Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][O:10][CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)[CH:5]=[CH:4][CH:3]=1.[NH:35]([CH3:37])[CH3:36]>O1CCCC1.[Pd]>[CH3:36][N:35]([CH3:37])[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][O:10][CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)[CH:5]=[CH:4][CH:3]=1
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc3ccccc3n2COCCc2cccc(Br)n2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Product: CN(C)c1cccc(CCOCn2c(NC3CCN(C(=O)OC(C)(C)C)CC3)nc3ccccc32)n1
Temperature: 100 °C
Reaction time: 16 h
Yield: 85.6 %

Procedure:
A mixture of (±)-1,1-dimethylethyl 4-[[1-[(6-bromo-2-pyridinyl]ethoxymethyl]-1H-benzimidazol-2-yl]amino]-1-piperidinecarboxylate (0.00189 mol) (interm. 33), Pd (0.026 g), (R)-(+)-2,2′-bis(diphenyl-phosphino)-1,1′-binaphtyl (0.046 g) and NH(CH3)2 gas (10 g) in tetrahydrofuran (200 ml) was stirred in an autoclave at 100° C. for 16 hours under pressure of CO (30 atm). The mixture was filtered and the filtrate was evaporated. The residue was purified over silica gel on a glass filter (eluent: CH2Cl2/(CH3OH/NH3) 99/1). The pure fractions were collected and the solvents was evaporated, yielding 0.8 g of (±)-1,1-dimethylethyl 4-[[1-[[6-(dimethylamino)-2-pyridinyl]ethoxymethyl]-1H-benzimidazol-2-yl]amino]-1-piperidinecarboxylate (86%) (interm. 14).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)[CH3:2].[P:13]([O-:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16]>C(#N)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.CN1CCOCC1>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([P:13]([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])=[O:20])=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOP([O-])OCC
Reactant: CCOC(=O)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CN1CCOCC1
Product: CCOC(=O)c1ccc(P(=O)(OCC)OCC)cc1
Temperature: 25 °C
Reaction time: 0.12 h
Yield: 67.9 %

Procedure:
A sealed pressure flask, flushed with N2, containing a mixture of 4-bromo-benzoic acid ethyl ester (2a) (5 g, 0.0218 mol), diethyl phosphite (3.093 mL, 0.024 mol), NMM (2.88 mL, 0.0262 mmol) and Pd(PPh3)4 (2.017 g, 0.00175 mol) in acetonitrile (20 mL) was stirred at ambient temperature for 5-10 min, then heated at 90° C. for 18 hours. The reaction mixture was filtered through celite, and the celite was washed with EtOAc (3×30 mL) until the filtrate showed little or no evidence of product by HPLC. The combined organics were dried over Na2SO4 and concentrated on a rotary evaporator. The desired product was purified by silica gel flash chromatography to give a pale yellow oil (4.24 g). 1H NMR (300 MHz, CDCl3) δ (ppm)) 1.36 (m, 6H), 1.42 (t, J=7 Hz, 3H), 4.16 (m, 4H), 4.42 (q, J=7 Hz, 2H), 7.93 (m, 2H), 8.15 (m, 2H). 31P NMR (121 MHz, CDCl3) δ 17.63.
Reaction SMILES: [F:1][C@@H:2]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][CH2:4][OH:5].[CH3:10][S:11](Cl)(=[O:13])=[O:12]>N1C=CC=CC=1>[CH3:10][S:11]([O:5][CH2:4][CH2:3][C@@H:2]([F:1])[CH2:6][CH2:7][CH2:8][CH3:9])(=[O:13])=[O:12]
Reactant: CS(=O)(=O)Cl
Reactant: CCCC[C@H](F)CCO
Solvent: c1ccncc1
Product: CCCC[C@H](F)CCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 5 h
Yield: 92.3 %

