Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]([CH2:5][CH2:6]Br)[CH2:3]Br.[NH2:8][C@@H:9]([CH3:12])[CH2:10][OH:11].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][C@H:2]1[CH2:5][CH2:6][N:8]([C@@H:9]([CH3:12])[CH2:10][OH:11])[CH2:3]1
Reactant: C[C@H](N)CO
Reactant: C[C@H](CBr)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@H]1CCN([C@@H](C)CO)C1
Temperature: 25 °C

Procedure:
A solution of 2-(S)-methyl-1,4-dibromobutane (2.70 g, 0.012 moles) in anhydrous acetonitrile (8 mL) was added to a mixture of of (S)-(+)-2-amino-1-propanol (0.882 g, 0.012 moles, Aldrich) and potassium carbonate (3.25 g, 0.024 moles) in anhydrous acetonitrile (92 mL). The resulting mixture was refluxed for 22 hours then cooled to room temperature and concentrated under vacuum to an oily white solid. Dichloromethane (50 mL) and saturated aqueous potassium carbonate (10 mL) were added followed by just enough water to dissolve all solid. The layers (upper layer organic, lower layer aqueous) were separated and the aqueous layer was saturated with sodium chloride and extracted with dichloromethane (2×50 mL). The combined organic layers were dried over magnesium sulfate and potassium carbonate, filtered and evaporated to a light yellow liquid. This crude product was purified by column chromatography on silica gel eluted with 10:7:2:1 ethyl acetate:hexane:methanol:triethylamine to afford the title compound as a light yellow liquid. NMR: (CDCl3, 600 MHz) δ 3.52 & 3.32 (2H, 2 dd, J=5, 10 Hz, H1), 3.36 (1H, br s, OH), 2.79 (1H, t, J=8 Hz, H2′a), 2.54–2.58 (1H, m, H2), 2.66–2.72 & 2.56–2.62 (4H, 2m, H5′), 2.13–2.21 (1H, m, H3′), 2.08 (1H, td, J=8 Hz, H2′b), 1.92–2.00 & 1.25–1.33 (4H, 2m, & H4′), 1.00 (3H, d, J=7 Hz, H3′Me), 0.99 (3H, d, J=7 Hz, H3); MS (electrospray): m/e 144 (M+H), 126 (M−OH). [α]D+3.4°.
Reaction SMILES: [OH-].[Li+].C([O:5][C:6]([CH:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[O:25][C:26]([NH:29][C:30]4[CH:35]=[C:34]([F:36])[C:33]([F:37])=[C:32]([F:38])[CH:31]=4)=[N:27][N:28]=3)=[O:23])=[C:17]([F:39])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])C.C1COCC1.CO>O>[F:39][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[NH:21][C:22]([C:24]1[O:25][C:26]([NH:29][C:30]2[CH:31]=[C:32]([F:38])[C:33]([F:37])=[C:34]([F:36])[CH:35]=2)=[N:27][N:28]=1)=[O:23])[O:14][C@@H:11]1[CH2:10][CH2:9][C@H:8]([C:6]([OH:7])=[O:5])[CH2:13][CH2:12]1
Reactant: CCOC(=O)C1CCC(Oc2ccc(NC(=O)c3nnc(Nc4cc(F)c(F)c(F)c4)o3)c(F)c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Nc1ccc(O[C@H]2CC[C@@H](C(=O)O)CC2)cc1F)c1nnc(Nc2cc(F)c(F)c(F)c2)o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.1 %

Procedure:
