Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH2:7])[CH2:2][CH2:3][CH2:4][CH3:5].CC(C)([O-])C.[K+].[CH:19]([Br:22])(Br)[Br:20].Cl>O>[Br:20][C:19]1([Br:22])[CH2:7][C:6]1([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: BrC(Br)Br
Reactant: C=C(CCCCC)CCCCC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: CCCCCC1(CCCCC)CC1(Br)Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
To a solution of 4.16 g (0.0247 mol) of 2-pentyl-hept-1-ene in 31 ml of pentanes, was added 4.95 g (0.0441 mol) of potassium t-butoxide. While cooling the resulting mixture to an internal temperature of 5° C., 4.01 ml ( 0.0459 mol) of bromoform was added slowly via addition funnel. The reaction mixture was allowed to warm naturally to room temperature and left overnight. To the reaction mixture was added 25 ml of water then 36 ml of 1 N hydrochloric acid. The resulting mixture was transferred to a separatory funnel and the phases were separated. The organic layer was dried over MgSO4 and filtered. The solvent was removed from the filtrate in vacuo to yield 7.00 g (83.4% of theory) of 2,2-dibromo-1,1-dipentyl-cyclopropane as an oil.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4]1([CH2:10][C:11](Cl)=[O:12])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C1C=CC=CC=1>[CH3:1][N:2]([CH3:3])[C:11](=[O:12])[CH2:10][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CNC
Reactant: O=C(Cl)Cc1ccccc1
Solvent: c1ccccc1
Product: CN(C)C(=O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In 204 ml of anhydrous benzene was dissolved 77.5 g (0.5 mole) of commercially available phenylacetyl chloride, and the solution was added dropwise to a 50% aqueous solution of 180 g (2.0 moles) of dimethyl amine, 50 g of ice and 100 ml of benzene at an inner temperature of 5° to 25° C. After completion of the dropwise addition, the mixture was agitated for 1 hour at the same temperature.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH:15]2[CH2:17][CH2:16]2)[CH2:10][C:11](O)=[O:12])=[CH:5][C:4]=1[C:18]([F:21])([F:20])[F:19])#[N:2].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.[N:37]1C=CC=CC=1.[NH4+]>C(#N)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH:15]2[CH2:17][CH2:16]2)[CH2:10][C:11]([NH2:37])=[O:12])=[CH:5][C:4]=1[C:18]([F:21])([F:20])[F:19])#[N:2]
Reactant: N#Cc1ccc(N(CC(=O)O)CC2CC2)cc1C(F)(F)F
Reactant: c1ccncc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [NH4+]
Solvent: CC#N
Product: N#Cc1ccc(N(CC(N)=O)CC2CC2)cc1C(F)(F)F
Reaction time: 12 h
Yield: 39.7 %

Procedure:
A mixture of N-[4-cyano-3-(trifluoromethyl)phenyl]-N-(cyclopropylmethyl)glycine (0.298 g, 1 mmol), di-tert-butyl dicarbonate (0.436 g, 2 mmol), pyridine (0.100 g, 1.25 mmol), and ammonium hydrocarbonate (0.160 g, 2.25 mmol) was stirred for 24 h in acetonitrile (8 mL). The solvent was removed under reduced pressure, then water (10 mL) was added to the residue. The resulting solid was filtered, washed with water (3×5 mL), and then dried. After drying, the solid was suspended in diethyl ether (10 mL) and stirred for 12 h. The mixture was filtered, washed with diethyl ether (5 mL), and dried to obtain 0.118 g (40%) of the title compound as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J=8.6 Hz, 1H), 7.03 (d, J=2.3 Hz, 1H), 6.84 (dd, J=8.8, 2.5 Hz, 1H), 6.02 (bs, 1H), 5.57 (bs, 1H), 4.10 (s, 2H), 3.38 (d, J=6.6 Hz, 2H), 1.08 (m, 1H), 0.67 (m, 2H), 0.33 (m, 2H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=3)[C:26](O)=[O:27])=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].Cl.[Br:35][C:36]1[C:37]([CH3:44])=[C:38]([CH2:42][NH2:43])[CH:39]=[CH:40][CH:41]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Br:35][C:36]1[C:37]([CH3:44])=[C:38]([CH2:42][NH:43][C:26]([C:25]2[CH:29]=[CH:30][CH:31]=[C:23]([C:21]([NH:20][CH2:19][C:10]3[C:11]([NH:12][CH:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[C:6]4[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]4=[N:8][C:9]=3[CH2:32][CH3:33])=[O:22])[CH:24]=2)=[O:27])[CH:39]=[CH:40][CH:41]=1
Reactant: Cc1c(Br)cccc1CN
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(Br)c2C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 110.5 %

