Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([OH:22])[C@@H:9]2[O:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH2:26][C:27]#[N:28]>CC#N>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:22][CH2:26][C:27]#[N:28])[C@@H:9]2[O:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H]([C@@H](O)c2cccc(Cl)c2)C1
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCO[C@@H]([C@@H](OCC#N)c2cccc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (R)-tert-butyl 2-((S)-(3-chlorophenyl)(hydroxy)methyl)morpholine-4-carboxylate (1.3 g, 3.98 mmol) in MeCN (20 mL), NaH (230 mg, 9.55 mmol) was added at 0° C. The mixture was stirred for 1 h at rt. The mixture was cooled to −40° C., and bromoacetonitrile (1.14 g, 9.55 mmol) was added in portions. The mixture was stirred for 0.5 h at −20° C. The solution was evaporated and H2O (50 mL) was added. 1N aq HCl was added and the mixture was extracted with CH2Cl2. The organic layer was washed with aq NaHCO3 and brine, dried over Na2SO4 and concentrated. The crude product was used directly in the next step.
Reaction SMILES: [O:1]([CH:8]1[CH2:17][CH2:16][C:11]2(OCC[O:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1>[O:1]([CH:8]1[CH2:9][CH2:10][C:11](=[O:12])[CH2:16][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(OC2CCC3(CC2)OCCO3)cc1
Solvent: C1CCOC1
Product: O=C1CCC(Oc2ccccc2)CC1

Procedure:
A solution of 8-phenoxy-1,4-dioxaspiro[4.5]decane (1.05 g, 4.48 mmol) in 20 mL of THF 3N HCl (1:1) was stirred overnight at room temperature. The aqueous was extracted with EtOAc (3×). The combined organic layers were dried (MgSO4), and concentrated to give 4-phenoxycyclohexanone as an oil. MS (EI) calcd: M+H=191.1; found: 191.0.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[CH:5]([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:4]2[CH:21]=[CH:22][CH:23]=[CH:24][C:3]1=2.CC([O-])(C)C.[K+].Br[CH:32]([CH3:38])[C:33]([O:35][CH2:36][CH3:37])=[O:34]>CN(C=O)C.C(Cl)Cl>[C:17]([O:16][C:14](=[O:15])[CH2:13][CH:5]1[C:4]2[CH:21]=[CH:22][CH:23]=[CH:24][C:3]=2[C:2](=[O:1])[N:8]([CH2:38][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]1=2)([CH3:19])([CH3:20])[CH3:18]
Reactant: CC(C)(C)OC(=O)CC1c2ccccc2NC(=O)c2ccccc21
Reactant: CCOC(=O)C(C)Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)CCN1C(=O)c2ccccc2C(CC(=O)OC(C)(C)C)c2ccccc21
Reaction time: 0.33 h
Yield: 45.8 %

Procedure:
tert-Butyl (6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl)acetate 4 (2 g, 6.18 mmol) was dissolved in 25 ml of dry DMF and, at 10° C., 2.1 eq. of KOtBu (1.5 g) were added, and the mixture was stirred for about 20 min. Then, at RT 2.5 g of ethyl bromopropionate were added dropwise and, after stirring at RT for 1 h, further KOtBu (0.2 g) and ethyl bromopropionate (0.8 g) were added. After a further 2 h, the mixture was diluted with CH2Cl2, washed with H2O, dried and concentrated. Chromatography on silica gel (CH2Cl2CH3OH 1 to 25%) afforded 1.2 g of the required product and 2.0 g of nonreacted precursor.
Reaction SMILES: Br[C:2]1[C:3]2[N:10]([CH2:11][CH3:12])[C:9]([C:13]3[C:14]([NH2:18])=[N:15][O:16][N:17]=3)=[N:8][C:4]=2[CH:5]=[N:6][CH:7]=1.[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[CH2:26])=[CH:23][CH:22]=1.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:11]([N:10]1[C:3]2[C:2](/[CH:26]=[CH:25]/[C:24]3[CH:27]=[CH:28][C:21]([O:20][CH3:19])=[CH:22][CH:23]=3)=[CH:7][N:6]=[CH:5][C:4]=2[N:8]=[C:9]1[C:13]1[C:14]([NH2:18])=[N:15][O:16][N:17]=1)[CH3:12]
Reactant: CCn1c(-c2nonc2N)nc2cncc(Br)c21
Reactant: C=Cc1ccc(OC)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Product: CCn1c(-c2nonc2N)nc2cncc(/C=C/c3ccc(OC)cc3)c21

