Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.[CH3:5][O:6][P:7]([CH2:27][NH2:28])([CH2:9][CH:10]([C:15](=[O:26])[NH:16][C@H:17]([C:22](=[O:25])[NH:23][CH3:24])[CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8].[CH3:29][C:30]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:32]2[C:33]([O:35][C:36](=O)[C:31]=12)=[O:34]>>[CH3:5][O:6][P:7]([CH2:27][N:28]1[C:33](=[O:34])[C:32]2=[C:38]([O:41][CH3:42])[CH:39]=[CH:40][C:30]([CH3:29])=[C:31]2[C:36]1=[O:35])([CH2:9][CH:10]([C:15](=[O:26])[NH:16][C@H:17]([C:22](=[O:25])[NH:23][CH3:24])[CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8]
Reactant: COc1ccc(C)c2c1C(=O)OC2=O
Reactant: CNC(=O)[C@H](CC(C)C)NC(=O)C(CC(C)C)CP(=O)(CN)OC
Solvent: CC(=O)O
Product: CNC(=O)[C@H](CC(C)C)NC(=O)C(CC(C)C)CP(=O)(CN1C(=O)c2c(C)ccc(OC)c2C1=O)OC
Yield: 47.1 %

Procedure:
In a manner analogous to that described in Example 3(A), from 0.41 g of (aminomethyl)[(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid methyl ester acetate and 0.21 g of 3-methyl-6-methoxyphthalic anhydride there was obtained 0.245 g of [(3-methoxy-6-methylphthalimido)methyl][(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid methyl ester in the form of a white foam.
Reaction SMILES: Br[C:2]1[C:3]([CH3:21])([CH3:20])[O:4][C:5]2[C:10]([C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)=[CH:9][CH:8]=[C:7]([Cl:19])[CH:6]=2.[CH2:22]([Sn](CCCC)(CCCC)C=C)[CH2:23]CC.[F-].[K+]>O1CCOCC1.C(OCC)(=O)C.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>[Cl:19][C:7]1[CH:6]=[C:5]2[C:10]([C:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[C:2]([CH:22]=[CH2:23])[C:3]([CH3:21])([CH3:20])[O:4]2)=[CH:9][CH:8]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CC1(C)Oc2cc(Cl)ccc2C(c2ccc(F)cc2)=C1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C=CC1=C(c2ccc(F)cc2)c2ccc(Cl)cc2OC1(C)C
Temperature: 25 °C

Procedure:
A mixture of 3-bromo-7-chloro-4-(4-fluorophenyl)-2,2-dimethyl-2H-chromen (a compound obtained in Reference Example 8(1); 220 mg), tributyl(vinyl)tin (350 μL) and tetrakis(triphenylphosphine)palladium(0) (140 mg) in dioxane was heated under reflux for 23 hours. After cooling, the reaction solution was diluted with ethyl acetate, a saturated aqueous solution of potassium fluoride was added thereto, and the mixture was stirred at room temperature for an hour. The reaction solution was filtered through Celite and the filtrate was extracted with ethyl acetate. The organic layer was washed successively with water and brine, filtered through a column of porous diatomite (Chem Elut) and the filtrate was concentrated in vacuo. The resultant residue was purified by column chromatography on silica gel (Solvent: n-hexane/chloroform=100/0 to 95/5) to give the titled compound (157 mg) as a pale yellow viscous oil.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=O)[O:13][C:14](=[O:21])[C:15]=2[C:16]2[CH:20]=[CH:19][NH:18][CH:17]=2)=[CH:3]1.C[N:24](C=O)C.N>O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:13])[NH:24][C:14](=[O:21])[C:15]=2[C:16]2[CH:20]=[CH:19][NH:18][CH:17]=2)=[CH:3]1
Reactant: Cn1cc(C2=C(c3cc[nH]c3)C(=O)OC2=O)c2ccccc21
Reactant: CN(C)C=O
Agent: N
Solvent: O
Product: Cn1cc(C2=C(c3cc[nH]c3)C(=O)NC2=O)c2ccccc21
Temperature: 140 °C

