Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.C(Cl)Cl.[CH3:11][O:12][C:13]1[CH:42]=[CH:41][C:16]([C:17]([NH:19][C:20](=[S:40])[NH:21][C:22]2[S:32][C:25]3[CH2:26][O:27][C:28]([CH3:31])([CH3:30])[CH2:29][C:24]=3[C:23]=2[C:33]([O:35]C(C)(C)C)=[O:34])=[O:18])=[CH:15][CH:14]=1>>[CH3:11][O:12][C:13]1[CH:42]=[CH:41][C:16]([C:17]([NH:19][C:20](=[S:40])[NH:21][C:22]2[S:32][C:25]3[CH2:26][O:27][C:28]([CH3:31])([CH3:30])[CH2:29][C:24]=3[C:23]=2[C:33]([OH:35])=[O:34])=[O:18])=[CH:15][CH:14]=1
Reactant: COc1ccc(C(=O)NC(=S)Nc2sc3c(c2C(=O)OC(C)(C)C)CC(C)(C)OC3)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(=O)NC(=S)Nc2sc3c(c2C(=O)O)CC(C)(C)OC3)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.5 %

Procedure:
A solution of 40% v/v TFA/DCM (2.5 mL total) was added to tert-butyl 2-(3-(4-methoxybenzoyl)thioureido)-5,5-dimethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylate (34 mg, 0.071 mmol) and the mixture was stirred at room temperature for 1 h. The volatiles were removed at 30° C. and the material was purified by mass-directed reverse-phase chromatography. 2-(3-(4-Methoxybenzoyl)thioureido)-5,5-dimethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylic acid (14 mg, 0.033 mmol, 46% yield) as a white solid. 1H NMR (500 MHz, DMSO) δ 14.86 (s, 1H), 13.38 (s, 1H), 11.59 (s, 1H), 8.04-7.97 (m, 2H), 7.11-7.03 (m, 2H), 4.65 (s, 2H), 3.86 (s, 3H), 2.73 (s, 2H), 1.22 (s, 6H). 13C NMR (126 MHz, DMSO) δ 174.55, 165.94, 165.28, 163.16, 146.98, 131.01, 129.02, 123.95, 123.75, 116.39, 113.76, 70.12, 58.80, 55.58, 37.25, 26.16. LCMS retention time: 3.264 min; LCMS purity at 214 nm=99%. HRMS m/z calculated for C19H21N2O5S2 [M++1]: 421.0886. found 421.0893. Melting point 213.2° C., decomposition.
Reaction SMILES: [CH:1]1([NH:7][C:8](=[O:28])[CH2:9][C:10]2[CH:15]=[C:14]([I:16])[C:13]([O:17][C:18]3[CH:23]=[C:22]([I:24])[C:21]([OH:25])=[C:20]([I:26])[CH:19]=3)=[C:12]([I:27])[CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:35]([CH:37]1[O:39][CH2:38]1)Br.CCOC(C)=O>O1CCOCC1>[CH:1]1([NH:7][C:8](=[O:28])[CH2:9][C:10]2[CH:15]=[C:14]([I:16])[C:13]([O:17][C:18]3[CH:23]=[C:22]([I:24])[C:21]([O:25][CH2:35][CH:37]4[CH2:38][O:39]4)=[C:20]([I:26])[CH:19]=3)=[C:12]([I:27])[CH:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: BrCC1CO1
Reactant: O=C(Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(Cc1cc(I)c(Oc2cc(I)c(OCC3CO3)c(I)c2)c(I)c1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 4.8 %

