Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH:20]1[CH2:22][O:21]1)[CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:23].[Na+].C[Si](C)(C)Cl>C(#N)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[CH:20]([OH:21])[CH2:22][I:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@@H](CC1CCCCC1)C1CO1)OCc1ccccc1
Reactant: [I-]
Agent: C[Si](C)(C)Cl
Agent: [Na+]
Solvent: CC#N
Product: O=C(N[C@@H](CC1CCCCC1)C(O)CI)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
42.3 g of (1(S)-benzyloxycarbonylamino-2-cyclohexyl-ethyl)-oxirane are taken up in 200 ml of acetonitrile and the resulting solution is cooled to 0°. After the addition of 20.9 g of sodium iodide, there are added dropwise at 0°, over a period of 30 minutes, 17.7 ml of trimethylchlorosilane. The mixture is stirred at 0°-3° for 40 minutes and then poured onto 700 ml of ice-cold water. The aqueous mixture is extracted with ether, and the organic phase is washed with 750 ml of 5% aqueous sodium thiosulphate solution and 750 ml of saturated, aqueous sodium chloride solution. After drying over sodium sulphate and concentrating by evaporation, an oily mixture of the title compound is obtained which is further processed directly.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:13]=[CH:12][C:7]2[N:8]=[C:9]([NH2:11])[S:10][C:6]=2[CH:5]=1.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[CH3:37][O:38][C:39]1[CH:49]=[CH:48][C:47](/[CH:50]=[CH:51]\[C:52]2[CH:57]=[C:56]([O:58][CH3:59])[C:55]([O:60][CH3:61])=[C:54]([O:62][CH3:63])[CH:53]=2)=[CH:46][C:40]=1[O:41][CH2:42][C:43](O)=[O:44]>ClCCl.O>[F:15][C:2]([F:1])([F:14])[O:3][C:4]1[CH:13]=[CH:12][C:7]2[N:8]=[C:9]([NH:11][C:43](=[O:44])[CH2:42][O:41][C:40]3[CH:46]=[C:47](/[CH:50]=[CH:51]\[C:52]4[CH:57]=[C:56]([O:58][CH3:59])[C:55]([O:60][CH3:61])=[C:54]([O:62][CH3:63])[CH:53]=4)[CH:48]=[CH:49][C:39]=3[O:38][CH3:37])[S:10][C:6]=2[CH:5]=1
Reactant: COc1ccc(/C=C\c2cc(OC)c(OC)c(OC)c2)cc1OCC(=O)O
Reactant: Nc1nc2ccc(OC(F)(F)F)cc2s1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: COc1ccc(/C=C\c2cc(OC)c(OC)c(OC)c2)cc1OCC(=O)Nc1nc2ccc(OC(F)(F)F)cc2s1
Yield: 795.8 %

Procedure:
To a solution of 6-(trifluoromethoxy)-2-aminobenzothiazole (234 mg, 1.0 mmol) in dichloromethane (20 mL) was added 1-Ethyl-3-(3-Dimethylaminopropyl)carbodiimide (EDC) (191 mg, 1.0 mmol) and 1-hydroxy-1,2,3-benzotriazole (HOBt) (13.5 mg, 0.1 mmol). Then added 2-{2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)-1-ethenyl]phenoxy}acetic acid (1) (374 mg, 0.1 mmol) and the reaction mixture was stirred at a temperature of 25° C. for 24 h and the reaction was monitored by TLC. Then to this water is added and extracted with dichloromethane. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate and hexane as solvent system to obtain the pure product (8j) (470 mg, 80% yield)
Reaction SMILES: C[O:2][C:3](=[O:41])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:15]3[CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:8][CH:7]=1.[OH-].[K+]>C1COCC1.CO>[CH2:21]([N:17]1[C:18]2[C:14](=[CH:13][C:12]([C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:41])=[O:2])=[CH:7][CH:8]=3)=[CH:20][CH:19]=2)[C:15]([CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)=[C:16]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)COc1ccc(-c2ccc3c(c2)c(Cc2ccccc2)c(-c2ccccc2)n3Cc2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)COc1ccc(-c2ccc3c(c2)c(Cc2ccccc2)c(-c2ccccc2)n3Cc2ccccc2)cc1

