Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(P(C1C=CC(C(F)(F)F)=CC=1)C1C=CC(C(F)(F)F)=CC=1)C.[NH2:24][C:25]([C:34]1[CH:35]=[N:36][CH:37]=[C:38]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:39]=1)=[CH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].[H][H]>FC(F)(F)CO.[Rh].C1CC=CCCC=C1.C1CC=CCCC=C1.[Cl-].[Cl-].[Rh].[Rh]>[NH2:24][C@H:25]([C:34]1[CH:35]=[N:36][CH:37]=[C:38]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:39]=1)[CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)C=C(N)c1cncc(OCc2ccccc2)c1
Agent: [Rh]
Agent: C1=C\CC/C=C\CC/1
Agent: CCP(c1ccc(C(F)(F)F)cc1)c1ccc(C(F)(F)F)cc1
Solvent: OCC(F)(F)F
Solvent: C1=CCCC=CCC1
Product: CC(C)(C)OC(=O)C[C@H](N)c1cncc(OCc2ccccc2)c1
Reaction time: 0.67 h

Procedure:
To chloro(1,5-cyclooctadien)rhodium(I) dimer (29 mg, 60 μmol) and (R)-(−)-1-[(S)-2-Di-tert.-butyl-phosphino)ferrocenyl]ethyldi-(4-trifluormethylphenyl)phosphine (81 mg, 120 μmol) under an argon atmosphere was added 2,2,2-trifluoroethanol (4 mL) and the solution was stirred for 40 minutes. To tert-butyl 3-amino-3-[5-(benzyloxy)pyridin-3-yl]prop-2-enoate (1.95 g/5.97 mmol) in degassed 2,2,2-trifluoroethanol (10 mL) in a pressure vessel was added the rhodium catalyst solution and the solution was stirred for 22 hours at 50° C. under hydrogen pressure of 10 bar. The addition of an identically prepared rhodium catalyst solution in 2,2,2-trifluoroethanol (4 mL) was repeated and stirring under 10 bar hydrogen pressure at 50° C. was continued for additional 16 hours. The solution was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (ethyl acetate in hexane, 12 to 100% followed by methanol in ethyl acetate 0 to 15%) to yield 1.16 g of enantiomerically enriched tert-butyl (3S)-3-amino-3-[5-(benzyloxy)pyridin-3-yl]propanoate.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([F:11])[CH:5]=1)=[O:3].[Se](=O)=[O:13]>>[Cl:10][C:8]1[CH:9]=[C:4]([C:2](=[O:3])[CH:1]=[O:13])[CH:5]=[C:6]([F:11])[CH:7]=1
Reactant: O=[Se]=O
Reactant: CC(=O)c1cc(F)cc(Cl)c1
Product: O=CC(=O)c1cc(F)cc(Cl)c1
Yield: 83 %

Procedure:
(3-Chloro-5-fluorophenyl)(oxo)acetaldehyde (27 g, 84%) was prepared from 3-chloro-5-fluoro acetophenone (30.0 g, 174.4 mmol) and selenium dioxide (21.28 g, 191.8 mmol) according to the typical procedure used for Preparation 1.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1.C([O:36][C@@H:37]([CH3:41])[C:38](Cl)=[O:39])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][CH:27]4[CH2:28][CH2:29][N:30]([C:38](=[O:39])[C@@H:37]([OH:36])[CH3:41])[CH2:31][CH2:32]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)NC1CCNCC1
Agent: Cl
Product: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)NC1CCN(C(=O)[C@H](C)O)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-6-methyl-N-piperidin-4-yl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f6) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](SC)=[CH:9][N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.CCO.[NH3:20]>C1COCC1>[NH2:20][C:8]([NH:7][CH2:6][C:5]1[CH:15]=[CH:16][C:2]([Cl:1])=[CH:3][CH:4]=1)=[CH:9][N+:10]([O-:12])=[O:11]
Reactant: N
Reactant: CSC(=C[N+](=O)[O-])NCc1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CCO
Product: NC(=C[N+](=O)[O-])NCc1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 5.5 h
Yield: 48.8 %

