Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][N:3]=1.[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>O1CCOCC1.C(OCC)(=O)C>[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:2]2[N:7]=[CH:6][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][N:3]=2)=[CH:16][CH:15]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cnc(Cl)nc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc(Nc2ccc(Cl)cc2)nc1
Temperature: 100 °C
Yield: 57.8 %

Procedure:
A mixture of ethyl 2-chloropyrimidine-5-carboxylate (0.5 g, 2.68 mmol) and 4-chloroaniline (0.684 g, 5.36 mmol) in dioxane (15 mL) was heated at 100° C. for 8 h, diluted with ethyl acetate and filtered. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel using 0-30% ethyl acetate in hexanes. The desired fractions were concentrated to give ethyl 2-(4-chlorophenylamino)pyrimidine-5-carboxylate as an orange solid (0.43 g, 58%). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.96 (2H, s), 7.57-7.64 (2H, m), 7.45 (1H, br. s.), 7.29-7.36 (2H, m), 4.37 (2H, q, J=7.02 Hz), 1.38 (3H, t, J=7.02 Hz). LCMS: R.T.=4.16 min; [M+H]+=277.96.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[O:9][C@H:8]3[NH:13][C@H:14]([C:16]([O:18][C@@H:19]4[C@:28]5([OH:29])[C@H:23]([C@H:24]([C:31]([CH3:33])=[CH2:32])[CH2:25][CH2:26][C@H:27]5[CH3:30])[CH:22]=[C:21]([CH3:34])[C@H:20]4[O:35][C:36](=[O:38])[CH3:37])=[O:17])[CH2:15][C@@:7]3([OH:39])[C:6]=2[CH:5]=[CH:4][CH:3]=1.B.C[N+]1([O-])CC[O:45]CC1>O1CCCC1>[Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[O:9][C@H:8]3[NH:13][C@H:14]([C:16]([O:18][C@@H:19]4[C@:28]5([OH:29])[C@@H:23]([C@H:24]([CH:31]([CH3:33])[CH2:32][OH:45])[CH2:25][CH2:26][C@H:27]5[CH3:30])[CH:22]=[C:21]([CH3:34])[C@H:20]4[O:35][C:36](=[O:38])[CH3:37])=[O:17])[CH2:15][C@@:7]3([OH:39])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=C(C)[C@@H]1CC[C@@H](C)[C@@]2(O)[C@H]1C=C(C)[C@@H](OC(C)=O)[C@@H]2OC(=O)[C@@H]1C[C@@]2(O)c3cccc(Cl)c3N(C)O[C@H]2N1
Agent: B
Solvent: C1CCOC1
Product: CC(=O)O[C@@H]1C(C)=C[C@@H]2[C@H](C(C)CO)CC[C@@H](C)[C@]2(O)[C@H]1OC(=O)[C@@H]1C[C@@]2(O)c3cccc(Cl)c3N(C)O[C@H]2N1
Yield: 25.6 %