Procedure:
135 mg of 3-(1-methyl-3-indolyl)-4-(3-pyrrolyl)furan-2,5-dione were treated with 5 ml of DMF and 5 ml of 33% aqueous ammonia. The solution was heated at 140° C. for 4 hours. The cooled solution was diluted with water and extracted with dichloromethane. The dichloromethane extracts were dried and concentrated. Chromatography of the residue on silica gel with ethyl acetate/hexane (1:1) followed by crystallization from ethyl acetate/hexane gave 50 mg of 3-(1-methyl-3-indolyl)-4-(3-pyrrolyl)-1H-pyrrole-2,5-dione, m.p. 240°-241° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:14]([F:27])[CH:13]=1)=[O:11].[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH:36]=[C:35]([Sn](C)(C)C)[CH2:34][CH2:33]2>>[F:27][C:14]1[CH:13]=[C:12]([C:10]([C:3]2[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=2[C:35]2[CH2:34][CH2:33][C:32]3[C:37](=[CH:38][CH:39]=[C:30]([O:29][CH3:28])[CH:31]=3)[CH:36]=2)=[O:11])[CH:17]=[CH:16][C:15]=1[O:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: COc1ccc(C(=O)c2ccc(OCCN3CCCCC3)c(F)c2)c(Br)c1
Reactant: COc1ccc2c(c1)CCC([Sn](C)(C)C)=C2
Product: COc1ccc2c(c1)CCC(c1cc(OC)ccc1C(=O)c1ccc(OCCN3CCCCC3)c(F)c1)=C2
Yield: 59.4 %

Procedure:
Synthesized from (2-bromo-4-methoxyphenyl)[3-fluoro-4-(2-piperidin-1-ylethoxy)phenyl]methanone (420 mg) and (6-methoxy-3,4-dihydronaphthalen-2-yl)trimethyltin (352 mg) according to an analogous synthetic method to Example 1, the title compound (295 mg) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[C:5]([O:7][CH2:8][CH2:9][CH2:10][Cl:11])=[O:6].[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].N1C=CN=C1>CN(C=O)C.O>[Si:15]([O:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[C:5]([O:7][CH2:8][CH2:9][CH2:10][Cl:11])=[O:6])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: O=C(OCCCCl)c1cccc(O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C(=O)OCCCCl)c1
Reaction time: 1 h
Yield: 92 %

Procedure:
To a solution of 3-chloropropyl 3-hydroxybenzoate (12.0 g, 0.055 mol) and tert-butyldimethylsilyl chloride (TBDMS-Cl, 10.00 g, 0.067 mol) in anhydrous DMF (10 mL) was added imidazole (7.61 g, 0.11 mol). The reaction mixture was stirred for 1 hour after which it was diluted with water (50 mL) and extracted with hexane (4×20 mL). The hexane layer was washed with water (2×10 mL) and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the desired compound (16.64 g, 0.0506 mol, 90%): 1H NMR (CDCl3) δ0.216 (s, 6H), 0.994 (s, 9H), 2.19-2.27 (m, 2H), 3.69 (t, 2H, J=6.3 Hz), 4.46 (t, 2H, J=6.3 Hz), 7.01-7.64 (m, 4H); MS exact mass; calcd. 328.1264, found 328.1257.
Reaction SMILES: [OH:1][CH:2]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.[H-].[Na+].[C:20]([NH:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1)(=[O:22])[CH3:21].O>O1CCCC1>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][CH2:9][CH:2]([O:1][CH2:28][C:27]2[CH:26]=[CH:25][C:24]([NH:23][C:20](=[O:22])[CH3:21])=[CH:31][CH:30]=2)[CH2:3][N:4]2[CH:8]=[CH:7][N:6]=[CH:5]2)=[CH:16][CH:15]=1
Reactant: OC(CCc1ccc(Cl)cc1)Cn1ccnc1
Reactant: CC(=O)Nc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Nc1ccc(COC(CCc2ccc(Cl)cc2)Cn2ccnc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1.25 g of 1-[2-hydroxy-4-(4-chlorophenyl)-n-butyl]imidazole and 0.26 g of sodium hydride (50% dispersion in mineral oil) in 20 ml of tetrahydrofuran was stirred under nitrogen at room temperature for one hour, and at 60° C. for one hour. The mixture was then cooled to 0° C. and treated dropwise with stirring with 4-acetylaminobenzyl chloride in 10 ml tetrahydrofuran, keeping the temperature below 10° C. After stirring for one hour, the mixture was heated to 60° C. for 2 hours and poured into water. The product was extracted with ethyl acetate and the extracts dried (MgSO4) and evaporated. The residue was chromatographed on silica gel eluting with 2% water in ethyl acetate to give 1-[4-(4-chlorophenyl)-2-(4-acetylaminobenzyloxy)-n-butyl]imidazole.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]1[O:17][C:16]2[CH:15]=[CH:14][C:13]([CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:12][C:11]=2[O:10]1>C(Cl)(Cl)(Cl)Cl>[Br:1][CH:18]([C:13]1[CH:14]=[CH:15][C:16]2[O:17][CH2:9][O:10][C:11]=2[CH:12]=1)[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)Cc1ccc2c(c1)OCO2
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)c1ccc2c(c1)OCO2