Procedure:
To 2.59 g (0.01 mole) of 1-(4-chlorobenzyl)amino-1-methylthio-2-nitroethylene were added 45 ml of EtOH, 10 ml of THF and 1.02 g of 25% aqueous ammonia and the mixture was stirred at an external temperature of 60° C. for 5.5 hours. During this period, 1.02 g each of 25% aqueous ammonia was added after 1, 2 and 3 hours of reaction. The reaction mixture was ice-cooled and stirred, whereupon crystals separated out. The crystals were collected by filtration, washed with EtOH and ether in that order, and dried. The procedure gave 1.11 g of the title compound as white crystals.
Reaction SMILES: [O:1]=[CH:2][C:3]([Cl:6])([Cl:5])[Cl:4].[CH2:7]([OH:10])[CH:8]=[CH2:9]>C1C=CC=CC=1>[Cl:4][C:3]([Cl:6])([Cl:5])[CH:2]([O:10][CH2:7][CH:8]=[CH2:9])[OH:1]
Reactant: C=CCO
Reactant: O=CC(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: C=CCOC(O)C(Cl)(Cl)Cl

Procedure:
A mixture of 7 g of chloral, 2.9 of allyl-alcohol and 15 ml of benzene is left standing for a night at room temperature, then distilled.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:22]1[O:26][C:25](=[O:27])[C@H:24]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:31][CH:30]=2)[CH2:23]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[Li+].[NH4+].[Cl-].C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:50]>C(COC)OC.O.CO.C(Cl)Cl>[C:1]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:15][CH:16]=1)[C@@H:22]([OH:50])[CH2:23][C@@H:24]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[CH:31][CH:30]=1)[C:25]([OH:26])=[O:27])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: COCCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)[C@@H]2C[C@@H](Cc3ccc(OCc4ccccc4)cc3)C(=O)O2)cc1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: COCCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C[C@@H](Cc2ccc(OCc3ccccc3)cc2)C(=O)O)cc1
Temperature: 0 °C
Reaction time: 17 h

Procedure:
3.85 g (6.68 mmol) of 5(S)-[1(S)-(Boc-amino)-2-[p-(2-methoxyethoxy)phenyl]ethyl]-3(R)-[(p-benzyloxyphenyl)methyl]dihydrofuran-2-(3H)-one in 107 ml of dimethoxyethane and 54 ml of water are hydrolysed, under a protective gas, with 26.5 ml of a 1M lithium hydroxide solution. After 17 h at RT, the reaction mixture is treated with an ice-cold mixture of 324 ml of sat. NH4Cl solution, 27 ml of 10% citric acid solution and 134 ml of methylene chloride. Methanol is added in order to dissolve the product completely. The aqueous phase is separated off and extracted 2× with methylene chloride. The organic phases are washed with saline, dried with Na2SO4 and evaporated: tRet (II)=15.8 min; FAB-MS (M+H)+ =594.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:6][C:7]1[C:12](Cl)=[CH:11][C:10]([NH2:14])=[C:9]([N+:15]([O-:17])=[O:16])[CH:8]=1>O>[Cl:6][C:7]1[C:12]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:11][C:10]([NH2:14])=[C:9]([N+:15]([O-:17])=[O:16])[CH:8]=1
Reactant: C1CCNC1
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Solvent: O
Product: Nc1cc(N2CCCC2)c(Cl)cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 99 %