A solution of lithium hydroxide (1.61 g, 38.3 mmol) in water (10 mL) was added in one portion to a solution of 4-(3-fluoro-4-{[5-(3,4,5-trifluoro-phenylamino)-[1,3,4]oxadiazole-2-carbonyl]-amino}-phenoxy)-cyclohexanecarboxylic acid ethyl ester (Intermediate 2, 2.0 g, 3.83 mmol) in a 1:1 mixture of THF and methanol (60 mL) was added and the mixture stirred at ambient temperature for 4 h. The mixture was concentrated in vacuo, acidified with a 1M aqueous solution of citric acid and then filtered to leave a solid. The solid was washed with water, dried and recrystallised from ethanol (30 mL) to give the title compound as a white solid (1.1 g, 58%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][C:39]=1[F:40])[CH2:5][C:6]1([C:29]([NH:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[O:30])[CH2:11][CH2:10][CH2:9][N:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][C:24]([CH3:26])=[N:23][CH:22]=4)=[C:17]([O:27][CH3:28])[CH:16]=3)=[N:13][N:14]=[C:7]12.[H-].[Na+].[CH3:43]I>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][C:39]=1[F:40])[CH2:5][C:6]1([C:29]([N:31]([CH3:43])[CH2:32][C:33]([F:36])([F:34])[F:35])=[O:30])[CH2:11][CH2:10][CH2:9][N:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][C:24]([CH3:26])=[N:23][CH:22]=4)=[C:17]([O:27][CH3:28])[CH:16]=3)=[N:13][N:14]=[C:7]12
Reactant: CI
Reactant: COc1cc(-c2nnc3n2CCCC3(Cc2ccc(F)c(F)c2)C(=O)NCC(F)(F)F)ccc1-c1cnc(C)o1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(-c2nnc3n2CCCC3(Cc2ccc(F)c(F)c2)C(=O)N(C)CC(F)(F)F)ccc1-c1cnc(C)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 8-(3,4-difluorobenzyl)-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-N-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxamide (200 mg) in DMF (2 mL) was added sodium hydride (60%, 7.8 mg) at 0° C., and the mixture was stirred at room temperature for 1 hr. Methyl iodide (0.012 mL) was added to the reaction mixture at 0° C., and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, the mixture was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and further recrystallized from ethyl acetate/methanol to give the title compound (25.3 mg).
Reaction SMILES: [C:1]1([CH:7]2[O:12][C@H:11]3[CH2:13][C@H:14]([OH:17])[CH2:15][O:16][C@@H:10]3[CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:18][S:19]([O:17][C@@H:14]1[CH2:15][O:16][C@H:10]2[C@@H:11]([O:12][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][CH2:9]2)[CH2:13]1)(=[O:21])=[O:20]
Reactant: O[C@@H]1CO[C@@H]2COC(c3ccccc3)O[C@H]2C1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CS(=O)(=O)O[C@@H]1CO[C@@H]2COC(c3ccccc3)O[C@H]2C1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of (4aR,7S,8aS)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-ol (850 mg, 3.60 mmol) and DMAP (22 mg, 0.180 mmol) under nitrogen in anhydrous pyridine (10.0 mL) at 0° C. was added methanesulfonyl chloride (0.51 mL, 742 mg, 6.48 mmol) dropwise over 2 minutes. After stirring at 0° C. for 1.5 hours, the mixture was diluted with toluene (10 mL) and concentrated under reduced pressure. The resultant white solid was dissolved in DCM and filtered to remove solids. The filtrate was then chromatographed using a Biotage™ 50 g silica gel cartridge eluted with 0-50% EtOAc in 1:1 Hexane/DCM over 20 column volumes. The product fractions were combined and concentrated under reduced pressure to provide the title compound as a white solid. LC-MS: calculated for C14H18O6S 314.08, observed m/e: 315.06 (M+H)+ (Rt 1.56/4 min).
