Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10](O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(S(F)(F)[F:20])CC>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([F:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: CCN(CC)S(F)(F)F
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(F)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A −70° C. solution of (R)-(−)-3-Hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (5 g, 26.7 mmol) in anhydrous EtOAc (250 mL) was treated dropwise with DAST (4.6 mL, 1.3 equiv.) and stirred for 1.5 h. The reaction was allowed to warm to room temperature over a period of 3 h. The reaction mixture was poured into ice cold saturated aqueous sodium bicarbonate solution (300 mL). The EtOAc layer was separated and washed with additional saturated aqueous sodium bicarbonate solution (2×300 mL) and then with brine (300 mL). The organics were dried over anhydrous Na2SO4, filtered and evaporated in vacuo. The crude residue was purified by silica gel chromatography (Hexanes to 1:9 EtOAc:Hexanes, gradient eluant) to yield 3-Fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester as an oil (1.7 g).
Reaction SMILES: C[Al](C)C.[F:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH2:9][NH2:10].C([O:16][C:17]([C:19]1[C:20]([S:34][CH2:35][CH3:36])=[N:21][C:22]2[C:27]([C:28]=1[OH:29])=[CH:26][CH:25]=[C:24]([C:30]([F:33])([F:32])[F:31])[CH:23]=2)=O)C.CCCCCC>C1(C)C=CC=CC=1.O>[CH2:35]([S:34][C:20]1[C:19]([C:17]([NH:10][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[C:6]([F:5])[CH:7]=2)=[O:16])=[C:28]([OH:29])[C:27]2[C:22](=[CH:23][C:24]([C:30]([F:33])([F:31])[F:32])=[CH:25][CH:26]=2)[N:21]=1)[CH3:36]
Reactant: NCc1cccc(F)c1
Reactant: CCOC(=O)c1c(SCC)nc2cc(C(F)(F)F)ccc2c1O
Agent: C[Al](C)C
Solvent: O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCSc1nc2cc(C(F)(F)F)ccc2c(O)c1C(=O)NCc1cccc(F)c1
Temperature: 80 °C
Yield: 72.4 %

Procedure:
5.8 ml (11.6 mmol, 2M in toluene)trimethyl aluminium and 1.5 g (11.6 mmol) 3-fluorobenzylamine were added in succession to a solution of 1.0 g (2.9 mmol) 2-(ethylthio)-4-hydroxy-7-(trifluoromethyl)quinoline-3-carboxylic acid ethyl ester in toluene (18 ml) and the mixture was then heated for 2 h at 80° C. Then it was diluted with water and extracted with EE. The organic phase was washed with 1M hydrochloric acid, water and brine, dried over Na2SO4, filtered and concentrated to small volume under vacuum. Column chromatography (hexane/EE 17:3) of the residue yielded 0.9 g (2.1 mmol, 73%) 2-(ethylthio)-N-(3-fluorobenzyl)-4-hydroxy-7-(trifluoromethyl)quinoline-3-carboxamide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][C@H:8]([C:17]1[NH:18][C:19]([C:22]2[CH:27]=[CH:26][C:25](I)=[CH:24][C:23]=2[F:29])=[CH:20][N:21]=1)[C@H:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10])([CH3:4])([CH3:3])[CH3:2].O.C(O)C.C1(B(O)O)CC1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.Cl[Pd]Cl>[C:1]([O:5][C:6](=[O:30])[NH:7][C@H:8]([C:17]1[NH:18][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[F:29])=[CH:20][N:21]=1)[C@H:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](c1ccccc1)[C@H](NC(=O)OC(C)(C)C)c1ncc(-c2ccc(I)cc2F)[nH]1
Agent: Cl[Pd]Cl
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: C[C@@H](c1ccccc1)[C@H](NC(=O)OC(C)(C)C)c1ncc(-c2ccccc2F)[nH]1
Yield: 107.1 %

