.57-9.54 (m, 1H), 8.99-8.98 (m, 1H), 8.49-8.41 (m, 2H), 7.89-7.79 (m, 10H), 7.30-7.26 (m, 1H), 4.92-4.84 (dd, J=18 Hz, 9 Hz, 2H), 4.65-4.63 (d, J=5.4 Hz, 2H), 3.89 (s, 2H), 2.63-2.59 (m, 4H). MS (ES, m/z): 692 [M+H]+.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH:17]([CH2:21][C:22]([O:24]CC)=[O:23])[CH2:16][CH2:15][CH2:14]2.[Li+].[OH-].Cl>C1COCC1.O>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH:17]([CH2:21][C:22]([OH:24])=[O:23])[CH2:16][CH2:15][CH2:14]2
Reactant: CCOC(=O)CC1CCCc2cc(OC3Cc4ccccc4C3)ccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CC1CCCc2cc(OC3Cc4ccccc4C3)ccc21
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of (R/S)-ethyl 2-(6-(2,3-dihydro-1H-inden-2-yloxy)-1,2,3,4-tetrahydronaphthalen-1-yl)acetate 52 (85 mg, 0.24 mmol) and LiOH (40 mg) in THF-H2O (1/1, 4 mL) was stirred at room temperature for 6 hours. 2N HCl was added to acidify the mixture to pH 2-3. The mixture was then extracted with EtOAc (2×20 mL). The combined organic layers were washed with water and brine, and dried over Na2SO4. The residue obtained after filtration and concentration was purified with flash chromatography (0-60% EtOAc in hexane). (R/S)-2-(6-(2,3-Dihydro-1H-inden-2-yloxy)-1,2,3,4-tetrahydronaphthalen-1-yl)acetic acid (53) was obtained as colorless oil (79 mg, 96%). MS ESI (neg.) m/e: 321 (M−H). 1H NMR (500 MHz) (CDCl3) δ 7.11-7.28 (m, 5H); 6.65-6.75 (m, 2H); 5.16 (m, 1H); 3.36-3.40 (m, 3H); 3.19 (dd, J=16.6, 3.0 Hz, 2H); 2.62-2.80 (m, 3H), 2.59 (q, J=9.9 Hz, 1H), 1.99 (m, 1H), 1.78-1.87 (m, 3H).
Reaction SMILES: I[CH2:2][CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].[CH2:12]([NH2:16])[CH2:13][CH2:14][CH3:15]>C1COCC1>[CH2:12]([NH:16][CH2:2][CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5])[CH2:13][CH2:14][CH3:15]
Reactant: CCCCN
Reactant: OC(CCI)c1ccccc1
Solvent: C1CCOC1
Product: CCCCNCCC(O)c1ccccc1

Procedure:
(Compound 15) (12.5 g) was treated with butylamine (40 ml) in THF (75 ml) at RT for 4 h. The mixture evaporated and the residue extracted with OH- /ether. The ether phase washed with H2O and saturated NaCl-solution, dried (MgSO4) and evaporated giving 6.2 g of 3-butylamino-1-phenyl-1-propanol (compound 16). Identified by 1H NMR.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH2:4][CH2:5][CH:6]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[CH2:9][C:8](=[O:18])[NH:7]1.C[O:21][C:22](=[O:38])[CH2:23][CH:24]([C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=1)[CH:25]1[CH2:29][CH2:28][C:27](=[O:30])[NH:26]1.Cl>[OH-].[Na+]>[CH3:37][C:34]1[CH:35]=[CH:36][C:31]([CH:24]([CH:25]2[CH2:29][CH2:28][C:27](=[O:30])[NH:26]2)[CH2:23][C:22]([OH:38])=[O:21])=[CH:32][CH:33]=1.[CH3:17][C:14]1[CH:15]=[CH:16][C:11]([CH:10]2[CH2:9][C:8](=[O:18])[NH:7][CH:6]2[CH2:5][CH2:4][C:3]([OH:19])=[O:2])=[CH:12][CH:13]=1
Reactant: COC(=O)CC(c1ccc(C)cc1)C1CCC(=O)N1
Reactant: COC(=O)CCC1NC(=O)CC1c1ccc(C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(C(CC(=O)O)C2CCC(=O)N2)cc1
Product: Cc1ccc(C2CC(=O)NC2CCC(=O)O)cc1

Procedure:
A solution of 93.4 g of 3-(4-methylphenyl)-5-oxo-2-pyrrolidinepropanoic acid methyl ester and β-(4methylphenyl)-5-oxo-2-pyrrolidinepropanoic acid methyl ester in 370 ml of 1 N aqueous sodium hydroxide solution is heated to 60° C. for four hours. Excess aqueous hydrochloric acid (1 N, 380 ml) is added and the solution is concentrated under reduced pressure to give β-(4-methylphenyl)-5-oxo-2-pyrrolidinepropanoic acid and 3-(4-methylphenyl)-5-oxo-2-pyrrolidinepropanoic acid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[SH:6].C(O)(=O)C.[OH2:11].ClCl.[Cl-:14].[Na+].[OH2:16]>C(OCC)C>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[S:6]([Cl:14])(=[O:16])=[O:11]
Reactant: [Cl-]
Reactant: Sc1nccs1
Reactant: O
Agent: ClCl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=S(=O)(Cl)c1nccs1
Temperature: 0 °C
Yield: 84 %

Procedure:
A mixture of 1,3-thiazole-2-thiol (5.0 g), acetic acid (150 mL) and water (50 mL) was cooled to 0° C., and chlorine gas was blown into the reaction mixture at less than 20° C. When the reaction temperature ceased to rise, blowing of the chlorine gas was stopped, and nitrogen gas was blown thereinto. The reaction mixture was diluted with diethyl ether (100 mL) and saturated brine (100 mL). The organic layer was washed successively with 10% aqueous sodium sulfite solution (100 mL), aqueous sodium hydrogencarbonate (300 mL) and saturated brine (300 mL), dried over sodium sulfate, and filtrated, the filtrate was concentrated to give the title compound (6.61 g, yield 84%) as a red oil.