Procedure:
Compound 4 (2.0 g, 2.1 mmol, 1.0 eq.) was dissolved in anhydrous dioxane (30 mL), then anhydrous Cs2CO3 (684 mg, 2.1 mmol, 1.0 eq.) was added and then epibromohydrin (1.8 mL, 21.0 mmol, 10.0 eq.) was added dropwise. The reaction medium was then slowly heated to reflux. The mixture was stirred during 12 hours upon reflux then cooled to room temperature. EtOAc (10 mL) was then poured and the precipitate was filtered. EtOH (20 mL) was then added to the solution and the precipitate was filtered off. The remaining solution was analyzed by TLC. The first precipitate was washed thoroughly with EtOAc (30 mL). The organic solution was then evaporated and purified by column chromatography using silica gel (DCM/hexanes 80/20). The product was further recrystallized to give N-cyclohexyl-2-(4-(3,5-diiodo-4-(oxiran-2-ylmethoxy)phenoxy)-3,5-diiodophenyl)acetamide (93 mg, 0.1 mmol) as a powder. The second filtrate and the remaining solution were revealed by TLC to be the starting material which did not react.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([Cl:14])[CH:8]=1.[CH3:15][C:16]1([CH3:23])[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1.Cl>CCCCCC.O1CCCC1>[Cl:14][C:9]1[CH:8]=[C:7]([C:19]2([OH:22])[CH2:20][CH2:21][C:16]([CH3:23])([CH3:15])[CH2:17][CH2:18]2)[CH:12]=[CH:11][C:10]=1[OH:13]
Reactant: Oc1ccc(Br)cc1Cl
Reactant: CC1(C)CCC(=O)CC1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1(C)CCC(O)(c2ccc(O)c(Cl)c2)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
100 ml of a 1.6 M solution of n-butyllithium in hexane are added at −78° C. to 15.1 g of 4-bromo-2-chlorophenol in 150 ml of tetrahydrofuran, and the reaction mixture is stirred at −78° C. for 1 hour. 10.1 g of 4,4-dimethylcyclohexanone (compound 3.1) are added and the reaction mixture is stirred at −78° C. for a further 30 minutes and then at room temperature for 12 hours. The reaction mixture is hydrolysed with 1 N hydrochloric acid solution and extracted with ethyl acetate. The organic phase is dried over magnesium sulphate and the solvents are evaporated off under reduced pressure. The solid obtained is purified by chromatography on a column of silica gel, eluting with a cyclohexane/ethyl acetate mixture varying from 98/2 to 90/10 (v/v). 11.8 g of solid are obtained.
Reaction SMILES: C([C@:5]1([C:23]2[NH:24][C:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]4[CH:39]=[CH:38][C:37]([C:40]5[NH:44][C:43]([C@@H:45]6[CH2:49][CH2:48][CH2:47][N:46]6[C:50](=[O:60])[C@@H:51]([NH:55][C:56](=[O:59])[O:57][CH3:58])[CH:52]([CH3:54])[CH3:53])=[N:42][CH:41]=5)=[CH:36][CH:35]=4)=[CH:30][CH:29]=3)=[CH:26][N:27]=2)[CH2:9][C@H:8]([CH2:10][O:11][CH3:12])[CH2:7][N:6]1[C:13](=[O:22])[C@H:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(C)(C)C.Cl.[CH:62]1([C:65]([OH:67])=O)[CH2:64][CH2:63]1.CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CO>[CH:62]1([C:65]([NH:21][C@H:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:13]([N:6]2[CH2:7][C@@H:8]([CH2:10][O:11][CH3:12])[CH2:9][C@H:5]2[C:23]2[NH:24][C:25]([C:28]3[CH:29]=[CH:30][C:31]([C:34]4[CH:35]=[CH:36][C:37]([C:40]5[NH:44][C:43]([C@@H:45]6[CH2:49][CH2:48][CH2:47][N:46]6[C:50](=[O:60])[C@@H:51]([NH:55][C:56](=[O:59])[O:57][CH3:58])[CH:52]([CH3:54])[CH3:53])=[N:42][CH:41]=5)=[CH:38][CH:39]=4)=[CH:32][CH:33]=3)=[CH:26][N:27]=2)=[O:22])=[O:67])[CH2:64][CH2:63]1
Reactant: COC[C@@H]1CN(C(=O)[C@H](N)c2ccccc2)[C@](c2ncc(-c3ccc(-c4ccc(-c5cnc([C@@H]6CCCN6C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]5)cc4)cc3)[nH]2)(C(C)(C)C)C1
Reactant: O=C(O)C1CC1
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: ClCCl
Product: COC[C@H]1C[C@@H](c2ncc(-c3ccc(-c4ccc(-c5cnc([C@@H]6CCCN6C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]5)cc4)cc3)[nH]2)N(C(=O)[C@H](NC(=O)C2CC2)c2ccccc2)C1
Reaction time: 16 h
Yield: 36.6 %

