Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C=C(CN)C=NC=1.[CH3:10][N:11]1[CH:15]=[CH:14][C:13]([CH2:16][NH2:17])=[N:12]1.[CH2:18]([N:22]1[CH2:26][CH2:25][N:24]([C:27]2[S:28][C:29]([C:33](O)=[O:34])=[C:30]([CH3:32])[N:31]=2)[C:23]1=[O:36])[CH:19]([CH3:21])[CH3:20]>>[CH2:18]([N:22]1[CH2:26][CH2:25][N:24]([C:27]2[S:28][C:29]([C:33]([NH:17][CH2:16][C:13]3[CH:14]=[CH:15][N:11]([CH3:10])[N:12]=3)=[O:34])=[C:30]([CH3:32])[N:31]=2)[C:23]1=[O:36])[CH:19]([CH3:21])[CH3:20]
Reactant: Cn1ccc(CN)n1
Reactant: Cc1nc(N2CCN(CC(C)C)C2=O)sc1C(=O)O
Agent: NCc1cncc(F)c1
Product: Cc1nc(N2CCN(CC(C)C)C2=O)sc1C(=O)NCc1ccn(C)n1
Yield: 58 %

Procedure:
Following the procedure as describe in Example 12, making variations as required to replace (5-fluoropyridin-3-yl)methanamine with (1-methyl-1H-pyrazol-3-yl)methanamine to react with 2-(3-isobutyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid in place of 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 58% yield: mp 158-161° C. (dichloromethane/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.43 (s, 1H), 7.37 (s, 1H), 5.80-5.78 (m, 1H), 4.39 (d, J=5.3 Hz, 2H), 4.12-4.07 (m, 2H), 3.86 (s, 3H), 3.60-3.55 (m, 2H), 3.11 (d, J=7.4 Hz, 2H), 2.59 (s, 3H), 1.96-1.87 (m, 1H), 0.93 (d, J=7.4 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 162.4, 157.4, 155.6, 152.9 152.6, 138.6, 129.5, 118.3, 117.0, 51.5, 42.8, 41.9, 38.8, 34.3, 26.7, 19.9, 17.1; MS (ES+) m/z 376.8 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[O:5][C:6]1[CH:27]=[CH:26][C:9]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([OH:23])=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][C:12]=2[C:24]#[N:25])=[CH:8][CH:7]=1.[Cl:32][CH2:33][CH2:34][CH2:35]Br.[O-]CCCC.[K+].O>CS(C)=O>[CH3:1][O:2][C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[O:5][C:6]1[CH:27]=[CH:26][C:9]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH2:35][CH2:34][CH2:33][Cl:32])=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][C:12]=2[C:24]#[N:25])=[CH:8][CH:7]=1
Reactant: COc1cc2c(Nc3ccc(Oc4ccccc4OC)cc3)c(C#N)cnc2cc1O
Reactant: ClCCCBr
Agent: CCCC[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2c(Nc3ccc(Oc4ccccc4OC)cc3)c(C#N)cnc2cc1OCCCCl
Reaction time: 18 h
Yield: 77.2 %