Procedure:
3-[({[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]benzoic acid (918 mg, 0.002 mol) and [(3-bromo-2-methylphenyl)methyl]amine hydrochloride (521 mg, 0.0022 mol) in DCM (25 mL) was treated with HATU (912 mg, 0.0024 mol) followed by TEA (0.404 g, 0.56 mL, 0.004 mol). The reaction was stirred overnight at room temperature. LC-MS showed that the reaction was complete. The reaction was quenched with sat. aq. NaHCO3. The aqueous phase was re-extracted with DCM (2×). Combined organic extracts were washed with H2O, then sat. aq. NaCl and dried (Na2SO4), then concentrated to give a residue (1.4 g). This was purified on the ‘CombiFlash’ using 40 g silica gel column [DCM-MeOH, 0-10%]. This afforded the title compound as a glassy, pale yellow foam [1.35 g (Quant.)]. LC-MS m/z 634.7 (M+H)+.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1(C)C=CC=CC=1.[OH:18][C@@:19]1([C:47]([F:50])([F:49])[F:48])[CH2:35][C:24]2[N:25]([CH3:34])[N:26]=[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[C:23]=2[C@@H:22]([C:36]2[CH:45]=[CH:44][C:39]([C:40]([O:42]C)=O)=[CH:38][C:37]=2[CH3:46])[CH2:21][CH2:20]1.[CH3:51][C:52]1[C:57]([NH2:58])=[CH:56][CH:55]=[CH:54][N:53]=1>C1COCC1>[OH:18][C@@:19]1([C:47]([F:49])([F:48])[F:50])[CH2:35][C:24]2[N:25]([CH3:34])[N:26]=[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[C:23]=2[C@@H:22]([C:36]2[CH:45]=[CH:44][C:39]([C:40]([NH:58][C:57]3[C:52]([CH3:51])=[N:53][CH:54]=[CH:55][CH:56]=3)=[O:42])=[CH:38][C:37]=2[CH3:46])[CH2:21][CH2:20]1
Reactant: Cc1ncccc1N
Reactant: COC(=O)c1ccc([C@H]2CC[C@](O)(C(F)(F)F)Cc3c2c(-c2ccccn2)nn3C)c(C)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1cc(C(=O)Nc2cccnc2C)ccc1[C@H]1CC[C@](O)(C(F)(F)F)Cc2c1c(-c1ccccn1)nn2C
Temperature: 25 °C
Reaction time: 2 h
Yield: 13.3 %

