Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([F:11])[C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.[CH3:18][O:19][CH2:20][CH2:21][NH2:22].CCN(C(C)C)C(C)C>CC#N>[F:11][C:4]1[C:3]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[C:2]([NH:22][CH2:21][CH2:20][O:19][CH3:18])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: COCCN
Reactant: O=[N+]([O-])c1ccc(F)c(-c2ccccn2)c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COCCNc1c([N+](=O)[O-])ccc(F)c1-c1ccccn1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 54 %

Procedure:
A mixture of 2-(2-chloro-6-fluoro-3-nitrophenyl)pyridine* (618 mg, 2.6 mmol), 2-methoxyethylamine (0.23 mL, 2.6 mmol) and DIPEA (0.48 mL, 2.7 mmol) in MeCN (5 mL) was stirred for 1.5 h at 0° C. After warming to RT, the volatiles were removed in vacuo. The resulting residue was purified by column chromatography (Si—PPC, gradient 0-70% EtOAc/cyclohexane) to afford the title compound as a yellow oil (414 mg, 54%). LCMS (Method C): RT 2.95 min [M+H]+ 292. 1H NMR (CDCl3, 400 MHz): δ 8.73 (1H, ddd, J=5.0, 2.0, 1.0 Hz), 8.47 (1H, bs), 8.26 (1H, dd, J=9.5, 6.0 Hz), 7.79 (1H, ddd, 8.0, 8.0, 2.0 Hz), 7.45-7.43 (1H, m), 7.32 (1H, ddd, J=7.5, 5.0, 1.0 Hz), 6.52 (1H, dd, 9.5, 8.0 Hz), 3.29-3.26 (2H, m), 3.28 (3H, s), 2.63-2.60 (2H, m)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CC(C)=O.Cl>O>[C:2]1([NH:1][C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccccc1
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: O=C(Nc1ccccc1)c1ccccc1
Reaction time: 1.5 h

Procedure:
N-phenylbenzamide (Structure II) is synthesized from aniline and benzoyl chloride using acetone as a reaction media and an aqueous solution of NAOH to neutralize the HCl generated. A 20 ml aqueous solution of NAOH (2.57 grams, 0.064 moles) and 6.0 grams (0.064 moles) of aniline are first added to a stirred 250 ml flask containing 75 ml of acetone. Benzoyl chloride (9.06 grams, 0.064 moles) is next added over a five minute period. This reaction mixture which now contains a white precipitate is stirred for 1.5 hours and then diluted with 50 ml of deionized water. This solution is next filtered and the filter cake obtained is sequentially washed with 50 ml of deionized water (two times) followed by 50 ml of methanol. The washed filter cake is recovered and DSC analysis of this product showed a sharp melting endotherm at 169° C. ##STR10##
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2.[SH:13][C:14]1[CH:15]=[C:16]([C:20]2([C:26]#[N:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:17]=[CH:18][CH:19]=1.CCN(C(C)C)C(C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:12]=[C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([S:13][C:14]3[CH:15]=[C:16]([C:20]4([C:26]#[N:27])[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)[CH:17]=[CH:18][CH:19]=3)[CH:3]=2)[NH:8]1
Reactant: O=c1ccc2cc(I)ccc2[nH]1
Reactant: N#CC1(c2cccc(S)c2)CCOCC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#CC1(c2cccc(Sc3ccc4[nH]c(=O)ccc4c3)c2)CCOCC1
Temperature: 80 °C