Procedure:
Pyrrolidine (6 mL) was added to 4,5-dichloro-2-nitro-phenylamine (2.58 g, 12.5 mmol) in a sealed tube and the mixture heated to 100° C. for 6 h. The mixture was cooled to 23° C., poured into water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (50 mL), dried, filtered, and concentrated under reduced pressure to afford the titled compound (3.00 g, 99%). MS (ESI/CI): mass calcd. for C10H12ClN3O2, 241.1; m/z found, 242.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.08 (s, 1H), 6.06 (s, 2H), 5.82 (s, 1H), 3.58 (ddd, J=6.6, 4.2, 2.7 Hz, 4H), 2.02-1.90 (m, 4H).
Reaction SMILES: [F:1]C(F)(N(CC)CC)C(F)C(F)(F)F.[CH3:15][N:16]([CH3:32])[C:17]([C@@H:19]1[CH2:23][C@@H:22](O)[CH2:21][N:20]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[O:18].[F-].[Na+].C(=O)([O-])[O-].[K+].[K+]>ClCCl.C(OCC)(=O)C.CCCCCC>[CH3:15][N:16]([CH3:32])[C:17]([C@@H:19]1[CH2:23][C@@H:22]([F:1])[CH2:21][N:20]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[O:18]
Reactant: CCN(CC)C(F)(F)C(F)C(F)(F)F
Reactant: CN(C)C(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: CN(C)C(=O)[C@@H]1C[C@@H](F)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
26.6 g of a mixture (approximately 3:1) of 1,1,2,3,3,3-hexafluoro-1-(diethylamino)propane and 1,2,3,3,3-pentafluoro-1-(diethylamino)-2-propene was added dropwise over a period of 10 minutes under ice cooling to a suspension of 25.7 g of the compound obtained in step 1-1a and 5.00 g of sodium fluoride in 260 mL of dichloromethane, after which the reaction mixture was stirred for 16 hours at room temperature. 100 mL of a 5% potassium carbonate aqueous solution was added under ice cooling to the reaction solution, and the reaction mixture was stirred for 30 minutes at the same temperature. After liquid separation, the aqueous layer thus obtained was extracted with chloroform, and the combined organic layer was washed with 50 mL of saturated brine and dried with magnesium sulfate, after which the drying agent was filtered off and the solvent was distilled off under reduced pressure. The residue thus obtained was subjected to column chromatography (silica gel 60, mobile phase: ethyl acetate/n-hexane=1/1 to 10/0; v/v) to obtain 12.2 g of the titled compound (pale yellow solid).
Reaction SMILES: [N+](C1C=CC=CC=1O[C:11](=[O:35])[C@@H:12]([CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])([O-])=O.Cl.[CH2:37]([O:44][C:45]1[CH:53]=[CH:52][C:48]([C@H:49]([NH2:51])[CH3:50])=[CH:47][CH:46]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(Cl)Cl>[C:14]([NH:13][C@@H:12]([C:11]([NH:51][C@@H:49]([C:48]1[CH:52]=[CH:53][C:45]([O:44][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:46][CH:47]=1)[CH3:50])=[O:35])[CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15]
Reactant: C[C@@H](N)c1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N[C@H](CCCNC(=O)OCc1ccccc1)C(=O)Oc1ccccc1[N+](=O)[O-]
Agent: Cl
Solvent: ClCCl
Product: C[C@@H](NC(=O)[C@@H](CCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)c1ccc(OCc2ccccc2)cc1

Procedure:
Prepared according to the method described in Example 4(b) above from Nα -Boc-Nδ -Cbz-(R)-ornithine-o-nitrophenyl ester (3.11 g; 6.37 mmol), (R)-4-benzyloxy-α-methylbenzylamine hydrochloride (1.68 g; 6.37 mmol), TEA (1.94 g; 19.10 mmol) and CH2Cl2 (200 mL), 18 hours reaction time. The resultant yellow solution was concentrated to afford the crude sub-title compound which was used directly in the next step.
Reaction SMILES: FC1C=C(CCC(O)=O)C=CC=1OC.[CH:15]1([O:20][C:21]2[C:26]([C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)=[CH:25][C:24]([CH2:37][CH2:38][C:39]([O:41]C)=[O:40])=[CH:23][C:22]=2[N:43](C)[C:44](=O)C(F)(F)F)[CH2:19][CH2:18][CH2:17][CH2:16]1>[OH-].[Na+]>[CH:15]1([O:20][C:21]2[C:26]([C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)=[CH:25][C:24]([CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[CH:23][C:22]=2[NH:43][CH3:44])[CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: COC(=O)CCc1cc(-c2ccc3ccccc3c2)c(OC2CCCC2)c(N(C)C(=O)C(F)(F)F)c1
Agent: COc1ccc(CCC(=O)O)cc1F
Agent: [Na+]
Agent: [OH-]
Product: CNc1cc(CCC(=O)O)cc(-c2ccc3ccccc3c2)c1OC1CCCC1
Reaction time: 6 h
Yield: 24.6 %

