Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:125])[CH2:7][N:8]([CH2:117][C:118](=[O:124])[O:119]C(C)(C)C)[C:9](=[O:116])[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[C:12]1[CH2:16][N:17]([CH2:59][C:60]1[CH:65]=[CH:64][C:63]([O:66][CH2:67][C:68]2[N:69]=[N:70][N:71]([CH2:73][CH2:74][CH2:75][NH:76][C:77](=[O:115])[CH2:78][N:79]3[CH2:90][CH2:89][N:88]([CH2:91][C:92](=[O:98])[O:93]C(C)(C)C)[CH2:87][CH2:86][N:85]([CH2:99][C:100](=[O:106])[O:101]C(C)(C)C)[CH2:84][CH2:83][N:82]([CH2:107][C:108]([O:110]C(C)(C)C)=[O:109])[CH2:81][CH2:80]3)[CH:72]=2)=[CH:62][CH:61]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](=[O:58])[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][C@@H:29]([C:51]([O:53]C(C)(C)C)=[O:52])[NH:30][C:31](=[O:50])[NH:32][C@H:33]([C:43]([O:45]C(C)(C)C)=[O:44])[CH2:34][CH2:35][C:36]([O:38]C(C)(C)C)=[O:37])(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[C:118]([CH2:117][N:8]([CH2:7][C:6]([OH:125])=[O:5])[C:9](=[O:116])[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[C:12]1[CH2:16][N:17]([CH2:59][C:60]1[CH:61]=[CH:62][C:63]([O:66][CH2:67][C:68]2[N:69]=[N:70][N:71]([CH2:73][CH2:74][CH2:75][NH:76][C:77](=[O:115])[CH2:78][N:79]3[CH2:90][CH2:89][N:88]([CH2:91][C:92]([OH:98])=[O:93])[CH2:87][CH2:86][N:85]([CH2:99][C:100]([OH:106])=[O:101])[CH2:84][CH2:83][N:82]([CH2:107][C:108]([OH:110])=[O:109])[CH2:81][CH2:80]3)[CH:72]=2)=[CH:64][CH:65]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](=[O:58])[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][C@@H:29]([C:51]([OH:53])=[O:52])[NH:30][C:31](=[O:50])[NH:32][C@H:33]([C:43]([OH:45])=[O:44])[CH2:34][CH2:35][C:36]([OH:38])=[O:37])([OH:124])=[O:119]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCNC(=O)CCCCCN(Cc1ccc(OCc2cn(CCCNC(=O)CN3CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC3)nn2)cc1)Cc1nccn1CC(=O)N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CC[C@H](NC(=O)N[C@@H](CCCCNC(=O)CCCCCN(Cc1ccc(OCc2cn(CCCNC(=O)CN3CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC3)nn2)cc1)Cc1nccn1CC(=O)N(CC(=O)O)CC(=O)O)C(=O)O)C(=O)O

Procedure:
A solution of ((14S,18S)-tri-tert-butyl 1-(1-(2-(bis(2-(tert-butoxy)-2-oxoethyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)-8,16-dioxo-2-(4-((1-(3-(2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetamido)propyl)-1H-1,2,3-triazol-4-yl)methoxy)benzyl)-2,9,15,17-tetraazaicosane-14,18,20-tricarboxylate (21 mg, 0.012 mmol) in TFA (2.0 mL) and DCM (2.0 mL) was stirred at rt overnight. The solvent was removed under a stream of nitrogen to give a crude ((14S,18S)-1-(1-(2-(bis(carboxymethyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)-8,16-dioxo-2-(4-((1-(3-(2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetamido)propyl)-1H-1,2,3-triazol-4-yl)methoxy)benzyl)-2,9,15,17-tetraazaicosane-14,18,20-tricarboxylic acid, (MIP-1459), which was dissolved in ammonium acetate (0.30 mL, 0.50 N) solution in water (0.50 mL) with InCl3 (10 mg). The reaction mixture was heated at
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][N:38]=[C:37]([C:41]#[N:42])[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[C:11]([C:20]([F:21])([F:22])[F:23])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][N:38]=[C:37]([C:41]#[N:42])[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccnc(C#N)c1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)c(C(F)(F)F)cc1N
Product: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)c(C(F)(F)F)cc1NC(=O)CC(=O)c1ccnc(C#N)c1

