Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[CH:5][CH:4]=1.[OH-].[K+].[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>C(COC)OC>[C:20]1([S:26]([N:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]([C:6]3[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][CH:7]=3)=[CH:10]2)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CSc1ccc(-c2c[nH]c3ccccc23)cc1
Agent: [K+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: CSc1ccc(-c2cn(S(=O)(=O)c3ccccc3)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.3 %

Procedure:
To a solution of 3-(4-methylthiophenyl)indole (7.34 g, 30.7 mmol), prepared as in step 1, in dimethoxyethane (75 mL) was added powdered KOH (85%, 7.01 g, 125 mmol) and benzenesulfonyl chloride (4.25 mL, 33.3 mmol). A white precipitate formed immediately and the reaction mixture became quite warm. The reaction mixture was stirred for 1 hour during which time it cooled to ambient temperature. Water (50 mL) was added and the mixture was extracted with ethyl acetate. The organic phase was washed with H2O and brine, dried over Na2SO4, filtered, and concentrated in vacuo. 1-phenylsulfonyl-3-(4-methylthiophenyl)indole (8.89 g, 76% yield) was obtained by chromatography on silica gel (10%, then 20% ethyl acetate/hexanes).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]2[CH2:16][CH2:17][C:18]([OH:20])=O.[C:21]1([NH2:31])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]2[CH2:16][CH2:17][C:18]([NH:31][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1)=[O:20]
Reactant: CCOC(=O)c1[nH]c2c(Br)cccc2c1CCC(=O)O
Reactant: Nc1cccc2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Product: CCOC(=O)c1[nH]c2c(Br)cccc2c1CCC(=O)Nc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 3-(7-bromo-2-(ethoxycarbonyl)-1H-indol-3-yl)propanoic acid (0.68 g), naphthalen-1-amine (0.294 g), DMAP (0.363 g) and 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide hydrochloride (0.576 g) was stirred for 3 days at room temperature. The product precipitated and was filtered, washed with dichloromethane, and dried under vacuum.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])#[N:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])#[N:2]
Reactant: COC(=O)c1cc(C#N)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(C#N)ccc1OCc1ccccc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A suspension of methyl 5-cyano-2-hydroxybenzoate (may be prepared as described in Description 12; 531 mg, 3 mmol), potassium carbonate (1037 mg, 7.50 mmol) and (bromomethyl)benzene (1026 mg, 6.00 mmol) in acetone (60 ml) was stirred at 50° C. overnight. The mixture was cooled and filtered. The filtrate was concentrated. The crude product was purified by silica gel chromatography eluting with hexane:ethyl acetate (10:1) to yield the title compound as a white solid. 480 mg.
Reaction SMILES: [CH2:1]1[C:3]([NH2:7])([C:4]([OH:6])=[O:5])[CH2:2]1.[C:8]1([CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH2:21][O:22][C:23](ON2C(=O)CCC2=O)=[O:24])=[O:18])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:8]1([CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH2:21][O:22][C:23]([NH:7][C:3]2([C:4]([OH:6])=[O:5])[CH2:2][CH2:1]2)=[O:24])=[O:18])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(CCCc1ccccc1)OCCOC(=O)ON1C(=O)CCC1=O
Reactant: NC1(C(=O)O)CC1
Product: O=C(CCCc1ccccc1)OCCOC(=O)NC1(C(=O)O)CC1
Yield: 45.5 %