Procedure:
To a 100 ml flask were added 8.7 g of (S)-3-fluoroheptanol and 21.5 g of pyridine under a nitrogen atmosphere, and the solution was kept at 5° to 10° C. To the solution was added dropwise 7.5 g of methanesulfonyl chloride over 30 minutes, followed by stirring at 15° C. or less for 5 hours. The reaction mixture was poured into 200 ml of ice-water and extracted with ethyl acetate. The organic layer was washed successively with a diluted hydrochloric aqueous solution and water, dried over magnesium sulfate, and the solvent was removed by distillation at 30° C. or lower to obtain 12.7 g (yield=93.18%) of the titled compound. NMR (ppm): 0.92 (3H, t, J=7.1 Hz), 1.35-1.8 (6H, m), 2.03 (2H, m), 3.02 (3H, s), 4.37 (1H, t, J=6.2 Hz), 4.65 (2H, m)
Reaction SMILES: CC([N:4]=C=NC(C)C)C.[C:10]([C:13]1[CH:45]=[CH:44][C:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]([O:37][CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][O:39]3)[C:26]3[CH:27]=[CH:28][C:29]([O:35][CH3:36])=[C:30]([CH:34]=3)[C:31](O)=[O:32])=[CH:21][CH:20]=2)=[C:15]([CH2:46][CH2:47][CH3:48])[C:14]=1[OH:49])(=[O:12])[CH3:11].O.ON1C2C=CC=CC=2N=N1>ClCCl>[C:10]([C:13]1[CH:45]=[CH:44][C:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]([O:37][CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][O:39]3)[C:26]3[CH:27]=[CH:28][C:29]([O:35][CH3:36])=[C:30]([CH:34]=3)[C:31]([NH2:4])=[O:32])=[CH:21][CH:20]=2)=[C:15]([CH2:46][CH2:47][CH3:48])[C:14]=1[OH:49])(=[O:12])[CH3:11]
Reactant: CCCc1c(OCc2ccc(C(OC3CCCCO3)c3ccc(OC)c(C(=O)O)c3)cc2)ccc(C(C)=O)c1O
Reactant: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CCCc1c(OCc2ccc(C(OC3CCCCO3)c3ccc(OC)c(C(N)=O)c3)cc2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
Add N,N-diisopropylcarbodiimide (0.114 g, 0.902 mmol) to a solution of 5-[[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-2-methoxy-benzoic acid (0.450 g, 0.820 mmol) and 1-hydroxybenzotriazole hydrate (0.122 g, 0.902 mmol) in dichloromethane (0.2M). Stir the solution for 1 h at room temperature. Saturate the solution with ammonia gas and stir the solution for 24 h. Collect the precipitate as the title compound (0.440 g, 0.815 mmol, 98%): MS (m/z): 546 (M−1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[C:8]1(=O)[O:13][C:11](=[O:12])[C:10]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]12>C1(C)C=CC=CC=1>[C:8]1(=[O:13])[N:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7])[C:11](=[O:12])[C:10]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]12
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCCCCCO
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1CCCCCO
Yield: 73.4 %

Procedure:
10 g (96.9 mmol)of 5-amino-l-pentanol was dissolved in 300 ml of toluene and refluxed together with 17.2 g (116 mmol) of phthalic anhydride at 120° C. for 24 hours. The solvent was distilled off in vacuo, and the residue was purified by silica gel column chromatography (eluent; chloroform) to give 16.6 g of 5-phthalimido-1-pentanol in a yield of 74%.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10](Br)=[CH:9][N:8]([CH2:12][CH2:13][CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[CH2:35][C:36]([N:38]1[C:46]2[C:41](=[CH:42][C:43](B3OC(C)(C)C(C)(C)O3)=[CH:44][CH:45]=2)[CH2:40][CH2:39]1)=[O:37].C([O-])(O)=O.[Na+]>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.O1CCOCC1>[NH2:1][C:2]1[C:3]2[C:10]([C:43]3[CH:42]=[C:41]4[C:46](=[CH:45][CH:44]=3)[N:38]([C:36](=[O:37])[CH2:35][C:29]3[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:28]=3[F:27])[CH2:39][CH2:40]4)=[CH:9][N:8]([CH2:12][CH2:13][CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC1(C)OB(c2ccc3c(c2)CCN3C(=O)Cc2cc(F)ccc2F)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(CCn2cc(Br)c3c(N)ncnc32)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(CCn2cc(-c3ccc4c(c3)CCN4C(=O)Cc3cc(F)ccc3F)c3c(N)ncnc32)CC1
Temperature: 100 °C
Reaction time: 4 h
Yield: 47.3 %

