Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl([O-])(=O)=O.[K+].[I-:20].[K+].Cl>O.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([I:20])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Nc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: [I-]
Agent: Cl
Agent: [K+]
Agent: [O-][Cl+2]([O-])[O-]
Solvent: CO
Solvent: O
Product: Nc1ccc(-c2ccc(Cl)cc2)cc1I
Temperature: 80 °C
Yield: 89208.8 %

Procedure:
To a solution of 4′-chlorobiphenyl-4-ylamine (2.03 g, 0.01 mmol) in a mixed solvent system of methanol (10 ml) and distilled water (40 ml) is added potassium chlorate (0.830 g, 6.77 mmol) and potassium iodide (3.32 g, 0.02 mol). After heating the reaction mixture to 80° C., concentrated hydrochloric acid (0.60 ml) is added, and the mixture is further heated overnight at this temperature. The solution is cooled to room temperature and the crude product is extracted with diethyl ether (×3), followed by washing of the combined organic fractions with 5% aqueous sodium thiosulfate solution and distilled water. The organic phase is dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated in vacuo to give a dark solid, which is triturated with hexanes to afford 4′-chloro-3-iodobiphenyl-4-ylamine (2.94 g) as light brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:11]([CH2:13][C:14](OCC)=[O:15])[N:12]=2)=[CH:4][CH:3]=1.[NH3:25]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:11]([CH2:13][C:14]([NH2:25])=[O:15])[N:12]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1nc(-c2ccc(Cl)cc2)sc1-c1ccccc1
Reactant: N
Solvent: CO
Product: NC(=O)Cc1nc(-c2ccc(Cl)cc2)sc1-c1ccccc1
Reaction time: 72 h

Procedure:
Ethyl 2-(4-chlorophenyl)-5-phenylthiazol-4-ylacetate (4.5 g) was dissolved in methanol (50 ml), and ammonia was saturated in the solution at 0° C. and the resulting mixture was allowed to stand at room temperature for 3 days. After removing the solvent, methanol was added to the residue. The resulting precipitate was collected and dried to obtain 2-(4-chloro-phenyl)-5-phenylthiazol-4-yl acetamide (4.2 g).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]2[C:11](=[O:12])[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[NH:7][C:6]=12.[C:17](Cl)([Cl:19])=[O:18]>O1CCOCC1.C1(C)C=CC=CC=1>[Cl:19][C:17]([N:7]1[C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[NH:10][C:11](=[O:12])[C:5]2=[CH:4][S:3][C:2]([CH3:1])=[C:6]12)=[O:18]
Reactant: O=C(Cl)Cl
Reactant: Cc1scc2c1Nc1ccccc1NC2=O
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: Cc1scc2c1N(C(=O)Cl)c1ccccc1NC2=O

Procedure:
From 4,9-dihydro-3-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and phosgene in a mixture of dioxane and toluene, 4-chlorocarbonyl-4,9-dihydro-3-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one was obtained;
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)#[CH:22].C(N(CC)CC)C>CC(N(C)C)=O.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:21]#[C:22][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(I)cn2)CC1
Reactant: C#Cc1ccccn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C#Cc3ccccn3)cn2)CC1
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a stirred solution of tert-butyl 4-(5-iodopyridin-2-yl)piperazine-1-carboxylate (4.087 g, 10.5 mmol) in DMA (75 mL) at RT was added 2-ethynylpyridine, (CAS number 1945-84-2, 1.17 mL, 11.5 mmol), triethylamine (4.4 mL, 31.5 mmol), CuI (800 mg, 4.2 mmol) and Pd(PPh3)4 (1.21 g, 1.05 mmol). After stirring for 30 minutes, the DMA was removed in vacuo, and the residue diluted with EtOAc (100 mL). The dark solution was then washed with water (100 mL). The layers were separated and the aqueous phase extracted with EtOAc (3×50 mL). The combined organic extracts were then dried, (MgSO4), filtered and concentrated in vacuo. The residue was then purified by flash chromatography (silica gel, 50% EtOAc in hexanes) to give tert-butyl 4-[5-(pyridin-2-ylethynyl)pyridin-2-yl]piperazine-1-carboxylate as a brown oil (3.8 g, 10.5 mmol, 99%).