Procedure:
To a solution of (1S,2R,4aS,5R,8R,8aR)-2-(acetyloxy)-8a-hydroxy-3,8-dimethyl-5-(1-methylethenyl)-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl (2S,3aR,9bR)-6-chloro-9b -hydroxy-5-methyl-1,2,3,3a,5,9b-hexahydropyrrolo[2,3-c][2,1]benzoxazine-2-carboxylate (Preparation 1, 500 mg, 0.89 mmol) in tetrahydrofuran (8 ml) at −10° C. under nitrogen was added borane (1M solution in tetrahydrofuran, 2 ml, 2 mmol) and the resulting mixture stirred and allowed to come to room temperature. After 5 hours borane (1M solution in tetrahydrofuran, 1 ml, 1 mmol) was added and the reaction stirred at room temperature for 18 h. To the reaction mixture was added 4-methylmorpholine N-oxide (600 mg, 5.1 mmol) and the mixture heated to gentle reflux for 3 hours. The reaction mixture was concentrated in vacuo and the residue treated with water (30 ml) and extracted with ethyl acetate (2×30 ml). The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried (MgSO4) and the solvent removed in vacuo to give an orange glass. The crude product was purified by column chromatography on silica eluting with hexane:ethyl acetate (2:1 then 1:1) and then ethyl acetate. The pure fractions were combined and concentrated in vacuo to give a the title product as a yellow solid (132 mg, 26%).
Reaction SMILES: [OH-].[Na+].[F:3][CH:4]([F:22])[C:5]1([C:17]([O:19]CC)=[O:18])[CH2:10][C:9](=[CH2:11])[CH2:8][CH:7]([C:12]([O-:14])=[O:13])[N:6]1[CH:15]=[O:16].O>C(O)C>[F:22][CH:4]([F:3])[C:5]1([C:17]([OH:19])=[O:18])[CH2:10][C:9](=[CH2:11])[CH2:8][CH:7]([C:12]([OH:14])=[O:13])[N:6]1[CH:15]=[O:16]
Reactant: C=C1CC(C(=O)[O-])N(C=O)C(C(=O)OCC)(C(F)F)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=C1CC(C(=O)O)N(C=O)C(C(=O)O)(C(F)F)C1
Temperature: 25 °C
Reaction time: 60 h
Yield: 96 %

Procedure:
0.68 ml of 1N sodium hydroxide were added to a solution of 54 mg of the product of Step A in 4 ml of ethanol. The mixture was stirred at ambient temperature for 60 hours. 4 ml of water were added and the pH was neutralized to about 6 with Amberlyst 15 resin. After filtering and evaporating to dryness the residue was taken up in 8 ml of water and lyophilized to obtain 47 mg of the desired product in the form of its sodium salt.
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][C:9]([CH3:11])=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH:17]1([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:24][C:23]=2B2OC(C)(C)C(C)(C)O2)[CH2:19][CH2:18]1>>[CH:17]1([CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:26][C:27]=2[C:2]2[C:3]3[NH:10][C:9]([CH3:11])=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:18][CH2:19]1
Reactant: CC(C)c1ccc(OCC2CC2)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCOC(=O)c1c(C)[nH]c2c(Cl)ncnc12
Product: CCOC(=O)c1c(C)[nH]c2c(-c3cc(C(C)C)ccc3OCC3CC3)ncnc12

Procedure:
Starting from ethyl 4-chloro-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (example A4) and 2-[2-(cyclopropylmethoxy)-5-(propan-2-yl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (example B.c15) the title compound is obtained as off white solid.
Reaction SMILES: [CH3:1][CH2:2][C:3]1[C:21]2=[N:22][C:5](=[CH:6][C:7]3[NH:11][C:10]([CH:12]=[C:13]4[CH:34]([CH3:35])[CH:33]([CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])[C:15]([C:16]5[CH:27](C(OC)=O)[C:25](=[O:26])[C:24]6[C:17]=5[NH:18][C:19]([C:23]=6[CH3:32])=[CH:20]2)=[N:14]4)=[C:9]([CH3:42])[C:8]=3[CH:43]=[CH2:44])[C:4]=1[CH3:45].O>>[CH3:1][CH2:2][C:3]1[C:21]2=[N:22][C:5](=[CH:6][C:7]3[NH:11][C:10]([CH:12]=[C:13]4[C@@H:34]([CH3:35])[C@H:33]([CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])[C:15]([C:16]5[CH2:27][C:25](=[O:26])[C:24]6[C:17]=5[NH:18][C:19]([C:23]=6[CH3:32])=[CH:20]2)=[N:14]4)=[C:9]([CH3:42])[C:8]=3[CH:43]=[CH2:44])[C:4]=1[CH3:45]
Reactant: C=Cc1c(C)c2cc3nc(c4c5[nH]c(cc6nc(cc1[nH]2)C(C)=C6CC)c(C)c5C(=O)C4C(=O)OC)C(CCC(=O)OC)C3C
Solvent: O
Product: C=Cc1c(C)c2cc3nc(c4c5[nH]c(cc6nc(cc1[nH]2)C(C)=C6CC)c(C)c5C(=O)C4)[C@@H](CCC(=O)OC)[C@@H]3C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 81.8 %