Procedure:
To methyl (S)-1-((S)-2-(5-(4′-(2-((2S,4S)-(tert-butyl)-1-((R)-2-amino-2-phenylacetyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (187 mg, 0.22 mmol) in DCM (5 mL) and MeOH (1 mL) was added HCl (4M in dioxane, 1.0 mL). The solution was stirred for 16 h, and the solvent was removed. The intermediate was dissolved in DMF (5 mL). Cyclopropanecarboxylic acid (34 μL, 0.44 mmol), COMU (104 mg, 0.22 mmol), and DIPEA (0.19 mL, 1.09 mmol) were added sequentially. The solution stirred for 30 min. It was purified by HPLC to yield product (66.5 mg). LCMS-ESI+: calc'd for C47H50N8O7: 826.98 (M+); Found: 827.37 (M+H+).
Reaction SMILES: [CH3:1][Si:2]([CH3:12])([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH2:22])=[CH:16][CH:15]=1>>[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([Si:2]([CH3:12])([CH3:11])[CH3:1])=[CH:4][CH:5]=2)=[CH:16][CH:15]=1
Reactant: NCCc1ccc(F)cc1
Reactant: C[Si](C)(C)c1ccc(C=O)cc1
Product: C[Si](C)(C)c1ccc(CNCCc2ccc(F)cc2)cc1

Procedure:
[2-(4-fluoro-phenyl)-ethyl]-(4-trimethylsilanyl-benzyl)-amine was prepared in analogy to example 1 from 4-trimethylsilanyl-benzaldehyde and 2-(4-fluoro-phenyl)-ethylamine. MS (ISP): 302.2 (100) (M+H)+. 1H NMR (CDCl3, 300 MHz): δ 7.47 (d, 2H), 7.27 (d, 2H), 7.15 (dd, 2H), 6.97 (dt, 2H) 3.79 (s, 2H), 2.75-3.00 (m, 4H), 0.26 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[CH3:13].[CH3:14][CH:15]([CH2:17][CH:18]([NH2:22])[CH2:19][CH2:20][CH3:21])[CH3:16]>>[CH3:1][O:2][C:3]1[C:4]([CH3:13])=[CH:5][C:6]([C:7]([NH:22][CH:18]([CH2:19][CH2:20][CH3:21])[CH2:17][CH:15]([CH3:16])[CH3:14])=[O:9])=[CH:10][C:11]=1[CH3:12]
Reactant: CCCC(N)CC(C)C
Reactant: COc1c(C)cc(C(=O)O)cc1C
Product: CCCC(CC(C)C)NC(=O)c1cc(C)c(OC)c(C)c1

Procedure:
Prepared in a similar manner to example 4 using 4-methoxy-3,5-dimethylbenzoic acid and 2-methylheptan-4-amine (example 2a). MS (M+H, 292.2).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:13]=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[C:11]2[C:6](=[CH:7][C:8]([C:25]3[C:30]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:28]=[CH:27][N:26]=3)=[CH:9][CH:10]=2)[N:5]=1.[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>>[N:35]1([CH2:3][C:4]2[N:13]=[C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[C:11]3[C:6](=[CH:7][C:8]([C:25]4[C:30]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:28]=[CH:27][N:26]=4)=[CH:9][CH:10]=3)[N:5]=2)[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: C1CCNC1
Reactant: FC(F)(F)c1ccc(Nc2nc(CCl)nc3cc(-c4ncccc4C(F)(F)F)ccc23)cc1
Agent: Cl
Product: FC(F)(F)c1ccc(Nc2nc(CN3CCCC3)nc3cc(-c4ncccc4C(F)(F)F)ccc23)cc1

Procedure:
Heat a solution of [2-chloromethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine HCl (30 mg, 0.058 mmol) in pyrrolidine (1 mL) at 100° C. for 1 hour. Remove the excess pyrrolidine under reduced pressure and partition the residue between EtOAc and 10% NaOH solution. Dry the EtOAc layer (Na2SO4) and concentrate under reduced pressure to give [2-Pyrrolidin-1-ylmethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine as a foam. Mass Spec 517.2.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].[N:11]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>C1COCC1.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.[Fe+2]>[C:20]([O:19][C:17]([N:11]1[CH2:16][CH2:15][N:14]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[CH3:10])[CH2:13][CH2:12]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: Cc1cc(C#N)ccc1Br
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(C#N)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Yield: 86.9 %