Reaction SMILES: [NH2:1][C:2]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH:7]=[C:6]([C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[C:28]([O:33][CH2:34][CH2:35][N:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)[CH:27]=2)[C:3]=1[C:4]#[N:5].[C:42](Cl)(=[O:44])[CH3:43].N1C=CC=CC=1>C(Cl)Cl>[NH2:1][C:2]1[C:3]([C:4]#[N:5])=[C:6]([C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:42](=[O:44])[CH3:43])=[C:28]([O:33][CH2:34][CH2:35][N:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)[CH:27]=2)[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[N:9]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc(COc2ccccc2-c2cc(-c3ccc(N)c(OCCN4CCCCC4)c3)c(C#N)c(N)n2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(COc2ccccc2-c2cc(-c3ccc(NC(C)=O)c(OCCN4CCCCC4)c3)c(C#N)c(N)n2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 2-amino-4-{4-amino-3-[2-(1-piperidinyl)ethoxy]phenyl}-6-{2-[(4-methoxybenzyl)oxy]-phenyl}nicotinonitrile, acetyl chloride, pyridine and CH2Cl2 was stirred at 0° C. for 1 hr. and at room temperature for 2 hrs. The usual work-up and column chromatography gave N-{4-(2-amino-3-cyano-6-{2-[(4-methoxybenzyl)oxy]phenyl}-4-pyridinyl)-2-[2-(1-piperidinyl)ethoxy]-phenyl}acetamide.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[N:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>C(Cl)Cl>[F:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([N:10]2[CH2:11][CH2:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]2[C:6]2[CH:7]=[N:8][C:3]([C:2]([F:1])([F:19])[F:20])=[CH:4][CH:5]=2)=[O:30])=[CH:24][CH:23]=1
Reactant: FC(F)(F)c1ccc(C2NCCc3ccccc32)cn1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: ClCCl
Product: O=C(Nc1ccc(F)cc1)N1CCc2ccccc2C1c1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
The crude 1-(6-(trifluoromethyl)pyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline was dissolved in CH2Cl2 (1.0 mL) and 1-fluoro-4-isocyanatobenzene (32 μL, 273 μmol) was added. The reaction was stirred 17 h under N2 at RT. The reaction was directly purified by HPLC to give N-(4-fluorophenyl)-1-(6-(trifluoromethyl)-pyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide as a white solid. MS (ESI pos. ion) m/z: 416 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)#[CH:2].Br[C:20]1[CH:21]=[N:22][CH:23]=[C:24]([CH:37]=1)[C:25]([N:27]=[S@@:28]([CH3:36])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]([NH:9][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[C:2][C:20]3[CH:21]=[N:22][CH:23]=[C:24]([CH:37]=3)[C:25]([N:27]=[S@@:28]([CH3:36])(=[O:35])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])=[CH:8][CH:7]=2)=[O:18])=[CH:12][CH:13]=1
Reactant: C[S@@](=O)(=NC(=O)c1cncc(Br)c1)c1ccccc1
Reactant: C#Cc1ccc(NC(=O)c2ccc(C)cc2)cc1
Product: Cc1ccc(C(=O)Nc2ccc(C#Cc3cncc(C(=O)N=[S@@](C)(=O)c4ccccc4)c3)cc2)cc1
Yield: 81 %

Procedure:
In a manner similar to that described in Example 449, N-(4-ethynyl-phenyl)-4-methyl-benzamide (0.104 g, 0.443 mmol) and (S)-5-bromo-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide (100 mg, 0.295 mmol) were reacted to give the title compound as a solid (118 mg, 81%).