Procedure:
Methyl pheophorbide-a (23 g, 37.9 mmol) was added to distilled 2,4,6-collidine (700 mL, Aldrich) and the mixture was refluxed under argon with stirring. After 7 hours of reflux, TLC showed the majority of methyl pheophorbide-a remained. Distilled water (2.5 mL, 139 mmol, 3.7 equiv.) was added and the solution was continued to reflux under argon. After 45 min. the reaction was complete by TLC. The solution was cooled to room temperature and solvent removed under reduced pressure. The residue was precipitated from methylene chloride/methanol, then purified on a silica gel column. The desired fraction was collected, solvent was evaporated off, and the fraction was precipitated from methylene chloride/methanol to give methyl pyropheophorbide-a (17 g, 81%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[C:6]([O:8]C)=O.[Cl:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[Cl-].[NH4+]>O1CCCC1>[Cl:14][C:15]1[CH:20]=[C:19]([CH2:21][C:6]([C:5]2[CH:10]=[C:11]([CH3:13])[CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:8])[CH:18]=[CH:17][N:16]=1
Reactant: COC(=O)c1cc(C)cc(OC)c1
Reactant: Cc1ccnc(Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(C)cc(C(=O)Cc2ccnc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 3-methoxy-5-methylbenzoate (9.0 g, 50 mmol) and 2-chloro-4-methylpyridine (7.0 g, 55 mmol) in tetrahydrofuran (90 mL) was dropwise added lithium hexamethyldisilazide (75 mL, 75 mmol, 1M In THF) at 0° C. under a nitrogen atmosphere, and stirred at room temperature for 18 hours. After completion of the nucleophilic attack reaction, the reaction mixture was neutralized with a saturated ammonium chloride solution (150 mL) and extracted with ethyl acetate (300 mL×2). The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated by vacuum distillation, and the concentrate (9.92 g, 72%) was used in the next reaction without further purification.
Reaction SMILES: [NH2:1][C@H:2]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:7][CH2:6]1)=[O:4].CCN(C(C)C)C(C)C.[C:39]([NH:46][C@@H:47]1[CH2:51][CH2:50][C@H:49]([C:52](O)=[O:53])[CH2:48]1)([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][C@@H:2]([NH:1][C:52]([C@@H:49]2[CH2:50][CH2:51][C@H:47]([NH:46][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:48]2)=[O:53])[C:3]([N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[NH:17][S:18]([CH3:21])(=[O:19])=[O:20])[CH2:7][CH2:6]2)=[O:4])=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](C(=O)O)C1
Reactant: CS(=O)(=O)Nc1ccccc1C1CCN(C(=O)[C@H](N)Cc2ccc(Cl)cc2)CC1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)N[C@H](Cc2ccc(Cl)cc2)C(=O)N2CCC(c3ccccc3NS(C)(=O)=O)CC2)C1
Yield: 65 %

Procedure:
The title compound was prepared according to the procedure described in Example 1, Step (f) using (2R)-2-amino-3-(4-chlorophenyl)-1-(4-{2-[(methylsulfonyl)-amino]phenyl}piperidyl)propan-1-one (Example 1, Step g) (471 mg, 1.0 mmol), DIEA (Aldrich) (0.20 mL, 1.0 mmol), (+)-(1R, 3S)—N-Boc-aminocyclopentane-3-carboxylic acid (PepTech Corporation) (344 mg, 1.5 mmol), HOAT (Aldrich) (232 mg, 1.70 mmol) and EDC (Aldrich) (544, 2.84 mmol) in DMF (10 mL). Purification by silica gel chromatography (100% EtOAc) provided the title compound as a white foam (421 mg). MS (ESI, pos. ion) m/z: 647 (M+1); MS (ESI, neg ion) m/z: 645 (M−1). Calc'd for C32H43ClN4O6S: 647.23.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:22])([CH3:21])[C:6]=2[CH:23]=1.[CH3:24][N:25]1[CH2:30][CH2:29][CH:28](O)[CH2:27][CH2:26]1>>[CH3:22][C:7]1([CH3:21])[C:8]2[NH:9][C:10]3[C:15](=[CH:14][CH:13]=[C:12]([C:19]#[N:20])[CH:11]=3)[C:16]=2[C:17](=[O:18])[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH:28]3[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]3)=[CH:23][C:6]1=2
Reactant: CN1CCC(O)CC1
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Product: CN1CCC(Oc2ccc3c(c2)C(C)(C)c2[nH]c4cc(C#N)ccc4c2C3=O)CC1