Procedure:
The desired product was prepared using a procedure similar to step 2 of example 4. Thus, [4-(1,3-dibenzyl-2-phenyl-1H-indol-5-yl)-phenoxy]-acetic acid methyl ester (0.491 g, 0.913 mmol) was reacted with 1N KOH (1.8 ml) in THF/MeOH (6 ml/4 ml) to give the product (0.376 g, 0.713 mmol, 78%) as a white solid, mp 153-155° C. 1H NMR (DMSO-d6) δ 4.08 (s, 2H), 4.68 (s, 2H), 5.35 (s, 2H), 6.89 (d, J=7.2 Hz, 2H), 6.96 (d, J=8.9 Hz, 2H), 7.10-7.25 (m, 8H), 7.35 (dd, J=1.7, 8.5 Hz, 1H), 7.41-7.51 (m, 8H), 7.59 (d, J=1.1 Hz, 1H), 12.95 (broad s, 1H); IR (solid) 3020, 2900, 1750, 1600, 1520, 1470, 1450, 1430, 1350, and 1220 cm−1; [ESI(+)], m/z 524 (M+H)+; Anal. Calcd. for C36H29NO3.0.20H2O: C, 82.01; H, 5.62; N, 2.66; Found: C, 82.08, H, 5.58; N, 2.55.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][C:13]3[C:19]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]=[CH:28][C:27]=1[CH:36]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(O)(=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[S:12][C:13]3[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH2:36][C:27]5[CH:28]=[N:29][C:30]6[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=6)[N:26]=5)[CH2:22][CH2:21]4)=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1cnc2ccccc2n1
Reactant: CC(C)(C)c1ccc(-c2nc3cccc(N4CCNCC4)c3s2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(-c2nc3cccc(N4CCN(Cc5cnc6ccccc6n5)CC4)c3s2)cc1
Temperature: 25 °C
Yield: 55 %

Procedure:
The piperazine template (0.075 g, 0.213 mmol) of Example 24 was dissolved in 1,2-dichloroethane (3 mL) and treated with quinoxaline-2-carbaldehyde (0.044 g, 0.277 mmol) and glacial acetic acid (2 drops). Sodium triacetoxyborohydride (0.090 g, 0.426 mmol) was added, and the mixture was stirred at room temperature until the reaction was complete by LCMS analysis. The solvent was removed under reduced pressure, and the resulting residue was purified by RP-HPLC to yield the free base (0.0578 g, 55% yield). MS (ESI) m/z 494.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][C:13]([CH3:24])([CH3:23])[CH2:14][CH2:15][N:16]3[C:20](=[O:21])[CH2:19][S:18][C:17]3=[O:22])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:25](=O)[CH2:26][CH2:27][CH3:28].N1CCCCC1>C(O)C>[CH:25](=[C:19]1[S:18][C:17](=[O:22])[N:16]([CH2:15][CH2:14][C:13]([CH3:24])([CH3:23])[CH2:12][CH2:11][S:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:20]1=[O:21])[CH2:26][CH2:27][CH3:28]
Reactant: CCCC=O
Reactant: CC(C)(CCSc1cccc2nccn12)CCN1C(=O)CSC1=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCCC=C1SC(=O)N(CCC(C)(C)CCSc2cccc3nccn23)C1=O