Procedure:
The product of example 100 (309 mg, 1 mmol), 4-methoxystyrene (167 uL, 1.25 mmol), palladium(II) acetate (12 mg, 0.05 mmol), o-tolyltriphenylphosphine (30 mg, 0.10 mmol) and triethylamine (349 uL, 2.5 mmol) were heated at 130° C. for 4 hours. The solution was partitioned between ethyl acetate and water, extracting with ethylacetate (×3). Combined extracts were washed with water (×3), brine, dried over anhydrous magnesium sulfate and concentrated to a crude solid, 450 mg, then purified by column chromatography eluting with 1:9:90.880 ammonia:ethanol:dichloromethane affording the title product, 176 mg (49%); MS (ES+) m/e 363 [M+H]+.
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:13])[N:3]1[CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1B1OC(C)(C)C(C)(C)O1.Br[C:35]1[CH:36]=[CH:37][C:38]([F:45])=[C:39]([CH2:41][C:42]([OH:44])=[O:43])[CH:40]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.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>[F:45][C:38]1[CH:37]=[CH:36][C:35]([C:16]2[CH:17]=[CH:18][C:19]([C:21]([F:23])([F:22])[F:24])=[CH:20][C:15]=2[CH2:14][N:3]2[C@@H:2]([CH3:1])[C@@H:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:5][C:4]2=[O:13])=[CH:40][C:39]=1[CH2:41][C:42]([OH:44])=[O:43]
Reactant: C[C@H]1[C@@H](c2ccccc2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C(O)Cc1cc(Br)ccc1F
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: [K+]
Solvent: O
Solvent: COCCOC
Product: C[C@H]1[C@@H](c2ccccc2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1-c1ccc(F)c(CC(=O)O)c1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
(4S,5R)-4-Methyl-5-phenyl-3-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-oxazolidin-2-one (0.080 g, 0.17 mmol), 5-bromo-2-fluorophenylacetic acid (0.061 g, 0.26 mmol), potassium carbonate (0.084 g, 0.61 mmol), and tetrakis(triphenylphosphine)palladium (0) (0.021 g, 0.02 mmol) were combined in DME:H2O (2:1; 3 mL), and the mixture was purged with N2 for 5 minutes. The reaction was stirred under N2 at 90° C. overnight. After work-up with EtOAc and brine, the crude material was purified by silica gel chromatography (0-5% MeOH in CH2Cl2) to give the title compound. M+H is 488.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]([CH:12]1[N:20]([C:21](=[O:43])[C@@H:22]([NH:29][C:30](=[O:42])[C@@H:31]([N:33](C)[C:34](=O)OC(C)(C)C)[CH3:32])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[CH2:13]1)=[O:11].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[NH:9][C:10]([C@H:12]1[N:20]([C:21](=[O:43])[C@@H:22]([NH:29][C:30](=[O:42])[C@@H:31]([NH:33][CH3:34])[CH3:32])[CH:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[CH2:13]1)=[O:11]
Reactant: C[C@@H](C(=O)N[C@H](C(=O)N1c2ncccc2CC1C(=O)Nc1c(F)cccc1F)C1CCOCC1)N(C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@@H](C)C(=O)N[C@H](C(=O)N1c2ncccc2C[C@H]1C(=O)Nc1c(F)cccc1F)C1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a solution of tert-butyl (2S)-1-((1S)-2-(2-(2,6-difluorophenylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-2-oxo-1-(tetrahydropyran-4-yl)ethylamino)-1-oxopropan-2-yl(methyl)carbamate (54 mg, 89.8 μmol, Eq: 1.00) in DCM (1 mL) was added TFA (1 mL, 13.0 mmol, Eq: 145) and the resulting solution was stirred at rt for 1 h. The reaction mixture was concentrated in vacuo and the residue was treated with saturated aqueous NaHCO3 (10 mL). The resulting mixture was extracted with DCM (2×10 mL), the combined organic layers dried over Na2SO4, and then concentrated in vacuo. Treatment of the residue with diethyl ether/hexanes gave (S)-1-[(S)-2-((S)-2-methylamino-propionylamino)-2-(tetrahydropyran-4-yl)-acetyl]-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (2,6-difluoro-phenyl)-amide as a white solid (45 mg), m/z=502 (M+H).
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[CH:8][N:7]=[C:6]1[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17]N)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4].[CH3:19][C:20]1[CH:21]=[C:22]([C:27]2[NH:28][C:29]3[C:34]([C:35]=2CCNCCCCC2C=CC(NS(C)(=O)=O)=CC=2)=CC(C(N2CCOCC2)=O)=CC=3)[CH:23]=[C:24]([CH3:26])[CH:25]=1>COCCO>[CH2:1]([N:5]1[CH:9]=[CH:8][N:7]=[C:6]1[CH2:10][C:11]1[CH:16]=[C:15]2[C:14](=[CH:13][CH:12]=1)[NH:17][C:27]([C:22]1[CH:21]=[C:20]([CH3:19])[CH:25]=[C:24]([CH3:26])[CH:23]=1)=[C:35]2[CH2:34][CH2:29][NH2:28])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1ccnc1Cc1ccc(NN)cc1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(=O)N4CCOCC4)cc3c2CCNCCCCc2ccc(NS(C)(=O)=O)cc2)c1
Solvent: COCCO
Product: CCCCn1ccnc1Cc1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCN)c2c1
Yield: 8.7 %