Procedure:
The product of step 2 (206.5 mg, 0.5 mmole) and 1-chloro-3-bromopropane (95 mg, 0.6 mmole) was dissolved in dimethylsulphoxide (5 ml) in the presence of potassium butoxide (0.55 ml, 11.0M in THF, 0.55 mmole) in and the mixture held at room temperature for 18 hours. Water was added and the mixture extracted with ethyl acetate. The combined extracts were washed with water and brine then dried (MgSO4) and evaporated to give 4-(4-(2-methoxyphenoxy)-anilino)-3-cyano-6-methoxy-7-(3-chloropropoxy)quinoline (189 mg, 77%) as a yellow gum.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[OH:28][CH2:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1>>[OH:28][CH2:29][C:30]1[CH:35]=[C:34]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=[C:6]([CH:21]=2)[C:7]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:17]([F:19])([F:18])[F:20])=[CH:14][CH:15]=2)=[O:8])[CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: OCc1cccc(B(O)O)c1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cccc(CO)c2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 57 using (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 35.1) and (3-(hydroxymethyl)phenyl)boronic acid to afford a yellow foam. HPLC (Condition 4) tR=4.57 min, UPLC-MS (Condition 3) tR=0.99 min, m/z=474.4 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.62-1.73 (m, 1H) 1.80 (m, J=8.60 Hz, 1H) 2.85 (d, J=11.73 Hz, 1H) 3.12-3.26 (m, 2H) 3.34-3.47 (m, 1H) 4.09-4.19 (m, 1H) 4.55 (d, J=5.47 Hz, 2H) 4.80 (d, J=3.52 Hz, 1H) 5.24 (t, J=5.67 Hz, 1H) 7.22 (d, J=7.43 Hz, 1H) 7.27-7.43 (m, 5H) 7.79-7.90 (m, 2H) 7.94 (d, J=2.35 Hz, 1H) 8.71 (d, J=2.35 Hz, 1H) 10.16 (s, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:30][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[O:21][CH:22]3[CH2:29][CH:25]4[O:26][CH2:27][O:28][CH:24]4[CH2:23]3)[C:7]=2[C:6]=1[CH3:31])=[O:4].[OH-].[Li+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[F:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:12]2[C:7]3[C:6]([CH3:31])=[C:5]([C:3]([OH:4])=[O:2])[S:30][C:8]=3[N:9]=[CH:10][N:11]=2)=[C:15]([O:21][CH:22]2[CH2:23][CH:24]3[O:28][CH2:27][O:26][CH:25]3[CH2:29]2)[CH:16]=1
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC3CC4OCOC4C3)c2c1C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3OC3CC4OCOC4C3)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A reaction mixture of 2.1 g 4-[4-fluoro-2-(tetrahydro-cyclopenta[1,3]dioxol-5-yloxy)phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester and 0.56 g lithium hydroxide in 150 ml THF was stirred at rt overnight. Then the mixture was acidified by addition of 10% citric acid, concentrated and filtered. The solid was dried in vacuo at 60° C.
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].CO[C:8]1[CH:13]=[CH:12][C:11]([N:14]=[N:15][C:16]2[N:20]([CH3:21])[CH:19]=[CH:18][N+:17]=2[CH3:22])=[CH:10][CH:9]=1.[NH2:23][C:24]1[CH:28]=[CH:27][NH:26][N:25]=1>CC(O)C>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[NH2:23][C:24]1[CH:28]=[CH:27][N:26]([C:8]2[CH:13]=[CH:12][C:11]([N:14]=[N:15][C:16]3[N:20]([CH3:21])[CH:19]=[CH:18][N+:17]=3[CH3:22])=[CH:10][CH:9]=2)[N:25]=1
Reactant: Nc1cc[nH]n1
Reactant: COc1ccc(N=Nc2n(C)cc[n+]2C)cc1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC(C)O
Product: Cn1cc[n+](C)c1N=Nc1ccc(-n2ccc(N)n2)cc1
Reaction time: 3 h

Procedure:
2.5 g (7.6 mmol) of 2-(4-methoxyphenylazo)-1,3-dimethyl-3H-imidazol-1-ium perchlorate and 50 ml of 2-propanol are charged to a fully equipped round-bottomed flask. The mixture is brought to 60° C. 1.3 g (15.5 mmol) of 3-aminopyrazole are added. This mixture is brought, with stirring, to the reflux temperature of the solvent for 3 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH2:22][C:23]([CH3:25])=[CH2:24])=[C:6]([CH:20]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]([OH:19])=O)=[CH:13][CH:12]=1)[CH2:9][CH3:10].[O:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][S:34]([NH2:37])(=[O:36])=[O:35])[CH2:28][CH2:27]1>>[O:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][S:34]([NH:37][C:17]([C:14]2[N:15]=[N:16][C:11]([N:8]([CH2:7][C:6]3[CH:20]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:21][CH2:22][C:23]([CH3:25])=[CH2:24])[CH2:9][CH3:10])=[CH:12][CH:13]=2)=[O:19])(=[O:36])=[O:35])[CH2:28][CH2:27]1
Reactant: NS(=O)(=O)CCN1CCOCC1
Reactant: C=C(C)COc1ccc(Cl)cc1CN(CC)c1ccc(C(=O)O)nn1
Product: C=C(C)COc1ccc(Cl)cc1CN(CC)c1ccc(C(=O)NS(=O)(=O)CCN2CCOCC2)nn1

Procedure:
The title compound was prepared by reacting 6-[N-(5-chloro-2-(2-methylprop-2-enyloxy)benzyl)-N-ethylamino]pyridazine-3-carboxylic acid (example 19) and 2-(morpholino)ethanesulphonamide using a similar method to that described in example 20 (yield 43%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.Cl[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH:6]=[CH:5]2
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: OCCCCCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: OCCCCCCOc1ccc2cc(Br)ccc2c1
Temperature: 100 °C
Yield: 76.7 %