Procedure:
To a degassed mixture of {(1S,2S)-1-[5-(2-fluoro-4-iodo-phenyl)-1H-imidazol-2-yl]-2-phenyl-propyl}-carbamic acid tert-butyl ester (150 mg, 0.288 mmol) in toluene (5 mL) and 1:1 v/v deionized water/ethanol (2 mL) were added dichlorobis(tricyclohexylphosphine)palladium(II) (6.4 mg, 0.009 mmol), cyclopropylboronic acid (27 mg, 0.314 mmol), potassium carbonate (159 mg, 1.15 mmol) and the mixture refluxed for 3 hours under an atmosphere of nitrogen. The mixture was diluted with ethyl acetate (50 mL) and washed with water (50 mL). The aqueous layer was washed with ethyl acetate (50 mL) and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by chromatography over silica gel gradient eluted between 0 and 40% v/v ethyl acetate in hexanes to give {(1S,2S)-1-[5-(2-fluoro-phenyl)-1H-imidazol-2-yl]-2-phenyl-propyl}-carbamic acid tert-butyl ester (122 mg, 107%) which was then used in step 17-G. HR-MS: calcd for C29H27FN4O4 [M+H+] 515.2089. Found 515.2089.
Reaction SMILES: C[Si](C)(C)CCOC[N:7](COCC[Si](C)(C)C)[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([O:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:30][CH:29]=2)[C:9]=1[Br:39].C(O)(C(F)(F)F)=O.O>>[NH2:7][C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([O:27][C:28]2[CH:29]=[CH:30][C:31]([CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:32][CH:33]=2)[C:9]=1[Br:39]
Reactant: COC(=O)Cc1ccc(Oc2nc3c(-c4cnc5ccccc5c4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)cc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Cc1ccc(Oc2nc3c(-c4cnc5ccccc5c4)cnn3c(N)c2Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The crude methyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yloxy)phenyl)acetate from above step D was treated with 50% TFA/H2O (3 mL) and stirred at room temperature for 1 h. Solvent was removed to yield thick oil, methyl 2-(4-(7-amino-6-bromo-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yloxy)phenyl)acetate, which was used in the next step directly without further purification. HPLC-MS tR=1.60 min (UV254 nm); Mass calculated for formula C24H18BrN5O3, 503.1, observed LCMS m/z 504.1 (M+Na).
Reaction SMILES: Br.CC1C=C(C)N2OC(=N)N=C2[N:4]=1.[N+]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24])([O-])=O.C(N(CC)CC)C>C(Cl)Cl>[C:18]1([S:23]([NH2:4])(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=[CH:22][CH:17]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: Cc1cc(C)n2oc(=N)nc2n1
Agent: Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NS(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of 1.6 g of 5,7-dimethyl-2H-[1,2,4]oxadiazolo[2,3-a]pyrimidine-2-imine hydrobromide and 1.4 g of o-nitrobenzenesulfonyl chloride in 60 ml of anhydrous methylene chloride at 0° C. is added a solution of 1.0 g of triethylamine in 10 ml of anhydrous methylene chloride dropwise. After addition, the mixture is stirred at 0° C. for 0.5 hour and then at ambient temperature for 2.5 hours. The mixture is then filtered. The filtrate is concentrated under reduced pressure and then column chromatographied (silica gel) to yield 2-nitro-N-[5,7-dimethyl-2H-[1,2,4)oxadiazolo(2,3-a)pyrimidin-2-ylidene]]benzenesulfonamide.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:29]>C(O)C.O1CCOCC1>[ClH:29].[ClH:29].[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([C:18]2[CH:17]=[N:16][C:15]([NH:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[N:20][CH:19]=2)=[CH:22][CH:23]=1
Reactant: COc1ccc(-c2cnc(NC3CCN(C(=O)OC(C)(C)C)CC3)nc2)cc1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: COc1ccc(-c2cnc(NC3CCNCC3)nc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-piperidine-1-carboxylic acid tert-butyl ester (0.55 g, 1.43 mmol) in ethanol (10 mL) was added 4 M HCl in dioxane (10 mL) and the reaction mixture stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 285.5 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([O:22][CH3:23])[C:8]=1[S:9]([O:12][CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O)(=[O:11])=[O:10].[C:24]1([NH:30][NH2:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:24]1([NH:30][N:31]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:13][O:12][S:9]([C:8]2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=2[O:22][CH3:23])(=[O:11])=[O:10])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NNc1ccccc1
Reactant: COc1cccc(OC)c1S(=O)(=O)OCC(=O)c1ccccc1
Product: COc1cccc(OC)c1S(=O)(=O)OCC(=NNc1ccccc1)c1ccccc1
Yield: 100 %