Procedure:
A solution of 350 mg (1.43 mmol) of (4-(1-butyl-1H-imidazol-2-ylmethyl)phenyl]hydrazine and 362 mg (1.72 mmol) of 3-chloropropyl 3,5-dimethylphenyl ketone (EXAMPLE 4) in 3 mL of 2-methoxyethanol was stirred at reflux under nitrogen for 3 hours. The solution was then cooled and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (elution with 95:5 CH2Cl2-MeOH followed by 95:5:0.5 CH2Cl2-MeOH-concd. NH4OH) gave 50 mg (9%) of material that was satisfactory for use in the next step.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.[C:7]([O:11][C:12](=[O:22])[NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20]Br)=[CH:16][N:15]=1)([CH3:10])([CH3:9])[CH3:8].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[C:7]([O:11][C:12](=[O:22])[NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:4]2[CH2:5][CH2:6][C@@H:2]([OH:1])[CH2:3]2)=[CH:16][N:15]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)Nc1ccc(CBr)cn1
Reactant: O[C@@H]1CCNC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(CN2CC[C@@H](O)C2)cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 41.3 %

Procedure:
A mixture of (5-methyl-pyridin-2-yl)-carbamic acid tert-butyl ester (Step 100.3) (10.7 g, 51.4 mmol), NBS (10.1 g, 56.7 mmol, 1.1 equiv), AIBN (843 mg, 5.14 mmol, 0.1 equiv) in CCl4 (500 mL) was stirred for 1 h at relfux. NBS (1.8 g, 10.1 mmol, 0.2 equiv) was added and the mixture was stirred at reflux for additional 30 min. The reaction mixture was filtered hot and the filtrate was concentrated. Trituration of the residue in CH3CN afforded of 12.88 g of impure (5-bromomethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (intermediate 100.2). (R)-3-Hydroxypyrrolidine (181 mg, 2.1 mmol, 1.2 equiv) was added to a mixture of intermediate 100.2 (500 mg, 1.75 mmol) and Cs2CO3 (684 mg, 2.1 mmol, 1.2 equiv) in DMF (5 ml). The reaction mixture was stirred for 24 h at rt, quenched by addition of a saturated aqueous solution of NaHCO3 (150 mL) and extracted with EtOAc. The organic layer was washed with a saturated aqueous solution of NaHCO3, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography (DCM/NH3aq, 99:1→DCM/MeOH/NH3aq, 96:3:1) to afford 212 mg of the title compound as a white solid. Title compound: ESI-MS: 294.3 [M+H]+; tR=1.95 min (System 1); TLC: Rf=0.14 (DCM/MeOH, 9:1).
Reaction SMILES: [CH3:1][N:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17](S(CC)(=O)=O)[C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)[CH2:10][CH2:9]2)=[CH:6][C:5](=[O:32])[N:4]([CH3:33])[C:3]1=[O:34].[Cl:35]C1C=C([N+]([O-])=O)C=CC=1Cl.C(N(CC)CC)C>CN(C)C=O>[CH3:1][N:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:19]=3[Cl:35])[CH2:10][CH2:9]2)=[CH:6][C:5](=[O:32])[N:4]([CH3:33])[C:3]1=[O:34]
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Reactant: CCS(=O)(=O)N(CCCN1CCN(c2cc(=O)n(C)c(=O)n2C)CC1)c1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1c(N2CCN(CCCNc3ccc([N+](=O)[O-])cc3Cl)CC2)cc(=O)n(C)c1=O
Yield: 155.7 %

