Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[C:18]([O:19][CH3:20])=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([N+:21]([O-])=O)[CH:10]=1)C1C=CC=CC=1.[H][H]>[Pd].O1CCCC1>[NH2:21][C:11]1[CH:10]=[C:9]([OH:8])[C:18]([O:19][CH3:20])=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: [H][H]
Reactant: COC(=O)c1cc(OC)c(OCc2ccccc2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1cc(OC)c(O)cc1N
Temperature: 25 °C
Yield: 98.4 %

Procedure:
In a 1 l Schlenk flask filled with argon, methyl 4benzyloxy-5-methoxy-2-nitrobenzoate (11.60 g, 36.6 mmol) and palladium on charcoal (1.17 g, 10% Pd, 1.1 mmol Pd) were combined and tetrahydrofuran (250 mL) was added. The argon was replaced with hydrogen (1 bar), and the mixture was vigorously stirred at r.t. until completion of the reaction. The palladium was separated by filtration through a pad of celite and the solvent was removed to obtain methyl 2-amino-4-hydroxy-5-methoxybenzoate (6.56 g, 36.0 mmol, 98%) which was used without further purification LC/ESI-MS: m/z=166 [M−CH4O+H]+; Rt=2.17 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][C:13]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([NH2:23])[C:17]=2[CH:16]=[CH:15][N:14]=1.[Cl:24][C:25]1[CH:33]=[CH:32][C:31]([CH2:34][NH:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:30][C:26]=1[C:27](O)=[O:28].C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:24][C:25]1[CH:33]=[CH:32][C:31]([CH2:34][NH:35][C:36](=[O:41])[C:37]([CH3:39])([CH3:38])[CH3:40])=[CH:30][C:26]=1[C:27]([NH:23][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:17]=1[CH:16]=[CH:15][N:14]=[C:13]2[NH:12][C:3]1[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=1[F:1])=[O:28]
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1
Reactant: Nc1cccc2c(Nc3ccc(C(F)(F)F)cc3F)nccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3c(Nc4ccc(C(F)(F)F)cc4F)nccc23)c1
Yield: 18.2 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N1-(2-fluoro-4-(trifluoromethyl)phenyl)isoquinoline-1,5-diamine (Intermediate-39, 80 mg, 0.24 mmol), 2-chloro-5-(pivalamidomethyl)benzoic acid (Intermediate-5, 134 mg, 0.49 mmol), oxalyl chloride (93 mg, 0.74 mmol), DMF (1 drop) and DIPEA (93 mg, 0.72 mmol) in CH2Cl2 (5 mL) to afford 25 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.62 (s, 1H), 9.38 (s, 1H), 8.35 (d, J=8.4 Hz, 1H), 8.21 (t, 1H), 8.00-7.93 (m, 2H), 7.88 (t, J=7.5 Hz, 1H), 7.71 (d, J=9.3 Hz, 2H), 7.60-7.53 (m, 3H), 7.44 (d, J=5.7 Hz, 1H), 7.36 (d, J=9.0 Hz, 1H), 4.32 (d, J=5.4 Hz, 2H), 1.14 (s, 9H); MS (m/z): 573.29 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[C:5]2[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH3:21])[CH:14]=1.F[B-](F)(F)F.[CH3:27][O+](C)C.[OH-].[Na+]>ClC(Cl)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:27])[CH:6]=[C:5]2[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH3:21])[CH:14]=1
Reactant: C[O+](C)C
Reactant: CCOc1cccc(-c2cc(=O)[nH]c3ccc(Br)cc23)c1
Agent: F[B-](F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Product: CCOc1cccc(-c2cc(OC)nc3ccc(Br)cc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.2 %

Procedure:
To a suspension of 6-bromo-4-(3-ethoxy-phenyl)-1H-quinolin-2-one (7.4 g, 21.5 mmol) in 60 ml dichloroethane was added trimethyloxonium tetrafluoroborate (BF4OMe3, 3.66 g, 24.7 mmol). The resulting mixture was stirred at ambient temperature overnight. After cooling to 0 C, was added 60 ml of 10% aqueous NaOH dropwise. The reaction mixture was stirred for another six hours at ambient temperature. It was then partitioned between dichloromethane and water. The organic layer was washed brine, dried over MgSO4, filtered and concentrated under vacuum to give an off-white solid. The solid was chromatographed on flash silica gel eluting with dichoromethane to yield the titled compound of 23A as a white solid (4.48 g, 58% yield).
Reaction SMILES: [CH3:1][OH:2].[H-].[Na+].[Br:5][C:6]1[S:16][C:9]2[N:10]=[C:11]([CH3:15])[N:12]=[C:13](Cl)[C:8]=2[CH:7]=1.O>C1COCC1>[Br:5][C:6]1[S:16][C:9]2[N:10]=[C:11]([CH3:15])[N:12]=[C:13]([O:2][CH3:1])[C:8]=2[CH:7]=1
Reactant: CO
Reactant: Cc1nc(Cl)c2cc(Br)sc2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1nc(C)nc2sc(Br)cc12
Reaction time: 0.25 h