Procedure:
1 M lithium bis(trimethylsilyl)amide in toluene (0.24 mL, 0.24 mmol) was added dropwise to a solution of rac-methyl 4-((4R,7R)-7-hydroxy-1-methyl-3-(pyridin-2-yl)-7-(trifluoromethyl)-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazol-4-yl)-3-methylbenzoate (0.034 g, 0.07 mmol) and 2-methylpyridin-3-amine (0.012 g, 0.11 mmol, Appollo) in THF (2 mL) at about 0° C. The mixture was allowed to warm to rt. After about 2 h, the mixture was cooled to about 0° C. 2-Methylpyridin-3-amine (0.008 g, 0.07 mmol) and 1 M lithium bis(trimethylsilyl)amide in toluene (0.07 mL, 0.07 mmol) were added then the mixture was allowed to warm to rt. After about 5 h a saturated aqueous NH4 Cl solution (20 mL) was added and then mixture was extracted with EtOAc (2×20 mL). The combined organic extracts were washed with brine (20 mL), dried with Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 2-6% MeOH/DCM). The appropriate fractions were concentrated in vacuo. The product was recrystallized from Et2O to give rac-4-((4R,7R)-7-hydroxy-1-methyl-3-(pyridin-2-yl)-7-(trifluoromethyl)-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazol-4-yl)-3-methyl-N-(2-methylpyridin-3-yl)benzamide (0.005 g, 12%): LC-MS (Table 1, Method g) Rt=1.86 min, m/z 536 (M+H)+; 1H-NMR (DMSO, Bruker 400 MHz) δ 9.85 (s, 1H), 8.44-8.41 (m, 1H), 8.32-8.29 (m, 1H), 7.82-7.78 (m, 1H), 7.75-7.67 (m, 3H), 7.60-7.56 (m, 1H), 7.26-7.22 (m, 1H), 7.18-7.14 (m, 1H), 6.98 (d, J=8.0 Hz, 1H), 6.21 (s, 1H), 5.61-5.55 (m, 1H), 3.93 (s, 3H), 3.40-3.32 (m, 2H), 2.61 (s, 3H), 2.40 (s, 3H), 2.36-2.26 (m, 1H), 1.93-1.83 (m, 1H), 1.80-1.71 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5](Cl)=[O:6].[C:12]([N:16]1[C:20](=[O:21])[C:19]([NH:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[C:18]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[S:17]1(=[O:36])=[O:35])([CH3:15])([CH3:14])[CH3:13]>>[C:12]([N:16]1[C:20](=[O:21])[C:19]([NH:22][CH:23]2[CH2:28][CH2:27][N:26]([C:5](=[O:6])[C:4]3[CH:8]=[CH:9][C:10]([F:11])=[C:2]([F:1])[CH:3]=3)[CH2:25][CH2:24]2)=[C:18]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[S:17]1(=[O:36])=[O:35])([CH3:15])([CH3:13])[CH3:14]
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Reactant: CC(C)(C)N1C(=O)C(NC2CCNCC2)=C(c2ccccc2)S1(=O)=O
Product: CC(C)(C)N1C(=O)C(NC2CCN(C(=O)c3ccc(F)c(F)c3)CC2)=C(c2ccccc2)S1(=O)=O
Yield: 24 %

Procedure:
The title compound was prepared as described for Example 105 from 3,4-difluorobenzoyl chloride and 2-tert-butyl-5-phenyl-4-(piperidin-4-ylamino)isothiazol-3(2H)-one 1,1-dioxide (Example 75) to give the title compound (0.033 g, 24%). 1H NMR (500 MHz CDCl3): δ 7.54-7.50 (m, 2H), 7.48-7.42 (m, 3H), 7.22-7.14 (m, 2H), 7.10-7.04 (m, 1H), 5.23 (d, 1H), 4.40 (bs, 1H), 3.58 (bs, 1H), 3.22-3.12 (m, 1H), 2.58-2.46 (m, 2H), 1.80-1.60 (m, 11H), 1.42-1.14 (m, 2H); 13C NMR (125 MHz CDCl3): δ 168.3, 159.7, 152.6, 152.4, 151.6, 151.4, 150.6, 150.4, 149.6, 149.4, 133.9, 132.5, 131.8, 130.3, 129.0, 125.2, 123.7, 117.9, 117.8, 116.9, 116.8, 107.8, 61.9, 50.2, 46.0, 32.5, 27.8; Mass Spectrum: M−H+ 502.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1[S:8]([CH3:10])=O.[CH2:17](S)C.C1CCN2C(=NCCC2)CC1>O1CCOCC1>[Br:1][C:2]1[C:7]([S:8][CH2:10][CH3:17])=[N:6][C:5]([NH2:11])=[N:4][C:3]=1[C:12]1[O:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCS
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Br
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: CCSc1nc(N)nc(-c2ccco2)c1Br