Procedure:
6-Iodo-1H-quinolin-2-one (5.13 g, 18.9 mmol) and 4-(3-Mercapto-phenyl)-tetrahydro-pyran-4-carbonitrile (5f, 4.57 g, 20.8 mmol) were dissolved in 1,4-dioxane (160 mL) and degassed for 10 minutes with N2. iPr2NEt (6.6 mL, 37.9 mmol) was added, followed by Pd2dba3 (434 mg, 0.47 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (548 mg, 0.95 mmol), and the reaction was degassed for another 10 minutes with N2. The reaction was then sealed and heated to 80° C. overnight. After cooling to room temperature, the reaction was filtered and concentrated, and the residue was purified by silica gel chromatography (0-100% MeOH in EtOAc) to give the desired product, 5g.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8](/[C:9](=[C:15](/[NH:26][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][N:34]4[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]4)=[CH:29][CH:28]=3)\[C:16]3[CH:21]=[CH:20][C:19]4[O:22][CH2:23][CH2:24][O:25][C:18]=4[CH:17]=3)/[C:10](=[O:14])[NH:11]2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+].Cl.O>C(O)C>[C:3]([C:5]1[CH:13]=[C:12]2[C:8](/[C:9](=[C:15](/[NH:26][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][N:34]4[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]4)=[CH:29][CH:28]=3)\[C:16]3[CH:21]=[CH:20][C:19]4[O:22][CH2:23][CH2:24][O:25][C:18]=4[CH:17]=3)/[C:10](=[O:14])[NH:11]2)=[CH:7][CH:6]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCN(C)CC2)cc1)c1ccc2c(c1)OCCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN1CCN(Cc2ccc(N/C(=C3\C(=O)Nc4cc(C(=O)O)ccc43)c3ccc4c(c3)OCCO4)cc2)CC1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
0.36 g of 6-methoxycarbonyl-3-(Z)-{1-[4-(1-methylpiperazin-4-yl-methyl)-phenylamino]-1-(3,4-ethylenedioxyphenyl)-methylene}-2-indolinone (Example 1.57) in 5 ml of ethanol are combined at 80° C. with 1.6 ml of 1 molar sodium hydroxide solution and stirred for 2 hours at 80° C. After the addition of 1.6 ml of 1 molar hydrochloric acid and 2 ml of water the mixture is stirred overnight without any heating. The precipitate formed is suction filtered, washed successively with water, a little ethanol and finally diethyl ether and then dried at 80° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH:7]([OH:9])[CH3:8].[CH3:17][Si:18]([CH2:21][CH2:22][O:23][CH2:24]Cl)([CH3:20])[CH3:19].CCN(C(C)C)C(C)C.N#N>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH:7]([O:9][CH2:24][O:23][CH2:22][CH2:21][Si:18]([CH3:20])([CH3:19])[CH3:17])[CH3:8]
Reactant: COc1cc([N+](=O)[O-])ccc1OCC(C)O
Reactant: C[Si](C)(C)CCOCCl
Agent: N#N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc([N+](=O)[O-])ccc1OCC(C)OCOCC[Si](C)(C)C
Yield: 156.8 %

Procedure:
To a solution of 1-(2-methoxy-4-nitrophenoxy)propan-2-ol (1.537 g, 6.76 mmol) in DCM (20 mL) was added SEM-Cl (2.4 mL, 13.5 mmol) followed by DIPEA (4.7 mL, 27.1 mmol) dropwise under N2. The mixture was stirred O.N. at RT., diluted with DCM (20 mL), washed with 1N HCl, brine, dried (Na2SO4), and evaporated under reduced pressure to obtain a yellow oil (3.79 g) which was purified by flash chromatography (40 g silica, 0% to 100% EtOAc-Hexanes) to yield. Example 6A (2.03 g, 5.68 mmol, 84% yield) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([OH:10])=[C:4]([O:11][CH3:12])[CH:3]=1.[OH-].[K+].C(OP([C:23](Br)([F:25])[F:24])(=O)OCC)C>CC#N.O>[Br:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[C:5]([O:10][CH:23]([F:25])[F:24])=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: CCOP(=O)(OCC)C(F)(F)Br
Reactant: COc1cc(Br)cc(OC)c1O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: COc1cc(Br)cc(OC)c1OC(F)F
Temperature: -78 °C
Reaction time: 3.5 h
Yield: 62 %

