Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:14]2[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][N:15]=2)[C:8](N(OC)C)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:22]([Mg]Br)=[CH2:23].Cl>O1CCCC1>[CH:1]1([CH2:6][CH:7]([C:14]2[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][N:15]=2)[C:8](=[O:9])[CH:22]=[CH2:23])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=C[Mg]Br
Reactant: CON(C)C(=O)C(CC1CCCC1)c1ccc(SC)cn1
Agent: Cl
Solvent: C1CCOC1
Product: C=CC(=O)C(CC1CCCC1)c1ccc(SC)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
A solution of 3-cyclopentyl-N-methoxy-N-methyl-2-[5-(methylsulfanyl)pyridin-2-yl]propanamide (350 mg) in tetrahydrofuran (4.5 mL) was cooled to 0° C., and vinylmagnesium bromide (1.0M tetrahydrofuran solution, 4.54 mL) was added dropwise thereto. The reaction mixture was stirred at room temperature for 1 hr, and poured into 1M hydrochloric acid, and the mixture was stirred for 30 min. The reaction mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (171 mg, yield 54%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([I:9])[C:5]([NH2:8])=[N:6][CH:7]=1.Br[CH2:11][CH:12](OC)OC.Br>C(O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([I:9])[C:5]2[N:6]([CH:11]=[CH:12][N:8]=2)[CH:7]=1
Reactant: Nc1ncc(Br)cc1I
Reactant: COC(CBr)OC
Agent: Br
Solvent: O
Solvent: CCO
Product: Brc1cc(I)c2nccn2c1
Temperature: 25 °C

Procedure:
5-bromo-3-iodopyridin-2-amine (1.0 g, 3.34 mmol) and 2-bromo-1,1-dimethoxyethane were dissolved in ethanol (20 ml). To this solution was added a 50% mixture of HBr in water (4 ml). The mixture was stirred at reflux temperature overnight. After the completion of the reaction, the mixture was cooled to room temperature and filtered. The residue was suspended in DCM (10 ml) and stirred with the saturated aqueous solution of Na2CO3. The organic layer was separated and washed with saturated brine, dried over sodium sulfate and concentrated. The desired product was obtained as a yellow solid (950 mg, yield 88%). LC-MS: 323 [M+1]+, tR=1.299 min.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][NH:4][N:3]=1.[F:11][C:12]([F:24])([F:23])[O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1>>[CH3:1][C:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]([C:17]2[CH:16]=[CH:15][C:14]([O:13][C:12]([F:11])([F:23])[F:24])=[CH:19][CH:18]=2)[N:3]=1
Reactant: COC(=O)c1c[nH]nc1C
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Product: COC(=O)c1cn(-c2ccc(OC(F)(F)F)cc2)nc1C
Yield: 26.8 %

Procedure:
Using methyl 3-methyl-1H-pyrazole-4-carboxylate (6.8 g) synthesized in Example 1(3) and 4-trifluoromethoxyphenylboronic acid (20.0 g) and in the same manner as in Example 17(1), the title object compound (3.9 g, 27%) was obtained as a white solid.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=O)[CH:14]([Br:16])[CH3:15])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][CH:14]([Br:16])[CH3:15])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2cc(C(=O)C(C)Br)ccc21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CCc2cc(CC(C)Br)ccc21
Reaction time: 1 h
Yield: 76.5 %

Procedure:
To a solution of 1-acetyl-5-(2-bromopropionyl)indoline (210 g) in trifluoroacetic acid (700 ml) was added triethylsilane (190 g) over a period of 30 minutes with stirring under ice cooling, the mixture was stirred for 30 minutes under ice cooling, and then for 1 hour at room temperature. After the reaction mixture was concentrated under reduced pressure, the residue was poured into water (2 l), and to the mixture was added hexane (500 ml) and stirred. The precipitates were collected by filtration, washed with hexane, and recrystallized from ethyl acetate-hexane to give 153 g of 1-acetyl-5-(2-bromopropyl)indoline melting at 124°-126° C.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10](=[O:29])[CH2:11][CH2:12][C:13]([O:15][CH2:16][CH2:17][CH2:18][C:19]([O:21]CC1C=CC=CC=1)=[O:20])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H][H]>[Pd].C(O)C>[C:1]([NH:8][CH2:9][C:10](=[O:29])[CH2:11][CH2:12][C:13]([O:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NCC(=O)CCC(=O)OCCCC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCC(=O)CCC(=O)OCCCC(=O)O
Yield: 102.7 %

Procedure:
This compound was prepared from the product of 5a (5.40 g; 13.2 mmol), 10% palladium on activated carbon (250 mg), hydrogen gas, and 96% ethanol (100 mL) as described in Example 2c. 4.30 g product was obtained (yellowish oil) which was used in 5c without any further workup.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=2)[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:23]1([C:2]2[CH:3]=[C:4]([NH:14][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=3)[CH:5]=[N:6][C:7]=2[O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Nc1cnc(OCC(F)(F)F)c(Br)c1)c1cccnc1
Reactant: OB(O)c1ccccc1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(-c2ccccc2)c1)c1cccnc1

Procedure:
The title compound was synthesized in analogy to Example 39, using N-[5-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-nicotinamide (example G) and B-phenyl-boronic acid (CAN 98-80-6) as starting materials; LC-MS (UV peak area/ESI) 100%, 374.1107 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([NH:13]/[N:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:26]=[CH:25][N:24]([C:27]3[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=3)[N:23]=2)=[CH:18][CH:17]=1)=[S:12])([CH3:3])[CH3:2].[F:38][C:39]([F:51])([F:50])[C:40]1[CH:49]=[CH:48][CH:47]=[CH:46][C:41]=1[C:42](=[O:45])[CH2:43]Br>ClCCCl.C(OCC)(=O)C>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:42]([C:41]2[CH:46]=[CH:47][CH:48]=[CH:49][C:40]=2[C:39]([F:38])([F:50])[F:51])([OH:45])[CH2:43][S:12]/[C:11]/1=[N:13]/[N:14]=[CH:15]\[C:16]1[CH:17]=[CH:18][C:19]([C:22]2[N:26]=[CH:25][N:24]([C:27]3[CH:28]=[CH:29][C:30]([O:33][C:34]([F:37])([F:35])[F:36])=[CH:31][CH:32]=3)[N:23]=2)=[CH:20][CH:21]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccccc1NC(=S)N/N=C/c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: O=C(CBr)c1ccccc1C(F)(F)F
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CC(C)c1ccccc1N1/C(=N\N=C/c2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)SCC1(O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
A solution of (E)-N-(2-isopropylphenyl)-2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzylidene)hydrazinecarbothioamide (0.30 g, 0.57 mmol) and 2-(trifluoromethyl)phenacyl bromide (0.22 g, 0.85 mmol) in DCE (30 mL) was heated to reflux and stirred overnight. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), washed with water (2×50 mL), washed with brine solution (1×25 mL), and dried over anhydrous sodium sulfate. The solution was filtered, the filtrate concentrated, and the residue purified by flash chromatography (0-100% ethyl acetate/hexanes) to provide (Z)-3-(2-isopropylphenyl)-2-((E)-(4-(1-(4-(trifluoromethoxy)-phenyl)-1H-1,2,4-triazol-3-yl)benzylidene)hydrazono)-4-(2-(trifluoromethyl)-phenyl)thiazolidin-4-ol as a yellow solid (0.15 g, 38% yield): mp 115-117.5° C.; 1H NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 8.33 (s, 1H), 8.24 (d, J=8.4 Hz, 2H), 8.13 (s, 1H), 7.86-7.77 (m, 5H), 7.73 (d, J=7.2 Hz, 1H), 7.62 (dt, J=21.6, 7.2 Hz, 2H), 7.40 (d, J=8.2 Hz, 2H), 7.37-7.28 (m, 3H), 7.24-7.17 (m, 1H), 4.34 (s, 2H), 3.20 (dt, J=13.7, 6.8 Hz, 2H), 1.25 (d, J=6.9 Hz, 6H); 19F NMR (376 MHz, CDCl3) δ −57.99, −58.02; ESIMS m/z 711 ([M+H]+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([C:9]2[N:13]([C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[N:11][CH:10]=2)=[O:8])=[CH:3][CH:2]=1.C([Mg]Br)C1C=CC=CC=1>ClCCl>[N:1]1[CH:6]=[CH:5][C:4]([CH:7]([C:9]2[N:13]([C:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:12]=[N:11][CH:10]=2)[OH:8])=[CH:3][CH:2]=1
Reactant: O=C(c1ccncc1)c1cncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Br[Mg]Cc1ccccc1
Solvent: ClCCl
Product: OC(c1ccncc1)c1cncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of pyridin-4-yl(1-trityl-1H-imidazol-5-yl)methanone (500 mg, 1.19 mmol) in dichloromethane (25 mL) at room temperature was treated with benzyl magnesium bromide (0.595 mL, 1.78 mmol, 3M in ether) and allowed to react at room temperature and the reaction mixture was then stirred at room temperature for 16 hours. The mixture was quenched with water (20 mL) and a saturated solution of ammonium chloride (20 mL). The residue was isolated in a typical aqueous to give pyridin-4-yl(1-trityl-1H-imidazol-5-yl)methanol, (Intermediate 4) (526 mg, crude).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]3[C:15]([C:16]=2[C:17](=[O:20])[NH:18][CH3:19])=[CH:14][C:13]([C:21]2[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=2)[C:24]([OH:26])=O)=[CH:12][CH:11]=3)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:39]([NH2:48])([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([CH3:41])[CH3:40].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCCl.CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10]3[C:15]([C:16]=2[C:17]([NH:18][CH3:19])=[O:20])=[CH:14][C:13]([C:21]2[CH:29]=[CH:28][CH:27]=[C:23]([C:24](=[O:26])[NH:48][C:39]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)([CH3:41])[CH3:40])[CH:22]=2)=[CH:12][CH:11]=3)=[CH:6][CH:7]=1
Reactant: CC(C)(N)c1ccccc1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)[nH]c2ccc(-c3cccc(C(=O)O)c3)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)[nH]c2ccc(-c3cccc(C(=O)NC(C)(C)c4ccccc4)c3)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.2 %

Procedure:
To a solution of 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-1H-indol-5-yl)benzoic acid (12 mg, 0.031 mmol) and DIPEA (20 μL, 0.115 mmol) in 1,2-dichloroethane (0.5 mL)/DMF (0.1 mL) was added cumylamine (15 μL, 0.10 mmol) and HATU (15 mg, 0.039 mmol). The reaction was stirred at r.t. for 30 min, then the volatiles were evaporated and the residue was purified directly by prep HPLC. Concentration afforded the title compound as a white powder (11 mg, 68% yield). 1H NMR (500 MHz, MeOD) δ ppm 8.52 (s, 1H) 8.09 (d, J=7.93 Hz, 2H) 7.85 (d, J=7.63 Hz, 1H) 7.66-7.77 (m, 3H) 7.49-7.57 (m, 3H) 7.47 (d, J=8.24 Hz, 2H) 7.31 (t, J=7.78 Hz, 2H) 7.23 (t, J=8.85 Hz, 2 H) 7.19 (t, J=7.32 Hz, 1H) 2.89 (s, 3H) 1.78 (s, 6H). LC/MS was performed on a Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. LC/MS method: solvent A=10% CH3CN/90% H2O/0.1% TFA, solvent B=90% CH3CN/10% H2O/0.1% TFA, start % B=0, final % B=100, gradient time=3 min, stop time=4 min, flow rate=4 ml/min, column. Sunfire C18 5 μm 4.6×50 mm; HPLC Rt=1.49 min, (ES+) m/z (MH+)=506. Analytical HPLC method: solvent A=5% CH3CN/95% H2O/0.1% TFA, solvent B=95% CH3CN/5% H2O/0.1% TFA, start % B=10, final % B=100, gradient time=15 min, stop time=18 min, flow rate=1 ml/min. Column. Waters Sunfire C-18, 3.5 μm 4.6×150 mm, Rt=15.29 min, purity=97%; column. Waters Xbridge Phenyl 3.5 μm 4.6×150 mm, Rt=11.59 min, purity=98%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:21])[C:9](=[CH:17][N:18]([CH3:20])C)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[I:22][C:23]1[CH:29]=[CH:28]C(N)=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:21])[C:9](=[CH:17][NH:18][C:20]1[CH:28]=[CH:29][C:23]([I:22])=[CH:24][CH:25]=1)[C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11]
Reactant: CN(C)C=C(C(=O)OC(C)(C)C)C(=O)c1ccccc1Cl
Reactant: Nc1ccc(I)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)C(=CNc1ccc(I)cc1)C(=O)c1ccccc1Cl
Reaction time: 8 h

Procedure:
A solution of 1,1-dimethylethyl 2-chloro-α-[(dimethylamino)methylene]-β-oxo-benzenepropanoate (25.5 mg, 0.082 mmol) in 1 mL of toluene was treated with 4-iodoaniline (17.9 mg, 0.082 mmol) added as a solid in one portion. After stirring overnight, the reaction was concentrated in vacuo and the residue was adsorbed onto silica gel and added to 19.5 cm of flash silica in a 2 cm dia. column. Elution with 5:1 hexanes/EtOAc gave the title compound as a solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N+:8]#[C-:9].NCCCCCC[OH:17].C(OC)=O>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][CH:9]=[O:17]
Reactant: NCCCCCCO
Reactant: [C-]#[N+]CCCCCCO
Solvent: COC=O
Product: O=CNCCCCCCO

Procedure:
The 6-hydroxyhexyl isocyanide used in the preparation of the isocyano copolymer was synthesized as follows: To 214.4 g (2 moles) of 6-aminohexyl alcohol, which was stirred and heated to keep the material molten, was added dropwise 120.1 g (2 moles) of methyl formate. When the addition was completed, the mixture was stirred and heated at reflux for two hours. After removal of the methanol formed in vacuo, the residue was recrystallized from tetrahydrofuran to give 237.4 g of 6-hydroxyhexylformamide, m.p. 43.5°-45°.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][N:10]2[C:19](OC2C=CC([N+]([O-])=O)=CC=2)=[O:20])=[CH:5][CH:4]=1.[NH2:33][C:34]1[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[CH:36][C:35]=1[F:42].[H-].[Na+].O>CC#N>[C:38]([C:37]1[CH:40]=[CH:41][C:34]([NH:33][C:19]([N:10]2[CH2:11][CH2:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C@H:9]2[C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:31])([F:1])[F:32])=[CH:4][CH:5]=2)=[O:20])=[C:35]([F:42])[CH:36]=1)#[N:39]
Reactant: N#Cc1ccc(N)c(F)c1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCc2ccccc2[C@H]1c1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: N#Cc1ccc(NC(=O)N2CCc3ccccc3[C@H]2c2ccc(C(F)(F)F)cc2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (R)-4-nitrophenyl 1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (50 mg, 113 μmol, example 88) and 4-amino-3-fluorobenzonitrile (17 mg, 124 mop in MeCN (0.7 mL) was subjected to a microwave irradiation at 120° C. for 15 min and at 150° C. for 15 min. Then, NaH (60% dispersion in mineral oil, 20 mg) was added and the mixture was then stirred at RT for overnight. Then, H2O (1.0 mL) was added and the mixture was extracted with EtOAc (2×1.5 mL). The combined organic extracts were dried over MgSO4 and concentrated. The residue was then dissolved in a solution of DMSO and MeOH (1:1, 0.1 mL). The solution mixture was then purified by preparative HPLC (0%-100% MeCN 0.1% TFA/H2O 0.1% TFA) to give a desired product, which was then dissolved in MeOH (1.0 mL). The solution was then washed through PL-HCO3 MP-resin and the resin was washed with MeOH (2×0.5 mL). The combined washings were concentrated and dried under vacuum to give the title compound as a colorless solid. MS (ESI, positive ion) m/z: 440 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7](Cl)=[N:8][C:9]([NH:11][C:12]([NH:14][C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])=[O:13])=[CH:10][C:5]=2[NH:4][N:3]=1.[CH3:24][O-:25].[Na+].Cl>CO>[NH2:1][C:2]1[C:6]2[C:7]([O:25][CH3:24])=[N:8][C:9]([NH:11][C:12]([NH:14][C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])=[O:13])=[CH:10][C:5]=2[NH:4][N:3]=1
Reactant: C[C@@H](NC(=O)Nc1cc2[nH]nc(N)c2c(Cl)n1)c1ccccc1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1nc(NC(=O)N[C@H](C)c2ccccc2)cc2[nH]nc(N)c12
Temperature: 120 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (R)-1-(3-amino-4-chloro-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (0.12 g, 0.36 mmol) in methanol (3.0 mL) was added sodium methoxide (0.78 mL, 3.62 mmol, 25% solution in MeOH) and stirred at 120° C. for 1 h in a microwave reactor. After confirming the completion of reaction by TLC, the reaction mixture was acidified with 1.5N HCl and concentrated under reduced pressure and crude product which was purified by preparative HPLC to afford (R)-1-(3-amino-4-methoxy-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea. 1H NMR (ppm, 400 MHz, DMSO-d6): δ 11.48 (s, 1H), 8.76 (s, 1H), 7.94 (s, 1H), 7.35-7.33 (m, 4H), 7.26-7.21 (m, 1H), 6.86 (d, J=8.00 Hz, 1H), 5.12 (s, 2H), 4.88-4.85 (m, 1H), 3.87 (s, 3H), 1.41 (d, J=8.00 Hz, 3H), MS ES calc'd. for C16H18N6O2 [M+H]+ 327. Found 327.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([OH:12])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([CH3:3])[CH3:2].Cl[C:14]1[C:19]([CH3:20])=[CH:18][C:17]([N+:21]([O-:23])=[O:22])=[CH:16][C:15]=1[C:24]#[N:25].C(=O)([O-])[O-].[K+].[K+]>CC(CC)=O>[CH:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[O:12][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([N+:21]([O-:23])=[O:22])=[CH:16][C:15]=1[C:24]#[N:25])([CH3:3])[CH3:2]
Reactant: Cc1cc([N+](=O)[O-])cc(C#N)c1Cl
Reactant: COc1ccc(O)cc1C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C#N)cc1C(C)C
Yield: 90.4 %

Procedure:
A mixture of 3-isopropyl-4-methoxyphenol (200 mg), 4-chloro-3-cyano-5-methylnitrobenzene (200 mg) and potassium carbonate (211 mg) in methylethylketone (8 mL) was refluxed for 18 h. The dark mixture was concentrated in vacuo, partitioned between ethyl acetate/water, the organic layer washed with about 2N sodium hydroxide, brine, dried over sodium sulfate and concentrated to a dark oil. Flash chromatography (10% ethyl acetate/hexanes) afforded 2-(3-isopropyl-4-methoxy-phenoxy)-3-methyl-5-nitrobenzonitrile as a yellow oil (300 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([NH2:8])[N:5]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=[C:4]2[CH:3]=1.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>CN(C=O)C>[N:18]1([C:2]2[CH:7]=[C:6]([NH2:8])[N:5]3[N:9]=[C:10]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[N:11]=[C:4]3[CH:3]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: Nc1cc(Br)cc2nc(-c3ccccc3)nn12
Reactant: C1COCCN1
Solvent: CN(C)C=O
Product: Nc1cc(N2CCOCC2)cc2nc(-c3ccccc3)nn12
Yield: 49.1 %

Procedure:
A mixture of 40 mg (0.138 mmol) 7-bromo-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine, 241 μl (2.8 mmol) morpholin and 225 mg (0.69 mmol) CS2CO3 in 200 μl DMF was heated 20 h to 140° C. filtration and subsequent purification with reversed phase column chromatography with an acetonitrile/water gradient yielded 20 mg (49%) of the title compound, MS m/e M+H+ (100%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][C@@:8]1([CH2:14][C:15]([O:17]C)=[O:16])[CH2:12][CH2:11][C@@H:10]([CH3:13])[CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH3:1][O:5][C:6]([CH2:7][C@:8]1([CH2:14][C:15]([OH:17])=[O:16])[CH2:12][CH2:11][C@@H:10]([CH3:13])[CH2:9]1)=[O:19]
Reactant: COC(=O)C[C@]1(CC(=O)OC(C)(C)C)CC[C@@H](C)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C[C@]1(CC(=O)O)CC[C@@H](C)C1
Yield: 99.8 %

Procedure:
[(1S,3R)-1-Methoxycarbonylmethyl-3-methyl-cyclopentyl]-acetic acid tert-butyl ester (6.64 g, 24.6 mmol) and trifluoroacetic acid (10 mL) were stirred together in dichloromethane (30 mL) for 17 hours at room temperature. The mixture was carefully poured into aqueous sodium carbonate and extracted with ethyl acetate (200 mL). The aqueous was acidified to pH 1 with concentrated hydrochloric acid and re-extracted with ethyl acetate (3×200 mL), dried (MgSO4), and concentrated in vacuo. The residue was purified by chromatography (silica gel, eluting with a gradient of heptane to 1:1 heptane:ethyl acetate) to give 5.26 g (100%) of [(1R,3R)-1-methoxycarbonylmethyl-3-methyl-cyclopentyl]-acetic acid;
Reaction SMILES: C[N:2](C)[C:3]([C:5]1[CH:32]=[CH:31][C:8]2[N:9]([CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[C:10]([CH2:12][N:13]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[N:15]([CH:22]([CH3:24])[CH3:23])[C:14]3=[O:25])=[N:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[NH4+]>>[CH:22]([N:15]1[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:13]([CH2:12][C:10]2[N:9]([CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[C:8]3[CH:31]=[CH:32][C:5]([C:3]([NH2:2])=[O:4])=[CH:6][C:7]=3[N:11]=2)[C:14]1=[O:25])([CH3:23])[CH3:24]
Reactant: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2cc(C(=O)N(C)C)ccc21
Agent: [NH4+]
Agent: [OH-]
Product: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2cc(C(N)=O)ccc21

Procedure:
2-(3-Isopropyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazole-5-carboxylic acid amide was prepared by the same procedure as 2-(3-isopropyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazole-5-carboxylic acid dimethylamide, except using ammonium hydroxide.
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:13][C:14]2[N:18]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:17]3[CH:24]=[CH:25][C:26]([C:28]([OH:30])=O)=[CH:27][C:16]=3[N:15]=2)[C:5]1=[O:31])([CH3:3])[CH3:2].C(Cl)CCl.[CH3:36][NH:37][CH3:38]>CN(C1C=CN=CC=1)C>[CH3:36][N:37]([CH3:38])[C:28]([C:26]1[CH:25]=[CH:24][C:17]2[N:18]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:14]([CH2:13][N:6]3[C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[N:4]([CH:1]([CH3:3])[CH3:2])[C:5]3=[O:31])=[N:15][C:16]=2[CH:27]=1)=[O:30]
Reactant: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2cc(C(=O)O)ccc21
Reactant: CNC
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Product: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2cc(C(=O)N(C)C)ccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 49 %

Procedure:
A mixture of 2-(3-isopropyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazole-5 carboxylic acid (42 mg, 0.1 mmol), EDC (23 mg, 0.12 mmol), DMAP (14 mg, 0.12 mmol) and dimethylamine (1M in THF, 0.12 mL) was stirred for 12 h at ambient temperature. The solvent was evaporated and the residue purified by prep-HPLC (gradient 10%-100% B) to give 22 mg (49%) of 2-(3-isopropyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazole-5-carboxylic acid dimethylamide as a white solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]2[CH:9]=[C:10]([C:19]#[C:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=3)[CH:11]=[CH:12][C:13]=2[C:14]([CH3:18])([CH3:17])[CH2:15][CH:16]=1)(=O)=O.[CH:34]#[C:35][CH2:36][CH2:37][CH3:38]>C(NCC)C.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:17][C:14]1([CH3:18])[C:13]2[CH:12]=[CH:11][C:10]([C:19]#[C:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=3)=[CH:9][C:8]=2[C:7]([C:34]#[C:35][CH2:36][CH2:37][CH3:38])=[CH:16][CH2:15]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(OS(=O)(=O)C(F)(F)F)=CCC3(C)C)cc1
Reactant: C#CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCNCC
Product: CCCC#CC1=CCC(C)(C)c2ccc(C#Cc3ccc(C(=O)OCC)cc3)cc21
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A solution (flushed with argon) of 201.3 mg (0.42 mmol) of ethyl 4-[(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl]benzoate (Compound 66), 286.5 mg (4.21 mmol) of 1-pentyne, 59.5 mg (0.08 mmol) of bis(triphenylphosphine)palladium(II) chloride and 32.0 mg (0.17 mmol) of cuprous iodide in 2.5 ml of diethylamine was heated to 70° C. in a pressure vial for 6 hours. After stirring overnight at room temperature, the mixture was diluted with EtOAc (25 ml) and washed with water and brine. The organic phase was dried over MgSO4, concentrated in vacuo and purified by column chromatography (silica, 5% Et2O-hexanes) to give the title compound as a colorless, air-sensitive oil.