Procedure:
Part 4: To a nitrogen flushed flask containing PdCl2dppf (65.8 mg, 0.081 mmol), dppf (44.6 mg, 0.081 mmol) and 4-bromo-3-methylbenzonitrile (631 mg, 3.22 mmol) in THF (5 mL) at −78° C. was added tert-butyl 1-piperazinecarboxylate (500 mg, 2.68 mmol) as a solid. The resultant mixture was heated to 100° C. and vigorously stirred overnight under nitrogen. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with 0 to 30% ethyl acetate in hexane) to afford 4-(4-cyano-2-methyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (702 mg, 86.9%). MS (ESI): 302.0 (M+H+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:8][C:7]2[C:9]([CH3:23])=[C:10]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]([CH3:14])=[C:12]([CH3:13])[C:6]=2[O:5]1.[C:24](OC(=O)C)(=[O:26])[CH3:25].Cl>N1C=CC=CC=1>[C:24]([O:1][CH2:2][CH2:3][CH:4]1[CH2:8][C:7]2[C:9]([CH3:23])=[C:10]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:11]([CH3:14])=[C:12]([CH3:13])[C:6]=2[O:5]1)(=[O:26])[CH3:25]
Reactant: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CC(CCO)O2
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)OCCC1Cc2c(C)c(OCc3ccccc3)c(C)c(C)c2O1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 150 mg of 2-(RS)-(2-hydroxyethyl)-2,3-dihydro-5-benzyloxy-4,6,7-trimethylbenzofurane in 0.6 ml of pyridine is treated with 0.3 ml of acetic anhydride. The mixture is stirred in nitrogen atmosphere at room temperature for 6 hours. After acidifying with hydrochloric acid, the suspension is extracted with ethylic ether then the extracts are dried and evaporated 165 mg of a white crystalline solid are obtained. m.p. 80°-82° C.; IR(KBr): 1742 cm-1 (νAcO); 1H-NMR (CCl4): δ7.4-7.1 (5H,m), 5.0-4.6 (1H,m), 4.6 (2H,s), 4.2 (2H,t), 3.4-2.6 (2H,m), 2.2 (3H,s), 2.1 (3H,s), 2.0 (6H,s), 2.0-1.8 (2H,m).
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]([O:11][CH3:12])=[O:10].[F:13][C:14]1[CH:15]=[C:16]([N:24]2[CH2:28][C@H:27]([CH2:29][NH:30][C:31](=[O:33])[CH3:32])[O:26][C:25]2=[O:34])[CH:17]=[CH:18][C:19]=1[CH:20]1[CH2:23][NH:22][CH2:21]1>C(Cl)(Cl)Cl>[F:13][C:14]1[CH:15]=[C:16]([N:24]2[CH2:28][C@H:27]([CH2:29][NH:30][C:31](=[O:33])[CH3:32])[O:26][C:25]2=[O:34])[CH:17]=[CH:18][C:19]=1[CH:20]1[CH2:23][N:22]([C:9]([O:11][CH3:12])=[O:10])[CH2:21]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3CNC3)c(F)c2)C(=O)O1
Reactant: COC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)N1CC(c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)C1
Reaction time: 8 h

Procedure:
Triethylamine (150 μL, 1.08 mmol) and methyl chloroformate (65 μL, 0.84 mmol) were added to a chloroform (5 mL) suspension of (S)-N-[[3-[3-fluoro-4-[3-azetidinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (Example 82, 153 mg, 0.50 mmol) and stirred overnight. Additional chloroform (25 mL) was added and the solution washed with water (15 mL) and brine (15 mL). Drying over magnesium sulfate, filtration, and evaporation gave a foam. Chromatography over silica gel (50 g, 40-60 μm) eluting with 1-3% methanol-chloroform gave the title compound as a white solid. FAB-HRMS: theory 366.1465 (M+1); meas. 366.1468.
Reaction SMILES: C([O:4][C:5]1[CH:16]=[CH:15][C:8]2[CH:9]=[C:10]([C:12](=[O:14])[CH3:13])[O:11][C:7]=2[CH:6]=1)(=O)C.C(NC(C)C)(C)C.[Li].[C:25](Cl)(=[O:34])[CH:26]=[CH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl>O1CCCC1.C(OCC)(=O)C>[OH:4][C:5]1[CH:16]=[CH:15][C:8]2[CH:9]=[C:10]([C:12](=[O:14])[CH2:13][C:25](=[O:34])/[CH:26]=[CH:27]/[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:11][C:7]=2[CH:6]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: CC(=O)Oc1ccc2cc(C(C)=O)oc2c1
Agent: Cl
Agent: [Li]
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(/C=C/c1ccccc1)CC(=O)c1cc2ccc(O)cc2o1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 37.2 %