Procedure:
The 3,5-dimethoxy-4-benzenesulphonyloxy-acetophenone obtained as described above was reacted with phenylhydrazine following the procedure set out in Example 1b and 3,5-dimethoxy-4-benzenesulphonyloxy-acetophenone phenylhydrazone was obtained with a yield of 100% in crude product, which was recrystallized from methanol and directly used for the following step.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][CH2:26][C:27]1[C:28]([F:44])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:38]#[N:39])[C:30]([Cl:33])=[CH:31][CH:32]=1.[C:45]([C:48]1[C:49]([Cl:56])=[C:50]([C:53](O)=[O:54])[NH:51][CH:52]=1)(=[O:47])[CH3:46].CCN(C(C)C)C(C)C>CN(C=O)C>[C:45]([C:48]1[C:49]([Cl:56])=[C:50]([C:53]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([O:34][C:35]3[CH:36]=[C:37]([C:38]#[N:39])[CH:40]=[C:41]([Cl:43])[CH:42]=3)[C:28]=2[F:44])=[O:54])[NH:51][CH:52]=1)(=[O:47])[CH3:46]
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: CC(=O)c1c[nH]c(C(=O)O)c1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)c1c[nH]c(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2F)c1Cl
Reaction time: 8 h
Yield: 8.4 %

Procedure:
HATU (0.092 g, 0.241 mmol) was added to a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.050 g, 0.161 mmol), 4-acetyl-3-chloro-1H-pyrrole-2-carboxylic acid (0.030 g, 0.161 mmol) and DIPEA (0.042 mL, 0.241 mmol) in DMF (2 mL). The resulting solution was stirred overnight. The reaction mixture was partitioned between water and EtOAc. The organic layer was separated, dried over MgSO4 and evaporated to a residue. Purification was accomplished by reverse-phase HPLC (water/acetonitrile with 0.1% TFA) to afford the title compound (0.0065 g, 7%) as a white solid. 1H NMR (400 MHz, Acetone-d6) δ ppm ppm 11.46 (br. s., 1H), 7.88 (br. s., 1H), 7.79 (s, 1H), 7.63 (s, 1H), 7.36-7.50 (m, 4H), 4.73 (d, 2H), 2.41 (s, 3H). LCMS: m/z 480.0 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][CH2:12][CH3:13])[C:6]=2[C:5](=[O:14])[NH:4][C:3]1=[O:15].[CH3:16][O:17][C:18]1[CH:31]=[CH:30][C:21]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]Br)=[CH:20][CH:19]=1>>[CH3:16][O:17][C:18]1[CH:31]=[CH:30][C:21]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][N:4]2[C:5](=[O:14])[C:6]3[N:7]([CH2:11][CH2:12][CH3:13])[CH:8]=[N:9][C:10]=3[N:2]([CH3:1])[C:3]2=[O:15])=[CH:20][CH:19]=1
Reactant: CCCn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: COc1ccc(OCCCCCCBr)cc1
Product: CCCn1cnc2c1c(=O)n(CCCCCCOc1ccc(OC)cc1)c(=O)n2C
Yield: 47 %

Procedure:
3-Methyl-7-propylxanthine and 6-(4-methoxyphenoxy)hexyl bromide were reacted and treated in substantially the same manner as described in Example 9 (a) to give 1-[6-(4-methoxyphenoxy)hexyl]-3-methyl-7-propylxanthine (47%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])=[CH:6][N:5]=[CH:4][N:3]=1.[C:17](OC(=O)C)(=O)[CH3:18]>>[CH3:17][C:18]1[N:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:8](=[O:9])[C:7]2[C:2]([N:1]=1)=[N:3][CH:4]=[N:5][CH:6]=2
Reactant: Nc1ncncc1C(=O)Nc1ccccc1
Reactant: CC(=O)OC(C)=O
Product: Cc1nc2ncncc2c(=O)n1-c1ccccc1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
Compound 23 (70.0 mg, 0.32 mmol) was mixed with 6 mL of acetic anhydride and the reaction mixture was stirred at 120° C. for 2 h while monitored by MS. The reaction mixture was then concentrated in vacuo to yield 75 mg of crude compound 24 which was used for the next step without further purification.
Reaction SMILES: CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.Br[C:42]1[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=1.[C:48]1([C:54]2[N:59]=[CH:58][C:57]([C:60]3[N:61]=[C:62]([CH:65]4[CH2:70][CH2:69][NH:68][CH2:67][CH2:66]4)[NH:63][CH:64]=3)=[CH:56][N:55]=2)[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>C(O)(C)(C)C.C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:48]1([C:54]2[N:59]=[CH:58][C:57]([C:60]3[N:61]=[C:62]([CH:65]4[CH2:70][CH2:69][N:68]([C:42]5[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=5)[CH2:67][CH2:66]4)[NH:63][CH:64]=3)=[CH:56][N:55]=2)[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1
Reactant: Brc1cccnc1
Reactant: c1ccc(-c2ncc(-c3c[nH]c(C4CCNCC4)n3)cn2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CC(C)(C)O
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc(-c2ncc(-c3c[nH]c(C4CCN(c5cccnc5)CC4)n3)cn2)cc1
Temperature: 120 °C