Procedure:
According to the procedure described in the synthesis method of Intermediate 9 provided that the reaction was carried out for 6 hours, Intermediate 55 (198 mg) and 2 N aqueous sodium hydroxide (800 μl) were reacted and treated to obtain the title compound (Compound No. S-1, 38 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[C:21]3[CH2:22][C:23]([CH3:26])([CH3:25])[O:24][C:20]=3[CH:19]=[C:18]([C:27]([OH:29])=O)[CH:17]=2)[CH:5]=[N:6][C:7]=1[C:8]([N:10]1[CH2:13][CH:12]([F:14])[CH2:11]1)=[O:9].[NH2:30][C:31]1[CH:35]=[CH:34][N:33]([CH3:36])[N:32]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCCl>[F:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[C:21]3[CH2:22][C:23]([CH3:26])([CH3:25])[O:24][C:20]=3[CH:19]=[C:18]([C:27]([NH:30][C:31]3[CH:35]=[CH:34][N:33]([CH3:36])[N:32]=3)=[O:29])[CH:17]=2)[CH:5]=[N:6][C:7]=1[C:8]([N:10]1[CH2:11][CH:12]([F:14])[CH2:13]1)=[O:9]
Reactant: CC1(C)Cc2c(Oc3cnc(C(=O)N4CC(F)C4)c(F)c3)cc(C(=O)O)cc2O1
Reactant: Cn1ccc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: Cn1ccc(NC(=O)c2cc(Oc3cnc(C(=O)N4CC(F)C4)c(F)c3)c3c(c2)OC(C)(C)C3)n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 53.8 %

Procedure:
To a solution of 4-(5-fluoro-6-(3-fluoroazetidine-1-carbonyl)pyridin-3-yloxy)-2,2-dimethyl-2,3-dihydrobenzofuran-6-carboxylic acid (1.360 g, 3.363 mmol), 3-amino-1-methyl-pyrazole (653 mg, 6.730 mmol), and triethylamine (0.94 ml, 6.730 mmol) in 20 mL of DCE was added HATU (2.56 g, 6.730 mmol). The mixture was stirred at 60° C. for 2 hr, quenched with water, and extracted with 3×CHCl3. The combined organic layer was washed with 2×H2O, dried with Na2SO4, and concentrated to provide an oil that was purified by SFC to give a white solid (874 mg, 54% yield). 1H NMR (400 MHz, CDCl3) δ 9.30 (s, 1 H) 8.20 (d, J=2.02 Hz, 1 H) 7.24-7.33 (m, 2 H) 7.15-7.22 (m, 1 H) 7.09 (dd, J=10.86, 2.27 Hz, 1 H) 6.82 (d, J=2.27 Hz, 1 H) 5.37 (d, J=56.84 Hz, 1 H) 4.62-4.79 (m, 1 H) 4.53 (dd, J=12.13, 1.77 Hz, 2 H) 4.27-4.42 (m, 1 H) 3.80 (s, 3 H) 2.92 (s, 2 H) 1.50 (s, 6 H); LCMS for C24H23F2N5O4 m/z 484.20 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([SH:23])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:24][CH3:25].C([O-])([O-])=O.[K+].[K+].Br[CH2:33][C:34]1[C:35]([Cl:45])=[CH:36][C:37]([F:44])=[C:38]([S:40]([NH2:43])(=[O:42])=[O:41])[CH:39]=1>CC(C)=O>[Cl:45][C:35]1[C:34]([CH2:33][S:23][C:14]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:11]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:24][CH3:25])[CH:4]=3)([CH3:10])[CH3:9])=[CH:12][N:13]=2)=[CH:39][C:38]([S:40]([NH2:43])(=[O:41])=[O:42])=[C:37]([F:44])[CH:36]=1
Reactant: NS(=O)(=O)c1cc(CBr)c(Cl)cc1F
Reactant: COc1cc(C(C)(C)c2cnc(S)n2-c2ccc(F)cc2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(C(C)(C)c2cnc(SCc3cc(S(N)(=O)=O)c(F)cc3Cl)n2-c2ccc(F)cc2)ccc1Cl
Reaction time: 3 h
Yield: 81.2 %