Procedure:
To a solution of the crude 2-acetyl-1-benzofuran-6-yl acetate (0.23 g) in tetrahydrofuran (5 mL) at −78° C. was added lithium diisopropylamine (2.0 N solution in THF, 1.63 mL, 3.25 mmol). The mixture was stirred at the same temperature for 20 min prior to the addition of cinnamoyl chloride (0.22 g, 1.3 mmol). The reaction was warmed slowly to room temperature and stirred overnight. The reaction was treated with 1.0 N aqueous hydrochloric acid solution (10 mL) at 0° C. and diluted with ethyl acetate (250 mL). The organic layer was washed with 2N aqueous hydrochloric acid (100 mL), saturated aqueous sodium chloride (60 mL), dried over magnesium sulfate, filtered, and concentrated to afford crude product. Purification on silica (gradient 8:2 to 6:4, hexanes/ethyl acetate) afforded the product (0.12 g, 30% yield) as a yellow solid: MS (EI) for C19H14O4: 307 (MH+).
Reaction SMILES: [C:1]([CH:4]1[N:9]([C:10]2[CH:15]=[C:14]([C:16](=[O:18])[NH2:17])[N:13]=[C:12]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)=[CH:21][CH:20]=3)[N:11]=2)[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]1)(=[O:3])[NH2:2].Cl>O1CCOCC1>[C:1]([CH:4]1[CH2:5][NH:6][CH2:7][CH2:8][N:9]1[C:10]1[N:11]=[C:12]([C:19]2[CH:20]=[CH:21][C:22]([O:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)=[CH:23][CH:24]=2)[N:13]=[C:14]([C:16]([NH2:17])=[O:18])[CH:15]=1)(=[O:3])[NH2:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(C(N)=O)nc(-c3ccc(Oc4ccc(F)cc4)cc3)n2)C(C(N)=O)C1
Agent: Cl
Solvent: C1COCCO1
Product: NC(=O)c1cc(N2CCNCC2C(N)=O)nc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Reaction time: 72 h
Yield: 71.8 %

Procedure:
As To a milky suspension of the tert-butyl 3-carbamoyl-4-(6-carbamoyl-2-(4-(4-fluorophenoxy)phenyl)pyrimidin-4-yl)piperazine-1-carboxylate (0.363 g, 0.677 mmol) in dioxane (10 mL) was added 4M HCl in dioxane (2 mL, 8 mmol). After stirring for 3 days the reaction was concentrated in vacuo. The solid residue was partitioned between 10 mL EtOAc and 2 mL 2M aqueous Na2CO3 solution. The mixture was diluted with 25 mL EtOAc, 8 mL water and 25 mL brine. The organic layer was separated and the aqueous layer was extracted four times with 25 mL EtOAc. The combined organic layers were dried over MgSO4, filtered, and evaporated in vacuo. The residue was triturated with 2 mL 1:1 EtOAc/hexanes, filtered, and rinsed once with 2 mL 1:1 EtOAc/hexanes. The solid was dried under vacuum at 40° C. to give the product 6-(2-carbamoylpiperazin-1-yl)-2-(4-(4-fluorophenoxy)phenyl)pyrimidine-4-carboxamide as a pale tan powder (0.212 g, 0.486 mmol, 72% yield).
Reaction SMILES: [CH2:1]([C:3]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([OH:24])=O)[CH:17]=1)[CH3:2].[CH3:25][S:26]([NH2:29])(=[O:28])=[O:27]>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH2:1]([C:3]1[N:11]=[C:10]([C:12]([F:14])([F:15])[F:13])[N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([NH:29][S:26]([CH3:25])(=[O:28])=[O:27])=[O:24])[CH:17]=1)[CH3:2]
Reactant: CS(N)(=O)=O
Reactant: CCc1nc(C(F)(F)F)nc2c1ncn2-c1cccc(C(=O)O)c1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CCc1nc(C(F)(F)F)nc2c1ncn2-c1cccc(C(=O)NS(C)(=O)=O)c1
Temperature: 55 °C
Reaction time: 12 h
Yield: 59.5 %