Procedure:
A mixture of 6-bromo2-naphthol (22.30 g), 6-chloro-1-hexanol (20.50 g), potassium carbonate (20.50 g) and potassium iodide (1.50 g) in dimethylformamide (DMF, 100 ml) was heated at 100° C for 4 h. The mixture was then cooled and poured into 150 ml of HCl (3N) and extracted with ether (3×200 ml). The combined ether extracts were washed with saturated NaCl solution (200 ml), dried over magnesium sulfate, evaporated to give a brownish oil and filtered through a silica gel column (150 g,) using dichloromethane as eluent to give a brownish solid. The brown solid was recrystallised from hexane/dichloromethane (9/1) to give 24.8 g of 6-(6bromo-naphthalen-2-yloxy)hexan-1-ol as white needles.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@:10]21[C:43]1[CH:44]=[C:45]([CH2:49][C:50]3[CH:55]=[CH:54][C:53]([CH2:56][CH3:57])=[CH:52][CH:51]=3)[C:46]([Cl:48])=[CH:47][C:42]=1[O:41][C@H:40]2[OH:58])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.CCOC(C)=O>C(Cl)Cl>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@:10]21[C:43]1[CH:44]=[C:45]([CH2:49][C:50]3[CH:55]=[CH:54][C:53]([CH2:56][CH3:57])=[CH:52][CH:51]=3)[C:46]([Cl:48])=[CH:47][C:42]=1[O:41][C:40]2=[O:58])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1ccc(Cc2cc3c(cc2Cl)O[C@@H](O)[C@]32O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCc1ccc(Cc2cc3c(cc2Cl)OC(=O)[C@]32O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Reaction time: 120 h
Yield: 62.9 %

Procedure:
To a solution of 27 (8 mg, 10 μmol) in DCM was added pyridinium chlorochromate (9 mg, 42 μmol, 4.2 equiv). The mixture was stirred for 5 days until the reaction was complete. The mixture was directly loaded onto a preparatory TLC plate and developed using 15% EtOAc in petroleum ether to give 48 (5 mg, 62% yield). 1H NMR (300 MHz, CDCl3) δ 7.00-7.40 (m, 25H), 6.76 (d, J=6.6 Hz, 2H), 4.80-4.92 (m, 3H), 4.64 (d, J=10.8 Hz, 1H), 4.38-4.57 (m, 5H), 3.92-4.03 (m, 3H), 3.71-3.82 (m, 3H), 3.60 (dd, J=1.8, 11.1 Hz, 1H), 2.57 (q, J=7.5 Hz, 2H), 1.18 (t, J=7.5 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH2:11](O)[CH3:12].CN(C1C=CC=CN=1)C.Cl.CN(C)CCCN=C=NCC>O1CCCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:11][CH3:12])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CCO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 6.85 g (44 mmol) of 6-chloronicotinic acid dissolved in 50 mL of tetrahydrofuran was added ethanol (6 mL), dimethylaminopyridine (700 mg) and 1-(3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (EDCl) (9.4 g, 49 mmol). The reaction was stirred at ambient temperature for 4 hours and then concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with water (2×), saturated sodium bicarbonate (2×) and brine, dried over sodium sulfate and concentrated in vacuo. The residue obtained was flash chromatographed on silica gel eluting with 10% ethyl acetate in hexane to afford 6.00 g of the title compound as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ 1.40 (t, 3H), 4.40 (q, 2H), 7.40 (d, 1H), 8.25 (dd, 1H), 9.00 (d, 1H). MS (DCl/NH3) m/e 186/188 (M+H)+, 203/205 (M+H+NH3 )+.
Reaction SMILES: [CH2:1]([C:3]1[N:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[OH:22])=[CH:11][CH:10]=2)[C:7](=[O:23])[C:6]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]3[NH:41][C:40](=[O:42])[O:39][N:38]=3)=[CH:27][CH:26]=2)=[C:5]([CH2:43][CH2:44][CH3:45])[N:4]=1)[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(OCC)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl.O>[CH2:1]([C:3]1[N:8]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C:17]3=[O:22])=[CH:13][CH:14]=2)[C:7](=[O:23])[C:6]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]3[NH:41][C:40](=[O:42])[O:39][N:38]=3)=[CH:27][CH:26]=2)=[C:5]([CH2:43][CH2:44][CH3:45])[N:4]=1)[CH3:2]
Reactant: CCCc1nc(CC)n(-c2ccc(O[C@@H]3CCCC[C@H]3O)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCc1nc(CC)n(-c2ccc(OC3CCCCC3=O)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Reaction time: 2 h
Yield: 65.2 %