Procedure:
Following the general procedure for the synthesis of acyloxyalkyl carbamates, ACPC (0.218 g, 2.08 mmol) and (2,5-dioxoazolidinyloxycarbonyloxy)ethyl 4-phenylbutyrate (0.607 g, 1.73 mmol) were reacted to provide 0.264 g (46% yield) of the title compound (15) as a white semi-solid after work-up and mass-guided preparative HPLC purification. 1H NMR (CDCl3, 400 MHz): δ=7.32 (t, 2H), 7.19 (m, 3H), 6.81 (q, 1H), 6.22 (s, 0.3H), 5.43 (s, 0.7H), 2.62 (t, 2H), 2.31 (m, 2H), 1.98 (q, 2H), 1.61 (m, 2H), 1.42 (dd, 3H), 1.23 (m, 2H). MS (ESI) m/z 358.05 (M+Na)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:13]=[CH:12][C:9]([NH:10][CH3:11])=[CH:8][CH:7]=1)=[O:5])[CH3:2].B(Cl)(Cl)Cl.[CH:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>C1C=CC=CC=1.CCOCC.O>[CH3:11][NH:10][C:9]1[CH:12]=[CH:13][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][C:8]=1[CH:18]([OH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1ccc(NC)cc1
Reactant: O=Cc1ccccc1
Agent: ClB(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCOC(=O)c1ccc(NC)c(C(O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
To a solution of p-ethoxycarbonyl-methylaniline (179 mg) in dry benzene (2 ml), a solution of boron trichloride (129 mg) in dry benzene (2 ml), is added with ice cooling. A solution of benzaldehyde (0.1 ml) and triethylamine (222 mg) in dry benzene (3 ml) is added to the mixture, which is stirred at room temperature for 3 hours. The reaction mixture is mixed with water and shaken with ether. The organic layer is washed with water, dried, and evaporated to remove the solvents. The residue is washed with petroleum ether to give 2-methylamino-5-ethoxycarbonylbenzhydrol (196 mg) as crystals melting at 132° to 135° C. The yield is 69%.
Reaction SMILES: [Br:1][C:2]([F:16])([F:15])[C:3]([F:14])([F:13])[S:4][C:5]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].F[B-](F)(F)F.[O:22]=[N+:23]=[O:24]>>[Br:1][C:2]([F:15])([F:16])[C:3]([F:13])([F:14])[S:4][C:5]1[C:6]([Cl:12])=[CH:7][C:8]([N+:23]([O-:24])=[O:22])=[CH:9][C:10]=1[Cl:11]
Reactant: FC(F)(Br)C(F)(F)Sc1c(Cl)cccc1Cl
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Product: O=[N+]([O-])c1cc(Cl)c(SC(F)(F)C(F)(F)Br)c(Cl)c1
Temperature: 100 °C
Reaction time: 14 h
Yield: 38.8 %

Procedure:
A stirred mixture of 30.5 g (0.085 mole) 2-(2-bromo-1,1,2,2-tetrafluoroethylthio)-1,3-dichlorobenzene and 13.3 g (0.10 mole) nitronium tetrafluoroborate (0.5M in sulfone) was heated at 100° C. for approximately 18 hours. An additional 4.0 g of nitronium tetrafluoroborate (solid) was added to the reaction mixture and heating was continued for 14 hours. The mixture was cooled and poured into 200 g of ice water. The resultant mixture was extracted with four 100 ml portions of methylene chloride and the extracts were combined. The organic extract was extracted with three 100 ml portions of a 2N sodium hydroxide solution. The basic aqueous extracts were combined and washed with 100 ml of methylene chloride. The washed extract was made acidic with concentrated hydrochloric acid while cooling in an ice bath. The acidic solution was saturated with sodium chloride and then was extracted with three 150 ml portions of methylene chloride. The organic extracts were combined and dried over anhydrous magnesium sulfate. After filtering the filtrate was evaporated under reduced pressure to leave an oil. This oil was subjected to column chromatography on silica gel, elution with n-heptane, to leave an oil after combining and evaporating the appropriate fractions. This oil was dissolved in n-heptane, leaving a small amount of solid which was removed by filtration. The filtrate was reduced in volume by evaporation under reduced pressure. An oil separated from the n-heptane solution and was removed by pipette. This oil (20.4 g) was found to be unreacted 1-(2-bromo-1,1,2,2-tetrafluoroethylthio)-2,6-dichlorobenzene. The remaining n-heptane was evaporated under reduced pressure to leave 13.3 g of 4-(2-bromo-1,1,2,2-tetrafluoroethylthio)-3,5-dichloronitrobenzene as an oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][C:6]=1[O:13][CH3:14].[CH3:15][C:16]([CH3:18])=[O:17].[OH-].[Na+].O>C(O)C>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH:15][C:16](=[O:17])[CH3:18])=[CH:7][C:6]=1[O:13][CH3:14]
Reactant: CC(C)=O
Reactant: COCOc1ccc(C=O)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COCOc1ccc(C=CC(C)=O)cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97.7 %