Procedure:
To a mixture of 5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole-2-thiol (0.94 g, 2.49 mmol) and K2CO3 in acetone (5 mL) was added 5-(bromomethyl)-4-chloro-2-fluorobenzenesulfonamide (0.83 g, 2.73 mmol). After stirring 3 h, the reaction mixture was filtered. The filtrate was concentrated and purified by chromatography (silica, EtOAc-Hex) to afford the title compound (1.21 g). 1H-NMR (DMSO-d6, 400 MHz) δ 7.81 (d, J=7.8 Hz, 1H), 7.77 (s, 2H), 7.70 (d, J=9.7 Hz, 1H), 7.22-7.19 (m, 1H), 7.16 (s, 1H), 7.01-6.97 (m, 2H), 6.56-6.49 (m, 4H), 4.26 (s, 2H), 3.64 (s, 3H), 1.46 (s, 6H); MS (EI) m/z 598 [M]+.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[C:17]([C:18](O)=[O:19])[C:11]=2[N:10]=1.[CH3:23][C:24]1([CH3:38])[O:28][C@H:27]([CH2:29][O:30][C:31]2[CH:32]=[C:33]([CH:35]=[CH:36][CH:37]=2)[NH2:34])[CH2:26][O:25]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.O>[CH3:23][C:24]1([CH3:38])[O:28][C@H:27]([CH2:29][O:30][C:31]2[CH:32]=[C:33]([NH:34][C:18]([C:17]3[C:11]4[N:10]=[C:9]([C:4]5[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=5[C:2]([F:1])([F:21])[F:22])[NH:13][C:12]=4[CH:14]=[CH:15][CH:16]=3)=[O:19])[CH:35]=[CH:36][CH:37]=2)[CH2:26][O:25]1
Reactant: CC1(C)OC[C@@H](COc2cccc(N)c2)O1
Reactant: O=C(O)c1cccc2[nH]c(-c3ccccc3C(F)(F)F)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN1CCCC1=O
Product: CC1(C)OC[C@@H](COc2cccc(NC(=O)c3cccc4[nH]c(-c5ccccc5C(F)(F)F)nc34)c2)O1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2-(2-(Trifluoromethyl)phenyl)-1H-benzo[d]imidazole-4-carboxylic acid (3; 75 mg, 0.24 mmol) was taken up in NMP (2 mL) along with (R)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)aniline (133; 64.3 mg, 0.288 mmol) and HATU (186 mg, 0.49 mmol). DIEA (81 μL, 0.49 mmol) was added and the resulting reaction mixture was stirred at room temperature for 12 h. The temperature was then raised to 60° C. and the reaction mixture was allowed to stir for an additional 1 h. The reaction mixture was diluted with water and filtered. The collected solids were further purified by silica gel chromatography to afford the desired product 134, as a yellow solid (51.5 mg, 42%).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[CH2:6][NH:7][S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=1)(=[O:10])=[O:9].[Cl:23][C:24]1[N:29]=[C:28](Cl)[C:27]([Cl:31])=[CH:26][N:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:23][C:24]1[N:29]=[C:28]([NH:2][C:3]2[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=2)[CH2:6][NH:7][S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)(=[O:9])=[O:10])[C:27]([Cl:31])=[CH:26][N:25]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: Nc1cccc(CNS(=O)(=O)c2cccc([N+](=O)[O-])c2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(S(=O)(=O)NCc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28 %