Procedure:
To 1,1-dimethylethyl 4-[2-(4-amino-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl]-1-piperidinecarboxylate (220 mg, 0.518 mmol) and 1-[(2,5-difluorophenyl)acetyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indole (290 mg, 0.726 mmol) in a 5 ml sealable vial was added 1,4-Dioxane (2 mL) and saturated NaHCO3 (1 mL). The mixture was then bubbled with N2 for 10 minutes then Pd(Ph3P)4 (59.9 mg, 0.052 mmol) was added and N2 was bubbled for 5 minutes. The mixture was then capped and heated at 100° C. After 4 hours the reaction was complete. The reaction was diluted with water (5 ml) then extracted with EtOAc (3×10 ml). The organics were combined, washed with brine, dried over MgSO4, filtered and concentrated. The crude oil was then dissolved in 3 mL of DMSO and then purified on HPLC: (HPLC condition: Gilson using Trilution software with a Sunfire 5u C18(2) 100A. 50×30.00 mm 5 micron. 7.3-minute run (47 ml/min, 2% ACN/H2O, 0.1% TFA to 32% ACN/H2O, 0.1% TFA) with UV detection at 220 nm). Product fractions were combined and the volume was reduced to remove most of the MeCN. The water left behind was added saturated NaHCO3 and then extracted with EtOAc (3×15 mL). The organic was combined wash with saturated NaCl solution, dried over MgSO4, filtered and concentrated. Then the material was transferred to a 40 mL vial with MeCN, then water was added and it was freeze-dried to isolate 1,1-dimethylethyl 4-[2-(4-amino-5-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl]-1-piperidinecarboxylate (151 mg, 47.2% yield) as a white powder. LC-MS (ES) m/z=617.6 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@H:9]([NH2:11])[CH2:8][N:7]1[CH2:12][CH:13]1[CH2:16][CH2:15][CH2:14]1)=[O:5])[CH3:2].[OH:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[C:28](O)=[O:29]>>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@H:9]([NH:11][C:28]([C:19]2[CH:20]=[CH:21][C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:18]=2[OH:17])=[O:29])[CH2:8][N:7]1[CH2:12][CH:13]1[CH2:16][CH2:15][CH2:14]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1C[C@H](N)CN1CC1CCC1
Reactant: O=C(O)c1ccc2ccccc2c1O
Product: CCOC(=O)[C@@H]1C[C@H](NC(=O)c2ccc3ccccc3c2O)CN1CC1CCC1

Procedure:
(2S,4S)-1-Cyclobutylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic acid ethyl ester was prepared from (2S,4S)-4-amino-1-cyclobutylmethyl-pyrrolidine-2-carboxylic acid ethyl ester and 1-hydroxy-naphthalene-2-carboxylic acid in an analogous manner to example 1. MS calcd. for C23H29N2O4[(M+H)+] 397.0, obsd. 397.2.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.Br.BrCC1[CH:47]=[N:48][CH:49]=[C:50]([Cl:55])[C:51]=1[N:52]([CH3:54])[CH3:53]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[CH:47]=[N:48][CH:49]=[C:50]([Cl:55])[C:51]=3[N:52]([CH3:54])[CH3:53])[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)c1c(Cl)cncc1CBr
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Agent: Br
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CN(C)c1c(Cl)cncc1Cn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-(bromomethyl)-5-chloro-N,N-dimethylpyridin-4-amine hydrobromide and isolated as light yellow gum. MS (m/e): 451.4 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][N:15]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH3:16])=[CH:8][CH:7]=1.[OH-].[K+].O.Cl>C(O)C>[CH2:17]([N:15]([CH2:14][CH2:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:29])=[O:2])=[CH:7][CH:8]=1)[CH3:16])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCN(C)CCOc1ccc(CCC(=O)OC)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCN(C)CCOc1ccc(CCC(=O)O)cc1
Temperature: 22 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
A solution of 3-[4-[2-(N-dodecyl-N-methylamino)ethoxy]phenyl]propanoic acid methyl ester (2.30 g, 5.69 mmol) in ethanol (25 ml) was treated with potassium hydroxide (0.64 g, 11.4 mmol) and water (5 ml) and stirred at 22° C. for 2 h. The reaction mixture was then acidified to pH 4 with 1M hydrochloric acid and extracted twice with ethyl acetate. The combined extracts were washed with brine, dried (MgSO4) and evaporated under reduced pressure to give a white solid. Recrystallization from ethyl acetate gave 2.20 g (89%) of 3-[4-[2-(N-dodecyl-N-methylamino)ethoxy]phenyl]propanoic acid as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10][C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:33]=[C:32]4[C:27]([CH:28]=[CH:29][C:30]([C:34]([O:36]C)=[O:35])=[CH:31]4)=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)=[C:14]([CH:38]([CH3:40])[CH3:39])[O:13][N:12]=1.CO.[OH-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10][C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:33]=[C:32]4[C:27]([CH:28]=[CH:29][C:30]([C:34]([OH:36])=[O:35])=[CH:31]4)=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)=[C:14]([CH:38]([CH3:40])[CH3:39])[O:13][N:12]=1
Reactant: COC(=O)c1ccc2ccc(-c3ccc(OCc4c(CCc5c(Cl)cccc5Cl)noc4C(C)C)cc3)cc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1onc(CCc2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3ccc(C(=O)O)cc3c2)cc1
Temperature: 100 °C
Yield: 85.6 %