Procedure:
5-Bromo-2-(difluoromethoxy)-1,3-dimethoxybenzene was synthesized from 4-bromo-2,6-dimethoxyphenol according to the procedure of Zafrani, Y. Tetrahedron 2009, 65, 5278 as follows. To a solution of 4-bromo-2,6-dimethoxyphenol (1.08 g, 4.6 mmol) in MeCN (27 mL) was added a solution of KOH (5.0 g, 89 mmol) in H2O (27 mL). The mixture was immediately cooled over a −78° C. bath and diethyl(bromodifluoromethyl)phosphonate (1.6 mL, 8.9 mmol) was added. The flask was sealed with a septum and the cold bath was removed. The mixture was stirred for a total of 3.5 hrs during which time the septum was ejected from the flask. The reaction was diluted with EtOAc and the layers were separated. The aqueous layer was extracted with EtOAc and the combined organics were washed with 1 M NaOH, H2O and brine then dried over Na2SO4 and concentrated in vacuo. Purification by chromatography (0-30% EtOAc-hexanes) provided 5-bromo-2-(difluoromethoxy)-1,3-dimethoxybenzene as a white solid (0.808 g, 62% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[S:16][CH2:15][C:14]2([CH2:20][CH2:19][CH2:18][CH2:17]2)[NH:13]1.Br[CH2:22][C:23]([CH3:25])=[CH2:24]>>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[S:16][CH2:15][C:14]2([CH2:17][CH2:18][CH2:19][CH2:20]2)[N:13]1[CH2:24][C:23]([CH3:25])=[CH2:22]
Reactant: C=C(C)CBr
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C1NC2(CCCC2)CS1
Product: C=C(C)CN1C(=Nc2ccc([N+](=O)[O-])cc2C)SCC12CCCC2

Procedure:
1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1e to give 2-(2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with 3-bromo-2-methylpropene according to Method D2e to give 2-(2-methyl-4-nitrophenylimino)-1-(2-methylprop-1-en-3-yl)-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: [CH2:1]([N:9]1[CH:13]=[C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][C:26]([N:29]5[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]5)=[CH:25][CH:24]=4)[CH:21]=3)[N:16]([S:35]([C:38]3[CH:44]=[CH:43][C:41]([CH3:42])=[CH:40][CH:39]=3)(=[O:37])=[O:36])[CH:15]=2)[CH:11]=[N:10]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:45][C@H:46]1[CH2:48][O:47]1.CCN(C(C)C)C(C)C>C(O)C>[CH2:1]([N:9]1[CH:13]=[C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[CH:24]=[CH:25][C:26]([N:29]5[CH2:30][CH2:31][N:32]([CH2:45][C@@H:46]([OH:47])[CH3:48])[CH2:33][CH2:34]5)=[CH:27][CH:28]=4)[CH:21]=3)[N:16]([S:35]([C:38]3[CH:39]=[CH:40][C:41]([CH3:42])=[CH:43][CH:44]=3)(=[O:37])=[O:36])[CH:15]=2)[CH:11]=[N:10]1)[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: C[C@H]1CO1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(CCc4ccccc4)c3)c3cc(-c4ccc(N5CCNCC5)cc4)cnc32)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(CCc4ccccc4)c3)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)cc4)cnc32)cc1
Yield: 62 %