Procedure:
A mixed solution of MeOH (2 mL) and THF (15 mL) was cooled in an ice bath, and NaH (60% oil, 600 mg) was added thereto, followed by stirring for 15 minutes. Then, a solution of 6-bromo-4-chloro-2-methylthieno[2,3-d]pyrimidine (2.0 g) in THF (5 mL) was added thereto, followed by stirring at room temperature for 2 hours. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and then concentrated under reduced pressure. The residue was purified by silica gel column (hexane/EtOAc) to obtain 6-bromo-4-methoxy-2-methylthieno[2,3-d]pyrimidine (1.8 g).
Reaction SMILES: [CH2:1]([C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[N:16]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:17]=[O:18]>C(Cl)Cl>[CH2:1]([C:9]1[CH:10]=[CH:11][C:12]([NH:13][C:17](=[O:18])[NH:16][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1ccc(N)cc1
Reactant: CCOC(=O)CCN=C=O
Solvent: ClCCl
Product: CCCCCCCCc1ccc(NC(=O)NCCC(=O)OCC)cc1
Yield: 87.8 %

Procedure:
To 4-n-octylaniline (0.1 g; 0.49 mmol) ethyl 3-isocyanatopropionate (0.08 g; 0.54 mmol) was added at room temperature. The resulting mixture was diluted to 1 ml with CH2Cl2, refluxed for 30 min and evaporated to dryness. The residue was treated with Et2O (5 ml) and the solid formed was filtered off and dried to give the title compound (0.15 g; 87%), as colourless crystals. 1H-NMR (CDCl3) 7.22-7.07 (m, 4H); 6.34 (broad s, 1H); 5.34 (m, 1H); 4.15-4.07 (m, 2H); 3.54-3.46 (m, 2H); 2.73 (m, 4H); 2.57-2.51 (m, 4H); 1.58 (m, 2H); 1.27-1.19 (m, 13H); 0.86 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]=1[N+:14]([O-])=O.[Cl:17][CH2:18][C:19](O)=O>CO.[Pd]>[Cl:17][CH2:18][C:19]1[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:3]=2[N:14]=1
Reactant: Nc1cccc(-c2ccccc2)c1[N+](=O)[O-]
Reactant: O=C(O)CCl
Agent: [Pd]
Solvent: CO
Product: ClCc1nc2c(-c3ccccc3)cccc2[nH]1
Yield: 92.7 %

Procedure:
A solution of 2-amino-6-phenyl-nitrobenzene (0.600 g, 2.80 mmol) in MeOH (28 mL) was hydrogenated (30 psi) over palladium, 10 wt. % on activated carbon (0.121 g). The resultant crude 3-phenyl-1,2-phenylenediamine was reacted with chloroacetic acid (0.537 g, 5.68 mmol) in refluxing 4 N H1 (6 mL) overnight. After normal workup, 0.63 g (92%) of 2-chloromethyl-4-phenyl-1H-benzimidazole was isolated as a brown solid, which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4](S(C)(=O)=O)[N:3]=1.[CH:23]1([OH:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4]([O:29][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[N:3]=1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccc3c(c2)OCO3)c1C#N
Reactant: OC1CCCCC1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(OC2CCCCC2)nc(N)nc1-c1ccc2c(c1)OCO2