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([CH2:9][CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:7][CH:8]=1)([OH:3])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.CCN(CC)CC.Cl.Cl.[NH2:44][CH2:45][CH2:46][CH2:47][NH:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][N:50]=1>C(Cl)Cl>[C:17]1([CH:10]([CH2:9][C:6]2[O:7][CH:8]=[C:4]([C:1]([NH:44][CH2:45][CH2:46][CH2:47][NH:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][N:50]=3)=[O:3])[N:5]=2)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)CC(Cc1nc(C(=O)O)co1)c1ccccc1
Reactant: NCCCNc1ccccn1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(Cc1nc(C(=O)NCCCNc2ccccn2)co1)c1ccccc1
Reaction time: 2 h
Yield: 90.9 %

Procedure:
To a solution of ethyl (±)-4-(4-carboxy-1,3-oxazol-2-yl)-3-phenylbutanoate (100 mg, 0.33 mmole) in CH2Cl2 (2 mL) was added 1,1′-carbonyldiimidazole (80 mg, 0.49 mmole). After 2 hr, Et3N (0.14 mL, 0.98 mmole) and 2-[(3-amino-1-propyl)amino]pyridine dihydrochloride (110 mg, 0.49 mmole) were added. After 4 h, the mixture was concentrated under reduced pressure. The residue was chromatographed on silica gel (75% EtOAc/hexanes) to give the title compound (131 mg, 91%) as a yellow oil: MS (ES) m/e 437 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH2:14][C:15]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]=2[NH:27]CC(OC(C)(C)C)=O)=[O:16])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:36]([OH:42])([C:38](F)(F)F)=[O:37].C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH2:14][C:15]([C:17]2[C:26]([CH2:38][C:36]([OH:42])=[O:37])=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]=2[NH2:27])=[O:16])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: CCOC(=O)N1CCN(C(=O)CC(=O)c2ccc3ccccc3c2NCC(=O)OC(C)(C)C)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)N1CCN(C(=O)CC(=O)c2c(CC(=O)O)cc3ccccc3c2N)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-[((4-(ethoxycarbonyl)piperazin-1-yl)carbonylmethyl)carbonyl][(1,1-dimethylethoxycarbonyl)methyl]aminonaphthalene (147 mg, 0.30 mmol) in CH2Cl2 (2.0 mL) was added TFA (3.0 mL). The resulting reaction mixture was stirred at ambient temperature for 3 hours. The reaction mixture was evaporated in vacuo to afford an oil, which was diluted with water (15 mL), adjusted to pH 4.5 by saturated NaHCO3, then extracted by ethyl acetate (3×15 mL). The organic layer was evaporated in vacuo to afford 2-[((4-(ethoxycarbonyl)piperazin-1-yl)carbonylmethyl)carbonyl][carboxymethyl]-aminonaphthalene (90 mg) as a solid; NMR (CDCl3) 1.26 (t, 3), 3.24-3.30 (m, 2), 3.35-3.42 (m, 6), 3.57 (m, 2), 4.14 (q, 2), 4.52 (s, 2), 7.48 (d, 1), 7.58 (m, 2), 7.84-7.94 (m, 4) ppm.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.CSC.[N+:12]([C:15]1[CH:16]=[C:17](/[C:21](/[CH2:25][CH3:26])=[CH:22]/[CH2:23]O)[CH:18]=[CH:19][CH:20]=1)([O-:14])=[O:13]>ClCCl>[Cl:1][CH2:23]/[CH:22]=[C:21](/[C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=1)\[CH2:25][CH3:26]
Reactant: CC/C(=C\CO)c1cccc([N+](=O)[O-])c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: CSC