Procedure:
To a solution of 339 mg (0.93 mmol) of 3-[5-(imidazo[1,2-a]pyridin-5-ylthio)-3,3-dimethylpentyl]thiazolidine-2,4-dione and 90 μl (1.0 mmol) of n-butyraldehyde in 5 ml of ethanol, 10 μl (0.1 mmol) of piperidine was added, followed by refluxing for 1.5 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, hexane/ethyl acetate=2/1→1/2) to yield 310 mg (74.2%, light yellow oily substance) of the desired product.
Reaction SMILES: [H-].[Na+].Br[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:9]([OH:15])[CH2:10][CH2:11][CH2:12][CH2:13][OH:14].Cl>CN(C)C=O>[CH2:4]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][OH:15])[CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCBr
Reactant: OCCCCCO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCOCCCCCO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60%, 4.2 g) and then 12 ml of 1-bromopentane were added to a solution of 10 g of 1,5-pentanediol in 150 ml of N,N-dimethylformamide. The mixture was stirred at room temperature for 30 min. 3% hydrochloric acid was added to the reaction solution. After extraction with ether, the organic layer was dried and cencentrated. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=8/2) to obtain 6 g of the intended product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:12]2[NH:13]C(C3C=CC=C4C=3N=C(NC(C)(C)C)C(C)=N4)=C[C:16]=2[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:39][C:40]([C:42]1[CH:51]=[CH:50][CH:49]=[C:48]2[C:43]=1[N:44]=[C:45]([NH:53][CH2:54][CH:55]([F:57])[F:56])[C:46]([CH3:52])=[N:47]2)=O.C(OC(NC1(C(=O)CC(OCC)=O)CC1)=O)(C)(C)C>CCO.CC(O)=O>[C:1]([O:5][C:6]([NH:8][C:9]1([C:12]2[NH:13][C:40]([C:42]3[CH:51]=[CH:50][CH:49]=[C:48]4[C:43]=3[N:44]=[C:45]([NH:53][CH2:54][CH:55]([F:57])[F:56])[C:46]([CH3:52])=[N:47]4)=[CH:39][C:16]=2[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc2cccc(C(=O)CBr)c2nc1NCC(F)F
Reactant: CCOC(=O)c1cc(-c2cccc3nc(C)c(NC(C)(C)C)nc23)[nH]c1C1(NC(=O)OC(C)(C)C)CC1
Agent: CCOC(=O)CC(=O)C1(NC(=O)OC(C)(C)C)CC1
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(-c2cccc3nc(C)c(NCC(F)F)nc23)[nH]c1C1(NC(=O)OC(C)(C)C)CC1
Yield: 41 %

Procedure:
This compound (0.40 g, 41% yield) as a yellow amorphous solid was prepared according to the procedures described for Intermediate 324b, using 2-bromo-1-(34(2,2-difluoroethyl)amino)-2-methylquinoxalin-5-yl)ethanone (617) (583 mg, 2.26 mmol), ethyl 3-(1-((tert-butoxycarbonyl)amino)cyclopropyl)-3-oxopropanoate (604) (650 mg, 1.89 mmol) as the starting materials, followed by the subsequent treatment of the resulting 331a (m/z (ESI, +ve) 535.2 (M+H)+) with NH4OAc (728 mg, 9.44 mmol) in 3 mL of EtOH and 1.5 mL of HOAc at 50° C. for 4 h. m/z (ESI, +ve) 516.2 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([CH3:12])[CH:4]=1)#[N:2].[OH-:13].[K+]>C(O)(C)(C)C.[Cl-].[Na+].O>[NH2:2][C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([CH3:12])[CH:4]=1)=[O:13]
Reactant: Cc1cc(C#N)ccc1C(=O)O
Reactant: [OH-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: Cc1cc(C(N)=O)ccc1C(=O)O
Temperature: 25 °C
Yield: 48.2 %