Procedure:
N-Bromosuccinimide (3.95 g, 22.2 mmol) and AlBN (0.098 g, 0.06 mMol) were added to a solution of methyl (3,4-methylenedioxyphenyl)acetate (3.9 g, 21.2 mmol) in carbon tetrachloride and the mixture was refluxed for 2.5 h. The reaction was cooled and filtered. The flitrate was concentrated in vacuo and the residue obtained was purified by flash chromatography on silica-gel using 10% ethyl acetate-hexane. Yield 2.6 g (oil).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]2[CH2:17][CH2:16][C@@H:15]([NH:18][CH3:19])[C@H:14]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:13]2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:28][C:29]1[S:33][C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[N:31][C:30]=1[C:40]([OH:42])=O>>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([C:10]([N:12]2[CH2:17][CH2:16][C@@H:15]([N:18]([CH3:19])[C:40]([C:30]3[N:31]=[C:32]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[S:33][C:29]=3[CH3:28])=[O:42])[C@H:14]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:13]2)=[O:11])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: Cc1sc(-c2ccccc2)nc1C(=O)O
Reactant: CN[C@@H]1CCN(C(=O)C2CCN(C(C)=O)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Product: CC(=O)N1CCC(C(=O)N2CC[C@@H](N(C)C(=O)c3nc(-c4ccccc4)sc3C)[C@H](c3ccc(Cl)c(Cl)c3)C2)CC1

Procedure:
Using the compound obtained in Example 78 and 5-methyl-2-phenyl-1,3-thiazole-4-carboxylic acid, and by the reaction and purification in the same manner as in Example 3, the title compound was obtained.
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[CH:9][N:10]=[CH:11][C:6]2=[N:5][CH:4]=1)#[CH:2].[N:12]1([C:17]2[CH:18]=[C:19]([NH:27][C:28](=[O:37])[C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[C:31](I)[CH:30]=3)[CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=2)[CH:16]=[CH:15][N:14]=[CH:13]1.C(N(C(C)C)CC)(C)C>CN(C=O)C.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:12]1([C:17]2[CH:18]=[C:19]([NH:27][C:28](=[O:37])[C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[C:31]([C:2]#[C:1][C:3]4[N:7]5[CH:8]=[CH:9][N:10]=[CH:11][C:6]5=[N:5][CH:4]=4)[CH:30]=3)[CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: Cc1ccc(C(=O)Nc2cc(-n3ccnc3)cc(C(F)(F)F)c2)cc1I
Reactant: C#Cc1cnc2cnccn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)Nc2cc(-n3ccnc3)cc(C(F)(F)F)c2)cc1C#Cc1cnc2cnccn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.6 %

Procedure:
A mixture of 3-Ethynylimidazo[1,2-a]pyrazine (0.075 g, 0.52 mmol), 0.245 g (0.52 mmol) of N-(3-(1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-iodo-4-methylbenzamide, 0.030 g (0.026 mmol) of Pd(PPh3)4, 0.007 g (0.039 mmol) of Cul, and 0.14 mL (0.78 mmol) of diisopropylethylamine in 3.0 mL of DMF was stirred at ambient temperature overnight under an atmosphere of N2. The reaction mixture was concentrated and the crude product was purified by silica gel flash chromatography (eluted with 10% EtOAc/hexanes, then 100% EtOAc, then 10% MeOH/EtOAc) to provide 0.090 g of product as a solid: 487 m/z (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](/[CH:14]=[CH:15]/[C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24]([NH:26][C@H:27]([C:32]#[CH:33])[CH2:28][C:29]([OH:31])=[O:30])=[O:25])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].I[CH2:41][O:42][C:43](=[O:48])[C:44]([CH3:47])([CH3:46])[CH3:45].O>CN(C)C=O>[C:43]([O:42][CH2:41][O:30][C:29](=[O:31])[CH2:28][C@@H:27]([C:32]#[CH:33])[NH:26][C:24]([C@@H:20]1[CH2:21][CH2:22][CH2:23][N:18]([C:16](=[O:17])/[CH:15]=[CH:14]/[CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:13][CH2:12]2)[CH2:19]1)=[O:25])(=[O:48])[C:44]([CH3:47])([CH3:46])[CH3:45]
Reactant: C#C[C@H](CC(=O)O)NC(=O)[C@@H]1CCCN(C(=O)/C=C/C2CCN(C(=O)OC(C)(C)C)CC2)C1
Reactant: CC(C)(C)C(=O)OCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#C[C@H](CC(=O)OCOC(=O)C(C)(C)C)NC(=O)[C@@H]1CCCN(C(=O)/C=C/C2CCN(C(=O)OC(C)(C)C)CC2)C1
Temperature: 0 °C
Yield: 59.3 %