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]([OH:7])=O)#[N:2].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Cl:50][C:51]1[CH:52]=[C:53]([C:58]2([C:71]([F:74])([F:73])[F:72])[O:62][N:61]=[C:60]([C:63]3[S:67][C:66]([CH3:68])=[C:65]([CH2:69][NH2:70])[CH:64]=3)[CH2:59]2)[CH:54]=[C:55]([Cl:57])[CH:56]=1>ClCCl>[C:1]([CH2:3][CH2:4][C:5]([NH:70][CH2:69][C:65]1[CH:64]=[C:63]([C:60]2[CH2:59][C:58]([C:53]3[CH:54]=[C:55]([Cl:57])[CH:56]=[C:51]([Cl:50])[CH:52]=3)([C:71]([F:73])([F:74])[F:72])[O:62][N:61]=2)[S:67][C:66]=1[CH3:68])=[O:7])#[N:2]
Reactant: Cc1sc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1CN
Reactant: N#CCCC(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1sc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1CNC(=O)CCC#N
Reaction time: 4 h
Yield: 19.6 %

Procedure:
3-Cyanopropionic acid (104 mg) and PyBOP (400 mg) are added to a solution of DIPEA (0.36 ml) and C-{5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-thiophen-3-yl}-methylamine (286 mg, Example 1, step F) in dichloromethane (5 ml). After 4 hours at RT, the reaction is quenched with water. The aqueous phase is separated and further extracted two times with dichloromethane. The organic phases are combined, dried over MgSO4 and concentrated in vacuo. The crude product is purified on a semi-preparative HPLC to yield 3-cyano-N-{5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-thiophen-3-ylmethyl}-propionamide (compound 1.39, 67 mg) as a beige resin. MS (HPLC/MS): 491 (MH+). Retention time: 1.90 min.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:17][O:18][C:19]1[CH:24]=[C:23]([B:25]2[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]2)[CH:22]=[CH:21][C:20]=1[OH:34]>CN(C=O)C>[CH3:17][O:18][C:19]1[CH:24]=[C:23]([B:25]2[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]2)[CH:22]=[CH:21][C:20]=1[O:34][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1
Reactant: ClCCCN1CCOCC1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1OCCCN1CCOCC1
Temperature: 25 °C

Procedure:
A solution of 4-(3-Chloro-propyl)-morpholine (460 mg, 2.75 mmol), Cs2CO3 (493 mg, 1.515 mmol) and 2-Methoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (703 mg, 2.75 mmol) in dry DMF (15 ml) are heated at 80° C. under argon for 24 h and then allowed to cool to RT. DMF is removed under HV and the residue is re-taken in EtOAc and washed with de-ionized water. The aqueous phase is re-extracted with EtOAc and the combined organic extracts are washed with saturated brine, dried over Na2SO4, filtered and concentrated under vacuum to dryness. After drying under HV, the title compound is obtained as a solid, Rt=0.878 min (Acquity HPLC BEH C18, 2.1×50 mm, 1.7 micron, detection 215 nM, 0.1 min 2% CH3CN in H2O, 2% to 100% CH3CN in H2O in 1.5 min, 0.4 min 100% CH3CN+0.1% TFA, flow rate 1.0 ml/min); MS: 378 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:27]([F:30])([F:29])[F:28])[O:14][N:13]=[C:12]([C:15]3[N:16]4[C:20]([C:21]([C:24](O)=[O:25])=[CH:22][CH:23]=3)=[CH:19][CH:18]=[CH:17]4)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:56][CH2:57][C:58]1[CH:69]=[CH:68][C:61]2[B:62]([OH:67])[O:63][C:64]([CH3:66])([CH3:65])[C:60]=2[CH:59]=1.Cl>CC#N>[OH:67][B:62]1[C:61]2[CH:68]=[CH:69][C:58]([CH2:57][NH:56][C:24]([C:21]3[C:20]4[N:16]([CH:17]=[CH:18][CH:19]=4)[C:15]([C:12]4[CH2:11][C:10]([C:4]5[CH:3]=[C:2]([Cl:1])[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=5)([C:27]([F:30])([F:29])[F:28])[O:14][N:13]=4)=[CH:23][CH:22]=3)=[O:25])=[CH:59][C:60]=2[C:64]([CH3:66])([CH3:65])[O:63]1
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)n2cccc12
