Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)(=[O:16])=[O:15])[CH2:11][NH:10]2)=[O:8])[CH2:5][CH2:4]1)#[N:2].[CH2:27]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([N:38]2[CH2:41][CH2:40][CH:39]2[C:42]([O-])=[O:43])[CH2:34][CH2:33]1)=[O:31])[CH3:28].[Li+]>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:24])[F:25])[CH:18]=3)(=[O:16])=[O:15])[CH2:11][N:10]2[C:42]([CH:39]2[CH2:40][CH2:41][N:38]2[CH:35]2[CH2:34][CH2:33][N:32]([C:30]([O:29][CH2:27][CH3:28])=[O:31])[CH2:37][CH2:36]2)=[O:43])=[O:8])[CH2:4][CH2:5]1)#[N:2]
Reactant: CCOC(=O)N1CCC(N2CCC2C(=O)[O-])CC1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3cccc(C(F)(F)F)c3)CN2)CC1
Agent: [Li+]
Product: CCOC(=O)N1CCC(N2CCC2C(=O)N2C[C@H](S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@H]2C(=O)NC2(C#N)CC2)CC1

Procedure:
The reaction of (2S,4R)-N-(1-cyanocyclopropyl)-4-(3-(trifluoromethyl)phenylsulfonyl)pyrrolidine-2-carboxamide 7E and lithium 1-(1-(ethoxycarbonyl)piperidin-4-yl)azetidine-2-carboxylate 20J carried out according to the general procedure L yielded ethyl 4-(2-((2S,4R)-2-(1-cyanocyclopropylcarbamoyl)-4-(3-(trifluoromethyl)phenylsulfonyl)pyrrolidine-1-carbonyl)azetidin-1-yl)piperidine-1-carboxylate 1:1 epimers as a white solid (77%). MS ISP (m/e): 626.3 (100) [(M+H)]+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Br:26]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:26])[N:6]2[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrBr
Reactant: Nc1nc(SCc2ccccc2)nc2c1ncn2Cc1ccccc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Nc1nc(SCc2ccccc2)nc2c1nc(Br)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 9 %

Procedure:
6-Amino-9-benzyl-2-benzylthiopurine (176 mg, 0.51 mmol) and bromine (1 ml) were dissolved in 160 ml of methylene chloride and the solution was stirred at room temperature for 4 hours. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated, dried on magnesium sulfate and filtered. The solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (0.5% methanol/chloroform) to give the subject compound (19 mg, yield 9%).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([OH:14])=[CH:11][CH:12]=2)[C:7]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[C:6]1[CH3:22])[CH2:2][CH2:3][CH3:4].[CH2:23]([O:25][C:26](=[O:31])[C:27](Br)([CH3:29])[CH3:28])[CH3:24]>>[CH2:23]([O:25][C:26](=[O:31])[C:27]([O:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]([CH3:22])=[C:7]2[C:15]1[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=1)([CH3:29])[CH3:28])[CH3:24]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CCCCn1c(C)c(-c2ccc(F)cc2)c2cc(O)ccc21
Product: CCCCn1c(C)c(-c2ccc(F)cc2)c2cc(OC(C)(C)C(=O)OCC)ccc21