Product: CC/C(=C\CCl)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of N-chlorosuccinimide (52.3 g, 0.39 mol) in dichloromethane (1.2 l) at 0° C. was added dropwise over 20 minutes dimethylsulfide (27.9 ml, 0.38 mol). To the mixture was added dropwise over 20 minutes at 0° C. a solution of (E)-3-(3-nitrophenyl)-2-penten-1-ol (Preparation 14, 80 g, 0.39 mol) in dichloromethane (300 ml). The mixture was warmed to room temperature over 1 h, stirred at room temperature for 16 h, then partitioned between water (2 l) and dichloromethane (1 l). The layers were separated and the organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica column chromatography (2 kg), eluting with 10:1 hexane/diethyl ether. Appropriate fractions were combined and concentrated in vacuo to give the title compound as a very pale yellow oil (54 g, 62%).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:30])[NH:5][C:6]1[S:7][C:8]2[C:14]([C:15]3[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=3)=[CH:13][C:12](OS(C(F)(F)F)(=O)=O)=[CH:11][C:9]=2[N:10]=1)[CH3:2].[N:31]1[CH:36]=[CH:35][CH:34]=[C:33](B(O)O)[CH:32]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>CO>[CH2:1]([NH:3][C:4]([NH:5][C:6]1[S:7][C:8]2[C:14]([C:15]3[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=3)=[CH:13][C:12]([C:33]3[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=3)=[CH:11][C:9]=2[N:10]=1)=[O:30])[CH3:2]
Reactant: CCNC(=O)Nc1nc2cc(OS(=O)(=O)C(F)(F)F)cc(-c3cc(C)ccn3)c2s1
Reactant: OB(O)c1cccnc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1COCCO1
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(-c3cc(C)ccn3)c2s1
Temperature: 80 °C

Procedure:
A stirred mixture of the crude Trifluoro-methanesulfonic acid 2-(3-ethyl-ureido)-7-(4-methyl-pyridin-2-yl)-benzothiazol-5-yl ester (44 mg, 0.096 mmol), 3-pyridineboronic acid (13 mg, 0.106 mmol), powdered potassium phosphate tribasic (25 mg, 0.115 mmol), anhydrous 1,4-dioxane (0.7 ml) and anhydrous methanol (1.2 ml) was purged with nitrogen for 15 min. 1,1′-bis(diphenylphosphino)ferrocene palladium (II) chloride complex (12 mg, 0.0144 mmol) was added and the mixture heated at 80° C. for 16 h under an atmosphere of nitrogen. After cooling to ambient temperature, the mixture was filtered through celite and washed through with methanol. The filtrate was evaporated in vacuo to give the crude 1-Ethyl-3-[7-(4-methyl-pyridin-2-yl)-5-pyridin-3-yl-benzothiazol-2-yl]-urea.
Reaction SMILES: C[O-].[Na+].CN(C)C([N:8]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:12]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])=[C:11]([CH3:29])[NH:10][C:9]1=O)=O.Cl.C[S:34](C)=O>CO>[CH3:29][C:11]1[NH:10][C:9](=[S:34])[NH:8][CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:12]=1[C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24]
Reactant: CS(C)=O
Reactant: CC1=C(C(=O)OC(C)C)C(c2cccc([N+](=O)[O-])c2)N(C(=O)N(C)C)C(=O)N1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC1=C(C(=O)OC(C)C)C(c2cccc([N+](=O)[O-])c2)NC(=S)N1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Sodium methoxide in methanol (1.6 ml, 7.5 mmol, 2 eq) was added to a solution of isomer B [described in Example 20, part B] of 1,2,3,4-tetrahydro-6-methyl-4-(3-nitrophenyl)-2-thioxo-3,5-pyrimidinecarboxylic acid, 5-(1-methylethyl)ester, 3-[(S)-5-methoxycarbonyl)-3-pyrrolidinyl]ester (2.04 g, 3.7 mmol) in methanol (18 ml). The reaction was allowed to stir at room temperature. After 16 hours, the pH was adjusted to 2 with ethereal hydrochloric acid and the mixture was cooled to 0° C. for six hours. The resulting solid was collected by filtration. Three further crops were collected from the mother liquors, which when combined afforded 1.12 g (89%). [α]D =+85° (c=0.5, dimethylsulfoxide).