Procedure:
4-Methoxymethyloxy-3-methoxybenzaldehyde (1j, 2.30 g, 11.7 mmol) and acetone (19, 8.75 ml, 118.4 mmol) were combined in ethanol (20 ml) and stirred for 15 min at room temperature. A solution of sodium hydroxide (0.80 g, 20.0 mmol) and water (20 ml) was added and the mixture stirred for 1 hr at room temperature. The resulting mixture was extracted into ethyl acetate, washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to afford a solid. The crude solid was recrystallized from hexane to give 2.70 g (97%) of a white solid: mp 73-75° C.; 1H NMR: δ 2.34 (s, 3H), 3.48 (s, 3H), 3.89 (s, 3H), 5.24 (s, 2H), 6.58 (d, 1H, J=16.1 Hz), 7.07 (m, 2H), 7.13 (d, 1H, J=8.7 Hz), 7.43 (d, 1H, J=16.1 Hz); 13C NMR: δ 27.4, 55.9, 56.3, 95.2, 110.4, 115.9, 122.5, 125.7, 128.7, 143.1, 148.7, 149.8, 198.0.
Reaction SMILES: CCN(C(C)C)C(C)C.Br[CH2:11][CH2:12][C:13]([F:16])([F:15])[F:14].[CH3:17][C:18]1([CH3:51])[O:23][C:22]([NH:24][C:25]23[CH2:32][CH:31]4[CH2:33][C:27]([C:34]([NH2:36])=[O:35])([CH2:28][CH:29]2[CH2:30]4)[CH2:26]3)=[N:21][S:20](=[O:38])(=[O:37])[C@@H:19]1[C:39]1[CH:44]=[CH:43][C:42]([CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)=[CH:41][CH:40]=1>CN(C=O)C>[CH3:17][C:18]1([CH3:51])[O:23][C:22]([NH:24][C:25]23[CH2:32][CH:31]4[CH2:33][C:27]([C:34]([NH2:36])=[O:35])([CH2:28][CH:29]2[CH2:30]4)[CH2:26]3)=[N:21][S:20](=[O:37])(=[O:38])[C@@H:19]1[C:39]1[CH:40]=[CH:41][C:42]([CH:45]2[CH2:50][CH2:49][N:48]([CH2:11][CH2:12][C:13]([F:16])([F:15])[F:14])[CH2:47][CH2:46]2)=[CH:43][CH:44]=1
Reactant: FC(F)(F)CCBr
Reactant: CC1(C)OC(NC23CC4CC2CC(C(N)=O)(C4)C3)=NS(=O)(=O)[C@@H]1c1ccc(C2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1(C)OC(NC23CC4CC2CC(C(N)=O)(C4)C3)=NS(=O)(=O)[C@@H]1c1ccc(C2CCN(CCC(F)(F)F)CC2)cc1
Reaction time: 8 h

Procedure:
DIPEA (75 mg) and 3-bromo-1,1,1-trifluoropropane (500 mg) were added to a solution of 3a-[(R)-6,6-dimethyl-4,4-dioxo-5-(4-piperidin-4-yl-phenyl)-5,6-dihydro-4H-4lambda*6*-[1,4,3]oxathiazin-2-ylamino]hexahydro-2,5-methanopentalene-2-carboxamide (73 mg) in DMF (1.5 mL), and the mixture was stirred overnight. The resulting mixture was purified in a purification laboratory by means of preparative HPLC. This gave the product with a molecular weight of 596.7 g/mol (C29H39F3N4O4S); MS (ESI): m/e=597 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[C@H:7]([CH2:16][CH2:17][C:18](O)=[O:19])[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+].Cl>C1COCC1.O>[OH:19][CH2:18][CH2:17][CH2:16][C@H:7]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:21]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C
Agent: CCOC(=O)Cl
Agent: Cl
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](CCCO)C(=O)OC(C)(C)C
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-(t-butoxycarbonyl)-L-glutamic acid t-butyl ester (6.0 g, 19.78 mmol) and triethylamine (2.83 mL, 20.27 mmol) in THF at −10° C. is added ethyl chloroformate (1.94 mL, 20.27 mmol) dropwise, via syringe, and the solution is stirred at −10° C. for 30 minutes. The solution is filtered to remove precipitate, and the filtrate is added into a solution of NaBH4 (2.3 g, 60.86 mmol) in THF (40 mL) and water (50 mL). This solution is then stirred for 4 hours, after which time the solution is acidified with 1 N HCl to pH=5, and THF is evaporated. The aqueous residue is extracted with EtOAc (3×200 mL), and the organic layers is then washed with 1 N NaOH (2×300 mL), water (300 mL) and brine (300 mL), dried over MgSO4, and evaporated. Chromatography (silica, 20% EtOAc/hexane) yields t-butyl (S)-5-hydroxy-2-(t-butoxycarbonylamino)-pentanoate as a thick oil.
Reaction SMILES: [Cl:1][C:2]1[C:3](C(F)(F)F)=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[N:7]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:6]=2[CH:23]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(Cl)[Cl:51]>>[Cl:51][C:3]1[C:2]([Cl:1])=[CH:23][C:6]2[N:7]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]([CH2:10][CH2:11][CH2:12][CH:13]=[O:14])=[N:9][C:5]=2[CH:4]=1
Reactant: ClCCl
Reactant: C[Si](C)(C)CCOCn1c(CCCCO)nc2cc(C(F)(F)F)c(Cl)cc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Product: C[Si](C)(C)CCOCn1c(CCCC=O)nc2cc(Cl)c(Cl)cc21
Reaction time: 4 h