Procedure:
The above compound was prepared from 1-butyl-3-(4-fluoro-phenyl)-2-methyl-1H-indole-5-ol and 2-bromo-2-methylpropanoic acid ethylester using a procedure analogous to that of Example 10.
Reaction SMILES: [C:1]1(=O)[NH:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O.[CH2:15]([NH2:27])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>C1C=CC=CC=1>[CH2:15]([N:27]=[C:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8]1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: O=C1CCCCCCN1
Reactant: CCCCCCCCCCCCN
Solvent: c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCCCCCCCN=C1CCCCCCN1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 28.3 g (0.223 mole) of an enantholactam in 250 ml of benzene is added 34.1 g (0.223 mole) of phosphorous oxychloride over 30 minutes. The mixture is stirred at room temperature for 4 hours after which 41.2 g (0.223 mole) of dodecylamine is added. The reaction mixture is stirred at room temperature for 1 hour and refluxed for 4 hours then allowed to stand overnight. The resulting precipitate is washed with benzene, and the benzene wash is extracted with aqueous 2 N hydrochloric acid and combined with the precipitate. The combined fractions are made alkaline with 2N sodium hydroxide, extracted into ether-methylene chloride, dried and recrystallized from isopropyl alcohol to give 2-dodecyliminooctahydroazocine.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:12][CH2:13][NH2:14])=[CH:8][NH:9]2)=[CH:5][CH:4]=1.Br[C:16]1[CH:24]=CC=C2[C:17]=1C(CCN)=CN2.[O-]S([O-])(=O)=O.[Na+].[Na+]>CC(C)=O.C(O)CCC>[Br:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]3[CH2:12][CH2:13][NH:14][C:16]([CH3:24])([CH3:17])[C:8]=3[NH:9]2)=[CH:5][CH:4]=1
Reactant: NCCc1c[nH]c2cccc(Br)c12
Reactant: NCCc1c[nH]c2cc(Br)ccc12
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCCCO
Product: CC1(C)NCCc2c1[nH]c1cc(Br)ccc21
Temperature: 60 °C
Reaction time: 96 h
Yield: 15 %

Procedure:
Concentrated HCl (10 mL) was added to a suspension of a 2:1 mixture of 2-(6-bromo-1H-indol-3-yl)ethanamine and 2-(4-bromo-1H-indol-3-yl)ethanamine (9.90 g, 41.4 mmol) and Na2SO4 (30 g) in 1:1 acetone/n-butanol (100 mL). The resulting suspension was heated at 60° C. with stirring for 4 d. The suspension was cooled and concentrated under reduced pressure. The residue was diluted with EtOAc, and the suspension was filtered. The filtrate was washed with saturate NaHCO3 solution, dried over Na2SO4 and concentrated under reduced pressure. Flash chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1 CH2Cl2/MeOH/NH4OH) 100:0 to 0:100) yielded the title compound (1.68 g, 15%) as a red foam: 1H NMR (500 MHz, CDCl3) δ 7.66 (br s, 1H), 7.45 (d, J=1.5 Hz, 1H), 7.32 (d, J=8.5 Hz, 1H), 7.19 (dd, J=8.5, 1.5 Hz, 1H), 3.20 (t, J=5.5 Hz, 2H), 2.68 (t, J=5.5 Hz, 2H), 1.47 (s, 6H).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[C:14]2[CH2:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]=2[O:28][CH3:29])=[CH:9][CH:8]=1)(O)=[O:2].O1CCCC1.ClC(OCC(C)C)=O.[CH2:43]([N:45](CC)[CH2:46]C)C>>[CH3:43][N:45]([CH3:46])[C:1]([CH2:4][CH2:5][CH2:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[C:14]2[CH2:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]=2[O:28][CH3:29])=[CH:9][CH:8]=1)=[O:2]
Reactant: CCN(CC)CC
Reactant: COC(=O)c1ccc(Cc2cccc3ccc(CCCC(=O)O)cc23)c(OC)c1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cc2cccc3ccc(CCCC(=O)N(C)C)cc23)c(OC)c1
Reaction time: 0.5 h
Yield: 42.9 %