Procedure:
A solution of methyl 7-[4-({[3-[2-(2,6-dichlorophenyl)ethyl]-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-naphthalenecarboxylate (0.057 g, 0.1 mmol) in tetrahydrofuran (1.0 mL) was placed in a microwave reaction tube. Methanol (0.5 mL) was added followed by 1 N sodium hydroxide (0.15 mL, 0.15 mmol). The tube was sealed and heated in a microwave reactor to 100° C. for 600 seconds. The solution was neutralized and concentrated. Water was added and the mixture was filtered. The resulting solid was dried in a vacuum oven at 45° C. with P2O5 to yield the title compound (0.048 g, 76% as 0.20 tetrahydrofuran) 1H NMR (DMSO-d6) δ 13.4-12.8 (broad s, approximately 1H), 8.59 (s, 1H), 8.31 (s, 1H), 8.01 (d, J=9 Hz, 1H) 7.94-7.90 (m, 3H), 7.79 (d, J=8 Hz, 2H), 7.43 (d, J=8 Hz, 2H), 7.28-7.24 (m, 1H), 7.14 (d, J=8 Hz, 2H), 4.98 (s, 2H), 3.39-3.21 (2m, overlapping H2O, total 3H), 2.89-2.85 (m, 2H), 1.25 (d, J=7 Hz, 6H). HRMS C32H27NO4Cl2 m/z 560.1395 (M+H)+Cal; 560.1409 (M+H)+Obs.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11](S(C)(=O)=O)[C:10]([CH3:17])([CH3:16])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[F:18][C:19]1[CH:20]=[C:21]([CH2:27][OH:28])[CH:22]=[C:23]([F:26])[C:24]=1[F:25].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH3:16][C:10]1([CH3:17])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=[C:2]([O:28][CH2:27][C:21]3[CH:22]=[C:23]([F:26])[C:24]([F:25])=[C:19]([F:18])[CH:20]=3)[CH:3]=[C:4]2[NH:11]1
Reactant: CC1(C)Cn2c(cc(Cl)nc2=O)N1S(C)(=O)=O
Reactant: OCc1cc(F)c(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)Cn2c(cc(OCc3cc(F)c(F)c(F)c3)nc2=O)N1

Procedure:
To a solution of 7-chloro-2,2-dimethyl-1-(methylsulfonyl)-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (180 mg, 0.648 mmol) and (3,4,5-trifluorophenyl)methanol (210 mg, 1.30 mmol) in N,N-dimethylformamide (DMF) (3.5 mL) was added K2CO3 (269 mg, 1.94 mmol). The reaction mixture was sealed in a microwave vial and irradiated with a microwave using initial normal to 100° C. for 1 h. Purification via MDAP afforded the title product as a white solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[CH2:31][CH2:30][C@:12]2([O:16][CH2:15][C@@:14](O)([C:17]3[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=3[O:27][CH3:28])[CH2:13]2)[C@@H:11]1[C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O.C(OCC)(=O)C>[CH2:1]([O:8][CH2:9][C@H:10]1[CH2:31][CH2:30][C@:12]2([O:16][CH2:15][C@@H:14]([C:17]3[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=3[O:27][CH3:28])[CH2:13]2)[C@@H:11]1[C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(F)(F)F)cc1[C@]1(O)CO[C@]2(CC[C@H](COCc3ccccc3)[C@H]2c2ccc(F)cc2)C1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: COc1ccc(C(F)(F)F)cc1[C@@H]1CO[C@]2(CC[C@H](COCc3ccccc3)[C@H]2c2ccc(F)cc2)C1
Reaction time: 0.5 h
Yield: 24.5 %