Procedure:
To 4-cyano-2-methylbenzoic acid (0.071 g, 0.44 mmol) in 2 ml of t-butanol was added potassium hydroxide (0.13 g, 2.15 mmol). The reaction mixture was refluxed for 30 min and cooled to room temperature. To the reaction mixture was added 10 ml of brine and the reaction mixture was extracted with ethyl acetate (2×15 ml). The water layer was acidified to pH 1-2 with concentrated aqueous hydrochloric acid to give a white precipitate. The solid was collected by filtration, washed several times with water (3×15 ml) and dried in vacuo to provide 4-(aminocarbonyl)-2-methylbenzoic acid (0.038 g, 49% yield). 1H-NMR (400 MHz, DMSO-d6): 13.10 (br s, 1H), 8.07 (s, 1H), 7.87 (d, 1H), 7.78-7.72 (m, 2H), 7.50 (s, 1H), 2.54 (s, 3H).
Reaction SMILES: CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:34][C:35]([CH3:40])([CH3:39])[C:36](O)=[O:37].[NH2:41][C@H:42]1[C:50]2[C:45](=[CH:46][CH:47]=[C:48]([C:51]([O:53][CH3:54])=[O:52])[CH:49]=2)[CH2:44][CH2:43]1>C1COCC1>[F:34][C:35]([CH3:40])([CH3:39])[C:36]([NH:41][C@H:42]1[C:50]2[C:45](=[CH:46][CH:47]=[C:48]([C:51]([O:53][CH3:54])=[O:52])[CH:49]=2)[CH2:44][CH2:43]1)=[O:37]
Reactant: COC(=O)c1ccc2c(c1)[C@H](N)CC2
Reactant: CC(C)(F)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(c1)[C@H](NC(=O)C(C)(C)F)CC2
Reaction time: 0.25 h
Yield: 52 %

Procedure:
DIPEA (1.68 ml, 10.2 mmol, 3 eq) and HATU (1.29 g, 3.4 mmol, 1 eq) were added to a solution, cooled to 0° C., of 2-fluoro-2-methylpropanoic acid (360 mg, 3.4 mmol, 1 eq) in THF (15 ml). The reaction mixture was stirred for 15 min, then a solution of (R)-methyl 3-amino-2,3-dihydro-1H-indene-5-carboxylate (A-07) (650 mg, 3.4 mmol, 1 eq) in THF (5 ml) was added and stirring was carried out for 16 h at room temperature. The reaction mixture was concentrated under reduced pressure, taken up in dichloromethane (50 ml) and washed with saturated sodium hydrogen carbonate solution (20 ml), saturated ammonium chloride solution (20 ml), water (20 ml) and saturated sodium chloride solution (20 ml). It was then dried over sodium sulfate and concentrated under reduced pressure, and the crude product was purified by column chromatography (silica gel, 2% methanol/dichloromethane). Yield: 52% (500 mg, 1.79 mmol)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([N+:10]([O-])=O)=[CH:4][CH:3]=1.C[OH:14]>[Ni]>[NH2:10][C:5]1[C:6]([C:8]([NH2:9])=[O:14])=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: CO
Reactant: N#Cc1nc(Cl)ccc1[N+](=O)[O-]
Agent: [Ni]
Product: NC(=O)c1nc(Cl)ccc1N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
to a suspension of 6-chloro-3-nitro-pyridine-2-carbonitrile (11.01 g, 60 mmol) in methanol (120 ml), was added Raney-Nickel (3 g, washed with methanol to remove water) and the mixture was shaken under a H2-atmosphere at room temperature for 4 hours. The catalyst was removed by filtration, washed with methanol (500 ml). Both filtrates were combined and then evaporated to dryness. The residue was dissolved in dichloromethane and the solution was filtered through a short and wide column with silica gel (100 g). The column was additionally washed with CH2Cl2/MeOH (200 ml, 4:1). The filtrate and washings were combined and evaporated to small volume. The formed precipitate was filtered off to give 3-amino-6-chloro-pyridine-2-carboxamide (8.1 g). The final filtrate was evaporated to dryness and the residue purified by column chromatography on silica gel (30 g). The compound was eluted with the following solvent systems: CH2Cl2 (200 ml), CH2Cl2/MeOH 100:1 (200 ml). The appropriate fractions were evaporated in vacuo yielding an additional 1.15 g of 3-amino-6-chloro-pyridine-2-carboxamide (total yield 9.25 g, i.e. 90%) which was characterised as follows:
Reaction SMILES: CC([O-])(C)C.[K+].[O:7]([CH2:14][C:15]([NH:17][CH3:18])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:19]([O:23][C:24](=[O:34])[C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[S:33])=[CH:27][CH:26]=1)[CH2:20][CH2:21][CH3:22]>C1COCC1>[CH2:19]([O:23][C:24](=[O:34])[C:25]1[CH:26]=[CH:27][C:28]([NH:31][C:32]([N:17]([CH3:18])[C:15](=[O:16])[CH2:14][O:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[S:33])=[CH:29][CH:30]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCOC(=O)c1ccc(N=C=S)cc1
Reactant: CNC(=O)COc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCOC(=O)c1ccc(NC(=S)N(C)C(=O)COc2ccccc2)cc1
Reaction time: 0.08 h
Yield: 10 %