Procedure:
To a mixture of methyl 4-[7-(3-carboxypropyl)-naphth-1-ylmethyl]-3-methoxybenzoate (2.40 g), tetrahydrofuran (70 ml) and triethylamine (0.681 g) was added isobutyl chloroformate (0.87 ml) After stirring for 30 min, dimethylamine (2.0 g) was bubbled into the solution and stirring continued for 18 h. The reaction mixture was partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was washed (1N hydrochloric acid, aqueous sodium bicarbonate (5% w/w), brine) and dried (MgSO4). Evaporation and flash chromatography, eluting with ethyl acetate:methylene chloride (0:1, 1:10 and 2:10, successively), to give methyl 4-[7-(3-dimethylcarbamoylpropyl)naphth-1-ylmethyl]-3-methoxybenzoate (1.10 g, 43%) as a glassy solid; MS(CI), m/e=419(M+H).
Reaction SMILES: [CH3:1][C:2]([O:41][CH2:42][C@H:43]1[CH2:45][O:44]1)([CH3:40])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[F:24])[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[NH:13]2)=[O:11])=[N:5]1.C(N(C(C)C)CC)(C)C.[NH2:55][CH2:56][CH2:57][CH2:58][OH:59]>C(O)(C)C>[OH:44][C@H:43]([CH2:45][NH:55][CH2:56][CH2:57][CH2:58][OH:59])[CH2:42][O:41][C:2]([CH3:1])([CH3:40])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[F:24])[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:38])([CH3:37])[CH3:39])[NH:13]2)=[O:11])=[N:5]1
Reactant: NCCCO
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccn(CC(C)(C)OC[C@H]3CO3)n2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(C)(C)CC1NC(C(=O)Nc2ccn(CC(C)(C)OC[C@H](O)CNCCCO)n2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 20.8 %

Procedure:
A mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid {1-[2-methyl-2-((R)-1-oxiranylmethoxy)-propyl]-1H-pyrazol-3-yl}-amide (43.6 mg, 0.066 mmol), isopropyl alcohol (2 mL), diisopropylethyl amine (0.1 mL, 0.56 mmol) and 3-amino-1-propanol (0.1 mL, 1.3 mmol) was microwaved at 130° C. for 15 min. The mixture was then concentrated and purified by reverse phase chromatography (20-95% of ACN/water) to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (1-{2-[(R)-2-hydroxy-3-(3-hydroxy-propylamino)-propoxy]-2-methyl-propyl}-1H-pyrazol-3-yl)-amide (10.1 mg, 20.8%) as an off-white powder. HRMS (ES+) m/z Calcd for C36H46Cl2F2N6O4S+H [(M+H)+]: 735.2999. found: 735.2998.
Reaction SMILES: [CH:1]([S:4]([CH2:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:11]=[C:10]([C:20]2[CH:25]=[CH:24][C:23]([NH:26]C(=O)OC(C)(C)C)=[CH:22][CH:21]=2)[N:9]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH:1]([S:4]([CH2:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:11]=[C:10]([C:20]2[CH:21]=[CH:22][C:23]([NH2:26])=[CH:24][CH:25]=2)[N:9]=1)(=[O:5])=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)S(=O)(=O)Cc1cc(N2CCOCC2)nc(-c2ccc(NC(=O)OC(C)(C)C)cc2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)S(=O)(=O)Cc1cc(N2CCOCC2)nc(-c2ccc(N)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.4 %

Procedure:
Tert-butyl (4-{4-[(isopropylsulfonyl)methyl]-6-morpholin-4-ylpyrimidin-2-yl}phenyl)carbamate (2.7 g, 5.67 mmol) was dissolved in DCM (20 mL) and trifluoroacetic acid (10 mL) was added. The reaction mixture was stirred at room temperature for 2 hours then diluted with DCM (20 mL) and washed with saturated aqueous sodium bicarbonate (20 mL). Organic phase collected, dried over magnesium sulphate, filtered and concentrated in vacuo to give the desired material as a cream solid (2.1 g).
Reaction SMILES: C[Si](C)(C)[O:3][CH:4]1[CH2:8][CH:7]([C:9]2[CH:14]=[CH:13][C:12]([S:15][CH3:16])=[CH:11][CH:10]=2)[CH2:6][O:5]1>C(#N)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:16][S:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]2[CH2:6][O:5][C:4](=[O:3])[CH:8]=2)=[CH:10][CH:11]=1
Reactant: CSc1ccc(C2COC(O[Si](C)(C)C)C2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Product: CSc1ccc(C2=CC(=O)OC2)cc1
Reaction time: 10 h