Procedure:
To a solution of N-[(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)-(E)-acryloyl]-3-piperidylcarbonyl]-3(S)-ethynyl-β-alanine (0.5 g) in dimethylformamide (5 ml) was added K2CO3 (75 mg) under stirring at 0° C., stirred for 15 minutes, and pivalic acid iodomethyl ester (0.61 g) in dimethylformamide (3 ml) was added to the mixture. After stirring at room temperature for 1 hour, the mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and brine, dried over MgSO41 and evaporated in vacuo, subsequently. The residue was purified by column chromatography on silica gel eluting with CHCl3:MeOH=(98:2) to give N-[(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)-(E)-acryloyl]-3-piperidylcarbonyl]-3(S)-ethynyl-β-alanine pivaloyloxymethyl ester as a colorless oil (0.37 g, 59.3%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][C:15](=[O:18])[N:14]([C@H:19]([C:30]([O:32][CH3:33])=[O:31])[CH2:20][CH2:21][O:22]CC2C=CC=CC=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.B(Cl)(Cl)Cl>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][C:15](=[O:18])[N:14]([C@H:19]([C:30]([O:32][CH3:33])=[O:31])[CH2:20][CH2:21][OH:22])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](CCOCc1ccccc1)N1CCN(C(=O)OCc2ccccc2)CCC1=O
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](CCO)N1CCN(C(=O)OCc2ccccc2)CCC1=O
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 74.3 %

Procedure:
A solution of 0.50 g (1.10 mmol) of 4-((S)-3-benzyloxy-1-methoxycarbonyl-propyl)-5-oxo-[1,4]diazepane-1-carboxylic acid benzyl ester (evaporated twice with toluene) in 9 ml dichloromethane was treated with 1.10 ml (1.10 mmol, 1 M in dichloromethane) of boron trichloride. The solution was stirred 6.5 h at room temperature, cooled (0° C.) and treated with 0.99 ml (0.90 mmol, 1 M in dichloromethane) of boron trichloride, after 15 h at room temperature, additional 0.28 ml (0.28 mmol, 1 M in dichloromethane) of boron trichloride were added to the cooled (0° C.) reaction. After 24 h at room temperature, the mixture was extracted with cold sat. aq. sodium hydrogencarbonate solution and ethyl acetate (3×). The organic phases were washed with sat. aq. sodium hydrogencarbonate solution, 10% aq. sodium chloride solution, dried over Na2SO4 evaporated to give 0.298 g (75%) of the title compound as light yellow oil. MS: 365.0 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]1[CH2:26][CH2:25][C:16]2([O:20][C@H:19]([CH2:21][OH:22])[C@@H:18]([CH2:23][OH:24])[O:17]2)[CH:15]=[C:14]1[C:27]([O:29][CH2:30][CH3:31])=[O:28])(=[O:12])=[O:11].CI.[C:34](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:30]([O:29][C:27]([C:14]1[CH:13]([S:10](=[O:12])(=[O:11])[N:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[Cl:1])[CH3:34])[CH2:26][CH2:25][C:16]2([O:17][C@H:18]([CH2:23][OH:24])[C@@H:19]([CH2:21][OH:22])[O:20]2)[CH:15]=1)=[O:28])[CH3:31]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C1=CC2(CCC1S(=O)(=O)Nc1ccc(F)cc1Cl)O[C@H](CO)[C@@H](CO)O2
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CCOC(=O)C1=CC2(CCC1S(=O)(=O)N(C)c1ccc(F)cc1Cl)O[C@H](CO)[C@@H](CO)O2
Temperature: 50 °C
Reaction time: 3 h
Yield: 72.3 %

