Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH3:16])[CH2:11][CH2:10]2)=[CH:5][C:4]=1[Cl:17].[CH3:18][C:19]1[N:24]=[C:23]([SH:25])[N:22]=[C:21]([OH:26])[CH:20]=1.C(N(CC)CC)C>C(O)C>[Cl:17][C:4]1[CH:5]=[C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH3:16])[CH2:11][CH2:10]2)[CH:7]=[CH:8][C:3]=1[CH2:2][S:25][C:23]1[N:22]=[C:21]([OH:26])[CH:20]=[C:19]([CH3:18])[N:24]=1
Reactant: CCN1CCN(c2ccc(CBr)c(Cl)c2)CC1
Reactant: Cc1cc(O)nc(S)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCN1CCN(c2ccc(CSc3nc(C)cc(O)n3)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-[4-(bromomethyl)-3-chlorophenyl]-4-ethylpiperazine, 6-methyl-2-sulfanylpyrimidin-4-ol (1.42 g, 10 mmol) and triethylamine (2.8 mL, 20 mmol) were mixed in ethanol (50 mL). The mixture was stirred at room temperature for 2 hours. After evaporation, water (100 mL) was added. The suspension was filtered and washed with water and ethyl acetate to provide crude product, which was further purified by CombiFlash to yield a white solid (400 mg, 5% overall yield); 1H NMR (400 MHz, DMSO-d6): δ 1.16 (t, 3H), 2.20 (s, 3H), 2.48 (q, 4H), 3.06 (q, 4H), 4.35 (s, 2H), 5.98 (br, 1H), 6.88 (d, 1H), 7.00 (s, 1H), 7.42 (d, 1H); M+ 379.
Reaction SMILES: [CH3:1][Mg]Br.[CH2:4]([C:6]1[CH:7]=[CH:8][C:9]([F:33])=[C:10]([C:12]2[CH:13]=[N:14][C:15]([N:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:27]([O:29][CH3:30])=[O:28])[CH:25]=4)[C:20]([CH:31]=[O:32])=[CH:19]3)=[N:16][CH:17]=2)[CH:11]=1)[CH3:5]>C1COCC1>[CH2:4]([C:6]1[CH:7]=[CH:8][C:9]([F:33])=[C:10]([C:12]2[CH:17]=[N:16][C:15]([N:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:27]([O:29][CH3:30])=[O:28])[CH:25]=4)[C:20]([CH:31]([OH:32])[CH3:1])=[CH:19]3)=[N:14][CH:13]=2)[CH:11]=1)[CH3:5]
Reactant: CCc1ccc(F)c(-c2cnc(-n3cc(C=O)c4ccc(C(=O)OC)cc43)nc2)c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CCc1ccc(F)c(-c2cnc(-n3cc(C(C)O)c4ccc(C(=O)OC)cc43)nc2)c1
Reaction time: 6 h

Procedure:
Methylmagnesium bromide (3 M in ether, 0.45 mL, 1.33 mmol) was added at 0° C. to a solution of 331c) (0.36 g, 0.89 mmol) in THF (70 mL) and the resulting mixture was stirred at this temperature for 6 h. The mixture was quenched with ammonium chloride solution (20 mL) and extracted with ethyl acetate (2×50 mL). The organic phase was washed with brine, dried over sodium sulfate and evaporated. The residue was purified by flash column chromatography [silica; dichloromethane with 0-1.5% methanol]. Light yellow solid. Yield: 0.22 g (59% of theory)
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([CH:8]=[CH:9][CH:10]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:14][C:15]([CH2:21][C:22]#[N:23])=[C:16]([C:19]#[N:20])[C:17]#[N:18]>>[NH2:14][C:15](/[C:21](=[CH:10]\[CH:9]=[CH:8]\[C:7]1[CH:12]=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)/[C:22]#[N:23])=[C:16]([C:19]#[N:20])[C:17]#[N:18]
Reactant: O=CC=Cc1ccc([N+](=O)[O-])cc1
Reactant: N#CCC(N)=C(C#N)C#N
Product: N#CC(C#N)=C(N)/C(C#N)=C\C=C\c1ccc([N+](=O)[O-])cc1