Procedure:
To a solution of 4 g of Pd(OAc)2 in 100 ml of acetonitrile is added dropwise the crude product from Step 1(5 g) under nitrogen at room temperature. After 10 h at room temperature, the mixture is condensed under reduced pressure and the residue is purified by flash chromatography on silica gel eluted with 2:1 hexane/EtOAc to give the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[N:3]=1.[CH:13]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)([CH3:15])[CH3:14]>C(OCC)(=O)C>[O:9]1[CH2:10][CH2:11][O:12][CH:8]1[C:4]1[N:3]=[C:2]([N:19]2[CH2:20][CH2:21][N:16]([CH:13]([CH3:15])[CH3:14])[CH2:17][CH2:18]2)[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(C2OCCO2)n1
Reactant: CC(C)N1CCNCC1
Solvent: CCOC(C)=O
Product: CC(C)N1CCN(c2cccc(C3OCCO3)n2)CC1
Temperature: 120 °C
Yield: 54.1 %

Procedure:
A mixture of 2-bromo-6-(1,3-dioxolan-2-yl)pyridine (7, 0.23 g, 1.0 mmol) and 1-isopropylpiperazine (0.38 g, 3.0 mmol) in a sealed tube was heated at 120° C. for 18 h. The mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), washed with water (10 mL), brine (10 mL), dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 0-10% methanol in dichloromethane to afford the title compound (0.15 g, 55%) as a yellow oil: 1H NMR (500 MHz, CDCl3) δ 7.51-7.48 (m, 1H), 6.83-6.82 (m, 1H), 6.62-6.60 (m, 1H), 5.72 (s, 1H), 4.18-4.14 (m, 2H), 4.08-4.04 (m, 2H), 3.58 (br s, 4H), 2.71 (br s, 1H), 2.62 (br s, 2H), 1.08 (d, J=5.5 Hz, 6H); ESI MS m/z 278 [M+H]+.
Reaction SMILES: S(O)(=O)(=O)C.[NH2:6][C:7]1[CH:12]=[C:11]([Cl:13])[N:10]=[C:9]([SH:14])[N:8]=1.[H-].[Na+].Cl[CH:18]([C:20]1[N:21]=[CH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH3:19].O>CN(C)C=O>[NH2:6][C:7]1[CH:12]=[C:11]([Cl:13])[N:10]=[C:9]([S:14][CH:18]([C:20]2[N:21]=[CH:22][C:23]3[C:28]([CH:29]=2)=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH3:19])[N:8]=1
Reactant: CC(Cl)c1cc2ccccc2cn1
Reactant: Nc1cc(Cl)nc(S)n1
Agent: CS(=O)(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(Sc1nc(N)cc(Cl)n1)c1cc2ccccc2cn1
Reaction time: 1 h
Yield: 57.3 %

Procedure:
4-Amino-6-chloro-2-mercapto-pyrimidine mesylate salt (1.79 g, 6.94 mmole) is dissolved in 12 ml dry dimethylformamide in a 50 ml one neck round bottom flask under nitrogen. The solution is treated with 60% sodium hydride (605 mg, 15.1 mmole) (exotherm) and the mixture is stirred one hour. 3-(1-chloroethyl)-isoquinoline (1.33 g, 6.94 mmole) in 2×3 ml dry dimethylformamide, is added to the reaction and the mixture is stirred 6 hours at room temperature. The reaction mixture is poured into 300 ml water and is extracted with 3×100 ml ethyl acetate. The combined organics are backwashed with 4×50 ml 50% saturated sodium chloride. The organics are dried over potassium carbonate and are concentrated in vacuo to a yellow oil. The crude material is chromatographed over 75 g silica gel (230-400 mesh), eluting with 40% acetone/hexane while collecting 9 ml fractions. Fractions 26-39 are combined and concentrated to afford 1.26 g (57%) of 4-Amino-6-chloro-2-(1-(3-isoquinolyl)ethyl)thio-pyrimidine as a white solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][N:14]3[C:17]([C:20]4[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=4)=[CH:18][N:19]=[C:13]3[CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].ClC(Cl)(Cl)C[O:31][C:32](=O)[NH:33][C:34]1[N:35]([CH2:43][CH2:44][O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[N:36]=[C:37]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH:38]=1>>[C:39]([C:37]1[CH:38]=[C:34]([NH:33][C:32]([NH:25][CH2:24][C:23]2[CH:26]=[CH:27][C:20]([C:17]3[N:14]4[CH:15]=[CH:16][C:11]([C:8]5[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=5)=[CH:12][C:13]4=[N:19][CH:18]=3)=[CH:21][CH:22]=2)=[O:31])[N:35]([CH2:43][CH2:44][O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[N:36]=1)([CH3:42])([CH3:40])[CH3:41]
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(CCO[Si](C)(C)C(C)(C)C)n1
Reactant: CS(=O)(=O)c1ccc(-c2ccn3c(-c4ccc(CN)cc4)cnc3c2)cc1
Product: CC(C)(C)c1cc(NC(=O)NCc2ccc(-c3cnc4cc(-c5ccc(S(C)(=O)=O)cc5)ccn34)cc2)n(CCO[Si](C)(C)C(C)(C)C)n1