Procedure:
235 mg (0.49 mmol) of ethyl (2R,3R)-8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 17 was dissolved in 1.5 ml of acetone, and 84 mg (0.59 mmol) of methyl iodide and 138 mg (1.00 mmol) of potassium carbonate were added sequentially, followed by stirring for 3 hours at 50° C. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent; hexane ethyl acetate=1:3) to give 175 mg of the title compound as a white amorphous substance (yield: 73%).
Reaction SMILES: [CH2:1]([Mg]Cl)[CH2:2][CH3:3].Cl[SiH:7]1[CH2:12][CH2:11][CH:10]([C@H:13]2[CH2:18][CH2:17][C@H:16]([O:19][CH3:20])[CH2:15][CH2:14]2)[CH2:9][CH2:8]1>O1CCCC1>[CH3:20][O:19][CH:16]1[CH2:17][CH2:18][CH:13]([C@H:10]2[CH2:11][CH2:12][Si@H:7]([CH2:1][CH2:2][CH3:3])[CH2:8][CH2:9]2)[CH2:14][CH2:15]1
Reactant: CO[C@H]1CC[C@H](C2CC[SiH](Cl)CC2)CC1
Reactant: CCC[Mg]Cl
Solvent: C1CCOC1
Product: CCC[Si@H]1CC[C@H](C2CCC(OC)CC2)CC1

Procedure:
100 ml of a tetrahydrofuran solution of 1.0M n-propyl magnesium chloride was dripped into a mixture of 23.0 g (93.2 mmol) of 1-chloro-4-(trans-4-methoxycyclohexyl)-1-silacyclohexane and 100 ml of tetrahydrofuran. After a conventional after treatment, the product thus obtained was purified by means of silica-gel column chromatography to obtain 17.1 g (yield 72%) of the trans, trans isomer.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH2:48][C:49]1[CH:50]=[CH:51][C:52]2[C:56]([CH3:58])([CH3:57])[O:55][B:54]([OH:59])[C:53]=2[CH:60]=1>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH:48][C:49]1[CH:50]=[CH:51][C:52]2[C:56]([CH3:57])([CH3:58])[O:55][B:54]([OH:59])[C:53]=2[CH:60]=1)=[O:6]
Reactant: CC1(C)OB(O)c2cc(N)ccc21
Reactant: CC(C)c1ccc(C(=O)O)c(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1ccc(C(=O)Nc2ccc3c(c2)B(O)OC3(C)C)c(Cl)c1

Procedure:
To a solution of 2-chloro-4-isopropyl-benzoic acid (63 mg, 0.33 mmol) in DMF (4 mL) was added HATU (90 mg, 0.23 mmol) and DIEA (43 mg, 0.33 mmol). After 1 hour 6-amino-3,3-dimethyl-3H-benzo[c][1,2]oxaborol-1-ol hydrochloride salt (50 mg, 0.22 mmol) was added. After 12 hours the reaction was concentrated down under reduced pressure onto celite. The crude material was subjected to flash chromatography (Isco Companion, 4 g SiO2 cartridge, SiO2 solid load, neat DCM to 10% MeOH gradient) to give 2-Chloro-N-(1-hydroxy-3,3-dimethyl-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-isopropyl-benzamide as a white powder. Amount obtained: 6.3 mg (8%). Data: LCMS (M/Z): 358 (M+H); 1H NMR (DMSO-d6) δ: 1.23 (d, J=6.8 Hz, 6 H) 1.44 (s, 6 H) 2.97 (dt, J=13.8, 6.9 Hz, 1 H) 7.29-7.41 (m, 2H) 7.43 (d, J=1.4 Hz, 1 H) 7.49 (d, J=7.8 Hz, 1 H) 7.68 (dd, J=8.3, 1.9 Hz, 1 H) 8.05 (dd, J=1.7, 0.5 Hz, 1 H) 9.08 (br. s, 1 H) 10.45 (s, 1 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:24]3[C:19]([CH:20]=[CH:21][CH:22]=[CH:23]3)=[C:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]=2[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=2[CH3:39])=[O:15])[CH2:10][C@@H:9]1[CH2:40][C:41](O)=[O:42])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:44][CH2:45][C:46]([CH3:51])([CH3:50])[C:47]([NH2:49])=[O:48].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CC(=O)OCC>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:24]3[C:19]([CH:20]=[CH:21][CH:22]=[CH:23]3)=[C:18]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:17]=2[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=2[CH3:39])=[O:15])[CH2:10][C@@H:9]1[CH2:40][C:41](=[O:42])[NH:44][CH2:45][C:46]([C:47](=[O:48])[NH2:49])([CH3:51])[CH3:50])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1c(F)cccc1Cc1c(-c2ccccc2)c2ccccn2c1C(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](CC(=O)O)C1
Reactant: CC(C)(CN)C(N)=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1c(F)cccc1Cc1c(-c2ccccc2)c2ccccn2c1C(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](CC(=O)NCC(C)(C)C(N)=O)C1
Temperature: 25 °C
Reaction time: 60 h
Yield: 91.6 %