Procedure:
Under the same conditions as the method for synthesizing Compound A7-1, the title compound was prepared from Compound A6 and 1-methylpiperidin-4-ol.
Reaction SMILES: [CH2:1]([C@@H:3]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16]C)[CH:11]=1)[C@@H:4]([CH3:9])[CH2:5][N:6]([CH3:8])[CH3:7])[CH3:2].B(Br)(Br)Br.CO.[ClH:24]>ClCCl>[ClH:24].[CH3:8][N:6]([CH3:7])[CH2:5][C@H:4]([CH3:9])[C@H:3]([C:10]1[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=1)[CH2:1][CH3:2]
Reactant: CC[C@@H](c1cccc(OC)c1)[C@@H](C)CN(C)C
Agent: BrB(Br)Br
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CC[C@@H](c1cccc(O)c1)[C@@H](C)CN(C)C
Temperature: 25 °C
Yield: 90 %

Procedure:
The product of Example 16 (1.9 g, 8 mmol) was dissolved in dichloromethane, the mixture was cooled in an ice-water bath, and a solution of boron tribromide (1.9 ml, 20 mmol) in dichloromethane was slowly added dropwise, then it was gradually raised to room temperature to make it react for 15 hrs. After it was cooled in an ice-water bath, methanol was slowly added dropwise to quench the reaction, and the organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to 2 mL, then the concentrated hydrochloric acid (670 Ml, 8 mmol) was added dropwise, and the mixture was concentrated and recrystallized with isopropanol and ethyl acetate to obtain the target 1.8 g, yield: 90%. [α]D=+24.3° (c=1.10, CH3OH). 1HNMR (300 MHz, CD3OD): δ 7.2 (1H, t, J=7.9, 15.6), 6.6-6.8 (3H, m), 2.8-2.9 (2H, m), 2.7-2.8 (6H, br s), 2.2-2.3 (1H, m), 2.1-2.2 (1H, m), 1.8-1.9 (1H, m), 1.5-1.6 (1H, m), 1.2 (3H, d, J=6.7), 0.8 (3H, t, J=7.4, 14.4). ESI-MS: 222.4 (M+H).
Reaction SMILES: [NH2:1][C:2](=[O:27])[C@H:3]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([NH2:13])=O)=[C:9](NC2C=NC3C(C=2)=CC=CC=3)[N:8]=1)[CH2:4][CH3:5].[NH2:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[N:35]=[CH:34][CH:33]=[CH:32]2.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:11]([C:10]1[CH:14]=[CH:15][C:7]([NH:6][C@H:3]([CH2:4][CH3:5])[C:2]([NH2:1])=[O:27])=[N:8][C:9]=1[NH:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[N:35]=[CH:34][CH:33]=[CH:32]2)#[N:13]
Reactant: Nc1ccc2ncccc2c1
Reactant: CC[C@@H](Nc1ccc(C(N)=O)c(Nc2cnc3ccccc3c2)n1)C(N)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC[C@@H](Nc1ccc(C#N)c(Nc2ccc3ncccc3c2)n1)C(N)=O
Temperature: 105 °C
Reaction time: 8 h

Procedure:
The mixture of (R)-2-(6-chloro-5-cyanopyridin-2-ylamino)butanamide (compound J52 in Example 203) (140 mg, 0.59 mmol), 6-aminoquinoline (260 mg, 1.8 mmol), cesium carbonate (980 mg, 3.0 mmol), BINAP (75 mg, 0.12 mmol) and Pd(OAc)2 (27 mg, 0.12 mmol) in 20 mL dioxane was degassed with Ar. The mixture was stirred under Ar at 105° C. for overnight. It was concentrated in vacuo, taken into EtOAc, washed with brine, dried, concentrated in vacuo and subjected to flash column (0 to 8% MeOH in DCM) to isolate (R)-2-(5-cyano-6-(quinolin-6-ylamino)pyridin-2-ylamino)butanamide. It was then dissolved in 4 mL DMSO. To it were added 100 mg powder K2CO3 and 2 mL 50% H2O2 in water. The mixture was stirred at RT for 1 (65 h. To it was added 4 mL water, the mixture was vigorously stirred and subjected to reverse phase preparative HPLC to isolate the title compound. (65 mg). UV: 267, 299, 330 nm. M+H found for C19H20N6O2: 365.2. NMR (CD3OD): 9.25 (1H, d, J=8.8 Hz), 9.04 (1H, d, J=2.0 Hz), 8.85 (1H, dd, J=6.4; 2.4 Hz), 8.06 (1H, d, J=9.6 Hz), 7.99 (1H, dd, J=9.2; 2.4 Hz), 7.92 (1H, m), 7.88 (1H, d, J=8.8 Hz), 6.28 (1H, d, J=9.2 Hz), 4.31 (1H, m), 2.00 (2H, m), 1.14 (3H, t, J=7.6 Hz) ppm.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[CH:27]1([CH2:30][CH2:31][OH:32])[CH2:29][CH2:28]1>>[CH:27]1([CH2:30][CH2:31][O:32][C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=2[C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:10]=2)[CH2:29][CH2:28]1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Reactant: OCCC1CC1
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3OCCC3CC3)n2)c1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (75 mg; 0.19 mmol), intermediate 42.1, and 2-cyclopropylethanol (46.2 mg; 0.773 mmol), example 48 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: [CH2:1]([C@@H:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:9](=[O:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C.O>[CH2:1]([C@@H:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]([OH:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)[C@@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(O)[C@@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 18 h

Procedure:
A solution of 21 g of tert-butyl (1R)-1-benzyl-2-oxopropylcarbamate in 200 cm3 of ethanol under an inert atmosphere is cooled to a temperature in the region of 10° C., followed by portionwise addition of 4.55 g of sodium borohydride. The temperature of the reaction medium is allowed to rise to room temperature with stirring, and the stirring is then continued for 18 hours. The reaction medium is concentrated under reduced pressure (2 kPa) at a temperature in the region of 40° C., to give white crystals which are taken up in 150 cm3 of water. This mixture is stirred for 2 hours at room temperature and then filtered through a sinter funnel. The filter cake is washed with twice 150 cm3 of water. After drying overnight in a fume cupboard, 19.37 g of tert-butyl (1R)-1-benzyl-2-hydroxypropylcarbamate are obtained in the form of white crystals melting at 127° C. 1H NMR spectrum (300 MHz, (CD3)2SO-d6 with addition of a few drops of CD3COOD-d4, δ in ppm). A mixture of two diastereoisomers in 70/30 proportions is observed: 1.04 and 1.10 (2d, J=6 Hz: 3H); 1.29 and 1.32 (2s: 9H); from 2.40 to 3.10 (mt: 2H); from 3.35 to 3.70 (mt: 2H); 6.40 and 6.54 (2d, J=9 Hz: 1H); from 7.10 to 7.35 (mt: 5H).
Reaction SMILES: [C:1](Cl)(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[N:25]1([CH2:30][CH:31]([OH:33])[CH3:32])[CH:29]=[CH:28][N:27]=[CH:26]1.CN(C)C=O>C1(C)C=CC=CC=1>[C:1]([O:33][CH:31]([CH3:32])[CH2:30][N:25]1[CH:29]=[CH:28][N:27]=[CH:26]1)(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: CC(O)Cn1ccnc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)OC(C)Cn1ccnc1
Yield: 92.2 %

Procedure:
With ice cooling and stirring, 35.9 g of behenic chloride (16) was added to a mixture of 12.6 g of 1-(1H-imidazol-1-yl)-2-propanol (15) and 50 g of dimethylformamide. Then the mixture was stirred at room temperature for 2 hours. Toluene was added to the solution, followed by neutralization. Subsequent standard aqueous work-up and purification by column chromatography gave 41.3 g of [2-(1H-imidazol-1-yl)-1-methylethyl] behenate (Quencher 1). Yield 92%.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[O:4][C:5]1[CH2:9][N:8]([CH:10]([CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:11](O)=[O:12])[C:7](=[O:21])[CH:6]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)C(C)C)(C)C.[CH3:60][O:61][C:62](=[O:70])[C:63]1[CH:68]=[CH:67][C:66]([NH2:69])=[N:65][CH:64]=1>ClCCl>[CH3:60][O:61][C:62](=[O:70])[C:63]1[CH:68]=[CH:67][C:66]([NH:69][C:11](=[O:12])[CH:10]([N:8]2[CH2:9][C:5]([O:4][C:3]3[C:22]([F:26])=[CH:23][CH:24]=[CH:25][C:2]=3[F:1])=[CH:6][C:7]2=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[N:65][CH:64]=1
Reactant: O=C(O)C(CC1CCOCC1)N1CC(Oc2c(F)cccc2F)=CC1=O
Reactant: COC(=O)c1ccc(N)nc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)C(CC2CCOCC2)N2CC(Oc3c(F)cccc3F)=CC2=O)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.2 %

Procedure:
A solution of 2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-(tetrahydro-pyran-4-yl)-propionic acid (155 mg, 0.42 mmol) in dichloromethane (10 mL) was treated with bromotripyrrolidinophosphonium hexafluorophosphate (240 mg, 0.051 mmol), N,N-diisopropylethylamine (165 mg, 0.127 mmol) and 6-aminonicotinic acid methyl ester (80 mg, 0.51 mmol). The reaction mixture was stirred at 25° C. for 18 h under nitrogen. The reaction mixture was diluted with dichloromethane, washed with 2N aqueous hydrochloric acid, saturated sodium bicarbonate solution, a saturated sodium chloride solution and dried over magnesium sulfate. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g; 0% to 100% ethyl acetate/hexanes) to afford 6-[2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-(tetrahydro-pyran-4-yl)-propionylamino]-nicotinic acid methyl ester (110 mg, 55%), as an off-white solid: LR-ES-MS m/z calculated for C25H25F2N3O6 [M]+ 501, observed [M+H]+ 502; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.20-1.95 (m, 7H) 3.11-3.32 (m, 2H) 3.70-3.92 (m, 2H) 3.86 (s, 3H) 4.37 (d, J=18.1 Hz, 1H) 4.64 (d, J=18.1 Hz, 1H) 4.98-5.12 (m, 2H) 7.30-7.51 (m, 3H) 8.13-8.20 (m, 1H) 8.28 (dd, J=8.8, 2.4 Hz, 1H) 8.87 (d, J=2.4 Hz, 1H) 11.33 (s, 1H).
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:21])=[C:6]2[C:11](=[C:12]([Cl:14])[CH:13]=1)[S:10](=[O:16])(=[O:15])[CH2:9][CH2:8][C:7]12[O:20][CH2:19][CH2:18][O:17]1)([OH:3])=[O:2].[CH2:22]([N:24]1[C:28](O)=[CH:27][CH:26]=[N:25]1)[CH3:23].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[Cl:14][C:12]1[CH:13]=[C:4]([C:1]([O:3][C:28]2[N:24]([CH2:22][CH3:23])[N:25]=[CH:26][CH:27]=2)=[O:2])[C:5]([CH3:21])=[C:6]2[C:11]=1[S:10](=[O:16])(=[O:15])[CH2:9][CH2:8][C:7]12[O:20][CH2:19][CH2:18][O:17]1
Reactant: CCn1nccc1O
Reactant: Cc1c(C(=O)O)cc(Cl)c2c1C1(CCS2(=O)=O)OCCO1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCn1nccc1OC(=O)c1cc(Cl)c2c(c1C)C1(CCS2(=O)=O)OCCO1
Temperature: 25 °C
Reaction time: 5 h
Yield: 80.3 %

