Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:16]CN(C(C)C)C(C)C.Cl[C:26](=[O:32])[CH2:27][CH2:28][C:29]([O-:31])=[O:30]>C(Cl)Cl.C1COCC1>[CH3:16][O:31][C:29](=[O:30])[CH2:28][CH2:27][C:26]([NH:1][C:2]1[CH:11]=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[O:32]
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)c1ccc(C(F)(F)F)cc1N
Reactant: O=C([O-])CCC(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)CCC(=O)Nc1cc(C(F)(F)F)ccc1C(=O)OC
Reaction time: 3 h
Yield: 100 %

Procedure:
A 22 L reactor equipped with an overhead stirrer and a temperature probe was charged with methyl 2-amino-4-(trifluoromethyl)benzoate (680 g, 3.1 mol). DCM (5.4 L, 8 vol) was added to it and the resulting solution was cooled in an ice-water bath. DIEA (1.08 L, 6.2 mol, 2 equiv) was added to the solution. A solution of 4-chloro-4-oxo-butyrate (568 mL, 4.65 mol, 1.5 equiv) in DCM (1.4 L, 2 vol) was added dropwise maintaining the internal temperature below 15° C. (3 h). The ice-water bath was removed and the reaction was stirred for 3 h. The reaction was judged complete by HPLC analysis. Water (3.4 L, 5 vol) was added to the reaction and the biphasic mixture was stirred at ambient temperature overnight. The water layer was removed and saturated aqueous NaHCO3 (3.4 L, 5 vol) was added to the DCM layer. The mixture was stirred for 30 min. The two layers were separated and another 3.4 L (5 vol) of saturated aqueous NaHCO3 was added to the DCM layer. The mixture was stirred for 30 min. The two layers were separated and a 1:1 mixture of brine/water (3.4 L, 5 vol) was added to the DCM layer. The biphasic mixture was stirred for 30 min. The two layers were separated and the DCM layer was pumped down to a low volume (ca. 1.4 L, 2 vol). THF (6.8 L, 10 vol) was added to the solution and the solvent was evaporated under reduced pressure to a low volume (ca. 1.4 L) to obtain Methyl 2-(4-methoxy-4-oxobutanamido)-4-(trifluoromethyl)benzoate [1.032 kg, theoretical yield, 3.1 mol] as a solution in THF.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.Cl[C:12](=[O:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH:6][C:12](=[O:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:4]([F:10])[CH:3]=1
Reactant: Nc1c(F)cc(Br)cc1F
Reactant: CCOC(=O)CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)CC(=O)Nc1c(F)cc(Br)cc1F
Reaction time: 1 h
Yield: 65 %

Procedure:
To a solution of 4-bromo-2,6-difluoroaniline (10 g, 48 mmol) in DCM (15 mL) was added ethyl 3-chloro-3-oxopropanoate (6.8 mL, 53 mmol) and DIEA (9.2 mL, 53 mmol) at room temperature. After 1 hour, the reaction mixture was partitioned between H2O and DCM. The organic phase was washed with saturated NH4Cl, H2O, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give Compound B26a (10 g, 65% yield). HPLC: RT=1.6 (LCMS Method Q). MS (ES): m/z=321.9 [M+H]+. 1H NMR (500 MHz, CHLOROFORM-d) δ 8.89 (br. s., 1H), 7.20-7.15 (m, 2H), 4.29 (q, J=7.2 Hz, 2H), 3.54 (s, 2H), 1.36-1.31 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[N-]1C=CN=C1.[Cl:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[N:33]([C:37]([NH2:39])=[O:38])[C:32](=[O:40])[CH2:31]2>CN(C)C=O.CN(C1C=CN=CC=1)C>[Cl:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[N:33]([C:37]([NH2:39])=[O:38])[C:32](=[O:40])[CH:31]2[C:7](=[O:9])[C:4]1[CH:3]=[C:2]([Br:1])[S:6][CH:5]=1
Reactant: O=C(O)c1csc(Br)c1
Reactant: NC(=O)N1C(=O)Cc2cc(Cl)ccc21
Agent: CN(C)c1ccncc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: c1c[n-]cn1
Solvent: CN(C)C=O
Product: NC(=O)N1C(=O)C(C(=O)c2csc(Br)c2)c2cc(Cl)ccc21