Procedure:
The compound was prepared as described in Example 3 by adding 4-nitrocinnamaldehyde (0.051 g, 0.29 mmol) to 2-amino-1-propene-1,1,3-tricarbonitrile (0.038 g, 0.29 mmol). After refluxing for 4 h and recrystallization from ethanol a yellow solid was obtained (0.08 g, 51%). The product gave the following analytical data:
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21](O)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]2[CH2:37][CH2:36][N:35]([CH2:38][C:39]([NH2:41])=[O:40])[CH2:34][CH2:33]2)=[CH:28][CH:27]=1>>[C:1]([NH:5][S:6]([C:9]1[CH:10]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([CH:32]5[CH2:33][CH2:34][N:35]([CH2:38][C:39]([NH2:41])=[O:40])[CH2:36][CH2:37]5)=[CH:28][CH:27]=4)=[N:22]3)=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:7])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: NC(=O)CN1CCC(c2ccc(N)cc2)CC1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(O)nn23)c1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(Nc4ccc(C5CCN(CC(N)=O)CC5)cc4)nn23)c1

Procedure:
2-(4-{4-[7-(3-tert-Butylsulfamoyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-1-yl)-acetamide was prepared from N-tert-butyl-3-(2-hydroxy-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide and 2-[4-(4-amino-phenyl)-piperidin-1-yl]-acetamide in an analogous manner to Example 1052a. Product isolated as a red foam (68 mg, 70%). LCMS (m/e) 562 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.85 (s, 1H), 8.73 (s, 1H), 8.24 (d, 1H, J=8.0 Hz), 7.87 (d, 1H, J=7.9 Hz), 7.62-7.54 (m, 3H), 7.29 (d, 2H, J=8.4 Hz), 7.17 (bs, 1H), 7.07 (d, 1H, J=4.8 Hz), 6.98 (s, 1H), 6.85 (d, 1H, J=4.8 Hz), 5.65 (bs, 1H), 4.72 (s, 1H), 3.08-2.95 (m, 4H), 2.59-2.48 (m, 1H), 2.37-2.25 (m, 2H), 1.94-1.73 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[S:7][C:6]=2[CH:11]=1.[CH2:12]([C:14]1[CH:15]=[C:16]([N:20]=[C:21]=[O:22])[CH:17]=[CH:18][CH:19]=1)[CH3:13].C(N(CC)CC)C>C(C(C)=O)C>[CH2:12]([C:14]1[CH:15]=[C:16]([NH:20][C:21]([O:1][C:2]2[CH:3]=[CH:4][C:5]3[O:9][C:8](=[O:10])[S:7][C:6]=3[CH:11]=2)=[O:22])[CH:17]=[CH:18][CH:19]=1)[CH3:13]
Reactant: CCc1cccc(N=C=O)c1
Reactant: O=c1oc2ccc(O)cc2s1
Solvent: CCC(C)=O
Solvent: CCN(CC)CC
Product: CCc1cccc(NC(=O)Oc2ccc3oc(=O)sc3c2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
5-hydroxy-1,3-benzoxathiol-2-one (15.0 grams) was mixed with 3-ethylphenyl isocyanate (13.1 grams) in 180 milliliters of methyl ethyl ketone in the presence of 0.90 gram of triethylamine. This solution was heated at reflux temperature with stirring for 3 hours and 15 minutes. The solvent was then removed by evaporation in vacuo and the residual, viscous oil was dissolved in a hot mixture of ethyl acetate and methylcyclohexane. Upon slowly cooling to room temperature, the solution gave the purified 5-[(3-ethylphenyl)carbamoyloxy]-1,3-benzoxathiol-2-one as a white crystalline solid with a melting point of 96°-97° C. Elemental analysis calculated for C16H13NO4S (percent): carbon--60.94; hydrogen--4.15; nitrogen--4.44. Found: carbon--61.2; hydrogen--4.26; nitrogen--4.54.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5]([CH2:12][O:13][CH2:14][O:15][CH3:16])=[N:6][C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)[CH3:2].[CH:17]1([CH:22]=O)[CH2:21][CH2:20][CH2:19][CH2:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[CH:17]1([CH2:22][N:3]([CH2:1][CH3:2])[C:4]2[C:5]([CH2:12][O:13][CH2:14][O:15][CH3:16])=[N:6][C:7]([O:10][CH3:11])=[CH:8][CH:9]=2)[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: O=CC1CCCC1
Reactant: CCNc1ccc(OC)nc1COCOC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CCN(CC1CCCC1)c1ccc(OC)nc1COCOC
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.5 %

Procedure:
A solution of N-ethyl-6-methoxy-2-[(methoxymethoxy)methyl]pyridin-3-amine (7.20 g, 31.8 mmol) and cyclopentanecarbaldehyde (3.75 g, 38.2 mmol) in 1,2-dichloroethane (240 mL) was added with sodium triacetoxyborohydride (8.75 g, 41.3 mmol), and the mixture was stirred at room temperature for 12 hours. The reaction mixture was added with water, and extracted with chloroform. The organic layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:1) to obtain N-(cyclopentylmethyl)-N-ethyl-6-methoxy-2-[(methoxymethoxy)methyl]pyridin-3-amine (8.39 g, 86%) as pale yellow oil.
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][OH:7])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl>[S:18]([O:7][CH2:6][CH2:5][O:4][CH:1]([CH3:3])[CH3:2])(=[O:20])(=[O:19])[CH3:17]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)OCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)OCCOS(C)(=O)=O
Reaction time: 2 h

Procedure:
Combine 2-isopropoxyethanol (1.0 g, 9.6 mmol), N,N-diisopropylethylamine (2.73 g, 21.12 mmol), and dichloromethane (20 mL). Cool in an ice bath. Add dropwise methanesulfonyl chloride (1.43 g, 9.6 mmol). After 2 hours, dilute the reaction mixture with dichloromethane and extract with 1 M hydrochloric acid solution, a saturated solution of sodium bicarbonate, and then brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give a residue. Distill the residue to give 2-(isopropoxy)ethyl mesylate: bp; 84° C. at 0.1 mm Hg.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[N+:13]([C:5]1[CH:4]=[C:3]([OH:2])[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=1)([O-:15])=[O:14]
Reactant: COc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(O)cc(C(F)(F)F)c1
Reaction time: 8 h
Yield: 37.6 %

Procedure:
To 1-methoxy-3-nitro-5-(trifluoromethyl)benzene (2.21 g, 10.0 mmol) in DCM at 0° C. was added BBr3 (10 equivalents) dropwise over 5 minutes. The solution was allowed to warm to r.t overnight at which point it was quenched with sat. aqueous NaHCO3 and extracted with EtOAc. The organic layer was washed with H2O and brine, dried over MgSO4, filtered, and concentrated in vacuo to give 3-nitro-5-(trifluoromethyl)phenol (778 mg, 3.76 mmol, 37%), 1H NMR (300 MHz, DMSO-d6) δ 11.22 (s, 1H), 7.90 (s, 1H), 7.81 (s, 1H), 7.51 (s, 1H); LC-MS (ESI) m/z 208 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[CH:10][C:11]([CH2:14][N:15]2[C:20](=[O:21])[C:19]([C:22]([NH:24][CH2:25][C:26]([O:28]C(C)(C)C)=[O:27])=[O:23])=[C:18]([OH:33])[C:17]3[CH2:34][S:35][CH2:36][C:16]2=3)=[N:12][CH:13]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[CH:10][C:11]([CH2:14][N:15]2[C:20](=[O:21])[C:19]([C:22]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:23])=[C:18]([OH:33])[C:17]3[CH2:34][S:35][CH2:36][C:16]2=3)=[N:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)CNC(=O)c1c(O)c2c(n(Cc3cnc(-c4ccccc4F)cn3)c1=O)CSC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CNC(=O)c1c(O)c2c(n(Cc3cnc(-c4ccccc4F)cn3)c1=O)CSC2
Temperature: 25 °C

Procedure:
Product of Step A (110 mg, 0.215 mmol) was dissolved in DCM (1 mL) and TFA (1 mL) was added. The reaction was stirred at ambient temperature for 3½h. The reaction was concentrated and the residue was purified on a semi-preparative C-18 reverse phase chromatography column eluted with 0-100% MeCN in water. The desired fractions were concentrated affording the title compound (26-1). 457.0 (M+1); Rt=3.09 min.
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][C:13]([C:17]([O:19]CC)=O)=[C:14]([CH3:16])[N:15]=2)=[CH:7][CH:6]=1>C(O)C>[CH3:16][C:14]1[N:15]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)[S:12][C:13]=1[C:17]([NH:2][CH3:1])=[O:19]
Reactant: CCOC(=O)c1sc(-c2ccc(OC)cc2)nc1C
Reactant: CN
Solvent: CCO
Product: CNC(=O)c1sc(-c2ccc(OC)cc2)nc1C
Yield: 69 %

Procedure:
Into a mixed solvent of 80 ml of 40% methylamine and 600 ml of ethanol, 13.9 g of ethyl 2-(4-methoxyphenyl)-4-methylthiazole-5-carboxylate was dissolved. Then, in a similar manner as in Example 1, the object was obtained as colourless minute aciculate melting at 157.5° to 159° C. in an amount of 9.1 g corresponding to the yield of 69%.
Reaction SMILES: Br[C:2]1[N:11]=[C:5]2[CH:6]=[C:7]([Br:10])[CH:8]=[CH:9][N:4]2[N:3]=1.Cl.[F:13][CH2:14][CH2:15][NH:16][CH3:17].C(N(C(C)C)CC)(C)C>C(O)C>[Br:10][C:7]1[CH:8]=[CH:9][N:4]2[N:3]=[C:2]([N:16]([CH2:15][CH2:14][F:13])[CH3:17])[N:11]=[C:5]2[CH:6]=1
Reactant: CNCCF
Reactant: Brc1ccn2nc(Br)nc2c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CN(CCF)c1nc2cc(Br)ccn2n1
Temperature: 130 °C
Yield: 34.5 %

Procedure:
To the solution of 2,7-dibromo-[1,2,4]triazolo[1,5-a]pyridine (5 g, 18.05 mmol) and (2-fluoro-ethyl)-methyl-amine hydrochloride (20 g, 180.5 mmol) in ethanol (30 ml) was added di-isopropylethylamine (47 ml, 270.75 mmol) and the reaction mixture was heated at 130° C. in a sealed tube for 84 hours. The reaction mixture was concentrated under reduced pressure, the resulting residue was diluted with dichloromethane (100 ml). The organic layer was washed with water (2×75 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography over silicagel using 0.5% methanol/dichloromethane as eluent affording (7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-(2-fluoro-ethyl)-methyl-amine (1.7 g, 34.5%) as an off white solid. MS: m/z=275.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:8]=[CH:7]2.[Se](=O)=[O:19]>C(Cl)Cl>[C:12]1([C:9]2[CH:8]=[CH:7][C:6]3[C:11](=[C:2]([CH:1]=[O:19])[CH:3]=[CH:4][CH:5]=3)[N:10]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=[Se]=O
Reactant: Cc1cccc2ccc(-c3ccccc3)nc12
Solvent: ClCCl
Product: O=Cc1cccc2ccc(-c3ccccc3)nc12
Temperature: 140 °C
Reaction time: 5 h
Yield: 43.3 %

Procedure:
8.46 g of 8-methyl-2-phenylquinoline [compare Atwell, G. J. et al., J. Med. Chem. 32, 396-401 (1989)] are mixed with 8.9 g (80 mmol) of selenium dioxide and heated first to 140° C. with stirring, then to 160° C. for 5 hours. The mixture is cooled, a further 2.5 g of selenium dioxide are added and the mixture is stirred at 160° C. for 2.5 hours. It is cooled, stirred with methylene chloride, the solid is filtered off and the filtrate is concentrated. The mixture obtained is purified by flash chromatography on silica gel using toluene/hexane 1:1 and toluene. 3.9 g of beige-colored crystals of melting point 100-102° C. are obtained.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].[CH2:8]([N:14]1[C:23]2[C:18](=[CH:19][C:20]([CH3:24])=[CH:21][CH:22]=2)[C:17]([O:25][CH3:26])=[C:16]([CH2:27]Br)[C:15]1=[O:29])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>CN(C)C=O.C(OCC)(=O)C>[CH2:8]([N:14]1[C:23]2[C:18](=[CH:19][C:20]([CH3:24])=[CH:21][CH:22]=2)[C:17]([O:25][CH3:26])=[C:16]([CH2:27][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)[C:15]1=[O:29])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCn1c(=O)c(CBr)c(OC)c2cc(C)ccc21
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCn1c(=O)c(Cn2cncn2)c(OC)c2cc(C)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
A solution of 1,2,4-triazole (0.033 g) in dimethylformamide (0.7 ml) was stirred at ice-bath temperature with 60% sodium hydride (0.02 g) for 10 mins under nitrogen and then a solution of 1-hexyl-3-bromomethyl-4-methoxy-6-methyl-2(1H)-quinolinone (Example 14, 0.14 g) in dimethylformamide (1.7 ml) was added to it. The mixture was stirred at room temperature for 2 hours, then diluted with ethyl acetate and then washed several times with water. The organic layer was dried and evaporated under reduced pressure. The resulting crude reaction product was chromatographed on silica-gel (4 g). Elution with 2.5% methanol-ethyl acetate gave 1-hexyl-3-(1,2,4-triazol-1-ylmethyl)-4-methoxy-6-methyl-2(1H)-quinolinone as white crystals (80%). That the expected product was obtained was confirmed by the spectral data: MS: m/e 354 (M.+); NMR (CDCl3): δ4.15 (s, H, OCH3), 5.42 (s, 2H, CH2), 7.86, 8.5 (s, 2H, CH=).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[N:14]>>[N:1]1([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[N:14])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: N#CCCCCCCl
Product: N#CCCCCCN1CCOCC1

Procedure:
Using morpholine and 6-chloro-hexanenitrile as substrates. MS (ion spray) m/z 183.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].C(N(CC)CC)C.[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[F:29])[NH2:25].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[Cl:21][C:22]1[CH:23]=[C:24]([NH:25][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=2)[CH:26]=[CH:27][C:28]=1[F:29]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: Cc1ccc(C(=O)Cl)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C(=O)Nc2ccc(F)c(Cl)c2)cc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
To a solution of 4-methyl-3-nitrobenzoyl chloride (2.0 g) in dichloromethane (20 ml), a solution of triethylamine (0.7 ml) and 3-chloro-4-fluoroaniline (0.7 g) in dichloromethane (15 ml) was added dropwise in an ice-bath with the temperature no more than 5° C. After addition, the reaction was carried out for 30 min in an ice-bath, and then at room temperature overnight. The completion of reaction was indicated by TLC. Then potassium carbonate solution (10%) was added to precipitate a solid. The mixture was left to stand, and filtered. The filter cake was washed with water, and dried to give a pale yellow powdered solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[N:24]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:29]([N:24]5[CH2:28][CH2:27][CH2:26][CH2:25]5)=[O:30])=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: O=C(Cl)N1CCCC1
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)N4CCCC4)nc3cc21

Procedure:
Pyrrolidine-1-carboxylic acid[3-(5-ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-amide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (140 mg, 0.45 mmol) and 1-pyrolidine carbonyl chloride (154 μl, 1.40 mmol). The title compound was obtained as light grey powder (50 mg, 275).
Reaction SMILES: [CH3:1][Si:2]([CH3:17])([CH3:16])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[CH:8]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.CON(C)[C:31](=[O:47])[C:32]1[CH:37]=[CH:36][C:35]([B:38]2[O:42][C:41]([CH3:44])([CH3:43])[C:40]([CH3:46])([CH3:45])[O:39]2)=[CH:34][CH:33]=1.O>C1COCC1>[CH3:43][C:41]1([CH3:44])[C:40]([CH3:45])([CH3:46])[O:39][B:38]([C:35]2[CH:34]=[CH:33][C:32]([C:31]([C:8]3[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:17])([CH3:16])[CH3:1])[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[N:9]=3)=[O:47])=[CH:37][CH:36]=2)[O:42]1
Reactant: CON(C)C(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: C[Si](C)(C)CCOCn1cnc2ccccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)OB(c2ccc(C(=O)c3nc4ccccc4n3COCC[Si](C)(C)C)cc2)OC1(C)C
Reaction time: 1 h
Yield: 53.1 %

Procedure:
To a solution of 1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzo[d]imidazole (6.06 g) in THF (50 mL) was added LiHMDS (1 M solution in THF, 30 ml) dropwise at 0° C. After stirring for 1 h, a solution of N-methoxy-N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (7.10 g) in THF (50 mL) was added dropwise, and the mixture was stirred for 1 h at 0° C. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/AcOEt) and crystallized from hexane to give the title compound (6.20 g). 1H NMR (300 MHz, CDCl3) δ −0.11 (9H, s), 0.84-0.91 (2H, m), 1.37 (12H, s), 3.55-3.62 (2H, m), 6.03 (2H, s), 7.37-7.43 (1H, m), 7.45-7.50 (1H, m), 7.65-7.70 (1H, m), 7.91-7.98 (3H, m), 8.22-8.26 (2H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][CH2:11][C:10]2=O)[CH:6]=[CH:7][CH:8]=1.[CH3:18][O:19][C:20](=[O:41])[CH:21]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1(C)C=CC=CC=1.CCOCC>[CH3:18][O:19][C:20](=[O:41])[CH:21]=[C:10]1[CH2:11][CH2:12][C:13]([CH3:16])([CH3:15])[CH2:14][CH:9]1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1cccc(C2CC(C)(C)CCC2=O)c1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COC(=O)C=C1CCC(C)(C)CC1c1cccc(OC)c1
Yield: 33 %

Procedure:
Dissolve 2-(3-methoxy-phenyl)-4,4-dimethyl-cyclohexanone (13.1 g, 56.4 mmol) in toluene (135 ml), add (triphenyl-λ5-phosphanylidene)-acetic acid methyl ester (28.3 g, 84.6 mmol. Heat reaction mixture at reflux stirring over night. Dilute with ether, filter and concentrate. Chromatograph on a biotage eluting with 10% ethyl acetate in hexanes to give the title compound (5.3 g 33%): 1H NMR (CDCl3) δ 7.27-7.23(m, 1H), 6.88-6.77 (m, 3H),5.01 (s, 1H), 3.77 (s, 3H), 3.56 (s, 3H), 3.53-3.48 (m, 1H), 2.19-2.10 (m, 1H), 1.78-1.58 (m, 3H), 1.46-1.38 (m, 1H), 1.25-1.20 (m, 1H), 1.11 (s, 3H), 0.96 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)[N:6]=1.C(N(CC)CC)C.Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25]>O1CCCC1>[N+:13]([C:10]1[CH:9]=[CH:8][C:7]([C:5]2[N:6]=[C:2]([NH:1][C:24](=[O:25])[O:26][CH2:27][CH3:28])[S:3][CH:4]=2)=[CH:12][CH:11]=1)([O-:15])=[O:14]
Reactant: CCOC(=O)Cl
Reactant: Nc1nc(-c2ccc([N+](=O)[O-])cc2)cs1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)Nc1nc(-c2ccc([N+](=O)[O-])cc2)cs1
Temperature: 25 °C
Reaction time: 84 h

Procedure:
In 300 ml of tetrahydrofuran, was suspended 4.42 g of 2-amino-4-p-nitrophenylthiazole, followed by a further addition of 20 ml of triethylamine. The mixture was cooled to about 5° C., to which 10.5 ml of ethyl chloroformate was added dropwise. Then, the reaction mixture was stirred at room temperature for 3.5 days. Any insoluble matter was filtered off from the reaction mixture, and the filtrate was concentrated and then washed in ethyl acetate successively with water, dilute hydrochloric acid, and water. Then, the ethyl acetate solution was concentrated to about 50 ml and the resulting crystals were separated by filtration and then subjected to column chromatography on silica gel. The reaction product was eluted with a benzene/ethyl acetate mixed solvent. The resultant product was recrystallized from ethyl acetate to obtain 2.8 g of ethyl N-(4-p-nitrophenyl-2-thiazolyl)carbamate.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([I:14])=[N:10][NH:11]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:15]C([O-])(C)C.[K+].IC>C1COCC1>[C:1]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([I:14])=[N:10][N:11]2[CH3:15])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)c1ccc2c(I)n[nH]c2c1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: Cn1nc(I)c2ccc(C(C)(C)C)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
To a solution of 6-tert-butyl-3-iodo-1H-indazole (820 mg, 2.73 mmol) in THF (8 ml) at 0° C. was added KOt-Bu (429 mg, 3.82 mmol). The reaction mixture was stirred at 0° C. for 30 min then added iodomethane (0.24 ml, 3.82 mmol). Stirred at 0° C. for 30 min then warmed to room temperature and stirred for 1.5 h. The reaction was quenched with water and extracted with EtOAc (2×). The combined organics were washed with brine then dried over MgSO4 and concentrated. The crude residue was purified by silica gel chromatography with 10% to 50% EtOAc/heptane to afford 592 mg (69%) of 6-tert-butyl-3-iodo-1-methyl-1H-indazole as a white solid. 1H NMR (CDCl3, 300 MHz): δ (ppm) 7.37-7.43 (m, 1H), 7.31 (d, J=9.8 Hz, 2H), 4.10 (s, 3H), 1.41 (s, 9H). The minor 6-tert-butyl-3-iodo-2-methyl-1H-indazole regioisomer was also observed but not isolated.