Reactant: CC1(C)OB(O)c2ccc(CN)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Product: CC1(C)OB(O)c2ccc(CNC(=O)c3ccc(C4=NOC(c5cc(Cl)c(Cl)c(Cl)c5)(C(F)(F)F)C4)n4cccc34)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The solution of 5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)indolizine-8-carboxylic acid (0.665 mmol) and HATU (505.4 mg, 1.33 mmol) in CH3CN (15 mL) at rt can be stirred for 5 min. The mixture can be added to a solution of 5-(aminomethyl)-3,3-dimethyl-benzo[c][1,2]oxaborol-1(3H)-ol hydrochloride (181.1 mg, 0.798 mmol) and TEA (268.7 mg, 2.66 mmol) in CH3CN (15 mL). Then the mixture can be stirred at rt for 2 h. The solution can be acidified with HCl (1 N) and extracted with EA. The combined organic layers can be washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue can be purified by prep-TLC to give the final title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:26])[N:19]([CH2:23][CH2:24]O)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1.C(OC([N:40]1[CH2:44][CH2:43][NH:42][S:41]1(=[O:46])=[O:45])=O)(C)(C)C>>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:26])[N:19]([CH2:23][CH2:24][N:40]5[CH2:44][CH2:43][NH:42][S:41]5(=[O:46])=[O:45])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:31])([F:30])[F:32])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCNS1(=O)=O
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1CCO
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1CCN1CCNS1(=O)=O

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[2-(1,1-dioxido-1,2,5-thiadiazolidin-2-yl)ethyl]-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylene)-3-(2-hydroxyethyl)thiazolidine-2,4-dione and 1,1-dioxo-1λ6-[1,2,5]thiadiazolidine-2-carboxylic acid tert-butyl ester (compound described in Chemistry—A European Journal 2004, 10(22), 5581-5606) according to General Procedure C followed by deprotection (Procedure M).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][CH:34]=1)[C:6]([NH:8][CH2:9][C:10]([NH:12][C@@H:13]1[CH2:17][CH2:16][N:15]([CH:18]2[CH2:22][CH2:21][N:20]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][CH:24]=3)[CH2:19]2)[CH2:14]1)=[O:11])=[O:7].CN(C(ON1N=N[C:47]2C=[CH:49][CH:50]=[N:51][C:46]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.ON1C2C=CC=CC=2N=N1.C([O-])(O)=O.[Na+]>CN(C=O)C.ClCCl>[CH2:50]([N:51]([CH2:46][CH3:47])[C:27](=[O:29])[C:26]1[CH:25]=[CH:24][C:23]([N:20]2[CH2:21][CH2:22][CH:18]([N:15]3[CH2:16][CH2:17][C@@H:13]([NH:12][C:10](=[O:11])[CH2:9][NH:8][C:6](=[O:7])[C:5]4[CH:32]=[CH:33][CH:34]=[C:3]([C:2]([F:36])([F:1])[F:35])[CH:4]=4)[CH2:14]3)[CH2:19]2)=[CH:31][CH:30]=1)[CH3:49]
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN(C2CCN(c3ccc(C(=O)O)cc3)C2)C1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)C(=O)c1ccc(N2CCC(N3CC[C@@H](NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
To a solution of 4-{(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]-1,3′-bipyrrolidin-1′-yl}benzoic acid (35 mg, 0.069 mmol), HATU (0.032 g, 0.086 mmol), N,N-diisopropylethylamine (30.2 μL, 0.173 mmol), 1-Hydroxybenzotriazole (11.7 mg, 0.0867 mmol) in DMF (3.0 mL) was added diethylame (8.25 μL, 0.079 mmol). The reaction mixture was allowed to stir at room temperature overnight. To the mixture was added NaHCO3 (sat. aq., 10 mL) and dichloromethane (10 mL). The organic layer was separated and the aqueous layer was washed with an addition portion of dichloromethane (10 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The resulting crude product was subjected to flash chromatography (15% MeOH, 1% NH4OH in EtOAc) to afford, as a mixture of diastereomers, N,N-diethyl-4-{(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]-1,3′-bipyrrolidin-1′-yl}benzamide (32 mg, 82%) as a white solid. 