Procedure:
From 5-bromo-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine, ethanethiol and DBU in dioxane. EI-MS m/e (%): 301 (M{81Br}+, 28), 299 (M{79Br}+, 27), 220 ([M—Br]+, 100), 160 (30), 118 (24).
Reaction SMILES: [CH2:1]([C:4]1([CH2:11][CH2:12][CH3:13])[CH2:9][CH2:8][C:7](=[O:10])[CH:6]=[CH:5]1)[CH2:2][CH3:3].[H][H]>[Pd].C(OCC)(=O)C>[CH2:11]([C:4]1([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][C:7](=[O:10])[CH2:8][CH2:9]1)[CH2:12][CH3:13]
Reactant: [H][H]
Reactant: CCCC1(CCC)C=CC(=O)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCC1(CCC)CCC(=O)CC1
Yield: 98 %

Procedure:
To a suspension of 10% palladium on carbon (0.1 equivalents) in ethyl acetate was added 4,4 dipropylcyclohex-2-enone, prepared as described in Example 3. The reaction mixture was hydrogenated at 300N/m2 hydrogen in a Parr hydrogenation apparatus at room temperature until hydrogen uptake has ceased (0.5-5 hours). The catalyst was removed by filtration through celite and the filtrate was concentrated to give the desired product as a colorless oil. The product was used without further purification. Yield 98%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:10])=[N:8][CH:9]=1)([O-:3])=[O:2].ClC1C=CC=C(C(OO)=[O:19])C=1>C(Cl)Cl>[N+:1]([C:4]1[CH:9]=[N+:8]([O-:19])[C:7]([CH3:10])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc([N+](=O)[O-])cn1
Solvent: ClCCl
Product: Cc1ccc([N+](=O)[O-])c[n+]1[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.5 g of 5-nitro-2-picoline are dissolved in 60 ml of methylene chloride and 4.05 g (20 m mole) of 85% m-chloroperbenzoic acid are added while stirring at room temperature. Stirring is continued overnight and the mixture is washed twice with aqueous sodium bicarbonate and then with water. It is dried, evaporated and the residue crystallized from acetonitrile, to yield the 5-nitro-2-picoline-N-oxide melting at 149°-153°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:28])=[C:6]([C:8]2[O:12][N:11]=[C:10]([CH2:13][S:14][C:15]3[N:19]([CH2:20][CH2:21]O)[C:18]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)=[N:17][N:16]=3)[N:9]=2)[CH:7]=1.CCN(S(F)(F)[F:35])CC>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:28])=[C:6]([C:8]2[O:12][N:11]=[C:10]([CH2:13][S:14][C:15]3[N:19]([CH2:20][CH2:21][F:35])[C:18]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)=[N:17][N:16]=3)[N:9]=2)[CH:7]=1
Reactant: OCCn1c(SCc2noc(-c3cc(Cl)ccc3F)n2)nnc1-c1cccs1
Reactant: CCN(CC)S(F)(F)F
Solvent: C1CCOC1
Product: FCCn1c(SCc2noc(-c3cc(Cl)ccc3F)n2)nnc1-c1cccs1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 22.7 %