Procedure:
The title compound is prepared in a similar manner as described in Tetrahedron Letters, 2007, 48(14), 2519-2525. In this case, to a degassed solution of sodium tert-butoxide, palladium acetate, and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (X-phos) in tert-butanol and toluene is added 3-bromopyridine and 2-phenyl-5-(2-(piperidin-4-yl)-1H-imidazol-4-yl)pyrimidine. The reaction is stirred and heated at 120° C. under nitrogen for 18 hours. The reaction mixture is cooled, diluted with water and the organic material is extracted with ethyl acetate. The organic phase is washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is chromatographed on silica to give the title compound.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[C:3]=1[C:10]([F:13])([F:12])[F:11].[CH:14]1(B(O)O)[CH2:16][CH2:15]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.CCOCC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:14]1([C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[C:3]=2[C:10]([F:13])([F:12])[F:11])[CH2:16][CH2:15]1
Reactant: Nc1ccc(Br)c(C(F)(F)F)c1F
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOCC
Product: Nc1ccc(C2CC2)c(C(F)(F)F)c1F
Temperature: 90 °C

Procedure:
4-Bromo-2-fluoro-3-trifluoromethylaniline (5.0 g, 19.4 mmol), cyclopropylboronic acid (2.16 g, 25.2 mmol), K3PO4 (14.4 g, 67.8 mmol) and tricyclohexyl phosphine (0.54 g, 1.9 mmol) are dissolved in toluene (80 mL) and water (4 mL). The solution is degassed with N2, heated to 90° C., and Pd(OAc)2 (0.22 g, 1.0 mmol) is added. The reaction is heated at 90° C. for 5 hours, cooled, diluted with Et2O, filtered, washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue is purified by column chromatography (EtOAc/hexanes) to give 4-cyclopropyl-2-fluoro-3-trifluoromethylaniline.
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@@H:11]([N:13]([CH:20]2[CH2:25][CH2:24][C:23]([CH3:27])([CH3:26])[CH2:22][CH2:21]2)[C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:10][C@@H:9]1[C:28](N(OC)C)=[O:29])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:34][Mg]Br.CCOCC>C1COCC1>[C:1]([N:8]1[CH2:12][C@@H:11]([N:13]([CH:20]2[CH2:25][CH2:24][C:23]([CH3:26])([CH3:27])[CH2:22][CH2:21]2)[C:14](=[O:19])[C:15]([CH3:16])([CH3:18])[CH3:17])[CH2:10][C@@H:9]1[C:28](=[O:29])[CH3:34])([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)[C@H]1C[C@H](N(C(=O)C(C)(C)C)C2CCC(C)(C)CC2)CN1C(=O)OC(C)(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)[C@H]1C[C@H](N(C(=O)C(C)(C)C)C2CCC(C)(C)CC2)CN1C(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 46 %