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 3-(1-phenethyl-1H-pyrazol-4-yl)-5-(4-(piperazin-1-yl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (175 mg. 0.244 mmol) was alkylated using (S)-2-methyloxirane (26 mg, 0.488 mmol), DIPEA (171 μL, 0.977 mmol) and ethanol (5 mL) to get 100 mg (62.1% yield) of the titled compound. MS: m/z=661.7 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[CH:22]1([O:28][CH2:29][CH2:30]O)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C(OCC)(=O)C>ClCCl>[CH:22]1([O:28][CH2:29][CH2:30][O:20][C:19](=[O:21])[CH2:18][O:17][C:14]2[N:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:16][N:15]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: OCCOC1CCCCC1
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(COc1ncc(C(=O)Nc2ccc(F)cc2)cn1)OCCOC1CCCCC1
Yield: 51 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using 2-cyclohexyloxy-ethanol (37 mg, 0.26 mmol) as the coupling partner. Chromatography (1:1 ethyl acetate:dichloromethane) through SiO2 yielded 36 mg (51%) of the titled compound. ESI-MS m/z 418 (MH30 ), 416 (M−H−).
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH2:7][CH2:8][Cl:9])[N:5]=[C:4]([CH3:10])[CH:3]=1.[N+:11]([O-])([OH:13])=[O:12]>S(=O)(=O)(O)O>[Cl:1][C:2]1[N:6]([CH2:7][CH2:8][Cl:9])[N:5]=[C:4]([CH3:10])[C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(Cl)n(CCCl)n1
Agent: O=S(=O)(O)O
Product: Cc1nn(CCCl)c(Cl)c1[N+](=O)[O-]
Reaction time: 0.67 h

Procedure:
3.6 g (0.02 mole) of 5-chloro-1(beta-chloroethyl)-3-methylpyrazole was added slowly to 10 ml of concentrated sulfuric acid with swirling. Thereafter 5 ml of fuming nitric acid was then added slowly also with swirling. During the addition, the mixture became quite warm. It was allowed to stand at room temperature for 40 minutes and then poured onto ice. A white solid was formed and was filtered off, washed well with water and dried in vacuo at 56° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=3)[CH2:12][CH2:11]2)=[N:2]1.[CH2:25]([S:28](Cl)(=[O:30])=[O:29])[CH2:26][CH3:27]>N1C=CC=CC=1.ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][C:18]3[CH:19]=[CH:20][C:21]([NH:24][S:28]([CH2:25][CH2:26][CH3:27])(=[O:30])=[O:29])=[CH:22][CH:23]=3)[CH2:14][CH2:15]2)=[N:2]1
Reactant: Nc1ccc(CCN2CCN(c3nsc4ccccc34)CC2)cc1
Reactant: CCCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCS(=O)(=O)Nc1ccc(CCN2CCN(c3nsc4ccccc34)CC2)cc1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
4-[2-(4-Benzo[d]isothiazol-3-yl-piperazin-1-yl)-ethyl]-phenylamine was diluted to 0.3 M with anhydrous pyridine, then delivered to an 8 mL vial via pipette (0.225 mmol). Propane-1-sulfonyl chloride was diluted to 1.0 M with anhydrous dichloromethane, and added to the amine solution at rt (0.40 mmol). The solution was stirred overnight at 45° C. To the reaction mixture was added polyamine scavenging resin (0.30 mmol). The solution was stirred overnight at 45° C., then filtered into an 8 mL vial. The filtrate was evaluated by MS and concentrated via HT-12 GeneVac. Crude was purified by HPLC (30×100 mm ODS-A C(18) 5u column). Propane-1-sulfonic acid {4-[2-(4-1,2-benzisothiazol-3-yl-piperazin-1-yl)-ethyl]-phenyl}-amide was isolated in 100% purity @ 254 nm; LCMS (APCI): 445 [M+H]+
Reaction SMILES: [Cl:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:8](OCC)=[O:9].CC(C)([O-])C.[K+:18]>C1COCC1>[Cl:1]/[C:2](/[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:8]/[O-:9].[K+:18]
Reactant: CCOC=O
Reactant: CCOC(=O)CCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C(Cl)=C\[O-]
Temperature: 10 °C
Reaction time: 24 h
Yield: 90.2 %