Procedure:
To a solution of N-(3-aminobenzyl)-3-nitrobenzenesulfonamide hydrochloride (0.400 g, 1.16 mmol) and 2,4,5-trichloropyrimidine (0.12 mL, 1.06 mmol) in DMF (2.8 mL) was added potassium carbonate (0.51 g, 3.7 mmol). The resulting mixture was stirred overnight at room temperature. The reaction was quenched with saturated (sat'd) NH4Cl and water. EtOAc was added and the layers separated. The aqueous layer was extracted with EtOAc twice. The combined organics were washed with water, dried, filtered and concentrated to give 660 mg of crude residue, which was purified by Combi-Flash column chromatography (12 g column, 0 to 30% EtOAc in hexane) to give the desired product (135 mg, 28%). LCMS for C17H13Cl2N5O4S (M+H)+: m/z=453.9, 455.9, 457.9. 1H NMR (400 MHz, CD3OD): δ 8.85 (s, 1H), 8.48 (t, J=2.0 Hz, 1H), 8.29 (ddd, J=8.0, 2.0, 1.2 Hz, 1H), 8.21 (s, 1H), 8.08 (ddd, J=8.0, 1.6, 0.8 Hz, 1H), 7.64 (t, J=8.0 Hz, 1H), 7.41 (m, 2H), 7.17 (t, J=8.0 Hz, 1H), 4.21 (s, 2H).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Br[CH:6]1[C:11](=O)[CH2:10][CH2:9][N:8]([C:13](=[O:21])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[CH2:7]1.C([O-])(O)=O.[Na+]>CCO>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:13]([N:8]1[CH2:9][CH2:10][C:11]2[N:1]=[C:2]([NH2:4])[S:3][C:6]=2[CH2:7]1)=[O:21]
Reactant: NC(N)=S
Reactant: O=C1CCN(C(=O)c2ccccc2F)CC1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Nc1nc2c(s1)CN(C(=O)c1ccccc1F)CC2
Temperature: 80 °C
Reaction time: 2 h
Yield: 53.8 %

Procedure:
Thiourea (0.84 g, 6.7 mmol) was added to a stirred suspension of 3-bromo-1-(2-fluorobenzoyl)-4-piperidinone (2.0 g, 6.7 mmol) and NaHCO3 (0.56 g, 6.7 mmol) in EtOH (50 mL). The mixture was stirred at 80° C. for 2 hours, cooled to room temperature and filtered. The filtrate was evaporated in vacuo to yield 5-(2-fluorobenzoyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-amine (1.0 g, 54% yield) that was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]([F:15])([F:14])[F:13])=[CH:7][C:3]=1[C:4](O)=[O:5].OO.[OH-].[Na+].O>O1CCCC1.C(OCC)C>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]([F:13])([F:14])[F:15])=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: Nc1ccc(OC(F)(F)F)cc1C(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: Nc1ccc(OC(F)(F)F)cc1CO
Reaction time: 0.5 h
Yield: 101.9 %

Procedure:
The 2-amino-5-trifluoromethoxybenzoic acid (2.0 g, 9.0 mmol) in tetrahydrofuran (20 mL) was added dropwise to borane methyl sulfide complex (1.5 mL, 15.0 mmol) in tetrahydrofuran (5 mL). The reaction was refluxed overnight and allowed to cool. A solution of 30% aqueous hydrogen peroxide (0.5 mL), 2.5 N sodium hydroxide (0.5 mL) and water (10 mL) was added drop-wise and the reaction stirred 0.5 hours. After diluting with diethyl ether (50 mL), the organic layer was washed with 0.1 M aqueous sodium meta-bisulfite (2×10 mL) and 2.5 N aqueous sodium hydroxide (2×10 mL). The organic layer was diluted further with hexanes (50 mL) and washed with brine (2×20 mL), dried over anhydrous Na2SO4, and concentrated in vacuo leaving an amber oil (1.9 g) which solidified. The solid was recrystallized from ethyl acetate-hexanes to afford the 2-amino-5-trifluoromethoxybenzyl alcohol as a light amber solid (1.44 g, 77%): mp 75.9–77.6° C. 1H NMR (CDCl3, 300 MHz) 7.00 (m, 2H), 6.65 (d, 1H, J=8.0 Hz), 4.05 (s, 2H), 3.25 (brs, 3H). ESHRMS m/z 208.0592 (M+H+, Calc'd 208.0585). Anal. Calc'd for C8H8NO2F3: C, 46.39; H, 3.89; N, 6.76. Found: C, 46.61; H, 3.79; N, 6.71.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]2[CH:7]=[C:8]([CH2:10][C:11]([OH:13])=O)[S:9][C:5]=2[CH:4]=1.[CH2:16]([O:20][C:21](=[O:25])[C@H:22]([CH3:24])[NH2:23])[CH:17]([CH3:19])[CH3:18]>>[CH2:16]([O:20][C:21](=[O:25])[C@H:22]([CH3:24])[NH:23][C:11](=[O:13])[CH2:10][C:8]1[S:9][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:15]=[CH:14][C:6]=2[CH:7]=1)[CH:17]([CH3:19])[CH3:18]
Reactant: COc1ccc2cc(CC(=O)O)sc2c1
Reactant: CC(C)COC(=O)[C@H](C)N
Product: COc1ccc2cc(CC(=O)N[C@@H](C)C(=O)OCC(C)C)sc2c1