Procedure:
4-[6-chloro-5-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,3-benzodiazol-2-yl]butan-1-ol (1.00 g, 2.36 mmol) was dissolved in DCM (30 ml) and Dess-Martin reagent (1.10 g, 2.60 mmol) was added at r.t. The reaction was left for 4 hrs. The reaction was quenched by the addition of 1M Na2S2O3 solution (10 ml), sat. NaHCO3 solution (40 ml) and DCM (80 ml). The organic layer was separated and the aqueous layer was extracted with DCM (3×80 ml). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to give the crude product. The product was purified by silica flash column chromatography eluting with EtOAc:heptanes (1:1) as a light orange oil (0.53 g, 38%): MS (ESI+) for C18H24ClF3N2O2Si m/z 422.05 [M+H]+; LC purity 72% (ret. time, 1.81 min); 1H NMR (250 MHz, CHLOROFORM-d) δ ppm −0.21-0.21 (9H, m), 0.77-1.01 (2H, m), 2.17-2.36 (2H, m), 2.64-2.86 (2H, m), 3.02 (2H, td, J=7.39, 3.20 Hz), 3.35-3.74 (2H, m), 5.39-5.60 (2H, m), 7.34-8.18 (2H, m), 9.82 (1H, s).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[F:32][C:33]1[CH:38]=[CH:37][C:36]([C:39](=[O:45])[CH2:40][C:41](=O)[CH2:42][CH3:43])=[CH:35][CH:34]=1>>[CH2:42](/[C:41](/[NH:1][C@@H:2]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:23]=[CH:24][C:25]([O:28][CH:29]([CH3:31])[CH3:30])=[CH:26][CH:27]=3)[O:19][C:20]=2[CH3:21])=[CH:11][CH:12]=1)[C:3]([OH:5])=[O:4])=[CH:40]/[C:39]([C:36]1[CH:35]=[CH:34][C:33]([F:32])=[CH:38][CH:37]=1)=[O:45])[CH3:43]
Reactant: Cc1oc(-c2ccc(OC(C)C)cc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1
Reactant: CCC(=O)CC(=O)c1ccc(F)cc1
Product: CC/C(=C/C(=O)c1ccc(F)cc1)N[C@@H](Cc1ccc(OCCc2nc(-c3ccc(OC(C)C)cc3)oc2C)cc1)C(=O)O

Procedure:
The title compound was prepared (as described above for the preparation of Example 2) from 75 mg (0.177 mmol) of Intermediate 51 and 39 mg (0.194 mmol) of Intermediate 32 to yield 70 mg of Example 15: TLC (DCM/MeOH (4:1): Rf=0.55; 1H NMR (DMSO-d6, 300 MHz) δ11.53 (d, 1H, J=9.6), 7.89 (dd, 2H, J=8.8, 5.7), 7.85 (d, 2H, J=8.8), 7.26 (t, 2H, J=8.8), 7.18 (d, 2H, J=8.5), 7.05 (d, 2H, J=8.8), 6.86 (d, 2H, J=8.5), 5.60 (s, 1H), 4.73 (hept, 1H, J=6.0), 4.19 (t, 2H, J=6.7), 4.13 (br s, 1H), 3.19 (m, 1H), 2.92 (t, 2H, J=6.6), 2.80 (dd, 1H, J=14.0, 9.2), 2.36 (s, 3H), 2.07 (m, 2H), 1.34 (d, 6H, J=6.0), 0.99 (t, 3H, J=7.5); low resolution MS (ES+)m/e 601.1 (MH+).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:11](C(=O)C3C=CC(NC(=O)C4C=CC=CC=4OCCOS(C)(=O)=O)=NC=3)[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:37]=1.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].C(NC1CCNCC1)(=O)C>CN(C)C=O.O>[NH:11]1[C:5]2[CH:4]=[CH:3][CH:2]=[CH:37][C:6]=2[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: CS(=O)(=O)OCCOc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCCc3cc(Cl)ccc32)cn1
Agent: CC(=O)NC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc2c(c1)CCCCN2
Temperature: 110 °C
Reaction time: 2 h
Yield: 184.8 %

Procedure:
To a solution of 7-chloro-1-{6-[2-(2-methanesulfonyloxyethoxy)-benzoylamino]nicotinoyl}-2,3,4,5-tetrahydro-1H-benzazepine (0.6 g) in dimethylformamide (5 ml) are added sodium iodide (0.22 g), potassium carbonate (0.23 g) and 4-acetylaminopiperidine (0.2 g), and the mixture is heated with stirring at 110° C. for 2 hours. The mixture is cooled, and thereto is added water, and the mixture is extracted with dichloromethane. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography to give 7-chloro-1-{6-[2-(4-acetylamino-1-piperidinyl)-ethoxy]benzoylamino]nicotinoyl}-2,3,4,5-tetrahydro-1H-benzazepine (0.3 g) as white powder.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:21]=[CH:20][C:9]3[N:10]=[C:11]([C@H:13]4[CH2:18][CH2:17][C@H:16]([OH:19])[CH2:15][CH2:14]4)[O:12][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1.Cl[CH2:23][C:24]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:25].C(O[K])(C)(C)C>C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:21]=[CH:20][C:9]3[N:10]=[C:11]([C@H:13]4[CH2:18][CH2:17][C@H:16]([O:19][CH2:23][C:24]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)=[O:25])[CH2:15][CH2:14]4)[O:12][C:8]=3[CH:7]=2)[CH2:2][CH2:3]1
Reactant: O[C@H]1CC[C@H](c2nc3ccc(OCC4CC4)cc3o2)CC1
Reactant: O=C(CCl)N1CCOCC1
Agent: CC(C)(C)O[K]
Solvent: C1CCOC1
Product: O=C(CO[C@H]1CC[C@H](c2nc3ccc(OCC4CC4)cc3o2)CC1)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of trans-4-[6-(cyclopropylmethoxy)-1,3-benzoxazol-2-yl]cyclohexanol (311 mg), 4-(chloroacetyl)morpholine (532 mg) and tert-butoxy potassium (365 mg) in THF (5 mL) was stirred at room temperature overnight and extracted with ethyl acetate and water. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (427 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](OCCCCCCC)=[C:6]([CH:38]=1)[C:7]([NH:9][C@@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2OC2C=CC(C(F)(F)F)=CC=2)=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])=[O:8].[F:47][C:48]([F:60])([F:59])[O:49][C:50]1[CH:55]=[CH:54][C:53](B(O)O)=[CH:52][CH:51]=1>>[C:18]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:19]=[CH:20][C:15]([CH2:14][C@H:10]([NH:9][C:7]([C:6]2[CH:5]=[CH:4][C:3]([C:53]3[CH:52]=[CH:51][C:50]([O:49][C:48]([F:47])([F:59])[F:60])=[CH:55][CH:54]=3)=[CH:2][CH:38]=2)=[O:8])[C:11]([OH:13])=[O:12])=[CH:16][CH:17]=1
Reactant: CCCCCCCOc1ccc(Br)cc1C(=O)N[C@@H](Cc1ccc(-c2ccccc2Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)O
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Product: O=C(N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O)c1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Yield: 86.9 %