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25](=[S:27])[NH2:26])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:29][C:30](=O)[CH2:31][CH3:32]>>[CH2:31]([C:30]1[N:26]=[C:25]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[CH2:10]2)[S:27][CH:29]=1)[CH3:32]
Reactant: CCC(=O)CBr
Reactant: NC(=S)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: CCc1csc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)n1

Procedure:
220 mg (about 0.384 mmol) of the compound from Example 53A and 70 mg (0.460 mmol) of 1-bromobutan-2-one were reacted according to the General Method 3. Yield: 63 mg (36% of theory).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].[Br:9][C:10]1[CH:40]=[C:39](F)[C:13]([CH2:14][N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([C:24]3[N:29]=[C:28]([NH:30][C:31]4[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=4)[C:27]([O:37][CH3:38])=[CH:26][N:25]=3)=[N:16]2)=[C:12]([F:42])[CH:11]=1.O>CN(C=O)C>[Br:9][C:10]1[CH:40]=[C:39]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])[C:13]([CH2:14][N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([C:24]3[N:29]=[C:28]([NH:30][C:31]4[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=4)[C:27]([O:37][CH3:38])=[CH:26][N:25]=3)=[N:16]2)=[C:12]([F:42])[CH:11]=1
Reactant: COc1cnc(-c2nn(Cc3c(F)cc(Br)cc3F)c3ccccc23)nc1Nc1ccncc1
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cnc(-c2nn(Cc3c(F)cc(Br)cc3OCC(F)(F)F)c3ccccc23)nc1Nc1ccncc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
38.2 mg of 2,2,2-trifluoroethanol (0.382 mmol, 2 eq.) were dissolved in 1.5 ml of dry DMF under nitrogen atmosphere. 16.8 mg of 60% sodium hydrid in paraffin oil (0.42 mmol, 2.2 eq.) were added. The suspension was stirred at room temperature for 15 minutes. 100 mg of 2-[1-(4-bromo-2,6-difluorobenzyl)-1H-indazol-3-yl]-5-methoxy-N-(pyridin-4-yl)pyrimidin-4-amine (2-12-1, 0.191 mmol, 1 eq.) were added. The reaction mixture was stirred at room temperature for 18 hours. Water was added dropwise. The suspension was filtered off. The precipitate was dried at 50° C. under vacuo. The precipitate was purified by preparative HPLC to yield 34 mg (0.05 mmol, 28%) of the analytically pure target compound.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH:6]=[C:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:8]([OH:10])=O)=[O:4].[CH3:15][NH:16][C:17](=[O:29])[C@H:18]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[NH2:19]>ClCCl>[CH3:13][CH:12]([CH3:14])[CH2:11][C:7]([C:8]([NH:19][CH:18]([C:17]([NH:16][CH3:15])=[O:29])[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)=[O:10])=[CH:6][CH2:5][C:3]([O:2][CH3:1])=[O:4]
Reactant: CNC(=O)[C@@H](N)Cc1ccc(OC)cc1
Reactant: COC(=O)CC=C(CC(C)C)C(=O)O
Solvent: ClCCl
Product: CNC(=O)C(Cc1ccc(OC)cc1)NC(=O)C(=CCC(=O)OC)CC(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.3 %

Procedure:
N,N-Dicyclohexylcarbodiimide (515 mg, 2.5 mmol) was added to an ice-cooled solution of 4-methoxycarbonyl-2-(2-methylpropyl)but-2-enoic acid (500 mg, 2.5 mmol) and O-methyl-L-tyrosine N-methylamide (520 mg, 2.5 mmol) in dry dichloromethane (30 ml), and the mixture was stirred at room temperature for 18 h. The precipitated solid was filtered off and washed with a little dichloromethane, then the organic solution was washed successively with 1 N hydrochloric acid (20 ml), 1 N sodium bicarbonate (20 ml), and water. The solution was dried (MgSO4) and evaporated in vacuo. Column chromatography (30 g silica) of the residual solid, eluting with 5% methanol/dichloromethane gave the title compound (520 mg, 53%), m.p. 142°-144° C. (dichloromethane/pentane).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]\[C:11]([OH:13])=[O:12].FC(F)(F)C(O)=O.CO[CH2:23][N:24]([CH2:29][Si](C)(C)C)[C:25]([CH3:28])([CH3:27])[CH3:26]>ClCCl>[C:25]([N:24]1[CH2:29][C@@H:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[C@@H:10]([C:11]([OH:13])=[O:12])[CH2:23]1)([CH3:28])([CH3:27])[CH3:26]
Reactant: COCN(C[Si](C)(C)C)C(C)(C)C
Reactant: O=C(O)/C=C\c1ccc(F)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)N1C[C@H](C(=O)O)[C@H](c2ccc(F)cc2F)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of (2Z)-3-(2,4-difluorophenyl)acrylic acid, from preparation 35 (400 mg, 2.17 mmol) and trifluoroacetic acid (17 μL, 0.2 mmol) in dichloromethane (1 mL) was added N-(methoxymethyl)-2-methyl-N-[(trimethylsilyl)methyl]propan-2-amine, from preparation 23 (882 mg, 4.35 mmol) over 30 minutes at 0° C. The reaction mixture was warmed to room temperature and stirred for 24 hours. The solvent was removed in vacuo and the white residue formed was triturated with diethyl ether (5 mL) and the solid filtered off to give the desired product, 400 mg (65%).