Procedure:
The title compound was prepared from (2-amino-5-morpholin-4-yl-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example J1) (181 mg, 0.5 mmol) and 3-(2-cyano-pyridin-4-yl)-3-oxo-propionic acid tert.-butyl ester (Example K3) (123 mg, 0.5 mmol) according to the general procedure M. Obtained as an off-white solid (137 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH2:19]([OH:22])[C:20]#[CH:21]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C(N(CC)CC)C.[I-]>[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:21]#[C:20][CH2:19][OH:22])=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(I)cc1
Reactant: C#CCO
Agent: Cl[Pd]Cl
Agent: [I-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C(CC1CCCC1)c1ccc(C#CCO)cc1
Temperature: 70 °C
Yield: 91.4 %

Procedure:
A solution of 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid methyl ester (2.15 g, 6.00 mmol) and triethylamine (6 mL, 0.04 mmol) in N,N-dimethylformamide (6 mL) was treated with propargyl alcohol (0.87 mL, 15.0 mmol). The resulting reaction mixture was degassed with argon and then treated with cooper iodide (30 mg, 0.15 mmol) and bis(triphenylphosphine)palladium (II) chloride (45 mg, 0.06 mmol). The reaction was then heated at 70° C. for 24 h. At this time, the reaction was cooled to 25° C. and concentrated in vacuo. The residue was diluted with ethyl acetate (120 mL) and washed with a half-saturated aqueous sodium chloride solution (1×60 mL). The resulting aqueous layer was back extracted with ethyl acetate (1×120 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 60/40 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-[4-(3-hydroxy-prop-1-ynyl)-phenyl]-propionic acid methyl ester (1.57 g, 91%) as an amber oil.
Reaction SMILES: [O:1]=[C:2]1[CH:6]([N:7]2[CH2:11][CH2:10][CH2:9][C:8]2=[O:12])[CH2:5][CH2:4][O:3]1.[CH2:13]([NH2:17])[CH2:14][CH2:15][CH3:16]>CO>[CH2:13]([NH:17][C:2](=[O:1])[CH:6]([CH2:5][CH2:4][OH:3])[N:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:12])[CH2:14][CH2:15][CH3:16]
Reactant: O=C1OCCC1N1CCCC1=O
Reactant: CCCCN
Solvent: CO
Product: CCCCNC(=O)C(CCO)N1CCCC1=O
Temperature: 65 °C
Yield: 84.6 %

Procedure:
10.14 g (0.06 mol) of 1-(tetrahydro-2-oxo-3-furyl)-2-pyrrolidinone are dissolved in 50 ml of methanol and 8.78 g (0.12 mol) of n-butylamine are added to the solution. The reaction mixture is heated under reflux (65° C.) for 3 hours and then evaporated under a high vacuum. 12.3 g (yield: 85% of theory) of N-n-butyl-alpha-(2-hydroxyethyl)-2-oxo-1-pyrrolidineacetamide are obtained in the form of a syrup.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=2)[C:10]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[C:9]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1.ClCCl>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:40]3[CH:41]=[CH:42][C:37]([O:36][CH3:35])=[CH:38][CH:39]=3)=[CH:14][CH:15]=2)[C:10]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[C:9]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCc1c(-c2ccccc2)n(Cc2ccccc2)c2ccc(Br)cc12
Reactant: COc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCCCCc1c(-c2ccccc2)n(Cc2ccccc2)c2ccc(-c3ccc(OC)cc3)cc12