Procedure:
Prepare the title compound in a manner analogous to Example 1 from 4-[7-(4-methanesulfonyl-phenyl)-imidazo[1,2-a]pyridin-3-yl]-benzylamine and {5-tert-butyl-2-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-2H-pyrazol-3-yl}-carbamic acid 2,2,2-trichloro-ethyl ester. MS (ES), m/z 701 (M+1).
Reaction SMILES: C(OC([N:8]1[C:12]([C:13]2[C:14]([NH2:44])=[N:15][CH:16]=[N:17][C:18]=2[N:19]2[CH2:24][CH2:23][CH:22]([C:25]3[N:26]([CH2:38][CH2:39][N:40]4[CH2:43][CH2:42][CH2:41]4)[CH:27]=[C:28]([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[C:32]([CH3:37])[CH:31]=4)[N:29]=3)[CH2:21][CH2:20]2)=[CH:11][CH:10]=[N:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[N:40]1([CH2:39][CH2:38][N:26]2[CH:27]=[C:28]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([CH3:37])[CH:31]=3)[N:29]=[C:25]2[CH:22]2[CH2:21][CH2:20][N:19]([C:18]3[N:17]=[CH:16][N:15]=[C:14]([NH2:44])[C:13]=3[C:12]3[NH:8][N:9]=[CH:10][CH:11]=3)[CH2:24][CH2:23]2)[CH2:43][CH2:42][CH2:41]1
Reactant: Cc1cc(-c2cn(CCN3CCC3)c(C3CCN(c4ncnc(N)c4-c4ccnn4C(=O)OC(C)(C)C)CC3)n2)ccc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cn(CCN3CCC3)c(C3CCN(c4ncnc(N)c4-c4ccn[nH]4)CC3)n2)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-(4-amino-6-{4-[1-(2-azetidin-1-yl-ethyl)-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-yl)-pyrazole-1-carboxylic acid tert-butyl ester (1.00 eq.) in DCM (1 ml), was added trifluoro-acetic acid (0.5 ml). The reaction mixture was stirred at RT for 30 min. After removal of the solvent, the crude was purified by HPLC to yield the title compound. LC-MS (M+H=502, obsd=502).
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[CH3:11])[C:7]([OH:9])=O)(=[O:3])[CH3:2].[CH2:19]([O:26][C:27](=[O:31])[C@H:28]([CH3:30])[NH2:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([O:26][C:27](=[O:31])[C@H:28]([CH3:30])[NH:29][C:7](=[O:9])[CH:6]([CH2:5][S:4][C:1](=[O:3])[CH3:2])[CH:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[CH3:11])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C[C@H](N)C(=O)OCc1ccccc1
Reactant: CC(=O)SCC(C(=O)O)C(C)c1ccc(O)cc1
Product: CC(=O)SCC(C(=O)N[C@@H](C)C(=O)OCc1ccccc1)C(C)c1ccc(O)cc1
Yield: 69 %