Procedure:
To a solution of 2-ethyl-3-(4-{[(1R,2R)-2-hydroxycyclohexyl]oxy}phenyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one (0.2 g) in dichloromethane (5 mL) was added 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.21 g), and the mixture was stirred for 2 hr. Ethyl acetate, water and sodium thiosulfate were added to the reaction mixture, and the mixture was stirred for 30 min and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.13 g, 65%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH2:14](OB(C=C)OCCCC)[CH2:15]CC.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O>[N+:11]([C:3]1[CH:4]=[C:5]([C:8](=[O:10])[CH3:9])[CH:6]=[CH:7][C:2]=1[CH:14]=[CH2:15])([O-:13])=[O:12]
Reactant: CC(=O)c1ccc(Br)c([N+](=O)[O-])c1
Reactant: C=CB(OCCCC)OCCCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1ccc(C(C)=O)cc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 87 %

Procedure:
To a mixture of 4′-bromo-3′-nitroacetophenone (600 mg, 2.46 mmol), vinylboronic acid dibutyl ester (680 mg, 3.69 mmol), and sodium carbonate (1.83 g, 17.22 mmol) in THF/H2O (12 mL/4 mL) is added dichlorobis(triphenylphospine) palladium (II) (86 mg, 5% mmol). The reaction tube is sealed and the mixture is purged with N2 for 3 min and heated at 70° C. for 1.5 h. Then the mixture is cooled to room temperature and poured into saturated ammonia chloride aqueous solution. The mixture is extracted with ethyl acetate (3×20 mL). The organic extracts are combined, washed with brine and concentrated. The crude product is purified with silica gel column chromatography (20% ethyl acetate in hexanes) to afford 1-(3-Nitro-4-vinyl-phenyl)-ethanone as a yellow solid, 87% yield: ESMS m/z 192.0 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.Cl[C:17]1[N:22]=[C:21]([CH3:23])[CH:20]=[CH:19][N:18]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:17]3[N:22]=[C:21]([CH3:23])[CH:20]=[CH:19][N:18]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccnc(Cl)n1
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)c[nH]1
Product: Cc1ccnc(-n2cc(C#Cc3cccc(Cl)c3)nc2C)n1

Procedure:
The title compound, MS: m/e=309.1 (M+H+), was prepared in accordance with the general method of example 1 from 4-(3-chloro-phenylethynyl)-2-methyl-1H-imidazole and 2-chloro-4-methyl-pyrimidine (prepared according to Harden, D. B.; Makrosz, M. J.; Strekowski, L.; J. Org. Chem. 1988, 53, 4137).
Reaction SMILES: O=[C:2](C1C=CN=CC=1)CC(OCC)=O.[OH:15][C:16]1[C:21]([CH2:22][O:23]C)=[CH:20][C:19]([CH3:25])=[CH:18][C:17]=1[C:26](=[O:28])[CH3:27].CC(C)([O-])C.[K+]>C1COCC1.C(OCC)(=O)C.Cl[Pd]Cl>[C:26]([C:17]1[C:16]([OH:15])=[C:21]([C:22](=[O:23])[CH3:2])[CH:20]=[C:19]([CH3:25])[CH:18]=1)(=[O:28])[CH3:27]
Reactant: CCOC(=O)CC(=O)c1ccncc1
Reactant: COCc1cc(C)cc(C(C)=O)c1O
Agent: Cl[Pd]Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)c1cc(C)cc(C(C)=O)c1O