Procedure:
The title compound was prepared according to the procedure of Example 55. A 100 g (4.83 mmole) portion of 5-bromo-3-thiophenecarboxylic acid (prepared as described in J. Am. Chem. Soc., 76, 2445 (1954)) was combined with 848 mg (5.23 mmole) of 1,1'-carbonyl-diimidazole in 5 ml of N,N-dimethylformamide and the intermediate imidazolide coupled directly with 848 mg (4.02 mmole) of 5-chloro-2-oxindole-1-carboxamide in the presence of 1.33 g (10.89 mmole) of 4-(N,N-dimethylamino)pyridine. The resulting crude green product (1.22 g, 76% yield) was recrystallized to furnish 540 mg (1.35 mmole, 34% yield) of yellow solid, m.p. 238°-40° C. (acetic acid).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:21]#[N:22])([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-:24].[K+].[K+].OO>CS(C)=O.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:21](=[O:24])[NH2:22])([NH:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCCC(C#N)(Nc2ccccc2)C1
Agent: OO
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCCC(Nc2ccccc2)(C(N)=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-cyano-3-phenylamino-piperidine-1-carboxylic acid tert-butyl ester (1.1 g, 3.65 mmol) in DMSO (10 ml) was added potassium carbonate (76 mg, 0.54 mmol) and hydrogen peroxide (35% in water solution) (0.73 ml, 8.4 mmol). The reaction mixture was stirred at RT overnight. Further portions of potassium carbonate (76 mg, 0.54 mmol) and hydrogen peroxide (35% in water solution) (0.73 ml, 8.4 mmol) were added and stirring continued for 24 hrs. The mixture was diluted with EtOAc (10 ml) and washed with brine (30 ml). The organics were separated and the aqueous was extracted with EtOAc (10 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. Purification of the crude product by chromatography on silica eluting with 0-50% EtOAc in iso-hexane afforded the title compound.
Reaction SMILES: [C:1]([O:6][CH:7]1[CH:14]2[CH:10]3[CH:11]([CH:16]([C:17](Cl)=[O:18])[CH:8]1[CH2:9]3)[C:12](=[O:15])[O:13]2)(=[O:5])[C:2]([CH3:4])=[CH2:3].[F:20][C:21]([F:28])([S:24]([O-:27])(=[O:26])=[O:25])[CH2:22][OH:23].[C:29]1([S+:35]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[F:20][C:21]([F:28])([S:24]([O-:27])(=[O:26])=[O:25])[CH2:22][O:23][C:17]([CH:16]1[CH:11]2[CH:10]3[CH:14]([CH:7]([O:6][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])[CH:8]1[CH2:9]3)[O:13][C:12]2=[O:15])=[O:18].[C:42]1([S+:35]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: C=C(C)C(=O)OC1C2CC3C1OC(=O)C3C2C(=O)Cl
Reactant: O=S(=O)([O-])C(F)(F)CO
Agent: Cl
Agent: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)OC1C2CC3C1OC(=O)C3C2C(=O)OCC(F)(F)S(=O)(=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
To 2.8 g (10 mmol) of the 2-methacryloyloxy-5-oxo-4-oxa-tricyclo[4.2.1.03,7]-non-9-ylcarbonyl chloride were added 4.2 g (10 mmol) of triphenylsulfonium 1,1-difluoro-2-hydroxy-ethanesulfonate in Synthesis Example 1-13 and 20 g of methylene chloride. To the mixture under ice cooling, a solution containing 1.0 g (10 mmol) of triethylamine and 0.25 g (2 mmol) of N,N-dimethylaminopyridine in 5 g of methylene chloride was added at a temperature below 5° C., and the resulting mixture was stirred for 2 hours at room temperature. Thereafter, 11 g of 5% dilute hydrochloric acid was added to the reaction mixture. The organic layer was taken out and washed with water, from which methylene chloride was distilled off in vacuum. 30 g of methyl isobutyl ketone was added to the residue, from which the residual water was distilled off in vacuum together with methyl isobutyl ketone. The resulting residue was purified by silica gel chromatography, obtaining the target compound, triphenylsulfonium 1,1-difluoro-2-(9-methacryloyloxy-4-oxo-5-oxatricyclo[4.2.1.03,7]-non-2-ylcarbonyloxy)-ethane-1-sulfonate. Colorless solids, 4.0 g (yield 61%). The compound has the following structure.
Reaction SMILES: Br[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[N:11]([C:14]3[CH:19]=[C:18]([Cl:20])[C:17](=[O:21])[N:16]([CH3:22])[CH:15]=3)[C:12](=[O:13])[C:4]=2[CH:3]=1.[CH2:30]([O:32][C:33](=[O:52])[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=1)[CH3:31].BrC1N(C(C)C)C2C(C3C=CC(Cl)=CC=3)N(C3C=C(Cl)C=CC=3C)C(=O)C=2C=1.C(C1C=CC(OC)=C(B(O)O)C=1)#N>>[CH2:30]([O:32][C:33](=[O:52])[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([C:2]2[N:6]([CH:7]([CH3:8])[CH3:9])[C:5]3[CH:10]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)[N:11]([C:14]4[CH:19]=[C:18]([Cl:20])[C:17](=[O:21])[N:16]([CH3:22])[CH:15]=4)[C:12](=[O:13])[C:4]=3[CH:3]=2)[CH:36]=1)[CH3:31]
Reactant: CC(C)n1c(Br)cc2c1C(c1ccc(Cl)cc1)N(c1cc(Cl)c(=O)n(C)c1)C2=O
Reactant: CCOC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: COc1ccc(C#N)cc1B(O)O
Agent: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Product: CCOC(=O)Cc1ccc(OC)c(-c2cc3c(n2C(C)C)C(c2ccc(Cl)cc2)N(c2cc(Cl)c(=O)n(C)c2)C3=O)c1