Procedure:
From 2-amino-4-benzo[1,3]dioxol-5-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile, cyclohexanol and DBU in DME. ES-MS m/e (%): 339 (M+H+, 45), 257 (100).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]([F:28])([F:27])[F:26])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:30][OH:31].C(=O)([O-])O.[Na+].[NH4+].[Cl-]>C(O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]([F:28])([F:27])[F:26])[CH2:9]/[C:10](/[C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[N:30]\[OH:31])=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1cc(C(=O)CC(c2ccc(Br)cc2)c2ccccc2C(F)(F)F)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: Cc1cc(/C(CC(c2ccc(Br)cc2)c2ccccc2C(F)(F)F)=N/O)ccn1
Temperature: 50 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
A solution of 3-(4-bromo-phenyl)-1-(2-methyl-pyridin-4-yl)-3-(2-trifluoromethyl-phenyl)-propan-1-one (80 mg), hydroxylamine hydrochloride (37 mg) and sodium hydrogencarbonate (45 mg) in a mixture of ethanol (4 mL) and water (0.7 mL) was heated under reflux for 2 hours. A saturated solution of NH4Cl was added, the phases were separated and the inorganic one was extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was dissolved in DME (5 mL) and HCl in dioxane (4M, 0.45 mL) were added at rt. The reaction mixture was stirred at 50° C. overnight, was concentrated and dissolved in ethyl acetate (5 mL) and a saturated aqueous solution of NaHCO3 (0.1 mL). A saturated aqueous solution of NH4Cl was added, the phases were separated and the inorganic one was extracted with EtOAc (2×). The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (CH2Cl2/MeOH 95:5) to yield the title compound (65 mg, 79%) as a white foam, MS (ESI+): m/z=463.1 ([M+H]+, 1Br).
Reaction SMILES: [Mg].O1[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH:7](=[O:13])[C:8]1[O:12][CH:11]=[CH:10][CH:9]=1.ClC(C)C#C>[Cl-].[Zn+2].[Cl-].ClC(C)C#C.C1(C)C=CC=CC=1>[OH:13][CH:7]([C:8]1[O:12][CH:11]=[CH:10][CH:9]=1)[CH:5]([CH3:6])[C:4]#[CH:3]
Reactant: O=Cc1ccco1
Reactant: C1CCOC1
Agent: C#CC(C)Cl
Agent: [Cl-]
Agent: [Mg]
Solvent: Cc1ccccc1
Product: C#CC(C)C(O)c1ccco1
Temperature: 10 °C
Yield: 85 %

Procedure:
In the same flask as in Example 1, there were charged granular magnesium (18.2 g), dry zinc chloride (10.2 g) and dry tetrahydrofuran (100 g). 3-Chloro-1-butyne (0.66 g) was added thereto at 10° C. while stirring. The resultant mixture was kept in an adiabatic condition, whereupon the reaction proceeded. When the best generation stopped, a mixture of furfural (48 g), 3-chloro-1-butyne (45.88 g) and toluene (125 g) was dropwise added to the reaction mixture at 45° C. in 1.5 hours while stirring under cooling. The resultant mixture was kept at room temperature for 30 minutes while stirring. After completion of the reaction, the reaction mixture was treated in the same manner as in Example 1 and distilled under reduced pressure (66°-68° C./1 mmHg) to give 2-(1-hydroxy-2-methyl-3-butynyl)-furan (63.8 g) in a yield of 84% (based on the starting furfural).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH3:9].[Cl:10][S:11](O)(=[O:13])=[O:12]>>[Cl:8][C:5]1[CH:4]=[C:3]([CH3:9])[C:2]([Cl:1])=[CH:7][C:6]=1[S:11]([Cl:10])(=[O:13])=[O:12]
Reactant: Cc1cc(Cl)ccc1Cl
Reactant: O=S(=O)(O)Cl
Product: Cc1cc(Cl)c(S(=O)(=O)Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
A dry flask under argon was charged with chlorosulfonic acid (30 mL) and cooled to 0° C. 2,5-Dichlorotoluene (10 g, 62.1 mmol) was then added dropwise, and once the addition was complete, the reaction was heated to 60° C. and stirred for 30 min. After cooling to room temperature, the reaction mixture was poured slowly onto ice. The aqueous mixture was extracted twice with methylene chloride, and the organics were dried and concentrated to provide 2,5-dichloro-4-methylbenzenesulfonyl chloride (14.14 g, 88%) as a white solid.
Reaction SMILES: F[C:2]1[N:7]=[N:6][C:5]([N:8]([CH2:16][C:17]2([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][N:22]=3)[CH2:20][CH2:19][CH2:18]2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[C:28]([C:30]1[CH:34]=[CH:33][NH:32][CH:31]=1)#[N:29].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[C:28]([C:30]1[CH:34]=[CH:33][N:32]([C:2]2[N:7]=[N:6][C:5]([N:8]([CH2:16][C:17]3([C:21]4[C:26]([F:27])=[CH:25][CH:24]=[CH:23][N:22]=4)[CH2:20][CH2:19][CH2:18]3)[C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[CH:4][CH:3]=2)[CH:31]=1)#[N:29]
Reactant: N#Cc1cc[nH]c1
Reactant: CC(C)(C)OC(=O)N(CC1(c2ncccc2F)CCC1)c1ccc(F)nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CC1(c2ncccc2F)CCC1)c1ccc(-n2ccc(C#N)c2)nn1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 52.6 %

