Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]([C:13]2([OH:17])[CH2:16][CH2:15][CH2:14]2)[CH:10]=[CH:11][CH:12]=1.C([O-])(=O)C.[Na+].[NH:23]([S:25](O)(=[O:27])=[O:26])O.Cl>CCCCCC.O1CCCC1>[OH:17][C:13]1([C:9]2[CH:8]=[C:7]([S:25]([NH2:23])(=[O:27])=[O:26])[CH:12]=[CH:11][CH:10]=2)[CH2:16][CH2:15][CH2:14]1
Reactant: O=S(=O)(O)NO
Reactant: OC1(c2cccc(Br)c2)CCC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: NS(=O)(=O)c1cccc(C2(O)CCC2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 4.8 %

Procedure:
A 1.6M solution of n-butyllithium (8 ml, 12.8 mmol) in hexane was added to a solution of 1-(3-bromo-phenyl)-cyclobutanol (1.44 grams, 6.4 mmol) in tetrahydrofuran at -78° C. After 30 minutes, at the reaction was allowed to warm to 0° C. Sulfur dioxide was bubbled into the reaction mixture and stirred for an additional 30 minutes. The tetrahydrofuran was evaporated and an aqueous solution of sodium acetate (4.1 grams, 50 mmol) and of hydroxylamine-sulfonic acid (1.85 grams, 16 mmol) was added. After stirring at room temperature for 2 hours, the reaction was acidified with 2N hydrochloric acid then extracted with ethyl acetate. The ethyl acetate was dried over sodium sulfate and evaporated. The residue was purified on silica gel with dichloromethane/ether to give 70 mg of the titled compound.
Reaction SMILES: [CH3:1][NH2:2].O.[Cl:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8]Cl>CN(C)C=O>[Cl:4][C:5]1[CH:6]=[C:7]([CH2:8][NH:2][CH3:1])[CH:10]=[CH:11][CH:12]=1
Reactant: ClCc1cccc(Cl)c1
Reactant: CN
Solvent: CN(C)C=O
Solvent: O
Product: CNCc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a solution of methylamine (2.0 M solution in tetrahydrofuran, 30 ml) in N,N-dimethylformamide (30 ml), 3-chlorobenzyl chloride (2.5 ml) was added, and the mixture was stirred at room temperature for 4.5 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed with water and saturated saline in this order and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product of the title compound, which was used in the next reaction without being purified.
Reaction SMILES: [CH3:1][C:2]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])[CH3:3].CCN(CC)CC.[Br:16][C:17]1[CH:18]=[C:19]([CH2:23][OH:24])[CH:20]=[CH:21][CH:22]=1.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:16][C:17]1[CH:18]=[C:19]([CH2:23][O:24][Si:5]([C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:7])[CH3:6])[CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cccc(Br)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.2 %

Procedure:
TBSCl (18.7 g, 124.3 mmol), Et3N (14.08 g, 139.2 mmol) and DMAP (194.3 mg, 8.9 mmol) were dissolved in CH2Cl2 (120 mL) and the solution was cooled to 0-5° C. (3-Bromophenyl)methanol (18.5 g, 99.4 mmol) was added dropwise to the solution. After the addition of the (3-Bromophenyl)methanol, the mixture was warmed to room temperature and stirred for 2 h. 5% HCl was added to the reaction mixture to adjust the pH=4-5. Then the organic phase was separated and the aqueous layer was extracted with CH2Cl2 (50 mL×2). The combined organic phases were washed with water and dried over Na2SO4. After removing the solvent, 28.5 g of {[(3-bromophenyl)methyl]oxy}(1,1-dimethylethyl)dimethylsilane was obtained (Yield: 95.1%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:28])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]#[C:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[S:17][C:10]=12.[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:42](O)=[O:43])[C:37]2=[O:45])=[CH:32][CH:31]=1.O=C1C(C(OC)=O)=CC=CO1.FC1C=CC(N)=CC=1>>[F:1][C:2]1[CH:3]=[C:4]([NH:28][C:42]([C:38]2[C:37](=[O:45])[N:36]([C:33]3[CH:32]=[CH:31][C:30]([F:29])=[CH:35][CH:34]=3)[CH:41]=[CH:40][CH:39]=2)=[O:43])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]#[C:19][CH2:20][N:21]3[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]3)[S:17][C:10]=12
Reactant: CN1CCN(CC#Cc2cc3nccc(Oc4ccc(N)cc4F)c3s2)CC1
Reactant: O=C(O)c1cccn(-c2ccc(F)cc2)c1=O
Agent: COC(=O)c1cccoc1=O
Agent: Nc1ccc(F)cc1
Product: CN1CCN(CC#Cc2cc3nccc(Oc4ccc(NC(=O)c5cccn(-c6ccc(F)cc6)c5=O)cc4F)c3s2)CC1
Yield: 19 %