Procedure:
To a solution of BOC (2R,4S)-4-[(4,4-dimethylcyclohexyl)(2,2-dimethylpropanoyl)amino]-2-{[methoxy(methyl)amino]carbonyl}pyrrolidine (670 mg, 1.44 mmol) prepared in Step B in THF (5 ml) was added methylmagnesium bromide 3M in ether solution (1.2 ml, 3.66 mmol), and the solution was stirred for 3 h. After the reaction finished, the solution was concentrated in vacuo. The residue was diluted with EtOAc, and washed with water and brine. The organic solution was dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography (eluent: EtOAc:Hex=3/1) to give the title compound (280 mg, 46%).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([F:15])([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:4]([F:7])([F:6])[F:5].C(O)(=O)C.S(=O)(=O)(O)O.[N+:27]([O-])([OH:29])=[O:28]>O>[F:1][C:2]([F:16])([F:17])[C:3]([F:15])([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([N+:27]([O-:29])=[O:28])[CH:9]=1)[C:4]([F:7])([F:6])[F:5]
Reactant: Oc1ccc(C(F)(C(F)(F)F)C(F)(F)F)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1cc(C(F)(C(F)(F)F)C(F)(F)F)ccc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 3.60 g of mixture containing 4-(heptafluoroisopropyl)phenol, 8 ml of acetic acid, and 2.5 g of concentrated sulfuric acid, a mixture of 1.05 g of 69% nitric acid and 1 ml of acetic acid was added dropwise while ice-cooling, and then stirred at room temperature for two hours. The reaction mixture was poured into water, and extracted with ethyl acetate three times. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 2.96 g of 4-(heptafluoroisopropyl)-2-nitrophenol.
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7]2[S:15][CH:14]=[C:13]([CH2:16][CH2:17][CH3:18])[C:8]=2[N:9]=[C:10](Cl)[N:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:19]([NH2:22])[CH:20]=[CH2:21].C(=O)([O-])O.[Na+]>>[CH2:19]([NH:22][C:10]1[N:11]=[C:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:7]2[S:15][CH:14]=[C:13]([CH2:16][CH2:17][CH3:18])[C:8]=2[N:9]=1)[CH:20]=[CH2:21]
Reactant: CCCc1csc2c(NC(C)(C)C)nc(Cl)nc12
Reactant: C=CCN
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCNc1nc(NC(C)(C)C)c2scc(CCC)c2n1
Yield: 76.5 %

Procedure:
173 mg (0.61 mmol) of 4-t-butylamino-2-chloro-7-propylthieno[3,2-d]pyrimidine and 557 mg (9.8 mmol) of allylamine were heated in a sealed tube at 140° C. for 16 hours. After completion of the reaction, the reaction mixture was allowed to resume room temperature, followed by adding a saturated aqueous sodium hydrogen carbonate solution thereto and extraction with ethyl acetate (50 ml×2). After the organic layer was washed with brine and dried over anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/4) to give 142 mg (yield: 76.3%) of the title compound.
Reaction SMILES: [OH:1][C:2]([C:4](F)(F)F)=O.[OH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[O:10].[CH:15]12[O:22][CH:19]([CH2:20][CH2:21]1)[CH2:18][N:17]([C:23]1[N:28]=[C:27]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[N:26]=[C:25]([C:35]3[CH:40]=[CH:39][C:38]([NH:41][C:42]([NH:44][C:45]4[CH:50]=[CH:49][N:48]=[CH:47][CH:46]=4)=[O:43])=[CH:37][CH:36]=3)[N:24]=1)[CH2:16]2.C(Cl)(=O)C>ClCCl.C(N(CC)CC)C>[C:2]([N:32]1[CH2:33][CH2:34][N:29]([C:27]2[N:28]=[C:23]([N:17]3[CH2:16][CH:15]4[O:22][CH:19]([CH2:20][CH2:21]4)[CH2:18]3)[N:24]=[C:25]([C:35]3[CH:36]=[CH:37][C:38]([NH:41][C:42]([NH:44][C:45]4[CH:46]=[CH:47][N:48]=[CH:49][CH:50]=4)=[O:43])=[CH:39][CH:40]=3)[N:26]=2)[CH2:30][CH2:31]1)(=[O:1])[CH3:4].[C:9]([OH:10])([C:11]([F:14])([F:13])[F:12])=[O:8]
Reactant: O=C(Nc1ccncc1)Nc1ccc(-c2nc(N3CCNCC3)nc(N3CC4CCC(C3)O4)n2)cc1
Solvent: ClCCl
Solvent: CC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CCN(c2nc(-c3ccc(NC(=O)Nc4ccncc4)cc3)nc(N3CC4CCC(C3)O4)n2)CC1