Reaction SMILES: C([O:5][C:6](=[O:28])[CH2:7][N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)(C)(C)C.[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32]>ClCCl>[OH:33][C:31]([C:30]([F:35])([F:34])[F:29])=[O:32].[CH2:21]([C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][C@@H:9]2[CH2:10][CH2:11][CH2:12][N:8]2[CH2:7][C:6]([OH:28])=[O:5])=[CH:16][CH:17]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)CN1CCC[C@H]1COc1ccc(Cc2ccccc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CN1CCC[C@H]1COc1ccc(Cc2ccccc2)cc1
Reaction time: 4 h
Yield: 94 %

Procedure:
[(S)-2-(4-Benzyl-phenoxymethyl)-pyrrolidin-1-yl]-acetic acid tert-butyl ester (30 mg, 0.079 mmol) was added to a solution of trifluoroacetic acid and dichloromethane (1:3, 4 mL). The reaction was run at room temperature for 4 h. The Mixture was concentrated to dryness and dried in a vacuum over at 50° C. The residue was triturated with diethyl ether and dried to obtain the title product (24.1 mg, 0.074 mmol, 94% yield) was confirmed by LCMS: m/z 325.41 (free amine). found 325 (M); 1H NMR (400 MHz, DMSO-d6) δ 1.78-1.83 (m, 1H), 1.96-2.05 (m, 2H), 2.19-2.25 (m, 1H), 3.31 (s, 1H), 3.68 (s, 1H), 3.88 (s, 2H), 3.98 (s, 1H), 4.18-4.34 (m, 4H), 6.88-6.90 (d, J=8.8, 2H), 7.17-7.21 (m, 5H), 7.26-7.29 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][C@@H:13]([O:15][Si](C(C)(C)C)(C)C)[CH2:12][N:11]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][C@@H:13]([OH:15])[CH2:12][N:11]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN(C(=O)OCc2ccccc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](O)CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of (3S,5R)-benzyl 3-(tert-butoxycarbonylamino)-5-(tert-butyldimethylsilyloxy)piperidine-1-carboxylate (1 eq) in 30 mL of THF was added 5.2 mL of TBAF (1.2 eq). The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate, washed with brine, then dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (5% methanol in EtOAc:hexanes=1:1) to yield (3S,5R)-benzyl 3-(tert-butoxycarbonylamino)-5-hydroxypiperidine-1-carboxylate (100%). LC/MS (m/z): 251.2 (MH+), Rt:0.89. HPLC: Rt:3.26 min.
Reaction SMILES: [CH:1]([C:4]1[S:8][C:7]([NH:9][C:10](=[O:16])[C@@H:11]([NH2:15])[CH2:12][CH2:13][CH3:14])=[N:6][CH:5]=1)([CH3:3])[CH3:2].[CH2:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][C:18]1=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[CH:1]([C:4]1[S:8][C:7]([NH:9][C:10](=[O:16])[C@@H:11]([NH:15][CH:23]2[CH2:24][CH2:25][C:26]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:22]2)[CH2:12][CH2:13][CH3:14])=[N:6][CH:5]=1)([CH3:2])[CH3:3]
Reactant: CCC[C@H](N)C(=O)Nc1ncc(C(C)C)s1
Reactant: O=C1CCc2ccccc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCC[C@H](NC1CCc2ccccc2C1)C(=O)Nc1ncc(C(C)C)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(S)-amino-pentanoic acid (5-isopropyl-thiazol-2-yl)-amide (350 mg, 1.4 mmol) and 2-tetralone (318 mg, 2.2 mmol)in 20 mL of methylene chloride and 5 drops of acetic acid was treated with sodium triacetoxyborohydride (462 mg, 2.2 mmol) and stirred at room temperature overnight. The mixture was concentrated and eluted through SPEC SCX cartridge and concentrated to dryness. The residue was purified by silica gel column chromatography to give 2-(S)-(1,2,3,4-Tetrahydro-naphthalen-2-ylamino)-pentanoic acid (5-isopropyl-thiazol-2-yl)-amide as a solid, LC-MS, RT=1.9 min, M+1=372.