Procedure:
A mixture consisting of 0.4 g of Compound 158 obtained in Example 99-(1), 0.4 g of 3,4-dichloro-nitrobenzene, 0.43 ml of triethylamine and 6 ml of dimethylformamide was treated in a manner similar to Example 99-(2), thereby obtaining 0.55 g of 1,3-dimethyl-6-{4-[3-(2-chloro-4-nitroanilino)propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.C1C(=O)N([Cl:23])C(=O)C1>CN(C=O)C>[Cl:23][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:11]([C:12]#[N:13])[C:3]=2[C:2]([F:14])([F:1])[F:15])[NH:7][CH:6]=1
Reactant: N#Cc1ccc2[nH]ccc2c1C(F)(F)F
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: N#Cc1ccc2[nH]cc(Cl)c2c1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.6 %

Procedure:
To an ice-cold solution of 4-(trifluoromethyl)-1H-indole-5-carbonitrile (0.015 g, 0.071 mmol) in DMF (2 mL), under N2, was added a solution of NCS (0.011 g, 0.079 mmol) in DMF (0.5 mL). The mixture was stirred at rt for 1 h and then heated at 75° C. for 40 min. Upon cooling, the mixture was partitioned between Et2O and 0.1N HCl. The organic phase was washed with water and sat'd brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by radial chromatography (50-100% CH2Cl2 hexanes gradient, followed by 1-5% MeOH—CH2Cl2 gradient) to afford the title compound (0.014 g, 82% yield): MS (ES) m/z 245 (M+1).
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:21])[CH:14]([CH3:20])[CH2:15][S:16][C:17](=[O:19])[CH3:18])=[O:7])(C)(C)C.C1(OC)C=CC=CC=1>>[C:17]([S:16][CH2:15][C@H:14]([CH3:20])[C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:8]1[C:6]([OH:7])=[O:5])=[O:21])(=[O:19])[CH3:18]
Reactant: CC(=O)SCC(C)C(=O)N1CCCC1C(=O)OC(C)(C)C
Solvent: COc1ccccc1
Product: CC(=O)SC[C@H](C)C(=O)N1CCC[C@@H]1C(=O)O