Procedure:
A mixture of 6-ethyl-9-(3-carboxyphenyl)-2-trifluoromethylpurine (450 mg, 1.24 mmol), methylsulfonamide (238 mg, 2.48 mmol), N-ethyl-N′-3-dimethylaminopropylcarbodimide (238 mg, 1.24 mmol), 4-dimethylaminopyridine (151 mg, 1.24 mmol) and N,N -dimethylformamide (3 ml) were stirred at 50-60° C. for 12 hours. The solvent was concentrated under vacuum, and the residue was dissolved in 30 ml of ethyl acetate, washed with sodium bicarbonate (1×30 mL), brine (1×30 mL), dried (MgSO4), and concentrated. The residue was purified by chromatography over silica gel using a gradient elution from 10% to 20% MeOH/DCM to give 305 mg (56% yield) of 6-ethyl-9-(3-methylsulfonylaminocarbonylphenyl)-2-trifluromethylpurine. 1H NMR (300 MHz, CDCl3) δ 9.43 (b, 1H), 8.59 (s, 1H), 8.30 (s, 1H), 8.18 (d, J=7.5 Hz, 1H), 7.98 (d, J=7.5 Hz, 1H), 7.78 (t, J=7.5 Hz, 1H), 3.48 (s, 3H), 3.35 (q, J=7.2 Hz, 2H), 1.52 (t, J=7.5 Hz, 3H). [ESMS m/z (414.1 (M+H)+)]
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH2:13][N:14]([CH3:39])[C:15]([N:17]2[CH2:30][CH2:29][C@:20]3([NH:24][CH:23]([C:25]([O:27]C)=O)[CH2:22][CH2:21]3)[CH2:19][C@@H:18]2[C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=2[CH3:38])=[O:16])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CO.[NH3:44]>>[F:1][C:2]([F:40])([F:41])[C:3]1[CH:4]=[C:5]([CH2:13][N:14]([CH3:39])[C:15]([N:17]2[CH2:30][CH2:29][C@:20]3([NH:24][C@@H:23]([C:25]([NH2:44])=[O:27])[CH2:22][CH2:21]3)[CH2:19][C@@H:18]2[C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=2[CH3:38])=[O:16])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: N
Reactant: COC(=O)C1CC[C@@]2(CCN(C(=O)N(C)Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3ccc(F)cc3C)C2)N1
Solvent: CO
Product: Cc1cc(F)ccc1[C@H]1C[C@]2(CC[C@H](C(N)=O)N2)CCN1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 87 %

Procedure:
In a sealed tube a solution of methyl(5S,7R)-8-{[{[3,5-bis(trifluoromethyl)phenyl]methyl}(methyl)amino]carbonyl}-7-(4-fluoro-2-methylphenyl)-1,8-diazaspiro[4.5]decane-2-carboxylate (Intermediate 22, 63 mg, 0.107 mmol) in 7 N ammonia solution in MeOH (5 ml, 35.0 mmol) was shaken overnight. The solvent was evaporated to dryness and the crude was purified by flash-chromatography [Si cartridge (5 g), from 1:0 to 95:5 DCM/MeOH] to give the title compound (53.5 mg, 0.093 mmol, 87% yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.95 (s, 1H) 7.61 (s, 2H) 7.24-7.32 (m, 1H) 7.15-7.24 (m, 1H) 6.98-7.05 (m, 1H) 6.92 (d, 1H) 6.79 (t, 1H) 4.65 (d, 1H) 4.36 (d, 1H) 4.15 (d, 1H) 3.44-3.59 (m, 1H) 3.38 (d, 1H) 2.93 (s, 3H) 2.75 (t, 1H) 2.65 (br. s., 1 H) 2.33 (s, 3H) 1.99-2.21 (m, 1H) 1.51-1.93 (m, 6H) 1.45 (t, 1H); HPLC: Rt 4.88 mins; MS: m/z=575 [M+H]+.
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[CH3:32][O:33][CH:34]([O:51][CH3:52])[C:35]1[C:40]([O:41][CH2:42][O:43][CH3:44])=[C:39]([C:45]([F:48])([F:47])[F:46])[CH:38]=[CH:37][C:36]=1[CH2:49][OH:50].O[C:54]1[CH:59]=[CH:58][C:57]([C:60]2[CH:65]=[CH:64][C:63]([CH2:66][C:67]([O:69][CH3:70])=[O:68])=[CH:62][CH:61]=2)=[CH:56][CH:55]=1>O1CCCC1>[CH3:52][O:51][CH:34]([O:33][CH3:32])[C:35]1[C:40]([O:41][CH2:42][O:43][CH3:44])=[C:39]([C:45]([F:46])([F:47])[F:48])[CH:38]=[CH:37][C:36]=1[CH2:49][O:50][C:54]1[CH:55]=[CH:56][C:57]([C:60]2[CH:65]=[CH:64][C:63]([CH2:66][C:67]([O:69][CH3:70])=[O:68])=[CH:62][CH:61]=2)=[CH:58][CH:59]=1
Reactant: COC(=O)Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: COCOc1c(C(F)(F)F)ccc(CO)c1C(OC)OC
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COCOc1c(C(F)(F)F)ccc(COc2ccc(-c3ccc(CC(=O)OC)cc3)cc2)c1C(OC)OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 57.4 %