Procedure:
The desired product was prepared using a procedure similar to step 3 of example 3. Thus, 1-benzyl-5-bromo-3-pentyl-2-phenyl-1H-indole (1.282 g, 2.965 mmol) was reacted with aqueous 2M K2CO3 (3.0 ml), 4-methoxyphenylboronic acid (0.631 g, 4.151 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (0.073 g, 0.089 mmol) in dioxane (30 ml) to give the product (0.727 g, 1.582 mmol, 53%) as a yellow solid, mp 91-110° C. 1H NMR (DMSO-d6) δ 0.76 (t, J=7.0 Hz, 3H), 1.15-1.21 (m, 4H), 1.54-1.59 (m, 2H), 2.68 (t, J=7.3 Hz, 2H), 3.79 (s, 3H), 5.27 (s, 2H), 6.84 (d, J=7.0 Hz, 2H), 7.01 (d, J=8.9 Hz, 2H), 7.15 (t, J=7.2 Hz, 1H), 7.20 (t, J=6.9 Hz, 2H), 7.33-7.38 (m, 4H), 7.43 (t, J=7.2 Hz, 1H), 7.48 (t, J=6.9 Hz, 2H), 7.60 (d, J=8.9 Hz, 2H), 7.75 (d, J=0.8 Hz, 1H); [ESI(+)], m/z 460 (M+H)+.
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C:6]1[C:7]([C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][N:20]=2)=[O:17])=[CH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2.[O:26]=[C:27]1[CH2:31][CH2:30][CH2:29][N:28]1[C@H:32]1[CH2:37][CH2:36][C@H:35]([C:38](O)=[O:39])[CH2:34][CH2:33]1.Cl.C(N=C=NCCCN(C)C)C.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.CN(C)C=O.CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:16]([C:7]2[C:6]([NH:5][C:38]([C@H:35]3[CH2:36][CH2:37][C@H:32]([N:28]4[CH2:29][CH2:30][CH2:31][C:27]4=[O:26])[CH2:33][CH2:34]3)=[O:39])=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=2)=[O:17])=[N:20][CH:21]=1
Reactant: O=C1CCCN1[C@H]1CC[C@H](C(=O)O)CC1
Reactant: Nc1cc2ccccc2cc1C(=O)Nc1ccc(Cl)cn1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Cl)cn1)c1cc2ccccc2cc1NC(=O)[C@H]1CC[C@H](N2CCCC2=O)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Trans-4-(2-oxopyrrolidin-1-yl)cyclohexane-carboxylic acid (40 mg) obtained in Reference Example 2 is dissolved in chloroform (3 ml), and thereto are added thionyl chloride (15 μl) and N,N-dimethylformamide (1 drop) followed by stirring at room temperature for 15 hours. To the reaction solution are added 3-amino-N-(5-chloropyridin-2-yl)-2-naphthamide (31 mg) obtained in Example 34(1) and pyridine (1 ml), and the mixture is stirred at room temperature for 12 hours. After adding trans-4-(2-oxopyrrolidin-1-yl)cyclohexanecarboxylic acid (43 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (42 mg) and 4-(dimethylamino)pyridine (56 mg), the mixture is stirred at room temperature for another 12 hours. To the reaction solution is poured saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with chloroform. The extract is dried over sodium sulfate and evaporated to remove the solvent under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1, then 1/4) to give title compound (36 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([O:10][CH:11](O)[C:12]([F:15])([F:14])[F:13])[CH3:9]>C(O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:8]([O:10][CH:11]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:12]([F:15])([F:14])[F:13])[CH3:9]
Reactant: CCOC(O)C(F)(F)F
Reactant: Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: CCOC(Nc1ccccc1)C(F)(F)F
Yield: 86.7 %