Procedure:
Using the procedure described in Example 60, but starting with 2-acetylthiomethyl-3-(4-hydroxyphenyl)butanoic acid and alanine benzyl ester, N-[2-acetylthiomethyl-3-(4-hydroxyphenyl)-1-oxobutyl]alanine benzyl ester is obtained in a 69% yield, the characteristics of which are as follows: Rf =0.22 [hexane/ethyl acetate (65:35 by volume)].
Reaction SMILES: [Cl:1][C:2]1[C:29]([F:30])=[CH:28][CH:27]=[C:26]([F:31])[C:3]=1[C:4]([NH:6][CH2:7][C:8]1([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][N:20]2[CH3:25])[CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]1)=[O:5].FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:29]([F:30])=[CH:28][CH:27]=[C:26]([F:31])[C:3]=1[C:4]([NH:6][CH2:7][C:8]1([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][N:20]2[CH3:25])[CH2:9][NH:10][CH2:11]1)=[O:5]
Reactant: CN1CCCCC1C1(CNC(=O)c2c(F)ccc(F)c2Cl)CN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCCCC1C1(CNC(=O)c2c(F)ccc(F)c2Cl)CNC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.1 %

Procedure:
tert-butyl 3-{[(2-chloro-3,6-difluorobenzoyl)amino]methyl}-3-(1-methylpiperidin-2-yl)azetidine-1-carboxylate (0.40 g, 0.9 mmol) was dissolved in dichloromethane (3 ml) and trifluoroacetic acid (2 eq) was added. The reaction was stirred at room temperature overnight. The mixture was evaporated to dryness and the residue treated with saturated aqueous sodium carbonate. The product was extracted into dichloromethane. The organic phase was washed with brine, dried over anhydrous magnesium sulfate and evaporated to give 2-chloro-3,6-difluoro-N-{[3-(1-methylpiperidin-2-yl)azetidin-3-yl]methyl}benzamide (0.20 g, 64%) which was used without further purification. Propane-1-sulfonyl chloride (0.04 ml, 0.34 mmol) was added to 2-chloro-3,6-difluoro-N-{[3-(1-methylpiperidin-2-yl)azetidin-3-yl]methyl}benzamide (0.10 g, 0.28 mmol) and triethylamine (0.08 g, 0.56 mmol) in dichloromethane (2 ml) at 0° C. The reaction was then stirred at room temperature for 30 mins before quenching with N,N-dimethylethylenediamine (0.5 eq). The resulting mixture was partitioned between dichloromethane and water. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated to dryness. Purification by flash column chromatography on a silica cartridge eluting with dichloromethane (containing 1% ammonia) on a gradient of methanol (0-5%) led to 2-chloro-3,6-difluoro-N-{[3-(1-methylpiperidin-2-yl)-1-(propylsulfonyl)azetidin-3-yl]methyl}benzamide as an off-white solid. m/z (M++H) 464, 1H NMR (500 MHz, DMSO): δ 9.34 (s, 1 H); 7.58 (t, J=6.7 Hz, 1 H); 7.43 (s, 1 H); 4.07 (t, J=12.7 Hz, 1H); 3.91 (d, J=7.8 Hz, 1 H); 3.79 (d, J=7.8 Hz, 2 H); 3.65 (d, J=8.1 Hz, 1 H); 3.53 (d, J=10.8 Hz, 1 H); 3.17 (s, 2 H); 3.05 (t, J=7.4 Hz, 2 H); 2.80 (s, 1 H); 2.56 (s, 2 H); 1.75 (s, 1 H); 1.67 (dd, J=7.8, 15.0 Hz, 5 H); 1.39 (s, 2 H); 0.96 (t, J=7.3 Hz, 3 H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:21]=[CH:20][C:9]2[C:10]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[CH:11][O:12][C:8]=2[CH:7]=1)[CH2:2][C:3]#[CH:4].C([O:24][C:25](=[O:44])[C@@H:26]([O:42][CH3:43])[CH2:27][C:28]1[CH:33]=[CH:32][C:31](OS(C(F)(F)F)(=O)=O)=[CH:30][CH:29]=1)C.[O-]S(C(F)(F)F)(=O)=O>>[F:19][C:16]1[CH:15]=[CH:14][C:13]([C:10]2[C:9]3[CH:20]=[CH:21][C:6]([O:5][CH2:1][CH2:2][C:3]#[C:4][C:31]4[CH:30]=[CH:29][C:28]([CH2:27][C@H:26]([O:42][CH3:43])[C:25]([OH:44])=[O:24])=[CH:33][CH:32]=4)=[CH:7][C:8]=3[O:12][CH:11]=2)=[CH:18][CH:17]=1
Reactant: C#CCCOc1ccc2c(-c3ccc(F)cc3)coc2c1
Reactant: CCOC(=O)[C@H](Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1)OC
Agent: O=S(=O)([O-])C(F)(F)F
Product: CO[C@@H](Cc1ccc(C#CCCOc2ccc3c(-c4ccc(F)cc4)coc3c2)cc1)C(=O)O