Procedure:
To a cooled (−15° C.) solution of 2-{3-[5-(5-chloro-2-fluoro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-5-thiophen-2-yl-[1,2,4]triazol-4-yl}-ethanol (46 mg, 0.11 mmol) in anhydrous THF (15 ml) was dropwise added DAST (32 ml, 0.24 mmol). The mixture was stirred at room temperature for 1.5 h and was then quenched with MeOH (1 ml). The solvent was removed under reduced pressure and the residue was partitioned between brine and EtOAc. The aqueous layer was extracted with EtOAc (2×20 ml). The combined organic layers were washed with brine (10 ml), dried (MgSO4) and concentrated under reduced pressure. Purification by flash chromatography (EtOAc:heptane 2:1) and preparative HPLC afforded the title compound as a white solid (11 mg, 22%). 1H NMR (CDCl3) d (ppm): 8.05 (dd, 1H), 7.52 (m, 3H), 7.20 (m, 1H), 7.16 (m, 1H), 4.75 (t, 1H), 4.63 (m, 3H), 4.45 (m, 2H).
Reaction SMILES: [CH2:1](I)I.[Cl:4][C:5]1[CH:15]=[CH:14][C:8](/[CH:9]=[CH:10]/[C:11]([OH:13])=[O:12])=[CH:7][CH:6]=1>C(Cl)Cl.[Zn]>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([C@@H:9]2[CH2:1][C@H:10]2[C:11]([OH:13])=[O:12])=[CH:14][CH:15]=1
Reactant: O=C(O)/C=C/c1ccc(Cl)cc1
Reactant: ICI
Agent: [Zn]
Solvent: ClCCl
Product: O=C(O)[C@@H]1C[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A mixture of zinc dust (6.54 g, 0.1 mole) and cuprous chloride (1 g, 0.01 mole) in methylene chloride (30 mL) is stirred and heated to reflux under a nitrogen atmosphere for 30 min. After the mixture is cooled to room temperature, methylene iodide (13.4 g, 0.05 mole) is added to the mixture which is then refluxed for an additional hour. After cooling to 0° C., trans-4-chlorocinnamic acid (9.1 g) is added. The reaction is allowed to warm to room temperature over 2 hours and then refluxed for 3 days. The reaction is quenched at 0° C. by the addition of 30 ml of diethyl ether and 30 ml of ice cold 10% H2SO4 solution. The mixture is filtered washed with ether. The organic layer is dried over MgSO4 and concentrated to provide the desired product as a white solid. 1H NMR (CDCl3) 7.25 (d, J=7 Hz, 2H), 7.05 (d, J=7 Hz, 2H) , 2.58 (m, 1H), 1.85 (m, 1H), 1.65 (m, 1H), 1.37 (m, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][S:5]([C:8]1[CH:29]=[CH:28][C:11]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH:16]=2)=[O:13])=[C:10]([Cl:30])[CH:9]=1)(=[O:7])=[O:6].[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[Cl:30][C:10]1[CH:9]=[C:8]([S:5]([CH2:4][CH2:3][CH2:2][N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)(=[O:7])=[O:6])[CH:29]=[CH:28][C:11]=1[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH:16]=1)=[O:13]
Reactant: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(S(=O)(=O)CCCBr)cc1Cl
Reactant: C1COCCN1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(S(=O)(=O)CCCN2CCOCC2)cc1Cl

Procedure:
120 mg of 4-(3-bromopropylsulfonyl)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide was used in Procedure P with morpholine to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(3-morpholinopropylsulfonyl)benzamide. MS (Q1) 534.0 (M)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:8](C(=O)C)[NH2:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:13](O)(=O)[CH3:14]>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]2[N:4]([C:13]([CH3:14])=[N:9][N:8]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: CC(=O)N(N)c1ncccc1Br
Solvent: Cc1ccccc1
Product: Cc1nnc2c(Br)cccn12
Temperature: 25 °C
Yield: 84 %

Procedure:
To a solution of 0.17 g (0.74 mmol) of N-(3-bromopyridin-2-yl)acetohydrazide from step A above in 40 mL of anhydrous toluene was added 3 mL of glacial acetic acid and the resulting mixture was heated to reflux for 20 h employing a Dean-Stark trap. The reaction mixture was cooled to ambient temperature then evaporated to dryness in vacuo to afford the title compound (0.13 g, 84%) LC-MS: m/z (ES) 212, 214 (MH)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:15][OH:16])[CH2:9][CH2:8][S:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]1=[O:14].C(N(CC)CC)C.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[S:34])[CH:29]=[CH:30][CH:31]=1>O1CCCC1>[OH:16][CH2:15][C:3]1([CH2:2][O:1][C:33](=[S:34])[NH:32][C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([C:25]([F:24])([F:35])[F:36])[CH:27]=2)[CH2:9][CH2:8][S:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]1=[O:14]
Reactant: FC(F)(F)c1cccc(N=C=S)c1
Reactant: O=C1c2ccccc2SCCC1(CO)CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2SCCC1(CO)COC(=S)Nc1cccc(C(F)(F)F)c1