1H-NMR (MeOD) δ: 1.19 (t, J=6.6 Hz, 6H), 1.66-1.80 (m, 1H), 1.90-2.05 (m, 1H), 2.18-2.40 (m, 2H), 2.50-2.70 (m, 2H), 2.80-3.06 (m, 4H), 3.15-3.40 (m, 4H), 3.38-3.60 (m, 5H), 4.03 (s, 2H), 4.37-4.50 (m, 1H), 6.58 (d, J=8.4 Hz, 2H), 7.26 (d, J=8.1 Hz, 2H), 7.69 (t, J=7.2 Hz, 1H), 7.86 (d, J=7.2 Hz, 1H), 8.14 (d, J=7.5 Hz, 1H), 8.22 (s, 1H). MS m/z: 560 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[N:10][C:9]=2[O:17][C@@H:18]([CH3:23])[C:19]([F:22])([F:21])[F:20])=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.Cl.[CH3:34][O:35]/[N:36]=[C:37](\[CH:40]1[CH2:42][CH2:41]1)/[CH2:38][NH2:39]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([NH:39][CH2:38]/[C:37](/[CH:40]3[CH2:42][CH2:41]3)=[N:36]/[O:35][CH3:34])=[O:16])[CH:11]=[N:10][C:9]=2[O:17][C@@H:18]([CH3:23])[C:19]([F:22])([F:20])[F:21])=[CH:4][CH:3]=1
Reactant: CO/N=C(/CN)C1CC1
Reactant: C[C@H](Oc1ncc(C(=O)O)nc1-c1ccc(Cl)cc1)C(F)(F)F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CO/N=C(/CNC(=O)c1cnc(O[C@@H](C)C(F)(F)F)c(-c2ccc(Cl)cc2)n1)C1CC1
Yield: 45.5 %

Procedure:
To a suspension of (S)-6-(4-chlorophenyl)-5-(1,1,1-trifluoropropan-2-yloxy)-pyrazine-2-carboxylic acid (0.2 g, 577 μmol, Eq: 1.00) in dimethylformamide (4 ml) were added under argon TBTU (204 mg, 635 μmol, Eq: 1.1), ethyldiisopropylamine (373 mg, 478 μl, 2.88 mmol, Eq: 5) and (E)-2-amino-1-cyclopropylethanone O-methyl oxime hydrochloride (104 mg, 635 μmol, Eq: 1.1) and the mixture was stirred at room temperature for 18 h overnight. The reaction mixture was partitioned between ethyl acetate and 10% aqueous citric acid, the phases were separated and the organic phase was dried over MgSO4; filtered; concentrated and purified by flash chromatography (silica gel, 20 g, 5% to 50% ethyl acetate in heptane) to yield the title compound as white crystals (0.12 g, 45.5%, m.p.: 149-152° C.). MS (EI): 457.1 (M+H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[CH:7][C:6]([OH:9])=[CH:5][N:4]=1.F[C:13]1[CH:20]=[CH:19][C:18]([CH:21]=[O:22])=[CH:17][C:14]=1[C:15]#[N:16]>>[CH:21]([C:18]1[CH:19]=[CH:20][C:13]([O:9][C:6]2[CH:7]=[N:8][C:3]([C:2]([F:1])([F:10])[F:11])=[N:4][CH:5]=2)=[C:14]([CH:17]=1)[C:15]#[N:16])=[O:22]
Reactant: Oc1cnc(C(F)(F)F)nc1
Reactant: N#Cc1cc(C=O)ccc1F
Product: N#Cc1cc(C=O)ccc1Oc1cnc(C(F)(F)F)nc1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 2-(trifluoromethyl)pyrimidin-5-ol and 2-fluoro-5-formylbenzonitrile.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH:5]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[CH3:20][C:21]1([CH3:30])[N:25]2[CH2:26][CH2:27][NH:28][CH2:29][CH:24]2[CH2:23][O:22]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[F:12][C:9]1[CH:10]=[CH:11][C:6]([CH:5]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:4][CH2:3][CH2:2][N:28]2[CH2:27][CH2:26][N:25]3[C:21]([CH3:30])([CH3:20])[O:22][CH2:23][CH:24]3[CH2:29]2)=[CH:7][CH:8]=1
Reactant: Fc1ccc(C(CCCI)c2ccc(F)cc2)cc1
Reactant: CC1(C)OCC2CNCCN21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OCC2CN(CCCC(c3ccc(F)cc3)c3ccc(F)cc3)CCN21
Temperature: 70 °C
Reaction time: 5 h

Procedure:
A mixture of 30.7 parts of 1,1'-(4-iodobutylidene)bis[4-fluorobenzene], 11.5 parts of hexahydro-3,3-dimethyl-1H-oxazolo-[3,4-a]pyrazine, 14.8 parts of sodium carbonate and 270 parts of N,N-dimethylformamide was stirred for 5 hours at about 70° C. The reaction mixture was cooled overnight to room temperature and the solvent was evaporated. The residue was dissolved in trichloromethane. The organic phase was washed with water, dried, filtered and evaporated, yielding 34 parts of 7-[4,4-bis(4-fluorophenyl)butyl]hexahydro-3,3-dimethyl-1H-oxazolo[3,4-a]pyrazine as a residue (intermediate 94).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][CH2:13][C:14]1[C:15]([NH:22][CH3:23])=[N:16][C:17]([S:20][CH3:21])=[N:18][CH:19]=1.C(N(CC)CC)C.[Cl-].[NH4+]>O1CCCC1>[CH3:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:13][C:14]2[C:15](=[N:16][C:17]([S:20][CH3:21])=[N:18][CH:19]=2)[N:22]([CH3:23])[C:1]1=[O:2]
Reactant: CNc1nc(SC)ncc1CNc1ccccc1C