Procedure:
The title compound was prepared from 3-fluoro-4-(2-(3-(4-methylpiperazin-1-yl)prop-1-ynyl)thieno[3,2-b]pyridin-7-yloxy)aniline (Example 17, Step B) and 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (prepared from methyl 2-oxo-2H-pyran-3-carboxylate with 4-fluoroaniline and followed by hydrolysis using the methods described in US 2005/0239820) according to the procedure for Example 89. The crude was purified by silica gel flash column chromatography (5% MeOH in CH2Cl2) to afford 3 mg (19%) of the desired product. 1H NMR (400 MHz, CD3OD/CDCl3) δ 8.73 (dd, 1H), 8.45 (d, 1H), 7.98 (dd, 1H), 7.84 (dd, 1H), 7.58 (s, 1H), 7.48 (m, 2H), 7.40 (d, 1H), 7.31 (t, 2H), 6.74 (t, 1H), 6.63 (d, 1H), 3.64 (s, 2H), 2.60-2.76 (m, 8H), 2.33 (s, 3H); 19F NMR (376 MHz, CD3OD/CDCl3) δ −112.1, −127.6. LRMS (ESI pos) m/e 612.1 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:25]=[C:24]3[C:19]([C:20]([O:26][C:27]4[CH:32]=[CH:31][C:30]([NH:33][C:34]([NH:36][C:37]5[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=5)=[O:35])=[C:29]([F:44])[CH:28]=4)=[CH:21][CH:22]=[N:23]3)=[CH:18][C:17]=2[C:45]#[N:46])[CH2:10][CH2:9]1)=O)(C)(C)C.O.C(=O)(O)[O-].[Na+]>FC(F)(F)C(O)=O>[F:44][C:29]1[CH:28]=[C:27]([O:26][C:20]2[C:19]3[C:24](=[CH:25][C:16]([O:15][CH2:14][CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)=[C:17]([C:45]#[N:46])[CH:18]=3)[N:23]=[CH:22][CH:21]=2)[CH:32]=[CH:31][C:30]=1[NH:33][C:34]([NH:36][C:37]1[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=1)=[O:35]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2cc3nccc(Oc4ccc(NC(=O)Nc5ccc(F)cc5)c(F)c4)c3cc2C#N)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)c(F)c3)ccnc2cc1OCC1CCNCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78.3 %

Procedure:
After dissolving 4-(6-cyano-4-{3-fluoro-4-[3-(4-fluorophenyl)ureido]phenoxy}quinolin-7-yloxymethyl)piperidine-1-carboxylic acid tert-butyl ester (395 mg) in trifluoroacetic acid (2 ml), the solution was stirred for 10 minutes at room temperature. Water (20 ml) was added, the mixture was neutralized with sodium bicarbonate, and the precipitated crystals were filtered out to obtain the title compound (260 mg).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH3:16].[Br:17][C:18]1[N:19]=[C:20]([C:24](O)=[O:25])[NH:21][C:22]=1[CH3:23].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[Br:17][C:18]1[N:19]=[C:20]([C:24]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]2[O:15][CH3:16])=[O:25])[NH:21][C:22]=1[CH3:23]
Reactant: Cc1[nH]c(C(=O)O)nc1Br
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)c1nc(Br)c(C)[nH]1
Yield: 83 %