Procedure:
3-Biphenyl-4-yl-(2S)-[(5-bromo-benzoyl-amino)-propionic acid (100 mg, 0.23 mmol) was reacted with 4-trifluoromethoxyphenylboronic acid (0.145 mg, 0.69 mmol) by following general procedure D yielding the title compound (101 mg, 85%) as a white solid:
Reaction SMILES: [CH3:1][C:2]1[N:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:14]N1C(=O)N(Cl)C(=O)N(Cl)C1=O>C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>[Cl:14][CH2:1][C:2]1[N:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Reactant: CCOC(=O)c1cc(C)cnc1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1cc(C)cnc1CCl
Temperature: 25 °C
Reaction time: 18 h
Yield: 109.9 %

Procedure:
As shown in step 11-ii of Scheme 11, Compound 2035 (354 mg, 1.98 mmol) and 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione (689 mg, 2.96 mmol) were combined in DCM (1.8 mL). After stirring 18 hours at room temperature, the mixture was diluted with 20 mLs each of saturated sodium carbonate and dichloromethane. The organics were separated, washed with saturated sodium carbonate, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give ethyl 2-(chloromethyl)-5-methylnicotinate (Compound 2036, 465 mg) as a pale yellow oil: ESMS (M+1) 213.86.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:22])=[C:4]([C:9]([C:11]2[C:19]3[C:18]([O:20][CH3:21])=[N:17][CH:16]=[N:15][C:14]=3[NH:13][CH:12]=2)=[O:10])[C:5]([F:8])=[CH:6][CH:7]=1.[CH2:23]([C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1)[CH3:24]>>[F:22][C:3]1[C:4]([C:9]([C:11]2[C:19]3[C:18]([O:20][CH3:21])=[N:17][CH:16]=[N:15][C:14]=3[NH:13][CH:12]=2)=[O:10])=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:31]([C:28]1[CH:29]=[CH:30][C:25]([CH2:23][CH3:24])=[CH:26][CH:27]=1)(=[O:33])=[O:32]
Reactant: CCc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ncnc2[nH]cc(C(=O)c3c(F)ccc(N)c3F)c12
Product: CCc1ccc(S(=O)(=O)Nc2ccc(F)c(C(=O)c3c[nH]c4ncnc(OC)c34)c2F)cc1

Procedure:
N-[2,4-Difluoro-3-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-4-ethyl-benzenesulfonamide P-1008 is prepared in one step from (3-amino-2,6-difluoro-phenyl)-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone 36 and 4-ethyl-benzenesulfonyl chloride 59 as shown in Scheme 4.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH2:10]([O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH2:48][CH:49]([CH3:70])[C:50]([N:52]1[CH2:57][CH2:56][N:55]([C:58](=[O:69])[C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=2[C:65]([F:68])([F:67])[F:66])[CH2:54][CH2:53]1)=[O:51]>CN(C=O)C.O>[CH2:10]([O:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([NH:48][CH:49]([CH3:70])[C:50](=[O:51])[N:52]2[CH2:53][CH2:54][N:55]([C:58](=[O:69])[C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=3[C:65]([F:66])([F:68])[F:67])[CH2:56][CH2:57]2)=[O:24])=[CH:25][CH:26]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(N)C(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(NC(=O)c1ccc(OCc2ccccc2)cc1)C(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 48.2 %

Procedure:
DIPEA (131 mg, 0.17 mL, 0.76 mmol) was added to a stirred solution of 4-Benzyloxy-benzoic acid (58 mg, 0.25 mmol) in DMF (2 mL). HOBT (41 mg, 0.3 mmol) and EDCI (58 mg, 0.3 mmol) were then added at room temperature. After 2 minutes, 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-propan-1-one (85 mg, 0.25 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using 60-120 silica gel and 10% MeOH in CHCl3 as eluent) to afford 65 mg (47% yield) of 4-benzyloxy-N-{1-methyl-2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-benzamide. LCMS Purity: 95%. 1H NMR (CDCl3): δ 7.76 (m, 3H), 7.6 (m, 2H), 7.4-7.3 (m, 5H), 7.1 (d, 1H), 7.0 (d, 2H), 5.22 (s, 2H), 4.2 (d, 1H), 3.82 (m, 2H), 3.7-3.4.(m, 6H), 2.0 (m, 1H), 1.4 (dd, 3H).