Procedure:
A solution of aniline (2 mL, 21.9 mmol), trifluoroacetaldehyde ethyl hemiacetal (2.6 mL, 21.9 mmol) and p-toluenesulfonic acid monohydrate (220 mg, 1.16 mmol) in ethanol (25 mL) was heated to reflux for 3 h under continuous stirring. The reaction mixture was cooled, the solvent was removed under reduced pressure and the residue was dissolved in EtOAc. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to afford title compound 325 (4.16 g, crude) as a yellow oil which was used directly for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([N+:23]([O-])=O)[CH:20]=[CH:19][C:3]=1[C:4]([N:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[N:14][NH:15][C:9]=2[C:8]2[S:16][CH:17]=[CH:18][C:7]1=2)=[O:5].[Sn](Cl)Cl>C(O)C>[Cl:1][C:2]1[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:3]=1[C:4]([N:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[N:14][NH:15][C:9]=2[C:8]2[S:16][CH:17]=[CH:18][C:7]1=2)=[O:5]
Reactant: O=C(c1ccc([N+](=O)[O-])cc1Cl)N1CCc2cn[nH]c2-c2sccc21
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1ccc(C(=O)N2CCc3cn[nH]c3-c3sccc32)c(Cl)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 93.6 %

Procedure:
A mixture of 1.8 g of 6-(2-chloro-4-nitro-benzoyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]thieno[3,2-b]-azepine in 35 ml of absolute ethanol is added 5.42 g of tin (II) chloride followed by heating at reflux for 1 hour at 80° C. The volatiles are evaporated in vacuo to a residue which is partitioned between 150 ml of ethyl acetate and saturated aqueous NaHC3 the reactants are stirred at room temperature for 1 hour and filtered. The organic layer is separated and washed with 30 ml of brine, dried (Na2SO4) and filtered through a pad of hydrous magnesium silicate. The filtrate is evaporated in vacuo to give 1.55 g of a yellow-orange foam.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]2[CH:12]=[C:11]([N:13]([CH3:15])[CH3:14])[S:10][C:9]=2[CH:16]=1)[CH:2]=[CH2:3].[CH3:17][N:18]([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][C:22]=1[O:30][CH3:31])[CH3:19]>>[CH3:19][N:18]([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([C:12]2[C:8]3[CH:7]=[CH:6][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[CH:16][C:9]=3[S:10][C:11]=2[N:13]([CH3:14])[CH3:15])=[O:26])=[CH:23][C:22]=1[O:30][CH3:31])[CH3:17]
Reactant: C=CCOc1ccc2cc(N(C)C)sc2c1
Reactant: COc1cc(C(=O)O)ccc1CN(C)C
Product: C=CCOc1ccc2c(C(=O)c3ccc(CN(C)C)c(OC)c3)c(N(C)C)sc2c1
Yield: 73 %

Procedure:
The title compound was prepared in 73% yield (23% SM recovered) by essentially following the procedures outlined in Example 84, Part A from 6-allyloxy-2-(dimethylamino)benzo[b]thiophene (Part B) and 4-(dimethylamino)methyl-3-methoxybenzoic acid (Part D).
Reaction SMILES: [CH:1]([N:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:5][CH2:6]O)([CH3:3])[CH3:2].O=S(Cl)[Cl:16]>C(Cl)Cl>[Cl:16][CH2:6][CH2:5][N:4]([CH:1]([CH3:3])[CH3:2])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)N(CCO)c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)N(CCCl)c1ccccc1
Temperature: 25 °C
Yield: 31.9 %