Procedure:
The same operation as in Example (1g) was performed using tert-butyl cis(±)-4-amino-3-methoxypiperidine-1-carboxylate obtained by the method described in Example (1e) (0.88 g, 3.82 mmol), 4-bromo-5-methyl-1H-imidazole-2-carboxylic acid obtained in Example (31b) (0.37 g, 1.80 mmol), WSC hydrochloride (1.03 g, 5.37 mmol) and HOBT (0.25 g, 1.81 mmol), to obtain 0.63 g of the title compound as a white solid (83%).
Reaction SMILES: C([Li])CCC.[CH2:6]([S:8][C:9]1[N:13]2[C:14](C)=[CH:15][CH:16]=[CH:17][C:12]2=[CH:11][N:10]=1)[CH3:7].[CH2:19]([Sn:23](Cl)([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH3:22]>C1COCC1>[CH2:6]([S:8][C:9]1[N:13]2[C:14]([Sn:23]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:19][CH2:20][CH2:21][CH3:22])=[CH:15][CH:16]=[CH:17][C:12]2=[CH:11][N:10]=1)[CH3:7]
Reactant: CCSc1ncc2cccc(C)n12
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cccc2cnc(SCC)n12
Temperature: -78 °C
Reaction time: 1 h

Procedure:
n-Butyllithium (1.6 M, 4.2 mL, 6.7 mmol) is added slowly to a solution of the title B compound, 3-ethylsulfanyl-5-methyl-imidazo[1,5-a]pyridine (1.14 g, 6.4 mmol) in anhydrous THF (7 mL) at −78° C. The resulting solution is stirred at −78° C. for 1 h and tributyltinchloride (2.0 mL, 7.4 mmol) is added. The reaction is stirred at −78° C. for 1 h further, and then allowed slowly to warm to RT overnight. The reaction is quenched by addition of saturated aqueous ammonium chloride (15 mL) and the mixture is extracted two times with ethyl acetate. The organic extracts are combined, washed with aqueous potassium fluoride solution (3 M, 20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated. The residue is purified by flash column chromatography on silica using 10% ethyl acetate in hexanes as the eluant to yield 3-ethylsulfanyl-5-tributylstannyl-imidazo[1,5-a]pyridine as a dark oil: 1H-NMR (CDCl3) δ 7.51 (s, 1H), 7.38 (dd, J=8.7, 1.2, 1H), 6.71 (dd, J=6.3, 1.5, 1H), 6.63 (dd, J=8.7, 6.3, 1H), 2.98 (q, J=7.4, 2H), 1.58–1.48 (m, 6H), 1.40–1.17 (m, 15H), 0.88 (t, J=7.5, 9H); 13C-NMR (CDCl3) δ 140.27, 133.53, 132.20, 124.88, 124.76, 124.63, 121.89, 118.77, 118.65, 118.56, 32.22, 29.66, 29.37, 29.30, 29.22, 27.94, 27.79, 27.68, 27.42, 15.59, 15.52, 14.83, 14.12, 14.03, 12.71, 12.65; MS (M+1)+ 465, 466, 467, 468, 469 (tin isotope pattern).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)=[C:6]([C:8]2[CH:9]=[N:10][C:11]3[CH:12]([NH:17][C:18]([C:20]4([NH2:23])[CH2:22][CH2:21]4)=[O:19])[CH2:13][CH2:14][C:15]=3[CH:16]=2)[CH:7]=1.[CH3:31][O:32][C:33]1[N:38]=[CH:37][C:36]([C:39](O)=[O:40])=[CH:35][N:34]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)=[C:6]([C:8]2[CH:9]=[N:10][C:11]3[CH:12]([NH:17][C:18]([C:20]4([NH:23][C:39]([C:36]5[CH:35]=[N:34][C:33]([O:32][CH3:31])=[N:38][CH:37]=5)=[O:40])[CH2:22][CH2:21]4)=[O:19])[CH2:13][CH2:14][C:15]=3[CH:16]=2)[CH:7]=1
Reactant: COc1ncc(C(=O)O)cn1
Reactant: Cc1nc(-c2c(F)cc(Cl)cc2-c2cnc3c(c2)CCC3NC(=O)C2(N)CC2)no1
Product: COc1ncc(C(=O)NC2(C(=O)NC3CCc4cc(-c5cc(Cl)cc(F)c5-c5noc(C)n5)cnc43)CC2)cn1

Procedure:
In analogy to the procedure described for the preparation of intermediate A-1 [B], 1-amino-cyclopropanecarboxylic acid{(rac)-3-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-6,7-dihydro-5H-[1]pyrindin-7-yl}-amide (example 37) has been coupled with 2-methoxy-pyrimidine-5-carboxylic acid to yield the title compound as off-white solid. MS: 564.2 (MH+, 1Cl).
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:9].[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>C(O)CCC>[N:10]1([C:2]2[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N+:3]=2[O-:9])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: [O-][n+]1cccc(F)c1Cl
Reactant: C1CNCCN1
Solvent: CCCCO
Product: [O-][n+]1cccc(F)c1N1CCNCC1

Procedure:
A solution of 2-chloro-3-fluoropyridine N-oxide (400 mg, 3.0 mmol) and piperazine (1.3 g, 15 mmol) in n-butanol, 15 ml, is stirred at reflux for 20 hours. After concentrating under reduced pressure at 55°-60° C., the residue is chromatographed over silica gel and the crude N-oxide eluted with a 50% methanol-methylene chloride solvent mixture. The appropriate eluate is concentrated to an oily residue of the title compound.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH:6]=[N:7][OH:8].[Cl:14]N1C(=O)CCC1=O>C(Cl)Cl.O>[OH:8][N:7]=[C:6]([Cl:14])[C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:12])([F:13])[F:1])[CH:4]=1
Reactant: ON=Cc1cccc(C(F)(F)F)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: ClCCl
Product: ON=C(Cl)c1cccc(C(F)(F)F)c1
Temperature: 45 °C
Yield: 85.2 %

Procedure:
To a dried flask containing 3-(trifluoromethyl)benzaldehyde oxime (1.89 g, 10 mol) in methylene chloride (100 mL) was added N-chlorosuccinimide (1.40 g, 10.5 mmol) slowly at 0° C. The reaction mixture was warmed to 45° C. for 2 h, poured over ice, diluted with H2O (20 mL), and extracted with EtOAc (100 mL). The organic phase was washed with H2O (2×25 mL) and saline solution (25 mL), dried over sodium sulfate, concentrated in vacuo to give N-hydroxy-3-(trifluoromethyl)benzenecarboximidoyl chloride (2 g, 90%). LCMS: 224.4 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[O:8])=[CH:5][C:4]=1[CH3:22].C[Si]([N-][Si](C)(C)C)(C)C.[K+].Br[CH2:34][C:35]1[N:40]=[C:39]([C:41]#[N:42])[CH:38]=[CH:37][CH:36]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:34][C:35]3[N:40]=[C:39]([C:41]#[N:42])[CH:38]=[CH:37][CH:36]=3)[CH:10]=2)=[O:8])=[CH:5][C:4]=1[CH3:22]
Reactant: COc1ccc(C(=O)c2c[nH]c3ncccc3c2=O)cc1C
Reactant: N#Cc1cccc(CBr)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2cn(Cc3cccc(C#N)n3)c3ncccc3c2=O)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.5 %

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1, from 50 mg (0.17 mmol) of 3-(4-Methoxy-3-methyl-benzoyl)-1H-[1,8]naphthyridin-4-one in THF 2 ml, was added KHMDS in THF 0.4 ml (0.2 mmol ) slowly. The reaction mixture was stirred at room temperature for 60 min, followed by the addition of 40 mg (0.2 mmol) of 6-Bromomethyl-pyridine-2-carbonitrile. The mixture was heated to 60° C. for 60 min, then quenched with water and purified with HPLC to give the desired product (15 mg). LCMS (M+H)+: 411.1.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]2[S:9][C:10]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[CH:11][CH:12]=2)=[CH:5][CH:4]=1)=O.[C:18]([OH:23])(=[O:22])[C:19]([CH3:21])=[O:20].[OH-].[Na+].Cl>C(O)C.O>[C:18]([C:19](=[O:20])[CH:21]=[CH:1][C:3]1[S:7][C:6]([C:8]2[S:9][C:10]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[CH:11][CH:12]=2)=[CH:5][CH:4]=1)([OH:23])=[O:22]
Reactant: CC(=O)C(=O)O
Reactant: O=Cc1ccc(-c2ccc(-c3cccs3)s2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C(=O)C=Cc1ccc(-c2ccc(-c3cccs3)s2)s1
Reaction time: 0.17 h

Procedure:
0.5 g of 5-formyl-2,2':5',2"-terthiophene was dissolved in 40 ml of ethanol, followed by dropping in 3 ml of water containing 0.3 g of pyruvic acid salt and stirring for 10 minutes. 1 ml of 50% NaOH solution was dropped into the solution and stirred overnight. The reaction solution was acidified by diluted HCl and extracted with 100 ml of ethyl acetate. The extract was treated in situ and separated by column chromatography. Unreactive materials were eluted by ethyl acetate/n-hexane (1/9). The black solid product was eluted by ethyl acetate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:19]2[CH:20]=[C:21]([CH:24]=[C:25]([F:27])[CH:26]=2)[C:22]#[N:23])[CH:7]=[C:8]2[C:12]=1[NH:11][C:10](=[O:13])[C:9]12[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)([O-])=O.[Sn].CCOCC>C(O)(=O)C.Cl>[NH2:1][C:4]1[CH:5]=[C:6]([C:19]2[CH:20]=[C:21]([CH:24]=[C:25]([F:27])[CH:26]=2)[C:22]#[N:23])[CH:7]=[C:8]2[C:12]=1[NH:11][C:10](=[O:13])[C:9]12[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: N#Cc1cc(F)cc(-c2cc([N+](=O)[O-])c3c(c2)C2(CCCCC2)C(=O)N3)c1
Agent: Cl
Agent: [Sn]
Solvent: CC(=O)O
Solvent: CCOCC
Product: N#Cc1cc(F)cc(-c2cc(N)c3c(c2)C2(CCCCC2)C(=O)N3)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.2 %

Procedure:
To a solution of 3-(7′-nitro-1′,2′-dihydro-2′-oxospiro-[cyclohexane-1,3′-[3H]indol]-5′-yl)-5-fluorobenzonitrile (1.0 eq, 0.16 g, 0.4 mmol) in glacial acetic acid (4 mL) at room temperature was added a solution of tin II chloride dihydrate (0.25 g, 1.1 mmol) in hydrochloric acid (2 mL). The yellow mixture was boiled for 30 min at which point the yellow color disappeared. After cooling to room temperature, 1 N HCl (10 mL) and ether (20 mL) were added. The layers were separated and the aqueous phase was extracted with ether (2×20 mL). The organic layers were combined, washed sequentially with water (2×20 mL), saturated aqueous NaHCO3 (20 mL), and brine (20 mL). The solution was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with 40% EtOAc/hexane) to give the title compound (70 mg, 50%) as an oil which crystallized upon addition of 10% EtOAc/hexanes, mp 241-3° C. 1H NMR (DMSO-d6; 400 MHz) δ 1.50-1.75 (m, 8H), 1.82-1.95(m, 2H), 4.98 (s, 2H), 6.90 (d, 1H, J=Hz), 7.09 (d, 1H, J=1.5 Hz), 7.75 (m, 2H), 7.90 (‘s’, 1H), 9.96 (bs, 1H). MS ((+)-APCI) m/z 336 [(M+H)+]. Anal. Calcd for C20H18FN3O: C, 71.63; H, 5.41; N, 12.18. Found: C, 71.16; H, 5.58; N, 12.18.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][C:5]([NH2:8])=[N:6][CH:7]=1.[C:9](#N)[CH3:10].C[Si](C#C)(C)C.C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>[Cu]I>[C:9]([C:2]1[CH:3]=[N:4][C:5]([NH2:8])=[N:6][CH:7]=1)#[CH:10]
Reactant: CC#N
Reactant: Nc1ncc(I)cn1
Agent: [Cu]I
Agent: C#C[Si](C)(C)C
Agent: O=C([O-])[O-]
Solvent: CCN(CC)CC
Product: C#Cc1cnc(N)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A flask was charged with 5-iodopyrimidin-2-amine (25.0 g, 110 mmol), acetonitrile (900 ml, 110 mmol), trimethylsilylacetylene (35 ml, 241 mmol), triethylamine (93 ml, 658 mmol), Pd(PPh3)4Cl2 (3.9 g, 5.5 mmol) and finally copper(I) iodide (1.1 g, 5.5 mmol). The flask was put under vacuum then filled with argon and stirred at RT overnight using a mechanical stirrer. The solvent was removed under vacuum, the residue taken up in methanol (600 ml) and potassium carbonate (152 g, 1097 mmol) was added. The mixture was stirred at RT using mechanical stirring for 2 hrs. Activated carbon (˜50 mL) was added to the reaction and stirring continued for 15 min. The reaction mixture was then filtered through a plug of celite and the filtrate was concentrated to a volume of ˜400 mL and the precipitate was filtered. The filtrate was concentrated down to a thick paste which was slurried in ˜150 mL of 10% MeOH/H2O for 20 min at RT. The solids were then filtered off to afford 5-ethynylpyrimidin-2-amine.
Reaction SMILES: N1C=CC=CC=1[C:7]1[CH:12]=[CH:11]C=CN=1.[C:13]([O:17][CH3:18])(=[O:16])[CH:14]=[CH2:15].C1(C(Br)C)C=CC=CC=1>C1COCC1>[CH:13]([O:17][CH2:18][CH:12]([CH3:11])[CH3:7])=[CH2:14].[C:13]([O:17][CH3:18])(=[O:16])[CH:14]=[CH2:15]
Reactant: c1ccc(-c2ccccn2)nc1
Agent: CC(Br)c1ccccc1
Solvent: C=CC(=O)OC
Solvent: C1CCOC1
Product: C=COCC(C)C
Temperature: 50 °C

Procedure:
To 0.11 g (6.68×10−4 mole) 2,2′-bipyridyl and 0.036 g (2.34×10−4 mole) CuBr in a glass tube, were added 0.6 ml (0.55×10−2 mole) IBVE, 1.5 ml (1.65×10−2 mole) methyl acrylate and 0.034 ml (2.34×10−4 mole) 1-phenylethyl bromide under argon atmosphere. The glass tube was sealed under vacuum, and the reaction mixture was warmed at 50° C. for 12 hours. The reaction mixture was then dissolved in THF, and the conversion of MA and IBVE as determined by GC were 100%. The polymer was then precipitated in methanol (three times), filtered, dried at 60° C. under vacuum for 48 h and weighed. The content of IBVE in the copolymer was 25%, and Mn=7860, Mw/Mn=1.90 (Mth=8400). The glass transition temperatures of the product as determined by DSC were at −31.0° C. and 5.6° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:32])[CH:5]=[C:6]([Cl:31])[C:7]=1[CH2:8][C@@H:9]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1)[O:10][C:11](=[O:20])[C:12]1[CH:17]=[CH:16][C:15]([CH:18]=[O:19])=[CH:14][CH:13]=1.NC1N=NC=CC=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Cl:31][C:6]1[CH:5]=[N+:4]([O-:32])[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C@@H:9]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1)[O:10][C:11](=[O:20])[C:12]1[CH:13]=[CH:14][C:15]([CH2:18][OH:19])=[CH:16][CH:17]=1
Reactant: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2ccc(C=O)cc2)cc1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Nc1cccnn1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2ccc(CO)cc2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.1 %