Procedure:
A solution was prepared by dissolving 10 mg (0.019 mmol) of (3S,5R,6S,7S)-7-(benzyloxymethyl)-6-(4-fluorophenyl)-3-hydroxy-3-(2-methoxy-5-(trifluoromethyl)phenyl)-1-oxaspiro[4.4]nonane in 0.20 mL of trifluoroacetic acid at RT, and triethylsilane (0.009 mL, 7 mg, 0.06 mmol) was added immediately. After 30 min., the reaction was diluted with 25 mL of ethyl acetate and washed with 5 m L of saturated aqueous sodium bicarbonate and 5 mL of saturated aqueous sodium chloride. The organic solution was dried over sodium sulfate, decanted, and evaporated. The crude product was purified by preparative TLC, eluting with 3% ethyl ether in toluene, to yield 2.4 mg of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:44])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:11][C:10]=1[CH2:33][O:34][C:35](=[O:43])[NH:36][CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1)([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:1]([O:5][C:6](=[O:44])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH2:33][O:34][C:35](=[O:43])[NH:36][CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CCc1ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1COC(=O)NC1CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCc1ccc(O)cc1COC(=O)NC1CCCCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A 500 mL round bottomed flask was charged with 3-[4-(tert-butyldiphenylsilanyloxy)-2-cyclohexylcarbamoyloxymethylphenyl]propionic acid tert-butyl ester (3.1 g, 5.03 mmol) and anhydrous THF (180 mL). Tetrabutylammonium fluoride (15.1 mL, 15.1 mmol, 1.0M in THF) was added, and the reaction mixture was stirred at ambient temperature under a nitrogen atmosphere for 4 h. The mixture was concentrated, and the residue was diluted with EtOAc (100 mL), washed with brine, dried over (Na2SO4), and concentrated to give an oil. This crude oil was purified using the Biotage medium pressure chromatography system (EtOAc:hexanes 10:90 to 50:50) to a colorless oil (1.67 g, 88%). 1H NMR (400 MHz, CDCl3) δ 1.04-1.19 (m, 3H), 1.24-1.38 (m, 2H), 1.42 (s, 9H), 1.57-1.62 (m, 1H), 1.66-1.71 (m, 2H), 1.91-2.05 (m, 2H), 2.47 (t, J=7.8 Hz, 2H), 2.88 (t, J=7.8 Hz, 2H), 3.48-3.50 (m, 1H), 4.77-4.78 (m, 1H), 5.07 (s, 2H), 5.40 (s, 1H), 6.73 (dd, J=8.3, 2.9 Hz, 1H), 6.84 (d, J=2.4 Hz, 1H), 7.07 (d, J=8.3 Hz, 1H). MS (ES) m/e 378 (M+1).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[NH:10][C:11]([N:13]1[CH:17]=[CH:16]N=C1)=[S:12].[Cl:18][C:19]1[CH:24]=[CH:23][C:22](CCN)=[CH:21][CH:20]=1.C(OCC)(=O)C>CN(C)C=O>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:16][CH2:17][NH:13][C:11]([NH:10][C:2]2[NH:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[S:12])=[CH:21][CH:20]=1
Reactant: NCCc1ccc(Cl)cc1
Reactant: S=C(Nc1nc2ccccc2[nH]1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: S=C(NCCc1ccc(Cl)cc1)Nc1nc2ccccc2[nH]1
Temperature: 25 °C
Yield: 79.2 %