Procedure:
A mixture of a bromo derivative 1 (324 mg, 1 mmol), (R)-(+)-α-methylbenzylamine 2 (122 mg, 1 mmol), potassium t-butoxide (225 mg, 2 mmol) and PdCl2 (dppf) (35 mg, 0.05 mmol) in THF was stirred at refluxing temperature for 20 hours over a nitrogen atmosphere. The reaction mixture was cooled and diluted with ethyl acetate. The organic layer was washed with water, brine and dried over Na2SO4. The ethyl acetate layers was concentrated in vacuo and the residue was subjected to column chromatography (silica gel, ethylacetate) to give the required product 3. 1H NMR (300 MHz, CDCl3), δ 8.78 (br s, 2H), 8.21 (s, 1H), 7.92 (d, J=5.9 Hz, 2H), 7.4-7.26 (m, 5H), 6.90 (s, 1H), 6.50 (d, J=5.5 Hz, 1H, —NH), 6.27 (s, 1H), 4.60 (m, 1H), 2.23 (s, 3H), 1.71 (d, J=6.9 Hz, 3H). MS (m/z)=357.13 (m+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[C:10]([NH:24][C:25]2[S:29][N:28]=[C:27]([CH:30]3[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]3)[N:26]=2)=[N:11][CH:12]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]=[O:23])=[CH:18][CH:17]=2)[CH:14]=1.C(O)(C(F)(F)F)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[CH:17]=[CH:18][C:19]([CH:22]=[O:23])=[CH:20][CH:21]=2)[CH:12]=[N:11][C:10]=1[NH:24][C:25]1[S:29][N:28]=[C:27]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[N:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nsc(Nc3ncc(Oc4ccc(C=O)cc4)cc3Sc3ccccc3Cl)n2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=Cc1ccc(Oc2cnc(Nc3nc(C4CCNCC4)ns3)c(Sc3ccccc3Cl)c2)cc1
Reaction time: 0.5 h
Yield: 100.3 %

Procedure:
Tert-butyl 4-(5-(3-(2-chlorophenylthio)-5-(4-formylphenoxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidine-1-carboxylate (183 mg, 0.293 mmol) was dissolved in methylene chloride (1 mL) and TFA (1 mL) was added. After stirring for 30 minutes, the reaction was poured into saturated aqueous sodium bicarbonate. The mixture was extracted with methylene chloride and concentrated to afford 4-(5-(2-chlorophenylthio)-6-(3-(piperidin-4-yl)-1,2,4-thiadiazol-5-ylamino)pyridin-3-yloxy)benzaldehyde (154 mg, 0.294 mmol).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:22]=[CH:21][C:8]2[N:9]([CH2:18][O:19][CH3:20])[C:10](=[O:17])[C:11]3[CH:12]=[CH:13][CH:14]=[N:15][C:16]=3[C:7]=2[CH:6]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[CH3:20][O:19][CH2:18][N:9]1[C:8]2[CH:21]=[CH:22][C:5]([CH2:4][CH2:3][CH:2]=[O:1])=[CH:6][C:7]=2[C:16]2[N:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]1=[O:17]
Reactant: COCn1c(=O)c2cccnc2c2cc(CCCO)ccc21
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COCn1c(=O)c2cccnc2c2cc(CCC=O)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.1 %

Procedure:
The compound (200 mg, 0.67 mmol) prepared in step 6 was dissolved in dichloromethane, added with pyridinium chlorochromate (289 mg, 1.34 mmol) and silica gel (289 mg) at room temperature. The resulting mixture was stirred for 2 hours at room temperature and filtered to remove silica gel. The filtrate was extracted with dichloromethane, dried over anhydrous magnesium sulfate and concentrated to dryness. The residue was then purified by flash column chromatography (chloroform:methanol=15:1) to obtain the title compound (151 mg, yield: 76%, white solid).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([F:11])=[C:6]([N+]([O-])=O)[CH:7]=1.[Cl:13]Cl>[Fe]>[Cl:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([F:11])=[C:6]([Cl:13])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(F)cc1F
Reactant: ClCl
Agent: [Fe]
Product: Fc1cc(F)c(Cl)cc1Cl
Temperature: 200 °C
Reaction time: 5 h

Procedure:
3 kg (15.5 mol) of iron-free, dry 5-chloro-2,4-difluoronitrobenzene are introduced into a 2 l four-necked flask with stirrer, dropping funnel and gas inlet tube and, on top, a column with reflux condenser. After heating the reaction solution to 200° C., chlorine is passed through the solution at a rate of 15 l/h. After 4-6 hours, the solution begins to boil, and after a further 2-4 hours the 1,3-dichloro-4,6-difluorobenzene which is formed can be taken off at the head of the column. At the same time, fresh 5-chloro-2,4-difluoronitrobenzene is added to the reaction in accordance with the quantity of product removed.
Reaction SMILES: [CH3:1][NH:2][NH2:3].[CH3:4][S:5][C:6](S)=[N:7][C:8]#[N:9]>C(#N)C>[C:8]([N:7]=[C:6]([N:2]([CH3:1])[NH2:3])[S:5][CH3:4])#[N:9]
Reactant: CSC(S)=NC#N
Reactant: CNN
Solvent: CC#N
Product: CSC(=NC#N)N(C)N
Reaction time: 16 h

Procedure:
A mixture of methyl hydrazine (0.48 ml) and cyanocarbonimidodithioic acid methyl ester (1.3 g) in acetonitrile was stirred at 25° for 16 hours. The resulting solution was evaporated to a gum which was crystallised from acetonitrile/ether to give the title compound as colourless granules (210 mg) m.p. 69°-71°.
Reaction SMILES: [C:1]([S@@:5](/[N:7]=[CH:8]/[C:9]1[S:13][C:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:11][CH:10]=1)=[O:6])([CH3:4])([CH3:3])[CH3:2].[CH3:21][Mg]Br.[NH4+].[Cl-]>C(Cl)Cl>[C:17]([O:16][C:14]([C:12]1[S:13][C:9]([C@H:8]([NH:7][S@:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[O:6])[CH3:21])=[CH:10][CH:11]=1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)c1ccc(/C=N/[S@@](=O)C(C)(C)C)s1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: C[C@@H](N[S@@](=O)C(C)(C)C)c1ccc(C(=O)OC(C)(C)C)s1
Temperature: -45 °C
Reaction time: 4 h
Yield: 48.1 %

Procedure:
To an oven-dried 100-mL round-bottom flask was added (S,E)-tert-butyl 5-((tert-butylsulfinylimino)methyl)thiophene-2-carboxylate (1.00 g, 3.2 mmol) and DCM (15.8 mL). The solution was cooled to −45° C. under nitrogen, then methylmagnesium bromide (2.11 mL, 6.36 mmol, 3.0 M in ether) was slowly added via syringe. The resulting reaction mixture was stirred at −45° C. for 4 h, then gradually warmed to rt and stirred for 2 h. To the reaction was added DCM (50 mL) and sat. NH4Cl solution (10 mL). After separation, the aqueous layer was extracted with DCM (2×30 mL). The combined organic layers were washed with brine, dried (MgSO4), and concentrated. Purification via flash chromatography (20% EtOAc-hexanes to 50% EtOAc-hexanes) afforded major diastereomer tert-butyl-5-[(1R)-1-{[(S)-tert-butylsulfinyl]amino}ethyl]thiophene-2-carboxylate (0.51 g, 48%) as a white solid; 1H NMR (Methanol-d4, 400 MHz) δ 7.55 (d, J=3.8 Hz, 1H), 7.00 (d, J=3.8 Hz, 1H), 4.73 (q, J=6.5 Hz, 1H), 3.30 (br, 1H), 1.65 (d, J=6.8 Hz, 3H), 1.55 (s, 9H), 1.25 (s, 9H). Minor diastereomer tert-butyl-5-[(1S)-1-{[(S)-tert-butylsulfinyl]amino}ethyl]thiophene-2-carboxylate (0.061 g, 6%) was isolated as a white solid. 1H NMR (Methanol-d4, 400 MHz) δ 7.55 (d, J=3.5 Hz, 1H), 7.00 (d, J=3.5 Hz, 1H), 4.73 (q, J=6.8 Hz, 1H), 3.30 (br, 1H), 1.61 (d, J=6.8 Hz, 3H), 1.55 (s, 9H), 1.23 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[F:9][C:10]([F:20])([F:19])[C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(#N)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][CH2:15][C:14]2[CH:13]=[CH:12][C:11]([C:10]([F:9])([F:19])[F:20])=[CH:18][CH:17]=2)=[N:3][CH:4]=1
Reactant: Nc1ccc(Br)cn1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: FC(F)(F)c1ccc(CNc2ccc(Br)cn2)cc1

Procedure:
Into a round bottom flask fitted with stirrer and reflux condenser was added 2-amino-5-bromopyridine (15, 1.73 mol, 300 g) and p-trifluoromethylbenzaldehyde (16, 1.723 mol, 300 g) to a solution of trifluoroacetic acid (400 mL), triethylsilane (825 mL) and acetonitrile (7500 mL). The reaction was heated to reflux overnight (24 hours). Solvents were removed and the residue was poured into aqueous K2CO3 and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated. The crude compound was crystallized with diethyl ether/hexane to afford compound 17, 420 g (73.6%) as off white solid. MS (ESI) [M+H+]+=331.1 and 333.1 (1:1 ratio).