Procedure:
To a stirred solution of (S)-3,5-dichloro-4-(2-(3,4-dimethoxyphenyl)-2-((4-formylbenzoyl)oxy)ethyl)pyridine 1-oxide (412 mg, 0.87 mmol) in DCM (10 mL) was added 3-aminopyridazine (165 mg, 1.73 mmol) followed by glacial acetic acid (150 μL, 2.61 mmol). The reaction was stirred at room temperature for 30 minutes then NaB(OAc)3H (551 mg, 2.61 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours. The reaction was diluted with DCM (10 mL) and quenched with water. The organic phase was washed with saturated aqueous NaHCO3 solution, filtered through hydrophobic fit and evaporated to dryness. The residue was triturated with DCM (2 mL) and CH3CN (5 mL). The solid was collected by filtration, washed with DCM and dried to provide the title compound (300 mg, 72%) as white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17](=O)[CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:25][OH:26].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17](=[N:25][OH:26])[CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NO
Reactant: CC(C)(C)c1ccc(-c2ccc(C(=O)CCC(=O)O)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)c1ccc(-c2ccc(C(CCC(=O)O)=NO)cc2)cc1
Yield: 93.7 %

Procedure:
In a manner similar to Example 4, Step (c), 4-(4′-tert-butyl-biphenyl-4-yl)-4-oxo-butyric acid (0.277 g, 0.000892 mol) was allowed to react with hydroxylamine hydrochloride (0.0704 g, 0.00101 mol) in the presence of sodium carbonate (0.1074 g, 0.00101 mol) in absolute ethanol (7 mL) to give 0.272 g of 4-(4′-tert-butyl-biphenyl-4-yl)-4-hydroxyimino-butyric acid as a white solid; mp 170.5-171.5° C.
Reaction SMILES: N#N.Cl[CH2:4][C:5]1[O:9][C:8]([C:10]2([CH3:15])[O:14][CH2:13][CH2:12][O:11]2)=[CH:7][CH:6]=1.[C-:16]#[N:17].[Na+].O>CS(C)=O>[CH3:15][C:10]1([C:8]2[O:9][C:5]([CH2:4][C:16]#[N:17])=[CH:6][CH:7]=2)[O:14][CH2:13][CH2:12][O:11]1
Reactant: CC1(c2ccc(CCl)o2)OCCO1
Reactant: [C-]#N
Agent: N#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC1(c2ccc(CC#N)o2)OCCO1
Temperature: 80 °C
Reaction time: 0.75 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-(5-chloromethyl-furan-2-yl)-2-methyl-[1,3]dioxolane (2.37 mg, 11.68 mmol) in DMSO (50 mL) was treated with sodium cyanide (2.29 g, 46.72 mmol) and the reaction mixture was stirred at 80° C. for 45 min. Water (100 mL) was added to the cooled reaction mixture and the product was extracted with EA (2×100 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (2:1 hept-EA) gave the title compound as a yellow oil. LC-MS-conditions 02: tR=0.83 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[C:9]1([S:15]([O-:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Na+]>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:17])=[O:16])=[CH:4][CH:3]=1
Reactant: Fc1ccc(I)cc1
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)c1ccc(F)cc1
Temperature: 65 °C
Reaction time: 8 h
Yield: 29.1 %

Procedure:
To a mixture of 1-fluoro-4-iodobenzene (448 mg, 2.00 mmol) and sodium benzenesulfinate (755 mg, 1.50 mmol) in DMF (5 mL) under a nitrogen atmosphere was added copper (I) trifluoromethanesulfonate benzene complex (443 mg, 2.70 mmol). The reaction was stirred at 65° C. overnight, diluted with ethyl acetate then washed with water and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo to give the crude material which was purified by flash column chromatography (85:15 to 80:20 hexanes/ethyl acetate) to give 1-fluoro-4-(phenylsulfonyl)-benzene (103 mg, 22%) as a white solid: 1H NMR (CDCl3, 300 MHz) δ 7.99-7.92 (m, 4H), 7.58-7.49 (m, 3H), 7.18 (t, J=8.4 Hz, 1H), 7.21-7.15 (m, 1H).