Procedure:
The title compound was prepared in analogy to the procedure described for Example 17 but 2-bromo-5-(5-chloro-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one (Intermediate E) and [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester (Intermediate AQ) were used instead of 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one and 5-cyano-2-methoxyphenylboronic acid respectively. The title compound (partially hydrolyzed to the acid) was obtained as a yellow foam. tR: 6.78 min (HPLC 2); ESI-MS: tR=1.12 min, [M+H]+ 594/596 (LC-MS 1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13](O)=[O:14])=[C:11]([CH3:16])[O:10][N:9]=2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:21][NH:22][CH3:23]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]([N:22]([CH3:23])[CH3:21])=[O:14])=[C:11]([CH3:16])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1onc(-c2ccc(Cl)cc2)c1C(=O)O
Reactant: CNC
Solvent: O=S(Cl)Cl
Product: Cc1onc(-c2ccc(Cl)cc2)c1C(=O)N(C)C
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 23.6 %

Procedure:
To 3-(4-chlorophenyl)-5-methylisoxazol-4-carboxylic acid (25 mg, 0.10 mmol) was added thionyl chloride (1 mL) and the neat solution allowed to stir 60° C. After 30 min, excess thionyl chloride was evaporated and dimethyl amine (40 μL, 0.08 mmol, 2 M in THF) was added and allowed to stir overnight at ambient temperature. The residue was purified using reversed phase HPLC to afford the title compound (5 mg). HRMS (ESI, pos. ion) m/z calcd for C13H13ClN2O2: 264.0666, found 264.0671.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[NH:14][C:15]([C:17]1[CH:18]=[C:19]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[F:31])[CH:20]=[CH:21]C=1O)=[O:16].Cl>O1CCCC1.N1C=CC=CC=1>[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[N:14]1[C:15](=[O:16])[C:17]2[CH:18]=[C:19]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[F:31])[CH:20]=[CH:21][C:5]=2[O:4][C:2]1=[O:3]
Reactant: O=C(Nc1ccc(F)cc1F)c1cc(-c2ccc(F)cc2F)ccc1O
Reactant: COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=c1oc2ccc(-c3ccc(F)cc3F)cc2c(=O)n1-c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 10 h
Yield: 61 %

Procedure:
A solution of methyl chloroformate (1.2 mL, 12 mmol) was added drop wised to a stirred solution of compound 2 (1.44 g, 4 mmol) in dry anhydrous tetrahydrofuran/pyridine (30 mL) at 0° C. The mixture was refluxed for 3 h. After 10 h stirring at room temperature, the pH value of the mixture was adjusted to pH=6 by 5% HCl(aq). The mixture was cooled to obtain crystalline compound on an ice bath for 2-3 h. After cooling, precipitated crystals were filtered off and washed with diluted HCl and water. The crude product was purified by crystallization from hot ethanol to afford compound 14.
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[C:10](Cl)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:14])=[N:7]2.[CH3:15]C1C=CC2C(=CC(C)=C(O)C=2)N=1>>[Br:1][C:2]1[C:11]([OH:12])=[C:10]([CH3:15])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:14])=[N:7]2
Reactant: Cc1ccc2c(Br)c(O)c(Cl)cc2n1
Reactant: Cc1ccc2cc(O)c(C)cc2n1
Product: Cc1ccc2c(Br)c(O)c(C)cc2n1