Procedure:
In a mixture of compound 4b (483 mg, 2.7 mmol) and CH2Cl2 (50 mL), SOCl2 (0.24 ml, 3.2 mmol) was added dropwise over 20 min. After the addition was complete, the mixture was heated to reflux for one hour. After cooling to room temperature, the mixture was quenched carefully with cold, saturated aqueous K2CO3 (100 mL). The mixture was then extracted with CH2Cl2, and the combined organic layer was washed with saturated aqueous K2CO3, washed with brine, and dried over Na2SO4. The solvent was evaporated and the residue was purified by silica gel column chromatography with hexane/EtOAc (8/1) to provide the intermediate 4c (170 mg, 0.86 mmol, 31.8% yield) as a yellow brown oil. 1H NMR (400 MHz, CDCl3) δ 7.35-7.26 (m, 2H), 6.86-6.76 (m, 3H), 4.19-4.04 (hept, J=6.5 Hz, 1H), 3.65-3.50 (td, J=12.6, 7.3 Hz, 4H), 1.29-1.22 (d, J=6.6 Hz, 6H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:22]=[N:23][C:24](Cl)=[CH:25][CH:26]=3)[O:18][C:19]=2[CH3:20])=[CH:8][C:7]=1[CH3:28].[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3](=[O:29])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:22]=[N:23][C:24]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:25][CH:26]=3)[O:18][C:19]=2[CH3:20])=[CH:8][C:7]=1[CH3:28]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)CCc1ccc(OCCc2nc(-c3ccc(Cl)nc3)oc2C)cc1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)CCc1ccc(OCCc2nc(-c3ccc(-c4ccccc4)nc3)oc2C)cc1C
Temperature: 90 °C
Reaction time: 12 h
Yield: 98.6 %

Procedure:
A mixture of 3-(4-{2-[2-(6-Chloro-pyridin-3-yl)-5-methyl-oxazol-4-yl]-ethoxy}-2-methyl-phenyl)-propionic acid methyl ester (41 mg, 0.1 mmol) and phenyl boronic acid (25 mg, 0.2 mmol) and Na2CO3 (22 mg, 0.2 mmol) in toluene (0.5 mL) and water (0.1 mL) is degassed and filled with nitrogen for three times, then Pd(PPh3)4 (3 mg) is added under nitrogen. The reaction mixture is heated at 90° C. After 12 hrs, the reaction mixture is cooled to room temperature, diluted with ethyl acetate, washed with water, dried, concentrated. Column chromatography on silica gel (Hexane/ethyl acetate as eluent) gave 45 mg of product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.Br[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[N:47]=[C:46]([CH3:48])[O:45][N:44]=2)=[CH:38][C:37]=1[CH3:49].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:36]5[C:37]([CH3:49])=[CH:38][C:39]([C:43]6[N:47]=[C:46]([CH3:48])[O:45][N:44]=6)=[CH:40][C:41]=5[CH3:42])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: Cc1nc(-c2cc(C)c(Br)c(C)c2)no1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6noc(C)n6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 3-(4-bromo-3,5-dimethyl-phenyl)-5-methyl-[1,2,4]oxadiazole following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 11): tR=1.28 min; Mass spectrum (ESI+): m/z=551 [M+Na]+.
Reaction SMILES: [OH:1][C:2]([CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)([C:10]([OH:12])=[O:11])[CH2:3][C:4](=[N:8][OH:9])[C:5]([OH:7])=[O:6].Cl.C(=O)([O-])[O-].[Na+].[Na+].[C:30]1([C@H:36]([NH2:38])[CH3:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O.C(OCC)(=O)C>[C:30]1([C@H:36]([NH2:38])[CH3:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[OH:1][C@:2]([CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)([C:10]([OH:12])=[O:11])[CH2:3][C:4](=[N:8][OH:9])[C:5]([OH:7])=[O:6]
Reactant: O=C(O)C(CC(O)(Cc1c[nH]c2ccccc12)C(=O)O)=NO
Agent: C[C@@H](N)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)C(C[C@@](O)(Cc1c[nH]c2ccccc12)C(=O)O)=NO
Yield: 72.7 %