Procedure:
Following General Procedure I' above, and using (6-methoxybenzothiophen-2-yl)acetic acid and alanine iso-butyl ester (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH3:14])[C:6]=2[CH:15]=1.[CH3:16][C:17]1[C:18]([O:20][C:21](=O)[C:22]=1[CH3:23])=[O:19].O>C(O)(=O)C>[CH2:12]([N:7]1[C:6]2[CH:15]=[C:2]([N:1]3[C:18](=[O:19])[C:17]([CH3:16])=[C:22]([CH3:23])[C:21]3=[O:20])[CH:3]=[CH:4][C:5]=2[O:10][CH2:9][C:8]1=[O:11])[CH2:13][CH3:14]
Reactant: CC1=C(C)C(=O)OC1=O
Reactant: CCCN1C(=O)COc2ccc(N)cc21
Solvent: CC(=O)O
Solvent: O
Product: CCCN1C(=O)COc2ccc(N3C(=O)C(C)=C(C)C3=O)cc21
Yield: 49.1 %

Procedure:
2.27 g of 6-amino-4-propyl-2H-1,4-benzoxazin-3(4H)-one and 1.7 g of 2,3-dimethylmaleic anhydride were refluxed for 2 hours in acetic acid. After the reaction mixture was allowed to cool, 50 ml of water was added, and the precipitated crystals were collected by filtration and recrystallized from ethanol to give 1.7 g of 1-[4-propyl-2H-1,4-benzoxazin-3(4H)-on-6-yl]-3,4-dimethyl-2,5-dioxo-2,5-dihydropyrrole. m.p. 147°-149° C.
Reaction SMILES: [Si]([O:18][CH:19]([CH:57]([CH3:59])[CH3:58])[CH2:20][CH2:21][CH:22]([C:24]1([CH3:56])[CH2:28][CH2:27][CH:26](/[CH:29]=[CH:30]/[CH:31]=[C:32]2[CH2:37][CH:36]([O:38][Si](C(C)(C)C)(C)C)[CH2:35][CH:34]([O:46][Si](C(C)(C)C)(C)C)[CH2:33]2)[C:25]1([CH3:55])[CH3:54])[CH3:23])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:18][C@H:19]([CH:57]([CH3:59])[CH3:58])[CH2:20][CH2:21][C@@H:22]([C:24]1([CH3:56])[CH2:28][CH2:27][C@@H:26](/[CH:29]=[CH:30]/[CH:31]=[C:32]2[CH2:33][C@@H:34]([OH:46])[CH2:35][C@H:36]([OH:38])[CH2:37]2)[C:25]1([CH3:55])[CH3:54])[CH3:23]
Reactant: CC(C)C(CCC(C)C1(C)CCC(/C=C/C=C2CC(O[Si](C)(C)C(C)(C)C)CC(O[Si](C)(C)C(C)(C)C)C2)C1(C)C)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)[C@@H](O)CC[C@H](C)C1(C)CC[C@@H](/C=C/C=C2C[C@@H](O)C[C@H](O)C2)C1(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 44 %

Procedure:
To a solution of intermediate (21) (0.14 mmol) in THF (4 mL) was added n-Bu4NF (1 M solution in THF; 2.1 mL, 2.1 mmol). The reaction mixture was stirred at room temperature for 12 hours and then loaded onto a silica gel column. The reaction product was eluted (n-pentane/Me2CO) and further purified by HPLC over silica to afford 0.0035 g, (44% yield) of the desired product (22) which was characterized as follows: