Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[NH:8]1[CH2:11][CH:10]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)=[O:13])[CH2:9]1.N1CC(C(NC2C=CC(OC3CCN(C(OC(C)(C)C)=O)CC3)=CC=2)=O)[CH2:35]1>>[CH3:35][C:5]1[N:4]=[CH:3][C:2]([N:8]2[CH2:11][CH:10]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH:21]4[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26]4)=[CH:17][CH:16]=3)=[O:13])[CH2:9]2)=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NC(=O)C3CNC3)cc2)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(NC(=O)C3CNC3)cc2)CC1
Reactant: Brc1cccnc1
Product: Cc1ccc(N2CC(C(=O)Nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)C2)cn1

Procedure:
The title compound was prepared as described in Example 1C, substituting 5-bromo-2-methylpyridine for 3-bromopyridine and tert-butyl 4-(4-(azetidine-3-carboxamido)phenyl)piperidine-1-carboxylate for tert-butyl 4-(4-(azetidine-3-carboxamido)phenoxy)piperidine-1-carboxylate.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:5]P(=O)(OC)OC.[CH:20]([C:22]1[O:23][CH:24]=[CH:25][C:26](=[O:39])[C:27]=1[O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=O.C(O)(=O)C>C1COCC1>[O:3]=[C:4]([CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)/[CH:5]=[CH:20]/[C:22]1[O:23][CH:24]=[CH:25][C:26](=[O:39])[C:27]=1[O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]
Reactant: CCOC(=O)CCCCCOc1c(C=O)occc1=O
Reactant: COP(=O)(CC(=O)CCc1ccccc1)OC
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)CCCCCOc1c(/C=C/C(=O)CCc2ccccc2)occc1=O
Reaction time: 1 h
Yield: 61.6 %

Procedure:
To a solution, under nitrogen, of 0.187 g (3.9 mmole) of sodium hydride (50% dispersion in mineral oil) in 10 ml of dry THF was added dropwise 1.2 g (4.95 mmole) of dimethyl (2-oxo-4-phenylbutyl)-phosphonate. The heterogeneous mixture was stirred for 1.0 hour then a solution of 1.0 g (3.54 mmole) of 2-formyl-3-(5-carboethoxypentyloxy)-4-pyrone, prepared by the procedure of Examples 1 and 2, in 5 ml of THF was added. The mixture was stirred for 15 min then was neutralized to pH 7 with glacial acetic acid. The neutralized solution was concentrated by rotary evaporation and the residue dissolved in methylene chloride. The organic solution was washed with saturated brine solution and dried over magnesium sulfate. Removal of the solvent left an oil which was purified by chromatography on silica gel using ether as the eluent. Concentration of the fractions containing product furnished 0.90 g (64%) of pure 2-(3-oxo-5-phenyl-trans-1-pentenyl)-3-(5-carboethoxypentyloxy)-4-pyrone, m.p. 38.5-40°. NMR (CDCl3): δ1.26 (3H, t, J = 7 Hz); 2.35 (2H, t, J = 6.5 Hz).
Reaction SMILES: [Br:1][C:2]1[C:3](O[C:6](=[O:8])[CH:7]=1)=[O:4].C([O-])(=O)C.[Na+].O.[NH2:15][NH2:16].O>C(O)(=O)C.O>[Br:1][C:2]1[C:3](=[O:4])[NH:15][NH:16][C:6](=[O:8])[CH:7]=1
Reactant: O=C1C=C(Br)C(=O)O1
Reactant: NN
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=c1cc(Br)c(=O)[nH][nH]1
Temperature: 100 °C
Yield: 37 %

Procedure:
A mixture of bromomaleic anhydride (50 g, 283 mmol) and sodium acetate (76.5 g, 562 mmol) in 40% acetic acid/water (750 ml) was treated with hydrazine monohydrate (16.5 ml, 339 mmol) at room temperature under nitrogen. The brown solution was stirred and heated at 100° C. for 18 hours. Upon cooling the mixture was poured into water (11) and extracted with ethyl acetate (6×500 ml). The combined extracts were dried (MgSO4), filtered and evaporated to afford the title compound (20 g, 37%) as an orange solid. 1H NMR (250 MHz, d6-DMSO) δ7.68 (1H, br s). MS (ES+) m/e 193 [MH]+, 191 [MH]+. This material was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[C:11]([F:14])([F:13])[F:12])([O-:3])=[O:2].[C:15]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O.C1C=CC=CC=1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:15])=[CH:6][C:5]=1[C:11]([F:12])([F:13])[F:14])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Solvent: c1ccccc1
Product: COc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Reaction time: 16 h
Yield: 93.9 %

Procedure:
A solution of 4-nitro-3-trifluoromethylphenol (27 g, 130 mmol) in acetone (250 mL) was treated with K2CO3 (18 g, 130 mmol) and methyl iodide (16 mL, 260 mmol) and the mixture was heated at reflux under nitrogen. After 16 h, the cooled mixture was filtered to remove K2CO3 and the filtrate was concentrated in vacuo to give the crude product (32 g), which was taken up in benzene (250 mL). The organic solution was washed with water and brine (125 mL each), dried (MgSO4) and concentrated in vacuo to give the title compound (27 g, 94%) as a yellow oil which was pure enough for further use.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[CH:10]([CH2:19][CH2:20][CH:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[OH:22])[C:9]2=[O:30])=[CH:4][CH:3]=1.[Br:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][C:42]([CH2:45]Br)=[CH:41][CH:40]=2)=[CH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>>[Br:31][CH2:32][C:33]1[CH:34]=[CH:35][C:36]([C:39]2[CH:44]=[CH:43][C:42]([CH2:45][O:18][C:15]3[CH:14]=[CH:13][C:12]([CH:11]4[N:8]([C:5]5[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=5)[C:9](=[O:30])[CH:10]4[CH2:19][CH2:20][CH:21]([C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=4)[OH:22])=[CH:17][CH:16]=3)=[CH:41][CH:40]=2)=[CH:37][CH:38]=1
Reactant: BrCc1ccc(-c2ccc(CBr)cc2)cc1
Reactant: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(O)cc2)N1c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(OCc3ccc(-c4ccc(CBr)cc4)cc3)cc2)N1c1ccc(F)cc1

Procedure:
1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)-azetidin-2-one (11) was reacted with 4,4′-bisbromomethylbiphenyl and potassium carbonate analogously to Example IV, giving a colorless solid (21) of molecular weight 668.54 (C38H32BrF2NO3); MS (ESI): 668.1 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].C1COCC1.Br[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1>CS(C)=O>[N:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: Brc1ccccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: N#Cc1ccc(Oc2ccccn2)cc1
Temperature: 160 °C
Reaction time: 0.5 h
Yield: 63.2 %

Procedure:
4-Hydroxybenzonitrile (1.00 g, 8.39 mmol) was dissolved in anhydrous DMSO (5.0 mL) and was slowly added a solution of potassium tert-butoxide in THF (1.0 M, 16.8 mmol). The solution was stirred for 2 hours 30 minutes. A solution of 2-bromopyridine (2.65 g, 16.8 mmol) in DMSO (5.0 mL) was then added to the reaction mixture the whole was heated at 160° C. for 115 hours. The cooled mixture was partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The organic layers were dried with MgSO4, filtered and concentrated in vacuo. The crude solid was placed on a silica gel column and purified (EtOAc/Hex 1:6) to give the product as a light yellow solid (1.04 g, 63%). 1H NMR (500 MHz, CDCL3) δ(ppm): 7.01 (1H, d, J=8.2 Hz), 7.10 (1H, dd, J=7.2, 5.0 Hz), 7.24 (2H, d, J=9.0 Hz), 7.68 (2H, d, J=8.8 Hz), 7.77 (1H, ddd, J=8.3, 7.3, 2.0 Hz), 8.22 (1H, dd, J=5.0, 2.0 Hz). 13C NMR (125 MHz, CDCL3) δ(ppm): 108.0, 112.8 (CH), 118.9, 120.0 (CH), 121.6 (CH), 134.1 (CH), 140.2 (CH), 147.9 (CH), 158.2, 162.5. MS (FAB+): 197 (MH+). HRMS for C12H8N2O (MH+): calculated: 197.0713; found 197.0715.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]=[C:6]2[NH:16][N:17]=[C:18]([C:19]([F:22])([F:21])[F:20])[C:5]=12.Cl[CH2:24][C:25]([N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:26].O>CN(C=O)C.C(Cl)Cl>[Cl:3][C:4]1[C:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:8][N:7]=[C:6]2[N:16]([CH2:24][C:25]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:26])[N:17]=[C:18]([C:19]([F:22])([F:20])[F:21])[C:5]=12
Reactant: O=C(CCl)N1CCCC1
Reactant: FC(F)(F)c1n[nH]c2nnc(-c3ccccc3)c(Cl)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: O=C(Cn1nc(C(F)(F)F)c2c(Cl)c(-c3ccccc3)nnc21)N1CCCC1
Reaction time: 21 h
Yield: 14.8 %

Procedure:
Sodium hydride (18 mg, 0.45 mmol) was added to a solution of 4-chloro-5-phenyl-3-(trifluoromethyl)-1H-pyrazolo[3,4-c]pyridazine (115 mg, 0.38 mmol) and 2-chloro-1-pyrrolidin-1-yl-ethanone (81 mg, 0.55 mmol) in dry DMF (1.5 ml) and the reaction stirred for 21 h. Water and CH2Cl2 where added and the aqueous phase was extracted with CH2Cl2. The organic phases where combined, dried over MgSO4, filtered and evaporated. The residue was purified by column chromatography (silica gel, ethyl acetate/isohexane 2:8 to 1:0) followed by preparative HPLC yielding Compound Iaa as a white solid (23 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][N:6]=[C:5]([CH3:8])[N:4]=1.[Cl:9][C:10]1[CH:11]=[C:12]([OH:31])[CH:13]=[CH:14][C:15]=1[CH:16]([CH3:30])[C:17]([OH:29])([C:22]1[CH:27]=[N:26][C:25]([CH3:28])=[CH:24][N:23]=1)[C:18]([F:21])([F:20])[F:19]>>[Cl:9][C:10]1[CH:11]=[C:12]([O:31][CH2:2][C:3]2[S:7][N:6]=[C:5]([CH3:8])[N:4]=2)[CH:13]=[CH:14][C:15]=1[CH:16]([CH3:30])[C:17]([C:22]1[CH:27]=[N:26][C:25]([CH3:28])=[CH:24][N:23]=1)([OH:29])[C:18]([F:19])([F:21])[F:20]
Reactant: Cc1cnc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cn1
Reactant: Cc1nsc(CCl)n1
Product: Cc1cnc(C(O)(C(C)c2ccc(OCc3nc(C)ns3)cc2Cl)C(F)(F)F)cn1

Procedure:
The title compound was prepared in analogy to Example 74 from 5-chloromethyl-3-methyl-[1,2,4]thiadiazole [163009-79-8] and 3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(5-methyl-pyrazin-2-yl)-propyl]-phenol (Example 72). MS (m/e)=459.5 (MH+).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[N:17]([CH2:44][CH2:45][CH3:46])[N:18]=[C:19]2[C:28]=1[C:27]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:21]=[C:20]2[N:29]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].C(N(CC)CC)C>ClCCl>[O:11]=[CH:12][CH2:13][CH2:14][CH2:15][C:16]1[N:17]([CH2:44][CH2:45][CH3:46])[N:18]=[C:19]2[C:28]=1[C:27]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:21]=[C:20]2[N:29]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]
Reactant: CCCn1nc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc3ccccc3c2c1CCCCO
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCn1nc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc3ccccc3c2c1CCCC=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 107.7 %

Procedure:
To dichloromethane (5 mL) at −78° C. was added dimethylsulfoxide (0.12 mL, 1.6 mmol) and oxalyl chloride (0.11 mL, 1.2 mmol). After several minutes, a solution di(tert-butyl) 1-(4-hydroxybutyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate (0.5449 g, 1.093 mmol) and triethylamine (0.46 mL, 3.3 mmol) in dichloromethane (5 mL) was added dropwise to the −78° C. solution. After 15 minutes, the cooling bath was removed and the solution was allowed to warm to ambient temperature, during which time more dichloromethane (20 mL) was added. The solution was transferred to a separatory funnel and washed with aqueous potassium carbonate, water, and brine. The solution was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting oil was dried under vacuum to yield 0.5845 g of di(tert-butyl) 1-(4-oxobutyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate that contained a small amount of dimethylsulfoxide, but was used without further purification.
Reaction SMILES: O[CH2:2][C:3]1[N:7]([C:8]2[CH:9]=[C:10]([C:14]3[CH2:20][C:19](=[O:21])[NH:18][C:17]4[CH:22]=[C:23]([C:31]([F:34])([F:33])[F:32])[C:24]([N:26]([CH:28]([CH3:30])[CH3:29])[CH3:27])=[CH:25][C:16]=4[N:15]=3)[CH:11]=[CH:12][CH:13]=2)[N:6]=[N:5][CH:4]=1.S(Cl)(Cl)=O.[Cl-].[NH:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1>ClCCl.CN(C=O)C>[CH:28]([N:26]([CH3:27])[C:24]1[C:23]([C:31]([F:33])([F:34])[F:32])=[CH:22][C:17]2[NH:18][C:19](=[O:21])[CH2:20][C:14]([C:10]3[CH:11]=[CH:12][CH:13]=[C:8]([N:7]4[C:3]([CH2:2][N:40]5[CH2:44][CH2:43][CH2:42][CH2:41]5)=[CH:4][N:5]=[N:6]4)[CH:9]=3)=[N:15][C:16]=2[CH:25]=1)([CH3:30])[CH3:29]
Reactant: C1CCNC1
Reactant: CC(C)N(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)N(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CN3CCCC3)c1)=N2

Procedure:
The title compound was prepared from 4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-7-(isopropyl-methyl-amino)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 119) (200 mg, 0.42 mmol) by reaction with thionylchloride in dichloromethane and subsequent treatment of the corresponding chloride with pyrrolidine in DMF according to the method described in Example 45. Obtained as a light brown solid (140 mg, 63%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[CH:16]=[C:17]([C:20]([OH:22])=O)[NH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[CH:4][CH:3]=1.[OH:24][CH2:25][C:26]([NH2:29])([CH3:28])[CH3:27]>>[OH:24][CH2:25][C:26]([NH:29][C:20]([C:17]1[NH:18][N:19]=[C:15](/[CH:14]=[CH:13]/[C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9][O:10][C:11]=2[CH3:23])[CH:16]=1)=[O:22])([CH3:28])[CH3:27]
Reactant: Cc1onc(-c2ccc(F)cc2)c1/C=C/c1cc(C(=O)O)[nH]n1
Reactant: CC(C)(N)CO
Product: Cc1onc(-c2ccc(F)cc2)c1/C=C/c1cc(C(=O)NC(C)(C)CO)[nH]n1
Yield: 36 %

Procedure:
As described for example 132, 5-{(E)-2-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-vinyl}-2H-pyrazole-3-carboxylic acid was converted, using 2-hydroxy-1,1-dimethylethylamine instead of morpholine, to the title compound (11 mg, 36%) which was obtained as an off white solid. MS: m/e=385.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[OH:9].[C:10](=O)([O-])[O-].[K+].[K+].CI.CN(C)C=O>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: Oc1cc(Cl)ccc1Br
Reactant: O=C([O-])[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc(Cl)ccc1Br
Reaction time: 2 h
Yield: 96.9 %

Procedure:
A suspension of 2-bromo-5-chlorophenol (2.85 g, 13.7 mmol; synthesized in reference to International Patent Publication WO0109122), potassium carbonate (1.89 g, 13.7 mmol), n-Bu4NI (50 mg, 0.137 mmol), methyl iodide (1.28 mL, 20.6 mmol) and N,N-dimethylformamide (8.0 mL) was stirred for two hours. An iced water was added and the obtained mixture was extracted with ethyl acetate twice. The combined organic phase was washed with brine and dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=95:5) to obtain colorless oily 2-bromo-5-chloroanisole (2.94 g, 97%). Then, oxalyl chloride (1.23 mL, 15.1 mmol) and N,N-dimethylformamide (2 drops) were added to 4-ethoxybenzoic acid (2.28 g, 13.7 mmol) in chloroform (8 mL) and stirred for five hours. The yellow oil obtained by evaporating the solvent under reduced pressure was dissolved in chloroform (5 mL). To this solution, a chloroform solution (10 mL) of 2-bromo-5-chloroanisole (2.94 g, 13.3 mmol) was added and then aluminum chloride (2.07 g, 15.5 mmol) was added portion wise at −10° C. over five minutes. After stirred at 5° C. for one hour, the reaction mixture was to room temperature and stirred for 13 hours. The reaction mixture was poured into an iced water and extracted with chloroform three times. After washed with 1 M hydrochloric acid, water, brine, the combined organic layer was dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by NH type silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain (5-bromo-2-chloro-6-methoxyphenyl)(4-ethoxyphenyl)methanone (1.53 g, 31%) as a colorless crystal.
Reaction SMILES: C[Si](C)(C)[C:3]([F:6])([F:5])[F:4].[CH:9]([C:11]1[CH:12]=[C:13]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:14]=[CH:15][CH:16]=1)=[O:10].[F-].[Cs+].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CN(C=O)C.C1COCC1.O>[F:4][C:3]([F:6])([F:5])[CH:9]([C:11]1[CH:12]=[C:13]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:14]=[CH:15][CH:16]=1)[OH:10]
Reactant: CCOC(=O)Cc1cccc(C=O)c1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)Cc1cccc(C(O)C(F)(F)F)c1
Temperature: 2.5 °C
Reaction time: 1.5 h
Yield: 16.7 %

Procedure:
Trimethyl(trifluoromethyl)silane (3.13 mL, 21.20 mmol) was added to a mixture of ethyl 2-(3-formylphenyl)acetate (2.91 g, 15.14 mmol) and cesium fluoride (0.161 g, 1.060 mmol) in DMF (20.19 mL) cooled to 0-5° C. After stirring for 1.5 hour, a solution of TBAF 1M in THF (15.14 mL) was added. The resulting yellow solution was stirred at 0-5° C. and after 30 minutes, the mixture was poured into water (150 mL) and extracted with MTBE (1×150 mL, then 2×100 mL). The combined organic layers were washed with water (1×150 mL then 1×100 mL) and with brine (100 mL) and then the organic layer was dried over anh. MgSO4, filtered and concentrated to give 3.84 g as a light orange oil which was purified by flash chromatography to give ethyl 2-(3-(2,2,2-trifluoro-1-hydroxyethyl)phenyl)acetate (663 mg, 16% yield) as a colorless oil: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.17 (t, J=7.0 Hz, 3H) 3.68 (s, 2H) 4.08 (q, J=7.0 Hz, 2H) 5.13 (q, J=7.4 Hz, 1H) 6.82 (s, 1H) 7.24-7.31 (m, 1H) 7.37 (t, J=7.2 Hz, 3H); MS m/z 263.1 (M+H)+; HPLC 93.7% @ 220 nm, RT=1.82 minutes.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8](CC2C=CC=CC=2)CC2C=CC=CC=2)[C:5]2[N:23]=[C:24]([CH3:31])[N:25]([CH2:26][CH2:27][O:28][CH2:29][CH3:30])[C:4]=2[C:3]=1[CH3:32].Cl>CO.[OH-].[OH-].[Pd+2]>[CH2:29]([O:28][CH2:27][CH2:26][N:25]1[C:4]2[C:3]([CH3:32])=[CH:2][N:7]=[C:6]([NH2:8])[C:5]=2[N:23]=[C:24]1[CH3:31])[CH3:30]
Reactant: CCOCCn1c(C)nc2c(N(Cc3ccccc3)Cc3ccccc3)nc(Cl)c(C)c21
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: CCOCCn1c(C)nc2c(N)ncc(C)c21
Reaction time: 4 h
Yield: 49.2 %

Procedure:
6-Chloro-1-(2-ethoxyethyl)-2,7-dimethyl-N4,N4 -bis(phenylmethyl)-1H-imidazo[4,5-c]pyridin-4-amine (0.7 g, 1.56 mmole) was taken up in methanol saturated with anhydrous hydrochloric acid (100 mL), combined with palladium hydroxide on carbon and then hydrogenated on a Paar apparatus for four hours. The reaction mixture was filtered to remove the catalyst then concentrated under vacuum. The residue was partitioned between methylene chloride/water/sodium bicarbonate. The methylene chloride layer was separated, dried over magnesium sulfate then concentrated under vacuum to provide an off white solid. This material was recrystallized from ethyl acetate/hexane to provide 0.18 g of the desired product as a solid, m.p. 129°-130° C. Analysis: Calculated for: C12H18N4O+1/4H2O: % C, 60.35; % H, 7.81; % N, 23.46; Found: % C, 60.64; % H, 7.50; % N, 23.39.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:23]([F:26])([F:25])[F:24])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[C:16]([F:22])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cr](O)(O)(=O)=[O:28].S(=O)(=O)(O)O>CC(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:23]([F:25])([F:24])[F:26])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:28])=[O:21])=[C:16]([F:22])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=[Cr](=O)(O)O
Reactant: OCc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1F
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1F
Yield: 68.2 %

Procedure:
In a solution of 0.95 g of 5-(3,5-dichlorophenyl)-3-(3-fluoro-4-hydroxymethylphenyl)-5-trifluoromethyl-4,5-dihydroisoxazole in 25 ml of acetone, Johnes' Reagent prepared from 1.50 g of chromic acid, 1.2 ml of concentrated sulfuric acid and 7 ml of water was added dropwise under cooling with ice and with stirring, after the completion of the addition dropwise, continued to stir at room temperature for further 1.5 hour. After the completion of the reaction, the reaction mixture was poured in 50 ml of water and extracted with diethyl ether (50 ml×1). The organic phase was dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residual solid was washed with hexane to obtain 0.67 g of the aimed product as beige crystal.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]#[N:12])=[CH:8][C:7]([N+:13]([O-:15])=[O:14])=[CH:6][CH:5]=2.CO[CH:18](OC)[N:19]([CH3:21])[CH3:20].[CH3:24]N(C=O)C>>[CH3:18][N:19]([CH3:21])/[CH:20]=[CH:1]/[C:2]1[N:3]([CH3:24])[C:4]2[C:9]([C:10]=1[C:11]#[N:12])=[CH:8][C:7]([N+:13]([O-:15])=[O:14])=[CH:6][CH:5]=2
Reactant: CN(C)C=O
Reactant: COC(OC)N(C)C
Reactant: Cc1[nH]c2ccc([N+](=O)[O-])cc2c1C#N
Product: CN(C)/C=C/c1c(C#N)c2cc([N+](=O)[O-])ccc2n1C
Temperature: 80 °C

Procedure:
2-methyl-5-nitro-1H-indole-3-carbonitrile (200 mg, 0.98 mmol) was dissolved in DMF (4 mL) followed by the addition of N,N-dimethylformamide dimethyl acetal (452 mg, 505 μL, 3.8 mmol). The mixture was heated at 80° C. for 0.5 h and turned from amber-colored to dark red over the course of the reaction. The solvent was removed in vacuo and the crude solid was washed with 5:1 EtOAc/hexane (6×10 mL), followed by hexane (2×10 mL) to obtain 2-((E)-2-(dimethylamino)vinyl)-1-methyl-5-nitro-1H-indole-3-carbonitrile as a dark burgundy solid (235 mg, 89% yield) after drying. Mass and purity were confirmed by LC/MS using an acetonitrile gradient with 5 mM ammonium formate pH 6.5. Theoretical (M+H)+ m/z for C14H14N4O2=271.11; Found 271.07. 1H NMR (400 mHz, DMSO-d6) δ 8.12 (d, J=2.2 Hz, 1H), 7.99 (dd, J=9.0, 2.3 Hz, 1H), 7.72 (d, J=13.3 Hz, 1H), 7.61 (d, J=9.0 Hz, 1H), 5.17 (d, J=13.3 Hz, 1H), 3.73 (s, 3H), 3.00 (s, 6H).
Reaction SMILES: [CH3:1][C:2](=O)[C:3]([CH3:6])([CH3:5])[CH3:4].Cl.[NH2:9][NH:10][C:11]([NH2:13])=[O:12].C([O-])(=O)C.[Na+]>O>[CH3:1][C:2](=[N:9][NH:10][C:11]([NH2:13])=[O:12])[C:3]([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(=O)C(C)(C)C
Reactant: NNC(N)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(=NNC(N)=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 17 h
Yield: 70.6 %

Procedure:
Pinacolone (10 g, 99.8 mmol) was added to a solution of semicarbazide hydrochloride (11.13 g, 99.8 mmol) and sodium acetate (16.4 g, 199 mmol) in water (60 mL). The mixture was stirred for 17 h at ambient temperature. The white precipitate was filtered and washed with water and diethyl ether. The solid was dried under vacuo at 50° C. to yield the desired product (11.09 g, 70.5 mmol, 71%).