Procedure:
Ammonium salt (44.7 g, 0.131 mol) of 4-hydroxy-4-(3-indolylmethyl)-2-hydroxyiminoglutaric acid was dissolved in 500 mL of water at 25° C., and subsequently the pH value of the aqueous solution was adjusted to 2 with 25.5 g of 36% hydrochloric acid. The acidic solution was subject to extraction with 1300 mL of ethyl acetate, and the ethyl acetate solution was washed with 200 mL of saturated aqueous NaCl solution. An aqueous solution (500 mL) of sodium carbonate (13.9 g, 0.131 mol) was added to the resulting ethyl acetate solution, and stirred to separate an alkali aqueous solution from ethyl acetate. The pH value of the resulting alkali aqueous solution was adjusted to 2 by adding 23.1 g of 36% hydrochloric acid. (R)-(+)-1-Phenylethylamine (6.99 g, 57.6 mmol) was dripped into the resulting acidic aqueous solution, and stirred at 25° C. for one hour. The yielded crystal was filtered, and dried under reduced pressure to yield 21.8 g (47.8 mmol) of (R)-(+)-1-phenylethylamine salt of (4S)-4-hydroxy-4-(3-indolylmethyl)-2-hydroxyiminoglutaric acid (yield: 72.7%, optical purity: 87.4%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:20])=[C:4]([CH:13]2[CH2:18][NH:17][C:16](=[O:19])[CH2:15][O:14]2)[C:5]([O:11][CH3:12])=[C:6]([CH:8](Cl)[CH3:9])[CH:7]=1.[CH3:21][C:22]1[C:30]2[C:25](=[N:26][CH:27]=[N:28][C:29]=2[NH2:31])[NH:24][N:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>CN(C)C=O.CCOCC>[NH2:31][C:29]1[N:28]=[CH:27][N:26]=[C:25]2[N:24]([CH:8]([C:6]3[C:5]([O:11][CH3:12])=[C:4]([CH:13]4[CH2:18][NH:17][C:16](=[O:19])[CH2:15][O:14]4)[C:3]([CH3:20])=[C:2]([Cl:1])[CH:7]=3)[CH3:9])[N:23]=[C:22]([CH3:21])[C:30]=12
Reactant: Cc1n[nH]c2ncnc(N)c12
Reactant: COc1c(C(C)Cl)cc(Cl)c(C)c1C1CNC(=O)CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CNC(=O)CO1
Temperature: 140 °C

Procedure:
A mix of 6-[3-chloro-5-(1-chloroethyl)-6-methoxy-2-methylphenyl]morpholin-3-one (19.0 mg, 0.0597 mmol) (racemic mixture of two diastereomers from step 6) 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (11 mg, 0.072 mmol), cesium carbonate (29 mg, 0.090 mmol) and potassium iodide (0.99 mg, 0.006 mmol) in N,N-dimethylformamide (0.19 mL) was heated at 140° C. for 1 hour. The mixture was diluted with ether, washed with water, concentrated and purified by preparative LCMS (pH 10) using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give 2.5 mg, 10% of Peak 1 (single enantiomer, retention time 10.15 min): LCMS calculated for C20H24ClN6O3 (M+H)+: m/z=431.2; found: 431.1, and 2.7 mg, 10% of Peak 2 (single enantiomer, retention time 10.76 min): LCMS calculated for C20H24ClN6O3 (M+H)+: m/z=431.2; found: 431.1.
Reaction SMILES: C[O:2][P:3]([CH2:7][NH:8][S:9]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)(=[O:11])=[O:10])(=[O:6])[O:4]C.Br[Si](C)(C)C>>[S:13]1[CH:14]=[CH:15][CH:16]=[C:12]1[S:9]([NH:8][CH2:7][P:3](=[O:2])([OH:4])[OH:6])(=[O:10])=[O:11]
Reactant: COP(=O)(CNS(=O)(=O)c1cccs1)OC
Agent: C[Si](C)(C)Br
Product: O=P(O)(O)CNS(=O)(=O)c1cccs1