Procedure:
Compound 2C was prepared following the procedure used to prepare compound 1D of Example 1, except that 2,7-dimethylquinolin-6-ol (2B) was used instead of compound 1C. LCMS-ESI+ (m/z): 252.2, 254.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2=[N:12][N:13]=[C:14]([C:15]3[O:19][N:18]=[C:17]([CH3:20])[CH:16]=3)[N:4]2[N:3]=1.CC1C=C(C2N3N=C(OCC4C=CC=CN=4)C4C(C3=NN=2)=CC=CC=4)ON=1.Cl[CH2:49][C:50]1[CH:55]=[N:54][CH:53]=[CH:52][N:51]=1>>[CH3:20][C:17]1[CH:16]=[C:15]([C:14]2[N:4]3[N:3]=[C:2]([O:1][CH2:49][C:50]4[CH:55]=[N:54][CH:53]=[CH:52][N:51]=4)[C:11]4[C:6]([C:5]3=[N:12][N:13]=2)=[CH:7][CH:8]=[CH:9][CH:10]=4)[O:19][N:18]=1
Reactant: Cc1cc(-c2nnc3c4ccccc4c(O)nn23)on1
Reactant: ClCc1cnccn1
Agent: Cc1cc(-c2nnc3c4ccccc4c(OCc4ccccn4)nn23)on1
Product: Cc1cc(-c2nnc3c4ccccc4c(OCc4cnccn4)nn23)on1

Procedure:
The title-compound was prepared from 6-hydroxy-3-(3-methylisoxazol-5-yl)-1,2,4-triazolo[3,4-a]phthalazine (generated from the product of Example 120 part a using the conditions described for the preparation of Intermediate 2) and 2-chloromethylpyrazine (prepared as described in Example 15 part a) using the procedure described in Example part b. 1H NMR (360 MHz, CDCl3) δ 2.48 (3H, s, CH3), 5.83 (2H, s, CH2), 7.03 (1H, s, Ar—H), 7.87 (1H, m, Ar—H), 8.01 (1H, m, Ar—H), 8.32 (1H, d, J=7.8 Hz, Ar—H), 8.62-8.68 (2H, m, 2 of Ar—H), 8.72 (1H, d, J=7.8 Hz, Ar—H), 8.99 (1H, s, Ar—H); MS (ES+) m/e 360 [MH]+; Anal. Found C, 60.24; H, 3.44; N, 27.03. C18H13N7O2 requires C, 60.16; H, 3.63; N, 27.28%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C:11]2([O:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH:25][CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:27][OH:28])=[CH:20][CH:19]=1>C(O)C>[OH:13][C:11]1([CH2:12][N:25]([CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:27][OH:28])[CH2:24][C:21]2[CH:20]=[CH:19][C:18]([O:17][CH3:16])=[CH:23][CH:22]=2)[CH2:14][CH2:15][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Reactant: COc1ccc(CNC(CO)c2ccccc2)cc1
Solvent: CCO
Product: COc1ccc(CN(CC2(O)CCN(C(=O)OC(C)(C)C)CC2)C(CO)c2ccccc2)cc1
Yield: 82 %