Procedure:
To a solution of 4,4-bis(hydroxymethyl)-3,4-dihydro-2H-benzo[b]thiepin-5-one (555 mg, 2.33 mmol) in 29 ml of tetrahydrofuran were added, at room temperature, triethylamine (0.35 ml, 2.56 mmol) and 3-(trifluoromethyl)phenyl isothiocyanate (885 μl, 5.82 mmol). The mixture was heated to reflux for 72 hours, concentrated and purified by column chromatography on silica gel (eluent: 1:2 ethyl acetate/hexane). The product was obtained in a yield of 320 mg (31%).
Reaction SMILES: Br[C:2]1[CH:13]=[C:12]([O:14][C@@H:15]([C@H:17]2[CH2:21][NH:20][C:19](=[O:22])[CH2:18]2)[CH3:16])[C:5]2[N:6]([CH:9]3[CH2:11][CH2:10]3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=2)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[CH:9]1([N:6]2[C:5]3[C:12]([O:14][C@@H:15]([C@@H:17]4[CH2:18][C:19](=[O:22])[NH:20][CH2:21]4)[CH3:16])=[CH:13][C:2]([C:39]4[CH:38]=[CH:37][C:36]([N:33]5[CH2:32][CH2:31][N:30]([C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])[CH2:35][CH2:34]5)=[CH:41][CH:40]=4)=[CH:3][C:4]=3[N:8]=[CH:7]2)[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B(O)O)cc2)CC1
Reactant: C[C@@H](Oc1cc(Br)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H](Oc1cc(-c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Temperature: 100 °C

Procedure:
Intermediate 2.75 (120 mg, 0.33 mmol), (4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)boronic acid (180 mg, 0.59 mmol), K3PO4 (240 mg, 1.1 mmol) and Bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium (II) (12 mg, 0.017 mmol) were taken up in 1,4-dioxane (5.3 mL) and water (0.53 mL). The stirred reaction mixture was heated to 100° C. for 2 h and was then cooled and partitioned between EtOAc, water and brine. The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic phase was dried over Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel chromatography (0-25% MeOH in DCM) to provide tert-butyl 4-(4-(1-cyclopropyl-7-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)-1H-benzo[d]imidazol-5-yl)phenyl)piperazine-1-carboxylate. LCMS-ESI+ (m/z): [M+H]+ calcd for C31H40N5O4: 546.3; found: 546.1.
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7]([C:9]1[C:10]2[CH2:11][C@@H:12]3[CH2:24][C@@H:13]3[C:14]=2[N:15]([C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][N:18]=2)[N:16]=1)=[O:8])([CH3:5])[CH3:4].[CH:25]1(B(O)O)[CH2:27][CH2:26]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.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>[OH:1][CH2:2][C:3]([NH:6][C:7]([C:9]1[C:10]2[CH2:11][C@@H:12]3[CH2:24][C@@H:13]3[C:14]=2[N:15]([C:17]2[CH:22]=[CH:21][C:20]([CH:25]3[CH2:27][CH2:26]3)=[CH:19][N:18]=2)[N:16]=1)=[O:8])([CH3:5])[CH3:4]
Reactant: CC(C)(CO)NC(=O)c1nn(-c2ccc(Br)cn2)c2c1C[C@@H]1C[C@H]21
Reactant: OB(O)C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(CO)NC(=O)c1nn(-c2ccc(C3CC3)cn2)c2c1C[C@@H]1C[C@H]21
Temperature: 100 °C
Yield: 28.4 %