Procedure:
18.9 g (60.0 mmol) 1-(3-acetylsulfanyl-2-methyl-propionyl)-pyrrolidine-2-carboxylic acid tert-butyl ester were stirred with 120 ml trifluoric acid and 75 ml anisole under argon for three hours. The mixture was evaporated under vacuum. The residue was dissolved in icecold ethylacetate and washed with an icecold aqueous solution of sodiumbicarbonate. Concentrated hydrochloric acid was added unter icecooling until ph 2-3. The aqueous phase was extracted three times with icecold ethylacetate, dried with sodium sulfate and evaporated. The yield was 15.3 g (98%) 1-[(R)3-acetylsulfanyl-2-methyl-propionyl]-(R)-pyrrolidine-2-carboxylic acid that was used without further purification. [a]D =+127.8° (1% EtOH).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:9]2[CH2:11][CH2:10]2)=[C:6](I)[CH:7]=1.C([Mg]Cl)(C)C.C([O:20][B:21](OC(C)C)[O:22]C(C)C)(C)C>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:9]2[CH2:11][CH2:10]2)=[C:6]([B:21]([OH:22])[OH:20])[CH:7]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1ccc(C2CC2)c(I)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: OB(O)c1cc(Br)ccc1C1CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 5-bromo-2-cyclopropyliodobenzene (5.67 g, 0.018 mol) in anhydrous tetrahydrofuran (32 ml) at −78° C. is added isopropylmagnesium chloride (9.5 ml, 0.019 mol, 2M solution in THF) at such a rate as to maintain a temperature below −60° C. Once addition is complete the reaction mixture is stirred for 20 minutes at this temperature and then allowed to warm to room temperature and stir for an additional 2 hours. The solution is then cooled again to −78° C. and triisopropylborate (8.3 ml, 0.036 mol) is added dropwise. After stirring at this temperature for 10 minutes the solution is allowed to warm to room temperature and stir for an additional 2 hours. After quenching with 2M aqueous hydrochloric acid (20 ml) the reaction mixture is diluted with distilled water then extracted with ethyl acetate (×3). Organic fractions are combined, washed with distilled water and brine, then dried over magnesium sulfate and concentrated in vacuo. The crude solid is azeotroped with toluene (×3) then triturated with isohexane to afford 5-bromo-2-cyclopropylphenyl boronic acid as a cream solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:21]([N:24]=[C:25]=[O:26])([CH3:23])[CH3:22]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:25]([NH:24][CH:21]([CH3:23])[CH3:22])=[O:26])[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)N=C=O
Reactant: CC(C)(C)OC(=O)NC[C@H]1CCN(CCCCCN)C1
Solvent: ClCCl
Product: CC(C)NC(=O)NCCCCCN1CC[C@H](CNC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
5-((3R)-3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)pentylamine (2.0 g) was dissolved in methylene chloride (20 ml) and a solution of isopropyl isocyanate (0.69 ml) in methylene chloride was dropwise added under ice-cooling. The mixture was stirred at room temperature for 0.25 hr, and the reaction mixture was concentrated under reduced pressure to give (3R)-3-tert-butoxycarbonylaminomethyl-1-(5-(3-isopropylureido)pentyl)pyrrolidine.
Reaction SMILES: [C:1]1(=[O:9])[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH2:2]1.S(=O)(=O)(O)O.[N+:15]([O-])([OH:17])=[O:16].[K+].[Br-]>O>[N+:15]([C:6]1[CH:7]=[CH:8][C:3]2[CH2:2][C:1](=[O:9])[C:4]=2[CH:5]=1)([O-:17])=[O:16]
Reactant: O=C1Cc2ccccc21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Br-]
Agent: [K+]
Solvent: O
Product: O=C1Cc2ccc([N+](=O)[O-])cc21
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
Benzocyclobutenone (3.0 g, 25.42 mmol) was added slowly to concentrated sulfuric acid (6 mL) at -5° C.-0° C. with vigorous stirring. The resulting solution was further cooled to -10° C. and the mixture of concentrated sulfuric acid (3 mL) and nitric acid (70%, d 1.42, 2.0 mL) was added at such a rate that the solution temperature remained between -10° C. and -5° C. After the completion of addition of nitrating solution, stirring continued for 10 min. The reaction mixture was then poured into an ice slurry (30 g of ice in 30 mL of water). The product which precipitated out as yellow solids from water was collected by suction filtration and washed with water twice, aqueous sodium carbonate solution (10%) twice, and water twice consecutively. The solid product was recrystallized from methanol to give white fine crystals: 3.44 g (83.1%); mp 126°-127° C.; IR (KBr) 1342, 1522, 1785 cm-1 ; 1H NMR (200 MHz, CDCl3) 4.16 (s, 2H), 7.95 (d, 1H), 8.22 (s, 1H), 8.51 (d, 1H); MS (EI, m/e, relative intensity %) 163 (M+., 99.3), 135 (M+. -CO, 39.3), 89 (135 -.NO2, 100).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:10]=1[C:11]([F:14])([F:13])[F:12])=[O:5])C.[Li+].[OH-]>CO.O>[C:15]([N:9]1[C:10]([C:11]([F:13])([F:14])[F:12])=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CCOC(=O)c1cnn(C(C)(C)C)c1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)n1ncc(C(=O)O)c1C(F)(F)F
Yield: 80.3 %

Procedure:
To a solution of 1-tert-butyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (5 g, 21.2 mmol, purchased from Bionet) in CH3OH (45 mL) and water (45 mL) was added LiOH (0.54 g, 22.5 mmol). The reaction mixture was stirred at reflux for 4 h, and then the solution was concentrated under reduced pressure to remove the methanol. The residue was diluted with water and the solution was acidified to pH 2 with concentrated HCl. The resulting mixture was then extracted with ethyl acetate three times. The combined organic extracts were concentrated in vacuo to give 1-tert-butyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (4.02 g, 80%), which was used without further purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]([CH2:18][C:19]([F:22])([F:21])[F:20])[C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:7]=1.[C:23]([C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]>>[CH3:24][C:23]([C:27]1[CH:32]=[CH:31][C:30]([O:1][CH2:2][CH2:3][CH2:4][N:5]([CH2:18][C:19]([F:20])([F:21])[F:22])[C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([C:14]([F:16])([F:15])[F:17])[CH:7]=2)=[CH:29][CH:28]=1)([CH3:26])[CH3:25]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: N#Cc1ccc(N(CCCO)CC(F)(F)F)cc1C(F)(F)F
Product: CC(C)(C)c1ccc(OCCCN(CC(F)(F)F)c2ccc(C#N)c(C(F)(F)F)c2)cc1