Procedure:
A solution of tert-butyl-1-oxa-6-azaspiro[2.5]octane-6-carboxylate (0.7 g, 3.42 mmol) and 2-[(4-methoxyphenyl)methylamino]-2-phenyl-ethanol (800 mg, 3.109 mmol) in ethanol (5 mL) was stirred at 60° C. for 72 hours. The reaction mixture was concentrated in vacuo and purified by silica gel column chromatography using 0 to 10% MeOH in DCM as eluent to yield tert-butyl 4-hydroxy-4-[[(2-hydroxy-1-phenyl-ethyl)-[(4-methoxyphenyl)methyl]amino]methyl]piperidine-1-carboxylate (1.2 g, 82%). ESI-MS m/z calc. 470.6. Found 471.5 (M+1)+; Retention time: 1.45 minutes (3 min run).
Reaction SMILES: [CH2:1]([C:8]1[CH:20]=[CH:19][C:11]([O:12][CH2:13][C@H:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28]Cl.C(N(CC)CC)C>CN(C=O)C>[CH2:1]([C:8]1[CH:20]=[CH:19][C:11]([O:12][CH2:13][C@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[CH2:28][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=2)=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Cc2ccc(OC[C@H]3CCCN3)cc2)cc1
Reactant: ClCc1ccccn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: c1ccc(Cc2ccc(OC[C@H]3CCCN3Cc3ccccn3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
To a solution of Example 1 (0.20 g, 0.66 mmol) in DMF (5 mL) was added 2-picolyl chloride hydrochloride (0.10 g, 0.61 mmol) and triethylamine (0.24 mL, 1.72 mmol). The subsequent mixture was stirred at ambient temperature overnight. The reaction mixture was concentrated under reduced pressure. The crude residue was extracted into ethyl acetate (25 mL) and washed with water (25 mL) followed by brine (25 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography using hexane/EtOAc (gradient system) to give the title compound (0.07 g, 36%); 1H NMR (400 MHz, CDCl3); δ 1.73-1.80 (m, 3H), 2.05 (m, 1H), 2.40 (m, 1H), 3.02-3.08 (m, 2H), 3.71 (d, J=13.6 Hz, 1H), 3.83 (m, 1H), 3.91 (s, 2H), 3.95 (m, 1H), 4.25 (d, J=13.6 Hz, 1H), 6.79 (d, J=8.8 Hz, 2H), 7.07 (d, J=8.8 Hz, 2H), 7.15-7.20 (m, 4H), 7.25-7.27 (m, 2H), 7.41 (m, 1H), 7.61 (m, 1H), 8.53 (m, 1H); MS (m/z) 359.2 (M+1); LC (100.0%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:9][CH:10]([CH3:12])[CH3:11])[C:5]([Cl:8])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:21]2[CH:33]=[CH:32][C:24]3[N:25]=[C:26]([NH:28][C:29](=[O:31])[CH3:30])[S:27][C:23]=3[CH:22]=2)O1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O>[Cl:8][C:5]1[N:6]=[CH:7][C:2]([C:21]2[CH:33]=[CH:32][C:24]3[N:25]=[C:26]([NH:28][C:29](=[O:31])[CH3:30])[S:27][C:23]=3[CH:22]=2)=[CH:3][C:4]=1[NH:9][CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)Nc1cc(Br)cnc1Cl
Reactant: CC(=O)Nc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(=O)Nc1nc2ccc(-c3cnc(Cl)c(NC(C)C)c3)cc2s1
Temperature: 100 °C
Reaction time: 1.67 h
Yield: 35 %

Procedure:
5-bromo-2-chloro-N-isopropylpyridin-3-amine (127.6 mg, 0.511 mmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide (191.5 mg, 0.602 mmol), potassium carbonate (317.8 mg, 2.299 mmol), and Pd(dppf)C12-DCM complex (42.9 mg, 0.0526 mmol) were suspended in 1,2-dimethoxyethane (2.0 ml) and water (0.5 ml). Argon was bubbled through the suspension for about 15 seconds, and then the flask was fit with a reflux condensor and placed in a preheated oil bath (100° C.) and stirred under argon for 100 minutes. The reaction was cooled to room temperature, concentrated, and treated with DCM and MeOH. These organic washings were decanted, concentrated, treated with water, and filtered. The solid was washed with water and the filtrate was discarded. Solid also washed with MeOH and Et2O, but the filtrate and solid contain product. The solid and filtrate were combined, concentrated, and purified on a silica gel column (25:1 to 20:1 DCM/MeOH to 15:1 DCM/2 N ammonia in MeOH) to afford N-(6-(6-chloro-5-(isopropylamino)pyridin-3-yl)benzo[d]thiazol-2-yl)acetamide (64.5 mg, 35% yield). MS (ESI pos. ion) m/z: 361. Calculated exact mass for C17H17ClN4OS 360.
Reaction SMILES: [CH2:1]1CCN2C(=NCCC2)CC1.[NH2:12][CH2:13][CH2:14][O:15][C:16]1[N:21]=[CH:20][N:19]=[C:18]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[C:17]=1[C:36]1[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=1.[S:43](Cl)([C:46]1[CH:52]=[CH:51][C:49](C)=[CH:48][CH:47]=1)(=[O:45])=[O:44]>>[C:32]([C:29]1[CH:30]=[CH:31][C:26]([S:23]([NH:22][C:18]2[C:17]([C:36]3[CH:37]=[CH:38][C:39]([CH3:42])=[CH:40][CH:41]=3)=[C:16]([O:15][CH2:14][CH2:13][NH:12][S:43]([C:46]3[C:47]([CH3:1])=[CH:48][CH:49]=[CH:51][CH:52]=3)(=[O:44])=[O:45])[N:21]=[CH:20][N:19]=2)(=[O:24])=[O:25])=[CH:27][CH:28]=1)([CH3:35])([CH3:34])[CH3:33]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCN)cc1
Reactant: C1CCC2=NCCCN2CC1
Product: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCNS(=O)(=O)c2ccccc2C)cc1