Procedure:
To a stirring solution of t-butyl 6-fluoropyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate (200 mg, 551 μmol) in DMF (2 mL) was added 3-cyanopyrrole (61 mg, 661 μmol) and potassium carbonate (152 mg, 1.1 mmol). The reaction was heated to 110° C. and stirred for 30 min. The reaction was then poured into ethyl acetate (100 mL), washed with water (3×25 mL), and the organic layer was separated, dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography (EtOAC/hexanes) to afford 130 mg of t-butyl 6-(3-cyano-1H-pyrrol-1-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[I:11].CO>C1COCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[I:11]
Reactant: O=C(O)c1ccc(Cl)c(I)c1
Solvent: C1CCOC1
Solvent: CO
Product: OCc1ccc(Cl)c(I)c1
Reaction time: 2 h
Yield: 86.4 %

Procedure:
Borane-THF complex (10 ml) was added dropwise over 20 minutes to a solution of 4-chloro-3-iodobenzoic acid (1.4 g) in THF (25 ml). The reaction mixture was stirred for 2 hours and then cooled (ice bath) and methanol (20 ml) was added cautiously. The solvent was removed and the residue was dissolved in methanol (10 ml) and stirred with aq. 2M sodium hydroxide (10 ml) for 2 hours. Ethyl acetate (50 ml) was added and the mixture was washed with saturated aq. sodium bicarbonate solution (50 ml). The aqueous extracts were washed with ethyl acetate (2×50 ml) and the combined ethyl acetate extracts were washed with water (50 ml) and brine (50 ml) and died. Removal of the solvent gave 4-chloro-3-iodobenzyl alcohol (1.15 g). NMR (CD3SOCD3): d 4.45 (d, 2H), 5.3 (t, 1H), 7.3 (m, 1H), 7.5 (m, 1H), 7.8 (s, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:22])[CH2:11][NH:12][C:13](=[O:21])[C@H:14]([CH2:16][O:17][CH2:18][CH:19]=[CH2:20])[NH2:15].[C:23]([O:27][C:28]([NH:30][C@H:31]([C:37]([NH:39][C:40]([CH3:52])([CH3:51])[C:41]([NH:43][C@H:44]([C:48](O)=[O:49])[CH:45]([CH3:47])[CH3:46])=[O:42])=[O:38])[CH2:32][O:33][CH2:34][CH:35]=[CH2:36])=[O:29])([CH3:26])([CH3:25])[CH3:24].C(N(CC)C(C)C)(C)C.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH3:8][O:9][C:10](=[O:22])[CH2:11][NH:12][C:13](=[O:21])[C@H:14]([CH2:16][O:17][CH2:18][CH:19]=[CH2:20])[NH:15][C:48](=[O:49])[C@H:44]([CH:45]([CH3:46])[CH3:47])[NH:43][C:41](=[O:42])[C:40]([CH3:52])([CH3:51])[NH:39][C:37](=[O:38])[C@H:31]([CH2:32][O:33][CH2:34][CH:35]=[CH2:36])[NH:30][C:28]([O:27][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:29]
Reactant: C=CCOC[C@H](NC(=O)OC(C)(C)C)C(=O)NC(C)(C)C(=O)N[C@H](C(=O)O)C(C)C
Reactant: C=CCOC[C@H](N)C(=O)NCC(=O)OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: C=CCOC[C@H](NC(=O)OC(C)(C)C)C(=O)NC(C)(C)C(=O)N[C@H](C(=O)N[C@@H](COCC=C)C(=O)NCC(=O)OC)C(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
O-allyl L-seryl glycine methyl ester trifluoroacetate 20 (4.42 g, 13.4 mmol) was dissolved in CH2Cl2 (40 mL) and N-tert-butoxycarbonyl O-allyl L-seryl α,α-dimethylglycyl L-valine 16 (5.75 g, 13.4 mmol) added. N,N-diisopropylethyl amine (1.73 g, 13.4 mmol) and HOBt hydrate (2.05 g, 13.4 mmol) were added and the solution cooled to 0° C. EDC hydrochloride (2.82 g, 14.7 mmol) was added in small portions together with 10 mL CH2Cl2. The reaction mixture was stirred for 1 h 30 min at 0° C. after which the icebath was removed and the mixture stirred for an additional 26 hours. The solution was diluted by addition of CH2Cl2 (60 mL) and washed with 2 M aqueous H2SO4 (3×90 mL), 7.5% (w/w) aqueous K2CO3 (3×90 mL) and saturated brine (90 mL). The volume was increased by addition of CH2Cl2, the solution dried with anhydrous MgSO4 and the solvent evaporated affording a slightly orange solid (6.14 g, 73%); δH (300 MHz; d6-DMSO) 8.25 (1H, t, J 6, NH(Gly)), 8.14 (1H, s, NH(Aib)), 7.88 (1H, d, J 8, NH(Ser(All))), 7.14 (1H, d, J 8, NH(Val)), 6.84 (1H, d, J 7, NH (Ser(All)1)), 5.92-5.74 (2H, m, CH═CH2), 5.28-5.11 (4H, m, CH═CH2), 4.50 (1H, m, CαH(Ser(All)2)), 4.17-4.09 (2H, m, CαH(Ser(All)1)/CαH(Val)), 3.95 (4H, m, CH2CH═CH2), 3.85 (2H, d, J 6, CαH2(Gly)), 3.61 (3H, s, OCH3), 3.58-3.46 (4H, m, CH2), 2.06-1.95 (1H, m, CH(CH3)2), 1.38 (9H, s, (CH3)3), 1.35 (3H, s, CH3(Aib)), 1.34 (3H, s, CH3(Aib)), 0.83 (3H, d, J 7, CH3(Val)), 0.78 (3H, d, J 7, CH3(Val)); δC (75 MHz; d6-DMSO) 173.9, 170.7, 169.9, 169.8, 169.7, 155.3, 134.8, 116.4, 116.3, 78.4, 71.0, 69.4, 58.2, 56.2, 54.8, 54.5, 52.5, 51.6, 40.6, 30.0, 28.0, 24.9, 24.7, 19.0, 17.8; m/z 650.3366 ([M+Na]+; C29H49N5O10Na requires 650.3377)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([O:11][CH3:12])=[C:9](Cl)[N:8]=[C:7]([Cl:14])[N:6]=1)=[O:4].[NH3:15]>C(Cl)(Cl)Cl.CO>[CH3:1][O:2][C:3]([C:5]1[C:10]([O:11][CH3:12])=[C:9]([NH2:15])[N:8]=[C:7]([Cl:14])[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(Cl)nc(Cl)c1OC
Reactant: N
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)c1nc(Cl)nc(N)c1OC
Reaction time: 0.5 h
Yield: 29 %