Procedure:
t-BuOK (0.55 mL of 1.0 N solution) in THF is added to a solution of phenoxy-N-methylacetamide (83 mg, 0.5 mmol) in THF (5 mL). After 5 minutes, butyl-4-isothiocyanatobenzoate (118 mg, 0.5 mmol) is added in one portion and the resultant mixture is stirred overnight. The crude mixture is filtered through a silica pad. After purification on silica eluting with 25% EtOAc in llexaiie, the desired acyithiouraea is obtained as a yellow oil (20 mg).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10]([NH2:12])=[O:11])[CH:5]=[CH:4][CH:3]=1.[CH2:13](C(CC)(CC)C([O-])([O-])[O-])[CH3:14]>>[F:1][C:2]1[N:7]=[C:6]([N:8]2[C:13]([CH3:14])=[N:12][C:10]([OH:11])=[N:9]2)[CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)NNc1cccc(F)n1
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Product: Cc1nc(O)nn1-c1cccc(F)n1
Temperature: 25 °C
Yield: 58.7 %

Procedure:
A solution was prepared by admixing 17.02 g (0.10 m) of 2-(6-fluoro-2-pyridinyl)hydrazinecarboxamide with 100 ml of triethylorthoacetate. The mixture was refluxed overnight and the reaction mixture cooled to room temperature and poured over ice water. The solids which precipitated out were recovered by filtration. The solids were washed with methylene chloride and dried under vacuum to yield 11.4 g (58.7 percent of theoretical) of the desired 1-(6-fluoro-2-pyridinyl)-5-methyl-1H-1,2,4-triazol-3-ol. The product melted at 272°-274° C. and upon analysis was found to have carbon, hydrogen and nitrogen contents of 49.58, 3.83 and 28.88 percent, respectively, as compared with the theoretical contents of 49.48, 3.63 and 28.85 percent, respectively, as calculated for the above named compound.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4][C:5]1[NH:10][C:9]2=[N:11][C:12]([CH2:14][CH3:15])=[CH:13][C:8]2=[C:7]([Cl:16])[N:6]=1.[F:17][C:18]([F:28])([F:27])[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]Br>O1CCCC1.C(Cl)Cl>[CH3:3][S:4][C:5]1[N:6]=[C:7]([Cl:16])[C:8]2[CH:13]=[C:12]([CH2:14][CH3:15])[N:11]([CH2:22][C:21]3[CH:24]=[CH:25][CH:26]=[C:19]([C:18]([F:17])([F:27])[F:28])[CH:20]=3)[C:9]=2[N:10]=1
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: CCc1cc2c(Cl)nc(SC)[nH]c-2n1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCc1cc2c(Cl)nc(SC)nc2n1Cc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.9 %

Procedure:
To a suspension of 48 mg (2.00 mmol) of sodium hydride in 4.0 mL of tetrahydrofuran was added 227 mg (1.00 mmol) of 2-(methylthio)-4-chloro-6-ethyl-1H-pyrrolo[2,3-d]pyrimidine and 478 mg (2.00 mmol) of 3-(trifluoromethyl)benzyl bromide. The reaction was stirred at ambient temperature for 18 hours then diluted with 30 mL of methylene chloride and washed with 20 mL of saturated sodium bicarbonate solution. The organic phase was dried with sodium sulfate and concentrated. The crude product was purified by flash chromatography (25 g silica, methylene chloride-heptane gradient 1:1 to 100:0) to provide 320 mg (83%) of 2-(methylthio)-4-chloro-6-ethyl-7-[[3-(trifluoromethyl)-phenyl]methyl]-7H-pyrrolo[2,3-d]pyrimidine as a white solid. nmr (500 MHz, CDCl3) δ1.31 (t, J=7.3 Hz, 3H), 2.58 (s, 3H), 2.59 (q, J=7.3 Hz, 2H), 5.44 (s, 2H), 6.31 (s, 1H), 7.18 (d, J=7.8 Hz, 1H), 7.41 (t, J=7.8 Hz, 1H), 7.45 (s, 1H), 7.54 (d, J=7.8 Hz, 1H)
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([B:10]([OH:12])[OH:11])=[CH:6][CH:5]=1)([OH:3])=[O:2].O[N:14]1[C:18](=[O:19])[CH2:17][CH2:16][C:15]1=[O:20].C1(N=C=NC2CCCCC2)CCCCC1.ClCl>CN(C=O)C.ClCCl>[C:15]1(=[O:20])[N:14]([O:2][C:1]([C:4]2[CH:5]=[CH:6][C:7]([B:10]([OH:12])[OH:11])=[CH:8][CH:9]=2)=[O:3])[C:18](=[O:19])[CH2:17][CH2:16]1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: ClCl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(ON1C(=O)CCC1=O)c1ccc(B(O)O)cc1
Reaction time: 0.17 h

Procedure:
4-Carboxyphenyl-boronic acid (CPBA, Example 1, 0.25 g, 1.51 mmol) and N-hydroxysuccinimide (0.26 g, 2.26 mmol) were dissolved in 8.5 ml DMF using a magnetic stirrer. 20 ml of dichloromethane (CH2Cl2) was then added, and the solution was stirred for 10 minutes. N,N'-dicyclohexyl-carbodiimide (DCC, 0.93 g, 4.52 mmol) in 3 ml CH2 Cl2 was then added. The solution was left to react under a nitrogen atmosphere overnight (approx. 12 hours) at ambient temperature, and then filtered to remove the insoluble urea byproduct (DCU). The title compound was used in subsequent reactions without further purification.
Reaction SMILES: [CH2:1]([NH:7][C:8](=[O:33])[NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)(=[O:18])=[O:17])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH2:34][CH2:35][C@H:36]([OH:51])[CH2:37][O:38][C:39]1[CH:48]=[CH:47][C:46]([OH:49])=[C:45]2[C:40]=1[CH2:41][CH2:42][C:43](=[O:50])[NH:44]2>>[CH2:1]([NH:7][C:8]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:27][CH2:28][CH:29]([NH:34][CH2:35][C@H:36]([OH:51])[CH2:37][O:38][C:39]4[CH:48]=[CH:47][C:46]([OH:49])=[C:45]5[C:40]=4[CH2:41][CH2:42][C:43](=[O:50])[NH:44]5)[CH2:30][CH2:31]3)=[CH:22][CH:21]=2)(=[O:18])=[O:17])=[CH:12][CH:11]=1)=[O:33])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCNC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Reactant: NC[C@H](O)COc1ccc(O)c2c1CCC(=O)N2
Product: CCCCCCNC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NC[C@H](O)COc4ccc(O)c5c4CCC(=O)N5)CC3)cc2)cc1

Procedure:
The title compound was prepared from 4-(3-hexyl-ureido)-N-[4-(4-oxo-piperidine-1-yl)-phenyl]-benzensulfonamide (which was obtained in Example 225) and 5-(3-amino-(2S)-2-hydroxy-propoxy)-8-hydroxy-3,4-dihydro-1H-quinolin-2-one (which was obtained in Example 12) according to the procedure of Example 278 as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.86 (t, J=5.1 Hz, 3H), 1.20-1.35 (m, 8H), 1.35-1.50 (m, 2H), 1.75-1.90 (m, 2H), 2.39 (t, J=5.1 Hz, 2H), 2.50-2.75 (m, 5H), 2.82 (t, J=5.1 Hz, 2H), 3.05 (q, J=5.1 Hz, 2H), 3.40-3.55 (m, 2H), 3.75-3.85 (m, 3H), 4.90 (brs, 1H), 6.30 (t, J=5.1 Hz, 1H), 6.44 (d, J=6.6 Hz, 1H), 6.59 (d, J=6.6 Hz, 1H), 6.76 (d, J=6.9 Hz, 1H), 6.85 (d, J=6.9 Hz, 1H), 7.46 (d, J=6.9 Hz, 2H), 7.50 (d, J=6.9 Hz, 2H), 8.67 (s, 1H), 8.84 (s, 1H), 9.10 (brs, 1H), 9.50 (brs, 1H); MS (ES) m/z: 709.2 (MH+); HRMS Calcd. for C36H49N6O7S(MH+): 709.3383. Found: 709.3391.
Reaction SMILES: [NH:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C:3]([OH:5])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:37][CH2:38][C:39]1([C:45]([O:47][CH3:48])=[O:46])[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:9]([O:8][C:6]([NH:1][CH2:2][C:3]([N:42]1[CH2:43][CH2:44][C:39]([CH2:38][OH:37])([C:45]([O:47][CH3:48])=[O:46])[CH2:40][CH2:41]1)=[O:5])=[O:7])([CH3:12])([CH3:11])[CH3:10]
Reactant: COC(=O)C1(CO)CCNCC1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C1(CO)CCN(C(=O)CNC(=O)OC(C)(C)C)CC1
Reaction time: 1 h
Yield: 98.5 %

Procedure:
To a solution of Boc-Gly-OH (331 mg, 1.89 mmol, 1.1 equiv.) in DMF (1 mL) was added HBTU (718 mg, 1.89 mmol, 1.1 equiv.), followed by addition of methyl 4-(hydroxymethyl)piperidine-4-carboxylate (1.72 mmol, 1 equiv.) and DIEA (749 μL, 4.30 mmol, 2.5 equiv.) at rt. The reaction mixture was stirred for 1 h. The mixture was partitioned between EtOAc and H2O. The organic layer was washed by saturated NaHCO3, water and brine, dried over Na2SO4, and concentrated. The resulting residue was purified by column chromatography to give methyl 1-(2-(tert-butoxycarbonylamino)acetyl)-4-(hydroxymethyl)piperidine-4-carboxylate (560 mg, 98%, two steps). LRMS (M-Boc+H+) m/z 231.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][OH:27])[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1.[H-].[Na+].[Br:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Br)=[CH:34][CH:33]=1.P([O-])([O-])([O-])=O>CN(C=O)C.O>[Br:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][N:14]2[CH2:13][C@@H:12]([C:10]3[CH:9]=[CH:8][C:6]4[O:7][C:2]([CH3:28])([CH3:1])[O:3][CH2:4][C:5]=4[CH:11]=3)[O:16][C:15]2=[O:17])=[CH:34][CH:33]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCO)C(=O)O3)ccc2O1
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4ccc(Br)cc4)C(=O)O3)ccc2O1
Reaction time: 0.25 h
Yield: 74.3 %

Procedure:
A solution of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-3-{6-[(2-hydroxyethyl)oxy]hexyl}-1,3-oxazolidin-2-one (2.00 g) in DMF (25 ml) under nitrogen was treated with sodium hydride (244 mg, 60% in oil) and the mixture was stirred at 200 for 15 min. 4-Bromobenzyl bromide (1.40 g) was added and the mixture was stirred at 200 for 18 h. Phosphate buffer solution (50 ml, pH6.5) and water (50 ml) were added and the mixture was extracted with EtOAc. The extract was washed with water, dried (Na2SO4) and the solvent evaporated in vacuo to give a residue. The residue was purified by chromatography on flash silica gel (40 mm diameter column). Elution with EtOAc-PE (1:1) gave the title compound (2.125 g). LCMS RT=3.77 min.