Procedure:
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea-2TFA (230 mg) in dichloromethane (4 mL) and triethylamine (1 mL) was treated with acetyl chloride. The mixture was concentrated to dryness and purified on HPLC to give the title compound as its TFA salt; MS (ES+) 530.3 (M+H)+.
Reaction SMILES: [N:1]1([CH2:7][CH:8]([OH:11])[CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:15]1[CH:20]=[CH:19][C:18]([S:21]([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22])=[CH:17][C:16]=1[N+:28]([O-:30])=[O:29]>C(#N)C>[N+:28]([C:16]1[CH:17]=[C:18]([S:21]([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22])[CH:19]=[CH:20][C:15]=1[O:11][CH:8]([CH2:9][O:10][C:15]1[CH:20]=[CH:19][C:18]([S:21]([C:24]([F:26])([F:27])[F:25])(=[O:23])=[O:22])=[CH:17][C:16]=1[N+:28]([O-:30])=[O:29])[CH2:7][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)([O-:30])=[O:29]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)C(F)(F)F)ccc1Cl
Reactant: OCC(O)CN1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: O=[N+]([O-])c1cc(S(=O)(=O)C(F)(F)F)ccc1OCC(CN1CCCCC1)Oc1ccc(S(=O)(=O)C(F)(F)F)cc1[N+](=O)[O-]

Procedure:
Using the same procedure as for example 54, a mixture of 3-piperidino-1,2-propanediol (40 mg, 0.25 mmol), sodium hydride (60%, 30 mg) and 1-chloro-2-nitro-4-trifluoromethanesulfonyl-benzene (174 mg, 0.6 mmol) in acetonitrile (1 mL+0.6 mL) was heated to reflux for 18 hours, worked-up and purified on silica gel to give the title compound. MS +ve APCI 666 [M+1].
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:16])[CH3:15])[CH2:10][C@@H:9]1[C:17](=[O:29])[NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=1)=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)(Cl)Cl.C(OC(C)C)(C)C>[CH:26]([C:23]1[CH:22]=[CH:21][C:20]([CH2:19][NH:18][C:17]([C@H:9]2[CH2:10][N:11]([C:14](=[O:16])[CH3:15])[CH2:12][CH2:13][NH:8]2)=[O:29])=[CH:25][CH:24]=1)([CH3:28])[CH3:27]
Reactant: CC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)NCc2ccc(C(C)C)cc2)C1
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCN[C@@H](C(=O)NCc2ccc(C(C)C)cc2)C1
Temperature: 25 °C
Yield: 91 %

Procedure:
To a solution of the compound (4.72 g) obtained in Step 2 in chloroform (5 ml) was added, with stirring at room temperature, 4N hydrogen chloride/1,4-dioxane solution (20 ml). After stirring at room temperature for 3 hr, the reaction mixture was concentrated under reduced pressure. Toluene was added to the residue, and the mixture was concentrated again under reduced pressure. The obtained crude crystals were suspended in diisopropyl ether, collected by filtration and dried to give the title compound (3.23 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([F:14])[CH:8]=1)[CH3:2].[F:19][C:20]([F:36])([F:35])[C:21]1[CH:26]=[CH:25][C:24]([C:27]2[S:28][CH:29]=[C:30]([CH2:32][CH2:33]O)[N:31]=2)=[CH:23][CH:22]=1.ClCC1N=C(C2C=CC(C(F)(F)F)=CC=2)SC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:33][CH2:32][C:30]2[N:31]=[C:27]([C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:36])([F:19])[F:35])=[CH:26][CH:25]=3)[S:28][CH:29]=2)=[C:9]([F:14])[CH:8]=1)[CH3:2]
Reactant: OCCc1csc(-c2ccc(C(F)(F)F)cc2)n1
Reactant: CCOC(=O)C(Cc1ccc(O)c(F)c1)OCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: FC(F)(F)c1ccc(-c2nc(CCl)cs2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(OCCc2csc(-c3ccc(C(F)(F)F)cc3)n2)c(F)c1)OCC

Procedure:
In analogy to the procedure described in example 1 d], [rac]-2-ethoxy-3-(3-fluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (example 7 a]) was reacted with 2-[2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethanol (prepared from 4-chloromethyl-2-(4-trifluoromethyl-phenyl)-thiazole (example 18 a] and 4 a]) in analogy to the sequence described in examples 13 a] to 13 d]) in tetrahydrofuran in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-2-ethoxy-3-(3-fluoro-4-{2-[2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethoxy}-phenyl)-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 4 e], to yield [rac]-2-ethoxy-3-(3-fluoro-4-{2-[2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethoxy}-phenyl)-propionic acid as a colorless gum.