Procedure:
0.92 Gram (2.8 mmol) of 6-carboxy-8-chloro-4,4-ethylenedioxy-5-methylthiochroman-1,1-dioxide was dissolved in 10 ml of methylene chloride, and 0.34 g (1.1 eq., 3.0 mmol) of 1-ethyl-5-hydroxypyrazole and 0.63 g (1.1 eq., 3.1 mmol) of N,N'-dicyclohexylcarbodiimide were added. The mixture was stirred at room temperature for 5 hours. Then, an insoluble substance was removed by filtration, and the filtrate was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off to give 0.96 g (yield 81%) of 8-chloro-6-(1-ethylpyrazol-5-yl)oxycarbonyl-4,4-ethylenedioxy-5-methylthiochroman-1,1-dioxide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[CH2:19][O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:4][CH:3]=1.Cl[CH2:27][CH2:28][C:29]1[CH:30]=[CH:31][C:32]([O:39][CH3:40])=[C:33]([S:35]([NH2:38])(=[O:37])=[O:36])[CH:34]=1.[I-].[Na+].C(N(C(C)C)CC)(C)C>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([N:13]3[CH2:18][CH2:17][N:16]([CH2:27][CH2:28][C:29]4[CH:30]=[CH:31][C:32]([O:39][CH3:40])=[C:33]([S:35]([NH2:38])(=[O:36])=[O:37])[CH:34]=4)[CH2:15][CH2:14]3)=[N:10][C:9]=2[CH2:19][O:20][CH2:21][C:22]([F:25])([F:23])[F:24])=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2oc(N3CCNCC3)nc2COCC(F)(F)F)cc1
Reactant: COc1ccc(CCCl)cc1S(N)(=O)=O
Agent: [I-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CCN2CCN(c3nc(COCC(F)(F)F)c(-c4ccc(F)cc4)o3)CC2)cc1S(N)(=O)=O
Reaction time: 16 h
Yield: 58.2 %

Procedure:
A solution of 1-[5-(4-fluoro-phenyl)-4-(2,2,2-trifluoro-ethoxymethyl)-oxazol-2-yl]-piperazine (0.15 g; 0.42 mmol) in dry dioxane (5 ml) is treated with 5-(2-chloroethyl)-2-methoxy-benzenesulfonamide (0.25 g; 1.0 mmol), sodium iodide (0.15 g; 1.0 mmol) and diisopropylethylamine (0.36 ml; 2.09 mmol) and heated to 100 C. for 16 hours. The reaction mixture is partitioned between ethyl acetate (40 ml) and dilute sodium bicarbonate (20 ml). The aqueous phase is extracted with ethyl acetate (20 ml). The combined organic phases are washed with saturated brine (10 ml), dried over sodium sulfate and concentrated to dryness. Purification by radial chromatography on silica gel using a methanol-ethyl acetate gradient (1%-20%) is followed by a second chromatography using a methanol-dichloromethane gradient (1%-5%). Crystallization from ethyl acetate/hexane affords the product as a white solid (0.14 g; 56%). HNMR (CDCL3): 7.81 (d, 1H, J=2.4 Hz), 7.54 (m, 2H), 7.42 (dd, 1H, J=8.7, 2.0 Hz), 7.14 (t, 2H, J=8.8 Hz), 7.02 (d, 1H, J=8.7 Hz), 5.16 (s, 2H), 4.04 (s, 3H), 4.01 (qt, 2H, J=8.8 Hz), 3.62 (m, 4H), 2.85 (m, 2H), 2.66 (m, 6H).