Procedure:
2,6-Dichloro-5-methoxypyrimidine-4-carboxylic acid methyl ester (750 mg, 3.16 mmol; see J. Med. Chem. 49(5), 1693-1705; 2006 for preparation) was dissolved in chloroform and 2N ammonia in methanol (2 eq) was added dropwise while in a cooling bath. The reaction mixture was stirred for 30 min, after which an additional 2 eq of 2N ammonia in methanol was added. The reaction was stirred at ambient temperature for 16 h. Additional 2N ammonia in methanol (2 eq) was added. The reaction was stirred for 2 h during which time a solid precipitated. The solid was filtered off and water was added to the filtrate. The crude material was extracted from the filtrate with dichloromethane three times and the combined organic phases were washed with brine, dried and concentrated under vacuum. The product was purified by flash chromatography on silica gel (hexane/ethyl acetate gradient) to provide the title compound (202 mg, 29% yield): mp 162-167° C.; 1H NMR (CDCl3): δ 5.75 (br s, 2H), 3.97 (s, 3H), 3.92 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[CH:26]=[C:27]([C:29]4[N:30]([CH3:40])[C:31]([CH2:34][NH:35][CH2:36][CH2:37][O:38][CH3:39])=[CH:32][N:33]=4)[S:28][C:21]=23)=[C:15]([F:41])[CH:14]=1)=[O:11].[C:42]([O:46][C:47]([NH:49][C@@H:50]([CH:54]([CH3:56])[CH3:55])[C:51](O)=[O:52])=[O:48])([CH3:45])([CH3:44])[CH3:43].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>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:11])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[CH:26]=[C:27]([C:29]4[N:30]([CH3:40])[C:31]([CH2:34][N:35]([CH2:36][CH2:37][O:38][CH3:39])[C:51](=[O:52])[C@@H:50]([NH:49][C:47](=[O:48])[O:46][C:42]([CH3:45])([CH3:44])[CH3:43])[CH:54]([CH3:56])[CH3:55])=[CH:32][N:33]=4)[S:28][C:21]=23)=[C:15]([F:41])[CH:14]=1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COCCNCc1cnc(-c2cc3nccc(Oc4ccc(NC(=O)Nc5ccc(F)cc5F)cc4F)c3s2)n1C
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: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc(NC(=O)Nc5ccc(F)cc5F)cc4F)c3s2)n1C)C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Reaction time: 8 h
Yield: 53.2 %