Procedure:
The dimethyl ester (vii) was treated with bromotrimethylsilane according to the procedure described in Example 1, step 3, to afford the title compound: 1H NMR (300 MHz, CD3OD) δH 7.79 (dd, J=4.8, 1.2 Hz, 1H), 7.64 (dd, J=3.9, 1.2 Hz, 1H), 7.17 (dd, J=4.8, 3.9 Hz, 1H), 3.16 (d, J=13.2 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([C@H:17]3[CH2:22][CH2:21][C@H:20]([CH:23]=[CH2:24])[CH2:19][CH2:18]3)[CH2:13][CH2:12]2)[CH:5]=[CH:4][C:3]=1[OH:25].[CH2:26]([C@H:28]1[CH2:33][CH2:32][C@H:31]([CH2:34]Br)[CH2:30][CH2:29]1)[CH3:27].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>COCCOC.C1(C)C=CC=CC=1>[F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][C@H:11]2[CH2:12][CH2:13][C@H:14]([C@H:17]3[CH2:22][CH2:21][C@H:20]([CH:23]=[CH2:24])[CH2:19][CH2:18]3)[CH2:15][CH2:16]2)[CH:5]=[CH:4][C:3]=1[O:25][CH2:34][C@H:31]1[CH2:32][CH2:33][C@H:28]([CH2:26][CH3:27])[CH2:29][CH2:30]1
Reactant: CC[C@H]1CC[C@H](CBr)CC1
Reactant: C=C[C@H]1CC[C@H]([C@H]2CC[C@H](COc3ccc(O)c(F)c3F)CC2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Solvent: Cc1ccccc1
Product: C=C[C@H]1CC[C@H]([C@H]2CC[C@H](COc3ccc(OC[C@H]4CC[C@H](CC)CC4)c(F)c3F)CC2)CC1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
6.5 g of 2,3-difluoro-4-(trans-4-(trans-4-vinylcyclohexyl)cyclohexyl)methoxyphenol was dissolved in 35 mL of DME, and 4.9 g of (trans-4-ethylcyclohexyl)methyl bromide and 6.4 g of tripotassium phosphate were added thereto, and then stirred for 2 hours at 80 to 100° C. Water and toluene were added thereto, and the organic layer was fractioned. The resultant product was washed with saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by recrystallization and column chromatography, to thereby obtain 3.8 g of 2,3-difluoro-1-(trans-4-ethylcyclohexyl)methoxy-4-(trans-4-(trans-4-vinylcyclohexyl)cyclohexyl)methoxybenzene (1a) in the form of colorless crystals.
Reaction SMILES: [C:1]([NH2:4])(=[S:3])[CH3:2].[CH2:5]([O:7][C:8](=[O:14])[CH2:9][C:10]([CH2:12]Cl)=O)[CH3:6]>C(O)C>[CH2:5]([O:7][C:8](=[O:14])[CH2:9][C:10]1[N:4]=[C:1]([CH3:2])[S:3][CH:12]=1)[CH3:6]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: CC(N)=S
Solvent: CCO
Product: CCOC(=O)Cc1csc(C)n1
Yield: 75.2 %

Procedure:
Prepare a solution of thioacetamide (10 g, 133 mmol) in ethanol (75 mL). Add ethyl-4-chloroacetoacetate (16.5 mL, 122 mmol). Stir the reaction overnight at 50° C. and then concentrate in vacuo. Dissolve the resulting oil in water (75 mL) and extract with diethyl ether (3×50 mL). Extract the aqueous layer with CHCl3 (3×50 mL). Wash the combined organic layers with brine (50 mL), dry (Na2SO4), filter, and concentrate in vacuo to afford (2-methylthiazol-4-yl)acetic acid ethyl ester (17 g) as a solid. 1H NMR (CDCl3) δ 7.02 (s, 1H), 4.15-4.25 (m, 2H), 3.79 (s, 2H), 2.71 (s, 3H), 1.25 (t, J=7 Hz, 3H).