Procedure:
Synthesized as described in Example 1C from 4-[(3-hydroxypropyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile and 4-tert-butylphenol: MS (ES) m/z 459 (M+1).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9](=[O:11])[CH3:10])[CH2:4][CH:3]1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1.[CH3:22][O:23][C:24](=[O:34])[C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1.Cl.C(N=C=NCCCN(C)C)C.Cl>ClCCl>[CH3:22][O:23][C:24]([C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:1][CH:2]2[CH2:7][CH2:6][CH:5]([O:8][C:9](=[O:11])[CH3:10])[CH2:4][CH:3]2[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)=[O:30])=[CH:27][CH:26]=1)=[O:34]
Reactant: COc1ccc(C2CC(OC(C)=O)CCC2N)cc1OC
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)NC2CCC(OC(C)=O)CC2c2ccc(OC)c(OC)c2)cc1

Procedure:
1.6 g of (±)-acetic acid (1RS,3RS,4RS)-4-amino-3-(3,4-dimethoxyphenyl)cyclohexyl ester (compound B1) are dissolved in 30 ml of dichloromethane. 982 mg (5.45 mmol) of terephthalic acid monomethyl ester and 1.25 g (6.74 mmol) of N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride are added successively under stirring. After 3 h further 18 mg (0.1 mmol) of terephthalic acid monomethyl ester are added. After 15 h the reaction is treated with aqueous hydrochloric acid and extracted several times with dichloromethane. After evaporation of the combined organic phases, the crude product is crystallized from ethyl acetate/cyclohexane to give 1.87 g (73% of theory) of the title compound as colourless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][OH:10])[CH:5]=[C:4]([Cl:11])[C:3]=1[OH:12].CC(C)([O-])C.[K+].[Cl:19][C:20]1[N:21]=[N:22][C:23](Cl)=[CH:24][C:25]=1[CH:26]([CH3:28])[CH3:27]>CN(C)C(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][OH:10])[CH:5]=[C:4]([Cl:11])[C:3]=1[O:12][C:23]1[N:22]=[N:21][C:20]([Cl:19])=[C:25]([CH:26]([CH3:28])[CH3:27])[CH:24]=1
Reactant: OCCc1cc(Cl)c(O)c(Cl)c1
Reactant: CC(C)c1cc(Cl)nnc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(C)c1cc(Oc2c(Cl)cc(CCO)cc2Cl)nnc1Cl
Temperature: 100 °C
Yield: 43.2 %

Procedure:
A mixture of 2,6-dichloro-4-(2-hydroxy-ethyl)-phenol (16) (12.5 g, 60.2 mmol) in N,N-dimethyl acetamide (28 mL) was treated with potassium tert-butoxide (6.5 g, 57.8 mmol) under nitrogen at room temperature. The suspension was heated to 100° C. and stirred until a solution formed. The reaction was then treated with 3,6-dichloro-4-isopropyl pyridazine (7) (9.2 g, 48 mmol) followed by a rinse with N,N-dimethyl acetamide (3 mL). The reaction mixture was stirred at 135° C. for 24 h. The reaction was cooled to room temperature, diluted with water (30 mL) and extracted with tert-butyl methyl ether (1×60 mL) followed by isopropyl acetate (1×60 mL). The organic layers were combined and were washed with a 1N aqueous sodium hydroxide solution (1×25 mL) and water (2×25 mL). The organic layer was separated and distilled to a volume of approximately 30 mL. This solution was treated with heptane (30 mL). The mixture was stirred under reflux for 30 min and then cooled to room temperature. The resulting solid was filtered, washed with ether and dried overnight to afford 2-[3,5-dichloro-4-(6-chloro-5-isopropyl-pyridazin-3-yloxy)-phenyl]-ethanol (17) (7.5 g, 44%) as a white solid; LRMS for C15H15Cl3N2O2 (M+H) m/z=363. Molecular Weight=361.6580; Exact Mass=360.0199