Procedure:
A solution of 1-[(2-benzimidazolyl)thiocarbamoyl]imidazole (! .22 g, 5.0 mmol) and 2-(4-chlorophenyl)ethylamine (0.79 g, 5.0 mmol) in N,N-dimethylformamide (20 mL) was stirred at 90 ° C. for 2 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, 1N aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was crystallized from EtOAc to provide 1.31 g (79%) of the titled product as a white solid:
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:26])[C:4](=[O:25])[C:5]1[CH:10]=[C:9]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[NH:13][C:12]2=[O:22])[C:8]([F:23])=[CH:7][C:6]=1[Cl:24].S(OC)(O[CH3:31])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[CH3:1][O:2][N:3]([CH3:26])[C:4](=[O:25])[C:5]1[CH:10]=[C:9]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:19])([F:20])[F:21])[N:13]([CH3:31])[C:12]2=[O:22])[C:8]([F:23])=[CH:7][C:6]=1[Cl:24]
Reactant: CON(C)C(=O)c1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CON(C)C(=O)c1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A mixture of 19.8 g of N-methoxy-N-methyl-2-chloro-5-[3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1(2H)-pyrimidinyl]-4-fluorobenzamide, 5.7 ml of dimethyl sulphate as well as 14.0 g of sodium carbonate in 80 ml of acetonitrile is stirred at 50° C. for 1 hour. The mixture is then treated with 150 ml of ice-water and the aqueous mixture is extracted three times with 150 ml of ethyl acetate each time. The combined organic phases are washed to neutrality, dried over anhydrous sodium sulphate and the solvent is evaporated. The crude product is recrystallized from diethyl ether/n-hexane and gives N-methoxy-N-methyl-2-chloro-5-[3,6-dihydro-2,6-dioxo-3-methyl-4-trifluoromethyl-1(2H)-pyrimidinyl]-4-fluorobenzamide, m.p. 158° C.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][CH:14]=[CH2:15])[C:7]=12.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][SH:24])=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][S:24][C:2]2[N:3]=[N:4][CH:5]=[C:6]3[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][CH:14]=[CH2:15])[C:7]=23)=[CH:19][CH:18]=1
Reactant: C=CCn1c(C)c(C)c2cnnc(Cl)c21
Reactant: SCc1ccc(Cl)cc1
Product: C=CCn1c(C)c(C)c2cnnc(SCc3ccc(Cl)cc3)c21
Yield: 70.6 %

Procedure:
The title compound was prepared as a yellow solid in 70.6% yield in a similar procedure to that described in Example 1 by using 7-chloro-2,3-dimethyl-1-(2-propenyl)pyrrolo[2,3-d]pyridazine and 4-chlorophenylmethanethiol.
Reaction SMILES: C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C([O:19][C:20](=[O:41])[CH2:21][O:22][CH2:23][CH2:24][N:25]([S:27]([C:30]1[C:35]([CH3:36])=[CH:34][C:33]([O:37][CH3:38])=[C:32]([CH3:39])[C:31]=1[CH3:40])(=[O:29])=[O:28])[CH3:26])(C)(C)C>>[CH3:38][O:37][C:33]1[CH:34]=[C:35]([CH3:36])[C:30]([S:27]([N:25]([CH3:26])[CH2:24][CH2:23][O:22][CH2:21][C:20]([OH:41])=[O:19])(=[O:28])=[O:29])=[C:31]([CH3:40])[C:32]=1[CH3:39]
Reactant: COc1cc(C)c(S(=O)(=O)N(C)CCOCC(=O)OC(C)(C)C)c(C)c1C
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C)c(S(=O)(=O)N(C)CCOCC(=O)O)c(C)c1C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
First triethylsilane (1.12 g, 1.54 ml, 9.6 mmol) and then trifluoroacetic acid (5 ml) were added to a solution of {2-[(4-methoxy-2,3,6-trimethylbenzenesulfonyl)-methylamino]-ethoxy}-acetic acid tert-butyl ester (2.48 g, 6.18 mmol) in MC (50 ml) and the mixture was stirred at RT for 5 h. The mixture was then concentrated i. vac., and the residue was taken up repeatedly in toluene and the mixture in each case concentrated again. The crude product was dissolved in EtOAc and the solution was extracted with 5% strength NaHCO3 soln. (3×50 ml). The combined aqueous phases were adjusted to pH 1 with conc. hydrochloric acid and extracted again with EtOAc (3×50 ml). The combined EtOAc phases were dried with Na2SO4 and concentrated i. vac. Yield: 2.41 g (>99%)