Procedure:
To a mixture of (1aS,5aS)-2-(5-bromo-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (0.020 g, 0.051 mmol), cyclopropylboronic acid (6.59 mg, 0.077 mmol) and potassium phosphate (0.033 g, 0.153 mmol) in toluene/H2O (1.5 mL/0.050 mL) under nitrogen atmosphere, tetrakis(triphenylphosphine)palladium (5.91 mg, 5.11 μmol) was added. The reaction was heated at 100° C. for 30 min in a heavy walled sealed tube under microwave irradiation. Additional cyclopropylboronic acid (6.59 mg, 0.077 mmol) was added and the reaction was heated at 100° C. for 2 more hours. The mixture was purified by HPLC to give the titled compound (5.1 mg) as a white solid. LCMS m/z=353.5 [M+H]+.
Reaction SMILES: O[CH2:2][CH:3]1[CH2:7][S:6][C:5]2([CH2:12][CH2:11][CH2:10][CH:9]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:8]2)[S:4]1.S(Cl)([Cl:21])=O>C1C=CC=CC=1>[Cl:21][CH2:2][CH:3]1[CH2:7][S:6][C:5]2([CH2:12][CH2:11][CH2:10][CH:9]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:8]2)[S:4]1
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)CC1CCCC2(C1)SCC(CO)S2
Solvent: c1ccccc1
Product: CCOC(=O)CC1CCCC2(C1)SCC(CCl)S2

Procedure:
The titled compound was prepared according to the procedure described in Example E using 6.2 g (0.021 mole) of the product of Example D and 2.75 g (0.025 mol) of thionyl chloride in benzene (60 ml). The crude product was chromatographed on silica gel using 5% ethyl acetate/hexane to give two sets of two racemates. The less polar pair of racemates weighed 0.62 g. The more polar pair of racemates weighed 1.3 g.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9].[N+:10]([C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([N+]([O-])=O)[C:14]=1[C:15]#[N:16])([O-:12])=[O:11]>>[N+:10]([C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([O:1][CH2:2][CH2:3][N:4]2[CH2:8][CH2:7][CH2:6][C:5]2=[O:9])[C:14]=1[C:15]#[N:16])([O-:12])=[O:11]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: O=C1CCCN1CCO
Product: N#Cc1c(OCCN2CCCC2=O)cccc1[N+](=O)[O-]
Yield: 74 %

Procedure:
Prepared as in Example 166d from 1-(2-hydroxyethyl)pyrrolidin-2-one and 2,6-dinitrobenzonitrile in 74% yield. MS 276 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([N:18]=COC)=[CH:16][C:15]([C:22]2[N:26]=[CH:25][O:24][N:23]=2)=[N:14]1.S(=O)(=O)(O)O>CC(C)=O.O>[NH2:18][C:17]1[N:13]([C:3]2[C:4]([Cl:12])=[CH:5][C:6]([C:8]([F:11])([F:9])[F:10])=[CH:7][C:2]=2[Cl:1])[N:14]=[C:15]([C:22]2[N:26]=[CH:25][O:24][N:23]=2)[CH:16]=1
Reactant: COC=Nc1cc(-c2ncon2)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Product: Nc1cc(-c2ncon2)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Yield: 78.4 %

Procedure:
1-(2,6-Dichloro-4-trifluoromethylphenyl)-5-methoxymethylideneamino-3-(1,2,4-oxadiazol-3-yl)pyrazole (2.80 g, 6.89 mmol) was dissolved in a mixed solvent of 50 ml of acetone and 5 ml of water, and then concentrated sulfuric acid (0.70 g, 6.92 mmol) was added with stirring at room temperature. The mixture was stirred at room temperature for 48 hours and the reaction solution was concentrated under reduced pressure. The pH of the residue was adjusted to about 8 by adding an aqueous saturated sodium hydrogencarbonate solution, followed by extracting three times with 30 ml of ethyl acetate. The organic layer was washed three times with 100 ml of water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting concentrated residue was subjected to silica gel column chromatography [eluent: mixed solvent of ethyl acetate and hexane (volume ratio=1:2)] to obtain 1.96 g (5.40 mmol) of the title compound as a colorless crystal.