Procedure:
The compound of step 5 (0.176 g, 0.30 mmol) was dissolved in 2.5 ml of anhydrous DCM at 0° C. 3-Amino-2,2-dimethyl-propionamide (0.044 g, 0.38 mmol), EDIA (0.13 ml, 0.75 mmol) and TBTU (0.120 g, 0.38 mmol) were added and the solution was stirred at room temperature for 60 h. EA (15 ml) was then added and the solution was washed with water, 1 N hydrochloric acid, a saturated solution of sodium hydrogencarbonate and brine. The organic phase was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by chromatography on silica gel (EA/MOH, 100:0, then 97:5, then 95:5) to give 0.188 g of the title compound as a greenish-brown wax.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[CH:10]([O:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[FH:14].F.F.C(N(CC)CC)C.C([O-])([O-])=O.[Na+].[Na+]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([OH:11])[C@H:10]([F:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC2OC2C1
Reactant: F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](F)C1
Temperature: 90 °C

Procedure:
A mixture of 6-oxa-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (5.4 mmol, from Example 316) and triethylamine trihydrofluoride (5.4 mmol) was heated at 90° C. for 2 h, then cooled to rt. Aq. Na2CO3 was added and the mixture was extracted with EtOAc. The organic phase was dried (Na2SO4), concentrated and purified by silica gel chromatography (0-40% EtOAc in heptane) to afford (trans)-3-fluoro-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester as a colorless oil.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[CH3:32][C:33]1[S:34][C:35]2[CH:41]=[C:40]([S:42](Cl)(=[O:44])=[O:43])[CH:39]=[CH:38][C:36]=2[N:37]=1.N1C=CC=CC=1>ClCCl>[F:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH:8][S:42]([C:40]1[CH:39]=[CH:38][C:36]2[N:37]=[C:33]([CH3:32])[S:34][C:35]=2[CH:41]=1)(=[O:43])=[O:44]
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Reactant: Cc1nc2ccc(S(=O)(=O)Cl)cc2s1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1nc2ccc(S(=O)(=O)Nc3ccc(F)c(Nc4ncccc4-c4ncnc5c4ncn5C4CCCCO4)c3F)cc2s1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. 2-methylbenzo[d]thiazole-6-sulfonyl chloride (17 mg, 0.07 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that the target compound was obtained.
Reaction SMILES: CS([C:5]1[N:17]=[C:8]2[N:9]=[C:10]([CH2:15][CH3:16])[CH:11]=[C:12]([CH2:13][CH3:14])[N:7]2[N:6]=1)(=O)=O.[Cl:18][C:19]1[CH:28]=[CH:27][C:22]([O:23][CH2:24][CH2:25][OH:26])=[CH:21][CH:20]=1>>[CH2:15]([C:10]1[CH:11]=[C:12]([CH2:13][CH3:14])[N:7]2[N:6]=[C:5]([O:26][CH2:25][CH2:24][O:23][C:22]3[CH:27]=[CH:28][C:19]([Cl:18])=[CH:20][CH:21]=3)[N:17]=[C:8]2[N:9]=1)[CH3:16]
Reactant: CCc1cc(CC)n2nc(S(C)(=O)=O)nc2n1
Reactant: OCCOc1ccc(Cl)cc1
Product: CCc1cc(CC)n2nc(OCCOc3ccc(Cl)cc3)nc2n1
Yield: 80 %

Procedure:
The title compound was prepared according to the experimentals described for Example 14 above from 2-methanesulfonyl-5,7-diethyl-[1,2,4]triazolo[1,5-a]pyrimidine and 2-(4-chlorophenoxy)ethan-1-ol in 80% yield. EM (calc.): 346.1; MS (ESI) m/e: 347.3 (M+H)+.