Procedure:
To a solution of the compound 351 (280 mg, 0.481 mmol) in DMF (10 ml) was added (S)-2-(tert-butoxycarbonylamino)-3-methylbutanoic acid (209 mg, 2 eq, 0.961 mmol), iPr2NEt (0.252 ml, 3 eq, 0.1.442 mmol) and HATU (365 mg, 2 eq, 0.961 mmol) and the reaction mixture was stirred overnight. The reaction mixture was diluted with EtOAc and washed with water, saturated NAHCO3 solution then brine. The organic phase was collected, dried over Na2SO4, filtered then concentrated. Purification of the residue by column chromatography (eluent 20% MeOH in EtOAc) afforded the desired compound 352 as an off-white solid (200 mg, 53% yield). MS (m/z)=782.7 (M+H).
Reaction SMILES: C([O:7][CH2:8][C@@H:9]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:10]1[C:18]([CH3:19])=[CH:17][C:13]2[N:14]=[CH:15][S:16][C:12]=2[C:11]=1[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)(=O)C(C)(C)C.[OH-].[Na+]>CO.C1COCC1.C(OCC)(=O)C>[C:28]([O:27][C@@H:9]([C:10]1[C:18]([CH3:19])=[CH:17][C:13]2[N:14]=[CH:15][S:16][C:12]=2[C:11]=1[C:20]1[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=1)[CH2:8][OH:7])([CH3:31])([CH3:29])[CH3:30]
Reactant: Cc1cc2ncsc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc2ncsc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)ethyl pivalate (5J) (8 mg, 0.0174 mmol) in MeOH (0.5 mL) and THF (1 mL) was added sodium hydroxide (2 M, 0.1 mL, 0.2 mmol) and the reaction mixture was stirred at room temperature overnight. Reaction mixture diluted with ethyl acetate and washed with saturated sodium bicarbonate solution. Aqueous layer back-extracted with ethyl acetate and combined organic layer was dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 0 to 50% ethyl acetate/hexanes). LCMS-ESI+: calc'd for C20H22ClNO2S: 376.1 (M+H+). Found: 376.1 (M+H+).
Reaction SMILES: [C:1]1([N:7]2[CH:15]=[C:14]3[C:9]([N:10]=[CH:11][C:12]([NH2:16])=[CH:13]3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CC#N>[C:1]1([N:7]2[CH:15]=[C:14]3[C:9]([N:10]=[CH:11][C:12]([NH:16][S:29]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)(=[O:31])=[O:30])=[CH:13]3)=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1cnc2nn(-c3ccccc3)cc2c1
Solvent: CC#N
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cnc2nn(-c3ccccc3)cc2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.1 %

Procedure:
To a solution of 3C (305 mg, 1.458 mmol) and pyridine (0.7 mL) in CH3CN (30 mL) cooled to 0° C. was added bezenesulfonyl chloride (274 mg, 1.550 mmol). After addition, the reaction mixture was stirred at RT for 1 hour, then concentrated under reduced pressure. The resultant residue was dissolved in CH2Cl2 (100 mL), washed with water (2×50 mL), saturated NaCl (50 mL). The organic layer was dried (MgSO4), filtered and concentrated. The residue was purified by silica gel column chromatography eluting with 2% of 2 M NH3 in MeOH/CH2Cl2 to give the title compound as a light brown solid (200 mg, 40% yield). LC/MS (method A): retention time=2.78 min, (M+H)+=351.