Procedure:
The title compound was prepared from 6-But-3-ynyloxy-3-(4-fluoro-phenyl)-benzofuran and (2S)-2-methoxy-3-(4-trifluoromethanesulfonyloxy-phenyl)-propionic acid ethyl ester Example 1, Step A) following the procedure described in Example 40, Step C. The ethyl ester derivative was contaminated with starting triflate. The mixture was hydrolyzed using the Standard Procedure C. The residue was purified by chromatography. MS(ES) for C28H23FO5 [M−H]−: 457.2.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:9].[OH:16][C:17]1[C:22]2[N:23]=[C:24]([NH:26][C:27](=[O:29])[CH3:28])[S:25][C:21]=2[CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH2:11]([NH:10][C:8](=[O:9])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:16][C:17]1[C:22]2[N:23]=[C:24]([NH:26][C:27](=[O:29])[CH3:28])[S:25][C:21]=2[CH:20]=[CH:19][CH:18]=1)[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CC(=O)Nc1nc2c(O)cccc2s1
Reactant: CCCCCNC(=O)NCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCNC(=O)NCCCCCOc1cccc2sc(NC(C)=O)nc12
Temperature: 60 °C
Reaction time: 6 h
Yield: 40.6 %

Procedure:
A mixture of 1-(5-bromopentyl)-3-n-pentylurea (100 mg, 0.37 mmol), commercial N-(4-hydroxybenzo[d]thiazol-2-yl)acetamide (100 mg, 0.48 mmol), and K2CO3 (67 mg, 0.48 mmol) in DMF (5 mL) was heated at 60° C. After 6 h, the reaction mixture was cooled to rt, diluted with water (25 mL), and extracted into EtOAc (3×10 mL). The combined organic extracts were washed with water (2×5 mL), brine (10 mL), dried (Na2SO4) and concentrated in vacuo. The residue thus obtained was purified by silica gel column chromatography to give 31 (61 mg, 40%), mp 61.6-61.8° C. TLC:EtOAc/hexane (3:2), Rf˜0.40; 1H NMR (300 MHz) δ 7.39 (dd, J=0.9, 7.3 Hz, 1H), 7.20 (dd, J=7.8, 7.3 Hz, 1H), 6.86 (dd, J=0.9, 7.8 Hz, 1H), 4.42 (br s, —NH, 2H), 4.17 (t, J=5.4 Hz, 2H), 3.19-3.30 (m, 4H), 2.33 (s, 3H), 1.82-1.98 (m, 2H), 1.64-1.80 (m, 4H), 1.42-1.60 (m, 2H), 1.24-1.40 (m, 4H), 0.88 (t, J=7.3 Hz, 3H); 13C NMR (75 MHz) δ 170.16, 159.91, 158.94, 151.37, 139.10, 133.67, 124.40, 113.94, 108.68, 68.21, 40.64, 39.98, 30.27, 29.30, 28.33, 26.54, 23.25, 22.64, 22.33, 14.26. HRMS (ESI-neg) calcd for C20H29N4O3S [M−1]− 405.1960, found 405.1938.