Procedure:
A mixture of ethyl 2-chloroacetate (110.0 g; 897.6 mmol) and ethyl formate (73.14 g; 987.4 mmol) was added slowly to a suspension of potassium t-butoxide (110.8 g; 987.4 mmol) in THF (1000 mL) at −5° C. (maintaining the temperature<10° C.) with mechanical stirring. The mixture was stirred at ambient temperature for 24 hours. The solids were collected by filtration and washed with THF (200 mL) and acetonitrile (200 mL). The material was dried under vacuum to give the product (152.7 g) which was used without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6](Br)[N:5]=1)(=[O:3])[CH3:2].[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cccc(Br)n1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(=O)c1cccc(-c2ccccc2)n1
Temperature: 80 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
To a Schlenk tube charged with a solution of 200 mg (1.0 mmol) of 2-acetyl-6-bromopyridine and 23 mg (0.02 mmol) of (Ph3P)4Pd in 10 mL of degassed toluene was added a solution of 150 mg (1.2 mmol) phenylboronic acid and 270 mg (2.5 mmol) Na2CO3 in 8 mL of degassed 4:1 H2O/MeOH. The biphasic mixture was heated to 80° C. with rapid stirring for 1 h. On cooling to RT, Et2O (50 mL) was added and the layers were separated. The organic layer was dried over Na2SO4 and the volatiles were removed by rotary evaporation. The resulting oil was chromatographed on silica with 10-50% CH2Cl2/hexanes eluent to provide 176 mg (89%) of 2-acetyl-6-phenylpyridine as a white powder. 1H NMR (CDCl3); δ2.84 (s, 3H); 7.43-7.62 (m, 3H); 7.91-8.08 (m, 3H); 8.18 (d, J=6.6 Hz, 2H). Mass Spec.: m/e 197.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([OH:16])=[O:15])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[Cl:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][C:19]=1[F:27].C(=O)([O-])[O-].[Na+].[Na+].Cl>C1(C)C=CC=CC=1.CN(C=O)C>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:3]=[C:4]([C:14]([OH:16])=[O:15])[CH:5]=[N:6][C:7]=2[O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:20][C:19]=1[F:27]
Reactant: OB(O)c1ccc(Cl)c(F)c1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(Br)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)c(F)c2)c1
Temperature: 25 °C
Yield: 55.3 %

Procedure:
5-Bromo-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid (4.00 g, 13.3 mmol; CAN 1211586-75-2) was dissolved in toluene (90 mL) and DMF (2.0 mL) to give a colorless solution. Then B-(4-chloro-3-fluorophenyl)-boronic acid (2.56 g, 14.7 mmol; CAN 137504-86-0), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (544 mg, 667 μmol) and aqueous sodium carbonate solution (53.3 ml, 107 mmol, 2 M) were successively added under stirring in an argon atmosphere. The reaction mixture was stirred 2.5 h at 90° C. Subsequently the reaction mixture was cooled to ambient temperature, poured into ice-water (300 mL), acidified with 2 N HCl (120 mL) and extracted with isopropyl acetate (3×200 mL). The organic layers were combined, dried with Na2SO4 and concentrated in vacuo. The residue was digested with a mixture of n-heptane and isopropyl acetate (10 mL/2 mL) at ambient temperature, filtered off and washed with isopropyl acetate/n-heptane 1:5 (2×3 ml). The resulting brown solid was digested with dichloromethane (10 mL) at ambient temperature to give the title compound (2.57 g, 55%) after filtration and drying as off-white solid; MS (EI) 347.9 (M+H)+.
Reaction SMILES: O1CCCCC1ON[C:9]([C:11]1[S:25][C:14]2[NH:15][C:16](=[O:24])/[C:17](=[CH:18]\[C:19]3[NH:20][CH:21]=[CH:22][CH:23]=3)/[C:13]=2[CH:12]=1)=[O:10].C1(C)C=CC(S(O)(=O)=[O:33])=CC=1>CO>[O:24]=[C:16]1[NH:15][C:14]2[S:25][C:11]([C:9]([OH:10])=[O:33])=[CH:12][C:13]=2/[C:17]/1=[CH:18]/[C:19]1[NH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C1Nc2sc(C(=O)NOC3CCCCO3)cc2/C1=C/c1ccc[nH]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: O=C1Nc2sc(C(=O)O)cc2/C1=C/c1ccc[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.7 %