Procedure:
According to Example 4a) with DBU instead of Hünig's base, 200 mg N-[6-(2-amino-ethoxy)-5-p-tolyl-pyrimidin-4-yl]-4-tert.-butyl-benzenesulfonamide was reacted with tosylchloride to give 147 mg 4-tert.-butyl-N-{6-[2-(toluenesulfonyl-amino)-ethoxy]-5-p-tolyl-pyrimidin-4-yl}-benzenesulfonamide. LC-MS: tR=5.85 min, [M−1]−=593.50.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.FC(F)(F)[C:13]([O:15]C(=O)C(F)(F)F)=[O:14].O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:13]([OH:15])=[O:14]
Reactant: Clc1cccc2cc[nH]c12
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1c[nH]c2c(Cl)cccc12
Temperature: 7.5 °C
Reaction time: 2 h
Yield: 80.9 %

Procedure:
A solution of 7-chloroindole (7.1 g, 47.0 mmol) in dimethylformamide (60 ml) was cooled to 5° C. under nitrogen and trifluoroacetic anhydride (7.6 ml, 54.0 mmol) was added over 10 mins, maintaining the temperature below 10° C. The mixture was stirred at 5-10° C. for 2 h, then poured into water (600 ml). The resulting suspension was stirred for 15 mins and the 7-chloro-3-[(trifluoromethyl)carbonyl]-1H-indole precipitate was filtered off, washing with water to neutrality. The damp solid was suspended in 4 M aqueous sodium hydroxide (500 ml) and heated to reflux with stirring for 1 h. The mixture was cooled and washed with diethyl ether (2×100 ml). The aqueous phase was then acidified to pH 1 using 5 M hydrochloric acid and the resulting fine precipitate filtered off, washed with water to neutrality and dried to afford 7-chloro-1H-indole-3-carboxylic acid as a pink solid (7.5 g, 38.0 mmol).
Reaction SMILES: [CH:1]1([N+:4]#[C-:5])[CH2:3][CH2:2]1.[O:6]=[CH:7][C@@H:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:9][CH2:10][CH3:11].C(O)(=[O:22])C>C(Cl)Cl.C(OCC)(=O)C>[CH:1]1([NH:4][C:5](=[O:22])[CH:7]([OH:6])[C@@H:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:9][CH2:10][CH3:11])[CH2:3][CH2:2]1
Reactant: [C-]#[N+]C1CC1
Reactant: CC(=O)O
Reactant: CCC[C@@H](C=O)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCC[C@H](NC(=O)OC(C)(C)C)C(O)C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 88.2 %

Procedure:
To a solution of cyclopropylisonitrile (1.91 g, 28.5 mmol), (S)-tert-butyl 1-oxopentan-2-ylcarbamate (3.8 g, 19 mmol) in methylene chloride (100 mL) was added acetic acid (2.28 g, 38 mmol) at 0° C. After the addition was complete the reaction mixture was allowed to warm to 25° C. and stirred for 6 hours. The reaction mixture was diluted with ethyl acetate (200 mL), then washed with a saturated solution of sodium bicarbonate and brine (30 mL) and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the crude product was crystallized from 50 mL of ethyl acetate and hexane(v/v=1/1) to give tert-butyl (3S)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-ylcarbamate (4.8 g) as a white solid.
Reaction SMILES: [CH3:1][CH:2]([C:4]1C=CC=C(C(C)C)[C:5]=1[CH2:13][C:14]([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=[O:15])C.C(C1C=CC=C(C(C)C)C=1CC(O)=O)(C)C.[S:49]1C=CC=C1CC(O)=O>>[S:49]1[CH:1]=[CH:2][CH:4]=[C:5]1[CH2:13][C:14]([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=[O:15]
Reactant: O=C(O)Cc1cccs1
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)c1ccc(C(C)C)c(OS(N)(=O)=O)c1C(C)C
Agent: CC(C)c1cccc(C(C)C)c1CC(=O)O
Product: CC(C)c1ccc(C(=O)Cc2cccs2)c(C(C)C)c1OS(N)(=O)=O

Procedure:
This compound was prepared in the same manner as for the title compound of Example 1, except that 2,6-diisopropylphenylacetic acid was replaced with 2-thiopheneacetic acid, mp 133°-136° C.