Reactant: O=C(Cl)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CSc1ncc2c(n1)N(C)C(=O)N(c1ccccc1C)C2
Reaction time: 1 h
Yield: 101.3 %

Procedure:
A stirred solution, cooled in ice, of 0.7 ml (1.3 mmol) of phosgene (20% in toluene) in 5 ml of tetrahydrofuran was treated dropwise with a solution containing 189 mg (0.69 mmol) of 5-(2-methylphenyl)aminomethyl-4-methylamino-2-methylthiopyrimidine and 0.2 ml (1.4 mmol) of triethylamine in 5 ml of tetrahydrofuran. The mixture was stirred for 1 hour. To the mixture were added 20 ml of tetrahydrofuran and 20 ml of saturated aqueous ammonium chloride solution. The phases were separated and the organic phase was dried over magnesium sulfate, filtered and evaporated to give 210 mg (100%) of 3-(2-methylphenyl)-7-methylthio-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one as a cream-colored solid. [Mass spectrum (ESI) MH+ =301].
Reaction SMILES: [CH:1]1([CH:7]([C:18]2[O:19][C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[CH:21][C:22]=2[CH3:23])[O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:34][NH:35][CH2:36][CH2:37][C:38]([O:40]CC)=[O:39].Cl.C(N=C=NCCCN(C)C)C.O.OC1C2N=NNC=2C=CC=1>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[CH:1]1([CH:7]([C:18]2[O:19][C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][CH:25]=3)=[CH:21][C:22]=2[CH3:23])[O:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([N:35]([CH3:34])[CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:14])=[CH:16][CH:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)oc1C(Oc1ccc(C(=O)O)cc1)C1CCCCC1
Reactant: CCOC(=O)CCNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)oc1C(Oc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
A solution of 4-(cyclohexyl{3-methyl-5-[4-(trifluoromethyl)phenyl]furan-2-yl}methoxy)benzoic acid (69 mg), ethyl 3-(methylamino)propanoate (24 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (35 mg), hydroxybenzotriazole monohydrate (28 mg) and triethylamine (25 μL) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 4 hr. Ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and 1N hydrochloric acid, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure. To the residue were added ethanol (2 mL), tetrahydrofuran (2 mL) and 1N lithium hydroxide (0.3 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (45 mg, 55%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C@@H:8]1[CH2:12][C:11](=[O:13])[NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Br[C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH2:26][O:27][CH3:28])[C:20]=2[CH:29]=1.C(=O)([O-])[O-].[K+].[K+].CNCCNC>[Cu]I.ClCCl.C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:14])[NH:7][C@@H:8]1[CH2:12][C:11](=[O:13])[N:10]([C:16]2[CH:17]=[CH:18][C:19]3[O:24][CH2:23][C:22](=[O:25])[N:21]([CH2:26][O:27][CH3:28])[C:20]=3[CH:29]=2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCN1C(=O)COc2ccc(Br)cc21
Reactant: CC(C)(C)OC(=O)N[C@H]1CNC(=O)C1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COCN1C(=O)COc2ccc(N3C[C@H](NC(=O)OC(C)(C)C)CC3=O)cc21
Temperature: 100 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
A mixture of [(3R)-5-oxopyrrolidin-3-yl]carbamic acid tert-butyl ester (synthesized with reference to WO2004/22536; 200 mg, 0.999 mmol), 6-bromo-4-(methoxymethyl)-2H-1,4-benzoxazin-3(4H)-one (272 mg, 0.999 mmol), potassium carbonate (415 mg, 3.0 mmol), copper (I) iodide (190 mg, 0.999 mmol), N,N′-dimethylethylenediamine (0.107 ml, 0.999 mmol) and toluene (4 ml) was stirred overnight at 100° C. under a stream of nitrogen gas. After cooling, dichloromethane was added to the reaction solution and insoluble material was removed by filtration. The solvent of the filtrate was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to yield 375 mg (96%) of the title compound in the form of a colorless foamy solid.