Procedure:
(Z)-5-Oxo-4-[1H-pyrrol-2-ylmethylene]-5,6-dihydro-4H-thieno[2,3-b]pyrrole-2-carboxylic acid (tetrahydro-pyran-2-yloxy)-amide (65 mg, 0.18 mmol) was dissolved in methanol (2 ml). 4-Toluene sulfonic acid (0.09 mmol, 15 mg) was added in one portion and the solution stirred at room temperature for 2 hours. The solvent was evaporated and the residue triturated with diethyl ether to give 10 mg of (Z)-5-Oxo-4-[1H-pyrrol-2-ylmethylene]-5,6-dihydro-4H-thieno[2,3-b]pyrrole-2-carboxylic acid hydroxamide as a brown solid. MS(ES): m/e 276 [M+H].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])/[CH:5]=[CH:6]/[C:7]1[CH:24]=[CH:23][C:10]2[N:11]([CH2:21][CH3:22])[C:12](=[O:20])[C:13]([CH3:19])([CH3:18])[C:14](=[O:17])[N:15]([CH3:16])[C:9]=2[CH:8]=1)[CH3:2]>[Pd].CO>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH2:6][C:7]1[CH:24]=[CH:23][C:10]2[N:11]([CH2:21][CH3:22])[C:12](=[O:20])[C:13]([CH3:19])([CH3:18])[C:14](=[O:17])[N:15]([CH3:16])[C:9]=2[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)/C=C/c1ccc2c(c1)N(C)C(=O)C(C)(C)C(=O)N2CC
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCc1ccc2c(c1)N(C)C(=O)C(C)(C)C(=O)N2CC
Yield: 80.1 %

Procedure:
10% Palladium on carbon (0.1 g) was added to a methanol solution (10 ml) of (E)-3-(1-ethyl 3,3,5-trimethyl 2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl) acrylic acid ethyl ester (0.36 g). The mixture was subjected to catalytic reduction at room temperature and under normal pressure. The catalyst was removed by celite filtration, followed by concentration under reduced pressure to give the title compound (0.29 g) as a brown solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1.O.NN>CO.[Ni]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][C:10]1[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=1
Reactant: O=[N+]([O-])c1ccc(Oc2cc(F)ccc2F)cc1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: Nc1ccc(Oc2cc(F)ccc2F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.2 %

Procedure:
Into a 500 mL 3-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed a solution of 1,4-difluoro-2-(4-nitrophenoxy)benzene (19.5 g, 77.63 mmol, 1.00 equiv) in methanol (200 mL), and Raney Nickel (2 g). This was followed by the addition of a solution of hydrazine hydrate (11.66 g) in methanol (50 mL) dropwise with stirring at 25° C. over 15 min. The resulting solution was stirred for 12 h at 25° C. and then filtrated and the filtrate was concentrated under vacuum. The residue was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 16 g (93%) of 4-(2,5-difluorophenoxy)aniline as black oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]#[C:6][C:7]([O:9][CH3:10])=[O:8])=[O:4].[CH3:11][NH:12][NH2:13]>C(OCC)C>[CH3:1][O:2][C:3](=[O:4])/[C:5](/[N:12]([CH3:11])[NH2:13])=[CH:6]\[C:7]([O:9][CH3:10])=[O:8]
Reactant: CNN
Reactant: COC(=O)C#CC(=O)OC
Solvent: CCOCC
Product: COC(=O)/C=C(\C(=O)OC)N(C)N
Temperature: -20 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
To a solution of dimethylacetylene dicarboxylate (50.0 g, 344.8 mmol) in diethylether (1 L) under argon at 0° C. was added a solution of methylhydrazine (18.52 mL, 344.8 mL) in diethylether (100 mL) and the resulting mixture stirred for 2 h. The precipitate was filtered off, dissolved in ethanol (300 mL) at 50° C. and then the solution cooled to −20° C. whereupon the solid was filtered off and dried to afford the title compound (46.8 g, 72%) as a light yellow solid. MS: m/e=189.3 [M+H]+.