Procedure:
1,1′-(Azodicarbonyl)dipiperidine (3.10 g, 12.3 mmol) and tri-n-butylphosphine (3.10 ml, 12.4 mmol) were successively added to a solution of [2-(dimethoxymethyl)-3-(methoxymethoxy)-4-(trifluoromethyl)phenyl]methanol (3.20 g, 10.3 mmol) obtained in Example (6-6) and methyl (4′-hydroxy-1,1′-biphenyl-4-yl)acetate (2.50 g, 10.3 mmol) obtained in Example (6-2) in tetrahydrofuran (40 ml) and the mixture was stirred at room temperature for 5 hours. After the formed white precipitate was removed by filtration, the precipitate was washed with ethyl acetate. After the filtrate was poured into water and the mixture was extracted with ethyl acetate (three times), the organic layer was successively washed with a 3N aqueous sodium hydroxide solution, water and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=4/1) to give methyl (4′-{[2-(dimethoxymethyl)-3-(methoxymethoxy)-4-(trifluoromethyl)benzyl]oxy}-1,1′-biphenyl-4-yl)acetate (3.16 g, yield: 58%).
Reaction SMILES: [C:1]([N:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:17]=1[O:25][CH3:26].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCCCCC.C(OCC)(=O)C.O>[C:4]([O:3][C:1]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:17]=2[O:25][CH3:26])[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: COc1cccc([N+](=O)[O-])c1Br
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COc1cccc([N+](=O)[O-])c1N1CCCN(C(=O)OC(C)(C)C)CC1
Temperature: 60 °C
Yield: 28.5 %

Procedure:
A mixture of BOC-homopiperazine (1.0 g, 5 mmol, 1 equiv), 2-bromo-1-methoxy-3-nitrobenzene (1.16 g, 1 equiv), cesium carbonate (1.7 g, 1 equiv) in 10 mL of DMF was heated at 60° C. over 72 hrs. After cooling down to room temperature, ethyl acetate (100 mL) and water (50 mL) were added. The organic layer was subjected to flash chromatography (5 to 40% ethyl acetate in hexane) to give 4-(2-methoxy-6-nitrophenyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (0.50 g, 25%), which was then treated with 50 mL of 4N HCl in dioxane at 60° C. for 2 hrs. The mixture was then evaporated to dryness and used in the next step directly. MS (ES) m/z 252.1 (M+H+).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12](O)=[O:13].B>O1CCCC1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13]
Reactant: O=C(O)CCCCCCCCCCBr
Agent: B
Solvent: C1CCOC1
Product: OCCCCCCCCCCCBr
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 5 g. of 11-bromoundecanoic acid and 20 ml. of tetrahydrofuran is stirred at 0° C. while 16 ml. of 1 M borane in tetrahydrofuran is added during 15 minutes. The mixture is stirred 18 hours at ambient temperature, poured into ice-water, and extracted with ether. The dried extract is evaporated and the residual oil crystallized from hexane to yield 11-bromoundecanol as a white solid.